PMID- 22099029 TI - Feasibility of electromagnetic transponder use to monitor inter- and intrafractional motion in locally advanced pancreatic cancer patients. AB - PURPOSE: The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined. METHODS AND MATERIALS: During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System's localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode. RESULTS: Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p < 0.01); anterior: 4.9 mm (0.5, p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions. CONCLUSIONS: Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway. PMID- 22099030 TI - A single-institutional experience of 15 years of treating T3 laryngeal cancer with primary radiotherapy, with or without chemotherapy. AB - PURPOSE: To retrospectively analyze the outcomes, toxicity, quality of life, and voice quality of patients with T3 laryngeal cancer treated with radiotherapy and to identify subgroups of patients in whom the addition of chemotherapy to radiotherapy is necessary. METHODS AND MATERIALS: Between March 1996 and November 2009, 170 consecutive patients with T3 tumor were treated with (chemo)radiotherapy. Endpoints of the study were local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), late toxicity, quality of life, and voice handicap index. RESULTS: After a median follow-up time of 32 months (range, 7-172), the 3-year actuarial rates of LC, LRC, DFS, and OS were 73%, 70%, 64%, and 61%, respectively, and the 5-year figures were 68%, 65%, 60%, and 49%, respectively. At last follow-up, 84 patients (49.5%) were still alive, 65 of them (77.3%) without local progression. Laryngectomy was performed in 16 patients, leaving 49 patients with anatomic organ preservation, corresponding to an actuarial laryngectomy-free survival of 58.3% at 3 years. The figures for patients treated with chemoradiotherapy and radiotherapy alone were 76.8% and 53.5%, respectively (p = 0.001). Chemoradiotherapy was the only significant predictor for LC on multivariate analysis. The overall 5-year cumulative incidence of late Grade >=2 toxicity was 28.2%. Chemoradiotherapy, compared with radiotherapy alone, resulted in slight increase in late toxicity and slight deterioration of quality of life and voice-handicap-index scores. However, the differences were statistically not significant. CONCLUSION: The addition of chemotherapy to radiotherapy in T3 laryngeal cancer significantly improved LC and laryngectomy-free survival without statistically significant increases in late toxicity or deterioration of quality of life or voice handicap index. PMID- 22099031 TI - Indications for pelvic nodal treatment in prostate cancer should change. Validation of the Roach formula in a large extended nodal dissection series. AB - PURPOSE: Previous studies have criticized the predicting ability of the Roach formula in assessing the risk of lymph node invasion (LNI) in contemporary patients with prostate cancer (PCa) due to a significant overestimation of LNI rates. However, all those studies included patients treated with limited pelvic lymph node dissection (PLND), which is associated with high rates of false negative findings. We hypothesized that the Roach formula is still an accurate tool for LNI predictions if an extended PLND (ePLND) is performed. METHODS AND MATERIALS: We included 3,115 consecutive patients treated with radical prostatectomy and ePLND between 2000 and 2010 at a single tertiary referral center. Extended PLND consisted of removal of obturator, external iliac, and hypogastric lymph nodes. We externally validated the Roach formula by using the area under the receiver operating characteristics curve and calibration plot method. Moreover, we tested the performance characteristics of different formula generated cutoff values ranging from 1% to 20%. RESULTS: The accuracy of the Roach formula was 80.3%. The calibration showed only a minor underestimation of the LNI risk in high-risk patients (6.7%). According to the Roach formula, the use of 15% cut off would have allowed 74.2% (2,311/3,115) of patients to avoid nodal irradiation, while up to 32.7% (111/336) of all patients with LNI would have been missed. When the cut off was lowered to 6%, nodal treatment would have been spared in 1,541 (49.5%) patients while missing 41 LNI patients. The sensitivity, specificity, and negative predictive values associated with the 6% cut off were 87.9%, 54%, and 97.3%, respectively. CONCLUSIONS: The Roach formula is still accurate and does not overestimate the rate of LNI in contemporary prostate cancer patients if they are treated with ePLND. However, the recommended cut off of 15% would miss approximately one-third of patients with LNI. Based on our results, the cut off should be lowered to 6%. PMID- 22099032 TI - Intensity-modulated radiotherapy causes fewer side effects than three-dimensional conformal radiotherapy when used in combination with brachytherapy for the treatment of prostate cancer. AB - PURPOSE: To measure the benefits of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3D-CRT) when used in combination with brachytherapy for the treatment of prostate cancer. METHODS AND MATERIALS: We conducted a retrospective review of all patients with localized prostate cancer who received external-beam radiotherapy (EBRT) in combination with brachytherapy with at least 1 year follow-up (n = 812). Combination therapy consisted of (103)Pd or (125)I implant, followed by a course of EBRT. From 1993 to March 2003 521 patients were treated with 3D-CRT, and from April 2003 to March 2009 291 patients were treated with IMRT. Urinary symptoms were prospectively measured with the International Prostate Symptom Score questionnaire with a single quality of life (QOL) question; rectal bleeding was assessed per the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. The Pearson chi(2) test was used to compare toxicities experienced by patients who were treated with either IMRT or 3D-CRT. Logistic regression analyses were also performed to rule out possible confounding factors. RESULTS: Within the first 3 months after treatment, patients treated with 3D-CRT scored their urinary symptoms as follows: 19% mild, 44% moderate, and 37% severe; patients treated with IMRT scored their urinary symptoms as follows: 36% mild, 47% moderate, and 17% severe (p < 0.001). The 3D CRT patients rated their QOL as follows: 35% positive, 20% neutral, and 45% negative; IMRT patients rated their QOL as follows: 51% positive, 18% neutral, and 31% negative (p < 0.001). After 1 year of follow-up there was no longer any difference in urinary morbidity between the two groups. Logistic regression confirmed the differences in International Prostate Symptom Score and QOL in the acute setting (p < 0.001 for both). Grade >= 2 rectal bleeding was reported by 11% of 3D-CRT patients and 7% of IMRT patients (p = 0.046); logistic regression analysis also confirmed this observation (p = 0.040). CONCLUSIONS: When used in combination with brachytherapy, IMRT offers less Grade >= 2 rectal bleeding, less acute urinary toxicities, and is associated with a higher QOL compared with 3D CRT. PMID- 22099033 TI - Diffusion-weighted magnetic resonance imaging in monitoring rectal cancer response to neoadjuvant chemoradiotherapy. AB - PURPOSE: To prospectively monitor the response in patients with locally advanced nonmucinous rectal cancer after chemoradiotherapy (CRT) using diffusion-weighted magnetic resonance imaging. The histopathologic finding was the reference standard. METHODS AND MATERIALS: The institutional review board approved the present study. A total of 62 patients (43 men and 19 women; mean age, 64 years; range, 28-83) provided informed consent. T(2)- and diffusion-weighted magnetic resonance imaging scans (b value, 0 and 1,000 mm(2)/s) were acquired before, during (mean 12 days), and 6-8 weeks after CRT. We compared the median apparent diffusion coefficients (ADCs) between responders and nonresponders and examined the associations with the Mandard tumor regression grade (TRG). The postoperative nodal status (ypN) was evaluated. The Mann-Whitney/Wilcoxon two-sample test was used to evaluate the relationships among the pretherapy ADCs, extramural vascular invasion, early percentage of increases in ADCs, and preoperative ADCs. RESULTS: Low pretreatment ADCs (<1.0 * 10(-3)mm(2)/s) were correlated with TRG 4 scores (p = .0011) and associated to extramural vascular invasion with ypN+ (85.7% positive predictive value for ypN+). During treatment, the mean percentage of increase in tumor ADC was significantly greater in the responders than in the nonresponders (p < .0001) and a >23% ADC increase had a 96.3% negative predictive value for TRG 4. In 9 of 16 complete responders, CRT-related tumor downsizing prevented ADC evaluations. The preoperative ADCs were significantly different (p = .0012) between the patients with and without downstaging (preoperative ADC >=1.4 * 10( 3)mm(2)/s showed a positive and negative predictive value of 78.9% and 61.8%, respectively, for response assessment). The TRG 1 and TRG 2-4 groups were not significantly different. CONCLUSION: Diffusion-weighted magnetic resonance imaging seems to be a promising tool for monitoring the response to CRT. PMID- 22099034 TI - Inverse relationship between biochemical outcome and acute toxicity after image guided radiotherapy for prostate cancer. AB - PURPOSE: Prostate cancer patients exhibit variability in normal tissue reactions and biochemical failure. With the use of image-guided radiotherapy (IGRT), there is a greater likelihood that the differences in normal tissue and tumor response are due to biological rather than physical factors. We tested the hypothesis that prospectively scored acute toxicity is associated with biochemical failure-free rate (BFFR) in prostate cancer patients treated with IGRT. METHODS AND MATERIALS: We retrospectively analyzed BFFR in 362 patients with localized prostate cancer treated with IGRT. We compared BFFR with prospectively collected Radiation Therapy Oncology Group (RTOG) maximum acute gastrointestinal (GI) and genitourinary (GU) toxicity scores. Median follow-up for all patients was 58.3 months after total radiotherapy doses of 75.6-79.8 Gy. RESULTS: Patients reporting RTOG acute GU or GI toxicity scores of >= 2 were considered "sensitive" (n = 141, 39%) and patients reporting scores <2 were considered "nonsensitive" (n = 221, 61%). When calculating biochemical failure (BF) using the American Society for Therapeutic Radiology and Oncology definition at 5 years, 76% (CI 70-82%) of the "nonsensitive" patients were failure free, compared with only 53% (CI 43-62%) of the "sensitive" patients (log-rank test, p < 0.0001). This difference was also observed using the Phoenix definition; "nonsensitive" 5-year BFFR was 81% (CI 74 86%) vs. "sensitive" BFFR was 68% (CI 58-76%; log-rank test p = 0.0012). The difference in BF between cohorts remained significant when controlled for radiation dose (75.6 vs. 79.8 Gy), prognostic stratification (T category, prostate-specific antigen, and Gleason score), and prostate volume. CONCLUSIONS: This study unexpectedly shows that prostate cancer patients who develop >= Grade 2 RTOG acute toxicity during radiotherapy are less likely to remain BFF at 5 years. These results deserve further study and, if validated in other large IGRT cohorts, additional models would be required to study interaction between normal tissue and tumor biology in prostate cancer patients. PMID- 22099035 TI - An endorectal balloon reduces intrafraction prostate motion during radiotherapy. AB - PURPOSE: To investigate the effect of endorectal balloons (ERBs) on intrafraction and interfraction prostate motion during radiotherapy. METHODS AND MATERIALS: Thirty patients were treated with intensity-modulated radiotherapy, to a total dose of 80 Gy in 40 fractions. In 15 patients, a daily-inserted air-filled ERB was applied. Prostate motion was tracked, in real-time, using an electromagnetic tracking system. Interfraction displacements, measured before each treatment, were quantified by calculating the systematic and random deviations of the center of mass of the implanted transponders. Intrafraction motion was analyzed in timeframes of 150 s, and displacements >1 mm, >3 mm, >5 mm, and >7 mm were determined in the anteroposterior, left-right, and superoinferior direction, and for the three-dimensional (3D) vector. Manual table corrections, made during treatment sessions, were retrospectively undone. RESULTS: A total of 576 and 567 tracks have been analyzed in the no-ERB group and ERB group, respectively. Interfraction variation was not significantly different between both groups. After 600 s, 95% and 98% of the treatments were completed in the respective groups. Significantly fewer table corrections were performed during treatment fractions with ERB: 88 vs. 207 (p = 0.02). Intrafraction motion was significantly reduced with ERB. During the first 150 s, only negligible deviations were observed, but after 150 s, intrafraction deviations increased with time. This resulted in cumulative percentages of 3D-vector deviations >1 mm, >3 mm, >5 mm, and >7 mm that were 57.7%, 7.0%, 0.7%, and 0.3% in the ERB-group vs. 70.2%, 18.1%, 4.6%, and 1.4% in the no-ERB group after 600 s. The largest reductions in the ERB group were observed in the AP direction. These data suggest that a 5 mm CTV-to-PTV margin is sufficient to correct for intrafraction prostate movements when using an ERB. CONCLUSIONS: ERB significantly reduces intrafraction prostate motion, but not interfraction variation, and may in particular be beneficial for treatment sessions longer than 150 s. PMID- 22099036 TI - Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. AB - PURPOSE: To investigate the clinical features, prognostic factors, and toxicity of treatment for unresectable carcinomas of the nasal cavity and paranasal sinus (NCPS) treated with proton beam therapy (PBT). METHODS AND MATERIALS: Seventeen patients (13 men, 4 women) with unresectable carcinomas of the NCPS who underwent PBT at the University of Tsukuba between 2001 and 2007 were analyzed. The patients' median age was 62 years (range, 30-83 years). The tumors were located in the nasal cavity in 3 patients, the frontal sinus in 1, the ethmoid sinus in 9, and the maxillary sinus in 4. The clinical stage was Stage IVA in 5 cases, IVB in 10, and recurrent in 2. The tumors were deemed unresectable for medical reasons in 16 patients and because of refusal at a previous hospital 4 months earlier in 1 patient. All the patients received PBT irradiation dose of 22-82.5 GyE and a total of 72.4-89.6 GyE over 30-64 fractions (median 78 GyE over 36 fractions) with X-ray, with attention not exceeding the delivery of 50 GyE to the optic chiasm and brainstem. RESULTS: The overall survival rate was 47.1% at 2 years and 15.7% at 5 years, and the local control rate was 35.0% at 2 years and 17.5% at 5 years. Invasion of the frontal or sphenoid sinus was a prognostic factor for overall survival or local control. Late toxicity of more than Grade 3 was found in 2 patients (brain necrosis in 1 and ipsilateral blindness in 1); however, no mortal adverse effects were observed. CONCLUSION: Proton beam therapy enabled a reduced irradiation dose to the optic chiasm and brainstem, enabling the safe treatment of unresectable carcinomas in the NCPS. Superior or posterior extension of the tumor influenced patient outcome. PMID- 22099037 TI - Image guidance during head-and-neck cancer radiation therapy: analysis of alignment trends with in-room cone-beam computed tomography scans. AB - PURPOSE: On-board cone-beam computed tomography (CBCT) is currently available for alignment of patients with head-and-neck cancer before radiotherapy. However, daily CBCT is time intensive and increases the overall radiation dose. We assessed the feasibility of using the average couch shifts from the first several CBCTs to estimate and correct for the presumed systematic setup error. METHODS AND MATERIALS: 56 patients with head-and-neck cancer who received daily CBCT before intensity-modulated radiation therapy had recorded shift values in the medial-lateral, superior-inferior, and anterior-posterior dimensions. The average displacements in each direction were calculated for each patient based on the first five or 10 CBCT shifts and were presumed to represent the systematic setup error. The residual error after this correction was determined by subtracting the calculated shifts from the shifts obtained using daily CBCT. RESULTS: The magnitude of the average daily residual three-dimensional (3D) error was 4.8 +/- 1.4 mm, 3.9 +/- 1.3 mm, and 3.7 +/- 1.1 mm for uncorrected, five CBCT corrected, and 10 CBCT corrected protocols, respectively. With no image guidance, 40.8% of fractions would have been >5 mm off target. Using the first five CBCT shifts to correct subsequent fractions, this percentage decreased to 19.0% of all fractions delivered and decreased the percentage of patients with average daily 3D errors >5 mm from 35.7% to 14.3% vs. no image guidance. Using an average of the first 10 CBCT shifts did not significantly improve this outcome. CONCLUSIONS: Using the first five CBCT shift measurements as an estimation of the systematic setup error improves daily setup accuracy for a subset of patients with head-and-neck cancer receiving intensity-modulated radiation therapy and primarily benefited those with large 3D correction vectors (>5 mm). Daily CBCT is still necessary until methods are developed that more accurately determine which patients may benefit from alternative imaging strategies. PMID- 22099038 TI - Postoperative chemotherapy followed by conformal concomitant chemoradiotherapy in high-risk gastric cancer. AB - PURPOSE: To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemotherapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treatment of completely resected high-risk gastric cancer. METHODS AND MATERIALS: This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36-75 years). Postoperative treatment consisted of 5 fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy consisted of a 2-h infusion of leucovorin (200 mg/m2) followed by a bolus of 5-fluorouracil (400 mg/m2) and then a 44-h continuous infusion of 5-fluorouracil (2400-3600 mg/m2) given every 14 days, for three cycles (LV5FU2 protocol). RESULTS: Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivariate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarction and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy. CONCLUSION: Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locoregional control. PMID- 22099039 TI - A double-blind placebo-controlled randomized clinical trial with magnesium oxide to reduce intrafraction prostate motion for prostate cancer radiotherapy. AB - PURPOSE: To investigate whether magnesium oxide during external-beam radiotherapy for prostate cancer reduces intrafraction prostate motion in a double-blind, placebo-controlled randomized trial. METHODS AND MATERIALS: At the Department of Radiotherapy, prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. The primary outcome was the proportion of patients with clinically relevant intrafraction prostate motion, defined as the proportion of patients who demonstrated in >= 50% of the fractions an intrafraction motion outside a range of 2 mm. Secondary outcome measures included quality of life and acute toxicity. RESULTS: In total, 46 patients per treatment arm were enrolled. The primary endpoint did not show a statistically significant difference between the treatment arms with a percentage of patients with clinically relevant intrafraction motion of 83% in the magnesium oxide arm as compared with 80% in the placebo arm (p = 1.00). Concerning the secondary endpoints, exploratory analyses demonstrated a trend towards worsened quality of life and slightly more toxicity in the magnesium oxide arm than in the placebo arm; however, these differences were not statistically significant. CONCLUSIONS: Magnesium oxide is not effective in reducing the intrafraction prostate motion during external-beam radiotherapy, and therefore there is no indication to use it in clinical practice for this purpose. PMID- 22099040 TI - Detection of mucosal recurrent nasopharyngeal carcinomas after radiotherapy with narrow-band imaging endoscopy. AB - PURPOSE: This study evaluated the feasibility of screening mucosal recurrent nasopharyngeal carcinoma with narrow-band imaging (NBI) endoscopy. METHODS AND MATERIALS: One hundred and six patients were enrolled. All patients underwent conventional white-light (WL) endoscopic examination of the nasopharynx followed by NBI endoscopy. Biopsies were performed if recurrence was suspected. RESULTS: We identified 32 suspected lesions by endoscopy in WL and/or NBI mode. Scattered brown spots (BS) were identified in 22 patients, and 4 of the 22 who had negative MRI findings were histopathologically confirmed to be neoplasias that were successfully removed via endoscopy. A comparison of the visualization in NBI closer view corresponded to histopathological findings in 22 BS, and the prevalence rates of neoplasias in tail signs, round signs, and irregularities signs were 0% (0/6), 0% (0/7), and 44.4% (4/9), respectively (p = 0.048). The sensitivity, specificity, and diagnostic capability were 37.5%, 92.9% and 0.652 for WL, 87.5%, 74.5% and 0.810 for NBI, and 87.5%, 87.8%, and 0.876 for NBI closer view, respectively. NBI closer view was effective in increasing specificity compared with NBI alone (87.8% vs. 74.5%, p < 0.05), and in increasing sensitivity and diagnostic capability compared to WL alone (87.5% vs. 37.5%, p < 0.05; 0.876 vs. 0.652, p = 0.0001). CONCLUSIONS: Although NBI in endoscopy can improve sensitivity of mucosal recurrent nasopharyngeal neoplasias, false-positive (nonneoplasia BS) results may be obtained in areas with nonspecific inflammatory changes due to postradiation effects. NBI closer view not only can offer a timely, convenient, and highly reliable assessment of mucosal recurrent nasopharyngeal carcinoma, it can also make endoscopic removal possible. PMID- 22099041 TI - Factors associated with the development of breast cancer-related lymphedema after whole-breast irradiation. AB - PURPOSE: To determine the rates of breast cancer-related lymphedema (BCRL) in patients undergoing whole-breast irradiation as part of breast-conserving therapy (BCT) and to identify clinical, pathologic, and treatment factors associated with its development. METHODS AND MATERIALS: A total of 1,861 patients with breast cancer were treated at William Beaumont Hospital with whole-breast irradiation as part of their BCT from January 1980 to February 2006, with 1,497 patients available for analysis. Determination of BCRL was based on clinical assessment. Differences in clinical, pathologic, and treatment characteristics between patients with BCRL and those without BCRL were evaluated, and the actuarial rates of BCRL by regional irradiation technique were determined. RESULTS: The actuarial rate of any BCRL was 7.4% for the entire cohort and 9.9%, 14.7%, and 8.3% for patients receiving a supraclavicular field, posterior axillary boost, and internal mammary irradiation, respectively. BCRL was more likely to develop in patients with advanced nodal status (11.4% vs. 6.3%, p = 0.001), those who had a greater number of lymph nodes removed (14 nodes) (9.5% vs. 6.0%, p = 0.01), those who had extracapsular extension (13.4% vs. 6.9%, p = 0.009), those with Grade II/III disease (10.8% vs. 2.9%, p < 0.001), and those who received adjuvant chemotherapy (10.5% vs. 6.7%, p = 0.02). Regional irradiation showed small increases in the rates of BCRL (p = not significant). CONCLUSIONS: These results suggest that clinically detectable BCRL will develop after traditional BCT in up to 10% of patients. High-risk subgroups include patients with advanced nodal status, those with more nodes removed, and those who receive chemotherapy, with patients receiving regional irradiation showing a trend toward increased rates. PMID- 22099042 TI - Dose--effect relationships for femoral fractures after multimodality limb-sparing therapy of soft-tissue sarcomas of the proximal lower extremity. AB - PURPOSE: We investigated the clinical and dosimetric predictors for radiation associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). METHODS AND MATERIALS: We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (>=30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. RESULTS: Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 +/- 8.9 Gy, V30 of 14.5 +/- 2.3 cc, V45 of 11.8 +/- 1.1 cc, and V60 of 7.2 +/- 2.2 cc at the femoral neck compared with 22.9 +/- 20.8 Gy, 4.8 +/- 5.6 cc, 2.5 +/- 3.9 cc, and 0.8 +/- 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. CONCLUSIONS: These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients. PMID- 22099043 TI - Percentage of positive biopsy cores: a better risk stratification model for prostate cancer? AB - PURPOSE: To assess the prognostic value of the percentage of positive biopsy cores (PPC) and perineural invasion in predicting the clinical outcomes after radiotherapy (RT) for prostate cancer and to explore the possibilities to improve on existing risk-stratification models. METHODS AND MATERIALS: Between 1993 and 2004, 1,056 patients with clinical Stage T1c-T3N0M0 prostate cancer, who had four or more biopsy cores sampled and complete biopsy core data available, were treated with external beam RT, with or without a high-dose-rate brachytherapy boost at William Beaumont Hospital. The median follow-up was 7.6 years. Multivariate Cox regression analysis was performed with PPC, Gleason score, pretreatment prostate-specific antigen, T stage, PNI, radiation dose, androgen deprivation, age, prostate-specific antigen frequency, and follow-up duration. A new risk stratification (PPC classification) was empirically devised to incorporate PPC and replace the T stage. RESULTS: On multivariate Cox regression analysis, the PPC was an independent predictor of distant metastasis, cause specific survival, and overall survival (all p < .05). A PPC >50% was associated with significantly greater distant metastasis (hazard ratio, 4.01; 95% confidence interval, 1.86-8.61), and its independent predictive value remained significant with or without androgen deprivation therapy (all p < .05). In contrast, PNI and T stage were only predictive for locoregional recurrence. Combining the PPC (<=50% vs. >50%) with National Comprehensive Cancer Network risk stratification demonstrated added prognostic value of distant metastasis for the intermediate risk (hazard ratio, 5.44; 95% confidence interval, 1.78-16.6) and high-risk (hazard ratio, 4.39; 95% confidence interval, 1.70-11.3) groups, regardless of the use of androgen deprivation and high-dose RT (all p < .05). The proposed PPC classification appears to provide improved stratification of the clinical outcomes relative to the National Comprehensive Cancer Network classification. CONCLUSIONS: The PPC is an independent and powerful predictor of clinical outcomes of prostate cancer after RT. A risk model replacing T stage with the PPC to reduce subjectivity demonstrated potentially improved stratification. PMID- 22099044 TI - High dose-rate versus low dose-rate brachytherapy for lip cancer. AB - PURPOSE: To analyze the outcome after low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy for lip cancer. METHODS AND MATERIALS: One hundred and three patients with newly diagnosed squamous cell carcinoma of the lip were treated between March 1985 and June 2009 either by HDR (n = 33) or LDR brachytherapy (n = 70). Sixty-eight patients received brachytherapy alone, and 35 received tumor excision followed by brachytherapy because of positive resection margins. Acute and late toxicity was assessed according to the Common Terminology Criteria for Adverse Events 3.0. RESULTS: Median follow-up was 3.1 years (range, 0.3-23 years). Clinical and pathological variables did not differ significantly between groups. At 5 years, local recurrence-free survival, regional recurrence-free survival, and overall survival rates were 93%, 90%, and 77%. There was no significant difference for these endpoints when HDR was compared with LDR brachytherapy. Forty-two of 103 patients (41%) experienced acute Grade 2 and 57 of 103 patients (55%) experienced acute Grade 3 toxicity. Late Grade 1 toxicity was experienced by 34 of 103 patients (33%), and 5 of 103 patients (5%) experienced late Grade 2 toxicity; no Grade 3 late toxicity was observed. Acute and late toxicity rates were not significantly different between HDR and LDR brachytherapy. CONCLUSIONS: As treatment for lip cancer, HDR and LDR brachytherapy have comparable locoregional control and acute and late toxicity rates. HDR brachytherapy for lip cancer seems to be an effective treatment with acceptable toxicity. PMID- 22099045 TI - A mechanism-based approach to predict the relative biological effectiveness of protons and carbon ions in radiation therapy. AB - PURPOSE: The physical and potential biological advantages of proton and carbon ions have not been fully exploited in radiation therapy for the treatment of cancer. In this work, an approach to predict proton and carbon ion relative biological effectiveness (RBE) in a representative spread-out Bragg peak (SOBP) is derived using the repair-misrepair-fixation (RMF) model. METHODS AND MATERIALS: Formulas linking dose-averaged linear-quadratic parameters to DSB induction and processing are derived from the RMF model. The Monte Carlo Damage Simulation (MCDS) software is used to quantify the effects of radiation quality on the induction of DNA double-strand breaks (DSB). Trends in parameters alpha and beta for clinically relevant proton and carbon ion kinetic energies are determined. RESULTS: Proton and carbon ion RBE are shown to increase as particle energy, dose, and tissue alpha/beta ratios decrease. Entrance RBE is ~1.0 and ~1.3 for protons and carbon ions, respectively. For doses in the range of 0.5 to 10 Gy, proton RBE ranges from 1.02 (proximal edge) to 1.4 (distal edge). Over the same dose range, the RBE for carbon ions ranges from 1.5 on the proximal edge to 6.7 on the distal edge. CONCLUSIONS: The proposed approach is advantageous because the RBE for clinically relevant particle distributions is guided by well established physical and biological (track structure) considerations. The use of an independently tested Monte Carlo model to predict the effects of radiation quality on DSB induction also minimizes the number of ad hoc biological parameters that must be determined to predict RBE. Large variations in predicted RBE across an SOBP may produce undesirable biological hot and cold spots. These results highlight the potential for the optimization of physical dose for a uniform biological effect. PMID- 22099046 TI - Accelerated partial breast irradiation with low-dose-rate interstitial implant brachytherapy after wide local excision: 12-year outcomes from a prospective trial. AB - PURPOSE: To evaluate the long-term toxicity, cosmesis, and local control of accelerated partial breast irradiation with implant brachytherapy after wide local excision for Stage T1N0 breast cancer (BCa). MATERIALS AND METHODS: Between 1997 and 2001, 50 patients with Stage T1N0M0 BCa were treated in a Phase I-II protocol using low-dose-rate accelerated partial breast irradiation with implant brachytherapy after wide local excision and lymph node surgery. The total dose was escalated in three groups: 50 Gy (n = 20), 55 Gy (n = 17), and 60 Gy (n = 13). Patient- and physician-assessed breast cosmesis, patient satisfaction, toxicity, mammographic abnormalities, repeat biopsies, and disease status were prospectively evaluated at each visit. Kendall's tau (tau(beta)) and logistic regression analyses were used to correlate outcomes with dose, implant volume, patient age, and systemic therapy. RESULTS: The median follow-up period was 11.2 years (range, 4-14). The patient satisfaction rate was 67%, 67% reported good excellent cosmesis, and 54% had moderate-severe fibrosis. Higher dose was correlated with worse cosmetic outcome (tau(beta) 0.6, p < .0001), lower patient satisfaction (tau(beta) 0.5, p < .001), and worse fibrosis (tau(beta) 0.4, p = .0024). Of the 50 patients, 35% had fat necrosis and 34% developed telangiectasias >=1 cm(2). Grade 3-4 late skin and subcutaneous toxicities were seen in 4 patients (9%) and 6 patients (13%), respectively, and both correlated with higher dose (tau(beta) 0.3-0.5, p <= .01). One patient had Grade 4 skin ulceration and fat necrosis requiring surgery. Mammographic abnormalities were seen in 32% of the patients, and 30% underwent repeat biopsy, of which 73% were benign. Six patients had ipsilateral breast recurrence: five elsewhere in the breast, and one at the implant site. One patient died of metastatic BCa after recurrence. The 12-year actuarial local control, recurrence-free survival, and overall survival rate was 85% (95% confidence interval, 70-97%), 72% (95% confidence interval, 54-86%), and 87% (95% confidence interval, 73-99%), respectively. CONCLUSION: Low-dose-rate accelerated partial breast irradiation with implant brachytherapy provides acceptable local control in select early stage BCa patients. However, treatment-related toxicity and cosmetic complications were significant with longer follow-up and at higher doses. PMID- 22099047 TI - Radiosurgery to the postoperative surgical cavity: who needs evidence? AB - There is a growing interest in adjuvant radiosurgery after resection of hematogenous brain metastases. This is exemplified by the approximately 1000 cases reported in mainly retrospective series. These cases fall into four paradigms: adjuvant radiosurgery as an alternative to whole-brain radiotherapy (WBRT), radiosurgery neoadjuvant to the surgical resection, radiosurgery as an intensification of adjuvant WBRT, and adjuvant radiosurgery for patients having failed prior WBRT. These procedures seem well tolerated, with an approximate 5% risk of radiation necrosis. Although crude local control rates for each strategy seem improved over surgery alone, multiple biases make comparisons with standard WBRT difficult without prospective data. Because evidence lags behind clinical practice, an upcoming intergroup trial will aim to clarify the value of the most common tumor bed radiosurgery strategy by randomizing oligometastatic patients between adjuvant WBRT and adjuvant radiosurgery. PMID- 22099048 TI - Dose-volume analysis of predictors for gastrointestinal toxicity after concurrent full-dose gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma. AB - PURPOSE: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT). METHODS AND MATERIALS: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity. RESULTS: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V(20Gy) to V(35Gy) of duodenum were significantly associated with GI toxicity (all p <= 0.05). On MVA, the V(25Gy) of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V(25Gy) of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V(25Gy) <= 45% and V(25Gy) > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V(35Gy) is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V(35Gy) <= 20% and V(35Gy) > 20%, respectively (p = 0.04). CONCLUSIONS: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity. PMID- 22099049 TI - Repeat brachytherapy for patients with residual or recurrent tumors of oral cavity. AB - PURPOSE: To analyze data from patients receiving repeat brachytherapy (re-BT) for the treatment of residual or recurrent tumor in the oral cavity. METHODS AND MATERIALS: Between January 2003 and December 2007, 62 patients who had undergone definitive BT as an initial treatment of oral cancer subsequently underwent re-BT for the treatment of residual or recurrent tumors at the diagnostic radiology and oncology department (Tokyo Medical and Dental University Hospital). Re-BT was performed 0.9-73 months (median, 5.7) after the initial BT. Au-198 grains were used as the re-BT source in all 62 patients, and an area of 0.8-6.3 cm(2) (median, 3.1) was permanently irradiated with 60-110 Gy (median, 83) according to the system of Paterson-Parker. RESULTS: The 2-year local control and overall survival rate was 53% and 66%, respectively, and local control significantly affected overall survival. Both local control and overall survival were affected by the initial tumor characteristics and the macroscopic appearance of the residual or recurrent tumor. Grade 3 or 4 complications were seen in 5 patients. The incidence of mandibular and mucosal complications was significantly related to a biologic effective dose of alpha/beta of 3 Gy to the surface of the gingiva and mucosa, respectively. CONCLUSION: Re-BT using Au-198 grains for the treatment of residual or recurrent tumor after definitive BT in the oral cavity is effective and well tolerated. PMID- 22099050 TI - Planned two-fraction proton beam stereotactic radiosurgery for high-risk inoperable cerebral arteriovenous malformations. AB - PURPOSE: To evaluate patients with high-risk cerebral arteriovenous malformations (AVMs), based on eloquent brain location or large size, who underwent planned two fraction proton stereotactic radiosurgery (PSRS). METHODS AND MATERIALS: From 1991 to 2009, 59 patients with high-risk cerebral AVMs received two-fraction PSRS. Median nidus volume was 23 cc (range, 1.4-58.1 cc), 70% of cases had nidus volume >= 14 cc, and 34% were in critical locations (brainstem, basal ganglia). Median AVM score based on age, AVM size, and location was 3.19 (range, 0.9-6.9). Many patients had prior surgery or embolization (40%) or prior PSRS (12%). The most common prescription was 16 Gy radiobiologic equivalent (RBE) in two fractions, prescribed to the 90% isodose. RESULTS: At a median follow-up of 56.1 months, 9 patients (15%) had total and 20 patients (34%) had partial obliteration. Patients with total obliteration received higher total dose than those with partial or no obliteration (mean dose, 17.6 vs. 15.5 Gy (RBE), p = 0.01). Median time to total obliteration was 62 months (range, 23-109 months), and 5-year actuarial rate of partial or total obliteration was 33%. Five-year actuarial rate of hemorrhage was 22% (95% confidence interval, 12.5%-36.8%) and 14% (n = 8) suffered fatal hemorrhage. Lesions with higher AVM scores were more likely to hemorrhage (p = 0.024) and less responsive to radiation (p = 0.026). The most common complication was Grade 1 headache acutely (14%) and long term (12%). One patient developed a Grade 2 generalized seizure disorder, and two had mild neurologic deficits. CONCLUSIONS: High-risk AVMs can be safely treated with two-fraction PSRS, although total obliteration rate is low and patients remain at risk for future hemorrhage. Future studies should include higher doses or a multistaged PSRS approach for lesions more resistant to obliteration with radiation. PMID- 22099051 TI - Effect of recombinant human endostatin on radiosensitivity in patients with non small-cell lung cancer. AB - PURPOSE: To observe the effects of recombinant human endostatin (RHES) on the radiosensitivity of non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: First, 10 hypoxia-positive cases of pathology-diagnosed NSCLC selected from 15 patients were used to determine the normalization window, a period during which RHES improves NSCLC hypoxia. Second, 50 hypoxia-positive cases of pathology diagnosed NSCLC (Stages I-III) were randomly divided into a RHES plus radiotherapy group (25 cases) and a radiotherapy-alone group (25 cases). Intensity = modulated radiotherapy with a total dose of 60 Gy in 30 fractions for 6 weeks was adopted in the two groups. The target area included primary foci and metastatic lymph nodes. In the RHES plus radiotherapy group, RHES (15 mg/day) was intravenously given during the normalization window. RESULTS: After RHES administration, the tumor-to=normal tissue radioactivity ratio and capillary permeability surface were first decreased and then increased, with their lowest points on the fifth day compared with the first day (all p < 0.01). Blood flow was first increased and then decreased, with the highest point on the fifth day, compared with the first and tenth day (all p < 0.01). In the RHES plus radiotherapy group and the radiotherapy-alone group, the total effective rates (complete response plus partial response) were 80% and 44% (p = 0.009), respectively. The median survival times were 21.1 +/- 0.97 months and 16.5 +/- 0.95 months (p = 0.004), respectively. The 1-year and 2-year local control rates were 78.9 +/- 8.4% and 68.1 +/- 7.8% (p = 0.027) and 63.6 +/- 7.2% and 43.4 +/- 5.7% (p = 0.022), respectively. The 1-year and 2-year overall survival rates were 83.3 +/- 7.2% and 76.6 +/- 9.3% (p = 0.247) and 46.3 +/- 2.4% and 37.6 +/- 9.1% (p = 0.218), respectively. CONCLUSION: The RHES normalization window is within about 1 week after administration. RHES combined with radiotherapy within the normalization window has better short-term therapeutic effects and local control rates and no severe adverse reactions in the treatment of NSCLC, but it failed to significantly improve the 1-year and 3-year overall survival rates. PMID- 22099052 TI - A short food frequency questionnaire to assess intake of seafood and n-3 supplements: validation with biomarkers. AB - BACKGROUND: Seafood intake is associated with beneficial effects for human health. Seafood provides a number of nutrients beyond the traditionally known long chain marine n-3 fatty acids EPA, DPA and DHA, such as protein, vitamin D, iodine, selenium and vitamin B12. Valid assessment of dietary seafood and n-3 supplement intakes are becoming increasingly crucial when giving recommendations to populations as seafood consumption is regarded as an important part of a healthy and balanced diet. METHODS: The aim was to validate a short FFQ developed for assessment of dietary intake of seafood and n-3 supplements using the biomarkers marine n-3 fatty acids in erythrocytes and 25(OH)D in serum. RESULTS: Fifty-three healthy Norwegians aged 30-64 years with a mean BMI of 25 kg/m2 were compliant with the study protocol. 70% reported eating seafood for dinner one to two times per week, and 45% reported to eat seafood as spread, in salads or as snack meal three to five times or more per week. The FFQ correlated significantly with both the levels of marine n-3 fatty acids (r=0.73, p<0.0001) and with 25(OH)D (r=0.37, p<0.01). Mean level of marine n-3 and of 25(OH)D were 232+/-65 MUg/g erythrocytes and 73+/-33 nmol/L serum, respectively. CONCLUSION: The present short FFQ predicted strongly the levels of marine n-3 fatty acids in erythrocytes, and predicted fairly good the level of serum 25(OH)D and may therefore be a valid method for assessment of seafood and n-3 supplements intake among adults. PMID- 22099053 TI - Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. AB - The present study aimed to analyze the expression profile of the microRNAs previously described as associated with childhood ALL, miR-92a, miR-100, miR-125a 5p, miR-128a, miR-181b, miR-196b and let-7e, and their association with biological/prognostic features in 128 consecutive samples of childhood acute lymphoblastic leukemia (ALL) by quantitative real-time PCR. A significant association was observed between higher expression levels of miR-196b and T-ALL, miR-100 and patients with low white blood cell count at diagnosis and t(12;21) positive ALL. These findings suggest a potential activity of these microRNAs in pediatric ALL biology. PMID- 22099054 TI - The effects of ischemia with and without remote conditioning on hyperemia induced decline in carotid-radial pulse wave velocity. AB - Ischemic conditioning has long held promise for preventing ischemic-reperfusion (I-R) injury. Although a number of studies have evaluated the effects of brief repeated episodes of ischemia before a prolonged ischemic episode on the cardiovascular system using clinical endpoints, more sensitive techniques by which to measure its effects are lacking. Since endothelial function is sensitive to I-R injury, flow mediated dilation of the brachial artery has been proposed for this purpose, but has significant limitations. Hyperemia normally decreases carotid to radial pulse wave velocity (PWV). Accordingly, we sought to determine the effects of I-R injury and ischemic conditioning on the hyperemic change (Delta) in PWV. We induced hyperemia by release of arterial cuff occlusion before and after ipsilateral arm I-R injury (7.5min occlusion) in 25 healthy males, age 29+/-6 years. The protocol was repeated on 2 occasions in combination with either pre- or post- conditioning stimuli (3* 30s contralateral arm occlusions). Hyperemia resulted in a significant decrease (-13.7%, p<.001) before but not after prolonged ischemia (-0.88%, p=0.40). I-R along with either pre- or post ischemic conditioning restored the PWV decline (pre: -11.0%, p<0.001; post: 9.9%, p<0.001). In conclusion, 7.5min ischemia blunts the normal PWV decline produced by hyperemia. Remote pre- and post-conditioning restores this response. This technique may be useful for the assessment of novel treatment strategies and mechanisms underlying remote pre- and post-ischemic conditioning in protecting the cardiovascular system. PMID- 22099055 TI - Ankle-brachial index and cardiovascular risk prediction: an analysis of 11,594 individuals with 10-year follow-up. AB - BACKGROUND: Low ankle-brachial index (ABI) is associated with increased risk of subsequent cardiovascular disease events, independent of Framingham risk factors, but its ability to improve risk prediction prospectively has not been examined. METHODS: We conducted post-hoc analysis of data from Atherosclerosis Risk in Communities Study (ARIC Study), a large prospective cohort study. 11,594 white and African American (24.2%) men and women, aged 45-64 years, with available Framingham Risk Score (FRS) variables and ABIs at baseline, and without known history of cardiovascular disease or diabetes mellitus or known peripheral arterial disease at baseline were assessed for hard cardiovascular events (hCVD; defined as heart attack, coronary death or stroke) over median follow-up of 10 years. Hazard ratios, C statistic, and net reclassification indexes were calculated to determine the independent predictive ability of ABI compared with FRS. RESULTS: 659 hCVD events occurred. Standardized ABI was significantly associated with hCVD events but with a relatively small effect on events (hazard ratios of 0.85 per standard deviation (95% CI 0.79-0.91) (p-value<0.0001)). The C statistic of FRS modified with ABI was only modestly improved (0.756-0.758). Net reclassification improvement, an indicator of prospective prediction performance, using an ABI threshold of 0.9 was small and statistically insignificant (0.8%, p=0.50). CONCLUSIONS: Although the ABI adjusted for Framingham risk variables was independently associated with subsequent events in terms of hazard ratios, the independent effect of ABI when adjusted for FRS was small in magnitude, and the FRS performed similarly with or without integration or supplementation with ABI. These findings do not provide strong evidence to support FRS modification to include ABI. PMID- 22099056 TI - Synthesis of cross-linked epoxy microparticles: effect of the synthesis parameters. AB - Epoxy crosslinked microparticles were synthesized from the reaction between diglycidyl ether of bisphenol A and a diamino hardener, through precipitation polymerization in a polypropylene glycol solvent. The influence of the monomer concentration, the amine/epoxy stoichiometric ratio, the reaction temperature and the structure of the diamine (aromatic or cycloaliphatic) were investigated, since these parameters may affect the structure and properties of the particles. Morphological analysis revealed that, in all cases, spherical particles were obtained with diameters ranging from 1 to 6 MUm. The glass transition temperatures of the particles was found to vary between 130 and 160 degrees C using the aromatic diamine and between 116 and 141 degrees C using the cycloaliphatic diamine. It was also found that the effective stoichiometry of the particles was different from the initial stoichiometry in the feed solution. PMID- 22099057 TI - Fabrication and characterization of biocompatible nacre-like structures from alpha-zirconium hydrogen phosphate hydrate and chitosan. AB - Composite materials with an ordered layered structure resembling that of nacre were fabricated by layer-by-layer assembly making use of presynthesized alpha zirconium hydrogenphosphate hydrate (ZrP) platelets and chitosan. These two biocompatible materials were chosen in view of possible applications in the biomedical field, e.g., as bone or joint replacement implants. The effect of different concentrations of the inorganic ZrP platelets and the organic components (chitosan) on the composite assembly and structure was investigated. A high concentration of chitosan (0.1 wt.%) resulted in a misalignment of the inorganic platelets, while at very low concentrations (0.001 wt.%), the substrate was not fully covered by the polymer, again leading to misalignment. Also, the concentration of the alpha-ZrP platelets affected the composite assembly and structure. The number of dipping cycles was varied between 70 and 220, yielding a maximum thickness of approximately 6 MUm. The pH value of the chitosan solution was also varied to investigate its influence on the composite assembly. The mechanical properties of the composites were tested with a nanoindenter. For samples prepared with the same number of dipping cycles, higher values of Young's modulus and hardness were obtained with improved alignment of the platelets in the samples. For samples prepared with 220 dipping cycles, a Young's modulus of 2.6 GPa and a hardness of 70 MPa were observed. Important general relationships are recognized between the preparation parameters, the degree of order within the nacre-like films and the resulting mechanical properties. PMID- 22099058 TI - Distinct effects of cevimeline and pilocarpine on salivary mechanisms, cardiovascular response and thirst sensation in rats. AB - OBJECTIVE: Cevimeline and pilocarpine (muscarinic receptor agonists) are used as sialogogues in xerostomia treatment. It is important to know the different effects on their salivary mechanisms and the side effects. The aim of the present study was to clarify and compare the comprehensive effects of cevimeline to pilocarpine on salivary, cardiovascular and central mechanisms in rats. DESIGN: Under anaesthesia, whole saliva secretion, parotid blood flow and blood pressure were measured following intra-peritoneal administrations of the sialogogues. In digested parotid cells, intracellular Ca(2+) concentrations were measured after the sialogogue application. In the conscious condition, changes in angiotensin II induced water intake were observed after cevimeline administration. In the subfornical organ, which is a thirst-related central nucleus, the effect of cevimeline on the neuronal activity was electrophysiologically investigated. RESULTS: Cevimeline at 80MUmolkg(-1) showed slowly increasing and lasting salivation, a similar blood flow increment in the parotid gland and higher pressor response when compared to pilocarpine at 4MUmolkg(-1). In parotid cells, cevimeline increased the intracellular Ca(2+) concentration in a similar manner to pilocarpine, but at a higher concentration than pilocarpine. Cevimeline inhibited angiotensin II-induced water intake and neuronal activity in the subfornical organ, which is in contrast to reported effects of pilocarpine. CONCLUSIONS: Cevimeline activates common salivary mechanism with pilocarpine but has a slower onset of activation, longer duration of salivation and an increased pressor response at higher doses. The anti-dipsogenic effect of cevimeline is due to the inhibitory neuronal effect on the thirst-related central nuclei. PMID- 22099059 TI - EMBRYONIC FACTOR 19 encodes a pentatricopeptide repeat protein that is essential for the initiation of zygotic embryogenesis in Arabidopsis. AB - Early embryogenesis is the most fundamental developmental process in biology. Screening of ethyl methanesulfonate (EMS)-mutagenized populations of Arabidopsis thaliana led to the identification of a zygote-lethal mutant embryonic factor 19 (fac19) in which embryo development was arrested at the elongated zygote to octant stage. The number of endosperm nuclei decreased significantly in fac19 embryos. Genetic analysis showed fac19 was caused by a single recessive mutation with typical mendelian segregation, suggesting equal maternal and paternal contributions of FAC19 towards zygotic embryogenesis. Positional cloning showed that FAC19 encodes a putative mitochondrial protein with 16 conserved pentatricopeptide repeat (PPR) motifs. The fac19 mutation caused a conversion from hydrophilic serine located in a previously unknown domain to hydrophobic leucine. Crosses between FAC19/fac19 and the T-DNA insertion mutants in the same gene failed to complement the fac19 defects, confirming the identity of the gene. This study revealed the critical importance of a PPR protein-mediated mitochondrial function in early embryogenesis. PMID- 22099060 TI - Discrimination of zeolites and beryllium containing silicates using portable Raman spectroscometric equipment with near-infrared excitation. AB - In this paper Raman spectra were obtained for a series of zeolites (thomsonite, stilbite, natrolite) and beryllium containing silicates (beryl, chrysoberyl, euclase, phenacite, bavenite, milarite) using a portable Raman specrometer with a 785 nm laser excitation to show the possibility to apply this setting for unambiguous detection and discrimination of these silicate minerals. Obtained spectra contain the most intense Raman bands at the same positions +/-2-4 cm(-1) as reported in the literature. The use of these bands permits the unambiguous identification of these phases. Data show the possibility to discriminate individual species of similar whitish color and aspect. Measurements showed an excellent correspondence of Raman bands obtained using the portable system and a laboratory Raman microspectrometer (with the same excitation laser wavelenght). However, for several minerals of these groups (chrysoberyl, bertrandite, chiavennite) Raman spectra were not of sufficient quality to permit unambiguous identification. The reasons are discussed. Raman spectrum of chiavennite CaMnBe(2)Si(5)O(13)(OH)(2).2(H(2)O) - a transformation product occurring together with bavenite on the surface of beryl crystals was obtained for the first time using the laboratory Raman spectrometer. PMID- 22099061 TI - Stigmatization, empathy, and the ego depletion hypothesis. PMID- 22099062 TI - New journal section on musculoskeletal pain. PMID- 22099063 TI - Respecting the will of the patient: between illusions and realities. PMID- 22099064 TI - Medical students need training to approach chronic pain. PMID- 22099067 TI - Genomic alterations in rectal tumors and response to neoadjuvant chemoradiotherapy: an exploratory study. AB - BACKGROUND: Neoadjuvant chemoradiotherapy is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. METHODS: Forty-eight candidates for neoadjuvant chemoradiotherapy were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade. RESULTS: Both Hidden Markov Model and Smoothing approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 3q29, 7p22-21, 7q21, 7q36, 8q23-24, 10p14-13, 13q12, 13q31-34, 16p13, 17p13-12 and 18q23 chromosomal regions. CONCLUSIONS: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information on response to neoadjuvant chemoradiotherapy and could help to optimize therapy in rectal cancer patients.The data discussed in this study are available on the NCBI Gene Expression Omnibus [GEO: GSE25885]. PMID- 22099068 TI - Relaxant effect of a novel calcium-activated potassium channel modulator on human myometrial spontaneous contractility in vitro. AB - AIM: To investigate the effect of 4,5-dichloro-1,3-diethyl-1,3-dihydro benzoimidazol-2-one (NS4591), a novel SK/IK channels positive modulator, on human myometrial activity. METHODS: Organ bath studies were performed on myometrial preparations obtained from women undergoing elective caesarean section at term (N = 11) or hysterectomy (N = 11). NS4591 was added cumulatively in the concentration range of 0.3-30 MUm. In separate experiments, the effects of pre incubation of muscle preparation with the SK or IK channel blockers apamin (1 MUm) and TRAM34 (10 MUm) on the outcomes of NS4591 were evaluated. Simultaneous vehicle controls were performed for all experiments. The effects of drugs were studied on spontaneous contractions. RESULTS: NS4591 exerted an inhibitory effect on myometrial contractions in muscle strips from non-pregnant and pregnant women. The contractility in non-pregnant and pregnant myometrium was reduced to the following values respectively: amplitude 20.65 +/- 7.38% (P < 0.001) and 42.85 +/ 11.04% (P < 0.05) and area under the curve 11.72 +/- 7.39% (P < 0.001) and 34.84 +/- 10.50% (P < 0.001) and are reflective of 30 MUm NS4591 compared to vehicle control. In non-pregnant tissue, apamin partially reduced the inhibitory effects of NS4591, but we observed relaxation mediated by NS4591 despite pre-incubation with TRAM34. In contrast, in pregnant tissue, neither apamin nor TRAM34 could reverse the relaxatory effects of NS4591. CONCLUSION: Our findings imply that SK/IK channels are present and functional in myometrium from pregnant and non pregnant women. The SK/IK channel-positive modulator NS4591 exerts relaxation of human myometrium in vitro, and this may have implications for the clinical management of preterm labour. PMID- 22099069 TI - Differential expression of cysteine desulfurases in soybean. AB - BACKGROUND: Iron-sulfur [Fe-S] clusters are prosthetic groups required to sustain fundamental life processes including electron transfer, metabolic reactions, sensing, signaling, gene regulation and stabilization of protein structures. In plants, the biogenesis of Fe-S protein is compartmentalized and adapted to specific needs of the cell. Many environmental factors affect plant development and limit productivity and geographical distribution. The impact of these limiting factors is particularly relevant for major crops, such as soybean, which has worldwide economic importance. RESULTS: Here we analyze the transcriptional profile of the soybean cysteine desulfurases NFS1, NFS2 and ISD11 genes, involved in the biogenesis of [Fe-S] clusters, by quantitative RT-PCR. NFS1, ISD11 and NFS2 encoding two mitochondrial and one plastid located proteins, respectively, are duplicated and showed distinct transcript levels considering tissue and stress response. NFS1 and ISD11 are highly expressed in roots, whereas NFS2 showed no differential expression in tissues. Cold-treated plants showed a decrease in NFS2 and ISD11 transcript levels in roots, and an increased expression of NFS1 and ISD11 genes in leaves. Plants treated with salicylic acid exhibited increased NFS1 transcript levels in roots but lower levels in leaves. In silico analysis of promoter regions indicated the presence of different cis elements in cysteine desulfurase genes, in good agreement with differential expression of each locus. Our data also showed that increasing of transcript levels of mitochondrial genes, NFS1/ISD11, are associated with higher activities of aldehyde oxidase and xanthine dehydrogenase, two cytosolic Fe-S proteins. CONCLUSIONS: Our results suggest a relationship between gene expression pattern, biochemical effects, and transcription factor binding sites in promoter regions of cysteine desulfurase genes. Moreover, data show proportionality between NFS1 and ISD11 genes expression. PMID- 22099070 TI - Assessment of transmitral vortex formation in patients with diastolic dysfunction. AB - BACKGROUND: Previous experimental models have related transmitral vortex formation to the longitudinal recoil of left ventricle. However, little is known about the relationships among left ventricular (LV) longitudinal relaxation, transmitral filling patterns, and LV vortex formation in clinical settings. The aim of this study was to compare the vortex formation time index among a heterogeneous group of patients with diastolic dysfunction to understand the relationship between transmitral vortex formation and abnormal diastolic filling patterns. METHODS: Echocardiographic data from 107 subjects were retrospectively evaluated. The study population was categorized into four groups on the basis of transmitral early and late diastolic Doppler filling patterns as normal (n = 45), impaired relaxation (n = 14), pseudonormal (n = 26), and restrictive (n = 22). Vortex formation time was computed from the governing equations based on transmitral flow and ejection fraction. RESULTS: Differences in vortex formation time index were found to be significant among all the studied groups (P < .0001). The trend of vortex formation during a cardiac cycle was compared in normal hearts and those with diastolic dysfunction. Mitral annular velocity (e') was found to decrease significantly (P < .0001) in subjects with abnormal transmitral filling patterns compared with normal subjects. The difference in e' among all the affected groups was not found to be significant (P = .68). CONCLUSIONS: The findings of this study suggest that patients with different patterns of transmitral diastolic filling show significant changes in LV vortex formation time despite the absence of significant differences in mitral annulus recoil during diastole. PMID- 22099071 TI - Comparison of the efficacies of lamivudine versus entecavir in patients with hepatitis B virus-related decompensated cirrhosis. AB - BACKGROUND: Suppression of hepatitis B virus (HBV) DNA is more potent, and occurrence of resistant strain is rare with entecavir than lamivudine, but whether these merits result in a more favourable outcome in HBV-related decompensated cirrhosis patients is unclear. AIMS: To compare virologic response, changes in liver function, clinical course and predictive factors for early mortality after treatment between patients treated with lamivudine and those with entecavir in HBV-related decompensated cirrhosis patients. METHODS: HBV-related decompensated cirrhosis patients [Child-Turcotte-Pugh (CTP) score >= 7] treated with either lamivudine or entecavir were enrolled. Serum HBV DNA levels, CTP score and Model for End-stage Liver Disease (MELD) score were monitored every 3 months. RESULTS: Eighty-six patients were enrolled; mean age was 54 +/- 11 years, and 63 (73.3%) patients were men; 41 (47.7%) and 45 (52.3%) patients were assigned to the lamivudine group and entecavir group respectively. Although suppression of serum HBV DNA level was more potent in the entecavir group, CTP or MELD scores during the course of treatment did not differ between the two groups. Similarly, 6-month survival rates did not differ between the two groups (95.1 vs 93.2%, P = 0.684). Baseline CTP score and MELD score at 3 months of treatment were significantly associated with 6-month mortality. The 6- and 12-month mortality rates for patients with baseline CTP score >= 11 and MELD score >= 17.5 after 3 months of treatment were 42.9 and 61.9% respectively. CONCLUSIONS: Although HBV DNA suppression was more potent in the entecavir group than the lamivudine group, early mortality rates did not differ between the two groups. The baseline CTP score and MELD score 3 months after initiating antiviral treatment were significant predictors of early mortality. PMID- 22099072 TI - A patient with anaphylaxis after alteplase infusion. AB - Anaphylaxis to alteplase is a rare but reported complication of intravenous thrombolysis. We report a patient with a documented episode of anaphylaxis that occurred following an initial bolus and a subsequent delayed infusion of alteplase for thrombolysis of acute ischaemic stroke. The patient was treated with hydrocortisone, adrenaline, prochlorperazine and ranitidine, as per the hospital anaphylaxis protocol, intubation and admission to the intensive care unit. Serum tryptase levels performed during the anaphylactic event (at the end of the infusion) and 1.5 hours later showed an increase of 2 MUg/L, suggestive of an anaphylactic reaction. Anaphylaxis remains largely a clinical diagnosis even in the absence of an elevated serum tryptase. The patient would benefit from further allergen testing given the severity of the reaction to alteplase. We report this patient to indicate that although rare, anaphylaxis is a recognised adverse event following alteplase. In the case of any symptoms suggestive of a minor anaphylactic reaction to alteplase, further infusion should be ceased to avoid a dose dependent major reaction. PMID- 22099073 TI - Intraspinal migration of a clavicular Steinmann pin: case report and management strategy. AB - Spine injury resulting from migration of previously implanted appendicular skeleton fixation hardware is rare. We present a 41-year-old man who had Steinmann fixation pins placed for a left clavicular fracture 2 years prior. He presented with a burning sensation over his biceps bilaterally and numbness over the left anterior chest and abdomen following a significant blunt traumatic injury. A CT scan revealed migration of a fractured Steinmann pin entering the left C8 neural foramen, traversing anterior to the spinal cord. The patient underwent a left C7 hemilaminectomy, foraminal decompression, and first rib resection to identify the extraforaminal portion of the pin and remove it under direct vision. He recovered uneventfully. We conclude that a principle of safe surgical removal includes adequate exposure to allow for direct visualization of the pin and neural structures. We review the evaluation and management strategies of this unusual condition. PMID- 22099074 TI - Glioblastoma multiforme and cerebral cavernous malformations: intersection of pathophysiologic pathways. AB - Cerebral cavernous malformations (CCM) are known to occur in both sporadic and familial forms. To date, there has been no identified association of CCM with glioblastoma multiforme. We present a 69-year-old woman with a 14 year history of multiple CCM who developed progressive aphasia. She had no radiation exposure and had only undergone a single computed tomography scan in her entire life. MRI demonstrated irregular gadolinium enhancement in the area of a prior stable CCM, suspicious for a high grade tumor. Stereotactic biopsy revealed a glioblastoma multiforme. This is a unique case of glioblastoma multiforme arising from the "site" of a known CCM. We review the literature on the genetics of cavernous malformations and propose a mechanism for the tumorigenic potential of these vascular malformations. PMID- 22099075 TI - Clinical presentation and outcome of patients with intradural spinal cord tumours. AB - We aimed to retrospectively investigate the clinical presentation and outcome of surgical intervention of patients with intradural spinal cord tumours (IDSCT), and to assess the predictors of surgical outcome. A total of 109 patients with IDSCT (57 males and 52 females) (130 admissions; mean age, 45.9 years; range, 14 89 years) underwent surgery between 1 January 1994 and 30 June 2009 at The Royal Melbourne Hospital. Ninety per cent of tumours were classified as low grade. Pain was the most common symptom at presentation (60%) and the mean duration of symptoms was 37.8 weeks (0-4 years). Total resection was achieved in 72.3% of patients with IDSCT. An extramedullary location was the strongest predictor of greater extent of tumour resection (odds ratio [OR]=4.367, 95% confidence interval [CI]=1.876-10.204, p=0.001), whereas a rostral location was also a significant predictor of greater resection (OR=1.393, 95% CI=1.014-1.908, p=0.040). The surgical mortality rate was 0.92%. A good pre-operative clinical grade was the strongest predictor of a positive post-operative neurological status at discharge for IDSCT (OR=7.382, 95% CI=4.575-11.912, p<0.001). The mean follow-up was 37.9 months (16 days-165 months). A good post-operative clinical grade was the most significant predictor of a positive neurological outcome at short-term follow-up (OR=9.953, 95% CI=4.941-20.051, p<0.001), while a good pre morbid clinical grade was the most significant predictor of a positive outcome at long-term follow-up (OR=9.498, 95% CI=2.780-32.451, p<0.001). We concluded that surgical outcome was influenced by pre-morbid, pre-operative and post-operative clinical grades, the extent of resection, tumour grade and tumour location with respect to the spinal parenchyma. Surgical intervention has a high success rate for tumour control and we recommend total resection where possible. PMID- 22099076 TI - A 6.5-year follow-up of 14 patients who underwent ProDisc total disc arthroplasty for combined long-standing degenerative lumbar disc disease and recent disc herniation. AB - A highly selected cohort of nine women and five men (mean age+/-standard error of the mean, 39.6+/-10.2 years) with discogenic low-back pain (duration: 75.4+/-97.5 months) and radiculopathy due to disc herniation (duration: 9.4+/-11.8 months) underwent anterior microdiscectomy and ProDisc-L II arthroplasty (Synthes, Oberdorf, Switzerland) (L5/S1 in 13 patients, L4/5 in one). As reported earlier, initial results were excellent in 11 and good in three patients at 17.8+/-4.7 months. At an average of 6.5 years after surgery, all were reassessed using the SWISSDISC-questionnaire, which involves the EuroQol-5D and North American Spine Society evaluations (general health, low-back and lower limb status), and a telephone call. Patients reporting an unsatisfactory outcome were re-examined clinically and radiologically. Results were excellent for 10, good for two, satisfactory for one, and poor for one patient. Visual analog scores for back and leg pain at 6.5 years had improved significantly relative to preoperative values (p<0.01), and were only slightly higher than at 1.48 years (p=0.3). This study confirms the initial favorable results. PMID- 22099077 TI - The "combined eye" of surgeon and artist: evaluation of the artists who illustrated for Cushing, Dandy and Cairns. AB - Medical illustration is an essential device for the teaching of anatomy, physiology and pathology. In surgery, illustration is more than a teaching aid and has been instrumental in the development the surgical art. This has required a close collaboration between surgeon and artist. This has been particularly evident in neurosurgery where surgeon and artist worked together with a "combined eye", to help develop and disseminate surgical techniques. In this article we review the lineage of medical illustration in neurosurgery and three important partnerships between artist and neurosurgeon that have helped forge a lineage of surgical and artistic technique. Max Brodel and Harvey Cushing worked closely together at The Johns Hopkins Hospital, a collaboration which led to the opening of the Department of Art as Applied to Medicine. Brodel trained two talented artists, Hager Padget and Audrey Arnott, who worked for Walter Dandy and Hugh Cairns respectively. The techniques used in these collaborations between artist and surgeon were inspired by the art of Da Vinci, and the work of the anatomist Vesalius and the artist Jan Stefan van Calcar in the 16th century. We discuss how the combined eye of artist and surgeon is an important aspect of art history and we consider whether the illustrations of Brodel, Padget and Arnott can be considered as works of art. PMID- 22099086 TI - Deaths associated with pandemic (H1N1) 2009 among children, Japan, 2009-2010. AB - To clarify the cause of deaths associated with pandemic (H1N1) 2009 among children in Japan, we retrospectively studied 41 patients <20 years of age who had died of pandemic (H1N1) 2009 through March 31, 2010. Data were collected through interviews with attending physicians and chart reviews. Median age of patients was 59 months; one third had a preexisting condition. Cause of death was categorized as unexpected cardiopulmonary arrest for 15 patients, encephalopathy for 15, and respiratory failure for 6. Preexisting respiratory or neurologic disorders were more frequent in patients with respiratory failure and less frequent in patients with unexpected cardiopulmonary arrest. The leading causes of death among children with pandemic (H1N1) 2009 in Japan were encephalopathy and unexpected cardiopulmonary arrest. Deaths associated with respiratory failure were infrequent and occurred primarily among children with preexisting conditions. Vaccine use and public education are necessary for reducing influenza associated illness and death. PMID- 22099087 TI - Global distribution and epidemiologic associations of Escherichia coli clonal group A, 1998-2007. AB - Escherichia coli clonal group A (CGA) was first reported in 2001 as an emerging multidrug-resistant extraintestinal pathogen. Because CGA has considerable implications for public health, we examined the trends of its global distribution, clinical associations, and temporal prevalence for the years 1998 2007. We characterized 2,210 E. coli extraintestinal clinical isolates from 32 centers on 6 continents by CGA status for comparison with trimethoprim/sulfamethoxazole (TMP/SMZ) phenotype, specimen type, inpatient/outpatient source, and adult/child host; we adjusted for clustering by center. CGA prevalence varied greatly by center and continent, was strongly associated with TMP/SMZ resistance but not with other epidemiologic variables, and exhibited no temporal prevalence trend. Our findings indicate that CGA is a prominent, primarily TMP/SMZ-resistant extraintestinal pathogen concentrated within the Western world, with considerable pathogenic versatility. The stable prevalence of CGA over time suggests full emergence by the late 1990s, followed by variable endemicity worldwide as an antimicrobial drug-resistant public health threat. PMID- 22099088 TI - Group A Streptococcus emm gene types in pharyngeal isolates, Ontario, Canada, 2002-2010. AB - Group A Streptococcus (GAS) is a human-adapted pathogen that causes a variety of diseases, including pharyngitis and invasive infections. GAS strains are categorized by variation in the nucleotide sequence of the gene (emm) that encodes the M protein. To identify the emm types of GAS strains causing pharyngitis in Ontario, Canada, we sequenced the hypervariable region of the emm gene in 4,635 pharyngeal GAS isolates collected during 2002-2010. The most prevalent emm types varied little from year to year. In contrast, fine-scale geographic analysis identified inter-site variability in the most common emm types. Additionally, we observed fluctuations in yearly frequency of emm3 strains from pharyngitis patients that coincided with peaks of emm3 invasive infections. We also discovered a striking increase in frequency of emm89 strains among isolates from patients with pharyngitis and invasive disease. These findings about the epidemiology of GAS are potentially useful for vaccine research. PMID- 22099090 TI - Dynamics of cholera outbreaks in Great Lakes region of Africa, 1978-2008. AB - Cholera outbreaks have occurred in Burundi, Rwanda, Democratic Republic of Congo, Tanzania, Uganda, and Kenya almost every year since 1977-1978, when the disease emerged in these countries. We used a multiscale, geographic information system based approach to assess the link between cholera outbreaks, climate, and environmental variables. We performed time-series analyses and field investigations in the main affected areas. Results showed that cholera greatly increased during El Nino warm events (abnormally warm El Ninos) but decreased or remained stable between these events. Most epidemics occurred in a few hotspots in lakeside areas, where the weekly incidence of cholera varied by season, rainfall, fluctuations of plankton, and fishing activities. During lull periods, persistence of cholera was explained by outbreak dynamics, which suggested a metapopulation pattern, and by endemic foci around the lakes. These links between cholera outbreaks, climate, and lake environments need additional, multidisciplinary study. PMID- 22099089 TI - Close similarity between sequences of hepatitis E virus recovered from humans and swine, France, 2008-2009. AB - Frequent zoonotic transmission of hepatitis E virus (HEV) has been suspected, but data supporting the animal origin of autochthonous cases are still sparse. We assessed the genetic identity of HEV strains found in humans and swine during an 18-month period in France. HEV sequences identified in patients with autochthonous hepatitis E infection (n = 106) were compared with sequences amplified from swine livers collected in slaughterhouses (n = 43). Phylogenetic analysis showed the same proportions of subtypes 3f (73.8%), 3c (13.4%), and 3e (4.7%) in human and swine populations. Furthermore, similarity of >99% was found between HEV sequences of human and swine origins. These results indicate that consumption of some pork products, such as raw liver, is a major source of exposure for autochthonous HEV infection. PMID- 22099091 TI - International spread of MDR TB from Tugela Ferry, South Africa. AB - We describe a death associated with multidrug-resistant tuberculosis and HIV infection outside Africa that can be linked to Tugela Ferry (KwaZulu-Natal, South Africa), the town most closely associated with the regional epidemic of drug resistant tuberculosis. This case underscores the international relevance of this regional epidemic, particularly among health care workers. PMID- 22099092 TI - Seasonal influenza A virus in feces of hospitalized adults. AB - In a cohort of hospitalized adults with seasonal influenza A in Hong Kong, viral RNA was frequently (47%) detected in stool specimens. Viable virus was rarely isolated. Viral RNA positivity had little correlation with gastrointestinal symptoms and outcomes. In vitro studies suggested low potential for seasonal influenza viruses to cause direct intestinal infections. PMID- 22099093 TI - Influenza B viruses with mutation in the neuraminidase active site, North Carolina, USA, 2010-11. AB - Oseltamivir is 1 of 2 antiviral medications available for the treatment of influenza B virus infections. We describe and characterize a cluster of influenza B viruses circulating in North Carolina with a mutation in the neuraminidase active site that may reduce susceptibility to oseltamivir and the investigational drug peramivir but not to zanamivir. PMID- 22099094 TI - Hepatitis E virus in rabbits, Virginia, USA. AB - We identified hepatitis E virus (HEV) in rabbits in Virginia, USA. HEV RNA was detected in 14 (16%) of 85 serum samples and 13 (15%) of 85 fecal samples. Antibodies against HEV were detected in 31 (36%) of 85 serum samples. Sequence analyses showed that HEV from rabbits is closely related to genotype 3. PMID- 22099096 TI - New dengue virus type 1 genotype in Colombo, Sri Lanka. AB - The number of cases and severity of disease associated with dengue infection in Sri Lanka has been increasing since 1989, when the first epidemic of dengue hemorrhagic fever was recorded. We identified a new dengue virus 1 strain circulating in Sri Lanka that coincided with the 2009 dengue epidemic. PMID- 22099095 TI - Astrovirus MLB2 viremia in febrile child. AB - Astroviruses cause diarrhea, but it is not known whether they circulate in human plasma. Astrovirus MLB2 was recently discovered in diarrhea samples from children. We detected MLB2 in the plasma of a febrile child, which suggests that MLB2 has broader tropism than expected and disease potential beyond the gastrointestinal tract. PMID- 22099097 TI - Ultrastructural characterization of pandemic (H1N1) 2009 virus. AB - We evaluated pandemic influenza A (H1N1) 2009 virus isolates and respiratory tissues collected at autopsy by electron microscopy. Many morphologic characteristics were similar to those previously described for influenza virus. One of the distinctive features was dense tubular structures in the nuclei of infected cells. PMID- 22099098 TI - Molecular subtyping in cholera outbreak, Laos, 2010. AB - A cholera outbreak in Laos in July 2010 involved 237 cases, including 4 deaths. Molecular subtyping indicated relatedness between the Vibrio cholerae isolates in this and in a 2007 outbreak, uncovering a clonal group of V. cholerae circulating in the Mekong basin. Our finding suggests the subtyping methods will affect this relatedness. PMID- 22099099 TI - Clonal origins of Vibrio cholerae O1 El Tor strains, Papua New Guinea, 2009-2011. AB - We used multilocus sequence typing and variable number tandem repeat analysis to determine the clonal origins of Vibrio cholerae O1 El Tor strains from an outbreak of cholera that began in 2009 in Papua New Guinea. The epidemic is ongoing, and transmission risk is elevated within the Pacific region. PMID- 22099101 TI - Fatal infectious diseases during pandemic (H1N1) 2009 outbreak. PMID- 22099102 TI - Epidemic meningococcal meningitis, Cameroon. PMID- 22099103 TI - Foodborne-associated Shigella sonnei, India, 2009 and 2010. PMID- 22099104 TI - Mosquito-associated dengue virus, Key West, Florida, USA, 2010. PMID- 22099105 TI - Mycobacterium doricum osteomyelitis and soft tissue infection. PMID- 22099106 TI - Disseminated Mycobacterium abscessus infection and showerheads, Taiwan. PMID- 22099107 TI - Antimicrobial drug resistance in Corynebacterium diphtheriae mitis. PMID- 22099108 TI - Transfusion-transmitted syphilis in teaching hospital, Ghana. PMID- 22099109 TI - Congenital syphilis, Reunion Island, 2010. PMID- 22099110 TI - Reduced susceptibility to vancomycin in Staphylococcus aureus. PMID- 22099111 TI - Lessons learned during public health response to cholera epidemic in Haiti and the Dominican Republic. AB - After epidemic cholera emerged in Haiti in October 2010, the disease spread rapidly in a country devastated by an earthquake earlier that year, in a population with a high proportion of infant deaths, poor nutrition, and frequent infectious diseases such as HIV infection, tuberculosis, and malaria. Many nations, multinational agencies, and nongovernmental organizations rapidly mobilized to assist Haiti. The US government provided emergency response through the Office of Foreign Disaster Assistance of the US Agency for International Development and the Centers for Disease Control and Prevention. This report summarizes the participation by the Centers and its partners. The efforts needed to reduce the spread of the epidemic and prevent deaths highlight the need for safe drinking water and basic medical care in such difficult circumstances and the need for rebuilding water, sanitation, and public health systems to prevent future epidemics. PMID- 22099112 TI - Rapid development and use of a nationwide training program for cholera management, Haiti, 2010. AB - When epidemic cholera appeared in Haiti in October 2010, the medical community there had virtually no experience with the disease and needed rapid training as the epidemic spread throughout the country. We developed a set of training materials specific to Haiti and launched a cascading training effort. Through a training-of-trainers course in November 14-15, 2010, and department-level training conducted in French and Creole over the following 3 weeks, 521 persons were trained and equipped to further train staff at the institutions where they worked. After the training, the hospitalized cholera patients' case-fatality rate dropped from 4% to <2% by mid-December and was <1% by January 2011. Continuing in service training, monitoring and evaluation, and integration of cholera management into regular clinical training will help sustain this success. PMID- 22099113 TI - Cholera--modern pandemic disease of ancient lineage. AB - Cholera has affected humans for at least a millennium and persists as a major cause of illness and death worldwide, with recent epidemics in Zimbabwe (2008 2009) and Haiti (2010). Clinically, evidence exists of increasing severity of disease linked with emergence of atypical Vibrio cholerae organisms that have incorporated genetic material from classical biotype strains into an El Tor biotype background. A key element in transmission may be a recently recognized hyperinfectious phase, which persists for hours after passage in diarrheal feces. We propose a model of transmission in which environmental triggers (such as temperature) lead to increases in V. cholerae in environmental reservoirs, with spillover into human populations. However, once the microorganism is introduced into a human population, transmission occurs primary by "fast" transmission from person to person (taking advantage of the hyperinfectious state), without returning to the aquatic environment. PMID- 22099114 TI - Considerations for oral cholera vaccine use during outbreak after earthquake in Haiti, 2010-2011. AB - Oral cholera vaccines (OCVs) have been recommended in cholera-endemic settings and preemptively during outbreaks and complex emergencies. However, experience and guidelines for reactive use after an outbreak has started are limited. In 2010, after over a century without epidemic cholera, an outbreak was reported in Haiti after an earthquake. As intensive nonvaccine cholera control measures were initiated, the feasibility of OCV use was considered. We reviewed OCV characteristics and recommendations for their use and assessed global vaccine availability and capacity to implement a vaccination campaign. Real-time modeling was conducted to estimate vaccine impact. Ultimately, cholera vaccination was not implemented because of limited vaccine availability, complex logistical and operational challenges of a multidose regimen, and obstacles to conducting a campaign in a setting with population displacement and civil unrest. Use of OCVs is an option for cholera control; guidelines for their appropriate use in epidemic and emergency settings are urgently needed. PMID- 22099115 TI - Comparative genomics of Vibrio cholerae from Haiti, Asia, and Africa. AB - Cholera was absent from the island of Hispaniola at least a century before an outbreak that began in Haiti in the fall of 2010. Pulsed-field gel electrophoresis (PFGE) analysis of clinical isolates from the Haiti outbreak and recent global travelers returning to the United States showed indistinguishable PFGE fingerprints. To better explore the genetic ancestry of the Haiti outbreak strain, we acquired 23 whole-genome Vibrio cholerae sequences: 9 isolates obtained in Haiti or the Dominican Republic, 12 PFGE pattern-matched isolates linked to Asia or Africa, and 2 nonmatched outliers from the Western Hemisphere. Phylogenies for whole-genome sequences and core genome single-nucleotide polymorphisms showed that the Haiti outbreak strain is genetically related to strains originating in India and Cameroon. However, because no identical genetic match was found among sequenced contemporary isolates, a definitive genetic origin for the outbreak in Haiti remains speculative. PMID- 22099116 TI - Characterization of toxigenic Vibrio cholerae from Haiti, 2010-2011. AB - In October 2010, the US Centers for Disease Control and Prevention received reports of cases of severe watery diarrhea in Haiti. The cause was confirmed to be toxigenic Vibrio cholerae, serogroup O1, serotype Ogawa, biotype El Tor. We characterized 122 isolates from Haiti and compared them with isolates from other countries. Antimicrobial drug susceptibility was tested by disk diffusion and broth microdilution. Analyses included identification of rstR and VC2346 genes, sequencing of ctxAB and tcpA genes, and pulsed-field gel electrophoresis with SfiI and NotI enzymes. All isolates were susceptible to doxycycline and azithromycin. One pulsed-field gel electrophoresis pattern predominated, and ctxB sequence of all isolates matched the B-7 allele. We identified the tcpETCIRS allele, which is also present in Bangladesh strain CIRS 101. These data show that the isolates from Haiti are clonally and genetically similar to isolates originating in Africa and southern Asia and that ctxB-7 and tcpET(CIRS) alleles are undergoing global dissemination. PMID- 22099117 TI - Cholera in Haiti and other Caribbean regions, 19th century. AB - Medical journals and other sources do not show evidence that cholera occurred in Haiti before 2010, despite the devastating effect of this disease in the Caribbean region in the 19th century. Cholera occurred in Cuba in 1833-1834; in Jamaica, Cuba, Puerto Rico, St. Thomas, St. Lucia, St. Kitts, Nevis, Trinidad, the Bahamas, St. Vincent, Granada, Anguilla, St. John, Tortola, the Turks and Caicos, the Grenadines (Carriacou and Petite Martinique), and possibly Antigua in 1850-1856; and in Guadeloupe, Cuba, St. Thomas, the Dominican Republic, Dominica, Martinique, and Marie Galante in 1865-1872. Conditions associated with slavery and colonial military control were absent in independent Haiti. Clustered populations, regular influx of new persons, and close quarters of barracks living contributed to spread of cholera in other Caribbean locations. We provide historical accounts of the presence and spread of cholera epidemics in Caribbean islands. PMID- 22099118 TI - Risk factors early in the 2010 cholera epidemic, Haiti. AB - During the early weeks of the cholera outbreak that began in Haiti in October 2010, we conducted a case-control study to identify risk factors. Drinking treated water was strongly protective against illness. Our results highlight the effectiveness of safe water in cholera control. PMID- 22099119 TI - Rapid assessment of cholera-related deaths, Artibonite Department, Haiti, 2010. AB - We evaluated a high (6%) cholera case-fatality rate in Haiti. Of 39 community decedents, only 23% consumed oral rehydration salts at home, and 59% did not seek care, whereas 54% of 48 health facility decedents died after overnight admission. Early in the cholera epidemic, care was inadequate or nonexistent. PMID- 22099120 TI - Epidemic cholera in a crowded urban environment, Port-au-Prince, Haiti. AB - We conducted a case-control study to investigate factors associated with epidemic cholera. Water treatment and handwashing may have been protective, highlighting the need for personal hygiene for cholera prevention in contaminated urban environments. We also found a diverse diet, a possible proxy for improved nutrition, was protective against cholera. PMID- 22099121 TI - Toxigenic Vibrio cholerae O1 in water and seafood, Haiti. AB - During the 2010 cholera outbreak in Haiti, water and seafood samples were collected to detect Vibrio cholerae. The outbreak strain of toxigenic V. cholerae O1 serotype Ogawa was isolated from freshwater and seafood samples. The cholera toxin gene was detected in harbor water samples. PMID- 22099122 TI - Drug-resistance mechanisms in Vibrio cholerae O1 outbreak strain, Haiti, 2010. AB - To increase understanding of drug-resistant Vibrio cholerae, we studied selected molecular mechanisms of antimicrobial drug resistance in the 2010 Haiti V. cholerae outbreak strain. Most resistance resulted from acquired genes located on an integrating conjugative element showing high homology to an integrating conjugative element identified in a V. cholerae isolate from India. PMID- 22099123 TI - Cholera management and prevention at Hopital Albert Schweitzer, Haiti. AB - In October 2010, Hopital Albert Schweitzer Haiti treated some of the first patients with cholera in Haiti. Over the following 10 months, a strategic plan was developed and implemented to improve the management of cases at the hospital level and to address the underlying risk factors at the community level. PMID- 22099124 TI - Acute phase proteins and white blood cell levels for prediction of infectious complications in status epilepticus. AB - INTRODUCTION: Infections in status epilepticus (SE) patients result in severe morbidity making early diagnosis crucial. As SE may lead to inflammatory reaction, the value of acute phase proteins and white blood cells (WBC) for diagnosis of infections during SE may be important. We examined the reliability of C-reactive protein (CRP), procalcitonin (PCT), and WBC for diagnosis of infections during SE. METHODS: All consecutive SE patients treated in the ICU from 2005 to 2009 were included. Clinical and microbiological records, and measurements of CRP and WBC during SE were analyzed. Subgroup analysis was performed for additional PCT measurements in the first 48 hours of SE. RESULTS: A total of 22.5% of 160 consecutive SE patients had infections during SE. Single levels of CRP and WBC had no association with the presence of infections. Their linear changes over the first three days after SE onset were significantly associated with the presence of infections (P = 0.0012 for CRP, P = 0.0137 for WBC). Levels of PCT were available for 31 patients and did not differ significantly in patients with and without infections. Sensitivity of PCT and CRP was high (94% and 83%) and the negative predictive value of CRP increased over the first three days to 97%. Specificity was low, without improvement for different cut-offs. CONCLUSIONS: Single levels of CRP and WBC are not reliable for diagnosis of infections during SE, while their linear changes over time significantly correlate with the presence of infections. In addition, low levels of CRP and PCT rule out hospital-acquired infections in SE patients. PMID- 22099125 TI - International connections. PMID- 22099126 TI - Re: a simple thank you. PMID- 22099127 TI - Re: a simple thank you. PMID- 22099128 TI - An additional perspective to a simple thank you .... PMID- 22099129 TI - Measurement of postdischarge nausea and vomiting for ambulatory surgery patients: a critical review and analysis. AB - Approximately one-third of patients experience nausea and vomiting after discharge from ambulatory surgery settings, yet there have been no clear and definitive instruments used to measure it. A critical review and analysis of the measurement of postdischarge nausea and vomiting was conducted. Twenty-eight articles met the inclusion criteria. Four studies (14.3%) used instruments with documented reliability and validity. Telephone calls were used in 21 (76%) studies to interview patients, and seven studies (25%) used a mail-in investigator-developed diary or questionnaire. Most studies (22) obtained data at 48 hours; 13 of those obtained data exclusively at 24 hours. Definitions, measurement, and clinical outcomes were defined differently in each study. Of the instruments examined, the Ambulatory Surgery Inventory of Nausea, Vomiting, and Retching and Functional Living Index-Emesis provide the possibility for outcome standardization. Although both instruments possess strengths, more study is needed to advance the measurement of nausea and vomiting in the postdischarge ambulatory surgery patient. PMID- 22099130 TI - Carvedilol compared with metoprolol on left ventricular ejection fraction after coronary artery bypass graft. AB - A number of elective coronary artery bypass graft (CABG) surgery patients have impaired underlying left ventricular function (poor ejection fraction). This study was performed to compare the effect of postoperative oral carvedilol versus metoprolol on left ventricular ejection fraction (LVEF) after CABG compared with metoprolol. In a double-blind clinical trial, 60 patients with coronary artery disease, aged 35 to 65 years, who had an ejection fraction of 15% to 35% were included. Either carvedilol or metoprolol was administered the day after CABG. The patients were evaluated by the same cardiologist 14 days before and 2 and 6 months after elective CABG. The results demonstrated better improvements in LVEF in the carvedilol group. No difference regarding postoperative arrhythmias or mortality was detected. The results suggest that carvedilol may exert more of an improved myocardial effect than metoprolol for the low ejection fraction patients undergoing CABG in the early postoperative months. PMID- 22099131 TI - Critical thinking, collaboration, and communication: the three "Cs" of quality preoperative screening. AB - The Preoperative Clinic at Children's Hospital Boston has established a unique collaborative approach to ensure that individualized perioperative plans of care are created for patients, which goes beyond traditional preoperative screening. This article describes the Preoperative Clinic's operational model and explains the significant role the health care record review nurse plays in developing these perioperative plans of care. PMID- 22099132 TI - Use of picture communication aids to assess pain location in pediatric postoperative patients. AB - Children undergoing surgical procedures may have difficulty communicating. Augmentative and alternative communication (AAC) picture communication may provide a standard communication strategy for postoperative children and facilitate nurse-patient communication. The study purposes were to (1) determine if inconsistency exists between nurse assessments of pain location versus identification of pain location using AAC picture communication aids and (2) determine parent satisfaction with use of AAC picture communication aids. A convenience sample of patients aged 3 to 9 years were recruited in a Midwestern freestanding pediatric hospital's postanesthesia care unit (PACU). The patient's pain location was assessed using an AAC picture communication aid and compared with the PACU nurses' pain assessment. Nurses did not consistently document location of pain, and, when documented, the surgical site was inaccurately identified as the location of pain. Parent satisfaction was measured through completion of a 10-item satisfaction survey. Respondents were satisfied with the use of AAC picture communication aids. PMID- 22099133 TI - Multidrug-resistant organisms: practice considerations in the ambulatory surgery setting--part two. PMID- 22099134 TI - Where does capnography fit into the PACU? PMID- 22099135 TI - Epidural blood patching for preventing and treating postdural puncture headache. PMID- 22099136 TI - Adopting a cosmopolitan nursing practice. PMID- 22099137 TI - Colleagues in caring: pastoral care at the bedside. PMID- 22099138 TI - Dabigatran: a new oral anticoagulant. PMID- 22099139 TI - Spiking of intravenous fluid solutions. PMID- 22099140 TI - The big(ger) aim: an always event. PMID- 22099141 TI - Challenges and opportunities for policy decisions to address health equity in developing health systems: case study of the policy processes in the Indian state of Orissa. AB - INTRODUCTION: Achieving health equity is a pertinent need of the developing health systems. Though policy process is crucial for planning and attaining health equity, the existing evidences on policy processes are scanty in this regard. This article explores the magnitude, determinants, challenges and prospects of 'health equity approach' in various health policy processes in the Indian State of Orissa - a setting comparable with many other developing health systems. METHODS: A case-study involving 'Walt-Gilson Policy Triangle' employed key-informant interviews and documentary reviews. Key informants (n = 34) were selected from the departments of Health and Family Welfare, Rural Development, and Women and Child Welfare, and civil societies. The documentary reviews involved various published and unpublished reports, policy pronouncements and articles on health equity in Orissa and similar settings. RESULTS: The 'health policy agenda' of Orissa was centered on 'health equity' envisaging affordable and equitable healthcare to all, integrated with public health interventions. However, the subsequent stages of policy process such as 'development, implementation and evaluation' experienced leakage in the equity approach. The impediment for a comprehensive approach towards health equity was the nexus among the national and state health priorities; role, agenda and capacity of actors involved; and existing constraints of the healthcare delivery system. CONCLUSION: The health equity approach of policy processes was incomprehensive, often inadequately coordinated, and largely ignored the right blend of socio-medical determinants. A multi-sectoral, unified and integrated approach is required with technical, financial and managerial resources from different actors for a comprehensive 'health equity approach'. If carefully geared, the ongoing health sector reforms centered on sector-wide approaches, decentralization, communitization and involvement of non-state actors can substantially control existing inequalities through an optimally packaged equitable policy. The stakeholders involved in the policy processes need to be given orientation on the concept of health equity and its linkage with socio-economic development. PMID- 22099142 TI - General Comment no. 13 to the Convention on the Rights of the Child: the right of the child to freedom from all forms of violence. PMID- 22099143 TI - Head injury secondary to suspected child maltreatment: results of a prospective Canadian national surveillance program. AB - OBJECTIVE: We sought to determine the incidence, clinical features, and demographic profile of head injury secondary to suspected child maltreatment (abuse or neglect) in Canada to help inform the development and evaluation of prevention programs for abusive head injuries. METHODS: From March 1, 2005 to February 28, 2008, an average of 2,545 paediatricians and paediatric subspecialists were surveyed monthly through the established network of the Canadian Paediatric Surveillance Program. We calculated incidence rates using the number of confirmed cases over the product of the duration of the study (3 years) and population estimates by age group. RESULTS: There were 220 confirmed cases of head injury from suspected child maltreatment. The annual incidence rate was 14.1 per 100,000 for children less than 1 year of age and 1.4 per 100,000 for those less than 15 years. Seventy three percent (141) of cases involved infants less than 12 months of age and 52% (100) of cases involved infants less than 6 months of age. Seventy-five percent (165) of cases presented to the emergency room. With regard to outcome, 12% (27) of cases resulted in death and 45% (75) of survivors had neurological sequelae at discharge. Thirty percent (67) of all cases, as well as 30% (8) of deaths were previously known to child welfare authorities. CONCLUSION: This study provides an estimate of the rate of head injury secondary to suspected child maltreatment in Canada. The young age and poor medical outcomes of those involved highlights the need for prevention efforts that are implemented early in life. Given that a significant percentage of injured infants and children were already known to child welfare authorities, the study also highlights the need to establish and evaluate additional preventive efforts for parents and caregivers already in the child welfare system. PMID- 22099144 TI - The disease burden of childhood adversities in adults: a population-based study. AB - OBJECTIVES: There is much evidence showing that childhood adversities have considerable effects on the mental and physical health of adults. It could be assumed therefore, that the disease burden of childhood adversities is high. It has not yet been examined, however, whether this is true. METHOD: We used data of a large representative sample (N=7,076) of the general population in the Netherlands. We calculated the disability weight (DW) for each respondent. The DW is a weight factor that reflects the severity of a disease or condition on a scale from 0 (perfect health) to 1 (equivalent to death). We used an algorithm based on the SF-6D to estimate DW. Because the DW indicates the proportion of a healthy life year that is reduced by the specific health state of the individual, it also possible to calculate the total number of years lost due to disability (YLD) in the population. We calculated the years lived with disability (YLD) for 9 different childhood adversities (in the areas of parental psychopathology; abuse and neglect; major life events), as well as for major categories of mental disorders and general medical disorders. RESULTS: All 9 adversities resulted in a significantly increased DW, except death of a parent before the age of 16. Adversities in the category of abuse and neglect are associated with the highest DWs (0.057), followed by parental psychopathology (0.031) and life events during childhood (0.012). All adversities (46.4% of the population reports one or more adversity) are associated with 20.7 YLD/1,000, which is more than all mental disorders together (12.9 YLD/1,000). The category of abuse/neglect has the highest YLD/1,000 (15.8), which is also higher than all mental disorders together. Adjustment for the presence of mental and general medical disorders resulted in comparable outcomes. CONCLUSIONS: Childhood adversities are more important from a public health point of view than all common mental disorders together, and should be a priority for public health interventions. PMID- 22099145 TI - Child protection assessment in humanitarian emergencies: case studies from Georgia, Gaza, Haiti and Yemen. AB - OBJECTIVES: The paper reviews the experiences of conducting child protection assessments across four humanitarian emergencies where violence and insecurity, directly or indirectly, posed a major threat to children. We seek to identify common themes emerging from these experiences and propose ways to guide the planning and implementation of assessments that effectively identify, and suggest means of response to, threats to children's rights and well-being in emergency settings. METHODS: In the context of a field evaluation of an inter-agency resource kit, crisis settings where an inter-agency assessment of child protection had been considered in the period August 2008 to July 2010 were identified. Email correspondence, telephone-based structured interviews and documentary review collated information from child protection coordinating agencies from a total of twenty sites, the minority of which had proceeded to complete an assessment. This paper presents case studies of the experience in Georgia (following the conflict between Russian and Georgian forces in August 2008), Gaza (following the Israeli military incursion beginning in December 2008), Haiti (following the earthquake of January 2010), and Yemen (following the ceasefire agreement between the government and rebel forces in early 2010). CASE STUDY FINDINGS: In each setting the context of the humanitarian emergency is outlined. The processes of the planning (and, where appropriate, implementation) of the child protection assessment is described. Where available, the findings of the child protection assessment and their use in shaping interventions are summarized. PRACTICE IMPLICATIONS: Case studies document experience across humanitarian settings widely divergent in terms of the nature of the emergency, social-political context, and institutional capacity. Despite such differences, analysis suggests securing inter-agency coordination, preparation and capacity building, and means of ensuring timeliness of findings to be recurrent themes in the effective mobilization of an effective assessment able to inform programming. PMID- 22099146 TI - Three-dimensional assessment of zygomatic malunion using computed tomography in patients with cheek ptosis caused by reduction malarplasty. AB - BACKGROUND: Reduction malarplasty is one of the most popular aesthetic surgical procedures for reshaping facial contour in oriental people. Especially for those who have a wide midface and a prominent zygoma. Although malunion and cheek ptosis are known as major complications in reduction malarplasty, but there have been few reports about their causes and patterns. The authors experienced many revision reduction malarplasty using the coronal approach to correct cheek ptosis with malunion and were able to categorize the types of malunion by analyzing 3 dimensional CT imaging prior to revision surgery. METHODS: A total of 24 patients underwent revision reduction malarplasty with the coronal approach to correct the unfavorable result after primary malarplasty. Most patients complained of various degrees of cheek ptosis associated with malunion. In all cases, the status of zygomatic malunion was evaluated through 3D CT imaging. The operative procedures during revision surgery including repositioning of the inferolaterally displaced malar complex to the appropriate position and obtaining bone-to-bone contact with rigid fixation. If bony absorption at non-union margin was found during the operation, bihalved calvarial bone was grafted into the bony gap. Midface and forehead lifts were also performed when indicated. RESULTS: The types of zygomatic malunion could be categorized into four patterns according to the shape of displacement. The degree of displacement was relevant to the condition of the fixation in all cases. The higher the grade of malunion was evaluated in 3D CT imaging, the more difficult procedures it required during revision surgery. The postoperative results in all cases were satisfactory without any complications. CONCLUSIONS: In reduction malarplasty, inappropriate fixation and the ignorance of repositioning vector can lead to cheek ptosis and malunion by the action of masseter muscle. The malunion types apprehended by the preoperative 3D CT scanning enabled precise operative planning before revision surgery. In all grades of zygomatic malunion with cheek ptosis, revision reduction malarplasty with coronal approach was a very useful solution because it offers a wide surgical field, enables accurate repositioning along with firm fixation and easily allows simultaneous midface lift. PMID- 22099147 TI - Novel ex-vivo mechanobiological intervertebral disc culture system. AB - Intervertebral disc degeneration, a leading cause of low back pain, poses a significant socioeconomic burden with a broad array of costly treatment options. Mechanical loading is important in disease progression and treatment. Connecting mechanics and biology is critical for determining how loading parameters affect cellular response and matrix homeostasis. A novel ex-vivo experimental platform was developed to facilitate in-situ loading of rabbit functional spinal units (FSUs) with relevant biological outcome measures. The system was designed for motion outside of an incubator and validated for rigid fixation and physiologic environmental conditions. Specimen motion relative to novel fixtures was assessed using a digitizer; fixture stiffness exceeded specimen stiffness by an order of magnitude. Intradiscal pressure (IDP), measured using a fiber-optic pressure transducer, confirmed rigidity and compressive force selection. Surrounding media was controlled at 37 degrees C, 5% O(2)/CO(2) using a closed flow loop with an hypoxic incubator and was validated with probes in the specimen chamber. FSUs were subjected to cyclic compression (20 cycles) and four-hour creep at 1.0 MPa. Disc tissue was analyzed for cell viability using 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT), which showed high viability (>90%) regardless of loading. Conditioned media was assayed for type-II collagen degradation fragments (CTX-II) and an aggrecan epitope (CS-846) associated with new aggrecan synthesis. CTX-II concentrations were not associated with loading, but CS-846 concentrations appeared to be increased with loading. Preservation of the full FSU allows physiologic load transmission and future multi-axis motion and identification of load-responsive proteins, thereby forming a new niche in intervertebral disc organ culture. PMID- 22099148 TI - Mechanical work performed by the individual legs during uphill and downhill walking. AB - Previous studies of the mechanical work performed during uphill and downhill walking have neglected the simultaneous negative and positive work performed by the leading and trailing legs during double support. Our goal was to quantify the mechanical work performed by the individual legs across a range of uphill and downhill grades. We hypothesized that during double support, (1) with steeper uphill grade, the negative work performed by the leading leg would become negligible and the trailing leg would perform progressively greater positive work to raise the center of mass (CoM), and (2) with steeper downhill grade, the leading leg would perform progressively greater negative work to lower the CoM and the positive work performed by the trailing leg would become negligible. 11 healthy young adults (6 M/5 F, 71.0+/-12.3 kg) walked at 1.25 m/s on a dual-belt force-measuring treadmill at seven grades (0, +/-3, +/-6, +/-9 degrees ). We collected three-dimensional ground reaction forces (GRFs) and used the individual limbs method to calculate the mechanical work performed by each leg. As hypothesized, the trailing leg performed progressively greater positive work with steeper uphill grade, and the leading leg performed progressively greater negative work with steeper downhill grade (p<0.005). To our surprise, unlike level-ground walking, during double support the leading leg performed considerable positive work when walking uphill and the trailing leg performed considerable negative work when walking downhill (p<0.005). To understand how humans walk uphill and downhill, it is important to consider these revealing biomechanical aspects of individual leg function and interaction during double support. PMID- 22099149 TI - A physician reminder to improve postpartum diabetes screening in women with gestational diabetes mellitus. AB - AIMS: Women with gestational diabetes (GDM) have a 20% risk of developing diabetes in the 10 years following pregnancy, but the risk may be as high as 70% in higher risk populations. Guidelines recommend screening for diabetes postpartum, but screening rates are low. We evaluated the effect of a physician reminder on postpartum screening and in women with GDM. METHODS: We conducted a retrospective chart review among women with GDM seen at our urban, academic endocrine clinic in Toronto, Canada between 2006 and 2010. Our primary outcome was to evaluate the effect of a reminder checklist on postpartum diabetes screening rates. RESULTS: We included 314 women in our study, 173 had a checklist on their chart. Women had a mean age of 34.9 years, 45% were Caucasian and 23% had a previous GDM. The checklist was associated with a 3 fold increase in odds of being screened postpartum, and nearly 4 fold increase in postpartum follow up visits (OR 2.99, 95% CI 1.84-4.85 and OR 3.71, 95% CI 2.26-6.11). CONCLUSION: A physician based reminder system is an effective way to improve postpartum screening rates. To further increase screening rates, a multilevel approach targeting both patients and physicians is required. PMID- 22099150 TI - Hemisphere-dependent holistic processing of familiar faces. AB - In two behavioral experiments involving lateralized stimulus presentation, we tested whether one of the most commonly used measures of holistic face processing the composite face effect-would be more pronounced for stimuli presented to the right as compared to the left hemisphere. In experiment 1, we investigated the composite face effect in a verbal identification task, similar to its original report (Young, Hellawell, & Hay, 1987). Aligning top and bottom halves of composite face stimuli led to performance decreases irrespective of hemifield, indicating holistic processing of comparable magnitude for inputs provided separately to either hemisphere. However, when matching of the same top parts was required in experiment 2, an alignment-dependent performance decrease was found for stimuli presented in the left, but not right visual field. These observations suggest that the right hemisphere dominates in early stages of holistic processing, as indexed by the composite face effect, but that later processes such as face identification and naming are based on unified representations that are independent of input lateralization. Moreover, the composite face effect may not rely on the exact same representation(s) when measured in matching and identification tasks. PMID- 22099151 TI - Investigation of stimulus-response compatibility using a startling acoustic stimulus. AB - We investigated the processes underlying stimulus-response compatibility by using a lateralized auditory stimulus in a simple and choice reaction time (RT) paradigm. Participants were asked to make either a left or right key lift in response to either a control (80dB) or startling (124dB) stimulus presented to either the left ear, right ear, or both ears. In the simple RT paradigm, we did not find a compatibility effect for either control or startle trials but did find a right-ear advantage which we attribute to anatomical asymmetry of auditory pathways. In the choice RT paradigm, we found compatibility effects for both startle and control trials as well a high incidence of error for contralateral stimulus-response mapping. We attribute these results to automatic activation of the ipsilateral response, which must then be inhibited prior to initiation of the correct response. The presence of compatibility effects for startle trials also suggest that similar pathways are being used to initiate movements in a choice RT situation, as opposed to involuntary triggering that is thought to occur in a simple RT situation. PMID- 22099152 TI - Guest editorial. PMID- 22099153 TI - Up-regulation of NF-kB-sensitive miRNA-125b and miRNA-146a in metal sulfate stressed human astroglial (HAG) primary cell cultures. AB - Micro RNAs (miRNAs) constitute a unique class of small, non-coding ribonucleic acids (RNAs) that regulate gene expression at the post-transcriptional level. The presence of two inducible miRNAs, miRNA-125b and miRNA-146a, involved in respectively, astroglial cell proliferation and in the innate immune and inflammatory response, is significantly up-regulated in human neurological disorders including Alzheimer's disease (AD). In this study we analyzed abundances miRNA-125b and miRNA-146a in magnesium-, iron-, gallium, and aluminum sulfate-stressed human-astroglial (HAG) cells, a structural and immune-responsive brain cell type. The combination of iron- plus aluminum-sulfate was found to be significantly synergistic in up-regulating reactive oxygen species (ROS) abundance, NF-kB-DNA binding and miRNA-125b and miRNA-146a expression. Treatment of metal-sulfate stressed HAG cells with the antioxidant phenyl butyl nitrone (PBN) or the NF-kB inhibitors curcumin, the metal chelator-anti-oxidant pyrollidine dithiocarbamate (PDTC), or the resveratrol analog CAY10512, abrogated both NF-kB signaling and induction of these miRNAs. Our observations further illustrate the potential of physiologically relevant amounts of aluminum and iron sulfates to synergistically up-regulate specific miRNAs known to contribute to AD relevant pathogenetic mechanisms, and suggest that antioxidants or NF-kB inhibitors may be useful to quench metal-sulfate triggered genotoxicity. PMID- 22099154 TI - A QM/MM study of the complexes formed by aluminum and iron with serum transferrin at neutral and acidic pH. AB - Serum transferrin (sTf) transports iron in serum and internalizes in cells via receptor mediated endocytosis. Additionally, sTf has been identified as the predominant aluminum carrier in serum. Some questions remain unclear about the exact mechanism for the metal release or whether the aluminum and iron show the same binding mode during the entire process. In the present work, simulation techniques at quantum and atomic levels have been employed in order to gain access into a molecular level understanding of the metal-bound sTf complex, and to describe the binding of Al(III) and Fe(III) ions to sTf. First, hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations were carried out in order to analyze the dynamics of the aluminum-loaded complex, taking into account the different pH conditions in blood and into the cell. Moreover, the complexes formed by transferrin with Al(III) and Fe(III) were optimized with high level density functional theory (DFT)/MM methods. All these results indicate that the interaction mode of Al(III) and Fe(III) with sTf change upon different pH conditions, and that the coordination of Al(III) and Fe(III) is not equivalent during the metal intake, transport and release processes. Our results emphasize the importance of the pH on the metal binding and release mechanism and suggest that Al(III) can follow the iron pathway to get access into cells, although once there, it may show a different binding mode, leading to a different mechanism for its release. PMID- 22099155 TI - Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide induced macrophagic myofasciitis (MMF). AB - Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations. PMID- 22099156 TI - Aluminium effects on thyroid gland function: iodide uptake, hormone biosynthesis and secretion. AB - The effects of aluminium (Al) on thyroid function were evaluated in adult Wistar rats intraperitoneally (i.p) injected with 7 mg Al (as lactate)/kg body weight (b.w) per day during a six week period. The time-course kinetics of Na(125)I (3 MUCi per 100 g b.w, i.p) was analysed by measuring gamma-radioactivity of thyroid, serum, serum protein precipitate and bile, at times ranging from 2 to 96 h post-dosing. In Al-treated group the (125)I(-) thyroid uptake at 24 h (15,840 +/- 570 vs. 18,030 +/- 630 dpm/mg, P<0.05) as well as the rate of (125)I(-) release from the gland, calculated as the slope of the plot between 24 and 96 h (84 +/- 8 vs. 129 +/- 11 dpm/mg/h, P<0.05) were significantly reduced as compared to control. The biliary (125)I(-) excretion was not modified at all studied times. The Al content and lipid peroxidation (69.1 +/- 8.5 vs. 53.2 +/- 7.0 nmol MDA/g wet weight, P<0.05) of thyroid tissue were increased in Al-treated rats. The serum concentrations of total thyroxine (T4, 3.78 +/- 0.14 vs. 4.68 +/- 0.12 MUg/dL, P<0.05) and total triiodothyronine (T3, 47 +/- 4 vs. 66 +/- 5 ng/dL, P<0.05) were decreased by effect of Al, but free-T4 (1.05 +/- 0.05 vs. 1.04 +/- 0.04 ng/dL, NS) and thyrotropin (TSH, 2.7 +/- 0.4 vs. 2.6 +/- 0.5 ng/ml, NS) remain unchanged. In spite of the Al could indirectly affect thyroid iodide uptake and hormones secretion by a mechanism involving the induction of an oxidative stress state, however, these changes could be managed by the hypothalamus-pituitary-thyroid endocrine axis. We can conclude that in adult rats the Al would not act as a thyroid disruptor. PMID- 22099157 TI - Aluminium-induced changes in root epidermal cell patterning, a distinctive feature of hyperresistance to Al in Brachiaria decumbens. AB - Brachiaria, a genus of forage grasses of African origin, is gaining considerable importance because of both its nutritional value and its high stress resistance. An extraordinary resistance to Al toxicity has been reported in B. decumbens. The mechanisms of this hyperresistance are still unknown. This study explores the localization of Al in two contrasting Brachiaria species, the hyperresistant B. decumbens and the less resistant B. brizantha. Scanning Electron Microscope/Energy Dispersive Spectrometry, confocal fluorescence microscopy and optical microscopy of lumogallion or morin-stained roots was performed. Species differences in Al resistance were evident at 32 MUM Al(3+) activity in low ionic strength full nutrient solution containing Si. Roots of B. decumbens accumulated less Al than those of B. brizantha. Moreover, location and Al form seemed different. In B. decumbens Al accumulation was localized in hot spots of high Al concentrations. These sites with high Al accumulation mainly correspond to root hairs. B. brizantha exhibited a more even distribution of Al in cell walls of the root tip. Analysis of soluble phenolic substances in roots revealed species differences in response to Al. An Al-induced increase of chlorogenic acid concentrations was found in B. decumbens but not in B. brizantha. Taken together the results suggest a possible role for chlorogenic acid as a primer for changes in root epidermal cell patterning that may contribute to the Al hyperresistance in B. decumbens. PMID- 22099158 TI - Aluminium and human breast diseases. AB - The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 +/- 28 MUg/l) compared with control healthy subjects (mean 131 +/- 10 MUg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 MUg/l) compared with human serum (median 6 MUg/l) or human milk (median 25 MUg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate. PMID- 22099159 TI - Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? AB - Autism spectrum disorders (ASD) are serious multisystem developmental disorders and an urgent global public health concern. Dysfunctional immunity and impaired brain function are core deficits in ASD. Aluminum (Al), the most commonly used vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator. Hence, adjuvant Al has the potential to induce neuroimmune disorders. When assessing adjuvant toxicity in children, two key points ought to be considered: (i) children should not be viewed as "small adults" as their unique physiology makes them much more vulnerable to toxic insults; and (ii) if exposure to Al from only few vaccines can lead to cognitive impairment and autoimmunity in adults, is it unreasonable to question whether the current pediatric schedules, often containing 18 Al adjuvanted vaccines, are safe for children? By applying Hill's criteria for establishing causality between exposure and outcome we investigated whether exposure to Al from vaccines could be contributing to the rise in ASD prevalence in the Western world. Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades (Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4 months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The application of the Hill's criteria to these data indicates that the correlation between Al in vaccines and ASD may be causal. Because children represent a fraction of the population most at risk for complications following exposure to Al, a more rigorous evaluation of Al adjuvant safety seems warranted. PMID- 22099161 TI - Aluminum toxicity and astrocyte dysfunction: a metabolic link to neurological disorders. AB - Aluminum (Al) has been implicated in a variety of neurological diseases. However, the molecular mechanisms that enable Al to be involved in these disorders have yet to be fully delineated. Using astrocytes as a model of the cerebral cellular system, we have uncovered the biochemical networks that are affected by Al toxicity. In this review, we reveal how the inhibitory influence of Al on ATP production and on mitochondrial functions help generate globular astrocytes that are fat producing machines. These biological events may be the contributing factors to Al-triggered brain disorders. PMID- 22099160 TI - Towards the prevention of potential aluminum toxic effects and an effective treatment for Alzheimer's disease. AB - In 1991, treatment with low dose intramuscular desferrioxamine (DFO), a trivalent chelator that can remove excessive iron and/or aluminum from the body, was reported to slow the progression of Alzheimer's disease (AD) by a factor of two. Twenty years later this promising trial has not been followed up and why this treatment worked still is not clear. In this critical interdisciplinary review, we provide an overview of the complexities of AD and involvement of metal ions, and revisit the neglected DFO trial. We discuss research done by us and others that is helping to explain involvement of metal ion catalyzed production of reactive oxygen species in the pathogenesis of AD, and emerging strategies for inhibition of metal-ion toxicity. Highlighted are insights to be considered in the quests to prevent potentially toxic effects of aluminum toxicity and prevention and intervention in AD. PMID- 22099162 TI - Thermodynamic remarks on chelating ligands for aluminium related diseases. AB - Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the actions that have drastically reduced the occurrence of dialysis diseases, they so far constitute a cause of great medical concern. Being aluminium chelators strictly related to iron chelators, a comparison is made of the complex formation properties of these two hard metal ions towards ligands characterized by charged oxygen donor groups. Empirical correlations between aluminium(III) and iron(III) complex formation constants, and their behavior are discussed in terms of structural and thermodynamic stabilities. Insertion of proper substituents to enhance the chelator binding capacity is debated on the bases of substituent effects on protonation and complex formation constants. PMID- 22099163 TI - Aluminum induces changes in oxidative burst scavenging enzymes in Coffea arabica L. suspension cells with differential Al tolerance. AB - The accumulation of reactive oxygen species (ROS) and concomitant oxidative stress have been considered deleterious consequences of aluminum toxicity. However, several lines of evidence suggest that ROS can function as important signaling molecules in the plant defense system for protection from abiotic stress and the acquisition of tolerance. The role of ROS-scavenging enzymes was assayed in two different coffee cell suspension lines. We treated L2 (Al sensitive) and LAMt (Al-tolerant) Coffea arabica suspension cells with 100 MUM AlCl(3) and observed significant differences in catalase activity between the two cell lines. However, we did not observe any differences in superoxide dismutase or glutathione reductase activity in either cell line following Al treatment. ROS production was diminished in the LAMt cell line. Taken together, these results indicate that aluminum treatment may impair the oxidative stress response in L2 cells but not in LAMt cells. We suggest a possible role for Al-induced oxidative bursts in the signaling pathways that lead to Al resistance and protection from Al toxicity. PMID- 22099164 TI - A bold step toward 2012: JIPB's 2011 Editorial Board Meeting report. PMID- 22099165 TI - Control of working memory: effects of attention training on target recognition and distractor salience in an auditory selection task. AB - Behavioral and electrophysiological measures of target and distractor processing were examined in an auditory selective attention task before and after three weeks of distractor suppression training. Behaviorally, training improved target recognition and led to less conservative and more rapid responding. Training also effectively shortened the temporal distance between distractors and targets needed to achieve a fixed level of target sensitivity. The effects of training on event-related potentials were restricted to the distracting stimulus: earlier N1 latency, enhanced P2 amplitude, and weakened P3 amplitude. Nevertheless, as distractor P2 amplitude increased, so too did target P3 amplitude, connecting experience-dependent changes in distractor processing with greater distinctiveness of targets in working memory. We consider the effects of attention training on the processing priorities, representational noise, and inhibitory processes operating in working memory. PMID- 22099166 TI - Osteocytes: central conductors of bone biology in normal and pathological conditions. AB - Osteocytes are the most abundant and longest-living cells in the adult skeleton. For a long time, osteocytes were considered static and inactive cells, but in recent years, it has been suggested that they represent the key responder to various stimuli that regulate bone formation and remodelling as well as one of the key endocrine regulators of bone metabolism. Osteocytes respond to mechanical stimuli by producing and secreting several signalling molecules, such as nitric oxide and prostaglandin E(2) , that initiate local bone remodelling. Moreover, they can control bone formation by modulating the WNT signalling pathway, an essential regulator of cell fate and commitment, as they represent the main source of sclerostin, a negative regulator of bone formation. Osteocytes can also act as an endocrine organ by releasing fibroblast growth factor 23 and several other proteins (DMP-1, MEPE, PHEX) that regulate phosphate metabolism. It has been demonstrated that various bone diseases are associated with osteocyte abnormalities, although it is not clear if these changes are the direct cause of the pathology or if they are secondary to the pathological changes in the bone microenvironment. Thus, a better understanding of these cells could offer exciting opportunities for new advances in the prevention and management of different bone diseases. PMID- 22099167 TI - The development of visual working memory capacity during early childhood. AB - The change detection task has been used in dozens of studies with adults to measure visual working memory capacity. Two studies have recently tested children in this task, suggesting a gradual increase in capacity from 5 years to adulthood. These results contrast with findings from an infant looking paradigm suggesting that capacity reaches adult-like levels within the first year. The current study adapted the change detection task for use with children younger than 5 years to test whether the standard version of the task was too difficult and may have underestimated children's capacity. Results showed that 3- and 4 year-olds could successfully complete this modified task and that capacity increased roughly linearly, from 2 or 3 items during this period to 3 or 4 items between 5 and 7 years. Furthermore, performance did not differ significantly between the modified version and a replication of the standard version with 5- and 7-year-olds. Thus, there is no evidence that previous research with the change detection task underestimated children's capacity. Further research is needed to understand how performance relates across the infant looking task and change detection to provide a more complete picture of visual working memory capacity over development. PMID- 22099168 TI - Abdominal wall hernias as complications of cirrhosis. PMID- 22099169 TI - The suitability of an uncemented hydroxyapatite coated (HAC) hip hemiarthroplasty stem for intra-capsular femoral neck fractures in osteoporotic elderly patients: the Metaphyseal-Diaphyseal Index, a solution to preventing intra-operative periprosthetic fracture. AB - This study will seek to identify a measurable radiographic index, the Metaphyseal Diaphyseal Index (MDI) score to determine whether intra-operative fracture in osteoporotic bone can be predicted.A 5 year prospective cohort of 560 consecutive patients, undergoing hemiarthroplasty (cemented or uncemented), was evaluated. A nested case-control study to determine risk factors affecting intra-operative fracture was carried out. The Vancouver Classification was used to classify periprosthetic fracture. The MDI score was calculated using radiographs from the uncemented group. As a control (gold standard), Yeung et al's Canal Bone Ratio (CBR) score was also calculated. From this, a receiver operating characteristic (ROC) curve was formulated for both scores and area under the curve (AUC) compared. Intra and inter-observer correlations were determined. Cost analysis was also worked out for adverse outcomes. Four hundred and seven uncemented and one hundred and fifty-three cemented stems were implanted. The use of uncemented implants was the main risk factor for intra-operative periprosthetic fracture. Sixty-two periprosthetic fractures occurred in the uncemented group (15.2%), nine occurred in the cemented group (5.9%), P < 0.001. The revision rate for sustaining a periprosthetic fracture (uncemented group) was 17.7%, P < 0.001 and 90 day mortality 19.7%, P < 0.03. MDI's AUC was 0.985 compared to CBR's 0.948, P < 0.001. The MDI score cut-off to predict fracture was 21, sensitivity 98.3%, specificity 99.8%, positive predictive value 90.5% and negative predictive value 98%. Multivariate regression analysis ruled out any other confounding factors as being significant. The intra and inter-observer Pearson correlation scores were r = 0.99, P < 0.001. JRI uncemented hemiarthroplasty has a significantly higher intra-operative fracture rate. We recommend cemented arthroplasty for hip fractures. We propose a radiographic system that may allow surgeons to select patients who are good candidates for uncemented arthroplasty, but it needs prospective validation. PMID- 22099170 TI - Sex differences in the relationship between inflammatory and hemostatic biomarkers and metabolic syndrome: British 1958 Birth Cohort. AB - BACKGROUND: Circulating levels of C-reactive protein (CRP), fibrinogen, fibrin D dimer, tissue plasminogen activator antigen (t-PA) and von Willebrand factor (VWF) are associated with incident coronary heart disease (CHD). However, their associations with metabolic syndrome and its components in large populations of men and women have not been well defined. OBJECTIVES: We compare the sex associations of these biomarkers with established CHD risk factors, metabolic syndrome and its components in a large cohort. PATIENTS AND METHODS: 8302 men and women aged 45 years from the British 1958 birth cohort provided a blood sample. Analyses were restricted to 3457 men and 3464 women with complete data on all risk factors and no history of cardiovascular disease. Multiple regression analyses adjusted for smoking, social class, alcohol consumption and variables related to biomarker measurement error. RESULTS: Adjusted sex differences in levels of all biomarkers (except VWF) varied according to presence/absence of metabolic syndrome, its components and obesity (BMI >=30 kg m(-) (2)). Associations in women were up to twice as strong for CRP, fibrinogen and t-PA with markers of obesity (body mass index, waist circumference), blood pressure, blood lipids and metabolic syndrome. D-dimer showed weaker associations and less heterogeneity by sex. There was no evidence of sex interaction in associations with VWF. CONCLUSIONS: Associations between CRP, fibrinogen and t-PA and metabolic syndrome and its components were stronger in women than in men. Understanding the reasons for these differences across sex will be important in understanding the pathophysiology of cardiovascular and metabolic disease in men and women. PMID- 22099171 TI - A natural compound induced cardiogenic differentiation of endogenous MSCs for repair of infarcted heart. AB - An intra-myocardial injection of a cardiogenic factor (cardiogenin) was reported to induce myocardial regeneration of exogenous mesenchymal stem cell (MSCs) origin. In this study, replacement of the dangerous intra-myocardial injection with a safe method and whether the endogenous MSCs contribute to the cardiogenin mediated myocardial regeneration were investigated. Bone marrow transplantation with labeled MSCs was performed in rats, which were subsequently subject to a permanent ligation of left anterior descending coronary artery one week after the transplantation. The rats were then treated with the cardiogenin through oral administration for 2 weeks. We not only demonstrated the substantial therapeutic effects of cardiogenin on myocardial infarction through an oral administration, but also provided direct evidences that the bone marrow derived endogenous MSCs are the major cellular source of the regenerating myocardium. Preliminary mechanistic studies suggested that miR-9 and its target E-cadherin may be required for intercalated disc formation. PMID- 22099172 TI - Transcription factors TP53 and SP1 and the osteogenic differentiation of dental stem cells. AB - Dental follicle is a loose connective tissue that surrounds the developing tooth. Dental follicle cells (DFCs) have a promising potential for tissue engineering applications including periodontal and bone regeneration. However, little is known about the molecular mechanisms underlying osteogenic differentiation. In a previous study we detected that more than 35% of genes that are regulated during osteogenic differentiation of DFCs have promoter binding sites for the transcription factors TP53 and SP1. However, the role of these transcription factors in dental stem cells is still unknown. We hypothesize that both factors influence the processes of cell proliferation and differentiation in dental stem cells. Therefore, we transiently transfected DFCs and dental pulp stem cells (SHED; Stem cells from human exfoliated decidiuous teeth) with expression vectors for these transcription factors. After overexpression of SP1 and TP53, SP1 influenced cell proliferation and TP53 osteogenic differentiation in both dental cell types. The effects on cell proliferation and differentiation were less pronounced after siRNA mediated silencing of TP53 and SP1. This indicates that the effects we observed after TP53 and SP1 overexpression are indirect and subject of complex regulation. Interestingly, upregulated biological processes in DFCs after TP53-overexpression resemble the downregulated biological processes in SHED after SP1-overexpression. Here, regulated processes are involved in cell motility, wound healing and programmed cell death. In conclusion, our study demonstrates that SP1 and TP53 influence cell proliferation and differentiation and similar biological processes in both SHED and DFCs. PMID- 22099173 TI - Stem cell factor and granulocyte colony-stimulating factor promote neuronal lineage commitment of neural stem cells. AB - Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) were originally discovered as growth factors for hematopoietic stem cells (HSCs). It has been well defined that SCF and G-CSF contribute to regulation of lineage commitment for HSCs. However, little is known about whether SCF and G-CSF play roles in the determination and differentiation of neural stem cells (NSCs). Here we demonstrate the novel function of SCF and G-CSF in controlling cell cycle and cell fate determination of NSCs. We also observe that SCF and G-CSF promote neuronal differentiation and inhibit astroglial differentiation at the early stage of differentiation. In addition, our research data reveal that SCF in combination with G-CSF has a dual function in promoting cell cycle exit and directing neuronal fate commitment at the stage of NSC dividing. This coordination effect of SCF+G-CSF on cell cycle arrest and neuronal differentiation is through enhancing neurogenin 1 (Ngn1) activity. These findings extend current knowledge regarding the role of SCF and G-CSF in the regulation of neurogenesis and provide insights into the contribution of hematopoietic growth factors to brain development and remodeling. PMID- 22099175 TI - Neph3 associates with regulation of glomerular and neural development in zebrafish. AB - Neph3 (filtrin) is a membrane protein expressed in the glomerular epithelial cells (podocytes), but its role in the glomerulus is still largely unknown. To characterize the function of Neph3 in the glomerulus, we employed the zebrafish as a model system. Here we show that the expression of neph3 in pronephros starts before the onset of nephrin and podocin expression, peaks when the nephron primordium differentiates into glomerulus and tubulus, and is then downregulated upon glomerular maturation. By histology, we found that neph3 is specifically expressed in pronephric podocytes at 36hpf. Furthermore, disruption of neph3 expression by antisense morpholino oligonucleotides results in distorted body curvature and transient pericardial edema, the latter likely reflecting perturbation of glomerular osmoregulatory function. Histological analysis of neph3 morphants reveals altered glomerular morphology and dilated pronephric tubules. The phenotype of neph3 morphants, curved body and pericardial edema, is rescued by wild-type zebrafish neph3 mRNA. In addition to glomerulus, neph3 is highly expressed in the developing brain and specific regions of mature midbrain and hindbrain. In line with this, neph3 morphants show aberrant brain morphology. Collectively, the expression of neph3 in glomerulus and brain together with the morphant phenotype imply that neph3 is a pleiotropic gene active during distinct stages of tissue differentiation and associates directly in the regulation of both glomerular and neural development. PMID- 22099174 TI - Laterality defects are influenced by timing of treatments and animal model. AB - The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across laboratories, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs, and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance. PMID- 22099177 TI - The influence of peroxisome proliferator-activated receptor gamma(1) during differentiation of mouse embryonic stem cells to neural cells. AB - Peroxisome proliferator activated receptor gamma, belongs to PPARs, which exerts various metabolic functions including differentiation process. To testify the importance of PPARgamma in neural differentiation of mouse embryonic stem cells (mESCs), its expression level was assessed. Data revealed an elevation in expression level of PPARgamma when neural precursors (NPs) are formed upon retinoic acid treatment. Thus, involvement of PPARgamma in two stages of neural differentiation of mESCs, during and post-NPs formation was examined by application of its agonist and antagonist. Our results indicated that PPARgamma inactivation via treatment with GW9662 during NPs formation, reduced expression of neural precursor and neural (neuronal and astrocytes) markers. However, PPARgamma inactivation by antagonist treatment post-NPs formation stage only decreased the expression of mature astrocyte marker (Gfap) suggesting that inactivation of PPARgamma by antagonist decreased astrocyte differentiation. Here, we have demonstrated the stage dependent role of PPARgamma modulation on neural differentiation of mESCs by retinoic acid treatment for the first time. PMID- 22099176 TI - The GM-CSF receptor utilizes beta-catenin and Tcf4 to specify macrophage lineage differentiation. AB - Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes the growth, survival, differentiation and activation of normal myeloid cells and is essential for fully functional macrophage differentiation in vivo. To better understand the mechanisms by which growth factors control the balance between proliferation and self-renewal versus growth-suppression and differentiation we have used the bi potent FDB1 myeloid cell line, which proliferates in IL-3 and differentiates to granulocytes and macrophages in response to GM-CSF. This provides a manipulable model in which to dissect the switch between growth and differentiation. We show that, in the context of signaling from an activating mutant of the GM-CSF receptor beta subunit, a single intracellular tyrosine residue (Y577) mediates the granulocyte fate decision. Loss of granulocyte differentiation in a Y577F second-site mutant is accompanied by enhanced macrophage differentiation and accumulation of beta-catenin together with activation of Tcf4 and other Wnt target genes. These include the known macrophage lineage inducer, Egr1. We show that forced expression of Tcf4 or a stabilised beta-catenin mutant is sufficient to promote macrophage differentiation in response to GM-CSF and that GM-CSF can regulate beta-catenin stability, most likely via GSK3beta. Consistent with this pathway being active in primary cells we show that inhibition of GSK3beta activity promotes the formation of macrophage colonies at the expense of granulocyte colonies in response to GM-CSF. This study therefore identifies a novel pathway through which growth factor receptor signaling can interact with transcriptional regulators to influence lineage choice during myeloid differentiation. PMID- 22099178 TI - Cellular signals underlying beta-adrenergic receptor mediated salivary gland enlargement. AB - We examined the cellular signaling pathways involved in parotid gland enlargement induced by repeated isoproterenol administration in rats. Immunoblot analysis revealed early (1h) activation of the mitogen activated protein kinase (MAPK) ERK1/2, and progressive activation of epidermal growth factor receptor (EGFR), p38MAPK and p70S6 kinase (p70S6K) during 72h of isoproterenol treatment. Expression of beta-adrenergic receptors (ARs) of the beta2, but not beta1, subtype increased over time in parallel with increases in the proliferation marker PCNA and parotid gland weight. Levels of beta2-AR mRNA, assessed by quantitative RT-PCR and Northern blot analysis, were upregulated in parotid glands of isoproterenol treated rats. cAMP response element binding protein (CREB), a positive regulator of beta2-AR transcription, was activated at 1h after isoproterenol administration, as evidenced by increased nuclear translocation and DNA binding using immunohistochemical staining and electrophoretic mobility shift assay. ELISA of NF-kappaB, also a beta2-AR transcriptional regulator, revealed an increase in p65 and p50 subunits in nuclear protein extracts from parotid glands of isoproterenol treated rats. Together, these results demonstrate that beta adrenergic stimulation activates diverse cell survival and progrowth signaling pathways, including cAMP and EGFR linked activation of ERK1/2, p38MAPK, and p70S6K, and also induction of beta2-ARs, possibly mediated by CREB and NF-kappaB, resulting in salivary gland enlargement. We propose that during isoproterenol treatment activation of the beta1-AR, the predominant beta-AR subtype in unstimulated salivary glands, initiates proliferative signaling cascades, and that upregulation of the beta2-AR plays an essential role in later stages of salivary gland growth. PMID- 22099179 TI - More than nervous: the emerging roles of plexins. AB - Plexins are the receptors for semaphorins, a large family of axon guidance cues. Accordingly, the role of plexins in the development of the nervous system was the first to be acknowledged. However, the expression of plexins is not restricted to neuronal cells, and recent research has been increasingly focused on the roles of plexin-semaphorin signalling outside of the nervous system. During embryogenesis, plexins regulate the development of many organs, including the cardiovascular system, skeleton and kidney. They have also been shown to be involved in immune system functions and tumour progression. Analyses of the plexin signalling in different tissues and cell types have provided new insight to the versatility of plexin interactions with semaphorins and other cell-surface receptors. In this review we try to summarise the current understanding of the roles of plexins in non-neural development and immunity. PMID- 22099180 TI - New culture system for human embryonic stem cells: autologous mesenchymal stem cell feeder without exogenous fibroblast growth factor 2. AB - Human embryonic stem (hES) cells have been successfully maintained using human cell feeder systems or feeder-free systems. However, despite advances in culture techniques, hES cells require supplementation with fibroblast growth factor 2 (FGF-2), an exogenous stemness factor, which is needed to sustain the authentic undifferentiated status. We developed a new culture system for hES cells; this system does not require supplementation with FGF-2 to obtain hES cells that are suitable for tissue engineering and regenerative medicine. This culture system employed mesenchymal stem cells derived from hES cells (hESC-MSCs) as autologous human feeder cells in the absence of FGF-2. The hES cell line SNUhES3 cultured in this new autologous feeder culture system maintained the typical morphology of hES cells and expression of pluripotency-related proteins, SSEA-4, TRA-1-60, OCT4, and alkaline phosphatase, without development of abnormal karyotypes after more than 30 passages. RNA expression of the pluripotency-related genes OCT4 and NANOG was similar to the expression in SNUhES3 cells maintained on xenofeeder STO cells. To identify the mechanism that enables the cells to be maintained without exogenous FGF-2, we checked the secretion of FGF-2 from the mitomycin-C treated autofeeder hESC-MSCs versus xenofeeder STO cells, and confirmed that hESC-MSCs secreted FGF-2 whereas STO cells did not. The level of FGF-2 in the media from the autofeeder system without exogenous FGF-2 was comparable to that from the xenofeeder system with addition of FGF-2. In conclusion, our new culture system for hES cells, which employs a feeder layer of autologous hESC-MSCs, supplies sufficient amounts of secreted FGF-2 to eliminate the requirement for exogenous FGF-2. PMID- 22099181 TI - Uncontrolled blood pressure in tubercular patients on hemodialysis: think rifampicin. PMID- 22099182 TI - Interactions between gastrointestinal nematode parasites and diarrhoea in sheep: pathogenesis and control. AB - Diarrhoea is a major impediment to profitable sheep production in many countries as it predisposes animals to blowfly strike and contaminates wool and meat carcasses. While it is accepted that nematode parasites are a major cause of diarrhoea in grazing animals, less is known about what facets of the host parasite relationship lead to diarrhoea and what the most appropriate control strategies are. In this review, the relationship between gastrointestinal nematode infection and diarrhoea is discussed and it is concluded that in many cases, particularly in immunologically mature sheep, diarrhoea is not due to parasite infection per se but rather due to immunopathological processes. Mechanisms that lead to faecal softening in immune sheep are considered, and the question addressed as to whether anthelmintic treatment and selective breeding of naturally parasite-resistant sheep will effectively reduce the occurrence of diarrhoea. PMID- 22099183 TI - Electroencephalographic recordings in dogs suffering from idiopathic and symptomatic epilepsy: diagnostic value of interictal short time EEG protocols supplemented by two activation techniques. AB - The diagnostic value of interictal short time electroencephalographic (EEG) recordings in epileptic dogs under general anaesthesia with propofol and the muscle relaxant rocuronium bromide was investigated. Two activation techniques, namely photic stimulation and hyperventilation, were evaluated for their potential to enhance the diagnostic validity of these recordings. Sixty-one dogs suffering from idiopathic epilepsy and 28 dogs suffering from symptomatic epilepsy were included. Electroencephalograms were recorded using five subdermal EEG electrodes (F3, F4, Cz, O1 and O2). All 89 EEGs were analysed visually and 61 were also evaluated quantitatively with fast Fourier transformation. Interictal paroxysmal epileptiform activity was found in 25% of idiopathic and in 29% of symptomatic epileptic dogs. Quantitative analysis of the EEGs (qEEGs) detected significant differences of frequency analysis in single reading points without any continuous changes of frequency bands. A comparison between healthy and affected brain hemispheres in seven dogs with focal lesions of one hemisphere did not show any significant differences in qEEG analysis. qEEG was not more sensitive than visual evaluation. Despite the use of activation techniques, the results showed that short time EEG recordings in epileptic dogs can detect interictal epileptic activity in less than one third of all seizuring dogs and is not a useful screening method. PMID- 22099184 TI - Effects of obesity on lung function and airway reactivity in healthy dogs. AB - The present study investigated the effects of bodyweight (BW) gain on respiratory function and airway responsiveness in healthy Beagles using barometric whole body plethysmography (BWBP). Six adult dogs were examined before and after a fattening diet. The high-energy diet induced a mean increase in BW of 41+/-6%. BWBP basal parameters were recorded prior to airway reactivity testing (using increasing concentrations of histamine nebulisations). An airway responsiveness index (H Penh300) was calculated as the histamine concentration necessary to reach 300% of basal enhanced pause (Penh, bronchoconstriction index). The same dogs underwent a doxapram hydrochloride (Dxp) stimulation testing 2 weeks later. Basal measurements showed that obese dogs had tidal volume per kg (TV/BW) that was significantly decreased whilst respiratory rate (RR) increased significantly. H Penh300 decreased significantly in obese Beagles, indicating increased bronchoreactivity. Dxp administration induced a significant increase in TV/BW, minute volume per kg (MV/BW), peak inspiratory and expiratory flows per kg (PIF/BW and PEF/BW) in both normal and obese dogs although the TV/BW increase was significantly less marked in the obese group. In conclusion, obesity induced changes in basal respiratory parameters, increased bronchoreactivity and a blunted response to Dxp-induced respiratory stimulation. This combination of basal respiratory parameters, bronchoreactivity testing and pharmacological stimulation testing using non-invasive BWBP can help characterize pulmonary function and airway responsiveness in obese dogs. PMID- 22099185 TI - Surgery in the early middle ages: evidence of cauterisation from Pisa. PMID- 22099186 TI - SCF ubiquitin ligases in the maintenance of genome stability. AB - In response to genotoxic stress, eukaryotic cells activate the DNA damage response (DDR), a series of pathways that coordinate cell cycle arrest and DNA repair to prevent deleterious mutations. In addition, cells possess checkpoint mechanisms that prevent aneuploidy by regulating the number of centrosomes and spindle assembly. Among these mechanisms, ubiquitin-mediated degradation of key proteins has an important role in the regulation of the DDR, centrosome duplication and chromosome segregation. This review discusses the functions of a group of ubiquitin ligases, the SCF (SKP1-CUL1-F-box protein) family, in the maintenance of genome stability. Given that general proteasome inhibitors are currently used as anticancer agents, a better understanding of the ubiquitylation of specific targets by specific ubiquitin ligases may result in improved cancer therapeutics. PMID- 22099187 TI - The enzymes of bacterial census and censorship. AB - N-Acyl-L-homoserine lactones (AHLs) are a major class of quorum-sensing signals used by Gram-negative bacteria to regulate gene expression in a population dependent manner, thereby enabling group behavior. Enzymes capable of generating and catabolizing AHL signals are of significant interest for the study of microbial ecology and quorum-sensing pathways, for understanding the systems that bacteria have evolved to interact with small-molecule signals, and for their possible use in therapeutic and industrial applications. The recent structural and functional studies reviewed here provide a detailed insight into the chemistry and enzymology of bacterial communication. PMID- 22099188 TI - [Assessment and management of rotation and angulation of lower limbs in children]. AB - Most rotational and angulational variations in young children are benign and resolved spontaneously. However, they may cause great concerns to parents. In order to provide a deliberate assessment and management of lower limb rotational and angulational problems, it is necessary for pediatricians to understand the normal variations of lower limb development in healthy children combined with the features of child growth and development and detail physical examinations. PMID- 22099189 TI - [Therapeutic effects of erythropoietin on hypoxic-ischemic encephalopathy in neonates]. AB - OBJECTIVE: To study the efficacy of erythropoietinin (EPO) in the treatment of moderate or severe hypoxic-ischemic encephalopathy (HIE) in neonates. METHODS: Seventy neonates with moderate or severe HIE were randomly assigned to two groups: EPO treatment and control (n=35 each). The EPO treatment group included 22 cases of moderate HIE and 13 cases of severe HIE. The control group included 24 cases of moderate HIE and 11 cases of severe HIE. Thirty-five healthy full term infants served as normal group. The control group received a conventional treatment. Beside the conventional treatment, the EPO treatment group was intravenously injected with EPO of 200 IU/kg*d, 3 times weekly. Routine blood test was performed every 6 days. EPO dose was adjusted based on the results of the routine blood test. The course of EPO treatment was 2 to 4 weeks. Neonatal Behavioral Neurological Assessment (NBNA) was performed at age of 28 days. The infant development test of Child Development Centre of China (CDCC) was performed at ages of 3 months and 6 months. RESULTS: The percentage of normal NBNA scores in the EPO treatment group was significantly higher than that in the control group at age of 28 days (P<0.05), but was significantly lower than that in the normal group (P<0.01). The CDCC test including physical development index (PDI) and physical development index (MDI) showed the percentage of normal results in the EPO treatment group was significantly higher than in the control group at age of 3 months (P<0.05), but was significantly lower than in the normal group (P<0.01). The CDCC test including PDI and MDI showed that the percentage of normal results in the EPO treatment group was significantly higher than in the control group at age of 6 months. The MDI test results in the EPO treatment group were not significantly different from those in the normal group at age of 6 months, but the percentage of normal results in the PDI test in the EPO treatment group was still significantly lower than that in the normal group (P<0.05). CONCLUSIONS: EPO treatment has neuroprotective effects against moderate or severe HIE and improves long-term behavioral neurological developments in neonates. PMID- 22099190 TI - [Factors influencing the bone mineral density in preterm infants]. AB - OBJECTIVE: To study the bone mineral development and the factors influencing the development in preterm infants. METHODS: Ninety preterm and 90 term infants followed up by the child health care service were randomly enrolled. Tibia quantitative ultrasound measurements were used to evaluate bone mineral density described as supersonic speed of sound (SOS) and Z scores at 6 months old (corrected gestational age for preterm infants). The factors influencing bone mineral development were investigated by questionnaire. RESULTS: The SOS values and Z scores in term infants were significantly higher than those in preterm infants at 6 months old. In the preterm group, the SOS values and Z scores were significantly different in infants with different birth weights or gestational ages (P<0.05). The SOS values in preterm infants with different weaning time were significantly different. The Z scores in female preterm infants were significantly higher than that in males (P<0.05). Multiple regression analysis indicated that weaning time and daily time of outdoor activities were independent factors influencing SOS values in preterm infants. CONCLUSIONS: It is helpful to promote bone mineral development by an appropriate weaning time or increasing the time of outdoor activities in preterm infants. PMID- 22099191 TI - [FLT3 mutations in children with acute myeloid leukemia: a single center study]. AB - OBJECTIVE: To study the clinical significance of FMS-like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) mutation and point mutation of tyrosine kinase domain (TKD) in children with acute myeloid leukemia (AML). METHODS: Bone marrow samples from 116 children with newly-diagnosed AML were obtained. Gene mutations of FLT3/ITD and FLT3/TKD were detected by RT-PCR. The relationship of FLT3 gene mutations with the clinical characteristics and the therapeutic efficacy was observed. RESULTS: FLT3/ITD and FLT3/TKD mutations were detected in 9 cases (7.8%) and 13 cases (11.2%) respectively out of the 116 children. FLT3/ITD mutations were observed in 3 cases of AML-M3 (3/9; 33.3%) and in 3 cases of AML-M5 (3/9; 33.3%). FLT3/TKD mutations were the most common in AML M3 patients (10/13; 76.9%). The patients with FLT3/ITD mutations had a significantly higher peripheral WBC count and marrow blast percentage compared with the patients without FLT3/ITD mutations at diagnosis (P<0.01). The 3-year overall survival rate in patients with FLT3/ITD mutations was significantly lower than that in patients without FLT3/ITD mutations (38.9% vs 64.3%; P<0.05). CONCLUSIONS: FLT3/TKD mutations are common in children with AML-M3. The AML children with FLT3/ITD mutations present a high peripheral WBC count and a high marrow blast percentage at diagnosis and have an unfavorable outcome. PMID- 22099192 TI - [Comparisons of clinical features of chronic aplastic anemia and myelodysplastic syndrome in children]. AB - OBJECTIVE: This study compared the differences in clinical features between chronic aplastic anemia (CAA) and myelodysplastic syndrome (MDS) in children in order to provide a basis for the differential diagnosis of the two diseases. METHODS: A retrospective study of 23 cases of CAA and 9 cases of MDS from September 2007 to September 2010 was performed. The clinical data including routine blood test results, reticulocyte counts, serum lactate dehydrogenase level, serum ferritin level, cytological examination of bone marrow, bone marrow CD34+ cell counts, bone marrow chromosome and FISH test results were compared between the CAA and MDS groups. RESULTS: Neutrophils, reticulocytes, and serum ferritin and lactate dehydrogenase levels increased in the MDS group compared with those in the CAA group. There were significant differences in bone marrow blast cell counts and dyshematopoiesis phenomena of three lines blood cells between the CAA and MDS groups. The bone marrow CD34+ cell counts and the rate of chromosomal abnormalities detected in bone marrow cytogenetic analysis in the MDS group were significantly higher than those in the CAA group. CONCLUSIONS: There are differences in the results of laboratory examinations and morphological and cytogenetic examinations of bone marrow between the children with CAA and MDS. The differences are useful to the differential diagnosis of the two diseases. PMID- 22099193 TI - [Prognosis of 212 children with asthma: a 5-year follow-up study]. AB - OBJECTIVE: To study the prognosis of childhood asthma and the factors influencing asthmatic attacks and prognosis. METHODS: The medical data of 212 children with asthma who were followed up for more than 5 years were retrospectively studied. RESULTS: During the 5-year follow up, asthmatic attacks termination was found in 121 cases (57.1%) and asthma persistence was observed in 91 cases. Respiratory tract infections were found as the major factors inducing asthmatic attacks (71.7%), followed by inhaled allergens (17.0%).The children with asthma induced by respiratory tract infections had a higher remission rate of asthmatic attacks (61.2%) than those induced by allergens (41.7%) or exercises (26.3%). Three risk factors for asthma persistence were identified: concurrent allergic rhinitis and eczema, parental asthma and allergy-induced wheezing. CONCLUSIONS: The 5-year follow-up study demonstrated that asthmatic attacks stopped in the majority of children with asthma. Respiratory tract infections may be the major factors inducing acute asthma attacks. The children with asthma induced by respiratory infections may experience a better outcome. Atopic children or children with the genetic background of atopy are at high risks for the development of persistent asthma. PMID- 22099194 TI - [Evaluation of efficacy and safety of loratadine in the treatment of childhood asthma]. AB - OBJECTIVE: To evaluate the efficacy and safety of loratadine, a new generation of antihistaminics, in the treatment of childhood asthma. METHODS: The papers related to loratadine treatment for childhood asthma were searched in the database of PubMed, MEDLINE, EMBASE, Cochrance, CNKI and CBMdisc (January 1990 to December 2010) electronically and manually. According to the Cochrane reviewer's handbook, the quality of the enrolled papers was assessed and a systematic review was performed. RESULTS: A total of 179 papers were obtained. Eleven randomized controlled trials met the criteria and were included in this study. The 11 trials included 317 children with asthma: 159 cases in the loratadine treatment group and 158 cases in the control group. All included studies belonged to the B class according to the quality evaluation criteria. Meta analysis showed that the clinical symptoms were improved more, the forced expiratory volume in 1 second (FEV1) 4 and 8 weeks posttreatment and the peak expiratory flow rate (PEFR) 8 weeks posttreatment were higher in the loratadine treatment group than in the control group. The treatment-related adverse effects, fatigue, tachycardia and palpitation, occurred less in the loratadine treatment group compared with the control group. CONCLUSIONS: Loratadine is safe and effective for the treatment of childhood asthma. PMID- 22099196 TI - [Relationship between angiotensin converting enzyme gene polymorphism and essential hypertension in children]. AB - OBJECTIVE: To study the relationship between insertion/deletion (I/D) polymorphism of 287 bp in the 16th intron of angiotensin converting enzyme (ACE) and essential hypertension in children. METHODS: I/D polymorphism of 287 bp in the 16th intron of ACE was detected using PCR in 105 children with essential hypertension and 105 normal children as control group. RESULTS: There was an I/D polymorphism in the 16th intron of ACE in the hypertension and the control groups: type II, type ID and type DD. The genotype frequencies of type DD, type ID and type II in the hypertension group were 30.5%, 47.6% and 21.9%, respectively. The genotype frequencies of type DD, type ID and type II in the control group were 14.3%, 46.7% and 39.1%, respectively. There were significant differences in the genotype frequencies of types DD and II between the two groups (P<0.01). The allele frequency of type D (54.3% vs 37.6%) was significantly higher in the hypertension group; in contrast, the allele frequency of type I (45.7% vs 62.4%) was significantly lower than in the control group (P<0.01). CONCLUSIONS: Polymorphism of type II, type ID and type DD exits in ACE. The deletion of 287 bp in the 16th intron of ACE might be associated with the occurrence of essential hypertension in children. PMID- 22099195 TI - [Correlation of renal AQP1-4 protein expression with renal parenchyma thickness and glomerular filtration rate in children with congenital hydronephrosis]. AB - OBJECTIVE: To study the relationship of renal aquaporin -1, -2, -3, and -4 (AQP1 4) expression with renal parenchymal thickness and glomerular filtration rate (GFR) in children with congenital hydronephrotis. METHODS: Renal tissue samples were obtained from 10 kidneys of 10 children (age: 62.3+/-18.3 months) with hydronephrosis and who underwent Anderson-Hynes pyeloplasty. Renal control samples were obtained from 6 children (age: 62.7+/-17.1 months) undergoing nephrectomy for nephroblastoma and were confirmed histologically as normal renal tissues. Renal parenchymal thickness of the hydronephrotic kidneys was measured by ultrasound preoperatively and was verified at operation. Renal GFR was assessed using 99mTc-DTPA scintigraphy preoperatively. Western blot was used to examine the expression of AQP1-4 in the renal tissues. The correlations of renal AQP1-4 expression with the renal parenchymal thickness and GFR were assessed by Pearson correlation analysis. RESULTS: The expression of AQP1-4 in the hydronephrotis group was markedly reduced compared to that in the control group (P<0.05). The mean renal parenchymal thickness of the hydronephrotic kidney was 4.59+/-2.25 mm measured by ultrasound preoperatively. The mean GFR of the obstructed kidney was significantly lower than that of the contralateral kidney in the hydronephrosis group (40+/-12 mL/min vs 105+/-20 mL/min; P<0.05). The expression of AQP1, 2, 3 and 4 was positively correlated with preoperative renal GFR and renal parenchymal thickness in the hydronephrosis group (P<0.05). Renal parenchymal thickness was positively correlated with renal GFR (P<0.05). CONCLUSIONS: The expression of renal AQP1-4 is reduced in children with congenital hydronephrosis. The expression levels of AQP1-4 are positively correlated with renal parenchymal thickness and GFR. PMID- 22099197 TI - [Diagnosis of vasovagal syncope in children with postural orthostatic tachycardia syndrome]. AB - OBJECTIVE: To study the diagnosis of vasovagal syncope (VVS) in children with postural orthostatic tachycardia syndrome (POTS). METHODS: The clinical data of 57 children with POTS diagnosed by the head-up tilt test between January 2007 and December 2010 were studied retrospectively. Of the 57 children, there were 29 boys and 28 girls who were aged from 5 to 16 years (12.2+/-1.9 years). RESULTS: Twenty-four (42%) out of 57 children were diagnosed with VVS by prolonging the duration of the head-up tilt test (for the children with orthostatic tolerance): cardioinhibitory (20 cases), mixed (3 cases) and vasoinhibitory (1 case). The POTS children with VVS were older than those without (13.0+/-1.4 years vs 11.5+/ 2.1 years; P<0.05). There were no significant differences in gender and clinical symptoms between the POTS children with and without VVS. CONCLUSIONS: Some children with POTS may have coexisting VVS, suggesting that it is important to avoid misdiagnosis of VVS by prolonging the duration of head-up tilt test in POTS children with orthostatic tolerance. There are no obvious differences in gender and clinical symptoms between the POTS children with and without VVS. PMID- 22099198 TI - [Changes of regulatory T cells in the peripheral blood of children with epilepsy]. AB - OBJECTIVE: To study the levels of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) in the peripheral blood of children with epilepsy and the roles of Tregs in the pathogenesis of epilepsy. METHODS: Forty-one children with epilepsy and thirty eight healthy children were enrolled. The percentage of CD4+ CD25+ Foxp3+ Tregs in CD4+ T cells and the percentages of CD4+ T cells, CD8+ T cells, nature killer (NK) cells and B cells in lymphocytes were evaluated by flow cytometry. RESULTS: The percentages of peripheral blood CD4+ CD25+ Foxp3+ Tregs and CD4+ T cells and the ratio of CD4+ T cells to CD8+ T cells in epileptic children were (2.4+/ 0.5)%, (35+/-5)% and 1.32+/-0.24 respectively, which were significantly lower than those in healthy children [(6.1+/-1.2)%, (38+/-4)% and 1.60+/-0.24 respectively; P<0.05]. In contrast, the percentages of CD8+ T cells, NK cells and B cells in lymphocytes in epileptic children were significantly higher than those in healthy children[(27+/-3)% vs (24+/-3)%, (11.1+/-5.1)% vs (8.5+/-1.9)% and (24+/-9)% vs (16+/-5)% respectively; P<0.05]. CONCLUSIONS: The abnormal percentage of CD4+ CD25+ Foxp3+ Tregs in the peripheral blood may be involved in the pathogenesis of epilepsy. PMID- 22099199 TI - [Relationship between congenital heart disease and bronchial dysplasia]. AB - OBJECTIVE: To study the relationship of the incidence of bronchial dysplasia (bronchial anomalous origin and bronchial stenosis) with congenital heart disease. METHODS: A total of 185 children with congenital heart disease or bronchial dysplasia were enrolled. Bronchial dysplasia was identified by the 64 MSCT conventional scanning or thin slice scanning with three-dimensional reconstruction. RESULTS: Forty-five children (25.3%) had coexisting bronchial dysplasia and congenital heart disease. The incidence rate of bronchial dysplasia in children with congenital heart disease associated with ventricular septal defect was higher than in those without ventricular septal defect (33.7% vs 15.0%; P<0.05). There were no significant differences in the incidence rate of bronchial dysplasia between the children with congenital heart disease who had a large vascular malformation and who did not. CONCLUSIONS: Bronchial dysplasia often occurs in children with congenital heart disease. It is necessary to perform a tracheobronchial CT scanning with three-dimensional reconstruction to identify tracheobronchial dysplasia in children with congenital heart disease, especially associated with ventricular septal defect. PMID- 22099200 TI - [Impact of gonadotropin-releasing hormone analogs on body mass index in girls with idiopathic central precocious puberty: a long-term follow-up study]. AB - OBJECTIVE: To study the impact of gonadotropin-releasing hormone analogs (GnRHa) on body mass index (BMI) in girls with idiopathic central precocious puberty (ICPP). METHODS: One hundred and thirty-four girls with ICPP were enrolled. Fifty seven out of the 134 girls were treated with GnRHa for 1.69+/-0.43 years. The height, weight, bone age and BMI were measured before treatment, at the end of the treatment and after reaching near adult height and compared with those in the untreated 77 girls. RESULTS: The adult predicted height standard deviation score (SDS) at the end of treatment was significantly higher than that before treatment (P<0.01) and was similar to the target height SDS in the GnRHa treatment group (P>0.05). With GnRHa treatment, the near-adult height SDS was higher than the target height SDS (P<0.01). At the end of treatment, the BMI SDS slightly increased compared with pretreatment level (P>0.05). A significant reduction in the BMI was observed when reaching the near-adult height in the GnRHa treatment group compared to the level of pretreatment and the untreated group (P<0.01). However, the BMI in the GnRHa treatment group before treatment, at the end of the treatment and after reaching near adult height remained in the normal range (+/-1 SD). CONCLUSIONS: GnRHa may improve the final height in girls with ICPP. The alterations of BMI after GnRHa therapy fluctuate in a normal range. PMID- 22099201 TI - [Investigation on the behavior problems of children aged 3 to 5 years in Changsha and comparison of the norm of Conners Parent Symptom Questionnaire in Chinese and American urban children]. AB - OBJECTIVE: To investigate the behavior problems of children aged 3 to 5 years in Changsha and to compare the differences of the results detected by the norm of Conners Parent Symptom Questionnaire (PSQ) in Chinese and American urban children. METHODS: A total of 854 children aged 3 to 5 years were randomly sampled from 5 districts in Changsha City and their parents completed the Conners PSQ. RESULTS: The assessment by the norm of PSQ in American urban children demonstrated that the average prevalence of behavior problems was 20.4%, with 28.1% for boys and 12.4% for girls. There were significant differences between boys and girls (P<0.01). The factor score of anxiety in girls was markedly higher than that in boys (P<0.01). Learning and psychosomatic problems were the main problems in the children. The prevalences of conduct problems and impulse restlessness, and abnormal restlessness index detected by the norm of PSQ in Chinese urban children were higher than those detected by the American norm. The prevalences of conduct problems and psychosomatic problems in boys by the norm of PSQ in Chinese urban children were significantly lower than those detected by the American norm, while the total prevalence of behavior problems was higher than that detected by American norm. There was a poor consistency in the assessment results of most factors of the PSQ and the total prevalence of behavior problems detected by the Chinese and American norms (KappP<0.4). CONCLUSIONS: The prevalence of behavior problems especially learning problems and psychosomatic problems in children aged 3 to 5 years is higher in Changsha. The consistency of assessment results is poor between the norms of China and America. It is recommended to use the China norm of PSQ in Chinese children aged 3 to 5 years because the Chinese norm is in line with China's national conditions and cultural background. PMID- 22099202 TI - [Social-psychological factors contributing to male juvenile delinquency]. AB - OBJECTIVE: To study the major social-psychological factors contributing to male juvenile delinquency. METHODS: One hundred and thirty-seven cases of male juvenile delinquents (delinquent group) and 145 aged-matched male students (control group) were enrolled in this case-control study. A questionnaire survey was conducted using the Adolescent Self-Rating Life Events Check List, the Coping Style Questionnaire, the Family Environment Scale-Chinese version, and the Social Support Rating Scale. RESULTS: The monovariate analysis showed that the total score and the scores of some factors of negative life events, the scores of immature coping styles and family conflicts, and the proportion of broken families in the delinquent group were significantly higher than those in the control group. In contrast, the scores of educational levels, study stress factor in the negative life events, mature coping styles, family environments and social supports were significantly lower in the delinquent group than those in the control group. The multivariate factors analysis showed that 7 variables were enrolled into the discriminatory equations, including negative life events (interpersonal relationship and healthy adaptation), self-condemn styles, family conflicts, subjective supports, objective supports, and utilization of social supports. The total accuracy of this equation was 92.2%. CONCLUSIONS: Negative life events in the interpersonal relationship and healthy adaptation, self condemn styles, family conflicts, and weak social support system may be major social-psychological factors contributing to male juvenile delinquency. PMID- 22099204 TI - [Expression of erythropoietin and its receptor in the brain of newborn rats suffering from fetal distress]. AB - OBJECTIVE: To study the expression of erythropoietin (EPO) and its receptor (EPOR) in the brain of newborn rats suffering fetal distress. METHODS: A model of fetal distress was prepared by ligating bilateral uterine arteries of the rats with full-term pregnancy for 10 minutes before cesarean sections. The expression levels of EPO and EPOR in the brain of newborn rats were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot at 0, 2, 6, 12, 24, 48, 72 hrs and 7 days after birth. Serum EPO levels were measured using ELISA simultaneously. The newborn rats born by cesarean sections which were not subjected to uterine artery ligation were used as the control group. RESULTS: The expression of EPO protein and mRNA in brain tissues in the fetal distress group increased significantly compared with the control group 2, 6 and 12 hrs after birth (P<0.05). The expression of EPOR protein and mRNA in brain tissues in the fetal distress group increased significantly compared with the control group 2, 6, 12, 24 and 48 hrs, and 3 days after birth (P<0.05). Serum EPO levels in the fetal distress group were significantly higher than in the control group 2 hrs after birth. CONCLUSIONS: The EPO and EPOR levels in the brain increase quickly after birth in newborn rats suffering from fetal distress. The EPOR is high expressed for a longer time than EPO. This can provide a basis for the treatment of neonatal brain damage induced by fetal distress by exogenous EPO. PMID- 22099203 TI - [Influence of lipopolysaccharide on the permeability of rat brain microvascular endothelial cells and the molecular mechanism]. AB - OBJECTIVE: To study the influence of lipopolysaccharide (LPS) on the permeability of rat brain microvascular endothelial cells (BMECs) and possible molecular mechanism. METHODS: Monolayers of primary rat BMECs were separated and cultured, and then treated with (LPS group) or without LPS (control group). The barrier integrity was measured by transendothelial electrical resistance (TEER) assay. The degrees of RhoA activation were determined by Pull-down assay. The expression levels of p115RhoGEF, zonula occludens-1 (ZO-1), occludin and claudin-5 proteins were detected by Western blot analysis. RESULTS: The average TEER values of rat BMECs in the LPS group were 108.3+/-4.2 Omega*cm2 and 85.4+/-2.5 Omega*cm2 respectively 3 and 12 hrs after LPS treatment, which were significantly lower than that in the control group (159.0+/-8.6 Omega*cm2). Compared with the control group, the activity of RhoA started to increase 5 minutes after LPS treatment, and the expression of p115RhoGEF protein started to increase 1 hr after LPS treatment and the cellular protein levels of ZO-1, occludin and claudin-5 decreased significantly 3 hrs after LPS treatment in the LPS group (P<0.05). CONCLUSIONS: LPS may activate the p115RhoGEF/RhoA pathway and decrease protein expression of ZO-1, occludin and claudin-5, resulting in an increased permeability of rat BMECs. PMID- 22099205 TI - [Effects of Mycobacterium phlei F.U.36 on regulatory T cells and TLR4 expression in asthmatic mice]. AB - OBJECTIVE: To study the effects of early intervention on CD4+CD25+ regulatory T cells and TLR4 expression with Mycobacterium phlei F.U.36 in asthmatic mice. METHODS: Thirty female BALB/c mice were randomly divided into three groups: control, asthma model and Mycobacterium phlei F.U.36 treated asthma groups. Asthma was induced by sensitization and challenges with ovalbumin (OVA) in the later two groups. Mycobacterium phlei F.U.36 was intraperitoneally injected 2 weeks before the first sensitization (0.57 MUg/time, once every other day for three times) in the intervention group. After 24 hrs of the last challenge, the mice were sacrificed and the left lung tissues were obtained for the observation of lung pathological changes. Splenic mononuclear cells were isolated. The percentage of CD4+CD25+ regulatory T cells in CD4+ T cells and the mean fluorescence intensity of TLR4 on CD4+ CD25+ T cells were detected by flow cytometry. RESULTS: The percentage of CD4+CD25+ regulatory T cells in the asthma model group was significantly lower than that in the control group (P<0.01), but the mean fluorescence intensity of TLR4 on CD4+CD25+ regulatory T cells was not significantly different from the control group. The percentage of CD4+CD25+ regulatory T cells and the mean fluorescence intensity of TLR4 on CD4+CD25+ regulatory T cells increased significantly in asthmatic mice receiving Mycobacterium phlei F.U.36 treatment compared with the asthma group (P<0.01). CONCLUSIONS: Early intervention with Mycobacterium phlei F.U.36 can increase TLR4 expression on CD4+CD25+ cells and the number of CD4+CD25+ regulatory T cells, and thus provides therapeutic effects in asthmatic mice. PMID- 22099206 TI - [Curative effects of low-dose heparin combined with urokinase on primary nephritic syndrome complicated by severe hypercoagulabale state in children]. PMID- 22099207 TI - [Peripheral nerve function in children with hand foot and mouth disease complicated by acute flaccid paralysis of lower limbs]. PMID- 22099208 TI - [Active immunotherapy for women with unexplained recurrent spontaneous abortion: a follow-up study on growth and development of offspring]. PMID- 22099209 TI - [Osteopoikilosis complicated by short stature: a case report and a family survey]. PMID- 22099210 TI - Role of hepatic HCV-RNA level on the severity of chronic hepatitis C and response to antiviral therapy. AB - BACKGROUND: Correlation between hepatic HCV-RNA and serum HCV-RNA, severity of liver disease and response to therapy is poorly known. OBJECTIVES: To assess the influence of hepatic HCV-RNA level on severity of liver disease and response to therapy in a large cohort of chronic hepatitis C (CHC) patients. STUDY DESIGN: HCV-RNA was measured in frozen liver biopsies and serum samples from 130 CHC patients the day of liver biopsy prior to treatment. Liver fibrosis was assessed by Ishaq scoring. A Sustained Virological Response (SVR) was observed in 52% of the patients, non-response (NR) in 34%. RESULTS: Mean+/-standard deviation hepatic HCV-RNA level was 7.69+/-0.67 log(10) copies/mg of liver. Mean serum HCV RNA level was 6.21+/-0.72 log(10) copies/ml. There was a correlation between hepatic and serum HCV-RNA in genotype 1 and 4 (p=0.008 and p=0.03) and age (p=0.006). Mean hepatic HCV-RNA was 7.70+/-0.69 vs 7.67+/-0.68 log(10) copies/mg of liver, in patients with significant fibrosis vs those with mild fibrosis, respectively (p=0.7); 8.04+/-0.68; 7.44+/-0.47; 7.43+/-0.49 and 7.44+/-0.71 log(10) copies/mg of liver in genotypes 1, 2, 3 and 4, respectively (p=0.0001); higher in women than in men (p=0.04); 7.60+/-0.63, 7.71+/-0.54 and 7.96+/-0.73 log(10) copies/mg in SVR, relapsers and NR, respectively (p=0.1). Multivariate analysis showed that high hepatic HCV-RNA level was independently associated with genotype and response to therapy was associated with genotype independently from hepatic HCV-RNA level. CONCLUSIONS: Hepatic HCV-RNA level was not associated with severity of liver disease. High level was strongly associated with HCV genotype independently from response to therapy. PMID- 22099211 TI - Lipid-related residual risk and renal function for occurrence and prognosis among patients with first-event acute coronary syndrome and normal LDL cholesterol. AB - BACKGROUND: We investigated relationship of low levels of high density lipoprotein cholesterol (HDL-C), high levels of triglycerides, and renal function for the odds, prognosis and survival following acute coronary events among patients with a first event and normal low density lipoprotein cholesterol levels. RESULTS: A case-control study based on 557 patients and 1086 matched control subjects was conducted. Case patients were followed up for survival with a median of 1.9 years. Participants in the higher quintiles of HDL-C had lower odds to develop acute coronary events (the adjusted odds ratios were 0.24 for the second, 0.24 for the third, 0.10 for the fourth and 0.05 for the fifth quintile). Patients with normal glomerular filtration rate were at a lower risk for all cause death. However, a reverse association between triglycerides and death risk was found: patients with higher triglycerides were at a lower risk for all-cause death (adjusted relative risk, 0.38 for triglycerides ranging from 82 to 132.9 mg/dL, and 0.14 for triglycerides > = 133 mg/dL). CONCLUSIONS: Low HDL-C was significantly associated with acute coronary events, and triglyceride levels as well as renal function were inversely related to all-cause deaths after the coronary event. PMID- 22099212 TI - Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) after cardiac operations (postcardiotomy) is commonly used for the treatment of acute heart failure refractory to drug treatment. Bleeding and thromboembolic events are the most common complications of postcardiotomy ECMO. The present study is a retrospective comparison of the conventional heparin-based anticoagulation protocol with a bivalirudin-based, heparin-free protocol. Endpoints of this study are blood loss, allogeneic blood product use, and costs during the ECMO procedure. METHODS: A retrospective study was undertaken in the setting of cardiac surgery, anesthesia, and intensive care departments of a university research hospital. Twenty-one patients (12 adults and nine children) who underwent postcardiotomy ECMO from 2008 through 2011 were retrospectively analyzed. The first consecutive eight patients were treated with heparin-based anticoagulation (H-group) and the next 13 consecutive patients with bivalirudin-based anticoagulation (B-group). The following parameters were analyzed: standard coagulation profile, thromboelastographic parameters, blood loss, allogeneic blood products use, thromboembolic complications, and costs during the ECMO treatment. RESULTS: Patients in the B-group had significantly longer activated clotting times, activated partial thromboplastin times, and reaction times at thromboelastography. The platelet count and antithrombin activity were not significantly different, but in the H-group a significantly higher amount of platelet concentrates, fresh frozen plasma, and purified antithrombin were administered. Blood loss was significantly lower in the B-group, and the daily cost of ECMO was significantly lower in pediatric patients treated with bivalirudin. Thromboembolic complications did not differ between groups. CONCLUSIONS: Bivalirudin as the sole anticoagulant can be safely used for postcardiotomy ECMO, with a better coagulation profile, less bleeding, and allogeneic transfusions. No safety issues were raised by this study, and costs are reduced in bivalirudin-treated patients. PMID- 22099213 TI - Integrating historical clinical and financial data for pharmacological research. AB - BACKGROUND: Retrospective research requires longitudinal data, and repositories derived from electronic health records (EHR) can be sources of such data. With Health Information Technology for Economic and Clinical Health (HITECH) Act meaningful use provisions, many institutions are expected to adopt EHRs, but may be left with large amounts of financial and historical clinical data, which can differ significantly from data obtained from newer systems, due to lack or inconsistent use of controlled medical terminologies (CMT) in older systems. We examined different approaches for semantic enrichment of financial data with CMT, and integration of clinical data from disparate historical and current sources for research. METHODS: Snapshots of financial data from 1999, 2004 and 2009 were mapped automatically to the current inpatient pharmacy catalog, and enriched with RxNorm. Administrative metadata from financial and dispensing systems, RxNorm and two commercial pharmacy vocabularies were used to integrate data from current and historical inpatient pharmacy modules, and the outpatient EHR. Data integration approaches were compared using percentages of automated matches, and effects on cohort size of a retrospective study. RESULTS: During 1999-2009, 71.52%-90.08% of items in use from the financial catalog were enriched using RxNorm; 64.95%-70.37% of items in use from the historical inpatient system were integrated using RxNorm, 85.96%-91.67% using a commercial vocabulary, 87.19%-94.23% using financial metadata, and 77.20%-94.68% using dispensing metadata. During 1999 2009, 48.01%-30.72% of items in use from the outpatient catalog were integrated using RxNorm, and 79.27%-48.60% using a commercial vocabulary. In a cohort of 16304 inpatients obtained from clinical systems, 4172 (25.58%) were found exclusively through integration of historical clinical data, while 15978 (98%) could be identified using semantically enriched financial data. CONCLUSIONS: Data integration using metadata from financial/dispensing systems and pharmacy vocabularies were comparable. Given the current state of EHR adoption, semantic enrichment of financial data and integration of historical clinical data would allow the repurposing of these data for research. With the push for HITECH meaningful use, institutions that are transitioning to newer EHRs will be able to use their older financial and clinical data for research using these methods. PMID- 22099214 TI - Uses of cardiomyocytes generated from induced pluripotent stem cells. PMID- 22099215 TI - Longitudinal change in HbA1c after insulin initiation in primary care patients with type 2 diabetes: a database analysis in UK and Germany. AB - AIMS: To evaluate the 3-year change in HbA1c values after start of insulin therapy among patients with type 2 diabetes in primary care practices in UK and Germany. METHODS: Longitudinal data from general practices in Germany and UK (Disease Analyser, IMS HEALTH) from 2005 to 2009 were analysed, including 779 patients (mean age+/-SD: 63+/-11yrs, HbA1c: 8.1+/-1.3%) in Germany and 646 patients (55+/-12yrs; 9.3+/-1.5%) in UK with first time insulin prescriptions in 2005 (index date). The mean individual relative changes in HbA1c over 3 years after index date were adjusted for age, sex, diabetes duration, oral antidiabetics, insulin type, comorbidity and visits using general linear models. RESULTS: The average adjusted HbA1c improvements in the first 12 months in primary care patients were 0.5% (95%CI: 0.4-0.6%) in Germany and 1.0% (0.7-1.3%) in UK. Between 12 and 36 months these improvements in glycemic control were maintained in both patient groups. DISCUSSION: Initiation of insulin therapy in primary care patients in Germany and UK was associated with a similar moderate improvement in glycemic control over the first 12 months. After this period, insulin therapy only maintained HbA1c values without additional improvement in glycemic control. PMID- 22099217 TI - [Prolonged pregnancy term and beyond - method and organization]. PMID- 22099218 TI - Lipid MALDI profile classifies non-small cell lung cancers according to the histologic type. AB - We investigated whether direct tissue matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) analysis on lipid may assist with the histopathologic diagnosis of non-small cell lung cancers (NSCLCs). Twenty-one pairs of frozen, resected NSCLCs and adjacent normal tissue samples were initially analyzed using histology-directed, MALDI MS. 2,5-dihydroxybenzoic acid/alpha-cyano-4-hydroxycinnamic acid were manually deposited on areas of each tissue section enriched in epithelial cells to identify lipid profiles, and mass spectra were acquired using a MALDI-time of flight instrument. A lipid profile that could differentiate cancer and adjacent normal samples with a median accuracy of 92.9% was discovered. Several phospholipids including phosphatidylcholines (PC) {34:1} were overexpressed in lung cancer. Squamous cell carcinomas and adenocarcinomas were found to have different lipid profiles. Discriminatory lipids correctly classified the histology of 80.4% of independent NSCLC surgical tissue samples (41 out of 51) in validation set. MALDI MS image of 11 discriminatory lipids validated their differential expression according to the histologic type in cancer cells of bronchoscopic biopsy samples. PC {32:0} [M+Na](+) (m/z 756.68) and ST-OH {42:1} [M-H](-) (m/z 906.89) were overexpressed in adenocarcinomas. Thus, lipid profiles accurately distinguish tumor from adjacent normal tissue and classify non-small cell lung cancers according to the histologic type. PMID- 22099219 TI - Characterizing plant cell wall derived oligosaccharides using hydrophilic interaction chromatography with mass spectrometry detection. AB - Analysis of complex mixtures of plant cell wall derived oligosaccharides is still challenging and multiple analytical techniques are often required for separation and characterization of these mixtures. In this work it is demonstrated that hydrophilic interaction chromatography coupled with evaporative light scattering and mass spectrometry detection (HILIC-ELSD-MS(n)) is a valuable tool for identification of a wide range of neutral and acidic cell wall derived oligosaccharides. The separation potential for acidic oligosaccharides observed with HILIC is much better compared to other existing techniques, like capillary electrophoresis, reversed phase and porous-graphitized carbon chromatography. Important structural information, such as presence of methyl esters and acetyl groups, is retained during analysis. Separation of acidic oligosaccharides with equal charge yet with different degrees of polymerization can be obtained. The efficient coupling of HILIC with ELSD and MS(n)-detection enables characterization and quantification of many different oligosaccharide structures present in complex mixtures. This makes HILIC-ELSD-MS(n) a versatile and powerful additional technique in plant cell wall analysis. PMID- 22099220 TI - Enhancement of molecular shape selectivity by in situ anion-exchange in poly(octadecylimidazolium) silica column. AB - This paper demonstrates that in situ anion exchange could be successfully applied as a new method for modifying the surface properties of a poly(octadecylimidazolium)-grafted silica stationary phase to tune and enhance selectivity. Specifically, the original stationary phase was prepared by surface initiated radical chain-transfer polymerization of 1-vinyl-3-octadecylimidazolium bromide as an ionic liquid monomer; the Br(-) counter anion was then exchanged for methyl orange via an in-column process. As evaluated via the separation of constrained isomers of polycyclic aromatic hydrocarbons (PAHs), the in situ exchange enhanced the molecular shape-selectivity performance. Enhanced selectivity was also confirmed using Standard Reference Material (SRM) 869b (column selectivity test mixture) and SRM 1647e (16 priority pollutant PAHs). The reproducibility of new column was tested via the separation of pyrene, triphenylene, benzo[a]anthracene and chrysene with methanol as eluent at 10 degrees C and the RSD values (n=12) of the retention factors of them are within 0.27-0.77%. PMID- 22099216 TI - The health of HIV-exposed children after early weaning. AB - There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared with 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-h dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex stratified models were used to evaluate anthropometric differences between the two groups. BAN-exited children consumed adequate energy, protein and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN exited girls gained weight at a significantly lower rate {0.02 g kg(-1) per day [95% confidence interval (CI): 0.01, 0.03]} than their matched comparison [0.05 g kg(-1) per day (95% CI: 0.03, 0.07)]; BAN girls grew significantly slower [0.73 cm month(-1) (95% CI: 0.40,1.06)] than their matched comparison (1.55 cm month( 1) [95% CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programmes must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breast milk can be provided. PMID- 22099221 TI - Is it really necessary to validate an analytical method or not? That is the question. AB - Method validation is an important requirement in the practice of chemical analysis. However, awareness of its importance, why it should be done and when, and exactly what needs to be done, seems to be poor amongst analytical chemists. Much advice related to method validation already exists in the literature, especially related to particular methods, but more often than not is underused. Some analysts see method validation as something that can only be done by collaborating with other laboratories and therefore do not go about it. In addition, analysts' understanding of method validation is inhibited by the fact that many of the technical terms used in the processes for evaluating methods vary in different sectors of analytical measurement, both in terms of their meaning and the way they are determined. Validation applies to a defined protocol, for the determination of a specified analyte and range of concentrations in a particular type of test material, used for a specified purpose. In general, validation should check that the method performs adequately for the purpose throughout the range of analyte concentrations and test materials to which it is applied. It follows that these features, together with a statement of any fitness-for-purpose criteria, should be completely specified before any validation takes place. PMID- 22099222 TI - Capillary bioreactors based on human purine nucleoside phosphorylase: a new approach for ligands identification and characterization. AB - The enzyme purine nucleoside phosphorylase (PNP) is a target for the discovery of new lead compounds employed on the treatment severe T-cell mediated disorders. Within this context, the development of new, direct, and reliable methods for ligands screening is an important task. This paper describes the preparation of fused silica capillaries human PNP (HsPNP) immobilized enzyme reactor (IMER). The activity of the obtained IMER is monitored on line in a multidimensional liquid chromatography system, by the quantification of the product formed throughout the enzymatic reaction. The K(M) value for the immobilized enzyme was about twofold higher than that measured for the enzyme in solution (255 +/- 29.2 MUM and 133 +/ 14.9 MUM, respectively). A new fourth-generation immucillin derivative (DI4G; IC(50)=40.6 +/- 0.36 nM), previously identified and characterized in HsPNP free enzyme assays, was used to validate the IMER as a screening method for HsPNP ligands. The validated method was also used for mechanistic studies with this inhibitor. This new approach is a valuable tool to PNP ligand screening, since it directly measures the hypoxanthine released by inosine phosphorolysis, thus furnishing more reliable results than those one used in a coupled enzymatic spectrophotometric assay. PMID- 22099223 TI - An automated method for the analysis of phenolic acids in plasma based on ion pairing micro-extraction coupled on-line to gas chromatography/mass spectrometry with in-liner derivatisation. AB - A new method is presented for the analysis of phenolic acids in plasma based on ion-pairing 'Micro-extraction in packed sorbent' (MEPS) coupled on-line to in liner derivatisation-gas chromatography-mass spectrometry (GC-MS). The ion pairing reagent served a dual purpose. It was used both to improve extraction yields of the more polar analytes and as the methyl donor in the automated in liner derivatisation method. In this way, a fully automated procedure for the extraction, derivatisation and injection of a wide range of phenolic acids in plasma samples has been obtained. An extensive optimisation of the extraction and derivatisation procedure has been performed. The entire method showed excellent repeatabilities of under 10% and linearities of 0.99 or better for all phenolic acids. The limits of detection of the optimised method for the majority of phenolic acids were 10ng/mL or lower with three phenolic acids having less favourable detection limits of around 100 ng/mL. Finally, the newly developed method has been applied in a human intervention trial in which the bioavailability of polyphenols from wine and tea was studied. Forty plasma samples could be analysed within 24h in a fully automated method including sample extraction, derivatisation and gas chromatographic analysis. PMID- 22099224 TI - The selective cleanup of complex matrices and simultaneous separation of benzo[a]pyrene by solid-phase extraction with MgO microspheres as sorbents. AB - A new method for the selective cleanup of complex matrices and simultaneous separation of benzo[a]pyrene (BaP) was developed in this study. This method was based on solid-phase extraction (SPE) using magnesium oxide microspheres as sorbents, and it eliminated interferences from various impurities, such as lipids, sulphur, pigments, halobenzenes, polychlorodibenzo-p-dioxins and polychlorodibenzofurans. Several parameters, including the volume of rinsing and eluting solvents, the type of loading solvents and SPE sorbents, were optimized systematically. The capability for impurity removal was verified by gel permeation chromatography, gas chromatography, and liquid chromatography. Compared to commercial sorbents (silica gel, florisil and alumina), MgO microspheres exhibited excellent performance in the selective isolation of BaP and removal of impurities. The proposed method was applied to detect BaP in complex samples (sediments, soils, fish, and porcine liver). The limit of quantification (LOQ) was 1.04 ngL(-1), and the resulting regression coefficient (r(2)) was greater than 0.999 over a broad concentration range (9.5-7600 ngL( 1)). In contrast to traditional methods, the proposed method can give rise to higher recovery (85.1-100.8%) and better selectivity with simpler operation and less consumption of organic solvents (20-40 mL). PMID- 22099225 TI - Development of liquid phase microextraction based on manual shaking and ultrasound-assisted emulsification method for analysis of organochlorine pesticides in aqueous samples. AB - A novel method using sample preparation method, "ultrasound-assisted emulsification microextraction" (USAEME) with manual shaking, coupled with gas chromatography using and an electron capture detector (GC-ECD) was developed for the analysis of organochlorine pesticides (OCPs) in aqueous samples. The apparatus is simple and easy to operate. After manual shaking for 10s, ultrasound was used to accelerate emulsification of the organic solvent (1-decanol) in aqueous solution. Only 10 MUL of the low-toxicity extraction solvent is used in this method; no dispersive solvent is required and the total extraction time is ~4 min. Manual shaking before ultrasound-assisted emulsification enhances the extraction efficiency by >100%. The effects of horizontal and vertical orientation as well as the location of the sample within the ultrasonic bath were studied. After centrifugation, we used an improved solvent collection system (ISCS) to reduce the amount of extraction solvent required. A 1 MUL sample of the extract was injected into the GC column. Under optimum conditions, the linear range of the method is 5-2500 ngL(-1) for most of the OCPs, and the limit of detection of the method ranged from 0.6 to 2.9 ngL(-1).The relative recoveries ranged from 75 to 107% for sea water and from 70 to 99% for field fresh water. The method, which provides good enrichment factors, low LODs and minimization of the consumption of organic solvent, provides a rapid, simple and environment friendly procedure for determining OCPs in aqueous samples. PMID- 22099226 TI - The use of ethylene glycol solution as the running buffer for highly efficient microchip-based electrophoresis in unmodified cyclic olefin copolymer microchips. AB - An ethylene glycol solution was used as the electrophoretic running buffer in unmodified cyclic olefin copolymer (COC) microchips to minimize the interactions between the analytes and the hydrophobic walls of the plastic microchannels, enhance the resolution of the analytes and eliminate the uncontrollable dispersion caused by uneven liquid levels and non-uniform surfaces of the separation channels. Five amino acids that were labeled with fluorescein isothiocyanate (FITC) were used as model analytes to examine the separation efficiency. The effects of ethylene glycol concentration, pH and sodium tetraborate concentration were systematically investigated. The five FITC-labeled amino acids were effectively resolved using a COC microchip with an effective length of 2.5 cm under optimum conditions, which included using a running buffer of 20 mmol/L sodium tetraborate in ethylene glycol:water (80:20, v/v), pH 6.7. A theoretical plate number of 4.8 * 10(5)/m was obtained for aspartic acid. The system exhibited good repeatability, and the relative standard deviations (n=5) of the peak areas and migration times were no more than 3.4% and 0.7%, respectively. Furthermore, the system was successfully applied to elucidate these five amino acids in human saliva. PMID- 22099227 TI - Development of multiwalled carbon nanotubes based micro-solid-phase extraction for the determination of trace levels of sixteen polycyclic aromatic hydrocarbons in environmental water samples. AB - Micro-solid-phase extraction (MU-SPE) was developed for the determination of trace level of 16 United States Environmental Protection Agency priority polycyclic aromatic hydrocarbons (PAHs) in river water samples with gas chromatography-mass spectrometry (GC-MS). In the MU-SPE device, multiwalled carbon nanotubes was employed as sorbent and was packed inside an porous polypropylene membrane "envelope" whose edges were heat-sealed to secure the contents. The MU-SPE device was placed in a stirred sample solution to extract the analytes. The porous polypropylene membrane envelope in MU-SPE device acts as a filter to exclude potential interferences, such as eliminating or reducing the influence of particles that are bigger than the pore size. After extraction, analyte desorption was carried out with a suitable organic solvent under ultrasonication. Important extraction parameters were optimized in detail, including the selection and amount of sorbent materials, the extraction temperature and extraction time, desorption solvent and desorption time, amount of organic modifier, agitation speed and sample ionic strength. Under the developed extraction conditions, the proposed method provided good linearity in the range of 0.1-50 MUg/L, low limits of detection (4.2-46.5 ng/L), and good repeatability of the extractions (relative standard deviations, <12%, n=5). The developed MU-SPE method was successfully applied to the extraction of PAHs in river water samples. The MU-SPE method was demonstrated to be a fast and efficient method for the determination of PAHs from environmental water samples. PMID- 22099228 TI - Retention mechanism for polycyclic aromatic hydrocarbons in reversed-phase liquid chromatography with monomeric stationary phases. AB - Reversed-phase liquid chromatography (RPLC) is the foremost technique for the separation of analytes that have very similar chemical functionalities, but differ only in their molecular shape. This ability is crucial in the analysis of various mixtures with environmental and biological importance including polycyclic aromatic hydrocarbons (PAHs) and steroids. A large amount of effort has been devoted to studying this phenomenon experimentally, but a detailed molecular-level description remains lacking. To provide some insight on the mechanism of shape selectivity in RPLC, particle-based simulations were carried out for stationary phases and chromatographic parameters that closely mimic those in an experimental study by Sentell and Dorsey [J. Chromatogr. 461 (1989) 193]. The retention of aromatic hydrocarbons ranging in size from benzene to the isomeric PAHs of the formula C(18)H(12) was examined for model RPLC systems consisting of monomeric dimethyl octadecylsilane (ODS) stationary phases with surface coverages ranging from 1.6 to 4.2 MUmol/m(2) (i.e., stationary phases yielding low to intermediate shape selectivity) in contact with a 67/33 mol% acetonitrile/water mobile phase. The simulations show that the stationary phase acts as a very heterogeneous environment where analytes with different shapes prefer different spatial regions with specific local bonding environments of the ODS chains. However, these favorable retentive regions cannot be described as pre existing cavities because the chain conformation in these local stationary phase regions adapts to accommodate the analytes. PMID- 22099229 TI - Preparation and chromatographic evaluation of a cysteine-bonded zwitterionic hydrophilic interaction liquid chromatography stationary phase. AB - A cysteine-bonded zwitterionic hydrophilic interaction chromatography (HILIC) stationary phase (Click TE-Cys) was prepared based on the "thiol-ene" click chemistry. The Click TE-Cys material was characterized by solid state 13C cross polarization/magic-angle spinning (CP/MAS) NMR and elemental analysis. The dynamic evaluation for cytosine, cytidine and orotic acid was performed using Van Deemter plots. The plate height values were no more than 24 MUm for the flow rate between 0.5 and 5.4 mm s-1 (0.3-3.5 mL min-1), which proved the excellent separation efficiency of Click TE-Cys stationary phase. The influences of the content of water, concentration of salt and pH of the buffer solution on the retention of model compounds were investigated. The results demonstrated that the separation of polar analytes was dominated by the partitioning mechanism, while the contribution of electrostatic interaction was minor. The thermodynamic characteristic of Click TE-Cys stationary phase was also studied according to van't Hoff plot. An exothermic process for transferring analytes from the mobile phase to the stationary phase was observed and a linear relationship for ln k and 1/T was achieved, indicating no change of retention mechanism within the measured temperature range. Besides, the zwitterionic stationary phase exhibited good stability. Considering the high hydrophilicity of Click TE-Cys stationary phase, the application in the separation of protein tryptic digests was carried out using hydrophilic interaction chromatography-electrospray ionization mass spectrometry (HILIC-ESI-MS). More peaks were adequately resolved on the Click TE Cys column comparing with that on the TSK Amide-80 column. In addition, the orthogonality between HILIC and RPLC system was investigated utilizing geometric approach. The XTerra MS C18 and Click TE-Cys column displayed great difference in separation selectivity, with the orthogonality reaching 88.0%. On the other hand, the orthogonality between Click TE-Cys and TSK Amide-80 system was 21.4%, i.e. the selectivity was similar but slightly different from each other. The successful separation of protein digests indicated the great potential of Click TE-Cys stationary phase in the separation of complex samples and applicability in two-dimensional liquid chromatography (2D-LC). PMID- 22099230 TI - Healthy People 2010 objectives for unintentional injury and violence among adolescents. Trends from the National Youth Risk Behavior Survey, 1999-2009. AB - BACKGROUND: In 2000, the USDHHS released Healthy People 2010 (HP2010), a series of disease prevention and health promotion objectives for the nation. Thirty-nine of these objectives were dedicated to injury prevention and six of these objectives related to adolescents, who were tracked through CDC's National Youth Risk Behavior Survey (YRBS). PURPOSE: This paper uses national YRBS data from 1999 to 2009 to analyze overall and subgroup trends and determine progress toward targets for the following HP2010 objectives: seatbelt use (HP2010 objective 15 19); motorcycle helmet use (15-21); riding with a driver who had been drinking alcohol (26-6); physical fighting (15-38); weapon carrying on school property (15 39); and suicide attempts requiring medical attention (18-2). METHODS: The CDC conducted the national YRBS biennially from 1999 to 2009 and used similar three stage cluster-sample designs to obtain representative samples of high school students in the U.S. This study was conducted in 2010 and used linear and quadratic time variables simultaneously in logistic regression models while controlling for gender, race/ethnicity, and grade to test for secular trends over time. RESULTS: Only two objectives met their HP2010 targets: riding with a driver who had been drinking alcohol (26-6) and physical fighting (15-38). Progress was seen for four additional objectives and within some subgroups. CONCLUSIONS: Substantial policy and practice changes must occur if the recently released Healthy People 2020 targets are to be met. School-, community-, and state-level policies and programs may be effective tools to prevent injuries and victimizations. PMID- 22099231 TI - Home smoking bans among U.S. households with children and smokers. Opportunities for intervention. AB - BACKGROUND: Public health campaigns have reduced the exposure of U.S. children to secondhand smoke at home; however, these may not have been equally effective across subgroups. PURPOSE: To examine prevalence of home smoking bans among U.S. households with both children and smokers, over time and by demographic subgroups. METHODS: The Tobacco Use Supplement to the Current Population Survey (TUS-CPS) is a nationally representative household survey of tobacco use. The 1992/1993 and 2006/2007 TUS-CPS interviewed 22,746 households from a major racial/ethnic group with both children and adult smokers. Predictors of complete home smoking bans among demographic subgroups were identified using multivariate logistic regression. Analyses were conducted in 2010-2011. RESULTS: Complete home smoking bans among U.S. households with children and smokers (smoking families) more than tripled, from 14.1% in 1992/1993 to 50.0% in 2006/2007. However, non Hispanic white and African-American smoking families lagged behind Asian/Pacific Islanders and Hispanics. In 2006/2007, 67.2% of African-American smoking families allowed smoking in the home, as did 59.2% of smoking families with all children aged >=14 years. Bans were more likely among more-educated households and in states with lower adult smoking prevalence; however, these differences were attenuated in some racial/ethnic groups. CONCLUSIONS: As of 2006/2007, only half of U.S. households with both children and smokers had complete home smoking bans. Home bans were less common among smoking families with older children, in African American households, and in Hispanic or non-Hispanic white households in states with high smoking prevalence. Interventions are needed to promote smoke-free homes among these groups. PMID- 22099232 TI - Association between smokefree laws and voluntary smokefree-home rules. AB - BACKGROUND: More states and localities are passing restrictions on smoking in public places and workplaces. PURPOSE: To determine what, if any, association exists between enactment of strong laws making public places or workplaces smokefree on adoption of voluntary smokefree-home policies, particularly whether such laws are associated with increased smoking at home. METHODS: Logistic regressions were used to estimate the OR of a person living with a 100% smokefree home rule as a function of individual characteristics, household composition, and whether or not the residential region is covered by clean indoor air laws. The data came from successive waves of the Tobacco Use Supplement to Current Population Survey (TUS-CPS) for the years 1992-2007, and the American Nonsmokers' Rights Foundation database of state and local government clean indoor air laws. Analysis was conducted in 2010 and 2011. RESULTS: Living in a county fully covered by a 100% clean indoor air law in workplaces or restaurants or bars is associated with an increased likelihood of having a voluntary 100% smokefree-home rule both for people living with smokers (OR=7.76, 95% CI=5.27, 11.43) and not living with smokers (OR=4.12, 95% CI=3.28, 5.16). CONCLUSIONS: Strong clean indoor air laws are associated with large increases in voluntary smokefree-home policies both in the homes with and without smokers. These results support the hypothesis of norm spreading of clean indoor air laws. PMID- 22099233 TI - Serosurvey of bacterial and viral respiratory pathogens among deployed U.S. service members. AB - BACKGROUND: Respiratory illnesses can cause substantial morbidity during military deployments. Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, adenovirus, parainfluenza, and respiratory syncytial virus (RSV) are hypothesized causes. PURPOSE: To determine pathogen-specific seroprevalence prior to and after deployment in support of Operation Enduring Freedom (OEF). METHODS: A retrospective cohort study of 1000 service members deployed between June 30, 2004, and June 30, 2007, was conducted from 2008 through 2009. Pre- and post deployment sera were tested for the presence of antibody to each pathogen. RESULTS: Pre-deployment IgG seropositivity was high for adenovirus, RSV, and parainfluenza (98.7%, 97.8%, and 81.6%, respectively), whereas seropositivity for B. pertussis, M. pneumoniae, and C. pneumoniae was 14.2%, 21.9%, and 65.1%, respectively. As defined by seroconversion in 1000 subjects, the following were identified: 43 new parainfluenza infections (24% of susceptibles); 37 new pertussis infections (4% of susceptibles); 33 new C. pneumoniae infections (10% of susceptibles); and 29 new M. pneumoniae infections (4% of susceptibles). B. pertussis seroconversion was two to four times higher than reports for the general U.S. population. Overall, 14.2% of the service members seroconverted to at least one of these six pathogens; this increased to 30.1% seroconversion when influenza was included. However, serologic testing was not clearly associated with clinical illness in this report. CONCLUSIONS: Serologic evidence for respiratory infections was common among the 2004-2007 OEF-deployed military, sometimes at a higher rate than the general U.S. population. Awareness of this risk and implementation of preventive measures should be emphasized by leadership prior to and during deployment. PMID- 22099234 TI - Timing of adolescent meningococcal conjugate vaccination attitudes and practices of pediatricians and family medicine physicians. AB - BACKGROUND: The meningococcal conjugate vaccine (MCV4) was recommended for those aged 11-18 years in 2005. Initial supply issues led to an emphasis on immunizing older adolescents. When supply improved in 2007, routine immunization was recommended for those aged 11-12 years. PURPOSE: Among a U.S. sample of pediatricians and family medicine physicians, describe (1) recommendation and administration practices for MCV4; (2) preferences regarding MCV4 administration; and (3) attitudes and characteristics associated with recommendation for those aged >12 years. METHODS: A mail and Internet survey in a nationally representative sample of physicians was conducted between December 2009 and March 2010. Analysis was conducted between March 2010 and October 2010, including a multivariable analysis to examine factors associated with deferring MCV4 to ages >12 years. RESULTS: Response rates were 88% (pediatricians 367/419) and 63% (family medicine physicians 268/423). In all, 95% of pediatricians and 73% of family medicine physicians reported administering MCV4 routinely to those aged 11 18 years (p<0.0001); 83% (pediatricians) and 45% (family medicine physicians) reported strongly recommending MCV4 for those aged 11-12 years (p<0.0001); 27% (pediatricians) and 40% (family medicine physicians) preferred to administer MCV4 to those aged >12 years (p<0.0001). Compared with those who strongly recommend for those aged 11-12 years, physicians who do not regularly stock MCV4, family medicine physicians, and physicians concerned about waning immunity were more likely to defer their recommendation, whereas physicians practicing in the Northeast and those with more Latino patients were less likely to defer. CONCLUSIONS: Most pediatricians and family medicine physicians administer MCV4, but many, especially family medicine physicians and those concerned about waning immunity, defer their recommendation for MCV4 to patients aged >12 years. PMID- 22099235 TI - Blood pressure and cholesterol screening prevalence among U.S. women of reproductive age opportunities to improve screening. AB - BACKGROUND: Blood pressure and cholesterol screening among women of reproductive age are important for early disease detection and intervention, and because hypertension and dyslipidemia are associated with adverse pregnancy outcomes. PURPOSE: The objective of this study was to examine associations of sociodemographic characteristics, cardiovascular disease risk factors, and healthcare access indicators with blood pressure and cholesterol screening among women of reproductive age. METHODS: In 2011, prevalence estimates for self reported blood pressure screening within 2 years and cholesterol screening within 5 years and AORs for screenings were calculated for 4837 women aged 20-44 years, using weighted 2008 National Health Interview Survey data. RESULTS: Overall, recommended blood pressure and cholesterol screening was received by 89.6% and 63.3% women, respectively. Those who were underinsured or uninsured had the lowest screening percentage at 76.6% for blood pressure (95% CI=73.4, 79.6) and 47.6% for cholesterol (95% CI=43.8, 51.5) screening. Suboptimal cholesterol screening prevalence was also found for women who smoke (54.5%, 95% CI=50.8, 58.2); obese women (69.8%, 95% CI=66.3, 73.0); and those with cardiovascular disease (70.3%, 95% CI=63.7, 76.1), prediabetes (73.3%, 95% CI= 64.1, 80.8), or hypertension (81.4%, 95% CI=76.6, 85.4). CONCLUSIONS: Most women received blood pressure screening, but many did not receive cholesterol screening. Universal healthcare access may improve screening prevalence. PMID- 22099236 TI - Sufficient sleep, physical activity, and sedentary behaviors. AB - BACKGROUND: Insufficient sleep among adolescents is common and has adverse health and behavior consequences. Understanding associations of physical activity and sedentary behaviors with sleep duration could shed light on ways to promote sufficient sleep. PURPOSE: The purpose of this study is to determine whether physical activity and sedentary behaviors are associated with sufficient sleep (8 or more hours of sleep on an average school night) among U.S. high school students. METHODS: Data were from the 2009 national Youth Risk Behavior Survey and are representative of 9th-12th-grade students nationally (n=14,782). Associations of physical activity and sedentary behaviors with sufficient sleep were determined using logistic regression models controlling for confounders. Data were analyzed in October 2010. RESULTS: Students who engaged in >=60 minutes of physical activity daily during the 7 days before the survey had higher odds of sufficient sleep than those who did not engage in >=60 minutes on any day. There was no association between the number of days students were vigorously active >=20 minutes and sufficient sleep. Compared to their respective referent groups of 0 hours on an average school day, students who watched TV >=4 hours/day had higher odds of sufficient sleep and students who played video or computer games or used a computer for something that was not school work >=2 hours/day had lower odds of sufficient sleep. CONCLUSIONS: Daily physical activity for >=60 minutes and limited computer use are associated with sufficient sleep among adolescents. PMID- 22099237 TI - Health information systems in small practices. Improving the delivery of clinical preventive services. AB - BACKGROUND: Despite strong evidence that clinical preventive services (CPS) reduce morbidity and mortality, CPS performance has not improved in adult primary care. In addition to implementing electronic health records (EHRs), key factors for improving CPS include providing actionable information at the point of care, technical support staff, and quality-improvement assistance. These resources are not typically available in small practices. PURPOSE: Estimate the impact on CPS delivery after a software upgrade to embed a clinical decision support system and practice-level quality-improvement support services. METHODS: Practices were recruited from the Primary Care Information Project, a citywide initiative assisting practices adopt health information technology. Data were collected in 2009 and 2010, and analyses were conducted in 2010 and 2011. Across two time periods, receipt of CPS was calculated for 56 practices. Period 1 measured CPS delivery 2-37 months following implementation of an EHR. Period 2 measured CPS delivery within the first 6 months after an EHR software upgrade. RESULTS: Substantial increases in the delivery of selected CPS were observed after the EHR software upgrades. Blood pressure control for patients with hypertension increased from 46.0% to 54.8%. Breast cancer screening, recorded BMI, and HbA1c testing for patients with diabetes also increased. More than half of the practices increased their patients' blood pressure control, recorded BMI, breast cancer screening, and HbA1c screening by >=5 percentage points. CONCLUSIONS: Delivery of CPS can increase in small primary care practices that implement an EHR that includes comprehensive quality-improvement support. PMID- 22099238 TI - Efficacy of a weight-loss website based on positive deviance. A randomized trial. AB - BACKGROUND: Web-based interventions for weight control could promote more widespread dissemination of weight-loss opportunities; however, they remain limited in effectiveness. Incorporating weight-control practices used by individuals with long-term weight-loss success ("positive deviants") may improve the efficacy of web-based weight control interventions. PURPOSE: To evaluate the efficacy of AchieveTogether, a web-based weight-loss intervention for adults based on user-generated weight-loss strategies from successful weight losers. DESIGN: In 2009-2010, participants were randomized to either a 12-week web-based intervention, AchieveTogether, or a wait-list control condition. SETTING/PARTICIPANTS: 100 overweight or obese adults participated in the study. INTERVENTION: AchieveTogether was designed to help individuals implement weight control practices used by others who successfully lost and maintained weight. MAIN OUTCOME MEASURES: The primary outcome was change in weight. Secondary outcomes included blood pressure, daily caloric intake, quality of life, and use of weight control practices. ANCOVA, with adjustment for baseline values on outcome measures, was used to assess differences between groups in primary and secondary outcomes. Statistical analyses were conducted in 2010-2011. RESULTS: Most participants were women (69.7%) and white (90.8%), with a mean age of 50.3 years and baseline BMI of 33.2; 88% completed post-program assessments. Mean weight loss among intervention participants was -1.4 kg (95% CI= -2.2, -0.5), compared with a mean weight gain of 0.6 kg (95% CI= -0.3, 1.4) in control participants (p<0.01). CONCLUSIONS: User-generated weight-loss practices from "positive deviants" could promote weight control in web-based interventions; however, further research is needed to improve program efficacy. TRIAL REGISTRATION: This study is registered at ClinicalTrials.govNCT00709501. PMID- 22099240 TI - Influenza A (H1N1) 2009 monovalent vaccination among adults with asthma, U.S., 2010. AB - BACKGROUND: The 2009 pandemic influenza A (H1N1) virus (2009 H1N1) was first identified in April 2009 and quickly spread around the world. The first doses of influenza A (H1N1) 2009 monovalent vaccine (2009 H1N1 vaccine) became available in the U.S. in early October 2009. Because people with asthma are at increased risk of complications from influenza, people with asthma were included among the initial prioritized groups. PURPOSE: To evaluate 2009 H1N1 vaccination coverage and identify factors independently associated with vaccination among adults with asthma in the U.S. METHODS: Data from the 2009-2010 BRFSS (Behavioral Risk Factor Surveillance System) influenza supplemental survey were used; responses from March through June 2010 were analyzed to estimate vaccination levels of 2009 H1N1 vaccine among respondents aged 25-64 years with asthma. Multivariable logistic regression and predictive marginal models were performed to identify factors independently associated with vaccination. RESULTS: Among adults aged 25-64 years with asthma, 25.5% (95% CI=23.9%, 27.2%) received the 2009 H1N1 vaccination. Vaccination coverage ranged from 9.9% (95% CI=6.4%, 15.1%) in Mississippi to 46.1% (95% CI=33.3%, 61.2%) in Maine. Characteristics independently associated with an increased likelihood of vaccination among adults with asthma were as follows: had a primary doctor, had other high-risk conditions, and received seasonal influenza vaccination in the 2009-2010 season. CONCLUSIONS: Vaccination coverage among adults aged 25-64 years with asthma was only 25.5% and varied widely by state and demographic characteristics. National and state-specific 2009 H1N1 vaccination coverage data for adults with asthma are useful for evaluating the vaccination campaign and for planning and implementing strategies for increasing vaccination coverage in possible future pandemics. PMID- 22099239 TI - A cluster randomized trial of sun protection at elementary schools. Results from year 2. AB - BACKGROUND: Elementary schools are one potential venue for sun protection interventions that reduce childhood sun exposure. PURPOSE: To assess Year-2 results from a cluster randomized trial promoting hat use at schools. DESIGN: Block randomization was used to assign intervention/control status to participating schools. Data were collected from 2006 to 2008 and analyzed in 2007 2010. SETTING/PARTICIPANTS: Of the 24 schools in the School District of Hillsborough County, Florida enrolled, 4th-graders were targeted in the first year and followed through their 5th-grade year. INTERVENTION: Classroom sessions were conducted to improve sun protection knowledge, foster more positive attitudes about hat use, and change the subjective norm of wearing hats when at school. MAIN OUTCOME MEASURES: Year-2 outcomes assessed included hat use at school (measured by direct observation), hat use outside of school (measured by self-report) and skin pigmentation and nevi counts (measured for a subgroup of 439 students). RESULTS: The percentage of students observed wearing hats at control schools remained unchanged during the 2-year period (range 0%-2%) but increased significantly at intervention schools (2% at baseline, 41% at end of Year 1, 19% at end of Year 2; p<0.001 for intervention effect). Measures of skin pigmentation, nevi counts, and self-reported use of hats outside of school did not change during the study period. CONCLUSIONS: This intervention increased use of hats at school through Year 2 but had no measurable effect on skin pigmentation or nevi. Whether school-based interventions can ultimately prevent skin cancer is uncertain. PMID- 22099241 TI - Medical costs attributable to child maltreatment a systematic review of short- and long-term effects. AB - CONTEXT: Child maltreatment is a serious and prevalent public health problem, which has been shown to be associated with numerous short- and long-term effects on mental and physical health. Few estimates of the medical costs of these effects have been published to date. To determine the range and quality of currently available estimates and identify the gaps and needs for future research, this article reviews research on medical costs of child maltreatment. EVIDENCE ACQUISITION: Peer-reviewed literature on child maltreatment and medical costs was identified by searching major databases. Twelve articles on the medical costs of child maltreatment were identified. EVIDENCE SYNTHESIS: Eight studies describe short-term costs among children; four describe adult, long-term costs. Most studies used convenience samples, captured a partial share of the total costs, and did not follow best practices for econometric analysis of medical costs. CONCLUSIONS: Child maltreatment is associated with substantial medical costs in childhood and adulthood, but estimates vary widely because of differences in research designs, types of cost data, and study quality. Econometric estimates of the annual medical costs in adulthood range from zero to about $800. Per-episode estimates of child costs, based on mean comparisons, range from $0 to >$24,000. PMID- 22099242 TI - Public health surveillance and knowing about health in the context of growing sources of health data. AB - The past decade has brought substantial changes in how data related to a community's health are collected, stored, and used to inform decisions about health interventions. Despite these changes, the purpose of public health surveillance has remained constant for more than a century. Public health surveillance is the ongoing, systematic collection, analysis, and interpretation of health-related data with the a priori purpose of preventing or controlling disease or injury, or of identifying unusual events of public health importance, followed by the dissemination and use of information for public health action. Surveillance is an important and necessary contributor to knowledge of a community's health. The public health system is responsible for ensuring that public health surveillance is conducted with appropriate practices and safeguards in order to maintain the public's trust. PMID- 22099243 TI - The in-service examination score as a predictor of success on the American Board of Preventive Medicine certification examination. AB - BACKGROUND: To date, there has been no study correlating the American College of Preventive Medicine (ACPM) in-service exam (ISE) with the American Board of Preventive Medicine (ABPM) certification exam. PURPOSE: To validate the ACPM ISE as a predictor of success on the ABPM certification exam. METHODS: ISE and ABPM certification exam scores were standardized by year using z-scores. The correlation between practicum year ISE scores and certification exam scores for military preventive medicine residencies in the National Capital and Washington State areas (core component only) was analyzed. A multivariable linear regression model included adjustments for age, gender, Master of Public Health grade point average (GPA), prior specialty board certification, and board deferral >=1 year after graduation. Data were collected in 2010 and analyzed in 2011. RESULTS: Performance on the ISE was correlated with performance on the ABPM certification core exam (r=0.61, p<0.001). Performance on the ISE was still significant after adjusting for relevant demographic and educational variables (p<0.001). Other significant covariates included GPA (p=0.001) and board deferral (p=0.04) in the linear regression model. CONCLUSIONS: Performance on the ISE is moderately correlated with performance on the board certification core exam, and this correlation remained significant after adjustment in the linear regression model. These results serve to validate the ISE as a means for program directors to identify residents at academic risk and as encouragement for residents to take the certification exam as soon as possible after graduation. PMID- 22099244 TI - Attack on protections against air pollution. PMID- 22099245 TI - Public health surveillance in the context of growing sources of health data: a commentary. PMID- 22099246 TI - Smokefree community policies promote home smoking bans. Unknown mechanisms and opportunities for preventive medicine. PMID- 22099248 TI - Patient-centeredness in long-term care of older patients - a structured interview. AB - AIM: The aim of this study was to describe assessments of older people about patient-centeredness in the long-term care of Estonian hospitals, and to determine correlations between patients' assessments and their socio-demographic characters. BACKGROUND: Patient-centeredness increases patients' satisfaction and enhances their recovery. Still, patients' opinions are not always taken into account. METHOD: A cross-sectional study included 111 older people in long-term care of 14 Estonian hospitals. Data were collected in 2008 by means of structured interviews. RESULTS: What patients agreed most was that they were given enough opportunity to carry out activities they were capable of performing themselves. Two thirds of participants had not been sufficiently consulted on who would be providing their care. Half of the participants were not given sufficient opportunity to decide what kind of care was needed and how they would receive it. The more assistance patients needed in daily living activities, the less they considered the care as patient-centred. CONCLUSIONS: From the perspective of older people, the patient-centeredness in Estonian long-term care is above average. Providing patient-centred long-term care in Estonian hospitals deserves more attention. RELEVANCE TO CLINICAL PRACTICE: Older people should be more involved in decision-making, especially those who need more assistance in daily living activities. PMID- 22099250 TI - Structural studies of the lipopolysaccharide of Moritella viscosa strain M2-226. AB - The structure of the O-specific side chain of the lipopolysaccharide from the Gram-negative psychrophilic bacterium Moritella viscosa strain M2-226, responsible for the winter ulcer in Atlantic salmon, has been determined. Monosaccharide analysis and (1)H and (13)C NMR spectroscopy were employed to elucidate the structure. It was concluded that the polysaccharide is composed of a trisaccharide repeating unit with the following structure: ->3)-beta-D-GlcpNAc (1->4)-[alpha-D-GlcpA-(1->3)]-alpha-L-Fucp-(1-> . PMID- 22099251 TI - A method for determining reactive hydroxyl groups in natural fibers: application to ramie fiber and its modification. AB - The hydrophilic features of natural fibers (NFs) hinder the widespread application of natural fiber/polymer composites due to the hydroxyl groups (-OH) presented in the cellulose molecule. Detecting reactive hydroxyl groups in NFs is very important for optimizing the modification process of natural fibers. This paper proposes a simple and practical methodology to measure reactive hydroxyl groups in NFs using a isocyanate group, a method we term the isocyanate group back titration (IBT) method. Application of the IBT method to ramie fiber with toluene-2,4-diisocyanate (TDI) and hexadecanol indicated that the measured value of reactive hydroxyl groups was about 150 mg KOH/g, which was less than the theoretical value of hydroxyl groups in the ramie fiber being tested. The FTIR analysis revealed that the TDI and hexadecanol were grafted onto the surface of the ramie fiber, leading the modified ramie fiber to be hydrophobic. Thus, the IBT method is also useful for modifying the surface properties of NFs and improving their compatibility with polymers, and finally leading to good mechanical properties of NF/polymer composites. PMID- 22099252 TI - Air-coupled MUMPs capacitive micromachined ultrasonic transducers with resonant cavities. AB - This work reports performance improvements of air-coupled capacitive micromachined ultrasonic transducers (CMUTs) using resonant cavities. In order to perform this work, we have designed and manufactured a CMUT employing multi-user microelectromechanical systems (MEMS) processes (MUMPs). The transducer was designed using Helmholtz resonator principles. This was characterised by the dimensions of the cavity and several acoustic ports, which had the form of holes in the CMUT plate. The MUMPs process has the advantage of being low cost which allows the manufacture of economic prototypes. In this paper we show the effects of the resonant cavities and acoustic ports in CMUTs using laser Doppler vibrometry and acoustical measurements. We also use Finite Element (FE) simulations in order to support experimental measurements. The results show that it is possible to enhance the output pressure and bandwidth in air by tuning the resonance frequency of the plate (f(p)) with that of the Helmholtz resonator (f(H)). The experimental measurements show the plate resonance along with an additional resonance in the output pressure spectrum. This appears due to the effect of the new resonant cavities in the transducer. FE simulations show an increase of 11 dB in the output pressure with respect to that of a theoretical vacuum-sealed cavity MUMPs CMUT by properly tuning the transducer. The bandwidth has been also analyzed by calculating the mechanical Q factor of the tuned CMUT. This has been estimated as 4.5 compared with 7.75 for the vacuum-sealed cavity MUMPs CMUT. PMID- 22099253 TI - Interaction between parallel polymer fibers insonificated by ultrasound of low/mild intensity: an analytical theory and experiments. AB - The purpose of this article is to develop a simple mathematical model to address some bioeffects which may be caused by a static attractive force between two long neighboring parallel thin fibers (for example, a pair of collagen bundles of connective tissue) when they are insonificated by a continuous (CW) traveling plane ultrasound (US) under the condition that the fiber length (L)?the distance between them (h) and h?the wavelength of US (lambda). The theory predicts that there is an attractive force between these fibers when they are exposed to the CW US with an intensity of a magnitude of 100mW/cm(2). The relationship between the relative approaching velocity of the fibers and the acoustic pressure amplitude can be calculated using the theory. An experiment was performed to verify the theoretical predictions. A plastic test chamber (diameter * height=6mm * 3.5mm) with a cap made of a sound-absorbing material and filled full with distilled water was placed on a microscope stage. A polymer fiber pair of 100MUm diameter (d) and 4mm length (L) were immersed in water and aligned parallel in a plane which is normal to the US propagation direction. They floated at the central area of the chamber and h <=10d. A 25mm diameter, 1MHz quartz crystal was used as an ultrasound source as well as the bottom of the test chamber. The quartz crystal was gold-coated on both sides, but a 5mm diameter center was left transparent (electrode free) to enable optical observation via a microscope. The maximum acoustic intensity, I(max), of the CW wave generated by the source was set at 300mW/cm(2); the corresponding acoustic pressure amplitude was 100kPa. The magnitude of the average approaching velocity of the fiber pair due to the attractive force was found in agreement with that predicted by the theory. PMID- 22099254 TI - Modeling powder encapsulation in dosator-based machines: II. Experimental evaluation. AB - A theoretical model was previously derived to predict powder encapsulation in dosator-based machines. The theoretical basis of the model was discussed earlier. In this part; the model was evaluated experimentally using two powder formulations with substantially different flow behavior. Encapsulation experiments were performed using a Zanasi encapsulation machine under two sets of experimental conditions. Model predicted outcomes such as encapsulation fill weight and plug height were compared to those experimentally obtained. Results showed a high correlation between predicted and actual outcomes demonstrating the model's success in predicting the encapsulation of both formulations. The model is a potentially useful in silico analysis tool that can be used for capsule dosage form development in accordance to quality by design (QbD) principles. PMID- 22099255 TI - Tunneled-cuffed catheter implanted into the accessory hemiazygos vein because of occlusion of the left innominate vein. AB - Hemodialyzed patients are at risk of multiple catheterizations. Nephrologists performing such procedures need to be familiar with congenital and acquired vascular abnormalities. We describe a successful insertion and use of a cuffed tunneled catheter in a patient with unusual anatomy of the central venous system. Computed tomography angiography revealed thrombosis of the right subclavian vein and bilateral occlusion of innominate veins. The left internal jugular and subclavian veins joined to form a large vessel that drained through the accessory hemiazygos and azygos veins into the superior vena cava. The catheter was implanted through the left internal jugular vein into the accessory hemiazygos vein. The presented case demonstrates that the catheter can be implanted into distended collateral, especially when no other location is possible. PMID- 22099256 TI - Synthesis of 5-aryl-1,4-benzodiazepine derivatives attached in resorcinaren-PAMAM dendrimers and their anti-cancer activity. AB - A series of resorcinaren-PAMAM dendrimers with benzodiazepines in the periphery were synthesized and their anticancer properties studied. The synthesized dendrimers showed potential anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4 benzodiazepine. The dendrimers were characterized by IR, (1)H and (13)C NMR, UV vis absorption, electrospray (ES) and/or MALDI-TOF mass spectrometries. PMID- 22099257 TI - Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. AB - Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The existing vaccination program is variably effective from year to year, and drug resistance to available antivirals is a growing problem, making the development of additional antivirals an important challenge. Influenza virus non-structural protein 1 (NS1) is the centerpiece of the viral response to the host interferon (IFN) system. NS1 was demonstrated previously to be a potential therapeutic target for antiviral therapy by the identification of specific small molecule inhibitors. One inhibitory compound, NSC125044, was subjected to chemical evaluation. Initial synthetic work comprised simplifying the core structure by removing unwanted functionality and determination of key features important for activity. Several subclasses of molecules were designed and synthesized to further probe activity and develop the basis for a structure activity relationship. Apparent potency, as judged by activity in virus replication assays, increased dramatically for some analogs, without cytotoxicity. Results suggest that the target binding site tolerates hydrophobic bulk as well as having a preference for weakly basic substituents. PMID- 22099258 TI - Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): an atypical phenotype and review of the literature. AB - Spinal muscular atrophy with respiratory distress (SMARD 1) is a very rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, symmetrical distal muscular weakness, muscle atrophy, peripheral sensory neuropathy and autonomic nerve dysfunction. SMARD 1 is inherited as an autosomal recessive trait and the mutations have been identified in the gene encoding immunoglobulin MU-binding protein 2 (IGHMBP2), located on chromosome 11q13. It is considered a fatal form of infantile motoneuron disease and most of the patients dies within the first 13 months of life. We present a female child with genetically confirmed SMARD 1 displaying a mild phenotype and no severe signs of respiratory involvement, typically found in this form, up to 38 months despite a diaphragmatic palsy diagnosed at 6 months of age. Therefore, our clinical observation suggests that respiratory failure is not secondary, in any case, to the diaphragmatic palsy but other pathogenetic mechanisms might be involved. PMID- 22099259 TI - Neurophysiology of the brainstem-structure and function of brainstem circuits. PMID- 22099260 TI - Choosing to improve or to impair. PMID- 22099261 TI - Cognitive load impacts error evaluation within medial-frontal cortex. AB - In the present experiment we investigated the impact of cognitive load on feedback evaluation by a learning system within medial-frontal cortex. Participants completed a task in which they had to use feedback to learn to accurately estimate the duration of one second. In two experimental conditions, we manipulated the cognitive load of the feedback stimuli (low load versus high load). Our results revealed that the amplitude of the feedback error-related negatvity (fERN), a component of the event-related brain potential (ERP) thought to index a learning system within medial-frontal, was reduced in the high load condition. Further, an analysis of the behavioural data revealed that in the high load condition participants made less effective adjustments to their estimates following error feedback. Taken together, our data suggest that the functional efficacy of the medial-frontal learning system is reduced as the cognitive load of feeback signals increase. Moreover, our data indicate that the effect of increased cognitive load is to increase the trial-to-trial temporal variability of feedback stimulus evaluation. PMID- 22099262 TI - Mild hypothermia enhanced the protective effect of protein therapy with transductive anti-death FNK protein using a rat focal transient cerebral ischemia model. AB - We previously reported that the protein transduction domain fused FNK (PTD-FNK) protein, which was derived from anti-apoptotic Bcl-xL protein and thereby gained higher anti-cell death activity, has a strong neuroprotective effect on rat focal brain ischemia models. The aim of this study was to investigate the effect of PTD FNK protein and hypothermia combined therapy on cerebral infarction. Male SD rats were subjected to 120min middle cerebral artery occlusion (MCAO) with intraluminal thread. Rats were divided into 4 groups: 1) 37 degrees C vehicle administration (37V); 2) 37 degrees C PTD-FNK administration (37F); 3) 35 degrees C vehicle administration (35V); and 4) 35 degrees C PTD-FNK administration (35F). PTD-FNK protein was intravenously administered 60min after the induction of MCAO. Hypothermia (35 degrees C) was applied during 120min MCAO. Rats were sacrificed 24h later; infarct volumes were measured, and Bax, Bcl-2, TUNEL and caspase-12 immunostaining was evaluated. There was significant infarct volume reduction in 37F, 35V, and 35F groups compared to 37V. There was also a significant difference between 37F and 35F. This suggests that hypothermia enhanced the effect of PTD FNK. Similar results were found in neurological symptoms. Caspase-12 and TUNEL staining showed a significant difference between 37F and 35F; however, Bax and Bcl-2 staining failed to show a difference. In this study we showed an additive protective effect of hypothermia on PTD-FNK treatment, and immunohistological results showed that the protective mechanisms might involve the inhibition of apoptotic pathways through caspase-12, but not through Bcl-2. PMID- 22099264 TI - The benefits of using anchorage miniplates: are they compatible with everyday orthodontic practice? AB - Nowadays, it is difficult to ignore the major role played by orthodontic anchorage. Given our convictions and after several years of using these systems, we believe it is time to take stock. Is there any real benefit to using them? And if so, when? What systems should we use? Miniscrews or miniplates? What are the indications for each of these systems? Are they compatible with everyday orthodontic practice? In a nutshell, are these orthodontic anchorage devices myth or practical reality? PMID- 22099266 TI - Comparative study between trimetazidine and ice slush hypothermia in protection against renal ischemia/reperfusion injury in a porcine model. AB - PURPOSE: The aim of the study was to compare the effects of renal ice slush hypothermia and the use of trimetazidine in the protection against ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: Fifteen farm pigs were submitted to left kidney ischemia and right nephrectomy during the same procedure. Animals were divided into three groups. Group 1 was submitted to warm ischemia; Group 2 was submitted to cold ischemia with ice slush; and Group 3 received trimetazidine 20 mg one day and 4 hours before surgery. Ischemia time was 120 minutes in all three groups. Serum creatinine (SCr) and plasma iohexol clearance (CLioh) were measured before surgery and on postoperative days (PODs) 1,3,7, and 14. Semi-quantitative analyses of histological alterations were performed by a pathologist. A p value of < 0.05 was considered significant. RESULTS: All groups showed elevation of serum creatinine in the first week. Serum creatinine was higher in Group 3 in the first and third postoperative days (Mean Cr: 5.5 and 8.1 respectively). Group 2 showed a lower increase in creatinine and a lower decrease in iohexol clearance than the others. Renal function stabilized in the fourteenth POD in all three groups. Analyses of histological alterations did not reach statistical significance between groups. CONCLUSION: Trimetazidine did not show protection against renal I/R injury in comparison to warm ischemia or hypothermia in a porcine model submitted to 120 minutes of renal ischemia. PMID- 22099267 TI - Editor's comment. PMID- 22099268 TI - Sperm retrieval techniques for assisted reproduction. AB - Different surgical methods such as PESA, MESA, TESA, TESE and micro-TESE have been developed to retrieve spermatozoa from either the epididymis or the testis according to the type of azoospermia, i.e., obstructive or non-obstructive. Laboratory techniques are used to remove contaminants, cellular debris, and red blood cells following collection of the epididymal fluid or testicular tissue. Surgically-retrieved spermatozoa may be used for intracytoplasmic sperm injection (ICSI) and/or cryopreservation. In this article, we review the surgical procedures for retrieving spermatozoa from both the epididymis and the testicle and provide technical details of the commonly used methods. A critical analysis of the advantages and limitations of the current surgical methods to retrieve sperm from males with obstructive and non-obstructive azoospermia is presented along with an overview of the laboratory techniques routinely used to process surgically-retrieved sperm. Lastly, we summarize the results from the current literature of sperm retrieval, as well as the clinical outcome of ICSI in the clinical scenario of obstructive and nonobstructive azoospermia. PMID- 22099269 TI - Significant heterogeneity in terms of diagnosis and treatment of renal cell carcinoma at a private and public hospital in Brazil. AB - PURPOSE: A great number of small renal lesions have now been detected. Nowadays, partial nephrectomy has more frequently been adopted for surgical treatment of earlier stage disease. Previous studies have associated patient, institutional, and health care system factors with surgery type. The aim of this study was to compare the diagnosis and treatment of renal cell carcinoma (RCC) according to hospital type, public versus private, in our country. MATERIALS AND METHODS: We retrospectively evaluated 183 patients with RCC who underwent radical nephrectomy or nephron-sparing surgery between 2003 and 2007 in two hospitals, one private and one public. Patient demographic, clinical, surgery, and pathologic characteristics were analyzed. RESULTS: The radical nephrectomy rate was higher at the public hospital than at the private hospital (75% vs. 57%, p = 0.008). Overall, patients at the public hospital presented larger tumors than did the patients who were cared for privately. Furthermore, small renal masses were significantly more prevalent in private care (57.8% vs. 28.3%). Patients at the public hospital showed a higher incidence of capsular invasion (p = 0.008), perirenal fat invasion (p < 0.01), lymph node involvement (p < 0.001), and a lower incidence of initial tumors. pT1 tumors were reported in 41% of patients at the public hospital and in 72% at the private hospital (p < 0.001). CONCLUSION: Patients with RCC cared for at our public referral hospital showed a more advanced stage than RCC treated at the private institution. PMID- 22099270 TI - Age-related testosterone decline in a Brazilian cohort of healthy military men. AB - INTRODUCTION: Androgen decline in the aging man has become a topic of increasing clinical relevance worldwide, as the reduction in testosterone levels has been reported to be accompanied by loss of muscle mass, accumulation of central adiposity, impaired mobility and increase risk of bone fractures. Although well established in studies conducted in developed countries, progressive decline in serum testosterone levels with age has been poorly investigated in Brazil. AIM: To determine the pattern of blood testosterone concentrations decline with age in a cohort of Brazilian healthy military men. MATERIALS AND METHODS: We retrospectively reviewed data on serum testosterone measurements of healthy individuals that had undergone a routine check-up at the Military Biology Institute. Blood samples were obtained early in the morning, and total testosterone concentration was determined using a commercial chemoluminescent immunoassay. Mean values were analyzed in five age groups: <= 40, 41 to 50, 51 to 60, 61 to 70, and > 70 years. MAIN OUTCOME MEASURE: Mean total testosterone levels. RESULTS: 1,623 subjects were included in the analysis; mean age was 57 years (24 to 87), and mean testosterone level was 575.5 ng/dL (25.0 to 1308.0 ng/dL). The evaluation of age-related changes in total testosterone levels revealed a progressive reduction in serum levels of this hormone with increasing age. Testosterone levels below 300 ng/dL were reported in 321 participants, a prevalence of nearly 20% in the study population. CONCLUSION: In agreement with other findings, a reduction of total testosterone levels with age was reported for healthy Brazilian men. PMID- 22099271 TI - Prostatic carcinomas with neuroendocrine differentiation diagnosed in needle biopsies, a morphologic study of 7 cases among 465 sequential biopsies in a tertiary cancer center. AB - PURPOSE: Neuroendocrine carcinomas (NEC) of the prostate are rare, with only a few series hitherto reported. The objective of this study was to assess in a single institution the clinical and morphologic characteristics of neuroendocrine carcinomas diagnosed in needle core biopsies. MATERIALS AND METHODS: The current study analyses seven cases diagnosed in needle biopsies at a large tertiary regional cancer center from Northeastern Brazil. Two pathologists reviewed specimens retrospectively, and demographic and morphologic characteristics were compared to 458 acinar tumors diagnosed in the same period. RESULTS: There were five small cell carcinomas and two low-grade neuroendocrine carcinomas (carcinoid). NEC were associated with an acinar component in 5/7 cases and the Gleason score of the acinar component was always > 6. The number of cores involved in prostates with NEC was greater (65% compared to 24% of acinar tumors, p < 0.05). The mean PSA at diagnosis was 417.7 (range 5.7-1593, SD 218.3), compared to 100.5 (p = 0.1) of acinar tumors (range 0.3-8545, SD 22.7). Prostates harboring NEC were bigger (p < 0.001, mean volume 240 mL vs. 53 mL of acinar tumors). Treatment of NEC included palliative surgery, chemotherapy, and hormonal therapy. CONCLUSIONS: NEC of the prostate is rare and often associated with a high-grade acinar component. Prostates with NEC tend to be larger and involve a greater number of cores than acinar tumors. PSA at diagnosis does not seem to predict the presence of NE tumors in needle biopsy. PMID- 22099272 TI - Bladder exstrophy: reconstructed female patients achieving normal pregnancy and delivering normal babies. AB - PURPOSE: Bladder exstrophy (BE) is an anterior midline defect that causes a series of genitourinary and muscular malformations, which demands surgical intervention for correction. Women with BE are fertile and able to have children without this disease. The purpose of this study is to assess the sexual function and quality of life of women treated for BE. MATERIALS AND METHODS: All patients in our institution treated for BE from 1987 to 2007 were recruited to answer a questionnaire about their quality of life and pregnancies. RESULTS: Fourteen women were submitted to surgical treatment for BE and had 22 pregnancies during the studied period. From those, 17 pregnancies (77.2%) resulted in healthy babies, while four patients (18.1%) had a spontaneous abortion due to genital prolapse, and there was one case (4.7%) of death due to a pneumopathy one week after delivery. There was also one case (5.8%) of premature birth without greater repercussions. During pregnancy, three patients (21.4%) had urinary tract infections and one patient (7.14%) presented urinary retention. After delivery, three patients (21.4%) presented temporary urinary incontinence; one patient (7.14%) had a vesicocutaneous fistula and seven patients (50%) had genital prolapsed. All patients confirmed to have achieved urinary continence, a regular sexual life and normal pregnancies. All patients got married and pregnant older than the general population. CONCLUSIONS: BE is a severe condition that demands medical and family assistance. Nevertheless, it is possible for the bearers of this condition to have a satisfactory and productive lifestyle. PMID- 22099273 TI - Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. AB - OBJECTIVE: To evaluate the preventive effects of alkaline citrate on stone recurrence as well as stone growth post-ESWL or PCNL in patients with calcium containing stones. MATERIALS AND METHODS: A total of 76 patients with calcium calculi who were stone-free or had residual stones less than 4 mm following ESWL and PCNL were enrolled. All patients were independently randomized into two groups. The treated group (N = 39) was given 81 mEq per day of oral potassium sodium citrate (27 mEq three times a day), and the untreated group (N = 37) serving as controls. Blood, twenty-four hour urine analysis, and plain KUB were measured and compared at the baseline and after 12 months. RESULTS: At baseline, hypocitraturia was found in 20 of 39 patients (46.05%) of Group I and 15 of 37 patients (40.5%) of Group II. At 12 months, hypocitraturia was found in 3 of 39 (7.69%) and 14 of 37 (37.83%) of Group I and Group II, respectively (p = 0.007). At the 12 month follow-up, of the stone-free group, 92.3% of the treated group and 57.7% of the control group were still stone free. Of the residual stone group, 30.8% and 9.1% of treated and control group were stone-free, respectively. The increased stone size found in 7.7%) and 54.5%) of treated and control groups, respectively. CONCLUSION: Sodium-potassium citrate provides positive effects on stone-forming activities in calcium stone patients suffering from urolithiasis following treatment with ESWL and PCNL procedures at the 12-month follow-up. PMID- 22099274 TI - Inflammation and endothelial activation in benign prostatic hyperplasia and prostate cancer. AB - PURPOSE: Emerging insights underline a link among chronic inflammation and endothelial activation with benign prostatic hyperplasia (BPH) and prostate cancer (PCa). We aim to investigate whether specific plasma markers of inflammation and endothelial activation allow to discriminate BPH and PCa. MATERIALS AND METHODS: Fifteen patients affected by BPH, 15 by PCa and 15 controls, were enrolled. Interleukin-6 (IL-6), CD40 ligand (CD40L), endothelial selectin (E-selectin), platelet-selectin (P-selectin), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were measured. RESULTS: In systemic blood samples, IL-6 has been found increased in patients affected by BPH (4.25 +/- 0. pg/mL) and PCa (5.08 +/- 0.24) respect to controls (2.62 +/- 0.34; p < 0.05). CD40L was higher in BPH (4.25 +/- 0.65 ng/mL; p < 0.05) than in control (2.31 +/- 0.20) and PCa group (2.60 +/- 0.56). E-selectin, P-selectin and VCAM-1 did not show any significant difference. Higher levels of ICAM-1 were detected in patients with PCa (573.04 +/- 52.23) and BPH (564.40 +/- 74.67) than in the controls (215.30 +/- 11.53 ng/mL; p < 0.05). In local blood samples, IL-6 has been found significantly increased in PCa in comparison with patients with BPH; there was no difference in CD40L, E-selectin, P-selectin, VCAM 1 ed ICAM-1. CONCLUSIONS: Changes in inflammation and endothelial activation markers may be not considered to be of value in discriminating BPH and PCa. PMID- 22099275 TI - Vasectomy occlusion technique combining thermal cautery and fascial interposition. AB - INTRODUCTION: Recent research on vasectomy shows that combining cautery and fascial interposition (FI) achieves the most effective occlusion of the vas and minimizes the risk of failure. We present a technique that combines cautery and FI and is suitable for low-resource settings. SURGICAL TECHNIQUE: The surgical technique consists of 1) exposing the vas with the no-scalpel approach; 2) cauterizing the epithelium of lumen of the vas using a portable battery-powered cautery device; 3) performing FI by grasping internal spermatic fascia and applying a free tie with suture material on the fascia to cover the prostatic stump of the vas and separate the two ends of the cut vas; and 4) excising a small 0.5 to 1 cm of the testicular stump. COMMENTS: To maximize vasectomy effectiveness, vasectomy providers should consider learning thermal cautery and FI to occlude vas deferens. PMID- 22099276 TI - Percutaneous intervention of large bladder calculi in neuropathic voiding dysfunction. AB - PURPOSE: To report our results and rationale for treating large bladder calculi in patients with neuropathic voiding dysfunction (NVD) using percutaneous cystolithalopaxy. MATERIALS AND METHODS: Ten patients with a previously diagnosed NVD presenting with a large stone burden were identified from our department database and a retrospective review of case notes and imaging was performed. RESULTS: Percutaneous access to remove bladder stones (range 8x7 to 3x2 cm) had a mean surgery length of 150 min and blood loss of 23 mL. Six of the seven patients treated percutaneously were discharged on the day of surgery and suffered no complications, while one patient experienced poor suprapubic tube drainage and required overnight admission with discharge the following day. Transurethral removal of stone burden (range 4x4 to 4x3 cm) had a mean surgery length of 111 min and blood loss of 8 mL. Each of these three patients were under our care for less than 23 hours, and one patient required a second attempt to remove 1x0.5 cm of stone fragments. There was no statistical difference between mean operative times and estimated blood loss, p = 0.5064 and p = 0.0944 respectively, for the two treatment methods. CONCLUSION: In this small series, percutaneous cystolithalopaxy was a safe, effective, and often preferred minimally invasive option for removal of large calculi in patients with NVD. We suggest possible guidelines for best endoscopic approach in this population, although a larger and prospectively randomized series will be ideal for definitive conclusions. PMID- 22099277 TI - Botulinum toxin A for the treatment of neurogenic detrusor overactivity in multiple sclerosis patients. AB - PURPOSE: Neurogenic detrusor overactivity (NDO) is common in patients who suffer from multiple sclerosis (MS). When the usual pharmacological treatment fails, botulinum toxin type A (BTX-A) injections can be proposed. The safety and efficacy of this treatment are already well known, but only a few studies focus on its use in patients with MS. MATERIALS AND METHODS: Seventy-one patients with MS underwent their first BTX-A injection for refractory NDO. They had clinical and urodynamic cystometry assessment before and three months after injection. The patients were divided in three groups according to treatment efficacy: full success (total urinary continence, no overactive detrusor), improvement, or total failure (urge incontinence and overactive detrusor). RESULTS: 77% of the patients had clinical improvement or full success of the treatment with a reduction of their urgency and incontinence. Significant urodynamic improvement after treatment was shown on different parameters: volume at first involuntary bladder contraction (p = 0.0000001), maximum cystometric capacity (p = 0.0035), maximum detrusor pressure (p = 0.0000001). 46% of the patients were in the "full success" group. 31% of the patients had a partial improvement. 23% of the patients had no efficacy of the treatment. Duration of MS was a predictive factor of treatment failure (p = 0.015). CONCLUSIONS: Despite that a full success was obtained in 46% of the cases, BTX-A injection therapy failed to treat refractory NDO in 23% of patients suffering from MS. Duration of the disease was a predictive factor for an inefficient treatment. The injection therapy should be considered as soon as oral anti cholinergic drugs fail to reduce NDO. PMID- 22099278 TI - Urethral skip metastasis from cancer penis or a second malignancy? A dilemma! PMID- 22099292 TI - The one-stop clinic as the standard of out-patient care in a hospital urology department. AB - PURPOSE: To evaluate the performance of a 'one-stop' clinic in terms of proportion of discharges or inclusion in surgical waiting lists. MATERIALS AND METHODS: All patients were referred from primary care facilities (population 220,646) and from different departments in the hospital. Eight senior urologists, two registered nurses and two nurse attendants participated in the experience. Prior to the start of the project, referral protocols had been agreed with the primary care physicians involved. Compliance with the protocols was periodically tested. Eventually 5537 first visits (January-December 2009) where evaluable. RESULTS: Overall, the 'one-stop' format proved feasible in 74.2% of the patients (4108/5537). Patients, who successfully used the 'one-stop' format, were significantly younger than those who required additional consultations (43 vs 50 years old, respectively, Student 's t test < 0.001). For obvious reasons the 'one stop' format was universally possible in male sterilization and penile phimosis patients. Similarly, the 'one-stop' policy was applied in most consultations due to male sexual dysfunction (75%) and urinary tract infection (73%). Other health problems, such as haematuria (62%) and renal colic (46%), required more than one visit so that care of the patient reverted to the traditional, outpatient care model. CONCLUSION: A 'one-stop' philosophy is feasible for a number of procedures in a urological outpatient clinic. The costs to implement such an approach would be limited to managerial expenditure. PMID- 22099298 TI - Staying alive: defensive strategies in the BCL-2 family playbook. AB - Much debate surrounds how prosurvival members of the BCL-2 family repress opening of the BAX/BAK channel to block apoptosis; in this issue Llambi et al. (2011) identify two modes of apoptosis inhibition that exhibit surprisingly different behavior upon repeat proapoptotic challenges by BH3-only proteins. PMID- 22099299 TI - A20: more than one way to skin a cat. AB - In this issue of Molecular Cell, Skaug et al. (2011) propose a polyubiquitin dependent, noncatalytic mechanism by which the deubiquitinase A20 inhibits IkappaB kinase and NF-kappaB activation. PMID- 22099300 TI - Mitosis hit with an ATM transaction fee: aurora B-mediated activation of ATM during mitosis. AB - In this issue of Molecular Cell, Yang et al. (2011) demonstrate that Aurora B phosphorylates ATM, leading to its mitotic activation and ability to phosphorylate Bub1 and regulate the spindle checkpoint, thus maintaining genomic integrity. PMID- 22099301 TI - PGC1alpha confers specificity-metabolic stress and p53-dependent transcription. AB - In this issue of Molecular Cell, Sen et al. (2011) report the involvement of PGC1alpha in modulating the transcriptional activity of p53 in metabolically challenged cells. They provide important insights into the mechanisms linking length and strength of the metabolic stress stimuli to the specific activation of p53 target genes. PMID- 22099302 TI - Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. AB - Defining the mechanisms underlying the control of mitochondrial fusion and fission is critical to understanding cellular adaptation to diverse physiological conditions. Here we demonstrate that hypoxia induces fission of mitochondrial membranes, dependent on availability of the mitochondrial scaffolding protein AKAP121. AKAP121 controls mitochondria dynamics through PKA-dependent inhibitory phosphorylation of Drp1 and PKA-independent inhibition of Drp1-Fis1 interaction. Reduced availability of AKAP121 by the ubiquitin ligase Siah2 relieves Drp1 inhibition by PKA and increases its interaction with Fis1, resulting in mitochondrial fission. High AKAP121 levels, seen in cells lacking Siah2, attenuate fission and reduce apoptosis of cardiomyocytes under simulated ischemia. Infarct size and degree of cell death were reduced in Siah2(-/-) mice subjected to myocardial infarction. Inhibition of Siah2 or Drp1 in hatching C. elegans reduces their life span. Through modulating Fis1/Drp1 complex availability, our studies identify Siah2 as a key regulator of hypoxia-induced mitochondrial fission and its physiological significance in ischemic injury and nematode life span. PMID- 22099303 TI - Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. AB - Cellular antioxidant enzymes play crucial roles in aerobic organisms by eliminating detrimental oxidants and maintaining the intracellular redox homeostasis. Therefore, the function of antioxidant enzymes is inextricably linked to the redox-dependent activities of multiple proteins and signaling pathways. Here, we report that the VEGFR2 RTK has an oxidation-sensitive cysteine residue whose reduced state is preserved specifically by peroxiredoxin II (PrxII) in vascular endothelial cells. In the absence of PrxII, the cellular H(2)O(2) level is markedly increased and the VEGFR2 becomes inactive, no longer responding to VEGF stimulation. Such VEGFR2 inactivation is due to the formation of intramolecular disulfide linkage between Cys1199 and Cys1206 in the C-terminal tail. Interestingly, the PrxII-mediated VEGFR2 protection is achieved by association of two proteins in the caveolae. Furthermore, PrxII deficiency suppresses tumor angiogenesis in vivo. This study thus demonstrates a physiological function of PrxII as the residential antioxidant safeguard specific to the redox-sensitive VEGFR2. PMID- 22099304 TI - Direct, noncatalytic mechanism of IKK inhibition by A20. AB - A20 is a potent anti-inflammatory protein that inhibits NF-kappaB, and A20 dysfunction is associated with autoimmunity and B cell lymphoma. A20 harbors a deubiquitination enzyme domain and can employ multiple mechanisms to antagonize ubiquitination upstream of NEMO, a regulatory subunit of the IkappaB kinase complex (IKK). However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood. Here we show that A20 can directly impair IKK activation without deubiquitination or impairment of ubiquitination enzymes. We find that polyubiquitin binding by A20, which is largely dependent on A20's seventh zinc-finger motif (ZnF7), induces specific binding to NEMO. Remarkably, this ubiquitin-induced recruitment of A20 to NEMO is sufficient to block IKK phosphorylation by its upstream kinase TAK1. Our results suggest a noncatalytic mechanism of IKK inhibition by A20 and a means by which polyubiquitin chains can specify a signaling outcome. PMID- 22099305 TI - Heterotypic piRNA Ping-Pong requires qin, a protein with both E3 ligase and Tudor domains. AB - piRNAs guide PIWI proteins to silence transposons in animal germ cells. Reciprocal cycles of piRNA-directed RNA cleavage--catalyzed by the PIWI proteins Aubergine (Aub) and Argonaute3 (Ago3) in Drosophila melanogaster--expand the population of antisense piRNAs in response to transposon expression, a process called the Ping-Pong cycle. Heterotypic Ping-Pong between Aub and Ago3 ensures that antisense piRNAs predominate. We show that qin, a piRNA pathway gene whose protein product contains both E3 ligase and Tudor domains, colocalizes with Aub and Ago3 in nuage, a perinuclear structure implicated in transposon silencing. In qin mutants, less Ago3 binds Aub, futile Aub:Aub homotypic Ping-Pong prevails, antisense piRNAs decrease, many families of mobile genetic elements are reactivated, and DNA damage accumulates in nurse cells and oocytes. We propose that Qin enforces heterotypic Ping-Pong between Aub and Ago3, ensuring that transposons are silenced and maintaining the integrity of the germline genome. PMID- 22099306 TI - RAM/Fam103a1 is required for mRNA cap methylation. AB - The 7-methylguanosine cap added to the 5' end of mRNA is required for efficient gene expression in eukaryotes. In mammals, methylation of the guanosine cap is catalyzed by RNMT (RNA guanine-7 methyltransferase), an enzyme previously thought to function as a monomer. We have identified an obligate component of the mammalian cap methyltransferase, RAM (RNMT-Activating Mini protein)/Fam103a1, a previously uncharacterized protein. RAM consists of an N-terminal RNMT-activating domain and a C-terminal RNA-binding domain. As monomers RNMT and RAM have a relatively weak affinity for RNA; however, together their RNA affinity is significantly increased. RAM is required for efficient cap methylation in vitro and in vivo, and is indirectly required to maintain mRNA expression levels, for mRNA translation and for cell viability. Our findings demonstrate that RAM is an essential component of the core gene expression machinery. PMID- 22099307 TI - Aurora-B mediated ATM serine 1403 phosphorylation is required for mitotic ATM activation and the spindle checkpoint. AB - The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell-cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in shortened mitotic timing and a defective spindle checkpoint, and that abrogation of ATM Ser1403 phosphorylation leads to this spindle checkpoint defect. We also demonstrate that mitotically activated ATM phosphorylates Bub1, a critical kinetochore protein, on Ser314. ATM-mediated Bub1 Ser314 phosphorylation is required for Bub1 activity and is essential for the activation of the spindle checkpoint. Collectively, our data highlight mechanisms of a critical function of ATM in mitosis. PMID- 22099308 TI - NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. AB - The histone lysine methyltransferase NSD2 (MMSET/WHSC1) is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here, we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation upon t(4;14)-negative cells and promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together, our findings establish H3K36me2 as the primary product generated by NSD2 and demonstrate that genomic disorganization of this canonical chromatin mark by NSD2 initiates oncogenic programming. PMID- 22099309 TI - PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. AB - Metabolic stress results in p53 activation, which can trigger cell-cycle arrest, ROS clearance, or apoptosis. However, what determines the p53-mediated cell fate decision upon metabolic stress is not very well understood. We show here that PGC 1alpha binds to p53 and modulates its transactivation function, resulting in preferential transactivation of proarrest and metabolic target genes. Thus glucose starvation results in p53-dependent cell-cycle arrest and ROS clearance, but abrogation of PGC-1alpha expression results in extensive apoptosis. Additionally, prolonged starvation results in PGC-1alpha degradation concomitant with induction of apoptosis. We have also identified RNF2, a Polycomb group (PcG) protein, as the cognate E3 ubiquitin ligase. Starvation of mice where PGC-1alpha expression is abrogated results in loss of p53-mediated ROS clearance, enhanced p53-dependent apoptosis, and consequent severe liver atrophy. These findings provide key insights into the role of PGC-1alpha in regulating p53-mediated cell fate decisions in response to metabolic stress. PMID- 22099310 TI - Applied force provides insight into transcriptional pausing and its modulation by transcription factor NusA. AB - Transcriptional pausing by RNA polymerase (RNAP) plays an essential role in gene regulation. Pausing is modified by various elongation factors, including prokaryotic NusA, but the mechanisms underlying pausing and NusA function remain unclear. Alternative models for pausing invoke blockade events that precede translocation (on-pathway), enzyme backtracking (off-pathway), or isomerization to a nonbacktracked, elemental pause state (off-pathway). We employed an optical trapping assay to probe the motions of individual RNAP molecules transcribing a DNA template carrying tandem repeats encoding the his pause, subjecting these enzymes to controlled forces. NusA significantly decreased the pause-free elongation rate of RNAP while increasing the probability of entry into short- and long-lifetime pauses, in a manner equivalent to exerting a ~19 pN force opposing transcription. The effects of force and NusA on pause probabilities and lifetimes support a reaction scheme where nonbacktracked, elemental pauses branch off the elongation pathway from the pretranslocated state of RNAP. PMID- 22099311 TI - Telomere protection by TPP1/POT1 requires tethering to TIN2. AB - To prevent ATR activation, telomeres deploy the single-stranded DNA binding activity of TPP1/POT1a. POT1a blocks the binding of RPA to telomeres, suggesting that ATR is repressed through RPA exclusion. However, comparison of the DNA binding affinities and abundance of TPP1/POT1a and RPA indicates that TPP1/POT1a by itself is unlikely to exclude RPA. We therefore analyzed the central shelterin protein TIN2, which links TPP1/POT1a (and POT1b) to TRF1 and TRF2 on the double stranded telomeric DNA. Upon TIN2 deletion, telomeres lost TPP1/POT1a, accumulated RPA, elicited an ATR signal, and showed all other phenotypes of POT1a/b deletion. TIN2 also affected the TRF2-dependent repression of ATM kinase signaling but not to TRF2-mediated inhibition of telomere fusions. Thus, while TIN2 has a minor contribution to the repression of ATM by TRF2, its major role is to stabilize TPP1/POT1a on the ss telomeric DNA, thereby allowing effective exclusion of RPA and repression of ATR signaling. PMID- 22099313 TI - A variant of the Ekman-Westborg and Julin trait. AB - Ekman-Westborg and Julin is a trait that shows multiple macrodontia and multituberculism affecting only the teeth with no other anomalies (E-WJ). The aim of this report is to present a case which appears to manifest all the clinical signs of the E-WJ trait including odontoma formation. A 18-year-old girl with gingival inflammation particularly in the maxillary insicor area was referred to the authors' department. Panoramic, periapical and cephalometric radiographs were examined and complex odontoma associated with unerupted maxillary permanent lateral incisors was revealed. Intraoral examination revealed anterior crossbite, Angle Class III type malocclusion with mandibulary prominence and macrodontia of teeth 37, 12, 11 and 21. The patient was accepted as a new sporadic case of E-WJ. More case reports are needed to elucidate the causes and pathogenesis of this condition. PMID- 22099314 TI - Maxillary sinus lift with solely autogenous bone compared to a combination of autogenous bone and growth factors or (solely) bone substitutes. A systematic review. AB - Literature regarding the outcome of maxillary sinus floor elevation to create sufficient bone fraction to enable implant placement was systematically reviewed. Bone fraction and implant survival rate were assessed to determine whether grafting material or applied growth factor affected bone fraction. Trials where sinus floor elevations with autogenous bone (controls) were compared with autogenous bone combined with growth factors or bone substitutes, or solely with bone substitutes (test groups) were identified; 12 of 1124 fulfilled all inclusion criteria. Meta-analyses comparing the bone fraction after applying: autogenous bone; autologous bone with growth factors (platelet rich plasma); or autogenous bone and bone substitutes (bovine hydroxyapatite, bioactive glass, corticocancellous pig bone) revealed no significant differences in bone formation after 5 months. A significantly higher bone fraction was found in the autogenous bone group compared to the sole use of beta-tricalciumphosphate (P=0.036). The one-year overall implant survival rate showed no significant difference between implants. Bone substitutes combined with autogenous bone provide a reliable alternative for autogenous bone as sole grafting material to reconstruct maxillary sinus bony deficiencies, for supporting dental implants after 5 months. Adding growth factors (platelet rich plasma) to grafting material and the sole use of beta-tricalciumphosphate did not promote bone formation. PMID- 22099312 TI - rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells. AB - How pseudouridylation (Psi), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Psi is important because the rRNA Psi synthase, DKC1, is mutated in X linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5 D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Psi modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans. PMID- 22099315 TI - Insulin promotes bone formation in augmented maxillary sinus in diabetic rabbits. AB - The role of insulin during the formation of bone in the augmented space of the maxillary sinus in patients with diabetes is unclear. The authors compared the differences in bone formation after maxillary sinus floor elevation in diabetic and healthy animals and evaluated the effects of insulin on osteogenesis and the differentiation and activities of the osteoblasts. 10 male Japanese white rabbits were divided into two groups after diabetic induction by a single injection of monohydrated alloxan and having maintained steady blood glucose levels. The groups included the diabetes mellitus group (DM; n=5) and the DM+insulin group (n=5); another five healthy rabbits comprised the control group. Maxillary sinus floor elevation was performed by grafting hydroxyapatite particles. Compared with the control group, the newly formed bone area, number of blood vessels and osteoblasts, collagen I content and serum osteocalcin levels were significantly decreased in DM rabbits (P<0.01). Insulin treatment reversed the decrease in bone formation, blood vessels, osteoblasts, collagen I and serum osteocalcin (P<0.01). Insulin treatment also promoted osteogenesis in the augmented space of the diabetic rabbits, which might have resulted from promotion of osteoblast differentiation and upregulation of neovascularization. PMID- 22099316 TI - Single stage repair of a complex pathology: end stage ischaemic cardiomyopathy, ascending aortic aneurysm and thoracic coarctation. AB - The not uncommon combination of ascending aortic pathology with late presenting coarctation is a difficult surgical challenge. The two stage approach is usually adopted. The necessity for cardiac transplantation adds to the complexity: a trans-sternal approach and single stage repair become mandatory. PMID- 22099317 TI - Pregnancy during postgraduate surgical training. PMID- 22099318 TI - CAGS and ACS Evidence Based Reviews in Surgery. Access to emergency operative care: a comparative study between the Canadian and American health care systems. PMID- 22099320 TI - Global health conferences: are they truly "global"? The Bethune Round Table paradigm for promoting global surgery. PMID- 22099321 TI - Introduction to the Canadian Forces supplement on war surgery. PMID- 22099322 TI - Lessons learned from the war in Afghanistan: a commander's perspective. PMID- 22099323 TI - The Canadian Forces trauma care system. AB - According to the Trauma Association of Canada, a trauma system is a preplanned, organized and coordinated injury-control effort in a defined geographic area. An effective trauma system engages in comprehensive injury surveillance and prevention programs; delivers trauma care from the time of injury to recovery; engages in research, training and performance improvement; and establishes linkages with an all-hazards emergency preparedness program. To support Canada's combat mission in Afghanistan, the Canadian Forces (CF) developed a comprehensive trauma system based around its trauma hospital--the Role 3 Multinational Medical Unit (R3MMU) at Kandahar Airfield. This article reviews the essential components of a modern trauma system, outlines the evidence that trauma systems improve care to injury victims and describes how the current CF trauma system was developed. PMID- 22099324 TI - Tactical combat casualty care in the Canadian Forces: lessons learned from the Afghan war. AB - Tactical Combat Casualty Care (TCCC) is intended to treat potentially preventable causes of death on the battlefield, but acknowledges that application of these treatments may place the provider and even the mission in jeopardy if performed at the wrong time. Therefore, TCCC classifies the tactical situation with respect to health care provision into 3 phases (care under fire, tactical field care and tactical evacuation) and only permits certain interventions to be performed in specific phases based on the danger to the provider and casualty. In the 6 years that the Canadian Forces (CF) have been involved in sustained combat operations in Kandahar, Afghanistan, more than 1000 CF members have been injured and more than 150 have been killed. As a result, the CF gained substantial experience delivering TCCC to wounded soldiers on the battlefield. The purpose of this paper is to review the principles of TCCC and some of the lessons learned about battlefield trauma care during this conflict. PMID- 22099325 TI - The Role 3 Multinational Medical Unit at Kandahar Airfield 2005-2010. AB - In late 2005, Canadian Forces Health Services (CFHS) was tasked with the command of the NATO Role 3 Multinational Medical Unit (R3MMU) on Kandahar Airfield in southern Afghanistan. Preparations drew on past experience and planning. Eight complete hospital contingents were trained and deployed in rotation. Near-reality simulation training was undertaken with the combat brigade, including complete deployment of the field hospital in the exercise area. Standard operating procedures (SOP) were developed and applied by each rotation so successfully that they were adopted by the new command in late 2009. The Canadian period at R3MMU had the highest survival rate ever recorded for victims of war. Lessons learned are being applied among victims of the conflict and trauma. The experience of the R3MMU was used to successfully deploy a hospital as part of the earthquake relief effort in Haiti in 2010.The training protocols and SOP are being applied to disaster preparedness in Canadian civilian hospitals. PMID- 22099326 TI - Utilization profile of the trauma intensive care unit at the Role 3 Multinational Medical Unit at Kandahar Airfield between May 1 and Oct. 15, 2009. AB - BACKGROUND: In the war against the Taliban, Canada was the lead North Atlantic Treaty Organization (NATO) nation to provide medical and surgical care to NATO soldiers, Afghanistan National Army soldiers, Afghanistan Nation Police, civilians working in and outside Kandahar Airfield and Afghanistan civilians at the Role 3 Multinational Medical Unit (R3MMU) from February 2006 to October 2009. METHODS: We obtained data from the Joint Theatre Trauma Registry between May 1 and Oct. 15, 2009; 188 patients were admitted to the R3MMU intensive care unit (ICU). We analyzed the ICU data according to types and causes of trauma, mechanical ventilation prevalence, ICU medical and surgical complications, blood products utilization, length of stay in the ICU and mortality. RESULTS: The admitting services were general surgery (35%), neurosurgery (29%), orthopedic surgery (18%) and internal medicine (3%). Improvised explosive devices (46%) and gunshot wounds (26%) were the main causes of ICU admissions. The mean injury severity score for all patients admitted to the ICU was 37, and 81% of ICU patients required mechanical ventilation for a mean duration of 3 days. The main ICU complications were coagulopathy (6.4%), aspiration pneumonia (4.3%), pneumothorax (3.7%) and wound infection (2.7%). The following blood products were most used: packed red blood cells (55%), fresh frozen plasma (54%), platelets (29%) and cryoprecipitate (23%). The average length of stay in the ICU was 4.3 days, and the survival rate was 93%. CONCLUSION: The high survival rate suggests that ICU care is a necessary and vital resource for a trauma hospital in a war zone. PMID- 22099327 TI - Physical rehabilitation following polytrauma. The Canadian Forces Physical Rehabilitation Program 2008-2011. AB - As a consequence of Canada's involvement in the war in Afghanistan, many members of the Canadian Forces have experienced debilitating injuries. Despite the Canadian Forces Health Services (CFHS) having outstanding relationships with many civilian care providers for the rehabilitation of injured soldiers, it became apparent early on that the high-level goals and aspirations of these returning soldiers were sometimes beyond the capability of these centres to facilitate. From this reality grew the need to develop a Physical Rehabilitation Program within the CFHS. This article describes the lessons learned since the creation of the program and outlines the future vision in terms of unique challenges and opportunities. The primary purpose of this article is to describe a hybrid model of civilian-military rehabilitation for injured soldiers and discuss the benefits and challenges of such a model of care. PMID- 22099328 TI - Psychiatric lessons learned in Kandahar. AB - Not since the Korean War have the Canadian Forces engaged in combat missions like those in Afghanistan. Combat, asymmetric warfare, violent insurgency and the constant threat of improvised explosive devices all contribute to the psychological stressors experienced by Canadian soldiers. Mental health teams deployed with the soldiers and provided assessment, treatment and education. Lessons learned included refuting the myth that all psychological disorders would be related to trauma; confirming that most patients do well after exposure to trauma; confirming that treating disorders in a war zone requires flexible and creative adaptation of civilian treatment guidelines; and confirming that in a combat mission mental health practice is not limited to the clinical setting. PMID- 22099329 TI - Left atrial volume predicts adverse cardiac and cerebrovascular events in patients with hypertrophic cardiomyopathy. AB - AIMS: To prospectively evaluate the relationship between left atrial volume (LAV) and the risk of clinical events in patients with hypertrophic cardiomyopathy (HCM). METHODS: We enrolled a total of 141 HCM patients with sinus rhythm and normal pump function, and 102 patients (73 men; mean age, 61+/-13 years) who met inclusion criteria were followed for 30.8+/-10.0 months. The patients were divided into two groups with or without major adverse cardiac and cerebrovascular events (MACCE), a composite of stroke, sudden death, and congestive heart failure. Detailed clinical and echocardiographic data were obtained. RESULTS: MACCE occurred in 24 patients (18 strokes, 4 congestive heart failure and 2 sudden deaths). Maximum LAV, minimum LAV, and LAV index (LAVI) corrected for body surface area (BSA) were significantly greater in patients with MACCE than those without MACCE (maximum LAV: 64.3+/-25.0 vs. 51.9+/-16.0 ml, p=0.005; minimum LAV: 33.9+/-15.1 vs. 26.2+/-10.9 ml, p=0.008; LAVI: 40.1+/-15.4 vs. 31.5+/-8.7 ml/mm2, p=0.0009), while there were no differences in the other echocardiographic parameters.LAV/BSA of >=40.4 ml/m2 to identify patients with cardiovascular complications with a sensitivity of 73% and a specificity of 88%. CONCLUSION: LAVI may be an effective marker for detecting the risk of MACCE in patients with HCM and normal pump function. PMID- 22099330 TI - The new COSMIN guidelines confront traditional concepts of responsiveness. AB - The recently published "COSMIN" guidelines aim to rate properties of outcome instruments and state two issues with regard to responsiveness which is the instrument's ability to detect change over time. These issues are comparison of score changes with change of an external criterion using correlations and the judgement of traditional methods as inappropriate. The latter are the "transition" concept, a global rating of change, and parametric measures of responsiveness, for example, effect sizes. It can be shown that the methodology proposed by the guidelines has important weaknesses and that denunciation of traditional methods is not appropriate. Some claims of the guidelines about responsiveness do not match the demands of clinical reality and confront findings of numerous epidemiological studies. PMID- 22099331 TI - The complex dialogue between (myo)fibroblasts and the extracellular matrix during skin repair processes and ageing. AB - The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. The (myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. The composition of the ECM around (myo)fibroblasts is variable depending on the situation and, in addition to the secretion of the ECM, the (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases can remodel this ECM. The (myo)fibroblasts and their microenvironment form a changing network with reciprocal actions leading to cell differentiation, proliferation, quiescence or apoptosis, and also acting on growth factor biodisponibility. In pathological situations (such as chronic wounds or excessive scarring), or during ageing, especially due to ultraviolet exposition, this dialogue between the (myo)fibroblasts and their microenvironment is disrupted, leading to repair defects or to skin injuries with unaesthetic alterations such as wrinkles. Knowing the intimate exchanges between the (myo)fibroblasts and their microenvironment represents a fascinating domain important not only for characterizing new targets and drugs able to prevent pathological developments but also for interfering with skin alterations observed during ageing. PMID- 22099332 TI - The role of elastin peptides in modulating the immune response in aging and age related diseases. AB - It is now well accepted that aging is associated with the occurrence of a low grade inflammation called Inflamm-aging. This leads to the imbalance between the various mediators of the inflammatory response in favour of the pro-inflammatory response represented by pro-inflammatory cytokines and oxidative stress. The question that arises, and is still under investigation, what is the origin of the driving force leading to these changes. One of the current hypotheses is that chronic stimulation of the immune system contributes to the pro-inflammatory shift. The chronic stimulation can be of viral origin such as cytomegalovirus, from tumor antigens or from other sources such as the extracellular matrix, especially from elastin fibres and collagens. Aging and various inflammatory diseases such as atherosclerosis, abdominal aortic aneurysms, chronic obstructive pulmonary diseases (COPD), cancer and type 2 diabetes are characterized by the destruction of elastin fibers and the consequent generation of elastin peptides which are biologically active. This review will describe the putative contribution of elastin peptides to inflamm-aging and extend on their role on immunosenescence, as well as on age-associated chronic inflammatory diseases. PMID- 22099333 TI - [Editorial]. PMID- 22099334 TI - [Surgical excision of giant congenital naevi: how far can we go with surgery?]. AB - Surgical excision of giant congenital nevi is recommended by principle for dermatological reasons. Malignant potential is real but its incidence remains widely discussed. Their excision represents a surgical challenge but is also a real assault course for the child and his family. The sequelae and the psychological effects can be important. Can an incomplete excision to limit these aesthetic after-effects and relieve the surgical treatment be acceptable? We present the case of a child affected by a giant congenital nevi of the cephalic extremity where the excision was partial. A review of the literature on the degenerative risk of the giant congenital nevi allowed us of noticed that this one tends to be overestimated. The advantages and the disadvantages to practise a preventive, premature excision and complete of the giant congenital nevi are approached. We discuss the possibility to resort to a partial excision in certain cases delicate of reconstruction under the cover of a strict and moved closer dermatological surveillance. PMID- 22099335 TI - Correlation of vitamin A nutritional status on alpha-tocopherol in the colostrum of lactating women. AB - The adequate supply of vitamins A and E to newborns is essential. However, factors such as maternal nutritional status and nutrient interaction may limit its bioavailability. The aim of this study was to establish nutritional status for vitamins A and E and evaluate the correlation of retinol on colostrum alpha tocopherol in lactating women. A total of 103 lactating women were recruited at a Brazilian public maternity hospital. Fasting serum and colostrum samples were collected in the immediate post-partum. Retinol and alpha-tocopherol levels were determined by high-performance liquid chromatography and nutritional status for these vitamins was defined from specific cut-off points for serum and colostrum. Mean serum and colostrum retinol (1.49 umol L(-1) , 2.18 umol L(-1) ) and alpha tocopherol (26.4 umol L(-1) , 26.1 umol L(-1) ) indicated satisfactory biochemical status. However, we found a prevalence of subclinical deficiency of vitamin A and vitamin E in serum (15.5% and 16%) and colostrum (50% and 60%). Lactating women with serum retinol >= 1.05 umol L(-1) showed an inverse correlation between serum retinol and alpha-tocopherol concentration in the colostrum (P = 0.008, r = -0.28). This association was not observed in serum level < 1.05 umol L(-1) . The nutritional status of lactating women for vitamins A and E was adequate, although there is a risk of subclinical deficiency. The negative correlation of serum retinol on alpha-tocopherol concentration in the colostrum must be carefully evaluated in situations of vitamin A supplementation, because alpha-tocopherol bioavailability in maternal milk may be compromised. PMID- 22099336 TI - Synthesis of a thermosensitive surface by construction of a thin layer of poly (N isopropylacrylamide) on maleimide-immobilized polypropylene. AB - Thermosensitive surfaces were developed by the grafting of a thin layer of PNIPAAm through an UV-induced photopolymerization reaction of vinyl monomers with a free radical-activated polypropylene (PP) surface. PNIPAAm layer covering the PP surface corrected, to some extension, both depressions and fissures of the previously modified PP surfaces. The layered surfaces have morphological characteristic different from those of the non-layered surfaces, and their thickness was dependent on irradiation time. Water contact angles of the layered surfaces revealed a transition at approximately 33.5-36.5 degrees C as a result of a response to the variation of temperature. There was an increase in the values of the contact angles with an increase in temperature from 26 degrees C to 44 degrees C, revealing the nature both hydrophilic and hydrophobic of the surfaces due to a conformational rearrangement of PNIPAAm exposing its isopropyl groups to the liquid drop. This work offers a chemically stable thermosensitive surface (because it is covalently structured) with great potential for use as sensors and actuators. PMID- 22099337 TI - Particle sizing of colloidal suspensions by low-coherence fiber optic dynamic light scattering. AB - A low-coherence fiber optic dynamic light scattering technique is used to measure the particle size distributions of colloidal suspensions with different volume fractions. We detect electric field autocorrelation function of the singly backscattered light from a sample and use the CONTIN algorithm to obtain the particle size distributions. As a result, in the range of volume fractions from 0.01 to 0.10 of monodispersive colloidal suspensions, the mean particle size with the deviation within 4% and the polydispersity approximate 5% can be determined for particles of different radii. The results demonstrate that the low-coherence fiber optic dynamic light scattering technique is effective in measuring particle size of colloidal suspensions. PMID- 22099338 TI - Jubileum issue: aquatic toxicology 30 years. PMID- 22099339 TI - The two faces of DOC. AB - Dissolved organic carbon (DOC), through its ability to complex metals and thereby reduce their bioavailability, plays a major role in ameliorating metal toxicity in natural waters. Indeed DOC is a key variable in the Biotic Ligand Model (BLM) for predicting metal toxicity on a site-specific basis. However, recent evidence indicates that all DOCs are not alike, but rather heterogeneous in their ability to protect organisms against metal toxicity, at least in fresh water. The degree of protection appears to correlate with optical properties, such that dark, aromatic-rich compounds of allochthonous origin, with greater humic acid content, are more effective in this regard, particularly against Cu, Ag, and Pb toxicity. The specific absorption coefficient of the DOC in the 300-350nm range (SAC(300 350)) has proven to be a simple and effective index of this protective ability. PARAFAC, a multivariate statistical technique for analysis of excitation-emission fluorescence spectroscopy data, also holds promise for quantifying the humic-like and fulvic-like fluorophores, which tend to be positively and negatively correlated with protective ability, respectively. However, what has been largely missing in the toxicological realm is any appreciation that DOC may also affect the physiology of target organisms, such that part of the protection may occur by a mechanism other than metal complexation. Recently published evidence demonstrates that DOC has effects on Na(+) transport, diffusive permeability, and electrical properties of the gills in fish and crustaceans in a manner which will promote Na(+) homeostasis. These actions could thereby protect against metal toxicity by physiological mechanisms. Future research should investigate potential direct interactions of DOC molecules with the branchial epithelium. Incorporation of optical properties of DOC could be used to improve the predictive capabilities of the BLM. PMID- 22099340 TI - Incorporating exposure into aquatic toxicological studies: an imperative. AB - The field of aquatic toxicology has been expanding rapidly in recent years. The ecotoxicological study of environmental toxicants encompasses three basic frameworks: environmental behavior/transport, bioavailability/bioaccumulation (exposure), and toxicity at different biological levels. Environmental risk assessments are then based on this knowledge to provide sound advice for environmental management and policies. In this article I will highlight the need to further understand the exposure to toxicants and its direct relationship with toxicological responses at different levels. Exposure considerations generally include the route, species, concentration and duration of exposure, among which the importance of the exposure route has been little considered. A typical aquatic toxicological study simply exposes the organisms to toxicants in the water for a certain period of time under different concentrations. This approach may not be environmentally relevant. Future studies should attempt to understand the toxicology under different exposure regimes. Incorporating exposure will allow aquatic toxicology to be placed in a context of environmental relevance and enhance our understanding of the impacts of toxicants on our living environments. PMID- 22099341 TI - Functional genomics in aquatic toxicology-do not forget the function. AB - Toxicological responses of an organism are disturbances of function. This as a starting point we review and discuss issues that we consider important in applying functional genomics to aquatic toxicology. Functional genomics includes all the steps in gene expression pathway. Thus, ultimately the goal is to relate genome information to protein activity. In ecotoxicogenomics the toxicological responses must further be combined with responses to natural environmental changes. We focus on fish, but also consider commonly used invertebrates, mainly Daphnia. We first go through the toxicologically important features of genomes of aquatic animals, and then review the reference gene approach to quantify transcript amount. Thereafter we emphasize the need to relate the mRNA and protein levels, and protein activity of individual genes. Finally we discuss how functional genomic investigations may be important in resolving current environmental problems and give our views of valuable future research topics. PMID- 22099342 TI - Progress and promises in toxicogenomics in aquatic toxicology: is technical innovation driving scientific innovation? AB - In the last decade, new technologies have been invented to analyze large amounts of information such as gene transcripts (transcriptomics), proteins (proteomics) and small cellular molecules (metabolomics). Many studies have been performed in the last few years applying these technologies to aquatic toxicology, mainly in fish. In this article, we summarize the current state of knowledge and question whether the application of modern technology for descriptive purposes truly represents scientific advancement in aquatic toxicology. We critically discuss the advantages and disadvantages of these technologies and emphasize the importance of these critical aspects. To date, these techniques have been used mainly as a proof of principle, demonstrating effects of model compounds. The potential to use these techniques to better analyze the mode-of-action of a toxicant or the effects of a compound within organisms has rarely been met. This is partly due to a lack of baseline data and the fact that the expression of mRNA and protein profiles is rarely linked to physiology or toxicologically meaningful outcomes. It seems premature to analyze mixtures or environmental samples until more is known about the expression profiles of individual toxicants. Gene transcription, protein, or metabolic data give only a partial view of these effects. Thus, we emphasize that data obtained by these technologies must be linked to physiological changes to fully understand their significance. The use of these techniques in aquatic toxicology is still in its infancy, data cannot yet be applied to environmental risk assessment or regulation until more emphasis is placed on interpreting the data within their physiological and toxicological contexts. PMID- 22099343 TI - A genomic and ecotoxicological perspective of DNA array studies in aquatic environmental risk assessment. AB - Ecotoxicogenomics is developing into a key tool for the assessment of environmental impacts and environmental risk assessment for aquatic ecosystems. This review aims to report achievements and drawbacks of this technique and to explore potential conceptual and experimental procedures to improve future investigations. Ecotoxicogenomic literature evidences the ability of genomic technologies to characterize toxicant specific gene transcriptome patterns that can be used to identify major toxicants affecting aquatic species. They also contribute decisively to the development of new molecular biomarkers and, in many cases, to the determination of new possible gene targets. Primary transcriptomic responses obtained after short exposures provided more information of putative gene targets than secondary responses obtained after long, chronic exposures, which in turn are usually more accurate to describe actual environmental impacts in natural populations. Several problems need to be addressed in future investigations: the lack of studies (and genomic information) on key ecological species and taxa, the need to better understand the different transcriptomic responses to high and low doses and, especially, short and long exposures, and the need to improve experimental designs to minimize false transcriptome interpretations of target genes. PMID- 22099344 TI - Moving beyond a descriptive aquatic toxicology: the value of biological process and trait information. AB - In order to improve the ability to link chemical exposure to toxicological and ecological effects, aquatic toxicology will have to move from observing what chemical concentrations induce adverse effects to more explanatory approaches, that are concepts which build on knowledge of biological processes and pathways leading from exposure to adverse effects, as well as on knowledge on stressor vulnerability as given by the genetic, physiological and ecological (e.g., life history) traits of biota. Developing aquatic toxicology in this direction faces a number of challenges, including (i) taking into account species differences in toxicant responses on the basis of the evolutionarily developed diversity of phenotypic vulnerability to environmental stressors, (ii) utilizing diversified biological response profiles to serve as biological read across for prioritizing chemicals, categorizing them according to modes of action, and for guiding targeted toxicity evaluation; (iii) prediction of ecological consequences of toxic exposure from knowledge of how biological processes and phenotypic traits lead to effect propagation across the levels of biological hierarchy; and (iv) the search for concepts to assess the cumulative impact of multiple stressors. An underlying theme in these challenges is that, in addition to the question of what the chemical does to the biological receptor, we should give increasing emphasis to the question how the biological receptor handles the chemicals, i.e., through which pathways the initial chemical-biological interaction extends to the adverse effects, how this extension is modulated by adaptive or compensatory processes as well as by phenotypic traits of the biological receptor. PMID- 22099345 TI - Molecular and biochemical biomarkers in environmental monitoring: a comparison of biotransformation and antioxidant defense systems in multiple tissues. AB - The cytochrome P450 pathway and antioxidant responses are known for their responsiveness to environmental pollutants and are frequently used as biomarkers at the transcriptional, translational and catalytic levels. Although molecular responses are often assumed to reflect similar changes in enzyme function, several factors can influence intracellular effects, including mRNA stability and protein turnover, signal sensing and transduction, post-translational modifications of proteins, and multiple mode of action of chemicals in complex mixtures. The aim of this study was to use experimental data for a general discussion on the importance of mechanisms modulating transcriptional and catalytic responses of these pathways, and the resulting implications for environmental monitoring. The European eel Anguilla anguilla was selected as fish model to compare the effects of polluted sediments on gene expression and functional levels of cytochrome P450, glutathione S-transferases, UDP glucoronosyl transferases, catalase, glutathione peroxidases, superoxide dismutase, glutathione, glutathione reductase, glucose 6-phosphate dehydrogenase and gamma-glutamylcysteine ligase in the liver and gills. The overall results confirmed significant changes in gene transcription related to biotransformation and oxyradical metabolism, but also supported the evidence of a frequent dissociation between mRNA expression and protein activity. More similar trends of variations and exposure-dependent relationships was observed in the liver for transcriptional and catalytic responses of those pathways closely regulated by specific interactions between substrate, transcription factors, gene and metabolizing protein (i.e. phase I and phase II). On the other hand, the lower metabolism and the cellular machinery of gill cells may prevent elevated transcriptional responsiveness to be translated to an adequate functional response of a protein. Relationships between transcriptional and catalytic effects were often inconsistent for antioxidant responses confirming the complexity of interactions between exposure to chemical pollutants and regulation of oxidative stress responses. Oxidative stress responses may not necessarily be associated with transcriptional variations of genes, but rather with post translational modifications of proteins. These mechanisms are just beginning to be revealed in marine organisms, but their characterization will be fundamental for better understanding of the implications of variations in gene expressions according to system, tissue, intensity and duration of exposure. PMID- 22099346 TI - Mechanistic research in aquatic toxicology: perspectives and future directions. AB - On the 30th anniversary of the journal, I provide a perspective on some of the questions and opportunities for new understanding that will interest aquatic toxicologists during the next 30 years. I focus on mechanisms of toxicity involving transcription factors, signalling pathways, and gene networks involved in toxic and adaptive responses in aquatic animals. Prominent questions address the value of a toxicity pathways approach in aquatic systems, issues involving extrapolation among species, identification of susceptibility genes and useful biomarkers of adverse effect, new emerging contaminants, the importance of epigenetic mechanisms, effects of multiple stressors, evolutionary toxicology, and the relative roles of technical and conceptual limitations to our understanding of chemical effects on aquatic systems. PMID- 22099347 TI - Cocktail effects on biomarker responses in fish. AB - One of today's greatest challenges in environmental toxicology is to understand effects of mixture toxicity, commonly referred to as cocktail effects, in humans and in wildlife. Biomarker responses in fish are routinely used to assess exposure of anthropogenic chemicals in the aquatic environment. However, little is known about how cocktail effects affect these biomarker responses. For this reason, there is an obvious risk for misinterpretation of biomarker-data and this can have profound negative effects on stakeholder's decisions and actions, as well as on legislations and remediation-plans initiated in order to reduce exposure to certain chemicals. Besides, chemical safety-levels are traditionally based on experiences from lab-studies with single chemicals, which is unfortunate as a chemical can be more toxic when it is mixed with other chemicals, because of the cocktail effect. This review focuses on pharmacokinetic interactions between different classes of pollutants on detoxification mechanisms and how that affects two commonly used biomarkers in the aquatic environment: (1) induction of cytochrome P450 1A (CYP1A) that is mediated via activation of the arylhydrocarbon receptor (AhR), used to assess exposure to aromatic hydrocarbons; (2) induction of vitellogenin (VTG) that is mediated via activation of the estrogen receptor (ER), used to assess exposure to estrogenic chemicals. These responses can be either directly or indirectly affected by the presence of other classes of pollutants as a result of cocktail effects. For example, chemicals that inhibit the function of key metabolic enzymes and transporter pumps that are involved in elimination of AhR- and ER agonists, can result in bioaccumulation of aromatic hydrocarbons and estrogenic chemicals resulting in increased biomarker responses. This cocktail effect can lead to overestimation of the actual exposure pressure. On the contrary, induction of expression of key metabolic enzymes and transporter activities can result in increased elimination of AhR- and ER agonists that can lead to possible underestimation of the exposure. Another type of cocktail effect is inhibiting receptor cross-talk that may cause decreased biomarker responses that can also lead to underestimation of the actual exposure. To address the possible involvement of pharmacokinetic interactions including receptor cross talks, we need to combine analyses on receptor signaling with studies on function of key biotransformation enzymes such as major catabolic CYP enzymes (e.g. CYP1 4) as well as efflux pumps (e.g. ATP-binding cassette transporter proteins). Besides, studies of inhibition of these enzymes and pumps activities pose a great potential to be used as future biomarkers as they are more clearly liked to adverse outcomes, compared to for example induction of CYP1A and VTG expression. PMID- 22099348 TI - Impacts of climate change on hypersaline conditions of estuaries and xenobiotic toxicity. AB - Climate change has had significant impacts on the hydrologic cycle of the planet. Of particular concern are estuarine environments, such as San Francisco Bay (USA) which is fed by diminishing snow pack runoff leading to gradual increases in salinity. Salinity enhances the acute toxicity of several agricultural chemicals in anadromous fish through augmented biochemical activation catalyzed by enzymes that are induced during hypersaline acclimation. This review discusses the mechanisms of the enhanced toxicity, the enzymes involved and the regulation of the enzymes by hypersaline conditions. Given the rapid changes taking place in the world's waterways, environmental modification of toxicological pathways should be a significant focus of the research community as the toxicity of multiple xenobiotics may be enhanced. PMID- 22099349 TI - [N.O.T.E.S. What have learned?]. PMID- 22099350 TI - Peptidoglycan recognition protein 3 (PglyRP3) has an anti-inflammatory role in intestinal epithelial cells. AB - Intestinal epithelial cells produce cytokines in response to bacterial peptidoglycan (PGN), which is detected by several classes of pattern-recognition receptors (PRRs) as peptidoglycan recognition proteins (PGlyRPs), Toll-like receptor 2 (TLR2) and NOD receptors. All types of PGlyRPs recognize bacterial peptidoglycan and function in antibacterial innate immunity. In this study, we investigated the role of PGlyRP3 in the response of intestinal epithelial cells (Caco-2) to PGN from pathogenic (Staphylococcus aureus), opportunistic pathogenic (Micrococcus luteus) and non-pathogenic (Bacillus subtilis and Lactobacillus rhamnosus GG) bacteria found in the gut as commensals or in gastroenteritis. All PGNs induced the proinflammatory cytokines IL-12p35, IL-8 and TNF-alpha and, time dependently, PGlyRP3, at both the transcription and protein levels. In this context, no differences were observed among the distinct PGN obtained from different bacterial sources. The inflammatory response to PGN is mediated via the TLR2 pathway, since blocking this pathway by inhibiting MyD88 reduced the expression of proinflammatory cytokines. In addition, PGlyRP3 overexpression suppressed, while PGlyRP3 knocking down enhanced the expression of PGN-induced inflammatory cytokines. It is concluded that PGN stimulates inflammatory responses in the intestinal epithelia through activation of the TLR pathway. PGlyRP3 is also stimulated by PGN and has, in contrast to activation of the TLR pathway, an anti-inflammatory effect. PMID- 22099351 TI - A balance between tissue-destructive and tissue-protective immunities: a role of toll-like receptors in regulation of adaptive immunity. AB - The immune system has been shown to be involved in not only the host defense against infectious pathogens but also in tissue repair processes continuously occurring in the body. Our review presents the hypothesis about the mechanism of TLR-mediated regulation of adaptive immune responses linked to the tissue destruction. In our opinion following injury to a tissue, the expression of tissue-specific determinant/MHC class II complexes on dendritic cells and macrophages are upregulated significantly due to the increased uptake of tissue debris. Consequently, T-cells become activated as a result of low affinity, but high avidity interactions between self-reactive CD4+T cells and antigen presenting cells (APCs). The type of self antigen-induced immune responses depends on the multiple downstream signals generated by intracellular toll-like receptors (TLRs) 3, 7, 8, and 9, that discriminate "self" and "non-self" nucleic acids. Accumulating data suggest that ligation of intracellular TLRs by endogenous DNA/RNA released from necrotic cells may result in developing Th2-like responses, as well as in the alternative activation of macrophages (M2), that favor local tissue protection and compensatory cell growth. In contrast, ligation of intracellular TLRs by exogenous pathogen-derived DNA/RNA may promote Th1 driven responses, as well as classical activation of macrophages (M1), that contribute to local tissue destruction and suppress cell growth. We suggest here that the balance between the host- and pathogen-derived nucleic acids interacting with intracellular TLRs contributes to the balance between immune-mediated tissue protective and tissue-destructive events occurring in the body. PMID- 22099352 TI - Muscular strengthening activity patterns and metabolic health risk among US adults. AB - BACKGROUND: Many studies have examined the relationship between physical activity and metabolic disorders. However, few have focused on specific associations between these disorders and muscular strengthening activity (MSA) patterns. The aim of the present study was to examine the association(s) for each metabolic syndrome criterion and MSA patterns. METHODS: The study sample (n = 5618) consisted of adults >=20 years of age who participated in the 1999-2004 National Health and Nutrition Examination Survey. Cut-off points for metabolic syndrome criteria were derived from the American Heart Association/National Heart, Lung, and Blood Institute definition. The aggregate of data on weight lifting, push ups, and sit-ups was used to establish patterns of MSA. Participants reporting >=2 days/week MSA were coded as meeting current US MSA guidelines. RESULTS: Following adjustments, participants reporting >=2 days/week MSA were found to be 28% (OR 0.72; 95% CI 0.62, 0.83) less likely to have dyslipidemia, 29% (OR 0.71; 95% CI 0.54, 0.93) less likely to have impaired fasting glucose, 19% (OR 0.81; 95% CI 0.65, 0.99) less likely to have prehypertension, and 43% (OR 0.57; 95% CI 0.46, 0.72) less likely to have augmented waist circumference compared with those reporting engaging in no MSA. No association was found for hypertension and MSA. CONCLUSION: Engaging in >=2 days/week MSA as part of an overall physical activity regimen may be prudent in preserving metabolic health. These findings strengthen the relationship between MSA and metabolic health; thus, clinicians should include MSA when discussing lifestyle approaches to better health. PMID- 22099353 TI - A public health framework for rare blood disorders. PMID- 22099354 TI - Knowledge and therapeutic gaps: a public health problem in the rare coagulation disorders population. AB - Rare coagulation disorders (RCDs) present a considerable and multifaceted public health risk. Although inherited RCDs affect a minor segment of any local healthcare delivery system, their global impact is major and highlight the challenges of delivering healthcare services to any rare disease population. These include but are not limited to: (1) a general lack of knowledge about and familiarity with the genetic and clinical implications of the disorder among affected patients, and both urgent and specialty care providers; (2) the potential for preventable morbidity and mortality related to delayed diagnosis and treatment; (3) the lack of safe and effective therapies; and (4) minimal research activity to establish and improve standards of care. A multiagency national partnership has established an approach to address these problems through development of a clinical, genetic, and treatment-related web-based data collection tool that will: (1) generate a reliable, sufficient knowledge base for these disorders; (2) facilitate new product licensure through subject identification and access to comparative historical treatment data; and (3) serve as an effective tool for outcomes research and post-licensure product surveillance. To maximize impact, this database is being harmonized with a European data-collection effort. Database development and harmonization is in progress. A resource library was completed and disseminated to major national and international bleeding disorder websites to provide state-of-the-art patient and provider education on each RCD. We believe that this model is effective and adaptable to other rare conditions. PMID- 22099355 TI - A community-based partnership to promote information infrastructure for bleeding disorders. AB - Specialists in rare disorders often face challenges in collecting surveillance and research data. As movement toward more fully realizing the potential of electronic health information gains momentum, practitioners who treat individuals with rare disorders are in need of public-private support to tap into the advantages offered by the developing electronic information technologies and the interoperability standards promulgated by the USDHHS. The not-for-profit American Thrombosis and Hemostasis Network (ATHN) was created in 2006 to provide stewardship of a secure, national, web-based database to support federally funded hemophilia treatment centers (HTCs) across the country. In pursuit of its mission to support clinical outcomes analysis, research, advocacy, and public health reporting in the hemostasis and thrombosis community, ATHN has established a spectrum of community-based partnerships. This paper describes the process and public health benefits of creating formal relationships with 127 of the 134 HTCs from 12 regional networks across the U.S., government agencies such as the CDC, Health Resources and Services Administration, and NIH; consumer-based organizations; and industry leaders. This community-based partnership model can be applied to other rare disorders communities with high economic and public health impact. PMID- 22099356 TI - Insurance, home therapy, and prophylaxis in U.S. youth with severe hemophilia. AB - BACKGROUND: Home infusion therapy, particularly on a prophylactic regimen, is linked with reduced morbidity among youth with severe hemophilia. However, the association of insurance coverage with these home therapies is unknown. PURPOSE: This study explores the connections among insurance, home infusion therapy, and prophylaxis treatment in a nationwide cohort of 3380 boys and young men (aged 2 to 20 years) with severe hemophilia. These youth obtained care at one of 129 federally supported hemophilia treatment centers (HTCs), and enrolled in the CDC's bleeding disorder surveillance project. METHODS: Multiple regression was used to analyze the independent association among risk factors, including insurance, and both home infusion and prophylaxis. Data were obtained between January 1, 2008, and December 31, 2010, and analyzed in 2011. RESULTS: Ninety percent used home therapy and 78% a prophylaxis regimen. Only 2% were uninsured. Health insurance was significantly associated with prophylaxis, but not with home therapy. Lower prophylaxis utilization rates were independently associated with having Medicaid, "other," and no insurance as compared to having private insurance. Race, age, inhibitor status, and HTC utilization were also independently associated with both home therapy and prophylaxis. CONCLUSIONS: Youth with severe hemophilia who annually obtain care within the U.S. HTC network had a high level of health insurance, home therapy, and prophylaxis. Exploration of factors associated with insurance coverage and yearly HTC utilization, and interventions to optimize home infusion and prophylaxis among youth of African American and "other" race/ethnic backgrounds are warranted. PMID- 22099357 TI - Self-reported barriers to hemophilia care in people with factor VIII deficiency. AB - BACKGROUND: In 1975, a national network of hemophilia treatment centers (HTCs) was created to increase access to healthcare services for individuals with hemophilia. Studies demonstrate that care in HTCs improves outcomes and reduces costs. PURPOSE: The objective of the study was to assess the association of demographic, insurance, and clinical characteristics with self-reported barriers to HTC utilization. METHODS: Data were collected from six HTCs from 2005 through 2007. Adult participants and parents of children aged <18 years were interviewed. Barriers were assessed by asking whether it was difficult to obtain care in the past 12 months. Chi-square test and logistic regression were used to assess factors associated with self-reported barriers to care. All analyses were performed in 2010-2011. RESULTS: Data for 327 participants (50% adult, 64% severe hemophilia) were analyzed in 2010-2011. Most participants/parents did not report barriers to HTC utilization. However, 46 participants/parents (14%) reported one to six barriers, and 23 reported one barrier. Most frequently reported barriers were "distance to the clinic" for children (44%) and "insurance coverage" for adults (40%). Factors significantly associated with self-reported barriers were: lower income (<$20,000; OR=3.11, 95% CI=1.14-8.45), difficulty finding insurance or obtaining full-year coverage (OR=5.71, 95% CI=2.63-12.41), and decreased state Medicaid coverage for low-income, non-elderly individuals (OR=0.93, 95% CI=0.89 0.98). CONCLUSIONS: This study indicates that, although few people with hemophilia have barriers to care at HTCs, those with lower income, difficulty finding or maintaining adequate insurance coverage, or living in states with lower Medicaid generosity are more likely to report barriers. Identifying and resolving such barriers may improve care access and patient-reported outcomes. PMID- 22099358 TI - Surveillance of bleeding disorders, Texas, 2007. AB - BACKGROUND: In 2007, some 1261 patients with hemophilia or other bleeding disorders were seen at federally funded hemophilia treatment centers (HTCs) in Texas. Although HTCs function as sites for passive surveillance of bleeding disorders, annual HTC visit data likely underestimate true prevalence of the disease due to the infrequent nature of healthcare utilization for this population. PURPOSE: The main aim of this study was to compare two alternative methods for estimating prevalence of hemophilia and to describe the challenges associated with making valid prevalence estimates. Each method utilized a separate data source, with the goal of validating one or both of the methods, compared to the gold standard of active case finding. METHODS: Two data sets, one describing treatment of hemophilia in an outpatient setting at HTCs and one describing treatment and care of patients in a hospital inpatient setting, were used to calculate annual prevalence estimates of hemophilia among men in Texas in 2007. The prevalence estimates resulting from each of the two methods were compared to each other and to past estimates based on active surveillance. RESULTS: Calculations based on HTC data resulted in estimated prevalence rates of 8.9 and 2.1/100,000 male population for hemophilia A and B, respectively. Prevalence estimates based on hospital discharge data yielded rates of 12.3 and 2.9/100,000 males for hemophilia A and B, respectively. CONCLUSIONS: Hemophilia is a rare, chronic disease with high treatment costs. Prevalence estimates based on HTC and hospital discharge data were similar to each other as well as to active surveillance prevalence estimates in published literature. PMID- 22099359 TI - Physical functioning in boys with hemophilia in the U.S. AB - BACKGROUND: Hemophilia is the most common inherited severe bleeding disorder. Although the most frequent complication of repeated hemorrhages is a crippling joint disease that begins in childhood, the extent of resultant joint functional impairment varies widely within the hemophilia population. PURPOSE: The goal of this exploratory analysis was to examine a national database that collects information on boys with hemophilia, an X-linked severe congenital bleeding disorder, to determine characteristics associated with increased risk of developing limitations in physical functioning as an outcome of recurrent hemorrhages. METHODS: A standard set of data is collected annually at ~130 U.S. comprehensive hemophilia treatment centers (HTCs) in a voluntary surveillance program called the Universal Data Collection (UDC) program. Fifteen potential predictors for poor outcomes of physical functioning related to bleeding were examined for boys (aged <= 18 years) from 1998 to 2008. Bivariate and multivariate analyses of these predictors performed in 2009 examined associations with self-reported limitation of activities, absenteeism from work or school, and reliance on assistive devices for ambulation and mobility. RESULTS: Multiple characteristics of underlying hemophilia severity and disease chronicity (in particular, increasing age, presence of joint bleeding, and inhibitor antibodies) were independently associated with increased risk of limitations of physical function. Nonwhite race/ethnicity was associated with each of the poorer functional outcomes in bivariate analyses. After controlling for the potential confounding effects of the multiple population characteristics on race, only African-American race was independently associated with activity restrictions, and African-American and Asian/Pacific Island ethnicity with absenteeism. With the exception of indicators of underlying disease severity, only obesity and medical insurance coverage with Medicaid rather than commercial insurance were independently associated with multiple poor outcomes. CONCLUSIONS: Interventions focused on eliminating inhibitors, improving outcomes for African-American children with hemophilia, and maintaining healthy body weight are warranted. In addition, strategies are needed to assure adequate insurance coverage for all people with hemophilia to eliminate economic barriers to optimal functional outcomes. PMID- 22099360 TI - Overweight and obesity in hemophilia: a systematic review of the literature. AB - CONTEXT: As life expectancy in individuals with congenital hemophilia approaches that of the general population, we hypothesize that public health risks, including overweight and obesity, also follow a similar trend. EVIDENCE ACQUISITION: A search of the literature included terms relating to overweight, sequelae of being overweight, and hemophilia. Studies were included if they reported the frequency or clinical significance of known complications of overweight and obesity, including musculoskeletal disease, aerobic capacity, cardiovascular disease, diabetes, hyperlipidemia, decreased quality of life, and change in pharmacokinetics of infused clotting factor in hemophilia. Recommendations from medical organizations were searched for preventive and management strategies applicable to this population. EVIDENCE SYNTHESIS: Overweight and obesity are now more prevalent in the hemophilia population than previous generations, with rates similar to and, in certain subsets even higher, than that of the general population. Increased BMI leads to limitations in joint range of motion in the general population and even more so in persons with hemophilia. CONCLUSIONS: Overweight and obesity in hemophilia are an increasing problem. Simple steps can be taken to encourage patients to decrease caloric intake and increase physical activity. Prevention and management of overweight, obesity, and their sequelae must be addressed in clinical practice in order to maximize the overall health of the hemophilia population. PMID- 22099361 TI - Sickle cell disease: the need for a public health agenda. AB - Sickle cell disease (SCD) is a collection of inherited blood disorders that affect a substantial number of people in the U.S., particularly African Americans. People with SCD have an abnormal type of hemoglobin, Hb S, which polymerizes when deoxygenated, causing the red blood cells to become misshapen and rigid. Individuals with SCD are at higher risk of morbidity and mortality from infections, vaso-occlusive pain crises, acute chest syndrome, and other complications. Addressing the public health needs related to SCD is an important step toward improving outcomes and maintaining health for those affected by the disorder. The objective of this study was to review public health activities focusing on SCD and define the need to address it more comprehensively from a public health perspective. We found that there has been some progress in the development of SCD-related public health activities. Such activities include establishing newborn screening (NBS) for SCD with all states currently having universal NBS programs. However, additional areas needing focus include strengthening surveillance and monitoring of disease occurrence and health outcomes, enhancing adherence to health maintenance guidelines, increasing knowledge and awareness among those affected, and improving healthcare access and utilization. These and other activities discussed in this paper can help strengthen public health efforts to address SCD. PMID- 22099362 TI - Hemoglobinopathy newborn screening knowledge of physicians. AB - BACKGROUND: Hawai'i has a diverse population, including many individuals of Asian descent. A relatively high proportion of Hawai'i infants are born with inherited hemoglobinopathies; about 2% have alpha-thalassemia trait. The Hawai'i Genetics Program engages in genetics services and public health activities, including a hemoglobinopathy clinic and provider education. PURPOSE: This study was undertaken to assess baseline pediatrician hemoglobinopathy knowledge that would then inform the development of education programs. METHODS: In 2008-2009, a brief survey assessed Hawai'i pediatrician hemoglobinopathy and newborn screening (NBS) knowledge. To place results in context, pediatricians in San Francisco (SF) and Salt Lake City (SLC) (similar and different patient demographics, respectively) were surveyed; 660 surveys were mailed to pediatricians from the NBS Program database (Hawai'i) or telephone listings (SF and SLC). Results were analyzed in 2011. Total and individual knowledge scores were calculated based on four questions. RESULTS: Overall, 226 (34%) pediatricians responded: 113 from Hawai'i, 54 from SF, and 59 from SLC (45%, 23%, and 34% response rates, respectively). Overall, 89.4% of participants had either good or perfect knowledge scores: 16% of participants had attended a hemoglobinopathy educational session in the past 6 months; 32.4% give iron to all anemic patients; 29% reported that beta thalassemia is not detected by NBS, and 8% were unsure. Results identified significant knowledge differences regarding sickle cell disease and whether or not a complete blood count diagnoses alpha-thalassemia. CONCLUSIONS: Knowledge gaps between and within the pediatrician populations present opportunities for education regarding hemoglobinopathies and NBS panels. The results will inform the development of hemoglobinopathy education materials to assure a knowledgeable healthcare workforce in the growing area of genetics and newborn screening. PMID- 22099363 TI - Disability among individuals with sickle cell disease: literature review from a public health perspective. AB - CONTEXT: Young people with blood disorders face challenges in maintaining their physical health as they age. Sickle cell disease has well-documented complications in various organ systems. Increasingly, professionals, consumers, and advocates involved in blood disorders are concerned about the cumulative and ongoing effect of organ-specific complications on function and participation. EVIDENCE ACQUISITION: Publications were identified that looked at the relationship between sickle cell disease and associated impairments and restrictions in participation as defined by the International Classification of Function, Disability, and Health (ICF). EVIDENCE SYNTHESIS: This article organizes a literature review in PubMed using ICF terms that define functional limitations and participation restrictions in sickle cell disease. CONCLUSIONS: Individuals with sickle cell disease experience complications in multiple organ systems that affect related functions and, consequently, participation in community living. The effects begin early in childhood and accumulate across the life course into adulthood. Intervention research is needed to understand how contextual factors can promote optimal function and participation in the face of mounting impairments. PMID- 22099365 TI - Screening U.S. college athletes for their sickle cell disease carrier status. AB - There are many issues surrounding the screening of collegiate athletes for their sickle cell disease carrier status (or sickle cell trait), a genetic condition. This paper summarizes the establishment of expert advice given to the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) on the issue. The SACHDNC has developed a report to advise the Secretary of the USDHHS about the 2010 rule of the National Collegiate Athletic Association (NCAA) requiring testing for sickle cell trait in all incoming Division I student athletes. The SACHDNC does not support the NCAA's rule to screen collegiate athletes for sickle cell trait. PMID- 22099366 TI - First conference of the worldwide initiative on social studies of haemoglobinopathies: sickle cell over the next 100 years. PMID- 22099364 TI - Sickle cell disease in Africa: a neglected cause of early childhood mortality. AB - Sickle cell disease (SCD) is common throughout much of sub-Saharan Africa, affecting up to 3% of births in some parts of the continent. Nevertheless, it remains a low priority for many health ministries. The most common form of SCD is caused by homozygosity for the beta-globin S gene mutation (SS disease). It is widely believed that this condition is associated with very high child mortality, but reliable contemporary data are lacking. We have reviewed available African data on mortality associated with SS disease from published and unpublished sources, with an emphasis on two types of studies: cross-sectional population surveys and cohort studies. We have concluded that, although current data are inadequate to support definitive statements, they are consistent with an early life mortality of 50%-90% among children born in Africa with SS disease. Inclusion of SCD interventions in child survival policies and programs in Africa could benefit from more precise estimates of numbers of deaths among children with SCD. A simple, representative, and affordable approach to estimate SCD child mortality is to test blood specimens already collected through large population surveys targeting conditions such as HIV, malaria, and malnutrition, and covering children of varying ages. Thus, although there is enough evidence to justify investments in screening, prophylaxis, and treatment for African children with SCD, better data are needed to estimate the numbers of child deaths preventable by such interventions and their cost effectiveness. PMID- 22099367 TI - Concerted global effort to combat sickle cell disease: the first global congress on sickle cell disease in Accra, Ghana. AB - The First Global Congress on Sickle Cell Disease was held in Accra, Ghana, on July 20-23, 2010, to commemorate 100 years since the first published report of sickle cell disease (SCD). The idea of the Global Congress was conceived following the 2007 meeting in Nicosia, Cyprus, jointly organized by the WHO and the Thalassaemia International Federation (TIF), which recommended that groups working in SCD around the world needed to consolidate efforts into a stronger and more unified umbrella organization. The need for a united global effort received further endorsements at the 2009 International Symposium and Workshop held in Cotonou, Benin, and the 2009 inaugural commemoration of World Sickle Cell Disease Awareness Day, UN Headquarters, New York, New York. The overall goals of the Global Congress were to promote international cooperation and foster collaboration in advancing clinical care and furthering basic and applied research in SCD. Issues covered at the conference included health education, psychosocial needs, public health, medical care, research, program development, and development of international community-based organizations. The Congress participants included medical and research scientists, public health officials, community-based SCD organizations, other nongovernmental organizations, and people with SCD and their families. The Congress concluded with a call on patients and families affected by SCD, as well as advocacy groups, healthcare professionals, scientists, and national governments working to combat SCD to endorse the formation of the World Sickle Cell Disease Federation. PMID- 22099368 TI - Iron overload: what is the role of public health? AB - Hereditary hemochromatosis type 1, also known as hereditary hemochromatosis classical (HHC), is an iron overload disorder associated, in most cases, with mutations of the hemochromatosis (HFE) gene. Although suggested algorithms for diagnosing iron overload are available, there are still questions about options for genetic and biochemical screening for hemochromatosis and duration of treatment. This article provides a summary of an expert workgroup meeting convened on September 24-25, 2009, entitled "Iron Overload: What is the Role of Public Health?" The purpose of the meeting was to enable subject matter experts to share their most recent clinical and scientific iron overload information and to facilitate the discussion of future endeavors, with special emphasis on the role of public health in this field. The two main topics were the research priorities of the field, including clinical, genetic, and public health issues, and the concerns about the validity of current screening recommendations for the condition. PMID- 22099369 TI - Developing public health surveillance for deep vein thrombosis and pulmonary embolism. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively known as venous thromboembolism (VTE), are an important and growing public health issue, associated with considerable morbidity and mortality. Presently, there is no national surveillance for DVT and PE. This article provides a summary of an expert workgroup meeting convened January 12, 2010, by the CDC. The purpose of the meeting was to inform CDC on the development of U.S. population-based public health surveillance activities for DVT/PE. Topics discussed included: (1) stakeholders, needs, gaps, and target populations; (2) requirements of surveillance systems; (3) challenges, limitations, and potential barriers to implementation of surveillance activities; and (4) integration of research and education with surveillance activities. PMID- 22099370 TI - Public health implications of sickle cell trait: a report of the CDC meeting. AB - Although the issue of whether sickle cell trait (SCT) is clinically benign or a significant health concern has not yet been resolved, the potential health risk to affected individuals is of vital importance and represents a tremendous challenge in protecting, promoting, and improving the health of the approximately 300 million people worldwide and 3 million people in the U.S. who possess the trait. In response to a request by the Sickle Cell Disease Association of America, in December 2009, the CDC convened a meeting of partners, stakeholders, and experts to identify the gaps in public health, clinical health services, epidemiologic research, and community-based outreach strategies and to develop an agenda for future initiatives. Through facilitated discussion and presentations in four topic areas, participants discussed pertinent issues, synthesized clinical research findings, and developed a coherent framework for establishing an agenda for future initiatives. A primary outcome of the meeting was to provide the first step of an iterative process to move toward agreement regarding appropriate counseling, care, and, potentially, treatment of people with SCT. PMID- 22099371 TI - Management of severe acute to fulminant hepatitis B: to treat or not to treat or when to treat? AB - Despite a decline in cases of acute hepatitis B and the low hepatitis B virus (HBV) chronicity rates in adults, still some patients progress to HBV-related fulminant liver failure. In this review, we discuss treatment options that may prevent the progression of severe acute hepatitis B to fulminant liver failure and death. In severe acute HBV with prolonged prothrombin time and increased bilirubin, interferon failed to be effective while antiviral treatment, particularly with lamivudine, appears to improve survival (mean survival almost 80%). Outcome without antiviral therapy has remained considerably poor, whereas there is no convincing evidence of amelioration of HBV-targeted immunity. Of note, most patients who died or required transplantation despite lamivudine therapy, were started on lamivudine at advanced stages compared with those survived. This suggests that prompt and timely antiviral therapy is crucial. Owing to the abovementioned results the design of randomized placebo-control trials in the setting of severe acute hepatitis B seems unethical. On the contrary, the design of multicentre double-blind randomized trials to compare the efficacy between lamivudine and entecavir or even tenofovir in acute severe HBV cases is ideally needed, but these studies appear to be very difficult to perform considering that these cases are not frequent and therefore, it is almost impossible to have two arms adequately numerous and homogenous for statistical evaluation. Thus, in the absence of solid evidence based data, the hepatologists could treat their patients with severe acute hepatitis B with lamivudine or the most potent antivirals entecavir or tenofovir. PMID- 22099372 TI - Incidental diagnosis of a deep vein thrombosis in consecutive patients undergoing a computed tomography scan of the abdomen: a retrospective cohort study. PMID- 22099373 TI - l-Arabinose production from sugar beet arabinan by immobilized endo- and exo arabinanases from Caldicellulosiruptor saccharolyticus in a packed-bed reactor. AB - The immobilized endo- and exo-arabinanases from Caldicellulosiruptor saccharolyticus produced continuously an average of 16.5 gl(-1)l-arabinose from 20 gl(-1) sugar beet arabinan at pH 5.0 and 75 degrees C for 216 h, with a productivity of 9.9 gl(-1)h(-1) and a conversion yield of 83%. PMID- 22099374 TI - Stability of lactobacilli encapsulated in various microbial polymers. AB - Various microbial polymers, namely xanthan gum, gellan gum, pullulan gum and jamilan, were tested as a suitable encapsulating material for Lactobacillus plantarum CRL 1815 and Lactobacillus rhamnosus ATCC 53103. Resulting capsules were also studied for their pH and simulated gastrointestinal conditions tolerance. The morphology of the microcapsules was studied using scanning electron microscopy. pH tolerance was tested at pH 2.0, 3.5, 5.0 and 6.5 over a 6h incubation period. Simulated gastrointestinal conditions were assayed with simulated gastric and pancreatic juices and simulated bile over a 24h incubation period. Suspensions of probiotic organisms were used as a control. The results from encapsulation with microbial polymers indicate that mixtures of 1% xanthan gum with 0.75% gellan gum and 1% jamilan with 1% gellan gum were the most suitable for microencapsulation. Results for the pH tolerance tests showed no improvement in the viability of cells in relation to the control, except for pH 2.0 where lactobacilli encapsulated in xanthan:gellan gum (1%:0.75%) prolonged their viability by 6h exposure. Xanthan:gellan gum (1%:0.75%) was the most effective of the encapsulating materials tested in protecting L. plantarum and L. rhamnosus against simulated bile, improving its viability in 1-2 logCFU when compared with control. The results of this study suggest that microbial polymers are an interesting source of encapsulating material that should be taken into account for prospective studies of probiotic encapsulation for oral delivery applications. PMID- 22099375 TI - Metabolic engineering of hydrophobic Rhodococcus opacus for biodesulfurization in oil-water biphasic reaction mixtures. AB - An organic solvent-tolerant bacterium, Rhodococcus opacus B-4, was metabolically engineered to remove sulfur from dibenzothiophene (DBT), a component of crude oil. The resulting recombinant strain ROD2-8 constitutively expressed the Rhodococcus erythropolis IGTS8 genes dszA, dszB, and dszC, encoding dibenzothiophene sulfone monooxygenase, 2-(2'-hydroxyphenyl) benzenesulfinate desulfinase, and dibenzothiophene monooxygenase, respectively, of the 4S pathway to avoid transcriptional inhibition by the sulfate end-product. Unlike the wild type strain, ROD2-8 grew in mineral salts medium containing DBT as the sole sulfur source. Under aqueous conditions, ROD2-8 resting cells converted greater than 85% of DBT to 2-hydroxybiphenyl (2-HBP), although the consumption rate by ROD2-8 cells precultured on DBT as the sole sulfur source was 3.3-fold higher than that of cells cultured in complex medium. Notably, DBT consumption rates increased by 80% in oil-water biphasic reaction mixtures with n-hexadecane as the organic solvent, and resting cells were predominantly localized in the emulsion layer. Desulfurization activity in biphasic reaction mixtures increased with increasing concentrations of DBT and was not markedly inhibited by 2-HBP accumulation. Intracellular concentrations of DBT and 2-HBP were significantly lower under biphasic conditions than aqueous conditions. Our findings suggest that the enhanced desulfurization activity under biphasic conditions results from the combined effects of attenuated feedback inhibition and reduced mass transfer limitations due to 2-HBP diffusion from cells and accumulation of both substrate and biocatalyst in the emulsion layer, respectively. Therefore, the solvent tolerant and hydrophobic bacterium R. opacus B-4 appears suitable for biodesulfurization reactions in solvents containing a minimum ratio of water. PMID- 22099376 TI - Intracellular co-expression of Vitreoscilla hemoglobin enhances cell performance and beta-galactosidase production in Pichia pastoris. AB - Pichia pastoris has been used to produce various recombinant proteins under high oxygen demand conditions. To improve the heterologous production of beta galactosidase, the vgb gene encoding Vitreoscilla hemoglobin (VHb) was co expressed in the P. pastoris cytoplasm under the control of the methanol inducible promoter. Co-expression of VHb under different aeration conditions improved cell performance in terms of growth, viability, respiratory rate, and beta-galactosidase production. Under limiting aeration conditions, the VHb(+) strain produced 28.2% more biomass but 31.2% less total beta-galactosidase activity than the VHb(-) strain. Under non-limiting aeration conditions, the VHb(+) strain showed 20.3% higher cell growth and 9.9% more total beta galactosidase activity than the VHb(-) strain. Moreover, under these conditions, the VHb(+) strain was 7.7% more viable and had a 28.2% higher oxygen uptake rate (OUR) than the VHb(-) strain. Evidently, VHb can enhance the OUR and promote methanol metabolism, thereby improving cell performance and beta-galactosidase production. PMID- 22099377 TI - Efficient propagation of archetype BK and JC polyomaviruses. AB - BKPyV and JCPyV are closely related, ubiquitous human pathogens that cause disease in immunocompromised patients. The DNA sequence of the regulatory regions distinguishes two forms of these viruses, designated archetype and rearranged. Although cell culture systems exist for rearranged BKPyV and JCPyV, currently there is no robust cell culture system to study the archetype viruses. Large T antigen (TAg) is a virally encoded protein required to initiate viral DNA synthesis. Because archetype virus produces undetectable levels of TAg, we hypothesized that TAg overexpression would stimulate archetype virus replication. Efficient propagation of the archetype forms of BKPyV and JCPyV was observed in 293TT cells, human embryonic kidney cells overexpressing SV40 TAg. Importantly, the archetypal structure of the regulatory region was maintained during viral growth. Significant replication was not observed for Merkel cell, KI, or WU polyomaviruses. 293TT cells provide a means of propagating archetype BKPyV and JCPyV for detailed study. PMID- 22099378 TI - An adaptive mutation in NS2 is essential for efficient production of infectious 1b/2a chimeric hepatitis C virus in cell culture. AB - The development of JFH1 based intergenotypic recombinants which exploit the unique replication characteristics of JFH1 has made it possible to study infectious HCV encoding the structural genes of additional HCV genotypes including genotype 1b. Although, intergenotypic 1b/2a chimeric genomes replicate efficiently in transfected cells they produce very low viral titers, limiting the utility of this system. Here, intergenotypic 1b/2a variants were generated by serially passaging the virus in a novel highly permissive Huh-7 cell clone. The adapted virus was 1000-fold more infectious than the parental unadapted virus and six adapted mutations were identified throughout the genome. Of the mutations identified, L839S in the NS2 gene was the most critical for the adapted phenotype by enhancing the infectivity of assembled viral particles. Overall, the efficient production of infectious 1b/2a virus particles will facilitate the discovery and characterization of inhibitors targeting steps that involve the structural genes of genotype 1b HCV. PMID- 22099379 TI - Internal jugular vein catheterization-induced mediastinal hematoma. PMID- 22099380 TI - An improved rapid method for the preparation of D-rhamnose. AB - A method is developed for the preparation of D-rhamnose from an O-polysaccharide (OPS) isolated by mild acid hydrolysis of Azospirillum brasilense SR75 cell mass. After the OPS hydrolysis, D-rhamnose was recovered by gel-permeation chromatography on Toyopearl TSK HW-40 and was crystallized. The sugar activity was demonstrated immunochemically. The advantages of the method are that it expedites and simplifies the extraction of D-rhamnose and increases its yield. PMID- 22099381 TI - Structure of the O-polysaccharide from the lipopolysaccharide of Providencia alcalifaciens O48. AB - An O-polysaccharide was isolated by mild acid degradation of the lipopolysaccharide of Providencia alcalifaciens O48 and studied by sugar and methylation analyses along with (1)H and (13)C NMR spectroscopy, including 2D COSY, TOCSY, ROESY and (1)H,(13)C HSQC and HMBC experiments. It was found that the polysaccharide is acidic and has a linear mono-O-acetylated tetrasaccharide repeating unit with the following structure: ->3)-alpha-D-Manp-(1->2)-alpha-L Fucp-(1->2)-beta-D-GlcpA4Ac-(1->3)-alpha-D-GalpNAc-(1->. PMID- 22099382 TI - Synthesis and characterization of pH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole. AB - In the present study, carboxymethyl chitosan was prepared from chitosan, crosslinked with glutaraldehyde and evaluated in vitro as a potential carrier for colon targeted drug delivery of ornidazole. Ornidazole was incorporated at the time of crosslinking of carboxymethyl chitosan. The chitosan was evaluated for its degree of deacetylation (DD) and average molecular weight; which were found to be 84.6% and 3.5*10(4) Da, respectively. The degree of substitution on prepared carboxymethyl chitosan was found to be 0.68. All hydrogel formulations showed more than 85% and 74% yield and drug loading, respectively. The swelling behaviour of prepared hydrogels checked in different pH values, 1.2, 6.8 and 7.4, indicated pH responsive swelling characteristic with very less swelling at pH 1.2 and quick swelling at pH 6.8 followed by linear swelling at pH 7.4 with slight increase. In vitro release profile was carried out at the same conditions as in swelling and drug release was found to be dependant on swelling of hydrogels and showed biphasic release pattern with non-fickian diffusion kinetics at higher pH. The carboxymethylation of chitosan, entrapment of drug and its interaction in prepared hydrogels were checked by FTIR, (1)H NMR, DSC and p-XRD studies, which confirmed formation of carboxymethyl chitosan from chitosan and absence of any significant chemical change in ornidazole after being entrapped in crosslinked hydrogel formulations. The surface morphology of formulation S6 checked before and after dissolution, revealed open channel like pores formation after dissolution. PMID- 22099383 TI - Isolation of human nasoseptal chondrogenic cells: a promise for cartilage engineering. AB - In cartilaginous tissues, perichondrium cambium layer may be the source of new cartilage. Human nasal septal perichondrium is considered to be a homogeneous structure in which some authors do not recognize the perichondrium internal zone or the cambium layer as a layer distinct from adjacent cartilage surface. In the present study, we isolated a chondrogenic cell population from human nasal septal cartilage surface zone. Nasoseptal chondrogenic cells were positive for surface markers described for mesenchymal stem cells, with exception of CD146, a perivascular cell marker, which is consistent with their avascular niche in cartilage. Although only Sox-9 was constitutively expressed, they also revealed osteogenic and chondrogenic, but not adipogenic, potentials in vitro, suggesting a more restricted lineage potential compared to mesenchymal stem cells. Interestingly, even in absence of chondrogenic growth factors in the pellet culture system, nasoseptal chondrogenic cells had a capacity to synthesize sulfated glycosaminoglycans, large amounts of collagen type II and to a lesser extent collagen type I. The spontaneous chondrogenic potential of this population of cells indicates that they may be a possible source for cartilage tissue engineering. Besides, the pellet culture system using nasoseptal chondrogenic cells may also be a model for studies of chondrogenesis. PMID- 22099384 TI - Impact of polydextrose on the faecal microbiota: a double-blind, crossover, placebo-controlled feeding study in healthy human subjects. AB - In this placebo-controlled, double-blind, crossover human feeding study, the effects of polydextrose (PDX; 8 g/d) on the colonic microbial composition, immune parameters, bowel habits and quality of life were investigated. PDX is a complex glucose oligomer used as a sugar replacer. The main goal of the present study was to identify the microbial groups affected by PDX fermentation in the colon. PDX was shown to significantly increase the known butyrate producer Ruminococcus intestinalis and bacteria of the Clostridium clusters I, II and IV. Of the other microbial groups investigated, decreases in the faecal Lactobacillus-Enterococcus group were demonstrated. Denaturing gel gradient electrophoresis analysis showed that bacterial profiles between PDX and placebo treatments were significantly different. PDX was shown to be slowly degraded in the colon, and the fermentation significantly reduced the genotoxicity of the faecal water. PDX also affected bowel habits of the subjects, as less abdominal discomfort was recorded and there was a trend for less hard and more formed stools during PDX consumption. Furthermore, reduced snacking was observed upon PDX consumption. This study demonstrated the impact of PDX on the colonic microbiota and showed some potential for reducing the risk factors that may be associated with colon cancer initiation. PMID- 22099385 TI - [Post-traumatic pseudoaneurysm of the innominate artery: a rare presentation of tracheal stenosis]. PMID- 22099386 TI - [Spontaneous pneumothorax as the initial manifestation of medullary thyroid carcinoma]. PMID- 22099387 TI - Impact of medication adherence on health care utilization and productivity: self reported data from a cohort of postmenopausal women on osteoporosis therapy. AB - BACKGROUND: Many pharmacologic agents are approved for the prevention and treatment of osteoporosis, which is common among postmenopausal women. Evidence exists relating treatment persistence to fracture risk. Less is known about treatment persistence and the use of health care service and individual productivity. OBJECTIVE: This study was undertaken to describe health care use and productivity loss relative to osteoporosis medication persistence using women's self-reported data from the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE USTM), a large, longitudinal (October 2004-December 2009) osteoporosis cohort study of postmenopausal women. METHODS: Analyses included women on pharmacologic osteoporosis therapy (alendronate, risedronate, ibandronate, calcitonin, raloxifene, or teriparatide) who provided health care use/productivity data collected using semiannual questionnaires over 1 year of follow-up. Participant characteristics, use, and productivity metrics were summarized. Logistic regression models and generalized linear models were used to examine use, time missed from usual activities, number of days spent in bed, and lost work time relative to treatment persistence, adjusting for potential confounders. RESULTS: At entry, of the 2528 women studied (91% white, 3.1% Hispanic/Latino, 2.3% African American/black, 1.1% Asian, and 2.1% American Indian/Native Alaskan, Native Hawaiian/Pacific Islander, or other; mean age, 64.6 [range, 37-97] years), 43.1% had osteoporosis and 23.4% had a previous fracture. After adjustment, subjects who switched therapies during follow-up were more likely to have had any kind of diagnostic testing (95.2% of switchers vs 91.2% of persistent subjects and 88.9% of discontinuers, P < 0.05). Discontinuers were less likely than persistent subjects to visit their primary care physicians (92.0% vs 94.4%, P = 0.0337). Variations in the number of days spent in bed, time missed from usual activities, and work loss (n = 852 employed subjects) by treatment persistence were not significant. CONCLUSIONS: Use of diagnostic testing differed significantly by osteoporosis treatment status. Compared with women who persisted with treatment, primary care provider visits were less common among those who discontinued treatment. Treatment persistence was not associated with significant differences in productivity measures. PMID- 22099388 TI - Quality evaluation of microscopy and scanned histological images for diagnostic purposes. AB - In this work we present a study for assessing and comparing the fidelity of biopsy and cytology images captured with two different devices, that is optical microscopes and scanners, at 40* magnification in bright field. The devices use different ways to magnify images. Microscopes use a set of lenses while scanners capture light through arrays of micro-photoreceptors. The objective is to carry out a quantitative evaluation to discern which of the two devices provides better image quality in terms of contrast, colour and stain. Since there is no unanimous consensus on quality metrics, we will make use of both an objective metric based on perceptual features, together with a subjective psychophysical test as the International Telecommunications Union (ITU) recommends in ITU-R BT.500 for such type of tests. Both techniques indicate a slight preference for the scanner over the microscope in terms of better image quality, considering defocus as the main problem followed by colour distortions. However, the image quality of both devices is suitable for clinical, educational and research purposes. PMID- 22099389 TI - Analysis on surface nanostructures present in hindwing of dragon fly (Sympetrum vulgatum) using atomic force microscopy. AB - The present study involves the analysis of surface nanostructures and its variation present in the hind wing of dragon fly (Sympetrum vulgatum) using atomic force microscopy (AFM). The hindwing was dissected into 4 parts (D1-D4) and each dissected section was analyzed using AFM in tapping mode at different locations. The AFM analysis revealed the presence of irregular shaped nanostructures on the surface of the wing membrane with size varying between 83.25+/-1.79 nm to 195.08+/-10.25 nm. The size and shape of the nanostructure varied from tip (pterostigma) to the costa part. The membrane surface of the wing showed stacked arrangement leading to increase in size of the nanostructure. Such arrangement of the nanostructures has lead to the formation of nanometer sized valleys of different depth and length on the membrane surface giving them ripple wave morphology. The average roughness of the surface nanostructures varied from 18.58+/-3.12 nm to 24.25+/-8.33 nm. Surfaces of the wings had positive skewness in D1, D2 and D4 regions and negative skewness in D3 region. These surface nanostructures may contribute asymmetric resistance under mechanical loading during the flight by increasing the bending and torsional resistance of the wing. PMID- 22099390 TI - SNP-based analysis of neuroactive ligand-receptor interaction pathways implicates PGE2 as a novel mediator of antipsychotic treatment response: data from the CATIE study. PMID- 22099391 TI - Brief review on systematic hypothermia for the protection of central nervous system during aortic arch surgery: a double-sword tool? AB - Antegrade selective cerebral perfusion in conjunction with hypothermia attenuate postoperative neurological injury, which in turn still remains the main cause of mortality and morbidity following aortic arch surgery. Hypothermic circulatory arrest however could be a useful tool during arch surgery, surgery for chronic thromboembolic disease, air on the arterial line during CPB, during cavotomy for extraction of renal cell carcinoma with level IV extension, or when dealing with difficult trauma to the SVC or IVC. Cerebral protective effects with hypothermic procedures including inhibition of neuron excitation, and discharge of excitable amino acids, and thereby, prevention of an increase in intercellular calcium ions, hyperoxidation of lipids in cell membranes, and free radical production.The authors are briefly discussing the fundamental principles of using hypothermia as an adjunct tool of the cardiothoracic surgeon's practice. The relationship between temperature, flow, metabolic requirements and adverse effects is addressed. PMID- 22099392 TI - DNA-nanostructure-assembly by sequential spotting. AB - BACKGROUND: The ability to create nanostructures with biomolecules is one of the key elements in nanobiotechnology. One of the problems is the expensive and mostly custom made equipment which is needed for their development. We intended to reduce material costs and aimed at miniaturization of the necessary tools that are essential for nanofabrication. Thus we combined the capabilities of molecular ink lithography with DNA-self-assembling capabilities to arrange DNA in an independent array which allows addressing molecules in nanoscale dimensions. RESULTS: For the construction of DNA based nanostructures a method is presented that allows an arrangement of DNA strands in such a way that they can form a grid that only depends on the spotted pattern of the anchor molecules. An atomic force microscope (AFM) has been used for molecular ink lithography to generate small spots. The sequential spotting process allows the immobilization of several different functional biomolecules with a single AFM-tip. This grid which delivers specific addresses for the prepared DNA-strand serves as a two-dimensional anchor to arrange the sequence according to the pattern. Once the DNA-nanoarray has been formed, it can be functionalized by PNA (peptide nucleic acid) to incorporate advanced structures. CONCLUSIONS: The production of DNA-nanoarrays is a promising task for nanobiotechnology. The described method allows convenient and low cost preparation of nanoarrays. PNA can be used for complex functionalization purposes as well as a structural element. PMID- 22099393 TI - Medical marijuana laws in 50 states: investigating the relationship between state legalization of medical marijuana and marijuana use, abuse and dependence. AB - BACKGROUND: Marijuana is the most frequently used illicit substance in the United States. Little is known of the role that macro-level factors, including community norms and laws related to substance use, play in determining marijuana use, abuse and dependence. We tested the relationship between state-level legalization of medical marijuana and marijuana use, abuse, and dependence. METHODS: We used the second wave of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a national survey of adults aged 18+ (n=34,653). Selected analyses were replicated using the National Survey on Drug Use and Health (NSDUH), a yearly survey of ~68,000 individuals aged 12+. We measured past-year cannabis use and DSM-IV abuse/dependence. RESULTS: In NESARC, residents of states with medical marijuana laws had higher odds of marijuana use (OR: 1.92; 95% CI: 1.49-2.47) and marijuana abuse/dependence (OR: 1.81; 95% CI: 1.22-2.67) than residents of states without such laws. Marijuana abuse/dependence was not more prevalent among marijuana users in these states (OR: 1.03; 95% CI: 0.67-1.60), suggesting that the higher risk for marijuana abuse/dependence in these states was accounted for by higher rates of use. In NSDUH, states that legalized medical marijuana also had higher rates of marijuana use. CONCLUSIONS: States that legalized medical marijuana had higher rates of marijuana use. Future research needs to examine whether the association is causal, or is due to an underlying common cause, such as community norms supportive of the legalization of medical marijuana and of marijuana use. PMID- 22099394 TI - PP3 forms stable tetrameric structures through hydrophobic interactions via the C terminal amphipathic helix and undergoes reversible thermal dissociation and denaturation. AB - The milk protein proteose peptone component 3 (PP3), also called lactophorin, is a small phosphoglycoprotein that is expressed exclusively in lactating mammary tissue. The C-terminal part of the protein contains an amphipathic helix, which, upon proteolytic liberation, shows antibacterial activity. Previous studies indicate that PP3 forms multimeric structures and inhibits lipolysis in milk. PP3 is the principal component of the proteose peptone fraction of milk. This fraction is obtained by heating and acidifying skimmed milk, and in the dairy industry milk products are also typically exposed to treatments such as pasteurization, which potentially could result in irreversible denaturation and inactivation of bioactive components. We show here, by the use of CD, that PP3 undergoes reversible thermal denaturation and that the alpha-helical structure of PP3 remains stable even at gastric pH levels. This suggests that the secondary structure survives treatment during the purification and possibly some of the industrial processing of milk. Finally, asymmetric flow field-flow fractionation and multi-angle light scattering reveal that PP3 forms a rather stable tetrameric complex, which dissociates and unfolds in guanidinium chloride. The cooperative unfolding of PP3 was completely removed by the surfactant n-dodecyl-beta-d maltoside and by oleic acid. We interpret this to mean that the PP3 monomers associate through hydrophobic interactions via the hydrophobic surface of the amphipathic helix. These observations suggest that PP3 tetramers act as reservoirs of PP3 molecules, which in the monomeric state may stabilize the milk fat globule. PMID- 22099396 TI - Assessing smoking status in disadvantaged populations: is computer administered self report an accurate and acceptable measure? AB - BACKGROUND: Self report of smoking status is potentially unreliable in certain situations and in high-risk populations. This study aimed to determine the accuracy and acceptability of computer administered self-report of smoking status among a low socioeconomic (SES) population. METHODS: Clients attending a community service organisation for welfare support were invited to complete a cross-sectional touch screen computer health survey. Following survey completion, participants were invited to provide a breath sample to measure exposure to tobacco smoke in expired air. Sensitivity, specificity, positive predictive value and negative predictive value were calculated. RESULTS: Three hundred and eighty three participants completed the health survey, and 330 (86%) provided a breath sample. Of participants included in the validation analysis, 59% reported being a daily or occasional smoker. Sensitivity was 94.4% and specificity 92.8%. The positive and negative predictive values were 94.9% and 92.0% respectively. The majority of participants reported that the touch screen survey was both enjoyable (79%) and easy (88%) to complete. CONCLUSIONS: Computer administered self report is both acceptable and accurate as a method of assessing smoking status among low SES smokers in a community setting. Routine collection of health information using touch-screen computer has the potential to identify smokers and increase provision of support and referral in the community setting. PMID- 22099397 TI - BMP-7/TGF-beta1 signalling in myoblasts: components involved in signalling and BMP-7-dependent blockage of TGF-beta-mediated CTGF expression. AB - We and others have recently described the antagonistic role of Bone morphogenetic protein-7 (BMP-7) in TGF-beta signalling and myogenic differentiation. To specify the underlying mechanism(s), we here analysed the expression and function of the individual components mediating TGF-beta1 and BMP-7 responses. We found that BMP 7 at a concentration of 25 ng/ml induces signalling exclusively via ALK2 and ALK3 leading to the activation of Smad1 and Smad5 and subsequent expression of Id proteins. In contrast, low doses of TGF-beta1 (0.1 ng/ml) lead to an exclusive activation of ALK5 and phosphorylation of Smad2 and Smad3 that regulate specific target genes including connective tissue growth factor (CTGF). CTGF is rapidly induced by TGF-beta1 already 1h after stimulation and reduced by BMP-7 application. Smad1/Smad5 or Id1/2 overexpression reduced the TGF-beta1-mediated expression of CTGF. However, although siRNA-mediated knock down of Alk2/3 or Smad1/5 counteracts the BMP-7 effect on basal CTGF expression there was no consistent reversion of the observed BMP-7 effect on TGF-beta1-mediated CTGF expression. Moreover, ALK5 inhibition using the SB431542 inhibitor significantly affected CTGF expression only at later time points whereas ERK1/2 inhibition completely abrogated CTGF expression. These findings point towards a regulatory role of BMP-7 that relies on modulation of Mitogen-activated protein kinases rather than mechanisms that are exclusively driven by differential Smad activation. PMID- 22099398 TI - Low prevalence of cardiac valve abnormalities in patients with autosomal dominant polycystic liver disease. PMID- 22099399 TI - [Looking for the best molecule. A short history of anticoagulants]. PMID- 22099400 TI - [Managing multidrug-resistant tuberculosis]. PMID- 22099401 TI - [Indications for surgery in non-small cell lung cancer with lymph node invasion]. AB - Surgery is indicated for N1 non-small cell lung cancer and performed, with good results in some patients, when N2 disease is not diagnosed preoperatively "minimal N2". Following the publication of the "EORTC 08941" and "Intergroup 0139" trials, it remains debatable for patients with proven N2 disease. Good prognostic factors before treatment or post-induction favour surgery, which seems superior to radiochemotherapy if the operative risk is low (lobectomies, and some pneumonectomies). N3 status is a contraindication to surgery, except in some rare cases with a strong response to induction treatment. PMID- 22099402 TI - [Patent foramen ovale and hypoxaemia with or without elevated right heart pressures]. AB - The prevalence of patent foramen ovale (PFO) is high. As identified at autopsy it is found in approximately 25% of the general population. Anatomically a PFO represents a channel through which unidirectional blood flow from the right to the left atrium may occur. This potential interatrial shunt of unoxygenated venous blood into the oxygenated arterial system may lead to hypoxaemia. Usually right to left shunting across a PFO is transient and without clinical significance. Increased pulmonary arterial pressure may give rise to left-right pressure gradient reversal and right to left shunting across a PFO. High pressure in the right heart chambers, even without pulmonary arterial hypertension, can potentially lead to the reopening of a foramen ovale. In other cases inferior vena cava flow deviation might lead to right to left shunting across a PFO. Right to left shunting without pressure increase inside the right heart chambers is usually transient and even positional and its diagnosis is more difficult. PMID- 22099403 TI - [Smokeless tobacco]. AB - Use of smokeless tobacco (ST) (chewing tobacco and snuff) can lead to a number of consequences detrimental to health. ST rapidly delivers high doses of nicotine, which can lead to dependence and is also a source of carcinogenic nitrosamines. Changes usually develop in the mouth area where the ST is most often placed. Non malignant oral lesions include leuko-oedema, hyperkeratotic lesions of the oral mucosa and localised periodontal disease. Oral premalignant lesions are leukoplakia, erythroplakia, submucosal fibrosis and lichen planus. Betel chewing, with or without tobacco, may increase the incidence of oral cancer. There is conflicting evidence with regard to snuff users about the risk of oral and gastro oesophageal cancer. ST use is a risk factor for pancreatic cancer and may increase the risk of fatal myocardial infarction and ischemic stroke. During pregnancy, ST is associated with an increase in pre-eclampsia, preterm delivery and stillbirth. Nicotine replacement therapy and bupropion reduce withdrawal symptoms and tobacco craving during ST cessation. However, they have not been shown to help long-term abstinence. Information concerning the potential hazards of ST products should be incorporated into educational programmes to discourage its use and to help users to quit. Smokeless tobacco is not recommended to help smoking cessation. PMID- 22099404 TI - [What counselling to give to workers occupationally exposed to asbestos?]. AB - When one approaches the issue of the follow-up of workers occupationally exposed to asbestos the first question to resolve is "what counselling to give?" This constitutes an essential first step because it allows people to decide whether or not they wish to accept the proposed follow up programme. The difficulty relates to the idea of exposure to a carcinogen. Facing this question is never easy and generates emotional responses that cannot be ignored. Therefore the content should include elements that allow an understanding of the diseased concerned, the risk (depending on the type of exposure), the benefits and limits of screening, and an awareness of the possible consequences of follow up. The programme should allow enough time for one to one discussion with a professional to consider all aspects. It may be necessary to meet for a second time. This counselling may be given, to subjects over 50 years old, in the framework of either the occupational health or social security services. The counselling of people exposed to asbestos justifies, in itself, a follow up programme and represents its main benefit. It should guarantee the worker's most elementary right: to decide for himself in full knowledge of the facts. PMID- 22099405 TI - [Pilot data from the Spirale project -- follow-up of occupational respiratory exposures]. AB - INTRODUCTION: The medical follow-up of individuals who have had occupational exposures to potential respiratory hazards is little known and under-utilised. The Spirale program aims to deliver this intervention effectively to all potential beneficiaries. METHODS: Spirale was introduced in two stages; i) identification of occupational exposures to asbestos or wood dust through a postal questionnaire; ii) for those initially identified, confirmation of exposure through attendance at a health centre for examination and further medical follow-up as necessary. RESULTS: In 2007, Spirale contacted 50,662 men born between 1942 and 1943, living in 13 departments in France. The initial response rate was 24%, rising to 50% after reminders. Seventy-two percent of people were identified as possibly having been exposed; 50% to asbestos, 3% to wood dust and 19% reporting a mixed exposure. Among the 8641 people located, 3843 (44.5%) benefited from an evaluation of their exposure. In total, 73.4% of people had their exposure to asbestos confirmed and in 1751 (64.2%) this was at a level to justify follow-up. CONCLUSION: TheSpirale program largely achieved its objective of location and initiation of medical monitoring of people who have been exposed through their work to respiratory carcinogens. It should now be implemented throughout the country. PMID- 22099406 TI - [New antithrombotic drugs for the treatment of venous thromboembolism]. AB - Numerous newer anticoagulants are under advanced clinical development for the treatment of venous thromboembolism. These new drugs specifically inhibit activated factors II or X, with predictable effects and no need for dose modification and laboratory monitoring. The main direct activated factor X (FXa) inhibitors are rivaroxaban, apixaban and edoxaban. They are taken orally once or twice per day. Dabigatran is the main inhibitor of activated factor II (IIa) and is administered orally once daily. Dabigatran and rivaroxaban are already licensed for the prevention of thromboembolic events following major orthopedic surgery such as total hip and knee replacement. They will probably soon be authorized for the treatment of venous thromboembolism, if they both confirm their efficacy and safety, and can demonstrate their cost-effectiveness. However, only rivaroxaban has been tested as a stand-alone treatment, whereas dabigatran was compared to vitamin K antagonism after a standard treatment regimen based on heparin or its derivates. PMID- 22099407 TI - [Prenatal diagnosis and management of foetal lung lesions]. AB - INTRODUCTION: Foetal lung lesions are uncommon (<1/1000 deliveries). Prenatal ultrasound can distinguish echogenic and cystic lesions. BACKGROUND: The most frequently diagnosed abnormalities are congenital cystic adenomatoid malformation (echogenic and/or cystic), pulmonary sequestration (echogenic), congenital lobar emphysema (echogenic) and bronchogenic cyst (cystic). Most of them carry a good prognosis but complications, including foetal hydrops, may occur and should be looked for regularly prenatally. Congenital upper airway obstruction syndromes are very rare and carry a very poor prognosis. VIEWPOINT: The follow-up of these pregnancies should be undertaken in a tertiary centre and information regarding postnatal management should be given prenatally by the doctors who will care for the infant after birth. Serial ultrasound examinations are required to evaluate the natural history and detect complications. Spontaneous regression may occur. The occurrence of foetal hydrops is usually fatal in the absence of treatment and should be managed as an emergency. CONCLUSIONS: Congenital malformations of the lung are rare and usually carry a good prognosis. Careful follow-up and delivery should be performed in a tertiary centre and postnatal investigation should include clinical and radiological evaluation. PMID- 22099408 TI - [Multidrug resistant tuberculosis -- its extent, hazard and possible solutions]. AB - Multidrug resistant tuberculosis (MDR-TB) has spread to most regions of the world and represents a serious threat to the success of the struggle against tuberculosis. It can result from errors in management that favour the selection of drug resistant organisms and can in the worst case lead to the development of extremely resistant organisms (XDR-TB) which are practically untreatable. The current strategies for combating this problem are, on the one hand, the rapid identification and tracking of resistant strains using molecular genetic techniques and, on the other hand, careful drug management in individual cases using second line agents. At the level of public health, the most important measures are those which prevent or correct the processes which can drive the creation of new cases of MDR-TB. This can have implications for the modification and development of national strategies. The future of the fight against tuberculosis depends in part on the success of strategies to combat the development and spread of MDR-TB. PMID- 22099409 TI - [Bacteriological tests for tuberculosis]. AB - This review describes current developments for the bacteriological diagnosis of active tuberculosis. It deals mainly with molecular methods, describing their performance and how they can be integrated into more traditional diagnostic approaches. At present, microscopic examination and culture are still essential for the diagnosis of TB and to guide therapeutic decisions. Nucleic acid amplification and line probe assays speed up the identification and susceptibility testing of mycobacteria in AFB smear positive specimens or in culture. They are also efficient for comparison of M. tuberculosis strains with each other (genotyping). On the other hand, at present, molecular tests are not applicable for diagnosis in smear negative specimens and even less so for diagnosis of culture-negative tuberculosis. The use of serology for antibody/antigen detection is not useful and it is not appropriate to assays based on the release of interferon-gamma release as they are currently available. Notable progress has been made but more sensitive diagnostic tests for TB are still urgently needed. PMID- 22099410 TI - [Epidemiological novelties in lung cancer]. AB - Lung cancer is the most common cause of cancer-related mortality throughout the world representing around 18% of the total. There is still a male predominance but this is becoming less pronounced and in the US, lung cancer is now the most common cause of cancer-related mortality in women. In France, it had risen to second place in women in 2005 after having been in 6th place in 1975. Median age at diagnosis differs according to countries and health system and is around 70 years in the US and around 65 years in France. The distribution of histological subtypes has changed considerably during recent decades with an increasing frequency of adenocarcinoma at the expense of squamous cell carcinoma. The main risk factor for lung cancer remains active tobacco smoking but the attributable risk of smoking varies from one country to another and according to gender. In Japan, the great majority of lung cancer in women is not attributable to active tobacco smoking. Environmental tobacco smoke exposure has a less important role than active tobacco smoking although it is not negligible. The specific impact of smoking cannabis is difficult to assess precisely as, in most cases, it is mixed with tobacco. However, despite important differences with tobacco smoke, cannabis exposure doubles the risk of developing lung cancer. Occupational risk factors have for a long time been neglected and thus occupational lung cancers have been under-reported. Finally, lung cancer in never-smokers is driving considerable interest as it represents by itself the 7th largest cause of mortality due to cancer. Risk factors involved might be air pollution (indoors and outdoors) but also hormone replacement therapy in women. PMID- 22099411 TI - [Exacerbations of asthma--precipitating factors: drugs]. AB - Asthmatic exacerbations are sometimes triggered by medications, primarily the non steroidal anti-inflammatory agents (NSAIDS) and beta-blockers. Asthma attacks induced by NSAIDS occur rapidly and can be severe. Widal syndrome is a specific disease entity whose physiopathology remains incompletely explained. Asthma is characteristically severe and steroid dependent; desensitisation with aspirin has been proposed, but this remains controversial. Beta-blockers are contra-indicated in asthma; the beta1 "cardioselectivity" of some agents is not absolute, disappearing at high doses and the "partial agonists" are not better tolerated. However, certain authors have called into question the harmful effect of beta blockade in moderate and stable asthma. More studies are needed, but the current data suggest that in some cases beta-blockers may be safe but their use requires close supervision. Other molecules can pose problems in asthmatics (dipyridamole, synthetic sex hormones and certain excipients). On the whole, there has been little innovation concerning the hazard that drugs can pose for some asthmatics. The task for the future will be to specify the physiopathology of Widal syndrome, and to clarify the categories of patients in whom beta-blockers can be safely employed as the public health consequences of cardiovascular pathologies make this an important issue for lung specialists. PMID- 22099412 TI - [Symptoms and natural history of COPD: role of the distal airways]. AB - Symptoms and natural history of COPD: role of the distal airways. The natural history of chronic obstructive pulmonary disease (COPD) is characterized by a progressive worsening of airway obstruction and health-related quality of life, and an increased risk of death. Symptoms of COPD are dominated by cough, sputum production and dyspnoea whose intensity varies between individuals and during the progression of the disease. The symptoms and natural history of COPD result from damage to the airways, including remodelling and inflammation, which commence and are predominant in the distal airways (DA). This article examines the relationship between symptoms and the natural history of COPD in the light of large cohorts published in the literature. The role of the DA in the development and intensity of symptoms and in the natural history of COPD is difficult to define. We have attempted to examine this role using either published studies which have evaluated the relationship between lung structure and the clinical phenotypes of COPD or studies involving the earlier stages of the disease when damage to the DA are known to be predominant. These data suggest a potential role for early therapies targeting remodelling and inflammation in the distal airways of patients suffering from COPD. PMID- 22099413 TI - [Why isn't there more controversy on long-acting beta2-agonists in asthma?]. PMID- 22099415 TI - Bronchoscopic treatments for emphysema. AB - In late stage chronic obstructive pulmonary disease, emphysema can worsen respiratory symptoms, not only via the loss of surface for gas exchange, but also via alterations in mechanical properties of the respiratory system (dynamic and static hyperinflation). Emphysematous lung volume reduction aims at improving respiratory mechanics and symptomatology in patients with advanced emphysema. Lung volume reduction surgery (LVRS) has been shown to be effective in selected patient populations, but its morbidity and costs are quite elevated. Alternatives to LVRS do not remove emphysematous lung tissue per se, but rather consist of devices aiming to: 1) reduce the volume that affected lung parenchyma occupies (unidirectional endobronchial valves or plugs, parenchymal injection of bioactive scarring agents); 2) redistribute ventilatory flow (airway bypass systems). Preliminary studies of these devices have shown that they are relatively safe. These also show modest benefits in exercise capacity, although individual subjects can experience spectacular improvement. Current objective is to identify predictors of response to therapy with such devices. PMID- 22099416 TI - Respiratory effects of manufactured nanoparticles. AB - Nanotechnology is the set of techniques used to engineer, characterize, and produce materials that have at least one dimension within the nanoscale. These nanomaterials, or nanoobjects, include nanoparticles and nanotubes. As dictated by the laws of quantum physics, a size within the nanoscale results in unique physicochemical properties and distinctive behaviors. Nanotechnology has a host of applications in fields ranging from cosmetology to the industry and medicine. The production and use of nanomaterials are expanding at a brisk pace. However, concerns are emerging about the potential health effects of nanoparticles in the short and long terms. These concerns are rooted in data on the harmful health effects of micrometric airborne particulate matter. Conceivably, these adverse effects might be amplified when the particles are within the nanoscale. This article is a nonexhaustive overview of current data on the penetration, deposition, translocation, and elimination of inhaled nanoparticles and on the respiratory effects of metallic nanoparticles (with special attention to titanium dioxide) and carbon nanotubes. Both in vivo and in vitro studies consistently found biological effects of nanoparticles on the respiratory system, including oxidative stress generation, proinflammatory and prothrombotic effects, pulmonary fibrosis and emphysema, and DNA damage. Improved knowledge of the potential biological effects of nanoparticles is needed to guide preventive strategies for the workplace and/or general population if needed. PMID- 22099417 TI - Swallowing disorders, pneumonia and respiratory tract infectious disease in the elderly. AB - Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patient's oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures). PMID- 22099418 TI - Endothelin receptor antagonists -- their role in pulmonary medicine. AB - INTRODUCTION: Understanding of the function of endothelin-1 in the pathophysiology of endothelial disease, in particular pulmonary arterial hypertension (PAH), has paved the way for the development of endothelin-receptor antagonists (ERAs) and explains the leading role they now play in the treatment armamentarium for this disease. BACKGROUND: Three active ERA drugs (bosentan, sitaxentan, ambrisentan) are currently approved for the treatment of PAH in France. Several randomised clinical trials have demonstrated their efficacy and safety in PAH. PERSPECTIVES AND CONCLUSION: Besides its vasoconstrictor effect, endothelin-1 (ET-1) plays a pivotal role in cell proliferation and apoptosis. ERAs are innovative drugs potentially useful in some pulmonary disorders such as idiopathic pulmonary fibrosis or systemic sclerosis, even though the preliminary results published remain insufficient or controversial. CONCLUSION: ERAs play a major role in the management of pulmonary vascular disease. Other drugs, still under study, could prove useful in the treatment of infiltrating pneumonias. PMID- 22099419 TI - Snapshot of Quantiferon TB gold testing in Northern Mexico. AB - Most people infected with Mycobacterium tuberculosis have an asymptomatic condition named latent tuberculosis. These people do not have bacilli in the corporal secretions and are hard to diagnose by conventional laboratory tests. Diagnosis of latent tuberculosis infection (LTBI) in Mexico is based on the tuberculin skin test (TST). This test has disadvantages, principally because the vaccine containing the Bacille Calmette-Guerin (BCG) is applied to 99% of this population and causes false positive TST outcomes. Recently, interferon-gamma release assays (IGRA) have been demonstrated to be a good test to detect latent tuberculosis with equal or better sensitivity to TST and without interference from BCG. However, in Mexico the IGRA are an uncommon test due to the higher cost compared to TST. The main objective of this work was demonstrate the potential utility of the Quantiferon TB((r)) gold in tube (QTB((r))-GIT) test to detect latent TB in a population from northern Mexico. Samples from 106 subjects with close contact, or without contact, with actively infected TB patients were tested to detect LTBI. Our results show a significant difference between individuals in close contact with active TB patients (39.7%) compared to those without contact (3.2%), p < 0.01. The concordance between TST and QTB((r))-GIT was poor (kappa = 0.31). Our preliminary results show that the QTB((r))-GIT has better capacity than TST to detect latent tuberculosis infection. PMID- 22099420 TI - The beta-propeller gene Rv1057 of Mycobacterium tuberculosis has a complex promoter directly regulated by both the MprAB and TrcRS two-component systems. AB - The beta-propeller gene Rv1057 of Mycobacterium tuberculosis is activated by envelope stress and was first characterized as a regulatory target of the TrcRS two-component system (TCS). Rv1057 expression is repressed by TrcRS, and the Rv1057 proximal promoter contains a TrcR binding site. In this study, we determined that Rv1057 is also directly regulated by MprAB, a TCS associated with envelope stress. Multiple potential MprA binding sites (MprA boxes) were identified in the 1 kb intergenic region upstream of Rv1057, and four sites were shown to bind MprA. Although MprA boxes were found in the proximal promoter, analyses suggest that MprA and TrcR do not compete for binding in this region. An MprAB-dependent, detergent-inducible transcriptional start point for Rv1057 was identified downstream of the MprA boxes, and a second TrcR binding site and small ORF of the 13E12 family were discovered in the distal promoter. MprAB was required for activation of Rv1057 during growth in macrophages and under detergent stress, and lacZ promoter constructs suggest the entire intergenic region is utilized during MprAB-dependent activation of Rv1057. These findings indicate that Rv1057 has an extensive and complex promoter, and provide evidence for coordinated regulation of stress response genes by TCSs. PMID- 22099421 TI - Activation of NK cell granulysin by mycobacteria and IL-15 is differentially affected by HIV. AB - NK cells play an important role in innate immunity to mycobacteria and are a significant source of the bactericidal effector molecule granulysin. Defects in NK cells have been described in HIV-infected patients, though mechanistic studies have focused on effector molecules relevant to anti-viral, and not anti bacterial, function. Here we used primary NK cells from healthy human donors and an in vitro system to identify the phenotype of granulysin expressing NK cells, characterize activation stimuli that regulate granulysin, and to study the immediate effects of HIV on innate activation of NK cell granulysin expression. We observe that granulysin expression is co-associated with cytotoxicity receptors (NKp46, NKG2D) known to have important function in the cytotoxic response to M.tb-infected macrophages. Granulysin expression is significantly increased following exposure to IL-15 or Mycobacterium bovis BCG, but in contrast to our previous findings with CD8(+)T cells, expression is weakly activated by IL 21. Infection of PBMC with HIV-1 suppresses NK cell induction of granulysin by IL 15, but does not impair activation by BCG. These effects of HIV-1 are associated with reduced STAT5 phosphorylation in the IL-15 activated signaling cascade. These observations suggest that HIV may impair the anti-bacterial function of NK cells and have implications for clinical use of IL-15 to augment innate cell mediated immunity in HIV+ patients. PMID- 22099422 TI - [Ileal gastrointestinal stromal tumour (GIST) as a cause of a liver abscess]. PMID- 22099423 TI - Adiponectin and atherosclerosis risk factors in African hemodialysis patients: a population at low risk for atherosclerotic cardiovascular disease. AB - Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in hemodialysis (HD) patients. Adiponectin (ADPN), a recently discovered collagen-like protein, is secreted exclusively by adipocytes. It has anti-atherogenic properties and reduced serum ADPN levels have been shown to be predictive of cardiovascular events. In this study, we determined the atherosclerotic risk and the significance of ADPN levels in our HD patients and also examined its relationship to other traditional CVD risk factors. A cross sectional study of 84 patients on maintenance HD (58 Blacks and 26 non-Blacks) and 63 healthy controls matched for age, sex and race (35 Blacks and 28 non Blacks) was undertaken. Serum ADPN levels and other risk factors, including blood pressure, serum lipid, and C-reactive protein, were studied in HD patients and were compared with the controls. Carotid artery intima-media thickness and plaque occurrence was measured by B-mode ultrasonography while echocardiography was done according to American Society of Echocardiography guidelines. Serum ADPN levels were higher in the HD group compared with the control subjects (22.19 +/- 0.98 mg/mL vs. 9.93 +/- 0.68 mg/mL; P < 0.001). Higher ADPN levels in HD patients were associated with lower triglyceride levels. ADPN correlated positively (r = 0.49, P < 0.0001) with left ventricular mass index (LVMI) in the total study population. ADPN levels were raised in HD patients and correlated with LVMI, possibly because of the confounding effect of low glomerular filtration rate. ADPN levels were inversely related to risk factors for atherosclerosis and may provide possible targets for therapeutic interventions. PMID- 22099424 TI - Cancers in patients with hemophilia: a retrospective study from the Italian Association of Hemophilia Centers. AB - BACKGROUND: The increased life expectancy of the hemophilia population, primarily as a result of advances in factor replacement therapy, has enabled hemophiliacs to reach an older age. Consequently, age-related diseases, such as cardiovascular disorders and cancers, are being increasingly recognized in such patients. However, only few data are available on such co-morbidities, their management and impact on the primary bleeding disorders. OBJECTIVES: With the aim of investigating several still unclear issues regarding cancers in hemophilia patients, we conducted, on behalf the Italian Association of Hemophilia Centers (AICE), a study on cancers among Italian hemophiliacs. PATIENTS: Data pertaining to 122 hemophiliacs with 127 cancers between 1980 and 2010 were retrospectively collected in 21 centers of the AICE which chose to participate. RESULTS: Sixty nine percent of cancers were recorded during the decade 2001-2010. Eighty-three percent of patients were infected with hepatitis C virus (HCV) and 22% of them were also co-infected with human immunodeficiency virus (HIV). Forty-three percent of cancers were HCV-related, whereas 9%were HIV related. Virus-related cancers were more frequent and non-virus-related cancers less frequent in patients with severe hemophilia than in those with mild/moderate forms (P = 0.0004). The non-virus-related standardized mortality ratio (SMR) was 0.3. Hemorrhagic complications occurred more frequently in patients undergoing chemotherapy (14%) or radiotherapy (19%). CONCLUSIONS: The results of the present study confirm that cancers have become a new challenge for physicians working in hemophilia centers and underline the need for prospective trials to better assess the epidemiology and to optimize the management of hemophiliacs with cancer. PMID- 22099425 TI - Improvement of sulphur mustard-induced chronic pruritus, quality of life and antioxidant status by curcumin: results of a randomised, double-blind, placebo controlled trial. AB - Skin is among the first and most heavily damaged organs upon sulphur mustard (SM) exposure. Pruritus is the most common chronic skin complication of SM, which adversely affects the quality of life (QoL). However, current therapies for the management of SM-induced pruritus are very limited and associated with side effects. The present trial investigated the efficacy of curcumin in the alleviation of SM-induced chronic pruritic symptoms. A total of ninety-six male Iranian veterans (age 37-59 years) were randomised to receive either curcumin (1 g/d, n 46) or placebo (n 50) for 4 weeks. Serum concentrations of substance P and activities of antioxidant enzymes were measured at baseline and at the end of the trial. Assessment of pruritus severity was performed using the pruritus score, visual analogue scale (VAS) and scoring atopic dermatitis (SCORAD) index. QoL was evaluated using the Dermatology Life Quality Index (DLQI) questionnaire. Serum concentrations of substance P (P<0.001) as well as activities of superoxide dismutase (P=0.02), glutathione peroxidase (P=0.006) and catalase (P<0.001) were significantly reduced in the curcumin group, while no significant change was observed in the placebo group. Curcumin supplementation was also associated with significant reductions in measures of pruritus severity including the pruritus score (P<0.001), VAS score (P<0.001), overall (P<0.001) and objective SCORAD (P=0.009), and DLQI's first question (P<0.001). None of these measures was significantly changed in the placebo group. As for the QoL, although DLQI scores decreased in both groups (P<0.001 and P=0.003 in the curcumin and placebo groups, respectively), the magnitude of reduction was significantly greater in the curcumin group (P<0.001). In conclusion, curcumin may be regarded as a natural, safe, widely available and inexpensive treatment for the management of SM-induced chronic pruritus. PMID- 22099428 TI - Cardiovascular disease in the elderly: comment. PMID- 22099430 TI - Noninvasive assessment of endothelial function in clinical practice. AB - In the fight against cardiovascular diseases, preventive strategies are becoming the focus of attention. One of these strategies proposes to identify individuals who are at a high risk of developing cardiovascular disease. Endothelial dysfunction could improve patient risk stratification and the implementation of preventive strategies. In this review we focus on noninvasive techniques that have recently become available to assess endothelial function: flow-mediated vasodilation as measured by ultrasound of the brachial artery, pulse wave analysis, and finger plethysmography during postischemic hyperemia. We describe the basic principles, the main protocols to perform these techniques, and their clinical value based on the scientific evidence. PMID- 22099429 TI - New evidence, new controversies: a critical review of the European Society of Cardiology 2010 clinical practice guidelines on atrial fibrillation. PMID- 22099431 TI - Low frequency of human papillomavirus infection in conjunctival squamous cell carcinoma of Mexican patients. AB - BACKGROUND: The relationship between Human Papillomavirus (HPV) infection and conjunctiva cancer is controversial. HPV detection will provide more information about the role of this infectious agent in the biology of conjunctiva cancer. In the present study, DNA extracted and purified from 36 Conjunctival Squamous Cell Carcinomas (CSCC) was evaluated by PCR for HPV DNA sequences. The results were correlated with the clinical and histopathological variables. RESULTS: The results showed that HPV DNA was present in 8 CSCC samples (22%); HPV16 was the sole type detected. Significant association was found between HPV detection and the limbus tumor subtype (p = 0.03). All the samples were non-metastatic squamous cell carcinoma. CONCLUSIONS: The HPV presence in CSCC from Mexican patients is not a common event. PMID- 22099432 TI - From biology to policy: the link between maternal health and current and future burden of chronic noncommunicable disease. PMID- 22099433 TI - Anemia and pregnancy: a link to maternal chronic diseases. AB - Anemia is a global public health problem. It has serious short- and long-term consequences during pregnancy and beyond. The anemic condition is often worsened by the presence of other chronic diseases such as malaria, tuberculosis, HIV, and diabetes. Untreated anemia also leads to increased morbidity and mortality from these chronic conditions as well. It is surprising that despite these chronic conditions (such as malaria, tuberculosis, and HIV) often being preventable, they still pose a real threat to public health. This article aims to review the current understanding of the pathophysiology, risks, prevention, and treatment of anemia in the light of these chronic conditions. PMID- 22099434 TI - Physiological adaption to maternal malaria and other adverse exposure: low birth weight, functional capacity, and possible metabolic disease in adult life. AB - The concept of developmental origins of health and disease and the epidemic of noncommunicable diseases in low- and middle-income countries has increased the focus on low birth weight (LBW). Most studies linking LBW to future risk of metabolic diseases have focused on maternal nutrition and anemia. Several studies have shown that LBWis linked to skeletal muscle insulin resistance and future risk of type 2 diabetes, possibly caused by permanent modifications in skeletal muscle morphology and biochemistry leading to lowered functional capacity and physical activity in adult life. In some parts of the world, malaria infection during pregnancy is the most common cause of anemia and LBW. By causing disruption to nutrient supply, as well as hypoxia, placental malaria and anemia negatively impact intrauterine fetal development. Thus, in utero exposure to placental malaria and consequent LBW may impart a higher risk of developing type 2 diabetes in early adult life. This has not been investigated systematically. Worldwide, an estimated 125 million pregnancies occur annually in malarial areas with a vast potential for intrauterine growth restriction, LBW, and subsequent risk of metabolic dysfunction, including type 2 diabetes; this potential link also opens an opportunity for early prevention of future metabolic diseases by paying greater attention to malaria during pregnancy. PMID- 22099435 TI - Development of a model to assess the cost-effectiveness of gestational diabetes mellitus screening and lifestyle change for the prevention of type 2 diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is increasingly recognized as an opportunity for early prevention of diabetes and other diseases over the lifespan, and may be responsible for up to 30% of cases of type 2 diabetes. A newly developed mathematical model (the GDModel) provides provisional estimates of the cost and health impact of various GDM screening and management choices, and calculates averted disability-adjusted life-years (DALYs). The model was piloted in 5 different healthcare facilities in India and Israel. Universal screening of pregnant women followed by postpartum lifestyle management yielded net savings of US$78 per woman with GDM in India and US$1945 per woman in Israel. The estimated DALYs averted were 2.33 in India and 3.10 in Israel. With lower GDM prevalence, intervention efficacy, and type 2 diabetes incidence, the intervention had a net cost in India, with a cost per DALY averted of US$11.32. This was far below the WHO definition of "very cost-effective," set at annual GDP per capita. The intervention in Israel remained cost-saving. GDM screening and postpartum lifestyle management are either cost-saving or have a net cost but an attractive cost-effectiveness ratio. Some input values are currently being refined. Nevertheless, the current findings of cost-savings or favorable cost effectiveness are robust to a wide range of plausible input values, including highly unfavorable values. The GDModel will be further developed into a user friendly tool that can guide policy-makers on decisions regarding GDM screening strategies and guidelines. PMID- 22099436 TI - Matching diagnosis and management of diabetes in pregnancy to local priorities and resources: an international approach. AB - The International Association of the Diabetes and Pregnancy Study Groups' (IADPSG) criteria for the diagnosis and classification of hyperglycemia in pregnancy are described and application of these in differing healthcare contexts on a worldwide basis is reported. Existing local protocols and known epidemiologic and clinical data regarding the detection and management of overt diabetes and gestational diabetes in the context of human pregnancy are considered. Although the IADPSG criteria are uniform, their introduction poses a variety of practical and technical challenges in differing healthcare contexts, both between and within countries. Knowledge of local factors will be vital in the implementation of the new guidelines and will require extensive liaison with local clinical and health policy groups. Resource availability will be critical in determining the type of treatment available in this context. The IADPSG criteria offer an important opportunity for a uniform approach to diabetes in pregnancy. Scaled implementation of these criteria adapted to a variety of local healthcare contexts should improve both research endeavors and patient care. PMID- 22099437 TI - Developmental origins of health and disease: moving from biological concepts to interventions and policy. AB - The rising incidence of noncommunicable diseases (NCDs), especially in young adults, presents great humanitarian and economic challenges to high-resource and, increasingly, to low-resource countries. No longer considered to be diseases of affluence, NCDs are exacerbated by urbanization and changes in social and lifestyle factors such as diet and family size. New research emphasizes the importance of early life factors in establishing the risk of NCDs through inadequate responses to later challenges, such as an obesogenic environment. A new focus on interventions to promote a good start to life in at-risk populations necessitates revision of public health policy, with implications for the health, education, and empowerment of women and children in particular. PMID- 22099438 TI - Gestational diabetes screening: the low-cost algorithm. AB - The American Diabetes Association has endorsed the demanding recommendation by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) that every pregnant woman should undergo the oral glucose tolerance test (OGTT) for the screening of gestational diabetes mellitus (GDM). The aim of this study was to find out if the fasting plasma glucose (FPG) and newer emerging technologies could simplify the cumbersome IADPSG algorithm. Two FPG thresholds (of the OGTT) were used to rule in and rule out GDM in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort (n = 23316) and a population at high risk for GDM (n = 10283). For the HAPO cohort and the high-risk population, respectively, FPG thresholds of: (a) >= 5.1 mmol/L (specificity 100%) independently ruled in GDM in 1769 (8.3%) women and 2975 (28.9%) women; and (b) <= 4.4 mmol/L ruled out GDM in 11526 (49.4%) women (84.1% sensitivity) and 2228 (21.7%) women (95.4% sensitivity). Use of the FPG independently could have avoided 13295 (57.0%) and 5203 (50.6%) OGTTs in the 2 groups. The initial FPG-by significantly reducing the number of cumbersome OGTTs needed-can make the IADPSG recommendations more acceptable worldwide. The number of GDM women missed is population dependent. For low-resource countries, alternative newer and cheaper tests in development hold an exciting future. PMID- 22099439 TI - Integrating noncommunicable disease prevention into maternal and child health programs: can it be done and what will it take? AB - Noncommunicable diseases (NCDs) are the leading cause of mortality worldwide. However, these diseases have not been adequately addressed by health systems, especially in low-resource countries. Similarly, there is no equitable allocation of global resources for health commensurate with the burden of diseases occasioned by NCDs. This has resulted in poor access to care for women, girls, and other vulnerable groups affected by NCDs. Owing to their position in most societies, women lack control over resources and, hence, cannot afford quality care to treat NCDs. Women also face sociocultural, geographic, and economic barriers to access to care. They are less recognized and catered for in terms of accessibility, comprehensiveness, and responsiveness of healthcare systems. Considering that NCDs affect women more than the general population, tackling them as part of an integrated program for women's health will improve the coverage of the most vulnerable groups. This paper describes how NCD prevention and control could be integrated into maternal and child health programs to improve access to NCD services. It presents the effectiveness, benefits, and challenges of this approach when applied at the primary healthcare level. PMID- 22099440 TI - Designing feasible interventions for healthy pregnancies in low-resource settings. AB - In low-resource settings there is a need for effective interventions targeting women before and during pregnancy to improve their health outcomes and provide the best start to life for their infants. The aim of this paper is to provide an overview for designing, implementing, and evaluating such interventions. Drawing upon published literature and case studies, several key steps in the process of intervention design, implementation, and evaluation are identified. Pregnancy intervention studies in low-resource settings are challenging. Essential intervention process steps include: (1) selecting the optimal setting to pilot the intervention; (2) forming strong stakeholder collaborations; (3) identifying, understanding, and prioritizing community health problems; (4) facilitating the demand for intervention research and evidence utilization; (5) effectively implementing and evaluating the prototype intervention to provide evidence of effectiveness; and (6) planning with stakeholders for sustainability. Fundamental to any intervention for healthy pregnancies is the understanding that the process does not end with an evaluation study, but rather the end goal is to ensure successful interventions are sustainable, scalable, and integrated into health services. PMID- 22099441 TI - Gestational diabetes mellitus: advocating for policy change in India. AB - A multimedia awareness and advocacy campaign for mainstreaming gestational diabetes mellitus (GDM) in the public health domain is described. The multimedia campaign has created awareness about the relevance of GDM to women's health and the health of future generations through direct contact, reaching out to over half a million people in 7 districts of 4 states in northern India. Using mass media, over 3.7 million people have received information on GDM. Through multistakeholder forums, more than 1000 key stakeholders have been encouraged to mainstream GDM into the existing health delivery system. The Indian Ministry of Health has introduced free screening for GDM among the 5 services offered to pregnant women below the poverty line in the National Rural Health Mission (NRHM) program. In addition, several state governments, such as in Bihar, Delhi, Jharkhand, and Punjab, have pledged similar initiatives addressing GDM; the Government of Tamil Nadu is already implementing such a policy. Policy development is a complex process that requires action on many fronts. By showcasing evidence, raising awareness, creating public opinion through dialogue and discussion, media can help build a positive environment and momentum for effective policy creation as well as service utilization. PMID- 22099442 TI - Global adaptation of IADPSG recommendations: a national approach. AB - The current practice for diagnosing gestational diabetes mellitus (GDM) in Israel employs a two-step screening approach using a 50 g glucose challenge test (GCT) followed by a 3-hour 100 g oral glucose tolerance test (OGTT). The overall adherence to this process is more than 90%. Recently, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommended changing this practice to a single-step GDM screening, employing a 75 g OGTT. New plasma glucose cutoffs were recommended. To make recommendations for a new screening and diagnosis policy for GDM in Israel, a committee was assembled, including representatives of professional medical organizations, health maintenance organizations (HMOs), health policy makers, epidemiologists and biostatisticians. There was agreement that a consensus can be achieved only by clinical evidence and that consensus is a key factor for changing health policy. It was also realized that the availability of local data on the annual rates of GDM, its complications, and cost-effectiveness of screening and treatment are suboptimal. This generated two studies: the first provided additional analyses of data concerning Israeli women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, and the second was a cost-effectiveness analysis based on Clalit Health Service's (the largest HMO in the country) database. We found that the prevalence of GDM in Israel is approximately 6% and is expected to increase to 9% by adopting the new IADPSG recommendations. The conclusion was that a one-step approach is presumed to be not only cost-effective but cost saving, even under conservative estimates. We recommend such a process for other countries debating whether to change their GDM screening and diagnostic approach. PMID- 22099443 TI - FIGO--a professional nonprofit organization: reproductive, maternal, and child health policy and programs to address noncommunicable childhood disease. PMID- 22099444 TI - Pregnancy: a window of opportunity for improving current and future health. PMID- 22099445 TI - Taking on the challenge of noncommunicable diseases: we all hold a piece of the puzzle. AB - Two out of 3 deaths globally are attributable to noncommunicable diseases (NCDs), with 80% occurring in low-resource countries. The "cost of inaction" is estimated to be US$35 trillion between 2005 and 2030. We need to get behind the societal root causes of this global health challenge; we need a life-course approach to respond to the increasing evidence of intergenerational transmission of NCDs; and we need to focus on strengthening of health systems and integration of services for prevention, screening, and management across disease groups. There is a growing understanding that all actors, private or public, for-profit or not-for profit, can make substantial and positive contributions as long as they maintain transparency in their agenda, motivation, and actions. Effective and sustainable global public-private partnerships require trust between partners, a safe space for talks and negotiations, and a framework for governance and accountability. We need a neutral global convener to unite us all behind shared visions for a healthier future, where each player is encouraged to commit and contribute to the common cause and be recognized or held accountable for their respective commitments. Creation of such a platform could be a direct outcome of the United Nations High Level Meeting on NCDs to be held in September 2011. PMID- 22099446 TI - Maternal obesity: implications for pregnancy outcome and long-term risks-a link to maternal nutrition. AB - As obesity becomes a worldwide epidemic, its prevalence during reproductive age is also increased. Alarming reports state that two-thirds of adults in the USA are overweight or obese, with half of them in the latter category, and the rate of obese pregnant women is estimated at 18-38%. These women are of major concern to women's health providers because they encounter numerous pregnancy-related complications. Obesity-related reproductive health complications range from infertility to a wide spectrum of diseases such as hypertensive disorders, coagulopathies, gestational diabetes mellitus, respiratory complications, and fetal complications such as large-for-gestational-age infants, congenital malformations, stillbirth, and shoulder dystocia. Recent reports suggest that obesity during pregnancy can be a risk factor for developing obesity, diabetes, and cardiovascular diseases in the newborn later in life. This review will address the implication of obesity on pregnancy and child health, and explore recent literature on obesity during pregnancy. PMID- 22099447 TI - X-ray fluorescence in investigations of cultural relics and archaeological finds. AB - Some characteristic features of X-ray fluorescence (XRF) analysis make it an ideal method for investigations of cultural relics and archaeological finds. It has therefore become a standard method used in archaeometry. Paintings, frescos, manuscripts, pottery, metalwork, glass, and many other objects are analysed with the aim of recognising their materials, production technologies and origin, and for identifying counterfeits. This paper reviews various techniques used in XRF analyses of works of art, summarises the advantages and limitations of the method, and presents some typical examples of its use. The general review is supplemented by some techniques used and some results achieved at CTU-FNSPE in Prague. PMID- 22099448 TI - Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods. AB - BACKGROUND: Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE. METHODS: We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQLTM guidelines, and the consolidated criteria for reporting qualitative research (COREQ). Both child (ages 8-12 and 13-18) and parent-proxy (ages 2-4, 5-7, 8-12, and 13-18) interviews were conducted. RESULTS: We conducted 75 interviews to construct the new instrument. Items were identified and developed from individual focus interviews, followed by cognitive interviews for face and content validation. Initial domains of symptom frequency and severity were developed, and open-ended questions were used to generate specific items during the focus interviews. Once developed, the instrument construct, instructions, timeframe, scoring, and specific items were systematically reviewed with a separate group of patients and their parents during the cognitive interviews. CONCLUSIONS: To capture the full impact of pediatric EoE, both histologic findings and PROs need to be included as equally important outcome measures. We have developed the face and content validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESSTM v2.0). The PEESSTM v2.0 metric is now undergoing multisite national field testing as the next iterative instrument development phase. PMID- 22099449 TI - Selling sex in unsafe spaces: sex work risk environments in Phnom Penh, Cambodia. AB - BACKGROUND: The risk environment framework provides a valuable but under-utilised heuristic for understanding environmental vulnerability to HIV and other sexually transmitted infections among female sex workers. Brothels have been shown to be safer than street-based sex work, with higher rates of consistent condom use and lower HIV prevalence. While entertainment venues are also assumed to be safer than street-based sex work, few studies have examined environmental influences on vulnerability to HIV in this context. METHODS: As part of the Young Women's Health Study, a prospective observational study of young women (15-29 years) engaged in sex work in Phnom Penh, we conducted in-depth interviews (n = 33) to explore vulnerability to HIV/STI and related harms. Interviews were conducted in Khmer by trained interviewers, transcribed and translated into English and analysed for thematic content. RESULTS: The intensification of anti-prostitution and anti-trafficking efforts in Cambodia has increased the number of women working in entertainment venues and on the street. Our results confirm that street-based sex work places women at risk of HIV/STI infection and identify significant environmental risks related to entertainment-based sex work, including limited access to condoms and alcohol-related intoxication. Our data also indicate that exposure to violence and interactions with the police are mediated by the settings in which sex is sold. In particular, transacting sex in environments such as guest houses where there is little or no oversight in the form of peer or managerial support or protection, may increase vulnerability to HIV/STI. CONCLUSIONS: Entertainment venues may also provide a high risk environment for sex work. Our results indicate that strategies designed to address HIV prevention among brothel-based FSWs in Cambodia have not translated well to street and entertainment-based sex work venues in which increasing numbers of women are working. There is an urgent need for targeted interventions, supported by legal and policy reforms, designed to reduce the environmental risks of sex work in these settings. Future research should seek to investigate sex work venues as risk environments, explore the role of different business models in mediating these environments, and identify and quantify exposure to risk in different occupational settings. PMID- 22099450 TI - Vitiligo as an inflammatory skin disorder: a therapeutic perspective. AB - From a therapeutic standpoint, vitiligo is still regarded by many physicians as a simple problem of regenerative medicine, with the main aim to repopulate the depigmented skin with functional melanocytes from the margins of the lesions or from intact progenitors in hair follicles. However, recent research in vitiligo suggests that various local triggers alert the skin immune innate system and may precede adaptive immune responses targeting melanocytes. This scenario is close to that of other common skin inflammatory disorders like psoriasis and atopic, and suggests to target as a priority this clinically silent inflammatory component of he disease. This perspective highlights possible targets for intervention. PMID- 22099451 TI - Identification of Tyr74 and Tyr177 as substrate oxidation sites in cationic cell wall-bound peroxidase from Populus alba L. AB - Cationic cell wall-bound peroxidase (CWPO-C) has the capability to oxidize sinapyl alcohol, ferrocytochrome c, and synthetic lignin polymers, unlike most peroxidases that have been characterized in flowering plants, such as horseradish peroxidase and Arabidopsis thaliana peroxidase A2. It has been suggested that the oxidation site is located on the CWPO-C surface, and homology modeling and chemically modified CWPO-C studies suggest that Tyr74 and/or Tyr177 are possible participants in the catalytic site. The present study clarifies the importance of these Tyr residues for substrate oxidation, using recombinant CWPO-C and recombinant mutant CWPO-C with phenylalanine substitution(s) for tyrosine. Such recombinant proteins, produced in Escherichia coli as inclusion bodies, were successfully refolded to yield the active form, and purified recombinant protein solutions exhibited typical spectra of high-spin ferric protein and displayed H(2) O(2) -dependent oxidation of guaiacol, 2,6-dimethoxyphenol, and syringaldazine. Measurement of peroxidase activity with these guaiacyl and syringyl compounds as reducing substrates indicated that a single mutation, Y74F or Y177F, resulted in substantial loss of oxidation activity (~ 40-60% and 82%, respectively). Also, over 95% of the oxidation activity was lost with a double mutation, Y74F/Y177F. These results indicated that Tyr74 and Tyr177, rather than the heme pocket, play a central role in the oxidation of these substrates. This is the first report of active residues on an enzyme surface being identified in a plant peroxidase. This study also suggests that sinapyl alcohol incorporation into lignin is performed by a peroxidase that generates Tyr radicals on its surface. PMID- 22099452 TI - Mapping genetic influences on cortical regionalization. AB - In this issue of Neuron, Chen and colleagues combine structural MRI and a twin study design to investigate the influence of genetics on human cortical regionalization. Their results resonate with findings from animal studies and certain human syndromes of developmental cortical malformation. PMID- 22099453 TI - DISC1: a schizophrenia gene with multiple personalities. AB - Two papers address the contribution of DISC1 to neural development and schizophrenia risk in this issue of Neuron. These complementary studies elegantly bridge the gap between genetic and cellular studies of schizophrenia, providing a level of functional validation that is often lacking in the field. PMID- 22099454 TI - A surprisingly singular role for endophilin in synaptic vesicle recycling. AB - Synaptic vesicle endocytosis requires membrane curvature, fission, and uncoating. Endophilin has been proposed to play a role in all three steps, but in this issue of Neuron, De Camilli and colleagues show that at mammalian central synapses it is primarily involved in clathrin uncoating. PMID- 22099455 TI - Cortical processing of odor objects. AB - Natural odors, generally composed of many monomolecular components, are analyzed by peripheral receptors into component features and translated into spatiotemporal patterns of neural activity in the olfactory bulb. Here, we will discuss the role of the olfactory cortex in the recognition, separation and completion of those odor-evoked patterns, and how these processes contribute to odor perception. Recent findings regarding the neural architecture, physiology, and plasticity of the olfactory cortex, principally the piriform cortex, will be described in the context of how this paleocortical structure creates odor objects. PMID- 22099456 TI - Memory: enduring traces of perceptual and reflective attention. AB - Attention and memory are typically studied as separate topics, but they are highly intertwined. Here we discuss the relation between memory and two fundamental types of attention: perceptual and reflective. Memory is the persisting consequence of cognitive activities initiated by and/or focused on external information from the environment (perceptual attention) and initiated by and/or focused on internal mental representations (reflective attention). We consider three key questions for advancing a cognitive neuroscience of attention and memory: to what extent do perception and reflection share representational areas? To what extent are the control processes that select, maintain, and manipulate perceptual and reflective information subserved by common areas and networks? During perception and reflection, to what extent are common areas responsible for binding features together to create complex, episodic memories and for reviving them later? Considering similarities and differences in perceptual and reflective attention helps integrate a broad range of findings and raises important unresolved issues. PMID- 22099457 TI - Genetic influences on cortical regionalization in the human brain. AB - Animal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. "Marching seeds" and a data-driven, hypothesis-free, fuzzy-clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in nonhuman mammalian models. Broad similarities in genetic patterning between rodents and humans might suggest a conservation of cortical patterning mechanisms, whereas dissimilarities might reflect the functionalities most essential to each species. PMID- 22099458 TI - Common DISC1 polymorphisms disrupt Wnt/GSK3beta signaling and brain development. AB - Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3beta signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes. PMID- 22099459 TI - Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. AB - Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia. PMID- 22099460 TI - An imbalancing act: gap junctions reduce the backward motor circuit activity to bias C. elegans for forward locomotion. AB - A neural network can sustain and switch between different activity patterns to execute multiple behaviors. By monitoring the decision making for directional locomotion through motor circuit calcium imaging in behaving Caenorhabditis elegans (C. elegans), we reveal that C. elegans determines the directionality of movements by establishing an imbalanced output between the forward and backward motor circuits and that it alters directions by switching between these imbalanced states. We further demonstrate that premotor interneurons modulate endogenous motoneuron activity to establish the output imbalance. Specifically, the UNC-7 and UNC-9 innexin-dependent premotor interneuron-motoneuron coupling prevents a balanced output state that leads to movements without directionality. Moreover, they act as shunts to decrease the backward-circuit activity, establishing a persistent bias for the high forward-circuit output state that results in the inherent preference of C. elegans for forward locomotion. This study demonstrates that imbalanced motoneuron activity underlies directional movement and establishes gap junctions as critical modulators of the properties and outputs of neural circuits. PMID- 22099461 TI - Recruitment of endophilin to clathrin-coated pit necks is required for efficient vesicle uncoating after fission. AB - Endophilin is a membrane-binding protein with curvature-generating and -sensing properties that participates in clathrin-dependent endocytosis of synaptic vesicle membranes. Endophilin also binds the GTPase dynamin and the phosphoinositide phosphatase synaptojanin and is thought to coordinate constriction of coated pits with membrane fission (via dynamin) and subsequent uncoating (via synaptojanin). We show that although synaptojanin is recruited by endophilin at bud necks before fission, the knockout of all three mouse endophilins results in the accumulation of clathrin-coated vesicles, but not of clathrin-coated pits, at synapses. The absence of endophilin impairs but does not abolish synaptic transmission and results in perinatal lethality, whereas partial endophilin absence causes severe neurological defects, including epilepsy and neurodegeneration. Our data support a model in which endophilin recruitment to coated pit necks, because of its curvature-sensing properties, primes vesicle buds for subsequent uncoating after membrane fission, without being critically required for the fission reaction itself. PMID- 22099462 TI - XPORT-dependent transport of TRP and rhodopsin. AB - TRP channels have emerged as key biological sensors in vision, taste, olfaction, hearing, and touch. Despite their importance, virtually nothing is known about the folding and transport of TRP channels during biosynthesis. Here, we identify XPORT (exit protein of rhodopsin and TRP) as a critical chaperone for TRP and its G protein-coupled receptor (GPCR), rhodopsin (Rh1). XPORT is a resident ER and secretory pathway protein that interacts with TRP and Rh1, as well as with Hsp27 and Hsp90. XPORT promotes the targeting of TRP to the membrane in Drosophila S2 cells, a finding that provides a critical first step toward solving a longstanding problem in the successful heterologous expression of TRP. Mutations in xport result in defective transport of TRP and Rh1, leading to retinal degeneration. Our results identify XPORT as a molecular chaperone and provide a mechanistic link between TRP channels and their GPCRs during biosynthesis and transport. PMID- 22099463 TI - Activation of central orexin/hypocretin neurons by dietary amino acids. AB - Hypothalamic orexin/hypocretin (orx/hcrt) neurons regulate energy balance, wakefulness, and reward; their loss produces narcolepsy and weight gain. Glucose can lower the activity of orx/hcrt cells, but whether other dietary macronutrients have similar effects is unclear. We show that orx/hcrt cells are stimulated by nutritionally relevant mixtures of amino acids (AAs), both in brain slice patch-clamp experiments, and in c-Fos expression assays following central or peripheral administration of AAs to mice in vivo. Physiological mixtures of AAs electrically excited orx/hcrt cells through a dual mechanism involving inhibition of K(ATP) channels and activation of system-A amino acid transporters. Nonessential AAs were more potent in activating orx/hcrt cells than essential AAs. Moreover, the presence of physiological concentrations of AAs suppressed the glucose responses of orx/hcrt cells. These results suggest a new mechanism of hypothalamic integration of macronutrient signals and imply that orx/hcrt cells sense macronutrient balance, rather than net energy value, in extracellular fluid. PMID- 22099464 TI - Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. AB - How transmitter receptors modulate neuronal signaling by regulating voltage-gated ion channel expression remains an open question. Here we report dendritic localization of mRNA of Kv4.2 voltage-gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by fragile X mental retardation protein (FMRP) linked to fragile X syndrome (FXS), the most common heritable mental retardation. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice and in neurons expressing Kv4.2 3'UTR that binds FMRP. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation induced by moderate stimuli. Surprisingly, recovery of Kv4.2 after N-methyl-D-aspartate receptor (NMDAR)-induced degradation also requires FMRP, likely due to NMDAR-induced FMRP dephosphorylation, which turns off FMRP suppression of Kv4.2. Our study of FMRP regulation of Kv4.2 deepens our knowledge of NMDAR signaling and reveals a FMRP target of potential relevance to FXS. PMID- 22099465 TI - Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. AB - Hippocampal CA1 and CA3 pyramidal neuron place cells encode the spatial location of an animal through localized firing patterns called "place fields." To explore the mechanisms that control place cell firing and their relationship to spatial memory, we studied mice with enhanced spatial memory resulting from forebrain specific knockout of the HCN1 hyperpolarization-activated cation channel. HCN1 is strongly expressed in CA1 neurons and in entorhinal cortex grid cells, which provide spatial information to the hippocampus. Both CA1 and CA3 place fields were larger but more stable in the knockout mice, with the effect greater in CA1 than CA3. As HCN1 is only weakly expressed in CA3 place cells, their altered activity likely reflects loss of HCN1 in grid cells. The more pronounced changes in CA1 likely reflect the intrinsic contribution of HCN1. The enhanced place field stability may underlie the effect of HCN1 deletion to facilitate spatial learning and memory. PMID- 22099466 TI - Dissociable reward and timing signals in human midbrain and ventral striatum. AB - Reward prediction error (RPE) signals are central to current models of reward learning. Temporal difference (TD) learning models posit that these signals should be modulated by predictions, not only of magnitude but also timing of reward. Here we show that BOLD activity in the VTA conforms to such TD predictions: responses to unexpected rewards are modulated by a temporal hazard function and activity between a predictive stimulus and reward is depressed in proportion to predicted reward. By contrast, BOLD activity in ventral striatum (VS) does not reflect a TD RPE, but instead encodes a signal on the variable relevant for behavior, here timing but not magnitude of reward. The results have important implications for dopaminergic models of cortico-striatal learning and suggest a modification of the conventional view that VS BOLD necessarily reflects inputs from dopaminergic VTA neurons signaling an RPE. PMID- 22099468 TI - P-selectin, E-selectin, and CD40L over time in chronic hemodialysis patients. AB - The aim of this study was to measure P-selectin, E-selectin, and CD-4L levels over time in chronic hemodialysis (HD) patients. Thirty stable patients with end stage renal failure undergoing chronic HD were included in the study. Blood samples were obtained before HD for measurement of P-selectin, E-selectin, and CD 40L. Measurements were performed at month 0 (T0), 3 (T2), 8 (T3), and 13 (T4). The levels of P-selectin, E-selectin, and CD40L were also analyzed according to the occurrence of cardiovascular disease (CVD) and to CVD-related mortality. The levels of CD40L and P-selectin changed significantly over time, decreasing at month 3 and 6 and returning at the T0 levels at month 13. Conversely, E-selectin levels did not. The levels of CD40L, P-selectin and E-selectin over time did not differ significantly between patients with age <= 65 or > 65 years, between patients with or without CVD, or between patients who died or who survived during the follow-up. In end-stage renal failure patients undergoing chronic HD, CD40L and P-selectin, but not E-selectin, showed a transient decrease over time, and the serum levels of these molecules were not associated with CVD or with CVD related mortality. PMID- 22099467 TI - Functional network organization of the human brain. AB - Real-world complex systems may be mathematically modeled as graphs, revealing properties of the system. Here we study graphs of functional brain organization in healthy adults using resting state functional connectivity MRI. We propose two novel brain-wide graphs, one of 264 putative functional areas, the other a modification of voxelwise networks that eliminates potentially artificial short distance relationships. These graphs contain many subgraphs in good agreement with known functional brain systems. Other subgraphs lack established functional identities; we suggest possible functional characteristics for these subgraphs. Further, graph measures of the areal network indicate that the default mode subgraph shares network properties with sensory and motor subgraphs: it is internally integrated but isolated from other subgraphs, much like a "processing" system. The modified voxelwise graph also reveals spatial motifs in the patterning of systems across the cortex. PMID- 22099469 TI - A self-directed adherence management program for patients with heart failure completing combined aerobic and resistance exercise training. AB - This study measured the impact of the Exercise Adherence Management Program (EAMP) provided to 20 patients with heart failure (HF) who participated in a combined resistance and aerobic exercise training program during two 12-week phases. The EAMP included strategies designed to support exercise self-efficacy and adherence. Results indicate that an improvement in exercise self-efficacy occurred during the study period, whereas exercise adherence declined during the unsupervised phase. The highest rated adherence strategy for helpfulness and self efficacy was group sessions. The study supports the use of adherence strategies based on self-efficacy in exercise programs for patients with HF. PMID- 22099470 TI - Nurses' perceptions of how physical environment affects medication errors in acute care settings. AB - The work that nurses perform in hospital environments is physically and psychologically intense, with the potential for burnout and stress. This issue is compounded by crowded and poorly designed work spaces in nursing units that can contribute to medical mistakes, including medication errors. This article is based on a study that examined the nurses' perception of how the physical environment in hospitals affects medication errors. Literature suggests that reduction of staff stress can be achieved through physical environmental considerations, such as improved air quality, acoustics, and lighting. However, there is no empirical study specifically exploring the relationship between aspects of the physical environment and medication errors. In this study, a cross sectional survey was conducted with nursing staff (N = 84) in four hospitals in the Pacific Northwest region of the United States. The survey included questions on nursing unit design, medication room configurations, perceived incidence of errors, and adverse events. Respondents noted several physical environmental factors that are potentially problematic in the nursing station area and can lead to medication, documentation, and other types of nursing errors. These factors include inadequate space in charting and documentation area, lengthy walking distances to patient rooms, insufficient patient surveillance opportunity/lack of visibility to all parts of the nursing unit, small size of the medication room, inappropriate organization of medical supplies, high noise levels in nursing unit, poor lighting, and lack of privacy in the nursing stations. As administrators in acute care facilities consider strategies for organizational and staff interventions to reduce medication errors, it is important to consider physical environmental factors to have a comprehensive understanding of the issue. PMID- 22099471 TI - Comparison of oxygen saturation values and measurement times by pulse oximetry in various parts of the body. AB - The aim of this study, which included 40 patients, was to compare the values pulse oximetry and the measurement times in various regions of the body. Data were analyzed using intraclass correlation coefficient test and paired-sample test. The confidence power value was found to be .81 for the comparison of oxygen saturation values by arterial blood gas analysis and measurement by the forehead probe. It was found that the time for oxygen saturation measurement using the forehead probe was shorter than those using the finger and toe probes. PMID- 22099472 TI - Binding of oxindole-Schiff base copper(II) complexes to DNA and its modulation by the ligand. AB - Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential antitumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria. Herein, we better characterize the interactions between some of these copper(II) complexes and DNA. Investigations on its binding ability to DNA were carried out by fluorescence measurements in competitive experiments with ethidium bromide, using plasmidial or calf-thymus DNA. These results indicated an efficient binding process similar to that observed with copper(II)-phenanthroline species, [Cu(o phen)(2)](2+), with binding constants in the range 3 to 9*10(2) M(-1). DNA cleavage experiments in the presence and absence of distamycin, a recognized binder of DNA, indicated that this binding probably occurs at major or minor groove, leading to double-strand DNA cleavage, and being modulated by the imine ligand. Corroborating these data, discrete changes in EPR spectra of the studied complexes were observed in the presence of DNA, while more remarkable changes were observed in the presence of nucleotides (AMP, GMP, CMP or UMP). Additional evidence for preferential coordination of the copper centers to the bases guanine or cytosine was obtained from titrations of these complexes with each nucleotide, monitored by absorption spectral changes. Therefore, the obtained data point out to their action as groove binders to DNA bases, rather than as intercalators or covalent cross-linkers. Further investigations by SDS PAGE using (32)P-ATP or (32)P-oligonucleotides attested that no hydrolysis of phosphate linkage in DNA or RNA occurs, in the presence of such complexes, confirming their main oxidative mechanism of action. PMID- 22099473 TI - Interaction of arsenite with a zinc finger CCHC peptide: evidence for formation of an As-Zn-peptide mixed complex. AB - The interaction of arsenite with a Cys(3)His (CCHC) zinc finger model (34-51) HIV 1 nucleocapsid protein p7 (NCp7) peptide in the absence and presence of Zn(II) was studied using fluorescence spectroscopy, CD (circular dichroism) and ESI-MS (Electrospray Ionization Mass Spectrometry). We found that arsenic forms different complexes with the free peptide and the zinc finger peptide. In the former case the peptide conformation differed greatly from that of the zinc finger, whereas in the second case a mixed As-Zn-peptide complex was formed with partial preservation of zinc finger conformation. An apparent stability constant was estimated for the mixed As-Zn-peptide complex (K=2083 M(-1) and 442 M(-1) at 25 degrees C and pHs 6 and 7, respectively). Our study also shows that the interaction of arsenic with the CCHC motif is facilitated by glutathione (GSH), through formation of a GS-As-peptide conjugate. PMID- 22099474 TI - Schizophrenia, culture and neuropsychology: sensory deficits, language impairments and social functioning in Chinese-speaking schizophrenia patients. AB - BACKGROUND: While 20% of schizophrenia patients worldwide speak tonal languages (e.g. Mandarin), studies are limited to Western-language patients. Western language patients show tonal deficits that are related to impaired emotional processing of speech. However, language processing is minimally affected. In contrast, in Mandarin, syllables are voiced in one of four tones, with word meaning varying accordingly. We hypothesized that Mandarin-speaking schizophrenia patients would show impairments in underlying basic auditory processing that, unlike in Western groups, would relate to deficits in word recognition and social outcomes. METHOD: Altogether, 22 Mandarin-speaking schizophrenia patients and 44 matched healthy participants were recruited from New York City. The auditory tasks were: (1) tone matching; (2) distorted tunes; (3) Chinese word discrimination; (4) Chinese word identification. Social outcomes were measured by marital status, employment and most recent employment status. RESULTS: Patients showed deficits in tone-matching, distorted tunes, word discrimination and word identification versus controls (all p<0.0001). Impairments in tone-matching across groups correlated with both word identification (p<0.0001) and discrimination (p<0.0001). On social outcomes, tonally impaired patients had 'lower-status' jobs overall when compared with tonally intact patients (p<0.005) and controls (p<0.0001). CONCLUSIONS: Our study is the first to investigate an interaction between neuropsychology and language among Mandarin-speaking schizophrenia patients. As predicted, patients were highly impaired in both tone and auditory word processing, with these two measures significantly correlated. Tonally impaired patients showed significantly worse employment-status function than tonally intact patients, suggesting a link between sensory impairment and employment status outcome. While neuropsychological deficits appear similar cross culturally, their consequences may be language- and culture-dependent. PMID- 22099475 TI - Decoding the molecular design principles underlying Ca(2+) binding to betagamma crystallin motifs. AB - Numerous proteins belonging to the recently expanded betagamma-crystallin superfamily bind Ca(2+) at the double-clamp N/D-N/D-X(1)-X(2)-S/T-S motif. However, there have been no attempts to understand the intricacies involving Ca(2+) binding, such as the determinants of Ca(2+)-binding affinity and their contributions to gain in stability. This work is an in-depth analysis of understanding the modes and determinants of Ca(2+) binding to betagamma crystallin motifs. We have performed extensive naturally occurring substitutions from related proteins on the betagamma-crystallin domains of flavollin, a low affinity Ca(2+)-binding protein, and clostrillin, a moderate-affinity protein. We monitored the consequences of these modifications on Ca(2)(+) binding by isothermal titration calorimetry, thermal stability and conformational and crystal structure analyses. We demonstrate that Ca(2)(+) binding to the two sites of a betagamma-domain is interdependent and that the presence of Arg at the fifth position disables a site. A change from Thr to Ser, or vice versa, influences Ca(2+)-binding affinity, highlighting the basis of diversity found in these domains. A subtle change in the first site has a greater influence on Ca(2)(+) binding than a similar alteration in the second site. Thus, the second site is more variable in nature. Replacing an acidic or hydrophobic residue in a binding site alters the Ca(2+)-binding properties drastically. While it appears from their binding site sequence that these domains have evolved randomly, our examination illustrates the subtlety in the design of these modules. Decoding such design schemes would aid in our understanding of the functional themes underlying differential Ca(2)(+) binding and in predicting these in emerging sequence information. PMID- 22099476 TI - Lower urinary tract symptoms after feminizing genitoplasty. AB - OBJECTIVE: To investigate the prevalence of lower urinary tract symptoms (LUTS) in a Finnish cohort of patients who had undergone feminizing genitoplasty in childhood. PATIENTS AND METHODS: Information on LUTS was assessed using the Danish Prostatic Symptom Score questionnaire: 24 out of 45 females (53%) returned the questionnaire; 16 patients with prenatal androgen exposure (congenital adrenal hyperplasia = CAH group) and eight with androgen insensitivity (AIS group). RESULTS: Urge urinary incontinence was reported by 13% of the patients in both the CAH and AIS groups and by 15% of the controls. Stress urinary incontinence was reported by 31% of the patients in the CAH group, 13% of the patients in the AIS group and 22% of the controls. Distressing voiding symptoms were reported by 19% of the patients in the CAH group, 13% of the patients in the AIS group and 28% of the controls, and of these straining and incomplete emptying were the most prevalent. CONCLUSIONS: LUTS are as common in female DSD patients with feminizing genitoplasty as they are in controls. Some degree of distressing incontinence occurred in 13%-25% of the young female patients and the controls. PMID- 22099477 TI - Tamsulosin for the management of distal ureteral stones in children: a prospective randomized study. AB - PURPOSE: Based on efficacy demonstrated in the adult population, tamsulosin was evaluated with regard to facilitating ureteral stone expulsion in children presenting with distal ureteric calculi. PATIENTS AND METHODS: A prospective randomized controlled study involving 61 children with distal ureteric calculi <12 mm was performed. The children were randomly divided into two groups. Group I (study group, n = 33) received tamsulosin and standard analgesia, and Group II (placebo group, n = 28) received standard analgesia and placebo. Patients were offered a closely monitored trial for spontaneous stone passage in the 4-week period prior to definitive therapy. The stone expulsion rate, number and duration of pain episodes, need for analgesia and possible side effects of medications were observed. RESULTS: All patients completed the study and none were excluded due to side effects. No significant differences were found between the groups for age, gender and stone size. Mean patient age was 8.1 +/- 6.8 years. There were 25 females and 36 males. The stone-free rate was 87.8% in Group I (29/33), compared with 64.2% (18/28) in Group II. A mean stone expulsion time of 8.2 and 14.5 days was recorded for Group I and II respectively, and this difference was statistically significant (P < 0.001). CONCLUSIONS: Medical expulsion therapy for lower ureteric stones is a successful procedure in children. Tamsulosin demonstrated no clinically significant adverse effect, while proving to be a safe and effective treatment option. PMID- 22099478 TI - Effect of increased intra-abdominal pressure on urinary system development in fetal rabbits. AB - AIM: To investigate the effect of increased intra-abdominal pressure (IAP) on the fetal urinary system. MATERIALS AND METHODS: Pregnant rabbits (15-day gestation) were used. Control (n = 5) and experimental (EG, n = 4) groups underwent intraperitoneal catheter placement. The IAP was increased by intraperitoneal air insufflations during the third trimester in the EG. At term, organ weight and organ weight/body weight (BW) ratios were noted, histological examination of the urinary system organs was performed, and the apoptotic indexes were calculated. RESULTS: BW and total renal weight were significantly increased in the EG (38.65 +/- 8.34 g vs 49.36 +/- 8.81 g, p = 0.008; and 0.406 +/- 0.132 g vs 0.531 +/- 0.129 g, p = 0.02). Total renal weight/BW ratio did not differ between groups (0.0103 +/- 0.001 vs 0.0107 +/- 0.001; p = 0.33). Bladder weight and bladder weight/BW ratio was also significantly increased in the EG (0.067 +/- 0.014 g vs 0.114 +/- 0.026 g, p = 0.00; and 0.00175 +/- 0.00026 vs 0.00229 +/- 0.00036, p = 0.001). Immature glomeruli and collecting tubules, and a thin and underdeveloped muscular layer in the ureter and bladder were encountered in the EG, and the apoptotic cell index was significantly increased (p < 0.05). CONCLUSION: Increased IAP has an adverse effect on fetal urinary system development, and may play a role in the pathogenesis of various congenital abnormalities of the urinary system. PMID- 22099479 TI - Religiousness, mental health, and quality of life in Brazilian dialysis patients. AB - Patients with chronic kidney disease often use religion as a coping strategy to relieve suffering and serve as a source of strength. The aim of this study was to identify religious aspects associated with mental health and quality of life in Brazilian dialysis patients. A cross-sectional study was performed involving two dialysis centers in Brazil. Patients were selected consecutively over three typical dialysis treatment days. The questionnaire was self-administered and covered the following aspects: socio-demographic aspects, religiousness (using the Portuguese version of the Private and Social Religious Practice Scale), quality of life (World Health Organization Quality of Life brief Scale Brief Version), depression and anxiety (Beck Inventory), and pain grade. For statistical analysis, the hypothesis that different religious variables are associated (positively or negatively) with depressive/anxiety symptoms and quality of life in these patients was tested using linear regression, controlling for confounding variables. A total of 205 patients were invited to participate and 133 (64.8%) agreed to fill out the questionnaire. On the adjusted model, reading religious literature was found to be inversely associated with depressive symptoms (P < 0.001). In addition, the psychological domain of quality of life was positively associated with an increase in patient religiosity (P = 0.030) and greater religious importance for recovery from their dialysis condition (P = 0.016), whereas the environmental domain was positively associated with greater religious importance for recovery (P = 0.032). No religious aspects were associated with anxiety symptoms. Religiousness is associated with less depressive symptoms and better quality of life in Brazilian dialysis patients. Nephrologists should evaluate the patient's spirituality and religion in order to provide more integrative care. PMID- 22099481 TI - Hydraulic performance of grass swales for managing highway runoff. AB - The hydraulic performance of grass swales as a highway stormwater control measure was evaluated in a field-scale study adjacent to a Maryland highway. Two common swale design alternatives, pretreatment grass filter strips and vegetated check dams, were compared during 52 storm events over 4.5 years. Swale performance is described via three regimes, dependent on the relative size of the rainfall event. Overall, half of the events were small enough that the entire flow was stored, infiltrated, and evapotranspirated by the swales, resulting in no net swale discharge. Swales significantly reduced total volume and flow magnitudes generally during events with rainfall less than 3 cm. While the majority of improvement can be attributed to the swales, inclusion of check dams increases swale effectiveness. Pretreatment grass filter strips produced mixed effects. The swales demonstrated essentially no volumetric reduction during large storm events, functioning instead as conveyance, and smoothing fluctuations in flow. PMID- 22099480 TI - Prometheus's heart: what lies beneath. AB - A heart attack kills off many cells in the heart. Parts of the heart become thin and fail to contract properly following the replacement of lost cells by scar tissue. However, the notion that the same adult cardiomyocytes beat throughout the lifespan of the organ and organism, without the need for a minimum turnover, gives way to a fascinating investigations. Since the late 1800s, scientists and cardiologists wanted to demonstrate that the cardiomyocytes cannot be generated after the perinatal period in human beings. This curiosity has been passed down in subsequent years and has motivated more and more accurate studies in an attempt to exclude the presence of renewed cardiomyocytes in the tissue bordering the ischaemic area, and then to confirm the dogma of the heart as terminally differentiated organ. Conversely, peri-lesional mitosis of cardiomyocytes were discovered initially by light microscopy and subsequently confirmed by more sophisticated technologies. Controversial evidence of mechanisms underlying myocardial regeneration has shown that adult cardiomyocytes are renewed through a slow turnover, even in the absence of damage. This turnover is ensured by the activation of rare clusters of progenitor cells interspersed among the cardiac cells functionally mature. Cardiac progenitor cells continuously interact with each other, with the cells circulating in the vessels of the coronary microcirculation and myocardial cells in auto-/paracrine manner. Much remains to be understood; however, the limited functional recovery in human beings after myocardial injury clearly demonstrates weak regenerative potential of cardiomyocytes and encourages the development of new approaches to stimulate this process. PMID- 22099484 TI - Strategies for reducing radiation exposure in multi-detector row CT. AB - Many tools and strategies exist to enable the reduction of radiation exposure from computed tomography (CT). The common CT metrics of x-ray output, CTDI(vol) and DLP, are explained and serve as the basis for monitoring radiation exposure from CT scans. Many strategies to dose optimize CT protocols are explored that, in combination with available hardware and software tools, allow robust diagnostic quality CT scans to be performed with a radiation exposure appropriate for the clinical scenario and the size of the patients. Specific emergency department example protocols are used to demonstrate these techniques. PMID- 22099485 TI - Updated imaging of traumatic brain injury. AB - Computed tomography (CT) and magnetic resonance (MR) play important roles in the evaluation of traumatic brain injury. Modern CT scanners allow for rapid and accurate diagnosis of intracranial hemorrhage and mass effect and allow the efficient implementation of emergent CT angiography. Newer sequences, such as gradient recalled echo, susceptibility-weighted imaging, and diffusion-weighted imaging, can provide greater sensitivity for specific types of diffuse posttraumatic brain injury. MR spectroscopy can provide additional chemical information, and diffusion tensor imaging can provide information about white matter injury. Patient treatment can be optimized using the diagnostic and prognostic information derived from current imaging techniques. PMID- 22099486 TI - The imaging of maxillofacial trauma and its pertinence to surgical intervention. AB - Maxillofacial skeletal injuries account for a large proportion of emergency department visits and often result in surgical consultation. Although many of the principles of detection and repair are basic, the evolution of technology and therapeutic strategies has led to improved patient outcomes. This article aims to provide a review of the imaging aspects involved in maxillofacial trauma and to delineate its relevance to management. PMID- 22099487 TI - Multi-detector row CT angiography of the neck in blunt trauma. AB - Blunt cerebrovascular injury (BCVI) is uncommon but potentially catastrophic; 80% are caused by vehicle collisions. Ischemic events secondary to untreated BCVI are common, with high injury-specific mortality. This has led to implementation of screening programs based on mechanism of injury, clinical presentation, and injury patterns identified on noncontrast computed tomography (CT) imaging. The standard of reference for diagnosis is four-vessel digital subtraction angiography. Given its availably in trauma service institutions, use of multidetector CT angiography has increased. This article presents the evidence and the controversies surrounding its use. Available protocols, injury description, and grading, as well as potential pitfalls are reviewed. PMID- 22099488 TI - Imaging of acute head and neck infections. AB - Tonsillar infection is the most common cause of infections of the neck in children and young adults whereas odontogenic infection is the most common cause in older population groups. Other sources of neck infection include the salivary glands, nasal sinuses, middle ear and mastoids, cervical lymph nodes, and trauma. Computed tomography and magnetic resonance imaging have excellent sensitivity for the recognition of deep infections, particularly for the identification of abscess formation and its precise location and extension of disease. A careful assessment of potential severe complications, such as vascular compromise, osteomyelitis, and airway narrowing, should be performed routinely. PMID- 22099489 TI - Imaging of aortic and branch vessel trauma. AB - Although infrequently encountered in busy trauma centers, injuries to the aorta and branch vessels remain an important cause of trauma-related mortality. Advances in the diagnosis and management of these injuries have led to more accurate and timely imaging, and improved patient outcomes. Despite these advances, several challenges in evaluating the severely injured trauma patient remain. This review provides an overview of current concepts in the imaging of aortic and branch vessel injuries, and provides pointers to improve detection and interpretation of more challenging injuries. PMID- 22099490 TI - Splenic trauma: what is new? AB - Evaluation for splenic injury is an important component of patient assessment after blunt abdominal trauma. Key imaging modalities include ultrasound, particularly for rapid identification of hemoperitoneum, and computed tomography (CT), which permits a more detailed and accurate determination of splenic integrity. Specific findings at contrast-enhanced multidetector CT (MDCT) should prompt the consideration of catheter angiography with arterial embolization as an adjunct to nonsurgical management. This article reviews the roles of imaging in the management of splenic trauma, illustrates the MDCT appearance of various splenic injuries, and discusses imaging-based indications for operative and angiographic intervention. PMID- 22099491 TI - CT imaging of blunt traumatic bowel and mesenteric injuries. AB - Delayed diagnosis of a bowel or mesenteric injury resulting in hollow viscus perforation leads to significant morbidity and mortality from hemorrhage, peritonitis, or abdominal sepsis. The timely diagnosis of bowel and mesenteric injuries requiring operative repair depends almost exclusively on their early detection by the radiologist on computed tomography examination, because the clinical signs and symptoms of these injuries are not specific and usually develop late. Therefore, the radiologist must be familiar with the often-subtle imaging findings of bowel and mesenteric injury that will allow for appropriate triage of a patient who has sustained blunt trauma to the abdomen or pelvis. PMID- 22099492 TI - Multi-detector row CT of acute non-traumatic abdominal pain: contrast and protocol considerations. AB - This article discusses the critical protocol considerations in imaging patients with abdominal pain in the emergency department, specifically, the use of oral contrast, intravenous contrast, image postprocessing, and radiation dose. These considerations related to the use of computed tomography imaging of abdominal pain are reviewed in an evidence-based fashion. PMID- 22099493 TI - Imaging of abdominal pain in pregnancy. AB - This article reviews the evolving radiology and clinical literature on imaging of suspected common and relatively common maternal nonobstetric conditions of the abdomen and pelvis, including appendicitis, urolithiasis, and biliary disease, as well as on trauma to the maternal abdomen and pelvis and to the fetus. Recommendations for imaging these conditions, based on the literature to date and on the authors' experiences at two tertiary-care institutions with busy obstetric services, are proposed. The potential and theoretical fetal and maternal risks from such imaging are also reviewed. PMID- 22099494 TI - Diagnosis of acute gastrointestinal hemorrhage and acute mesenteric ischemia in the era of multi-detector row CT. AB - Gastrointestinal hemorrhage and mesenteric ischemia are two conditions that require rapid and accurate diagnosis. In this article, the author discusses these conditions in the light of current available diagnosing modalities, such as multi detector computed tomography. PMID- 22099495 TI - Emergency radiology. PMID- 22099496 TI - Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis. AB - BACKGROUND: Apoptosis of lymphocytes is considered a late sequelum in the sepsis cascade. The role of apoptosis of lymphocytes as a driver of final outcome was investigated. METHODS: Abdominal sepsis was induced after cecal ligation and puncture (CLP) in 31 rabbits. Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured through flow cytometric analysis. PBMCs were stimulated with LPS and Pam3Cys for the release of tumor necrosis factor alpha (TNFalpha). Tissue bacterial growth was quantitatively measured. In a second set of experiments, CLP was performed in another 40 rabbits; 20 received single intravenous infusions of ciprofloxacin and of metronidazole 4 hours after surgery. RESULTS: Animals were divided into two groups based on the percentage of lymphocyte apoptosis at 4 hours after surgery; less than or equal to 32% and more than 32%. Survival of the former was shorter than the latter (p: 0.017). Tissue growth was similar between groups. Apoptosis of lymphocytes and of monocytes was lower in the former group over follow-up. Release of TauNFalpha did not differ. The above findings on survival were repeated in the second set of experiments. Administration of antimicrobials prolonged survival of the former group (p: 0.039) but not of the latter group (pNS). CONCLUSIONS: Lymphocyte apoptosis at an early time point of experimental peritonitis is a major driver for death. A lower percentage of apoptosis leads earlier to death. Antimicrobials were beneficial even at that disease state. PMID- 22099497 TI - Activity in vitro of hydrogen peroxide vapour against Clostridium difficile spores. AB - Clostridium difficile spores are shed in high numbers by infected patients and are resistant to desiccation and some disinfectants. We explored the in vitro activity of hydrogen peroxide vapour (HPV) against several strains of C. difficile spores using a spore-carrier test. Spores were dried on polyvinyl chloride or laminate carriers at mean concentrations of 4.7-6.9 log(10) spores/carrier, which were then decontaminated using HPV. C. difficile was completely eradicated from the exposed carriers regardless of the C. difficile strain or surface used. HPV can be considered for the eradication of C. difficile spores from the hospital environment. PMID- 22099498 TI - Nosocomial outbreak of Myroides odoratimimus urinary tract infection in a Tunisian hospital. AB - We report a nosocomial outbreak of urinary tract infection caused by Myroides odoratimimus, previously called Flavobacterium odoratum, in the urology unit of a Tunisian hospital. From May to November 2010, seven isolates of M. odoratimimus were recovered from urine. Pulsed-field gel electrophoresis clearly differentiated these isolates into two possibly related clones from two different periods. All patients but one had urinary calculi and underwent endourological surgery. All Myroides isolates were resistant to all antibiotics tested. Three patients were successfully treated with ciprofloxacin and rifampicin. Clinicians should be aware that M. odoratimimus may induce serious and prolonged nosocomial outbreaks of urinary tract infections. PMID- 22099499 TI - Clostridium difficile infection ward rounds. PMID- 22099500 TI - Family history of non-hematologic cancers among Waldenstrom macroglobulinemia patients: a preliminary study. AB - BACKGROUND: Little is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM. METHODS: All probands aged 20-79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for >=1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype. RESULTS: Family history of prostate cancer had the largest overall rate ratio (RR=1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR=1.3, 95% CL: 1.1, 1.7; breast: RR=1.3, 95% CL: 1.2, 1.6). CONCLUSION: Our study suggests that it may be worthwhile to pursue these associations in a case-control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history. PMID- 22099501 TI - Primary hepatic carcinoid tumor. AB - Primary hepatic carcinoid tumor is rare and poses a challenge for diagnosis and management. We presented a case of primary hepatic carcinoid tumor in a 53-year old female with a complaint of right upper abdominal pain. Computer tomography scans revealed a hypervascular mass in segment 4 of the liver. An ultrasonography guided biopsy showed a carcinoid tumor. No other lesions were found by the radiological investigations. Surgery resection was performed and histopathological examination revealed a primary hepatic carcinoid tumor. Three years later, recurrence was found and transcatheter arterial chemoembolization was performed. After transcatheter arterial chemoembolization, the patient has been free of symptom and had no radiological disease progression for over 6 months. Surgical resection combination with transcatheter arterial chemoembolization is effective to offer excellent palliation. PMID- 22099502 TI - Tularemia in Alaska, 1938 - 2010. AB - Tularemia is a serious, potentially life threatening zoonotic disease. The causative agent, Francisella tularensis, is ubiquitous in the Northern hemisphere, including Alaska, where it was first isolated from a rabbit tick (Haemophysalis leporis-palustris) in 1938. Since then, F. tularensis has been isolated from wildlife and humans throughout the state. Serologic surveys have found measurable antibodies with prevalence ranging from < 1% to 50% and 4% to 18% for selected populations of wildlife species and humans, respectively. We reviewed and summarized known literature on tularemia surveillance in Alaska and summarized the epidemiological information on human cases reported to public health officials. Additionally, available F. tularensis isolates from Alaska were analyzed using canonical SNPs and a multi-locus variable-number tandem repeats (VNTR) analysis (MLVA) system. The results show that both F. t. tularensis and F. t. holarctica are present in Alaska and that subtype A.I, the most virulent type, is responsible for most recently reported human clinical cases in the state. PMID- 22099503 TI - Diuretics: introduction. PMID- 22099504 TI - Diuretics and salt transport along the nephron. AB - The clinical use of diuretics almost uniformly predated the localization of their site of action. The consequence of diuretic specificity predicts clinical application and side effect, and the proximity of the sodium transporters, one to the next, often dictates potency or diuretic efficiency. All diuretics function by inhibiting the normal transport of sodium from the filtrate into the renal tubular cells. This movement of sodium into the renal epithelial cells on the apical side is facilitated by a series of transporters whose function is, in turn, dependent on the adenosine triphosphate (ATP)-dependent Na-K cotransporter on the basolateral side of the cell. Our growing understanding of the physiology of sodium transport has spawned new possibilities for diuretic development. PMID- 22099505 TI - Update in diuretic therapy: clinical pharmacology. AB - All diuretics except spironolactone exert their effects from the lumen of the nephron. Thus, to exert an effect, they must reach the urine. Pharmacokinetics (PK) describes this access. Different edematous disorders can affect access to this site of action and therein affect response to a diuretic. In addition, once a diuretic reaches the site of action, a response ensues. The characteristics of this response that can be affected by a patient's clinical condition are described by the pharmacodynamics (PD) of a diuretic. To understand the mechanisms of abnormal response to a diuretic one must dissect its PK and PD in different edematous disorders. For example, in patients with renal insufficiency, the mechanism of poor diuretic response is PK. In contrast, in patients with cirrhosis or in those with congestive heart failure, it is PD. In patients with nephrotic syndrome, both PK and PD are operative. These different mechanisms mandate differences in therapeutic strategy, as explained in this article. PMID- 22099506 TI - Diuretics in the treatment of hypertension. AB - Diuretics are powerful agents that impair sodium reabsorption in renal tubules. Their ability to alter long-term sodium balance induces important hemodynamic changes that result in a reduction in peripheral resistance and sustained reduction in blood pressure. A pharmacologically diverse group of drugs, they remain a mainstay in the therapy of hypertension. Clinical trials over the past 4 decades consistently have shown that blood pressure lowering obtained from a diuretic-based regimen reduces cardiovascular events. The ability of diuretics to augment the efficacy of nearly all other classes of antihypertensives makes them highly versatile and an important pharmacotherapeutic intervention to achieve blood pressure control. This article reviews key aspects of the use of diuretics relevant to the clinical management of hypertension. PMID- 22099507 TI - Use of diuretics in heart failure and cirrhosis. AB - Sodium and water retention in cardiac failure and cirrhosis is pivotal in the morbidity and mortality of patients with these disorders. Moreover, the pathophysiology of these edematous disorders is quite similar. Both disorders have activation of the renin-angiotensin-aldosterone system, increased sympathetic activity, and nonosmotic stimulation of arginine vasopressin, which is initiated by unloading of the arterial baroreceptors; this occurs secondary to diminished cardiac output with heart failure and primary systemic arterial vasodilation with cirrhosis. With this common pathophysiology causing pulmonary congestion, ascites, and peripheral edema, diuretics are pivotal in the therapy of patients with heart failure and cirrhosis. Advanced cardiac failure and cirrhosis both show secondary hyperaldosteronism and impaired renal escape from the sodium-retaining effect of aldosterone. However, currently there are contradictory uses of mineralocorticoid-receptor antagonists in cardiac failure (non-natriuretic doses) versus cirrhosis (natriuretic doses). This disparity relates to the greater potential of hyperkalemia in cardiac failure patients receiving inhibitors of the renin-angiotensin-aldosterone system. This review discusses the beneficial and potentially deleterious effects of diuretic use in patients with cardiac failure and cirrhosis. PMID- 22099508 TI - Intravenous high-dose furosemide and hypertonic saline solutions for refractory heart failure and ascites. AB - Several studies have shown the efficacy of hypertonic saline solution infusion in conditions in which regional organ blood flow is impaired. Our group has shown that treatment of patients with diuretic-resistant heart failure with high-dose furosemide plus hypertonic saline is effective and well tolerated, improving symptoms of congestion, reducing plasma levels of markers of neurohormonal and inflammatory activation, decreasing hospital readmission rates, and reducing long term mortality. The same regimen was shown to be better than repeated paracentesis in patients with cirrhosis and refractory ascites, yielding better control of ascites, pleural effusions, and/or leg edema without an increase of common adverse effects linked to high-dose furosemide such as hepatic encephalopathy. PMID- 22099509 TI - Diuretics in acute kidney injury. AB - Acute kidney injury (AKI) is common in hospitalized patients and is associated with significant morbidity and mortality. The incidence of AKI is increasing and despite clinical advances there has been little change in the outcomes associated with AKI. A variety of interventions, including loop diuretics, have been tested for the prevention and treatment of AKI; however, none to date have shown convincing benefits in clinical studies, and the management of AKI remains largely supportive. In this article, we review the pharmacology and experimental and clinical evidence for loop diuretics in the management of AKI. In addition, we also review evidence for other agents with diuretic and/or natriuretic properties such as thiazide diuretics, mannitol, fenoldopam, and natriuretic peptides in both the prevention and treatment of AKI. Implications for current clinical practice are outlined to guide clinical decisions in this field. PMID- 22099510 TI - Diuretics and disorders of calcium homeostasis. AB - Diuretics commonly are administered in disorders of sodium balance. Loop diuretics inhibit the Na-K-2Cl transporter and also increase calcium excretion. They are often used in the treatment of hypercalcemia. Thiazide diuretics block the thiazide-sensitive NaCl transporter in the distal convoluted tubule, and can decrease calcium excretion. They are often used in the treatment of nephrolithiasis. Carbonic anhydrase inhibitors decrease bicarbonate absorption and the resultant metabolic acidosis can increase calcium excretion. Their use can promote nephrocalcinosis and nephrolithiasis. This review will address the use of diuretics on disorders of calcium homeostasis. PMID- 22099511 TI - Metabolic complications associated with use of diuretics. AB - Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses. PMID- 22099512 TI - Diuretic-associated hyponatremia. AB - Soon after their introduction in 1957, thiazide diuretics became a recognized cause of hyponatremia. Thiazides may be the sole cause and they may exacerbate hyponatremia in patients with disorders that cause the syndrome of inappropriate antidiuretic hormone secretion. Although thiazides do not inhibit the ability to concentrate the urine, they impair diluting ability in several ways: inhibition of sodium and chloride transport at cortical diluting sites; stimulation of vasopressin release; reduction of glomerular filtration and enhanced proximal water reabsorption, which reduce delivery to the distal diluting sites; and, possibly, a direct effect on water flow in the collecting duct. Water retention caused by impaired water excretion combined with cation depletion may result in severe hyponatremia. Thiazides should be avoided in frail elderly patients with chronically high water intake or in others who depend on the excretion of maximally dilute urine to maintain fluid balance, such as patients with psychogenic polydipsia or heavy beer drinking. Inadvertent rapid correction of hyponatremia is common in thiazide-induced hyponatremia because the ability to dilute the urine is restored when the diuretic is discontinued and volume deficits are repaired. Hypokalemia, which often is present, increases the susceptibility to osmotic demyelination syndrome and replacement of potassium deficits contributes to the increase in serum sodium concentration. PMID- 22099513 TI - Brittle leaf disease induces an oxidative stress and decreases the expression of manganese-related genes in date palm (Phoenix dactylifera L.). AB - In Tunisia, date orchards are being decimated by a disease called brittle leaf disease of unknown origin. Previous studies reported that affected soils, roots and leaves were manganese deficient. In this study, we investigated the biochemical and molecular response of MFC-affected date palms to the oxidative stress generated by manganese deficiency. Both the malondialdehyde (MDA) content which is indicative of lipid peroxidation and the activities of antioxidant enzyme were measured in affected leaves and roots. The expression profiles of oxidative stress-related genes encoding superoxide dismutases and peroxidases were also investigated. The data show that the MDA concentration increased but not significantly in affected leaves. However, such MDA increase was significant in roots of MFC-affected plants. The total superoxide dismutase (SOD) activity increased in affected leaves and roots, while RT-PCR experiments showed that MnSOD RNA decreased in affected leaves and roots unlike FeSOD and Cu/Zn-SOD RNA expression increased in these organs. In addition ascorbate peroxidase (APx) and glutathione peroxidase (GPx) RNA expression increased in diseased leaves and roots. PMID- 22099514 TI - Acclimation to intense light implies changes at the level of trimeric subunits involved in the structural organization of the main light-harvesting complex of photosystem II (LHCII) and their isoforms. AB - When plants are grown under stable light conditions their photosynthetic apparatus undergoes a long-term acclimation process. Acclimation to different light intensities involves changes in the organization and/or abundance of protein complexes in the thylakoid membranes. In this study, spinach plants were exposed to differing light intensities, and the structural organization of the major light-harvesting chlorophyll a/b-protein complex of photosystem II (LHCII) was investigated by analysing their trimeric subunits. Plants were exposed to three different light intensities, 100 MUmol quanta m-2 s-1, 200 MUmol quanta m-2 s-1 and an elevated light intensity, 400 MUmol quanta m-2 s-1, sufficient to provoke a moderate stress response in the form of down regulation of PSII. "MicroRotofor" analysis showed the presence of LHCII with different pIs and revealed a clear decline in their abundance as light intensity increased from 100 to 400 MUmol quanta m-2 s-1. The three subunits (Lhcb1, Lhcb2, Lhcb3) behaved differently from each other as: Lhcb1 decreased more significantly than Lhcb2, whereas Lhcb3 was reduced only at a light window at which Lhcb1 and Lhcb2 abundance has already been depleted under intense irradiation. Interestingly, we also found that isoforms of Lhcb1 subunit (Lhcb1.1; 1.2; 1.3) behaved differently in response to elevated light intensity, suggesting an essential role of these isoforms to light adaption and consequently explaining the presence of this multigenic family, often identified among higher plants. PMID- 22099515 TI - Developmental stage is an important factor that determines the antioxidant responses of young and old grapevine leaves under UV irradiation in a green house. AB - The impact of UV irradiation was studied on photosynthesis, photosystem II photochemical yields and antioxidant responses using green-house grown grapevine (Vitis vinifera L. cv. Chardonnay) leaves. Supplemental UV irradiation (280-400 nm) was centred in the UV-B region, and corresponded to 8.95 kJ m-2 d-1 global (280-400 nm) or 8.04 kJ m-2 d-1 UV-B (280-315 nm) biologically effective dose. UV irradiation was applied daily and its effects were evaluated after 4-days. Younger (1-3 weeks-old) leaves (YL) and older (4-6 weeks-old) leaves (OL) were affected differently, UV irradiation decreased their photochemical yields to 78% and 56%, respectively. Unlike OL, YL responded by an increase in UV-B absorbing pigment, anthocyanin and total phenolics contents. UV irradiation increased total antioxidant capacities in YL but not in OL. YL were also different in their ability to increase specific hydroxyl radical and singlet oxygen neutralizing capacities in response to the supplemental UV irradiation, which is reported here for the first time. Our results suggest that the ability of maintaining photosynthesis under supplemental UV is not necessarily determined by base levels of antioxidants but rather by their inducibilities in response to the irradiation and emphasise the importance of comparing leaves of the same age in UV studies. Correlations between various antioxidant capacities, pigment contents and photosynthesis parameters were also examined. However, no single element of the defence system can be picked up as decisive factor of sensitivity to UV. PMID- 22099516 TI - Potato cytosine methylation and gene expression changes induced by a beneficial bacterial endophyte, Burkholderia phytofirmans strain PsJN. AB - Burkholderia phytofirmans strain PsJN is a highly effective plant-beneficial endophyte. We have used a combination of capillary electrophoresis and methylation-sensitive amplification length polymorphism (CE-MSAP) analysis to investigate the potato genomic DNA cytosine methylation changes that occur in response to PsJN bacterization. Six weeks after PsJN inoculation, over 6800 loci were identified and assessed in two in vitro grown potato varieties, the strongly responsive Red Pontiac and the poorly-responsive Superior. Compared to non bacterized control, bacterized Red Pontiac exhibited little change in the overall cytosine methylation, although methylation polymorphisms did occur. In contrast, poorly-responsive Superior exhibited significantly higher levels of overall cytosine methylation and a decrease in the number of non-methylated sites in the bacterized plants compared to controls. Superior had significantly higher DNA methylation and DNA hyper-methylation than Red Pontiac, suggesting that enhanced DNA loci methylation is involved in the suppression of PsJN-induced plant growth stimulation. Several DNA fragments, corresponding to different open reading frames exhibiting methylation polymorphisms in Red Pontiac or Superior were sequenced. Gene expression analysis of a subset of those genes was carried out using real time PCR. We identified several genes whose transcript levels were either enhanced or decreased in response to PsJN in a variety-specific way, as well as genes that were specifically enhanced in both varieties in response to the endophyte. PMID- 22099517 TI - Generation of poly-beta-hydroxybutyrate from externally provided acetate in rice root. AB - During the investigation of the metabolism of 14C-acetate or 14C-succinate in rice seedlings, an unknown organic acid (X) with a high specific radioactivity was detected in 10,000 * g 30 min precipitate-fraction of rice roots. The X was hardly extracted by 0.1 N-H2SO4 boiling, but was extracted by 0.5 N-KOH boiling. The X was co-chromatographed with several known organic acids, and the radioactive peak of the X matched beta-hydroxybutyric acid (beta hydroxybutyrate). The radioactive X and beta-hydroxybutyrate were then heated with concentrated H2SO4. The radioactivity and the titration value were completely converted to crotonic acid. Thus, it was concluded that the X was beta hydroxybutyrate, and the original form of this acid was presumed to be poly-beta hydroxybutyrate (PHB). Then rice root incubated with 2-14C-acetate was extracted with hot-ethanol, ethanol/ether, and hot-chloroform. Approximately 10% of the radioactivity absorbed was detected in the chloroform fraction. The chloroform fraction was co-precipitated with authentic PHB by the addition of acetone/ether, and almost all the radioactivity was co-precipitated with the PHB. The radioactive co-precipitate was then heated with 0.5 N-NaOH, and chromatographed. The radioactivity of beta-hydroxybutyrate plus crotonic acid almost matched that of the co-precipitate before alkaline-hydrolysis. Hence the radioactive co precipitate was confirmed to be PHB. In wheat and radish seedlings, 2-14C-acetate was also assimilated into PHB. It is concluded that externally provided acetate was rapidly converted to PHB in higher plants. PMID- 22099518 TI - Identification of water stress genes in Pinus pinaster Ait. by controlled progressive stress and suppression-subtractive hybridization. AB - Climate change is a major challenge particularly for forest tree species, which will have to face the severe alterations of environmental conditions with their current genetic pool. Thus, an understanding of their adaptive responses is of the utmost interest. In this work we have selected Pinus pinaster as a model species. This pine is one of the most important conifers (for which molecular tools and knowledge are far more scarce than for angiosperms) in the Mediterranean Basin, which is characterised in all foreseen scenarios as one of the regions most drastically affected by climate change, mainly because of increasing temperature and, particularly, by increasing drought. We have induced a controlled, increasing water stress by adding PEG to a hydroponic culture. We have generated a subtractive library, with the aim of identifying the genes induced by this stress and have searched for the most reliable expressional candidate genes, based on their overexpression during water stress, as revealed by microarray analysis and confirmed by RT-PCR. We have selected a set of 67 candidate genes belonging to different functional groups that will be useful molecular tools for further studies on drought stress responses, adaptation, and population genomics in conifers, as well as in breeding programs. PMID- 22099519 TI - Identification of genes up-regulated during somatic embryogenesis of cucumber. AB - Somatic embryogenesis is a method of plant regeneration, but it can also be used as a model to study plant development. A normalized library of cDNA fragments representing genes up-regulated after the induction of somatic embryogenesis in cucumber suspension cultures was constructed using the suppression subtractive hybridization technique. Candidate cDNA fragments (119) were classified according to their similarity to genes encoding known proteins and the presence of potential functional domains. Of the translation products with homology to known proteins, about 23% were possibly involved in metabolism, 13% represented proteins with a probable role in cellular communication and signal transduction, about 12% were likely to participate in protein synthesis, while around 10% were potential transcription factors. The genes corresponding to four of the cDNAs were subsequently analyzed in more detail: CsSEF2, CsSEM1 and CsSESTK1 encoding putative transcription factors or co-activators, and CsSECAD1 encoding cinnamyl alcohol dehydrogenase. Full-length cDNAs were isolated and analyzed. RT-PCR confirmed the up-regulation of these genes after the induction of somatic embryogenesis and showed the presence of their transcripts in other tissues. The in situ localization of transcripts of the CsSEF2 and CsSEM1 genes demonstrated that signalling in somatic embryo tissues involving these factors is concentrated in the cotyledon primordia and roots. PMID- 22099520 TI - Sexual functioning in chronic kidney disease: the association with depression and anxiety. AB - Sexual functioning is composed of both physiological and psychological factors among patients with chronic kidney disease (CKD). However, the role of depression and anxiety has not yet been studied extensively. This study aimed to investigate the relation of depressive and anxiety symptoms to sexual functioning among hemodialysis (HD) and peritoneal dialysis patients. A sample of 144 patients was recruited from three general hospitals in the broader area of Athens, consisting of 84 patients undergoing in-center HD and 60 patients in continuous ambulatory peritoneal dialysis. Measurements were conducted with the following instruments: the World Health Organization Quality of Life instrument, the General Health Questionnaire (GHQ-28), the State-Trait Anxiety Inventory (STAI 1/STAI 2), and the Center for Epidemiologic Studies Depression Scale. The results indicated that satisfaction about sexual life had negative association with all the subscales of GHQ-28 questionnaire (somatic symptoms, anxiety/insomnia, social dysfunction, severe depression). Sexual functioning was also related negatively to depression as well as state and trait anxieties. Findings provide evidence that the presence of depressive and anxiety symptoms relates significantly to the negative evaluation of sexual functioning in patients with CKD. PMID- 22099521 TI - Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. AB - The Mycobacterium simiae complex bacteria can cause opportunistic infections in humans. In the case of definite disease, there are no evidence-based treatment regimens and outcomes are very disappointing. To increase the evidence base underpinning treatment regimens for M. simiae complex disease, drug susceptibility patterns and rifampicin/ethambutol synergy were assessed retrospectively in 69 clinical M. simiae complex isolates from 60 patients (22 patients with M. simiae, 24 with Mycobacterium lentiflavum, 8 with Mycobacterium triplex, 5 with Mycobacterium parascrofulaceum and 1 with Mycobacterium stomatepiae) submitted to the mycobacteriology laboratory at National Jewish Health (Denver, CO). Quantitative drug susceptibility testing (DST) was performed using the radiometric BacTec 460 macrodilution method. Results were related to pharmacokinetic (PK) measurements, where available. All M. simiae complex species proved susceptible to clarithromycin and, to a lesser extent, rifabutin, clofazimine, streptomycin and moxifloxacin. Synergy or additive action between rifampicin and ethambutol was observed for all species except M. simiae. Mycobacterium simiae is poorly susceptible in vitro to rifampicin and ethambutol alone as well as in combination; PK measurements support the limited efficacy of these drugs against M. simiae. The triple-drug regimen of a rifamycin, ethambutol and a macrolide may be advised to treat disease caused by M. lentiflavum, M. triplex, M. parascrofulaceum and M. stomatepiae; for M. simiae, this regimen appears less active. These findings may partly explain the limited treatment results in M. simiae disease. A treatment regimen including a macrolide, moxifloxacin and one or two additional drugs based on DST results may be advisable; clofazimine and amikacin or streptomycin are potential candidates. PMID- 22099522 TI - Neurodevelopmental outcomes in infants requiring resuscitation in developing countries. AB - OBJECTIVE: To determine whether resuscitation of infants who failed to develop effective breathing at birth increases survivors with neurodevelopmental impairment. STUDY DESIGN: Infants unresponsive to stimulation who received bag and mask ventilation at birth in a resuscitation trial and infants who did not require any resuscitation were randomized to early neurodevelopmental intervention or control groups. Infants were examined by trained neurodevelopmental evaluators masked to both their resuscitation history and intervention group. The 12-month neurodevelopmental outcome data for both resuscitated and non-resuscitated infants randomized to the control groups are reported. RESULTS: The study provided no evidence of a difference between the resuscitated infants (n = 86) and the non-resuscitated infants (n = 115) in the percentage of infants at 12 months with a Mental Developmental Index <85 on the Bayley Scales of Infant Development-II (primary outcome; 18% versus 12%; P = .22) and in other neurodevelopmental outcomes. CONCLUSIONS: Most infants who received resuscitation with bag and mask ventilation at birth have 12-month neurodevelopmental outcomes in the reference range. Longer follow-up is needed because of increased risk for neurodevelopmental impairments. PMID- 22099523 TI - Plasma pro-endothelin-1 and respiratory distress in newborn infants. AB - Plasma concentrations of the stable endothelin-1 precursor, C-terminal portion of the endothelin-1 precursor, determined prospectively in 293 newborn infants (gestational age, 24-41 weeks) at birth and on day 3 of life were unrelated to gestational age at birth, but strongly associated with respiratory distress when measured on day 3 of life. PMID- 22099524 TI - 3 T MRI of hepatocellular carcinomas in patients with cirrhosis: does T2-weighted imaging provide added value? AB - AIM: To assess whether T2-weighted imaging (T2WI) provides any added value for the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis, especially for lesions smaller than 2 cm. MATERIALS AND METHODS: Sixty-five patients with cirrhosis underwent liver 3 T MRI. Images were qualitatively analysed independently by two observers in two separate sessions, including a dynamic enhanced session and a combination of dynamic and T2WI. The diagnostic accuracy was evaluated using the alternating free-response receiver operating characteristic. Sensitivity and positive predictive values were calculated for all HCCs and for the subgroup of HCCs that were smaller than 2 cm. Additionally, artefacts on T2WI were evaluated by two observers in consensus. RESULTS: Ninety HCCs (>2 cm n = 36; <=2 cm n = 54) were detected in 46 patients. For all HCCs and for lesions smaller than 2 cm, the sensitivities were significantly higher for the combined session than the dynamic session alone (p < 0.05). Conversely, for the Az and positive predictive values, there was no significant difference between the two sessions. For smaller HCC, 9% (5/54) and 7% (4/54) of the 54 HCCs were correctly interpreted by observers 1 and 2, respectively, only when T2WI was included. Three false-positive lesions (<=2 cm) were correctly diagnosed by one of the observers after combining T2WI. Conspicuity of only one large HCC was severely reduced by the artefacts from massive ascites. CONCLUSION: At 3 T liver imaging, combining with T2WI can improve the sensitivity of detection of HCC compared with dynamic MRI alone by increasing observer confidence, especially for lesions smaller than 2 cm. Additionally, T2 image quality was not significantly affected by artefacts. PMID- 22099525 TI - A longitudinal study on the effects of maternal smoking and secondhand smoke exposure during pregnancy on neonatal neurobehavior. AB - Maternal smoking during pregnancy is one of the most modifiable causes of morbidity and mortality for both pregnant women and their fetuses. The long-term effects of prenatal exposure to smoke on child behavior and development have been the subject of more extensive research than have the short-term effects. Therefore, the aim of this work is to examine the effects of smoke exposure during pregnancy on neonatal behavior, including in our study a group of mothers exposed to secondhand smoke. The behavior of 282 healthy full-term newborns was assessed using the Neonatal Behavior Assessment Scale (NBAS) at 48-72 h of life. Sixty-two mothers smoked during pregnancy (no mother smoked more than 15 cig/day) and 17 were exposed to secondhand smoke. After adjusting for socio-demographic and obstetric factors, both newborns whose mothers smoked and those whose mothers were exposed to secondhand smoke showed significantly lower scores in the habituation cluster than non-smoking mothers. Exposure to secondhand smoke was also related to lower motor system cluster scores as well as some supplementary items and the newborns of smoking mothers showed significantly lower scores in the state regulation cluster and in some items of the state organization cluster than the newborns of non-smoking mothers. We conclude that active and passive smoking during pregnancy affects several aspects of neurobehavioral development, regardless of socio-demographic, obstetric and pediatric factors. PMID- 22099526 TI - Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation. AB - OBJECTIVE: The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC). METHODS: A retrospective longitudinal chart review was performed, selecting patients who received multiple neuropsychological assessments. Intellectual/Developmental Quotients, Adaptive Behavior Composite scores, and clinical data were collected. On available EEGs, interictal epileptiform discharges were counted. RESULTS: Sixty-six (18%) patients with TSC received multiple cognitive and adaptive development assessments. The mean intelligence of this study group remained relatively stable, albeit variable. Significant decline in adaptive functioning was observed, associated with lower age at seizure onset. Patients who underwent neurosurgery prior to baseline testing showed cognitive improvement. Developmental declines were significantly associated with increased numbers of antiepileptic drugs, with a trend toward association with mutation type and interictal epileptiform discharges. CONCLUSION: This study suggests that the developmental course of patients with TSC may be altered by epilepsy comorbidity and neurosurgery, underlining the need for early and effective interventions in this population. PMID- 22099527 TI - Cortical thickness abnormalities associated with depressive symptoms in temporal lobe epilepsy. AB - Depression in patients with temporal lobe epilepsy (TLE) is highly prevalent and carries significant morbidity and mortality. Its neural basis is poorly understood. We used quantitative, surface-based MRI analysis to correlate brain morphometry with severity of depressive symptoms in 38 patients with TLE and 45 controls. Increasing severity of depressive symptoms was associated with orbitofrontal cortex (OFC) thinning in controls, but with OFC thickening in TLE patients. These results demonstrate distinct neuroanatomical substrates for depression with and without TLE, and suggest a unique role for OFC, a limbic region for emotional processing strongly interconnected with medial temporal structures, in TLE-related depressive symptoms. PMID- 22099528 TI - Perceived benefits of sharing health data between people with epilepsy on an online platform. AB - An epilepsy community was developed on PatientsLikeMe.com to share data between patients to improve their outcomes by finding other patients like them. In a 14 day response period, 221 patients with epilepsy (mean age: 40 years, SD: 12, range: 17-72, 66% female) completed a survey about benefits they perceived. Prior to using the site, a third of respondents (30%) did not know anyone else with epilepsy with whom they could talk; of these, 63% now had at least one other patient with whom they could connect. Perceived benefits included: finding another patient experiencing the same symptoms (59%), gaining a better understanding of seizures (58%), and learning more about symptoms or treatments (55%). Number of benefits was associated with number of relationships with other patients, F(4,216)=8.173, P<0.001). Patients with epilepsy reported an array of perceived benefits similar to those reported by populations with other diseases. Controlled sharing of health data may have the potential to improve disease self management of people with epilepsy. PMID- 22099529 TI - Unmet needs in patients with first-episode schizophrenia: a longitudinal perspective. AB - BACKGROUND: This study aimed to identify the course of unmet needs by patients with a first episode of schizophrenia and to determine associated variables. METHOD: We investigated baseline assessments in the European First Episode Schizophrenia Trial (EUFEST) and also follow-up interviews at 6 and 12 months. Latent class growth analysis was used to identify patient groups based on individual differences in the development of unmet needs. Multinomial logistic regression determined the predictors of group membership. RESULTS: Four classes were identified. Three differed in their baseline levels of unmet needs whereas the fourth had a marked decrease in such needs. Main predictors of class membership were prognosis and depression at baseline, and the quality of life and psychosocial intervention at follow-up. Depression at follow-up did not vary among classes. CONCLUSIONS: We identified subtypes of patients with different courses of unmet needs. Prognosis of clinical improvement was a better predictor for the decline in unmet needs than was psychopathology. Needs concerning social relationships were particularly persistent in patients who remained high in their unmet needs and who lacked additional psychosocial treatment. PMID- 22099530 TI - Wound healing in pre-tibial injuries--an observation study. AB - Pre-tibial lacerations are complex wounds affecting a primarily aged population, with poor healing and a potentially significant impact on social well-being. Management of these wounds has changed little in 20 years, despite significant advances in wound care. A retrospective observational study was undertaken to observe current wound care practice and to assess the effect of various medical factors on wound healing time on 24 elderly patients throughout their wound journey. Wound length was found to be substantively and significantly associated with wound healing time, with a reduction in instantaneous healing rate of about 30% for every increase of 1 cm in wound length. Hence, longer wounds are associated with longer wound healing times. Prescription of several categories of drugs, including those for ischaemic heart disease (IHD), hypertension, respiratory disease or asthma; and the age of the patient were not significantly associated with wound healing times, although substantive significance could be inferred in the case of prescription for IHD and asthma. Despite the small sample size, this study identified a clear association between healing and length of wound. Neither the comorbidities nor prescriptions explored showed any significant association although some seem to be more prevalent in this patient group. The study also highlighted other issues that require further exploration including the social and economic impact of these wounds. PMID- 22099531 TI - Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND: Xanthine oxidase inhibition (XOI) reduces oxidative stress in the vasculature. Moreover it reduces uric acid levels, a risk factor for the development of cardiovascular disease. As such, XOI holds a potentially dual mechanism for the treatment of cardiovascular disease. AIMS: Through systematic review, we sought to clarify the extent of available evidence that has evaluated the effect of XOI upon clinical or surrogate markers of cardiovascular disease and function in humans. METHODS: A systematic search strategy was used to interrogate the Ovid Medline (1950-June Week 4 2010) and Embase (1980-2010 Week 25) databases, to identify relevant studies. Meta-analysis was planned for frequently studied endpoints. RESULTS: Thirty-eight publications (reporting 40 studies) were identified. There was heterogeneity between studies in all aspects of study design, including the outcome measures of interest. Prospective assessment of surrogate markers predominated. Combined meta-analysis was feasible for three outcome parameters, with favorable modifications in each following xanthine oxidase inhibition: brachial artery flow mediated dilatation (five studies: XOI n = 75, control n = 69) increased by 2.50% (95% CI, 0.15-4.84); forearm blood flow responses to acetylcholine infusion (five studies: XOI n = 74, control n = 74) increased by 68.80 (95% CI, 18.70-118.90; percent change relative to noninfused control arm); circulating markers of oxidative stress (malondialdehyde, six studies: XOI n = 78, control n = 68) reduced by 0.56 nmol/mL (95% CI, 0.26-0.87). CONCLUSIONS: XOI improves endothelial function and circulating markers of oxidative stress in patients with, or at risk of, cardiovascular disease. Large prospective studies examining definitive end points are lacking but now appear indicated. PMID- 22099532 TI - Fracture strength of incisor crowns after intracoronal bleaching with sodium percarbonate. AB - OBJECTIVES: To compare the fracture resistance of bovine teeth after intracoronal bleaching with sodium percarbonate (SPC) or sodium perborate (SP) mixed with water or 20% hydrogen peroxide (HP). MATERIALS AND METHODS: Fifty extracted bovine teeth were divided into four experimental groups (G1-G4) and one control (n = 10) after endodontic treatment. Following root canal obturation, a glass ionomer barrier was placed at the cemento-enamel junction. After that, the pulp chambers were filled with: G1 - SP with water; G2 - SP with 20% HP; G3 - SPC with water; and G4 - SPC with 20% HP. No bleaching agent was used in the control group. Coronal access cavities were sealed with glass ionomer and specimens were immersed in artificial saliva. The bleaching agents were replaced after 7 days, and teeth were kept in artificial saliva for an additional 7 days, after which the pastes were removed and the coronal access cavities were restored with glass ionomer. Crowns were subjected to compressive load at a cross head speed of 0.5 mm min(-1) applied at 135 degrees to the long axis of the root by an EMIC DL2000 testing machine, until coronal fracture. Data were statistically analysed by anova and Tukey test. RESULTS: No differences in fracture resistance were observed between the experimental groups (P > 0.05). However, all experimental groups presented lower fracture resistance than the control group (P < 0.05). CONCLUSION: SPC and SP led to equal reduction on fracture resistance of dental crowns, regardless of being mixed with water or 20% HP. PMID- 22099533 TI - Mitochondrial complex I deficiency of nuclear origin II. Non-structural genes. AB - Complex I deficiency is the most frequent cause of respiratory chain diseases. This large multiprotein complex is composed in human of 45 structural subunits, of which 7 are mitochondrial-encoded and 38 are nuclear-encoded. Most of the pathological mutations responsible for complex I deficiencies have been identified to date in complex I structural subunits. Numerous studies from last decade gave some insight into the biogenesis of this huge multi subunit complex of double genetic origin. A sequential incorporation of the structural subunits as well as ten complex I assembly factors has been described. Here, we present a short overview of the human complex I biogenesis and we review the pathological mutations identified to date in eight of the ten known complex I assembly factors. PMID- 22099534 TI - A renal HIT. PMID- 22099535 TI - The effect of the hormonal milieu of pregnancy on deep infiltrating endometriosis: serial ultrasound assessment of changes in size and pattern of deep endometriotic lesions. AB - BACKGROUND: Deep infiltrating endometriosis (DIE) is associated with severe painful symptoms and represents a complex management challenge. OBJECTIVE: To analyse the effect of pregnancy on deep infiltrating lesions and related symptomatology. STUDY DESIGN: As part of a longitudinal study performed over the past 3 years to determine the efficacy of hormonal treatment in treating women with DIE, we identified three cases of advanced pelvic endometriosis, all with DIE (deep recto-vaginal and recto-sigmoid involvement) where patients achieved spontaneous pregnancies. They were followed up by transvaginal ultrasound (TV US). The main outcome measures were analysis of the size and echographic pattern of deep infiltrating lesions of endometriosis and evaluation of clinical symptoms during pregnancy. RESULTS: We observed modifications in lesion size and pattern. In the two patients observed in the third trimester, the lesions were more homogeneous with less evident limits of nodules and band-like echoes, less fibrotic-like. All patients showed complete resolution of symptoms during pregnancy. CONCLUSIONS: The hormonal environment produced by pregnancy might determine significant modifications of endometriotic lesions and reduce painful symptoms. As surgery for DIE is difficult, complex and can lead to major complications, the achievement of a pregnancy-specific hormonal state, through pregnancy or hormonal treatment, may be a valid option in selected cases. PMID- 22099536 TI - Physiological responses of Egeriadensa to high ammonium concentration and nitrogen deficiency. AB - High ammonia (i.e. the total of NH(3) and NH(4)(+)) concentration or nitrogen deficiency in water can exert stress on growth and health of many aquatic plants. To investigate the physiological impacts of high ammonia-N (NH(4)Cl) concentration and nitrogen deficiency on plant physiology, apical shoots of submerged macrophyte Egeriadensa were first treated with five levels of nitrogen: 0, 1, 10, 30, 60 mg L(-1) ammonia-N (NH(4)Cl) for 5d. After having explored the stress range of ammonia-N, its effect on E. densa was further examined at three levels of ammonium (0, 1, 30 mg L(-1) ammonia-N) and at six exposure times (0, 1, 2, 3, 5 and 7d). In testing the concentration-dependent stress, the increase of ammonia-N reduced the amounts of total chlorophyll (chl a and b), soluble proteins and soluble carbohydrates, but increased the activity levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase and peroxidase in E. densa. In the N-free medium, total chlorophyll, soluble proteins, soluble carbohydrates and the activities of SOD and peroxidase in E. densa decreased significantly compared with the control (1 mg L(-1) ammonia-N). When comparing the ammonia-N impacts over time, the plants showed a declining trend in total chlorophyll, soluble proteins and soluble carbohydrates, but an rising trend in MDA, SOD, peroxidase and catalase in 30 mg L(-1) ammonia-N over 7d. Compared with the control, the N-free medium significantly decreased the amounts of total chlorophyll, soluble proteins, soluble carbohydrates, SOD and peroxidase in E. densa over time. Our study indicates that high ammonium (ammonia-N >= 10 mg L( 1)) affects the growth of E. densa through inducing oxidative stress and inhibiting photosynthesis, and nitrogen deficiency can also induce an abiotic stress condition for the E. densa growth by reducing photosynthetic pigments, soluble proteins, soluble carbohydrates, and the activity of antioxidant enzymes. PMID- 22099537 TI - Levels of organochlorine pesticides and polychlorinated biphenyls in the critically endangered Iberian lynx and other sympatric carnivores in Spain. AB - Accumulation of organochlorine compounds is well studied in aquatic food chains whereas little information is available from terrestrial food chains. This study presents data of organochlorine levels in tissue and plasma samples of 15 critically endangered Iberian lynx (Lynx pardinus) and other 55 wild carnivores belonging to five species from three natural areas of Spain (Donana National Park, Sierra Morena and Lozoya River) and explores their relationship with species diet. The Iberian lynx, with a diet based on the consumption of rabbit, had lower PCB levels (geometric means, plasma: <0.01 ng mL(-1), liver: 0.4ngg(-1) wet weight, fat: 87 ng g(-1)lipid weight) than other carnivores with more anthropic and opportunistic foraging behavior, such as the red fox (Vulpes vulpes; plasma: 1.11 ng mL(-1), liver: 459 ng g(-1), fat: 1984 ng g(-1)), or with diets including reptiles at higher proportion, such as the Egyptian mongoose (Herpestes ichneumon; plasma: 7.15 ng mL(-1), liver: 216 ng g(-1), fat: 540 ng g( 1)), or the common genet (Genetta genetta; liver: 466 ng g(-1), fat: 3854 ng g( 1)). Chlorinated pesticides showed interspecific variations similar to PCBs. Organochlorine levels have declined since the 80s in carnivores from Donana National Park, but PCB levels are still of concern in Eurasian otters (Lutra lutra; liver: 3873-5426 ng g(-1)) from the industrialized region of Madrid. PMID- 22099538 TI - Metal (Cu, Cd and Zn) removal and stabilization during multiple soil washing by saponin. AB - The influence of multiple saponin washing on copper, cadmium and zinc removal and stability in three types of soils (loamy sand, loam, silty clay) was investigated. Distribution of metals and their mobility measured as the ratio of exchangeable form to the sum of all fractions in soils was differential. After single washing the highest efficiency of metal removal was obtained in loamy sand (82-90%) and loam (67-88%), whereas the lowest in silty clay (39-62%). In loamy sand and loam metals had higher mobility factors (44-61% Cu, 60-76% Cd, and 68 84% Zn) compared to silty clay (9% Cu, 28% Cd and 36% Zn). Triplicate washing led to increase both efficiency of metal removal and percentage content of their stable forms. In consequence, fractional patterns for metals before and after treatment changed visibly as a result of their redistribution. Based on the redistribution index, the most stable metal (mainly in residual and organic fractions) after triplicate washing was Cu in loamy sand and loam. For silty clay contaminated with Cd, effective metal removal and its stabilization required a higher number of washings. PMID- 22099539 TI - Zinc tolerance and accumulation in the salt-marsh shrub Halimione portulacoides. AB - The halophytic shrub Halimione portulacoides is known to be capable of growth in soils containing extremely high concentrations of Zn. This study evaluated in detail the tolerance and accumulation potential of H. portulacoides under moderate and high external Zn levels. A greenhouse experiment was conducted in order to investigate the effects of a range of Zn concentrations (0-130 mmol L( 1)) on growth and photosynthetic performance by measuring relative growth rate, total leaf area, specific leaf area, gas exchange, chlorophyll fluorescence parameters and photosynthetic pigment concentrations. We also determined the total zinc, nitrogen, phosphorus, calcium, magnesium, sodium, potassium, iron and copper concentrations in the plant tissues. H. portulacoides demonstrated hypertolerance to Zn stress, since it survived with leaf concentrations of up to 2300 mg Zn kg(-1)dry mass, when treated with 130 mmol Zn L(-1). Zinc concentrations greater than 70 mmol L(-1) in the nutrient solution negatively affected plant growth, in all probability due to the recorded decline in net photosynthesis rate. Our results indicate that the Zn-induced decline in the photosynthetic function of H. portulacoides may be attributed to the adverse effect of the high concentration of the metal on photosynthetic electron transport. Growth parameters were virtually unaffected by leaf tissue concentrations as high as 1500 mg Zn kg(-1)dry mass, demonstrating the strong capability of H. portulacoides to protect itself against toxic Zn concentrations. The results of our study indicate that this salt-marsh shrub may represent a valuable tool in the restoration of Zn-polluted areas. PMID- 22099540 TI - Lactate oxidation in pyrite suspension: a Fenton-like process in situ generating H2O2. AB - Pyrite is a common mineral at many mining sites. In this study, the mineral pyrite was studied as a Fenton-like reagent for environmental concerns. We selected lactate as a model target molecule to evaluate the Fenton-like catalytic efficiency of pyrite upon organic oxidation. A complete set of control experiments in both aerobic and anaerobic atmospheres unequivocally established that the pyrite in aqueous solution could spontaneously in situ generate (.)OH and H(2)O(2), serving as a Fenton-like reagent to catalyze the oxidation of lactate to pyruvate with no need for additional H(2)O(2). We called it the pyrite only Fenton-like (PF) reagent. Monitoring concentration changes of lactate and pyruvate with the time indicated that the pyrite mediated the favorable pyruvate formation at pH 4.5, 60 degrees C, under air atmosphere. The PF reaction could be stimulated by visible light illumination. Under the optimum conditions, up to 50% of lactate was degraded within 10d. The results suggest that pyrite and its Fenton-like processes may be potentially practical in wastewater treatment. PMID- 22099542 TI - Inconvenience due to travelers' diarrhea: a prospective follow-up study. AB - BACKGROUND: Limited data exist documenting the degree to which travelers are inconvenienced by travelers' diarrhea (TD). We performed a prospective follow-up study at the travel clinic of Leiden University Medical Center in The Netherlands to determine the degree of inconvenience and to determine how experiencing TD affects travelers' perception. METHODS: Healthy adults who intended to travel to the (sub)tropics for less than two months were invited to take part. Participants filled out a web-based questionnaire before departure and after returning home. TD was defined as three or more unformed stools during a 24-hour period. RESULTS: 390 of 776 Eligible travelers completed both questionnaires. Participants' median age was 31 years and mean travel duration 23 days. Of 160 travelers who contracted TD (incidence proportion 41%, median duration of TD episode 2.5 days) the majority (107/160, 67%) could conduct their activity program as planned despite having diarrhea. However, 21% (33/160) were forced to alter their program and an additional 13% (20/160) were confined to their accommodation for one or more daylight days; 53 travelers (33%) used loperamide and 14 (9%) an antibiotic. Eight travelers (5%) consulted a physician for the diarrheal illness. When asked about the degree of inconvenience brought on by the diarrheal illness, 39% categorized it as minor or none at all, 34% as moderate and 27% as large or severe. In those who regarded the episode of TD a major inconvenience, severity of symptoms was greater and use of treatment and necessity to alter the activity program were more common. Travelers who contracted travelers' diarrhea considered it less of a problem in retrospect than they had thought it would be before departure. CONCLUSION: Conventional definitions of TD encompass many mild cases of TD (in our study at least a third of all cases) for which treatment is unlikely to provide a significant health benefit. By measuring the degree of inconvenience brought on by TD, researchers and policy makers may be able to better distinguish 'significant TD' from mild TD, thus allowing for a more precise estimation of the size of the target population for vaccination or stand by antibiotic prescription and of the benefit of such measures. PMID- 22099543 TI - A claw is like my hand: comparison supports goal analysis in infants. AB - Understanding the intentional relations in others' actions is critical to human social life. Origins of this knowledge exist in the first year and are a function of both acting as an intentional agent and observing movement cues in actions. We explore a new mechanism we believe plays an important role in infants' understanding of new actions: comparison. We examine how the opportunity to compare a familiar action with a novel, tool use action helps 7- and 10-month-old infants extract and imitate the goal of a tool use action. Infants given the chance to compare their own reach for a toy with an experimenter's reach using a claw later imitated the goal of an experimenter's tool use action. Infants who engaged with the claw, were familiarized with the claw's causal properties, or learned the associations between claw and toys (but did not align their reaches with the claw's) did not imitate. Further, active participation in the familiar action to be compared was more beneficial than observing a familiar and novel action aligned for 10-month-olds. Infants' ability to extract the goal-relation of a novel action through comparison with a familiar action could have a broad impact on the development of action knowledge and social learning more generally. PMID- 22099544 TI - Relatively certain! Comparative thinking reduces uncertainty. AB - Comparison is one of the most ubiquitous and versatile mechanisms in human information processing. Previous research demonstrates that one consequence of comparative thinking is increased judgmental efficiency: comparison allows for quicker judgments without a loss in accuracy. We hypothesised that a second potential consequence of comparative thinking is reduced judgmental uncertainty. We examined this possibility in three experiments using three different domains of judgment and three different measures of uncertainty. Results consistently demonstrate that procedurally priming participants to rely more heavily on comparative thinking during judgment induces them to feel more certain about their judgment. PMID- 22099545 TI - Rapid screening method for multiple gastroenteric pathogens also detects novel enterohemorrhagic Escherichia coli O104:H4. PMID- 22099546 TI - Recurrent Ochrobactrum anthropi and Shewanella putrefaciens bloodstream infection complicating hemodialysis. AB - Bloodstream infections (BSIs) are common in hemodialysis, especially when the access is a catheter. These infections are more commonly gram-positive bacteria or gram-negative bacilli and on some occasions, fungi. Ochrobactrum anthropi and Shewanella putrefaciens are ubiquitous hydrophilic gram-negative bacilli. There have been three cases of O. anthropi BSI reported in hemodialysis patients (one from the United States and two from Vienna) and two cases of S. putrefaciens BSI in hemodialysis patients (one from the United States and the other from Japan). There have been few more cases reported of infections with these bacteria in peritoneal dialysis, especially outside the United States. We present a novel case of a patient with both recurrent O. anthropi and S. putrefaciens BSI complicating hemodialysis. There have been no reports in the literature of such a case. We also discuss the microbiology, clinical features, and the challenging aspects of treatment of such infections. PMID- 22099547 TI - Estimating the cost-effectiveness of lifestyle intervention programmes to prevent diabetes based on an example from Germany: Markov modelling. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) poses a large worldwide burden for health care systems. One possible tool to decrease this burden is primary prevention. As it is unethical to wait until perfect data are available to conclude whether T2D primary prevention intervention programmes are cost effective, we need a model that simulates the effect of prevention initiatives. Thus, the aim of this study is to investigate the long-term cost-effectiveness of lifestyle intervention programmes for the prevention of T2D using a Markov model. As decision makers often face difficulties in applying health economic results, we visualise our results with health economic tools. METHODS: We use four-state Markov modelling with a probabilistic cohort analysis to calculate the cost per quality-adjusted life year (QALY) gained. A one-year cycle length and a lifetime time horizon are applied. Best available evidence supplies the model with data on transition probabilities between glycaemic states, mortality risks, utility weights, and disease costs. The costs are calculated from a societal perspective. A 3% discount rate is used for costs and QALYs. Cost-effectiveness acceptability curves are presented to assist decision makers. RESULTS: The model indicates that diabetes prevention interventions have the potential to be cost-effective, but the outcome reveals a high level of uncertainty. Incremental cost-effectiveness ratios (ICERs) were negative for the intervention, ie, the intervention leads to a cost reduction for men and women aged 30 or 50 years at initiation of the intervention. For men and women aged 70 at initiation of the intervention, the ICER was EUR27,546/QALY gained and EUR19,433/QALY gained, respectively. In all cases, the QALYs gained were low. Cost-effectiveness acceptability curves show that the higher the willingness-to-pay threshold value, the higher the probability that the intervention is cost-effective. Nonetheless, all curves are flat. The threshold value of EUR50,000/QALY gained has a 30-55% probability that the intervention is cost-effective. CONCLUSIONS: Lifestyle interventions for primary prevention of type 2 diabetes are cost-saving for men and women aged 30 or 50 years at the start of the intervention, and cost-effective for men and women aged 70 years. However, there is a high degree of uncertainty around the ICERs. With the conservative approach adopted for this model, the long-term effectiveness of the intervention could be underestimated. PMID- 22099548 TI - Imaging mass spectrometry evaluation of the effects of various irrigation fluids in a rat model of postoperative cerebral edema. AB - BACKGROUND: Using imaging mass spectrometry (IMS), we investigated the cerebral protective effect of an artificial cerebrospinal fluid (CSF), ARTCEREB (Artcereb, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan), as an irrigation and perfusion solution for neurosurgical procedures in a rat craniotomy model. METHODS: Wounds created in the rat cerebral cortex were continuously irrigated with Artcereb, normal saline, or lactated Ringer's solution at a steady rate for 4 hours, after which brain tissue was collected. Brain slices were prepared and analyzed using IMS. RESULTS: In tissue surrounding the injury, the signal intensity for Na adduct ions to phosphatidylcholine was high and that for K adduct ions to phosphatidylcholine was low. This is thought to reflect the level of water retention in brain cells and to be a change accompanying edema. The signal intensity with Na adduct ions to phosphatidylcholine was significantly lower in the Artcereb group than in the physiological saline or lactated Ringer's solution groups. CONCLUSIONS: IMS analysis in a rat craniotomy model indicated that the level of water retention in brain cells, calculated from the signal intensity of Na-adducted phosphatidylcholine around the wound area, was lowest in the Artcereb group, suggesting that artificial CSF that has similar composition and properties to human CSF can minimize edema in the brain surrounding the surgical wound. PMID- 22099549 TI - Barber surgeon, or surgeon barber? PMID- 22099550 TI - Lasers in neurosurgery. PMID- 22099551 TI - The value of teleradiology in neurosurgery. PMID- 22099552 TI - Direct percutaneous puncture approach versus surgical cut down technique for intracranial neuroendovascular procedures. PMID- 22099553 TI - To clip or not to clip, that is the question? PMID- 22099554 TI - Iatrogenic brachial plexus injuries complicating video-assisted thoracic surgery. PMID- 22099555 TI - Utility and safety of the flexible-fiber CO2 laser in endoscopic endonasal transsphenoidal surgery. PMID- 22099556 TI - Intraoperative brachial plexus injuries: association with thoracic surgery and current management. PMID- 22099557 TI - If you want to learn new things, read old books: cutdown techniques are well described in the old literature. PMID- 22099558 TI - Should a picture ever replace a thousand words? Harnessing technology without compromising neurosurgical resident education and patient care. PMID- 22099559 TI - Outpatient-based scalp surgery without shaving and allowing use of shampoo. AB - OBJECTIVE: To assess the authors' experience of wound management following scalp mass surgery after introducing a policy of leaving hair unshaved and allowing patients to use shampoo. METHODS: The authors retrospectively reviewed 93 patients who underwent outpatient-based excision of a scalp or skull mass. Surgical complications, mass depth, and maximal mass size were analyzed. All of the surgeries were performed without shaving around the lesion; the hair was simply parted along the proposed incision, and the parting was maintained using adhesive plasters. Routine antiseptic scalp preparations, skin closure with staples after mass excision, and topical ointment on the day following surgery were used, and use of shampoo was allowed. The staples were removed on postoperative days 7-10. RESULTS: The masses were located in the skin (23 cases), subcutaneously (64 cases), and subgaleally (6 cases). All patients except one had satisfactory wound healing. No infections occurred. CONCLUSIONS: Leaving hair unshaved and allowing patients to use shampoo can be applied in wound management after scalp mass surgery. PMID- 22099560 TI - Temporary occlusion test using a microcatheter. AB - BACKGROUND: The balloon occlusion test (BOT) is a well-accepted technique for the treatment of large or complex aneurysms. However, this procedure may not be feasible for small arteries such as the posterior inferior cerebellar artery (PICA). We report our experience with endovascular treatment of a fusiform PICA aneurysm employing a microcatheter occlusion test. CASE DESCRIPTION: A 46-year old male had a fusiform Type I aneurysm with irregular wall in the lateral medullary segment of left PICA. Because the BOT cannot be safely performed in the PICA, we performed a temporary occlusion test using a microcatheter. RESULTS: The microcatheter occlusion test was successfully performed, and endovascular treatment was performed afterward. The patient remained symptom free after the embolization and at one-year follow-up. CONCLUSION: The microcatheter occlusion test is an excellent option for performing an occlusion test for vessels that cannot accommodate a balloon because of their diminutive size. PMID- 22099561 TI - Direct percutaneous puncture approach versus surgical cutdown technique for intracranial neuroendovascular procedures: technical aspects. AB - OBJECTIVE: To present the authors' experience with a direct transcervical or transbrachial puncture approach in neuroendovascular procedures in which cranial access via the commonly used percutaneous transfemoral route was impossible because of tortuous upstream angioarchitecture. METHODS: During 1992-2007, 23 neuroendovascular procedures were performed in 21 patients via a direct puncture approach. In 12 patients, surgical cutdown (SCD) and cannulation of the targeted artery (carotid, n = 8; vertebral, n = 4) were done. A direct percutaneous puncture (PP) of either the carotid (n = 5) or the brachial (n = 4) artery was done in nine patients. Treated pathologies were as follows: 10 ruptured and 6 unruptured cerebral aneurysms including two stent-assisted coiling and one internal carotid artery (ICA) balloon occlusion, four brain arteriovenous malformations (AVMs) and one carotid cavernous fistula (CCF). RESULTS: Of 21 patients, 19 (90.5%) had a direct puncture introduction of the microcatheter and successful endovascular procedure. No complications related to the technique were encountered either in the PP or in the SCD group. CONCLUSIONS: Transcervical or transbrachial direct puncture accomplished with PP or by SCD is an effective and safe access route in patients in whom neuroendovascular interventions cannot be done transfemorally. In cases where extensive perioperative anticoagulation is mandatory, bleeding at the puncture site may be a serious problem and can be controlled more effectively through an open surgical approach than by percutaneous maneuvers. PMID- 22099562 TI - How can we manage difficult access for neuroendovascular procedures? PMID- 22099563 TI - Use of multimedia messaging system (MMS) by junior doctors for scan image transmission in neurosurgery. AB - BACKGROUND: Multimedia Messaging Service (MMS) is used by neurosurgical residents to transmit scan images to the attending neurosurgeon in conjunction with telephone consultation. This service has been well received by the attending neurosurgeons, who felt that after viewing scan images on their phones, they felt increased confidence in clinical decision making and that it reduced the need for recall to the hospital. OBJECTIVE: The use of MMS can be extended to junior doctors making referrals from regional hospitals with no neurosurgical cover. This study aims to validate the competency of non-neurosurgically trained junior doctors in selecting optimal images to transmit via MMS to the attending neurosurgeon on call. METHODS: Ten junior doctors with no formal neurosurgical training and five neurosurgical residents were interviewed. They were shown the full complement of images together with relevant clinical history and assessment. They were then asked to make the radiological diagnosis and then select two images for MMS transmission to the attending neurosurgeon that they thought would best aid the neurosurgeon in clinical decision making. The attending neurosurgeon was asked to comment, on each image, whether his management plan would differ if he was shown the entire series of the images. RESULTS: All the images chosen are deemed appropriate, and the decision made based on the MMS images would be similar if the entire series of images were available to the neurosurgeon. However, 7 of 10 junior doctors were unable to read magnetic resonance images of lumbar spine. There was no significant difference in the images chosen by the neurosurgical residents and the junior doctors. CONCLUSION: It is feasible and safe for junior doctors to utilize MMS to transmit computed tomographic images to a neurosurgeon while making an urgent referral. The images selected are representative of the disease pathology and facilitate clinical decision making. PMID- 22099564 TI - Is there a benefit of using artificial cerebrospinal fluid for irrigation? PMID- 22099565 TI - How large is the typical subarachnoid hemorrhage? A review of current neurosurgical knowledge. AB - BACKGROUND: Despite the morbidity and mortality of subarachnoid hemorrhage (SAH), the average volume of a typical hemorrhage is not well defined. Animal models of SAH often do not accurately mimic the human disease process. OBJECTIVE: The purpose of this study is to estimate the average SAH volume, allowing standardization of animal models of the disease. METHODS: We performed a MEDLINE search of SAH volume and erythrocyte counts in human cerebrospinal fluid as well as for volumes of blood used in animal injection models of SAH, from 1956 to 2010. We polled members of the American Association of Neurological Surgeons (AANS) for estimates of typical SAH volume. Using quantitative data from the literature, we calculated the total volume of SAH as equal to the volume of blood clotted in basal cisterns plus the volume of dispersed blood in cerebrospinal fluid. The results of the AANS poll confirmed our estimates. RESULTS: The human literature yielded 322 publications and animal literature, 237 studies. Four quantitative human studies reported blood clot volumes ranging from 0.2 to 170 mL, with a mean of ~20 mL. There was only one quantitative study reporting cerebrospinal fluid red blood cell counts from serial lumbar puncture after SAH. Dispersed blood volume ranged from 2.9 to 45.9 mL, and we used the mean of 15 mL for our calculation. Therefore, total volume of SAH equals 35 mL. The AANS poll yielded 176 responses, ranging from 2 to 350 mL, with a mean of 33.9 +/- 4.4 mL. CONCLUSIONS: Based on our estimate of total SAH volume of 35 mL, animal injection models may now become standardized for more accurate portrayal of the human disease process. PMID- 22099566 TI - A systematic review of instruments to measure depressive symptoms in patients with schizophrenia. AB - BACKGROUND: Depressive symptoms require accurate recognition and monitoring in clinical practice of patients with schizophrenia. Depression instruments developed for use in depressed patients may not discriminate depressive symptoms from negative psychotic symptoms. OBJECTIVE: We reviewed depression instruments on their reliability and validity in patients with schizophrenia. METHODOLOGY: A systematic literature search was carried out in three electronic databases. Psychometric properties were extracted for those instruments of which reliability, divergent, concurrent and predictive validity were reported in one or more publications. RESULTS: Forty-eight publications described the reliability and validity of six depression instruments in patients with schizophrenia. The only self-report was the Beck Depression Inventory (BDI). The Brief Psychiatric Rating Scale-Depression subscale (BPRS-D), Positive and Negative Syndrome Scale Depression subscale (PANSS-D), Hamilton Rating Scale for Depression (HAMD), Montgomery Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS) were clinician rated. All instruments were reliable for the measurement of depressive symptoms in patients with schizophrenia. The CDSS most accurately differentiated depressive symptoms from other symptoms of schizophrenia (divergent validity), correlated well with other depression instruments (concurrent validity), and was least likely to miss cases of depression or misdiagnose depression (predictive validity). CONCLUSIONS: We would recommend to use the CDSS for the measurement of depressive symptoms in research and in daily clinical practice of patients with schizophrenia. A valid self report instrument is to be developed for the use in clinical practice. PMID- 22099567 TI - What is the goal with endogenous filtration markers--estimation of GFR or prediction of kidney outcomes? PMID- 22099568 TI - Clinical decision support systems and the management of CKD by primary care physicians. PMID- 22099569 TI - Posttransplant lymphoproliferative disorders: a continued threat for kidney transplant recipients. PMID- 22099570 TI - Use of real-time ultrasound guidance for the placement of hemodialysis catheters: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Insertion of percutaneous hemodialysis catheters is an invasive procedure with a small but definite risk of morbidity and mortality. OBJECTIVES: Assessing potential benefits of using real-time 2-dimensional Doppler ultrasound imaging guidance for the insertion of hemodialysis catheters compared with insertion based solely on anatomic landmarks. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), Cochrane Renal Group Specialised Register, and Cochrane Central Register of Controlled Trials (CENTRAL). SETTING & POPULATION: Patients requiring hemodialysis catheter insertion. SELECTION CRITERIA FOR STUDIES: We included all randomized controlled trials regardless of publication status or language. INTERVENTIONS: Real-time 2-dimensional Doppler ultrasound image guidance. OUTCOMES: Catheter placement failures, catheters failed to be placed in the first attempt, attempts per catheter inserted, time taken for successful venous puncture, and complications (carotid artery puncture, pneumo- or hemothorax, neck hematoma, and brachial plexus injury). Treatment effects were summarized with the RR measure for dichotomous outcomes and mean difference for continuous outcomes. RESULTS: 7 trials with 830 catheters were identified. Ultrasound guidance significantly decreased the risk of the following outcomes: catheter placement failure (7 studies, 830 catheters; RR, 0.12; 95% CI, 0.04-0.37), failure to place catheter on first attempt (5 studies, 595 catheters; RR, 0.40; 95% CI, 0.29-0.56), arterial punctures (6 trials, 785 catheters; RR, 0.22; 95% CI, 0.06-0.81), and hematoma formation (4 trials, 323 catheters; RR, 0.27; 95% CI, 0.08-0.88). It also significantly decreased the time to cannulate the vein (1 trial, 73 catheters; mean difference, -1.40; 95% CI, -2.17 to -0.63), and number of attempts per catheter insertion (1 trial, 110 catheters; mean difference, -0.35; 95% CI, -0.54 to -0.16). LIMITATIONS: Only 7 studies were identified, of which 3 were reported in only a conference abstract form. Some outcomes were reported in only 1 study. CONCLUSIONS: Use of real-time Doppler ultrasound guidance has benefits with respect to several important clinical outcomes, and its routine use in the insertion of hemodialysis catheters is strongly recommended. PMID- 22099571 TI - Albuminuria, proteinuria, and graft survival in kidney transplantation. PMID- 22099574 TI - Development of thrombotic microangiopathy in a patient with granulomatosis with polyangiitis. PMID- 22099576 TI - Population prevalence of proteinuria and diagnostic accuracy of urine dipsticks. PMID- 22099577 TI - Prolonged immobilization as a potential etiology of metabolic alkalosis in hemodialysis patients. PMID- 22099579 TI - Genetic basis of congenital and infantile nephrotic syndromes. PMID- 22099580 TI - Quiz page December 2011: An unusual cause of renal colic. PMID- 22099581 TI - Neither bipolar nor obsessive-compulsive disorder: compulsive buyers are impulsive acquirers. AB - INTRODUCTION: Compulsive buying (CB) is currently classified as an impulse control disorder (ICD) not otherwise classified. Compulsive buying prevalence is estimated at around 5% of the general population. There is controversy about whether CB should be classified as an ICD, a subsyndromal bipolar disorder (BD), or an obsessive-compulsive disorder (OCD) akin to a hoarding syndrome. To further investigate the appropriate classification of CB, we compared patients with CB, BD, and OCD for impulsivity, affective instability, hoarding, and other OCD symptoms. METHOD: Eighty outpatients (24 CB, 21 BD, and 35 OCD) who were neither manic nor hypomanic were asked to fill out self-report questionnaires. RESULTS: Compulsive buying patients scored significantly higher on all impulsivity measures and on acquisition but not on the hoarding subdimensions of clutter and "difficulty discarding." Patients with BD scored higher on the mania dimension from the Structured Clinical Interview for Mood Spectrum scale. Patients with OCD scored higher on obsessive-compulsive symptoms and, particularly, higher on the contamination/washing and checking dimensions from the Padua Inventory; however, they did not score higher on any hoarding dimension. A discriminant model built with these variables correctly classified patients with CB (79%), BD (71%), and OCD (77%). CONCLUSION: Patients with CB came out as impulsive acquirers, resembling ICD- rather than BD- or OCD-related disorders. Manic symptoms were distinctive of patients with BD. Hoarding symptoms other than acquisition were not particularly associated with any diagnostic group. PMID- 22099582 TI - Building capacity in mental health interventions in low resource countries: an apprenticeship model for training local providers. AB - BACKGROUND: Recent global mental health research suggests that mental health interventions can be adapted for use across cultures and in low resource environments. As evidence for the feasibility and effectiveness of certain specific interventions begins to accumulate, guidelines are needed for how to train, supervise, and ideally sustain mental health treatment delivery by local providers in low- and middle-income countries (LMIC). MODEL AND CASE PRESENTATIONS: This paper presents an apprenticeship model for lay counselor training and supervision in mental health treatments in LMIC, developed and used by the authors in a range of mental health intervention studies conducted over the last decade in various low-resource settings. We describe the elements of this approach, the underlying logic, and provide examples drawn from our experiences working in 12 countries, with over 100 lay counselors. EVALUATION: We review the challenges experienced with this model, and propose some possible solutions. DISCUSSION: We describe and discuss how this model is consistent with, and draws on, the broader dissemination and implementation (DI) literature. CONCLUSION: In our experience, the apprenticeship model provides a useful framework for implementation of mental health interventions in LMIC. Our goal in this paper is to provide sufficient details about the apprenticeship model to guide other training efforts in mental health interventions. PMID- 22099583 TI - A review of factors that affect mortality following colectomy. AB - BACKGROUND: The tightening focus on optimizing surgical outcomes has pushed tracking perioperative mortality to the forefront of interest. The goal of this study is to analyze factors affecting mortality after colorectal resection at a single tertiary care center. MATERIALS AND METHODS: Data were collected from a prospective database for all patients undergoing a colorectal resection at our institution over a 12-y period. Data points included patient demographics, comorbidities, operative details, clinical presentation, postoperative complications, and mortality. RESULTS: A total of 1245 patients were evaluated with 41 deaths (3.3%). Our population was 51% male with an average age of 60.1 +/ 15.2 y, mean BMI of 27.5 +/- 6.4 kg/m(2), average ASA score of 2.6 +/- 0.9, and average of 2.2 +/- 1.9 comorbidities. Preoperative factors associated with increased mortality included age, high ASA score, emergent surgery, and the presence of bowel perforation or obstruction (P < 0.05). Intra- and postoperative factors including the transfusion of blood products, length of resection, subtotal colectomy, open versus laparoscopic procedures, the need for reoperation, diagnosis and postoperative complications negatively impact survival (P < 0.05). Stepwise logistic regression demonstrated that high ASA score, emergent procedure, subtotal colectomy, age, obstruction, and open resection as the independent predictors of mortality in a stepwise logistic regression model (P < 0.10). CONCLUSION: Preoperative ASA, emergent procedure, age, open procedure, subtotal colectomy, and obstruction were the independent predictors of mortality in our review. Preoperative optimization and counseling of elderly patients with a high ASA score and/or those requiring an emergency operation should be utilized by surgeons in an effort to improve surgical mortality and patient education. PMID- 22099584 TI - Multiple kinase pathways involved in the different de novo sensitivity of pancreatic cancer cell lines to 17-AAG. AB - BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) specifically targets heat shock protein (HSP)90 and inhibits its chaperoning functions for multiple kinases involved in cancer cell growth and survival. To select responsive patients, the molecular mechanisms underlying the sensitivity of cancer cells to 17-AAG must be elucidated. MATERIALS AND METHODS: We used cytotoxicity assays and Western blotting to explore the effects of 17-AAG and sorafenib on cell survival and expression of multiple kinases in the pancreatic cancer cell lines AsPC-1 and Panc-1. Gene cloning and transfection, siRNA silencing, and immunohistochemistry were used to evaluate the effects of mutant p53 protein on 17-AAG sensitivity. RESULTS: AsPC-1 and Panc-1 responded differently to 17-AAG, with half maximal inhibitory concentration (IC(50)) values of 0.12 and 3.18 MUM, respectively. Comparable expression of HSP90, HSP70, and HSP27 was induced by 17-AAG in AsPC-1 and Panc-1 cells. P-glycoprotein and mutant p53 did not affect 17-AAG sensitivity in these cell lines. Multiple kinases are more sensitive to HSP90 inhibition in AsPC-1 than in Panc-1 cells. After 17-AAG treatment, p-Bad (S112) decreased in AsPC-1 cells and increased in Panc-1 cells. Sorafenib markedly increased p-Akt, p ERK1/2, p-GSK-3beta, and p-S6 in both cell lines. Accordingly, 17-AAG and sorafenib acted antagonistically in AsPC-1 and Panc-1 cells, except at high concentrations in AsPC-1 cells. CONCLUSIONS: Differential inhibition of multiple kinases is responsible for the different de novo sensitivity of AsPC-1 and Panc-1 cells to HSP90 inhibition. P-glycoprotein and mutant p53 protein did not play a role in the sensitivity of pancreatic cancer cells to 17-AAG. PMID- 22099585 TI - Comparison of different thoracic trauma scoring systems in regards to prediction of post-traumatic complications and outcome in blunt chest trauma. AB - BACKGROUND: As accurate assessment of thoracic injury severity in the early phase after trauma is difficult, we compared different thoracic trauma scores regarding their predictive ability for the development of post-traumatic complications and mortality. MATERIALS AND METHODS: Two hundred seventy-eight multiple trauma patients (ISS >= 16) age > 16 y with severe blunt chest trauma (AIS(chest) >= 3) admitted between 2000 and 2009 to Level I Trauma center were included. Exclusion criteria were severe traumatic brain injury (AIS(head) >= 3) and penetrating thoracic trauma. The association between AIS(chest), Pulmonary Contusion score (PCS), Wagner-score and Thoracic Trauma Severity score (TTS), and duration of ventilation, length of ICU stay, development of post-traumatic complications, and mortality was investigated. Statistical analysis was performed with chi(2)-test, ANOVA, logistic regression, and receiver operating characteristic (ROC) curve. RESULTS: Patients' mean age was 42.7 +/- 17.0 y, the mean injury severity score was 28.7 +/- 9.3 points. Overall, 60 patients (21.6%) developed ARDS, 143 patients (51.4%) SIRS, 110 patients (39.6%) sepsis, and 36 patients (13.0%) MODS. Twenty-two patients (7.9%) died. Among the examined thoracic trauma scores only the TTS was an independent predictor of mortality. With the TTS showing the best prediction power, the TTS, PCS, and Wagner-score were independent predictors of ventilation time, length of ICU stay, and the development of post-traumatic ARDS and MODS. CONCLUSIONS: Thoracic trauma scores combining anatomical and physiologic parameters like the TTS seem to be most suitable for severity assessment and prediction of outcome in multiple trauma patients with concomitant blunt chest trauma. PMID- 22099586 TI - Nonlinear mechanical behavior of the human common, external, and internal carotid arteries in vivo. AB - BACKGROUND: The mechanical environment and properties of the carotid artery play an important role in the formation and progression of atherosclerosis in the carotid bifurcation. The purpose of this work was to measure and compare the range and variation of circumferential stress and tangent elastic moduli in the human common (CCA), external (ECA), and internal (ICA) carotid arteries over the cardiac cycle in vivo. METHODS: Measurements were performed in the surgically exposed proximal cervical CCA, distal ECA, and distal ICA of normotensive patients (n = 16) undergoing carotid endarterectomy. All measurements were completed in vivo over the cardiac cycle in the repaired carotid bifurcation after the atherosclerotic plaque was successfully removed. B-mode Duplex ultrasonography was used for measurement of arterial diameter and wall thickness, and an angiocatheter placed in the CCA was used for concurrent measurement of blood pressure. A semiautomatic segmentation algorithm was used to track changes in arterial diameter and wall thickness in response to blood pressure. These measurements were then used to calculate the variation of circumferential (hoop) stresses, tangent elastic moduli (the slope of the stress-strain curve at specified stresses), and strain-induced stiffness of the arterial wall (stiffening in response to the increase of intraluminal blood pressure) for each patient. RESULTS: The diameter and wall thickness of the segments (CCA, ECA, and ICA) of the carotid bifurcation were found to decrease and strain-induced stiffness to increase from proximal CCA to distal ECA and ICA. The circumferential stress from end-diastole (minimum pressure) to peak-systole (maximum pressure) varied nonlinearly from 25 +/- 7 to 63 +/- 23 kPa (CCA), from 22 +/- 7 to 57 +/- 19 kPa (ECA), and from 28 +/- 8 to 67 +/- 23 kPa (ICA). Tangent elastic moduli also varied nonlinearly from end-diastole to peak-systole as follows: from 0.40 +/- 0.25 to 1.50 +/- 2.05 MPa (CCA), from 0.49 +/- 0.34 to 1.14 +/- 0.52 MPa (ECA), and from 0.68 +/- 0.31 to 1.51 +/- 0.69 MPa (ICA). The strain-induced stiffness of CCA and ECA increased more than 3-fold and the stiffness of ICA increased more than 2.5-fold at peak-systole compared with end diastole. CONCLUSIONS: The in vivo mechanical behavior of the three segments of the carotid bifurcation was qualitatively similar, but quantitatively different. All three arteries--CCA, ECA and ICA--exhibited nonlinear variations of circumferential stress and tangent elastic moduli within the normal pressure range. The variability in the properties of the three segments of the carotid bifurcation indicates a need for development of carotid models that match the in vivo properties of the carotid segments. Finally, the observed nonlinear behavior of the artery points to the need for future vascular mechanical studies to evaluate the mechanical factors of the arterial wall over the entire cardiac cycle. PMID- 22099587 TI - The importance of the "how to" article. PMID- 22099588 TI - The importance of negative studies and basic applied biomedical research in the development of biomedical devices. PMID- 22099589 TI - Is hemoglobin A1c an adequate marker for disease severity and outcome in limb threatening ischemia? PMID- 22099590 TI - Comparative analysis of histopathologic effects of synthetic meshes based on material, weight, and pore size in mice. AB - BACKGROUND: While synthetic prosthetics have essentially become mandatory for hernia repair, mesh-induced chronic inflammation and scarring can lead to chronic pain and limited mobility. Mesh propensity to induce such adverse effects is likely related to the prosthetic's material, weight, and/or pore size. We aimed to compare histopathologic responses to various synthetic meshes after short- and long-term implantations in mice. MATERIAL AND METHODS: Samples of macroporous polyester (Parietex [PX]), heavyweight microporous polypropylene (Trelex[TX]), midweight microporous polypropylene (ProLite[PL]), lightweight macroporous polypropylene (Ultrapro[UP]), and expanded polytetrafluoroethylene (DualMesh[DM]) were implanted subcutaneously in mice. Four and 12 wk post-implantation, meshes were assessed for inflammation, foreign body reaction (FBR), and fibrosis. RESULTS: All meshes induced varying levels of inflammatory responses. PX induced the greatest inflammatory response and marked FBR. DM induced moderate FBR and a strong fibrotic response with mesh encapsulation at 12 wk. UP and PL had the lowest FBR, however, UP induced a significant chronic inflammatory response. Although inflammation decreased slightly for TX, marked FBR was present throughout the study. Of the three polypropylene meshes, fibrosis was greatest for TX and slightly reduced for PL and UP. For UP and PL, there was limited fibrosis within each mesh pore. CONCLUSION: Polyester mesh induced the greatest FBR and lasting chronic inflammatory response. Likewise, marked fibrosis and encapsulation was seen surrounding ePTFE. Heavier polypropylene meshes displayed greater early and persistent fibrosis; the reduced-weight polypropylene meshes were associated with the least amount of fibrosis. Mesh pore size was inversely proportional to bridging fibrosis. Moreover, reduced-weight polypropylene meshes demonstrated the smallest FBR throughout the study. Overall, we demonstrated that macroporous, reduced-weight polypropylene mesh exhibited the highest degree of biocompatibility at sites of mesh implantation. PMID- 22099591 TI - Transcriptional targeting of bone morphogenetic protein receptors: is it ready for prime time? PMID- 22099592 TI - Use of autologous chondrocytes and bioinert perforated chambers to tissue engineer cartilage in vivo. AB - OBJECTIVE: To explore the potential applications of a chamber for in vivo tissue engineering, and to establish a novel model for in vivo tissue-engineered cartilage. METHODS: Four experimental groups were included in this study: (A) chambers + chondrocytes/collagen gel; (B) chambers + chondrocytes/PLGA gel; (C) chondrocytes/collagen gel alone; and (D) chondrocytes/PLGA gel alone. Groups C and D served as controls. The samples were implanted subcutaneously in the donor rabbit, and the contents were harvested at 8 wk after implantation. RESULTS: Histologic and immunohistochemical staining and RT-PCR results revealed regenerated cartilage-like tissue in group B and small, irregularly shaped islands of opalescent tissue in group A. In contrast, the control groups displayed vascular invasion and inflammatory reaction, which eventually led to fibrosis and absorption. CONCLUSIONS: Reproduced cartilages were obtained in an immunocompetent animal model through the use of a bioinert perforated chamber. PMID- 22099593 TI - Dynamics of short-term gene expression profiling in liver following thermal injury. AB - BACKGROUND: Severe trauma, including burns, triggers a systemic response that significantly impacts on the liver, which plays a key role in the metabolic and immune responses aimed at restoring homeostasis. While many of these changes are likely regulated at the gene expression level, there is a need to better understand the dynamics and expression patterns of burn injury-induced genes in order to identify potential regulatory targets in the liver. Herein we characterized the response within the first 24 h in a standard animal model of burn injury using a time series of microarray gene expression data. METHODS: Rats were subjected to a full thickness dorsal scald burn injury covering 20% of their total body surface area while under general anesthesia. Animals were saline resuscitated and sacrificed at defined time points (0, 2, 4, 8, 16, and 24 h). Liver tissues were explanted and analyzed for their gene expression profiles using microarray technology. Sham controls consisted of animals handled similarly but not burned. After identifying differentially expressed probe sets between sham and burn conditions over time, the concatenated data sets corresponding to these differentially expressed probe sets in burn and sham groups were combined and analyzed using a "consensus clustering" approach. RESULTS: The clustering method of expression data identified 621 burn-responsive probe sets in four different co-expressed clusters. Functional characterization revealed that these four clusters are mainly associated with pro-inflammatory response, anti inflammatory response, lipid biosynthesis, and insulin-regulated metabolism. Cluster 1 pro-inflammatory response is rapidly up-regulated (within the first 2 h) following burn injury, while Cluster 2 anti-inflammatory response is activated later on (around 8 h post-burn). Cluster 3 lipid biosynthesis is down-regulated rapidly following burn, possibly indicating a shift in the utilization of energy sources to produce acute phase proteins, which serve the anti-inflammatory response. Cluster 4 insulin-regulated metabolism was down-regulated late in the observation window (around 16 h post-burn), which suggests a potential mechanism to explain the onset of hypermetabolism, a delayed but well-known response that is characteristic of severe burns and trauma with potential adverse outcome. CONCLUSIONS: Simultaneous analysis and comparison of gene expression profiles for both burn and sham control groups provided a more accurate estimation of the activation time, expression patterns, and characteristics of a certain burn induced response based on which the cause-effect relationships among responses were revealed. PMID- 22099594 TI - Excorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia. AB - BACKGROUND: The shortage in donor livers has led to increased use of allografts derived from donation after cardiac death (DCD). The compromised viability in these livers leads to inferior post-transplantation allograft function and survival compared with donation after brain death (DBD) donor grafts. In this study, we reconditioned DCD livers using an optimized normothermic machine perfusion system. METHODS: Livers from 12 Yorkshire pigs (20-30 kg) were subjected to either 0 min (WI-0 group, n = 6) or 60 min (WI-60 group, n = 6) of warm ischemia and 2 h of cold storage in UW solution, followed by 4 h of oxygenated sanguineous normothermic machine perfusion. Liver viability and metabolic function were analyzed hourly. RESULTS: Warm ischemic livers showed elevated transaminase levels and reduced ATP concentration. After the start of machine perfusion, transaminase levels stabilized and there was recovery of tissue ATP, coinciding with an increase in bile production. These parameters reached comparable levels to the control group after 1 h of machine perfusion. Histology and gross morphology confirmed recovery of the ischemic allografts. CONCLUSION: Our data demonstrate that metabolic and functional parameters of livers with extended warm ischemic time (60 min) can be significantly improved using normothermic machine perfusion. We hereby compound the existing body of evidence that machine perfusion is a viable solution for reconditioning marginal organs. PMID- 22099595 TI - Use of decellularized porcine liver for engineering humanized liver organ. AB - BACKGROUND: New bioartificial liver devices are needed to supplement the limited supply of organ donors available for patients with end-stage liver disease. Here, we report the results of a pilot study aimed at developing a humanized porcine liver by transplanting second trimester human fetal hepatocytes (Hfh) co-cultured with fetal stellate cells (Hfsc) into the decellularized matrix of a porcine liver. MATERIAL AND METHODS: Ischemic livers were removed from 19 Yorkshire swine. Liver decellularization was achieved by an anionic detergent (SDS). The decellularized matrix of three separate porcine liver matrices was seeded with 3.5 * 10(8) and 1 * 10(9) of Hfsc and Hfh, respectively, and perfused for 3, 7, and 13 d. The metabolic and synthetic activities of the engrafted cells were assessed during and after perfusion. RESULTS: Immunohistologic examination of the decellularized matrix showed removal of nuclear materials with intact architecture and preserved extracellular matrix (ECM) proteins. During perfusion of the recellularized matrices, measurement of metabolic parameters (i.e., oxygen concentration, glucose consumption, and lactate and urea production) indicated active metabolism. The average human albumin concentration was 29.48 +/- 7.4 MUg/mL. Immunohistochemical analysis revealed cell differentiation into mature hepatocytes. Moreover, 40% of the engrafted cells were actively proliferating, and less than 30% of cells were apoptotic. CONCLUSION: We showed that our decellularization protocol successfully removed the cellular components of porcine livers while preserving the native architecture and most ECM protein. We also demonstrated the ability of the decellularized matrix to support and induce phenotypic maturation of engrafted Hfh in a continuously perfused system. PMID- 22099596 TI - The use of cognitive task analysis to improve instructional descriptions of procedures. AB - BACKGROUND: Surgical training relies heavily on the ability of expert surgeons to provide complete and accurate descriptions of a complex procedure. However, research from a variety of domains suggests that experts often omit critical information about the judgments, analysis, and decisions they make when solving a difficult problem or performing a complex task. In this study, we compared three methods for capturing surgeons' descriptions of how to perform the procedure for inserting a femoral artery shunt (unaided free-recall, unaided free-recall with simulation, and cognitive task analysis methods) to determine which method produced more accurate and complete results. Cognitive task analysis was approximately 70% more complete and accurate than free-recall and or free-recall during a simulation of the procedure. METHODS: Ten expert trauma surgeons at a major urban trauma center were interviewed separately and asked to describe how to perform an emergency shunt procedure. Four surgeons provided an unaided free recall description of the shunt procedure, five surgeons provided an unaided free recall description of the procedure using visual aids and surgical instruments (simulation), and one (chosen randomly) was interviewed using cognitive task analysis (CTA) methods. An 11th vascular surgeon approved the final CTA protocol. RESULTS: The CTA interview with only one expert surgeon resulted in significantly greater accuracy and completeness of the descriptions compared with the unaided free-recall interviews with multiple expert surgeons. Surgeons in the unaided group omitted nearly 70% of necessary decision steps. In the free-recall group, heavy use of simulation improved surgeons' completeness when describing the steps of the procedure. CONCLUSION: CTA significantly increases the completeness and accuracy of surgeons' instructional descriptions of surgical procedures. In addition, simulation during unaided free-recall interviews may improve the completeness of interview data. PMID- 22099597 TI - Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression. AB - Pancreatic adenocarcinoma remains among the most lethal of human malignancies. Overall 5-y survival is less than 5%, and only 20% of patients presenting with localized disease amenable to surgical resection. Even in patients who undergo resection, long-term survival remains extremely poor. A major contributor to the aggressiveness of multiple cancers, and pancreatic cancer in particular, is the process of epithelial-to-mesenchymal transition (EMT). This review highlights the growing evidence of EMT in pancreatic cancer progression, focusing on the contribution of EMT to the development of cancer stem cells and on interaction of EMT with other pathways central to cancer progression, such as Hedgehog signaling, the K-ras oncogene, and transforming growth factor-beta (TGF-beta). We will also discuss EMT-targeting agents currently in development and in clinical trials that may help to reduce the morbidity and mortality associated with pancreatic cancer. PMID- 22099598 TI - Decreased expression of hepatic signaling phosphoproteins after laparoscopic and hand-assisted surgery in a porcine model. AB - OBJECTIVE: Minimally-invasive surgery (MIS) is associated with a decreased activation of both systemic and peritoneal immunity compared with the open technique. However, hepatic response to laparoscopic (LAP) and hand-assisted laparoscopic (HAL) surgery has not been defined well. We postulated that both LAP and HAL approaches are associated with a diminished activation of hepatic inflammatory signaling pathways compared with the traditional open surgery. MATERIALS AND METHODS: Eighteen pigs underwent a transabdominal nephrectomy via Open, HAL, or LAP approach. Liver samples were obtained 24 h postoperatively and spot frozen. Frozen tissue samples were then homogenized and the nuclear pellets were separated and stored. Nuclear extracts were analyzed for activation of three nuclear signaling phosphoproteins: nuclear factor-kappaB (NFkappaB)-p65, heat shock protein 27 (HSP27), and p38 mitogen-activated protein kinases (p38MAPK) using a standard Bioplex technique. Statistical comparison was performed using ANOVA and Student's t-test. RESULTS: The average expression of HSP27 was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.028 and P = 0.039). The average expression of NFkappaB-p65 was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.032 and P = 0.049). The average expression of p38MAPK was significantly higher in the Open versus either the LAP or the HAL groups (P = 0.007 and P = 0.036). There was no significant difference in the expressions of HSP27 and NFkappaB-p65 between LAP and HAL groups (P = 0.38 and P = 0.20), however, detection of p38MAPK generated statistical difference between these two groups (P = 0.018). CONCLUSION: Hand assisted laparoscopic surgery has been widely accepted as an effective alternative to traditional laparoscopic procedures. We demonstrated that both laparoscopic and hand-assisted approaches resulted in blunted hepatic stress manifested by diminished expression of hepatic HSP27, NFkappaB, and p38-MAPK. In addition, the hand-assisted approach was equal to the laparoscopic approach in two of the three phosphoproteins studied. It appears that the use of hand assisted techniques did not abrogate immunologic benefits of pure laparoscopy. Overall, in addition to the clinical benefits of minimal access, both hand assisted and pure laparoscopic techniques may also confer an immunologic advantage over laparotomy. PMID- 22099599 TI - The effect of diabetes and poor left ventricular function on bone marrow cell induced myocardial protection. AB - OBJECTIVES: The myocardium of patients with diabetes and poor left ventricular (LV) function cannot be protected by interventions such as ischemic preconditioning (IP). We investigated whether these clinical conditions influence the protection elicited by the paracrine effect of bone marrow cells (BMCs) and whether the cause for loss in protection resides in the BMCs, the myocardium, or both. METHODS: BMCs and right atrial appendage were obtained from patients with and without diabetes and from poor (EF < 30%) and preserved LV function undergoing elective cardiac surgery. Muscles (n = 6/group) were co-cultured with BMCs and subjected to 90 min ischemia/120 min reoxygenation at 37 degrees C. The degree of protection was assessed by measuring creatine kinase (CK) released, and myocardial cell necrosis and apoptosis. RESULTS: Ischemia-induced CK release, cell necrosis, and apoptosis in the diabetic myocardium were not significantly affected by IP or by co-incubation with autologous or non-diabetic allogenic BMCs. Conversely, significant reduction in CK release, cell necrosis, and apoptosis were observed when non-diabetic myocardium was co-incubated with allogenic diabetic BMCs. Interestingly, while allogenic BMCs from subjects with preserved LV function exerted a modest but significant reduction in CK leakage and cell necrosis, but not apoptosis, on failing myocardium, the BMCs from patients with poor LV function failed to protect their own and the allogenic myocardium from subjects with normal LV function. CONCLUSIONS: The failure to protect the myocardium of patients with poor LV function against ischemia/reoxygenation-induced injury is mainly due to a deficit in their BMCs and the myocardium itself, whereas in patients with diabetes the deficit remains within the myocardium and not in the BMCs. PMID- 22099600 TI - The role of oxidative stress response revealed in preconditioning heat stimulation in skeletal muscle of rats. AB - BACKGROUND: Our previous study showed that preconditioned local somatothermal stimulation (LSTS) protected subsequent ischemia-reperfusion injury of the skeletal muscle. The exact mechanisms of LSTS preconditioning remain unknown. The aim of this study was to test the hypothesis stating that heat stimulation induces free radical production, increases enzymatic scavenging activity, and subsequently enhances the expression of heat shock protein 70 (HSP-70) in skeletal muscles. MATERIALS AND METHODS: After LSTS was applied onto the left quarter ventral abdomen muscle of male Sprague-Dawley rats, the underling muscles were collected at the intervals of baseline, 5-, 15-, 30-, and 60-min after LSTS. The time-dependent profiles of free radical production and enzymatic scavenging activity were measured. The influence of nitric oxide (NO) on HSP-70 expression was evaluated by pretreatment of an NO synthase inhibitor. RESULTS: The concentrations of reactive oxygen species, NO metabolites, and malondialdehyde increased significantly 5 min after LSTS, whereas the scavenging activity reduced to the lowest level 5 min (dismutase) and 15 min (catalase and glutathione) after LSTS. Expression of HSP-70 was significantly lower in the LSTS with NO synthase inhibitor group than in the LSTS group. CONCLUSIONS: LSTS induces oxidative stress and the scavenging response in the underlying skeletal muscle, which might explain the possible mechanisms of LSTS preconditioning-induced muscle plasticity. PMID- 22099602 TI - Up-regulated expression of MIF by interfacial membrane fibroblasts and macrophages around aseptically loosened implants. AB - BACKGROUND: Local chronic inflammatory reaction plays an important role in the process of aseptic loosening of implants after total joint replacement. In addition, macrophage migration inhibitory factor (MIF) is a key upstream regulator of inflammation, and it is a significant regulator of inflammatory diseases. The purpose of this study is to investigate if the fibroblasts and macrophages in the interfacial membranes overexpress MIF. MATERIALS AND METHODS: The 15 tissue samples of interfacial membranes were obtained from the tissues around the aseptically loosened femoral implants adjacent to osteolytic lesion in 15 patients. The 15 control synovial samples of hip joints were obtained from 15 patients who underwent primary hip arthroplasty because of the fresh fracture of the femoral neck. The levels of MIF protein and mRNA were evaluated by ELISA assay, immunofluorescence labeling, and real-time RT-PCR. Fibroblasts and macrophages were identified by immunofluorescence labeling. RESULTS: The levels of MIF protein and mRNA were significantly increased, as well as the numbers of MIF+ fibroblasts and macrophages in the interfacial membranes compared with the control synovium. CONCLUSION: Not only the macrophages, but also the fibroblasts in interfacial membranes overexpress MIF. MIF may play a significant role in the process of aseptic-loosening implants after total joint replacement. PMID- 22099601 TI - The role of estrogen receptor alpha and beta in regulating vascular smooth muscle cell proliferation is based on sex. AB - BACKGROUND: We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) in mediating proliferation in male and female VSMC. MATERIALS AND METHODS: Proliferation was assessed in primary rat aortic male and female VSMC using (3)H thymidine incorporation in the presence or absence of ER alpha (alpha) inhibitor methyl-piperidino-pyrazole, the ER beta (beta) inhibitor (R,R)-5,11-Diethyl 5,6,11,12-tetrahydro-2,8-chrysenediol, the combined ERalphabeta inhibitor ICI 182,780, and/or the NO donor DETA/NO. Proliferation was also assessed in primary aortic mouse VSMC harvested from wildtype (WT), ERalpha knockout (ERalpha KO), and ERbeta knockout (ERbeta KO) mice in the presence or absence of DETA/NO and the ERalpha, ERbeta, and ERalphabeta inhibitors. Protein levels were assessed using Western blot analysis. RESULTS: Protein expression of ERalpha and ERbeta was present and equal in male and female VSMC, and did not change after exposure to NO. Inhibition of either ERalpha or ERbeta had no effect on VSMC proliferation in the presence or absence of NO in either sex. However, inhibition of ERalphabeta in rat VSMC mitigated NO-mediated inhibition in female but not male VSMC (P < 0.05). Evaluation of proliferation in the knockout mice revealed distinct patterns. Male ERalphaKO and ERbetaKO VSMC proliferated faster than male WT VSMC (P < 0.05). Female ERbetaKO proliferated faster than female WT VSMC (P < 0.05), but female ERalphaKO VSMC proliferated slower than female WT VSMC (P < 0.05). Last, we evaluated the effect of combined inhibition of ERalpha and ERbeta in these knockout strains. Combined ERalphabeta inhibition abrogated NO-mediated inhibition of VSMC proliferation in female WT and knockout VSMC (P < 0.05), but not in male VSMC. CONCLUSIONS: These data clearly demonstrate a role for the ER in mediating VSMC proliferation in both sexes. However, these data suggest that the antiproliferative effects of NO may be regulated by the ER in females but not males. PMID- 22099603 TI - Removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration using a cellulose triacetate membrane: an ex vivo study. AB - BACKGROUND: Hemofiltration is often used to treat critically ill patients with renal failure and septic shock. Although hemofiltration has been reported to remove humoral mediators such as cytokines, most studies have investigated the removal of only limited kinds of cytokines. Here, we assessed the removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration (CHF) with a cellulose triacetate membrane (2.1 m(2) or 1.1 m(2)). METHODS: The subjects were six healthy volunteers. We collected 400 mL blood into containers with heparin. After adding 1 mg/mL lipopolysaccharide, the blood was incubated at 39 degrees C for 12 h and then filtered through a closed hemofiltration circuit (1 or 2 L/h). Sixty and 240 min after beginning hemofiltration, samples were collected from the outlet (arterial) side, inlet (venous) side, and filtrate port. Blood levels of cytokines, HMGB1, and albumin were determined at each time point. RESULTS: Increasing the flow rate significantly increased cytokine clearance. Increasing the membrane area of the hemofilter significantly changed the sieving coefficient of only five cytokines (IL-1beta, IL-6, MCP-1, MIP-1beta, HMGB1). For many cytokines, the sieving coefficient did not decline during the 240-min CHF procedure. CONCLUSION: Although all 17 cytokines, HMGB1, and albumin were detected in the filtrate, the SC and clearance varied widely. For numerous cytokines, clearance increased with the higher filtration flow rate. We demonstrated that CHF removed many cytokines and HMGB1, but was inefficient at removing albumin. PMID- 22099604 TI - Changing epidemiology of acute appendicitis in the United States: study period 1993-2008. AB - BACKGROUND: Addis et al. [5] described the epidemiology of appendicitis in the United States from 1970 to 1984. He reported that while overall incidence decreased, the highest incidence of appendicitis occurred in 10- to 19-y-olds. This study examines if the incidence of appendicitis and mean age of diagnosis has changed, and whether demographics are related to the frequency of admissions and incidence rate of acute appendicitis (AA). MATERIALS AND METHODS: Study questions were assessed using the Nationwide Inpatient Sample (NIS) discharge data and US Census data from 1993-2008. Operatively managed, uncomplicated, and complex cases of AA were included. Incidental appendectomy and right hemicolectomy were excluded. Descriptive, ANOVA, chi(2), and test of proportion statistics were used to evaluate frequency of admissions, incidence rate, and demographic changes in appendicitis. RESULTS: The annual rate of AA increased from 7.62 to 9.38 per 10,000 between 1993 and 2008. The highest frequency of AA was found in the 10-19 y age group, however occurrence in this group decreased by 4.6%. Persons between ages 30 and 69 y old experienced an increase of AA by 6.3%. AA rates remained higher in males. Hispanics, Asians, and Native Americans saw a rise in the frequency of AA, while the frequencies among Whites and Blacks decreased. CONCLUSIONS: While AA is most common in persons 10- to 19-y old, the mean age at diagnosis has increased over time. Minorities are experiencing an increase in the frequency of appendicitis. The changing demographics of the US plays a role in the current epidemiology of appendicitis, but is not solely responsible for the change observed. PMID- 22099605 TI - Pterostilbene and cancer: current review. AB - Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is an antioxidant that is primarily found in blueberries. Studies suggest that pterostilbene exhibits the hallmark characteristics of an effective anticancer agent based on its antineoplastic properties in several common malignancies. In vitro models have shown that pterostilbene inhibits cancer growth through alteration of the cell cycle, induction of apoptosis, and inhibition of metastasis. In vivo, pterostilbene inhibits tumorigenesis and metastasis with negligible toxicity. Pterostilbene has also been shown to be effective as an inducer of antioxidant capacity in multiple cancer cell lines that may facilitate its function as an anticarcinogenic compound. Additionally, preliminary studies show that pterostilbene exhibits much greater bioavailability compared with other stilbene compounds; however the exact pharmacologic mechanism of pterostilbene and its effects in humans are still under investigation. In this review, we present a comprehensive summary of the antineoplastic mechanisms of pterostilbene based on the results of preclinical studies and highlight recent advances in the study of this dietary compound. PMID- 22099606 TI - Abnormal anterior cingulate cortical activity during emotional n-back task performance distinguishes bipolar from unipolar depressed females. AB - BACKGROUND: Depression in the context of bipolar disorder (BDd) is often misdiagnosed as unipolar disorder depression (UDd) leading to poor clinical outcomes for many bipolar sufferers. We examined neural circuitry supporting emotion regulation in females with either BDd or UDd as a first stage toward identifying biomarkers that may differentiate BDd from UDd. METHOD: Fifty-seven females aged 18-45 years participated in this study: 23 with UDd, 18 with bipolar disorder type I depression (BDId) and 16 healthy females. During 3-T functional magnetic resonance imaging (fMRI), the participants performed an emotional face n back (EFNBACK) task, that is an n-back task with high (2-back) and low (0-back) memory load conditions flanked by two positive, negative or neutral face distracters. This paradigm examines executive control with emotional distracters emotion regulation. RESULTS: High memory load with neutral face distracters elicited greater bilateral and left dorsal anterior midcingulate cortex (dAMCC) activity in UDd than in healthy and BDId females respectively, and greater bilateral putamen activity in both depressed groups versus healthy females. High memory load with happy face distracters elicited greater left putamen activity in UDd than in healthy females. Psychotropic medication was associated with greater putamen activity to these contrasts in UDd females. CONCLUSIONS: During high memory load with neutral face distracters, elevated dAMCC activity in UDd suggests abnormal recruitment of attentional control circuitry to maintain task performance, whereas elevated putamen activity unrelated to psychotropic medication in BDId females may suggest an attentional bias toward ambiguous neutral face distracters. Differential patterns of functional abnormalities in neural circuitry supporting attentional control during emotion regulation, especially in the dAMCC, is a promising neuroimaging measure to distinguish UDd from BDId in females. PMID- 22099607 TI - Severe and anxious depression: combining definitions of clinical sub-types to identify patients differentially responsive to selective serotonin reuptake inhibitors. AB - Patients with severe major depressive disorder are more likely than those with mild/moderate depression to experience the relative benefits of antidepressant therapy versus placebo. Several studies have, unexpectedly, failed to show a similar antidepressant-placebo discrepancy between patients with versus without anxious depression, although patients with anxious depression are more likely to meet criteria for severe depression than those without. The aim of this study was to confirm the absence of treatment moderating effects for anxious depression in a general clinical trial population, and to examine for the presence of treatment moderating effects in severe depression. Patient-level outcome data from all randomized, double-blind, placebo-controlled trials involving the use of the selective serotonin reuptake inhibitor escitalopram for adults with major depressive disorder sponsored by H. Lundbeck A/S or Forest Laboratories were pooled. Studies focusing on patients with a specific axis-I or -III co-morbidity were excluded. Data from five trials were pooled. Anxious depression was not found to serve as a treatment moderator for selective serotonin reuptake inhibitor therapy versus placebo. However, when patients with severe depression were analyzed separately, anxious depression significantly influenced the relative degree of symptom reduction with selective serotonin reuptake inhibitors versus placebo (p=0.0094). In fact, the numbers needed to treat for remission for these two sub-types were the largest and smallest reported to date from analyses of large datasets of antidepressants (22 for severe anxious versus 4 for severe non-anxious depression). Subdividing patients with severe major depressive disorder into those with versus without anxious depression results in the characterization of sub-types that are particularly "responsive" (severe non anxious) and "unresponsive" (severe anxious) to selective serotonin reuptake inhibitor therapy (relative to placebo). These findings are preliminary, of yet undetermined clinical relevance, and warrant replication and further exploration. PMID- 22099608 TI - Physical activity and function in adolescents with chronic pain: a controlled study using actigraphy. AB - Physical functioning is often impaired in adolescents with chronic pain, which has largely been demonstrated through subjective self-report measures. Actigraphy uses motion monitoring as an objective means for assessing one dimension of physical functioning; physical activity level. This study used subjective and objective measures to assess multiple dimensions of physical functioning in a clinical sample of adolescents with chronic pain (n = 78) and a comparison group of healthy adolescents (n = 59). Individual and pain characteristics were also examined as predictors of actigraphy variables within the chronic pain sample. Results indicated that adolescents with chronic pain demonstrate significant impairment in subjective measures of physical functioning and evidence lower levels of physical activity. Actigraphic measures of physical activity were moderately correlated with self-report measures of physical functioning. Individual characteristics, including adolescent age, sex, and Body Mass Index percentile, were associated with physical activity levels among adolescents with chronic pain. Physical activity represents a distinct dimension of physical functioning. Assessing physical activity may provide additional description of physical functioning among adolescents with chronic pain, and may help identify targets for intervention in this population. PERSPECTIVE: This study demonstrates that adolescents with chronic pain have lower physical activity levels, as measured objectively via actigraphy, as well as poorer subjective reports of physical functioning, compared to healthy adolescents. Actigraphic measurement of physical activity provides objective source data about one dimension of physical functioning. PMID- 22099609 TI - Kyphectomy for congenital kyphosis due to meningomyelocele: a case treated with a modified approach to skin healing. AB - This study is a case report of a meningomyelocele patient with congenital kyphosis who was treated with kyphectomy and a special approach to soft tissue healing. The objective of this study is to show a step by step approach to surgical treatment and postoperative care of a meningomyelocele patient with congenital kyphosis. In meningomyelocele the incidence of kyphosis is around 12 20%. It may cause recurrent skin ulcerations, impaired sitting balance and respiratory compromise. Kyphectomy has first been described by Sharrard. This surgery is prone to complications including pseudoarthrosis, skin healing problems, recurrence of deformity and deep infections. A 15-year-old male presented with congenital kyphosis due to meningomyelocele. He had back pain, deformity and bedsores at the apex of the deformity. The wound cultures showed Staphylococcus epidermidis colonisation at the apex. He was given appropriate antibiotic prophylaxis. During surgery, the apex of the deformity was exposed through a spindle-shaped incision. After instrumentation and excision of the apex, correction was carried out by cantilever technique. Two screws were inserted to the bodies of L3 and T11. After the operation, the skin was closed in a reverse cross fashion. He was sent to hyperbaric oxygen treatment for prevention of a subsequent skin infection and for rapid healing of skin flaps post operation. The patient's deformity was corrected from a preoperative Cobb angle of 135 degrees -15 degrees postoperative. The skin healed without any problems. Preoperative culture and appropriate antibiotic prophylaxis, spindle shaped incision, reverse cross-skin closure and postoperative hyperbaric oxygen treatment can be useful adjuncts to treatment in congenital kyphosis patients with myelomeningocele to prevent postoperative wound healing and infection problems. Reduction screws and intracorporeal compression screws help to reduce the amount of screws and aid in corection of the deformity. PMID- 22099610 TI - Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. AB - BACKGROUND: Computed tomography (CT) is a commonly used noninvasive procedure for prostate cancer (PCa) staging. All previous studies addressing the ability of CT scan to predict lymph node invasion (LNI) were based on historical patients treated with limited pelvic lymph node dissection (PLND). OBJECTIVE: Assess the value of CT in predicting LNI in contemporary PCa patients treated with extended PLND (ePLND). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 1541 patients undergoing radical prostatectomy and ePLND between 2003 and 2010 at a single center. All patients were preoperatively staged using abdominopelvic CT scan. All lymph nodes with a short axis diameter >= 10 mm were considered suspicious for metastatic involvement. INTERVENTION: All patients underwent preoperative CT scan, radical retropubic prostatectomy, and ePLND, regardless of PCa features at diagnosis. MEASUREMENTS: The performance characteristics of CT scan were tested in the overall patient population, as well as according to the National Comprehensive Cancer Network (NCCN) classification and according to the risk of LNI derived from a nomogram developed on an ePLND series. Logistic regression models tested the relationship between CT scan findings and LNI. Discrimination accuracy was quantified with the area under the curve. RESULTS AND LIMITATIONS: Overall, a CT scan that suggested LNI was found in 73 patients (4.7%). Of them, only 24 patients (32.8%) had histologically proven LNI at ePLND. Overall, sensitivity, specificity, and accuracy of CT scan were 13%, 96.0%, and 54.6%, respectively. In patients with low-, intermediate-, or high-risk PCa according to NCCN classification, sensitivity was 8.3%, 96.3%, and 52.3%, respectively; specificity was 3.6%, 97.3%, and 50.5%, respectively; and accuracy was 17.9%, 94.3%, and 56.1%, respectively. Similarly, in patients with a nomogram-derived LNI risk >= 50%, sensitivity, specificity, and accuracy were only 23.9%, 94.7%, and 59.3%, respectively. At multivariable analyses, inclusion of CT scan findings did not improve the accuracy of LNI prediction (81.4% compared with 81.3%; p=0.8). Lack of a central scan review represents the main limitation of our study. CONCLUSIONS: In contemporary patients with PCa, the accuracy of CT scan as a preoperative nodal-staging procedure is poor, even in patients with high LNI risk. Therefore, the need for and the extent of PLND should not be based on the results obtained by CT scan. PMID- 22099611 TI - Biomarkers in the management and treatment of men with metastatic castration resistant prostate cancer. AB - CONTEXT: We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes. OBJECTIVE: In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy). EVIDENCE ACQUISITION: PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion. EVIDENCE SYNTHESIS: We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions. CONCLUSIONS: A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit. PMID- 22099612 TI - Chronic rhinosinusitis. AB - This article defines chronic rhinosinusitis (CRS) and shares contemporary principles for its diagnosis and management, focusing on practical considerations for rhinoplasty surgeons. Nasal obstruction, the most common symptom of CRS, is frequently the chief complaint of patients seeking functional rhinoplasty surgery. Because correcting sites of anatomic obstruction to nasal airflow alone is unlikely to adequately treat CRS, rhinoplasty surgeons must have a firm understanding of the origin, diagnosis, and management of this disease process. With no single cause identified, CRS is likely an umbrella diagnosis or syndrome encompassing numerous causative factors, with the common end point of chronic sinonasal inflammation. PMID- 22099613 TI - Allergic rhinitis. AB - Familiarity with the diagnosis and management of allergic rhinitis is important for physicians concerned with the nasal airway. Allergic rhinitis is a common and manageable condition that may cause persistent or intermittent symptoms that vary as to duration and severity. Allergic rhinitis impairs quality of life, sleep, school performance, and productivity on a scale that compares with other chronic diseases. Diagnosis is primarily clinical, but supported by allergy testing. Therapeutic options for allergic rhinitis include pharmacotherapy, environmental control, and immunotherapy. More recently, a role for sublingual immunotherapy and turbinate reduction has been reported. PMID- 22099614 TI - Nonallergic rhinitis. AB - This article reviews a uniform way to describe nonallergic rhinitis in its various forms. The insights into its pathophysiology are briefly reviewed. A classification scheme for the different forms is provided. This is followed by descriptions of the diagnosis, evaluation, and management of nonallergic rhinitis. PMID- 22099615 TI - Allergic skin disease. AB - The two most common allergic skin diseases in the world are often the least familiar to practicing surgeons: atopic dermatitis and contact dermatitis. When unrecognized, these disorders can cause great discomfort and decreased quality of life. This is only made worse by a surgical procedure which can exacerbate the disease process. Through proper recognition, management, and peri-surgical prophylaxis flares of these diseases can be avoided, leading to decreased morbidity and improved patient satisfaction. This article summarizes the pathophysiology and management of both atopic and contact dermatitis, with attention to implications for the surgeon. PMID- 22099616 TI - Concurrent rhinoplasty and endoscopic sinus surgery: a review of the pros and cons and a template for success. AB - Historically concurrent FESS/rhinoplasty was avoided due to concerns of increased risk of complication. Recent studies have shown that FESS/rhinoplasty can be performed simultaneously with good outcomes and no significant increase in complications. A thorough and effective approach to the patient with sinonasal obstruction requires attention to aesthetic, functional, and inflammatory issues. Medical treatment is an important adjuvant to surgery in order to optimize outcomes by improving patient symptoms long-term. Surgery for these patients should be performed in a careful, stepwise approach to address the nasal septum, inferior turbinates, paranasal sinuses, and external nasal structures. PMID- 22099617 TI - The unified airway. AB - The upper and lower respiratory tracts function as an interdependent physiologic mechanism, and stimuli that trigger pathophysiologic changes in one portion of the airway can provoke similar changes throughout the airway. The unified airway model acknowledges these shared airway features, suggesting the importance of comprehensive evaluation of patients with any respiratory symptoms. Two areas are of specific importance to the septoplasty/rhinoplasty surgeon: (1) preoperative evaluation of the patient with rhinitis undergoing nasal surgery, and (2) perioperative and postoperative management of the nose. Management of potential cardiopulmonary risks among susceptible individuals is vital in the perioperative management of these patients. PMID- 22099618 TI - Pharmacotherapy of rhinitis and rhinosinusitis. AB - Concerns for the cosmetic surgeon regarding allergic rhinoconjunctivitis and rhinosinusitis include diagnosis, treatment, and assessment of the disease and whether or not the timing or outcome of cosmetic procedures will be affected. In this article, the pharmacotherapy of allergic and nonallergic rhinoconjunctivitis and rhinosinusitis is discussed with emphasis on intranasal steroids, antihistamines, and antibiotics. PMID- 22099619 TI - The role of alternative medicine in rhinology. AB - Complementary and alternative medicine (CAM) includes treatments from traditional Chinese medicine, homeopathy, naturopathy, herbal medicine, Ayurvedic medicine, mind-body medicine, chiropractic or osteopathic manipulations, and massage. More than 40% of patients in the United States use CAM, with 17% of CAM use related to otolaryngology diagnoses, but nearly half of CAM users do not communicate their use of these medications to their physicians. Perioperative risk of bleeding is a particular concern in surgical specialties, and knowledge of these therapies and their potential adverse effects is critical. PMID- 22099620 TI - Sinonasal problems and reflux. AB - Extraesophageal reflux has been implicated in many disorders affecting the upper airway. This article reviews the recent literature regarding the relationship of refractory chronic rhinosinusitis with extraesophageal reflux. Recent studies have shown that patients with refractory chronic rhinosinusitis have an increased prevalence of extraesophageal reflux. An association may exist between gastroesophageal reflux and rhinosinusitis, especially in individuals with medically and surgically refractory disease. These studies have a poor level of evidence and data supporting causation are lacking. However, evaluation and treatment should be considered in patients with chronic rhinosinusitis, especially in those with refractory disease. PMID- 22099621 TI - Bacteriology and antibiotic resistance in chronic rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is a prevalent health care problem that may be commonly encountered in patients desiring aesthetic or reconstructive rhinoplasty. The purpose of this article is to review the common bacterial pathogens associated with CRS, as well as patterns of bacterial resistance in this patient subset. Close understanding of microbial pathogens involved in CRS and their associated resistance patterns will guide facial plastic surgeons in optimally managing this important potential comorbidity, and in turn positively influence the outcome of rhinoplasty. PMID- 22099622 TI - Smell and taste disorders. AB - Olfaction and taste promote satisfaction and protection in daily life. The astute facial plastic surgeon recognizes the importance of a baseline smell test to document the patients' olfactory status before surgery. After surgery, the surgeon must be alert to the possible mechanisms of hyposmia and anosmia and the pertinent treatment strategies. The surgeon must also understand the importance of counseling the patient and family regarding the cause of the dysfunction and the proper treatments. This article updates the facial plastic surgeon on the importance of smell and taste and associated disorders with a current review of the literature. PMID- 22099624 TI - Root trauma and tooth loss through the application of pre-drilled transgingival fixation screws. AB - Transgingival fixation screws are used for intermaxillary fixation in different situations. The aim of this study was to evaluate the risk of root trauma and tooth loss using pre-drilled transgingival fixation screws. MATERIAL AND METHODS: 521 patients with mean age 26.9 (SD 9.9) years who had orthognathic surgery or trauma to the maxilla or mandible were selected for the study. Postoperative orthopantomographs (OPT) taken before and after screw removal were examined. The location of the screws and dental-root "hits" were recorded. RESULTS: 1663 screws were inserted either to the maxilla or to the mandible. 285 teeth (17.1%) showed radiologically proven contact between the dental roots and the screws or the dental roots were hit by the screw (screw inserted with more than the screws radius into the root). In three cases (0.2%) teeth were lost due to apical or periradicular inflammation, four teeth (0.2%) had to be root filled and five teeth (0.3%) were persistent painful at the follow-up examination before miniplate removal 10.3 (SD 8.1) months post-surgery. CONCLUSION: Dental problems occurred in 0.7% at the screw insertions sites. The use of transgingival fixation screws showed a low risk of tooth loss. Root defects healed without any incident. However surgeons must be aware of possible consequences to provide a safe treatment. PMID- 22099625 TI - Acute effects of nicardipine and esmolol on the cardiac cycle, intracardiac hemodynamic and endothelial shear stress in patients with unstable angina pectoris and moderate coronary stenosis: results from single center, randomized study. AB - OBJECTIVE: This study aimed to compare the acute effects of nicardipine and esmolol on hemodynamic and endothelial shear stress (ESS) in patients with unstable angina (UA) and moderate coronary stenosis (MCS). BACKGROUND: Nicardipine and esmolol exhibit cardioprotection via different mechanisms. However, their acute effects on hemodynamic and ESS are still unknown. METHODS: One-hundred sixteen patients with UA and MSC were randomly divided into nicardipine (n = 59) and esmolol (n = 57) groups. Drugs were injected as a bolus followed by continuous infusion to achieve the steady states defined as the mean blood pressure (MBP) reduced by >= 10% or a heart-rate change by >= 15 bpm, lasting for at least 10 min. The aortic pressure (AP), EKG, blood velocity, right atrial pressure, distal coronary pressure (DCP), systolic time (ST), isovolumetric diastolic time (IVDT), speed filling time (SFT), and ESS were simultaneously calculated at baseline and steady states. RESULTS: Both drugs significantly reduced blood pressure and rate-pressure load. Infusion of nicardipine was associated with negative remodeling of the distal segment (P= 0.005). Esmolol, rather than nicardipine, increased minimal lumen diameter (P= 0.040), prolonged SFT (0.34 +/- 0.03 s vs. 0.41 +/- 0.03 s, P < 0.001), reduced DCP (P < 0.001) and increased blood velocity (33.65 +/- 1.07 cm/s vs. 43.36 +/- 1.25 cm/s, P < 0.001) at SFT stages, with increased blood-flow (P < 0.001). Both drugs increased downstream ESS. Esmolol significantly reversed abnormally increased ESS (P < 0.001) and increased upstream ESS compared with nicardipine (P < 0.001). CONCLUSION: Beyond a similar reduction of AP, patients with UA and MCS could benefit more from the reduction of heart rate induced by esmolol (ChiCTR TRC-10000964). PMID- 22099626 TI - Comminuted mandibular fracture in child victim of dog bite. AB - Dog bites represent lesions commonly found in Hospital Emergency Clinic. This type of lesion may cause severe harm to patients, but it rarely affects the underlying bone structure causes facial fracture. This study aims to illustrate a rare clinical case in which a pediatric patient presented a comminuted fracture in the mandible which evolved into a unilateral avulsion of the mandibular condyle, body fractures as well as a mandibular ramus and hemiface that had been deformed, with multiple lacerations and loss of soft-tissue mass. Intermaxillary fixation was performed using the Ivy method, followed by internal rigid fixation using miniplates and screws in attempt to reconstruct the child's mandible. After 2 years of follow-up, a satisfactory esthetics and functional results could be observed. PMID- 22099627 TI - Plasma BNP, a useful marker of fluid overload in hospitalized hemodialysis patients. AB - Hospitalization for intercurrent illness frequently disrupts the nutritional status of hemodialysis (HD) patients and jeopardizes the dry weight prescription. We report in this study the evolution of brain natriuretic peptide (BNP), blood pressure and body weight in hospitalized patients and the relationship between BNP plasma level and nutritional and inflammation parameters. We have studied 42 patients requiring hospitalization (F/M: 18/24; 72.5 +/- 12.5 years old; 19/42 with diabetes). The plasma BNP levels at baseline, during hospitalization (BNP Hosp), and in the recovery phase were compared. Predialysis and postdialysis blood pressure and postdialysis body weight were recorded and compared. BNP-Hosp increased significantly when compared with BNP levels at baseline, from 421 +/- 647.2 pg/mL to 1584 +/- 1584.4 pg/mL (P < 0.0001). Brain natriuretic peptide decreased from 1223 +/- 1342.1 pg/mL during hospitalization to 616 +/- 892.1 pg/mL after discharge (P = 0.005). The BNP-Hosp was positively correlated with C reactive protein (P = 0.003) and negatively correlated with serum prealbumin (P = 0.0001) and albumin (P = 0.0001). The postdialysis body weight prescription decreased from 71.0 +/- 15.7 kg at baseline to 70.5 +/- 15.4 kg during hospitalization and to 67.8 +/- 14.4 kg 4 months after discharge (P = 0.0032). Our study displays clearly the significant changes of plasma BNP levels occurring during intercurrent events. Fluid overload triggered by inflammation-associated catabolism and the lag time for dry weight adjustment is the cause of this finding. Hence, plasma BNP level may be used as a marker of fluid overload in patients with intercurrent events and may allow efficient dry weight adjustment. We cannot rule out an effect of inflammation on BNP synthesis. PMID- 22099628 TI - Identification of virtual signal transducers and activators of transcription response elements in the human insulin receptor gene promoter. AB - In this study, we look for the existence of signal transducers and activators of transcription response elements (STATREs) in the human insulin receptor (hIR) gene promoter and their possible relation with the estradiol-provoked transcriptional repression of the hIR gene and cellular insulin resistance in U 937 human promonocytic cells. Potential STATREs in the region from -1819 to -271 bp of the hIR gene promoter were identified by their homology with the consensus STATRE (5'TTCnnnGAA3') using the SEQFIND programme developed in our laboratory. We located five virtual STATRE-like sites: [(I): -1472/-1464], [(II): -1548/ 1540], [(III): -1552/-1544], [(IV): -1587/-1579] and [(V): -1678/-1670] showing a difference of only one base from this consensus. These STATREs-like sites were situated between 33 bp upstream the 5' half-element of the estrogen response element 1 (ERE1)-like (-1430/-1418) and 102 bp upstream the 5' half-element of the ERE2-like (-1567/-1555) complexed with AP-1-like sites. A principal complex constituted by STATREs (II-IV) the ERE2 and AP-1 sites (IV and V) was located between -1587/-1540 bp of the hIR gene promoter. In conclusion, these results represent the first identification of virtual STATREs in the hIR gene promoter. These STATREs appear to be specifically located in the surroundings of the two EREs overlapped by various AP-1 sites. These complexes could mediate crosstalk among STATs, estrogen receptor beta (ERbeta), and AP-1 regulating the ERbeta mediated transcriptional repression of the hIR gene and insulin resistance in U 937 cells. PMID- 22099629 TI - Tracing the evolution of the mitochondrial protein import machinery. AB - Mitochondria are eukaryotic organelles originated from a single bacterial endosymbiosis about 2 billion years ago. One of the earliest events in the evolution of mitochondria was the acquisition of a mechanism that facilitated the import of proteins from cytosol. The mitochondrial protein import machinery consists of dozens of subunits, and they are of modular design. However, to date, it is not clear when certain component was added to the machinery. Using extensive homology searches, the evolutionary history of the mitochondrial protein import machinery was reconstructed. The results indicated that 6 of the 35 subunits have homologs in prokaryote, suggesting that they were prokaryotic origin; the major subunit gains were occurred in the earliest stage of eukaryotic evolution; subsequent to the gain of these conserved set of subunits, the mitochondrial protein import machinery components diversified along the eukaryotic lineages and a number of lineage-specific subunits can be observed. Furthermore, protein import systems of mitochondria-like organelles (hydrogenosomes and mitosomes) have dramatically reduced their subunit contents, however, they share most of the prokaryotic origin components with mitochondrion. PMID- 22099630 TI - New insights on gene regulation in archaea. AB - Archaea represent an important and vast domain of life. This cellular domain includes a large diversity of organisms characterized as prokaryotes with basal transcriptional machinery similar to eukarya. In this work we explore the most recent findings concerning the transcriptional regulatory organization in archaeal genomes since the perspective of the DNA-binding transcription factors (TFs), such as the high proportion of archaeal TFs homologous to bacteria, the apparent deficit of TFs, only comparable to the proportion of TFs in parasites or intracellular pathogenic bacteria, suggesting a deficit in this class of proteins. We discuss an appealing hypothesis to explain the apparent deficit of TFs in archaea, based on their characteristics, such as their small length sizes. The hypothesis suggests that a large fraction of these small-sized TFs could supply the deficit of TFs in archaea, by forming different combinations of monomers similar to that observed in eukaryotic transcriptional machinery, where a wide diversity of protein-protein interactions could act as mediators of regulatory feedback, indicating a chimera of bacterial and eukaryotic TFs' functionality. Finally, we discuss how global experiments can help to understand in a global context the role of TFs in these organisms. PMID- 22099631 TI - A generalized graph-theoretical matrix of heterosystems and its application to the VMV procedure. AB - The extensions of generalized (molecular) graph-theoretical matrix and vector matrix-vector procedure are considered. The elements of the generalized matrix are redefined in order to describe molecules containing heteroatoms and multiple bonds. The adjacency, distance, detour and reciprocal distance matrices of heterosystems, and corresponding vectors are derived from newly defined generalized graph matrix. The topological indices, which are most widely used in predicting physicochemical and biological properties/activities of various compounds, can be calculated from the new generalized vector-matrix-vector invariant. PMID- 22099632 TI - Kernel-based data fusion improves the drug-protein interaction prediction. AB - Proteins are involved in almost every action of every organism by interacting with other small molecules including drugs. Computationally predicting the drug protein interactions is particularly important in speeding up the process of developing novel drugs. To borrow the information from existing drug-protein interactions, we need to define the similarity among proteins and the similarity among drugs. Usually these similarities are defined based on one single data source and many methods have been proposed. However, the availability of many genomic and chemogenomic data sources allows us to integrate these useful data sources to improve the predictions. Thus a great challenge is how to integrate these heterogeneous data sources. Here, we propose a kernel-based method to predict drug-protein interactions by integrating multiple types of data. Specially, we collect drug pharmacological and therapeutic effects, drug chemical structures, and protein genomic information to characterize the drug-target interactions, then integrate them by a kernel function within a support vector machine (SVM)-based predictor. With this data fusion technology, we establish the drug-protein interactions from a collections of data sources. Our new method is validated on four classes of drug target proteins, including enzymes, ion channels (ICs), G-protein couple receptors (GPCRs), and nuclear receptors (NRs). We find that every single data source is predictive and integration of different data sources allows the improvement of accuracy, i.e., data integration can uncover more experimentally observed drug-target interactions upon the same levels of false positive rate than single data source based methods. The functional annotation analysis indicates that our new predictions are worthy of future experimental validation. In conclusion, our new method can efficiently integrate diverse data sources, and will promote the further research in drug discovery. PMID- 22099633 TI - Analysis and recognition of the GAGA transcription factor binding sites in Drosophila genes. AB - The transcription factor GAGA, encoded by the gene Trl, controls expression of many Drosophila melanogaster genes. We have compiled the presently largest sample (120 sites) of published nucleotide sequences with experimentally confirmed binding to GAGA protein. Analysis of the sample has demonstrated that despite an apparent structural diversity of the GAGA sites, they fall into four distinct groups, namely, (1) the sites containing two GAG trinucleotides with no more than one nucleotide substitution in each and separated by spacers with a length of 1 or 3 nucleotides (GAGnGAG and GAGnnnGAG); (2) the sites containing a single GAGAG motif; (3) (GA)(3-9) microsatellite repeats; and (4) the sites corresponding to three and more direct repeats of GAG trinucleotide homolog and its inverted repeats separated by spacers of various lengths. Using the software package SITECON, the methods were elaborated for recognizing the sites of GAGnGAG (method 1) and GAGnnnGAG (method 2) types in DNA sequences. Experimental verification confirmed the ability to interact with the GAGA factor for 72% of the sites predicted using method 1 and 94.5% of the sites predicted by method 2. Application of the experimentally verified methods to analyzing the localization of potential GAGA binding sites in the target genes of this transcription factor has demonstrated that the 5'-untranslated regions (5'UTRs) and first introns are enriched for these sites (two-threefold relative to the average occurrence frequency in the D. melanogaster genome) as compared with a moderate enrichment (not exceeding 1.5-fold) of promoter regions (-4000/+200 bp or -1000/+100 bp). PMID- 22099634 TI - Detecting breakdown points in metabolic networks. AB - BACKGROUND: A complex network of biochemical reactions present in an organism generates various biological moieties necessary for its survival. It is seen that biological systems are robust to genetic and environmental changes at all levels of organization. Functions of various organisms are sustained against mutational changes by using alternative pathways. It is also seen that if any one of the paths for production of the same metabolite is hampered, an alternate path tries to overcome this defect and helps in combating the damage. METHODOLOGY: Certain physical, chemical or genetic change in any of the precursor substrate of a biochemical reaction may damage the production of the ultimate product. We employ a quantitative approach for simulating this phenomena of causing a physical change in the biochemical reactions by performing external perturbations to 12 metabolic pathways under carbohydrate metabolism in Saccharomyces cerevisae as well as 14 metabolic pathways under carbohydrate metabolism in Homo sapiens. Here, we investigate the relationship between structure and degree of compatibility of metabolites against external perturbations, i.e., robustness. Robustness can also be further used to identify the extent to which a metabolic pathway can resist a mutation event. Biological networks with a certain connectivity distribution may be very resilient to a particular attack but not to another. The goal of this work is to determine the exact boundary of network breakdown due to both random and targeted attack, thereby analyzing its robustness. We also find that compared to various non-standard models, metabolic networks are exceptionally robust. Here, we report the use of a 'Resilience based' score for enumerating the concept of 'network-breakdown'. We also use this approach for analyzing metabolite essentiality providing insight into cellular robustness that can be further used for future drug development. RESULTS: We have investigated the behavior of metabolic pathways under carbohydrate metabolism in S. cerevisae and H. sapiens against random and targeted attack. Both random as well as targeted resilience were calculated by formulating a measure, that we termed as 'Resilience score'. Datasets of metabolites were collected for 12 metabolic pathways belonging to carbohydrate metabolism in S. cerevisae and 14 metabolic pathways belonging to carbohydrate metabolism in H. sapiens from Kyoto Encyclopedia for Genes and Genomes (KEGG). PMID- 22099635 TI - BNP and NT proBNP and hemodialysis. PMID- 22099636 TI - Outcomes for depression and anxiety in primary care and details of treatment: a naturalistic longitudinal study. AB - BACKGROUND: There is little evidence as to whether or not guideline concordant care in general practice results in better clinical outcomes for people with anxiety and depression. This study aims to determine possible associations between guideline concordant care and clinical outcomes in general practice patients with depression and anxiety, and identify patient and treatment characteristics associated with clinical improvement. METHODS: This study forms part of the Netherlands Study of Depression and Anxiety (NESDA).Adult patients, recruited in general practice (67 GPs), were interviewed to assess DSM-IV diagnoses during baseline assessment of NESDA, and also completed questionnaires measuring symptom severity, received care, socio-demographic variables and social support both at baseline and 12 months later. The definition of guideline adherence was based on an algorithm on care received. Information on guideline adherence was obtained from GP medical records. RESULTS: 721 patients with a current (6-month recency) anxiety or depressive disorder participated. While patients who received guideline concordant care (N=281) suffered from more severe symptoms than patients who received non-guideline concordant care (N=440), both groups showed equal improvement in their depressive or anxiety symptoms after 12 months. Patients who (still) had moderate or severe symptoms at follow-up, were more often unemployed, had smaller personal networks and more severe depressive symptoms at baseline than patients with mild symptoms at follow-up. The particular type of treatment followed made no difference to clinical outcomes. CONCLUSION: The added value of guideline concordant care could not be demonstrated in this study. Symptom severity, employment status, social support and comorbidity of anxiety and depression all play a role in poor clinical outcomes. PMID- 22099638 TI - Prevalence of neuroleptic-induced restless legs syndrome in patients taking neuroleptic drugs. AB - Dopamine deficiency or dopamine dysfunction has been implicated as one of the factors involved in the pathophysiology of restless legs syndrome (RLS). Our objective is to determine the prevalence of primary RLS in patients taking neuroleptic drugs. One hundred patients taking neuroleptic drugs and 100 healthy age- and sex-matched controls were interviewed with the Cambridge-Hopkins diagnostic questionnaire for RLS. Patients with malignancy, end-stage renal disease, neuropathy, history of spinal cord diseases, pregnancy and Parkinson's disease were excluded. Only one patient had symptoms consistent with RLS (1%), similar to one patient in the control group. She was a 40 years old female with a diagnosis of depression. She started having RLS symptoms approximately four years after starting perphenazine. The symptoms persisted after the medications were discontinued but decreased in severity and frequency. Her serum ferritin level was 90.3 ng/ml. The prevalence of primary RLS is low in patients attending the out-patient clinic who are taking neuroleptic drugs. Other factors apart from dopaminergic dysfunction are likely to be involved in the pathogenesis of RLS. PMID- 22099639 TI - Influence of visual cues on gait in Parkinson's disease during treadmill walking at multiple velocities. AB - OBJECTIVE: To evaluate the interaction of different treadmill-induced gait velocities and visual cues on the gait performance in Parkinson's disease (PD). BACKGROUND: External cuing has been reported to facilitate hypokinetic gait patterns in PD. METHODS: 19 PD-patients and 17 controls volunteered for the study. Gait analyses were conducted using dynamic pressure sensors integrated in a treadmill at a given velocity of 1, 2, 3 or 4 km/h. For each velocity, measurements were performed under three conditions. The first condition was without visual cuing, the remaining two consisted of visual cuing e.g. white stripes put on the treadmill belt 25 or 50 cm apart. RESULTS: Visual cuing lowered the cadence and increased stride length and stride time while maintaining gait velocity in both PD-patients and controls. A significant interaction between this effect of visual cuing and gait velocity was observed. Visual cuing demonstrated a clear velocity-dependency with less influence on cadence, stride length, stride time and coefficient of variation in stride time at higher velocities. At lower velocities visual cuing was more effective in reducing gait variability as assessed by the coefficient of variation in stride time in PD patients than in controls. CONCLUSION: The current experiment shows that the gait patterns of PD-patients are not rigidly coupled to gait velocity and can be manipulated with visual cuing techniques. Our results suggest that visual cuing can improve the efficacy of treadmill training. Due to an interaction between the effect of visual cuing and gait velocity, the application of visual cues could enhance the efficacy of treadmill training particularly at lower velocities. PMID- 22099640 TI - Polyethylene glycol-coated solid-phase microextraction fibres for the extraction of polar analytes--a review. AB - The article discusses the merits and limitations of commercially available solid phase microextraction (SPME) fibres and compares them with the new type of extraction coatings, in particular those containing polyethylene glycol as sorbent, as well as the methods of the preparation of the latter. It also analyses their possible application for the extraction of a broad spectrum of analytes, with particular emphasis on the sampling of polar organic compounds from different media. PMID- 22099641 TI - Neptunium(III) application in extraction chromatography. AB - This paper describes a novel strategy for actinide separation by extraction chromatography with Np(III) valence adjustment. Neptunium(IV) was reduced to Np(III) using Cr(II) and then selectively separated from uranium (IV) on a TEVA resin. After elution, Np(III) was retained on a DGA resin in order to remove any detrimental chromium impurities. Neptunium(III) formation was demonstrated by the complete and selective elution of Np from TEVA resin (99 +/- 7%) in less than 12 mL of 9M HCl from U(IV) (0.7 +/- 0.7%). It was determined by UV-visible and kinetic studies that Cr(II) was the only species responsible for the elution of Np(IV) as Np(III) and that the Cr(II) solution could be prepared from 2 to 30 min before its use without the need of complex degassing systems to prevent the oxidation of Np(III) by oxygen. The methodology proposed here with TEVA/DGA resins provides removal of Cr(III) impurities produced at high decontamination factors (2.8 * 10(3) and 7.3 * 10(4) respectively). PMID- 22099642 TI - Preparation and characterization of bismuth oxide nanoparticles-multiwalled carbon nanotube composite for the development of horseradish peroxidase based H2O2 biosensor. AB - In this work, preparation and characterization of a novel nanocomposite containing bismuth oxide (Bi(2)O(3)) nanoparticles and multiwalled carbon nanotubes (MWCNTs) was presented. Powder X-ray diffraction (XRD) studies revealed that as-synthesized Bi(2)O(3) nanoparticles are crystalline and belong to alpha phase with monoclinic symmetry. Field emission scanning electron microscopy (FESEM) study results showed that the size of Bi(2)O(3) nanoparticles is 50 nm. Energy-dispersive X-ray (EDX) spectra of as-prepared Bi(2)O(3)-MWCNT nanocomposite displayed characteristic Bi and C peaks which confirmed the incorporation of Bi(2)O(3) with MWCNT. The prepared Bi(2)O(3)-MWCNT was also characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM) studies. The direct electron transfer of horseradish peroxidase (HRP) has been revealed at Bi(2)O(3)-MWCNT modified glassy carbon electrode (GCE). In order to firmly anchor the HRP molecules onto Bi(2)O(3)-MWCNT matrix, a thin layer of 1% nafion (NF) solution was coated as a binder. The fabricated NF/HRP/Bi(2)O(3) MWCNT/GCE exhibits well defined quasi-reversible redox peaks at a formal potential (E(0)') of -0.326V vs. Ag/AgCl reference electrode in 0.05M phosphate buffer solution (PBS), pH 7. NF/HRP/Bi(2)O(3)-MWCNT film remarkably lowers the over potential for H(2)O(2) reduction than MWCNT, Bi(2)O(3)-MWCNT and unmodified GCEs. The proposed composite film exhibits quick amperometric i-t response (5s) towards H(2)O(2) in the linear range of 8.34-28.88mM with a sensitivity of 26.54 MUA MUM(-1)cm(-2). The developed NF/HRP/Bi(2)O(3)-MWCNT biosensor has a good operational stability and high selectivity towards H(2)O(2). PMID- 22099643 TI - Multielement analysis of micro-volume biological samples by ICP-MS with highly efficient sample introduction system. AB - A method for multielement analysis of micro-volume biological sample by inductively coupled plasma mass spectrometry (ICP-MS) with a highly efficient sample introduction system was presented. The sample introduction system was the combination of (1) an inert loop injection unit and (2) a high performance concentric nebulizer (HPCN) coupled with a temperature controllable cyclone chamber. The loop injection unit could introduce 20 MUL samples into the carrier liquid flow of 10 MUL min(-1) producing a stable signal for 100s without any dilution. The injection loop is continuously washed with 0.1M HNO(3) carrier solution during the measurement, thereby much improving sample throughput. The HPCN is a triple tube concentric nebulizer, which can generate fine aerosols and provide a stable and highly measurement sensitivity in ICP-MS at a liquid flow rate less than 10 MUL min(-1). With the combination of the chamber heating at 60 degrees C, the sensitivity obtained with the proposed sample introduction system at the liquid flow rate of 10 MUL min(-1) was almost the same as that with a common concentric nebulizer and cyclone chamber system at the liquid flow rate of 1 mL min(-1), though the sample consumption rate of the HPCN was two orders of the magnitude lower than that of the common nebulizer. The validation of the proposed system was performed by analyzing the NIST SRM 1577b Bovine Liver. The observed values for 12 elements such as Na, P, S, K, Ca, Mn, Fe, Co, Cu, Zn, Mo, Cd were in good agreement with their certified values and information value. Satisfactory analytical results for 14 elements such as Na, Mg, P, S, K, Ca, Cr, Mn, Fe, Ni, Cu, Zn, Y, Ba in Escherichia coli sample were also obtained. The proposed sample introduction system was quite effective in the cases when only micro-volume of biological sample is available. PMID- 22099644 TI - Determination of biodiesel content in biodiesel/diesel blends using NIR and visible spectroscopy with variable selection. AB - This work is concerned of evaluate the use of visible and near-infrared (NIR) range, separately and combined, to determine the biodiesel content in biodiesel/diesel blends using Multiple Linear Regression (MLR) and variable selection by Successive Projections Algorithm (SPA). Full spectrum models employing Partial Least Squares (PLS) and variables selection by Stepwise (SW) regression coupled with Multiple Linear Regression (MLR) and PLS models also with variable selection by Jack-Knife (Jk) were compared the proposed methodology. Several preprocessing were evaluated, being chosen derivative Savitzky-Golay with second-order polynomial and 17-point window for NIR and visible-NIR range, with offset correction. A total of 100 blends with biodiesel content between 5 and 50% (v/v) prepared starting from ten sample of biodiesel. In the NIR and visible region the best model was the SPA-MLR using only two and eight wavelengths with RMSEP of 0.6439% (v/v) and 0.5741 respectively, while in the visible-NIR region the best model was the SW-MLR using five wavelengths and RMSEP of 0.9533% (v/v). Results indicate that both spectral ranges evaluated showed potential for developing a rapid and nondestructive method to quantify biodiesel in blends with mineral diesel. Finally, one can still mention that the improvement in terms of prediction error obtained with the procedure for variables selection was significant. PMID- 22099645 TI - Determination of fullerenes (C60) in artificial sediments by liquid chromatography. AB - In this new century, nanotechnology has evolved from a novel concept to an integral aspect of product advancement. With an increasing presence of nanomaterials in commercial products, more concern about the impact of nanomaterials on human health and also the environment has been considered and evaluated. Fullerenes (C60), have been studied in several different areas and applied widely. Wider application of fullerenes into different products in the recent decades has increased the potential of fullerene releases into the environment. Fullerene research involves physical and chemical characteristics, toxicity, environment fate, and interaction with other pollutions. However, few studies have addressed fullerene quantification in solid matrices. Standardized artificial sediment was prepared following OECD guideline 225, and extracted C60 was quantified by HPLC-UV. A normal shaking method was employed for extraction for two times. Extracts were concentrated and analyzed. Recovery results revealed up to 90.7 +/- 4.5%, 90.0 +/- 3.8%, 93.8 +/- 5.4%, respectively for 1.62, 0.65, and 0.32 MUg/g C60 in dry sediment, which shows no significant difference between different concentration levels. Furthermore, extraction efficiency did not show significant difference while using Telfon(TM) tubes (96.5 +/- 6.0%) or silanized glass vessels (90.7 +/- 4.5%). This indicated that relative low cost is required for the method to be initially started in any lab. This technique has also been applied in the determination of C60 in sediment samples collected after a 10 day benthic exposure study. Extraction precision has been increased from 4.5% (S.D.) as the validation value up to 15.4% (RSD%) or more. The increased inhomogeneity by bioturbation and matrix complexity of the sediment after the toxicity test could both lower the extraction precision. PMID- 22099646 TI - Novel PVC-membrane electrode for flow injection potentiometric determination of Biperiden in pharmaceutical preparations. AB - The construction and performance characteristics of Biperiden (BP) polyvinyl chloride (PVC) electrodes are described. Different methods for electrode fabrication are tested including; incorporation of BP-ion pairs (BP-IPs), incorporation of ion pairing agents, or soaking the plain electrode in BP-ion pairs suspension solution. Electrode matrices were optimized referring to the effect of modifier content and nature, plasticizer and the method of modification. The proposed electrodes work satisfactorily in the BP concentration range from 10(-5) to 10(-2)mol L(-1), with fast response time (7s) and adequate operational lifetime (28 days). The electrode potential is pH independent within the range 2.0-7.0, with good selectivity towards BP in presence of various interfering species. The developed electrodes have been applied for potentiometric determination of BP in pharmaceutical formulation under batch and flow injection analysis (FIA) conditions. FIA offers the advantages of accuracy and automation feasibility with high sampling frequency. The dissolution profile for Akineton tablets (2mg BP/tablet) was studied using the proposed electrode in comparison with the official methods. PMID- 22099647 TI - Wavelets and genetic algorithms applied to search prefilters for spectral library matching in forensics. AB - Currently, the identification of the make, model and year of a motor vehicle involved in a hit and run collision from only a clear coat paint smear left at a crime scene is not possible. Search prefilters for searching infrared (IR) spectral libraries of the paint data query (PDQ) automotive database to differentiate between similar but nonidentical Fourier transform infrared (FTIR) paint spectra are proposed. Applying wavelets, FTIR spectra of clear coat paint smears can be denoised and deconvolved by decomposing each spectrum into wavelet coefficients which represent the sample's constituent frequencies. A genetic algorithm for pattern recognition analysis is used to identify wavelet coefficients for underdetermined data that are characteristic of the model and manufacturer of the automobile from which the spectra of the clear coats were obtained. Even in challenging trials where the samples evaluated were all the same manufacturer (Chrysler) with a limited production year range, the respective models and manufacturing plants were correctly identified. Search prefilters for spectral library matching are necessary to extract investigative lead information from a clear coat paint smear; unlike the undercoat and color coat paint layers, which can be identified using the text based portion of the PDQ database. PMID- 22099648 TI - Laser-induced breakdown spectroscopy-based investigation and classification of pharmaceutical tablets using multivariate chemometric analysis. AB - We report the effectiveness of laser-induced breakdown spectroscopy (LIBS) in probing the content of pharmaceutical tablets and also investigate its feasibility for routine classification. This method is particularly beneficial in applications where its exquisite chemical specificity and suitability for remote and on site characterization significantly improves the speed and accuracy of quality control and assurance process. Our experiments reveal that in addition to the presence of carbon, hydrogen, nitrogen and oxygen, which can be primarily attributed to the active pharmaceutical ingredients, specific inorganic atoms were also present in all the tablets. Initial attempts at classification by a ratiometric approach using oxygen (~777 nm) to nitrogen (742.36 nm, 744.23 nm and 746.83 nm) compositional values yielded an optimal value at 746.83 nm with the least relative standard deviation but nevertheless failed to provide an acceptable classification. To overcome this bottleneck in the detection process, two chemometric algorithms, i.e. principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA), were implemented to exploit the multivariate nature of the LIBS data demonstrating that LIBS has the potential to differentiate and discriminate among pharmaceutical tablets. We report excellent prospective classification accuracy using supervised classification via the SIMCA algorithm, demonstrating its potential for future applications in process analytical technology, especially for fast on-line process control monitoring applications in the pharmaceutical industry. PMID- 22099649 TI - Assessment uncertainty associated to the analysis of tar from gasification of sewage sludge. AB - The uncertainty evaluation associated with the quantification of tar from gasification of sewage sludge is present. Each of the sources of uncertainty associated with the wet type sampling method and GC-MS analysis was identified to determine the critical stages of the analytical methodology in order to reduce them. The study shows that major contributions to the overall uncertainty are related to extraction steps. High expanded uncertainties were found for all compounds, due to the segregation of the tar in different samples because of the sampling method. However, the analytical method used was successfully applied for the evaluation of the tar cleaning filter in a real gasification plant. PMID- 22099650 TI - Modified gold surfaces by poly(amidoamine) dendrimers and fructose dehydrogenase for mediated fructose sensing. AB - An electrochemical biosensor for detection of fructose in food samples was developed by immobilization of fructose dehydrogenase (FDH) on cysteamine and poly(amidoamine) dendrimers (PAMAM)-modified gold electrode surface. Electrochemical analysis was carried out by using hexacyanoferrate (HCF) as a mediator and the response time was 35s at +300 mV vs. Ag/AgCl. Moreover, some parameters such as pH, enzyme loading and type of PAMAM (Generations 2, 3 and 4) were investigated. Then, the FDH biosensor was calibrated for fructose in the concentration range of 0.25-5.0mM. To evaluate its utility, the FDH biosensor was applied for fructose analysis in real samples. Finally, obtained data were compared with those measured with HPLC as a reference method. PMID- 22099651 TI - Molecularly imprinted polymers for separation of various sugars from human urine. AB - Molecularly imprinted polymers were the new, simple and unexpensive materials that can be used in several clinical applications. Phenylboronic acid has been frequently used as functional monomer for the covalent imprinting of diols. In this study, the phenylboronic acid esters of fructose, galactose, glucose and raffinose were synthesized and then used as template analytes. The adsorption capacities of fructose, galactose and glucose-phenylboronic acid imprinted polymers were 75, 10 and 30%, respectively. The batch rebinding studies and Scatchard analysis were done for all sugar imprinted polymer. Glucose is one of the mostly found sugar in the urine. The glucose:phenylboronic acid imprinted polymer was used for the analysis of glucose, fructose, galactose, sucrose, maltose, lactose and raffinose in spiked urine. The selectivity of glucose:phenylboronic acid imprinted polymer to urine monosaccharides was found as nearly 45-55% and to di- and polysaccharides was found as 30-35%, respectively. PMID- 22099652 TI - In vitro monitoring of natural thorium in urine using fluorimeter. AB - A relatively less expensive and less time consuming radio analytical technique for quantitative determination of Th(nat) in urine at mBq level is developed and reported in this paper. Th in urine is co-precipitated with Ca(3)(PO(4))(2) from wet oxidized urine matrix and the precipitate is dissolved in HNO(3) and evaporated to dryness. The residue is dissolved in 3M HCl and 200mg of Na-EDTA is added to mask Ca(2+), Mg(2+) and Fe(3+) ions. Th(4+) is extracted into 0.01M PC 88A (2-ethyl hexyl phosphonic acid mono-2-ethylhexyl ester), dissolved in toluene from the experimentally optimized pH 2.5 +/- 0.3 in aqueous phase. Th(4+) is stripped into 8.0M HCl and evaporated to dryness. The content of the beaker is dissolved in pH 1.8 HCl and complexed with 3-hydroxy flavone. The sample is excited at 397 nm and fluorescence intensity is measured at 462 nm. The detailed study of the method is presented in this paper. Interference study on elements that are normally present in urine and other actinides (if present) is also given. PMID- 22099653 TI - An adaptable automatic trace metal monitoring system for on line measuring in natural waters. AB - An adaptable automatic trace metal monitoring system (ATMS) was assembled and embedded in a mobile monitoring station belonging to the French Water Agency Artois-Picardie (AEAP) and deployed in the field to measure the concentration of trace metals (electroactive and acid leachable fractions) in natural waters by anodic stripping voltammetry with a hanging mercury drop electrode. Cathodic stripping voltammetry procedures were included to estimate the concentration of dissolved oxygen and reduced sulphur species. The concept of the measuring system enables easy adaptation of methods and procedures to analytes of concern and gives the opportunity to undertake in real-time a routine analysis of the dynamic behaviour of trace metals in river, pond and seawater. The system was tested in two aquatic bodies: in a pond where eutrophication processes occur recurrently and in the Deule River, where sediments are highly contaminated by several metals such as Pb and Zn and frequently resuspended because of the river traffic. Preliminary field studies demonstrated that trace metal concentrations can evolve quickly as a function of time, depending on the turbidity and luminescence, i.e. day-night cycles. The obtained results were compared with an Environmental Quality Standard (EQS), the Criteria Maximum Concentration (CMC) and the Criterion Continuous Concentration (CCC). The whole system is also prepared for the task of "early warning". PMID- 22099654 TI - Visual detection of organophosphorus pesticides represented by mathamidophos using Au nanoparticles as colorimetric probe. AB - With citrate-coated Au nanoparticles as colorimetric probe, a novel visual method for rapid assay of organophosphorus pesticides has been developed. The assay principle is based on catalytic hydrolysis of acetylthiocholine into thiocholine by acetylcholinesterase, which induces the aggregation of Au nanoparticles and the color change from claret-red to purple or even grey. The original plasmon absorption of Au nanoparticles at 522 nm decreases, and simultaneously, a new absorption band appears at 675 nm. The irreversible inhibition of organophosphorus pesticides on acetylcholinesterase prevents aggregation of Au nanoparticles. Under optimum conditions, the absorbance at 522 nm of Au nanoparticles is related linearly to the concentration of mathamidophos in the range of 0.02-1.42 MUg/mL with a detection limit of 1.40 ng/mL. This colorimetric method has been successfully utilized to detect mathamidophos in vegetables with satisfactory results. The proposed colorimetric assay exhibits good reproducibility and accuracy, providing a simple and rapid method for the analysis of organophosphorus pesticides. PMID- 22099655 TI - Label-free immunoassay for chloramphenicol based on hollow gold nanospheres/chitosan composite. AB - A novel label-free electrochemical immunosensor for rapid determination of chloramphenicol (CAP) was fabricated by entrapping monoclonal antibody to chloramphenicol (anti-CAP) in hollow gold nanospheres (HGNs)/chitosan composite modified on a glassy carbon electrode. The hollow gold nanospheres (HGNs) were prepared by using Co nanoparticles as sacrificial templates and characterized by transmission electron microscopy (TEM). The changes of the electrode behavior after each fabrication step were investigated by electrochemical impedance spectroscopy (EIS) technique. Under optimal conditions, the proposed immunosensor has a sensitive response to CAP in a linear range of 0.1-1000 ng mL(-1) with the detection limit of 0.06 ng mL(-1). Accurate detection of CAP in real meat samples was demonstrated by comparison with conventional HPLC method. The proposed method was proven to be a feasible quantitative method for CAP analysis with the properties of simple preparation, stability, high sensitivity and selectivity. PMID- 22099656 TI - Application of chitosan/Fe3O4 microsphere-graphene composite modified carbon ionic liquid electrode for the electrochemical detection of the PCR product of soybean Lectin gene sequence. AB - In this paper a Fe(3)O(4) microsphere, graphene (GR) and chitosan (CTS) nanocomposite material modified carbon ionic liquid electrode (CILE) was used as the platform for the construction of a new electrochemical DNA biosensor. The single-stranded DNA (ssDNA) probe was immobilized directly on the surface of the CTS/Fe(3)O(4)-GR/CILE, which could hybridize with the target ssDNA sequence at the selected conditions. By using methylene blue (MB) as the electrochemical indicator the hybridization reaction was investigated with the reduction peak current measured. By combining the specific properties such as the biocompatibility and big surface area of Fe(3)O(4) microspheres, the excellent electron transfer ability of GR, the good film-forming ability of CTS and the high conductivity of CILE, the synergistic effects of nanocomposite increased the amounts of ssDNA adsorbed on the electrode surface and then resulted in the greatly increase of the electrochemical responses. Under the optimal conditions differential pulse voltammetric responses of MB were proportional to the specific ssDNA sequences concentration in the range from 1.0*10(-12) to 1.0*10(-6)mol/L with the detection limit as 3.59*10(-13)mol/L (3sigma). This DNA biosensor showed good stability and discrimination ability to one-base and three-base mismatched ssDNA sequences. The polymerase chain reaction (PCR) product of soybean Lectin gene sequence was detected by the proposed method with satisfactory result, suggesting that the CTS/Fe(3)O(4)-GR/CILE was a suitable sensing platform for the sensitive detection of specific gene sequence. PMID- 22099657 TI - Simultaneous injection effective mixing analysis system for the determination of direct bilirubin in urinary samples. AB - A novel simultaneous injection effective mixing analysis system (SIEMA) for determination of direct bilirubin in urine sample was developed. Bilirubin reacts with diazotized sulfanilic acid in the presence of n-octyl-beta-d-thioglucoside (OTG) as a solubilizing agent to form OTG-azobilirubin. The flow and chemical variables were investigated. A linear calibration graph for direct bilirubin was obtained over the range of 0-1.0 mg L(-1) (r(2)=0.994) with the limit of detection (3sigma) of 4.7 MUg L(-1), and the relative standard deviation (RSD) being 1.9% (n=11, 0.5 mg L(-1) of direct bilirubin). The results in healthy adult urine obtained by the proposed approach were found in good agreement with those obtained by the batch-wise diazo method. PMID- 22099658 TI - SPME-GC determination of methanol as a hydrate inhibitor in crude oil. AB - This work focused on the quantitation of methanol as a hydrate inhibitor in the crude oil. The novelty is microextraction of a polar compound from a complex non polar matrix and selection of proper fiber with maximum selectivity, loading percent, and lifetime. This approach not only does not require specific instrumentation, such as multiple columns, and selective detectors, but also has eliminated the use of organic solvent and avoids the insertion of water inside the GC columns. The objective is optimization of extraction conditions, GC adjustments and data processing. Experiments were conducted on the real sample of Iranian offshore crude oil by a carboxen/PDMS fiber via a GC equipped with a cross-linked polyethylene glycol column and FID. The results revealed that this fiber adsorbed the alcohols among other light non-polar compounds of crude oil. Moreover, the interference effects of ethanol were solved by proper selection of thermal program. The LOD, LOQ and linear range of this approach were determined to be 3.9, 12.9 and 14-229 mg L(-1) for methanol, respectively. Moreover, the sensitivity was 30 area-counts per mg L(-1). Using the standard calibration and the standard addition methods, the relative errors of 1.6-7.2 and 5.3-14.0% were determined, respectively. PMID- 22099659 TI - Novel CeO2-based screen-printed potentiometric electrodes for pH monitoring. AB - Nuclear waste repositories are being installed in deep excavated rock formations in some places in Europe to isolate and store radioactive waste. In France, the Callovo-Oxfordian formation (COx) is a possible candidate for nuclear waste storage. This work investigates the applicability of CeO(2)-based oxides (CeO(2), Ce(0.8)Sm(0.2)O(2) and Ce(0.8)Zr(0.2)O(2)) for monitoring the pH of the COx pore water (T=25 degrees C). The study is limited to the pH range between 5.5 and 13.2, which includes the pH values that have been encountered or are anticipated in the COx formation during its evolution as radioactive waste repository due mainly to alkalinisation, an increase in salinity, and a decrease in redox potential. Screen-printing was done to assemble electrodes and rapidly generate data sets. The electrochemical behavior of CeO(2)-based screen-printed electrodes (CeO(2)-based SPEs) was determined by cyclic voltammetry and electrochemical impedance spectroscopy. The use of the electrodes for pH sensing was then evaluated by potentiometric measurements. The feasibility of measuring pH with CeO(2)-based SPEs was first tested in NH(4)Cl/NH(3) buffer solutions, leading to electrode calibration over the widest range of pH, from around neutral to basic pH. Experiments were then conducted in NaHCO(3)/Na(2)CO(3) buffer samples similar to conditions prevailing in the COx formation. Ce(0.8)Zr(0.2)O(2) SPEs exhibit a near-Nernstian behavior (sensitivity -(51+/-2)mV/pH) in the pH range of 5.5-13.2 at 25 degrees C. Electrode response was slightly affected by the direction of the pH change. Electrode reliability was clearly demonstrated for pH monitoring. Probes based on the same components, but more durably designed, could be considered for pH measurements in radioactive waste repositories. PMID- 22099660 TI - Discrimination and sensory description of beers through data fusion. AB - Beer samples of the same brand and commercialized as a same product, but brewed in four different factories were analyzed with three techniques, an MS e-nose, a mid-IR optical-tongue and a UV-visible, to see if the factories show differences and to find out if the differences found could be attributed to different sensory properties. The data from the three instruments were fused to improve the ability of classification with respect to the individual use of the techniques. Two levels of data fusion were studied: low and mid level fusion, and the classification was performed by linear discriminant analysis (LDA). Mid-level fusion provided better classification results (above 95% correct classification) than those of low-level fusion and also than those obtained when using the individual techniques. Moreover, by means of the score and loading plots obtained by Fisher-LDA, it was possible to interpret the chemical information provided by the three techniques, and we were able to relate the variables associated to each sensor to the main compounds responsible of the sensory perception. PMID- 22099661 TI - Application of low-temperature CP-Sil 88 column for the isomeric analysis of toxic 2,378-substituted PCDD/Fs in incinerator flyash and sewage sludge using a triple quadrupole GC-MS/MS. AB - The seventeen 2378-substituted polychlorinated dibenzo-p-dioxins and dibenzo-p furans (PCDD/Fs) congeners have been separated and analyzed in sewage sludge and incinerator flyash samples using a CP-Sil 88 column (50 m * 0.25 mm I.D., 0.25 MUm film thickness) operating at a maximum oven temperature of 240 degrees C. The column was used on a Varian 450-GC with a Varian 320-MS Triple Quadrupole. Calibration standards were used to determine the transition chemistries of the 2378-substituted PCDD/F congeners in the gas chromatography/mass spectrometry (GC MS/MS) system. The five-point calibration curve for each of the congeners showed very good linearity with R(2) values greater than 0.999. The recovery of labelled compounds ranged from 50% to 120%. Analytical results from a reference flyash (BCR-490) and a reference sewage sludge (BCR-677) compared very well with the certified values, giving percentage deviations in I-TEQ (international toxic equivalents) of 4.93% and 0.53%, respectively. Results from 'real' flyash samples underscored the level of progress made in the abatement of dioxin emissions from incinerators; the old incinerator flyash contained much higher PCDD/F concentrations than the modern one. In addition, the concentrations profiles of PCDD/Fs in the 'real' sewage sludge from two UK wastewater treatment plants (WWTPs) showed that one contained a total PCDD/Fs content of 314 ng I-TEQ kg(-1), while the other gave a total of 53 ng I-TEQ kg(-1). Over an 18-month period of operation, no significant loss of analytical performance was observed from the low-temperature column. PMID- 22099662 TI - Development of a screening method for the analysis of organic pollutants in water using dual stir bar sorptive extraction-thermal desorption-gas chromatography mass spectrometry. AB - The development of a method for screening of organic compounds with a wide range of physico-chemical properties in water, based on dual stir bar sorptive extraction coupled with thermal desorption and gas chromatography-mass spectrometry (dual SBSE-TD-GC-MS) is described. The investigated water sample is divided into two aliquots and extracted with stir bar sorptive extraction at two different conditions: using addition of methanol or sodium chloride, respectively. Following extraction, the two stir bars are inserted into the same glass thermal desorption liner and are simultaneously desorbed and analysed by GC MS. The method optimisation was performed using 45 environmentally harmful substances with different volatilities (boiling point from 193 to 495 degrees C), polarity (logK(ow) from 2.17 to 8.54) and acido-basic properties. The majority of model compounds was selected from the EU list of priority substances in the field of water policy and from the US EPA method 625, respectively. Optimisation was performed for extraction parameters (sample volume, extraction time, stirring rate, addition of modifiers) as well as for the thermal desorption conditions (desorption flow, desorption time, cryofocusing temperature). Performance characteristics (recovery, repeatability, carryover, linearity, limits of detection and quantification) were determined for the optimised method. An example of analysis of a contaminated groundwater sample is presented. PMID- 22099663 TI - Phosphate determination in seawater: toward an autonomous electrochemical method. AB - Initial steps to create an autonomous in situ electrochemical sensor for orthophosphate determination in seawater are presented. First, the optimal conditions to form the molybdophosphate complex in artificial seawater medium were determined by addition of sulphuric acid and sodium molybdate to the solution containing orthophosphate. Secondly, the anodic oxidation of molybdenum to form molybdate ions and protons was used to create the molybdophosphate complex without addition of any liquid reagents. The molybdophosphate complex is detectable by amperometry with an average precision of 2.2% for the concentration range found in the open ocean and the detection limit is 0.12 MUM. Three solutions are proposed to address the silicate interferences issue and one of these methods is used for the natural samples collected in the coastal waters offshore Peru during the Pelagico 1011-12-BIC OLAYA cruise in November-December 2010. Results showed a good precision with an average of 2.5% and a reasonable deviation of the amperometric analysis as compared with colorimetric measurements (4.9%). PMID- 22099664 TI - One-step coating of silica capillaries for selective protein retention by Cu(II) IDA IMAC. AB - A simple protocol to obtain Cu(II)-IDA (iminodiacetic acid)-modified capillaries was developed for immobilized metal ion affinity chromatography (IMAC). It consisted in the synthesis of IDA-silane used for a one-step coating of fused silica capillaries. The approach prevented the hydrolysis of silica potentially induced by two step coatings (gamma-GPTMS, then IDA) employed in the conventional method of bonding iminodiacetic acid. The IDA content was quantified using a model relating the electroosmotic flow generated in IDA-modified capillaries to the charges induced by IDA species. The retention behavior of holotransferrin and bovine serum albumin on these IMAC columns was then investigated. Holotransferrin revealed a high affinity for Cu(II)-supports through a specific interaction with Cu(II) ions whereas albumin did not show any retention. The use of such columns for sample pretreatment before an HPLC analysis was proved to be successful. PMID- 22099665 TI - Microdiffusion-based UV-LED spectrometric setup for determining low levels of ethanol in fruit juice. AB - A novel setup is described in which we combined the separation of a volatile substance from a sample with a complex matrix on the basis of a microdiffusion process with a kinetic on-line spectrometric monitoring of the reaction in the receptive medium at 365 nm. The fruit juice was selected as a model for testing the performance of the setup in real-life applications. The ethanol content in fruit juice can be considered as an indicator of the fruit-juice quality and should not exceed the regulatory limiting values. After optimising the microdiffusion process, blackcurrant, orange and two varieties of apple juice were analysed. The sample analysis lasted 15 min at 35 degrees C. The ethanol concentrations were found to be between 0.9 and 4.0 mmol/L, and were comparable to the results obtained using the SIST:ISO 2448:1998 standard method, which is time consuming, labour intensive and requires high sample volumes. The setup can easily be adapted for determining other volatile substances in low concentrations in complicated samples of different types by introducing different chemistry and replacing the light source if the light of a different wavelength is required. The measuring characteristics of the setup were critically assessed, the main sources of uncertainty recognised and the possibilities for further improvements of the setup and the procedure considered. PMID- 22099666 TI - Theil-Sen nonparametric regression technique on univariate calibration, inverse regression and detection limits. AB - This paper reports the combined use of the nonparametric Theil-Sen (TS) regression technique and of the statistics of Lancaster-Quade (LQ) concerning the linear regression parameters to solve typical analytical problems, like method comparison, calculation of the uncertainty in the inverse regression, determination of the detection limit. The results of this new approach are compared to those obtained with appropriate reference methods, using simulated and real data sets. The nonparametric Theil-Sen regression technique appears a new robust tool for the problems considered because it is free from restrictive statistical constraints, avoids searching for the error nature on x and y, which may require long analysis times, and it is easy to use. The only drawback is that the intrinsic nature of the method may lead to a possible enlargement of the uncertainty interval of the discriminated concentration and to the determination of larger detection limits than those obtainable with the commonly used, less robust, regression techniques. PMID- 22099667 TI - Amperometric biosensors based on deposition of gold and platinum nanoparticles on polyvinylferrocene modified electrode for xanthine detection. AB - In this study, new xanthine biosensors, XO/Au/PVF/Pt and XO/Pt/PVF/Pt, based on electroless deposition of gold(Au) and platinum(Pt) nanoparticles on polyvinylferrocene(PVF) coated Pt electrode for detection of xanthine were presented. The amperometric responses of the enzyme electrodes were measured at the constant potential, which was due to the electrooxidation of enzymatically produced H(2)O(2). Compared with XO/PVF/Pt electrode, XO/Au/PVF/Pt and XO/Pt/PVF/Pt exhibited excellent electrocatalytic activity towards the oxidation of the analyte. Effect of Au and Pt nanoparticles was investigated by monitoring the response currents at the different deposition times and the different concentrations of KAuCl(4) and PtBr(2). Under the optimal conditions, the calibration curves of XO/Au/PVF/Pt and XO/Pt/PVF/Pt were obtained over the range of 2.5 * 10(-3) to 0.56 mM and 2.0 * 10(-3) to 0.66 mM, respectively. The detection limits were 7.5 * 10(-4)mM for XO/Au/PVF/Pt and 6.0 * 10(-4)mM for XO/Pt/PVF/Pt. The effects of interferents, the operational and the storage stabilities of the biosensors and the applicabilities of the proposed biosensors to the drug samples analysis were also evaluated. PMID- 22099668 TI - Chemometric tools to evaluate the spatial distribution of trace metals in surface sediments of two Spanish rias. AB - A suite of relevant trace metals (Hg, Pb, Cd, Cu, Zn and Ni) was measured in surface sediment samples to assess the environmental situation of the largest two Atlantic Spanish 'rias' (a form of estuaries, ria of Pontevedra, ROP, and ria of Vigo, ROV). The level of contamination originated by these metals was assessed against international guidelines, the threshold effect, ERL, and the midrange effect, ERM. Six unsupervised and supervised multivariate chemometric techniques were applied to model each ria, compare them and select those metals that characterize the samples. This is first time that such a study is performed for these two important seafood-producing areas. Maximum concentrations at ROP occurred in the vicinities of an inner island, where Cu, Zn, Ni and Pb presented concentrations over the ERL and Hg over the ERM. Highest concentrations of metals in ROV were observed in the proximities of Vigo shipyards and port, except for Pb, with peak values in San Simon Bay. ERL limits were exceeded in the inner part of this ria for Cu, Zn and Hg and in a wider area for Pb and Ni. Levels for Pb went beyond the ERM boundary in the axial part of San Simon Bay. In general, the distribution of the metals was more homogeneous in ria of Pontevedra than in ria of Vigo (where three morphological zones were characterized). Both rias could be differentiated using only two metals: Ni and Hg, as deduced from the multivariate techniques. PMID- 22099669 TI - A copper interdigitated electrode and chemometrical tools used for the discrimination of the adulteration of ethanol fuel with water. AB - A new approach for the discrimination of the adulteration process of ethanol fuel with water is reported using a copper interdigitated electrode and chemometrical tools. The sensor was constructed using copper sheets with non-chemical modification of the electrode surface. The discrimination process was performed using capacitance values recorded at different frequencies (1,000 Hz to 0.1 MHz) as the input data for non-supervised pattern recognition methods (PCA: principal component analysis and HCA: hierarchical cluster analysis). The relative standard deviation for the capacitance signals obtained from ten independent interdigitated sensors was below 5.0%. The ability of the device to differentiate non-adulterated ethanol samples from those adulterated with water was demonstrated. In all analysed cases, there was good separation between the different samples in the score plots and the dendrograms obtained from PCA and hierarchical cluster analyses, respectively. Furthermore, the water content was quantified using a PCA approach. The results were consistent with those obtained using the Karl-Fischer method at a 95% confidence level, as measured using Student's t-test. PMID- 22099670 TI - A specific probe for two-photon fluorescence lysosomal imaging. AB - Lysosomes are vital organelles in physiological processes, as they receive and degrade macromolecules from the secretory and endocytic procedures. Evidences have shown that lysosomes were related to oncogenic activation and cancer progression, so lysosomes targeting and imaging probes make them convenient to be observed. In this study, a lysosome specific probe W-7 was designed and synthesized via convenient one-pot reaction and Heck reaction. This probe was derived from Troger's base with a dimethylaminomethyl end group. The optical properties of this compound were measured. W-7 also showed two-photon absorption (TPA) effect by using laser excitation at the wavelength of infrared light. In vivo experiment, W-7 showed high specificity and selectivity for lysosomes in living cells (HeLa cells, MRC-5 cells and NRK cells), compared with LT Red, GT Red and MT Red (R=0.96). Two-photon fluorescence images of HeLa cells stained by W-7 were obtained. And high resolution 3D reconstruction of lysosomes in one HeLa cell was provided by using two-photon confocal microscopy. The anantioseparation of racemic W-7 was carried out by chiral-HPLC, and the two enantiomers showed no significant difference in lysosomes imaging. PMID- 22099671 TI - Forced degradation study to develop and validate stability-indicating RP-LC method for the determination of ciclesonide in bulk drug and metered dose inhalers. AB - A simple, selective and precise stability-indicating reversed-phase liquid chromatographic method was developed and validated for the determination of ciclesonide. Ciclesonide was subjected to acid and alkali hydrolysis, oxidation, thermal and photo-degradation. The degradation products were well separated from the pure drug. The method was based on isocratic elution of ciclesonide and its degradation products on reversed phase C18 column (250 mm * 4.6 mm, 10 MUm) - Phenomenex using a mobile phase consisting of ethanol-water (70:30, v/v) at a flow rate of 1 mL min(-1). Quantitation was achieved with UV detection at 242 nm. Linearity, accuracy and precision were found to be acceptable over the concentration range of 5-200 MUg mL(-1). Desisobutyryl-ciclesonide was prepared by selective alkaline hydrolysis of the ester and proved to be the main degradation product. The proposed method was successfully applied to the determination of ciclesonide in bulk and in its pharmaceutical preparation. PMID- 22099672 TI - Cobalt(II) selective membrane electrode based on palladium(II) dichloro acetylthiophene fenchone azine. AB - A new cobalt(II) ion selective electrode based on palladium(II) dichloro acetylthiophene fenchone azine(I) has been developed. The best membrane composition is found to be 10:60:10:21.1 (I)/PVC/NaTPB/DOP (w/w). The electrode exhibits a Nerstian response in the range of 1.0 * 10(-1)-1.0 * 10(-6)M with a detection limit and slope of 8.0 * 10(-7)M and 29.6 +/- 0.2 mV per decade respectively. The response time is within the range of 20-25s and can be used for a period of up to 4 months. The electrode developed reveals good selectivity for cobalt(II) and could be used in pH range of 3-7. The electrode has been successfully used in the determination of cobalt(II) in water samples. PMID- 22099673 TI - Indirect determination of sulfite using a polyphenol oxidase biosensor based on a glassy carbon electrode modified with multi-walled carbon nanotubes and gold nanoparticles within a poly(allylamine hydrochloride) film. AB - The modification of a glassy carbon electrode with multi-walled carbon nanotubes and gold nanoparticles within a poly(allylamine hydrochloride) film for the development of a biosensor is proposed. This approach provides an efficient method used to immobilize polyphenol oxidase (PPO) obtained from the crude extract of sweet potato (Ipomoea batatas (L.) Lam.). The principle of the analytical method is based on the inhibitory effect of sulfite on the activity of PPO, in the reduction reaction of o-quinone to catechol and/or the reaction of o quinone with sulfite. Under the optimum experimental conditions using the differential pulse voltammetry technique, the analytical curve obtained was linear in the concentration of sulfite in the range from 0.5 to 22 MUmol L(-1) with a detection limit of 0.4 MUmol L(-1). The biosensor was applied for the determination of sulfite in white and red wine samples with results in close agreement with those results obtained using a reference iodometric method (at a 95% confidence level). PMID- 22099674 TI - An amperometric hydrogen peroxide chemical sensor based on graphene-Fe3O4 multilayer films modified ITO electrode. AB - In this article, poly(diallydimethylammonium chloride) (PDDA) functionalized graphene-Fe(3)O(4) (PDDA-G/Fe(3)O(4))(n) multilayer films were fabricated with layer-by-layer assembly of negatively charged Fe(3)O(4) nanoparticles (Fe(3)O(4) NPs) and positively charged PDDA-G through the electrostatic interaction to construct a H(2)O(2) chemical sensor. The multilayer films were characterized with UV-vis spectroscopy, atomic force microscopy and cyclic voltammetry. The participation of PDDA-G improved the catalytic ability of Fe(3)O(4) NPs due to its high surface area and excellent electric conductivity. Based on this, the obtained H(2)O(2) chemical sensor exhibited prominent electrocatalytic activity for the detection of H(2)O(2) with a wide linear range from 20 MUM to 6.25 mM, a rapid response upon the addition of H(2)O(2) and a low detection limit of 2.5 MUM with the signal to noise ratio of three. Furthermore, the fabricated nonenzymatic H(2)O(2) chemical sensor exhibited excellent stability and reproducibility. PMID- 22099675 TI - Rapid determination of pyridine derivatives by dispersive liquid-liquid microextraction coupled with gas chromatography/gas sensor based on nanostructured conducting polypyrrole. AB - Polypyrrole (PPy) gas sensor has been prepared by polymerization of pyrrole on surfaces of commercial polymer fibers in the presence of an oxidizing agent. The sensing behavior of PPy gas sensor was investigated in the presence of pyridine derivatives. The resistive responses of the PPy gas sensor to pyridine derivatives were in the order of quinoline>pyridine>4-methyl pyridine and 2 methyl pyridine. The PPy gas sensor was used as gas chromatography (GC) detector and exhibited linear responses to pyridine derivatives in the ranges 40-4,000 ng. Dispersive liquid-liquid microextraction (DLLME) combined with GC/PPy gas sensor has been developed for simultaneous determination of pyridine derivatives and quinoline. The purposed method was used for determination of pyridine derivatives from cigarette smoke. The GC runs were completed in 4 min. The reproducibility of this method is suitable and good standard deviations were obtained. RSD value is less than 10% for all analytes. PMID- 22099676 TI - Hydride generation in-atomizer collection atomic absorption spectrometry for the determination of antimony in acetic acid leachates from pewter cups. AB - Antimony is one of the constituents of pewter, an alloy composed of a minimum of 90% tin with the balance being made up with copper, antimony and perhaps some bismuth. A method has been developed to determine Sb in acetic acid leachates from pewter cups. The employed instrumentation, an atomic absorption spectrometer, equipped with a quartz trap-and-atomizer device, is simple and relatively inexpensive with low running costs. Interferences due to the presence of tin and ways to control them were investigated in detail. The applied approach made possible to overcome potentially serious interference of Sn leached from the cup material (which was shown to take place in the atomizer), by a combination of (i) high concentration of HCl, which decreases the efficiency of stannane generation and (ii) in-atomizer collection. The resulting Sn tolerance limit was between 10 and 20 mg L(-1). The advantages of the in-atomizer collection are a lower tin interference in the atomizer, and a much better limit of detection (LOD), which makes possible reducing the atomization interference further by working with more diluted sample solutions. Besides the Sn interference, an interference of an unknown volatile compound transported to the atomizer together with stibine was identified in the measured sample solutions. This interference could be controlled using the analyte addition technique. The applicability of the method was tested on solutions containing a wide range of interferents leached from the pewter cups, obtained at leaching times between 1 and 24h. The LOD in the sample solutions was found to be 0.03 MUg L(-1) Sb. PMID- 22099677 TI - Synthesized mercaptopropyl nanoporous resins in DGT probes for determining dissolved mercury concentrations. AB - 3-Mercaptopropyl functionalized SBA-15 (SH-SBA) and 3-mercaptopropyl functionalized ethenylene bridged periodic mesoporous organosilica (SH-PMO) were included in a Diffusive Gradients in Thin film (DGT) probe and compared to similar commercially available resins also containing thiol functional groups, such as Sumichelate Q10R (SQR) and 3-mercaptopropyl functionalized silica gel (SH KG), and also to the Chelex-100 resin for the determination of labile Hg concentrations. An agarose gel was used as the diffusive gel because the classic polyacrylamide gel shows more than 20% of Hg adsorption. According to our results, the Chelex-100 resin presents a much lower affinity for Hg than the thiol based resins. The non-linear accumulation profile of mercury with time for the Chelex-100 resin makes it in fact impossible to use Fick's law for estimating the diffusion coefficient of Hg. The 4 other resins all show a linear accumulation profile of Hg with time. Although the highest accumulation rate is observed for SH-PMO followed by SQR, SH-SBA and SH-KG, these values do not differ very much. PMID- 22099678 TI - Comparison of two derivatization reagents for the simultaneous determination of organolead and organomanganese compounds using solid-phase microextraction followed by gas chromatography with atomic emission detection. AB - Two procedures for the simultaneous determination of organolead (tetraethyllead, triethyllead and trimethyllead) and organomanganese compounds (cyclopentadienyl manganese tricarbonyl (CMT) and methylcyclopentadienyl manganese tricarbonyl (MMT)) are studied. Both procedures involve sample preconcentration by solid phase microextraction and capillary gas chromatography coupled to atomic emission detection, the main difference being the derivatizing agent used for the ionic alkylated lead species: sodium tetrapropylborate (NaBPr(4)) and sodium tetraphenylborate (NaBPh(4)). The parameters affecting the derivatization and preconcentration steps, chromatographic separation as well as detection of the compounds were optimized. Higher sensitivity was attained for all compounds with the method involving propylation derivatization. In this case, detection limits ranged between 0.04 and 0.1 ng L(-1), depending on the compound. Detection limits of between 0.1 and 24.5 ng L(-1) were obtained, when using phenylation derivatization. A low CMT concentration was found in one of the seawater samples analyzed. PMID- 22099679 TI - Dual fluorescence and electrochemical detection of the organophosphorus pesticides--ethion, malathion and fenthion. AB - Organophosphorus (OP) based pesticides are known powerful inhibitors of cholinesterases, thus the toxicity of this class of compounds causes serious environmental and human health concerns. We report that benzodipyrido[3,2-a:2',3' c]phenazine (BDPPZ) and 3,6-dimethylbenzodipyrido-[3,2-a:2',3'-c]phenazine (DM BDPPZ) provide independent fluorescent and electrochemical signal transductions in the presence of the organophosphorus (OP) pesticides; fenthion, malathion and ethion. The presence of the methyl groups at the 3 and 6 positions in DM-BDPPZ was found to significantly influence the sensor performance. The difference in the fluorescence and electrochemical signals produced by the interaction of the sensor compound with each of the OP pesticides provides a means for differentiating between the three pesticides. Detection limits of 10(-8)M, 10(-9) and 10(-12)M were obtained for fenthion, malathion and ethion, respectively. Due to the high sensitivity and ability to minimize false positives these new sensors will be useful for potential integration for future environmental use. PMID- 22099680 TI - Analytical method development using functionalized polysulfone membranes for the determination of chlorinated hydrocarbons in water. AB - In this study, functionalized polysulfone membrane has been utilized as a sorbent for the extraction of chlorinated hydrocarbons (CHCs) in water samples. Two different functionalized polysulfones (i) phosphonic acid functionalized polysulfone (PPSU-A) with different forms (cross-linked and non cross-linked) membranes and (ii) phosphonic ester functionalized polysulfone (PPSU-E) with different forms (cross-linked and non cross-linked) were evaluated for the extraction of CHCs in water. A 10 ml of spiked water sample was extracted with 50mg piece of the functionalized membrane. After extraction, the membrane was desorbed by organic solvent and the extract was analyzed by gas chromatography mass spectrometry. Eight CHCs, 1,3,5-trichlorobenzene (1,3,5-TCB), 1,2,3 trichlorobenzene (1,2,3-TCB), 1,1,2,3,4,4-hexachloro-1,3-butadiene (HCBD), 1,2,4 trichloro-3-methylbenzene (TCMB), 1,2,3,4-tetrachlorobenzene (1,2,3,4-TeCB), 1,2,4,5-tetrachlorobenzene (1,2,4,5-TeCB), pentachlorobenzene (PeCB) and hexachlorobenzene (HCB) were used as model compounds. Experimental parameters such as extraction time, desorption time, types of polymer membrane as well the nature of desorption solvent were optimized. Using optimum extraction conditions calibration curves were linear with coefficients of determination between 0.9954 and 0.9999 over wide range of concentrations (0.05-100 MUgl(-1)). The method detection limits (at a signal-to-noise ratio of 3) were in the range of 0.4-3.9 ng l(-1). The proposed method was evaluated for the determination of CHCs in drinking water samples. PMID- 22099681 TI - Thermo-optical determination of vapor pressures of TNT and RDX nanofilms. AB - Accurate thermodynamic parameters of thin films of explosives are important for understanding their behavior in the nanometer scale as well as in standoff detection. Using UV-absorbance spectroscopy technique, accurate thermodynamic parameters such as activation energies of sublimation, sublimation rates, and vapor pressures of the explosives cyclotrimethylenetrinitramine (RDX) and 2,4,6 trinitrotoluene (TNT) were determined. The values of these parameters are in excellent agreement with those reported using traditional experiments based on gravimetry. In terms of the Clapeyron equation, the dependence of RDX and TNT vapor pressures on temperature can be described by the relations LnP (Pa)=39.6 15459/T (K) and LnP (Pa)=34.9-12058/T (K), respectively. Heats of sublimation of RDX and TNT were also determined to be 128kJ/mol and 100.2kJ/mol, respectively. PMID- 22099682 TI - Selectivity coefficients of ion-selective magnesium electrodes used for simultaneous determination of magnesium and calcium ions. AB - Membrane ion-selective magnesium electrodes are commonly used to determine ionized magnesium concentration in blood serum and intracellular fluid by potentiometric clinical analyzers. The selectivity of these electrodes against calcium ion is typically insufficient to avoid calcium interference in blood serum analysis. For this reason the selectivity coefficient for calcium ion has to be studied to make possible any mathematical corrections for calcium ion influence. Existing methods relate to the thermodynamic concept of ISE response which suggest a single constant value of the selectivity coefficient and slope that are stable over the concentration ranges of calcium and magnesium ions in the samples. Unfortunately, this rarely happens, and we rather observe dependences on solution and membrane composition, readout time, matrices (anticoagulant, vial coats) that justify usage of apparent selectivities and slopes. To get the practical insight into the response of magnesium ion-selective electrodes a novel method for estimating the selectivity coefficients and the slope of the electrode characteristics is proposed. This method is an effective starting point for selecting electrodes and designing transient signal software in a potentiometric clinical analyzer. The method allows obtaining the ionized magnesium concentration in blood serum with minimal possible error by addressing the assessed targets, i.e. apparent selectivity and slope. The method is based on computer simulation and on the Nicolsky-Eisenman equation. Usually only a few iterations are needed to obtain stable congruent results. The method presented is particularly useful in conditions where is not possible to obtain calibration curve, which is typical for clinical analyzer where at most three point calibration is performed. PMID- 22099683 TI - Magnetic beads-based electrochemical immunosensor for detection of pseudorabies virus antibody in swine serum. AB - A novel magnetic electrochemical immunosensor has been developed for the detection of pseudorabies virus antibody in swine serum. The magnetic glass carbon electrode was fabricated to manipulate magnetic beads for the direct sensing applications. Magnetic beads were employed as the platforms for the immobilization and immunoreaction process, and gold nanoparticles were chosen as electroactive labels for the electrochemical detection. The parameters concerning the assay strategy were carefully investigated. Under the optimal conditions, the linear response range of pseudorabies virus antibody dilution ratio (standard positive serum) was 1:250 to 1:1000 with a detection limit of 1:1000. Finally, this developed immunoassay method was successfully applied in the detection of pseudorabies virus antibody in swine serum, and had a good diagnostic accordance in comparison with ELISA. PMID- 22099684 TI - Expanding the linear dynamic range for multiple reaction monitoring in quantitative liquid chromatography-tandem mass spectrometry utilizing natural isotopologue transitions. AB - We describe a method for expanding the linear dynamic range for multiple reaction monitoring (MRM) in quantitative liquid chromatography/tandem mass spectrometry (LC-MS/MS) using additional transitions for isotopologues. In addition to the regular transition for the highest possible sensitivity, a transition corresponding to the less abundant isotopologue ions was utilized. This decreases saturation at the ion detector; the sensitivity reduction increases the upper dynamic limit. We demonstrated this for a rat plasma assay for a candidate flavor compound; the linear dynamic range increased by an order of magnitude from 3 to 6,000 ng/mL with the regular MRM alone to 3-60,000 ng/mL using additionally the isotopologue transition. PMID- 22099685 TI - Comments on "recognition of molecularly imprinted polymers for a quaternary alkaloid of berberine". PMID- 22099686 TI - Metabolic syndrome in obese adolescents is associated with risk for nephrolithiasis. AB - OBJECTIVES: To examine the relationship between urinary pH and metabolic syndrome risk factors along with insulin resistance in obese adolescents, and to evaluate the relationship between other urinary stone-forming and -inhibiting markers and metabolic syndrome. STUDY DESIGN: A total of 46 obese adolescents were enrolled. Twenty-four hour and randomly obtained urine samples were analyzed for urinary pH, promoters of stone formation (ie, uric acid, oxalate, and relative saturation ratio of calcium oxalate [RSR-CaOx]), and inhibitors of stone formation (ie, citrate and osteopontin). Other data collected included height, weight, blood pressure, and fasting lipid, insulin, and glucose levels. RESULTS: The subjects had a mean age of 14.6+/-2.0 years and a mean body mass index of 36+/-6.3 kg/m(2). Random urine pH and the number of risk factors for metabolic syndrome were negatively correlated (r=-0.34; P=.02). RSR-CaOx was correlated with both homeostasis model assessment of insulin resistance score (r=0.38; P<.01) and number of risk factors for metabolic syndrome (r=0.47; P=.001) CONCLUSION: Decreased urinary pH and increased RSR-CaOx are associated with risk factors for metabolic syndrome in obese adolescents. PMID- 22099687 TI - 2009 influenza A in infants hospitalized at younger than 6 months. AB - OBJECTIVE: To describe the clinical characteristics and outcomes of infants hospitalized at <6 months of age with 2009 influenza A infection. STUDY DESIGN: Prospective laboratory surveillance and discharge International Classification of Disease, 9th edition codes for influenza infection were used to identify all infants hospitalized at <6 months of age with positive influenza A tests at Children's Medical Center Dallas from April 27, 2009 to March 23, 2010. Retrospective chart review then was performed. RESULTS: Seventy-three infants aged <6 months were hospitalized with laboratory-confirmed influenza A infection at a median age of 48 days (range, 3-179 days). The most common clinical characteristics were fever and respiratory signs, and 53% were given a bolus of intravenous fluid. Median length of hospitalization was 2 days (range, 1-162 days). Twenty (27%) infants developed influenza-related complications, including pneumonia (n = 3), hypoxia (n = 18), seizures (n = 2), need for intensive care (n = 8), or death (n = 2). Oseltamivir was administered to 60 (82%) infants and was well tolerated. CONCLUSIONS: The majority of infants hospitalized with 2009 influenza A had community-acquired infection that was associated with short hospital stays and favorable short-term outcomes. Complications including death occurred, emphasizing the need for preventive strategies. PMID- 22099688 TI - Rathke cleft cyst as cause of growth hormone deficiency in a 9-year-old girl. PMID- 22099689 TI - Co nanoparticle hybridization with single-crystalline Bi nanowires. AB - Crystalline Co nanoparticles were hybridized with single-crystalline Bi nanowires simply by annealing Co-coated Bi nanowires at elevated temperatures. An initially near-amorphous Co film of 2-7 nm in thickness began to disrupt its morphology and to be locally transformed into crystallites in the early stage of annealing. The Co film became discontinuous after prolonged annealing, finally leading to isolated, crystalline Co nanoparticles of 8-27 nm in size. This process spontaneously proceeds to reduce the high surface tension and total energy of Co film. The annealing time required for Co nanoparticle formation decreased as annealing temperature increased, reflecting that this transformation occurs by the diffusional flow of Co atoms. The Co nanoparticle formation process was explained by a hole agglomeration and growth mechanism, which is similar to the model suggested by Brandon and Bradshaw, followed by the nanoparticle refinement. PMID- 22099691 TI - Genetic and phenotypic consequences of introgression between humans and Neanderthals. AB - Strong evidence for introgression of Neanderthal genes into parts of the modern human gene pool has recently emerged. The evidence indicates that some populations of modern humans have received infusions of genes from two different groups of Neanderthals. One of these Neanderthal groups lived in the Middle East and Central Europe and the other group (the Denisovans) is known to have lived in Central Asia and was probably more widespread. This review examines two questions. First, how were these introgressions detected and what does the genetic evidence tell us about their nature and extent? We will see that an unknown but possibly large fraction of the entire Neanderthal gene complement may have survived in modern humans. Even though each modern European and Asian carries only a few percent of genes that can be traced back to Neanderthals, different individuals carry different subgroups of these introgressed genes. Second, what is the likelihood that this Neanderthal genetic legacy has had phenotypic effects on modern humans? We examine evidence for and against the possibility that some of the surviving fragments of Neanderthal genomes have been preserved by natural selection, and we explore the ways in which more evidence bearing on this question will become available in the future. PMID- 22099690 TI - Sensory functions for degenerin/epithelial sodium channels (DEG/ENaC). AB - All animals use a sophisticated array of receptor proteins to sense their external and internal environments. Major advances have been made in recent years in understanding the molecular and genetic bases for sensory transduction in diverse modalities, indicating that both metabotropic and ionotropic pathways are important in sensory functions. Here, I review the historical background and recent advances in understanding the roles of a relatively newly discovered family of receptors, the degenerin/epithelial sodium channels (DEG/ENaC). These animal-specific cation channels show a remarkable sequence and functional diversity in different species and seem to exert their functions in diverse sensory modalities. Functions for DEG/ENaC channels have been implicated in mechanosensation as well as chemosensory transduction pathways. In spite of overall sequence diversity, all family members share a unique protein topology that includes just two transmembrane domains and an unusually large and highly structured extracellular domain, that seem to be essential for both their mechanical and chemical sensory functions. This review will discuss many of the recent discoveries and controversies associated with sensory function of DEG/ENaC channels in both vertebrate and invertebrate model systems, covering the role of family members in taste, mechanosensation, and pain. PMID- 22099692 TI - Genomic approaches to understanding Hox gene function. AB - For many years, biologists have sought to understand how the homeodomain containing transcriptional regulators encoded by Hox genes are able to control the development of animal morphology. Almost a century of genetics and several decades of molecular biology have defined the conserved organization of homeotic gene clusters in animals and the basic molecular properties of Hox transcription factors. In contrast to these successes, we remain relatively ignorant of how Hox proteins find their target genes in the genome or what sets of genes a Hox protein regulates to direct morphogenesis. The recent deployment of genomic methods, such as whole transcriptome mRNA expression profiling and genome-wide analysis of protein-DNA interactions, begins to shed light on these issues. Results from such studies, principally in the fruit fly, indicate that Hox proteins control the expression of hundreds, if not thousands, of genes throughout the gene regulatory network and that, in many cases, the effects on the expression of individual genes may be quite subtle. Hox proteins regulate both high-level effectors, including other transcription factors and signaling molecules, as well as the cytodifferentiation genes or Realizators at the bottom of regulatory hierarchies. Insights emerging from mapping Hox binding sites in the genome begin to suggest that Hox binding may be strongly influenced by chromatin accessibility rather than binding site affinity. If this is the case, it indicates we need to refocus our efforts at understanding Hox function toward the dynamics of gene regulatory networks and chromatin epigenetics. PMID- 22099693 TI - GATA transcription factors in the developing reproductive system. AB - Previous work has firmly established the role for both GATA4 and FOG2 in the initial global commitment to sexual fate, but their (joint or individual) function in subsequent steps remained unknown. Hence, gonad-specific deletions of these genes in mice were required to reveal their roles in sexual development and gene regulation. The development of tissue-specific Cre lines allowed for substantial advances in the understanding of the function of GATA proteins in sex determination, gonadal differentiation and reproductive development in mice. Here we summarize the recent work that examined the requirement of GATA4 and FOG2 proteins at several critical stages in testis and ovarian differentiation. We also discuss the molecular mechanisms involved in this regulation through the control of Dmrt1 gene expression in the testis and the canonical Wnt/beta-catenin pathway in the ovary. PMID- 22099694 TI - [A rare cause of arterial hypertension in children: Takayasu arteritis]. AB - Takayasu arteritis, a nonspecific inflammatory arteritis, is particularly rare in children. We report the case of a 6-year-old girl presenting with severe arterial hypertension in the upper segment associated with an inflammatory syndrome. Investigations showed coarctation of the abdominal aorta at different levels, due to Takayasu arteritis. The patient was treated with percutaneous dilatation and stent implantation as well as prolonged anti-inflammatory therapy. Arterial hypertension in children needs to be investigated until its cause, which may be rare, such as Takaysu arteritis, is determined. PMID- 22099696 TI - [PELVIS or LUMBAR syndrome: the same entity. Two case reports]. AB - INTRODUCTION: The association of a pelvic hemangioma and malformations in the pelvic region are described as SACRAL or PELVIS syndrome. More recently, the acronym of LUMBAR syndrome has been used to describe the association of lower body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies. We report herein 2 representative cases. PATIENTS: Two girls presented with infantile hemangioma associated with genital malformation. One case was associated with spinal anomalies and the other one with the anus in the genital position. CONCLUSION: Segmented hemangiomas are commonly associated with extracutaneous abnormalities. By analogy with PHACE syndrome, PELVIS/SACRAL/LUMBAR syndromes describe the association of segmented hemangioma of the lower extremities associated with other trunk or lower-body malformations. The syndrome is often incomplete. PMID- 22099697 TI - Orthostatic hypotension: a common, serious and underrecognized problem in hospitalized patients. AB - Orthostatic hypotension (OH) is strongly age-dependent, with a prevalence ranging from 5% to 11% in middle age to 30% or higher in the elderly. It is also closely associated with other common chronic diseases, including hypertension, congestive heart failure, diabetes mellitus, and Parkinson's disease. Most studies of OH have been performed in population cohorts or elderly residents of extended care facilities, but in this review, we draw attention to a problem little studied to date: OH in hospitalized patients. The prevalence of OH in all hospitalized patients is not known because most studies have included only older individuals with multiple comorbid diseases, but in some settings as many as 60% of hospitalized adults have postural hypotension. Hospitalized patients are particularly vulnerable to the consequences of OH, particularly falls, because postural blood pressure (BP) regulation may be disturbed by many common acute illnesses as well as by bed rest and drug treatment. The temporal course of OH in hospitalized patients is uncertain, both because the reproducibility of OH is poor and because conditions affecting postural BP regulation may vary during hospitalization. Finally, OH during hospitalization often persists after discharge, where, in addition to creating an ongoing risk of falls and syncope, it is strongly associated with risk of incident cardiovascular complications, including myocardial infarction, heart failure, stroke, and all-cause mortality. Because OH is a common, easily diagnosable, remediable condition with important clinical implications, we encourage caregivers to monitor postural BP change in patients throughout hospitalization. PMID- 22099698 TI - Planer orientation of the bilateral semicircular canals in dizzy patients. AB - OBJECTIVE: Recent development of 3-dimensional analysis of eye movement enabled to detect the eye rotation axis, which is used to determine the responsible semicircular canal(s) in dizzy patients. Therefore, the knowledge of anatomical orientation of bilateral semicircular canals is essential, as all 6 canals influence the eye movements. SUBJECTS AND METHODS: Employing the new head coordinate system suitable for MR imaging, we calculated the angles of semicircular canal planes of both ears in 11 dizzy patients who had normal caloric response in both ears. RESULTS: The angles between adjacent canal pairs were nearly perpendicular in both ears. The angle between the posterior canal planes and head sagittal plane was 51 degrees and significantly larger the angle between the anterior canal planes and head sagittal plane, which was 35 degrees . The angle between the horizontal canal plane and head sagittal plane was almost orthogonal. Pairs of contralateral synergistic canal planes were not parallel, forming 10 degrees between right and left horizontal canal planes, 17 degrees between right anterior and left posterior canal planes and 19 degrees between the right posterior and left anterior canal planes. CONCLUSION: Our measurement of the angles of adjacent canal pairs and the angle between each semicircular canal and head sagittal plane coincided with those of previous reports obtained from CT images and skull specimens. However, the angles between contralateral synergistic canal planes were more parallel than those of previous reports. PMID- 22099699 TI - Endoscopic sinus surgery: a safe procedure among the less experienced surgeons? AB - OBJECTIVES: To determine the incidence of complications in endoscopic sinus surgery (ESS), in a surgical centre with 20 years of experience, and whether or not the surgeon's experience can be a predisposing factor for them to happen. METHODS: The clinical data of the 667 patients who were submitted to EES between January of 2006 and December 2009, was reviewed, and the perioperative and postoperative complications were evaluated, with a minimum follow up period of 3 months. For each surgery, the surgeon's experience as well as surgery particularities, were correlated with the presence of complications. RESULTS: In the 677 surgeries, the incidence of complications was of 7.39% (5.91% minor and 1.48% major). There was no correlation between surgery complications and the years of experience of the main surgeon. When comparing the complication rate between residents and specialists, there were no statistically significant differences between them. Extensive surgeries, revision surgeries and the presence and grade of polyposis, were associated with a higher rate of complications. CONCLUSIONS: ESS is not a risk free procedure. Complications can happen regardless of the surgeons experience. Patients who are submitted to surgery by residents, under the supervision of a senior doctor, are not at greater risks of complications. PMID- 22099700 TI - Retinal vessel segmentation using a multi-scale medialness function. AB - Recently, automated segmentation of retinal vessels in optic fundus images has been an important focus of much research. In this paper, we propose a multi-scale method to segment retinal vessels based on a weighted two-dimensional (2D) medialness function. The results of the medialness function are first multiplied by the eigenvalues of the Hessian matrix. Next, centerlines of vessels are extracted using noise reduction and reconnection procedures. Finally, vessel radii are estimated and retinal vessels are segmented. The proposed method is evaluated and compared with several recent methods using images from the DRIVE and STARE databases. PMID- 22099701 TI - Structural alphabet motif discovery and a structural motif database. AB - This study proposes a general framework for structural motif discovery. The framework is based on a modular design in which the system components can be modified or replaced independently to increase its applicability to various studies. It is a two-stage approach that first converts protein 3D structures into structural alphabet sequences, and then applies a sequence motif-finding tool to these sequences to detect conserved motifs. We named the structural motif database we built the SA-Motifbase, which provides the structural information conserved at different hierarchical levels in SCOP. For each motif, SA-Motifbase presents its 3D view; alphabet letter preference; alphabet letter frequency distribution; and the significance. SA-Motifbase is available at http://bioinfo.cis.nctu.edu.tw/samotifbase/. PMID- 22099702 TI - Intron identification approaches based on weighted features and fuzzy decision trees. AB - Current computational predictions of splice sites largely depend on the sequence patterns of known intronic sequence features (ISFs) described in the classical intron definition model (IDM). The computation-oriented IDM (CO-IDM) clearly provides more specific and concrete information for describing intron flanks of splice sites (IFSSs). In the paper, we proposed a novel approach of fuzzy decision trees (FDTs) which utilize (1) weighted ISFs of twelve uni-frame patterns (UFPs) and forty-five multi-frame patterns (MFPs) and (2) gain ratios to improve the performances in identifying an intron. First, we fuzzified extracted features from genomic sequences using membership functions with an unsupervised self-organizing map (SOM) technique. Then, we brought in different viewpoints of globally weighting and crossly referring in generating fuzzy rules, which are interpretable and useful for biologists to verify whether a sequence is an intron or not. Finally, the experimental results revealed the effectiveness of the proposed method in improving the identification accuracy. Besides, we also implemented an on-line intronic identifier to infer an unknown genomic sequence. PMID- 22099703 TI - Pretreatment of microcrystalline cellulose in organic electrolyte solutions for enzymatic hydrolysis. AB - BACKGROUND: Previous studies have shown that the crystalline structure of cellulose is negatively correlated with enzymatic digestibility, therefore, pretreatment is required to break down the highly ordered crystalline structure in cellulose, and to increase the porosity of its surface. In the present study, an organic electrolyte solution (OES) composed of an ionic liquid (1-allyl-3 methylimidazolium chloride ([AMIM]Cl)) and an organic solvent (dimethyl sulfoxide; DMSO) was prepared, and used to pretreat microcrystalline cellulose for subsequent enzymatic hydrolysis; to our knowledge, this is the first time that this method has been used. RESULTS: Microcrystalline cellulose (5 wt%) rapidly dispersed and then completely dissolved in an OES with a molar fraction of [AMIM]Cl per OES (chi [AMIM]Cl) of greater than or equal to 0.2 at 110 degrees C within 10 minutes. The cellulose was regenerated from the OES by precipitation with hot water, and enzymatically hydrolyzed. As the chi [AMIM]Cl of the OES increased from 0.1 to 0.9, both the hydrolysis yield and initial hydrolysis rate of the regenerated cellulose also increased gradually. After treatment using OES with chi [AMIM]Cl of 0.7, the glucose yield (54.1%) was 7.2 times that of untreated cellulose. This promotion of hydrolysis yield was mainly due to the decrease in the degree of crystallinity (that is, the crystallinity index of cellulose I). CONCLUSIONS: An OES of [AMIM]Cl and DMSO with chi [AMIM]Cl of 0.7 was chosen for cellulose pretreatment because it dissolved cellulose rapidly to achieve a high glucose yield (54.1%), which was only slightly lower than the value (59.6%) obtained using pure [AMIM]Cl. OES pretreatment is a cost-effective and environmentally friendly technique for hydrolysis, because it 1) uses the less expensive OES instead of pure ionic liquids, 2) shortens dissolution time, 3) requires lower energy for stirring and transporting, and 4) is recyclable. PMID- 22099704 TI - Prodromes and coping types in bipolar patients with nonpsychotic or psychotic mania. AB - BACKGROUND: Bipolar disorder is a recurrent and cyclical illness frequently accompanied by psychotic symptoms. Detecting prodromes and enhancing coping skills for prodromal symptoms in bipolar patients are very important for relapse prevention. Psychotic features in bipolar patients are related to poor prognosis. We aimed to investigate the differences in prodromal symptoms and coping styles in psychotic and nonpsychotic bipolar patients. METHODS: Eighty-three euthymic bipolar patients with or without a history of manic psychosis were interviewed about their demographic, diagnostic, and clinical information and completed a 40 item checklist for prodromal symptoms. After the interview, they completed the Coping Inventory for Prodromes of Mania. RESULTS: The differences between the psychotic patients and the nonpsychotic patients were found in the prodromal durations, and a few prodromal symptoms such as afraid of going crazy (P = .03), energetic-very active (P = .01), and hearing hallucination (P = .02). The psychotic patients showed a higher score of denial or blame than the nonpsychotic ones (1.92 +/- 0.73 in nonpsychosis, 2.32 +/- 0.84 in psychosis; P = .03). Logistic regression revealed that the duration of prodromes (P = .02) and hearing hallucination (P = .01) were related to the presence of psychotic features. CONCLUSION: Psychotic patients had a tendency to use denial or blame coping strategy and to experience attenuated psychotic symptoms a little more during the prodromal period. Timely psychosocial approaches for detecting signs and enhancing coping strategies would improve the outcomes. PMID- 22099705 TI - The first report of uncontrollable subchorionic and retroplacental haemorrhage inducing preterm labour in complete PAI-1 deficiency in a human. PMID- 22099706 TI - The inhibition of the integrin VLA-4 in MV3 melanoma cell binding by non anticoagulant heparin derivatives. AB - INTRODUCTION: The integrin VLA-4-mediated binding is important for the metastatic dissemination of melanoma cells. Recently we found that heparin possesses a binding capacity to VLA-4. This could contribute to the heparin function to attenuate metastasis in a selectin-dependent manner. Aiming to a purposive, anti adhesive heparin application, structural requirements of heparin for VLA-4 recognition have to be elucidated. MATERIALS AND METHODS: A series of non anticoagulant heparin derivatives were investigated concerning their inhibitory capacities for VLA-4 mediated binding of human melanoma MV3 cells to VCAM-1 under physiological flow conditions in vitro. A surface acoustic wave biosensor was applied to detect kinetic constants of selected derivatives binding to both, VLA 4 or P- and L-selectin. RESULTS: Experimental metastasis of MV3 cells in mice confirmed the relevance of VLA-4 for metastatic dissemination. LMWHs (enoxaparin, tinzaparin) efficiently blocked VLA-4 cell binding, dominantly via the integrin's alpha-chain. Desulfation at 2-O-position, N-acetylation or a size smaller than tetradecasaccharide disfavoured VLA-4 inhibition. Glycol-splitting of heparin and thus higher chain flexibility is a tolerable parameter. A derivative with 50% 6-O desulfation appeared promising and exceeded tinzaparin in VLA-4 inhibition, both compounds displayed binding affinities to VLA-4 in the low micromolar range. CONCLUSIONS: These findings provide structure-activity relationships for heparin VLA-4 binding, which partly differ from P- and L-selectin requirements. The data confirm that anti-coagulative and anti-adhesive function of heparin can be distinguished favouring applications of non-anticoagulant heparins in antimetastatic approaches without the risk of bleeding complications. The 50% 6-O desulfated heparin-derivative appears promising to further evaluate the interference with selectin and VLA-4 binding functions in vivo. PMID- 22099707 TI - Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis. AB - INTRODUCTION: Circulating tissue factor positive microparticles (MPTF) were reported in a wide range of diseases with thrombotic tendency. Though D-dimer assay had a high negative predictive value for deep venous thrombosis (DVT) recurrence, there are currently no reliable positive predictors for recurrent DVT. We therefore quantified MPTF in patients with acute recurrent DVT to determine whether MPTF levels could be used to predict recurrent DVT. MATERIALS AND METHODS: Microparticles (MPs) were isolated from plasma of initial DVT patients (n=25), recurrent DVT patients (n=25) and sex- and age-matched healthy individuals (n=25), stained with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed against tissue factor (TF), and analyzed by flow cytometry. We also determined the plasma procoagulant activity with a Human TF Chromogenic Activity Assay Kit. RESULTS: We found total MPTF to be elevated in recurrent DVT patients versus normal individuals (P=0.001). The number of monocyte-derived MPTF in both initial and recurrent DVT was higher than in normal individuals (P<0.01, respectively). The platelet and endothelial cell derived MPTF in recurrent DVT were significantly increased relative to other MPTF (P<0.05), although there was no difference between initial DVT patients and normal individuals. We demonstrated elevated procoagulant activity of platelet free plasma in DVT patients relative to normal individuals, and a positive correlation with MPTF. CONCLUSIONS: The elevated MPTF could be a potentially predictor for DVT recurrence. Further studies are needed to validate its sensitivity and specificity. PMID- 22099708 TI - Health care reform: 2012 update. AB - The recent landmark health care reform legislation seeks to expand health insurance coverage, change incentives, and improve the quality and flow of information. This article reviews the elements of health care reform most relevant to clinical gastroenterology, discusses the ongoing challenges that health care reform legislation faces, and considers the potential implications for clinical practice. PMID- 22099709 TI - Impact of health care reform on the independent GI practice. PMID- 22099710 TI - Impact of health care reform on academic medical centers. AB - The impact of health care reform on academic medical centers will be just as great as it is on community practices. The economics of academic medical centers and training programs has been challenging, and will become even more so as funding is cut and the demand for regional integrated systems mounts. This article is one of the first to articulate these challenges and is written by authors well positioned to understand this arena. PMID- 22099711 TI - Gastroenterologists and accountable care organizations. AB - Within the Patient Protection and Affordable Care Act of 2010 is a provision setting up a program for the implementation of accountable care organizations (ACOs). This article explains the proposed ACO model and discusses major implications regarding this model of health care reform including the following: What will it take to implement the program successfully? What are the opportunities for savings under the model? What are the potential downfalls of the program as proposed? What impact would the implementation of an ACO have on the practice of gastroenterology? PMID- 22099712 TI - Electronic medical records and the gastroenterologist. AB - This is an age of disruptive innovation in health care in which the business model is changing. Fee-for-service, volume-based systems are being replaced by fixed-fee, value-based systems. One of the major facilitating forces behind this change has been the development of the electronic health record, which is providing the medical community with the ability to have real-time quality metrics that will drive the development of web-based clinical decision support tools that will transform the current peer-review-based rules of practice with an eclectic fluid environment of continuous quality measurement and improvement. PMID- 22099713 TI - A letter to fellows: transitioning from training into practice in uncertain times. AB - The end of training marks the beginning of learning. Moving into practice is exciting, and there are good opportunities. Although there is still a great deal of uncertainty with the economy, you have a skill set that is in demand. By understanding your real priorities, being deliberate and organized in your search, and being willing to extend outside your comfort zone, you will find a practice that fits you. Each person has an ideal practice. Choose your new practice setting with your eyes wide open, especially regarding new changes that are expected with health care reform. PMID- 22099714 TI - Medical practice integration: going big in private practice. AB - Historically, gastroenterologists entered into solo, small group, or academic practices. The current economic environment and looming regulatory mandates have led to gastroenterologists integrating into large, single-specialty groups to acquire costly practice infrastructure, gain negotiating leverage with health plans, promote high-quality care, and benefit from professional practice management. Individual gastroenterologists must assess whether a large practice will meet their personal goals, financial needs, and professional visions. The decision to integrate into a large practice will also be affected by local practice patterns and regulatory issues. For these and other reasons, gastroenterologists are going big in private practice. PMID- 22099715 TI - Gastroenterologists and the triple aim: how to become accountable. AB - US medicine is fragmented and economically unsustainable and has vast opportunities for quality improvement. A current solution is to create large accountable care organizations. Fragmentation should be reduced and clinical coordination be improved, which means that gastroenterologists and other specialists will be challenged to change practices from traditional reactive and consultative care to a principal care model in which they manage appropriate clinical service lines. The pay-off in improved patient care and financial stability can be substantial. This article discusses a proposed evolution toward clinical service line management that might be achieved by an independent single specialty practice. PMID- 22099716 TI - The impact of health reform on gastroenterology reimbursement. AB - The budgetary impact of the cost of health care on the United States economy is far-reaching. An understanding of the provisions in the Affordable Care Act is essential to preparing one's practice to proactively deal with a rapidly changing and evolving system whereby local, regional, and national actions are affecting the ability of clinicians to maintain success on a daily basis. PMID- 22099717 TI - The impact of health care reform on innovation and new technology. AB - Health care reform has created special challenges and hurdles to the introduction of new technology and innovative medical devices in gastroenterology and other medical fields. The implication of new regulations will be enormous as we begin to see venture-capital funding flee our specialty for more lucrative and "sure bets." This article, written by an experienced entrepreneur and practicing gastroenterologist, outlines some of the implications of this emerging challenge. Few other sources of information are available that truly articulate the insider view of coming changes. PMID- 22099718 TI - The gastroenterologist and industry: changing winds. AB - The medical device and pharmaceutical industry is facing mounting pressure to produce cost-effectiveness and clinical-effectiveness data in order for their products to be acceptable for approval by the Federal Drug Administration and then for payer reimbursement. The implications of these increasing burdens on our field will become apparent in everyday practice. This article outlines these challenges and discusses possible ways to improve the situation. PMID- 22099719 TI - Demonstrating value: registries and beyond. AB - Patient registries have evolved to support goals within medical specialties that have traditionally fallen outside their core missions. Quality measurement and reporting can support payor advocacy, meet federal and state requirements, evolve practices into novel care environments, and facilitate coordination among multiple health care providers. Registries can additionally be of use in safety and event monitoring, and supporting comparative effectiveness research. Through integration with electronic health records, registries also serve as a vehicle for the delivery of guidelines and the implementation of decision support and care pathways. PMID- 22099720 TI - American Gastroenterological Association's Clinical Congress. Foreword. PMID- 22099721 TI - The practice of Gastroenterology and the practice of United States medicine. Preface. PMID- 22099722 TI - Cognitive behaviour therapy and supportive therapy for bipolar disorders: relapse rates for treatment period and 2-year follow-up. AB - BACKGROUND: The efficacy of adjunctive psychosocial interventions such as cognitive behaviour therapy (CBT) for bipolar disorder (BD) has been demonstrated in several uncontrolled and controlled studies. However, these studies compared CBT to either a waiting list control group, brief psycho-education or treatment as usual (TAU). Our primary aim was to determine whether CBT is superior to supportive therapy (ST) of equal intensity and frequency in preventing relapse and improving outcome at post-treatment. A secondary aim was to look at predictors of survival time. METHOD: We conducted a randomized controlled trial (RCT) at the Department of Psychology, University of Tubingen, Germany (n=76 patients with BD). Both CBT and ST consisted of 20 sessions over 9 months. Patients were followed up for a further 24 months. RESULTS: Although changes over time were observed in some variables, they were not differentially associated with CBT or ST. CBT showed a non-significant trend for preventing any affective, specifically depressive episode during the time of therapy. Kaplan-Meier survival analyses revealed that 64.5% of patients experienced a relapse during the 33 months. The number of prior episodes, the number of therapy sessions and the type of BD predicted survival time. CONCLUSIONS: No differences in relapse rates between treatment conditions were observed, suggesting that certain shared characteristics (e.g. information, systematic mood monitoring) might explain the effects of psychosocial treatment for BD. Our results also suggest that a higher number of prior episodes, a lower number of therapy sessions and a diagnosis of bipolar II disorder are associated with a shorter time before relapse. PMID- 22099723 TI - GM-CSF-induced regulatory T cells selectively inhibit anti-acetylcholine receptor specific immune responses in experimental myasthenia gravis. AB - We and others have demonstrated the ability of granulocyte-macrophage colony stimulating factor (GM-CSF) to suppress autoimmunity by increasing the number of CD4(+)CD25(+) regulatory T cells (Tregs). In the current study, we have explored the critical role of induced antigen specific Tregs in the therapeutic effects of GM-CSF in murine experimental autoimmune myasthenia gravis (EAMG). Specifically, we show that Tregs from GM-CSF treated EAMG mice (GM-CSF/AChR-induced-Tregs) adoptively transferred into animals with EAMG suppressed clinical disease more potently than equal numbers of Tregs from either GM-CSF untreated EAMG mice or healthy mice treated with GM-CSF. In addition, GM-CSF/AChR-induced-Tregs selectively suppressed antigen specific T cell proliferation induced by AChR relative to that induced by an irrelevant self antigen, (thyroglobulin) and failed to significantly alter T cell proliferation in response to an exogenous antigen (ovalbumin). These results are consistent with the hypothesized mechanism of action of GM-CSF involving the mobilization of tolerogenic dendritic cell precursors which, upon antigen (AChR) capture, suppress the anti-AChR immune response through the induction/expansion of AChR-specific Tregs. PMID- 22099724 TI - Case report of a male primary breast carcinoma of axillary accessory mammary gland. PMID- 22099725 TI - A multidisciplinary team approach to hydroxyurea-associated chronic wound with squamous cell carcinoma. AB - Hydroxyurea (HU) has been shown to induce a variety of cutaneous adverse reactions, including severe leg ulcers. This report shows a successful treatment of a HU-induced chronic wound associated with squamous cell carcinomas (SCC). A 62-year-old patient affected with polycythemia vera and treated with HU for 10 years, presented with a non healing ulcer on a left heel. The patient gave a history of suffering from the wound for over 2 years. Biopsy showed evidence of invasive SCC. The patient underwent Mohs surgery and a greater saphenous vein ablation for polycythemia vera-associated vascular complications. The wound consistently decreased in size following successive debridements and coverage with human skin equivalent. The wound healed completely after a 6-month period. A multidisciplinary team approach to the treatment proved to be effective resulting in healing of this multifactorial chronic ulcer. PMID- 22099726 TI - Parents' ability to recall past injuries to maxillary primary incisors in their children. AB - AIM: To evaluate the ability of parents to recall past injuries to their children's maxillary primary incisors. MATERIALS AND METHODS: Clinical and radiographic trauma-related major and minor signs observed in the first dental visit of 727 preschool children were recorded. Major signs included crown fracture, coronal discoloration, internal resorption, pulp canal obliteration, swelling, fistula, and periapical lesion. Minor signs included enamel cracks, sensitivity to percussion, dull or metallic sound on percussion, increased mobility, and widened periodontal ligament. Children were divided into groups: CT = certainly traumatized (presenting with at least one major sign or a combination of three minor signs), PT = probably traumatized (presenting with one or two minor signs) and NT = not traumatized. Accompanying parents were asked to recall past injuries to their children's teeth. Possible replies were 'no', 'yes' and 'probably yes'. Disagreement when both parents were present was recorded as 'yes'. Crown fractures involving dentin, coronal discoloration, swelling and fistula were defined as 'observable signs of trauma'. RESULTS: One-hundred and eighteen children were accompanied by fathers, 411 by mothers and 198 by both. The CT group comprised 464 children; the PT group, 103; and the NT group, 160, with no statistically significant differences by gender. Parents' positive recall was similar for boys (33.3%) and girls (31.0%). Mothers recalled trauma in 32.6% and fathers in 27.1% of their children. Parents failed to recall trauma in 52.6% of the CT-group children and in 43.5% of the PT-group children. Parents failed to recall trauma in 37.6% of the children who had observable signs of trauma. CONCLUSIONS: Parents' recall of dental trauma occurring in their children's maxillary primary incisors was reliable in <50% of the cases. PMID- 22099727 TI - New perspectives in the treatment of metastatic renal cell carcinoma. AB - Since 2007, the advent of so-called "targeted" therapy has revolutionized the management of renal cell carcinoma (RCC), replacing interferon or interleukin-2 immunotherapy. The present article first reviews the fundamentals of current practice in the management of metastatic-phase RCC. It then goes on to consider the new perspectives opening up in terms of treatment strategy (sequential or combined treatments and new drugs) in what can be seen as a second phase in this ongoing revolution in treatment. In the years to come, the challenge will be to learn to optimize the use of the many drugs available, possibly in association with micro-invasive techniques, so as to achieve the third phase of the revolution: long-term remission in metastatic RCC. The search for factors predictive of response and greater knowledge of tumor biology will be essential steps, yet to be made, toward this goal. PMID- 22099729 TI - Mood disorders. PMID- 22099730 TI - Premature thelarche in infants and toddlers: prevalence, natural history and environmental determinants. AB - STUDY OBJECTIVE: The aim of this study was to measure the prevalence of premature thelarche in infant and toddler girls and to determine if environmental sources of estrogen were associated with early breast development. DESIGN: Observational with mixed methods: Retrospective chart review, cross-sectional component involving an interview survey, along with longitudinal follow-up of girls with thelarche up to six months. SETTING: A general pediatric clinic within a teaching hospital located in a large Midwestern city. PARTICIPANTS: Girls, between the ages of 12 and 48 months, and their mothers, presenting for well-child care. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of premature thelarche; association of premature thelarche with selected environmental exposures. RESULTS: Among the 318 subjects, the overall prevalence of premature thelarche was measured at 4.7% (n = 15). The prevalence by race/ethnicity was 4.2% among White Non-Hispanics, 4.6% among Blacks and 6.5% among White Hispanics. The peak prevalence occurred between 12-17 months of age. All thelarche cases were Tanner stage 2. No statistically significant relationship was found between premature thelarche and environmental exposures. Upon follow-up, 44% of the cases of premature thelarche had persistent breast development. CONCLUSIONS: Our study demonstrated a higher prevalence of premature thelarche than has been previously reported. This study lacked power because of the small number of premature thelarche cases, the ubiquitous presence of environmental exposure as well as the potentially small effect of each environmental factor. Future studies need to employ a very large sample in order to accurately analyze the relationship between environmental toxicants and premature thelarche. PMID- 22099731 TI - Obstetric and perinatal outcomes of teenage pregnancies in Thailand. AB - STUDY OBJECTIVE: To determine whether, when controlling for confounding factors, there was still an association of adolescence with adverse outcomes. DESIGN: Retrospective case control study. SETTING: Seven Bangkok Metropolitan Administration General Hospitals. PARTICIPANTS: Charts of all women aged 19 and younger (n = 1,354) having singleton live births in 2004, 2005, and 2006 were retrieved. For the adult group, 1,389 charts of mothers between the ages of 20 and 34 delivering singleton babies were selected using proportionate systematic random sampling. Maternal age was divided into 3 groups: 11-15, 16-19, and 20-34. MAIN OUTCOME MEASURES: Obstetric and perinatal outcomes. RESULTS: After statistically controlling for known confounding factors, teenage pregnancy was associated with increased risks of anemia (11-15: AOR = 1.81, P < 0.001; 16-19: AOR = 1.48, P < 0.01), very preterm deliveries (11-15: AOR = 2.18, P < 0.05), very low birth weight babies (11-15: AOR = 6.98, P < 0.05; 16-19: AOR = 9.86, P < 0.01), newborn admission to Intensive Care Unit (11-15: AOR = 1.93, P < 0.01; 16 19: AOR = 2.10, P < 0.01), and postpartum complications (11-15: AOR = 3.33, P < 0.01). The rates of cesarean delivery (11-15: AOR 0.58, P < 0.01; 16-19: AOR = 0.57, P < 0.01), operative delivery (11-15: AOR = 0.49, P < 0.01), and oxytocin augmentation (16-19: AOR = 0.66, P < 0.01) were less frequent in younger mothers. CONCLUSION: Independent of known confounding factors, teenage pregnancy was associated with increased risks of adverse maternal and neonatal outcomes requiring clinical and outreach interventions from health care providers. PMID- 22099732 TI - Advance provision of emergency contraception in an urban pediatric emergency department. AB - STUDY OBJECTIVE: To assess whether a policy and educational intervention in an urban, pediatric emergency department (ED) increases advance provision of emergency contraception (EC) to patients. DESIGN/SETTING/PARTICIPANTS: A pre- and post-intervention, retrospective chart review was conducted in an urban, pediatric ED assessing provider care of sexually active female adolescents and young adults. INTERVENTION/MAIN OUTCOME MEASURES: A policy was instituted recommending that ED providers prescribe EC and provide an educational handout to all sexually active female adolescents and young adults. ED providers were educated about EC and this policy. Charts, subsequently reviewed, included sexually active female patients, age 13-21 years, presenting to the ED status post sexual assault, seeking EC, or with an abdominal, gynecologic, or urologic complaint. Student's t-tests, Pearson's chi-square and Fisher's Exact tests compared pre- and post-intervention provider and patient characteristics and outcomes. RESULTS: The mean age of the patient sample was 18.8 years (SD=1.7), 83% were Black or Hispanic, 43% were previously pregnant, 25% reported not using birth control. Last unprotected sexual intercourse was not documented for 87% of patients presenting with medical complaints. There was no difference in the advance prescribing of EC or the provision of the educational handout to patients pre- (3.3%) or post- (5.6%) intervention (P = 0.73). CONCLUSIONS: Despite a policy and an educational intervention for providers, little change occurred in advance EC prescribing in an urban, pediatric ED. Additionally, many providers were not documenting last unprotected sexual intercourse, potentially missing an opportunity to treat patients with EC at the time of their visit. PMID- 22099733 TI - A comparison of the prevalence of premenstrual dysphoric disorder and comorbidities among adolescents in the United States of America and Nigeria. AB - STUDY OBJECTIVE: Premenstrual dysphoric disorder (PMDD) often starts in adolescence, but there are limited data on its prevalence. The specific aims of this study were to (1) describe the prevalence of PMDD in adolescents presenting to clinics in the midwestern United States and 2 Nigerian cities, (2) identify cultural differences, and (3) screen for comorbidities. DESIGN: A cross-sectional survey was conducted among adolescents attending outpatient clinics in the 3 sites. Study participants provided demographic information and completed a modified version of the Premenstrual Symptoms Screening Tool. They also completed the modified Mini International Neuropsychiatric Interview screen for comorbid psychiatric conditions. RESULTS: Five-hundred thirty-seven patients participated in the study. The participants were between 13-21 years old (mean [SD] =16.9 [2.02] years). The overall prevalence of PMDD was 4.1% (Maiduguri, Nigeria 6.5%; Lagos, Nigeria 3.1%; and 2.9% in Akron, United States). The differences were not statistically significant (P = .167). The prevalence of moderate to severe premenstrual syndrome ranged from 12.4%-16.3% among the 3 sites, with an overall prevalence of 14.5%. There was a significantly higher prevalence of other mood disorders in Akron (19.3%) compared to the Nigerian sites (P < .001.). This difference across cultures was statistically significant. CONCLUSIONS: Premenstrual dysphoric disorder is prevalent across different cultures. It is a chronic condition that causes significant morbidity among adolescents. There is a need for simple diagnostic methods for early detection and evidence-based management guidelines. PMID- 22099734 TI - Teenage pregnancy and the influence of paternal involvement on fetal outcomes. AB - STUDY OBJECTIVE: We sought to assess the impact of paternal involvement on adverse birth outcomes in teenage mothers. DESIGN: Using vital records data, we generated odds ratios (OR) and 95% confidence intervals (CI) to assess the association between paternal involvement and fetal outcomes in 192,747 teenage mothers. Paternal involvement status was based on presence/absence of paternal first and/or last name on the birth certificate. SETTING: Data were obtained from vital records data from singleton births in Florida between 1998 and 2007. PARTICIPANTS: The study population consisted of 192,747 teenage mothers <= 20 years old with live single births in the State of Florida. MAIN OUTCOME MEASURES: Low birth weight, very low birth weight, preterm birth, very preterm birth, small for gestational age (SGA), neonatal death, post-neonatal death, and infant death. RESULTS: Risks of SGA (OR = 1.06; 95% CI: 1.03-1.10), low birth weight (OR = 1.19; 95% CI: 1.15-1.23), very low birth weight (OR = 1.53; 95% CI: 1.41-1.67), preterm birth (OR = 1.21; 95% CI: 1.17-1.25), and very preterm birth (OR = 1.49; 95% CI: 1.38-1.62) were elevated for mothers in the father-absent group. When results were stratified by race, black teenagers in the father-absent group had the highest risks of adverse birth outcomes when compared to white teenagers in the father-involved group. CONCLUSIONS: Lack of paternal involvement is a risk factor for adverse birth outcomes among teenage mothers; risks are most pronounced among African-American teenagers. Our findings suggest that increased paternal involvement can have a positive impact on birth outcomes for teenage mothers, which may be important for decreasing the racial disparities in infant morbidities. More studies assessing the impact of greater paternal involvement on birth outcomes are needed. PMID- 22099739 TI - Chloramine reduction by reverse osmosis membranes. PMID- 22099740 TI - Network of contacts between cattle herds in a French area affected by bovine tuberculosis in 2010. AB - France attained 'Officially Tuberculosis-Free' status in 2000. However, the Cote d'Or department (a French administrative unit) has since seen an increase in bovine tuberculosis (bTB) cases, with 35% of cases attributed to neighbourhood contamination. The aim of this study was to investigate the characteristics of neighbourhood contacts in an area affected by bTB in 2010, through the use of social network methods. We carried out a survey to determine the frequency and distribution of between-herd contacts in an area containing 22 farms. Contacts were weighted, as not all types of contact carried the same risk of bTB transmission. Cattle movement was considered to be associated with the highest risk, but was not observed within the studied area during the study period. Contact with wild boars was the most frequent type of contact, but was associated with a very low risk. Direct cattle-to-cattle contacts in pasture and contacts with badger latrines were less frequent, but entailed a greater risk of M. bovis transmission. Centrality values were heterogeneous in these two networks. This would enable the disease to spread more rapidly at the start of epidemics than in a perfect randomly mixed population. However, this situation should also result in the total number of infected herds being smaller. We attributed 95% of the contacts to direct contact in pasture or contact with wild boars or badger latrines. Other kinds of contact occurred less frequently (equipment sharing, cattle straying) or did not occur at all (attendance at a show). Most of the contact types were correlated, but none was sufficient in itself to account for all contacts between one particular farm and its neighbours. Contacts with neighbours therefore represent a challenge for the implementation or improvement of control measures. PMID- 22099741 TI - [Safety and effectiveness of salvage therapy in HIV patients]. AB - INTRODUCTION: The treatment used after failure of at least two lines of antiretroviral treatment in HIV patients is called salvage therapy. The study aims to describe the characteristics of HIV patients subjected to such a regimen, and determine the safety and effectiveness of treatment with tipranavir (TPV), darunavir (DRV), enfuvirtide (ENF) and etravirine (ETR) combined with an optimised antiretroviral regimen. PATIENTS AND METHODS: HIV patients treated with ENF, TPV, DRV or ETR in a tertiary hospital infectious diseases department subjected to at least 12 weeks treatment. The patient characteristics are described and the effectiveness, durability and adherence to the treatment analysed. RESULTS: There were 28 patients studied, with an average of 10 treatment regimens prior to starting salvage therapy (SD=3.5; 95% CI, 8.9-11.1). A total of 85.7% patients had treatment adherence >90%. For ENF, 70.8% of the treatment lines were suspended during follow-up. After salvage therapy, the percentage of patients with viral load (VL) <400 copies/ml doubled, and cases with undetectable CV (<50 copies/ml) almost tripled. The treatments used did not change the liver or kidney profiles; however, they changed the lipid profile and increased the percentage of patients with hyperglycaemia. CONCLUSIONS: The salvage therapy studied was effective. Good adherence to the therapy is critical for its effectiveness. PMID- 22099742 TI - Perinatal and psychosocial circumstances associated with risk of attempted suicide, non-suicidal self-injury and psychiatric service use. A longitudinal study of young people. AB - BACKGROUND: Past studies using large population based datasets link certain perinatal circumstances (birth weight, parity, etc) with mental health outcomes such as suicide, self-harm and psychiatric problems. Problematically, population datasets omit a number of social confounds. The aim of this study is to replicate past research linking perinatal circumstances and mental health (suicidality and use of psychiatric services) and to determine if such associations remain after adjusting for social circumstances. METHODS: A longitudinal school-based survey of 2157 young people (surveyed at age 11, 13, 15) followed up in early adulthood (age 19). At age 11 parents of participants provided information about perinatal circumstances (birth weight, birth complications, etc.) and psychiatric service use. Participants provided data about their mental health at age 15 (attempted suicide, suicidal thoughts) and at ages 19 (self-harm, psychiatric service use). In addition, data were collected about their social and psychosocial circumstances (gender, deprivation, religion, sexual behaviour, etc.). RESULTS: Predictably, social factors were linked to mental health outcomes. For example, those with same sex partners were more likely (OR 4.84) to self-harm than those without a same sex partner. With a single exception, in both unadjusted and adjusted models, perinatal circumstances were not or only marginally associated with mental health outcomes. The exception was the number of birth complications; young people with two or more complications were approximately 2-3 times more likely than those without complications to use psychiatric services. CONCLUSIONS: While we failed to replicate results found using large population based datasets, some of our results are compatible with prior research findings. Further, evidence from this study supports the influence of perinatal circumstances (birth complications) on later psychiatric problems, or at least higher than expected contact with psychiatric service. PMID- 22099743 TI - The relationship between glutathione peroxidase and bioimpedance parameters in nondiabetic hemodialysis patients. AB - There is growing evidence from experimental and clinical studies that oxidative stress is involved in the pathogenesis of malnutrition. This cross-sectional study aimed to investigate the relationship between glutathione peroxidase (GPx) levels as a marker of antioxidant status and the nutritional status assessed by bioimpedance analysis (BIA). Ninety-seven nondiabetic stable outpatient uremic adults undergoing chronic hemodialysis (HD) were recruited for this study. Impedance measurements were performed using a multifrequency bioelectrical impedance analyzer after dialysis. GPx levels correlated with intracellular water (ICW) (r = 0.341, P = 0.011), ICW/total body weight (r = 0.320, P = 0.017), lean body mass (r = 0.300, P = 0.026) and total body cell mass (r = 0.339, P = 0.011). When patients were divided into two groups according to mean GPx levels (83.9 U/gr hemoglobin), the patients with higher GPx (GPx > 83.9 U/gr hemoglobin) had higher albumin (P = 0.038), lean body mass (P = 0.026), ICW (P = 0.011), and total body cell mass (P = 0.011) compared with those with lower GPx (GPx <= 83.9 U/gr hemoglobin). Furthermore, in the patients with higher GPx, body fat; extracellular water/total body water; illness marker and body fat mass index were lower than other group. In conclusion, our results reveal correlation indicating a relationship between antioxidant status (as measured by GPx) and nutritional status as assessed by BIA in nondiabetic HD patients. PMID- 22099745 TI - High-mobility group box 1 expressions in hypoxia-induced damaged mouse islets. AB - INTRODUCTION: Discovering a new, accurate, and useful damage marker for isolated islets is critical for avoiding the transplantation of nontherapeutic preparations. Recently, we have reported that islets that contained uniquely high levels of high-mobility group box 1 (HMGB1) protein and cytokine induced damaged islets released HMGB1 in a mouse model. Islets are frequently exposed to hypoxic conditions during organ procurement, organ transportation, islet isolation, and islet storage before transplantation. In the present study, we analyzed HMGB1 expressions in hypoxia-induced damaged mouse islets. METHODS: Damaged mouse islets were generated by hypoxic conditions (1% O2, 5% CO(2), and 94% N(2)). HMGB1 expressions and production levels were assessed by quantitative real-time polymerase chain reaction (PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA) studies. In vivo islet function was analyzed using transplantation assay using streptozotocin-induced diabetic mice. RESULTS: HMGB1 was mainly stained in the nucleus in the intact islets; however, HMGB1 was present in not only the nucleus, but also the cytoplasm in hypoxia-induced damaged islets. HMGB1 messenger RNA (mRNA) levels were up-regulated in the hypoxia-induced damaged islets, suggesting that HMGB1 was intentionally generated during hypoxia. HMGB1 protein levels in the islets were gradually decreased with time under hypoxic conditions. The amount of released HMGB1 levels and the amount of released HMGB1 levels per hour were significantly increased in damaged (noncurable) islets. CONCLUSIONS: When islets were damaged by hypoxic condition, HMGB1 was synthesized and released from hypoxia-induced damaged islets. The amount of released HMGB1 and/or the amount of released HMGB1 per hour might be a useful marker for detecting damaged islets and might be used for islet potency assay. PMID- 22099746 TI - An effective method to release human islets from surrounding acinar cells with agitation in high osmolality solution. AB - INTRODUCTION: Islet purification is mainly performed by the density gradient method. However, purification of the embedded islets that are surrounded by exocrine tissue should be difficult, because their density is similar to exocrine tissue. In this study, we performed chart review to assess the relationship between the ratio of embedded islets and efficacy of purification. Then, we tested several conditions of a new method to free the islets from surrounded exocrine tissues using high osmolality solution with gentle agitation. MATERIALS AND METHODS: First, we performed chart review of our human islet isolation. Second, embedded islet-enriched human islet fractions (embedded islets >50%) were suspended in University of Wisconsin (UW) solution (UW group, 320 mOsm/kg/H(2)0) or osmolality-adjusted UW solution (400, 500, and 600 mOsm/kg/H(2)0; 400 group, 500 group, and 600 group, respectively). Each tube was gently shaken at 4 degrees C. The tissue samples were taken before shaking and after 15, 30, and 60 minutes. Islet yield, percentage of embedded islets, and viabilities were assessed. RESULTS: The chart review revealed that high ratio of embedded islets deteriorated the efficacy of islet purification. The islet yield in all groups except for the 600 group did not change at 15 minutes, but it decreased in all groups at 60 minutes. The average percentage of embedded islets before shaking was 62.6%. Although percentage of embedded islets were decreasing in all groups, it was < 20% at 15 minutes in the 500 and 600 groups whereas it was >44% in the UW group, which indicated that higher osmolality would have a greater effect. Viability was >95% in all groups at 30 minutes. CONCLUSIONS: The embedded islets deteriorated the efficacy of islet purification. Gentle agitation of embedded islets in high osmolality (500 mOsm/kg/H(2)O, 15 minutes) could release islets from surrounded exocrine tissue. PMID- 22099747 TI - Coculture of hepatocytes with islets. AB - Bioartificial liver support (BAL) systems are potential new therapeutic approaches for use as liver support to prevent nutrient deficiencies, hypoxia, or ischemia before the acquisition of donated organs. To investigate whether islets are beneficial for hepatocyte function and survival, we cocultured BALB/c mouse islets with C57BL/6J hepatocytes to assess hepatocyte viability, function, and apoptosis. We observe cell viability to decrease progressively by 50% from day 0 to day 3 among isolated hepatocytes (group A) and hepatocytes cocultured with islets (group B). However, group A was prone to necrosis and reduced albumin secretion during culture. In contrast, at day 7 group B maintained albumin secretion (0.3351 +/- 0.0581 vs 0.1451 +/- 0.0329 MUg/h/mL; P < .05). Early apoptosis was observed at day 3 among group A but at day 7 in group B. In addition, quantitative analysis of the apoptotic cells revealed group B to show a delayed phenotype of both early and late apoptosis compared with group A. Our results indicated that islets could retain hepatocyte function and delay apoptosis, suggesting that the coculture system is potentially applicable to develop a high-performance BAL. PMID- 22099748 TI - Characterization and functional assessment of Clostridium histolyticum class I (C1) collagenases and the synergistic degradation of native collagen in enzyme mixtures containing class II (C2) collagenase. AB - OBJECTIVES: Clostridium histolyticum expresses two classes of collagenases, C1 and C2. However, degradation of these enzymes by proteases during the fermentation or purification process may lead to numerous molecular forms that lead to inconsistent release of islets from human pancreata. This report defines the amino acid sequence of the truncated forms of C1 (C1b or C1c) that contain a single collagen-binding domain (CBD) and investigates the synergy between the different forms of C1 collagenase and C2 to degrade native collagen. METHODS: Highly purified collagenase isoforms were purified from C. histolyticum culture supernatants using established column chromatography techniques and analyzed using high-pressure liquid chromatograph (HPLC), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry (MS). The collagen-degrading activity (CDA) assay was used to investigate the synergy between different collagenase molecular forms. RESULTS: MS was used to confirm the sequence of full-length C2 and C1 from the reported gene sequence. These results were correlated with the molecular weights observed on the SDS- PAGE and elution after analytical anion-exchange HPLC. HPLC peaks designated as C1b and C1c were both confirmed to be C1 lacking the terminal CBD. The only difference being the cleavage site leading to a 12 amino acid difference between the two forms. A non-additive synergy in CDA relative to activity of individual collagenases was observed for C2 with each of the three C1 molecular forms. The C1 molecular forms did not display this synergy in the absence of C2. CONCLUSIONS: These observations support earlier reports that suggest the two collagenases bind to different portions of the collagen and have different specificities to cut native collagen. Although the implications of this are not yet understood, they are fundamental in advancing the understanding of how collagenases work together along with the neutral protease to breakdown the extracellular matrix for islet isolation. PMID- 22099749 TI - Effect of synthetic protease inhibitor gabexate mesilate on attenuation of coagulant activity and cytokine release in a rat model of islet transplantation. AB - BACKGROUND: The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of coagulation cascade plays a key role, is one of the serious obstacles to successful islet engraftment. Gabexate mesilate (GM) is well known to elicit anticoagulant and antiinflammatory effects. The aim of this study was to evaluate the effect of GM on syngeneic IBMIR. METHODS: Syngeneic rat islet grafts (2.5 IEQ/g) were transplanted intraportally into 2 groups (control group and GM group; n = 10-11) of streptozotocin-induced diabetic rats. The GM group was injected intravenously with GM for 30 minutes before islet infusion to 1 hour after. The control group was injected with equivalent amount of saline solution. Plasma samples were collected before and 0.5, 1, 3, 6, and 24 hours after transplantation, and several proinflammatory mediators, including interleukin-6 and high-mobility group Box 1 were measured. Curative rate, intravenous glucose tolerance test, and insulin amount in the recipients' livers were also evaluated. RESULTS: Little difference was observed in any proinflammatory mediators. Whereas none of the animals in the control group became normoglycemic, 2 of 6 rats transplanted with the same number of islets in the GM group became normoglycemic during the study period. The glucose tolerance response was significantly ameliorated in the GM group compared with the control group (P < 0.001). The insulin amount in the liver of the recipients was considerably higher in the GM group (5.6 +/- 4.1 vs 12.6 +/- 5.3 ng/IEQ; P < .05). CONCLUSIONS: These data suggest that GM improves islet engraftment not through suppressing the proinflammatory cytokines but as an anticoagulant. We therefore think that GM could be a useful anticoagulant to control IBMIR induced in clinical islet transplantation, although antiinflammatory reagents are considered to be needed for the ideal regimen. PMID- 22099750 TI - Expression of receptors for anaphylatoxins C3a and C5a on rat islet preparations. AB - BACKGROUND: Complement activation has been implicated in the development of the instant blood-mediated inflammatory reaction (IBMIR). In particular, anaphylatoxins C3a and C5a elicit a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. We have previously shown that 2 types of receptors for C5a are expressed on isolated islets. In the present study, we investigated this component in detail. METHODS: C3aR, C5aR, and C5L2, together with CD11b and CD31, on freshly isolated islets (fresh group) and islets cultured with (cytokine group) or without (culture group) TNF-alpha, IL-1beta, and IFN-gamma for ~12 hours were analyzed by flow cytometry. In addition, these 3 kinds of receptors were analyzed on nonendocrine cells. RESULTS: C5aR and C5L2 were expressed on the isolated islets (C5aR: 7.91 +/- 2.83%; C5L2: 2.45 +/- 1.34%) and the expression of both C5a receptors was markedly attenuated by culture for 12 hours (C5aR: P < .005; C5L2: P < .05). Compared with the culture group, the expression was significantly up-regulated in the cytokine group (C5aR: P < .05; C5L2: P = .05). C5aR-positive cells expressed CD11b but not CD31. In contrast to islets, nonendocrine cells expressed C5L2 predominantly. C3aR was scarcely expressed on isolated islets or nonendocrine cells. CONCLUSIONS: These data suggest that C5aR and C5L2 are expressed on CD11b positive leukocytes in islet preparations. Depletion of C5a receptors by culturing appropriately could be an attractive therapeutic strategy in clinical islet transplantation. PMID- 22099751 TI - Cryo-isolation: a novel method for enzyme-free isolation of pancreatic islets involving in situ cryopreservation of islets and selective destruction of acinar tissue. AB - BACKGROUND: A critical component of treating type I diabetes by transplantation is the availability of sufficient high-quality islets. Currently, islets can be obtained only by reliance on an expensive, inconsistent, and toxic enzyme digestion process. As an alternative, we hypothesize that cryobiologic techniques can be used for differential freeze destruction of the pancreas to release islets that are selectively cryopreserved in situ. METHODS: Pancreases were procured from juvenile pigs with the use of approved procedures. The concept of cryo isolation is based on differential processing of the pancreas in 5 stages: 1) infiltrating islets in situ preferentially with a cryoprotectant (CPA) cocktail via antegrade perfusion of the major arteries; 2) retrograde ductal infusion of water (or saline solution) to fully distend the gland; 3) freezing the entire pancreas to -160 degrees C, and stored in liquid nitrogen; 4) mechanically crushing and pulverizing the frozen pancreas into small fragments; and 5) thawing, filtering and washing the frozen fragments with RPMI 1640 culture medium to remove the CPA. Finally, the filtered effluent (cryo-isolate) was stained with dithizone for identification of intact islets, and samples were taken for static glucose-stimulated insullin release assessment. RESULTS: As predicted the cryo isolated contained small fragments of residual tissue comprising an amorphous mass of acinar tissue with largely intact embedded islets. The degree of cleavage of the cryoprotected islets from the freeze-destroyed exocrine cells, was variable. Islets were typically larger than their counterparts isolated from juvenile pigs with conventional enzyme-digestion techniques. Functionally, the islets from replicate cryo-isolates responded to a glucose challenge with a mean stimulation index = 3.3 +/- 0.7 (n = 3). CONCLUSIONS: An enzyme-free method of islet isolation relying on in situ cryopreservation of islets with simultaneous freeze-destruction of acinar tissue is feasible and proposed as a novel method that avoids the problems associated with conventional collagenase digestion methods. PMID- 22099752 TI - A scalable microfluidic device for the mass production of microencapsulated islets. AB - The objective of this research was to test the viability and function of islets microencapsulated using a scalable microfluidic device that is suitable for the mass production of encapsulated islets for transplantation. A 3-D microfluidic device consisting of eight outlets with an inner fluid inlet and an outer concentric inlet to the device has been designed and fabricated using the stereolithography rapid prototyping technique. Islets were isolated from normal Wistar-Furth rat pancreas using the procedure of collagenase digestion of pancreatic tissue. Following purification, islet suspensions in 1.5% sodium alginate were pumped into the fluid inlet of the microfluidic device, which distributed the flow equally to all the eight channels according to the design. The air plenum distributed compressed air uniformly through the eight concurrent outlets, and with one fluid pump and air source, the device produced eight microencapsulations simultaneously. After encapsulation, the islets were tested for functionality using the dynamic perifusion procedure with low- and high glucose concentrations. The device is capable of producing eight channels of steady stream of monodisperse microencapsulations of a range of diameters depending on the design and process parameters. Using this prototype device, encapsulated islets were shown to be viable in the functional tests that we performed. Thus, the mean +/- standard deviation rate of insulin secretion increased from a basal rate of 0.165 +/- 0.059 ng/10 islets/min to a stimulated rate of 0.422 +/- 0.095 ng/10 islets/min (P < .05, n = 3), when the glucose concentration was changed from 5.5 mmol/L to 27.5 mmol/L, and this glucose stimulation index was not different from that observed with unencapsulated islets under same conditions. In summary, the high-throughput prototype device that we have designed can produce encapsulated islets that are viable and suitable for transplantation studies. PMID- 22099753 TI - Production of islet cell sheets using cryopreserved islet cells. AB - BACKGROUND: To establish novel islet-based therapies, our group has recently developed technologies to create a contiguous, monolayered sheet made from freshly dispersed islet cells. Islet cell sheets generated from freshly isolated cells are easily transplantable for engraftment into subcutaneous sites in rodents. The use of a temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm), grafted culture dishes with laminin-5 coating is an important feature of this process. To expand the utility of this protocol, the present study was performed to assess whether sheets generated using cryopreserved islet cells maintained viability and normal cellular phenotypes. METHODS: Dispersed islet cells obtained from Lewis rats were, cryopreserved using University of Wisconsin solution and 10% dimethyl sulfoxide. Specially coated plastic dishes were prepared by covalently immobilizing PIPAAm onto the culture plastic, followed by a coating of rat laminin-5. After 1 month of cryopreservation, the thawed cells were plated onto the PIPAAm-coated dishes. RESULTS: Viability of the thawed islet cells as assessed by trypan blue exclusion test was 86% +/- 5%. Thawed dispersed islet cells favorably attached to PIPAAm dishes could be harvested as a contiguous cell sheet using a simple change in culture temperature conditions. Electron microscopy showed the harvested islet cell sheet to retain cell-cell connections and numerous secretion granules. CONCLUSIONS: The present data indicated that dispersed islet cells, which were appropriately frozen and thawed, represent another viable cells source to create functional islet sheets for tissue engineering and potential clinical applications. PMID- 22099754 TI - Instant blood-mediated inflammatory reaction during islet transplantation: the role of Toll-like receptors signaling pathways. AB - The instant blood-mediated inflammatory reaction (IBMIR) leads to massive destruction of transplanted islets. Islet isolation and time of culture may elicit the release of potent activators of Toll-like receptors (TLRs) signaling pathways during IBMIR. This work sought to evaluate the role of TLR signaling pathways to mediate inflammatory reactions. Isolated rat pancreatic islets were cultured for 12, 24, or 48 hours. Their viability was assessed by fluorescein diacetate/propidium iodide and their functionality, by glucose stimulation tests. Endotoxin levels were quantified using the Limulus Amebocyte Lysate assays. After RNA extraction and reverse transcription, we performed polymerase chain reaction (PCR) arrays. Samples obtained immediately after isolation were defined as controls. Eighty-four genes belonging to the TLR signaling pathways, were compared with control samples. After culture, islets were viable and functional with low endotoxin levels (< 0.1 endotoxin units/mL) showed TLR activation not due to exogenous contamination. Analysis of PCR arrays highlighted significant up regulation of TLR-2. After 24 hours of culture, TLR-2 was up-regulated to 6.8 +/- 0.6-fold (P < .001) compared with controls but decreased to 4.3 +/- 1.4-fold after 48 hours. In the same way, expression of myeloid differentiation primary response gene 88 (Myd88) was significantly up-regulated (3.2 +/- 0.4-fold [P < .001]) compared with controls. After 12 hours of culture, interleukin-10 gene expression was significantly up-regulated at 11.6 +/- 3.7- fold (P < .05), reaching 17.5 +/- 8.3 after 24 hours. Finally, the cyclo-oxygenase-2 gene expression was up-regulated to 509 +/- 67.1-fold (P < .05) after 12 hours of culture. These data confirmed the implication of TLR signaling pathways in early inflammatory events. PMID- 22099755 TI - Human islet distribution program for basic research at a single center. AB - The Clinical Islet Laboratory at the University of Alberta/Alberta Health Services distributes human islets for basic research when islet preparations fail to meet defined release criteria for transplantation. This report highlights our islet distribution activity for diabetes research over a 3-year period. Shipments of the acinar-enriched fraction for research were not included in this report. In 2010, we distributed 6.3 million islet equivalents (IEQs) of islets through 127 shipments to 8 researchers, locally, nationally, and internationally. The number of preparations for research use was stable over the 3-year period (26, 23, and 29 preparations in 2008, 2009, and 2010, respectively). Islet yield distributed for research per isolation was 201, 212, and 218 * 10(3) IEQs, respectively. The number of basic researchers was stable as well, although there were only 2 researchers before 2007. Recently, each researcher has received fewer islets per shipment (49,820 IEQs in 2010 vs 75,635 IEQs in 2008) but more frequently (21.5 in 2010 vs 11.2 times per year in 2008). This paradigm shift would be desirable for researchers, because in our experience, most require <30,000 IEQs per shipment, and more frequent islet shipments results in a larger sample size for experimentation. After an initial expansion in the number of researchers requesting islets, our islet distribution activity has remained stable over the years in terms of total productivity of islets utilized for research. The current supply-versus-demand ratio in our program appears to be appropriate. PMID- 22099756 TI - Modest effects of Fas-ligand and heme oxygenase-1 double transgenic mouse islets on transplantation outcomes. AB - Interactions of Fas with its ligand (FasL) play an important role in the maintenance of immunologic homeostasis and peripheral tolerance. Heme oxygenase-1 (HO-1) is a protein capable of cytoprotection via radical scavenging and apoptosis prevention. The aim of this study was to test whether overexpression of FasL and HO-1 in murine islets resulted in cell protection and improved functional performance after transplantation. We first generated FasL and HO-1 double transgenic mice to investigate the protective effect of transgenic islets on transplantation. Islets were isolated from FasL and HO-1 double transgenic and nontransgenic Balb/c mice, for transplantation of 300 islets under the left kidney capsule of each streptozotocin-diabetic Balb/c mouse. During 6 weeks after transplantation, the blood glucose gradually decreased in recipients of double transgenic and nontransgenic islets. However, the decrease in blood glucose was more pronounced in the former (450 +/- 16 mg/dL at day 0 to 302 +/- 55 mg/dL at day 42; P = .01) than the latter (468 +/- 17 mg/dL at day 0 to 379 +/- 71 mg/dL at day 42; P = .24). The areas under the curve of intraperitoneal glucose tolerance tests at 2, 4, and 6 weeks were not significantly different between recipients of double transgenic and nontransgenic islets. The body weight increased in recipients of double transgenic islets (21.1 +/- 1.4 g at day 0 to 26.2 +/- 0.8 g at day 42; P = .0002) and nontransgenic islets (21.0 +/- 1.4 g at day 0 to 25.1 +/- 0.4 g at day 42; P = .0448). Our data suggested modest beneficial effects of transgenic islets with FasL and HO-1 overexpression for transplantation. PMID- 22099757 TI - Role of islet culture on angiogenic and inflammatory mechanisms. AB - Early events hampering islet engraftment may relate to instant blood-mediated inflammatory reaction (IBMIR) and to insufficient islet revascularization inducing beta-cell death. We evaluated the influence of time of culture on angiogenic and inflammatory cellular mechanisms in islet loss in vitro. Rat pancreatic islets cultured for 0, 12, 24, and 48 hours were assessed for functionality using glucose stimulation tests and identification of signaling pathways using polymerase chain reaction (PCR) arrays. Islet functionality decreased significantly immediately. Index of stimulation (IS) was decreased to 2.29 +/- 1.05 after 48 hours of culture versus 18.47 +/- 4.84 at 0 hours (P < .001). Gene expression studies at 12 hours of culture showed significant overexpression of proinflammatory cytokines and chemokines--interleukin (IL)-6 884.22 +/- 282.58 (P < .001) and Cxcl-1 448.09 +/- 196.05-fold change (P < .01). Moreover, islets exhibited significant under-expression after 48 hours of genes encoding angiogenic growth factors, such as epidermal growth factor, vascular endothelial growth factor, platelet endothelial cell adhesion molecule 1, a major protein involved in angiogenesis: 0.07 +/- 0.02, 0.11 +/- 0.08 (P < .001), and 0.17 +/- 0.15-fold change (P < .01) respectively. Moreover, tissue inhibitor of metalloproteinases 1, an inhibitor of metallopeptidase, was significantly more over-expressed, namely 54.58 +/- 18.08 at 12 hours of culture versus 0.93 +/- 0.15/fold change at 0 hours. This study revealed current culture conditions to be deleterious for islet engraftment, possibly due to expression of angiogenic genes and proinflamatory genes during culture. PMID- 22099758 TI - Subcutaneous transplantation may not be an appropriate approach for the islets embedded in the collagen gel scaffolds. AB - BACKGROUND: Synthetic extracellular matrix (ECM) has been shown to be efficient to preserve the function of transplanted islets. In this study using a mouse model, we sought to determine whether subcutaneous transplantation was a convenient procedure for achieving normoglycemia. METHODS: We performed in vitro tests as well as morphologic observations and Western blotting to establish that embedded islets survived better than non-embedded islets. Streptozotocin-induced diabetic mice (BALB/c) were transplanted with ECM-embedded syngeneic islets via the subcutaneous (SC; n = 5) or subrenal capsule (SRC; n = 6) routes. We measured mean blood glucose levels at various points from pretransplantation to postoperative day 14, and examined immunohistochemistry staining for insulin in the transplant grafts on day 14. RESULTS: Islets transplanted with ECM gel retained better structure and developed a functional vasculature. Western blotting showed more caspase-3 expressed in the non-embedded islets, which indicated more islet cells undergoing apoptosis. On the first day after transplantation, glucose levels were significantly decreased in the SRC group compared with the SC group: 383.33 +/- 44.50 mg/dL to 80.67 +/- 16.85 mg/dL versus 414.00 +/- 92.33 mg/dL to 278.28 +/- 121.80 mg/dL (P < .05). Glucose levels were better maintained in the SRC group than the SC group over 14 days. Immunohistochemistry staining for insulin showed fewer islets in the SC group. CONCLUSION: Embedded islets with ECM gel functioned better than non-embedded ones in vitro. However, the subcutaneous route may not be an ideal site for islet transplantation. PMID- 22099759 TI - Endothelial cells promote pancreatic stem cell activation during islet regeneration in mice. AB - OBJECTIVES: Diabetes is the clinical consequence of the loss of the majority of the beta-cell population and failure to regenerate new pancreatic beta cells. The current therapies based on beta-cell replacement have failed to achieve beta-cell renewal and thus, long-term insulin freedom. We have hypothesized that early rejection of endothelial elements within the islet grafts may seriously hamper islet regeneration in both native and islet grafts. METHODS: In the present study, we analyzed the role of endothelial cells to activate pancreatic stem cells during islet regeneration. Mice were pretreated with or without endothelial pharmacological ablation of endothelial cells, followed by an acute beta-cell injury using a single intraperitoneal injection of streptozotocin. We performed comparative morphometric analyses of recovered pancreata on days 3, 7, 10, and 30 after streptozotocin injury, staining with bromodeoxyuridine (BrdU) for representative cell types, beta cells, endothelial elements, and stem cells. Blood glucose levels were measured continuously after the injury to monitor the capacity for metabolic control. RESULTS: Morphometric analyses revealed an increasing number of cells over time to be stained with a stem cell and BrdU markers among animals only injured with streptozotocin but not with endothelial ablation. Notably, on day 10, stem cell markers were dramatically decrease nearly to basal levels, with appearance of numerous insulin-positive cells. Intact vessels with cobblestone-shaped endothelial elements were observed in direct proportion to the better outcomes, both by morphometric and by metabolic parameters. In contrast, fewer insulin-positive cells were observed in pancreata that had been ablated of endothelial cells showing extensive collapse of endocrine functions. CONCLUSIONS: We observed that endothelial elements promoted stem cell proliferation and islet regeneration after a beta-cell insult. We believe that preservation of endothelial cells positively affects the process of pancreatic regeneration. PMID- 22099760 TI - The effect of epigenetic factors on differentiation of pancreatic progenitor cells into insulin-producing cells. AB - Differentiation of pancreatic progenitors into insulin-producing beta cells is regulated by various transcription factors. To be expressed the genes coding these transcription factors need to be in accessible DNA. Whether a particular gene is present in a form of active euchromatin structure with accessible DNA or in an inactive heterochromatin structure with inaccessible DNA is determined by various epigenetic modifications. We studied the effect of epigenetic modifiers on differentiation of human nonendocrine cells into insulin-producing cells with the aim to evaluate the effect of epigenetic modifications in that process. Within 3 days of cultivation nonendocrine cells form isletlike cell clusters (ILCCs) containing mainly cytokeratin-19-positive cells. After cultivation with epigenetic modifiers and further differentiation, the highest number of C-peptide positive cells (10.3% +/- 2.9%) as well as glucagon-positive cells (7.2% +/- 2.8%) was observed in a sample supplemented with a combination of 5-Aza-2' deoxycytidine modifiers, BIX01294 and MC1568. In response to glucose stimulation (5 vs 20 mmol/L) these ILCCs secreted increased amounts of C-peptide (0.45 vs 1.05 pmol C-peptide/MUg DNA). Control samples treated without any epigenetic modifiers showed significantly lower numbers of C-peptide-positive cells (3.5% +/ 1.6%). These results showed that a combination of epigenetic modifiers 5-Aza-2' deoxycytidine (BIX01294 and MC1568) significantly improved reproducible differentiation of nonendocrine pancreatic cells into insulin-producing cells. PMID- 22099761 TI - Stimulating beta-cell replication and improving islet graft function by AR231453, A GPR119 agonist. AB - OBJECTIVE: G protein-coupled receptor 119 (GPR119) is predominantly expressed in beta cells and intestinal L cells. AR231453 is a selective small-molecular GPR119 agonist that enhances glucose-dependent insulin secretion and glucagon-like peptide 1 (GLP-1) release. We investigated whether AR231453 can directly stimulate beta-cell replication and improve islet graft function in diabetic mice. METHODS: A total of 100 syngenic C57BL/6 mouse islets were transplanted under the left kidney of each chemically induced diabetic C57BL/6 mouse. Starting from the day of transplantation, these recipients were given bromodeoxyuridine (BrdU) daily with or without AR231453 at 10 mg/kg/d. Islet graft function was monitored by measuring blood glucose levels. At 4 weeks, left nephrectomy was performed to remove the kidney bearing the islet grafts to determine beta-cell replication in the islet grafts. Insulin and BrdU immunofluorescence staining was performed to detect replicated beta cells. Insulin(+) and BrdU(+) beta cells in islet grafts were counted using a confocal microscope. To determine whether AR231453 increases plasma GLP-1 levels, we collected plasma from AR231453 treated mice at 30 minutes after treatment and measured plasma active GLP-1 by enzyme linked immunosorbent assay. RESULTS: Although all recipient mice achieved normoglycemia at 28 days with or without treatment, normoglycemia was achieved in significantly fewer days in AR231453-treated mice. The vehicle-treated mice achieved normoglycemia in 16 +/- 6 days, while AR231453-treated mice only required only 8 +/- 3 days (P < .01). The percentage of insulin(+) and BrdU(+) beta cells in islet grafts was significantly higher in AR231453-treated mice than in vehicle-treated mice. The mean percentage of insulin(+) and BrdU(+) beta cells in islet grafts was 21.5% +/- 6.9% in AR231453-treated mice and 5.6% +/- 3.7% in vehicle-treated mice (P < .01). The plasma active GLP-1 levels were also significantly higher in AR231453-treated mice than in vehicle-treated mice (P < .05). CONCLUSION: Our data demonstrate that AR231453, a GPR119 agonist, can stimulate beta-cell replication and improve islet graft function. PMID- 22099763 TI - Dynamic contrast-enhanced magnetic resonance imaging as a tool to monitor the blood supply to an artificial cavity used as a site for islet transplantation in rats. AB - BACKGROUND: The transplantation of islets of Langerhans isolated from one donor pancreas can rarely release a diabetic recipient from insulin injections. The major reason is the destruction of 50%-60% of the transplanted tissue, which proceeds typically within a few hours after the insertion of the islets into the portal vein. Therefore, several groups have focused on development of an artificial site for islet transplantation. The main aim of the present study was to test the efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) to evaluate the blood supply feeding the artificially created cavities for islet transplantation. METHODS: Two rounded devices were implanted: one device subcutaneously and the second one into the greater omentum of each animal. On the day of implantation as well as 1, 3, and 4 weeks later, we quickly injected the vascular specific MR contrast agent Vasovist (0.05 mL/100 g) intravenously. Penetration of the contrast agent was monitored by DCE-MRI. The influence of the contrast agent on the signal intensity observed within selected target areas was calculated with the use of ImageJ software. RESULTS: The penetration of the contrast agent was detected by the increase in signal intensity within implanted devices. The signal increase caused by the contrast compound was normalized to kidney tissue. On day of implantation of the device, no signal due to the contrast agent was detected in all devices. However, over the following weeks, there was an increase in signal detection within the omental device to 34%, 21%, and 14% of that of the kidney. Within the subcutaneously implanted devices there was an increase in signal detection up to 11%, 10%, and 7% of that detected in the kidney. CONCLUSIONS: The optimal time for transplantation of pancreatic islets into our omental device was 1 week after implantation of the scaffold. Also, the blood supply feeding the subcutaneous devices was regarded to be inadequate. PMID- 22099762 TI - Assessment of tissue-engineered islet graft viability by fluorine magnetic resonance spectroscopy. AB - INTRODUCTION: Despite significant progress in the last decade, islet transplantation remains an experimental therapy for a limited number of patients with type 1 diabetes. Tissue-engineered approaches may provide promising alternatives to the current clinical protocol and would benefit greatly from concurrent development of graft quality assessment techniques. This study was designed to evaluate whether viability of tissue-engineered islet grafts can be assessed using fluorine magnetic resonance spectroscopy ((19)F-MRS), by the noninvasive measurement of oxygen partial pressure (pO(2)) and the subsequent calculation of islet oxygen consumption rate (OCR). METHODS: Scaffolds composed of porcine plasma were seeded with human islets and perfluorodecalin. Each graft was covered with the same volume of culture media in a Petri dish. Four scaffolds were seeded with various numbers (0-8000) of islet equivalents (IE) aliquoted from the same preparation. After randomizing run order, grafts were examined by (19)F-MRS at 37 degrees C using a 5T spectrometer and a single-loop surface coil placed underneath. A standard inversion recovery sequence was used to obtain characteristic (19)F spin-lattice relaxation times (T1), which were converted to steady-state average pO(2) estimates using a previously determined linear calibration (R(2) = 1.000). Each condition was assessed using replicate (19)F-MRS measurements (n = 6-8). RESULTS: Grafts exhibited IE dose-dependent increases in T1 and decreases in pO(2) estimates. From the difference between scaffold pO(2) estimates and ambient pO(2), the islet preparation OCR was calculated to be 95 +/ 12 (mean +/- standard error of the mean) nmol/(min.mg DNA) using theoretical modeling. This value compared well with OCR values measured using established methods for human islet preparations. CONCLUSIONS: (19)F-MRS can be used for noninvasive pre- and possibly posttransplant assessment of tissue-engineered islet graft viability by estimating the amount of viable, oxygen-consuming tissue in a scaffold. PMID- 22099765 TI - A precise analysis of C5a inhibitory peptide on inflammatory mediators induced after islet transplantation. AB - OBJECTIVE: We recently reported that C5a inhibitory peptide (C5aIP) prevents the instant blood-mediated inflammatory reaction by attenuating cross talk between complement and coagulation cascades. C5aIP has also been shown to possess a broad range of anti-inflammatory effects. Due to methodological limitations, it is difficult to perform detailed analyses on wide range of inflammatory mediators in rat model. Therefore, we examined whether C5aIP suppressed various inflammatory cytokines induced after islet transplantation using a mouse model. METHODS: Six islet equivalents per gram of syngeneic mouse islet grafts were transplanted intraportally into two groups of streptozotocin-induced diabetic mice: control group (n = 8) and C5aIP group (n = 6). The C5aIP group was treated with a bolus of 4 mg/kg just after islet infusion and a continuous infusion of 0.4 mg/kg/h, whereas the control group was injected with equivalent amounts of saline. Serum samples were collected at 0, 6, and 24 hours after transplantation. We analyzed 23 types of cytokines: interleukins-1a, -1b, -3, -4, -5, -6, -9, -10, -12, -13, and -17; eotaxin; G-CSF; GM-CSF; interferon (INF) gamma; KC; MCP-1; MIP-1 and 1b, RANTES and tumor necrosis factor-alpha. Leukocytes in the recipient liver were isolated at 6 hours after transplantation to examine IFN gamma production by fluorescence activated cell sorting (FACS). RESULTS: No significant difference was detected in terms of the major inflammatory cytokines between the two groups. INF gamma production on CD11b(+)Gr-1(+) cells in the liver was not significantly inhibited by C5aIP (control 30.0% vs C5aIP 24.1%). CONCLUSIONS: These data suggested that beneficial effects of C5aIP on islet engraftment are mainly due to blockade of cross talk between complement and coagulation cascades, rather than the suppression of inflammatory mediators. PMID- 22099764 TI - Effect of exenatide on gastric emptying and graft survival in islet allograft recipients. AB - OBJECTIVE: To evaluate the effect of exenatide on gastric emptying and long-term metabolic control. METHODS: Ten islet allograft recipients treated with exenatide up to 4 years. Data from a mixed meal test with (MMT+) versus without (MMT-) administration of exenatide before boost ingestion were analyzed at 6, 12, 24, 36, or 48 months after initiation of exenatide treatment. None of the subjects were symptomatic for gastroparesis before or during the study. The c-peptide, acetaminophen absorption and glucose responses to MMT were analyzed by Student t test and analysis of variance. RESULTS: Average exenatide dose was 12.75 +/- 9.46 MUg/dL. The MMT subjects included two groups those with acetaminophen peak <=120 minutes ("good gastric emptying; n = 4") versus those with an acetaminophen peak >=180 minutes ("delayed gastric emptying"). Among the MMT+, acetaminophen absorption was the same in both groups (P = .27). Up to 48 months exenatide delayed time to peak of glucose, c-peptide, and acetaminophen as well as suppressed the glucagon response to MMT mean peak: 70.89 +/- 12.45 versus 43.24 +/- 4.67. The mean values of c-peptide and glucose responses to MMT were not significantly different. CONCLUSIONS: Long-term exenatide administration up to 4 years was safe in islet transplant recipients, even in the presence of delayed gastric emptying. The effects of exenatide were acute and reversible when the agent was withdrawn. The main difficulty with the use of exenatide in islet transplant subjects is their poor tolerability, although the physiological effects are clearly evident even at low doses. Approximately 63% of total subjects under exenatide treatment discontinued the drug due to nausea and vomiting. The use of new GLP1 analogs with longer half lives and fewer side effects may help to attain higher GLP1 levels, therefore improving islet function and survival. PMID- 22099766 TI - Assessment for revascularization of transplanted pancreatic islets at subcutaneous site in mice with a highly sensitive imaging system. AB - BACKGROUND: The subcutaneous space is one of the ideal sites for pancreatic islet transplantation, owing to the minimal invasiveness and easy access. However, the results of pancreatic islet transplantation in subcutaneous sites remain unsatisfactory. One of the main obstacles to successful pancreatic islet transplantation in subcutaneous sites is poor revascularization. Therefore, the aim of this study was to evaluate the revascularization process at subcutaneous sites with a highly sensitive imaging system combining a dorsal skinfold chamber (DSC) technique and multiphoton laser scanning microscopy (MPLSM). METHODS: A few pancreatic islets isolated from C57BL/6-Tg (CAG-EGFP) mice were syngeneically transplanted into nonmetallic DSCs mounted on the backs of C57BL/6J mice. Time dependent changes in the newly formed vessels of pancreatic islets were imaged using MPLSM on days 1, 4, 7, 11, and 14 (n = 6). Texas Red was injected intravenously to visualize blood vessels. To evaluate islet graft revascularization, we measured vascular volume surrounding the islet using the Volocity system (Improvision). RESULTS: The percentages of vascular volume at days 1 and 14 were assumed to be 0 and 100%, respectively. The vascular volume on each day was 9.4 +/- 6.5% (day 4), 34.9 +/- 11.2% (day 7), and 21.1 +/- 4.6% (day 11). CONCLUSIONS: The present study showed that a highly sensitive imaging system combining the DSC technique and MPLSM was a useful tool to analyze the revascularization process of pancreatic islets in a subcutaneous site. PMID- 22099767 TI - Studies of circulating microparticle release in peripheral blood after pancreatic islet transplantation. AB - The loss of graft function after intraportal islet transplantation is likely multifactorial involving allogeneic rejection, recurrent autoimmunity, graft exhaustion due to a marginally implanted islet mass, immunosuppressant toxicity, and impaired beta-cell regeneration. Because early markers of the loss of beta cell mass or function are lacking, monitoring of islet function remains a challenging issue. We have reported herein monitoring of membrane procoagulant microparticles (MPs) as markers of cell stress in the plasma of three recipients with various clinical histories. Early kinetics of C-peptide and MPs followed identical patterns during the first weeks after transplantation; a major increase probably reflected processes related to cell infusion and islet engraftment. Importantly in the case of rejection, MPs and C-peptide showed opposite patterns. A fall in C-peptide was associated with enhanced insulin needs. Our results suggested that a peak in MP levels might indicate rejection with prognotic value. Treatment of the loss of islet function by a new islet infusion or steroid therapy returned MP and C-peptide levels to their baselines with concomitant restoration of islet function. In the patient with suspected acute cellular rejection, MPs also appeared to be sensors of immunosuppressive steroid therapy. PMID- 22099768 TI - Usefulness of the secretory unit of islet transplant objects (SUITO) index for evaluation of clinical autologous islet transplantation. AB - BACKGROUND: Assessing the engrafted islet mass is important in evaluating the efficacy of islet transplantation. We previously demonstrated that the average secretory unit of islet transplant objects (SUITO) index within 1 month of allogeneic islet transplantation was an excellent predictor of insulin independence. However, the usefulness of the SUITO index for evaluating autologous islet transplantation has not been explored. The purpose of the present study was to assess the relationship between the SUITO index and clinical outcomes after total pancreatectomy followed by autologous islet transplantation. METHODS: We performed 27 total pancreatectomies followed by autologous islet transplantation from October 2006 to January 2011. Cases were divided into an insulin-independent group (IIG; n = 12) and an insulin-dependent group (lDG; n = 15). The SUITO index was calculated by the formula [fasting C-peptide (ng/mL)/fasting glucose (mg/dL) -63] * 1,500. The average SUITO index within the first month of transplantation except for days 0, 1, and 2, maximum SUITO index, and most recent SUITO index were calculated in each case, and values were compared between the IIG and the IDG. RESULTS: The average SUITO index within 1 month was significantly higher in the IIG than in the IDG (24.6 +/- 3.4 vs 14.9 +/- 2.0, respectively; P < .02). The maximum SUITO indices were 45.7 +/- 7.7 in the IIG and 30.1 +/- 8.1 in the IDG (not significant), and the recent SUITO indices were 36.9 +/- 6.7 in the IIG and 22.8 +/- 6.1 in the IDG (not significant). CONCLUSIONS: The average SUITO index within 1 month was an excellent predictor of insulin independence after total pancreatectomy followed by autologous islet transplantation. PMID- 22099769 TI - Association between the secretory unit of islet transplant objects index and satisfaction with insulin therapy among insulin-dependent islet recipients. AB - INTRODUCTION: When patients do not become insulin independent after islet cell transplantation (ICT), another aim is to eliminate severe hypoglycemia. Previously we reported that a secretory unit of islet transplant objects (SUITO) index score >10 was associated with a reduction of severe hypoglycemia. In this study, we assessed patients' satisfaction with their insulin therapy based on the SUITO index. METHODS: The study involved 11 islet recipients with type 1 diabetes who underwent ICT but still used insulin. From those patients, 41 Insulin Therapy Satisfaction Questionnaires (ITSQ) were collected. The SUITO index (fasting C peptide [ng/mL] * 1500/blood glucose [mg/dL] - 63) was calculated at the same outpatient visits that the survey was administered. ITSQ scores were summarized using subscales and compared among 3 groups: the pre-ICT group, the low-SUITO group (SUITO index score <10 post-ICT), and the high-SUITO group (SUITO index score >=10). Higher survey scores indicated better satisfaction. RESULTS: Significant trend relationships across the 3 groups were observed in the ITSQ total score (P = .02 with Jonckheere-Terpstra test) and subscale scores of glycemic control (P < .001), hypoglycemic control (P = .01), and inconvenience of regimen (P = .004). The pairwise comparisons between the 3 groups found significant differences: high SUITO versus both pre-ICT and low SUITO for the total ITSQ score (P = .03 and .005, respectively) and glycemic control score (P = .008 and .001, respectively), and high SUITO versus low SUITO for hypoglycemic control score (P = .04) and inconvenience of regimen score (P = .008). CONCLUSION: Islet recipients with a SUITO index >=10 experienced higher satisfaction with insulin injection therapy compared with the pre-ICT group, even though they were insulin dependent. A SUITO index >=10 is a reasonable benchmark for successful ICT. PMID- 22099770 TI - Cellular immunoisolation for islet transplantation by a novel dual porosity electrospun membrane. AB - Immunoisolation strategies have the potential to impact the treatment of several diseases, such as hemophilia, Parkinson's and endocrine disorders, such as parathryroid disorders and diabetes. The hallmark of these disease states is the amelioration of the disease process by replacement of the deficient protein. Naturally, several cellular therapeutic strategies like genetically modified host cells, stem cells, donor cells, or even complex tissues like pancreatic islets have been investigated. Current evidence suggests that successful strategies must incorporate considerations for local hypoxia, vascularity, and immunoisolation. Additional regulatory concerns also include safe localization of implanted therapeutic cells to allow for monitoring, dose adjustment, or removal when indicated. Local hypoxia and cellular toxicity can be detrimental to the survival of freshly implanted pancreatic islets, leading to a need for a larger initial number of islets or repeated implantation procedures. The lack of adequate donors and the large number of islet equivalents needed to achieve euglycemic states amplify the nature of this problem. We have developed a novel immunoisolation device based on electrospun nylon, primarily for islet transplantation, such that the inner component functions as a cellular barrier while allowing diffusion, whereas the outer component can be optimized for tissue integration and accelerated vascularization. Devices explanted after subcutaneous implantation in wild-type B6 mice after a period of 30 days show vascular elements in the outer layer of the electrospun device. The inner layer when intact functioned as an effective barrier to cellular infiltration. The preimplantation of such a device, with a relatively thin inner barrier membrane, will allow for adequate vascularization and reduce postimplantation hypoxia. This study demonstrates the feasibility of an electrospun isolation device that can be easily assembled, modified by varying the electrospinning parameters, and functionalized with surface-active molecules to accelerate vascularization. PMID- 22099771 TI - New alginate microcapsule system for angiogenic protein delivery and immunoisolation of islets for transplantation in the rat omentum pouch. AB - Severe hypoxia caused by a lack of vascular supply and an inability to retrieve encapsulated islets transplanted in the peritoneal cavity for biopsy and subsequent evaluation are obstacles to clinical application of encapsulation strategies for islet transplantation. We recently proposed an omentum pouch model as an alternative site of encapsulated islet transplantation and have also described a multi-layer microcapsule system suitable for coencapsulation of islets with angiogenic protein in which the latter could be encapsulated in an external layer to induce vascularization of the encapsulated islet graft. The purpose of the present study was to determine the angiogenic efficacy of fibroblast growth factor (FGF-1) released from the external layer of the new capsule system in the omentum pouch graft. We prepared 2 groups of alginate microspheres, each measuring ~600 MUm in diameter with a semipermeable poly-L ornithine (PLO) membrane separating 2 alginate layers. While one group of microcapsules contained no protein (control), FGF-1 (1.794 MUg/100 microcapsules) was encapsulated in the external layer of the other (test) group. From each of the 2 groups, 100 microcapsules were transplanted separately in an omentum pouch created in each normal Lewis rat and were retrieved after 14 days for analysis of vessel density using the technique of serial sample sections stained for CD31 with quantitative three-dimensional imaging. We found that FGF-1 released from the external layer of the test microcapsules induced a mean +/- SD vessel density (mm(2)) of 198.8 +/- 59.2 compared with a density of 128.9 +/- 10.9 in pouches measured in control capsule implants (P = .03; n = 5 animals/group). We concluded that the external layer of our new alginate microcapsule system is an effective drug delivery device for enhancement of graft neovascularization in a retrievable omentum pouch. PMID- 22099772 TI - Function and viability of human islets encapsulated in alginate sheets: in vitro and in vivo culture. AB - Islet encapsulation offers an immune system barrier for islet transplantation, and encapsulation within an alginate sheetlike structure offers the ability to be retrievable after transplanted. This study aims to show that human islets encapsulated into islet sheets remain functional and viable after 8 weeks in culture or when transplanted into the subcutaneous space of rats. Human islets were isolated from cadaveric organs. Dissociation and purification were done using enzymatic digestion and a continuous Ficoll-UWD gradient. Purified human islets were encapsulated in alginate sheets. Human Islet sheets were either kept in culture, at 37 degrees C and 5% CO(2), or transplanted subcutaneously into Lewis rats. After 1, 2, 4, and 8 weeks, the human islet sheets were retrieved from the rats and assessed. The viability of the sheets was measured using fluorescein diacetate (FDA)/propidium iodide (PI), and function was measured through glucose-stimulated insulin release, in which the sheets were incubated for an hour in low-glucose concentration (2.8 mmol/L) and then high (28 mmol/L), then high (28 mmol/L) plus 3-isobutyl-1-methylxanthine (50 MUm). Human islet sheets remained both viable, above 70%, and functional, with a stimulation index (insulin secretion in high glucose divided by insulin secretion in low glucose) above 1.5, over 8 weeks of culture or subcutaneous transplantation. Islet transplantation continues to make advances in the treatment of type 1 diabetes. These preliminary results suggest that encapsulated islets sheets can survive and maintain islet viability and function in vivo, within the subcutaneous region. PMID- 22099773 TI - Ten years of simultaneous pancreas-kidney transplantation: a retrospective single center analysis of prospectively obtained data. AB - INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPK) is a standardized and life-saving procedure for a patient suffering from both insulin dependent diabetes mellitus type 1 (IDDM 1) and end-stage diabetic nephropathy. To expand the donor pool and to determine the influence of the preprocurement pancreas suitability scoring system (P-PASS) on pancreas graft survival we retrospectively analyzed our data on SPK. PATIENTS AND METHODS: From 1999 to 2010 we performed 55 SPKs, using systemic-enteric drainage as surgical approach. The immunosuppressive therapy was induced with basiliximab; maintenance therapy was based on tacrolimus, mycophenolate mofetil, and steroids. Data were prospectively obtained, analyzed, and correlated to the P-PASS. RESULTS: The overall 10-year patient survival rate was 78% with a 10-year pancreas survival rate of 53%. Three patients needed retransplantation of SPK and 6 patients needed singular pancreas retransplantation. Seventeen patients showed acute rejection episodes and 14 patients suffered from cytomegalovirus (CMV) infections. We compared 43 patients receiving organs from an "ideal" donor (P-PASS <17) with 12 patients receiving grafts from "marginal" donors (P-PASS >=17). Neither P-PASS nor donor age demonstrated significant influence on pancreas graft survival. However, the body mass index (BMI) of the donor showed a negative tendency (P = .059). CONCLUSION: The P-PASS showed no significant prediction of pancreas graft survival. In view of our data, expansion of the German donor pool is possible. A multicenter study of SPK using "marginal" pancreas grafts is mandatory to define a realistic "cut off" value for P-PASS. PMID- 22099774 TI - Effect of tacrolimus versus cyclosporine on glucose metabolism of pancreas and kidney recipients in the late (> 8 years) posttransplant period. AB - Diabetogenic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare the glucose metabolism in type 1 diabetic kidney and pancreas recipients on tacrolimus (Tacro) versus cyclosporine-based (Cyclo) immunosuppression in the late posttransplant period. We examined 26 insulin-independent patients with stabile good renal function. They were at least 7 years after simultaneous pancreas and kidney transplantation and with unchanged immunosuppressive therapy for at least 6 years. The mean follow-up in Tacro (n = 13) and Cyclo (n = 13) groups were 9.7 +/- 1.9 and 10.9 +/- 1.3 years, respectively (P = .08). Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA(1c)), a standard intravenous glucose tolerance test (IVGTT) with coefficient of glucose assimilation (K(G)) calculation and trough Tacro/Cyclo levels were assessed. Insulin sensitivity and insulin secretion were evaluated using the homeostasis model assessment (HOMA-IR, HOMA-B). Total C-peptide and insulin secretions were calculated as areas under the curves (AUC) from the serum levels during the IVGTT. Tacro and Cyclo groups did not differ in age and body mass index. We did not find any significant difference in any examined parameters of glucose metabolism (fasting glycemia, insulin and C-peptide levels, HbA(1c,) IVGTT with K(G), HOMA-IR, HOMA-B, AUC of C-peptide and AUC of insulin; P > .05). Two patients in the Tacro group and none in the Cyclo group had K(G) <0.8%/min. Seven recipients in the Tacro group and eight in the Cyclo group had the normal glucose tolerance with K(G) >= 1.2%/min. Trough Tacro or Cyclo levels did not correlate with any of examined parameters. The use of different types of calcineurin inhibitors in type 1 diabetic pancreas and kidney recipients had no effect on glucose metabolism in the late posttransplant period. PMID- 22099775 TI - Evaluation of segmental pancreatic function using 11C-methionine positron emission tomography for safe living donor operation of pancreas transplantation. AB - For a safe living pancreas donoration for transplantation, we evaluated the function of the residual pancreas head using 11C-methionine positron emission tomography (PET) in 13 cases before and after distal pancreatectomy. After 6 hours of fasting, we intravenously administered 11C-methionine (370 to 740 MBq), performing PET at 30 minutes thereafter. 11C-methionine PET uptake in the pancreas head was expressed as a standardized uptake value (SUV) for comparison before versus after surgery: 17.3 +/- 2.5 versus 17.4 +/- 4.9, respectively, demonstrating no significant difference. However, the changes in SUVs of the residual pancreas head showed three patterns after surgery. The SUVs were elevated in three donors after surgery, hypermetabolite type; maintained in five donors, normometabolite type; and decreased in five donors hypometabolite type. The percentages of subjects with a postoperative HbA1c value more than 5.8%, the upper normal limit, were 33% in hypermetabolite type; 40% in the normometabolite type; and 60% in the hypometabolite type. Although diabetes mellitus has not developed in any of the 13 donors, the pancreatic head function after distal pancreatectomy was slightly decreased, especially among the hypometabolite type. To avoid postoperative diabetes mellitus for a prolonged period, donors who show decreased SUVs after surgery should be strictly followed. In conclusion, 11C methionine PET may be a potent modality to evaluate segmental pancreatic function for a safe living donor pancreatectomy. PMID- 22099776 TI - Immunoregulatory effect of anti-thymocyte globulin monotherapy on peripheral lymphoid tissues of non-obese diabetic mice. AB - OBJECTIVE: Experimental and clinical studies have shown that autoimmunity-causing diabetes may be abrogated by immune intervention. Several anti-T-lymphocyte antibodies focus on distinct T-cell targets. We tested the effect of murine anti thymocyte globulin (ATG; Genzyme, Framingham, MA) in peripheral lymphoid organs of non-obese diabetic (NOD) mice after the onset of hyperglycemia. METHODS: Diabetic NOD mice were treated with two doses of ATG (1 mg totally) or maintained without treatment as controls. Blood glucose levels were monitored twice a week. The mice were terminated at day 0, 7, 14, or 28 after the initiation of the study. Subpopulations of T-lymphocytes and FoxP3+ (forkhead box P3 positive) regulatory T-cells were analyzed among elements isolated from the spleen and pancreatic lymph nodes. RESULTS: Mice with blood glucose levels greater than 13 mmol/L were included in the study. Diabetes remission occurred in 16% (3/19) of mice treated with ATG. Only one case of remission was observed in the control group (6%; 1/16). ATG therapy a significantly decreased the CD8+/CD4+ T lymphocyte ratio. Among splenocytes, a significant difference was detected only on day 7 (0.069 versus 0.198 T-lymphocyte ratio); in lymph nodes, a decrease was observed on day 28 (0.21 versus 0.51 T-lymphocytes ratio). The regulatory T-cells population increased after ATG administration compared with the control group at day 7 (16.2% versus 10.8% in CD4+ splenocytes; 20.7% versus 10.3% in CD4+ lymph node cells). However, the increased FoxP3+ cell population was not durable. CONCLUSIONS: ATG treatment of diabetic NOD mice showed an immunoregulatory effect in peripheral lymphoid tissue with a significantly deceased CD8+/CD4+ ratio, which, however, did not normalize the metabolic parameters in a short period after the onset of overt diabetes. PMID- 22099777 TI - Assessment of mitochondrial DNA as an indicator of islet quality: an example in Goto Kakizaki rats. AB - BACKGROUND: Diabetic Goto Kakizaki (GK) rats represent an established model of type 2 diabetes that exhibit an onset of pancreatic islet (PI) pathology characterized by islet hypertrophy with a decreased number of insulin-secreting beta-cells. Among the remaining beta-cells, oxidative phosphorylation (OXPHOS) and consequently glucose-stimulated insulin secretion (GSIS) are impaired, perhaps owing to a deficit in mitochondrial DNA (mtDNA). We sought to identify this abnormality. METHODS: beta-Cells were obtained from Accutase-dissolved PI isolated from GK or Wistar rats and sorted based on the positive Zn(2+) signal of Newport Green. The mtDNA copy number per cell was quantified as the amplicon ratio by polymerase chain reaction using specific primers against the rat ND5 mt gene and UCP2 nuclear gene. RESULTS: The 12-month-old GK rats exhibited drastically reduced copy numbers per remaining beta-cell, from 7,400 +/- 600 in 12-month old Wistar rats (100%) to 24 +/- 4%; mtDNA content in heart and liver was 70 +/- 25% and 60 +/- 20%, respectively. Versus age-paired Wistar rats, 6- and 4-month-old GK rats showed reductions to 60 +/- 15% and 50 +/- 20%, respectively. CONCLUSIONS: OXPHOS of remnant beta-cells in diabetic GK was drastically impaired due to the lack of sufficient mtDNA levels. We suggest the use of mtDNA quantification to quickly assess PI quality before transplantation. PMID- 22099778 TI - FTY720-loaded poly(DL-lactide-co-glycolide) electrospun scaffold significantly increases microvessel density over 7 days in streptozotocin-induced diabetic C57b16/J mice: preliminary results. AB - BACKGROUND: Nanofiber scaffolds could improve islet transplant success by physically mimicking the shape of extracellular matrix and by acting as a drug delivery vehicle. Scaffolds implanted in alternate transplant sites must be prevascularized or very quickly vascularized following transplantation to prevent hypoxia-induced islet necrosis. The local release of the S1P prodrug FTY720 induces diameter enlargement and increases in length density. The objective of this preliminary study was to evaluate length and diameter differences between diabetic and nondiabetic animals implanted with FTY720-containing electrospun scaffolds using intravital imaging of dorsal skinfold window chambers. METHODS: Electrospun mats of randomly oriented fibers we created from polymer solutions of PLAGA (50:50 LA:GA) with and without FTY720 loaded at a ratio of 1:200 (FTY720:PLAGA by wt). The implanted fiber mats were 4 mm in diameter and ~0.2 mm thick. Increases in length density and vessel diameter were assessed by automated analysis of images over 7 days in RAVE, a Matlab program. RESULTS: Image analysis of repeated measures of microvessel metrics demonstrated a significant increase in the length density from day 0 to day 7 in the moderately diabetic animals of this preliminary study (P < .05). Furthermore, significant differences in length density at day 0 and day 3 were found between recently STZ-induced moderately diabetic and nondiabetic animals in response to FTY720 local release (P < .05, Student t test). CONCLUSIONS: Driving the islet revascularization process using local release of factors, such as FTY720, from biodegradable polymers makes an attractive system for the improvement of islet transplant success. Preliminary study results suggest that a recently induced moderately diabetic state may potentiate the mechanism by which local release of FTY720 from polymer fibers increases length density of microvessels. Therefore, local release of S1P receptor-targeted drugs is under further investigation for improvement of transplanted islet function. PMID- 22099779 TI - Neoplasm incidence in simultaneous pancreas and kidney transplantation: a single center analysis. AB - BACKGROUND: Long-term immunosuppression is associated with an increased rate of cancer. The aim of this study was to analyze the incidence of newly diagnosed tumors in simultaneous kidney and pancreas transplantation (SPKT). METHODS: We retrospectively analyzed the incidence of a neoplasm among 360 diabetic subjects who consecutively underwent SPKT from 1985 to August 2010 in a single institution. Data were retrieved from the institutional registry. We evaluated the nature of all newly diagnosed malignant tumors, including posttransplantation lymphoproliferative disease (PTLD), to compare Kaplan-Meier survival rates with those of patients free of a neoplasm. RESULTS: The median follow-up was 8 years; the overall 5-year patient survival was 84%. In 25 patients the tumors were malignant. Almost one-fourth of the cancers represented skin tumors (3 squamous cell and 4 basal cell carcinomas). PTLD was diagnosed in 5 recipients. The cumulative survival of patients with malignancies was significantly lower than that in recipients without cancer (8-year survival by 38% vs 70%; P < .001). The mean (+/-SD) time to diagnosis was 6 +/- 3 years. Since 2004, the 12 recipients with malignancy who were switched to sirolimus at the time of diagnosis showed survivals that were not apparently better than those who remained on the established immunosuppression (46% vs 55%; P = .71). CONCLUSIONS: The risk of neoplasm development was similar to that reported by other centers. Recipients of SPKT show higher incidence of cancer, though their overall survival is still significantly better than in those usually remaining on dialysis. PMID- 22099780 TI - Nonmarginal-donor duodenal ulcers caused by rejection after simultaneous pancreas and kidney transplantation: a case report. AB - OBJECTIVE: Pancreas transplantation has been associated with the highest surgical complication rate among routinely performed organ transplant procedures. Complications can be caused not only from the pancreas itself but also from the simultaneously transplanted duodenum: gastrointestinal bleeding, duodenal ulcer, pseudoaneurysm, arterioenteric fistula, and severe rejection. Herein we report a patient who underwent simultaneous pancreas-kidney transplantation (SPKT) and experienced a duodenal perforation because of rejection. METHODS: The 60-year-old man with insulin-dependent diabetes underwent SPKT with enteric drainage. At 15 days there after he displayed melena. RESULTS: We suspected it to be caused by rejection and ischemic changes. We slightly increased the doses, of tacrolimus and methylprednisolone. But 17 days after SPKT, the ulcer perforated, requiring a repair operation and increased dose of mycophenolate mofetil. However, the ulcers perforated repeatedly, requiring 4 repair operations. Unfortunately the patient developed pneumonia that mitigated continues repairs or rejection therapies, so we expated the duodenum and pancreas but saved the kidney. The pathologic findings showed the ulcer to have been caused by severe rejection. Despite those episodes, the patient was weaned from hemodialysis. CONCLUSIONS: Perforation of the transplanted duodenum is one of the most difficult complications among SPKT patients. This potentially lethal complication may be caused by mucosal rejection, ischemic changes, and the exocrine output from the pancreatic graft. PMID- 22099781 TI - Resolution of long-standing necrobiosis lipoidica diabeticorum (NLD) lesion after restoration of euglycemia following successful pancreas after kidney (PAK) transplantation: a case report. AB - Necrobiosis lipoidica diabeticorum (NLD) is an inflammatory skin disorder of unknown cause which can be seen in patients with diabetes mellitus. Various treatments, including immunosuppressive agents have been tried, without consistent efficacy. NLD is generally thought not to correlate well with tight diabetic control. Pancreas transplantation is the only widely and clinically used treatment that restores euglycemia in type I diabetic recipients. We report a case of resolution of NLD that had been unchanged for decades before pancreas after kidney transplantation. Another unique aspect of our case was that immunosuppression was discounted as a confounding factor, because the patient had been exposed to the same antirejection regimen for 3 years preceding the pancreas transplantation. PMID- 22099782 TI - Rituximab therapy and reduction of immunosuppression to rescue graft function after renal posttransplantation lymphoproliferative disorder found by macrohematuria in a pancreas and kidney transplant recipient: a case report. AB - INTRODUCTION: Posttransplantation lymphoproliferative disorder (PTLD) remains an uncommon complication of solid organ transplantation, with a high mortality rate reported after conventional therapies. Epstein-Barr virus (EBV) may cause PTLD, but most EBV infections after transplantation are clinically silent reactivations, so the detection of PTLD is often delayed. Recently we experienced the rare case of intrarenal graft PTLD found by macrohematuria in a simultaneous pancreas and kidney transplant recipient. The grafts were saved by treatments with rituximab, cyclophosphamide, hydroxydaunorubicin, and prednisone-based chemotherapy (R-CHOP) after reduction of immunosuppression (IR). METHODS: This 37 year-old man with insulin-dependent diabetes underwent simultaneous pancreas and kidney transplantation (SPK) with enteric drainage. Six months after transplantation, he displayed macrohematuria, which we investigated by blood tests, computer tomography (CT) scan, positron emission tomography (PET)-CT, and magnetic resonance imaging, recognizing a tumor in the transplanted renal graft. An open biopsy showed a CD20-positive PTLD. We started treatments with IR, rituximab (375 mg/m(2), weekly for 2 cycles) and R-CHOP therapy: rituximab (375 mg/m(2)) plus CHOP every 3 weeks for 6 cycles. RESULTS: IR and R-CHOP therapy achieved a complete remission (CR). CR has continued for 14 months at the time of writing. The maximum level of EBV DNA was 259 copies/MUg DNA, but 2 months after these therapies, the level had decreased to normal. The patient had no impairment of pancreas and kidney graft functions. CONCLUSIONS: The outcome of intragraft PTLD in the kidney of an SPK recipient suggested that the negative impact of IR on graft function may be compensated by the immunosuppressive effects of rituximab, allowing reduced immunosuppression during chemotherapy. PMID- 22099783 TI - Hypersensitivity to rabbit antithymocyte globulin in an islet transplant recipient: a case report. AB - OBJECTIVE: The aim was to describe a case of hypersensitivity to rabbit antithymocyte globulin (rATG) occurring in the context of islet transplantation. METHODS: A 36-year-old woman with type 1 diabetes was admitted for islet transplantation. rATG was administered the first day (1.5 mg/kg) with methylprednisolone (2 mg/kg), and on the second day (1.5 mg/kg) without glucocorticoid to avoid potential toxicity to the anticipated islet transplant. RESULTS: At the end of the rATG infusion on the second day she developed hives over her face, chest, and back and tender erythema at her intravenous site (Arthus reaction). Islet transplantation was not performed. She reported exposure to a pet rabbit for 2 years in childhood. Overnight, fever developed and the rash evolved into an erythematous morbilliform eruption affecting the torso. Serum high-sensitivity C-reactive protein (hsCRP) and the erythrocyte sedimentation rate (ESR) were elevated; serum complements C3 and C4 were normal. She received prednisone (50 mg) with subsequent resolution of the rash. Nine days after her initial reaction, she developed a recurrence of the rash and fever with arthralgias; levels of C3 and C4 had fallen. Methylprednisolone (125 mg, twice) was required for symptom improvement, and was gradually tapered as prednisone over the next 4 weeks with resolution of the complement, ESR, and hsCRP abnormalities. Five months after the initial attempt at islet transplantation, she returned to receive 7,879 IE/kg via portal vein infusion under basiliximab, etanercept, tacrolimus, and sirolimus immunosuppression and has required no to low-dose (0.1 U/kg/d) insulin to maintain near-normal glycemic control for > 12 months after transplantation. CONCLUSIONS: Our patient's initial hypersensitivity reaction to rATG was followed by immune-complex type 3 hypersensitivity (serum sickness) requiring high-dose glucocorticoids. Canceling the initial islet infusion proved to be wise, and the patient subsequently did well with islet transplantation under an alternative induction agent. PMID- 22099785 TI - Organizational model for a national system of donation and transplantation from deceased donors in Nicaragua. AB - System organization is one of the principal elements for success of a country's donation and transplantation activities. Nicaragua still does not have a specific institution that organizes and coordinates donation and transplantation; it does not perform transplantations from brain dead donors. With the counsel of the Transplant Coordination Service of the Hospital Clinic, Barcelona, Spain, we documented the current donation and transplant situation of Nicaragua, its health services and institutions, and their relevant demographic aspects. We analyzed some organizational models implemented around the world and in Latin America as well as the essential elements of "The Spanish Model", proposing an organizational model adapted to the Nicaraguan reality. For a small country with specialized services concentrated in the capital, Managua, we envisioned the creation of a two-tier system: First, a national cooordination of transplants who leads a group that is decentralized and subordinate to the hierarchy of the Ministry of Health, to organize and coordinate donation and transplantation activities. Second, a hospital coordinator who works with doctors in intensive care units and neurosurgical intensive care units to detect potential organ donors and communicate with the national coordinator of transplants, who directs the process. Nicaragua has the basic conditions for implementation of donation and transplantation from deceased donor, as well as institutions with the capacity to maintain their function as documented by this viable, functional organizational model. PMID- 22099786 TI - Expanded criteria donors, histological scoring, and prolonged cold ischemia: impact on renal graft survival. AB - The use of expanded donors or kidneys with preexistent chronic damage remains controversial, but they offer the opportunity to expand the donor pool. We investigated the impact of these conditions as predictors of graft survival among a cohort of recipients with prolonged cold ischemia times and a high incidence of delayed graft function. We included 70 consecutive cadaveric kidney allografts implanted between 2001 and 2005, which had undergone an early graft biopsy. Delayed graft function was present in 84% of cases with moderate or severe preexistent chronic damage in 63% and 27% of biopsies, respectively, and acute rejection was diagnosed in 14.3% of overall cases. The graft survival was 73.3% at 48 months. Primary nonfunctioning kidneys were more frequent using kidneys from expanded compared with standard donors (20.0% vs 0.0%, P < .002). Multivariate analysis showed that only the donor condition (standard vs expanded) was independently associated with graft survival (hazard ratio: 0.12; 95% confidence interval: 0.01-0.87; P < .03). Our results suggested that the donor characteristics prevail over other variables to predict graft outcomes. PMID- 22099787 TI - Short-term immunossupressive treatment of the donor does not prevent ischemia reperfusion kidney damage in the rat. AB - INTRODUCTION: Ischemia-reperfusion (IR) kidney damage is an important factor for allograft survival in kidney transplantation. Recently it has been shown that immune factors from donor-derived cells are important in IR injury. The aim of this article was to evaluate the impact of short-term immunosuppressive treatment of the donor over a time frame relevant to cadaveric transplantation on IR damage to the rat kidney. METHODS: Male Sprague-Dawley rats served as donors and recipients. Three experimental groups were evaluated according to the donor treatment (n = 6); control (no treatment); sirolimus (1 mg/kg orally) or FTY720 (1 mg/kg intravenously) at 6 or 1 hours prior to left nephrectomy. Kidneys were flushed with cold Euro-Collins solution and after 2 hours transplanted using microsurgical techniques concomittant with a left nephrectomy. After 48 hours (day 0), we removed the right kidney. Serum creatinine (SCr) was determined daily thereafter as well as differential leukocyte counts prior to donor nephrectomy and sirolimus plasma levels thereafter. RESULTS: No difference was observed in SCr on day 1: control (3.97 +/- 0.73 mg/dL), sirolimus (4.02 +/- 1.44 mg/dL) and FTY 720 (3.27 +/- 1.79 mg/dL; P = NS), or thereafter. Mortality was 50% in each group. Animals receiving FTY 720 showed a significant reduction in lymphocyte count (8.0 +/- 3.1 to 1.1 +/- 0.3 (P < .01). Sirolimus levels were 9.3 +/- 1.5 ng/mL. CONCLUSION: We concluded that immunosuppressive treament of the donor within a time frame relevant to cadaveric kidney transplantation did not offer a benefit in terms of preventing IR injury. PMID- 22099788 TI - Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation. AB - Progress in transplantation has relied on similar human leukocyte antigen (HLA) matching between the donor and the patient, while the role of other immunologic factors like non-HLA markers including minor histocompatibility antigens (miHA) are currently in the forefront. miHA are polymorphic proteins that vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA (MHC class I chain-related gene A). miHA have been well studied in transplantation of hematopoietic precursors, but not in solid organ transplantation. The most important studies in this field relate to incompatibility of H-Y antigen as a risk factor in kidney transplantation, although the findings are still inconclusive. This review presents the role of minor histocompatibility antigens in solid organ transplantation, especially of the kidney. PMID- 22099789 TI - Effect of implementing anti-HLA antibody detection by Luminex in the kidney transplant program in Chile. AB - The development of new highly sensitive, specific technologies to detect HLA antibodies has allowed a better definition of the profile of non-permitted antigens for patients awaiting kidney transplantation. The use of calculated or virtual panel reactive antibodies (CPRA or vPRA) seeks to improve the prediction of positive crossmatches (XM), but increases the proportion of sensitized patients on the waiting list. In 2008-2009, we implemented detection of antibodies using Luminex technology and applied vPRA since 2009. The objective of this study was to evaluate the impact of these innovations in defecting patient sensitization on kidney transplant waiting lists for deceased donors and among transplanted patients. We analyzed the waiting list for 2007 through 2009 and the first semester of 2010, including the patients transplanted in these periods and the XM with deceased donors. We observed an increase in the mean peak PRA of transplanted patients from 7.2% in 2007 to 17.1% in 2010 (P = .001), and in the proportion of patients transplanted with a peak PRA > 50% from 2.8% in 2007 to 15.7% in 2010 (P = .0001), with no increase in the proportion of this population on the waiting lists. There was a concurrent decrease in positive XM among patients with a peak PRA > 50%. The use of vPRA and Luminex permitted a greater number of transplants of patients with peak PRA > 50% and was a good predictor of a positive XM. PMID- 22099790 TI - A comparative study of the traditional method, and a point-score system for allocation of deceased-donor kidneys: a national multicenter study in Mexico. AB - BACKGROUND: The National Transplant Center in Mexico has ruled that deceased donor kidney allocation is a function of each hospital's Internal Transplant Committee. The aim of this study was to compare and analyze results for of the traditional method and a point-score system in the allocation of deceased patient's kidneys. METHODS: The 12 major kidney transplant centers in the country having a deceased-donor program were invited to participate. Only 3 of them replied to the invitation during 2010. A point-score system was proposed to them, comprising blood group, waiting list time, HLA type, and donor and recipient ages. Once the final recipient was chosen, an explanation of reasons for the choice was requested. Thirty-eight transplants were presented. Kappa coefficient was used to measure degree of agreement in both allocation systems. Organs donated for transplantation came from patients between 4 and 54 years old, including 52% female, 52% O+ blood type, 31% A+, and 11% B+, 44% cranial encephalic trauma, and 44% brain hemorrhage. RESULTS: Global agreement was 52.6% (kappa = 0.343), and partial agreement was 76.3% (weighted kappa = 0.204), assigning more intensity to extreme values, but with a lower correlation index. A more intense agreement, without discriminating by hospital, was found for "A" category (blood group), followed by "B" category (waiting list time). DISCUSSION: Taking into consideration the determining factors for long-term graft survival, it is indispensable to include criteria such as donor and recipient ages and HLA typife in the allocation process. This first draft of a point-score system in organ allocation included waiting list time, blood group, urgency related to vascular/peritoneal access for dialysis, clinical condition, donor/recipient age ratio, and HLA antigenic compatibility. PMID- 22099791 TI - De novo use of everolimus with elimination or minimization of cyclosporine in renal transplant recipients. AB - BACKGROUND: The purpose of two similarly designed multicenter, prospective, parallel-group, open-label studies was to evaluate early cyclosporine (CsA) elimination versus minimization from an everolimus-CsA-steroid regimen in de novo renal transplant patients. METHODS: Within 24 hours after transplantation, 170 renal transplant patients received everolimus (trough levels 3-8 ng/mL), CsA, and steroids. Those eligible (n = 114) were randomized (1:1) at 3 months to have CsA elimination by month 4 to 6 (+/-1 week) with everolimus trough levels maintained at 6 to 12 ng/mL or CsA minimization, until 12 months. The randomized population excluded those who discontinued the study prior to randomization due to adverse events, acute rejection episodes of Banff grade IIb/III, or worsening renal function during the month prior to randomization. RESULTS: At 12 months, the estimated glomerular filtration rate (Nankivell) with CsA elimination was noninferior versus CsA minimization (P < .0001, alpha-level 0.05; 90% confidence interval 0.6-8.5) by 7 mL/min/1.73 m(2) (noninferiority margin). Composite efficacy failure was comparable with CsA elimination and CsA minimization (18.9% and 17.5%, respectively, P = 1.000) and no graft loss or death was reported after randomization. Cytomegalovirus infections were rare under everolimus treatment, and no pneumonitis episode was reported. CONCLUSION: In our selected randomized study population, immediate initiation of everolimus allowed CsA elimination. Renal function was stable on everolimus-based, CsA-free maintenance regimen without compromising efficacy. PMID- 22099792 TI - Utilization of advanced-age donors in renal transplantation. AB - The shortage of organ availability in recent years has made it necessary to use grafts from advanced-aged donors to maintain the rate of renal transplantation in our country. The objective of this study was to evaluate the graft function and patient survival using kidneys from deceased donors of over 65 year of age. From 2005 until 2010, we compared the outcomes of patients who received grafts from donors over 65 years old vs less than 65 years. We observed no significant difference in sex, time on dialysis, or cold ischemia time between the groups. As expected the recipient age was significantly different. For the analysis of survival, we used the Tablecloth-Haenzel test and the Kaplan-Meier survival estimator. Actuarial survivals at 3 years after transplantation showed 84.8% among patients transplanted with kidneys from donors over 65 years old versus 97.5% in the control group. The graft survival was 78.8% among expanded criteria versus 86.85% in the control group. When we analyzed graft survival using an "exitus-censured" analysis, we obtained graft survivals of 89.1% in the expanded criteria kidney group versus 88.6% among the controls. We concluded that the use of kidney from donors over 65 years of age allows us to increase the rate of renal transplantation to about 15 to 20 per million population, with good graft and patient survivals provided that the protocol for expanded criteria organs ensured proper macroscopic and microscopic evaluation of the organ for transplantation. PMID- 22099793 TI - Growth, chronic kidney disease and pediatric kidney transplantation: is it useful to use recombinant growth hormone in Colombian children with renal transplant? AB - Kidney transplantation has become the best treatment for children with chronic kidney disease (CKD). In recent times, knowledge concerning the effect of CKD and kidney transplantation over the normal growth rate has increased; now it is known that 40% of children with CKD do not reach the expected height for age. Growth retardation has been associated with the type of nephropathy, metabolic and endocrine disorders that are secondary to kidney disease, immunosuppressive therapy with glucocorticoids, and suboptimal function of renal allograft. Nowadays, we know better the role of the growth hormone/insulin-like growth factor 1 axis in growth retardation we can see it in children with CKD or recipients of renal allograft. Several studies have shown that administration of recombinant growth hormone (rhGH) has a positive effect on the longitudinal growth of children and teenagers who have received a kidney transplant. On the other hand, there have been reported side effects associated with using rhGH; however, these are not statistically significant. In this article, we show a small review about growth in children with CKD and/or recipients of renal allografts the growth pattern of three children who were known by the Transplant Group of National University of Colombia, and the results obtained with the use of rhGH in one of these cases. We want to show the possibility of achieving a secure use of rhGH in children with CKD and its use as a therapeutic option for treating the growth retardation in children with kidney transplantation, and set out the need of typifying the growth pattern of Colombian children with CKD and/or who are recipients of renal allografts through multicenter studies to propose and analyze the inclusion of rhGH in the therapeutic scheme of Colombian children with these two medical conditions. rhGH could be a useful tool for treating children with CKD or kidney transplantation who have not reached the expected longitudinal growth for age. However, it is necessary to know the growth pattern standards for Colombian children with CKD or kidney transplant in Bogota Colombia to include the rhGH in clinical protocols for treatment of these patients. PMID- 22099794 TI - Clinical description and evolution of renal transplant pediatric patients treated with alemtuzumab. AB - BACKGROUND: Renal transplantation is the most effective treatment for children with end-stage renal disease. Recent work suggests that induction with alemtuzumab in the pediatric population permits the use of lower doses of maintenance immunosuppressive therapy. In addition, it has a low cost compared with other induction therapies. OBJECTIVE: To conduct a clinical description of pediatric renal transplant patients comparing induction protocols to evaluate graft and patient survival, infections complications, and lymphoproliferative diseases. MATERIALS AND METHODS: This descriptive and retrospective study, of evaluated pediatric renal transplant patients between 2006 and 2010. RESULTS: The agents for induction therapy were: alemtuzumab (61.5%), daclizumab (19.25%), and thymoglobulin (19.25%). Graft survival was better among the alemtuzumab group (87.5%) compared with the other two induction therapies (80%). The frequency of acute rejection episodes during the first year posttransplantation as well as chronic rejection was lower among the alemtuzumab group. Cytomegalovirus infection was noted in 30% of patients with greater frequency among those induced with alemtuzumab. CONCLUSION: Induction therapy with alemtuzumab was safe in a pediatric population not predisposing to a greater risk of acute or chronic rejection. Except for a greater incidence of Cytomegalovirus, there was no difference in other complications. PMID- 22099795 TI - Preemptive kidney transplantation: experience in two centers. AB - INTRODUCTION: End-stage renal disease (ESRD) is a prevalent, important cause of death. Transplantation increases survival and improves the quality of life of patients with ESRD while long-term dialysis is related to poor outcomes even among patients who undergo subsequent transplantations. OBJECTIVES: To compare the advantages of preemptive procedures with kidney transplants among patients on renal replacement therapy. METHODS: This retrospective study was performed in two Cordoba city transplantation centers. Patients were divided into three groups: preemptive kidney transplant (PKT), patients on hemodialysis who received living donor kidney transplants (LDT), and subjects who received grafts from deceased donors (DDT). Serum creatinine, delayed graft function (DGF), subclinical rejection, and interstitial fibrosis/tubular atrophy (IF/TA) were evaluated at 6 months. RESULTS: Eighty patients were included: PKT (n = 28), LDT (n = 27), DDT (n = 25) mean age 29, 30, and 35 years, respectively. Women predominated among PKT and men in the other groups. In all groups, cyclosporine was the calcineurin inhibitor mostly used. Creatinine at 6 months was lower in the living donor groups (1.26 mg/dL PKT and 1.32 mg/dL LDT; P = NS) in relation to the deceased donor group (1.96 mg/dL; P < .05). DDT had the highest rate of DGF: 44% DDT versus 11.5% LDT vs 0% PKT (P < .05). Subclinical rejection was significantly lower among preemptive transplantations: PKT 7.6% versus LDT 18.5% versus DDT 24% (P < .05). IF/TA was higher in transplants from deceased donors: PKT 11.1%; LDT 11.5%; DDT 32%. CONCLUSIONS: Preemptive kidney transplantation offered the advantages of a lower creatinine, no DGF, as well as a reduced incidence of subclinical rejection and chronic allograft nephropathy at 6 months posttransplantation. PMID- 22099796 TI - Induction therapies in kidney transplantation: the experience of Hospital Pablo Tobon Uribe, Medellin, Colombia 2005-2010. AB - BACKGROUND: Induction therapies in kidney transplantation have led to prescriptions of lower doses of maintenance immunosuppression and fewer acute rejection episodes. We sought to assess the use of an affordable monoclonal antibody in terms of the incidences of rejection episodes as well as graft and patient survivals and cytomegalovirus (CMV) and opportunistic infections among our kidney transplant recipients between August 2005 and December 2010. Data were obtained for patients who had more than 20 months' follow-up. MATERIALS AND METHODS: We retrospectively analyzed data from kidney recipients between August 2005 and December 2010, using descriptive statistics and Kaplan-Meier survival analysis. We performed a multivariate analysis with logistic regression for the dependent variables of rejection episodes and death. RESULTS: Among 425 transplant patients graft survival was 89.2% and patient survival was 94.1% after 76.2% of patients received alemtuzumab, 10.7% daclizumab, 3.6% basiliximab, 2.4% thymoglobulin, and 7%, no induction therapy. Rejection incidence in general in the first year was 10.8% and CMV incidence 10%. There was an increased risk of rejection among subjects without any us with alemtuzumab induction therapy. CONCLUSION: Induction therapies show an important reduction in kidney transplant rejection incidence during the first year, allowing low doses of maintenance immunosuppressants, thereby diminishing long-term adverse effects. Alemtuzumab seemed to be a safe alternative with similar results to those obtained with standard immunosuppression. PMID- 22099797 TI - Barriers and strategies for taking medicines in adult patients with renal transplantation. AB - Adherence to the immunosuppressant medications is important for the proper function a renal graft, but there are factors that make this difficult. This study describes strategies and barriers to adequate intake of these medicines based upon 177 surveys in renal transplant patients. Medication adherence was reported to be high (84%), but there were barriers to taking medications (64.95%): the most common were that the pharmacy did not work medicines (28.81%), changes in medication or dose (24.29%), failure to remember (9.6%), and lack of time (6.78%). The most common strategies for taking medications were: the use of cell phone alarms (15.25%) or alarm clocks (9.04%), schedules (5.65%), drug related meals (5.08%), drug use book (2.26%), and visibility on the table (2.26%). Proper understanding of the barriers to medication adherence and strategies used by recipients may help physicians more adequately educate patients, thereby reducing the risk of rejection related to nonadherence and suggest, specific interventions for improvement. PMID- 22099798 TI - Cost-effectiveness analysis of the early conversion of tacrolimus to mammalian target of rapamycin inhibitors in patients with renal transplantation. AB - BACKGROUND: Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs. OBJECTIVE: The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia. METHODS: We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient's natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results. RESULTS: Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one. CONCLUSIONS: This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained. PMID- 22099799 TI - Cutaneous manifestations in 100 renal and reno-pancreatic recipients of Uruguay. AB - Uruguay is the second country of Latin America in prevalence of renal replacement therapies, including functioning kidney allografts. Long-term immunosuppressive therapy is essential for adequate graft function, but results in reduced immunosurveillance leading to an increased risk of complications such as infections and malignancies. A variety of cutaneous manifestations as well as an increase in non-melanoma skin cancers have been reported in this population. The objective of this study was to evaluate the frequency and clinical spectrum of cutaneous manifestations in renal and reno-pancreatic recipients in Uruguay. One hundred renal or reno-pancreatic recipients aged between 21- and 77-years-old were evaluated between September 2009 and September 2010. A total of 104 dermatoses were observed; 68% of the patients had at least one cutaneous manifestation. The most frequent dermatoses were cutaneous side effects due to immunosuppressive treatment (43.3%), followed by infections (27.9%), miscellaneous causes (22.1%), as well as malignant and premalignant lesions (6.7%). This is the first study evaluating dermatological complications in organ transplant recipients in our country. Most of the patients had at least one dermatological manifestation of immunosuppression, including a malignant or pre malignant lesion, highlighting that this is a high-risk dermatological population. Cancer is one of the most important causes of death in recipients with functioning grafts. Its prevention is a major goal in the care of transplant recipients. Physicians in transplant units should be aware of the importance of dermatological screening and skin cancer surveillance. PMID- 22099800 TI - Significance of cytomegalovirus prophylaxis strategies and development of cancer in kidney transplant recipients. AB - Cytomegalovirus (CMV) infection is one of the most common complications among kidney transplant recipients; two approaches preventing this complication are currently available: universal prophylaxis (UP) and pre-emptive therapy (PT). Despite some differences, similar effectiveness and safety have been proven in several studies for both strategies. However, Spinner et al compared both treatments in 115 renal transplant recipients showing deaths were more likely to occur in patients who received UP. Most of these deaths (2/4 cases) occurred because malignancies developed. This finding is paradoxical because CMV is considered a potentially oncogenic virus and, therefore, UP (a longer therapy compared with the PT) should not be linked with the emergence of a greater number of tumors. New evidence suggests that changes in host immune response triggered by CMV infection may have a mitigating effect on the development of tumors. It is now known CMV infection produces a clonal expansion of gamma delta T lymphocytes which can elicit an aggressive response against neoplastic cells. Currently, UP is the therapy most frequently used in Colombian transplant centers; however, doses administered vary depending on several clinical and laboratory factors. There are no clinical cohorts treated with PT. Reviewing the impact of different length dosing schemes is important for creating an immune response affecting malignancy development in kidney transplant recipients. PMID- 22099801 TI - Outpatient renal needle biopsy of the transplanted kidney: safety profile. AB - Since May 2005, we began performing renal graft biopsies as outpatient procedures when the patient's condition did not require hospitalization. To evaluate the safety profile of the 137 procedures performed in 111 patients, we performed a retrospective analysis of complications after all biopsies between 4 May 2005 and 6 January 6, 2011. The analysis focused on types of complications as well as needs for hospitalization with length of stay, for blood transfusion or for a further intervention. There were complications in 10.9% of procedures (n = 15) with 8% requiring hospitalization (n = 11). The complications were: gross hematuria (n = 10) including blockage of urinary flow (n = 2) with one subject requiring urologic intervention, and one patient experienced severe pain at the puncture site. Neither renal graft nor patient survival was threatened; there was no hemodynamic decompensation needing blood transfusions. The average hospital stay was 2.27 days (range = 1-8). Outpatient renal biopsies in 111 patients (137 procedures) had an 8% incidence of complications requiring admission and an average length of hospitalization of 2.27 days. Gross hematuria the most frequent problem, in no way compromised patient or graft survival showing it to be a safe outpatient procedure. PMID- 22099803 TI - Current practices of organ donation and transplantation among different French speaking countries and regions. AB - The aim of the "Transplantation Sans Frontieres" (TSF) questionnaire, which was sent to French-speaking centers in 6 different countries and regions, was to establish the current status of organ donation and transplantation in their environments. It was also to examine ways to collaborate and exchange scientific information, teaching, and training in the field of organ transplantation. The French Society of Transplantation and the Agency of Biomedicine already offer specific programs to expand local activities, and the World Health Organization (WHO) regulates them. Therefore, TSF could be a coordinating platform in the near future. PMID- 22099804 TI - Donor advocacy with special reference to Belgium. AB - Before any published Belgian law, EU Directive, and/or EU Action Plan, the donor advocate was naturally a member of the transplantation team performing living kidney donation. The need of donor advocacy appeared obvious with liver living donation, which was and is still a risky procedure. Today, it is clear that the donor advocacy must not be limited to living donation but extended to brain-dead and cardiac-dead donation. Nevertheless, its complexity will need experienced persons in the field of organ donation as well as transplantation, while remembering that patients' first right is the right to donate. PMID- 22099805 TI - Organ procurement from donors deceased from cardiac death: a single-center efficiency assessment. AB - Organ donation after cardiac death has been used for kidney and liver procurement in France since 2006. Until recently, most teams relied on in situ cold perfusion to prepare the donor before organ retrieval. Our team has used since 2007 normothermic abdominal recirculation. While this technique is presumed to be more difficult to implement, it also ensures a lower rate of primary nonfunction when compared to in situ cold perfusion. We present the efficiency results of our organ donation after cardiac death program. After 3 years, we have been able to establish a program in which we use normothermic abdominal recirculation in 97% of donors after cardiac death. The yearly efficiency of this program is comparable to the national efficiency of organ procurement from conventional deceased donors in France. PMID- 22099806 TI - Pancreas preservation for pancreas and islet transplantation: a minireview. AB - Pancreas preservation by cold storage using University of Wisconsin solution was the mainstay method used for pancreas transplantation during the past 2 decades. Other solutions, such as HTK, Celsior, and SCOT 15, could not demonstrate any advantage for short preservation periods. But the advent of clinical islet transplantation and the larger use of controlled non-heart-beating donors have prompted the transplantation community to develop methods for increasing pancreas graft quality while preventing ischemic reperfusion damages. Oxygenation by 1- or 2-layer methods during pancreas preservation, as well as the use of perfluorocarbons, might increase the islet yield. Based on the former methods, there is a renewed interest in machine perfusion and oxygenation in pancreas preservation for pancreas transplantation and islet preparation. PMID- 22099807 TI - Liver preservation with SCOT 15 solution decreases posttransplantation cholestasis compared with University of Wisconsin solution: a retrospective study. AB - BACKGROUND: SCOT 15 is a new solution to preserve abdominal organs for transplantation. Its principal characteristic is the use of polyethylene glycol. Herein We report our experience using SCOT 15 compared with the reference University of Wisconsin (UW) solution for hepatic transplantation. METHODS: We compared 2 groups: SCOT 15 (n = 33; 2009-2010) versus UW (n = 34; 2008-2010), which were paired for cold and warm ischemic times, donor ages, and graft weights. Endpoints were biologic tests in the first 2 months after the operation. A linear mixed model was used to evaluate longitudinal changes and influences of each solution. RESULTS: No primary failure was observed. At postoperative day 0, transaminase values were higher in the SCOT 15 than in the UW group: aspartate transaminase: 2,435 +/- 399 vs 589 +/- 83 IU/L (P < .01); alanine transaminase: ALT: 1,207 +/- 191 vs 484 +/- 64 IU/L (P < .05), then returned to low levels in both groups. From day 0 to 8, coagulation factors reached normal values; there was no difference between the 2 groups. Total bilirubin decreased similarly in the 2 groups. However, from the second postoperative week (W1) to W8, the SCOT 15 group showed a slow decrease in the mean values of gamma-glutamyltranspeptidase (gGT) from 233 +/- 125 to 130 +/- 161 IU/L, which were significantly lower than those in the UW group, where the gGT remained around 300 IU/L (P < .01). The End Stage Liver Disease, Child-Pugh, or United Network for Organ Sharing scores, primary liver diseases, hepatitic C virus status, arterial or biliary complications, and male/female ratio, which was different in the 2 groups, did not statistically influence these results. CONCLUSIONS: The main effect of cold storage of human liver using SCOT 15 compared with UW solution was to decrease cholestasis following transplantation. PMID- 22099808 TI - Landmarks in clinical solid organ transplantation in Vietnam. AB - Renal transplantation was first performed in Vietnam in 1992. Up to the end of 2010, there have been 400 kidney and 16 liver transplantations from related and unrelated living donors. From 8 brain-dead donors between 2008 and 2010, we performed 15 kidney, 1 liver, and 1 heart transplantation. Few people agree to donate their own or their relatives' after death, mainly owing to the traditional belief of the Vietnamese that "as a man lives, so shall he die." The demand for organs for transplantation therefore exceeds the organ availability. This article sought to present some achievements and challenges in the field of solid organ transplantation in Vietnam as well as the necessary measures to develop this young promising specialty. PMID- 22099809 TI - Impact of pretransplant human leukocyte antigen-C and -DP antibodies on kidney graft outcome. AB - The aim of our study was to determine whether the presence of specific human leukocyte antigen (HLA)-C and -DP antibodies before transplantation influenced graft outcomes in immunized recipients. Two groups of pretransplant immunized recipients were studied: patients with only classical HLA-A, -B, -DR, -DQ antibodies (n = 176) and those with classical plus HLA-C and/or -DP antibodies (n = 27). Acute antibody-mediated rejection was preferentially associated with the presence of pretransplant anti-HLA-C and -DP antibodies (5/6 cases). In four cases, acute rejection episodes were followed by graft loss within 15 months after transplantation. There was a significant increase in the number of acute rejection episodes especially antibody-mediated acute rejections (P = .036) and in the number of graft losses for immunologic reasons (P < .001) among the group with pretransplant anti-C and -DP antibodies. Pretransplant anti-DP antibodies seemed to be involved more frequently in poor graft outcomes as shown in several recent published cases. We need to investigate their specific role among a larger cohort, taking into account an epitope analysis. PMID- 22099810 TI - Use of elderly living kidney donors: twenty years' experience in the Balkans. AB - The Balkan region has dramatically changed during the last 20 years. Despite transplantation efforts, dialysis remains the usual way to treat end stage renal diseases. Living donor renal transplantation is still the predominant transplant activity. Seeking to solve the problem, we decided to accept expanded criteria living donors, including elderly, marginal, unrelated, and ABO-incompatible individuals. Herein we have presented our 20 years' experience with 230 living donor renal transplantations using elderly individuals, including 90 older than 65 years (mean age 68 +/- 4.5; range = 65-86; ED group). The predominantly haploidentical recipients had a mean age of 45 +/- 6 years (range = 18-66). Sequential immunosuppressive protocols were used in all cases including induction with anti-thymocyte-globulin or interleukin-2 receptor antagonists. We analyzed the 5-year Kaplan-Meier graft survival rate, rejection episodes, delayed graft function, and renal function for comparison with these outcomes of 110 kidneys from younger donors (mean age = 53.4 years; range = 25-62; YD group) and haploidethical recipients (mean age = 32.2, range = 16-42), performed within the same period. The 3- and 5-year cumulative graft survival rates in the ED group were 81% and 72% compared with 85% and 81% in the YD group respectively (P > .9; NS). The incidences of acute rejection episodes were also comparable for both groups (19% and 17%, respectively). Delayed graft function occurred in 15% of the ED group but only 8% of the YD group. The serum creatinine value at the end of 60 months' follow-up was 146.04 MUmol/L in the ED group versus 123.38 MUmol/L in the YD group (P < .001). There were no major surgical complications in either group. We recommend the use of elderly living donors as a valuable source of kidneys, especially in countries wherein deceased donor transplantation is not yet established. PMID- 22099811 TI - Increased body mass index after kidney transplantation in activating transcription factor 6 single polymorphism gene carriers. AB - OBJECTIVES: Endoplasmic reticulum stress has been implicated in the pathogenesis of new-onset diabetes after transplantation (NODAT) and of metabolic disorders. Activated Transcription Factor 6 (ATF6), which is activated during endoplasmic reticulum stress, is involved in lipogenesis and gluconeogenesis. Tacrolimus may induce endoplasmic reticulum stress in pancreatic beta cells. Since studies have demonstrated that single nucleotide polymorphisms (SNPs) of ATF6 are associated with type 2 diabetes, we sought to determine whether their mutations were associated with NODAT among renal transplant recipients treated with tacrolimus. METHODS: We genotyped 269 renal transplant recipients using TaqMan assays for allelic discrimination for 6 ATF6 gene polymorphisms: rs10918215, rs7514053, rs1058405, rs4479731, rs2340721, and rs13401. All patients received an immunosuppressive regimen including tacrolimus. We analyzed all previously known risk factors for NODAT. RESULTS: We could not confirm are association between ATF6 SNP and NODAT. We observed a significant association between ATF6 SNP rs2340721 and increased body weight and body mass index (BMI) both upon univariate and multivariate analyses. The average BMI was higher among patients with 2 mutant SNP2 (rs2340721) alleles (CC) than those with 2 wild-type alleles (AA): 23.8 +/- 3.7 versus 25.5 +/- 4.4 kg/m2 (P = .02). The odds ratio (95% confidence interval [CI]) for BMI associated with the CC genotype was 2.43 (1.16 5.09; P = .02). CONCLUSION: ATF6 polymorphisms were not associated with NODAT among our population of renal transplant recipients treated with tacrolimus. However, these data underscore the role of ATF6 and endoplasmic reticulum stress in the regulation of metabolic flux among patients treated with tacrolimus, suggesting that inherited disturbances of endoplasmic reticulum stress signaling could predispose people to obesity. PMID- 22099812 TI - Does kidney transplantation with multiple arteries affect graft survival? AB - INTRODUCTION: We compared short- and long-term outcomes of renal transplants with single versus multiple arteries. PATIENTS AND METHODS: We retrospectively analyzed data from kidney transplants from 208 living donors performed between 1994 and 2010. Renal grafts were divided into two groups: single renal artery (n = 164) versus multiple renal arteries (n = 44). The groups were compared regarding early and late vascular and urological complications. Patient and graft survivals were compared using Kaplan-Meier survivorship curves with comparisons using the log-rank test. RESULTS: Both groups were comparable regarding acute rejection episodes, posttransplant hypertension, postsurgery renal artery stenosis, and urologic complications. Only hemorrhagic complications and renal artery thrombosis were significantly higher in the multiple renal arteries group (P = .027 and .03, respectively). Warm ischemia time was significantly longer in the multiple renal arteries group without any influence on the incidence of acute tubular necrosis (P = .2). Mean creatinine clearance at 1 year was 65 versus 50 mL/min/1.73 m(2) (P = .5) and at 5 years, 60 versus 55 mL/min/1.73 m(2) (P = .1) for the single versus multiple renal arteries groups, respectively. Return to hemodialysis was necessary for 18.8% of the single and 16.1% of the multiple renal arteries group. CONCLUSION: The use of an allograft with multiple renal arteries is a safe, successful surgical procedure, that does not influence patient or graft survivals or increase surgical complication rates provided the surgical team is evolved with technical skill. PMID- 22099813 TI - Xenotransplantation of galactosyl-transferase knockout, CD55, CD59, CD39, and fucosyl-transferase transgenic pig kidneys into baboons. AB - Galactosyl-transferase knockout (GT-KO) pigs represent the latest major progress to reduce immune reactions in xenotransplantation. However, their organs are still subject to rapid humoral rejection involving complement activation requiring the ongoing development of further genetic modifications in the pig. In a pig-to-baboon renal transplantation setting, we have used donor pigs that are not only GT-KO, but also transgenic for human CD55 (hCD55), hCD59, hCD39, and fucosyl-transferase (hHT). We studied kidney xenograft survival, physiological and immunologic parameters, xenogeneic rejection characteristics, as well as viral transmission aspects among two groups of baboons: control animals (n = 2), versus those (n = 4) treated with a cocktail of cyclophosphamide, tacrolimus, mycophenolate mofetil, steroids, and a recombinant human C1 inhibitor. Whereas control animals showed clear acute humoral rejection at around day 4, the treated animals showed moderately improved graft survival with rejection at around 2 weeks posttransplantation. Biopsies showed signs of acute vascular rejection (interstitial hemorrhage, glomerular thrombi, and acute tubular necrosis) as well as immunoglobulin (Ig)M and complement deposition in the glomerular and peritubular capillaries. The low level of preformed non-Gal-alpha1.3Gal IgM detected prior to transplantation increased at 6 days posttransplantation, whereas induced IgG appeared after day 6. No porcine endogenous retrovirus (PERV) transmission was detected in any transplanted baboon. Thus, surprisingly, organs from the GT-KO, hCD55, hCD59, hCD39, and hHT transgenic donors did not appear to convey significant protection against baboon anti-pig antibodies and complement activation, which obviously continue to be significant factors under a suboptimal immunosuppression regimen. The association, timing, and doses of immunosuppressive drugs remain critical. They will have to be optimized to achieve longer graft survivals. PMID- 22099814 TI - The first two cadaveric renal transplantations in Blida, Algeria. AB - Currently, living related donor renal transplantation is the most common source for transplantation in Algeria. To develop cadaveric organ donation, the Blida Transplantation Team (BTT) started a local education program and campaign. On March 31, 2010, we procured and transplanted 2 kidneys from a 17-year-old brain dead donor. The BTT is conscious that the local initiative must be followed nationally, with the help of the health authorities. There is an urgent need to promote brain-dead donors and cadaveric organ retriveal throughout the country. It will also be necessary to create national waiting lists for candidates not only for renal, but also for other organ transplantations. PMID- 22099815 TI - Organ donation in Belgium 2010: an increase of combined organ transplants and living donor liver transplantations. PMID- 22099816 TI - End of life care in the operating room for non-heart-beating donors: organization at the University Hospital of Liege. AB - Non-heart-beating (NHB) organ donation has become an alternative source to increase organ supply for transplantation. A NHB donation program was implemented in our institution in 2002. As in many institutions the end of life care of the NHB donor (NHBD) is terminated in the operating room (OR) to reduce warm ischemia time. Herein we have described the organization of end of life care for these patients in our institution, including the problems addressed, the solution proposed, and the remaining issues. Emphasis is given to our protocol elaborated with the different contributors of the chain of the NHB donation program. This protocol specifies the information mandatory in the medical records, the end of life care procedure, the determination of death, and the issue of organ preservation measures before NHBD death. The persisting malaise associated with NHB donation reported by OR nurses is finally documented using an anonymous questionnaire. PMID- 22099817 TI - Hypothermic machine perfusion of the liver: is it more complex than for the kidney? AB - BACKGROUND: Hypothermic machine perfusion (HMP) is superior to simple cold storage (SCS) for the preservation of kidney grafts. Whether HMP is superior to SCS for liver preservation is not known. Before a HMP system can be used clinically for the liver, its superiority to SCS needs to be demonstrated in an in vivo large animal transplant model. OBJECTIVE: The aim was to compare outcomes after liver transplantation (LT) following preservation by SCS or HMP using technology/perfusion conditions similar to those for kidney HMP. METHODS: Pig livers were perfused via the hepatic artery and portal vein for 4 hours with nonoxygenated 4 degrees C University of Wisconsin machine perfusion solution. In the SCS group, flushed livers were stored in histidine-tryptophan-ketoglutarate solution. After preservation by SCS (n = 6) or HMP (n = 8) and LT, we assessed graft and recipient survivals, pH and lactate, hepatocellular damage [aspartate aminotransferase (AST)], Kupffer cell activation (beta-galactosidase), tumor necrosis factor (TNF) alpha production, endothelial cell function (hyaluronic acid), and expression of Kruppel-like factor (KLF) 2 and 4, which are mediators of the flow-dependent vasoprotective endothelial phenotype. RESULTS: No primary graft nonfunction was observed; livers recovered equally well from the postanhepatic metabolic acidosis in both groups. Pig survival was 5/6 (83%) in the SCS versus 2/8 (12.5%) in the HMP group (P = .04). Livers from both groups recovered equally well from the postanhepatic metabolic acidosis. AST in liver rinse-out samples obtained before LT were lower in the HMP than in the SCS group (P < .05). After reperfusion, AST and beta-galactosidase were equally increased in both groups (P = .13 and 0.962, respectively); TNF-alpha and hyaluronic acid levels were higher after HMP versus SCS (P = .001 and 0.043, respectively). KLF-2 and -4 expressions were equally up-regulated after reperfusion in the SCS and HMP groups. CONCLUSIONS: In this in vivo model, liver HMP with subsequent transplantation was feasible. However, we did not demonstrate an advantage of HMP, using perfusion conditions shown to be effective for the kidney, over SCS. Despite similar immediate graft function, TNF-alpha generation, and endothelial cell dysfunction were more pronounced after HMP. PMID- 22099818 TI - Presumed and actual concentrations of reduced glutathione in preservation solutions. AB - Reduced glutathione (GSH), an important radical scavenger, has been added to various organ preservation solutions. Because GSH oxidizes into oxidized glutathione (GSSG) and only GSH has scavenging capacity, only GSH in the solution at the time of clinical use is relevant. The concentrations of GSH (GSH(conc)) and GSSG(conc) were determined in 2 static preservation solutions--University of Wisconsin (UW) and Celsior--and in 1 machine preservation solution--Kidney Preservation Solution 1 (KPS-1). We determined the half-life (T(1/2)) of freshly added GSH. The GSH(conc) in UW and KPS-1 was 0.006 +/- 0.0018 mmol/L and 0.13 +/- 0.30 mmol/L, respectively. The GSH(conc) in Celsior was 2.7 +/- 0.17 mmol/L. The manufacturers of these solutions reported 3 mmol/L GSH. GSSG(conc) in UW, KPS-1, and Celsior was 1.58 +/- 0.61 mmol/L, 1.13 +/- 0.16 mmol/L, and 0.24 +/- 0.01 mmol/L, respectively. T(1/2) of GSH in UW, KPS-1, and Celsior was 18 days, 86 days, and 83 days, respectively. The actual GSH(conc) in UW and KPS-1 at the time of clinical use was substantially lower than reported by the manufacturer, owing to the relatively short T(1/2) of GSH. For Celsior, the GSH(conc) was maintained. Therefore, addition of fresh GSH to UW and KPS-1 before clinical use is recommended. PMID- 22099819 TI - Attempt to rescue discarded human liver grafts by end ischemic hypothermic oxygenated machine perfusion. AB - In a porcine liver transplant model, a brief period of oxygenated hypothermic machine perfusion (HMP) at the end of simple cold storage (SCS) has been shown to improve the viability of damaged liver grafts. To test the clinical validity of this strategy, we randomized SCS-discarded human liver grafts to either 4 hours of HMP (n = 13) or an additional 4 hours of SCS (n = 14). All livers were then warm reperfused to mimic ischemia-reperfusion injury ex vivo. The settings for HMP were: portal vein: 3 mm Hg, 300 mL/min and hepatic artery: 20 mm Hg, pO(2): 300 mm Hg. Perfusion used Kidney Machine Perfusion Solution at 4 degrees C to 8 degrees C. During warm reperfusion, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) values were higher (P < .015) among the SCS versus HMP methods at all times. The AST slope was lower in HMP versus SCS (P = .01). The LDH slope tended to be lower for HMP versus SCS (P = .07). Morphological scores were not different between HMP and SCS. At the start of warm reperfusion, MAPK was lower in HMP versus SCS (P = .02). Endothelin-1 (EDN1) and ICAM-1 tended to be lower in HMP versus SCS (P = .1 and .07, respectively). No difference was noted in MAPK, EDN1, and ICAM-1 after 60 or 120 minutes of warm reperfusion. In conclusion, HMP down-regulated MAPK and tended to reduce EDN1 and ICAM-1 mRNA in human liver grafts. During warm reperfusion, HMP versus SCS livers showed reduced AST and LDH release but no morphological difference. Further optimization of liver HMP may require different timing/duration of perfusion and/or an higher perfusion temperature. PMID- 22099820 TI - Differential gene expression profile of porcine livers subjected to warm ischemia alone. AB - BACKGROUND: Livers exposed to warm ischemia (WI) are increasingly used for transplantation. The molecular mechanisms activated by WI alone (prior to procurement and transplantation) are not understood. To elucidate the pathways involved, we used microarrays to investigate the gene expression in porcine livers exposed to WI. METHODS: Porcine livers (n = 6 group) were randomly subjected to WI periods of 15, 30 or 45 minutes. mRNA was extracted and gene expression determined by microarray analysis. Using bioinformatics software, we identified differentially expressed genes and related molecular pathways. We used the corresponding human annotation of the porcine microarray for the functional analysis. RESULTS: Between 0 and 15 minutes of WI, 3530 genes were altered with a 2-log-fold change of <-0.58 or >+0.58 and P < .05. Between 0 and 30 minutes of WI, 4141 genes were differentially expressed; and between 0 and 45 minutes of WI, 2814 genes. At each time point, ~50% of genes were up-regulated, whereas 50% were down-regulated. After pathway mapping, we found that the same pathways were induced for observed clustering of in the three WI periods: cell death, proliferation, inflammation, and metabolism pathways. Among the top genes that were up-regulated after 15 minutes of WI, the majority started to return to but did not reach baseline expression with increasing WI. A similar pattern was observed for the top suppressed genes. CONCLUSIONS: WI causes rapid changes in gene expression that affect several molecular pathways. This phenomenon seems to plateau at 15 to 30 minutes of WI. These new insights in the timing and the nature of molecular pathways induced by WI alone may help to design specific interventions to alter these changes and improve the outcome of livers from cardiac death donors. PMID- 22099821 TI - Incidence and risk factors for posttransplant subcapsular cataract: a long-term retrospective cohort study. AB - BACKGROUND: The occurrence and risk factors for posterior subcapsular cataract (PSC) after renal transplantation have received little attention. OBJECTIVES: To analyze the cumulative incidence of PSC after renal transplantation and identify risk factors for the development of PSC. METHODS: Retrospective review of the records of the patients who underwent kidney transplantation between May 1986 and December 2008. RESULTS: We included 94 renal transplant recipients who showed PSC incidence at 5, 10, and 15 years of 3.5%, 40.5%, and 50.1%, respectively. Cumulative incidence of PSC during the follow-up was 37.2%. On multivariate analysis, age, body mass index (BMI) and cumulative corticosteroid dose were significantly associated with PSC. Recipient age above 50 years (hazard ratio [HR] = 2.88, 95% confidence interval [CI]: 1.42-5.83; P = .003), BMI above 25 kg/m(2) (HR = 2.28, CI: 1.09-4.78; P = .029), and prednisolone dose above 3 mg/kg/mo (HR = 7.79, CI: 3.34-18.99; P < .001) were independent risk factors for PSC. Diabetes, renal diagnosis, duration, and type of dialysis and posttransplant immunosuppressive regimen did not influence the occurrence of PSC. CONCLUSION: The risk of PSC was low during the first years after transplantation reaching a plateau at 15 years posttransplantation. Among the risk factors for PSC, cumulative corticosteroid dose and body weight were the only modifiable risk factors. PMID- 22099822 TI - Long-term evolution of the mineral metabolism after renal transplantation: a prospective, single-center cohort study. AB - BACKGROUND: Abnormalities in bone and mineral metabolism are common after renal transplantation (RT) but information on their long-term time course is scarce. OBJECTIVES: (1) Evaluate the time course of biochemical parameters of bone and mineral metabolism over 60 months after RT; (2) identify predictors for persistent hyperparathyroidism (HPT). DESIGN: Prospective, longitudinal, single center cohort study. METHODS: We determined serum levels (mean values +/- standard deviations) of intact parathyroid hormone (iPTH), calcium (Ca), phosphorus (P), magnesium (Mg), alkaline phosphatase (APh), calcitriol, and creatinine (Cr) preoperatively as well as 6, 12, 24, 36, 48, and 60 months after cadaveric RT in 49 patients. We in addition recorded demographic, clinical, and therapeutic data. RESULTS: Pretransplantation iPTH stabilized from 194.2 +/- 273.5 to 71.5 +/- 50.7 ng/L at 6 months. Serum Ca (9.5 +/- 1.1 mg/dL) and APh (81.9 +/- 42.1 U/L) did not change. Baseline serum P (5.7 +/- 1.8 mg/dL) and serum Mg (2.4 +/- 0.4 mg/dL) decreased to normal ranges from month 6 onward. Low baseline calcitriol (22.4 +/- 21.8 pmol/L) normalized slowly by 12 months (95.4 +/- 46.7 pmol/L). Stable graft function (53.2 +/- 15.8 mL/min) was achieved from 6 months onward. By 60 months, 26.5% of patients had a serum Ca above 9.8 mg/dL and serum P below 2.7 mg/dL; 22.4%, an Mg below 1.7 mg/dL and 8.2%, a serum iPTH more than 2.5-fold the upper limit of normal. Upon multiple regression analyses the iPTH at 60 months was influenced by a dialysis duration >= 2 years (beta = 0.259, P = .003), body mass index > 25 kg/m(2) (beta = 0.257, P = .006), baseline iPTH (beta = 0.182, P = .036), serum Cr (beta = 0.268, P = .002) and Mg (beta = 0.242, P = .006). CONCLUSIONS: Hypercalcemia, hypophosphatemia, hypomagnesemia, and elevated iPTH persist in a subset of post-RT patients. Pretransplantation iPTH and obesity, dialysis duration, and posttransplant serum creatininemia and hypomagnesemia independently contribute to persistent HPT. PMID- 22099823 TI - The need for a new animal model for chronic rejection after lung transplantation. AB - The single most important cause of late mortality after lung transplantation is obliterative bronchiolitis (OB), clinically characterized by a decrease in lung function and morphologically by characteristic changes. Recently, new insights into its pathogenesis have been acquired: risk factors have been identified and the use of azithromycin showed a dichotomy with at least 2 different phenotypes of bronchiolitis obliterans syndrome (BOS). It is clear that a good animal model is indispensable to further dissect and unravel the pathogenesis of BOS. Many animal models have been developed to study BOS but, so far, none of these models truly mimics the human situation. Looking at the definition of BOS, a good animal model implies histological OB lesions, possibility to measure lung function, and airway inflammation. This review sought to discuss, including pros and cons, all potential animal models that have been developed to study OB/BOS. It has become clear that a new animal model is needed; recent developments using an orthotopic mouse lung transplantation model may offer the answer because it mimics the human situation. The genetic variants among this species may open new perspectives for research into the pathogenesis of OB/BOS. PMID- 22099824 TI - Neutrophil gelatinase-associated lipocalin, a new biomarker candidate in perfusate of machine-perfused kidneys: a porcine pilot experiment. AB - The enduring kidney graft shortage has led to the increasing use of expanded criteria donors as well as kidneys donated after cardiac death, triggering the revival of machine perfusion preservation. Indeed, machine perfusion not only preserves these kidneys better than static cold storage, but also has the potential to evaluate them. The presence of certain biomarkers, among them aspartate aminotransferase (AST) and heart-type fatty acid binding protein (H FABP), has been demonstrated in the perfusate of human kidneys, making them potentially useful as biomarkers of graft quality. Neutrophil gelatinase associated lipocalin (NGAL) which is believed to be released upon renal tubular cell injury is another biomarker candidate. However, because it is also released from neutrophils, it is currently unclear whether NGAL is a direct or indirect, inflammatory-mediated marker of kidney injury. To resolve this issue we established a pilot experiment to study the concentrations of AST, H-FABP, and NGAL in the perfusates of 6 porcine kidneys that were exposed to incremental periods of warm ischemia before machine perfusion for 22 hours. An ex vivo porcine model was chosen because preclinical large animal work remains necessary to refine machine perfusion technology and because the presence of these markers in perfusates of porcine kidneys had not been shown previously. All 3 biomarkers were detectable in the cold acellular perfusate; their release seemed to be proportionate to the degree of warm injury, albeit that this must be confirmed in a larger sample. In conclusion, NGAL is directly released by ischemically damaged kidneys, independent of neutrophil activation. In addition to NGAL, the determination of AST and H-FABP in perfusates of machine-perfused porcine kidneys is also feasible. Determination of these markers may be added to the arsenal of research tools for preclinical preservation research. PMID- 22099825 TI - Liver transplantation in cases of portal vein thrombosis in the recipient: a case report and review of the various options. AB - Several surgical techniques have been developed to allow liver transplantation in cases of complete portal vein thrombosis in the recipient. Despite this, these transplantations remain associated with a significant complication rate. We report herein a case of liver transplantation in a patient with complete portal vein thrombosis, underlying the potential pitfalls and the risk of intestinal sutures in case of hepaticojejunostomy. We discuss the technical options and their relative indications in such cases. PMID- 22099826 TI - Acute liver failure secondary to khat (Catha edulis)-induced necrotic hepatitis requiring liver transplantation: case report. AB - We describe the case of a 26-year-old man with acute liver failure secondary to ingestion of khat (Catha edulis) leaves. In fact, this is the first case of acute liver failure due to khat reported outside the United Kingdom. The combination of specific epidemiologic data (young man of East African origin) and clinical features (central nervous system stimulation, withdrawal reactions, toxic autoimmune-like hepatitis) led to the diagnosis. Mechanisms of action and potential side effects of khat are elaborated on. PMID- 22099829 TI - Vascularized composite allotransplantation at a crossroad. AB - Vascularized composite allotransplantation is a relatively young field that has shown significant growth in the past decade. The subspecialty offers opportunities that are not available with solid organ transplants. However, the field also faces significant hurdles in increasing clinical volumes. The development of innovative immune-reduction strategies will likely determine the pace and direction of growth in the field in the years to come. PMID- 22099830 TI - How reconstructive transplantation is different from organ transplantation--and how it is not. AB - An evolution of understanding and knowledge gained over more than 100 years in the field of solid organ transplantation (SOT) led to the first successful clinical cases of composite tissue allotransplantation. In many ways reconstructive transplantation (RT) is similar to SOT; however, certain characteristics make this novel type of transplantation unique, interesting, and challenging for both clinicians/scientists and patients. Currently, RT is a rapidly advancing multidisciplinary clinical reality. With over 100 clinical cases performed over the past 12 years, and encouraging early to midterm results, the relevance of RT for treatment of congenital and acquired tissue defects unsalvageable by conventional reconstruction is significant and holds great potential for the future. We herein report the extraordinary progress in this field with particular discussion of a comparative analysis of the similarities and differences regarding indications, end point, failure, patient and graft survival, and side effects between SOT and RT. PMID- 22099831 TI - Hand transplantation: is it an ethical decision, a bioethical one, or both? AB - Essays by Seigler and Emmanuel define some criteria and requirements when doing an innovative procedure such as hand transplantation to determine whether it is possible to conduct clinical research. These criteria and requirements take into account the patient, the medical team, and society. However, we think that there are still other considerations that have not been given sufficient emphasis to justify an innovative procedure and are mainly determined by the patient and his environment, along with other quality-of-life issues, including social acceptance (according to cultural norms), appearance (body image), and function. There should be a balance between the patient, the medical team, and societal considerations in the decision process. Progressive societies are responsible for the distribution of the necessary resources to perform innovative procedures while controlling the costs of integral treatment and ensuring related investigations, thus facilitating the evaluation and advancement of innovative surgery. If these factors are taken into account along with the criteria already outlined involving the patient's cultural dimensions and the involved costs a decision can be made whether to proceed with hand transplantation. Being a difficult complex decision, it is imperative that it be made not only by an individual or group, either the patient or the medical team (ethical decision), but in conjunction with public discussion (bioethical decision) that not only takes into account the risks, benefits, and costs, but by including all criteria must also be at least technical, human, and social. PMID- 22099832 TI - What is the true significance of donor-related cytomegalovirus transmission in the setting of facial composite tissue allotransplantation? AB - Face transplantation (FT) is fraught with complications parallel to solid organ transplantation (SOT). As such, donor-related cytomegalovirus (CMV) transmission remains one of the most commonly feared viruses associated with FT. With this in mind, a review of the literature seemed justified, knowing that two of the first four face transplant recipients acquired CMV donor-related viral infection. Although the risk of CMV transmission is acceptable in the setting of SOT, the scenario for those composite tissue allotransplantation (CTA) patients, who are often young and healthy, may be different. Experiences from France and Cleveland have both confirmed suboptimal events related to CMV transmission following transplantation. Therefore, using the information provided here, it is imperative that all FT teams remain aware of these potential risks. Furthermore, all patients pursuing facial CTA should be fully informed as to the risks of donor related CMV transmission, understand the importance of prophylaxis, and be aware of alternative therapies required to prevent symptomatic disease. PMID- 22099833 TI - Quadrimembral amputation: indications and contraindications for vascularized composite allotransplantation. AB - INTRODUCTION: Quadrimembral amputees, as patients who have lost both upper and lower extremities, may benefit greatly from hand transplantation. The objective of this study is to evaluate the indications and contraindications for transplantation in this subset of patients. METHODS: A retrospective review was conducted of five quadrimembral amputees evaluated by our program for transplantation. Information collected included age, sex, level of amputations, time since amputations, etiology, level of dependence, medical stability, psychosocial status, and the ability to tolerate immunosuppression. Indications and contraindications for transplantation were reviewed for each patient. RESULTS: All etiologies were based in extremity ischemia: three from septic shock, one from myocardial infarction, and one from drug overdose. All patients are completely dependent. Of the five patients, two needed further reconstructive surgery and two others had a history of resolved hepatic/renal insufficiency. After thorough evaluation, two patients were selected as potential transplant candidates. They demonstrated strong psychosocial support systems, a thorough understanding of hand transplantation, along with its risks and postoperative requirements. They had also completed a full regimen of rehabilitation along with prosthetic fitting and utilization. CONCLUSIONS: Clearance for transplantation is based on medical stability, absence of infection or systemic diseases, and strong psychosocial support systems. Contraindications for transplantation are drug dependence and noncompliant behavior. Relative contraindications include a history of hepatic/renal insufficiency which if not resolved may preclude the use of postoperative immunosuppression. PMID- 22099834 TI - Potential of a hand transplantation program in Colombia. AB - The protocols and published results on hand transplantation show acceptable results of this technology. None of the registered groups, however has a sufficient number of patients to allow continuity of the process. In Colombia the main problems are violence, drug traffic, and guerrillas. Thanks to the profitability of drug traffic, guerrillas, who initially were created based on ideologic differences, have become terrorist groups whose main source of income is drug traffic. From that interest comes the use of landmines to protect illicit crops. Colombia is the most mined country in the world, followed by Cambodia and Afghanistan, and the only country in Latin America where there are still landmines. The mines, violence, and trauma produce a large number of people with disabilities and amputations. From 1990 to 2006, the number of victims rose from 21 to 1,041 per year. In Colombia, amputations are more frequently due to trauma than to disease. The fact that 88% of the victims are children and people of working age, affects the political and economic development. These alarming numbers generate a challenge for government, which has led to the creation of policies and laws aimed at comprehensive action against mines. This program under the Presidency has among its objectives assistance to victims, including integrated treatment, prostheses, and other procedures, financed entirely by the government. The number, type of victims, and their motivation to be transplanted, along with government programs directed to their attention, are key factors that we think will enable the continuity of our hand transplantation program at the Fundacion Santa Fe de Bogota, giving Colombia the unfortunate privilege of having the largest number of potential patients for transplantation. PMID- 22099835 TI - Full face transplantation organization, development, and results--the Barcelona experience: a case report. AB - The initial experience in facial composite tissue allotransplantation has demonstrated that it is surgically feasible, safe, and reproducible. A robust team approach is necessary to warrant successful outcomes. We designed a specific face organ donation that limits facial donation requests followed by synchronous in situ dissection with the internal organs that has proved to be efficient and safe for face and solid organ procurement and transplantation. The first human full face transplantation in our institution was performed on March 27, 2010. The holistic team approach of donation and procurement proved to be effective and reproducible; the recipient showed excellent outcomes at 12 months. PMID- 22099836 TI - WITHDRAWN: The extended abdominal wall flap for transplantation. AB - INTRODUCTION: Patients with extensive loss of abdominal wall tissue have few options for restoring the abdominal cavity. Composite tissue allotransplantation has been used for limited abdominal wall reconstruction in the setting of visceral transplantation, yet replacement of the entire abdominal wall has not been described. The purpose of this study was to determine the maximal abdominal skin surface available through an external iliac/femoral cuff-based pedicle. MATERIALS AND METHODS: Five human cadaver abdominal walls were injected with methylene blue to analyze skin perfusion based on either the deep inferior epigastric artery (DIEA; n = 5) or a cuff of external iliac/femoral artery (n = 5) containing the deep circumflex iliac, deep inferior epigastric, superficial inferior epigastric, and the superficial circumflex iliac arteries. RESULTS: Abdominal wall flaps were taken full thickness from the costal margin to the mid axial line and down to the pubic tubercle and proximal thigh. In all specimens, the deep inferior epigastric, deep circumflex iliac, superficial inferior epigastric, and the superficial circumflex iliac arteries were found to originate within a 4-cm cuff of the external iliac/femoral artery. Abdominal wall flaps injected through a unilateral external iliac/femoral segment had a significantly greater degree of total flap perfusion than those injected through the DIEA alone (76.5 +/- 4% versus 57.2 +/- 5%; Student t test, P < .05). CONCLUSIONS: Perfusion of a large portion of the abdominal wall is possible using single-vessel anastomosis through a short segment of the external iliac/femoral system. Perfusion is significantly greater than that based on the DIEA vessel alone. PMID- 22099837 TI - Biologics and donor bone marrow cells for targeted immunomodulation in vascularized composite allotransplantation: a translational trial in swine. AB - INTRODUCTION: Bone marrow (BM) infusion following organ transplantation is a prerequisite for potential donor-antigen-specific tolerance induction. We developed a preclinical swine model to determine the optimal dose of BM cells to achieve microchimerism. Furthermore, induction therapy was optimized by augmenting the BM infusion with biologics in the form of costimulatory blockade: cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig). MATERIALS AND METHODS: Yucatan miniature swine (n = 12) underwent total body and thymic irradiation for cytodepletion. Animal groups received 15, 30, or 60 million cells per kilogram of whole unmodified BM. The optimal dose of BM cell infusion (BMT) was then applied to subsequent experiments evaluating the addition of CTLA4lg. Group 1 (control) received no treatment. Group 2 received FK506 only; group 3 received irradiation, BMT, and FK506; group 4 received FK506 and CTLA4-lg. RESULTS: Microchimerism was established in all animals after BM cell infusion; at postoperative day 9, it was significantly increased for 60 million cells per kilogram (P = .0001). Transplanted animals in group 1 rejected the allograft 5 to 8 days after transplantation. Group 2 rejected the allograft (skin and muscle) 30 to 32 days after transplantation (2 days after cessation of immunosuppression). Group 3 rejected the skin portion of the allograft at 50, 52, and 53 days posttransplant. Remaining allograft components (muscle, bone, nerve, vessel) survived indefinitely. Group 4 animals demonstrated significantly prolonged muscle survival beyond 150 days posttransplant; the skin component survived past 150 days in two of three animals. Skin and muscle histology in all long-term surviving animals were normal. CONCLUSIONS: BM cell infusion with 60 million cells per kilogram results in stable levels of microchimerism. The addition of costimulatory blockade (CTLA4lg) prolonged allograft skin survival and overall graft survival. Such targeted immunomodulatory protocols might facilitate immune tolerance and eliminate the need for multidrug immunosuppression to maintain graft survival after vascularized composite allotransplantation. PMID- 22099838 TI - Engineering of bone marrow cells with fas-ligand protein-enhances donor-specific tolerance to solid organs. AB - Effective immunomodulation to induce tolerance to tissue/organ allografts is attained by infusion of donor lymphocytes endowed with killing capacity through ectopic expression of a short-lived Fas-ligand (FasL) protein. The same approach has proven effective in improving hematopoietic stem and progenitor cell engraftment. This study evaluates the possibility of substitution of immune cells for bone marrow cells (BMC) to induce FasL-mediated tolerance to solid organ grafts. Expression of FasL protein on BMC increased the survival of simultaneously grafted vascularized heterotopic cardiac grafts to 90%, as compared to 30% in recipients of naive BMC. Similar results were obtained for skin allografts implanted into radiation chimeras at 1 week after bone marrow transplantation. Further reduction of preparative conditioning to busulfan resulted in acceptance of donor skin implanted at 2 weeks after transplantation of naive and FasL-coated BMC, whereas third-party grafts were acutely rejected. The levels of donor chimerism were in the range of 0.7% to 12% at the time of skin grafting, with higher levels in recipients of FasL-coated BMC. It is concluded that FasL-mediated abrogation of alloimmune responses can be effectively attained with BMC. There is no threshold of donor chimerism, but tolerance to solid organs evolves during the process of donor-host mutual acceptance. PMID- 22099839 TI - Vascularized bone marrow transplantation model in rats as an alternative to conventional cellular bone marrow transplantation: preliminary results. AB - The aim of the study was to follow the development of microchimerism after allogeneic vascularized bone marrow transplantation (VBMT) versus conventional bone marrow transplantation (BMT). In one group, a VBMT model consisted of donor Brown Norway rat hind limb heterotopic transplanted on recipient Lewis rats. An intravenous infusion of donor bone marrow cells in suspension equivalent to that grafted in the vascularized femur limb was administered intravenously to recipient rats in the second group. Cellular microchimerism was investigated in recipients of VBMT versus BMT. Donor-derived cells could be detected in VBMT recipients at 30 and 60 days but not in recipients of intravenous suspension of BMC. VBMT provides a theoretical alternative to conventional cellular bone marrow transplantation by addressing crucial clinical problems such as failure of engraftment or graft-versus-host disease. PMID- 22099840 TI - Vascularized anal autotransplantation model in rats: preliminary report. AB - Ostomy has served as an effective surgery for various anorectal disfunctions. However, it must also be noted that those patients suffered greatly from stresses caused by their stoma. Many alternative therapies have been developed, but none have solved this critical issue. Meanwhile, due to the improvements in operative methods and immunosuppressive therapy, allotranplantation has gained great popularity in recent years. Therefore, we began development of an anal transplantation model. The operation was performed in six adult Wistar rats that were divided into two groups. Group 1 underwent vascular anastomoses, while group 2 did not Group 1 grafts survived, fully recovering anal function. However, many of the group 2 grafts did not survive; those that did survive showed major defects in their anus, never recovering anal function. We succeeded in establishing the rat anal transplantation model utilizing super-microsurgery. While research in anal transplantation was behind compared to that in other fields, we hope that this model will bring significant possibilities for the future. PMID- 22099841 TI - The first (double) hand transplantation in Turkey. AB - In September 2010, a bilateral hand allotransplantation was performed on a 28 year-old man who had suffered amputations at the level of 1/3 of the proximal forearm on the right and 1/3 of the distal forearm on the left 2 years previously. This was the first hand transplantation case in Turkey. Preoperative organization, legal difficulties, technical aspects of the operation, and immunosuppressive regimen are detailed herein. The early results of the first composite tissue allograft (CTA) transplantation are also reported. The results were encouraging for all future types of CTA transplantation, including hand and face. Following the early promising outcome of the first case of hand transplantation in Turkey, we have accelerated preparation of regulations for CTA transplantation, including hand and face allotransplantation. PMID- 22099842 TI - San Antonio military and civilian hand transplantation program: a case report. AB - Presented is a report on the first female hand allotransplantation performed in the USA. The patient sustained a dominant hand amputation at the level of the wrist as a result of a bomb explosion while on active duty in the United States Air Force. A hand allotransplantation was performed at a military treatment facility by a team of physicians composed of representatives from private practice, academia, and military medical institutions. PMID- 22099843 TI - Unilateral arm transplant 28 years after amputation: fourteen-month result. AB - Hand transplantation now represents a therapeutic alternative for amputees. Arm transplantation poses a serious challenge regarding many respects of the reconstructive procedure. To the end of 2010, only seven such procedures had been performed in four patients. The goal of this article was to present the preliminary results of an arm transplant in a 30-year-old male patient at 14 months. The patient sustained an amputation at the elbow-joint level as a 2-year old child. The procedure was performed in October 2010. His postoperative course was complicated by one rejection episode (BANFF grade II), and a de novo cytomegalovirus infection. At this early stage, the patient is doing well regaining function. He can flex at the elbow joint, move his fingers, and experience protective sensitivity reaching the palm. The patient is satisfied with his transplantation. PMID- 22099844 TI - Physiology of skin aging. AB - Skin is the most voluminous organ of the body. It assumes several important physiological functions and represents also a "social interface" between an individual and other members of society. This is the main reason its age dependent modifications are in the forefront of dermatological research and of the "anti-aging" cosmetic industry. Here we concentrate on some aspects only of skin aging, as far as the cellular and extracellular matrix components of skin are concerned. Most well studied mechanisms of skin aging can be situated at the postgenetic level, both epigenetic and post-translational mechanisms being involved. Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging. PMID- 22099845 TI - Stiffening of human skin fibroblasts with age. AB - Changes in mechanical properties are an essential characteristic of the aging process of human skin. Previous studies attribute these changes predominantly to the altered collagen and elastin organization and density of the extracellular matrix. Here, we show that individual dermal fibroblasts also exhibit a significant increase in stiffness during aging in vivo. With the laser-based optical cell stretcher we examined the viscoelastic biomechanics of dermal fibroblasts isolated from 14 human donors aged 27 to 80. Increasing age was clearly accompanied by a stiffening of the investigated cells. We found that fibroblasts from old donors exhibited an increase in rigidity of ~60% with respect to cells of the youngest donors. A FACS analysis of the content of the cytoskeletal polymers shows a shift from monomeric G-actin to polymerized, filamentous F-actin, but no significant changes in the vimentin and microtubule content. The rheological analysis of fibroblast-populated collagen gels demonstrates that cell stiffening directly results in altered viscoelastic properties of the collagen matrix. These results identify a new mechanism that may contribute to the age-related impairment of elastic properties in human skin. The altered mechanical behavior might influence cell functions involving the cytoskeleton, such as contractility, motility, and proliferation, which are essential for reorganization of the extracellular matrix. PMID- 22099846 TI - Tissue engineering of skin. AB - Each one of us is a self-organizing mass of multiple cell types. From fertilization of the embryo our tissue structures develop until an adult morphology is achieved. At that point our capacity for self-organization is directed to maintaining that morphology in the face of the insults of our daily life and the processes of aging. When a given insult overwhelms our capacity to repair by regeneration the result is scar repair. PMID- 22099847 TI - Skin tissue engineering--in vivo and in vitro applications. AB - Significant progress has been made over the years in the development of in vitro engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin or for the establishment of human-based in vitro skin models. This review summarizes these advances in in vivo and in vitro applications of tissue-engineered skin. We further highlight novel efforts in the design of complex disease-in-a-dish models for studies ranging from disease etiology to drug development and screening. PMID- 22099848 TI - Pre- and probiotics for human skin. AB - Current research on the complex interplay between the microbiota, the barrier function and the innate immune system of the skin indicates that the skin's microbiota have a beneficial role, much like that of the gut microflora. As a consequence, interest in strategies beyond antibiotica that allow a more selective modulation of the skin microflora is constantly growing. This review will briefly summarize our current understanding of the cutaneous microbiota and summarize existing information on pre- and probiotic strategies for skin. PMID- 22099849 TI - Dermal substitutes do well on dura: comparison of split skin grafting +/- artificial dermis for reconstruction of full-thickness calvarial defects. AB - Large, full-thickness calvarial defects present a series of significant reconstructive challenges involving a range of techniques, including local and free flaps. Occasionally these conventional methods may not be possible due to technical, or patient, factors. Artificial dermis is already widely used in burns surgery and is increasing in oncological reconstruction. We believe that artificial dermis coupled with split-thickness skin grafting provides an excellent option for closure of these defects when other techniques are not appropriate. PMID- 22099850 TI - Management of wounds with exposed bone structures using an artificial dermis and skin grafting technique. AB - The task of managing an open wound complicated by exposed bony structures underneath is difficult, if not challenging. We have instituted a method of managing the problems in stages using an artificial dermis and skin grafting technique in 17 wounds in 15 individuals from Sept. 2006 to Feb. 2009. While all wounds were noted to assume aberrant healing processes, the majority of involved bony structures were devoid of periosteal covering compounded by various degrees of infection. Of 15 incidents, mechanical trauma was responsible for 10, chemical burns for two and electrical burns for two patients. A chronic non-healing ulcer with exposed bone formed in an old burn scar accounted for the remaining one. The regimen of surgical management consisted of initial debridement, the coverage of the resultant wound with an artificial dermis and a partial-thickness skin grafted over this dermis-like structure grown with granulation tissues. Complete wound healing was attained in 15 out of 17 with outstanding cosmetic and minimal donor-site morbidity. Despite initial failure encountered in two, the morbidities noted were low. It is especially useful in large defects that usually require flaps for coverage. PMID- 22099851 TI - Management of split skin graft donor sites-results of a national survey. AB - The authors wished to obtain a 'snapshot' of the range of practice in the management of split skin graft donor sites in the British Isles. Material/Methods Questionnaires were sent to all British consultants and locum consultant plastic surgeons on July 1, 2006. Of the 357 questionnaires, 279 were returned (a response rate of 78%). Results Alginates were the most popular dressings, especially in adult donor sites - first choice for 167 respondents (60%). Adhesive fabrics were less popular - first choice for small adult donor areas for 46 respondents (16%). Plastic film dressings and Biobrane were even less popular being the first choice for small and large donor areas, respectively, in children (for approximately 5% of respondents). Ten percent of respondents said they avoid paraffin gauze and another 10% avoid plastic film dressings in all cases. Five percent avoid hydrocolloid and another 5% avoid adhesive fabric in all cases. Conclusion on the basis of these results, the authors feel that any future study of donor-site dressings should incorporate the most commonly used dressing (alginate) as a control. PMID- 22099852 TI - Skin: histology and physiology of wound healing. AB - It is important to understand the histology and physiology of skin for the prediction and optimization of wound healing. Optimal postoperative wound healing to minimize scarring entails minimizing local, systemic, and environmental factors that lead to poor wound healing. Keeping the wound clean and moist, minimizing trauma, and infection are the local wound tenets. Systemic tenets include minimizing medications that inhibit processes of wound healing, maintaining adequate nutrition, pain palliation, UV protection, and smoking cessation. This article presents the dynamic process of wound healing and the basic tenets to minimize scarring. PMID- 22099854 TI - Caenorhabditis elegans: a model to monitor bacterial air quality. AB - BACKGROUND: Low environmental air quality is a significant cause of mortality and morbidity and this question is now emerging as a main concern of governmental authorities. Airborne pollution results from the combination of chemicals, fine particles, and micro-organisms quantitatively or qualitatively dangerous for health or for the environment. Increasing regulations and limitations for outdoor air quality have been decreed in regards to chemicals and particles contrary to micro-organisms. Indeed, pertinent and reliable tests to evaluate this biohazard are scarce. In this work, our purpose was to evaluate the Caenorhaditis elegans killing test, a model considered as an equivalent to the mouse acute toxicity test in pharmaceutical industry, in order to monitor air bacterial quality. FINDINGS: The present study investigates the bacterial population in dust clouds generated during crop ship loading in harbor installations (Rouen harbor, Normandy, France). With a biocollector, airborne bacteria were impacted onto the surface of agar medium. After incubation, a replicate of the colonies on a fresh agar medium was done using a velvet. All the replicated colonies were pooled creating the "Total Air Sample". Meanwhile, all the colonies on the original plate were isolated. Among which, five representative bacterial strains were chosen. The virulence of these representatives was compared to that of the "Total Air Sample" using the Caenorhaditis elegans killing test. The survival kinetic of nematodes fed with the "Total Air Sample" is consistent with the kinetics obtained using the five different representatives strains. CONCLUSIONS: Bacterial air quality can now be monitored in a one shot test using the Caenorhaditis elegans killing test. PMID- 22099855 TI - Brain networks in posterior cortical atrophy: a single case tractography study and literature review. AB - Posterior cortical atrophy (PCA) is rare neurodegenerative dementia, clinically characterized by a progressive decline in higher-visual object and space processing. After a brief review of the literature on the neuroimaging in PCA, here we present a study of the brain structural connectivity in a patient with PCA and progressive isolated visual and visuo-motor signs. Clinical and cognitive data were acquired in a 58-years-old patient (woman, right-handed, disease duration 18 months). Brain structural and diffusion tensor (DT) magnetic resonance imaging (MRI) were obtained. A voxel-based morphometry (VBM) study was performed to explore the pattern of gray matter (GM) atrophy, and a fully automatic segmentation was assessed to obtain the hippocampal volumes. DT MRI based tractography was used to assess the integrity of long-range white matter (WM) pathways in the patient and in six sex- and age-matched healthy subjects. This PCA patient had a clinical syndrome characterized by left visual neglect, optic ataxia, and left limb apraxia, as well as mild visuo-spatial episodic memory impairment. VBM study showed bilateral posterior GM atrophy with right predominance; DT MRI tractography demonstrated WM damage to the right hemisphere only, including the superior and inferior longitudinal fasciculi and the inferior fronto-occipital fasciculus, as compared to age-matched controls. The homologous left-hemisphere tracts were spared. No difference was found between left and right hippocampal volumes. These data suggest that selective visuo-spatial deficits typical of PCA might not result from cortical damage alone, but by a right-lateralized network-level dysfunction including WM damage along the major visual pathways. PMID- 22099856 TI - Teriparatide's potential role in jaw bone related diseases. PMID- 22099857 TI - Neural hyperplasia in maxillary bone of multiple endocrine neoplasia type 2B patient. AB - Multiple endocrine neoplasia (MEN) type 2B is the rarest and most aggressive form of MEN syndrome. MEN 2B patients manifest characteristic oral and facial features besides the neural crest cell-derived tumors, including medullary carcinoma, pheochromocytoma, mucosal neuroma, and ganglioneuromatosis of the gut. We report a case of MEN 2B diagnosed on the basis of the warning signs of mucosal neuroma and multiple neural hyperplasias in the maxillary bone resected during orthognathic surgery. A subsequent systemic examination under the pathologic diagnosis of neural lesions revealed medullary thyroid carcinoma, megacolon, thickened corneal nerves, and RET gene mutation, thus verifying the diagnosis of MEN 2B. An immunohistochemical study revealed an increased number of unmyelinated Schwann cells in the hyperplastic nerves. We suggest that intraosseous neural hyperplasia is a specific finding of the MEN 2B syndrome in addition to the known oral and facial manifestations. PMID- 22099858 TI - Efficacy of sodium hypochlorite, ethylenediaminetetraacetic acid, citric acid and phosphoric acid in calcium hydroxide removal from the root canal: a microscopic cleanliness evaluation. AB - Rooted molars were subjected to standardized canal instrumentation to a master apical file (MAF). The samples were dressed with Ca(OH)(2), and after 7 days, teeth were reopened and Ca(OH)(2) medication was removed by 1 of 4 different experimental procedures: 2.5% sodium hypochlorite (NaOCl) (n = 10); 17% EDTA-T (n = 10); 10% citric acid (n = 10); or 37% phosphoric acid (n = 10). This was followed by reinstrumentation with MAF plus 15 mL saline solution. The roots were prepared for scanning electron microscopic analysis of the cervical, middle, and apical thirds. Statistical analysis was performed with the Kruskal-Wallis test. EDTA-T and phosphoric acid gave the best results in the apical third, with significant statistical differences compared with other groups. NaOCl gave the worst results. Irrigation with 17% EDTA-T and 37% phosphoric acid is more effective than sodium hypochlorite and citric acid in the removal of calcium hydroxide from the apical third. PMID- 22099859 TI - A prospective cohort study of endodontic treatments of 1,369 root canals: results after 5 years. AB - OBJECTIVE: The purpose of this prospective study was: 1) to follow-up a large number of endodontic treatments performed by a single operator, periodically checked over a 5-year period; and 2) to correlate outcome to a number of clinical variables. STUDY DESIGN: This prospective study included all consecutive cases during the selected time period. All cases were followed regularly for a 5-year period. At the 5-year end point of the study, 470 patients with 816 treated teeth and with 1,369 treated root canals were available for evaluation. RESULTS: The overall rate of success among the 816 teeth/1,369 root canals available for evaluation was 88.6%/90.3%. The success rate for 435 teeth/793 root canals undergoing vital pulp therapy was 91.5%/93.1%. Teeth/root canals with necrotic pulp but without detectable periapical bone lesion were successfully treated in 89.5%/92.3%. If the pulp necrosis was complicated by apical periodontitis, the success rate fell to 82.7% for the teeth and 84.1% for the root canals (P = .037). Teeth with periapical lesion <5 mm had a success rate of 86.6%, and in cases where the lesion was >= 5 mm the rate of success was 78.2%. CONCLUSIONS: More severe disease conditions negatively affects outcome. An optimal working length was identified. Excess of root canal filling material decreases success. Infected pulp space should be treated with an effective intracanal dressing. The quality of the coronal restoration or the placement of intracanal post retentions does not affect treatment outcome. PMID- 22099860 TI - Effect of propolis on proliferation and apoptosis of periodontal ligament fibroblasts. AB - The most critical factors affecting the prognosis of an avulsed tooth are extraoral dry time and storage media used before replantation. Studies have analyzed different storage media to determine the ideal solution to preserve periodontal ligament (PDL) cell viability. Propolis has anti-inflammatory and antimicrobial properties, and has been previously suggested as a storage medium. The purpose of this study was to assess not only cell viability but also physiological health of PDL cells after exposure to propolis. PDL cells were exposed to different concentrations of propolis or Hanks balanced salt solution, and the apoptotic levels were determined using apoptosis assay and flow cytometry. Additional cell viability and proliferation were analyzed by XXT assay in dry and wet conditions. Propolis not only decreased apoptosis but also increased the metabolic activity and proliferation of PDL cells. This study suggests that propolis is a suitable storage medium for avulsed teeth. PMID- 22099861 TI - Home foreclosure and risk of psychiatric morbidity during the recent financial crisis. AB - BACKGROUND: A defining feature of the US economic downturn of 2008-2010 was the alarming rate of home foreclosure. Although a substantial number of US households have experienced foreclosure since 2008, the effects of foreclosure on mental health are unknown. We examined the effects of foreclosure on psychiatric symptomatology in a prospective, population-based community survey. METHOD: Data were drawn from the Detroit Neighborhoods and Health Study (DNHS), waves 1 and 2 (2008-2010). A probability sample of predominantly African-American adults in Detroit, Michigan participated (n=1547). We examined the association between home foreclosure between waves 1 and 2 and increases in symptoms of DSM-IV major depression and generalized anxiety disorder (GAD). RESULTS: The most common reasons for foreclosure were an increase in monthly payments, an increase in non medical expenses and a reduction in family income. Exposure to foreclosure between waves 1 and 2 predicted symptoms of major depression and GAD at wave 2, controlling for symptoms at wave 1. Even after adjusting for wave 1 symptoms, sociodemographics, lifetime history of psychiatric disorder at wave 1 and exposure to other financial stressors between waves 1 and 2, foreclosure was associated with an increased rate of symptoms of major depression [incidence density ratio (IDR) 2.4, 95% confidence interval (CI) 1.6-3.6] and GAD (IDR 1.9, 95% CI 1.4-2.6). CONCLUSIONS: We provide the first prospective evidence linking foreclosure to the onset of mental health problems. These results, combined with the high rate of home foreclosure since 2008, suggest that the foreclosure crisis may have adverse effects on the mental health of the US population. PMID- 22099862 TI - How drug policy should (not) be: institutionalised young people's perspectives. AB - BACKGROUND: Drug prevention is insufficiently tailored to the needs of vulnerable groups and often concentrates on the general population. METHODS: A qualitative youth-centred design, based on group techniques was used to ask vulnerable young people about their needs and expectations regarding drug prevention practices. Participants comprised 160 young people, aged 12-21 years who had emotional and behavioural disorders and who lived in institutions in the mental health care system in Flanders. RESULTS: Findings showed that common prevention and education practices are often insufficient or not applicable to the participants' situation. The young people criticised the institutions' reaction to drug use because it tried to control and sanction their use and paid scant attention to their reasons for drug use. They also held negative views about drug treatment. Their experiences had taught them that control and sanctioning were the dominant reactions to drug use. CONCLUSION: If drug (prevention) policy is to appeal to vulnerable young people, their views on what would make a good prevention policy must be taken into account. PMID- 22099863 TI - Windows of opportunity: adapting services to the needs of people who inject drugs. PMID- 22099864 TI - Can sacral neuromodulation improve minor incontinence symptoms in doubly incontinent patients successfully treated for major incontinence symptoms? AB - OBJECTIVE: To describe the effect of sacral nerve modulation (SNM) on less severe types of incontinence in patients who were successfully implanted for either urinary or fecal incontinence, and who presented with double incontinence. When conservative treatments fail, SNM is a first-line treatment for patients with urge urinary or fecal incontinence. METHODS: All patients who received SNM between 2005 and 2010 at 5 hospitals and who still had the implant were included in our survey. All received a urinary and fecal change and quality of life questionnaire by mail to complete. RESULTS: Of the 51 questionnaires sent out, 37 were returned, for a 72.5% response rate. The population was composed of 97.3% women, with a mean age of 56.8 years (SD 14). The main indication for SNM was urge urinary incontinence in 15 patients (40.5%) and fecal incontinence in 22 patients (59.5%). Eighteen patients (48.7%) had improvements in both urinary and fecal incontinence symptoms. The percentage increased to 53.3% (16/30) in the group of patients with urge urinary incontinence associated with fecal incontinence. Patients who reported an improvement in double incontinence symptoms complained more often of urge urinary incontinence than other patients (P=.04). CONCLUSIONS: Of the doubly incontinent patients who were successfully implanted for a predominant type of incontinence (ie, urinary or fecal incontinence), 48.7% had an improvement in the other type of incontinence. Patients with urge urinary incontinence associated with fecal incontinence were more likely to report an improvement in double incontinence than the other patients. PMID- 22099865 TI - Expression of PSA-NCAM and synaptic proteins in the amygdala of psychiatric disorder patients. AB - Neuroimaging has revealed structural abnormalities in the amygdala of different psychiatric disorders. The polysialylated neural cell adhesion molecule (PSA NCAM), a molecule related to neuronal structural plasticity, which expression is altered in schizophrenia, major depression and in animal models of these disorders, may participate in these changes. However, PSA-NCAM has not been studied in the human amygdala. To know whether its expression and that of presynaptic markers, was affected in psychiatric disorders, we have analyzed post mortem sections from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. PSA-NCAM was expressed in neuronal somata and neuropil puncta, many of which corresponded to interneurons. Depressed patients showed decreases in PSA-NCAM expression in the basolateral and basomedial amygdala; synaptophysin and GAD67 were also decreased, while VGLUT-1 was increased, in different nuclei. Increases in PSA-NCAM expression were found in the lateral nucleus of bipolar patients; synaptophysin and GAD67 were reduced, and VGLUT-1 increased, in their basolateral and lateral nuclei. The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. These results indicate that inhibitory and excitatory amygdaloid circuits are affected in these disorders and that abnormal PSA-NCAM expression in depressive and bipolar patients may underlie these alterations. PMID- 22099866 TI - White matter structure and symptom dimensions in obsessive-compulsive disorder. AB - There is evidence that the different symptom dimensions in obsessive-compulsive disorder (OCD) may be mediated by partially distinct neural systems. This DTI study investigated the relationship between symptom dimensions and white matter microstructure. Fractional anisotropy (FA), axial and radial diffusivity was analyzed in relation to the main OCD symptom dimensions. Symptom severity on the obsessing dimension was negatively correlated with FA in the corpus callosum and the cingulate bundle. Severity on the ordering dimension was negatively correlated with FA in, amongst others, the right inferior fronto-occipital fasciculus and the right optic radiation. All correlations were ascribable to alterations in radial diffusivity while there was no association between symptoms and axial diffusivity. Present results illustrate an association between alterations in visual processing tracts and ordering symptoms which are characterized by altered visual processing and increased attention towards irrelevant detail. They also indicate an association between obsessive thoughts and alterations in structures known to be relevant for cognitive control and inhibition. Hence, different symptom dimensions must be taken into account in order to disentangle the neurobiological underpinnings of OCD. PMID- 22099867 TI - A longitudinal test of video game violence influences on dating and aggression: a 3-year longitudinal study of adolescents. AB - BACKGROUND: In 2011 the field of video game violence experienced serious reversals with repudiations of the current research by the US Supreme Court and the Australian Government as non-compelling and fundamentally flawed. Scholars too have been calling for higher quality research on this issue. The current study seeks to answer this call by providing longitudinal data on youth aggression and dating violence as potential consequences of violent video game exposure using well-validated clinical outcome measures and controlling for other relevant predictors of youth aggression. METHOD: A sample of 165, mainly Hispanic youth, were tested at 3 intervals, an initial interview, and 1-year and 3-year intervals. RESULTS: Results indicated that exposure to video game violence was not related to any of the negative outcomes. Depression, antisocial personality traits, exposure to family violence and peer influences were the best predictors of aggression-related outcomes. INTERPRETATION: The current study supports a growing body of evidence pointing away from video game violence use as a predictor of youth aggression. Public policy efforts, including funding, would best be served by redirecting them toward other prevention programs for youth violence. PMID- 22099868 TI - Psychophysiological mechanisms underlying spatial attention in children with primary headache. AB - OBJECTIVE: Neurophysiological studies to evaluate spatial attention in children with primary headache are lacking. Tactile spatial attention modulates the N140 somatosensory evoked potential (SEP) amplitude. The aims of the study are: (1) to investigate the effect of spatial attention on the N140 amplitude in children with migraine and tension-type headache (TTH) and in healthy children, and (2) to correlate the neurophysiological results with a neuropsychological test for spatial attention. METHODS: We studied 16 patients with migraine without aura (MoA), 12 TTH children and 10 healthy subjects. "Deux Barrage" test for spatial attention was administered. SEPs were recorded in a neutral condition (NC) and in a spatial attention condition (SAC). RESULTS: No significant differences in neuropsychological measures were found between MoA, TTH and healthy subjects. The N140 amplitude increase during SAC, as compared to NC, was significantly higher in patients than in healthy controls. Migraineurs showed a positive correlation between the N140 amplitude increase during SAC and their neuropsychological performance. CONCLUSIONS: Although spatial attention performances in children with headache are as good as in controls, the N140 amplitude increase during SAC in headache patients suggests that the psychophysiological mechanisms subtending spatial attention are different from those in healthy children. PMID- 22099869 TI - Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study. AB - PURPOSE: To evaluate the GABA(A) receptor in the autistic brain, we performed (123)I-IMZ SPECT in patients with ASD. We compared (123)I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. SUBJECTS AND METHODS: The subjects consisted of 24 patients with ASD (mean age, 7.3+/-3.5 years), including 9 with autistic disorder (mean age, 7.0+/-3.7 years) and 15 with Asperger's disorder (mean age, 7.5+/-3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8+/-3.6 years) without intellectual delay as a control group. For an objective evaluation of the (123)I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. RESULTS: In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of (123)I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. CONCLUSION: The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of (123)I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind). PMID- 22099870 TI - Effect of transjugular intrahepatic portosystemic shunt on glycometabolism in cirrhosis patients. AB - OBJECTIVE: Patients with liver cirrhosis suffer from hyperinsulinemia, hyperglucagonemia and a certain degree of insulin resistance, and portosystemic shunts may be involved in the etiology. A transjugular intrahepatic portosystemic shunt (TIPS) as a treatment for the complications of portal hypertension leads to hemodynamic changes. The objective of the present study is to evaluate whether TIPS can also affect glycometabolism in cirrhosis patients. METHODS: Forty-six liver cirrhosis patients (experimental group [EG]) without diabetes who underwent TIPS were evaluated. Portal venous pressure (PVP), cardiac output (CO) and blood flow in the shunt (BFS) were measured or calculated before TIPS, after 15 minutes and, finally, after 90 days. Twenty-five liver cirrhosis patients without diabetes and without TIPS were included as the control group (CG). Oral glucose tolerance tests (OGTTs) were carried out at 0, 1, 7, 30 and 90 days after TIPS or after inclusion in the study. Indices related to glycometabolism and liver function, which included biochemical values, were also investigated. RESULTS: PVP changed immediately from 39.43 +/- 1.29 cmH(2)O to 21.43 +/- 1.42 cmH(2)O and remained stable thereafter. A pronounced increase in CO was observed after TIPS, while BFS did not change significantly. Also, glycosylated hemoglobin A(1c) (HbA(1c)), fasting plasma glucose (FPG), fasting plasma C-peptide (FPC), glucagon like peptide-1 (GLP-1) and 2-h post-challenge plasma glucose (2 hPG) were non significantly increased after the shunt. Statistically significant hyperinsulinemia and hyperglucagonemia persisted for 90 days after TIPS. In addition, TIPS was followed by an increase in insulin resistance (IR) and beta cell function. Thirty-four patients in the EG and 15 in the CG were diagnosed with diabetes or prediabetes after 90 days. No significant differences in biochemical values were observed 90 days after the shunt. CONCLUSION: In addition to causing hemodynamic changes, TIPS augments hyperglucagonemia because of increased secretion and decreased clearance of glucagon in the liver, whereas IR deteriorates after the procedure. However, glycemic control does not worsen after TIPS, and the procedure is not associated with a higher risk of diabetes largely because of the simultaneous increase in insulin. PMID- 22099871 TI - Open cap splint with circummandibular wiring for management of pediatric mandibular parasymphysis/symphysis fracture as a definitive treatment modality; a case series. AB - Management of pediatric maxillofacial injuries is mainly governed by their psychological, physiological, developmental, and anatomical characteristics. Pediatric mandibular fractures can have variable etiologies but have similar manifestations as those in adult patients. There are various treatment modalities to treat mandibular parasymphysis/symphysis fractures in children, which have their own limitations and complications. We currently describe our experience with open cap splint as a treatment modality which involves fewer risks in treating 10 pediatric parasymphysis/symphysis mandibular fractures. PMID- 22099872 TI - Adipose tissue inflammation and cancer cachexia: possible role of nuclear transcription factors. AB - Cancer cachexia is a multifaceted syndrome whose aetiology is extremely complex and is directly related to poor patient prognosis and survival. Changes in lipid metabolism in cancer cachexia result in marked reduction of total fat mass, increased lipolysis, total oxidation of fatty acids, hyperlipidaemia, hypertriglyceridaemia, and hypercholesterolaemia. These changes are believed to be induced by inflammatory mediators, such as tumour necrosis factor-alpha (TNF alpha) and other factors. Attention has recently been drawn to the current theory that cachexia is a chronic inflammatory state, mainly caused by the host's reaction to the tumour. Changes in expression of numerous inflammatory mediators, notably in white adipose tissue (WAT), may trigger several changes in WAT homeostasis. The inhibition of adipocyte differentiation by PPARgamma is paralleled by the appearance of smaller adipocytes, which may partially account for the inhibitory effect of PPARgamma on inflammatory gene expression. Furthermore, inflammatory modulation and/or inhibition seems to be dependent on the IKK/NF-kappaB pathway, suggesting that a possible interaction between NF kappaB and PPARgamma is required to modulate WAT inflammation induced by cancer cachexia. In this article, current literature on the possible mechanisms of NF kappaB and PPARgamma regulation of WAT cells during cancer cachexia are discussed. This review aims to assess the role of a possible interaction between NF-kappaB and PPARgamma in the setting of cancer cachexia as well as its significant role as a potential modulator of chronic inflammation that could be explored therapeutically. PMID- 22099873 TI - Selective killing of lung cancer cells using carcinoembryonic antigen promoter and double suicide genes, thymidine kinase and cytosine deaminase (pCEA-TK/CD). AB - The application of gene therapy in cancer treatment is limited by non-specific targeting. In the present study, we constructed a recombinant plasmid, containing a carcinoembryonic antigen (CEA) promoter and double suicide genes thymidine kinase (TK) and cytosine deaminase (CD), henceforth referred to as pCEA-TK/CD. Our results showed that the CEA promoter can specifically drive target gene expression in CEA-positive lung cancer cells. In the presence of prodrugs 5 flucytosine and ganciclovir, pCEA-TK/CD transfection decreased inhibitory concentration 50 and increased apoptosis and cyclomorphosis. Our result suggests that gene therapy using pCEA-TK/CD may be a promising new approach for treating lung cancer. PMID- 22099874 TI - Therapeutic approaches targeting midkine suppress tumor growth and lung metastasis in osteosarcoma. AB - Midkine (MK) plays important roles in tumorigenesis, however, the biological function of MK and whether MK can be a therapeutic target in osteosarcoma are unclear. Here, we found that osteosarcoma tissues showed high MK expression. MK knockdown by small interfering RNA significantly induced apoptosis in osteosarcoma cells, whereas recombinant MK increased cell proliferation. Inhibition of MK signaling by anti-MK monoclonal antibody (anti-MK mAb) suppressed growth of osteosarcoma cells both in vitro and in vivo. Moreover, inhibition of MK function significantly suppressed lung metastasis in xenograft transplantation model. Targeting MK by anti-MK mAb may have value in the treatment of osteosarcoma. PMID- 22099875 TI - Aberrant methylation of the PTPRO gene in peripheral blood as a potential biomarker in esophageal squamous cell carcinoma patients. AB - Epigenetic inactivation of protein tyrosine phosphatase receptor-type O (PTPRO), a new member of the PTP family, has been described in several forms of cancer. We evaluated PTPRO promoter hypermethylation as a potential biomarker in esophageal squamous cell carcinoma (ESCC). This alteration was observed in 27 (75%) of 36 primary tumors and correlated significantly with depth of invasion (T-stage, P = 0.013). Among matched peripheral blood samples from ESCC patients, 13 (36.1%) of 36 exhibited detectable methylated PTPRO in plasma, while 15 (41.7%) of 36 had this abnormality in buffy coat. No methylated PTPRO was observed in normal peripheral blood samples from 10 healthy individuals. In addition, demethylation by 5-aza-dC treatment led to gene reactivation in PTPRO-methylated and -silenced ESCC cell lines. To our knowledge, this is the first report of methylated PTPRO as a noninvasive tumor biomarker in peripheral blood. These findings suggest that hypermethylated PTPRO occurs frequently in ESCC. Further, detection in peripheral blood of ESCC patients suggests potential clinical application for noninvasive diagnosis and disease monitoring. PMID- 22099876 TI - Prostate cancer in the senior men from rural areas in east district of China: contemporary management and 5-year outcomes at multi-institutional collaboration. AB - OBJECTIVE: Prostate cancer is an underreported and emerging problem in China. Here we summarize the data for Chinese patients with prostate cancer (PCa), describe available treatment options, and report 5-year outcomes at multiple tertiary care institutions. PATIENTS AND METHODS: A series of 1611 patients (mean age 76.51 years) diagnosed with PCa were enrolled. Survival rates for patients were analyzed using the Kaplan-Meier method. Prognostic factors for disease specific survival were analyzed using the log-rank test and Cox proportional hazards model. RESULTS: Seven hundreds and thirty-two patients with a prostate tumor clinical stage of III or IV and 879 with a tumor clinical stage of I or II were diagnosed. The disease-specific survival rates at 1, 3 and 5 years were 94.6%, 81.3% and 72.6%, respectively. Five-year disease-specific survival rates were 99.2% for patients with low clinical stage PCa who underwent radical prostatectomy, 76.5% for those who underwent transurethral resection of the prostate plus hormone therapy, 38% for those who received hormone therapy plus radiation therapy and 29% for those that received hormone therapy alone. CONCLUSIONS: In keeping with a lack of prostate-specific antigen (PSA)-based screening, Chinese men present later in life and course of their disease, with over 27% men dying of PCa at five years. Debulking of tumors by surgery and radiation therapy for high grade tumor may provide some survival benefit in the senior men but further study is required to validate these findings. It is important of the annual use of PSA test for men over 50 years old to detect the PCa in the early stage in this nation. PMID- 22099877 TI - beta1 integrin is required for anchorage-independent growth and invasion of tumor cells in a context dependent manner. AB - Recent studies suggest that extracellular matrix (ECM) components within the tumor microenvironment can influence malignant progression, thus we investigated the influence of the ECM binding receptor beta1 integrin, on the hallmark properties of tumorigenesis. Small interfering (si) or short hairpin (sh) RNA approaches were used to deplete beta1 integrin in cancer cell lines. beta1 integrin-depleted cells were then assessed for their growth and invasive capabilities using 2-dimensional (2D) or 3D culture conditions. Depletion of beta1 integrin expression did not impact cell growth in 2D assay systems; however, beta1 integrin and its ligand fibronectin were required for growth in 3D. beta1 integrin-depleted cells also had reduced invasive capabilities, in part due to increased tissue inhibitor of metalloprotease (TIMP)-2 expression in conjunction with down-regulation of matrix metalloprotease (MMP)-9 levels in beta1 integrin-depleted cells. Our results suggest that despite no apparent effect on 2D cell growth, fibronectin-beta1 integrin signaling is a critical mediator of the 3D growth and invasive properties of tumor cells. These observations highlight the importance of investigating the role of adhesion molecules in the appropriate context and furthermore identify beta1 integrin as a possible therapeutic target to inhibit the aggressive growth and invasion of tumor cells. PMID- 22099878 TI - miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down regulates CCL20 expression in miR-21 transfected colorectal cancer cells. AB - As deregulation of miRNAs and chemokine CCL20 was shown to play a role in colorectal cancer (CRC) pathogenesis, we analyzed the functional interactions of candidate miRNAs with CCL20 mRNA. After target prediction software programs indicated a role for miR-21 in CCL20 regulation, we applied the luciferase reporter assay system to demonstrate that miR-21 functionally interacts with the 3'UTR of CCL20 mRNA and down-regulates CCL20 in miR-21 mimic transfected CRC cell lines (Caco-2, SW480 and SW620). Thus, regulation of CCL20 expression by miR-21 might be a regulatory mechanism involved in progression of CRC. PMID- 22099879 TI - Adoptive T-cell therapy of B-cell malignancies: conventional and physiological chimeric antigen receptors. AB - Hematological malignancies remain incurable diseases because of the high risk of relapse, even after complete remission. Adoptive T-cell therapy (ACT) using modified T cells with chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens expressed by B-cell malignancies represents an attractive approach for cancer immunotherapy. Investigators optimized the design of CARs to enhance receptor mediated T cell signaling and demonstrated that second and third generation CARs, including various costimulatory molecules, resulted in enhanced T-cell persistence and sustained antitumor activity in both in vitro and in vivo mouse models as well as clinical trials. We highlight advances in the use of CARs in the treatment of B-cell malignancies and future challenges in the use of adoptive therapy with CAR-engineered T cells. PMID- 22099880 TI - Orthostatic hypotension among outpatients with ischemic stroke. AB - BACKGROUND: The treatment of hypertension is an essential component of stroke prevention; however, the clinical management of patients with cerebrovascular disease is complicated by orthostatic hypotension (OH). The primary objectives were to: determine the prevalence of OH in a stroke outpatient clinic; describe categories of OH; and identify factors independently associated with the presence of OH. METHODS: Veterans with stroke, cared for in a multidisciplinary stroke clinic, were included. OH was defined as a >=20 mmHg fall in systolic blood pressure (BP), a >=10 mmHg fall in diastolic BP, or a >=10 mmHg fall in systolic BP with symptoms. Multivariable logistic regression was used to identify factors associated with OH including demographics, comorbidites, stroke severity, and baseline BP. RESULTS: Among 60 patients with stroke, 16 (27%) patients had OH. Among those with OH, half were hypertensive, seven were normotensive, and one was hypotensive. A history of coronary artery disease was independently associated with the presence of OH. CONCLUSIONS: Orthostatic hypotension is present in about one quarter of outpatients with stroke, and coronary artery disease appears to be a risk factor. Stroke patients should be screened for OH given that the presence of positional BP changes may alter clinical management. PMID- 22099881 TI - [Spontaneous electroencephalographic and magneto-encephalographic activity as a marker of Alzheimer's disease and mild cognitive impairment]. AB - The association between the electroencephalogram (EEG) and the study of cognitive impairment was observed from the beginning of using this technique. The introduction of the magnetoencephalogram (MEG) has enabled new lines of research to be developed with a potential for significant clinical applicability. Both techniques have a series of advantages, such as the direct detection of neuronal activity. The EEG-MEG spectral variations in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are also linked to essential physiological processes, such as neuronal disconnection or the deficiency in certain neurotransmitters. These spectral variations are basically characterised by a slowing down of the trace when spontaneous activity is registered, with an increase in the power of low frequency bands (delta and theta) and a decrease in the high frequency bands (alpha, beta, gamma). The spectral analysis gives sensitivity-specificity results of around 80%. By using MEG, it has been possible to specifically locate the sources of this low frequency activity, which has enabled the sensitivity of the test to be increased to 93.3%, particularly when combined with the nuclear resonance data. However, the most promising results come from longitudinal studies which attempt to predict those MCI patients with a higher risk of developing AD. In this case, some EEG studies have shown a sensitivity of 85% when detecting these patients. Even more important, some longitudinal MEG studies have been able to determine that high parietal delta activity increases the relative risk of developing AD by 350%. PMID- 22099882 TI - [Bullous pemphigoid: multidisciplinary approach to a dermatological syndrome in the elderly]. PMID- 22099883 TI - [Pneumococcal vaccination coverage and related factors among hospitalised patients aged 60 years and over]. PMID- 22099884 TI - [Prevalence of delirium in emergency department observation areas]. PMID- 22099885 TI - Coma, hyperammonemia, metabolic acidosis, and mutation: lessons learned in the acute management of late onset urea cycle disorders. AB - Urea cycle disorders are an important and treatable cause of hyperammonemia in the newborn and pediatric age group. Presentation in adolescence or adult life is rare and can manifest as frequent vomiting and behavioral changes. An inherited metabolic disorder should be considered in adults with obvious or occult encephalopathy. Failure to diagnose and treat rapidly may lead to irreversible neuronal damage. An improved understanding of the diagnosis and management of late-onset urea cycle disorders is needed to assist nephrologists in providing optimal care. This report describes the clinical characteristics of a young man with first presentation of hyperammonemia in adult life. PMID- 22099886 TI - Methicillin-resistant Staphylococcus aureus: an emerging pathogen of pets in Egypt with a public health burden. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged to be a pathogen of public health burden causing infections with significant concern. This study was conducted to investigate methicillin resistant Staphylococcus aureus (MRSA) infection in pet dogs and cats as an emerging zoonosis that could be disseminated in the community. A total of 184 (nasal, oral, ear and wound) swabs were collected from 70 pet dogs and 48 pet cats, whereas 50 nasal and oral swabs were collected from 28 apparently healthy companion persons in intimate contact with pets and without history of hospitalization. All samples were cultured for the isolation and identification of Staphylococcus aureus using selective media, biochemical and serological tests, while isolates were identified as MRSA after antimicrobial susceptibility testing and determination of the MIC. PCR was applied using specific primers to confirm MRSA. Three MRSA isolates have been recovered from two dogs of 70 (2.9%) and one isolate from 28 examined persons (3.6%), while none of the examined cats yielded MRSA. Furthermore, we found that two MRSA isolates recovered from one diseased dog seemed to be hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA), whereas the other dog isolate as well as the human isolate were considered as community-acquired (CA-MRSA). The occurrence of MRSA in apparently healthy and/or diseased pet dogs makes it an emerging veterinary pathogen which could be considered a public health burden if it is disseminated in our community outside hospitals. PMID- 22099887 TI - Incidence of vitiligo in children with Graves' disease and Hashimoto's thyroiditis. AB - BACKGROUND: Limited data are available on the association between vitiligo and autoimmune thyroid disease in pediatric patients. In addition, reported studies of pediatric patients have been based on a population known to have vitiligo and subsequently evaluated for the presence of thyroid function abnormalities. METHODS: A retrospective chart review was performed on 333 children who had been followed for thyroid disorders by endocrinologists at the Yale Pediatric Thyroid Center over the last 5 years for autoimmune thyroid disease. Demographical and clinical features of patients found to have thyroid disease and vitiligo were recorded. These studies were approved by the Yale Human Investigation Committee. RESULTS: Of the total 333 children and adolescents, 9 (2.7%) were noted to have vitiligo. Four patients (44%) had Graves' disease and 5 patients (66%) had Hashimoto's thyroiditis. For patients with Graves' disease and vitiligo, the average age of onset of thyroid disease was young at 4 +/- 0.7 years, and the diagnosis of vitiligo usually preceded that of thyroid disease. For children with Hashimoto's thyroiditis and vitiligo, thyroid disease was diagnosed at an average age of 13.25 +/- 2.8 years. CONCLUSION: In our population, 4.6% of children with Graves' disease and 2.0% of children with Hashimoto's thyroiditis had vitiligo. Interestingly, when vitiligo presents with Graves' disease, it occurs in younger rather than older children. PMID- 22099888 TI - Molecular detection and characterization of West Nile virus associated with multifocal retinitis in patients from southern India. AB - BACKGROUND: In late 2009/early 2010, approximately 2000 people were affected by a mysterious viral outbreak in a southern district of Tamil Nadu; this particularly affected those living in coastal areas. Blood samples from affected patients were sent for clinical analysis to determine the actual cause of the illness, but reports were inconclusive. METHODS: The present study describes the clinical observations and laboratory investigations involving molecular methods performed on 170 of the 2000 clinically suspected cases. These were patients who were admitted to Aravind Eye Hospital, Madurai, Tamil Nadu with ocular complications. Conventional reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and reverse transcription loop-mediated isothermal gene amplification (RT LAMP) assays were used to detect West Nile virus (WNV) infection. Further investigation of the genetic diversity of the WNV implicated in ocular complications was undertaken by sequence phylogeny. RESULTS: Out of 170 samples, 25 (15%) were positive for chikungunya IgM antibody, 10 (6%) for chikungunya antigen, and 30 (18%) were positive for dengue IgM antibody. The remaining 105 seronegative samples were further processed for WNV detection by IgM capture ELISA and molecular methods. Out of the 105 samples, 35 (33%) were positive for WNV IgM antibody, 15 (14%) were positive for WNV by RT-PCR, and 27 (26%) were found to be positive for WNV by both real-time RT-PCR and RT-LAMP assays. Comparative evaluation with acute-phase patient serum samples revealed 100% concordance between the real-time RT-PCR and RT-LAMP assays. These assays had an overall higher sensitivity than the conventional RT-PCR as they picked up 12 additional samples with a low copy number of template. Further genotyping through sequence phylogeny revealed that all the WNV isolates were grouped in lineage I. CONCLUSIONS: The association of West Nile virus with ocular infection in South India during an epidemic of mysterious fever in the first half of 2010 was clearly established through molecular approaches employing envelope gene-specific real-time RT-PCR and RT-LAMP assays followed by nucleotide sequencing. PMID- 22099889 TI - The 'Healthy Dads, Healthy Kids' community effectiveness trial: study protocol of a community-based healthy lifestyle program for fathers and their children. AB - BACKGROUND: The 'Healthy Dads, Healthy Kids' program was designed to help overweight fathers lose weight and positively influence the health behaviors of their children. The aim of the current study was to evaluate the previously established program in a community setting, in a large effectiveness trial. METHODS/DESIGN: The Healthy Dads, Healthy Kids community trial consists of three stages: (i) Stage 1 - program refinement and resource development (ii) Stage 2 - community randomized controlled trial (iii) Stage 3 - community effectiveness trial. The program will be evaluated in five Local Government Areas in the Hunter Valley Region of NSW, Australia. For the community randomized controlled trial, 50 overweight/obese men (aged 18-65 years) from one Local Government Area with a child aged between 5-12 years of age will be recruited. Families will be randomized to either the program or a 6-month wait-list control group. Fathers and their children will be assessed at baseline, post-intervention (3-months) and 6-months. Inclusion criteria are: body mass index 25-40 kg/m2; no participation in other weight loss programs during the study; pass a health-screening questionnaire; and access to a computer with Internet facilities. In the community trial, the program will be evaluated using a non-randomized, prospective design in five Local Government Areas. The exclusion criteria is body mass index < 25 kg/m2 or lack of doctor's approval. MEASURES will be collected at baseline, 3-, 6- and 12-months. The program involves fathers attending seven face to-face group sessions (three with children) over 3-months. MEASURES: The primary outcome is fathers' weight. Secondary outcomes for both fathers and children include: waist circumference, blood pressure, resting heart rate, physical activity, sedentary behaviors and dietary intake. Father-only measures include portion size, alcohol consumption, parenting for physical activity and nutrition and parental engagement. Process evaluation will determine the fidelity, dose (delivered and received), reach, recruitment and context of the program. DISCUSSION: As a unique approach to reducing obesity prevalence in men and improving lifestyle behaviours in children, our findings will provide important evidence relating to the translation of Healthy Dads, Healthy Kids, which will enable it to be delivered on a larger scale. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000608066. PMID- 22099890 TI - Anesthetic efficacy of four percent articaine for pulpal anesthesia by using inferior alveolar nerve block and buccal infiltration techniques in patients with irreversible pulpitis: a prospective randomized double-blind clinical trial. AB - INTRODUCTION: The study was designed as a randomized double-blind trial to evaluate the anesthetic efficacy of 4% articaine with 1:100,000 epinephrine in inferior alveolar nerve block (IANB) and infiltration anesthetic techniques to anesthetize mandibular molars with irreversible pulpitis. METHODS: The study was composed of 2 test arms and 1 control arm. Subjects in the test arms received either a standard IANB or a buccal infiltration (B Infil) of 4% articaine with 1:100,000 epinephrine, whereas the subjects in the control arm received a standard IANB of 2% lidocaine with 1:100,000 epinephrine. Subject's self-reported pain response was recorded on Heft Parker Visual Analogue Scale after local anesthetic administration during access preparation and pulp extirpation. RESULTS: For statistical analysis Pearson chi(2), Student's paired t test, 1-way analysis of variance, and Friedman tests showed no significant difference in success rates among the 3 arms of the trial. CONCLUSIONS: Although B Infil and IANB of 4% articaine were equally effective, B Infil can be considered a viable alterative in IANB for pulpal anesthesia in mandibular molars with irreversible pulpitis. PMID- 22099891 TI - Efficacy of Ibuprofen and ibuprofen/acetaminophen on postoperative pain in symptomatic patients with a pulpal diagnosis of necrosis. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind study was to determine ibuprofen versus ibuprofen/acetaminophen use for postoperative endodontic pain in symptomatic patients with a pulpal diagnosis of necrosis and an associated periapical radiolucency who were experiencing moderate to severe preoperative pain. We also recorded escape medication use. METHODS: Seventy-one adult patients presenting for emergency endodontic treatment with a symptomatic maxillary or mandibular tooth with a pulpal diagnosis of necrosis, periapical radiolucent area, and moderate to severe pain participated in this study. The patients were randomly divided into 2 groups by random assignment and numeric coding. An emergency debridement of the tooth was completed with hand and rotary instrumentation. At the end of the appointment, the patients randomly received capsules of either 600 mg ibuprofen or 600 mg ibuprofen combined with 1000 mg acetaminophen (blinded to both operator and patient). Patients also received a 6 day diary to be completed after anesthesia wore off and every morning for 5 days. Patients were asked to record pain, symptoms, and the number of capsules taken. Patients received escape medication (Vicodin) if the study medication did not control their pain. Postoperative data were analyzed by randomization test and step-down Bonferroni method of Holm. RESULTS AND CONCLUSIONS: There were decreases in pain levels and analgesic use over time for the ibuprofen and ibuprofen/acetaminophen groups. There was no statistically significant difference between the 2 groups for analgesic use or escape medication use. Approximately 20% of patients in both groups required escape medication to control pain. PMID- 22099892 TI - Immunohistochemical expression of fibronectin and tenascin in human tooth pulp capped with mineral trioxide aggregate and a novel endodontic cement. AB - INTRODUCTION: The purpose of the present study was the immunohistochemical study of fibronectin (FN) and tenascin (TN) in human tooth pulp capped with mineral trioxide aggregate (MTA) and novel endodontic cement (NEC) (calcium enriched mixture cement) after 2 and 8 weeks. METHODS: Thirty-two premolar teeth that were scheduled for extraction for orthodontic reasons were exposed and capped with either MTA or NEC. The teeth were randomly divided into 4 groups: group 1 (NEC for 2 weeks), group 2 (NEC for 8 weeks), group 3 (MTA for 2 weeks), and group 4 (MTA for 8 weeks). After capping the exposed pulps with either NEC (groups 1 and 2) or MTA (groups 3 and 4), half of the specimens underwent extraction and were prepared for histologic and immunohistochemical evaluation for FN and TN after 2 weeks, and the remaining half were assessed after 8 weeks. FN and TN expression was scored by a blinded pathologist on a scale of I-IV, and the results were analyzed by the Wilcoxon and Mann-Whitney U statistical tests. RESULTS: FN and TN staining was observed in all 4 experimental groups, and there was no significant difference between expression of FN and TN in any groups. FN and TN staining was observed in the dentinal bridge matrix after 2 weeks under MTA. Expression of both markers reduced significantly after 8 weeks under MTA, and staining was observed only in unmineralized parts of dentinal bridge. FN and TN expression was observed in the matrix of the dentinal bridge after 2 weeks under NEC, and staining of both markers was reduced after 8 weeks compared with 2 weeks. The staining pattern of TN in NEC groups was higher than in MTA groups in both time intervals. However, the difference was not significant. CONCLUSIONS: The present study demonstrated that both MTA and NEC are suitable biomaterials for direct pulp capping and are able to stimulate dentinal bridge formation. Moreover, the role of FN and TN as 2 major components of the matrix of a reparative dentinal bridge was observed. PMID- 22099893 TI - Evaluation of accuracy, reliability, and repeatability of five dental pulp tests. AB - INTRODUCTION: The aim of this study was to compare the clinical accuracy, reliability, and repeatability of laser Doppler flowmetry (LDF), an electric pulp test (EPT), and various thermal pulp sensibility tests. METHODS: Pulp tests were done on 121 teeth in 20 subjects by using LDF, EPT, and thermal pulp testing (CO(2), Endo Frost [EF], Ice) during 2 or 3 test sessions with at least 1-week intervals. The order of testing was reversed on the second visit. A laser Doppler flowmeter was used to measure mean pulp blood flow (Flux) calibrated against a brownian motion medium and zeroed against a static reflector. The laser source was 780 nm, with 0.5-mm fiber separation in the probe, 3.1 kHz as the primary bandwidth for filter set to 0.1-second time output constant. Customized polyvinylsiloxane splints were fabricated for each participant, and a minimum of 90-second recording time was used for each tooth. Raw data were analyzed by using repeated measure analysis of variance, pairwise comparisons, and interclass correlations (ICC). RESULTS: The accuracy of EPT, CO(2), and LDF tests was 97.7%, 97.0%, and 96.3%, respectively, without significant differences (P > .3). Accuracy of EF and Ice was 90.7% and 84.8%, respectively. EPT (P = .015) and CO(2) (P = .022) were significantly more accurate than EF. LDF was more accurate than EF, but this was not statistically significant (P = .063). Ice was significantly less accurate than EPT (P = .004), CO(2) (P = .005), LDF (P = .006), and EF (P = .019). With the exception of Ice (effect of visit: F(2,38) = 5.67, mean squared error = 0.01, P = .007, eta(2)(p) = 0.23), all tests were reliable. Ice (ICC = 0.677) and LDF (ICC = 0.654) were the most repeatable of the tests, whereas EPT (ICC = 0.434) and CO(2) (ICC = 0.432) were less repeatable. CONCLUSIONS: CO(2), EPT, and LDF were reliable and the most accurate tests, but CO(2) and EPT were less repeatable yet less time-consuming than LDF. EF was reliable but not as accurate as EPT and CO(2) and less repeatable than Ice and LDF. Ice was the most repeatable but the least accurate and least reliable test. PMID- 22099894 TI - Association of endodontic infection with detection of an initial lesion to the cardiovascular system. AB - INTRODUCTION: Dental infections might predispose toward the onset of cardiovascular disease (CVD). To date, only a few studies, yielding inconclusive findings, have investigated the potential correlation between apical periodontitis (AP) and CVD. The aim of this study (as the first part of a prospective study) was to evaluate, in the absence of CV risk factors, whether subjects with AP were more exposed to the pathogenetic indices of an atherosclerotic lesion. METHODS: Forty men between the ages of 20 and 40 years who were free from periodontal disease, CVD, and traditional CV risk factors were enrolled in the study; 20 subjects had AP, and 20 acted as controls. All subjects underwent dental examination and complete cardiac assessment: physical examination, electrocardiogram, conventional and tissue Doppler echocardiography, and measurement of endothelial flow reserve (EFR). The following laboratory parameters were tested: interleukins -1, -2, and -6 (IL-1, IL-2, IL-6), tumor necrosis factor alpha, and asymmetrical dimethylarginine (ADMA). Data were analyzed by using the 2-tailed Student's t test, Pearson t test (or Spearman t test for nonparametric variables), and multivariate linear regression analysis. RESULTS: Echocardiography revealed no abnormalities in any of the subjects studied. ADMA levels were inversely correlated with EFR (P < .05) and directly correlated with IL-2 (P < .001). Patients with AP presented with significantly greater blood concentrations of IL-1 (P < .05), IL-2 (P < .01), IL-6 (P < .05), and ADMA (P < .05) and a significant reduction of EFR (P < .05). CONCLUSIONS: Increased ADMA levels and their relationship with poor EFR and increased IL-2 might suggest the existence of an early endothelial dysfunction in young adults with AP. PMID- 22099895 TI - Radiographic study of the mandibular retromolar canal: an anatomic structure with clinical importance. AB - INTRODUCTION: The retromolar canal is an anatomic structure of the mandible with clinical importance. This canal branches off from the mandibular canal behind the third molar and travels to the retromolar foramen in the retromolar fossa. The retromolar canal might conduct accessory innervation to the mandibular molars or contain an aberrant buccal nerve. METHODS: Patients referred for panoramic radiography were consecutively enrolled, provided a limited cone-beam computed tomography (CBCT) scan had also been taken in the area of interest. Radiographs were retrospectively screened for the presence of a retromolar canal, and linear measurements (distance to second molar, height, width) were taken. RESULTS: One hundred twenty-one sides in 100 patients were evaluated (100 unilateral and 21 bilateral cases). A total of 31 retromolar canals were identified with CBCT (25.6%). Only 7 of these canals were also seen on the corresponding panoramic radiographs. The existence of a retromolar canal was not statistically related to gender or side. With regard to the linear measurements, the mean distance from the retromolar canal to the second molar was 15.16 mm (+/-2.39 mm), the mean height of the canal was 11.34 mm (+/-2.36 mm), and the mean width was 0.99 mm (+/ 0.31 mm). CONCLUSIONS: This radiographic study documents a frequency of 25% for the presence of a retromolar canal. The clinician is advised to preserve this anatomic variation when performing surgery in the retromolar area and to consider additional locoregional anesthesia in the case of failed mandibular block anesthesia. PMID- 22099896 TI - Immunohistological characterization of newly formed tissues after regenerative procedure in immature dog teeth. AB - INTRODUCTION: In a previous report, we showed that 2 types of mineralized tissues were formed in the canal spaces of dogs after tissue engineering treatments of immature teeth with apical periodontitis: (1) dentin- associated mineralized tissue (DAMT) and (2) bony islands (BIs). The objective of this study was to characterize these mineralized tissues. METHODS: The maturation and organization of collagen matrices in DAMT, BIs, and the interface between DAMT and the dentin wall were characterized using a histochemical method with picrosirius red staining under polarized light microscopy. In addition, the distribution of 2 noncollagenous proteins (ie, dentin sialoprotein and bone sialoprotein) in these tissues was investigated by immunohistochemical methods with specific antibodies. RESULTS: The results showed that DAMT is distinct from dentin, bone, or BIs. Although it resembled cementum to an extent showing similar immunoreactivity to the noncollagenous proteins, the organization and maturation of collagen matrix was significantly different from cementum. BIs resembled a bone matrix in terms of morphology, collagen organization, and immunoreactivity. CONCLUSIONS: The results indicate that DAMT and BIs formed in the canal space are distinct from each other, one exhibiting a unique mineralized tissue and the other a bone-like tissue. PMID- 22099897 TI - Immunohistochemical evaluation of angiogenesis and tryptase-positive mast cell infiltration in periapical lesions. AB - INTRODUCTION: Several studies have linked mast cells (MCs) with angiogenesis. The aim of this study was to correlate angiogenesis with MCs in radicular cyst (RC) and periapical granuloma (PG) cases. METHODS: Forty-eight samples of periapical lesions, diagnosed as RC (n = 24) and PG (n = 24), were included. The microvessel density and microvessel area measured through the immunoexpression of CD105 and CD34 and the MC density measured through the immunoexpression of tryptase were performed. RESULTS: MCs were detected in all RCs and PGs (P = .888), mainly in perivascular location and within fibrous stroma. CD34 stained all vessels present in all RC and PG cases. CD105 revealed differential expression, stained preferentially vessels of greater lumen, and showed variable location inside fibrous stroma in both lesions. There was a significant difference of microvessel density determinate by CD34 and CD105 in RCs (r = 0.634, P = .002) and in PGs (r = 0.5709, P = .0036). The difference was also observed when comparing age of the patient in both lesions. Considering the microscopic association between highest concentration of MCs and vascularization, CD105-positive vessels in 50% of RCs and 70.8% of PGs and CD34-positive vessels in 66.7% of RCs and 87.5% of PGs showed areas of close association with MCs. CONCLUSIONS: These results suggest differential expression of CD105 within RC and PG. There is no difference in angiogenesis and MC density between RC and PG. Moreover, because of the association between MCs with vessels and fibrous stroma, other possible roles of tryptase, in addition to the angiogenic properties, should also be considered. PMID- 22099898 TI - Potential characteristics of stem cells from human exfoliated deciduous teeth compared with bone marrow-derived mesenchymal stem cells for mineralized tissue forming cell biology. AB - INTRODUCTION: Tissue engineering and regenerative medicine using stem cell biology has been a promising field for treatment of local and systemic intractable diseases. Recently, stem cells from human exfoliated deciduous teeth (SHED) have been identified as a novel population of stem cells. This study focused on the characterization of SHED as compared with bone marrow-derived mesenchymal stem cells (BMMSCs). METHODS: We investigated potential characteristics of SHED by using DNA microarray, real-time reverse transcriptase polymerase chain reaction, and immunofluorescence analysis. RESULTS: Multiple gene expression profiles indicated that the expression of 2753 genes in SHED had changed by >=2.0-fold as compared with that in BMMSCs. One of the most significant pathways that accelerated in SHED was that of bone morphogenetic protein (BMP) receptor signaling, which contains several cascades such as PKA, JNK, and ASK1. When the BMP signaling pathway was stimulated by BMP-2, the expression of BMP-2, BMP-4, Runx2, and DSPP was up-regulated significantly in SHED than that in BMMSCs. Furthermore, the BMP-4 protein was expressed much higher in SHED but not in BMMSCs, as confirmed by immunofluorescence. CONCLUSIONS: By using the gene expression profiles, this study indicates that SHED is involved in the BMP signaling pathway and suggests that BMP-4 might play a crucial role in this. These results might be useful for effective cell-based tissue regeneration, including that of bone, pulp, and dentin, by applying the characteristics of SHED. PMID- 22099899 TI - Porphyromonas endodontalis lipopolysaccharides induce RANKL by mouse osteoblast in a way different from that of Escherichia coli lipopolysaccharide. AB - INTRODUCTION: Porphyromonas endodontalis lipopolysaccharide (LPS) has been shown to have a high positive rate in infected root canals and symptomatic apical periodontitis. It may play an integral role as a potent stimulator of inflammatory cytokines involved in apical lesions. The receptor activator of nuclear factor-kappaB ligand (RANKL) has been proven to be the key regulator of bone remodeling. This study investigated P. endodontalis LPS-induced RANKL production and LPS signaling in mouse osteoblasts. METHODS: LPS-induced RANKL production in mouse osteoblast MC3T3-E1 cells was measured by Western blot and real-time polymerase chain reaction, and the Toll-like receptors (TLRs) were determined by the blocking test using anti-TLRs antibodies. In addition, specific inhibitors were used to analyze the intracellular signaling pathways. Escherichia coli LPS was used as the control. RESULTS: Both of the anti-TLR2 and anti-TLR4 antibodies significantly (P < .05) inhibited the expression of RANKL from osteoblasts stimulated with P. endodontalis LPS; only anti-TLR2 antibody had a significant (P < .05) inhibitory effect on E. coli LPS signaling. SP600125 (c-Jun N-terminal kinase [JNK] inhibitor) prevented the up-regulation of RANKL expression in P. endodontalis LPS-infected osteoblasts (P < .05). The inhibitory effect of wortmannin (phosphatidylinositol 3-kinase inhibitor) and PD98059 (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] kinase-1/2 [MEK 1/2] inhibitor) were observed in E. coli LPS-treated mouse osteoblasts (P < .05). CONCLUSIONS: Results from this study showed that P. endodontalis LPS has the ability to promote the expression of RANKL in mouse osteoblasts, and this induction was mainly through the TLR2/4-JNK signaling pathway, a situation quite different from that of typical bacterial endotoxin (E. coli LPS). PMID- 22099900 TI - Cytokine analysis in lesions refractory to endodontic treatment. AB - INTRODUCTION: Failure in endodontic treatment is often caused by the persistence of microorganisms in the root canal after therapy. When treatment fails, an immune response develops that is characterized by an extensive network of immunologic mechanisms that lead to the production of cytokines and chemokines. METHODS: The objective of this study was to determine the relative messenger RNA (mRNA) expression of IFN-gamma, TNF-alpha, IL-1beta, IL-17A, IL-10, and MCP-1 in periapical dental lesions refractory to treatment. Clinical samples were taken from teeth presenting periapical lesions refractory to endodontic treatment (the experimental group) or from healthy teeth with pulp vitality (the control group). Three paper points passing through the root apex (2 mm) were used to collect the samples. The total RNA was extracted from each sample, complementary DNA was synthesized, and quantitative polymerase chain reaction analysis was performed. The Mann-Whitney U test was used to determine the statistical significance of our findings (P < .05). RESULTS: Significant differences in the levels of IFN-gamma, TNF-alpha, IL-17A, and MCP-1 mRNA expression were observed in cases refractory to endodontic treatment as compared with the control group. The expression of IL 1beta mRNA was not significantly different between the groups. The expression of IL-10 mRNA was insignificant in both the experimental and control groups. CONCLUSIONS: A significantly increased expression of TNF-alpha, IFN-gamma, IL 17A, and MCP-1 mRNA was observed in the periapical immune response in cases of endodontic failure. These results suggest that a proinflammatory cytokine profile predominates in these types of dental lesions. PMID- 22099901 TI - Matrix metalloproteinase-2 expression induced by two different adhesive systems on human pulp fibroblasts. AB - INTRODUCTION: This study evaluated the expression of matrix metalloproteinase-2 (MMP-2) in primary cultures of human pulp fibroblasts (HPFs) when exposed to extracts from dentin-bonding systems. METHODS: Polymerized resin disks of the bonding agent of a 2-step self-etch adhesive (TechBond, Isasan, Rovello Porro, Italy) or of the primer/bonding agent a 2-step etch-and-rinse adhesive (Optibond Solo; Sybron-Kerr, Orange, CA) were immersed in HPF culture medium for 24 or 96 hours. HPFs were incubated in the adhesive-conditioned or control (untreated) culture medium for 24 hours. Western blot and immunofluorescence analyses were performed to assay MMP-2 expression. RESULTS: MMP-2 expression levels in HPFs cultured for 24 hours in culture medium were similar in both the control and experimental media groups showing a faint band at 67 kDa. Conversely, the HPFs incubated in the medium that contain polymerized resin disks for 96 hours showed increased MMP-2 expression compared with the untreated medium. The self-etch adhesive displayed the most pronounced induction of MMP-2 expression. These findings were confirmed by immunofluorescence analysis. CONCLUSIONS: HPFs display increased MMP-2 expression after 96 hours of conditioning of the HPF culture medium with polymerized disks of dentin bonding systems. This MMP-2 expression/activation may represent a defence mechanism exhibited by HPFs towards monomers eluted from the dentin bonding systems. PMID- 22099902 TI - Bleaching agents increase metalloproteinases-mediated collagen degradation in dentin. AB - INTRODUCTION: Tooth bleaching is based on hydrogen peroxide application. The Objective of this study was to determine whether dental bleaching agents affect metalloproteinases-mediated dentin collagen degradation. METHODS: Human dentin specimens were subjected to different treatments: (1) untreated dentin; (2) demineralization by 37% phosphoric acid (PA); (3) demineralization by 37% PA, followed by application of Single Bond (SB); (4) 2 immersions of 7 days each in a nonvital bleaching agent, followed by PA; (5) 2 immersions of 7 days each in nonvital bleaching, followed by PA and SB application; (6) 3 immersions by using in-office bleaching gel for 20 minutes; (7) 3 immersions by using in-office bleaching gel for 20 minutes plus activation with a light source; and (8) immersion in home bleaching gel for 8 hours per day during 3 weeks. Specimens were stored in artificial saliva. C-terminal telopeptide determinations (radioimmunoassay) were performed after 24 hours, 1 week, and 4 weeks. RESULTS: Bleaching agents increased collagen degradation, but C-terminal telopeptide of type I collagen (ICTP) values were higher when dentin was PA-demineralized. Nonvital bleaching plus PA promoted the highest collagenolytic activity, which was reduced after SB infiltration. Halogen light application did not influence ICTP values. At 24 hours, home bleaching exhibited high collagenolytic activity, which decreased up to 4 weeks. After 4 weeks of storage, all bleaching procedures showed similar values of collagen degradation, which were not different from those of PA-demineralized and resin-infiltrated dentin. CONCLUSIONS: All tested bleaching agents increase matrix metalloproteinases-mediated collagen degradation in dentin. This effect was not completely reverted after 4 weeks. Home bleaching induced the highest collagen degradation. PMID- 22099903 TI - Heavy metal analysis of ortho MTA and ProRoot MTA. AB - INTRODUCTION: Recently, several kinds of mineral trioxide aggregate (MTA)-based products have been introduced in endodontics. Ortho MTA (BioMTA, Seoul, Republic of Korea) is one of those products, which was developed for retrograde filling, perforation repair, orthograde root canal obturation, and direct pulp capping. The inclusion of heavy metals in MTA-based materials is of concern because they come into direct contact with hard and soft tissues. The aim of this study was to investigate and compare the levels of arsenic (As), chromium (Cr), hexavalent chromium (Cr(6+)), and lead (Pb) in Ortho MTA and ProRoot MTA. METHODS: One gram of each MTA was digested using a mixture of hydrochloric and nitric acids and filtered. The As, Cr, and Pb in the resulting filtrates were analyzed by inductively coupled plasma-optical emission spectrometry. The level of Cr(6+) was measured by the methods suggested in the Korean Standard L 5221. The results were statistically analyzed using the Mann-Whitney U test. RESULTS: The concentration of As in ProRoot MTA was 1.16 ppm, but As was not detected in Ortho MTA. Cr(6+) and Pb were not detected in either MTA. Ortho MTA contained significantly less Cr than ProRoot MTA (P < .05). CONCLUSIONS: Ortho MTA and ProRoot MTA meet the ISO specification 9917-1 regarding the safety limits of As and Pb and are safe biomaterials when the purity of As, Cr(6+), and Pb is considered. PMID- 22099904 TI - Apical extrusion of sodium hypochlorite using different root canal irrigation systems. AB - INTRODUCTION: Root canal irrigation carries a risk of extrusion of irrigant into the periapical tissues. The objective of this study was to compare different irrigation systems in matched pairs of teeth prepared to an apical size of 35.06 and 50.06 by measuring the frequency and extent of apical extrusion of sodium hypochlorite (NaOCl) into a simulated periapical environment. The null hypothesis was tested that there is no difference between systems. METHODS: Bilaterally matched pairs (n = 10) of single-canal extracted human anterior teeth were instrumented to an apical size of either 35.06 or 50.06. Teeth were embedded in a gel containing the pH-sensitive dye M-cresol purple that changes from yellow at pH 7.4 to purple at pH 9. Root canals were irrigated with 6% NaOCl (pH 11) by using EndoActivator (EA), EndoVac (EV), Rispi-Sonic/MicroMega 1500 (MM), passive ultrasonic irrigation (PUI), and syringe irrigation with a slot-tipped needle (SN), so that each tooth underwent all irrigation procedures in a randomized crossover design. Apical extrusion was evaluated by image analyses. RESULTS: The frequency of extrusion was less in teeth with apical preparation size 35.06 (36%) compared with 50.06 (60%) (P = .014) and was dependent on the irrigation system in 35.06 (P = .039) but not 50.06 groups. In the 35.06 group the frequency of extrusion was less for EV than for MM and SN (both P = .029). The extent of extrusion was less for MM compared with PUI (P = .024) and SN (P = .046) in the 35.06 group and greater for SN compared with all other systems in the 50.06 group (P < .05). The null hypothesis was rejected. CONCLUSIONS: The frequency of apical extrusion of NaOCl was dependent on the type of root canal irrigation system and apical preparation size. The extent of extrusion depended on the irrigation system, with syringe and slotted-needle irrigation resulting in the greatest extent of extrusion. PMID- 22099905 TI - Micro-computed tomography study of the internal anatomy of mesial root canals of mandibular molars. AB - INTRODUCTION: The aim of this study was to determine the mesiodistal and buccolingual diameter, apical volume, and the presence of isthmuses at the apical level of mesial root canals of mandibular molars. METHODS: Sixty extracted first and second mandibular molars were scanned by using a SkyScan 1076 micro-computed tomography system with a voxel size of 18 MUm. The apical thirds of the samples were reconstructed to allow a perpendicular section of the apical third by using the multiplanar reconstruction tool of the OsiriX software. The mesiodistal and the buccolingual distances of root canals were measured between the 1- to 4-mm levels. The type of root canal isthmuses present at these levels was classified by using modified criteria of Hsu and Kim. The volume of the root canal anatomy between the 1- to 3-mm apical levels was obtained by using the CTAN-CTVOL software. RESULTS: The medians of the mesiodistal diameter at the 1-, 2-, 3-, and 4-mm levels in the mesiobuccal and mesiolingual canals were 0.22 and 0.23 mm, 0.27 and 0.27 mm, 0.30 and 0.30 mm, and 0.36 and 0.35 mm, respectively. The buccolingual lengths at the 1-, 2-, 3-, and 4-mm levels were 0.37-0.35 mm, 0.55 0.41 mm, 0.54-0.49 mm, and 0.54 and 0.60 mm, respectively. The presence of isthmuses was more prevalent at the 3- to 4-mm level. However, 27 cases presented complete or incomplete isthmuses at the 1-mm apical level. The mean of the volume of the apical third was 0.83 mm(3), with a minimum value of 0.02 and a maximum value of 2.4 mm(3). CONCLUSIONS: Mesial root canals of mandibular molars do not present a consistent pattern. A high variability of apical diameters exists. The presence of isthmuses at the apical third was not uncommon even at the 1-mm apical level. PMID- 22099906 TI - Effect of canal length and curvature on working length alteration with WaveOne reciprocating files. AB - INTRODUCTION: This study evaluated the working length (WL) modification after instrumentation with WaveOne Primary (Dentsply Maillefer, Ballaigues, Switzerland) reciprocating files and the incidence of overinstrumentation in relation to the initial WL. METHODS: Thirty-two root canals of permanent teeth were used. The angles of curvature of the canals were calculated on digital radiographs. The initial WL with K-files was transferred to the matched WaveOne Primary reciprocating files. After glide paths were established with PathFile (Dentsply Maillefer, Ballaigues, Switzerland), canals were shaped with WaveOne Primary referring to the initial WL. The difference between the postinstrumentation canal length and the initial canal length was analyzed by using a fiberoptic inspection microscope. Data were analyzed with a balanced 2 way factorial analysis of variance (P < .05). RESULTS: Referring to the initial WL, 24 of 32 WaveOne Primary files projected beyond the experimental apical foramen (minimum-maximum, 0.14-0.76 mm). A significant decrease in the canal length after instrumentation (95% confidence interval ranging from -0.34 mm to 0.26 mm) was detected. The canal curvature significantly influenced the WL variation (F(1) = 30.65, P < .001). The interaction between the initial canal length and the canal curvature was statistically significant (F(2) = 4.38, P = .014). CONCLUSIONS: Checking the WL before preparation of the apical third of the root canal is recommended when using the new WaveOne NiTi single-file system. PMID- 22099907 TI - Direct contact with mineral trioxide aggregate activates and differentiates human dental pulp cells. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) is routinely used for pulp-capping procedures. However, little is known about its direct interaction with the cells or whether MTA is capable of releasing soluble factors that could help in differentiating cells. There have been no previous studies showing this aspect of MTA. Hence, the aim of this study was to determine whether direct contact of the cells with MTA was necessary to help differentiate the pulp cells into odontoblast-like cells. METHODS: Human dental pulp cells were cultured on gray MTA, either in direct contact or away from the cells on a cell culture insert, and the levels of gene expression, secretion of vascular endothelial growth factor (VEGF), and the rates of cell proliferation were analyzed. RESULTS: MTA when placed in direct contact with the cells promoted up-regulated the expression of important odontoblastic genes like osteocalcin and dentin sialoprotein, thereby showing that direct contact of the cells with the MTA is necessary to promote differentiation of the pulp cells into odontoblast-like cells, which in turn are responsible for dentin bridge formation. MTA also induced an increase in the secretion of VEGF when placed in direct contact with the cells. CONCLUSIONS: Overall, our study supports the fact that direct contact of the cells with the MTA is necessary to help differentiate them into odontoblast-like cells, which in turn will lead to a successful treatment outcome. PMID- 22099908 TI - Persistent extraradicular infection in root-filled asymptomatic human tooth: scanning electron microscopic analysis and microbial investigation after apical microsurgery. AB - INTRODUCTION: Procedural accidents have a negative effect on healing and might contribute to the persistence of infections in inaccessible apical areas, requiring surgical intervention. This report describes a case of persistent apical periodontitis of a lower left first molar associated with the sinus tract and a periapical lesion that required nonsurgical endodontic retreatment and apical surgery for resolution. METHODS: The tooth had received endodontic treatment 3 years ago and had to be retreated using the crown-down technique with chemical auxiliary substance (2% chlorhexidine gel), foramen patency, and enlargement and was filled in a single appointment. The occlusal access cavity was immediately restored with composite resin. After 1 month, it could be observed that the sinus tract persisted and, radiographically, the lesion remained unaltered. Therefore, endodontic microsurgery was indicated. Apical microsurgery was performed under magnification with the use of a dental operating microscope including apicectomy, root end with ultrasound, and sealing with mineral trioxide aggregate. A microbiological sample was collected from the apical lesion. The resected distal root apex was observed by scanning electron microscopy. RESULTS: The following species were detected: Actinomyces naeslundii and Actinomyces meyeri, Propionibacterium propionicum, Clostridium botullinum, Parvimonas micra, and Bacteroides ureolyticus; scanning electron microscopic analysis revealed bacterial biofilm surrounding the apical foramen and external radicular surface. Gutta-percha overfilling at the apex because of a zip caused during initial endodontic treatment could be observed. A 6-month follow-up showed apparent radiographic periapical healing, which progressed after 24 months. CONCLUSION: Gram-positive anaerobic bacteria and extraradicular biofilm seem to participate in the maintenance of persistent periapical pathology, and endodontic retreatment followed by periapical microsurgery proved to be a successful alternative in the resolution of persistent extraradicular infections. PMID- 22099909 TI - [Quality standards for ultrasound assessment (CW-Doppler, Duplex US) of the lower limb arteries in vascular medicine. Report of the French Society for Vascular Medicine]. AB - The quality standards of the French Society of Vascular Medicine for the ultrasound assessment of lower limb arteries in vascular medicine practice are based on the principle that these examinations have to meet two requirements: technical know-how (knowledge of devices and methodologies); medical know-how (level of examination matching the indication and purpose of the examination, interpretation and critical analysis of results). OBJECTIVES OF THE QUALITY STANDARDS: To describe an optimal level of examination adjusted to the indication or clinical hypothesis; to homogenize practices, methodologies, terminologies, results description and report; to provide good practice reference points and to promote a high quality process. THEMES OF THE QUALITY STANDARDS: The three levels of examination, indications and objectives for each level; the reference standard examination (level 2) and its variants according to indications; the minimal content of the exam report, the medical conclusion letter to the corresponding physician (synthesis, conclusion and management suggestions); commented glossary (anatomy, hemodynamics, signs and symptoms); technical basis. Device settings. Here, we discuss CW-Doppler and Duplex ultrasound in various indications for lower limbs arteries assessment. PMID- 22099910 TI - [Post-stenotic pulmonary trunk aneurysm in a 70-year-old man]. PMID- 22099912 TI - Characterizing mortality effects of particulate matter size fractions in the two capital cities of the Canary Islands. AB - Most of the studies differentiating the effect of size-classified particulate matter (PM) exposure have been carried out in cities where the average levels of fine particles (PM(2.5)) were higher than those of coarse particles (PM(10-2.5)). These studies have suggested that PM(2.5) is associated with daily mortality, but there is only limited evidence that PM(10-2.5) is independently associated with mortality. The citizens of the Canary Islands are exposed to PM which is highly influenced by mineral dust because of the islands' proximity to the Western Coast of Morocco. This offers an excellent opportunity to analyze in detail the short term association between PM size fractions and total, respiratory and heart disease mortality. A time-series study from 2001 to 2004 was carried out. For each PM size fraction and mortality outcome, Generalized Additive Poisson Model was performed controlling for potential confounding. Different lag structures, unconstrained distributed lag models and two-pollutant models were examined. After assessing the linearity in the relationship, a piecewise linear analysis for exploring the existence of different slopes for different ranges of PM was carried out. The 10 MUg/m(3) increase in PM(2.5) and PM(10-2.5) levels was associated with a 7.5% (95% confidence interval=0.4-15.0) and a 7.4 (95% CI=1.5 13.7) increase in heart and respiratory disease mortality, respectively. Spline curves were quite linear over the PM concentrations seen on most days (dominated by combustion sources) in these cities, meanwhile on days with higher particulate levels (natural sources) a risk increase above certain PM levels was found, suggesting a curvilinear association and that, at least in some locations, PM(10 2.5) can play an important role in PM-related toxicity. The overall findings suggest that the establishment of new air quality standards for the short-term effect of PM(2.5) and PM(10-2.5) and further limiting levels of PM(10) in European Union is advisable. PMID- 22099913 TI - Cancer and environment: definitions and misconceptions. AB - BACKGROUND: Scientific evidence supports an association between environmental exposures and cancer. However, a reliable estimate for the proportion of cancers attributable to environmental factors is currently unavailable. This may be related to the varying definitions of the term "environment." The current review aims to determine how the reporting of the definition of the environment and of the estimates of environmentally attributable risks have changed over the past 50 years. METHODS: A systematic literature search was performed to retrieve all relevant publications relating to the environment and cancer from January 1960 to December 2010 using PubMed, EMBASE, Scopus, and Web of Science. Definitions of the environment and environmentally attributable risks for cancer were extracted from each relevant publication. RESULTS: The search resulted in 261 relevant publications. We found vast discrepancies in the definition of the environment, ranging from broad (including lifestyle factors, occupational exposures, pollutants, and other non-genetic factors) to narrow (including air, water, and soil pollutants). Reported environmentally attributable risk estimates ranged from 1% to 100%. CONCLUSIONS: Our findings emphasize the discrepancies in reporting environmental causation of cancer and the limits of inference in interpreting environmentally attributable risk estimates. Rather than achieving consensus on a single definition for the environment, we suggest the focus be on achieving transparency for any environmentally attributable risks. PMID- 22099914 TI - High fidelity simulation as a research tool. AB - Medical simulation has grown explosively over the last decade. Simulation is becoming commonplace in clinical education but can also be used as an investigative clinical tool in its own right. There are thus two arms of simulation in clinical research. The first is investigation of the clinical impact of simulation as an educational tool and the second as an instrument to assess the function of clinical practitioners and systems. This article reviews the terminology, current practice and current research in simulation. The use of simulation in assessment of the clinical performance of devices, people and systems will then be discussed and some current work in these areas presented. Finally, medical simulation will be discussed within the paradigm of translational research. Early examples of this 'tool-bench to bedside' model will be presented as possible prototypes for future work directed towards patient safety. PMID- 22099915 TI - Perioperative effectiveness research using large databases. AB - While the delivery of anaesthesia care is largely a safe process and adverse events are infrequent, they can have devastating consequences for patients and providers when they occur. Given concerns about the role of anaesthesia care in shaping long-term outcomes traditionally considered outside the scope of anaesthesiology, new avenues for perioperative research are being explored at a rapid rate by anaesthesia researchers. We propose that new research methodologies such as perioperative effectiveness research could shed useful insight into processes leading to improved clinical care if applied appropriately and optimally. In this article, we outline the basic concepts of perioperative outcomes and effectiveness research. We highlight many sources of data, both clinical and non-clinical, and evaluate their utility in perioperative research. We then discuss how to design a successful effectiveness study, focussing particularly on which questions in anaesthesiology would be most amenable to exploration with this method, thereby providing a guide for future research endeavours. PMID- 22099916 TI - In silico modelling of physiologic systems. AB - In silico modelling, in which computer models are developed to model a pharmacologic or physiologic process, is a logical extension of controlled in vitro experimentation. It is the natural result of the explosive increase in computing power available to the research scientist at continually decreasing cost. In silico modelling combines the advantages of both in vivo and in vitro experimentation, without subjecting itself to the ethical considerations and lack of control associated with in vivo experiments. Unlike in vitro experiments, which exist in isolation, in silico models allow the researcher to include a virtually unlimited array of parameters, which render the results more applicable to the organism as a whole. In silico modelling is best known for its extensive use in pharmacokinetic experimentation, the best-known example of which is the development of the three-compartment model. In addition, complex in silico models have been applied to pathophysiological problems to provide information which cannot be obtained practically or ethically by traditional clinical research methods. These experiments have led to the development of significant insights in subject matters ranging from pure physiology to congenital heart surgery, obstetric anaesthesia airway management, mechanical ventilation and cardiopulmonary bypass/ventricular support devices. The utility of these models is based on both the validity of the model framework as well as the corresponding assumptions. In vivo experimentation has validated some, but not all of the in silico strategies employed. We present a review illustrating by example how in silico modelling has been applied to a number of cardio-respiratory problems in states of health and disease, the purpose of which is to give the reader a sense of the complexity and assumptions which underlie this diverse and underappreciated research strategy, as well as an introduction to a research strategy that will likely continue to grow in importance. PMID- 22099917 TI - Improving outcomes in anaesthesiology education on research. AB - For more than 30 years in the United States, we have been lamenting the fate of the clinician-scientist in anaesthesiology. In the past 5 years, attention to the issues has escalated and a number of new training pathways have emerged. This chapter summarizes programs which have innovative curricula, analyzes current research needs and discusses the limited studies in regards to best practices for research training in graduate medical education. It also proposes further development of residency research curricula through the application of basic educational concepts and explores funding issues and resources that remain relevant to all faculty and departments training the residents. We hope the ideas proposed here will promote the academic caliber of our profession; however, much more data and outcomes research needs to be done to determine our best practices for the future. PMID- 22099918 TI - Research methods for meta-analyses. AB - Meta-analysis uses numerical tools to pool data and to estimate a summary effect size for the comparison of two interventions from a set of randomised controlled trials identified in a systematic review. An effect size is a single number that expresses the difference in outcome from the interventions. The most commonly used effect sizes for dichotomous outcomes, for example, mortality, are the odds ratio and the relative risk. The results of a meta-analysis are usually presented in a complex figure, known as a forest plot, which shows both the individual studies and the summary statistics. Sensitivity analyses are performed to clarify the effect of the experimental design bias on the effect size. Clinical and statistical heterogeneity of the included studies are explored by the additional tools of fixed effect versus random effects models and subgroup analyses. PMID- 22099919 TI - Perioperative comparative effectiveness research. AB - The goal of comparative effectiveness research (CER) is to improve effectiveness, efficacy and efficiency in health care. While CER seems to present a major opportunity to introduce accountability into health care by identifying and promoting best practices in medicine, many issues surrounding CER remain poorly understood by clinicians and researchers, including what study designs are most appropriate for such research and what analytic tools are most helpful. The goal of this review is therefore to provide background and definitions of what constitutes CER and to discuss the various study designs and their strengths and weaknesses in achieving the stated goals of CER, while relating them to examples relevant to perioperative research. We provide a brief outline of the types of analytic methods particularly useful for CER and connect the reader to references for their practice. Finally, we assess the role of CER in perioperative research and provide some thoughts on future paths. PMID- 22099921 TI - A novel approach to implementation of quality and safety programmes in anaesthesiology. AB - Far too many patients suffer preventable harm from medical errors that add to needless suffering and cost of care. Underdeveloped residency training programmes in patient safety are a major contributor to preventable harm. Consequently, the Institute of Medicine has called for health professionals to reform their educational programmes to advance health-care safety and quality. Additionally, the Accreditation Council for Graduate Medical Education (ACGME) now requires education in 'systems-based practice' and 'practice-based learning and improvement' as core competencies of residency training programmes. The specific aim of this article is to describe the implementation of a novel programme designed to enhance residency education, meet ACGME core competencies and improve quality and safety education in one residency programme at an academic medical institution. PMID- 22099920 TI - Perioperative genomics. AB - Since the completion of the Human Genome Project 10 years ago, the world has witnessed an incredible progress in human genetics and genomics.(1) This progress was largely driven by the availability of better, faster and cheaper sequencing technology.(2) While it took more than 10 years and more than 1 billion dollars to complete the Human Genome Project,(3-5) an individual in the year 2011 can have his whole genome sequenced within a week for less than $30,000. With cheaper and faster sequencing came a wealth of novel discoveries which makes it timely to review how these newly found insights into the human genome are relevant for perioperative medicine. This article summarises the basics of genetic inheritance, the human genome and modern sequencing methods, as well as genetic variation and how this knowledge may be applied to patient care and research in the perioperative setting. PMID- 22099922 TI - Best practice & research in anaesthesiology issue on new approaches in clinical research ethics in clinical research. AB - The history of ethics in clinical research parallels the history of abuse of human beings. The Nuremberg Code, Declaration of Helsinki, and the Belmont Report laid the foundations for modern research ethics. In the United States, the OHRP and the FDA provide guidelines for the ethical conduct of research. Investigators should be familiar with regulations concerning informed consent, doing research in vulnerable populations, and protection of privacy. PMID- 22099923 TI - The future of clinical research. PMID- 22099924 TI - Elementary school staff knowledge and attitude with regard to first-aid management of dental trauma in Iran: a basic premise for developing future intervention. AB - AIM: The purpose of this study was to evaluate Iranian teachers' knowledge and attitude with regard to emergency management of dental trauma. MATERIAL AND METHODS: A four-part questionnaire, including demographic data, knowledge, attitude, and self-assessment, was given to 422 teachers from 14 schools. Data obtained from 400 completed questionnaires were statistically analyzed using t test, one-way anova and Pearson correlation coefficient. RESULTS: It was found that there was no statistically significant difference between knowledge and demographic variations (P > 0.05). However, there was a moderate positive association between knowledge and attitude toward emergency management of dental trauma (r = 0.38, P = 0.0001). The outcome indicated completely inadequate knowledge regarding the management of tooth fracture and avulsion. Most participants (94.3%) were unsatisfied with their awareness and suggested that further education on the topic should be offered. CONCLUSIONS: The present study revealed considerably low knowledge of the participants regarding the first aid management of dental trauma for the study group. As teachers get an opportunity to attend a case of dental trauma, strategies to improve the teachers' knowledge seem crucial. PMID- 22099925 TI - Early detection of psychosis: positive effects on 5-year outcome? PMID- 22099926 TI - The environmental comparison of landfilling vs. incineration of MSW accounting for waste diversion. AB - This study evaluates the environmental performance and discounted costs of the incineration and landfilling of municipal solid waste that is ready for the final disposal while accounting for existing waste diversion initiatives, using the life cycle assessment (LCA) methodology. Parameters such as changing waste generation quantities, diversion rates and waste composition were also considered. Two scenarios were assessed in this study on how to treat the waste that remains after diversion. The first scenario is the status quo, where the entire residual waste was landfilled whereas in the second scenario approximately 50% of the residual waste was incinerated while the remainder is landfilled. Electricity was produced in each scenario. Data from the City of Toronto was used to undertake this study. Results showed that the waste diversion initiatives were more effective in reducing the organic portion of the waste, in turn, reducing the net electricity production of the landfill while increasing the net electricity production of the incinerator. Therefore, the scenario that incorporated incineration performed better environmentally and contributed overall to a significant reduction in greenhouse gas emissions because of the displacement of power plant emissions; however, at a noticeably higher cost. Although landfilling proves to be the better financial option, it is for the shorter term. The landfill option would require the need of a replacement landfill much sooner. The financial and environmental effects of this expenditure have yet to be considered. PMID- 22099927 TI - Saphenous vein graft bronchopulmonary fistula after coronary artery bypass grafting presenting as chronic cough and subsequent massive hemoptysis. PMID- 22099928 TI - Safety analysis of FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies. AB - PURPOSE: Oxaliplatin-based therapy, notably FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin), is a standard regimen approved globally for the treatment of metastatic colorectal cancer, and as adjuvant treatment of colon cancer. As part of the Japanese submission for the adjuvant indication, the safety profile of FOLFOX4 regimen was compared in Asian and Western patients. PATIENTS AND METHODS: A total of 3359 patients with colorectal cancer treated with the FOLFOX4 regimen were included in the analyses: 1515 from 2 Asian studies (Japanese Post Marketing Surveillance and Multicenter Asia Study in Adjuvant Treatment of Colon Cancer with Oxaliplatin/5-FU/LV), and 1844 from 4 Western studies (EFC2962, N9741, EFC4584, and Multicenter International Study of Oxaliplatin/5 Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer). Doses administered and safety parameters were analyzed by using common definitions and programs. RESULTS: Demographic and baseline characteristics were comparable between Asian and Western patients. Patients received FOLFOX4 for a median of 6 12 cycles, which ranged from 16 to 28 weeks. Median dose intensities of oxaliplatin and of 5-fluorouracil, bolus and infusion, were within the ranges of 33 to 36 mg/m(2)/week, 297 to 338 mg/m(2)/week, and 467 to 510 mg/m(2)/week, respectively. Most frequently reported adverse events (AE) included hematologic, gastrointestinal, and neurosensory adverse events (NSAE). The incidence of grade >=3 neutropenia ranged from 37% (422 of 1134) to 52% (83 of 159) in Asian and 41% (455 of 1108) to 56% (144 of 259) in Western studies; of diarrhea, ranged from 1.4% (3 of 222) to 6.3% (10 of 159) and 11% (30 of 268 or 120 of 1108) to 14% (36 of 259); of NSAEs, from 1.9% (21 of 1134) to 4.4% (7 of 159) and 9.3% (25 of 268) to 19% (39 of 209); and of allergic reactions, from 0.6% (7 of 1134) to 3.1% (5 of 159) and 1.1% (3 of 268) to 3.0% (33 of 1108), respectively. The probability of grade >=3 NSAEs and diarrhea was statistically significantly lower in Asian than in Western studies by using a log-rank test. CONCLUSION: There was no evidence that Asian patients experienced worse toxicity than did Western patients when treated with FOLFOX4, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed. PMID- 22099929 TI - Predictive models for anti-tubercular molecules using machine learning on high throughput biological screening datasets. AB - BACKGROUND: Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis (Mtb), affecting more than two billion people around the globe and is one of the major causes of morbidity and mortality in the developing world. Recent reports suggest that Mtb has been developing resistance to the widely used anti-tubercular drugs resulting in the emergence and spread of multi drug resistant (MDR) and extensively drug-resistant (XDR) strains throughout the world. In view of this global epidemic, there is an urgent need to facilitate fast and efficient lead identification methodologies. Target based screening of large compound libraries has been widely used as a fast and efficient approach for lead identification, but is restricted by the knowledge about the target structure. Whole organism screens on the other hand are target-agnostic and have been now widely employed as an alternative for lead identification but they are limited by the time and cost involved in running the screens for large compound libraries. This could be possibly be circumvented by using computational approaches to prioritize molecules for screening programmes. RESULTS: We utilized physicochemical properties of compounds to train four supervised classifiers (Naive Bayes, Random Forest, J48 and SMO) on three publicly available bioassay screens of Mtb inhibitors and validated the robustness of the predictive models using various statistical measures. CONCLUSIONS: This study is a comprehensive analysis of high-throughput bioassay data for anti-tubercular activity and the application of machine learning approaches to create target-agnostic predictive models for anti-tubercular agents. PMID- 22099930 TI - Assessment of tumor budding in colorectal carcinoma: correlation with beta catenin nuclear expression. AB - BACKGROUND: Tumor budding (TB) is showing increasing promise as a colorectal cancer (CRC) prognosticator that is independent of TNM staging. beta-Catenin is a component of the Wingless/Wnt signaling pathway that is bound to membrane associated E-cadherin and is essential for its correct position and function. METHODS: This study was designed to detect TB in 44 resected primary CRC cases and also to compare beta-catenin expression in the tumor budding sites (TBS) and in the tumor center. Tumor budding was assessed in both H&E and pankeratin immunostained sections. Agreement between TB scoring using pancytokeratin and H&E was tested. Also, typing of the tumor margin and determination of degree of cytoplasmic pseudo-fragmentation was done. Tumor budding, cytoplasmic pseudofragments and beta-catenin expression were related to known CRC prognosticators. RESULTS: Ten tumors (22.7%) showed low grade (LG) budding and 34 tumors (77.3%) showed high grade (HG) budding. The 34 HG budding tumors were further subdivided into moderate and severe (n=13, n=21, respectively) budding cancers. Twenty nine tumors (65.9%) showed LG cytoplasmic pseudofragments and 15 tumors (34.1%) showed HG pseudofragments. Scoring of TB on H&E and pankeratin stained sections revealed moderate agreement (Kappa=.558; p=<.000). A significant relation between TB and cytoplasmic pseudofragments was observed (p=.009). Both TB and cytoplasmic pseudofragments did not significantly associate with clinicopathologic parameters. Immunoreactivity of nuclear and cytoplasmic beta catenin was significantly higher at TBS compared to tumor center (p=.005, p=.000, respectively). In opposition, membranous beta-catenin expression was significantly higher in the tumor center than in TBS (p=.001). Although, nuclear beta-catenin accumulation at TBS was noted, yet, it did not relate significantly with both TB and cytoplasmic pseudofragments around TBS (p=.649; p=.675, respectively). Also, nuclear beta-catenin immunoreactivity did not relate significantly with the various clinicopathological variables. CONCLUSION: Pankeratin immunostaining facilitates typing of CRC invasive margin, and determination of the degree of TB and cytoplasmic pseudo-fragmentation. beta Catenin expression differs significantly between tumor center and TBS in CRC. Cut offs for TB assessment should be unified and further studies are recommended to allow a better understanding of this process before establishing TB as a prognostic factor beyond the TNM staging in CRC. PMID- 22099931 TI - Study of fibromodulin gene expression in B-cell chronic lymphocytic leukemia. AB - BACKGROUND AND OBJECTIVES: It has become evident that fibromodulin and other members of the proteoglycan family are not only involved in collagen fibrillogenesis and cell adhesion but they also contribute to modulation of cytokine activity, suppression of tumor growth, and prevention of apoptosis. Fibromodulin has been characterized as one of the tumor associated antigens (TAA) in B cell chronic lymphocytic leukemia (B-CLL) with the potential to elicit specific antitumor response and it is considered as good candidate for immunotherapy. AIM OF WORK: to study the expression of fibromodulin at the gene level of B-cell chronic lymphocytic leukemia patients, in comparison to normal controls and to asses its role in the pathophysiology of CLL. PATIENTS AND METHODS: Fibromodulin gene expression was tested by one step reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells of 30 patients with B-CLL as well as in 20 age and sex matched healthy volunteers. RESULTS: In this study, fibromodulin gene was expressed in 46.7% of patients with B-CLL which was significantly different from the control age and sex matched healthy volunteers in which none of them showed peripheral blood mononuclear cells positivity for fibromodulin gene expression (0%) (p-value =0.006). We also found significant associations between higher fibomodulin gene expression and some risk factors in the studied CLL cases such as hepatomegaly, lower haemoglobin level, lower RBCs count, lower platelet count and borderline significant associations with other risk factors as lymphadenopathy and splenomegaly. CONCLUSION: Our results suggest that fibromodulin can be used as a target for therapeutic intervention and it may play a role in the pathophysiology of CLL. PMID- 22099932 TI - Clinical prognostic factors of diffuse large B cell non-Hodgkin lymphoma: a retrospective study. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in Egypt. It represents about 49% of NHL presenting to the National Cancer Institute (NCI), Cairo University. CHOP regimen is the standard treatment used for NHL since the 1970s with only 30-40% overall survival. Recently, integration of Rituximab became a standard of care for patients with DLBCL. However, its widespread use in developing countries is still limited by the lack of financial coverage. Clinical prognostic factors, as well as the pathological markers, are mandatory to individualize treatment. AIM: The aim of the study was to evaluate the clinical risk stratification models including the age adjusted International prognostic index (aaIPI), patients profile and dose intensity (DI) of Cyclophosphamide and Doxorubicin as effective tools for predicting the outcome and prognosis of our DLBCL patients treated with first line CHOP regimen. PATIENTS AND METHODS: This retrospective study included 224 patients with diffuse large B cell lymphoma who were treated with 3-8 cycles of CHOP regimen at the Medical Oncology Department, NCI, Cairo University during the time period from 1999 to 2006. RESULTS: One hundred and seventy-eight patients (79.5%) achieved CR after the CHOP regimen with an observation period of 51 months. The median survival time was 12 months. The OS and DFS at 2 years were 82% and 68.8%, respectively. The univariate analysis of predictive factors for response to treatment showed that the CR rate was significantly affected by aa-IPI and its elements (performance status, stage & LDH), extranodal lesions and DI of Cyclophosphamide and Doxorubicin. The CR rate was 96.9%, 91.2%, 73.9% and 55.6% in cases with aa-IPI 0, 1, 2 and 3, respectively (p<0.001) and it was 82.4%, 81.9% versus 50% in cases with no extranodal site, one extranodal site and two extranodal sites, respectively (p=0.01). As regard DI of Cyclophosphamide, with DI below or equal to the median (249 mg/m(2)/week) the CR rate was 69%, while with DI above the median the CR rate was 87.7% (p=0.001). For Doxorubicin, the CR rate was 72.3% with DI below or equal to the median (16.5 mg/m(2)/week), however, it was 86.6% with DI above the median (p=0.008). The OS rate was significantly affected by aa-IPI as it was 89.8% in cases of aa-IPI 0+1 versus 75.8% in those of aa-IPI 2+3 (p=0.03). DI of Cyclophosphamide and Doxorubicin significantly influenced the OS. The OS rate was 74% with DI of Doxorubicin below or equal to the median versus 96% in cases with DI above the median (p=0.02). For Cyclophosphamide the OS rate was 72.7% with DI below or equal to the median versus 96.3% in cases with DI above the median (p=0.01). The tumor bulk (with a median tumor size of 5 cm) affected the OS, which was 91.23% versus 86.8% in the tumor bulk less than and more than or equal to the median, respectively (p=0.05). By multivariate analysis of predictive factors for response to treatment, the CR rate was significantly affected by the number of extranodal sites and the clinical staging of diffuse large B cell lymphoma. However, OS rate was strongly associated with the bulk of the tumor and the clinical staging of diffuse large B cell lymphoma. CONCLUSION: DI of Cyclophosphamide and Doxorubicin is important in the future treatment regimen plan for DLBCL especially in high risk cases. In addition to aa-IPI and its elements, extra nodal sites and bulk of the tumor proved to be significant predictors and prognostic factors for DLBCL treatment outcome. PMID- 22099933 TI - Distribution of axillary lymph node metastases in different levels and groups in breast cancer, a pathological study. AB - BACKGROUND: It was observed during dissection of heavy deposits of axillary lymph nodes (LNs) in breast cancer that there were grossly positive LNs outside the confines of classical axillary dissection. AIM OF STUDY: To know the extent of LN metastases in these new basins by dissecting and labeling them separately, for pathological examination and proper staging of those patients. PATIENTS AND METHODS: From 2005 to 2009, 59 private patients with breast cancer who had positive axillary LNs were subjected to axillary dissection with accurate leveling according to its relation to pectoralis minor. In addition to the classical three levels, the brachial, thoracoacromial, humeral, scapular and Rotter's lymph nodes were dissected. RESULTS: Levels I, II and III axillary LNs were involved in 91.5%, 62.7%, and 52.5%, respectively. Skip metastases (without the involvement of level one) were found in 5/59 patients (8.4%). Brachial, acromiothoracic, humeral and Rotter's LNs were involved in 10.1%, 15.2%, 5% and 1.7%, respectively, with no metastatic deposits encountered in scapular LNs. In our patients, lymphedema of the ipsilateral upper limb was nearly of the same incidence as after classical axillary dissection. CONCLUSION: In addition to the classic complete axillary lymph node dissection (ALND) indicated in patients with breast cancer with axillary LNs metastases, dissection of the brachial, acromiothoracic, humeral, Rotter's and scapular LNs, is recommended for proper staging. PMID- 22099934 TI - Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor. AB - BACKGROUND: Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor. MATERIAL AND METHODS: This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done. RESULTS: WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p=0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p<0.001). Stage affected the 3-year relapse free-survival (RFS) significantly (p=0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p=0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p=0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p=0.004). CONCLUSION: Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification. PMID- 22099935 TI - Assessment of Her-2/neu gene amplification status in breast carcinoma with equivocal 2+ Her-2/neu immunostaining. AB - BACKGROUND AND PURPOSE: Amplification of Her-2/neu gene occurs in 25-30% of breast carcinomas. FDA approved trastuzumab (Herceptin) is effective only in tumors having the gene amplification. Immunohistochemistry (IHC) for Her-2/neu protein is widely used but false positive and false negative results exist. Fluorescence in-situ hybridization (FISH) has both excellent sensitivity and specificity in detecting Her-2/neu amplification. Comparative studies have shown discordant results in proportion of cases with equivocal 2+ immunostain. This study is thus conducted to ascertain the frequency of Her-2/neu gene amplification by FISH in breast carcinoma specified as score 2+ by IHC and to correlate these findings with parameters of prognosis in breast cancer. METHODS: From October 2008 till May 2010 all paraffin blocks from cases with invasive breast carcinoma which were scored as 2+ by IHC were eligible for the study, there were 50 cases. Immunohistochemical evaluation of Her-2/neu was performed using the HercepTest. All cases were immunohistochemically evaluated for ER and PR. FISH was performed using FDA approved Path-Vysion Her-2/neu/CEP 17 dual color probe. RESULTS: Nine cases (18%) out of 50 cases scored as Her-2/neu 2+ by IHC showed true gene amplification with a median value of scoring ratio 4.28 ranging from 2.37 to 13.26. Another two cases showed low level of amplification but when corrected for Her-2/neu/CEP ratio they did not show true amplification as they were associated with polysomy 17. With the exception of tumor size, neither patient's age, histologic grade nor lymph node status were correlated with Her 2/neu gene amplification. Significant inverse correlation existed between Her 2/neu gene amplification and ER (P=0.01), PR status (P<0.001). CONCLUSION: Even though FISH is a more complex and expensive procedure, it should be considered the method of choice for assessment of Her-2/neu gene status especially for equivocal cases by IHC that are not accompanied by true gene amplification in the majority of breast carcinoma cases. PMID- 22099936 TI - Did salvage ICE chemotherapy improve the outcome in primary resistant/relapsing stage III/IV neuroblastoma? AB - BACKGROUND AND PURPOSE: Neuroblastoma is the most common extracranial and deadly solid tumor in children. It accounts for 15% of the deaths from cancer in the pediatric age group. Approximately half of the newly diagnosed children are at "high risk" of treatment failure. The aim of this study is to evaluate the response rate of salvage chemotherapy by the ICE (Ifosfamide, Carboplatin, and Etoposide) regimen when administered to previously treated primary refractory or progressive high risk neuroblastoma patients. PATIENTS AND METHODS: Sixty-six patients from the National Cancer Institute (NCI), Cairo University and the Children Cancer Hospital Egypt (CCHE) received salvage chemotherapy (ICE) either due to primary resistance in 51/66 (77.2%) or due to disease progression on primary chemotherapy in 15/66 (22.8%). RESULTS: They were 40 males (60.6%) and 26 females (39.4%). Patients' age ranged between 3 months and 12.5 years. The most common tumor site was suprarenal, followed by retroperitoneal mass. Two patients (3%) died from chemotherapy toxicity during ICE administration. Evaluation of tumor response in the remaining 64 patients showed the following: CR/PR in 24 patients (36.5%), SD in 11 patients (16.6%), and PD in 29 patients (43.9%). Fourteen patients (21.2%) were considered eligible for auto BMT, while 50/64 patients (78.8%) failed this second line (salvage) chemotherapy and had palliative lines of therapy. By the end of the study (May 2010), 47/66 (71.2%) of the patients were still alive, while 19/66 (28.8%) were dead. Two out of 14 patients (14.2%) who underwent HSCT died from post transplantation disease progression, while 12/14 (85.8%) were in CCR. CONCLUSION: Chemotherapy by ICE for primary resistant or progressive stage III/IV NB seems well tolerated. With a 36.6% response rate, 18% CCR, and 3% treatment mortality rate, it could be considered a good salvage therapy in the category of patients who are condemned for palliation. PMID- 22099937 TI - [Immunohistochemical study of Dlx1 and Msx1 expression during cephalic development of Dumbo and Wistar rats. Correlation with morphological data]. AB - The Dumbo rat is characterized by a short snout, low ears and relative hypoplasia of maxillar and zygomatic bones. It corresponds to an autosomal recessive genotype. Previous study demonstrated a global deficit of Dlx1 and Msx1 genes expression in comparison to Wistar embryos as considered as control animals. We performed a histological study of cephalic development of Dumbo rats compared to Wistar embryos and an immunohistochemical analysis of Dlx1 and Msx1 protein expression during cephalogenesis. Our data indicate that the pattern of expression of both genes is similar in both strains, but that quantitative differences in gene expression can be the result of delayed organogenesis in Dumbo rat in comparison to Wistar. Some data about gene expressions are discussed at the light of the postulated function of Dlx1 and Msx1 in cephalic development. PMID- 22099938 TI - [Cardiovascular risk factors and Primary Care: evaluation and intervention]. AB - There is high prevalence of major cardiovascular risk factors (MCVRF) in Spain, equal or greater than the rest of the countries in Europe, with a tendency to increase, while the their control is in general sub-optimal. In the clinical setting, and in Primary Care clinics in particular, preventive activities and early detection (screening) of MCVRF that are well established by the scientific evidence should be carried out. Smoking should be tackled and treated with decisively, even more so in the context of the favourable current legislation. The measurement of risk factors makes it easy to take decisions in clinical practice, but should not be substituted for clinical judgement, given the limitation of the currently available calculation methods. The concept of overall focus on cardiovascular risks can obtain a reduction of the risk by the synergetic action on the different MCVRF in each individual case. The aim must be to reduce the probability of having a cardiovascular disease in the future, as well as the loss in quality of life, incapacity and associated mortality. PMID- 22099940 TI - How obesity and bariatric surgery can affect asthma control. PMID- 22099941 TI - A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions. AB - BACKGROUND: Management of patients with carboplatin-induced hypersensitivity reactions (HSR) has been complicated by high false-negative rates of carboplatin skin test (ST) results. These patients might be at risk for future carboplatin induced HSRs. In this article we identify a strategy to improve risk stratification of patients with a history of carboplatin-induced HSRs by using a protocol that includes repeat skin testing and drug desensitization. OBJECTIVE: We sought to identify a management strategy for patients with a history of carboplatin-induced HSRs with negative carboplatin ST results. METHODS: From 2008 2010, patients with carboplatin-induced HSR underwent risk stratification per a protocol using 3 repeat STs with intervening drug desensitizations. RESULTS: Of the 44 patients with carboplatin-induced HSRs, 39 completed the protocol. Patients were classified as having positive ST results (n = 16), having negative ST results (n = 11), or ST converters when the ST result converted to positive after an initial negative result (n = 12). ST converters are more likely to have HSRs during subsequent desensitizations than patients with negative ST results (56.1% vs 4.5%, P < .001). ST converters had a significantly longer time interval between their initial HSR and initial ST evaluation compared with either patients with true-negative ST results (22.1 vs 6.0 months, P = .03) or patients with positive ST results (22.1 vs 1.8 months, P = .001). CONCLUSION: Our experience suggests that repeat STs are necessary for risk stratification in patients with a remote clinical history of HSR and an initial negative ST result because there is a significant rate of conversion to a positive ST result. ST converters have an increased risk of HSRs during subsequent carboplatin treatment. PMID- 22099942 TI - Integration of processes induced air flotation and photo-Fenton for treatment of residual waters contaminated with xylene. AB - Produced water in oil fields is one of the main sources of wastewater generated in the industry. It contains several organic compounds, such as benzene, toluene, ethyl benzene and xylene (BTEX), whose disposal is regulated by law. The aim of this study is to investigate a treatment of produced water integrating two processes, i.e., induced air flotation (IAF) and photo-Fenton. The experiments were conducted in a column flotation and annular lamp reactor for flotation and photodegradation steps, respectively. The first order kinetic constant of IAF for the wastewater studied was determined to be 0.1765 min(-1) for the surfactant EO 7. Degradation efficiencies of organic loading were assessed using factorial planning. Statistical data analysis shows that H(2)O(2) concentration is a determining factor in process efficiency. Degradations above 90% were reached in all cases after 90 min of reaction, attaining 100% mineralization in the optimized concentrations of Fenton reagents. Process integration was adequate with 100% organic load removal in 20 min. The results of the integration of the IAF with the photo-Fenton allowed to meet the effluent limits established by Brazilian legislation for disposal. PMID- 22099943 TI - Photocatalytic treatment of high concentration carbamazepine in synthetic hospital wastewater. AB - Effective and sustainable treatment of hospital wastewater containing high concentration of pharmaceutical compounds presents a pivotal challenge to wastewater and environmental engineers worldwide. In this study, a titanium dioxide (TiO(2)) nanofiber based wastewater treatment process was assessed as a pre-treatment system to treat and enhance the biodegradability of a representative pharmaceutical compound, 5000 MUg/L of carbamazepine (CBZ), in synthetic hospital wastewater. Results showed that the stand-alone TiO(2) pre treatment system was capable of removing 78% of CBZ, 40% of COD and 23% of PO(4) concentrations from the influent wastewater within a 4h reaction time. High performance size exclusion chromatography demonstrated that a simultaneous biodegradability enhancement of hospital wastewater was observed, whereby an apparent shift in molecular weight from higher fraction (>10-1000 kDa) to a lower fraction (<10 kDa) was induced after 0.5h of photocatalytic treatment. Eventually, it was found that the photodegradation profile for high concentration CBZ in synthetic hospital wastewater was perfectly fitted to the Langmuir Hinshelwood kinetics model. It is anticipated that this TiO(2) pre-treatment process can be further integrated with a biological wastewater treatment process to deliver treated hospital effluent of better quality that can minimise the associated human health and environmental risks. PMID- 22099944 TI - Pyrophosphate coupling with chelant-enhanced soil flushing of field contaminated soils for heavy metal extraction. AB - This study investigated the influence of flushing duration, [S,S] ethylenediaminedisuccinic acid (EDDS) dosage, humic acid and various combinations of ethylenediaminetetraacetic acid (EDTA), EDDS and tetrasodium pyrophosphate (Na(4)P(2)O(7)) on metal extraction during soil flushing, through column experiments. A lesser extent of enhancement in metal extraction efficiencies was found when the flushing duration and the dosage of EDDS was doubled, compared to their efficiencies measured at pore volume 100. Metal extraction efficiency was mainly influenced by the initial metal distribution in the soils rather than the flushing duration and the EDDS-to-metal molar ratio. Humic acid of less than 10mg/L as dissolved organic carbon (DOC) posed an insignificant effect on metal extraction during EDDS enhanced soil flushing. The extraction rate of Ni by EDTA and EDDS was time dependent, and was initially fast in the case of EDDS, whereas it was slow for EDTA. However, the overall Ni extraction efficiency by EDTA was higher when the flushing time was longer. Na(4)P(2)O(7) promoted the mineral dissolution which enhanced the metal extraction as a result of soil disruption. The order of metal extraction by Na(4)P(2)O(7) was Ni>Cr>Cu, probably be due to the different affinities between metals and P(2)O(7)(4-). PMID- 22099945 TI - Endemic and emerging chlamydial infections of animals and their zoonotic implications. AB - The Chlamydiae are a diverse group of obligate intracellular Gram-negative bacteria that are known to infect a wide variety of host species and are responsible for a wide range of diseases in animals and man. Many of these organisms have been extensively characterized and their zoonotic implications recognized. Studies of human disease first provided evidence for the disease causing potential of Chlamydia-related bacteria; however, there is now increasing evidence that a number of these organisms may also be the causative agents for a number of pathogenic conditions of livestock that had previously remained undiagnosed. The aim of this review is to draw together the evidence for the role of the newly emerging chlamydial infections in livestock disease, the current understanding of their roles in human disease and highlight the potential for zoonotic transmission. PMID- 22099946 TI - Influence of operative strategy for the aortic arch in DeBakey type I aortic dissection: analysis of the German Registry for Acute Aortic Dissection Type A. AB - OBJECTIVE: Patients treated with an extensive approach including total aortic arch replacement for acute aortic dissection type A may have a favorable long term prognosis by treating the residual false lumen. Our goal was to analyze the operative strategy for treatment of type I DeBakey aortic dissection from the German Registry for Acute Aortic Dissection Type A (GERAADA) data. METHODS: A total of 658 patients with type I DeBakey aortic dissection and entry only in the ascending aorta were identified in the GERAADA. Patients in group A underwent replacement of the ascending aorta with hemiarch replacement. Patients in group B received extensive treatment with total arch replacement or conventional or frozen elephant trunk. RESULTS: A total of 518 patients in group A and 140 patients in group B were treated. There was an overall 30-day mortality of 20.2% (n = 133). Group A had a slightly lower rate of mortality with 18.7% (n = 97) compared with 25.7% for group B (n = 36), but with no statistical significant difference (P = .067). The onset of new neurologic deficit (13.6% in group vs 12.5% in group B, P = .78) and new malperfusion deficit (8.4% in group A vs 10.7% in group B, P = .53) showed no statistical difference. CONCLUSIONS: On analysis of the GERAADA data, it seems that a more aggressive approach of aortic arch treatment can be applied without higher perioperative risk even in the onset of acute aortic dissection type A. Long-term follow-up data analysis will be necessary to offer the optimal surgical strategy for different patient groups. PMID- 22099947 TI - Optimization of culture conditions to produce high yields of active Acetobacter sp. CCTCC M209061 cells for anti-Prelog reduction of prochiral ketones. AB - BACKGROUND: Chiral alcohols are widely used in the synthesis of chiral pharmaceuticals, flavors and functional materials and appropriate whole-cell biocatalysts offer a highly enantioselective, minimally polluting route to these valuable compounds. The recently isolated strain Acetobacter sp. CCTCC M209061 showed exclusive anti-Prelog stereoselectivity for the reduction of prochiral ketones, but the low biomass has limited its commercialization and industrial applications. To tackle this problem, the effects of medium components and culture conditions on the strain's growth and reduction activity were explored. RESULTS: By using a one-at-a-time method and a central composite rotatable design (CCRD), the optimal medium and culture conditions were found to be as follows: glucose 8.26 g/L, fructose 2.50 g/L, soy peptone 83.92 g/L, MnSO4.H2O 0.088 g/L, pH 5.70, 30 degrees C and 10% (v/v) inoculum. Under the above-mentioned conditions, the biomass after 30 h cultivation reached 1.10 +/- 0.03 g/L, which was 9.5-fold higher than that obtained with basic medium. Also, the reduction activity towards 4'-chloroacetophenone was markedly enhanced to 39.49 +/- 0.96 MUmol/min/g from 29.34 +/- 0.65 MUmol/min/g, with the product e.e. being above 99%. Comparable improvements were also seen with the enantioselective bioreduction of 4-(trimethylsilyl)-3-butyn-2-one to the key pharmaceutical precursor (R) - 4-(trimethylsilyl)-3-butyn-2-ol. CONCLUSIONS: The biomass and reduction activity of Acetobacter sp. CCTCC M209061 can be greatly enhanced through the optimization strategy. This facilitates use of the strain in the anti Prelog stereoselective reduction of prochiral ketones to enantiopure chiral alcohols as building blocks for many industries. PMID- 22099948 TI - A promising approach in comparative research on care for the elderly. AB - Long-term care (LTC) in the form of care provided in nursing homes, homes for the aged and home care is considered an appropriate answer to the growing needs of the aging populations of the industrialized world. However, the provision of and expenditures on LTC vary considerably between these industrialized countries. Although one would expect LTC to be subject to many internationally comparative studies, including all European countries, this is not the case. A paper presented by Damiani et al. in BMC Health Services Research contains an internationally comparative model regarding the development of LTC in Europe (2003 to 2007). They achieve an intriguing compromise between depth and width in the sparsely populated domain of internationally comparative research on LTC by characterizing countries' LTC and interpreting the large north/south differences found. Their results also show that 'cash for care' schemes form a substantial alternative to traditional LTC provision. An additional time series analysis showed that many countries seem to be engaged in reorganizing the LTC sector. This study widens knowledge in a neglected area of health services research and should serve as a source of inspiration for further studies. PMID- 22099949 TI - FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients. AB - Fibroblast growth factor 23 (FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study. PMID- 22099950 TI - Sandwich sign of Borrmann type 4 gastric cancer on diffusion-weighted magnetic resonance imaging. AB - OBJECTIVE: To assess the appearance of Borrmann type 4 (BT-4) gastric cancer on diffusion-weighted magnetic resonance imaging (DWI) and to investigate the potential of qualitative and quantitative DW images analysis to differentiate BT 4 gastric cancer from poorly distended normal stomach wall. MATERIALS AND METHODS: DWI was performed on 23 patients with BT-4 gastric cancer and 23 healthy volunteers. The signal characteristics and correlated histopathological basis of the cancers on DWI were investigated. The contrast-to-noise ratios (CNR) of cancer were compared between DWI and T1WI/T2WI(.) The thickness and apparent diffusion coefficient (ADC) of cancer and normal stomach wall were compared. RESULTS: All of the gastric cancers displayed hyperintensity compared to the nearby normal gastric wall on DWI. A three-layer sandwich sign that demonstrated high signal intensity in the inner and outer layer, and low signal intensity in the intermediate layer was observed in 69.6% of cancers on DWI. The low signal intensity represents the muscularis propria through the comparison with pathology, and it is postulated that scattering distribution of the cancer cells in this layer causes less damage and subsequently less restriction of water movement, which causes the low signal intensity on DWI. The CNR obtained with DWI was higher than that with T1WI and T2WI (P<0.001). The mean ADC value of BT-4 gastric cancer was significantly lower than the poorly distended normal stomach wall (1.12 +/- 0.23 * 10(-3)mm(2)/s vs. 1.9 3 +/- 0.22 * 10(-3)mm(2)/s, P<0.01). CONCLUSION: DWI can highlight the signals of BT-4 gastric cancer which may present a characteristic three-layer sandwich sign, and ADC values are helpful in the discrimination of gastric cancer from poorly distended stomach wall. PMID- 22099951 TI - At the mercy of prior entry: Prior entry induced by invisible primes is not susceptible to current intentions. AB - If one of two events is attended to, it will be perceived earlier than a simultaneously occurring unattended event. Since 150 years, this effect has been ascribed to the facilitating influence of attention, also known as prior entry. Yet, the attentional origin of prior-entry effects(1) has been repeatedly doubted. One criticism is that prior-entry effects might be due to biased decision processes that would mimic a temporal advantage for attended stimuli. Although most obvious biases have already been excluded experimentally (e.g. judgment criteria, response compatibility) and prior-entry effects have shown to persist (Shore, Spence, & Klein, 2001), many other biases are conceivable, which makes it difficult to put the debate to an end. Thus, we approach this problem the other way around by asking whether prior-entry effects can be biased voluntarily. Observers were informed about prior entry and instructed to reduce it as far as possible. For this aim they received continuous feedback about the correctness of their temporal judgments. If elicited by invisible primes the effect could not be reduced at all and only by 12 ms if elicited by visible cues. This challenges decision biases as primary source of prior-entry effects - at least if attention is oriented exogenously. PMID- 22099952 TI - Assessment of knowledge, attitude and risk behaviors towards HIV/AIDS and other sexual transmitted infection among preparatory students of Gondar town, north west Ethiopia. AB - BACKGROUND: The first case of HIV in Ethiopia was reported in 1984. Since then, HIV/AIDS has become a major public health concern in the country, leading the Government of Ethiopia to declare a public health emergency in 2002. Although the epidemic is currently stable, HIV/AIDS remains a major development challenge for Ethiopia. The spread of HIV in any community is in part determined by the knowledge of attitude towards sexuality of its members and by their actual sexual practices. The aim of the study was to assess students' knowledge, attitudes and practices regarding HIV/AIDS and STDs in Gondar, North West Ethiopia. METHODS: A cross sectional study was conducted between February 1 to March 1, 2009 in preparatory high school students. Pre-tested questioner was used to generate the data and analysis was made by SPSS version 15. Chi -square value was calculated and p-value < 0.05 was considered statistically significant. RESULTS: All the students had heard about AIDS before the interview. Knowledge on some aspect of the disease was quite low in the study group. Only half of the students knew that at present, AIDs is incurable and that HIV infection can be acquired through sexual contact with a 'familiar' person. Knowledge about STI was also quite low, 39% knew that pus in the urine is a symptom of STI and 45.4% knew that acquisition of other STIs is increases the chance of HIV transmission following unsafe sex with known cases. 25% of the study group had previous sexual intercourse and exposed at least one risk behavior. About 34% of the respondents had negative attitude towards AIDS and STDs. CONCLUSION: Awareness about STDs and methods of prevention of HIV and STDs was low. More risk behavior was observed in male and those with alcohol and drugs of abuse. PMID- 22099953 TI - Limited efficacy of steam sterilization to inactivate vCJD infectivity. AB - BACKGROUND: The transmission of bovine spongiform encephalopathy (BSE) to humans as variant Creutzfeldt-Jakob Disease (vCJD) raised concerns about potential secondary transmissions due to the resistance of the agents causing transmissible spongiform encephalopathies (TSEs), sometimes known as prions, to commonly used methods of sterilization, notably steam sterilization (or autoclaving). It has been suggested that surgical instruments and other medical devices might retain sufficient infected tissue debris after cleaning and steam sterilization to infect patients on whom they are subsequently used. AIM: To determine whether concerns about the lack of efficacy of steam sterilization of vCJD were justified. METHODS: The reduction in infectivity of brain macerates of vCJD brain after steam sterilization using the standard temperatures and time recommended for autoclaving in UK hospitals (134-137 degrees C for 3 min) was measured. FINDINGS: Reductions in titre of 10(2.3) to >10(3.6) ID(50) were found. In three of four samples, infectivity was recovered after steam sterilization. CONCLUSION: As noted previously, TSE strains derived from BSE sources appear to be more resistant to steam sterilization and other forms of heat inactivation than other TSE sources. PMID- 22099955 TI - Enhanced electrochemiluminescence of CdSe quantum dots composited with graphene oxide and chitosan for sensitive sensor. AB - A novel strategy for the enhancement of electrochemiluminescence (ECL) was developed by combining CdSe quantum dots (QDs) with graphene oxide-chitosan (GO CHIT). The ECL sensor fabricated with CdSe QDs/GO-CHIT composite exhibited high ECL intensity, good biocompatibility and long-term stability, and was used to detect of cytochrome C (Cyt C). The results show that the ECL sensor has high sensitivity for Cyt C with the linear range from 4.0 to 324 MUM and the detection limit of 1.5 MUM. Furthermore, the ECL sensor can selectively sense Cyt C from glucose and bovine serum albumin (BSA). PMID- 22099956 TI - Electrochemical imprinted sensor for determination of oleanic acid based on poly (sodium 4-styrenesulfonate-co-acrylic acid)-grafted multi-walled carbon nanotubes chitosan and cobalt hexacyanoferrate nanoparticles. AB - A novel sensitive and selective imprinted electrochemical sensor for the determination of oleanic acid was constructed on a carbon electrode by stepwise modification of functional multi-walled carbon nanotubes, cobalt hexacyanoferrate nanoparticles and a thin imprinted sol-gel film. The fabrication of a homogeneous porous poly (sodium 4-styrenesulfonate-co-acrylic acid)-grafted multi-walled carbon nanotubes/SiO(2)-chitosan nanocomposite film was conducted by controllable electrodeposition technology. The surface morphologies of the modified electrodes were characterized by scanning electron microscope. The performance of the imprinted sensor was investigated by cyclic voltammetry, square wave voltammetry and electrochemical impedance spectroscopy in detail. The imprinted sensor displayed high sensitivity and selectivity towards oleanic acid. A linear relationship between the sensor response signal and the logarithm of oleanic acid concentrations ranging from 1.0*10(-8) to 1.0*10(-3) mol L(-1) was obtained with a detection limit of 2.0*10(-9) mol L(-1). It was applied to the determination of oleanic acid in real capsule samples successfully. PMID- 22099954 TI - Co-morbid anxiety disorders in bipolar disorder and major depression: familial aggregation and clinical characteristics of co-morbid panic disorder, social phobia, specific phobia and obsessive-compulsive disorder. AB - BACKGROUND: Co-morbidity of mood and anxiety disorders is common and often associated with greater illness severity. This study investigates clinical correlates and familiality of four anxiety disorders in a large sample of bipolar disorder (BP) and major depressive disorder (MDD) pedigrees. METHOD: The sample comprised 566 BP families with 1416 affected subjects and 675 MDD families with 1726 affected subjects. Clinical characteristics and familiality of panic disorder, social phobia, specific phobia and obsessive-compulsive disorder (OCD) were examined in BP and MDD pedigrees with multivariate modeling using generalized estimating equations. RESULTS: Co-morbidity between mood and anxiety disorders was associated with several markers of clinical severity, including earlier age of onset, greater number of depressive episodes and higher prevalence of attempted suicide, when compared with mood disorder without co-morbid anxiety. Familial aggregation was found with co-morbid panic and OCD in both BP and MDD pedigrees. Specific phobia showed familial aggregation in both MDD and BP families, although the findings in BP were just short of statistical significance after adjusting for other anxiety co-morbidities. We found no evidence for familiality of social phobia. CONCLUSIONS: Our findings suggest that co-morbidity of MDD and BP with specific anxiety disorders (OCD, panic disorder and specific phobia) is at least partly due to familial factors, which may be of relevance to both phenotypic and genetic studies of co-morbidity. PMID- 22099957 TI - LSPR biomolecular assay with high sensitivity induced by aptamer-antigen-antibody sandwich complex. AB - Herein we demonstrate a sensitive approach for protein detection based on peak shifts of localized surface plasmon resonance (LSPR) induced by aptamer-antigen antibody sandwich structures. The applicability of the proposed method is demonstrated using human alpha-thrombin as a model analyte. While the binding of thrombin to its specific receptor, thrombin binding aptamer (TBA) modified on Au nanorods (AuNRs), causes a measurable LSPR shift, a subsequent binding of an anti thrombin antibody to the captured thrombin can exhibit a nearly 150% amplification in the LSPR response. This enhanced signal essentially leads to an improvement of limit of detection (LOD) by more than one order of magnitude. In addition, the use of TBA as thrombin recognition units makes the biosensor reusable. The feasibility of the proposed method was further exploited by the detection of thrombin in human serum, opening the possibility of a real application for diagnostics and medical investigations. PMID- 22099958 TI - DNA-functionalized biosensor for riboflavin based electrochemical interaction on pretreated pencil graphite electrode. AB - The interaction of riboflavin with salmon sperm double-stranded DNA based on the decreasing of the oxidation signal of guanine and adenine bases was studied electrochemically with a pencil graphite electrode (PGE) using differential pulse voltammetry. The decrease in the intensity of the guanine and adenine oxidation signals after interaction with riboflavin was used as an indicator signals for the sensitive determination of riboflavin. Under the optimum conditions, a linear dependence of the guanine and adenine oxidation signals was observed for the riboflavin concentration in the range of 0.5-70 MUg mL(-1) with a detection limit of 0.34 MUg mL(-1) at ds-DNA modified PGE. The reproducibility and applicability of the analysis to pharmaceutical dosage forms and urine sample were also investigated. These results showed that this DNA biosensor could be used for the sensitive, rapid, simple and cost effective detection and determination of riboflavin-ds-DNA interaction. Pretreated pencil graphite electrode (PPGE) was also used for the determination of riboflavin by differential pulse adsorptive stripping voltammetry. With PPGE, a linear relationship was obtained for riboflavin over the concentration range of 0.003-0.88 MUg mL(-1) with differential pulse adsorptive stripping voltammetric signal and with a detection limit of 0.076 ng mL(-1). Both determination methods were fully validated and applied for the analysis of riboflavin. PMID- 22099959 TI - Fabrication of a chitosan/glucose oxidase-poly(anilineboronic acid)-Au(nano)/Au plated Au electrode for biosensor and biofuel cell. AB - Enzyme immobilization is one of the key factors in constructing high-performance enzyme biosensors and biofuel cells (BFCs). Herein, we propose a new protocol for efficient immobilization of a glycoprotein enzyme based on the interaction of the 1, 2- or 1, 3-diols in the glycoprotein with a boronic acid functionalized monomer. Briefly, casting a mixture of glucose oxidase (GOx) and anilineboronic acid (ABA) followed by a NaAuCl(4) solution to an Au-plated Au electrode surface yielded a GOx-poly(ABA) (PABA)-gold nanoparticle (Au(nano)) bionanocomposite, and chitosan (CS) was then cast and air-dried. In the present protocol, the small sized Au(nano) or Au subnanostructures can form near/on the enzyme molecule, which greatly promotes the electron transfer of enzymatic reaction and enhances the amperometric responses. The thus-prepared CS/GOx-PABA-Au(nano)/Au-plated Au electrode worked well in the first-/second generation biosensing modes and as a bioanode in a monopolar biofuel cell, with analytical or cell-power performance superior to those of most analogues hitherto reported. PMID- 22099960 TI - Evaluation of diffusive gradients in thin-films (DGTs) as a monitoring tool for the assessment of the chemical status of transitional waters within the Water Framework Directive. AB - In this contribution, the potential use of diffusive gradients in thin-films (DGTs) for the chemical evaluation of transitional water bodies within the Water Framework Directive (WFD) has been studied. The water metal concentration has been evaluated in 13 estuaries in the southeastern Bay of Biscay. The DGTs were deployed in triplicate at two stations in each estuary, delimiting the tidal influence. The DGT results were in the ranges of 2-1570 ng L(-1) for cadmium, 66 515 ng L(-1) for copper, 30-3650 ng L(-1) for nickel and 0.8-95.5 MUg L(-1) for zinc. The DGTs provided reliable average labile metal concentrations in highly dynamic systems that were comparable with DGT measurements in coastal and estuarine waters worldwide. In addition, it was possible to discriminate those estuaries more susceptible to environmental impacts, being consistent with the historical contamination of each estuary. Based on the obtained results, a sampling strategy for the monitoring of transitional water bodies using DGTs is proposed. PMID- 22099961 TI - Geometrical uncertainty margins in 3D conformal radiotherapy in the pediatric age group. AB - PURPOSE: To evaluate set-up variation of pediatric patients undergoing 3D conformal radiotherapy (3DCRT) using electronic portal image device (EPID), in an effort to evaluate the adequacy of the planning target volume (PTV) margin employed for the 3DCRT treatment of pediatric patients. MATERIALS AND METHODS: Set-up data was collected from 48 pediatric patients treated with 3DCRTfor head and neck (31 patients), abdomino-pelvic (9 patients) and chest (8 patients) sites during the period between September 2008 and February 2009. A total of 358 images obtained by EPID were analyzed. The mean (M) and standard deviation (SD) for systematic and random errors were calculated and the results were analyzed. RESULTS: All images were studied in anterior and lateral portals. The systematic errors along longitudinal, lateral and vertical directions in all patients showed an M equal to 1.9, 1.6, and 1.6mm with SD of 1.8, 1.4, and 1.8mm, respectively; (head and neck cases: M equal to 1.5, 1.2, and 1.6mm with SD 1.4, 1.2, and 1.8mm; chest cases: M equal to 2.5, 1.8, and 0.8mm with SD 2.7, 1.7, and 1.2mm, abdomino pelvic cases: M equal to 2.9, 2.8 and 2.3mm with SD 1.6, 1.2, and 2.3mm). Similarly, the random errors for all patients showed SD of 1.9, 1.6, and 1.8mm, respectively (head and neck cases: SD 1.7, 1.3, and 1.5mm; chest cases: SD 1.2, 1.9, and 2.5mm; abdomino-pelvic cases SD 2.5, 2, and 2.4mm, respectively). Using Van Herk's formula the suggested (PTV) margin around the clinical target volume (CTV) of 5.5mm appears to be adequate. CONCLUSION: The ranges of set-up errors are site specific and depends on many factors. PMID- 22099962 TI - Nephron-sparing surgery for renal tumors. AB - PURPOSE: To report National Cancer Institute (NCI) experience in managing various benign and malignant renal tumors with nephron sparing surgery (NSS), and to assess its safety and feasibility. PATIENTS AND METHODS: Literature review for NSS, and reviewing of the patients records who underwent NSS between the period from January-2000 to December-2009 at NCI-Cairo University was done. Tumor related characteristics, indication for NSS, operative techniques, postoperative complications, full histopathological data, and follow up results were reviewed. RESULTS: The total number of patients was 15. Median age at surgery was 32 years (range from 1.5 to 65 years). Five patients had bilateral tumors. The mean radiologic tumor size was 4.7+/-5.2cm. All patients had normal preoperative kidney functions. Six patients had an absolute indication for NSS, while 6 patients had a relative indication, and 3 patients were elective. All 5 patients with bilateral tumors underwent bilateral simultaneous surgery. Cold ischemia was used in 7 patients, 1 patient was exposed to warm ischemia. Manual compression was used in 2 patients, and no vascular control was applied in 5 patients. Complications were encountered in 2 patients, one of them had urinary leakage which needed reoperation, and the other had subcutaneous hematoma which was treated conservatively. Histopathological analysis revealed Wilm's tumor (7 patients), angiomyolipoma (4 patients), renal cell carcinoma (RCC) (3 patients), and Hydatid cyst (1 patient). All patients had negative surgical margin. For patients with Wilm's tumor, the median follow up was 24.4 months (range from 5 to 94 months), two patients had local recurrence, and 1 patient had distant metastasis. For patients with RCC, The median follow up was 14.7 months (range from 5 to 33 months) with no local recurrence or distant metastasis. All patients had normal kidney functions during postoperative and follow up periods. CONCLUSION: NSS is a feasible safe procedure that could be done with acceptable complications. It provides a good solution for patients with bilateral benign tumors and early localized RCC. PMID- 22099963 TI - Parotidectomy for benign parotid tumors: an aesthetic approach. AB - BACKGROUND/AIMS: The sternocleidomastoid (SCM) partial thickness muscle flap is among the various methods described to correct parotidectomy defects, but its indications and limitations are not clearly demonstrated in several reports. This study was done to test the aesthetic outcome of this method, its indications and limitations. The technique was combined with a face lift incision to further improve the outcome. PATIENTS AND METHODS: At the National Cancer Institute, Cairo University, Egypt, 23 patients presenting with benign tumors underwent parotidectomy, 19 had superficial parotidectomy and four had total parotidectomy done. The superiorly based (SCM) muscle flap was used to correct the contour deformity. The aesthetic result was evaluated by assessing and scoring the overall appearance of the scar, the degree of symmetry of the reconstructed parotid region and the site of the donor muscle to their contralateral normal sides. The overall aesthetic appearance was then calculated by the summation of the scores of the latter three parameters. Patients' satisfaction was assessed by patients' questionnaire. RESULT: The overall aesthetic appearance was good in 17 patients, and moderate in six patients. 16/23 patients had an overall deep satisfaction with the result. The residual hollowness of the parotid following reconstruction of the total parotidectomy defect and the poor quality of scars were the main reasons affecting the aesthetic outcome. CONCLUSION: Superficial parotidectomy through facelift incision with immediate reconstruction with superiorly based partial thickness SCM flap allows adequate resection of most benign parotid tumors with a satisfactory aesthetic outcome and minimal donor site morbidity. PMID- 22099964 TI - Novel mutations of the nucleophosmin (NPM-1) gene in Egyptian patients with acute myeloid leukemia: a pilot study. AB - Mutations of the nucleophosmin (NPM-1) gene have been reported in 50-60% of acute myeloid leukemia (AML) patients with normal karyotype. This work was designed to study the prevalence and nature of NPM1 gene mutations in a group of Egyptian patients with AML to get an idea about the profile of NPM1 gene mutations in our society. In 45 previously untreated patients with de novo AML, peripheral blood and/or bone marrow samples from all patients were subjected to microscopic morphologic examination, cytochemical analysis, immunophenotyping and karyotyping. Patients with normal cytogenetic results were selected for molecular analysis of NPM1 exon 12 by PCR amplification followed by DNA sequencing of the amplified product. Twenty-one patients (46.7%) had abnormal karyotype: six cases with t(15;17), five cases with t(8;21), five cases had trisomy 8, two cases carrying inv(3) and three cases had monosomy 7. The remaining 24 patients (53.3%) had normal karyotype. These patients were then subjected to molecular analysis. Out of these 24 patients with normal karyotype, mutant NPM-1 was detected in 11 patients (45.8%) by DNA sequencing; 2 cases showed type A mutation, 2 cases were harboring [ins 1015-1019 (CACG)], with point mutation [1006C>G], while the remaining 7 cases showed heterozygous deletion of nt A [del 1178 (A)]. CONCLUSION: Two novel NPM1 gene mutations were detected among our study population of AML patients identified as: the insertion CACG associated with point mutation, deletion of one base, or associated with point mutation. NPM1 gene mutations may become a new tool for monitoring minimal residual disease in AML with normal karyotype. Whether these previously unreported NPM-1 mutations will confer the same better outcome as previously reported mutations is currently unknown and warrants a larger study. CONCLUSION: Two novel NPM1 gene mutations were detected among our study population of AML patients identified as: the insertion CACG associated with point mutation, deletion of one base, or associated with point mutation. NPM1 gene mutations may become a new tool for monitoring minimal residual disease in AML with normal karyotype. Whether these previously unreported NPM-1 mutations will confer the same better outcome as previously reported mutations is currently unknown and warrants a larger study. PMID- 22099965 TI - Evaluation of morphological/immunohistochemical versus nuclear medicine imaging modalities in detecting metastatic bone and/or marrow deposits in neuroblastoma patients. AB - BACKGROUND & PURPOSE: In planning diagnostic or follow-up investigational strategies, neuroblastoma (NB) metastatic deposits in bone and/or bone marrow (BM) should be detected as early as possible. Therefore, all investigational detection tools should be conducted simultaneously for precise staging. However, because of the financial conditions in our developing countries and in view of the cost/benefit relationship, the question is, can one detection tool only become satisfactory and replacing others? The purpose of our study is to compare simultaneous results of bone and metaiodobenzylguanidine (MIBG) scans versus BM biopsies with immunohistochemical (IHC) staining; in detecting bone and/or BM metastatic deposits in NB patients. MATERIAL AND METHODS: This study included 138 NB patients; 46 were de novo and 92 were under follow-up. They were subjected to bilateral BM biopsies, IHC staining (using NSE McAb) and Tc-99m methylene diphosphonate (Tc-99m MDP) bone scan (BS). Only 57/138 patients were, in addition, subjected to I-131 MIBG scan. RESULTS: Matched results between IHC stained BM sections and bone scans (BSs) 107/138 (77.5%) were higher than the un matched ones 31/138 (22.5%). There was a moderate agreement between the two methods in all studied cases (Kappa=0.538) and it was higher among de novo (Kappa=0.603) than follow-up group (Kappa=0.511). Among the 31 un-matched results, the most frequent (17/31) were due to the presence of minute amount of infiltrating NB cells that could be detected by IHC-stained BM sections and not by BSs. The less frequent (12/31) were due to the presence of metastatic deposits outside pelvic bones that could be detected by BSs and not by IHC-stained BM sections mainly in the follow-up cases (11/12) rather than de novo cases (1/12). The matched results between IHC-stained BM sections and MIBG scans 54/57 (94.7%) were higher than the un-matched ones 3/57 (5.3%). The agreement between the two methods was higher among de novo (Kappa=1.000) than follow-up group (Kappa=0.847). The agreement between IHC-stained BM sections and MIBG scans was substantial (Kappa=0.890) while that between IHC-stained BM sections and BSs was moderate (Kappa=0.538). CONCLUSIONS: We suggest a step-wise strategy to be applied, at least in developing countries, in approaching de novo and follow-up NB cases for detecting bone and/or BM metastatic deposits. This strategy might be beneficial if it is considered during application of NB guide-lines for diagnosis and follow-up. PMID- 22099967 TI - The human papillomavirus type 16 E7 oncoprotein targets Myc-interacting zinc finger protein-1. AB - We demonstrate that HPV-16 E7 forms a complex with Miz-1. UV-induced expression of the CDK-inhibitor p21(Cip1) and subsequent cell cycle arrest depends upon endogenous Miz-1 in HPV-negative C33A cervical cancer cells containing mutated p53. Transient expression of E7 in C33A inhibits UV-induced expression of p21(Cip1) and overcomes Miz-1-induced G1-phase arrest. The C-terminal E7Delta79LEDLL83-mutant with reduced Miz-1-binding capacity was impaired in its capability to repress p21(Cip1) expression; whereas the pRB-binding-deficient E7C24G-mutant inhibited p21(Cip1) expression similar to wild-type E7. Using ChIP, we demonstrate that endogenous E7 is bound to the endogenous p21(Cip1) core promoter in CaSki cells and RNAi-mediated knock down of Miz-1 abrogates E7 binding to the p21(Cip1) promoter. Co-expression of E7 with Miz-1 inhibited Miz-1 induced p21(Cip1) expression from the minimal-promoter via Miz-1 DNA-binding sites. Co-expression of E7Delta79LEDLL83 did not inhibit Miz-1-induced p21(Cip1) expression. E7C24G retained E7-wild-type capability to inhibit Miz-1-dependent transactivation. These findings suggest that HPV-16 E7 can repress Miz-1-induced p21(Cip1) gene expression. PMID- 22099968 TI - Functional regulation of PVBV Nuclear Inclusion protein-a protease activity upon interaction with Viral Protein genome-linked and phosphorylation. AB - Regulation of NIa-Pro is crucial for polyprotein processing and hence, for successful infection of potyviruses. We have examined two novel mechanisms that could regulate NIa-Pro activity. Firstly, the influence of VPg domain on the proteolytic activity of NIa-Pro was investigated. It was shown that the turnover number of the protease increases when these two domains interact (cis: two-fold; trans: seven-fold) with each other. Secondly, the protease activity of NIa-Pro could also be modulated by phosphorylation at Ser129. A mutation of this residue either to aspartate (phosphorylation-mimic) or alanine (phosphorylation deficient) drastically reduces the protease activity. Based on these observations and molecular modeling studies, we propose that interaction with VPg as well as phosphorylation of Ser129 could relay a signal through Trp143 present at the protein surface to the active site pocket by subtle conformational changes, thus modulating protease activity of NIa-Pro. PMID- 22099969 TI - Impairments of speech fluency in Lewy body spectrum disorder. AB - Few studies have examined connected speech in demented and non-demented patients with Parkinson's disease (PD). We assessed the speech production of 35 patients with Lewy body spectrum disorder (LBSD), including non-demented PD patients, patients with PD dementia (PDD), and patients with dementia with Lewy bodies (DLB), in a semi-structured narrative speech sample in order to characterize impairments of speech fluency and to determine the factors contributing to reduced speech fluency in these patients. Both demented and non-demented PD patients exhibited reduced speech fluency, characterized by reduced overall speech rate and long pauses between sentences. Reduced speech rate in LBSD correlated with measures of between-utterance pauses, executive functioning, and grammatical comprehension. Regression analyses related non-fluent speech, grammatical difficulty, and executive difficulty to atrophy in frontal brain regions. These findings indicate that multiple factors contribute to slowed speech in LBSD, and this is mediated in part by disease in frontal brain regions. PMID- 22099970 TI - Neurofunctional (re)organization underlying narrative discourse processing in aging: evidence from fNIRS. AB - Relatively few studies have analyzed the mechanisms underlying the cognitive changes that affect language in the elderly, and fewer have done so for narrative discourse. The goal of this study was to explore the neurofunctional changes associated with aging for different components of narrative discourse. Functional near-infrared spectroscopy (fNIRS) and behavioral data on 10 younger adults and 10 healthy elderly participants were collected. Ten younger adults in a non proficient second language condition were included to explore the possibility that the age-related neurofunctional reorganization partly expresses demanding resource allocation. Results show within- and across-hemispheric differences in the neurofunctional pattern of activation in the older participants with reference to the younger ones, partially shared with the low-proficiency young adults, providing support for the recognized mechanisms underlying neural reserve and compensation. fNIRS was shown to be appropriate for studying the age-related neurofunctional reorganization of complex cognitive abilities. PMID- 22099971 TI - Neural dynamics of animacy processing in language comprehension: ERP evidence from the interpretation of classifier-noun combinations. AB - An event-related potential experiment was conducted to investigate the temporal neural dynamics of animacy processing in the interpretation of classifier-noun combinations. Participants read sentences that had a non-canonical structure, object noun +subject noun+verb+numeral-classifier+adjective. The object noun and its classifier were either (a) congruent, (b) incongruent, but matching in animacy, or (c) incongruent, mismatching in animacy. An N400 effect was observed for both incongruent conditions, but not for additional mismatch in animacy. When only data from participants who accepted the non-canonical structure were analyzed, the animacy mismatch elicited a P600 but still no N400. These findings suggest that animacy information is not used immediately for semantic integration of nouns and their classifiers, but is used in a later analysis reflected by P600. Thus, the temporal neural dynamics of animacy processing in sentence comprehension may be modulated by the relevance of animacy to thematic interpretation. PMID- 22099972 TI - Identification and correction of systematic error in high-throughput sequence data. AB - BACKGROUND: A feature common to all DNA sequencing technologies is the presence of base-call errors in the sequenced reads. The implications of such errors are application specific, ranging from minor informatics nuisances to major problems affecting biological inferences. Recently developed "next-gen" sequencing technologies have greatly reduced the cost of sequencing, but have been shown to be more error prone than previous technologies. Both position specific (depending on the location in the read) and sequence specific (depending on the sequence in the read) errors have been identified in Illumina and Life Technology sequencing platforms. We describe a new type of systematic error that manifests as statistically unlikely accumulations of errors at specific genome (or transcriptome) locations. RESULTS: We characterize and describe systematic errors using overlapping paired reads from high-coverage data. We show that such errors occur in approximately 1 in 1000 base pairs, and that they are highly replicable across experiments. We identify motifs that are frequent at systematic error sites, and describe a classifier that distinguishes heterozygous sites from systematic error. Our classifier is designed to accommodate data from experiments in which the allele frequencies at heterozygous sites are not necessarily 0.5 (such as in the case of RNA-Seq), and can be used with single-end datasets. CONCLUSIONS: Systematic errors can easily be mistaken for heterozygous sites in individuals, or for SNPs in population analyses. Systematic errors are particularly problematic in low coverage experiments, or in estimates of allele specific expression from RNA-Seq data. Our characterization of systematic error has allowed us to develop a program, called SysCall, for identifying and correcting such errors. We conclude that correction of systematic errors is important to consider in the design and interpretation of high-throughput sequencing experiments. PMID- 22099973 TI - [Extrapelvic sentinel lymph nodes in cervical cancer: a review]. AB - OBJECTIVE: To determine the frequency of extrapelvic sentinel lymph node in patients with cervical cancer. MATERIALS AND METHODS: We performed systematic searches (Medline, Pubmed; up to April 2010) to determine the route of lymphatic spread in cervical cancer and to review results on extrapelvic sentinel lymph nodes. RESULTS: According to our search, 2.51% of detected sentinel lymph nodes in patients with cervical cancer were extrapelvic: 2% in the inguinal chain and 98% in the lower paraaortic area. DISCUSSION AND CONCLUSION: The unusual localizations of sentinel lymph nodes impose to the gynaecologic surgeons to be hardened in performing lymph node dissection in all the territories potentially affected. PMID- 22099974 TI - [Contralateral breast outcome after breast reconstruction for carcinoma]. AB - OBJECTIF: Since the treatment of breast cancer must be followed by a rigorous surveillance of the contralateral breast, especially in breast reconstruction context, we sought to determine contralateral breast cancer frequency after breast reconstruction during the ulterior surveillance. PATIENTS AND METHODS: Retrospective cohort survey of 273 breast reconstructions led at Tours regional and university hospital. Cumulative incidence of sequential contralateral breast cancer has been evaluated. RESULTS: For 6.6 follow-up, the prevalence was 1.8% and cumulated incidence at 4.6 0/00 person/years. DISCUSSION AND CONCLUSION: The probability of localization to contralateral breast after a primitive tumor of the breast is raised. The diagnosis of a sequential cancer must not be delayed by mammaplasty scars overhauls. PMID- 22099975 TI - [Correcting occiput posterior position during labor: the role of maternal positions]. AB - Occipito-posterior presentation represents 10 to 34% of cephalic presentations in early labor. Spontaneous rotation during labor to occipito-anterior mode occurs in most cases, but 5 to 8% of fetuses will persist in posterior position for the expulsive phase of delivery. Previous research has shown that this presentation carries an increased risk of unusually long labor, maternal and fetal exhaustion, instrument-assisted delivery, severe perineal injury, and cesarean section. The diagnosis of posterior variety is usually made quite late at the end of dilation. Several researchers have reported the benefits of determining presentation during labor by transabdominal ultrasonography. Some obstetrical techniques to correct these presentations at complete dilation have also been described. In the case of diagnosis of posterior variety, the usual attitude is expectant management. Postural techniques to promote physiological labor and delivery have been documented in the literature. De Gasquet has described a very precise technique to facilitate fetal rotation, but its effectiveness has never been assessed scientifically. A Cochrane review on the topic has shown that similar positions are well accepted by women and reduce back pain. On the other hand, the sample size of included studies appeared inadequate to assess their interest for use in childbirth, in general, and for adverse outcomes associated with posterior presentation varieties in particular. Attempts to correct the fetal malposition during the expansion phase would allow to reduce adverse outcomes during the expulsive phase of delivery. Further research is necessary to assess the efficacity of specific maternal positions during labor for the correction of fetal posterior presentation. PMID- 22099976 TI - [Acardiac twins: pronostics markers' study]. AB - OBJECTIVES: To determine ultrasonographic markers that can help to predict prognosis in twins acardiac pathology in order to manage it. PATIENTS AND METHODS: A retrospective multicentric study has been led between 1997 and 2006. The following data were collected: frequency of monitoring, ultrasonographic markers studied according to the outcome of each pregnancy, associated with a review of the literature. RESULTS: Six twin pregnancies with this condition were identified. The main studied criteria are: foetal growth of the pump twin, congestive heart failure, resistance index of the umbilical arteries, ductus venosus Doppler and middle cerebral artery peak velocity. There was no consensus concerning the method of ultrasonographic monitoring. DISCUSSION AND CONCLUSION: According to our study and the literature, our management must take into account the ratio of (or the difference in) resistance indices between the twins, the middle cerebral artery peak velocity, the tricuspid regurgitation and the ratio of abdominal circumferences of the two twins. PMID- 22099977 TI - [Flow Index Vascularization dynamics in the preovulatory phase of controlled ovarian hyperstimulation: profile and relationship with conception rate]. AB - OBJECTIVES: To study the evolution of subendometrial vascularization flow index (VFI) in controlled ovarian hyperstimulation (COH+IIU) cycles and compare its dynamic changes in pregnant and non pregnant women. PATIENTS AND METHODS: This is a retrospective study on 61 couples. To determine the profile of IVF just before ovulation, patients had 3D-Power Doppler angiography (3D-PDA) in this precise preovulatory phase. RESULTS: We observed a decreasing profile of VFI in 52% (32/61) of the main group cycles, in 45% (14/31) of the subgroup with spontaneous peak of LH (luteinizing hormone), and in 60% (18/30) of the hCG (human chorionic gonadotropin) trigger subgroup. There were ten conceptions, (10/61, 16.4%), including eight (8/32, 30%) that were associated with a decreasing profile of VFI versus two (2/29, 7%) that were associated with an increasing profile (NS). In the detection of LH peak subgroup, we observed five conceptions (5/14, 36%) associated with a decreasing profile versus one conception (1/17, 6%) associated with an increasing profile of VFI (OR: 8.3; confidence interval [CI] 95%: 0.8 444; P=0.06 in favor of a of decreasing VFI profile). In the hCG subgroup, there were three conceptions in the decreasing VFI profile (3/18, 17%) and one conception with increasing VFI (1/12, 17%, P=0.6). DISCUSSION AND CONCLUSION: In controlled ovarian hyperstimulation, a decreasing VFI profile is more common compared to an increasing one. Such au profile seems to be associated with a higher conception rate in cycles with spontaneous LH surge. PMID- 22099978 TI - [Hodgkin's disease and breast cancer: for which patients is there an association? A series from Institut Bergonie]. AB - OBJECTIVE: Breast cancer is the most frequent secondary tumor for women treated for Hodgkin's disease. It is important to study the risk factors associated to be able to adapt the monitoring of these women. PATIENTS AND METHODS: This is a retrospective study from Institut Bergonie, a comprehensive French Cancer Center, concerning the women treated for Hodgkin's disease and having developed a breast cancer. RESULTS: Among 328 women treated for Hodgkin's disease between January 1968 and December 1994, 20 patients developed 25 breast cancers. The average age of the patients during the irradiation was 24 years and the average period of occurrence of the cancer was 19 years. An irradiation of the chest wall and an under-diaphragmatic irradiation in doses of 40Gy are risk factors for the occurrence of breast cancer. A young age, less than 30, in the treatment of Hodgkin's disease tend to be significant. DISCUSSION AND CONCLUSION: This population of women with a high risk of breast cancer thus has to benefit from an appropriate monitoring program, which is what we suggest setting up in the Institut Bergonie. PMID- 22099979 TI - [Evaluation of labia minora reduction by longitudinal resection]. AB - OBJECTIVES: To evaluate results, complications and the satisfaction of patients after labia minora, reduction. PATIENTS AND METHODS: It was a retrospective study. Twenty-six patients underwent a labia minora reduction by longitudinal resection in the service of gynecological surgery of the hospital Tenon during a two-year period. Patients were 14 to 64 years old (median=25 years old). The motivations were aesthetic or functional, with entry dyspareunia, discomfort with exercise, and discomfort in clothing. The anatomical result was estimated at the postoperative consultation, one month later. Patient satisfaction was estimated in the long term by a phone questionnaire. RESULTS: There was no complication to type haematoma or wound dehiscence. The anatomical result was satisfactory for 95% of the patients. Twenty questionnaires were completed. All the patients having answered were satisfied with the aesthetic result. Only one patient was dissatisfied of the functional result with a loss of clitoral "flexibility". DISCUSSION AND CONCLUSION: Reduction of labia minoria according to the amputation technique of is simple, safe, with few complications and high patient satisfaction. However, the size of the sample is low and further studies are warranted. PMID- 22099980 TI - [The etiologic diversity of vaginitis]. AB - OBJECTIVE: To establish the different etiologies of vaginitis and, especially, assess the distribution of responsible pathogens through a prospective study. PATIENTS AND METHODS: One hundred and sixty-nine women aged between 18 and 65 years (average age: 33.7 years old), consulting a physician for symptoms of vaginitis, were examined in 21 centers of gynaecology or infectious diseases. The clinical evaluation was completed by bacteriological sample that was tested for infections (including sexually transmitted infections (STIs)). RESULTS: One hundred and eighteen patients (69.8%) had one or several infectious etiologies distributed as follows: 79 (46.7%) candidiasis (3 of which were caused by non albicans Candida), 37 (21.9%) bacterial vaginitis and 16 (9.5%) bacterial vaginosis. To be noticed that there were 38 cases of mixed etiologies out of the 118 infectious etiologies (32.2%), 3 of them were STIs. DISCUSSION AND CONCLUSIONS: Although candidiasis was the most common etiology in this study, it only represented less than 1 out of every two patients. Among the infectious etiologies, 1 out of 3 women presented a bacterial or mixed vaginitis. The etiological diversity of vaginitis leads to consider broad-spectrum treatment as first-line therapy and to prescribe a microbiological analysis in case of failure. PMID- 22099981 TI - Binding of more than one Tva800 molecule is required for ASLV-A entry. AB - BACKGROUND: Understanding the mechanism by which viruses enter their target cell is an essential part of understanding their infectious cycle. Previous studies have focussed on the multiplicity of viral envelope proteins that need to bind to their cognate receptor to initiate entry. Avian sarcoma and leukosis virus Envelope protein (ASLV Env) mediates entry via a receptor, Tva, which can be attached to the cell surface either by a phospholipid anchor (Tva800) or a transmembrane domain (Tva950). In these studies, we have now investigated the number of target receptors necessary for entry of ASLV Env-pseudotyped virions. RESULTS: Using titration and modelling experiments we provide evidence that binding of more than one receptor, probably two, is needed for entry of virions via Tva800. However, binding of just one Tva950 receptor is sufficient for successful entry. CONCLUSIONS: The different modes of attachment of Tva800 and Tva950 to the cell membrane have important implications for the utilisation of these proteins as receptors for viral binding and/or uptake. PMID- 22099983 TI - G-protein coupled receptor kinase 5 regulates prostate tumor growth. AB - PURPOSE: The limited success of cancer therapeutics is largely attributable to the ability of cancer to become resistant to conventional cytotoxic chemotherapy. Thus, further identification of signaling molecules and pathways that influence tumorigenesis is needed to increase the overall therapeutic options. GRKs, originally recognized for their conserved role in GPCR signal control, have now emerged as regulators of additional biological molecules and functions. MATERIALS AND METHODS: We used Western blot analysis to determine GRK expression in prostate cancer and RNA interference to establish the role of GRK5 in prostate cancer growth and progression through the cell cycle. RESULTS: GRK5 was expressed highly in the aggressive prostate cancer PC3 cell line and its silencing by RNA interference attenuated in vitro cell proliferation. PC3 cells that stably expressed lentiviral small hairpin RNA and targeted GRK5 evidence reduced xenograft tumor growth in mice. This was reversed by rescuing expression with wild-type but not with kinase inactive K215R GRK5, implying the need of GRK5 kinase activity for tumor growth. To investigate possible cellular mechanism(s) for GRK5 in cell growth regulation we tested whether kinase activity would impact cell cycle progression. Like forced over expression of kinase-inactive K215R GRK5, GRK5 knockdown led to G2/M arrest in the cell cycle. Also, evidence revealed that the loss of GRK5 activity resulted in decreased cyclin D1 expression, Rb protein phosphorylation and E2F target gene expression involved in cell cycle control. CONCLUSIONS: Results provide direct evidence that GRK5 has an immediate role in the regulation of prostate tumor growth. PMID- 22099982 TI - Post-stimulation inhibitory effect on reflex bladder activity induced by activation of somatic afferent nerves in the foot. AB - PURPOSE: We determined whether transcutaneous electrical stimulation of somatic afferent nerves in the foot of cats would induce a post-stimulation increase in bladder capacity. MATERIALS AND METHODS: In 12 alpha-chloralose anesthetized cats electrical stimulation (5 Hz) was applied to the skin of the hind foot for 2, 30 minute periods via dual pad electrodes attached on the plantar and dorsal surfaces (combination 1 and 2) or at 2 sites on the plantar surface (combination 1 and 3). The post-stimulation effect was examined by repeat cystometrogram after 30-minute stimulation. In the control group of 12 cats isovolumetric contractions were allowed to continue during each 30-minute period without stimulation. RESULTS: Stimulation inhibited isovolumetric rhythmic bladder contractions. Bladder capacity was not increased after the first 30-minute foot stimulation via electrodes 1 and 2 but it was significantly increased a mean +/- SE of 47.5% +/- 2.9% after the second 30-minute stimulation via electrodes 1 and 3. After inducing the post-stimulation effect the foot stimulation applied during cystometrograms via electrodes 1 and 2 or 1 and 3 elicited a further increase in bladder capacity (mean 23.26% +/- 17.64% and 20.07% +/- 18.59%, respectively). CONCLUSIONS: Results show that the transcutaneous plantar electrical stimulation of somatic afferent nerves in the foot can induce a post-stimulation increase in bladder capacity, suggesting that an intermittent stimulation pattern rather than continuous stimulation might be effective as clinical application to treat overactive bladder symptoms. PMID- 22099987 TI - Relationship among total kidney volume, renal function and age. AB - PURPOSE: We measured kidney volume using software and investigated the relationship between kidney volume and renal function. MATERIALS AND METHODS: Age, gender, height, body weight, body mass index, body surface area and serum creatinine were recorded for 539 normal individuals. A tissue segmentation tool program was used to measure kidney volume from computerized tomography images. The glomerular filtration rate was calculated using the Cockcroft-Gault equation and an abbreviated modification of diet in renal disease equation. We looked for correlations of renal parenchymal volume with age and anthropometric measurements. We also tested for a correlation between kidney volume and renal function using the glomerular filtration rate according to the Cockcroft-Gault and modification of diet in renal disease equations. RESULTS: Mean kidney volume in all participants was 261.3 +/- 58.1 ml. Mean volume in men was approximately 14 ml greater than in women (266.1 vs 251.8 ml, p = 0.004). Kidney volume correlated significantly with height (r = 0.344, p <0.001), body weight (r = 0.343, p <0.001), body mass index (r = 0.177, p <0.001), body surface area (r = 0.371, p <0.001) and age (r = -0.418, p <0.001). Kidney volume also correlated with the glomerular filtration rate according to the Cockcroft-Gault and modification of diet in renal disease equations (p <0.001, r = 0.615 and p <0.001, r = 0.432, respectively). Kidney volume and the glomerular filtration rate decreased in parallel with increasing age. CONCLUSIONS: Kidney volume correlates well with renal function and anthropometric measurements. Knowledge of these relationships will be valuable in clinical urology and nephrology. PMID- 22099988 TI - Subcutaneous 5-azacitidine treatment of naturally occurring canine urothelial carcinoma: a novel epigenetic approach to human urothelial carcinoma drug development. AB - PURPOSE: We determined the efficacy, biological activity, pharmacokinetics and safety of the hypomethylating agent 5-azacitidine (Celgene Corp., Summit, New Jersey) in dogs with naturally occurring invasive urothelial carcinoma. MATERIALS AND METHODS: We performed a preclinical phase I trial in dogs with naturally occurring invasive urothelial carcinoma to examine once daily subcutaneous administration of 5-azacitidine in 28-day cycles at doses of 0.10 to 0.30 mg/kg per day according to 2 dose schedules, including days 1 to 5 (28-day cohort) or days 1 to 5 and 15 to 19 (14-day cohort). Clinical efficacy was assessed by serial cystosonography, radiography and cystoscopy. Urinary 5-azacitidine pharmacokinetic analysis was also done. Pretreatment and posttreatment peripheral blood mononuclear cell and invasive urothelial carcinoma DNA, respectively, was analyzed for global and gene specific [CDKN2A (p14ARF)] methylation changes. RESULTS: Enrolled in the study were 19 dogs with naturally occurring invasive urothelial carcinoma. In the 28-day cohort the maximum tolerated dose was 0.20 mg/kg per day with higher doses resulting in grade 3 or 4 neutropenia in 4 of 6 dogs. In the 14-day cohort the maximum tolerated dose was 0.10 mg/kg per day with grade 3 or 4 neutropenia seen in 2 of 3 dogs treated at higher doses. No grade 3 or 4 nonhematological toxicity was observed during either dosing schedule. Of 18 dogs evaluable for tumor response partial remission, stable disease and progressive disease were observed in 4 (22.2%), 9 (50.0%) and 4 (22.2%), respectively. Consistent 5-azacitidine levels (205 to 857 ng/ml) were detected in urine. Pretreatment and posttreatment methylation analysis revealed no significant correlation with clinical response. CONCLUSIONS: Subcutaneous 5 azacitidine showed promising clinical activity in a canine invasive urothelial carcinoma model, thus meriting further development in humans with urothelial carcinoma. PMID- 22099989 TI - The FGFR3 mutation is related to favorable pT1 bladder cancer. AB - PURPOSE: Stage pT1 bladder cancer comprises a heterogeneous group of tumors for which different management options are advocated. FGFR3 mutations are linked to favorable (low grade/stage) pTa bladder cancer while altered P53 is common in cases of high grade, muscle invasive (pT2 or greater) bladder cancer. We determined the frequency of FGFR3 mutations and P53 alterations in patients with pT1 bladder cancer and correlated these data to histopathological variables and clinical outcomes. MATERIALS AND METHODS: We included 132 patients with primary pT1 bladder cancer from a total of 2 academic centers. A uropathologist reviewed the slides for grade and confirmed the pT1 diagnosis. FGFR3 mutation status was examined by SNaPshot(r) analysis and P53 expression was determined by standard immunohistochemistry. Kaplan-Meier and multivariate analyses were used to assess progression. RESULTS: FGFR3 mutations were detected in 37 of 132 pT1 bladder cancer cases (28%) and altered P53 was seen in 71 (54%). Only 8% of patients had the 2 molecular alterations (p = 0.001). FGFR3 mutation correlated with lower grade and altered P53 correlated with high grade pT1 bladder cancer. Median followup was 6.5 years. FGFR3 mutation status and carcinoma in situ were significant for predicting progression on univariate and multivariate analyses but P53 status was not. CONCLUSIONS: FGFR3 mutations selectively identify patients with pT1 bladder cancer who have favorable disease characteristics. Further study may confirm that FGFR3 identifies those who would benefit from a conservative approach to the disease. PMID- 22099990 TI - Nomogram to preoperatively predict the probability of requiring epididymovasostomy during vasectomy reversal. AB - PURPOSE: Up to 6% of men who undergo vasectomy may later undergo vasectomy reversal. Most men require vasovasostomy but a smaller subset requires epididymovasostomy. Outcomes of epididymovasostomy depend highly on specialized training in microsurgery and, if predicted preoperatively, might warrant referral to a specialist in this field. We created a nomogram based on preoperative patient characteristics to better predict the need for epididymovasostomy. MATERIALS AND METHODS: We evaluated patients who underwent primary vasectomy reversal during a 5-year period. Preoperative and intraoperative patient data were collected in a prospectively maintained database. We evaluated the ability of age, years since vasectomy, vasectomy site, epididymal fullness and granuloma presence or absence to preoperatively predict the need for epididymovasostomy in a given patient. The step-down method was used to create a parsimonious model, on which a nomogram was created and assessed for predictive accuracy. RESULTS: Included in the study were 271 patients with a mean age of 42 years. Patient age was not positively associated with epididymovasostomy. Mean time from vasectomy to reversal was 9.7 years. Time to reversal and a sperm granuloma were selected as important predictors of epididymovasostomy in the final parsimonious model. The nomogram achieved a bias corrected concordance index of 0.74 and it was well calibrated. CONCLUSIONS: Epididymovasostomy can be preoperatively predicted based on years since vasectomy and a granuloma on physical examination. Urologists can use this nomogram to better inform patients of the potential need for epididymovasostomy and whether specialist referral is needed. PMID- 22099991 TI - Photodynamic therapy as novel nephron sparing treatment option for small renal masses. AB - PURPOSE: Photodynamic therapy has great potential as nephron sparing therapy for small renal masses. Using mTHPC [meso-tetra(hydroxyphenyl)chlorin] (BioLitec Pharma, Dublin, Ireland), a photosensitizer that targets vasculature and tissue, we determined whether renal tumors could be ablated using mTHPC mediated photodynamic therapy in a translational renal carcinoma mouse model. MATERIALS AND METHODS: We administered mTHPC intravenously in kidney tumor bearing mice. Tumor diameter was about 7 mm. At several drug-light intervals a cylindrical laser fiber was placed intratumorally for interstitial illumination using a wavelength of 652 nm. We determined mTHPC biodistribution up to 48 hours after administration and tumor destruction after mTHPC mediated photodynamic therapy. In vitro mTHPC uptake and photodynamic therapy induced cytotoxicity were studied in human endothelial, renal and renal cell carcinoma cell lines. RESULTS: Ablated regions with a maximum diameter of 9.3 mm and complete loss of cell viability were observed at a drug-light interval of 4 hours, when mTHPC was increased in blood and tissue. Viable renal tissue remained detectable outside the illuminated area. In endothelial cells mTHPC uptake and sensitivity to photodynamic therapy were increased compared to those in renal cell carcinoma and renal cells. CONCLUSIONS: mTHPC mediated photodynamic therapy is a nephron sparing therapy. The extent of renal tumor destruction is adequate for clinical translation. Localization of mTHPC in tumor vasculature and tissue produces a strong combined effect. Our findings justify further preclinical studies of the applicability of photodynamic therapy for renal cell carcinoma before photodynamic therapy can become a valuable addition to current minimally invasive treatments of small renal masses. PMID- 22099992 TI - Pad use and patient reported bother from urinary leakage after radical prostatectomy. AB - PURPOSE: To better understand clinically significant definitions of urinary incontinence we investigated the relationship between urinary leakage and patient reported bother from urinary leakage. MATERIALS AND METHODS: A consecutive series of 1,411 men who underwent radical prostatectomy at Karolinska University Hospital, Stockholm, Sweden, from 2002 to 2006 were invited to complete a study specific questionnaire with questions on pad status, urinary leakage and bother from urinary leakage. RESULTS: Questionnaires were received from 1,179 men with a followup of greater than 1 year (median 2.2). Results showed that even a small amount of urinary leakage resulted in a high risk of urinary bother. Of 775 survivors 46 (6%) reporting 0 pads indicated moderate or much bother compared to 38 of 123 (31%) who reported using a security pad. When comparing the 2 groups, the risk of bother from urinary leakage was more than 5 times higher in the safety pad vs the 0 pad group (RR 5.2, 95% CI 3.5-7.7). As the number of pads increased, we noted a higher bother risk. Cross-tabulation of pad use and urinary leakage revealed wide variation in pad requirements despite the same answer to urinary leakage questions. CONCLUSIONS: If the definition of continence is based on pad use, for example safety pads, a certain number of men who report moderate or much bother from urinary leakage will be defined as continent. Our results also show that for each stated rate of urinary leakage men prove to have a major variation in the pad requirement. PMID- 22099993 TI - Global evaluative assessment of robotic skills: validation of a clinical assessment tool to measure robotic surgical skills. AB - PURPOSE: We developed and validated a standardized assessment tool for robotic surgical skills, and report its usefulness, reliability and construct validity in a clinical setting. MATERIALS AND METHODS: The Global Evaluative Assessment of Robotic Skills is a tool developed by deconstructing the fundamental elements of robotic surgical procedures in consultation with expert robotic surgeons. Surgical performance was assessed during robot-assisted laparoscopic prostatectomy on a 5-point anchored Likert scale across 6 domains. An overall performance score was derived by summing the ratings in each domain. Expert surgeons and postgraduate year 4 to 6 urology residents were evaluated to determine construct validity. Assessments were completed by the attending surgeon, a trained observer and the operator. RESULTS: A total of 29 evaluations of 25 trainees and 4 attending surgeons were completed. Experts scored significantly higher on the assessment than novice operators (p = 0.004). Postgraduate year 4 and 5 residents scored significantly lower than the expert group (p <0.05) while no difference was observed between mean performance scores of postgraduate year 6 trainees and attending surgeons (p >0.05). The internal consistency of the assessment tool was excellent (Cronbach's alpha = 0.90 to 0.93). The overall assessment score ICC among raters was 0.80 (95% CI 0.65-0.90). CONCLUSIONS: The Global Evaluative Assessment of Robotic Skills is simple to administer and able to differentiate levels of robotic surgical expertise. This standardized assessment tool shows excellent consistency, reliability and validity. Further study is warranted to evaluate its usefulness for surgical education and the establishment of competency in robotic surgery. PMID- 22099994 TI - Minimal adenocarcinoma on prostate needle biopsy and false-negative diagnosis of malignancy. PMID- 22099995 TI - Gender trends of urology manuscript authors in the United States: a 35-year progression. AB - PURPOSE: The presence of women in urology has gradually increased in the last 35 years with an accelerated rate in the last decade. We evaluated manuscript authorship trends by gender. Manuscript authorship is a metric that has been used as a marker of academic productivity. We hypothesized that the number of first and last author publications by women has increased proportionately to the number of women in the field during the last 35 years. MATERIALS AND METHODS: We performed a bibliometric study to examine authorship gender in The Journal of Urology(r) and Urology(r). We reviewed all original articles published from American institutions in 1974, 1979, 1984, 1989, 1994, 1999, 2004 and 2009. RESULTS: Of the 8,313 articles reviewed 5,461 were from American institutions, including 97.5% for which we determined author gender. There were 767 articles with female authors, including 440 first and 327 last authors. First and last female authorship increased from 2.7% of all authors in 1979 to 26.5% in 2009 (test for trend p <0.001). This authorship rate surpasses the rate of growth of women in urology, which increased from 0.24% in 1975 to 6.2% in 2008. CONCLUSIONS: Based on authorship gender analysis women urologists produce manuscripts at a rate that exceeds their number in the field. Findings show that women in urology are productive, active members of the academic community. PMID- 22099996 TI - Posterior lumbar vein off the retrohepatic inferior vena cava: a novel anatomical variant with surgical implications. AB - PURPOSE: Resection of tumors involving the inferior vena cava requires vascular control of posteriorly draining lumbar veins to ensure a bloodless field. Surgical texts and atlases assert that lumbar veins do not insert into the inferior vena cava superior to the renal hilum. However, at our institution we have encountered patients undergoing inferior vena cava tumor thrombectomy who have a posterior lumbar vein cephalad to the renal veins. Since this represents an unrecognized source of hemorrhage, we investigated the frequency of a superior lumbar vein in cadaveric dissection. MATERIALS AND METHODS: Retroperitoneal cadaveric dissection of the inferior vena cava was done to assess the frequency of a lumbar vein draining into the inferior vena cava cephalad to the renal veins. RESULTS: Of the 49 cadaveric dissections performed 19 (38.8%) showed a single posterior lumbar vein between the diaphragm and the renal hilum. Of these 19 cadavers 15 (78.9%) were male. This vein was located an average +/- SD of 7.4 +/- 0.6 cm cephalad to the right renal vein and it was 3.7 +/- 1.6 cm in diameter. In all cadavers this vein inserted within 30 degrees to the left or right of the posterior (also termed dorsal) aspect of the inferior vena cava. CONCLUSIONS: The identification of a lumbar vein between the renal hilum and the diaphragm represents an important anatomical variant that occurs in a significant percent of individuals. Surgeons will benefit from the knowledge of this variant of inferior vena cava vasculature and should anticipate the presence of this vein to prevent unnecessary morbidity and mortality secondary to unexpected hemorrhage, particularly in male patients. PMID- 22099997 TI - Risk loci on chromosome 8q24 are associated with prostate cancer in northern Chinese men. AB - PURPOSE: Genome-wide association studies have identified several genetic variants at 8q24 that are strongly associated with prostate cancer risk in populations of European, American and Japanese ancestry. We investigated the contribution of these prostate cancer risk variants in the Chinese population. MATERIALS AND METHODS: We evaluated the association of 14 single nucleotide polymorphisms at 8q24 with prostate cancer risk using high resolution melting curve combined gene sequencing methods in case-control groups, including 265 cases and 288 controls. We explored the association between clinical covariates (age at diagnosis, prostate specific antigen, Gleason score and tumor stage) and risk loci in our study to infer their impact on aggressive prostate cancer. RESULTS: Four of the 14 single nucleotide polymorphisms were associated with prostate cancer risk, including rs16901966 (OR 1.343, 95% CI 1.029-1.754, p = 0.030), rs1447295 (OR 1.499, 95% CI 1.109-2.027, p = 0.008), rs11986220 (OR 1.589, 95% CI 1.160-2.178, p = 0.004) and rs10090154 (OR 1.571, 95% CI 1.146-2.154, p = 0.005). Haplotype based association analysis of the risk alleles revealed significant differences between cases and controls. The risk alleles of rs16901966, rs1447295, rs11986220 and rs10090154 were associated with age at diagnosis and tumor stage compared with controls while rs16901966 was associated with aggressive prostate cancer (OR 1.538, 95% CI 1.076-2.099, p = 0.018). CONCLUSIONS: For northern Chinese men rs16901966, rs1447295, rs11986220 and rs10090154 at 8q24 (region 1, region 2) are associated with prostate cancer and prostate cancer related clinical covariates. PMID- 22099998 TI - Molecular imaging of nuclear factor-kappaB in bladder as a primary regulator of inflammatory response. AB - PURPOSE: Nuclear factor-kappaB activation is implicated in chronic inflammatory disorders and it is a key regulator of genes involved in the response to infection, inflammation and stress. Interstitial cystitis and painful bladder syndrome are common inflammatory disorders of the bladder characterized by frequent urination and bladder pain. The role of nuclear factor-kappaB activation in bladder inflammation is not well defined. MATERIALS AND METHODS: Female transgenic nuclear factor-kappaB-luciferase Tag mice (The Jackson Laboratory, Bar Harbor, Maine) were used to perform serial, noninvasive in vivo and ex vivo molecular imaging of nuclear factor-kappaB activation in the whole body after administering arsenic trioxide (5 mg/kg), lipopolysaccharide (2 mg/kg) or cyclophosphamide (Sigma(r)) (200 mg/kg) to initiate acute transient bladder inflammation. Pretreatment with dexamethasone (Sigma) (10 mg/kg) was used to modulate cyclophosphamide induced nuclear factor-kappaB dependent luminescence in vivo. RESULTS: Treatment of nuclear factor-kappaB-luciferase Tag mice with chemicals increased luminescence in a time and organ specific manner in vivo and ex vivo. The highest levels of bladder nuclear factor-kappaB dependent luminescence were observed 4 hours after cyclophosphamide administration. Pretreatment with dexamethasone 1 hour before cyclophosphamide injection significantly down-regulated cyclophosphamide induced bladder nuclear factor kappaB dependent luminescence, ameliorated the grossly evident pathological features of acute inflammation and decreased cellular immunostaining for nuclear factor-kappaB in the bladder. CONCLUSIONS: Nuclear factor-kappaB activity may have an important role in the pathophysiology of bladder inflammation. Nuclear factor-kappaB-luciferase mice can serve as a useful model in which to screen potential candidate drugs for cystitis associated with aberrant nuclear factor kappaB activity. Such screening may significantly aid the development of therapeutic strategies to manage inflammatory bladder disorders. PMID- 22099999 TI - Long-term outcomes of percutaneous nephrolithotomy in 177 patients with chronic kidney disease: a single center experience. AB - PURPOSE: We evaluated the long-term outcomes of percutaneous nephrolithotomy in patients with chronic kidney disease. MATERIALS AND METHODS: Data on 1,904 patients who underwent percutaneous nephrolithotomy between 2002 and 2011 were retrospectively collected. The estimated glomerular filtration rate for each patient was retrospectively calculated using a 4-variable modification of diet in renal disease equation. Patients were staged for chronic kidney disease by National Kidney Foundation guidelines. RESULTS: A total of 242 patients (12.7%) had a preoperative glomerular filtration rate of less than 60 ml per minute/1.73 m(2). Those monitored a minimum of 1 year were included in analysis. The study included 177 patients with a mean +/- SD age of 54.3 +/- 12.1 years. Perioperative and postoperative complications were noted in 15.2% of patients. At a mean followup of 43.4 +/- 22.7 months renal function in 29.4% of patients had improved but it remained the same or deteriorated in 54.2% and 16.4%, respectively. On multivariate regression analysis diabetes and preoperative or postoperative complications predicted renal function. The stone-free rate 3 months postoperatively was 80.2% (142 of 177 cases). Stones recurred during long term followup in 36 of these patients (25.3%). Spontaneous stone passage was detected in 12 of the 35 patients (34.2%) with residual stones but 8 (22.8%) with residual stones experienced an increase in stone size. CONCLUSIONS: At long-term followup renal function was maintained or improved in greater than 80% of patients with chronic kidney disease who underwent percutaneous nephrolithotomy. Stones recurred or residual stones grew in approximately 25% of these patients. PMID- 22100000 TI - Time for improvement in semen parameters after varicocelectomy. AB - PURPOSE: While there are a number of studies documenting a positive effect of varicocelectomy on semen parameters, the length of time required following varicocelectomy for semen quality to improve is not well established. Therefore, in this study we identified the changes with time in semen parameters after varicocelectomy. MATERIALS AND METHODS: The records and database of 304 patients who underwent varicocele repair for subfertility were reviewed retrospectively. All men had at least 2 preoperative semen analyses as well as semen testing at 3 and 6 months postoperatively. RESULTS: For the 100 patients who met the study inclusion criteria mean sperm counts increased significantly by 3 and 6 months after varicocelectomy (by 53% and 38% by 3 and 6 months, p = 0.0003 and 0.001, respectively). By 3 and 6 months the combined groups had a mean 2.5 and 1.5-fold higher total motile count compared to the preoperative total motile count, respectively. There was no further improvement in semen parameters in those men followed for more than 6 months. There were no statistically significant differences in the improvement in semen volume, motility, count or total motile count comparing the results at 3, 6 and more than 9 months postoperatively. CONCLUSIONS: Sperm parameters improve by 3 months after varicocele repair and then do not improve further. This finding should allow physicians to decide quickly if varicocelectomy has been effective and, then, if required, plan on the use of other therapies to manage the couples' infertility. PMID- 22100001 TI - Predictors of sperm recovery and azoospermia relapse in men with nonobstructive azoospermia after varicocele repair. AB - PURPOSE: In this study we determined the recoverability and sustainability of motile sperm in semen of men with nonobstructive azoospermia after varicocelectomy as related to different variables. MATERIALS AND METHODS: Men with documented infertility for more than 1 year, with nonobstructive azoospermia and clinically palpable varicoceles were included in this prospective noncontrolled study. Participants underwent simultaneous subinguinal microsurgical varicocelectomy and testicular biopsies. Preoperative as well as initial and late followup semen analyses were performed. Outcomes of sperm recovery and relapse of azoospermia were correlated with the variables of patient age, infertility duration, varicocele grade, laterality, follicle-stimulating hormone, testicular volume and testicular histology. RESULTS: The study included 31 men with a mean +/- SD age of 34.9 +/- 8.7 years and mean followup of 19.3 +/- 3.3 months. Hypospermatogenesis, late maturation arrest, early maturation arrest and Sertoli-cell-only were observed in 13, 6, 2 and 10 patients, respectively. Overall, sperm recovery was evident in 10 of 31 (32.3%) patients (persistent recovery 19.4%, intermittent recovery 6.5%, relapse 6.5%). Sperm were recovered in patients with hypospermatogenesis (7 of 13, 53.8%) and late maturation arrest (3 of 6, 50%). No sperm were recovered in those with early maturation arrest or Sertoli-cell-only. Among the variables only histological patterns demonstrated a significant correlation with recovery (rho = 0.504, p = 0.004). None of variables was significantly correlated with relapse. Bilateral varicocele repair demonstrated a strong yet nonsignificant negative correlation with relapse (rho = -0.612, p = 0.06). CONCLUSIONS: Varicocelectomy could recover motile sperm in men with nonobstructive azoospermia, palpable varicoceles and hypospermatogenesis or late maturation arrest. No sperm was recovered with early maturation arrest or Sertoli-cell-only. Recovery might be persistent or intermittent, or involve relapse of azoospermia. Testicular histology was the sole parameter significantly correlated with recovery and no predictors of relapse could be identified. This prognostic role of testicular biopsy is imperative in couple counseling. PMID- 22100002 TI - Calcium phosphate content does not affect stone-free rate after percutaneous nephrolithotomy. AB - PURPOSE: Recent research suggests that the stone-free rate for percutaneous nephrostolithotomy is lower in patients with calcium phosphate stones than in those with stones of other compositions. We reviewed our percutaneous nephrostolithotomy outcomes to investigate this unexplained finding. MATERIALS AND METHODS: A total of 188 patients with sufficient data available for review underwent unilateral percutaneous nephrostolithotomy at our institution between September 2005 and May 2007. Patients were analyzed based on stone burden (including 2 cm or less, greater than 2 cm, partial staghorn calculus and complete staghorn calculus). Stones were also stratified by calcium phosphate content (0%, 1% to 10%, 11% to 60% and greater than 60%). To remain consistent with the previous study procedural failure was classified as greater than 2 mm residual stone fragments identified by unenhanced computerized tomography on postoperative day 1 regardless of the ultimate stone-free rate after secondary procedures. Multivariate logistic regression analysis was done to identify factors predicting a failed procedure. RESULTS: Of the patients 101 (54%) were male and 132 (71%) were recurrent stone formers. Overall 107 cases (57%) had calcium phosphate as a stone component and 37.8% were classified as failures. Increasing stone size was associated with a decreased stone-free rate (p = 0.009). The failure rate was 37%, 46.4%, 38.1% and 32.4% for patients with a 0%, 1% to 10%, 11% to 60% and greater than 60% calcium phosphate stone content (p = 0.68). On multivariate logistic regression analysis no association was noted between calcium phosphate content and greater than 2 mm residual stones (p = 0.67). CONCLUSIONS: Calcium phosphate stone composition does not predict a poor stone-free rate after percutaneous nephrostolithotomy. PMID- 22100003 TI - Prospective randomized study of treatment of large proximal ureteral stones: extracorporeal shock wave lithotripsy versus ureterolithotripsy versus laparoscopy. AB - PURPOSE: The best treatment modalities for large proximal ureteral stones are controversial, and include extracorporeal shock wave lithotripsy, ureterolithotripsy, percutaneous nephrolithotripsy, laparoscopic ureterolithotomy and open surgery. To the best of our knowledge extracorporeal shock wave lithotripsy, semirigid ureterolithotripsy and laparoscopic ureterolithotomy have not been previously compared for the treatment of large proximal ureteral stones. Therefore, we compared these modalities for the treatment of large proximal ureteral stones. MATERIALS AND METHODS: A total of 48 patients with large proximal ureteral stones (greater than 1 cm) were prospectively randomized and enrolled in the study at a single institution between 2008 and 2010. Eligible patients were assigned to extracorporeal shock wave lithotripsy, semirigid ureterolithotripsy or laparoscopic ureterolithotomy. RESULTS: Extracorporeal shock wave lithotripsy had a 35.7% success rate, semirigid ureterolithotripsy 62.5% and laparoscopic ureterolithotomy 93.3%. Stone-free rates showed a statistically significant difference among the groups (p = 0.005). Patients treated with laparoscopic ureterolithotomy vs semirigid ureterolithotripsy vs extracorporeal shock wave lithotripsy required fewer treatment sessions (mean +/- SD 1.9 +/- 0.3 vs 2.2 +/- 0.6 vs 2.9 +/- 1.4, p = 0.027). Neither major nor long term complications were observed. CONCLUSIONS: Proximal ureteral stone treatment requires multiple procedures until complete stone-free status is achieved. Laparoscopic ureterolithotomy is associated with higher success rates and fewer surgical procedures, but with more postoperative pain, longer procedures and a longer hospital stay. Although it is associated with the highest success rates for large proximal ureteral calculi, laparoscopic ureterolithotomy remains a salvage, second line procedure, and it seems more advantageous than open ureterolithotomy. At less well equipped centers, where semirigid ureterolithotripsy or extracorporeal shock wave lithotripsy is not available, it remains a good treatment option. PMID- 22100004 TI - Evaluating racial/ethnic disparities in lower urinary tract symptoms in men. AB - PURPOSE: We examined whether there are racial/ethnic disparities in lower urinary tract symptoms in men. MATERIALS AND METHODS: Racial/ethnic disparities were examined using the American Urological Association symptom index in 2 large cohorts, including the California Men's Health Study and the Research Program in Genes, Environment and Health. Prevalence and incidence were calculated in each age and race/ethnicity strata. Multivariate analysis was done to assess the association between race/ethnicity and lower urinary tract symptoms. RESULTS: The lower urinary tract symptom prevalence increased with age in each racial/ethnic category (p <0.05). The mean +/- SD age adjusted American Urological Association symptom index score for black, Hispanic, other/mixed, non-Hispanic white and Asian men was 9.57 +/- 5.83, 9.35 +/- 6.30, 9.32 +/- 6.22, 8.99 +/- 5.89 and 8.41 +/- 5.59, respectively. In multivariate models Hispanic and black men were at increased risk for moderate lower urinary tract symptoms than white men while only Hispanic men were at higher risk for severe lower urinary tract symptoms. Asian men were at lower risk for moderate or severe lower urinary tract symptoms than white men. The incident rate of lower urinary tract symptoms increased with increasing baseline age for almost all racial/ethnic groups (range 32% to 56%). Asian and Hispanic men were at lower risk for incident lower urinary tract symptoms than white men even after adjusting for sociodemographic factors, health related behaviors and comorbidity. CONCLUSIONS: Racial/ethnic disparities in lower urinary tract symptoms persist after accounting for putative and established risk factors. PMID- 22100005 TI - Monitoring the coupling of the lithotripter therapy head with skin during routine shock wave lithotripsy with a surveillance camera. AB - PURPOSE: With lithotripters today the shock waves are typically transmitted into the body via water filled bellows using coupling gel to make contact with the skin. Usually the coupling zone is not visible to the operator. We investigated coupling quality during routine clinical shock wave lithotripsy and the associated effect on shock wave disintegration efficiency. MATERIALS AND METHODS: During 30 routine shock wave lithotripsy treatments the coupling zone was continuously monitored by a video camera integrated into a DoLi SII lithotripter (Dornier MedTech, Wessling, Germany). However, it was not shown to the blinded operator to resemble the standard clinical situation. We used 3 coupling gels, including LithoClear(r), Sonogel(r) and a custom-made gel of low viscosity. The ratio of air in the relevant coupling area was measured. Lithotripter disintegration efficiency was evaluated by in vitro model stone tests at an air ratio of 0%, 5%, 10% and 20%. RESULTS: Only in 10 of 30 treatments was good coupling achieved with an air ratio of less than 5%. In 8 treatments the ratio was greater than 20%. The best coupling conditions were achieved with low viscosity gel. The mean +/- SD number of shock waves needed for complete fragmentation in the model stone tests was 100 +/- 4 for bubble-free coupling, and 126 +/- 3 for 5%, 151 +/- 8 for 10% and 287 +/- 5 for 20% air bubbles. CONCLUSIONS: At 20 of 30 shock wave lithotripsy sessions there was imperfect coupling, accompanied by significant loss of disintegration capability. A surveillance camera is useful to monitor and improve coupling. PMID- 22100006 TI - Cost-effectiveness of percutaneous tibial nerve stimulation versus extended release tolterodine for overactive bladder. AB - PURPOSE: We assessed the cost-effectiveness of percutaneous tibial nerve stimulation vs extended release tolterodine for the treatment of overactive bladder. MATERIALS AND METHODS: A 1-year time frame cost-effectiveness model from a societal perspective was developed by comparing medical costs and quality of life determined by improved continence and therapy side effects of percutaneous tibial nerve stimulation and tolterodine ER. Percutaneous tibial nerve stimulation therapy consisted of 12 sessions for 3 months followed by maintenance therapy. Significant side effects of both strategies can result in reduced quality of life or therapy termination. Parameter estimates included utilities of improved urinary incontinence (0.92) and continued urinary incontinence (0.73), reduction in quality of life from side effects (5%), cost of percutaneous tibial nerve stimulation per session ($203) and cost of tolterodine ER per month ($150). Our primary outcome was the incremental cost-effectiveness ratio, defined as the marginal cost per quality adjusted life-years gained. Less than $50,000 per quality adjusted life-year gained was considered cost-effective. The uncertainty of input parameters was addressed by 1-way sensitivity analyses and Monte Carlo simulation to assess the robustness of the model. RESULTS: Percutaneous tibial nerve stimulation added significant cost to the management of overactive bladder with modest improvement in quality of life. For every 100 patients treated with percutaneous tibial nerve stimulation the costs increased by $303,480 and resulted in an additional 4.3 quality adjusted life-years gained compared to tolterodine ER. The incremental cost-effectiveness ratio was $70,754 per quality adjusted life-year gained. In the Monte Carlo analysis percutaneous tibial nerve stimulation was cost-effective only 21% of the time. CONCLUSIONS: Percutaneous tibial nerve stimulation was not cost-effective for treating overactive bladder vs tolterodine ER under a wide range of clinical circumstances. PMID- 22100007 TI - Adrenal tuberculosis. PMID- 22100008 TI - The effect of body mass index on the outcomes of varicocelectomy. AB - PURPOSE: Obesity is recognized as a potential contributor to male factor infertility. There are no studies to date to our knowledge that have examined the success of varicocelectomy in obese men. We determined if body mass index significantly affects the outcome of varicocelectomy. MATERIALS AND METHODS: Retrospective chart review was performed for all patients who underwent varicocelectomy from September 2003 to December 2009. Patients were placed into 3 groups based on body mass index, and categorized as normal weight (group 1-38 patients, body mass index 18.5 to 24.9), overweight (group 2-59 patients, body mass index 25 to 29.9) or obese (group 3-46 patients, body mass index 30 or greater). Significant improvement was defined as a greater than 50% increase in the total motile per ejaculate parameter on postoperative semen analysis. RESULTS: A total of 143 patients were available for analysis. There were no significant differences among patients in the 3 groups except for body mass index. Significant improvement in total motile/ejaculate on semen analyses was 71.1% (group 1), 61.0% (group 2) and 58.7% (group 3). Pregnancy rates were 43.8% (group 1), 43.5% (group 2) and 46.3% (group 3). There were no significant differences in improvement in total motile per ejaculate (p = 0.21, p = 0.17) or pregnancy rate (p = 0.60, p = 0.51) between the normal body mass index group, and the overweight and obese groups. CONCLUSIONS: Varicocelectomy for men with clinically palpable varicoceles has a significant chance of improving semen parameters and pregnancy rates regardless of preoperative body mass index. The outcomes of varicocelectomy in overweight and obese patients were similar to those of normal weight men. Therefore, varicocelectomy can be performed effectively and safely in overweight and obese men. PMID- 22100009 TI - Prediction of moderate and high grade vesicoureteral reflux after a first febrile urinary tract infection in children: construction and internal validation of a clinical decision rule. AB - PURPOSE: Urinary tract infection leads to a diagnosis of moderate or high grade (III or higher) vesicoureteral reflux in approximately 15% of children. Predicting reflux grade III or higher would make it possible to restrict cystography to high risk cases. We aimed to derive a clinical decision rule to predict vesicoureteral reflux grade III or higher in children with a first febrile urinary tract infection. MATERIALS AND METHODS: We conducted a secondary analysis of prospective series including all children with a first febrile urinary tract infection from the 8 European participating university hospitals. RESULTS: A total of 494 patients (197 boys, reflux grade III or higher in 11%) were included. Procalcitonin and ureteral dilatation on ultrasound were significantly associated with reflux grade III or higher and then combined into a prediction model with an ROC AUC of 0.75 (95% CI 0.69-0.81). Given the prespecified constraint of achieving at least 85% sensitivity, our model led to the clinical decision rule, for children with a first febrile urinary tract infection cystography should be performed in cases with ureteral dilatation and serum procalcitonin level 0.17 ng/ml or higher, or without ureteral dilatation (ie ureter not visible) when serum procalcitonin level is 0.63 ng/ml or higher. The rule had 86% sensitivity (95% CI 74-93) with 47% specificity (95% CI 42-51). Internal cross-validation produced 86% sensitivity (95% CI 79-93) and 43% specificity (95% CI 39-47). CONCLUSIONS: A clinical decision rule was derived to enable a selective approach to cystography in children with urinary tract infection. The rule predicts high grade vesicoureteral reflux with approximately 85% sensitivity and avoids half of the cystograms that do not find reflux grade III or higher. Further validation is needed before its widespread use. PMID- 22100011 TI - The beneficial effect of statins on renal anemia in hemodialysis patients: another point of view. PMID- 22100010 TI - Reducing care-resistant behaviors during oral hygiene in persons with dementia. AB - BACKGROUND: Nursing home residents with dementia are often dependent on others for mouth care, yet will react with care-resistant behavior when receiving assistance. The oral health of these elders deteriorates in the absence of daily oral hygiene, predisposing them to harmful systemic problems such as pneumonia, hyperglycemia, cardiac disease, and cerebral vascular accidents. The purpose of this study is to determine whether care-resistant behaviors can be reduced, and oral health improved, through the application of an intervention based on the neurobiological principles of threat perception and fear response. The intervention, called Managing Oral Hygiene Using Threat Reduction, combines best mouth care practices with a constellation of behavioral techniques that reduce threat perception and thereby prevent or de-escalate care-resistant behaviors. METHODS/DESIGN: Using a randomized repeated measures design, 80 elders with dementia from 5 different nursing homes will be randomized at the individual level to the experimental group, which will receive the intervention, or to the control group, which will receive standard mouth care from research team members who receive training in the proper methods for providing mouth care but no training in resistance recognition or prevention/mediation. Oral health assessments and care-resistant behavior measurements will be obtained during a 7 day observation period and a 21-day intervention period. Individual growth models using multilevel analysis will be used to estimate the efficacy of the intervention for reducing care-resistant behaviors in persons with dementia, and to estimate the overall efficacy of the intervention using oral health outcomes. Activity-based costing methods will be used to determine the cost of the proposed intervention. DISCUSSION: At the conclusion of this study, the research team anticipates having a proven intervention that prevents and reduces care-resistant within the context of mouth care. Long-term objectives include testing the effect of the intervention on systemic illnesses among persons with dementia; examining the transferability of this intervention to other activities of daily living; and disseminating threat reduction interventions to nursing home staff, which may radically change the manner in which care is provided to persons with dementia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01363258. PMID- 22100012 TI - Wild-type MIC distribution and epidemiological cut-off values in clinical Legionella pneumophila serogroup 1 isolates. AB - OBJECTIVES: The purpose of this study was to establish wild-type (WT) distributions and determine the epidemiological cut-off values (ECOFF) in clinical L. pneumophila serogroup 1 isolates for 10 antimicrobials commonly used for the treatment of Legionella infections using a method feasible in a routine clinical laboratory. METHODS: MICs of 183 clinical L. pneumophila serogroup 1 isolates, collected as part of an outbreak detection program, were tested using E test methodology on buffered charcoal yeast extract agar supplemented with alpha ketoglutarate (BCYE-alpha). The MICs were read after 2 days of incubation at 35 degrees C with increased humidity and without CO(2). ECOFFs were determined according to EUCAST methodology and expressed as WT <= X mg/L. RESULTS: All antimicrobials showed a WT distribution, although the width varied from 2 two fold dilutions to 8 dilutions, depending on antibiotic class. The ECOFFs determined were 1.0 mg/L for ciprofloxacin, 0.50 mg/L for levofloxacin, 1.0 mg/L for moxifloxacin, 1.0 mg/L for erythromycin, 1.0 mg/L for azithromycin, 0.50 mg/L for clarithromycin, 1.0 mg/L for cefotaxime, 0.032 mg/L for rifampicin, 16 mg/L for tigecycline, and 8 mg/L for doxycycline. CONCLUSION: All isolates were inhibited by low concentrations of the fluoroquinolones and macrolides tested, with somewhat higher MICs for the fluoroquinolones. Rifampicin was found to be the most active against L. pneumophila isolates in vitro. These data can be used as a reference for the detection of resistance in clinical L. pneumophila isolates and as a setting of clinical breakpoints. PMID- 22100013 TI - Characteristics related to antimicrobial resistance and biofilm formation of widespread methicillin-resistant Staphylococcus epidermidis ST2 and ST23 lineages in Rio de Janeiro hospitals, Brazil. AB - Staphylococcus epidermidis is a leading cause of hospital-acquired infections, mostly associated with the use of medical devices in seriously ill or immunocompromised patients. Currently, the characteristics of methicillin resistant S. epidermidis (MRSE) isolates from Rio de Janeiro hospitals are unknown. In this study, staphylococcal chromosomal cassette mec (SCCmec) types, antimicrobial susceptibility profiles, biofilm formation genes, and multilocus sequence types (MLST) were investigated in 35 MRSE clinical isolates. The collection of isolates was previously well characterized by pulsed-field gel electrophoresis (PFGE) into 2 main genotypes (A and B, 22 isolates) and 10 sporadic genotypes (13 isolates). MLST revealed a total of 8 different sequence types (STs), but ST2 and ST23, which were icaAB-positive, represented the majority (71.4%) of MRSE isolates tested. Almost all isolates (91.4%) belonged to clonal complex 2. SCCmec types III and IV were identified among 71.4% of the isolates, while the remaining was nontypeable. The predominant MRSE genotypes were defined as SCCmec type III/ST2 (PFGE type A) and SCCmec type IV/ST23 (PFGE type B) isolates, which were both associated with high antimicrobial resistance and presence of biofilm-related genes. PMID- 22100014 TI - Radiographic measurements of the trachea in domestic shorthair and Persian cats. AB - Tracheal diameter can be assessed from a thoracic radiograph, with assessment of tracheal diameter in dogs based on ratios between tracheal diameter and a skeletal measurement. Reference intervals are not, however, available for the cat. Tracheal narrowing may cause significant clinical problems, although tracheal hypoplasia in dogs may be clinically silent, and is rarely reported in cats (both mesati- and brachycephalic). The tracheal diameter and trachea:thoracic inlet and trachea:rib ratios were calculated for populations of domestic shorthair (DSH) (n = 68) and Persian (n = 40) cats. This gave reference intervals for radiographic tracheal measurements in these breeds. It is proposed that the tracheal diameter in a normal DSH cat should be 18% of the diameter of the thoracic inlet, and compared to 20% in Persian cats. PMID- 22100015 TI - Recent advances in the treatment of Kawasaki disease. AB - Kawasaki disease (KD) is acute systemic vasculitis that occurs mainly in infants and children under 5 years of age. The etiology of KD remains unknown. KD is liable to be complicated by coronary artery lesions (CALs), which develop in approximately 15-25% of untreated KD children and in approximately 5% of KD children after intravenous immunoglobulin (IVIG) therapy. A single high dose of IVIG (2 g/kg) is the gold standard therapy in the acute stage of KD. However, approximately 8--38% of children are unresponsive to initial IVIG treatment and at increased risk for CAL development. Anti-inflammatory high doses of aspirin are recommended in conjunction with IVIG, but our study demonstrated that there is no evidence of efficacy in preventing CAL development. The usefulness of steroids in initial therapy for KD or treatment of IVIG-resistant patients is not well established. Other immunosuppressive therapies, including infliximab, have been used in the treatment of refractory KD, but merit additional investigation. Subclinical atherosclerosis may develop early in KD patients, which makes early initiation of therapy to improve chronic inflammation an important issue. Future multicenter studies may help to define the optimal management of KD patients. PMID- 22100016 TI - Can serum cytokines predict hepatic cytokine expression in liver cirrhosis? PMID- 22100017 TI - Pretreatment risk stratification for non-metastatic head and neck squamous cell carcinoma in a high-prevalence area. AB - BACKGROUND: This retrospective study was to establish a prognostic scoring system for patients with non-metastatic head and neck squamous cell carcinoma (HNSCC). METHODS: The medical records of 151 patients with HNSCC were evaluated. Clinical data were collected and statistical analyses were performed to determine the prognostic value of pretreatment variables and to build a risk stratification system. Analysis of the data for 94 additional patients validated the risk stratification system. RESULTS: Three independent adverse prognostic factors were identified: Age <65 years, LDH >= upper normal limit and performance status. The risk stratification was defined as two or more adverse factors presented at diagnosis versus one adverse factor or no adverse factors. Patients with two or more adverse factors had a shorter survival regardless of treatment. This was confirmed in both the training set and the validation set. CONCLUSION: This risk stratification provides additional information to the current tumor staging system, which could be useful in making decisions for individual patients and selecting more homogenous patients when designing clinical trials. PMID- 22100018 TI - A new classification scheme for recurrent or metastatic colon cancer after liver metastasectomy. AB - BACKGROUND: Metastasectomy is the standard treatment for patients with resectable liver metastasis from colon cancer. This study aimed to determine the impact of initial stage on overall survival (OS) after metastasectomy. METHODS: A retrospective analysis of 2804 patients diagnosed with colon cancer between 1999 and 2008. RESULTS: Of the cohort, 38.1% of the patients were stage IV or had recurrence after curative surgery, and 131 received liver metastasectomy. The 5 year survival rate for patients after liver metastasectomy was 42.1%. The 5-year survival rates after metastasectomy for initial stage I disease, stage II disease, stage III disease, and stage IV disease were 100%, 82.5%, 31.8%, and 36.9%, respectively (p = 0.014). When patients were grouped as initial stage I/II and stage III/IV, the 5-year survival rate after liver metastasectomy differed significantly (83.9% vs. 35.7%, p = 0.006). Patients with initial stage I/II disease after liver metastasectomy had a significantly better 5-year progression free period compared to those with stage III/IV disease (60% vs. 28%, p = 0.021), which was due to the lower recurrence rate in the stage I/II group. CONCLUSION: Our results suggest that patients who receive liver metastasectomy for metastatic colon cancer should be grouped into two groups: those with initial stages I and II disease, and those with stages III and IV disease, since the progression-free survivals (PFS) and OS after metastasectomy in these two groups differ significantly. PMID- 22100019 TI - XP11.2 translocation renal cell carcinoma: clinical experience of Taipei Veterans General Hospital. AB - BACKGROUND: Xp11.2 translocation renal cell carcinoma (RCC), a recently recognized distinct subtype of RCC, is characterized by various translocations, all involving the TFE3 transcription factor gene. These rare cancers occur predominantly in children and young adults and comprise about one-third of pediatric RCCs. In the present study, we review the clinical course of Xp11.2 translocation renal cell carcinoma in our institution. METHODS: We identified eight cases with Xp11.2 translocation RCC between 2007 and 2010 from the pathological archives of the Taipei Veterans General Hospital. We retrospectively analyzed the patients' characteristics, clinical manifestations, and specific pathological features for definitive diagnosis, surgical and systemic treatment and clinical outcome of these rare cancers. RESULTS: Patients were aged 20 years to 49 years (mean age 28 years) with female predominance (6 females, 2 males). One patient presented with asymptomatic renal mass detected incidentally during abdominal sonography. Four patients complained of flank or abdominal pain, and the other three complained of gross hematuria at initial presentation. The mean tumor size was 9.2 cm (range, 4 cm-17 cm). Seven patients underwent radical nephrectomy for the primary tumor, while one presented with multiple metastases. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of tumors with TFE3 gene fusion, which showed positive nuclear staining. Three patients presented initially with metastatic diseases, and another three patients progressed to lung, liver and bone metastases at eight, seven and nine months postoperatively. CONCLUSION: Although RT-PCR and DNA sequencing are the final diagnoses of the molecular identity of Xp11.2 translocation RCC, experienced pathologists could confirm the histologic diagnosis based on the distinctive morphologic features with positive TFE3 immunochemical nuclear stain. Surgical resection is the only treatment. The role of systemic therapy for local recurrence and metastasis remains to be determined. PMID- 22100020 TI - Reconstruction after esophagectomy for esophageal cancer: retrosternal or posterior mediastinal route? AB - BACKGROUND: The aim of this study is to investigate which reconstructive route is most appropriate for patients undergoing an esophagectomy for esophageal cancer. METHODS: Clinical data on 110 patients were retrospectively collected by reviewing their medical charts. In order to evaluate the effects of adjuvant radiotherapy, patients were interviewed about the adverse side effects they experienced during and after treatment. RESULTS: The leakage rate was significantly lower in group that received posterior mediastinal reconstruction compared with the group that received retrosternal reconstruction (7.1% vs. 39%, p = 0.01). There were no significant differences between groups in terms of side effects related to adjuvant chemoradiotherapy or radiotherapy. The quality-of life reports of patients who received adjuvant radiotherapy were not significantly different between the two study groups. CONCLUSION: For patients with esophageal cancer who undergo an esophagectomy followed by gastric conduit reconstruction, the posterior mediastinal route is superior to the retrosternal route in regard to anastomotic leakage and hospital mortality. Adjuvant radiotherapy did not influence the postoperative functions of the gastric conduit used for reconstruction in either route. PMID- 22100021 TI - Differences in serum biochemistry between breast-fed and formula-fed infants. AB - BACKGROUND: We investigated the differences in serum biochemistry levels between breast-fed and formula-fed infants. We provide reference values of serum biochemistry levels for 4-week-old (w/o) and 8 w/o infants for future clinical applications. METHODS: Sixty healthy infants were enrolled in this study (30 infants were included in the breast-fed and formula-fed groups, respectively). During hospital visits at 4 and 8 w/o, several parameters, including body weight, body length, and head circumference were recorded. Blood was drawn to measure 14 serum biochemistry markers. RESULTS: There were no significant differences between the two groups in terms of growth or anthropometric measurements. Serum cholesterol, triglyceride (TG), alanine aminotransferase (ALT), aspartataminotransferase (AST), gamma glutamyl transferase (GGT), total bilirubin (T-bil) and direct bilirubin (D-bil) levels were significantly higher in the breast-fed group compared with those measured in the formula-fed group at both 4 and 8 w/o. Serum blood urea nitrogen (BUN) and inorganic phosphate (IP) levels were significantly lower in the breast-fed group compared with the formula-fed group at 4 and 8 w/o. In the formula-fed group, serum total protein (TP), albumin, cholesterol, uric acid (UA), ALT, and AST levels were significantly higher in 8 w/o infants compared with 4 w/o infants; in addition, serum GGT, T bil, D-bil, IP, and iron (Fe) levels were significantly lower in 8 w/o infants compared with 4 w/o infants. In the breast-fed group, serum TP, albumin, and UA levels were significantly higher in 8 w/o infants compared with 4 w/o infants; in addition, serum BUN, GGT, T-bil, D-bil, IP, and Fe levels were significantly lower in 8 w/o infants compared with 4 w/o infants. CONCLUSION: Different sources of nutrition may result in different metabolic responses; these differences are reflected by different serum biochemistries. The reference values for serum biochemistry levels also differ according to the infant's postnatal age. PMID- 22100022 TI - Scimitar syndrome in an older adult. AB - Scimitar syndrome is a rare congenital heart disease. It is divided into subgroups of infantile, adult, and multiple cardiac and extracardiac malformation. Most patients are diagnosed during infancy and occasionally in adolescence, but very few patients are older than 20 years of age, and only some cases have severe symptoms that require surgical correction. We report a case of a man 54 years of age who was diagnosed with asymptomatic scimitar syndrome with insignificant left-to-right shunt (Qp/Qs = 1.51) with a medical history of type 2 diabetes mellitus and hyperlipidemia. Related literature on scimitar syndrome, particularly on older adults, is also reviewed. PMID- 22100023 TI - En bloc surgical removal of an asymptomatic glomus tympanicum tumor. AB - Glomus tympanicum (GT) tumors are usually characterized by pulsatile tinnitus and hearing loss. We report on a woman 53 years of age who was diagnosed with a GT tumor within her right ear with no associated tinnitus or hearing loss on presentation. An early GT tumor without the characteristic symptoms is seldom encountered. Although several papers have dealt with GT tumor diagnosis and management, very few have demonstrated such a condition in which the entire GT tumor appeared in the middle ear cavity and was totally removed during the operation. There was no recurrence at 24 months of follow-up. We describe a novel surgical technique in this article and demonstrate an en bloc GT surgical removal that has been seldom published before in the literature. PMID- 22100024 TI - Management of double-penetrating ocular injury with retained intraorbital metallic foreign body. AB - The prognosis of double penetrating ocular trauma is usually guarded. We report the good anatomical and functional outcome in a patient with double-penetrating ocular trauma associated with intraorbital foreign body. A 58-year-old man presented at the emergency room complaining of blurred vision of the left eye with stinging pain after he hammered an iron plate. Best-corrected visual acuity was hand movement/30 cm. Subconjunctival hemorrhage with one 1.4-mm laceration wound was noted over the nasal conjunctiva. Fundus examination showed vitreous hemorrhage with one whitish patch over the nasal retina. Orbital computed tomography scan revealed one metallic foreign body at the posterior nasal upper orbit. Double-penetrating globe injury with intraorbital foreign body was impressed, and immediate vitrectomy surgery with endolaser photocoagulation was carried out. One exit wound nasal to the disc was noted during operation. The intraorbital metallic foreign body was left alone. Vision recovered to 6/8.6 without ocular complication after a 20-month follow-up. Prompt, careful preoperative evaluation and meticulous vitrectomy intervention are essential in the successful management of such patients. Posteriorly located intraorbital metallic foreign body should be managed conservatively. Long-term regular electroretinography evaluation is needed for possible retinal toxicity from intraorbital foreign body. PMID- 22100025 TI - Relation of renal function to risk for incident atrial fibrillation in women. AB - Few prospective studies have explored the association between renal function and risk for incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women's Health Study who were free of cardiovascular disease and AF and provided blood samples at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease Epidemiology (CKD-EPI) equation. Cox models were used to estimate hazard ratios and 95% confidence intervals (CIs) for incident AF across eGFR categories controlling for AF risk factors. During a median of 15.4 years of follow-up, 786 incident AF events occurred. The multivariate-adjusted hazard ratios for incident AF across eGFR categories (<60, 60 to 74.9, 75 to 89, and >=90 ml/min/1.73 m(2)) were 1.36 (95% CI 1.00 to 1.84), 0.90 (95% CI 0.71 to 1.14), 0.99 (95% CI 0.84 to 1.18) and 1.00, respectively, without evidence of a linear association (P for trend = 0.48). Similarly, there was no significant curvilinear association (quadratic p = 0.10) in multivariate analysis across categories. Compared to women with eGFRs >=60 ml/min/1.73 m(2), the 1,008 women with eGFRs <60 ml/min/1.73 m(2) had a multivariate-adjusted hazard ratio for AF of 1.39 (95% CI 1.04 to 1.86, p = 0.03). In conclusion, no significant linear or curvilinear relation was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of <60 ml/min/1.73 m(2). PMID- 22100027 TI - Prognostic value of uric acid in patients with ST-elevated myocardial infarction undergoing primary coronary intervention. AB - Elevated uric acid (UA) levels have been associated with cardiovascular disease in epidemiologic studies. The relation between UA levels and long-term outcomes in patients with ST-segment elevation myocardial infarction who undergo primary percutaneous coronary intervention is not known. Data from 2,249 consecutive patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention were evaluated. Patients were divided into 2 groups with high or low UA using upper limits of normal of 6 mg/dl for women and 7 mg/dl for men. There were 1,643 patients in the low-UA group (mean age 55.9 +/- 11.6 years, 85% men) and 606 patients in the high-UA group (mean age 60.5 +/- 12.6 years, 76% men). Serum UA levels were 8.0 +/- 1.5 mg/dl in the high-UA group and 5.2 +/- 1.0 mg/dl in the low-UA group (p <0.001). The in-hospital mortality rate was significantly higher in patients with high UA levels (9% vs 2%, p <0.001), as was the rate of adverse outcomes in patients with high UA. The mean follow-up time was 24.3 months. Cardiovascular mortality, reinfarction, target vessel revascularization, heart failure, and major adverse cardiac events were all significantly higher in the high-UA group. In a multivariate analyses, high plasma UA levels were an independent predictor of major adverse cardiac events in the hospital (odds ratio 2.03, 95% confidence interval 1.25 to 3.75, p = 0.006) and during long-term follow-up (odds ratio 1.64, 95% confidence interval 1.05 to 2.56, p = 0.03). In conclusion, high UA levels on admission are independently associated with in-hospital and long-term adverse outcomes in patients with ST segment elevation myocardial infarction who undergo primary percutaneous coronary intervention. PMID- 22100026 TI - Comparison of role of early (less than six hours) to later (more than six hours) or no cardiac catheterization after resuscitation from out-of-hospital cardiac arrest. AB - Despite reports of patients with resuscitated sudden cardiac arrest (rSCA) receiving acute cardiac catheterization, the efficacy of this strategy is largely unknown. We hypothesized that acute cardiac catheterization of patients with rSCA would improve survival to hospital discharge. A retrospective cohort of 240 patients with out-of-hospital rSCA caused by ventricular tachycardia or fibrillation was identified from 11 institutions in Seattle, Washington from 1999 through 2002. Patients were grouped into those receiving acute catheterization within 6 hours (<=6-hour group, n = 61) and those with deferred catheterization at >6 hours or no catheterization during the index hospitalization (>6-hour group, n = 179). Attention was directed to survival to hospital discharge, neurologic status, extent of coronary artery disease, presenting electrocardiographic findings, and symptoms before arrest. Propensity-score methods were used to adjust for the likelihood of receiving acute catheterization. Survival was greater in patients who underwent acute catheterization (72% in the <=6-hour group vs 49% in the >6-hour group, p = 0.001). Percutaneous coronary intervention was performed in 38 of 61 patients (62%) in the <=6-hour group and 13 of 170 patients (7%) in the >6-hour group (p <0.0001). Neurologic status was similar in the 2 groups. A significantly larger percentage of patients in the acute catheterization group had symptoms before cardiac arrest and had ST-segment elevation on electrocardiogram after resuscitation. Age, bystander cardiopulmonary resuscitation, daytime presentation, history of percutaneous coronary intervention or stroke, and acute ST-segment elevation were positively associated with receiving cardiac catheterization. In conclusion, in this series of patients who sustained out-of hospital cardiac arrest, acute catheterization (<6 hours of presentation) was associated with improved survival. PMID- 22100028 TI - Comparison of osteoprotegerin to traditional atherosclerotic risk factors and high-sensitivity C-reactive protein for diagnosis of atherosclerosis. AB - Atherosclerosis is the main cause of cardiovascular disease, but the extent of atherosclerosis in individual patients is difficult to estimate. A biomarker of the atherosclerotic burden would be very valuable. The aim of the present study was to evaluate the association of plasma osteoprotegerin (OPG) to clinical and subclinical atherosclerotic disease in a large community-based, cross-sectional population study. In the Copenhagen City Heart Study, OPG concentrations were measured in 5,863 men and women. A total of 494 participants had been hospitalized for ischemic heart disease or ischemic stroke, and compared to controls, this group with clinical atherosclerosis had higher mean OPG (1,773 vs 1,337 ng/L, p <0.001) and high-sensitivity C-reactive protein (2.3 vs 1.6 mg/L, p <0.001). In a multivariate model with age, gender, body mass index, hypertension, diabetes, hypercholesterolemia, smoking status, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and OPG, OPG remained significantly associated with clinical atherosclerosis (p <0.01); high-sensitivity C-reactive protein, in contrast, did not (p = 0.74). In the control group without clinical atherosclerosis, OPG was independently associated with hypertension, diabetes, hypercholesterolemia, smoking, and subclinical peripheral atherosclerosis as measured by ankle brachial index. For each doubling of the plasma OPG concentration, the risk for subclinical peripheral atherosclerosis increased by 50% (p <0.001) after multivariate adjustment. In conclusion, OPG appears to be a promising biomarker of atherosclerosis that is independently associated with traditional risk factors of atherosclerosis, subclinical peripheral atherosclerosis, and clinical atherosclerotic disease such as ischemic heart disease and ischemic stroke. PMID- 22100029 TI - Accuracy of estimating resting oxygen uptake and implications for hemodynamic assessment. AB - The Fick principle (cardiac output [Q(c)] = oxygen uptake [Vo(2)]/arteriovenous oxygen difference) can be used to calculate Q(c), with VO(2) frequently estimated by derived equations. To compare the accuracy of measured versus estimated VO(2), data were analyzed from 2 studies in which VO(2) at rest was measured using the Douglas bag technique. One study comprised adults with diabetes, and the other was an exercise study of healthy adults. VO(2) at rest was estimated as VO(2) (ml/min) = 125 ml/min/m(2) * body surface area (m(2)), with sensitivity analyses evaluating 2 other commonly used equations. Mean absolute difference (milliliters per minute) and ordinary least products regression were used to assess agreement between measured and estimated VO(2). Overall, mean measured versus estimated VO(2) differed significantly (307.2 +/- 75.2 vs 259.9 +/- 36.7 ml/min, p <0.0001), with a mean absolute difference of 52.9 +/- 43.2 ml/min (p <0.0001); 20% of the estimates differed by >25% from the measured VO(2). Mean absolute difference increased from 36.7 ml/min in the lowest body mass index group (<25 kg/m(2)) to 91.7 ml/min in the highest group (>=40 kg/m(2)) (p for trend = 0.001) and was significantly higher in men than in women (65.6 vs 33.9 ml/min, p = 0.001); error was similar by median-split age (p = 0.65) and race (p = 0.34). Similar results were obtained when evaluating each of the other 2 estimating equations. Estimation of VO(2) at rest is inaccurate, especially in men and with increasing adiposity. In conclusion, when clinical hemodynamic assessment is performed, VO(2) should be measured, not estimated. PMID- 22100030 TI - White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study). AB - Several studies have reported that inflammatory markers are associated with atrial fibrillation (AF). The white blood cell (WBC) count is a widely available and broadly used marker of systemic inflammation. We sought to investigate the association between an increased WBC count and incident AF and whether this association is mediated by smoking, myocardial infarction, and heart failure. We examined the participants in the Framingham Heart Study original cohort. Cox proportional hazard regression analysis was used to examine the relation between the WBC count and incident AF during a 5-year follow-up period. We adjusted for standard AF risk factors, smoking, previous myocardial infarction, and interim myocardial infarction and heart failure before the incident AF. Our sample consisted of 936 participants (mean age 76 +/- 6 years and 61% women). The median WBC count was 6.4 * 10(9)/L (25th to 75th percentile 5.6 * 10(9)/L to 7.8 * 10(9)/L). During a median 5-year follow-up period, 82 participants (9%) developed new-onset AF. After adjusting for standard risk factors for AF, an increased WBC count was significantly associated with incident AF, with a hazard ratio per SD (0.26 * 10(9)/L) increase of 2.22 (95% confidence interval 1.10 to 4.48; p = 0.03). We found no substantive differences adjusting for smoking, previous myocardial infarction, interim myocardial infarction, or heart failure. In conclusion, in our community-based sample, an increased WBC count was associated with incident AF during 5 years of follow-up. Our findings provide additional evidence for the relation between systemic inflammation and AF. PMID- 22100031 TI - Light chain (AL) amyloidosis: update on diagnosis and management. AB - Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production of fibrillar proteins comprised of monoclonal light chains which deposit in tissues and cause organ dysfunction. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk adapted approach to SCT followed by novel agents as consolidation reduces treatment related mortality with promising outcomes. Immunotherapeutic approaches targeting pathologic plasma cells and amyloid precursor proteins or fibrils are being developed. Referral of patients to specialized centers focusing on AL amyloidosis and conducting clinical trials is essential to improving patient outcomes. PMID- 22100032 TI - Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C. PMID- 22100034 TI - Disruption of the hypothalamic-pituitary-thyroid axis in zebrafish embryo-larvae following waterborne exposure to BDE-47, TBBPA and BPA. AB - We performed waterborne exposures of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), tetrabromobisphenol A (TBBPA) or bisphenol A (BPA) on zebrafish (Danio rerio) embryo-larvae and quantitatively measured the expression of genes belonging to the hypothalamic-pituitary-thyroid (HPT) axis to assess for adverse thyroid function. For analysis on the effects of BDE-47, TBBPA and BPA on the hypothalamic-pituitary-thyroid genes, zebrafish embryo-larvae were acutely exposed to lethal concentrations of the chemical agents in order to determine the 96 h-LC50 (96 h lethal median concentration) and 96 h-EC50 (96 h effective median concentration) values. Further exposures at sub-lethal concentrations were then carried out and total RNA samples were extracted to quantify the mRNA expression levels of the genes of interest. In larvae, BDE-47 was found to have significantly induced many genes of interest, namely thyroglobulin, thyroid peroxidase, thyroid receptors alpha and beta, thyroid stimulating hormone, and transthyretin. TBBPA only significantly induced three genes of interest (thyroid receptor alpha, thyroid stimulating hormone, and transthyretin) while BPA only induced thyroid stimulating hormone. In embryos, BDE-47 significantly induced the sodium iodide symporter and thyroid stimulating hormone. TBBPA significantly induced thyroid receptor alpha and thyroid stimulating hormone, while BPA did not significantly induce any of the genes. Most genes were only induced at the 75% 96 h-LC50 or 96 h-EC50 value; however, thyroid peroxidase and thyroid stimulating hormone demonstrated upregulation in a level as little as the 10% 96 h-LC50 value. The present study provides a new set of data on zebrafish mRNA induction of hypothalamic-pituitary-thyroid genes from exposure to BDE-47, TBBPA, or BPA. This information would serve useful for elucidating the toxicological mechanism of brominated flame retardants, assessing appropriate safety levels in the environment for these compounds, as well as serve as a reference for other man made contaminants. PMID- 22100035 TI - Mass spectrometry-based signal networks elucidation. AB - Signalling networks regulate essentially all of the biology of cells and organisms under physiological and pathological states. Analysis of signalling networks by classical biochemical approaches such as antibody-based techniques is limited for large-scale and unbiased studies. Proteomics technique based on mass spectrometry now enables the system-wide characterization of signalling events at the levels of post-translational modifications, protein complex and changes in protein expression. This function can complement the system-side gene expression analysis since the expression of many proteins is regulated by posttranscriptional mechanisms. The application of these technologies provided a quantum leap in our understanding of the molecular properties of signalling networks in recently years. PMID- 22100036 TI - Development of functional gene microarrays for microbial community analysis. AB - Functional gene arrays (FGAs) are a special type of microarrays containing probes for key genes involved in microbial functional processes, such as biogeochemical cycling of carbon, nitrogen, sulfur, phosphorus and metals, virulence and antibiotic resistance, biodegradation of environmental contaminants, and stress responses. FGAs have been demonstrated to be a specific, sensitive, and quantitative tool for rapid analysis of microbial communities from different habitats, such as waters, soils, extreme environments, bioreactors, and human microbiomes. In this review, we first summarize currently reported FGAs, and then focus on the FGA development. We will also discuss several key issues of FGA technology as well as challenges and directions in future FGA development. PMID- 22100037 TI - Differentiation of ataxic and orthopedic gait abnormalities in the horse. AB - The differentiation of ataxia and orthopedic disease can be facilitated by the use of several additional tests, not commonly part of either neurologic or orthopedic examination protocols. However, a full neurologic and orthopedic examination and suitable diagnostic imaging will of course also be necessary in such cases. The common association of orthopedic and neurologic disease makes it even more necessary to correctly attribute movement or posture abnormalities to potentially treatable structures. PMID- 22100038 TI - Lesions of the equine neck resulting in lameness or poor performance. AB - Lesions of the neck are an uncommon primary cause of pain resulting in either lameness or poor performance but should be considered if local analgesic techniques of the limbs fail to abolish lameness or if there are clinical signs directly referable to the neck such as pain, abnormal neck posture, stiffness, or patchy sweating. Accurate diagnosis requires careful clinical examination, exclusion of other causes of lameness or poor performance, and accurate interpretation of diagnostic imaging findings. PMID- 22100039 TI - Advanced imaging of the nervous system in the horse. AB - Neuroimaging underwent a dramatic revolution during the past few decades due to the development of new technologies that produce exquisite images of patient morphology and function, new technologies that store and distribute information more efficiently, and research that has improved understanding of pathogenesis and effective clinical use of new imaging methods. Advanced equine neuroimaging is a specialized field with unique challenges associated with patient size, availability of equipment, using equipment designed for humans, small sample size for various diseases, and issues associated with recovering a horse with neurologic problems from general anesthesia. Despite these challenges, modern imaging techniques provide much useful information in horses with neurologic disease that are important for making a diagnosis, planning treatment, monitoring patient response, or providing prognostic information to guide owner choices regarding decisions about patient care. In particular, CT and MRI have been beneficial in diagnosing several equine neurologic diseases including congenital malformations (eg, hydrocephalus), equine protozoal myeloencephalitis, strangles (Streptococcus equi ssp. equi) abscesses, nigropallidal encephalomalacia, pituitary macroadenomas, cholesterinic granulomas, THO, CSM, trauma, and various neoplasms. Optimizing equine neuroimaging starts with selecting an appropriate examination, understanding the prior probability of disease and the capabilities of the different imaging technologies, understanding normal anatomy and pathogenesis, and having a systematic approach to review the images. Advanced equine neuroimaging will continue to evolve as more of the challenges are overcome and new research is produced on the effective use of imaging methods and understanding of specific diseases. PMID- 22100040 TI - Neuro-ophthalmology in horses. AB - A complete neuro-ophthalmologic assessment is relatively simple, requires minimal instrumentation and should be performed as part of every complete ophthalmic and neurologic examination. This article has summarized the tests that comprise and the species-specific details of the complete neuro-ophthalmologic of the equine patient. Selected causes of sudden blindness in the horse were summarized and some common neuro-ophthalmic conditions with significant ophthalmic consequences, such as facial nerve paralysis, were discussed. Split-lid tarsorrhaphies, which are indicated but rarely used in cases of facial nerve paralysis were strongly recommended for all facial paralysis cases and were described in detail. PMID- 22100041 TI - Miscellaneous neurologic or neuromuscular disorders in horses. AB - NMD is an important cause of morbidity in horses. Signs of dysfunction could be variable depending on the specific area affected. NM disease can go unrecognized if a thorough evaluation is not performed in diseased horses. Electrodiagnostic testing is an area that has the potential to document and improve our understanding of NM disease yet is uncommonly performed. Keeping an open and observant mind will enhance our ability to search and find answers. PMID- 22100042 TI - Toxins and adverse drug reactions affecting the equine nervous system. AB - This article provides an overview of the more common toxins and adverse drug reactions, along with more rare toxins and reactions (Table 1), that result in neurologic dysfunction in horses. A wide variety of symptoms, treatments, and outcomes are seen with toxic neurologic disease in horses. An in-depth history and thorough physical examination are needed to determine if a toxin or adverse drug reaction is responsible for the clinical signs. Once a toxin or adverse drug reaction is identified, the specific antidote, if available, and supportive care should be administered promptly. PMID- 22100043 TI - Evaluation and management of the recumbent adult horse. AB - Evaluation and management of recumbent horses are challenging. Familiarity with disorders that can result in recumbency will facilitate more rapid diagnosis and more appropriate formulation of a prognosis. With rapid and appropriate diagnosis, appropriate treatment can be pursued and, with good nursing care, can result in a favorable outcome. PMID- 22100044 TI - Guttural pouch diseases causing neurologic dysfunction in the horse. AB - The close relationship between guttural pouches, cranial nerves, and sympathetic structures make neurologic abnormalities due to diseases of the guttural pouches (especially mycosis) possible. Recognition of epistaxis or mucopurulent nasal discharge, together with signs of dysfunction of the cranial nerves in contact with the guttural pouches, are important key points in order to consider a comprehensive evaluation of these structures and further definitive diagnosis. Diseases of the guttural pouches can also cause signs such as dysphagia, abnormal soft palate positioning, laryngeal paralysis, and Horner syndrome due to lesions in one or more of the cranial nerves or sympathetic structures involved with these functions. Therefore, an accurate diagnosis is essential for treatment. PMID- 22100045 TI - Update on infectious diseases affecting the equine nervous system. PMID- 22100046 TI - Metabolic causes of encephalopathy in horses. PMID- 22100047 TI - Clinical neurology. PMID- 22100048 TI - [Severe acute flecainide intoxication]. PMID- 22100049 TI - [Analysis of microsatellite instability in laryngeal squamous cell carcinoma]. AB - INTRODUCTION AND OBJECTIVES: The literature on the involvement of microsatellite instability in head and neck squamous cell carcinoma shows great variability, probably due to differences in the testing methods. Using a consensus detection system, we aimed to reach a reliable estimate of microsatellite instability prevalence in a subset of head and neck squamous cell carcinoma cases. METHODS: The microsatellite instabilityI status of 43 patients with previously untreated primary laryngeal squamous cell carcinomas was analyzed by a multiplex polymerase chain reaction assay including 5 mononucleotide repeat markers. RESULTS: Thirty six cases showed a stable phenotype or a microsatellite stable phenotype (83.7%) and 7 cases (16.3%) showed an microsatellite instability-positive phenotype. One case showed instability in 3 of 5 markers, 1 case in 2 markers and 5 cases in 1 marker. The microsatellite instability-positive and stable cases did not differ with respect to age, tumour stage, lymph node or distant metastases. CONCLUSIONS: Our data showed that a proportion of laryngeal squamous cell carcinomas are microsatellite instability positive. Knowledge of microsatellite instability patient status will allow adjusting anticancer therapy at an individual level. PMID- 22100050 TI - [Molecular characterisation of methicillin resistant Staphylococcus aureus strains ST398 in patients with skin infections and their relatives]. AB - INTRODUCTION: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) of sequence type ST398 is a genetic lineage also described in human infections. METHODS: Cutaneous infections related with MRSA ST398 are described in 3 patients, two of them pig farmers. The MRSA nasal carriage by patients and their relatives was also studied. MRSA ST398 strains were typed (SCCmec, spa, agr and MLST) and the antimicrobial resistance pattern and virulence genes were determined. RESULTS: Twenty MRSA ST398 isolates were recovered in lesions of three patients, and in nasal samples of two patients and five relatives. Isolates were typed: spa-type t011 or t108; agr-type I and SCCmec IVa or V. MRSA strains were tetracycline-resistant and 15 of them showed a phenotype and genotype of multi-resistance, but they were free of tested virulence genes. CONCLUSIONS: LA MRSA ST398 is an emergent problem in our country, mainly associated with skin and soft tissue infections in people with professional relationships with pig farms. Tetracycline resistance is an important marker for MRSA ST398 detection. PMID- 22100051 TI - Urolithiasis risk factors in the bariatric population undergoing gastric bypass surgery. AB - BACKGROUND: Previous studies have suggested an increased risk of forming symptomatic urolithiasis after Roux-en-Y gastric bypass (RYGB) attributed to the development of hyperoxaluria. The objective of our investigation was to evaluate changes in the urine milieu after RYGB that might explain the increased risk of urolithiasis. METHODS: Patients underwent serum and urine chemistry tests 1 week before and 6 months after RYGB at a university hospital. The postoperative urolithiasis risk factors were compared with the preoperative values. Statistical analysis was performed using paired t tests. Significant changes were identified as P <= .05. RESULTS: A total of 38 patients (7 men and 31 women) submitted samples both before and after RYGB. The mean patient weight had decreased from 131 kg to 92 kg. The mean serum creatinine decreased from .83 to .72 mg/dL (P = .0004). Urinary changes known to increase the risk of urolithiasis include a decrease in volume (2-1.5 L/d, P = .03), an increase in calcium (139-182 mg/d, P = .04), and an increase in oxalate (38-48 mg/d, P < .001). The urinary supersaturation indexes for calcium oxalate (4.9-10.5, P < .001) increased. CONCLUSION: Our results confirm that patients undergoing RYGB develop changes in the urinary milieu predisposing them to forming urinary stones. Urolithiasis risk is multifactorial and is related to more than just hyperoxaluria. A patient's long-term risk of developing stones and the effect on renal function is unknown. Preoperative counseling of patients regarding their risk of forming stones and dietary counseling to minimize their risk of developing stones postoperatively is warranted. PMID- 22100052 TI - Late gastric perforation after insertion of intragastric balloon for weight loss- video case report and literature review. PMID- 22100053 TI - High diversity and differential persistence of fecal Bacteroidales population spiked into freshwater microcosm. AB - Bacteroidales markers are promising indicators of fecal pollution and are now widely used in microbial source tracking (MST) studies. However, a thorough understanding of the persistence of Bacteroidales population after being released into environmental waters is lacking. We investigated the persistence of two host specific markers (HF183 and CF193) and temporal change of Bacteroidales population over 14 days in freshwater microcosms seeded with human or bovine feces. The concentrations of HF183/CF193 and Escherichia coli were determined using quantitative polymerase chain reaction (qPCR) and standard cultivation method, respectively. Shifts in the Bacteroidales population structure were fingerprinted using PCR-denaturing gradient gel electrophoresis (DGGE) and subsequent sequencing analysis targeting both 16S rDNA and rRNA-transcribed cDNA. Both HF183 and CF193 decayed significantly faster than E. coli but the decay curves fit poorly with first-order model. High diversity of Bacteroidales population was observed for both microcosms, and persistence of different species in the population varied. Sequence analysis indicated that most of the bovine Bacteroidales populations in our study are unexplored. DGGE and decay curve indicated that RNA decayed faster than DNA, further supporting the use of rRNA as indicator of metabolically active Bacteroidales population. Evaluations with more realistic scenarios are warranted prior to extending the results of this study to real field settings. PMID- 22100054 TI - Novel ferromagnetic nanoparticle composited PACls and their coagulation characteristics. AB - Effects of magnetic nanoparticles on inorganic coagulants and their coagulation performances were studied in the present work. The Fe(3)O(4)-SiO(2) core-shell particle (FSCSP) and superfine iron (SI), were compounded with polyaluminium chloride of basicity 2.0 (PACl2.0), providing magnetic PACl2.0s (MPACl2.0s). The physiochemical properties of ferromagnetic nanoparticles were investigated using transmission electron microscopy (TEM), the BET method and a zeta potentiometric analyzer. The Al species distributions of the MPACl2.0s and PACl2.0 were examined by liquid (27)Al NMR. Jar tests were employed to evaluate the coagulation performances. Floc properties were assessed by use of the electromotive microscope (EM) and small angle laser light scattering (SALLS). The results showed that modified layers of nanoparticles mitigated agglomeration. FSCSP had a larger specific area and pore volume than SI. The addition of ferromagnetic nanoparticles obviously increased the content of Al(un). MPACl2.0s performed better than PACl2.0 in turbidity removal and DOC removal when dosed less than 0.06 mmol/L as Al. Generally, PACl2.0 + FSCSP (50 mg/L) performed best. Large, loose and weak flocs were produced by MPACl2.0s, which were preferred for the magnetic powder recycling. A plausible structure, Al species-nanoparticles cluster, contributing to the unique properties of MPACl2.0 flocs, was proposed. PMID- 22100055 TI - A review of water recovery by vapour permeation through membranes. AB - In vapour permeation the feed is a vapour, not a liquid as in pervaporation. The process employs a polymeric membrane as a semi-permeable barrier between the feed side under high pressure and the permeate side under low pressure. Separation is achieved by the different degrees to which components are dissolved in and diffuse through the membrane, the system working according to a solution diffusion mechanism. The materials used in the membrane depend upon the types of compounds being separated, so water transport is favoured by hydrophilic material, whether organic or inorganic. The process is used for the dehydration of natural gas and various organic solvents, notably alcohol as biofuel, as well as the removal of water from air and its recovery from waste steam. Waste steam can be found in almost every plant/factory where steam is used. It is frequently contaminated and cannot be reused. Discharging the spent steam to the atmosphere is a serious energy loss and environmental issue. Recycling the steam can significantly improve the overall energy efficiency of an industry, which is responsible for massive CO(2) emissions. Steam separation at high fluxes and temperatures has been accomplished with a composite poly(vinyl alcohol) membrane containing silica nanoparticles, and also, less efficiently, with an inorganic zeolite membrane. PMID- 22100056 TI - Orientation of orthotropic material properties in a femur FE model: a method based on the principal stresses directions. AB - Most work done on bone simulation has modeled the tissue as inhomogeneous and isotropic even though it is a recognized anisotropic material. Some recent investigations have included orthotropic behavior in bone finite elements (FE) models; however the problem regarding the orientation of these properties along the irregular bone anatomy remains. In this work, a procedure to orientate orthotropic properties in a proximal femur FE model using the directions of the principal stresses produced by a physiological load scheme was developed. Two heterogeneous material models, one isotropic and one orthotropic, were employed to test their influence on the mechanical behavior of the bone model. In the developed orthotropic material, the mechanical properties are aligned with the highest principal stress produced from the successive application of a multi load scenario corresponding to 10%, 30% and 45% of the gait cycle. A solid match between anatomical structures in the proximal femur and the corresponding directions of the main principal stress of the elements of the model suggests that the developed methodology works accurately. The differences found in the stress distributions were small (maximum 7.6%); nevertheless the changes in the strain distributions were important (maximum 27%) and located in areas of clinical relevance. PMID- 22100057 TI - Fetal habituation in assisted conception. AB - BACKGROUND: Neurodevelopment outcomes of children conceived by Assisted Reproductive Technology (ART)have been the subject of much recent attention. To date there are no reports of neurodevelopmental performance before birth in this group. AIMS: To compare habituation (a measure of brain function) in fetuses conceived by assisted reproduction techniques (ART) with naturally conceived (NC) fetuses. STUDY DESIGN: Case control study. SUBJECTS: Women with singleton pregnancies matched for maternal age, parity and smoking were recruited in 2 groups: ART (n=20) and NC (n=20). OUTCOME MEASURES: Sound stimuli (250 Hz, 110 dB) at 10 second intervals lasting 2 s were administered to the fetus. The end point was habituation (cessation of movement for five consecutive stimuli) or a maximum of 30 stimuli. Responses of the fetus were observed with ultrasound at 28, 32 and 36 weeks' gestation, video-recorded and anonymised for analysis. RESULTS: At 28 weeks' gestation significantly more ART fetuses responded to sound of 250 Hz, 110 dB (p=0.02) but this difference did not persist at 32 and 36 weeks'. There was a significant increase in nonresponders as gestation advanced in the ART group. There was no difference in habituation or mean number of trials to habituate at all three gestations. CONCLUSIONS: ART fetuses demonstrated no differences in habituation suggesting that there is no neurodevelopment delay. However, a decrease in response to sound as gestation advances might be a harbinger for poor perinatal outcomes and needs exploration. PMID- 22100058 TI - Atorvastatin 10 mg plus ezetimibe 10mg compared with atorvastatin 20 mg: impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease. AB - BACKGROUND: Oxidized low-density lipoprotein (LDL) cholesterol is a sensitive lipid marker for predicting atherosclerosis. Ezetimibe and statins are reported to decrease both LDL cholesterol and oxidized LDL cholesterol. This prospective randomized open-label crossover study compared combination therapy with atorvastatin plus ezetimibe versus high-dose atorvastatin monotherapy. Changes in serum lipids, including malondialdehyde-modified LDL (MDA-LDL) as a representative form of oxidized LDL cholesterol, and glucose metabolism were assessed. METHODS AND RESULTS: The subjects were 39 Japanese patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance who were taking 10 mg/day of atorvastatin (30 men and 9 women with a mean age of 67.8 years). They were randomized to a group that first received add-on ezetimibe (10 mg/day) or a group that first received atorvastatin monotherapy at a higher dose of 20 mg/day. Both treatments were given for 12 weeks each in a crossover fashion. Add-on ezetimibe significantly decreased MDA-LDL (109.0 +/- 31.9 mg/dl to 87.7 +/- 29.4 mg/dl, p=0.0009), while up-titration of atorvastatin did not. The decrease with add-on ezetimibe was significantly greater than with up titration of atorvastatin (p=0.0006). Total cholesterol and LDL cholesterol were significantly decreased by both treatments, but the percent reduction with add-on ezetimibe was significantly greater (p<0.05). High-density lipoprotein cholesterol was significantly increased by both treatments and there was no significant difference between them. The apolipoprotein B/apolipoprotein A-I ratio and remnant-like particle cholesterol were only significantly decreased by add-on ezetimibe. Both treatments caused similar elevation of hemoglobin A(1c). CONCLUSION: In Japanese patients with type 2 diabetes or impaired glucose tolerance and coronary artery disease, adding ezetimibe (10 mg/day) to atorvastatin (10 mg/day) significantly improved the lipid profile compared with atorvastatin monotherapy at 20 mg/day. PMID- 22100059 TI - Effect of clopidogrel on circulating biomarkers of angiogenesis and endothelial activation. AB - Angiogenic cytokines have been shown to influence vessel injury, and platelets represent a disposable circulating pool of angiogenic molecules. In the present study, objectives were to determine whether clopidogrel could have a potential effect on levels of circulating biomarkers of angiogenesis and endothelial activation. We explored 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/day. We quantified angiogenic growth factors that have been shown to be correlated to cardiovascular risk or endothelial progenitor cell mobilization such as vascular endothelial growth factor (VEGF)-A and its soluble receptor forms VEGFR1 and VEGFR2, placenta growth factor, and stromal cell derived factor-1. We also quantified soluble E-selectin and von Willebrand factor to evaluate endothelial activation. Blood samples were drawn just before the first clopidogrel intake on day 1, and after the last dosing (day 7). As expected, we observed a decrease in platelet reactivity in response to clopidogrel, confirmed by vasodilator-stimulated phosphoprotein phosphorylation assay. However, the 7-day intake of clopidogrel did not significantly modify the levels of the selected angiogenic factors or biomarkers of endothelial activation. These results show that circulating angiogenic factor level in healthy subjects is not driven by P2Y12 platelet receptor-induced activation and clopidogrel does not modify in a significant way the endothelial activation level. PMID- 22100060 TI - Enhanced cortical excitability in grapheme-color synesthesia and its modulation. AB - Synesthesia is an unusual condition characterized by the over-binding of two or more features and the concomitant automatic and conscious experience of atypical, ancillary images or perceptions. Previous research suggests that synesthetes display enhanced modality-specific perceptual processing, but it remains unclear whether enhanced processing contributes to conscious awareness of color photisms. In three experiments, we investigated whether grapheme-color synesthesia is characterized by enhanced cortical excitability in primary visual cortex and the role played by this hyperexcitability in the expression of synesthesia. Using transcranial magnetic stimulation, we show that synesthetes display 3-fold lower phosphene thresholds than controls during stimulation of the primary visual cortex. We next used transcranial direct current stimulation to discriminate between two competing hypotheses of the role of hyperexcitability in the expression of synesthesia. We demonstrate that synesthesia can be selectively augmented with cathodal stimulation and attenuated with anodal stimulation of primary visual cortex. A control task revealed that the effect of the brain stimulation was specific to the experience of synesthesia. These results indicate that hyperexcitability acts as a source of noise in visual cortex that influences the availability of the neuronal signals underlying conscious awareness of synesthetic photisms. PMID- 22100061 TI - A Galphaq-Ca2+ signaling pathway promotes actin-mediated epidermal wound closure in C. elegans. AB - BACKGROUND: Repair of skin wounds is essential for animals to survive in a harsh environment, yet the signaling pathways initiating wound repair in vivo remain little understood. In Caenorhabditis elegans, a p38 mitogen-activated protein kinase (MAPK) cascade promotes innate immune responses to wounding but is not required for other aspects of wound healing. We therefore set out to identify additional wound response pathways in C. elegans epidermis. RESULTS: We show here that wounding the adult C. elegans skin triggers a rapid and sustained rise in epidermal Ca(2+) that is critical for survival after wounding. The wound triggered rise in Ca(2+) requires the epidermal transient receptor potential channel, melastatin family (TRPM) channel GTL-2 and IP(3)R-stimulated release from internal stores. We identify an epidermal signal transduction pathway that includes the Galpha(q) EGL-30 and its effector PLCbeta EGL-8. Loss of function in this pathway impairs survival after wounding. The Galpha(q)-Ca(2+) pathway is not required for known innate immune responses to wounding but instead promotes actin dependent wound closure. Wound closure requires the Cdc42 small GTPase and Arp2/3 dependent actin polymerization and is negatively regulated by Rho and nonmuscle myosin. Finally, we show that the death-associated protein kinase DAPK-1 acts as a negative regulator of wound closure. CONCLUSIONS: Skin wounding in C. elegans triggers a Ca(2+)-dependent signaling cascade that promotes wound closure, in parallel to the innate immune response to damage. Wound closure requires actin polymerization and is negatively regulated by nonmuscle myosin. PMID- 22100062 TI - Evidence for extensive recent intron transposition in closely related fungi. AB - Though spliceosomal introns are a major structural component of most eukaryotic genes and intron density varies by more than three orders of magnitude among eukaryotes [1-3], the origins of introns are poorly understood, and only a few cases of unambiguous intron gain are known [4-8]. We utilized population genomic comparisons of three closely related fungi to identify crucial transitory phases of intron gain and loss. We found 74 intron positions showing intraspecific presence-absence polymorphisms (PAPs) for the entire intron. Population genetic analyses identified intron PAPs at different stages of fixation and showed that intron gain or loss was very recent. We found direct support for extensive intron transposition among unrelated genes. A substantial proportion of highly similar introns in the genome either were recently gained or showed a transient phase of intron PAP. We also identified an intron transfer among paralogous genes that created a new intron. Intron loss was due mainly to homologous recombination involving reverse-transcribed mRNA. The large number of intron positions in transient phases of either intron gain or loss shows that intron evolution is much faster than previously thought and provides an excellent model to study molecular mechanisms of intron gain. PMID- 22100063 TI - Cortical hypersynchrony predicts breakdown of sensory processing during loss of consciousness. AB - Intrinsic cortical dynamics modulates the processing of sensory information and therefore may be critical for conscious perception. We tested this hypothesis by electroencephalographic recording of ongoing and stimulus-related brain activity during stepwise drug-induced loss of consciousness in healthy human volunteers. We found that progressive loss of consciousness was tightly linked to the emergence of a hypersynchronous cortical state in the alpha frequency range (8-14 Hz). This drug-induced ongoing alpha activity was widely distributed across the frontal cortex. Stimulus-related responses to median nerve stimulation consisted of early and midlatency response components in primary somatosensory cortex (S1) and a late component also involving temporal and parietal regions. During progressive sedation, the early response was maintained, whereas the midlatency and late responses were reduced and eventually vanished. The antagonistic relation between the late sensory response and ongoing alpha activity held for constant drug levels on the single-trial level. Specifically, the late response component was negatively correlated with the power and long-range coherence of ongoing frontal alpha activity. Our results suggest blocking of intracortical communication by hypersynchronous ongoing activity as a key mechanism for the loss of consciousness. PMID- 22100064 TI - The P4-ATPase TAT-5 inhibits the budding of extracellular vesicles in C. elegans embryos. AB - BACKGROUND: Cells release extracellular vesicles (ECVs) that can influence differentiation, modulate the immune response, promote coagulation, and induce metastasis. Many ECVs form by budding outwards from the plasma membrane, but the molecules that regulate budding are unknown. In ECVs, the outer leaflet of the membrane bilayer contains aminophospholipids that are normally sequestered to the inner leaflet of the plasma membrane, suggesting a role for lipid asymmetry in ECV budding. RESULTS: We show that loss of the conserved P4-ATPase TAT-5 causes the large-scale shedding of ECVs and disrupts cell adhesion and morphogenesis in Caenorhabditis elegans embryos. TAT-5 localizes to the plasma membrane and its loss results in phosphatidylethanolamine exposure on cell surfaces. We show that RAB-11 and endosomal sorting complex required for transport (ESCRT) proteins, which regulate the topologically analogous process of viral budding, are enriched at the plasma membrane in tat-5 embryos, and are required for ECV production. CONCLUSIONS: TAT-5 is the first protein identified to regulate ECV budding. TAT-5 provides a potential molecular link between loss of phosphatidylethanolamine asymmetry and the dynamic budding of vesicles from the plasma membrane, supporting the hypothesis that lipid asymmetry regulates budding. Our results also suggest that viral budding and ECV budding may share common molecular mechanisms. PMID- 22100065 TI - Pre- and postictal, not ictal, heart rate distinguishes complex partial and psychogenic nonepileptic seizures. AB - Psychogenic nonepileptic seizures (PNES) remain poorly understood neurobiologically. Previously reported work suggests that adjunct ictal heart rates (HRs) may differentiate PNES from complex partial seizures (CPS). We retrospectively reviewed and compared preictal, ictal, and postictal HR differences in patients with PNES (n=42) and CPS controls (n=46) electively admitted for video/EEG monitoring to further characterize PNES autonomic patterns. Statistically significant preictal HR increases (P=0.006) and postictal (P=0.015) HR reductions normalized to baseline were identified in subjects with PNES compared with CPS controls. Ictal HRs were not found to differentiate between PNES and CPS events. This pattern of pre-event HR increases and postevent HR decreases in patients with PNES compared with those with CPS suggests frontolimbic neural circuit dysfunction and merits further exploration. PMID- 22100066 TI - Neuropsychological function in patients who have had epilepsy surgery: a long term follow-up. AB - We examined the relationship between seizure outcomes and long-term changes in memory and intellectual function in 70 patients who had undergone temporal lobe resection for medically intractable epilepsy. Patients were assessed on four occasions: preoperatively (T1), 3 months postoperatively (T2), 1 year postoperatively (T3), and more than 5 years postoperatively (T4). The majority of patients had stable memory function across the assessments. However, many were functioning below the 15th percentile on the test norms preoperatively, with little capacity for further decline. All patients who demonstrated a progressive decline in verbal or visual learning were female and continued to experience seizures postoperatively. Progressive postoperative declines in memory function are associated with poor postoperative seizure control. These patterns can be obscured in group analyses that do not take into account baseline levels of function. Neuropsychological scores must be set in the context of the norms of the test and the associated capacity for further significant change over time to maximize the clinical relevance of long-term surgical follow-up studies. PMID- 22100067 TI - Alien hand syndrome after epilepsia partialis continua: FDG PET and MRI studies. AB - Epilepsia partialis continua (EPC) is clinically defined as a syndrome of continuous focal jerking of a body part, usually a distal limb, occurring over hours, days, or even years. It is considered the status epilepticus equivalent of simple partial motor seizures. A 48-year-old right-handed man with a history of traumatic intracranial hemorrhage was admitted for right-sided hemiplegia and drowsiness after complex partial status epilepticus. An EEG showed periodic lateralized epileptiform discharges over the left hemisphere. Brain MRI revealed extensive multifocal encephalomalaciac changes in the left temporo-parieto occpital lobe and both frontal lobes with some hemorrhagic residual change. After administration of a loading dose of intravenous phenytoin, his mental status returned to normal. However, his weakness only partially improved. [(18)F]Fluorodeoxyglucose PET (FDG-PET) demonstrated severe hypometabolism in the left cerebral hemisphere, including the basal ganglia and thalamus, with cerebellar diaschisis. At the 3-month follow-up, he complained of symptoms of alien hand phenomenon. Follow-up MRI revealed more extensive encephalomalaciac changes in previously noted regions with thinning of the posterior end of the body of the corpus callosum. Moreover, FDG-PET demonstrated persistent severe hypometabolism over the left cerebral hemisphere. We suggest that the alien hand phenomenon was a result of thinning of the corpus callosum related to EPC. PMID- 22100068 TI - Distribution and seasonal variation in the partial pressure of CO2 during autumn and winter in Jiaozhou Bay, a region of high urbanization. AB - We investigated the partial pressure of carbon dioxide (pCO(2)) in Jiaozhou Bay (JZB), which is surrounded by the economically developed city of Qingdao, during two cruises undertaken in November, 2007 (autumn) and February, 2008 (winter). Results indicated that sea surface pCO(2) in autumn varied between 315 and 720 MUatm, with an average level of 418 MUatm. In winter the sea surface pCO(2) ranged from 145 to 315 MUatm with an average of 249 MUatm, which is below atmospheric pCO(2). Despite seasonal temperature variation between autumn and winter, it was noted that biological process (production and respiration) were responsible for both spatial and seasonal variation during these seasons. We found that Jiaozhou Bay served as a net atmospheric CO(2) source in autumn (November) (2.87 mmol m(-2)d(-1)), while in winter (February) it served as a net sink (-16.22 mmol m(-2)d(-1)). PMID- 22100069 TI - Early incontinence after radical prostatectomy: a community based retrospective analysis in 911 men and implications for preoperative counseling. AB - INTRODUCTION: Radical prostatectomy (RP) is curative for localized prostatic cancer. Incontinence after RP (P-RP-I) varies widely (2% to <60%) according to the definition and quantification of incontinence, timing of evaluation, and who evaluates (physician or patient). Conservative treatments, including pelvic floor muscle training (PFMT), anal electrical stimulation (AES), lifestyle adjustment, or combination are usually recommended at first for P-RP-I. METHODS: Between January 2002 and December 2004, a total of 911 patients, median age 63 years (46 78), with different grades of P-RP-I have been retrospectively examined for perioperative risk factors and effect of rehabilitation procedures. These consecutive patients were from 67 clinics with median postoperative interval of 26 days. Incontinence was graded by Stamey classification, number of used pads and pads' consistency (dry, lightly wet, and wet). Therapeutic measures were done by team of specialists in rehabilitation, psycho-oncology, physiotherapy, internal medicine, and urology. RESULTS: Ninety-six percent of patients suffered different grades of incontinence at beginning of hospitalization. This was reported as Stamey first grade (49.4%), second grade (36.4%), and third grade (10.3%). Analysis included patients' age, body mass index (BMI), prostate volume, surgical approach, nerve sparing, pelvic lymphadenectomy, previous therapy, and catheterization time. Analysis showed age, nerve sparing, and BMI as significant risk factors for P-RP-I. Conservative therapy, including PFMT, AES, or combinations has been performed on all patients. Grade of P-RP-I showed significant improvement after 3 weeks rehabilitation period. CONCLUSION: Preoperative counseling of patients should provide them with realistic expectations for P-RP-I and motivate them to conservative therapy, as it reduces the duration and degree of urinary incontinence. PMID- 22100070 TI - Discharge patterns after radical prostatectomy in the United States of America. AB - OBJECTIVE: Discharge patterns, including prolonged length of stay (LOS) and adverse discharge disposition (ADD), are important clinical indicators of quality of care. We examined the effect of several indicators on discharge patterns after radical prostatectomy (RP). METHODS: Within the Nationwide Inpatient Sample, we focused on RPs performed between 2001 and 2007. Multivariable logistic regression analyses predicting the likelihood of prolonged LOS and ADD were performed. RESULTS: Overall, 89,883 eligible RPs were identified, yielding a weighted national estimate of 442,400 eligible RPs. The rates of prolonged LOS decreased from 28.9 in the early period (2001-2003) to 14.4% in the late period (2006-2007) (P < 0.001). Similarly, the rates of ADD decreased from 7.4 in the early period to 5.0% in the late period (P < 0.001). In multivariable analyses adjusted for clustering, both annual hospital caseload (AHC) and insurance status were independent predictors of prolonged LOS and ADD. For example, RP performed at low AHC hospitals were more frequently associated with prolonged LOS than intermediate (OR = 0.45, P < 0.001) and high (OR = 0.21, P < 0.001) AHC hospitals. Similarly, RP performed at low AHC hospitals were more frequently associated with ADD than intermediate (OR = 0.54, P < 0.001) and high (OR = 0.63, P < 0.001) AHC hospitals. CONCLUSIONS: An improving temporal trend in discharge patterns was recorded in patients undergoing RP, with significant reductions in the rates of prolonged LOS and ADD. Nonetheless, important disparities were recorded when discharge patterns were stratified according to insurance status and AHC. Specifically, shorter LOS and lower rates of ADD should be expected in patients with private insurance and/or treated at high AHC institutions. PMID- 22100071 TI - Ischemic stroke with left hemiparesis or shock should be evaluated by computed tomography for aortic dissection. AB - An 82-year-old woman with consciousness disturbance, left hemeparesis, and dysarthria was discovered at home by her family and was transported to a hospital. On arrival, she remained in a sleepy and disorientated and shock state. She complained of nausea but no chest or back pain. She obtained stable circulation after infusion. Her chest roentgen results showed widening of the mediastinum and the existence of a separation of the intimal calcification from the outer aortic soft tissue border, thus suggesting a Stanford A-type aortic dissection. Her head computed tomography depicted no signs of cerebral infarction. Because she did not complain of any pain, the possibility of acute phase aortic dissection was rejected. A permissive hypertensive therapy was initiated. Next day, she suddenly died. We diagnosed that she had died of a Stanford A-type aortic dissection based on the following facts: (1) patients presenting with stroke due to a Stanford A-type aortic dissection tend to have left hemiparesis because of malcirculation of the innominate artery and (2) a patient presenting with stroke by aortic dissection may have hypotension, which is unusual in standard stoke cases. Ischemic stroke induced by aortic dissection is not common among the patients with aortic dissection. However, given the high morbidity and mortality after misdiagnosis of aortic dissection, patients with ischemic stroke with left hemiparesis or shock should be evaluated by enhanced truncal computed tomography. PMID- 22100072 TI - Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. AB - Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjogren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development. PMID- 22100074 TI - Overexpression of DMP1 accelerates mineralization and alters cortical bone biomechanical properties in vivo. AB - Dentin matrix protein-1 (DMP1) is a key regulator of biomineralization. Here, we examine changes in structural, geometric, and material properties of cortical bone in a transgenic mouse model overexpressing DMP1. Micro-computed tomography and three-point bending were performed on 90 femora of wild type and transgenic mice at 1, 2, 4, and 6 months. Fourier transform infrared imaging was performed at 2 months. We found that the transgenic femurs were longer (p<0.01), more robust in cross-section (p<0.05), stronger (p<0.05), but had less post-yield strain and displacement (p<0.01), and higher tissue mineral density (p<0.01) than the wild type femurs at 1 and 2 months. At 2 months, the transgenic femurs also had a higher mineral-to-matrix ratio (p<0.05) and lower carbonate substitution (p<0.05) compared to wild type femurs. These findings indicate that increased mineralization caused by overexpressing DMP1 led to increased structural cortical bone properties associated with decreased ductility during the early post-natal period. PMID- 22100075 TI - On phase transformation behavior of porous Shape Memory Alloys. AB - This paper is concerned on the phase transformation mechanism of porous Shape Memory Alloys (SMAs). A unit-cell model is adopted to establish the constitutive relation for porous SMAs, the stress distributions, the phase distributions and the martensitic volume fractions for the model are then derived under both pure hydrostatic stress and uniaxial compression. Further, an example for the uniaxial response under compression for a porous Ni-Ti SMA material considering hydrostatic stress is supplied. Good agreement between the theoretical prediction of the proposed model and published experimental data is observed. PMID- 22100076 TI - Porous titanium materials with entangled wire structure for load-bearing biomedical applications. AB - A kind of porous metal-entangled titanium wire material has been investigated in terms of the pore structure (size and distribution), the strength, the elastic modulus, and the mechanical behavior under uniaxial tensile loading. Its functions and potentials for surgical application have been explained. In particular, its advantages over competitors (e.g., conventional porous titanium) have been reviewed. In the study, a group of entangled titanium wire materials with non-woven structure were fabricated by using 12-180 MPa forming pressure, which have porosity in a range of 48%-82%. The pores in the materials are irregular in shape, which have a nearly half-normal distribution in size range. The yield strength, ultimate tensile strength, and elastic modulus are 75 MPa, 108 MPa, and 1.05 GPa, respectively, when its porosity is 44.7%. The mechanical properties decrease significantly as the porosity increases. When the porosity is 57.9%, these values become 24 MPa, 47.5 MPa, and 0.33 GPa, respectively. The low elastic modulus is due to the structural flexibility of the entangled titanium wire materials. For practical reference, a group of detailed data of the porous structure and the mechanical properties are reported. This kind of material is very promising for implant applications because of their very good toughness, perfect flexibility, high strength, adequate elastic modulus, and low cost. PMID- 22100077 TI - Tunable nanomechanics of protein disulfide bonds in redox microenvironments. AB - Disulfide bonds are important chemical cross-links that control the elasticity of fibrous protein materials such as hair, feather, wool and gluten in breadmaking dough. Here we present a novel computational approach using the first-principles based ReaxFF reactive force field and demonstrate that this approach can be used to show that the fracture strength of disulfide bonds is decreased under the presence of reducing agents, due to a loss of cross-link stability controlled by the chemical microenvironment. Simulations in explicit solvents and dithiothreitol (DTT) indicate an intermediate step involving weakened elongated bonds, illustrating the tunability of the elasticity, rupture mechanism and strength of proteins. We provide a mechanistic insight into the fracture mechanism of protein disulfide bonds and illustrate the importance of the redox microenvironment, where factors such as accessibility, mechanical strain and local redox potential govern the dominating rupture mechanism and location. The method used here provides a general computational protocol for studying mechanochemical fracture of large-scale protein materials concurrently with experimental efforts. PMID- 22100078 TI - A tissue-level anisotropic criterion for brain injury based on microstructural axonal deformation. AB - Different length scales from micrometers to several decimeters play an important role in diffuse axonal injury. The kinematics at the head level result in local impairments at the cellular level. Finite element methods can be used for predicting brain injury caused by a mechanical loading of the head. Because of its oriented microstructure, the sensitivity of brain tissue to a mechanical load can be expected to be orientation dependent. However, the criteria for injury that are currently used at the tissue level in finite element head models are isotropic and therefore do not consider this orientation dependence, which might inhibit a reliable assessment of injury. In this study, an anisotropic brain injury criterion is developed that is able to describe the effects of the oriented microstructure based on micromechanical simulations. The effects of both the main axonal direction and of local deviations from this direction are accounted for. With the anisotropic criterion for brain injury, computational head models will be able to account for aspects of diffuse axonal injury at the cellular level and can therefore more reliably predict injury. PMID- 22100079 TI - Effect of microwave irradiation and water storage on the viscoelastic properties of denture base and reline acrylic resins. AB - This study evaluated the effect of microwave irradiation and water storage on the viscoelastic properties of two denture base resins (Lucitone 550-L and Vipi Wave VW) and two reline resins (Kooliner-K and Tokuyama Rebase Fast II-TR II). Eight specimens (40*10*3.3 mm) of each material were evaluated by dynamic mechanical thermal analysis (DMTA) after processing, water storage for 7 days (WS), one (MW1) and 7 cycles of microwave irradiation (MW7). For each specimen, DMTA runs were carried out within different temperature intervals. Values of storage modulus (E(')) and loss tangent (tan delta) at 37 degrees C were obtained from the first and last runs. From the last run, values of E(') at the glass transition temperature (Tg) and maximum tan delta were also recorded. Data were analyzed by a 2-way ANOVA followed by Student-Newman-Keuls test (alpha=0.05). Measurements of the inside temperature of each specimen during microwave irradiation (650 W/3 min) were conducted using a fiber optic temperature sensor. Six specimens of each material were evaluated. During microwave irradiation, all specimens reached the boiling temperature of water at approximately 130 s. From the first DMTA run, MW1 and WS significantly increased the E(') and decreased the tan delta of K at 37 degrees C (P<0.05). From the last run, the tan delta of K and TR II was significantly decreased after MW 1 (P<0.05). MW 7 decreased the tan delta of K (P<0.05). The E(') of L and VW was similar and higher than K and TR II (P<0.05). At Tg, K produced the lowest E(') and its maximum tan delta was increased after MW1 (P<0.05). The Tg mean values were arranged as: L>V W>TR II>K (P<0.05). Microwave irradiation and WS did not detrimentally affect the viscoelastic properties of the denture base and reline resins evaluated. PMID- 22100073 TI - Blood pressure loci identified with a gene-centric array. AB - Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 * 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 * 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID- 22100080 TI - Damage initiation and progression in the cartilage surface probed by nonlinear optical microscopy. AB - With increasing interest in treating osteoarthritis at its earliest stages, it has become important to understand the mechanisms by which the disease progresses across a joint. Here, second harmonic generation (SHG) microscopy, coupled with a two-dimensional spring-mass network model, was used to image and investigate the collagen meshwork architecture at the cartilage surface surrounding osteoarthritic lesions. We found that minor weakening of the collagen meshwork leads to the bundling of fibrils at the surface under normal loading. This bundling appears to be an irreversible step in the degradation process, as the stress concentrations drive the progression of damage, forming larger bundles and cracks that eventually form lesions. PMID- 22100081 TI - Variability in the elastic properties of bovine dentin at multiple length scales. AB - Various methods are used to investigate the variability in elastic properties across a population of deciduous bovine incisor root dentin samples spanning different animals, incisor types, and locations within teeth. First, measurements of elastic strains by high-energy synchrotron X-ray scattering during compressive loading of dentin specimens provided the effective modulus--the ratio of applied stress to elastic phase strain--for the two main phases of dentin (hydroxyapatite crystals and mineralized collagen fibrils), shedding light on load transfer operating at the nanoscale between collagen and mineral phases. Second, Young's moduli were measured at the macroscale by ultrasonic time-of-flight measurements. Third, thermogravimetry quantified the volume fractions of hydroxyapatite, protein and water at the macroscale. Finally, micro-Computed Tomography determined spatial variations of the mineral at the sub-millimeter scale. Statistical comparison of the above properties reveals: (i) no significant differences for dentin samples taken from different animals or different incisor types but (ii) significant differences for samples taken from the cervical or apical root sections as well as from different locations between buccal and lingual edges. PMID- 22100082 TI - Nano and micro mechanical properties of uncross-linked and cross-linked chitosan films. AB - The aim of this study is to determine the nano and micro mechanical properties for uncross-linked and cross-linked chitosan films. Specifically, we looked at nanoindentation hardness, microhardness, and elastic modulus. It is important to study the nano and microscale mechanical properties of chitosan since chitosan has been widely used for biomedical applications. Using the solvent-cast method, the chitosan films were prepared at room temperature on the cleaned glass plates. The chitosan solution was prepared by dissolving chitosan in acetic acid 1% (v/v). Tripolyphosphate (TPP) was used to create the cross-links between amine groups in chitosan and phosphate groups in TPP. In this study, atomic force microscopy was used to measure the nanoindentation hardness and surface topography of the uncross-linked and cross-linked chitosan films. Elastic modulus was then calculated from the nanoindentation results. The effective elastic modulus was determined by microhardness with some modifications to previous theories. The microhardness of the chitosan films were measured using Vicker's hardness meter under three different loads. Our results show that the microhardness and elastic modulus for cross-linked chitosan films are higher than the uncross-linked films. However, the cross-linked chitosan films show increased brittleness when compared to uncross-linked films. By increasing the load magnitude, the microhardness increases for both uncross-linked and cross-linked chitosan films. PMID- 22100083 TI - Constitutive equations for Ca2+-alginate gels. AB - Constitutive equations accounting for the coupling between chemical and mechanical phenomena are developed for the Ca(2+) alginate gel from the framework of thermodynamics of irreversible processes with internal variables. The development of the model is based on the Gibbs-Duhem relation and kinetic relations acting on generalized non-equilibrium forces. The constitutive equations are then compared to mechanical data obtained from uniaxial compressive tests at different velocities. A good agreement is observed between model and data. Furthermore, the model is able to predict the evolution of the mechanical response when the initial quantity of crosslinked Ca(2+) ions varies. PMID- 22100084 TI - The nonlinear elastic and viscoelastic passive properties of left ventricular papillary muscle of a guinea pig heart. AB - The mechanical behavior of the heart muscle tissues is the central problem in finite element simulation of the heart contraction, excitation propagation and development of an artificial heart. Nonlinear elastic and viscoelastic passive material properties of the left ventricular papillary muscle of a guinea pig heart were determined based on in-vitro precise uniaxial and relaxation tests. The nonlinear elastic behavior was modeled by a hypoelastic model and different hyperelastic strain energy functions such as Ogden and Mooney-Rivlin. Nonlinear least square fitting and constrained optimization were conducted under MATLAB and MSC.MARC in order to obtain the model material parameters. The experimental tensile data was used to get the nonlinear elastic mechanical behavior of the heart muscle. However, stress relaxation data was used to determine the relaxation behavior as well as viscosity of the tissues. Viscohyperelastic behavior was constructed by a multiplicative decomposition of a standard Ogden strain energy function, W, for instantaneous deformation and a relaxation function, R(t), in a Prony series form. The study reveals that hypoelastic and hyperelastic (Ogden) models fit the tissue mechanical behaviors well and can be safely used for heart mechanics simulation. Since the characteristic relaxation time (900 s) of heart muscle tissues is very large compared with the actual time of heart beating cycle (800 ms), the effect of viscosity can be reasonably ignored. The amount and type of experimental data has a strong effect on the Ogden parameters. The in vitro passive mechanical properties are good initial values to start running the biosimulation codes for heart mechanics. However, an optimization algorithm is developed, based on clinical intact heart measurements, to estimate and re-correct the material parameters in order to get the in vivo mechanical properties, needed for very accurate bio-simulation and for the development of new materials for the artificial heart. PMID- 22100085 TI - Porcelain monolayers and porcelain/alumina bilayers reinforced by Al2O3/GdAlO3 fibers. AB - AIM: This work tested the effect of the addition of Al(2)O(3)/GdAlO(3) longitudinal fibers in different contents to veneering porcelain of two dental all ceramic systems. METHODS: Fibers (0.5 mm diameter) obtained by the Laser Heated Pedestal Growth (LHPG) method were added to bar-shaped specimens made by veneer porcelain (monolayers) or both the veneer and the core ceramic (bilayers) of two all-ceramic systems: In-Ceram Alumina-glass infiltrated alumina composite (GIA) and In-Ceram 2000 AL Cubes-alumina polycrystal (AP) (VITA Zahnfabrik). The longitudinal fibers were added to veneering porcelain (VM7) in two different proportions: 10 or 17 vol%. The bars were divided into nine experimental conditions (n=10) according to material used: VM7 porcelain monolayers, VM7/GIA, VM7/AP; and according to the amount of fibers within the porcelain layer: no fibers, 10 vol% or 17 vol%. After grinding and polishing the specimens were submitted to a three point bending test (crosshead speed = 0.5 mm/min) with porcelain positioned at tensile side. Data were analyzed by means of one-way ANOVA and a Tukey's test (alpha=5%). Scanning electronic microscopy (SEM) was conducted for fractographic analysis. RESULTS: Regarding the groups without fiber addition, VM7/AP showed the highest flexural strength (MPa), followed by VM7/GIA and VM7 monolayers. The addition of fibers led to a numerical increase in flexural strength for all groups. For VM7/GIA bilayers the addition of 17 vol% of fibers resulted in a significant 48% increase in the flexural strength compared to the control group. Fractographic analysis revealed that the crack initiation site was in porcelain at the tensile surface. Cracks also propagated between fibers before heading for the alumina core. CONCLUSIONS: The addition of 17 vol% of Al(2)O(3)/GdAlO(3) longitudinal fibers to porcelain/glass infiltrated alumina bilayers significantly improved its flexural strength. 10 vol% or 17 vol% of fibers inclusion increased the flexural strength for all groups. PMID- 22100086 TI - 3D constitutive modeling of the biaxial mechanical response of intact and layer dissected human carotid arteries. AB - Human arteries with non-atherosclerotic intimal thickening consist of three distinct layers: adventitia, media and intima. From a series of axial extension and inflation tests on intact and layer-dissected human carotid arteries (adventitia and media-intima composite), a 3D structurally-based strain-energy function (SEF) is calibrated, and a set of five material parameters is identified which is not yet available in the literature. The zero-stress states of the artery tubes investigated are considered in the calibration process, and the related kinematics for the finite deformation of the individual continuum are described in detail. The SEF employed is capable of describing the different mechanical properties of the intact and layer-dissected tissue tubes (arterial segments) investigated at different pressure domains and axial stretches. The correlation coefficients and error measures determined indicate good correlation between the model and the experimental data for all tested tubes. Mean values of each individual material parameter provide a kind of 'master model' that characterizes the mean response of all mechanical data obtained from the human carotid arteries. The material parameters and the 3D constitutive model serve as a foundation for finite element simulations, and hence the analysis of more complex patient-specific boundary-value problems in the human carotid physiology and pathology. PMID- 22100087 TI - Effect of vacuum-treatment on deformation properties of PMMA bone cement. AB - Deformation behavior of polymethyl methacrylate (PMMA) bone cement is explored using microindentation. Two types of PMMA bone cement were prepared. Vacuum treated samples were subjected to the degassing of the material under vacuum of 270 mbar for 35 s, followed by the second degassing under vacuum of 255 mbar for 35 s. Air-cured samples were left in ambient air to cool down and harden. All samples were left to age for 6 months before the test. The samples were then subjected to the indentation fatigue test mode, using sharp Vickers indenter. First, loading segment rise time was varied in order to establish time-dependent behavior of the samples. Experimental data showed that viscous part of the deformation can be neglected under the observed test conditions. The second series of microindentation tests were realized with variation of number of cycles and indentation hardness and modulus were obtained. Approximate hardness was also calculated using analysis of residual impression area. Porosity characteristics were analyzed using CellC software. Scanning electron microscopy (SEM) analysis showed that air-cured bone cement exhibited significant number of large voids made of aggregated PMMA beads accompanied by particles of the radiopaque agent, while vacuum treated samples had homogeneous structure. Air-cured samples exhibited variable hardness and elasticity modulus throughout the material. They also had lower hardness values (approximately 65-100 MPa) than the vacuum treated cement (approximately 170 MPa). Porosity of 5.1% was obtained for vacuum treated cement and 16.8% for air-cured cement. Extensive plastic deformation, microcracks and craze whitening were produced during indentation of air-cured bone cement, whereas vacuum treated cement exhibited no cracks and no plastic deformation. PMID- 22100088 TI - Characterization of the anisotropic mechanical properties of excised human skin. AB - The mechanical properties of skin are important for a number of applications including surgery, dermatology, impact biomechanics and forensic science. In this study, we have investigated the influence of location and orientation on the deformation characteristics of 56 samples of excised human skin. Uniaxial tensile tests were carried out at a strain rate of 0.012 s(-1) on skin from the back. Digital Image Correlation was used for 2D strain measurement and a histological examination of the dermis was also performed. The mean ultimate tensile strength (UTS) was 21.6+/-8.4 MPa, the mean failure strain 54%+/-17%, the mean initial slope 1.18+/-0.88 MPa, the mean elastic modulus 83.3+/-34.9 MPa and the mean strain energy was 3.6+/-1.6 MJ/m(3). A multivariate analysis of variance has shown that these mechanical properties of skin are dependent upon the orientation of the Langer lines (P<0.0001-P=0.046). The location of specimens on the back was also found to have a significant effect on the UTS (P=0.0002), the elastic modulus (P=0.001) and the strain energy (P=0.0052). The histological investigation concluded that there is a definite correlation between the orientation of the Langer lines and the preferred orientation of collagen fibres in the dermis (P<0.001). The data obtained in this study will provide essential information for those wishing to model the skin using a structural constitutive model. PMID- 22100089 TI - Influence of SEM vacuum on bone micromechanics using in situ AFM. AB - The mechanical properties of rat bone at micron length scales have been evaluated as a function of environmental conditions using an in situ atomic force microscope (AFM) setup while observing using scanning electron microscopy (SEM). Focused ion beam fabricated rat bone cantilever samples were tested in both low and high vacuum conditions in the SEM as well as wet in air using the AFM to measure their elastic modulus. The elastic modulus of rat bone at micron length scales is shown to be independent of the environmental testing conditions and indicates water is bound to bone material even under relatively high vacuum conditions. Our work therefore shows how in situ mechanical testing of bone while observing using high resolution SEM can provide results similar to testing wet in air. PMID- 22100090 TI - Mechanistic modeling of a nanoscratch test for determination of in situ toughness of bone. AB - The objective of this study was to develop a nanoscratch technique that can be used to measure the in situ toughness of bone at micro/nanostructural levels. Among the currently possible techniques, the surface scratch test may be conducted on very small regions, thus exhibiting a potential in determining the in situ failure behavior of materials. To adapt such a technique for assessing bone toughness at the micro/nanostructural levels and for limited stocks in small animal bone models (e.g. zebra finish and mice), a simple but reasonably accurate mechanistic model for the nanoscratch test was developed in this study. This model was based on the assumption that the removal energy of the tissue required during the nanoscratch test is the manifestation of the in situ toughness and the shear flow stress during the removal process is a measure of the in situ strength of bone. In addition, the experimental methodologies were developed to determine the elastic recovery force and frictional coefficients between the scratch tip and bone specimens that are required by the model. Finally, the efficacy of the nanoscratch technique was verified by testing bone samples from control (wild type), mild, and severe osteogenesis imperfecta (OI) mice, which have a distinct degree of brittleness. The experimental results indicated that the nanoscratch test could sensitively detect the in situ brittleness and strength of bone from the animal models. PMID- 22100091 TI - Dynamic mechanical analysis of collagen fibrils at the nanoscale. AB - Low frequency (0.1-2 Hz) dynamic mechanical analysis on individual type I collagen fibrils has been carried out using atomic force microscopy (AFM). Both the elastic (static) and viscous (dynamic) responses are correlated to the characteristic axial banding, gap and overlap regions. The elastic modulus (~5 GPa) on the overlap region, where the density of tropocollagen is highest, is 160% that of the gap region. The amount of dissipation on each region is frequency dependent, with the gap region dissipating most energy at the lowest frequencies (0.1 Hz) and crossing over with the overlap region at ~0.75 Hz. This may reflect an ability of collagen fibrils to absorb energy over a range of frequencies using more than one mechanism, which is suggested as an evolutionary driver for the mechanical role of type I collagen in connective tissues and organs. PMID- 22100092 TI - Improving the mechanical properties of chitosan-based heart valve scaffolds using chitosan fibers. AB - Chitosan is being widely studied for tissue engineering applications due to its biocompatibility and biodegradability. However, its use in load-bearing applications is limited due to low mechanical properties. In this study, we investigated the effectiveness of a chitosan fiber reinforcement approach to enhancing the mechanical properties of chitosan scaffolds. Chitosan fibers were fabricated using a solution extrusion and neutralization method and incorporated into porous chitosan scaffolds. The effects of fiber/scaffold mass ratio, fiber mechanical properties and fiber length on scaffold mechanical properties were studied. The results showed that incorporating fibers improved scaffold strength and stiffness in proportion to the fiber/scaffold mass ratio. A fiber-reinforced, heart valve scaffold achieved leaflet tensile strength values of 220+/-17 kPa, comparable to the radial values of human pulmonary valve leaflets. Additionally, the effects of 2 mm fibers were found to be up to threefold greater than 10 mm fibers at identical mass ratios. Heparin crosslinking of fibers produced a reduction in fiber strength, and thus failed to produce additional improvements to fiber-reinforced scaffold properties. Despite this reduction in fiber strength, heparin-modified fibers still improved the mechanical properties of reinforced scaffolds, but to a lesser extent than unmodified fibers. The results demonstrate that chitosan fiber reinforcement can be used to achieve porous chitosan scaffold strength approaching that of tissue, and that fiber length and mechanical properties are important parameters in defining the degree of mechanical improvement. PMID- 22100093 TI - Corrosion fatigue behavior of a biocompatible ultrafine-grained niobium alloy in simulated body fluid. AB - The present study reports on the corrosion fatigue behavior of ultrafine-grained (UFG) Niobium 2 wt-% Zirconium (NbZr) alloy in simulated body fluid (SBF). The alloy was processed using multipass equal channel angular processing at room temperature, resulting in a favorable combination of high strength and ductility along with superior biocompatibility and excellent corrosion resistance. Electrochemical measurements revealed stable passive behavior in SBF saline solutions, similar to conventional Ti-6Al-4V alloy. High-cycle fatigue tests showed no alteration in the crack initiation behavior due to the SBF environment, and an absence of pitting and corrosion products. More severe test conditions were obtained in the fatigue crack growth experiments in saline environments. Crack growth rates in UFG NbZr were marginally increased in SBF as compared to laboratory air at a constant test frequency of 20 Hz. Upon a 100 fold decrease in the test frequency, slightly higher crack growth rates were observed only in the near-threshold region. Such excellent corrosion and corrosion fatigue properties of UFG NbZr recommend it as an attractive new material for biomedical implants. PMID- 22100094 TI - Fibre-matrix interaction in the human annulus fibrosus. AB - Although the mechanical behaviour of the human annulus fibrosus has been extensively studied, the interaction between the collagen fibres and the ground matrix has not been well understood and is therefore ignored by most constitutive models. The objective of this study is to identify the significance of the fibre matrix interaction in the human annulus fibrosus by careful investigation of the experimental data, the theoretical constitutive models, and the numerical simulation results in the literature. Based on the experimental results from biaxial and uniaxial tests, it is shown that the mechanical behaviour of the matrix can be well simulated by an incompressible neo-Hookean type model, but the effective stiffness of the matrix depends on fibre stretch ratio, which can only be explained by fibre-matrix interaction. Furthermore, we find that this interaction takes place anisotropically between the matrix and the fibres distributed in different proportions in different directions. The dependence of the tangent stiffness of the matrix on the first invariant of the deformation tensor can also be explained by this fibre orientation dispersion. PMID- 22100095 TI - Macro-, micro- and ultrastructural investigation of how degeneration influences the response of cartilage to loading. AB - Articular cartilage functions as a load-bearing tissue by virtue of a functional coupling between its hydrated proteoglycan component and its zonally differentiated fibrillar network. How degeneration influences this relationship at the macro-, micro-, and ultrastructural levels is investigated in this study. Healthy bovine patellae (N=9) and patellae exhibiting varying degrees of degeneration (N=16) formed the basis of the study. Cartilage-on-bone blocks obtained from each patella were subjected to creep loading under a nominal stress of 4.5 MPa via a rectangular planar indenter which incorporated a narrow channel relief space to create a defined region where the cartilage would not be directly loaded. Following the attainment of creep equilibrium each sample was chemically fixed while under load so as to preserve the deformed state of the cartilage matrix. The structural response of the matrix was then analysed using differential interference contrast (DIC) optical microscopy and scanning electron microscopy (SEM). The morphology of the cartilage matrix extruded into the channel relief region was dramatically influenced by the severity of degeneration. The microscopic and ultrastructural characteristics of the extruded matrix showed that the load response of bulk cartilage is determined primarily by the microstructural integrity of the strain-limiting tangential layer and the nano-level interconnectivity of the fibrillar network. In conclusion, this study showed that three mechanically significant structural features of cartilage are important: (1) the strain limiting surface layer; (2) the micro-level boundaries in its zonally differentiated structure, and (3) the extent of fibrillar interconnectivity. Degeneration degrades or destroys the articular surface and 'destructures' the fibrillar network such that the latter functions less effectively as a proteoglycan entrapment system. PMID- 22100096 TI - A numerical model for investigating the mechanics of calcaneal fat pad region. AB - The present paper pertains to the definition of a numerical model of the calcaneal fat pad region, considering a structure composed of adipose and connective tissues organized in fibrous septae and adipose chambers. The mechanical response is strongly influenced by the structural conformation, as the dimension of adipose chambers, the thickness of connective septae walls and the mechanical properties of the different soft tissues. In order to define the constitutive formulation of adipose tissues, experimental data from pig specimens are considered, according to the functional similarity, while the mechanical response of connective tissue septae is assumed with regard to the mechanical behaviour that characterize ligaments. Different numerical models are provided accounting for the variation of chambers dimensions, septae wall thickness and tissues characteristics. The spiral angles of collagen fibres within the septae influence the capability of the structure to withstand the bulging of chambers. The analysis considers different orientation of the fibres. The response of calcaneal fat pad region is evaluated in comparison with experimental data from unconfined compression tests. The present work provides a preliminary approach to enhance the correlation between the structural conformation and tissues mechanical properties towards the biomechanical response of overall heel pad region. PMID- 22100097 TI - A molecular dynamics study of Young's modulus change of semi-crystalline polymers during degradation by chain scissions. AB - This paper presents a molecular dynamics study on the change in Young's modulus of semi-crystalline polymers during degradation by chain scissions, which is relevant to the study of mechanical properties of biodegrading polymers. Using a simple polymer model whose structural and mechanical properties are similar to that of a commonly used biodegrading polymer poly(glycolic acid), we combine molecular dynamics and Monte Carlo to model a system of two polymer crystals separated by an amorphous region between them. The polymer chains in the amorphous region are cut randomly to mimic hydrolysis chain scissions. In a series of virtual tensile tests, the systems with various numbers of chain scissions are subjected to a unidirectional deformation. We find that at temperatures below the glass transition temperature of the model polymer, the Young's modulus of the system reduces quickly with the number of chain scissions, while at temperatures above the glass transition temperature, the Young's modulus reduction lags behind the polymer chain scissions. This observation supports the entropy-spring model of amorphous polymers proposed by Wang et al., which suggests that Young's modulus above the glass transition temperature is dominated by the internal energy of the system, while below the glass transition temperature it is dominated by the entropy of the amorphous phase. The numerical study therefore provides a molecular understanding of the widely observed behaviours of semi-crystalline biodegradable polymers. PMID- 22100098 TI - On the effect of marrow in the mechanical behavior and crush response of trabecular bone. AB - The present paper focuses on the mechanical behavior analysis of bones at mesoscopic scale, paying a special attention to the trabecular bone and the bone marrow filling the porosities. Uni-axial quasi-static compression tests under unconfined conditions have been performed to identify the mechanical behavior of 46 trabecular bone samples. The bone marrow for 22 samples has been preserved to analyze the fluid flow effects on the crushing response. Although deformation patterns do not differ significantly, the average crush behavior of the trabecular bone shows an unexpected decrease of the mechanical properties when the marrow is kept in the sample (26% for the elastic modulus (E(a)), 38% for the maximum compressive stress (sigma(max)) and 33% for the average stress (sigma(mean))). An explanation is given by analyzing the contribution of the bone marrow viscosity which smooths the mechanical response. A numerical analysis on an idealized trabecula confirms that the marrow induces transverse pressure and extra local stress on trabeculae during its flow, causing the premature collapse of the trabecular network. PMID- 22100099 TI - The effect of the addition of hydroxyapatite graft substitutes upon the hoop strain and subsequent subsidence of a femoral model during impaction bone grafting. AB - Impaction bone grafting using morcellised allograft can successfully restore bone stock in revision surgery. However, concerns exist regarding supply of bone and transmission of infection. Bone-graft extenders, such as tricalcium phosphate (TCP) and hydroxyapatite (HA), are used to minimise the use of donor bone. However, concerns exist around a reported increased risk of femoral fracture during impaction bone grafting with a 1:1 mixture of TCP/HA and morcellised bone graft (MBG) during impaction grafting in human cadaveric femora. Using a sawbones model, it was evaluated whether there was increased femoral cortical strain with a HA:MBG mixture during impaction grafting compared to MBG impacted at the same and a greater force. Subsequently the subsidence behaviour of the different graft mixes was compared by using a loaded femoral stem in an endurance test. It was demonstrated that the femora with the MBG:HA graft had greater cortical hoop stresses but improved subsidence behaviour compared to a graft composed of pure MBG impacted at the same force. PMID- 22100100 TI - Fracture susceptibility of worn teeth. AB - An experimental simulation study is made to determine the effects of occlusal wear on the capacity of teeth to resist fracture. Tests are carried out on model dome structures, using glass shells to represent enamel and epoxy filler to represent dentin. The top of the domes are ground and polished to produce flat surfaces of prescribed depths relative to shell thickness. The worn surfaces are then loaded axially with a hard sphere, or a hard or soft flat indenter, to represent extremes of food contacts. The loads required to drive longitudinal cracks around the side walls of the enamel to failure are measured as a function of relative wear depth. It is shown that increased wear can inhibit or enhance load-bearing capacity, depending on the nature of the contact. The results are discussed in the context of biological evolutionary pressures. PMID- 22100101 TI - Long-term anisotropic mechanical response of surgical meshes used to repair abdominal wall defects. AB - Routine hernia repair surgery involves the implant of synthetic mesh. However, this type of procedure may give rise to pain and bowel incarceration and strangulation, causing considerable patient disability. The purpose of this study was to compare the long-term behaviour of three commercial meshes used to repair the partially herniated abdomen in New Zealand White rabbits: the heavyweight (HW) mesh, Surgipro((r)) and lightweight (LW) mesh, Optilene((r)), both made of polypropylene (PP), and a mediumweight (MW) mesh, Infinit((r)), made of polytetrafluoroethylene (PTFE). The implanted meshes were mechanical and histological assessed at 14, 90 and 180 days post-implant. This behaviour was compared to the anisotropic mechanical behaviour of the unrepaired abdominal wall in control non-operated rabbits. Both uniaxial mechanical tests conducted in craneo-caudal and perpendicular directions and histological findings revealed substantial collagen growth over the repaired hernial defects causing stiffness in the repair zone, and thus a change in the original properties of the meshes. The mechanical behaviour of the healthy tissue in the craneo-caudal direction was not reproduced by any of the implanted meshes after 14 days or 90 days of implant, whereas in the perpendicular direction, SUR and OPT achieved similar behaviour. From a mechanical standpoint, the anisotropic PP-lightweight meshes may be considered a good choice in the long run, which correlates with the structure of the regenerated tissue. PMID- 22100102 TI - Computational comparison of the bending behavior of aortic stent-grafts. AB - Secondary interventions after endovascular repair of abdominal aortic aneurysms are frequent because stent-graft (SG) related complications may occur (mainly endoleak and SG thrombosis). Complications have been related to insufficient SG flexibility, especially when devices are deployed in tortuous arteries. Little is known on the relationship between SG design and flexibility. Therefore, the aim of this study was to simulate numerically the bending of two manufactured SGs (Aorfix--Lombard Medical (A) and Zenith--Cook Medical Europe (Z)) using finite element analysis (FEA). Global SG behavior was studied by assessing stent spacing variation and cross-section deformation. Four criteria were defined to compare flexibility of SGs: maximal luminal reduction rate, torque required for bending, maximal membrane strains in graft and maximal Von Mises stress in stents. For angulation greater than 60 degrees , values of these four criteria were lower with A-SG, compared to Z-SG. In conclusion, A-SG was more flexible than Z-SG according to FEA. A-SG may decrease the incidence of complications in the setting of tortuous aorto-iliac aneurysms. Our numerical model could be used to assess flexibility of further manufactured as well as newly designed SGs. PMID- 22100103 TI - In silico evaluation of stress distribution after vertebral body augmentation with conventional acrylics, composites and glass polyalkenoate cements. AB - There exists clinical evidence of fractures in adjacent vertebrae subsequent to vertebral augmentation procedures, such as vertebroplasty (VP) and kyphoplasty (KP). A potential contributory factor to such fractures may be the excessive mismatch of mechanical properties between contemporary bone cements (i.e. polymethyl methacrylate (PMMA) and bisphenol-a-glycidyl dimethacrylate (BIS-GMA)) and bone. Aluminum-free glass polyalkenoate cements (GPCs) present an interesting alternative to conventional bone cements. GPCs adhere to the philosophy that implant materials should have mechanical characteristics similar to those of the bone, and also offer chemical adhesion and intrinsic bioactivity. However, their influence on the loading patterns of augmented vertebrae (as compared with conventional bone cements) is not available in the literature. The present work investigates how the moduli of PMMA, BIS-GMA and GPC implants affect the stress distribution within a single, augmented vertebra, in both healthy and osteoporotic states. Using a finite element model of the L4 vertebra derived from computed tomography data, with simulated augmentation, it was found that, as cement stiffness increased, stress was redistributed from the cortical and trabecular bone to the cement implant. The GPC implant exhibited the least effect on stress redistribution in both the healthy and osteoporotic models compared to its acrylic counterparts. The significance of this work is that, under simulated physiological loading conditions, aluminum-free GPCs exhibit stress distribution throughout the vertebral body similar to that of the healthy bone. In comparison to conventional augmentation materials, the use of aluminum-free GPCs in VP and KP may help to ameliorate the clinical complication of adjacent vertebral body compression fractures. PMID- 22100104 TI - Computation methods affect the reported values of in vivo human tendon stiffness. AB - PURPOSE: Scientific validity is questionable when findings from studies cannot be used to make sense of physiological and/or biomechanical data. In particular, is the case of in vivo determination of tendon stiffness (K). Here, approaches range from taking the gradient (a) throughout the data range of resting to Maximal Voluntary Contraction (MVC), (b) tangents at individual data points, (c) linear regressions at discrete force levels ((b) and (c) being 'reference standard' as they utilise a number of distinct regions of the Force-Elongation Relationship (FER)). STUDY DESIGN: A mathematical model approach is used to develop simple curvilinear FERs as seen when determining tendon mechanical properties, to allow variable calculations of K. OBJECTIVES: To compare variability in K estimates using the various approaches currently seen in the literature. METHODS: Three FER models were developed, representing low, medium and high K. Values of K were determined and compared using the approaches reported in the literature to estimate the magnitude of the difference between values attained of K. RESULTS: Through mathematical modelling, we demonstrate that the impact on the recorded value of K is substantial: relative to the reference standard methods, computation methods published range from underestimating K by 26% to overestimating it by 51%. CONCLUSION: This modelling helps by providing a 'scaling factor' through which the between studies variability associated with computational methods differences is minimised. This is especially important where researchers or clinicians require values which are consistent in the context of establishing the 'true' tendon mechanical properties to inform models or materials based on the biological properties of the human tendon. PMID- 22100105 TI - Meningococcemia presenting as acute painful mononeuritis multiplex. PMID- 22100106 TI - Multifocal lateral and fourth ventricular B-cell primary CNS lymphoma. PMID- 22100107 TI - Atypical cystic meningiomas arising from the trigeminal nerve: surgical and neuroradiological consideration. PMID- 22100108 TI - The validity of an assessment of maximum angular velocity of knee extension (KE) using a gyroscope. AB - Although it is more important to assess the muscular power of the lower extremities than the strength, no simplified method for doing so has been found. The aim of this study was to assess the validity of the assessment of the angular velocity of KE using a gyroscope. Participants included 105 community-dwelling older people (55 women, 50 men, age +/- standard deviation (SD) 75+/-5.3). Pearson correlation coefficients and Spearman rank-correlation coefficients were used to examine the relationships between the angular velocity of KE and functional performance measurements, a self-efficacy scale and health-related quality of life (HRQOL). The data from the gyroscope were significantly correlated with some physical functions such as muscle strength (r=0.304, p<0.01), and walking velocity (r=0.543, p<0.001). In addition, the joint angular velocity was significantly correlated with self-efficacy (r=0.219-0.329, p<0.01 0.05) and HRQOL (r=0.207-0.359, p<0.01-0.05). The absolute value of the correlation coefficient of angular velocity tended to be greater than that of the muscle strength for mobility functions such as walking velocity and the timed-up and-go (TUG) test. In conclusion, it was found that the assessment of the angular velocity of the knee joint using a gyroscope could be a feasible and meaningful measurement in the geriatrics field. PMID- 22100109 TI - Comparison of a combination of upper extremity performance measures and usual gait speed alone for discriminating upper extremity functional limitation and disability in older women. AB - Although usual gait speed (UGS) is considered an indicator of overall well-being, it is unclear whether upper extremity performance (UEP) measures provide a similar, additive contribution to functional status. We aimed to identify whether combining UEP measures can more accurately discriminate upper extremity functional limitation (UE limitation) and disability compared to UGS. We conducted a cross-sectional analysis on data from 322 community-dwelling older women, aged 65-96 years. Trained testers assessed UGS, and hand-grip strength (GRIP), functional reach (FR), back scratch, manipulating pegs (PEG), and moving beans with chopsticks as UEP measures. We assessed three functional statuses: UE limitation, activities of daily living (ADLs) and instrumental ADLs (IADLs) disabilities using self-reported questionnaires. Areas under the receiver operating characteristic curves (AUCs) were used to compare the discriminating power of UGS, with the individual and combined UEP measures for each status. Among UEP measures, only GRIP (AUC=0.68 for UE limitation, 0.81 for IADLs disability, and 0.84 for ADLs disability) could accurately discriminate each status as well as UGS (AUC=0.65, 0.83, and 0.91, respectively). Furthermore, UGS alone could discriminate UE limitation almost as well as the combination of GRIP, PEG, and FR (AUC=0.70). Combining other UEP measures did not help discriminate further. There were few advantages to combining UEP measures, and UGS or GRIP alone may suffice for assessing UE limitation and disability. However, the UGS should be the test of first choice, certainly more than GRIP, in routine assessment of functional limitation and disability, including UE limitation. PMID- 22100110 TI - Assessment of vulnerable older adults' physical function according to the Japanese Long-Term Care Insurance (LTCI) system and Fried's criteria for frailty syndrome. AB - This study aimed to evaluate the physical frailty status of vulnerable older adults as classified in the Japanese LTCI system and to compare this with Fried's definition. A total of 444 older adults were classified based on the LTCI system as independent, vulnerable, or dependent, and 400 of these participants also fit Fried's criteria for not frail, pre-frail or frail. We evaluated their physical function with a 12 item physical function test. We derived a physical function score (PFS) from these 12 items and a principal component analysis was used to make comparisons. The receiver operating characteristic (ROC) curve analysis was performed to identify the sensitivity and specificity of the PFS cut-off points to distinguish the dependent category from the other categories. We found significant differences and a hierarchical order for the PFSs among the three groups of the LTCI system (the independent, 0.41 +/- 0.54; the vulnerable, -0.40 +/- 0.76; and the dependent, -1.49 +/- 0.73) and of Fried's definition (not frail, 0.50 +/- 0.51; pre frail, -0.11 +/- 0.63; and frail, -1.25 +/- 0.98). The optimal cut-off value (OCV) was -0.593. This study showed that the range of physical function of people considered frail category (pre-frail, vulnerable, and frail) is wide and overlapping. That is, the physical function of vulnerable older adults is worse than the pre-frail, but better than the frail. To better recognize older adults in need of greater support, the vulnerable should also receive assessment of their frailty status according to Fried's definition. PMID- 22100112 TI - Enteric neuromuscular pathology update. AB - The recent development of consensus guidelines for the preparation and staining of tissues, the publication of the London Classification, and reviews of what is normal in the enteric neuromusculature have been significant steps forward in this field. Increased accessibility to full-thickness biopsies of the bowel wall facilitated by advances in laparoscopic surgery have also played a part in making the decision to ask for a tissue diagnosis easier. Better antibodies for immunohistochemistry and a better understanding of disease processes at work, such as those seen in filamin mutations, all help inform the range of information that can be gleaned from what is usually a very limited sample. Clinical phenotyping remains difficult in many patients, but the availability of specialist pathologic review and the standardization of staining between laboratories are leading to better defined histologic phenotypes, that inform, in turn, possible biological processes at work in these patients. In many instances, a diagnosis may come to light only after some time, and the retention of pathologic samples in paraffin wax, as is standard practice in most laboratories, is of great value in reassessing samples, often after many years, in the light of new advances. The highest quality information, and the best answer for the patient, is, as ever, achieved by close working relationships and excellent communication between clinicians and pathologists. PMID- 22100111 TI - Analyzing conformational changes in the transport cycle of EmrE. AB - The small multidrug resistance transporters represent a unique model system for studying the mechanism of secondary active transport and membrane protein evolution. However, this seemingly simple protein has been highly controversial. Recent studies have provided experimental evidence that EmrE exists as an asymmetric dimer that exchanges between identical inward-facing and outward facing states. Re-examination of the published literature in light of these findings fills in many details of the microscopic steps in the transport cycle. Future work will need to examine how the symmetry observed in vitro affects EmrE function in the asymmetric environment of its native Escherichia coli membrane. PMID- 22100113 TI - A 21st century look at the spectrum of gastrointestinal motility disorders. What is dysmotility; what is functional? AB - Taken together, the above examples indicate that physiology-based diagnosis has a substantial overlap with symptom-based diagnosis. Neither symptomatic treatment nor therapy aimed at restoring normal physiology has had much success. It is still uncertain if measurement of physiologic parameters facilitates the doctor patient relationship, whether results are abnormal or normal. However, the addition of physiology parameters to the evaluation of therapeutic interventions aimed at symptom reduction in FGIDs can possibly facilitate the identification of subgroups with a higher probability of treatment success. Unfortunately, our experience from clinical trials in this area is that physiology testing usually disappears as a new drug moves from phase II to phase III trials. In the ideal situation, the development of measurement methods with better availability and standardization, like different ingestible capsules, will help us to merge physiology and symptoms regarding both diagnosis and treatment evaluation. PMID- 22100114 TI - Gastrointestinal dysmotility: clinical consequences and management of the critically ill patient. AB - Gastrointestinal dysmotility is a common feature of critical illness, with a number of significant implications that include malnutrition secondary to reduced feed tolerance and absorption, reflux and aspiration resulting in reduced lung function and ventilator-associated pneumonia, bacterial overgrowth and possible translocation causing nosocomial sepsis. Prokinetic agent administration can improve gastric emptying and caloric delivery, but its effect on nutrient absorption and clinical outcomes is, as yet, unclear. Postpyloric delivery of nutrition has not yet been demonstrated to increase caloric intake or improve clinical outcomes. PMID- 22100115 TI - Motility disorders in the patient with neurologic disease. AB - Gastrointestinal symptoms are common in the patient with chronic neurologic disease and may loom large in terms of impact on quality of life and on nutrition and mobility. A knowledge of the range of gastrointestinal disorders associated with a given neurologic disease, together with an understanding of the risks and benefits of various therapeutic options and approaches, should aid gastroenterologists in their efforts to contribute to the care of these patients. In most instances a multidisciplinary team (neurologist/neurosurgeon, gastroenterologist, nutritionist, therapist, specialist nurse) aware of the wishes and needs of the family and their carers and mindful of the nature and the natural history of the underlying disease process are best placed to assess and manage these problems. PMID- 22100116 TI - Motility problems in the intellectually challenged child, adolescent, and young adult. AB - Gastrointestinal (GI) motility problems represent an important cause of morbidity and sometimes mortality in patients affected by developmental disorders. This article describes motility disorders in Down syndrome, cerebral palsy, familial dysautonomia, and Williams syndrome. These problems do not often receive appropriate attention, either because priority is given to other medical aspects of the disorder, or because of the inability of affected children to communicate their symptoms. A better approach to the diagnosis and treatment of GI disorders is required to improve quality of life and minimize morbidity and mortality among patients with developmental disorders. PMID- 22100117 TI - Paraneoplastic gastrointestinal dysmotility: when to consider and how to diagnose. AB - In this review of dysmotility in cancer patients, we have focused on paraneoplastic GI dysmotility as it provides an excellent example of how derangements of the neuromuscular apparatus of the gut can affect GI motility. A high index of clinical suspicion, together with serologic evaluation using a panel of autoantibodies in selected patients, is important in ensuring the early diagnosis of paraneoplastic GI dysmotility and may help guide management. Although it remains unproved that paraneoplastic antibodies are pathogenic, they are useful diagnostic markers. A better understanding of the pathogenesis of these disorders, including the role of paraneoplastic antibodies, will, hopefully, lead to earlier diagnosis and improved adjunctive, immunology-based treatments. Furthermore, even though successful treatment of the underlying cancer may not lead to reversal of the GI dysmotility, the recognition of a paraneoplastic syndrome may lead to early cancer diagnosis and a better chance of successful treatment of the cancer and overall survival. Although rare, it is imperative that clinicians be aware of the association between malignancy and GI dysmotility so that they know when to investigate for an underlying malignancy. PMID- 22100118 TI - Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. AB - CIPO is the very "tip of the iceberg" of functional gastrointestinal disorders, being a rare and frequently misdiagnosed condition characterized by an overall poor outcome. Diagnosis should be based on clinical features, natural history and radiologic findings. There is no cure for CIPO and management strategies include a wide array of nutritional, pharmacologic, and surgical options which are directed to minimize malnutrition, promote gut motility and reduce complications of stasis (ie, bacterial overgrowth). Pain may become so severe to necessitate major analgesic drugs. Underlying causes of secondary CIPO should be thoroughly investigated and, if detected, treated accordingly. Surgery should be indicated only in a highly selected, well characterized subset of patients, while isolated intestinal or multivisceral transplantation is a rescue therapy only in those patients with intestinal failure unsuitable for or unable to continue with TPN/HPN. Future perspectives in CIPO will be directed toward an accurate genomic/proteomic phenotying of these rare, challenging patients. Unveiling causative mechanisms of neuro-ICC-muscular abnormalities will pave the way for targeted therapeutic options for patients with CIPO. PMID- 22100119 TI - Postoperative problems 2011: fundoplication and obesity surgery. AB - Although the surgical treatment of both GERD and obesity is very successful, these procedures have a significant impact on the physiology and function of the proximal GI tract. With the increasing prevalence of both GERD and obesity, more and more patients present at the motility outpatient clinic with symptoms related to surgical interventions for these medical problems. In this review, we describe the main complications following antireflux surgery: dysphagia, gas bloat syndrome, recurrent (persistent) GERD symptoms, and dyspeptic symptoms. The most common motility-related complications of obesity surgery are dumping syndrome and esophageal dysmotility. PMID- 22100120 TI - Challenges in the swallowing mechanism: nonobstructive dysphagia in the era of high-resolution manometry and impedance. AB - Esophageal high-resolution manometry (HRM) improves the management of patients with nonobstructive dysphagia. It has increased the diagnostic yield for detecting achalasia and defined three clinically relevant achalasia subtypes. Esophagogastric junction (EGJ) outflow obstruction, defined as an impaired EGJ relaxation in association with some preserved peristalsis, might also represent an achalasia variant in some cases. Using the concept of distal latency, the criteria for defining distal esophageal spasm, have been revised as the occurrence of premature distal contractions. Finally, the combination of HRM and impedance monitoring allows for a functional definition of weak peristalsis associated with incomplete bolus transit. PMID- 22100121 TI - Difficult defecation: difficult problem assessment and management; what really helps? AB - Difficult defecation is a common and perhaps underrecognized cause of chronic constipation. While the history and a careful digital rectal examination are very useful for diagnosing defecatory disorders, the diagnosis needs to be confirmed by anorectal tests. Anorectal manometry and a rectal balloon expulsion test generally suffice to diagnose defecatory disorders; barium or MR defecography may necessary in selected cases. Colonic transit is normal or slow in patients with defecatory disorders. Pelvic floor retraining by biofeedback therapy is superior to laxatives for managing defecatory disorders. PMID- 22100122 TI - Nutritional support in the severely compromised motility patient: when and how? AB - The management of CIPO remains difficult and requires a multidisciplinary approach. In adult patients with CIPO on HPN, the 10-year survival rate was 68%. Long-term HPN dependence does not seem to be associated with a significant increase in mortality and morbidity. HPN could be a safe and efficient approach to the management of intestinal failure caused by CIPO, with restoring oral intake and lowering hospitalization frequency as major goals of treatment. PMID- 22100123 TI - The motility consultation. PMID- 22100124 TI - New insights into thyroid hormone function and modulation of reproduction in goldfish. AB - A number of studies have provided evidence for a link between thyroid hormones and physiological or pathophysiological conditions associated with reproduction. Most of the information available is based on clinical observations in human or research in mammals. There are also a number of studies in non-mammalian species, primarily investigating thyroid and reproductive endocrinology in isolation. The findings demonstrate that hyperthyroidism or hypothyroidism are associated with altered fertility due to changes in the levels and activities of hormones of the brain-pituitary-gonadal axis. There appears to be a consistent pattern based on a number of studies in mammalian and non-mammalian species, linking thyroid with reproduction. Results obtained in goldfish suggest that increased levels of thyroid hormones may reduce overall reproductive function. Since thyroid hormones influence metabolism and are known to stimulate growth in most species, it is likely that increased thyroid hormone levels may divert energy from reproduction and promote somatotropic functions. This is particularly important in oviparous species such as fish since energy investment in females during reproductive season is very significant, and increasing thyroid hormone levels after ovulation may be a contributing factor in promoting growth response. Thyroid hormones will likely work in concert with other hormones to influence reproduction in fish and other vertebrates. PMID- 22100125 TI - Nanotechnological advances for the delivery of CNS therapeutics. AB - Effective non-invasive treatment of neurological diseases is often limited by the poor access of therapeutic agents into the central nervous system (CNS). The majority of drugs and biotechnological agents do not readily permeate into brain parenchyma due to the presence of two anatomical and biochemical dynamic barriers: the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Therefore, one of the most significant challenges facing CNS drug development is the availability of effective brain targeting technology. Recent advances in nanotechnology have provided promising solutions to this challenge. Several nanocarriers ranging from the more established systems, e.g. polymeric nanoparticles, solid lipid nanoparticles, liposomes, micelles to the newer systems, e.g. dendrimers, nanogels, nanoemulsions and nanosuspensions have been studied for the delivery of CNS therapeutics. Many of these nanomedicines can be effectively transported across various in vitro and in vivo BBB models by endocytosis and/or transcytosis, and demonstrated early preclinical success for the management of CNS conditions such as brain tumors, HIV encephalopathy, Alzheimer's disease and acute ischemic stroke. Future development of CNS nanomedicines need to focus on increasing their drug-trafficking performance and specificity for brain tissue using novel targeting moieties, improving their BBB permeability and reducing their neurotoxicity. PMID- 22100126 TI - Working and short-term memories are impaired in postpartum depression. AB - BACKGROUND: Postpartum depression affects parents of newborns. Major depression causes cognitive prejudice. Nothing is known about memory impairment in those affected of postpartum depression. This study has a purpose to assess working and short-term memories during the postpartum period in mothers and fathers in the city of Pelotas, RS, Brazil and also to correlate the changes in memory with postpartum depression, sociodemographic factors and possible confounding factors. METHODS: This cross-sectional study includes families assisted by the public health system. The sample consisted of fathers and mothers of live births, born from March to December 2008. The participants were evaluated during home visits using the Edinburg Postnatal Depression Scale (EPDS) and the word span test. The cutoff point for depression in the EPDS scores was >=13, and the word span scores were evaluated as discrete variables. RESULTS: The sample consisted of 395 individuals (222 women and 173 men). The prevalence of depression was 16.2% among mothers and 5.2% among fathers. Depressed individuals performed worse on the memory test. LIMITATIONS: The number of men evaluated was smaller than that of women. That's a transversal study, so we have the prevalence bias. CONCLUSIONS: This study shows that postpartum depression affects both men and women, and the symptoms of depression affect the working and short-term memories of affected individuals. Given that this was a larger study than those in the literature, the results emphasize the importance of detecting and treating postpartum depression and helping affected families. PMID- 22100127 TI - Suicidal intention and negative spiritual coping one year after the earthquake of L'Aquila (Italy). AB - BACKGROUND: This study investigated the rate of suicidal intention and its relationship with the features of religious involvement in a non-clinical sample of the adult population exposed to the L'Aquila earthquake. METHODS: The study population was composed of 426 people who had experienced the earthquake (188 males and 238 females). For comparison, 522 people were recruited from nearby unaffected areas. The sample was investigated for suicidal intention screening, distinguishing Suicidal Screen-Negative (SSN) subjects from Positive (SSP) subjects. Brief Multidimensional Measure of Religiousness/Spirituality (BMMRS) and Impact of Event Scale (IES) assessments were administered. RESULTS: More SSP subjects were observed in the population exposed to the earthquake (Odds Ratio 3.54). A higher proportion of females showed suicidal ideation. Multivariate analysis showed overall significance for the between-subject factor. Univariate F tests for each BMMRS variable that contributed to significant overall effect showed that negative spiritual coping was significantly different. No differences were observed for IES scores between the two groups, but correlations with negative spiritual coping were found. LIMITATIONS: The samples are relatively small and data are based on self-reports. CONCLUSIONS: Negative religious coping such as expression of conflict and doubt regarding matters of faith, as well as a feeling of being punished or abandoned by God, can prevail in response to prolonged stress without relief, as was experienced by the population exposed to the earthquake. These features are more associated with suicide ideation. Degree of religious affiliation and commitment examination by mental health practitioners can be useful when suicidal ideation is investigated. PMID- 22100128 TI - Gender-specific role of the protein tyrosine phosphatase receptor type R gene in major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a common, chronic, and recurrent mental disease affecting millions of individuals worldwide. The precise mechanism by which the illness is developed remains unknown, but it has been accepted that a genetic component is very likely to be involved. Studies of the pathogenesis of MDD have implicated a reduced activity of the extracellular regulated kinase (ERK) signaling system. Protein tyrosine phosphatase, receptor type R (PTPRR) is a key negative regulator of the ERK signaling pathway and its expression is regulated by androgen. Therefore, it is worth testing whether the PTPRR gene could confer a risk of MDD. METHODS: We genotyped 16 SNPs in the PTPRR locus with the MALDI-TOF-MS-based genotyping protocol in 517 patients with MDD and 455 controls among a Chinese Han population. The UNPHASED program was applied to analyze the genotyping data. RESULTS: Of the 16 SNPs selected, rs1513105 was the only one showing allelic association (chi2=9.019, p=0.0027) and genotypic association (chi2=8.813, df=2, p=0.012), of which the rs1513105(C) allele was associated with an increased risk of MDD (OR=1.331, 95% CI 1.104-1.604), but the rs1513105 association resulted mainly from female subjects (chi2=12.35, p=0.00044 for allelic association; chi2=11.26, df=2, p=0.0036 for genotypic association). LIMITATIONS: Replication and functional study may be required to draw a firm conclusion. CONCLUSIONS: Our results suggest that the PTPRR gene may play a role in conferring risk of MDD in the female subjects. PMID- 22100129 TI - Quality of life among caregivers of individuals with affective disorders. AB - OBJECTIVE: The aims of this study were as follows: 1. to assess the quality of life (QoL) of caregivers of individuals with affective disorders (major depressive disorder and bipolar disorder); 2. to compare QoL levels with those observed in caregivers of individuals with schizophrenia and in the general population; 3. to determine the impact of sociodemographic and clinical factors on the caregivers' QoL. METHODS: Data were collected from the psychiatric departments of a French public teaching hospital. QoL was measured with the SF-36 questionnaire. The QoL of 232 caregivers of individuals with affective disorders was compared with 246 caregivers of individuals with schizophrenia and 232 French age-sex-matched controls. RESULTS: Caregivers of individuals with affective disorders experienced lower QoL levels than French age-sex-matched controls. The most severe impairment concerned psychological distress, social and role disability due to emotional problems (SF36-mental composite score=38.2). In contrast, caregivers of individuals with affective disorders reported higher SF36 dimension scores than caregivers of individuals with schizophrenia. Among caregivers of individuals with affective disorders, women (p=0.010), parents/family or spouse (p=0.017), caregivers living in the same home (p=0.003) and caregivers of individuals with MDD (p=0.005) were significantly associated with a lower SF36-mental composite score. CONCLUSION: The QoL of caregivers of individuals with affective disorders is seriously impaired, mainly because of an altered psychological or mental well-being and social life. QoL adds interesting and complementary information to information that has been traditionally collected (burden, stress, perceived stigma) and facilitates the identification of specific needs that should be addressed in support groups for caregivers. PMID- 22100130 TI - Sustained medically unexplained physical symptoms in euthymic patients with recurrent depression: predictive value for recurrence and associations with omega 3- and 6 fatty acids and 5-HTTLPR? AB - BACKGROUND: Identification of potentially modifiable risk factors for recurrence in recurrent depression could provide opportunities to improve preventive interventions. In this study we aimed to examine the predictive value of medically unexplained physical symptoms (MUPS) on time to recurrence in recurrent depression. Additionally, to elucidate pathophysiological mechanisms that could explain the relations between MUPS and depression, we investigate the association between a sustained high level of MUPS, and (I) omega (omega)-3 and -6 fatty acid (FA)-status and (II) functional polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR). METHODS: Based on three Physical Symptom Checklist (PCS) scores over 12 months, we defined two groups of remitted recurrently depressed patients: 41 patients with a sustained high number of MUPS and 34 patients with a sustained low number or no MUPS. Patients were followed-up for 3.5 years while recurrence of their depression was monitored. In addition, we analyzed patients' erythrocyte's FA-profiles and triallelically genotyped their 5 HTTLPR. RESULTS: A sustained high level of MUPS predicted consecutive depression recurrence over 3.5 years (adjusted relative risk 2.8). FA-status and distribution of 5-HTTLPR variant frequencies did not differ between patients with sustained high compared to low/absent MUPS-levels. LIMITATIONS: Our sample was relatively small. CONCLUSION: Remitted recurrently depressed patients with sustained MUPS have a considerably increased risk of recurrence. Having sustained MUPS is not associated with either erythrocyte omega-3 or -6 FA-levels or 5 HTTLPR polymorphism. Recognition and reducing MUPS in an early state could prevent a (depressive) relapse. PMID- 22100131 TI - 'It's a double edged sword': a qualitative analysis of the experiences of exercise amongst people with Bipolar Disorder. AB - BACKGROUND: Little is known about the therapeutic or iatrogenic effects of exercise in individuals with Bipolar Disorder, despite its potential to benefit physical and mental health. Consequently the aim of the current study was to gather data on experiences of the relationship between exercise and Bipolar Disorder from people with personal experience of the condition. In particular we sought to determine the aspects of this relationship that are pertinent to Bipolar Disorder. METHODS: Twenty five individuals with a diagnosis of Bipolar Disorder participated in a semi-structured interview concerning their views on the relationship between exercise and Bipolar Disorder. The data were subjected to qualitative analysis using an Interpretative Phenomenological Analysis approach. RESULTS: Both a descriptive content analysis and a population-specific thematic analysis were conducted. The latter revealed three themes, all present in the majority of participants, which reflected key aspects of the relationship between Bipolar Disorder and exercise: regulating exercise for mood regulation, exercise as a double-edged sword, and bringing structure to chaos. LIMITATIONS: Information on past and current treatment regimes was not collected, and additional lifestyle factors, such as diet and alcohol use, were not investigated. Interviews were conducted by telephone. CONCLUSIONS: The data reveal a number of aspects of the relationship between exercise and Bipolar Disorder that require further investigation and that should be taken into account by clinicians or researchers designing exercise-based interventions for individuals with Bipolar Disorder. PMID- 22100132 TI - Affective temperaments in clinical practice: a validation study in mood disorders. AB - BACKGROUND: We sought to examine correlations between clinical validators and temperaments in clinical practice. METHODS: We provided the self-report TEMPS-A (50 item long) to 123 consecutive patients seen in the Mood Disorders Program of Tufts Medical Center. Temperament was assessed as cyclothymia, dysthymia, irritable or hyperthymia. Cut-offs were tested using (50%) and (75%) thresholds of affirmative responses, as well as highest percent for dominant temperament. We reported no dominant temperament at 75% cut-off . Multivariate regression modeling was conducted to assess confounding bias. RESULTS: Using clinical and demographic validators, cyclothymia was the most strongly validated temperament, followed by dysthymia and hyperthymia. Irritable temperament did not appear to be valid in this sample. A 75% item endorsement cut-off appeared to identify clinically important temperaments in slightly less than half of this sample. Those without any temperament at 75% cut-off had better prognostic features. 50% cut-off was highly nonspecific, and poorly correlated with diagnostic validators. CONCLUSIONS: Affective temperaments correlate with clinical validators, most robustly for cyclothymia. 75% cut-off on the TEMPS may provide a useful categorical definition of abnormal affective temperaments in mood disorders. With that definition, slightly less than one-half of patients with mood disorders have affective temperaments. Those without abnormal affective temperaments have better prognostic features. PMID- 22100133 TI - New treatment guidelines for acute bipolar mania: a critical review. AB - A number of treatment guidelines for bipolar disorder have been published and updated in the last few years. They are aimed at providing a synthesis of the best available scientific knowledge, and their application to every-day work should be helpful to clinicians. The aim of this report is to critically review recent guidelines focusing on the treatment of manic/hypomanic and mixed episodes. Guidelines are quite heterogeneous in methodology and conclusions, but they all agree that the treatment of manic/hypomanic and mixed episodes should generally be initiated with a medication such as lithium (Li), valproate (VPA) or atypical antipsychotics (AAP), including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone as monotherapy. All guidelines agree on stopping ongoing antidepressant medication during mania. Combination therapy including Li or VPA with an AAP is suggested usually as second-line choice, sometimes as first choice treatment for severe mania. Carbamazepine is mostly suggested as second line and not recommended in combination. Other antiepileptic drugs are not recommended for the treatment of mania, although lamotrigine may be maintained if it was prescribed previously for the prevention of depressive episodes. Main sources of discrepancies among guidelines include benefit-risk ratio issues (how much priority is given to efficacy over safety and tolerability), starting with combination versus monotherapy, and how to deal with treatments which are more experience-based than evidence-based (i.e.: electroconvulsive therapy). PMID- 22100134 TI - The activation of alternative response candidates: when do doubts kick in? AB - In the current study, we investigated at which moment during visual object categorization alternative interpretations are most strongly activated. According to an early activation account, we are uncertain about how to interpret the visual information early in the categorization process. This uncertainty will vanish over time and therefore, the number of possible response candidates decreases over time. According to a late activation account, the visual information is categorized quickly, but after extensive viewing alternative interpretations become more strongly activated. Therefore, the number of possible response candidates increases over time. To increase perceptual uncertainty we used morphed figures composed of a dominant and nondominant object. The similarity rating between morphed figures and their nondominant object was taken as indicator for the activation of the nondominant response candidate: high similarity indicates that the nondominant object is relatively strongly activated as an alternative response candidate. Presentation times were varied in order to distinguish between the early and late activation account. Using a Bayesian model selection approach, we found support for the late activation account, but not for the early activation account. It thus seems that in a late stage of the categorization process the influence of the nondominant response candidate is strongest. PMID- 22100135 TI - Effects of altered auditory feedback across effector systems: production of melodies by keyboard and singing. AB - We report an experiment that tested whether effects of altered auditory feedback (AAF) during piano performance differ from its effects during singing. These effector systems differ with respect to the mapping between motor gestures and pitch content of auditory feedback. Whereas this action-effect mapping is highly reliable during phonation in any vocal motor task (singing or speaking), mapping between finger movements and pitch occurs only in limited situations, such as piano playing. Effects of AAF in both tasks replicated results previously found for keyboard performance (Pfordresher, 2003), in that asynchronous (delayed) feedback slowed timing whereas alterations to feedback pitch increased error rates, and the effect of asynchronous feedback was similar in magnitude across tasks. However, manipulations of feedback pitch had larger effects on singing than on keyboard production, suggesting effector-specific differences in sensitivity to action-effect mapping with respect to feedback content. These results support the view that disruption from AAF is based on abstract, effector independent, response-effect associations but that the strength of associations differs across effector systems. PMID- 22100136 TI - Studies on the synthesis and antibacterial activity of 3,6-disubstituted 1,2,4 triazolo[3,4-b]1,3,4-thiadiazoles. AB - Treating infections caused by drug-resistant bacterial strains constitutes one of the most essential challenges for medicine nowadays. A range of new derivatives of 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole have been synthesized and evaluated for their in vitro antimicrobial activity. Compounds 1-8 indicated high activity towards Gram-positive bacteria, which was up to 16 times more than currently used antibiotics. To the best of our knowledge, the derivatives obtained by us are the most active among the 3-aryl-6-arylamino-1,2,4-triazolo[3,4-b]1,3,4-thiadiazoles known until now. PMID- 22100137 TI - 6-alkylsalicylates are selective Tip60 inhibitors and target the acetyl-CoA binding site. AB - Histone acetyltransferases are important enzymes that regulate various cellular functions, such as epigenetic control of DNA transcription. Development of HAT inhibitors with high selectivity and potency will provide powerful mechanistic tools for the elucidation of the biological functions of HATs and may also have pharmacological value for potential new therapies. In this work, analogs of the known HAT inhibitor anacardic acid were synthesized and evaluated for inhibition of HAT activity. Biochemical assays revealed novel anacardic acid analogs that inhibited the human recombinant enzyme Tip60 selectively compared to PCAF and p300. Enzyme kinetics studies demonstrated that inhibition of Tip60 by one such novel anacardic acid derive, 20, was essentially competitive with Ac-CoA and non competitive with the histone substrate. In addition, these HAT inhibitors effectively inhibited acetyltransferase activity of nuclear extracts on the histone H3 and H4 at micromolar concentrations. PMID- 22100138 TI - Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model. AB - A simple and efficient synthetic method for the preparation of quinazoline type phosphodiesterase 7 (PDE7) inhibitors, based on microwave irradiation, has been developed. The use of this methodology improved yields and reaction times, providing a scalable procedure. These compounds are pharmacologically interesting because of their in vivo efficacy both in spinal cord injury and Parkinson's disease models, as shown in previous studies from our group. Herein we describe for the first time that administration of one of the PDE7 inhibitors here optimized, 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline (compound 5), ameliorated brain damage and improved behavioral outcome in a permanent middle cerebral artery occlusion (pMCAO) stroke model. Furthermore, we demonstrate that these PDE7 inhibitors are potent anti-inflammatory as well as neuroprotective agents in primary cultures of neural cells. These results led us to propose PDE7 inhibitors as a new class of therapeutic agents for neuroprotection. PMID- 22100139 TI - Synthesis, antiproliferative activities and telomerase inhibition evaluation of novel asymmetrical 1,2-disubstituted amidoanthraquinone derivatives. AB - A series of diversely asymmetrical mono- or disubstituted 1,2 diamidoanthraquinone derivatives were synthesized and evaluated for drug-induced cytotoxicity by SRB assay, telomerase inhibitory activity by TRAP assay, and hTERT expression by SEAP assay. Interestingly, compounds 4, 11, 21, 32 and 36 exhibited selective potent antiproliferative activities by NCI with IC(50) values in the micromolar range. Of these, only compound 8 showed an IC(50) value of 0.95 MUM against PC-3 cell lines (human prostate cancer) by SRB assay. All the synthesized compounds exhibited a poor or modest telomerase inhibitory activity by TRAP assay suggesting another mode of action for these compounds. Compound 11 showed broad inhibition against different types of cancer cell lines in the micromolar and submicromolar range. PMID- 22100140 TI - Antifungal activities of novel non-azole molecules against S. cerevisiae and C. albicans. AB - Because of the increasing number of immunocompromised patients and due to problems with antifungal treatment, especially with the most widely used antifungals, azoles, there is an urgent need for new, potent and safe antifungals with fewer cytochrome P450 (CYP)-mediated interactions with other drugs. In the present study, 54 novel non-azole molecules were selected with the help of molecular modelling and virtual molecule database screening to identify new fungistatic or fungicidic compounds with functional groups that would produce reactive intermediates killing the yeast cells. Database screening and selection of tested compounds were based on the construction of two pharmacophores and docking hits to the active site of the CYP51 homology model. Inhibition potency of the compounds was tested against Saccharomyces cerevisiae and/or Candida albicans. Two new structured compounds, 2-({4-[(2-cyanoethyl)(methyl) amino]benzylidene} amino)-5-(3,4-dimethoxyphenyl)-4-methylthiophene-3 carbonitrile and 2-[([1,1'-biphenyl]-4-ylmethylene)amino]-5-(3,4-dimethoxyphenyl) 4-methylthiophene-3-carbonitrile were discovered to have promising antifungal properties based on bioassays. Inhibition screen of human hepatic CYP enzymes revealed that these two compounds did not inhibit potently five human recombinant CYP enzymes. The results of this study indicate that the functional groups of the two compounds may produce reactive intermediates when located at the active site of CYP51. PMID- 22100141 TI - Anthelmintic resistance in equine parasites - detection, potential clinical relevance and implications for control. AB - During the past two decades anthelmintic resistance in equine parasites has been found in the group of small strongyle species (cyathostomins) and in the ascarid species Parascaris equorum. The ubiquitous nature and possible severe consequences of disease with these nematodes make them the prime targets of current worm control programmes. Traditional control strategies mainly rely on the strategic application of anthelmintics, currently represented by three major drug classes: benzimidazoles (BZ), the tetrahydropyrimidine pyrantel (PYR) and macrocyclic lactones (ML). Following decades of routine and frequent anthelmintic applications, many cyathostomin populations on horse farms in industrialised countries must be considered as resistant to BZ anthelmintics. However, to date no published cases of cyathostomin disease specifically associated with anthelmintic resistance were reported. Possibly this is due to the generally subclinical and unspecific symptoms associated with cyathostomin infections. Nevertheless, exclusive reliance on the ML drug class may increase the threat of clinical disease due to drug-resistant cyathostomins. More recently, P. equorum has been reported as having developed resistance against ivermectin and moxidectin, two representatives of the ML-class. These anthelmintics are currently the most frequently used drug class in horses. This nematode species is mainly found in foals and in younger horses due to the development of immunity following exposure to infection. Infection with P. equorum can result in clinically drastic consequences such as obstruction and/or penetration of the small intestine, the latter usually leading to death. In conclusion, on horse farms the efficacy of anthelmintic treatments should be examined routinely for each drug class. Several factors can influence the rate at which anthelmintic resistance develops; high frequency of treatment being one of the most important. Modern control strategies should therefore attempt to significantly reduce anthelmintic treatments. Several pasture and farm management practices found to be negatively associated with nematode and anthelmintic resistance prevalence will be discussed in the review presented here. PMID- 22100142 TI - Monoamine oxidase inhibition by C4-substituted phthalonitriles. AB - It was recently reported that a series of C5-substituted phthalimides are remarkably potent reversible inhibitors of recombinant human monoamine oxidase (MAO) B. Modeling studies suggested that the phthalimide ring forms numerous polar interactions with the polar region of the MAO-B substrate cavity while the C5 side chain extends to, and interacts via Van der Waals interactions with the hydrophobic regions of the enzyme entrance cavity. Interactions with both cavities appear to be requirements for high affinity binding. In the present study we have examined an analogs series of C4-substituted phthalonitriles as potential human MAO inhibitors. The phthalonitriles were found to be highly potent reversible MAO-B inhibitors with most analogs exhibiting IC(50) values in the low nM range. The phthalonitriles also interacted with human MAO-A, although with lower binding affinities compared to MAO-B. Modeling studies suggest that the high binding affinities of the phthalonitriles to MAO-B may depend, at least in part, on the formation of polar interactions between the nitrile functional groups and the enzyme substrate cavity. Examination of a homologs series of benzonitriles established that the phthalonitrile moiety is more optimal for MAO B inhibition than the corresponding benzonitrile moiety, and that C3-substituted benzonitriles are better MAO-B inhibitors than C4-substituted benzonitriles. Since elimination of the nitrile functional group yielded compounds with only moderate MAO-B inhibition potencies, it may be concluded that this functional group is privileged for MAO-B inhibition. PMID- 22100143 TI - Motor and non-motor predictors of illness-related distress in Parkinson's disease. AB - OBJECTIVE: To identify motor and non-motor symptoms independently associated with distress in Parkinson's disease (PD). METHOD: Clinical and patient-reported data from 118 people with PD (mean age and PD-duration, 64 and 8 years) were analyzed regarding associations with patient-reported distress using multiple regressions (controlling for age). RESULTS: Non-motor symptoms independently associated with distress were pain, fatigue, sleep, depression and anxiety (R(2), 0.81). The only significant motor aspect was mobility (R(2), 0.31). When considering both motor and non-motor symptoms, fatigue, pain, depression and sleep showed independent associations with distress (R(2), 0.76). CONCLUSION: Distress in PD is primarily associated with non-motor features. PMID- 22100144 TI - A meta-analytic review of Berzonsky's Identity Style Inventory (ISI). AB - Identity formation is an essential developmental challenge associated with adolescence (Cote, 2009; Erikson, 1950, 1968). Berzonsky (1988) developed a social-cognitive model that distinguishes three styles by which adolescents engage the tasks associated with identity formation: informational, normative, and diffuse-avoidant. Focusing on studies (K = 62) that employed the Identity Style Inventory (ISI; Berzonsky, 1989), three meta-analytic reviews were performed. First, results show a medium positive association between the informational and normative styles, a medium negative association between informational and diffuse-avoidant styles, and a negligible negative association between the normative and diffuse-avoidant styles. Second, results show large positive associations between commitment and both the informational and normative identity styles, and a large negative association between commitment and the diffuse-avoidant style. Finally, results show a small positive association between gender and the diffuse-avoidant identity style, with men scoring higher than women. Age and country of origin were evaluated as moderators. PMID- 22100145 TI - EMAS position statement: Vitamin D and postmenopausal health. AB - INTRODUCTION: There is emerging evidence on the widespread tissue effects of vitamin D. AIMS: To formulate a position statement on the role of vitamin D in postmenopausal women. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Epidemiological and prospective studies have related vitamin D deficiency with not only osteoporosis but also cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However the evidence is robust for skeletal but not nonskeletal outcomes where data from large prospective studies are lacking. The major natural source of vitamin D is cutaneous synthesis through exposure to sunlight with a small amount from the diet in animal-based foods such as fatty fish, eggs and milk. Vitamin D status is determined by measuring serum 25-hydroxyvitamin D [25(OH)D] levels. Optimal serum 25(OH)D levels are in the region of 30-90 ng/mL (75-225 nmol/L) though there is no international consensus. Levels vary according to time of the year (lower in the winter), latitude, altitude, air pollution, skin pigmentation, use of sunscreens and clothing coverage. Risk factors for low serum 25(OH)D levels include: obesity, malabsorption syndromes, medication use (e.g. anticonvulsants, antiretrovirals), skin aging, low sun exposure and those in residential care. Fortified foods do not necessarily provide sufficient amounts of vitamin D. Regular sunlight exposure (without sunscreens) for 15 min, 3-4 times a week, in the middle of the day in summer generate healthy levels. The recommended daily allowance is 600 IU/day increasing to 800 IU/day in those aged 71 years and older. Supplementation can be undertaken with either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) with monitoring depending on the dose used and the presence of concomitant medical conditions such as renal disease. PMID- 22100146 TI - Dynamics of frequency flow in epileptic brain during extra-temporal partial and idiopathic generalized epilepsy. AB - Temporal lobe epilepsy has been known to be associated with buildup of 4-7 Hz activity preceded by attenuation near the seizure focus. Using a wavelet based algorithm, we recently showed that for the patients with temporal lobe epilepsy, frequency flow on the scalp EEG builds up to 5-12 Hz range just prior to and during the initial stages of the seizure. Here we present frequency flow analysis on EEG of patients with extra-temporal partial epilepsy and patients with idiopathic generalized epilepsy (IGE) to investigate any characteristic frequency flow patterns in these patients. We found that frequency flow in these patients also stays sustained in the 5-12 Hz range for longer periods of time just prior to and during the initial stages of the seizure compared to their respective baseline interictal recordings. The 5-12 Hz frequency flow was seen uniformly in all the channels in patients with IGE although it was seen most prominently adjacent to the seizure focus and to a lesser extent in other channels in patients with partial epilepsy. PMID- 22100147 TI - Frontal lobe function in temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is typically associated with long-term memory dysfunction. The frontal lobes support high-level cognition comprising executive skills and working memory that is vital for daily life functioning. Deficits in these functions have been increasingly reported in TLE. Evidence from both the neuropsychological and neuroimaging literature suggests both executive function and working memory are compromised in the presence of TLE. In relation to executive impairment, particular focus has been paid to set shifting as measured by the Wisconsin Card Sorting Task. Other discrete executive functions such as decision-making and theory of mind also appear vulnerable but have received little attention. With regard to working memory, the medial temporal lobe structures appear have a more critical role, but with emerging evidence of hippocampal dependent and independent processes. The relative role of underlying pathology and seizure spread is likely to have considerable bearing upon the cognitive phenotype and trajectory in TLE. The identification of the nature of frontal lobe dysfunction in TLE thus has important clinical implications for prognosis and surgical management. Longitudinal neuropsychological and neuroimaging studies assessing frontal lobe function in TLE patients pre- and postoperatively will improve our understanding further. PMID- 22100148 TI - Non-invasive continuous EEG-fNIRS recording of temporal lobe seizures. AB - PURPOSE: Functional near-infrared spectroscopy (fNIRS) is a technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. By using combined EEG-fNIRS recordings, we sought to better understand the pathophysiology of temporal lobe seizures. RESULTS: Nine patients (5 males; mean age 35 years; range 11-56 years) with refractory mesial temporal lobe epilepsy underwent combined EEG-fNIRS recordings. Eight complex partial seizures from 3 patients were successfully recorded. All seizures were associated with significant local and remote haemodynamic changes which outlasted the duration of seizures. Over the epileptogenic temporal lobe, increased oxygenation [increase in cerebral blood volume (CBV) and oxyhaemoglobin (HbO), decrease in deoxyhaemoglobin (HbR)] was followed by a deoxygenated state [increase in HbR]. A similar haemodynamic profile was seen over the contralateral temporal lobe (even without evidence of epileptic propagation) though variations generally had lower amplitudes. Heterogeneous haemodynamic changes in remote frontal and/or parietal areas were also noted early on when epileptic activity was limited to the temporal lobe. CONCLUSION: EEG-fNIRS reveals complex local and remote oxygenation changes during temporal lobe seizures. PMID- 22100149 TI - Targeted and cytotoxic therapy in coordinated sequence (TACTICS): erlotinib, bevacizumab, and standard chemotherapy for non-small-cell lung cancer, a phase II trial. AB - BACKGROUND: This trial focused on optimally combining existing targeted therapies and cytotoxic chemotherapy in the treatment of unselected patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with previously untreated advanced-stage nonsquamous NSCLC were eligible for this trial. In module A, patients received up to 4 cycles of erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients then received carboplatin (AUC = 6), paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for 4 cycles in module B. Patients who did not have progressive disease in module A received maintenance erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks in module C. RESULTS: Forty-eight patients were enrolled in this multicenter phase II trial. Most patients were male (62.5%) and white (77.1%) with stage IV disease (93.8%) and adenocarcinoma histologic type (66.7%). The overall response rate in module A was 10.4%, in module B it was 15.1%, and in module C it was 5.5%. The study achieved its primary endpoint, with a nonprogression rate of 45.8% in module A. The median overall survival (OS) was 12.6 months. CONCLUSION: The novel systemic therapy regimen is feasible in patients with advanced NSCLC. However there is no further role for developing this regimen in unselected patients with NSCLC. PMID- 22100150 TI - The value of frozen section biopsy in diagnosing necrotizing fasciitis: proposal of a new grading system. AB - GOALS AND OBJECTIVES: Necrotizing fasciitis is a serious disease entity, with only limited pathognomic features. PURPOSE: In necrotizing fasciitis a rapid diagnosis is necessary in order to reduce morbidity and mortality. In this study the investigation focused on specific features in the frozen section biopsy for diagnosing necrotizing fasciitis. METHODS: A total of ten patients are described with final pathological examination of resected tissue. RESULTS: A new grading system is suggested for frozen section biopsy in patients with necrotizing fasciitis. In the herein reported study it was found that granulocytes were present in both the frozen section biopsy and in the definitive paraffin coupes, in the subcutis and fascia layer. CONCLUSION: Frozen section biopsy could be useful in diagnosing necrotizing fasciitis. PMID- 22100151 TI - EMG spectral characteristics of masticatory muscles and upper trapezius during maximum voluntary teeth clenching. AB - To assess the surface electromyographic spectral characteristics of masticatory and neck muscles during the performance of maximum voluntary clench (MVC) tasks, 29 healthy young adults (15 men, 14 women, mean age 22years) were examined. Electromyography of masseter, temporalis and upper trapezius muscles was performed during 5-s MVCs either on cotton rolls or in intercuspal position. Using a fast Fourier transform, the median power frequency (MPF) was obtained for the first and last seconds of clench, and compared between sexes, muscles, sides, tests and time intervals using ANOVAs. On average, the MPFs did not differ between sexes or sides (p>0.05), but significant effects of muscle (MPF temporalis larger than masseter, larger than trapezius muscles), test (larger MPFs when clenching in intercuspal position than when clenching on cotton rolls) and time (larger MPFs in the first than in the fifth second of clench) were found. In conclusion, a set of data to characterize the sEMG spectral characteristics of jaw and neck muscles in young adult subjects performing MVC tasks currently in use within the dental field was obtained. Reference values may assist in the assessment of patients with alterations in the cranio-cervical mandibular system. PMID- 22100152 TI - Effects of local elastic compression on muscle strength, electromyographic, and mechanomyographic responses in the lower extremity. AB - The purpose of this study was to investigate the effect of elastic compression on muscle strength, electromyographic (EMG), and mechanomyographic (MMG) responses of quadriceps femoris during isometric and isokinetic contractions. Twelve participants performed 5s isometric maximal voluntary contractions (MVC) and 25 consecutive and maximal isokinetic knee extensions at 60 and 300 degrees /s with no (control, CC), medium (MC), and high (HC) compression applied to the muscle. The EMG and MMG signals were collected simultaneously with muscle isometric and isokinetic strength data. The results showed that the elevated compression did not improve peak torque, peak power, average power, total work, and regression of torque in the isometric and isokinetic contractions. However, the root mean squared value of EMG in both HC and MC significantly decreased compared with CC at 60 and 300 degrees /s (p<0.01). Furthermore, the EMG mean power frequency in HC was significantly higher than that in CC at 60 degrees /s (p<0.05) whereas no significant compression effect was found in the MMG mean power frequency. These findings provide preliminary evidence suggesting that the increase in local compression pressure may effectively increase muscle efficiency and this might be beneficial in reducing muscle fatigue during concentric isokinetic muscle contractions. PMID- 22100153 TI - Appropriate cervical cancer screening remains essential: the case of women with inflammatory bowel disease. PMID- 22100154 TI - [Twenty years of liver transplantation: looking backward and moving forward]. PMID- 22100155 TI - [Resuscitation: Place of care and a place to live]. PMID- 22100156 TI - [Day-case surgery: postoperative pain relief not so easy!]. PMID- 22100157 TI - iNKTs foil fungi. AB - Fungal cell wall polysaccharides are potent inducers of immune responses. Cohen et al. (2011) demonstrate that innate recognition of fungal beta-(1,3) glucan triggers effector functions of invariant natural killer T (iNKT) cells through indirect, cytokine-driven activation, a process that mediates optimal protection against the opportunistic mold Aspergillus fumigatus. PMID- 22100158 TI - Porphyromonas gingivalis sinks teeth into the oral microbiota and periodontal disease. AB - Periodontitis is linked to polymicrobial interactions and the presence of Porphyromonas gingivalis. In this issue of Cell Host & Microbe, Hajishengallis et al. (2011) demonstrate that P. gingivalis colonization in the oral cavity changes the composition of the oral commensal microbiota and accelerates microbiota mediated bone-destructive periodontitis, indicating that this single, low abundance species is a keystone in periodontal disease. PMID- 22100159 TI - The control of HIV transcription: keeping RNA polymerase II on track. AB - Thirteen years ago, human cyclin T1 was identified as part of the positive transcription elongation factor b (P-TEFb) and the long-sought host cofactor for the HIV-1 transactivator Tat. Recent years have brought new insights into the intricate regulation of P-TEFb function and its relationship with Tat, revealing novel mechanisms for controlling HIV transcription and fueling new efforts to overcome the barrier of transcriptional latency in eradicating HIV. Moreover, the improved understanding of HIV and Tat forms a basis for studying transcription elongation control in general. Here, we review advances in HIV transcription research with a focus on the growing family of cellular P-TEFb complexes, structural insights into the interactions between Tat, P-TEFb, and TAR RNA, and the multifaceted regulation of these interactions by posttranscriptional modifications of Tat. PMID- 22100160 TI - Innate recognition of cell wall beta-glucans drives invariant natural killer T cell responses against fungi. AB - iNKT cells are innate T lymphocytes recognizing endogenous and foreign lipid antigens presented in the MHC-like molecule CD1d. The semi-invariant iNKT cell TCR can detect certain bacterial and parasitic lipids and drive iNKT cell responses. How iNKT cells respond to fungi, however, is unknown. We found that CD1d-deficient mice, which lack iNKT cells, poorly control infection with the fungal pathogen Aspergillus fumigatus. Furthermore, A. fumigatus rapidly activates iNKT cells in vivo and in vitro in the presence of APCs. Surprisingly, despite a requirement for CD1d recognition, the antifungal iNKT cell response does not require fungal lipids. Instead, Dectin-1- and MyD88-mediated responses to beta-1,3 glucans, major fungal cell-wall polysaccharides, trigger IL-12 production by APCs that drives self-reactive iNKT cells to secrete IFN-gamma. Innate recognition of beta-1,3 glucans also drives iNKT cell responses against Candida, Histoplasma, and Alternaria, suggesting that this mechanism may broadly define the basis for antifungal iNKT cell responses. PMID- 22100161 TI - A critical role of perinuclear filamentous actin in spatial repositioning and mutually exclusive expression of virulence genes in malaria parasites. AB - Many microbial pathogens, including the malaria parasite Plasmodium falciparum, vary surface protein expression to evade host immune responses. P. falciparium antigenic variation is linked to var gene family-encoded clonally variant surface protein expression. Mututally exclusive var gene expression is partially controlled by spatial positioning; silent genes are retained at distinct perinuclear sites and relocated to transcriptionally active locations for monoallelic expression. We show that var introns can control this process and that var intron addition relocalizes episomes from a random to a perinuclear position. This var intron-regulated nuclear tethering and repositioning is linked to an 18 bp nuclear protein-binding element that recruits an actin protein complex. Pharmacologically induced F-actin formation, which is restricted to the nuclear periphery, repositions intron-carrying episomes and var genes and disrupts mutually exclusive var gene expression. Thus, actin polymerization relocates var genes from a repressive to an active perinuclear compartment, which is crucial for P. falciparium phenotypic variation and pathogenesis. PMID- 22100162 TI - cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization. AB - RhoA-inhibitory bacterial toxins, such as Staphylococcus aureus EDIN toxin, induce large transendothelial cell macroaperture (TEM) tunnels that rupture the host endothelium barrier and promote bacterial dissemination. Host cells repair these tunnels by extending actin-rich membrane waves from the TEM edges. We reveal that cyclic-AMP signaling produced by Bacillus anthracis edema toxin (ET) also induces TEM formation, which correlates with increased vascular permeability. We show that ET-induced TEM formation resembles liquid dewetting, a physical process of nucleation and growth of holes within a thin liquid film. We also identify the cellular mechanisms of tunnel closure and reveal that the I-BAR domain protein Missing in Metastasis (MIM) senses de novo membrane curvature generated by the TEM, accumulates at the TEM edge, and triggers Arp2/3-dependent actin polymerization, which induces actin-rich membrane waves that close the TEM. Thus, the balance between ET-induced TEM formation and resealing likely determines the integrity of the host endothelium barrier. PMID- 22100163 TI - Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. AB - The lengthy course of treatment with currently used antimycobacterial drugs and the resulting emergence of drug-resistant strains have intensified the need for alternative therapies against Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. We show that Mtb and Mycobacterium marinum use ABL and related tyrosine kinases for entry and intracellular survival in macrophages. In mice, the ABL family tyrosine kinase inhibitor, imatinib (Gleevec), when administered prophylactically or therapeutically, reduced both the number of granulomatous lesions and bacterial load in infected organs and was also effective against a rifampicin-resistant strain. Further, when coadministered with current first-line drugs, rifampicin or rifabutin, imatinib acted synergistically. These data implicate host tyrosine kinases in entry and intracellular survival of mycobacteria and suggest that imatinib may have therapeutic efficacy against Mtb. Because imatinib targets host, it is less likely to engender resistance compared to conventional antibiotics and may decrease the development of resistance against coadministered drugs. PMID- 22100164 TI - Minimization of bacterial size allows for complement evasion and is overcome by the agglutinating effect of antibody. AB - The complement system, which functions by lysing pathogens directly or by promoting their uptake by phagocytes, is critical for controlling many microbial infections. Here, we show that in Streptococcus pneumoniae, increasing bacterial chain length sensitizes this pathogen to complement deposition and subsequent uptake by human neutrophils. Consistent with this, we show that minimizing chain length provides wild-type bacteria with a competitive advantage in vivo in a model of systemic infection. Investigating how the host overcomes this virulence strategy, we find that antibody promotes complement-dependent opsonophagocytic killing of Streptococcus pneumoniae and lysis of Haemophilus influenzae independent of Fc-mediated effector functions. Consistent with the agglutinating effect of antibody, F(ab')(2) but not Fab could promote this effect. Therefore, increasing pathogen size, whether by natural changes in cellular morphology or via antibody-mediated agglutination, promotes complement-dependent killing. These observations have broad implications for how cell size and morphology can affect virulence among pathogenic microbes. PMID- 22100165 TI - Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines. AB - Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in latency and lymphomagenesis. Using PAR-CLIP, a technology which allows the direct and transcriptome-wide identification of miRNA targets, we delineate the target sites for all viral and cellular miRNAs expressed in PEL cell lines. The resulting data set revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs, including many involved in pathways relevant to KSHV pathogenesis. Moreover, 58% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of cellular miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, this study identifies an extensive list of KSHV miRNA targets, which are likely to influence viral replication and pathogenesis. PMID- 22100166 TI - Adverse obstetric outcomes associated with sonographically identified large uterine fibroids. AB - STUDY OBJECTIVE: To determine the impact of sonographically identified large uterine fibroids (>5 cm in diameter) on obstetric outcomes. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENT(S): Women with singleton gestations (n = 95) noted to have uterine fibroids on obstetric ultrasonography from September 2009 through April 2010 and age-matched controls (n = 95). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Obstetric outcomes including short cervix, preterm premature rupture of membranes, and preterm delivery. RESULT(S): Compared to women with no fibroids or small fibroids (<=5 cm), women with large fibroids (>5 cm) delivered at a significantly earlier gestational age (38.6 vs. 38.4 vs. 36.5 weeks). Short cervix, preterm premature rupture of membranes, and preterm delivery were also significantly more frequent in the large fibroid group, and were associated with number of fibroids >5 cm in diameter. Blood loss at delivery was significantly higher in the large fibroid group (486.8 vs. 535.6 vs. 645.1 mL), as was need for postpartum blood transfusion (1.1 vs. 0.0 vs. 12.2%). CONCLUSION(S): Women with large uterine fibroids in pregnancy are at significantly increased risk for delivery at an earlier gestational age compared to women with small or no fibroids, as well as obstetric complications including excess blood loss and increased frequency of postpartum blood transfusion. PMID- 22100167 TI - Comprehensive management of severe Asherman syndrome and amenorrhea. AB - OBJECTIVE: To describe a comprehensive approach to women with severe Asherman syndrome and amenorrhea, including preoperative, operative, and postoperative care and subsequent resumption menses, and pregnancy. DESIGN: Retrospective case series. SETTING: Tertiary care teaching hospital. PATIENT(S): Twelve women with severe Asherman syndrome and amenorrhea. INTERVENTION(S): Preoperative administration of prolonged preoperative and postoperative oral E(2) to enhance endometrial proliferation, intraoperative abdominal ultrasound-directed hysteroscopic lysis of uterine synechia to ensure that the dissection is performed in the proper tissue plane, placement of a triangular uterine balloon catheter during surgery, and postoperative removal with placement of a copper intrauterine device (IUD) to maintain separation of the cavity and mechanically lyse newly formed adhesions during removal. MAIN OUTCOME MEASURE(S): Resumption of menses, pregnancy, and delivery. RESULT(S): All women resumed menses, although 5 of 12 had a preoperative maximal endometrial thickness of 4 mm or less, with follow-up ranging from 6 months to 10 years. Six of nine women less than age 39 years (67%) became pregnant, and four of six achieved a term or near-term delivery. CONCLUSION(S): Comprehensive management provides the best possible outcomes in poor-prognosis women with severe Asherman syndrome. PMID- 22100168 TI - Ultrasonographic measurement of the femoral cartilage thickness in patients with polycystic ovary syndrome. AB - OBJECTIVE: To compare the femoral cartilage thickness values of polycystic ovary syndrome (PCOS) patients with those of age-matched, healthy women and to find out whether cartilage thickness changes with the clinical parameters. DESIGN: A cross sectional controlled study. SETTING: A secondary care center and a tertiary care center. PATIENT(S): Thirty-three women with PCOS (mean age: 23.7 +/- 3.5 years; 66 knees) and 30 healthy control women matched for age and body mass index (mean age: 24.8 +/- 4.2 years; 60 knees). INTERVENTION(S): Measurement of knee cartage thickness of infertile PCOS patients. MAIN OUTCOME MEASURE(S): The thickness of femoral articular cartilage measured with an ultrasound with a linear probe (7-12 MHz) as well as three midpoint measurements taken from each knee: the lateral condyle, intercondylar area, and medial condyle. RESULT(S): The demographic and clinical features of the PCOS patients, the laboratory evaluations, and the endometrial thickness values were recorded, and the three midpoint measurements were taken from each knee. The PCOS patients had thicker cartilage values than the control group at all measurement sites. There was no correlation between the clinical parameters and the cartilage thickness values of PCOS patients. CONCLUSION(S): Our findings support the possible favorable effects of estrogen and androgens in PCOS patients. However, our data cannot determine whether PCOS patients have less risk of developing osteoarthritis later in life because they also have higher BMI values. The possible long-term changes in cartilage thickness in PCOS patients require further study. PMID- 22100169 TI - Insufficient histone-3 lysine-9 deacetylation in human oocytes matured in vitro is associated with aberrant meiosis. AB - OBJECTIVE: To characterize histone acetylation during meiosis in human oocytes matured in vitro or in vivo. DESIGN: Experimental study. SETTING: University reproductive medical center. PATIENT(S): Patients undergoing routine intracytoplasmic sperm injection (ICSI) cycles. INTERVENTION(S): Immature and mature oocytes were collected from patients undergoing intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Immunohistochemical assessment of the levels of acetylated lysine-9 of histone-3 (H3K9) and lysine-12 of histone-4 (H4K12) combined with spindle and chromosome configurations in in vitro- and in vivo matured human oocytes. Transcript levels of histone deacetylases (HDACs) 1 and 2 were measured by single-cell quantitative polymerase chain reaction. RESULT(S): Acetylation of H3K9 and H4K12 decreased during human oocyte maturation. Residual H3K9 acetylation was found in 37.7% of oocytes matured in vitro, compared with 11.8% in oocytes matured in vivo. Abnormal metaphase spindle was more frequent in oocytes with residual histone acetylation than without (51.6% vs. 25.4%, respectively). Treatment with the HDAC inhibitor trichostatin A increased the incidence of an abnormal metaphase but had no adverse effect on maturation efficiency. Furthermore, expression of HDAC1 transcripts was significantly lower in oocytes matured in vitro versus in vivo. CONCLUSION(S): Reduced HDAC1 expression and insufficient histone deacetylation are associated with metaphase defects in human oocytes matured in vitro. PMID- 22100170 TI - Comparison of Cryotip vs. Cryotop for mouse and human blastomere vitrification. AB - OBJECTIVE: Compare the efficiency of two vitrification methods for single blastomere cryopreservation with mouse or human embryos. DESIGN: Experimental prospective controlled study. SETTING: Research center. PATIENT(S): Human Blastomeres were obtained after biopsy. INTERVENTION(S): Mouse blastomeres were obtained after diluting the zona pellucida of embryos with Tyrode acid and manual isolation. Individual human blastomeres were biopsied from embryos following established clinical protocols. The modified open Cryotop and classical closed Cryotip vitrification systems were assayed. After thawing, some mouse blastomeres were fixed and analyzed for apoptotic markers annexin V and caspase 3 with the use of immunofluorescence and confocal microscopy. Ultrastructural morphology was examined using electron microscopy. The human blastomere division rate was assessed 24 hours after thawing. MAIN OUTCOME MEASURE(S): Blastomere survival and division rates after thawing, apoptotic markers, and electron microscopy; adhesion and outgrowth rates of human blastomeres. RESULT(S): After thawing, survival rates in mouse blastomeres using Cryotop vs. Cryotip were 38.46% vs. 85.41%, respectively. As expected, thawed morphologically alive blastomeres were classified negative for annexin V and caspase 3, whereas degenerated blastomeres were positive for both. Further, nuclear chromatin was compacted. Survival rates of human blastomeres vitrified with Cryotop were 22.78% vs. 53.77% with Cryotip. Division capabilities were 16.6% and 47.16%, respectively, in Cryotop and Cryotip. CONCLUSION(S): The closed system is more efficient in preserving mouse and human blastomeres in terms of acceptable survival and division rates, and it also complies with European Union directives. PMID- 22100171 TI - Efficient cryopreservation of testicular tissue: effect of age, sample state, and concentration of cryoprotectant. AB - OBJECTIVE: To study the effect of age and sample state on cryopreservation of testicular tissue, evaluate toxicity of commonly used cryoprotectants (CPs), and determine their optimal concentration for use. DESIGN: Prospective experimental study. SETTING: Academic research unit. PATIENT(S): Patients with prostate carcinoma undergoing orchidectomy. We also studied immature and adult male Holtzman rats. INTERVENTION(S): Toxicity of CPs before freezing, morphology, and relative viability after freezing were evaluated for rat testicular cell suspensions (CS) and tubular fragments (TUB). Relative viability of adult human testicular CS and TUB after thaw was evaluated. Human TUB were cultured after thaw for 48 hours in medium containing epidermal growth factor (EGF), and effects on viability, morphology, and gene expression were determined. MAIN OUTCOME MEASURE(S): Viability and ploidy were measured with flow cytometry, postthaw cryodamage of immature rat tissue was studied by transmission electron microscopy, cell proliferation and differentiation were evaluated by immunohistochemistry and by real-time polymerase chain reaction. RESULT(S): Immature testicular tissue was more susceptible to toxic assault by CP than adult tissue and displayed cell-specific sensitivity to CP, with glycerol, dimethyl sulfoxide and ethylene glycol being effective in protecting spermatid (1N), spermatogonia (2N) and spermatocyte (4N) populations respectively. Preservation as TUB may be preferred over CS and DMSO is an effective CP for immature and ethylene glycol for adult testicular tissue. CONCLUSION(S): Differential sensitivity of immature testicular tissue to CPs warrants judicious selection of CP on the basis of end application for prepubertal tissue. PMID- 22100172 TI - Polydeoxyribonucleotide administration improves the intra-testicular vascularization in rat experimental varicocele. AB - OBJECTIVE: To study the effect of PDRN on angiogenesis in a model of varicocele in rats. DESIGN: After the creation of experimental varicocele, rats were randomized to one of the four treatments: vehicle, PDRN, DMPX, and PDRN plus DMPX. Twenty-one days after randomization, all animals were euthanized and the left testis was harvested. SETTING: Academic hospital. ANIMAL(S): Male Sprague Dawley rats were used. INTERVENTION(S): A clamp was passed behind the left renal vein distally to the spermatic vein insertion. A silk ligature was placed around the left renal vein at this site and was tied over the top of a probe. The latter was then withdrawn and the vein was allowed to expand. In shams, a suture was placed but it was not tied. MAIN OUTCOME MEASURE(S): To assess testicular microvascular density using CD34 immunostaining. RESULT(S): Microvascular density in the varicocele plus PDRN group was significantly higher than in other groups. CONCLUSION(S): PDRN could represent a novel therapeutic strategy for varicocele treatment in subfertile patients, improving the innate pathophysiologic mechanism of neoangiogenesis, through compensatory oxygen and metabolite supply to tubular and extratubular testicular compartments. PMID- 22100173 TI - Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI). AB - OBJECTIVE: To evaluate the significance of NR5A1 mutations in a large, well phenotyped cohort of women with primary ovarian insufficiency (POI). Mutations in the NR5A1 gene (SF-1) were previously described in disorders of sexual development and adrenal insufficiency. Recently, a high frequency of NR5A1 gene mutations was reported in a small group of women with POI. DESIGN: Cross sectional cohort study. SETTING: University hospital. PATIENT(S): Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The entire coding region and splice sites of the NR5A1 gene were PCR-amplified and sequenced. The pathogenicity of identified mutations was predicted in silico by assessing Align-GVGD class and Grantham score. RESULT(S): Sequencing was successful in 356 patients with POI. In total, 9 mutations were identified in 10 patients. Five of these mutations concerned novel nonconservative mutations occurring in 5 patients. Prediction of effect on protein function showed low to intermediate pathogenicity for all nonconservative mutations. The overall NR5A1 gene mutation rate was 1.4%. CONCLUSION(S): The current study demonstrates that mutations in the NR5A1 gene are rare in women with POI. Primary ovarian insufficiency remains unexplained in the great majority of patients; therefore, continued efforts are needed to elucidate its underlying genetic factors. PMID- 22100174 TI - ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. AB - Glycogen synthase kinase-3 beta (GSK-3beta), a serine/threonine protein kinase, plays a vital role in the tumorigenesis of many cancers, but its role in pancreatic cancer remains unknown. In this study, we showed that GSK-3beta was aberrantly activated in pancreatic cancer. GSK-3beta knockdown resulted in arrested proliferation and increased apoptosis in pancreatic cancer cell lines. Expression of Bcl-2 and vascular endothelial growth factor (VEGF) decreased significantly in a GSK-3beta knockdown group. In a xenograft tumor model, GSK 3beta knockdown inhibited tumor growth and angiogenesis. Our study showed that GSK-3beta may become a promising therapeutic target for human pancreatic cancer. PMID- 22100175 TI - Vertebral body reconstruction system B-Twin(r) versus corset following non osteoporotic Magerl A1.2 thoracic and lumbar fracture. Functional and radiological outcome at 12 month follow-up in a prospective randomized series of 50 patients. AB - INTRODUCTION: Kyphoplasty and percutaneous vertebroplasty are two effective procedures for osteoporotic vertebral compression fractures, but there have been few publications on their use in non-osteoporotic forms. B-Twin((r)) vertebral body reconstruction is a new minimally invasive vertebral body reconstruction technique developed for non-osteoporotic vertebral compression fractures of the thoracolumbar junction and lumbar spine. OBJECTIVES: The present study describes this novel technique and assessed efficacy compared to a conservative method. PATIENTS AND METHODS: Inclusion criteria were: Magerl type A1.2 non-osteoporotic thoracolumbar or lumbar spinal compression fractures in patients aged over 18 years, free of neurologic compromise. Patients were randomized to management by corset (group 1) or by the B-Twin((r)) spacer (group 2). Follow-up used a visual analog scale (VAS) to assess pain, the Oswestry Disability Index (ODI) and, on radiology, the vertebral (VK) and regional (RK) kyphosis angles and anterior and medial height indices at baseline, 3 months and 12 months. RESULTS: Group 1 comprised 26 patients; group 2 comprised 24 patients, with 44 implants. In group 1, mean VK was 10.7 degrees (+/- 1.73 degrees ) at baseline, 11.9 degrees (+/- 1.56 degrees ) at 3 months and 12.3 degrees (+/- 1.6 degrees ) at 12 months. Mean RK was respectively 9.7 degrees (+/- 0.97 degrees ), 11.10 degrees (+/- 1.07 degrees ) and 11.8 degrees (+/- 1.27). Mean medial height (medial-to posterior [MH/PH] height ratio was respectively 0.75 [+/-0.05], 0.70 [+/-0.06] and 0.65 [+/-0.04]). Mean anterior height (anterior-to-posterior [AH/PH] height ratio) was respectively 0.79 [+/- 0.06], 0.76 [+/- 0.05] and 0.73 [+/- 0.05]). Mean VAS score was respectively 8.6 (+/- 0.52), 3.8 (+/- 0.82) and 2.3 (+/- 0.83). In group 2, mean VK was 13.8 degrees (+/- 0.47 degrees ) at baseline, 4.88 degrees (+/- 0.65 degrees ) at 3 months and 4.88 degrees (+/- 0.65 degrees ). Mean RK was respectively 9.82 degrees (+/- 1.67 degrees ), 4.47 degrees (+/- 0.86 degrees ) and 4.82 degrees (+/- 0.98 degrees ). Mean MH/PH ratio was respectively 0.69 (+/- 0.05), 0.86 (+/- 0.03) and 0.86 (+/- 0.03). Mean AH/PH ratio was respectively 0.73 (+/- 0.04), 0.90 (+/- 0.03) and 0.90 (+/- 0.03). Mean VAS score was 8.88 (+/- 0.47) at baseline, 2 (+/- 1) at 1-day post-surgery, 1.71 (+/- 0.88) at 3 months and 1.12 (+/- 0.23) at 12 months. The increase in vertebral body height in patients managed by B-Twin((r)) was maintained at 6 and 12 months (P<0.0001). The study showed better results with the vertebral spacer than on conservative treatment, with a 95% reduction in bed-rest: 4-6 weeks in the conservative group vs. 2-3 days in the surgical group. CONCLUSIONS: The vertebral body reconstruction technique provided anatomic vertebral body reconstruction and quick return to household activity without resort to a corset. Deformity was durably reduced. At 12-month follow-up, pain reduction and stasis were achieved. The risk of injected cement leakage was slight. PMID- 22100176 TI - Comments on: "Posterior reversible encephalopathy syndrome in a context of isolated cervical spine fracture: CT angiogram as an early detector of blunt carotid artery trauma" by R. El Rachkidi, M. Soubeyrand, C. Vincent, V. Molina and C. Court, published in Orthop Traumatol Surg Res 2011;97:454-8. PMID- 22100177 TI - Comments on: "Pyoderma Gangrenosum following an orthopedic surgical procedure" by E. de Thomasson, and I. Caux, published in Orthop Traumatol Surg Res 2010;96:600 602. PMID- 22100178 TI - Hepatotoxicity associated with lapatinib in an experimental rat model. AB - BACKGROUND: The current study is the first to evaluate the biochemical and histopathological features of hepatic toxicity of lapatinib. METHODS: Twenty Wistar albino rats were allocated into three groups: experimental toxicity was induced with lapatinib (10mg/kg) administered for 28 days (Group 1), 42 days (Group 2) orally in a single dose by gavage. Control group received only sterile water. Rats in Group 1 and Group 2 were sacrificed after the collection of blood and tissue samples on the 28th and 42nd days, respectively. RESULTS: Subjects in Group 1 and Group 2 had significantly higher levels of alanin aminotransferase (ALT), albumin, triglyceride and very low density lipoprotein (VLDL) when compared with the control group. None of the subjects in the two experimental groups showed normal histology. There were parenchymal acinar transformation zones, sinusoidal dilatation, hydropic degeneration of hepatocytes, vacuolisation of hepatocytes around the portal areas, and mild inflammation with dominance of mononuclear cells besides neutrophil and eosinophil leucocytes in portal areas, especially pronounced in Group 2. CONCLUSION: This study demonstrated that lapatinib brings about deterioration of lipid profile and triggers hepatic toxicity mainly as sinusoidal injury with elevation in transaminase levels, especially ALT. PMID- 22100179 TI - Intermittent versus continuous exercise training in chronic heart failure: a meta analysis. AB - INTRODUCTION: We conducted a meta-analysis of randomized, controlled trials of combined strength and intermittent aerobic training, intermittent aerobic training only and continuous exercise training in heart failure patients. METHODS: A systematic search was conducted of Medline (Ovid) (1950-September 2011), Embase.com (1974-September 2011), Cochrane Central Register of Controlled Trials and CINAHL (1981-September 19 2011). The search strategy included a mix of MeSH and free text terms for the key concepts heart failure, exercise training, interval training and intermittent exercise training. RESULTS: The included studies contained an aggregate of 446 patients, 212 completed intermittent exercise training, 66 only continuous exercise training, 59 completed combined intermittent and strength training and 109 sedentary controls. Weighted mean difference (MD) in Peak VO2 was 1.04mlkg(-1)min(-1) and (95% C.I.) was 0.42-1.66 (p=0.0009) in intermittent versus continuous exercise training respectively. Weighted mean difference in Peak VO2 was -1.10mlkg(-1)min(-1) (95% C.I.) was 1.83-0.37 p=0.003 for intermittent only versus intermittent and strength (combined) training respectively. In studies reporting VE/VCO2 for intermittent versus control groups, MD was -1.50 [(95% C.I. -2.64, -0.37), p=0.01] and for intermittent versus continuous exercise training MD was -1.35 [(95% C.I. -2.15, 0.55), p=0.001]. Change in peak VO2 was positively correlated with weekly exercise energy expenditure for intermittent exercise groups (r=0.48, p=0.05). CONCLUSIONS: Combined strength and intermittent exercise appears superior for peak VO2 changes when compared to intermittent exercise of similar exercise energy expenditure. PMID- 22100180 TI - Current antithrombotic agents for acute coronary syndromes: focus on bleeding risk. AB - The formation of an intravascular thrombus underlies the clinical symptoms associated with acute coronary syndromes (ACS). Plaque rupture signals the recruitment and activation of platelets, initiation of the coagulation cascade, and generation of thrombin, resulting in the formation of a platelet-rich thrombus. Use of antithrombotic therapy, including antiplatelet and anticoagulant agents, is a crucial element in reducing the overall morbidity and mortality in patients with ACS. Current antiplatelet and anticoagulant therapies act on distinct sites in platelet activation pathways and the coagulation cascade, but because these agents target pathways necessary for protective hemostasis, their use increases the risk for bleeding complications. Previously, bleeding was considered an unavoidable side effect of ACS management with few clinical implications; however, bleeding has since been shown to be an independent predictor of short- and long-term mortality in patients with ACS. Therefore, the prevention of bleeding has become equally as important as the prevention of further ischemic events. Strategies to limit bleeding include bleeding risk stratification, appropriate dosing of antithrombotic drugs, use of the lowest dose of aspirin with proven efficacy, avoidance of combinations of antithrombotic agents unless for a proven indication, use of drugs proven to reduce the risk of bleeding, and choice of radial access over femoral access in case of invasive strategy. In this context, several novel therapeutic approaches are currently under clinical evaluation, including new antiplatelet agents, such as protease activated receptor 1 antagonists, and new anticoagulants, such as direct-acting antagonists of factor Xa and factor IIa (thrombin). This review discusses antiplatelet and anticoagulant treatment strategies for the management of ACS, with a particular focus on their associated bleeding risks. PMID- 22100181 TI - Peripartum cardiomyopathy in Turkey. PMID- 22100182 TI - Insufficient compliance with current implantable cardioverter defibrillator (ICD) therapy guidelines in post myocardial infarction patients is associated with increased mortality. AB - Current clinical guidelines advocate implantable cardioverter defibrillator (ICD) therapy for the prevention of sudden cardiac death among post myocardial infarction (MI) patients. However, there are scarce data regarding compliance with the guidelines and utilization of this life-saving treatment. We aimed to assess the rate of ICD utilization among post MI patients with left ventricular ejection fraction (LVEF) <= 35%. METHODS: All patients admitted with a ST elevation MI at a single tertiary care center from 2005 to 2009, discharged alive with LVEF<=35% and surviving 40 days were included. Patients already implanted with an ICD and whose residence was outside the hospital's area of coverage were excluded. ICD utilization, LVEF re-assessment and mortality were assessed during mean follow up time of 2 years. RESULTS: Of the 285 subjects, only 26 (9%) received an ICD. There were significant differences in ICD use among different medical health organizations (insurers). Among the 259 subjects not implanted with an ICD, repeat echocardiography study for the re-assessment of LVEF was performed in only 176 (68%). Of those, LVEF remained severely impaired in 47%. After excluding subject whose LVEF improved at follow up, the ICD utilization rate was 14%. In a multi-variable analysis, significant predictors of ICD utilization were age below the median of 61 years, and a repeat echocardiography. Using propensity score and matching of subjects implanted with ICD with those not implanted, ICD implantation was found to be associated with survival benefit. CONCLUSIONS: ICDs are underutilized in post MI patients and compliance with current guidelines is insufficient. Failure to re-assess LVEF is a barrier for this life-saving treatment. Withholding ICD therapy among unselected post MI patients with depressed LVEF is associated with a markedly increased mortality. PMID- 22100184 TI - Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: from central release to sites of action. AB - In the mammalian peripartum period, the activity of both the brain oxytocin and vasopressin system is elevated as part of the physiological adaptations occurring in the mother. This is reflected by increased expression and intracerebral release of oxytocin and vasopressin, as well as increased neuropeptide receptor expression and binding. In this review we discuss the functional role of the brain oxytocin and vasopressin system in the context of maternal behavior, specifically maternal care and maternal aggression in rodents. In order to enable the identification of significant and peptide-specific contributions to the display of maternal behavior, various complementary animal models of maternal care and/or maternal aggression were studied, including rats selectively bred for differences in anxiety-related behavior (HAB and LAB dams), monitoring of local neuropeptide release during ongoing maternal behavior, and local pharmacological or genetic manipulations of the neuropeptide systems. The medial preoptic area was identified as a major site for oxytocin- and vasopressin-mediated maternal care. Furthermore, both oxytocin and vasopressin release and receptor activation in the central amygdala and the bed nucleus of the stria terminalis play an important role for maternal aggression. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22100185 TI - Oxytocin receptor knockout mice display deficits in the expression of autism related behaviors. AB - A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the ability to synthesize the oxytocin receptor itself, Oxtr knockout (KO) mice, as compared to their wild-type (WT) littermates. In the visible burrow system, Oxtr KO mice showed robust reductions in frontal approach, huddling, allo-grooming, and flight, with more time spent alone, and in self-grooming, as compared to WT. These results were corroborated in the three-chambered test: unlike WT, Oxtr KO mice failed to spend more time in the side of the test box containing an unfamiliar CD-1 mouse. In the social proximity test, Oxtr KO mice showed clear reductions in nose to nose and anogenital sniff behaviors oriented to an unfamiliar C57BL/6J (B6) mouse. In addition, our study revealed no differences between Oxtr WT and KO genotypes in the occurrence of motor and cognitive stereotyped behaviors. A significant genotype effect was found in the scent marking analysis, with Oxtr KO mice showing a decreased number of scent marks, as compared to WT. Overall, the present data indicate that the profile for Oxtr KO mice, including consistent social deficits, and reduced levels of communication, models multiple components of the ASD phenotype. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID- 22100187 TI - Brisk walking reduces ad libitum snacking in regular chocolate eaters during a workplace simulation. AB - Workplace snacking can contribute to obesity. Exercise reduces chocolate cravings but effects on chocolate consumption are unknown. This study investigated the effect of brief exercise on ad libitum consumption during breaks in a computerised task. Seventy-eight regular chocolate eaters, age: 24.90+/-8.15 years, BMI: 23.56+/-3.78 kg/m(2) abstained for 2 days. They were randomly assigned to one of four conditions, in a 2 * 2 factorial design, involving either a 15 min brisk walk or quiet rest, and then computerised Stroop tasks with low or high demanding conditions, in three 180 s blocks with a 90 s interval. Throughout, a pre-weighed bowl of chocolates was available for ad libitum eating. A two-way ANOVA revealed no interaction effect of exercise and stress on total chocolate consumption, or main effect of stress, but a main effect of exercise [F(1, 74)=7.12, p<.01]. Mean (SD) chocolate consumption was less (t(73.5)=2.69, 95% CI for difference 3.4-22.9, ES=0.61) for the exercise (15.6 g) than control (28.8 g) group. Exercise also increased affective activation, but there was no mediating effect of change in affect on chocolate consumption. A brief walk may help to reduce ad libitum snacking in regular chocolate eaters. PMID- 22100186 TI - Parental feeding practices and socioeconomic status are associated with child adiposity in a multi-ethnic sample of children. AB - Parental feeding practices have been associated with children's weight status, but results have been inconsistent across populations. Research is needed to elucidate the relationship between parental feeding practices and adiposity in diverse populations. The present study tested if: (1) parental feeding practices differed by race/ethnicity, (2) parental pressure to eat and parental restriction were associated with adiposity levels, and (3) to investigate the relationship between parental feeding practices and/or child adiposity with socioeconomic status (SES). Structural equations modeling was conducted to test the model in 267 children aged 7-12 years self-identified as African American (AA), European American (EA), or Hispanic American (HA) from economically diverse backgrounds. Dual energy X-ray absorptiometry and computed tomography scanning were used to determine body composition and abdominal fat distribution, respectively. Parental restriction was a significant predictor of child adiposity while parental pressure to eat had an inverse relationship with child adiposity. HA parents reported significantly higher levels of restriction and pressure to eat, whereas EA parents reported the lowest. SES was positively associated with child adiposity and inversely related to parental restriction and pressure to eat. Thus, parental feeding practices differ across racial/ethnic groups and SES and may contribute to population differences in child adiposity. PMID- 22100188 TI - Ascophyllum nodosum enriched bread reduces subsequent energy intake with no effect on post-prandial glucose and cholesterol in healthy, overweight males. A pilot study. AB - It is well recognised that the consumption of seaweed isolates (such as alginate) successfully reduce energy intake and modulate glycaemic and cholesterolaemic responses. However, to date, the effect of adding whole seaweed to bread has not been widely investigated. Hence, this study aims to investigate the acceptability of Ascophyllum nodosum enriched bread as part of a meal, and measure its effect on energy intake and nutrient absorption in overweight, healthy males to see if it has a similar impact. Results from the acceptability study, (79 untrained sensory panellists) indicated that it is acceptable to incorporate seaweed (A. nodosum) into a staple food such as bread at concentrations of up to 4% per 400 g wholemeal loaf. A single blind cross over trial (n=12 males, aged 40.1+/-12.5 years; BMI 30.8+/-4.4 kg/m(2)) was used to compare energy intake and nutrient uptake after a breakfast meal using the enriched bread (4% A. nodosum) against the control bread (0% A. nodosum). Consumption of the enriched bread at breakfast led to a significant reduction (16.4%) in energy intake at a test meal 4 h later. Differences between treatment arms for area under the curve, peak values, and time of peak for blood glucose and cholesterol were not significant. Further investigation of potential mechanisms of action is warranted. PMID- 22100189 TI - Moist occlusive dressing (Aquacel((r)) Ag) versus moist open dressing (MEBO((r))) in the management of partial-thickness facial burns: a comparative study in Ain Shams University. AB - INTRODUCTION: The face is the central point of the physical features; it transmits expressions and emotions, communicates feelings and allows for individual identity. Facial burns are very common and are devastating to the affected patient and results into numerous physical, emotional and psychosocial sequels. Partial thickness facial burns are very common especially among children. This study compares the effect of standard moist open technique management and a moist closed technique for partial thickness burns of the face. PATIENTS AND METHODS: Patients with partial-thickness facial burns admitted in the burn unit, Ain Shams University, Cairo, Egypt in the period from April 2009 to December 2009 were included in this study. They were divided into two groups to receive either open treatment with MEBO((r)) (n=20) or coverage with Aquacel((r)) Ag (n=20). Demographics (age, gender, ethnicity, TBSA, burn areas), length of hospital stay (LOS), rate of infections, time to total healing, frequency of dressing changes, pain, cost benefit and patient discomfort were compared between the two groups. The long-term outcome (incidence of hypertrophic scarring) was assessed for up to 6 months follow-up period. RESULTS: There were no significant differences in demographics between the two groups. In the group treated with the Aquacel((r)) Ag, the mean time for re-epithelialization was 10.5 days, while it was 12.4 days in the MEBO((r)) group (p<0.05). Frequency of changes, pain and patient discomfort were less with Aquacel((r)) Ag. Cost was of no significant difference between the two groups. Scar quality improved in the Aquacel((r)) Ag treatment group. Three and 6 months follow-up was done and long term outcomes were recorded in both groups. CONCLUSION: Moist occlusive dressing (Aquacel((r)) Ag) significantly improves the management and healing rate of partial thickness facial burns with better long-term outcome compared to moist open dressing (MEBO((r))). PMID- 22100190 TI - Oral immunization of the African clawed frog (Xenopus laevis) upregulates the mucosal immunoglobulin IgX. AB - The frog Xenopus laevis is a model species for developmental biology but is also of significant interest to comparative immunologists. Amphibians are the oldest group of organisms in which both the B lymphocytes of some species undergo immunoglobulin (Ig) class switch recombination and also have a dedicated mucosal Ig isotype. The purpose of this study was to test the hypothesis that frog IgX would be produced in response to oral immunization. In order to facilitate studies of humoral, and especially mucosal immunity, in this model species, we developed a gavage technique for oral immunization. The result of this oral administration of antigen to frogs was assayed by the induction of the mucosal antibody isotype, IgX, in plasma by enzyme linked immunosorbant assay (ELISA), and a significant IgX upregulation was detected compared to frogs receiving systemic immunization into the coelom. These data are consistent with the view that IgX is the functional analog of mammalian IgA and mandate further studies of the relationship between IgX and IgA. Additionally, the gavage technique should be adaptable for functional studies of gut-associated immunology in other small aquatic vertebrates. PMID- 22100191 TI - Improvements of immune status, intestinal integrity and gain performance in the early-weaned calves parenterally supplemented with L-alanyl-L-glutamine dipeptide. AB - Glutamine (Gln) is an important substrate for the innate immune cells including lymphocytes and macrophages. In this report, the effects of alanyl-glutamine dipeptide (Ala-Gln) on the naive immune system, intestinal integrity and gain performance of early-weaned calves were investigated. Early-weaned Chinese Holstein calves were intravenously administered different dosages of Ala-Gln. The effects of Ala-Gln administration were ascertained by evaluating the blood for naive T lymphocyte subpopulations, the concentrations of serum IgG, serum IgA and intestinal mucosal secretory IgA (s-IgA), the intestinal integrity, as well as the gain performance. Results demonstrated that intravenous administration of Ala Gln dipeptide (1.01 g/kg*d(-1)) for 7 days had a positive effect on gain performance, intestinal integrity and the immune system. Calves administered doses of Ala-Gln displayed an improvement in gain performance and health status concurrent with increases in blood CD2(+) and CD4(+) lymphocytes, the ratio of CD4(+)/CD8(+), serum IgA and IgG, intestinal mucosal s-IgA while decreasing the occurrence of diarrhea. Moreover, we found that animals given the effective dose (1.01 g/kg*d(-1)) of Ala-Gln resulted in improved immune status and intestinal integrity relative to those given a lower (0.49 g/kg*d(-1)) or higher dose (1.99 g/kg*d(-1)) of Ala-Gln. These findings suggest that maintaining a certain concentration of plasma and/or tissue glutamine in the early stages of weaning is an effective alternative approach for improvement of growth performance in early wean calves. PMID- 22100192 TI - Serum amyloid A isoforms in serum and milk from cows with Staphylococcus aureus subclinical mastitis. AB - Serum amyloid A proteins (SAA) are very sensitive acute phase proteins, displaying multiple isoforms in plasma and different body fluids. They are currently under investigation as biomarkers of diseases. The aim of the present study was to compare the concentration and isoform expression of SAA in serum and milk of cows with bacteriologically negative milk (control group) and naturally occurring Staphylococcus aureus (S. aureus) subclinical mastitis (subclinical mastitis group). Somatic cell count (SCC) and bacteriological analyses were performed to establish the control and subclinical mastitis group. SAA concentration was evaluated using a commercial ELISA kit, while expression of different isoforms (serum A-SAA and milk M-SAA3 isoforms) was visualized by denaturing isoelectrical focusing and immunoblotting. The SAA concentrations in sera and milk of cows in the subclinical mastitis group were three and 100 times higher than in those from the control group of cows, respectively. Cows in the subclinical mastitis group had more acidic SAA isoforms in serum with the most prominent one at pI 5.5. This isoform was not detected in sera from the control group. Milk samples in the subclinical mastitis group contained abundant highly alkaline M-SAA3 isoforms and most of the serum isoforms, except for that at pI 5.5. In the subclinical mastitis group SAA isoforms with equivalent pI as serum isoforms accounted for 20% of the total SAA concentration in milk. There were significant differences in the concentrations and isoform patterns of SAA in serum and milk between the control and subclinical mastitis groups of cows. Also, we demonstrated that serum SAA isoforms were not transferred to milk proportion to their plasma content. PMID- 22100193 TI - Extracellular hsp70 release in canine Steroid Responsive Meningitis-Arteritis. AB - The role of extracellular 70 kDa heat shock protein 70 (ehsp70) in central nervous system inflammation is vastly understudied, despite evidence supporting the ability to drive a pro-inflammatory state. We investigated the presence of ehsp70 in cerebrospinal fluid (CSF) and serum of dogs with Steroid Responsive Meningitis-Arteritis (SRMA), with the hypothesis that an ehsp70 response would occur, and might play a role in the pathogenesis of this disease. Samples from 30 dogs acutely affected with SRMA, and 30 dogs treated with corticosteroids and currently in clinical remission from SRMA were compared with normal dogs. Serum and CSF concentrations of ehsp70 were quantified using an enzyme-linked immunosorbent assay. An ehsp70 response occurred in the CSF of dogs with SRMA and this response was attenuated by corticosteroid treatment. There was no correlation between serum and CSF concentrations of ehsp70, supporting local production and release of ehsp70 and not simply leakage from serum. Dogs with SRMA thus represent a powerful spontaneous model by which to study the role of ehsp70 in CNS inflammation. PMID- 22100194 TI - Candesartan-based therapy and risk of cancer in patients with systemic hypertension (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease [HIJ-CREATE] substudy). AB - The aim of the present study was to clarify the influence of candesartan-based therapy on subsequent carcinogenesis and cancer death in patients with coronary artery disease with hypertension in a substudy of a multicenter, prospective, randomized, controlled trial. That trial compared the effects of candesartan based therapy with those of non-angiotensin receptor blocker (ARB)-based standard therapy on major adverse cardiovascular events. Hypertensive patients with coronary artery disease were randomly assigned to receive either candesartan based (n = 1,024) or non-ARB-based pharmacotherapy, including angiotensin converting enzyme inhibitors (n = 1,025). During a median follow-up of 4.2 years, 1,606 adverse events (798 in the candesartan group and 808 in the non-ARB standard group) were reported. Among them, new cancer occurred in 5.37% of subjects in the candesartan group and 5.66% of subjects in the standard therapy group (hazard ratio 0.95, 95% confidence interval 0.65 to 1.38). Cancer deaths occurred in 1.66% in the candesartan group and 2.44% in the standard therapy group, respectively (hazard ratio 0.74, 95% confidence interval 0.39 to 1.39). Kaplan-Meier estimates of survival without new cancer and cancer deaths demonstrated that candesartan-based therapy does not accelerate the occurrence of new cancer (log-rank, p = 0.84) or cancer death (p = 0.39) compared to standard therapy. Advanced age and male gender were independently and significantly correlated with the subsequent incidence of cancer. In conclusion, the results of the present study suggest that candesartan-based therapy is not associated with either carcinogenesis or cancer death compared to non-ARB standard therapy. PMID- 22100195 TI - Atrial fibrillation registries, administrative databases, clinical trials, and outcomes. PMID- 22100196 TI - Comparison of women versus men hospitalized with heart failure (from a 20-year registry in a middle-eastern country 1991-2010). AB - The aim of the present study was to compare the clinical characteristics, treatment, and outcomes of women and men hospitalized with heart failure (HF) in a Middle-Eastern country. A retrospective analysis of all patients hospitalized with HF in the State of Qatar from 1991 through 2010 was made. The clinical characteristics, management, and outcomes of the patients with HF were compared according to gender. A subset analysis according to ethnicity was also done (Middle Eastern Arabs vs South Asians). During the 20-year period, 2,379 women and 4,689 men were hospitalized for HF. The women were older and more likely to have diabetes mellitus, hypertension, and chronic renal impairment compared to the male patients. The women were less likely to be current smokers and to have ischemic heart disease compared to the men. Impaired left ventricular function was more common among men. The in-hospital mortality rates were comparable between the 2 groups (7.7% in women vs 8.2% in men; p = 0.4) and significantly improved with time in the 2 groups (p = 0.001). The mortality rates were comparable among the women, regardless of the ethnicity. In conclusion, overall improvement occurred in survival in patients hospitalized with HF in a Middle Eastern country, regardless of gender. Women hospitalized with HF had mortality rates comparable to those of men. PMID- 22100197 TI - [Antiphospholipid antibodies in practice]. AB - Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of thrombotic or obstetrical events associated with the presence in the serum of patients of antibodies that are associated with thrombosis. For the diagnosis of APS, the presence of either lupus anticoagulant, anticardiolipin or anti-beta2-glycoprotein1 antibodies of IgG or IgM isotype is required through laboratory testing. Other autoantibodies such as antiphosphatidylethanolamin or antiphosphatidylserin/prothrombin complex antibodies may be interesting in the diagnosis of APS when common antiphospholipid antibodies are missing. These autoantibodies are still under evaluation for their diagnostic contribution. Despite numerous attempts, the assays that are available for the identification of antiphospholipid antibodies have not been standardized yet, which leads to high variability between reagents and laboratories. Thus, to optimize the biological monitoring of APS syndromes, it is mandatory to have consecutive samples analyzed in the same laboratory. PMID- 22100198 TI - [Do we need to be afraid of biosimilars?]. PMID- 22100199 TI - [A pigmented rash]. PMID- 22100200 TI - [Buttock pain]. PMID- 22100201 TI - The natural history of self-harm from adolescence to young adulthood: a population-based cohort study. AB - BACKGROUND: Knowledge about the natural history of self-harm is scarce, especially during the transition from adolescence to young adulthood, a period characterised by a sharp rise in self-inflicted deaths. From a repeated measures cohort of a representative sample, we describe the course of self-harm from middle adolescence to young adulthood. METHODS: A stratified, random sample of 1943 adolescents was recruited from 44 schools across the state of Victoria, Australia, between August, 1992, and January, 2008. We obtained data pertaining to self-harm from questionnaires and telephone interviews at seven waves of follow-up, commencing at mean age 15.9 years (SD 0.49) and ending at mean age 29.0 years (SD 0.59). Summary adolescent measures (waves three to six) were obtained for cannabis use, cigarette smoking, high-risk alcohol use, depression and anxiety, antisocial behaviour and parental separation or divorce. FINDINGS: 1802 participants responded in the adolescent phase, with 149 (8%) reporting self harm, More girls (95/947 [10%]) than boys (54/855 [6%]) reported self-harm (risk ratio 1.6, 95% CI 1.2-2.2). We recorded a substantial reduction in the frequency of self-harm during late adolescence. 122 of 1652 (7%) participants who reported self-harm during adolescence reported no further self-harm in young adulthood, with a stronger continuity in girls (13/888) than boys (1/764). During adolescence, incident self-harm was independently associated with symptoms of depression and anxiety (HR 3.7, 95% CI 2.4-5.9), antisocial behaviour (1.9, 1.1 3.4), high-risk alcohol use (2.1, 1.2-3.7), cannabis use (2.4, 1.4-4.4), and cigarette smoking (1.8, 1.0-3.1). Adolescent symptoms of depression and anxiety were clearly associated with incident self-harm in young adulthood (5.9, 2.2-16). INTERPRETATION: Most self-harming behaviour in adolescents resolves spontaneously. The early detection and treatment of common mental disorders during adolescence might constitute an important and hitherto unrecognised component of suicide prevention in young adults. FUNDING: National Health and Medical Research Council, Australia, and operational infrastructure support programme, Government of Victoria, Australia. PMID- 22100202 TI - Self-harm in adolescence and future mental health. PMID- 22100203 TI - Perinatal complications and cesarean delivery among foreign-born and Australian born women in Western Australia, 1998-2006. AB - OBJECTIVE: To determine whether common perinatal complications could explain variation in risk of cesarean among foreign-born and Australian-born women in Western Australia (WA). METHODS: Complication prevalence was calculated using the linked records of 208 982 confinements to non-indigenous women in WA between 1998 and 2006. Logistic regression was used to estimate differences in risk of elective cesarean and emergency cesarean compared with vaginal delivery for foreign-born women from different regions. RESULTS: The most common complications in emergency cesareans were failure to progress (36.7%) and fetal distress (35.7%). The most common complications in elective cesareans were previous cesarean (56.2%) and malpresentation (16.3%). Women from Sub-Saharan Africa, Southeast Asia, and Southern and Central Asia had an increased risk of emergency cesarean compared with Australian-born women (P<0.05), whereas women from Oceania, North Africa and the Middle East, and Northeast Asia had a decreased likelihood of elective cesarean compared with Australian-born women (P<0.05). CONCLUSION: Complication prevalence varied by maternal region of birth. However, variation in these complications does not completely explain differences in mode of delivery among foreign-born and Australian-born women in WA. Sociocultural factors must be considered in future research and when establishing culturally appropriate guidelines for obstetric staff dealing with foreign-born women. PMID- 22100204 TI - Sublingual misoprostol versus intramuscular oxytocin for prevention of postpartum hemorrhage in low-risk women. AB - OBJECTIVE: To compare sublingual misoprostol with intramuscular oxytocin for prevention of postpartum hemorrhage (PPH) in low-risk vaginal birth. METHODS: In a prospective, randomized, double-blind trial, 530 women without risk of PPH were randomly allocated to receive either 400 MUg of misoprostol sublingually or 10 units of oxytocin intramuscularly within 1minute of delivery. The outcome measures were incidence of PPH, postpartum blood loss, drop in hemoglobin level in 24 hours, need for additional uterotonic drug, incidence of adverse effects, and need for blood transfusion. Student t, chi(2), Mann-Whitney U, and Fisher exact tests were used for comparison. RESULTS: Incidence of postpartum hemorrhage (>= 500 mL) and postpartum blood loss in the misoprostol group were similar to those in the oxytocin group (6% versus 5.7%, P=0.85; 153 mL versus 146 mL, P=0.36). Shivering and pyrexia were encountered more often in the misoprostol than in the oxytocin group (shivering: 19% versus 0.8%, P<0.001, relative risk [RR] 0.86, 95% confidence interval [CI] 0.82-0.90; pyrexia: 2.3% versus 0%, P=0.03, RR 0.97, 95% CI 0.95-0.99). CONCLUSION: The efficacy of 400 MUg of misoprostol administered sublingually was equivalent to that of 10 units of oxytocin given intramuscularly for prevention of PPH in low-risk vaginal delivery. PMID- 22100205 TI - Ultraviolet B irradiation induces the expression of IL-33 mRNA and protein in normal human epidermal keratinocytes. PMID- 22100206 TI - Military penetrating spine injuries compared with blunt. AB - BACKGROUND CONTEXT: The nature of blunt and penetrating injuries to the spine and spinal column in a military combat setting has been poorly documented in the literature. To date, no study has attempted to characterize and compare blunt and penetrating spine injuries sustained by American servicemembers. PURPOSE: The purpose of this study was to compare the military penetrating spine injuries with blunt spine injuries in the current military conflicts. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: All American military servicemembers who have been injured while deployed in Iraq (Operation Iraqi Freedom) and Afghanistan (Operation Enduring Freedom) whose medical data have been entered into the Joint Theater Trauma Registry (JTTR). METHODS: The JTTR was queried for all American servicemembers sustaining an injury to the spinal column or spinal cord while deployed in Iraq or Afghanistan. These data were manually reviewed for relevant information regarding demographics, mechanism of injury, surgical intervention, and neurologic injury. RESULTS: A total of 598 servicemembers sustained injuries to the spine or spinal cord. Isolated blunt injuries were recorded in 396 (66%) servicemembers and 165 (28%) sustained isolating penetrating injuries. Thirty servicemembers (5%) sustained combined blunt and penetrating injuries to the spine. The most commonly documented injuries were transverse process fractures, compression fractures, and burst fractures in the blunt-injured servicemembers versus transverse process fractures, lamina fractures, and spinous process fractures in those injured with a penetrating injury. One hundred four (17%) servicemembers sustained spinal cord injuries, comprising 10% of blunt injuries and 38% of penetrating injuries (p<.0001). Twenty-eight percent (28%) of blunt-injured servicemembers underwent a surgical procedure compared with 41% of those injured by penetrating mechanisms (p=.4). Sixty percent (n=12/20) of blunt-injured servicemembers experienced a neurologic improvement after surgical intervention at follow-up compared with 43% of servicemembers (n=10/23) who underwent a surgical intervention after a penetrating trauma (p=.28). Explosions accounted for 58% of blunt injuries and 47% of penetrating injuries, whereas motor vehicle collisions accounted for 40% of blunt injuries and 2% of penetrating injuries. Concomitant injuries to the abdomen, chest, and head were common in both groups. CONCLUSIONS: Blunt and penetrating injuries to the spinal column and spinal cord occur frequently in the current conflicts in Iraq and Afghanistan. Penetrating injuries result in significantly higher rates of spinal cord injury and trend toward increased rates of operative interventions and decreased neurologic improvement at follow-up. PMID- 22100207 TI - Complications associated with military spine injuries. AB - BACKGROUND CONTEXT: To assess the presence of complications associated with spine injuries in the Global War on Terror. PURPOSE: To characterize the effect of complications in and around the battlefield during Operation Enduring Freedom and Operation Iraqi Freedom from 2001 to 2009. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: American servicemembers sustaining spine injury during combat. METHODS: Extracted medical records of warriors identified by the Joint Theater Trauma Registry from October 2001 to December 2009. Complications were defined as unplanned medical events that required further intervention. Complications were classified as major or minor and further subdivided among groups, including surgical and nonsurgical management, mounted (in an armored vehicle) or dismounted at the time of injury, and blunt or penetrating trauma. RESULTS: Major complications were encountered in 55 servicemembers (9%), and 38 (6%) sustained minor complications. Forty-four percent (n=24) of those with major complications had more than one complication. Eleven servicemembers sustained three or more complications. There were five intraoperative complications, and 50 occurred in the perioperative period. Intraoperative complications included gastrointestinal injury, dural tear, and instrument malposition. Among patients who sustained complications, precipitating spinal injuries occurred primarily in combat (n=43 [78%]) and resulted from blunt (18) or penetrating (25) mechanisms. Complications occurred in 10 (3%) of those treated nonoperatively and 45 (25%) of those receiving surgery. Complications were higher in the dismounted group (80%) as compared with those who were mounted in vehicles at the time of injury (20%). Thirty-five percent (n=24) of surgically treated, dismounted, and penetrating injured servicemembers had complications. Seventeen percent (n=8) of surgically treated and blunt injured mounted servicemembers and 20% (n=13) of dismounted servicemembers had complications. Among the dismounted and nonspinal cord-injured servicemembers, both blunt (p=.002) and penetrating injured (p<.0005) treated with surgery were correlated with complications. Only the dismounted servicemembers with spinal cord injuries because of a penetrating mechanism were also at an increased risk for complications (p<.0005). CONCLUSIONS: Patients treated with surgery appear to be at increased complication risk regardless of the mechanism of injury. Uparmored vehicles may safeguard servicemembers from spine injuries and complications associated with their treatment. This may be reflective of the fact that less severe spinal and concomitant injuries are sustained in the precipitating trauma because of the protection afforded by the vehicle. Dismounted soldiers had more complications in all groups regardless of type of management or injury mechanism. PMID- 22100208 TI - Spine-area pain in military personnel: a review of epidemiology, etiology, diagnosis, and treatment. AB - BACKGROUND CONTEXT: Nonbattle illnesses and injuries are the major causes of unit attrition in modern warfare. Spine-area pain is a common disabling injury in service members associated with a very low return-to-duty (RTD) rate. PURPOSE: To provide an overview of the current understanding of epidemiology, possible causes, and relative prognosis of spine-area pain syndromes in military personnel, including a discussion of various treatment options available in theaters of operation. STUDY DESIGN: Literature review. METHODS: Search focusing on epidemiology, etiology and associative factors, and treatment of spinal pain using electronic databases, textbooks, bibliographic references, and personal accounts. RESULTS: Spine-area pain is the most common injury or complaint "in garrison" and appears to increase during training and combat deployments. Approximately three-quarters involve low back pain, followed by cervical and midback pain syndromes. Some predictive factors associated with spine-area pain are similar to those observed in civilian cohorts, such as psychosocial distress, heavy physical activity, and more sedentary lifestyle. Risk factors specific to military personnel include concomitant psychological trauma, g-force exposure in pilots and airmen, extreme shock and vibration exposure, heavy combat load requirements, and falls incurred during airborne, air assault, and urban dismounted ground operations. Effective forward-deployed treatment has been difficult to implement, but newer strategies may improve RTD rates. CONCLUSIONS: Spine-area pain syndromes comprise a major source of unit attrition and are often the result of duty-related burdens incurred during combat operations. Current strategies in theaters of operation that may improve the low RTD rates include individual and unit level psychological support, early resumption of at least some forward-area duties, multimodal treatments, and ergonomic modifications. PMID- 22100209 TI - Stirrup forces during horse riding: a comparison between sitting and rising trot. AB - Injuries of horses might be related to the force the rider exerts on the horse. To better understand the loading of the horse by a rider, a sensor was developed to measure the force exerted by the rider on the stirrups. In the study, five horses and 23 riders participated. Stirrup forces measured in sitting trot and rising trot were synchronised with rider movements measured from digital films and made dimensionless by dividing them by the bodyweight (BW) of the rider. A Fourier transform of the stirrup force data showed that the signals of both sitting and rising trot contained 2.4 and 4.8 Hz frequencies. In addition, 1.1 and 3.7 Hz frequencies were also present at rising trot. Each stride cycle of trot showed two peaks in stirrup force. The heights of these peaks were 1.17+/ 0.28 and 0.33+/-0.14 in rising and 0.45+/-0.24 and 0.38+/-0.22 (stirrup force (N)/BW of rider (N)) in sitting trot. A significant difference was found between the higher peaks of sitting and rising trot (P<0.001) and between the peaks within a single stride for both riding styles (P<0.001). The higher peak in rising trot occurred during the standing phase of the stride cycle. Riders imposed more force on the stirrups during rising than sitting trot. A combination of stirrup and saddle force data can provide additional information on the total loading of the horse by a rider. PMID- 22100210 TI - Repeatability in the assessment of multi-segment foot kinematics. AB - A recently published systematic review on 3D multi-segment foot models has illustrated the lack of repeatability studies providing evidence for appropriate clinical decision making. The aim of the current study was to assess the repeatability of the recently published model developed by Leardini et al. [10]. Foot kinematics of six healthy adults were analyzed through a repeated-measures design including two therapists with different levels of experience and four test sessions. For the majority of the parameters moderate or good repeatability was observed for the within-day and between-day sessions. A trend towards consistently higher within- and between-day variability was observed for the junior compared to the senior clinician. The mean inter-session variability of the relative 3D rotations ranged between 0.9-4.2 degrees and 1.6-5.0 degrees for respectively the senior and junior clinician whereas for the absolute angles this variability increased to respectively 2.0-6.2 degrees and 2.6-7.8 degrees . Mean inter-therapist standard deviations ranged between 2.2 degrees and 6.5 degrees for the relative 3D rotations and between 2.8 degrees and 7.6 degrees for the absolute 3D rotations. The ratio of inter-therapist to inter-trial errors ranged between 1.8 and 5.5 for the relative 3D rotations and between 2.4 and 9.7 for the absolute 3D rotations. Absolute angle representation of the planar angles was found to be more difficult. Observations from the current study indicate that an adequate normative database can be installed in gait laboratories, however, it should be stressed that experience of therapists is important and gait laboratories should therefore be encouraged to put effort in training their clinicians. PMID- 22100211 TI - Pulse pressure variation predicts fluid responsiveness in elderly patients after coronary artery bypass graft surgery. AB - OBJECTIVE: To assess the ability of pulse pressure variation to predict fluid responsiveness in mechanically ventilated elderly patients after coronary artery bypass graft surgery. DESIGN: A prospective, interventional study. SETTING: An academic, tertiary referral hospital. PARTICIPANTS: Sixty patients >70 years old and mechanically ventilated after coronary artery bypass graft surgery. INTERVENTIONS: Intravascular volume expansion using 6% hydroxyethyl starch solution, 7 mL/kg over 20 minutes. MEASUREMENTS AND MAIN RESULTS: Heart rate, arterial blood pressure, pulse pressure variation, central venous pressure, pulmonary artery occlusion pressure, and stroke volume index were measured immediately before and after volume expansion. Fluid responsiveness was defined as an increase in stroke volume index >= 15% after volume expansion. Forty-one patients were fluid responders and 19 patients were nonresponders. In contrast to central venous pressure or pulmonary artery occlusion pressure, pulse pressure variation was higher in the responders than in the nonresponders (22 +/- 6% v 9.3 +/- 3%, p = 0.001) and correlated with the percent changes in the stroke volume index after volume expansion (r = 0.47, p = 0.001). The area under the receiver operating characteristic curve for pulse pressure variation was 0.85 (95% confidence interval 0.75-0.94). The threshold value of 11.5% allowed the discrimination between responders and nonresponders with a sensitivity of 80% and a specificity of 74%. CONCLUSIONS: Pulse pressure variation is a reliable predictor of fluid responsiveness in mechanically ventilated elderly patients after coronary artery bypass graft surgery. PMID- 22100212 TI - Noncardiac surgery in the prone position in patients with ventricular assist devices. PMID- 22100213 TI - A randomized, double-blind trial comparing continuous thoracic epidural bupivacaine with and without opioid in contrast to a continuous paravertebral infusion of bupivacaine for post-thoracotomy pain. AB - OBJECTIVE: To compare the results of continuous epidural bupivacaine analgesia with and without hydromorphone to continuous paravertebral analgesia with bupivcaine in patients with post-thoracotomy pain. DESIGN: A prospective, randomized, double-blinded trial. SETTING: A teaching hospital. PARTICIPANTS: Patients at a tertiary care teaching hospital undergoing throracotomy for lung cancer. INTERVENTIONS: Subjects were assigned randomly to receive a continuous thoracic epidural or paravertebral infusion. Patients in the epidural group were randomized to receive either bupivacaine alone or in combination with hydromorphone. Visual analog scores as well as incentive spirometery results were obtained before and after thoracotomy. METHODS AND MAIN RESULTS: Seventy-five consecutive patients presenting for thoracotomy were enrolled in this institutional review board-approved study. On the morning of surgery, subjects were randomized to either an epidural group receiving bupvicaine with and without hydromorphone or a paravertebral catheter-infused bupvicaine. Postoperative visual analog scores and incentive spirometry data were measured in the postanesthesia care unit, the evening of the first operative day, and daily thereafter until postoperative day 4. Analgesia on all postoperative days was superior in the thoracic epidural group receiving bupivacaine plus hydromorphone. Analgesia was similar in the epidural and continuous paravertebral groups receiving bupivacaine alone. No significant improvement was noted by combining the continuous infusion of bupivacaine via the paravertebral and epidural routes. Incentive spirometry goals were best achieved in the epidural bupivacaine and hydromorphone group and equal in the group receiving bupivacaine alone either via epidural or continuous paravertebral infusion. CONCLUSIONS: The current study provided data that fill gaps in the current literature in 3 important areas. First, this study found that thoracic epidural analgesia (TEA) with bupivacaine and a hydrophilic opioid, hydromorphone, may provide enhanced analgesia over TEA or continuous paravertebral infusion (CPI) with bupivacaine alone. Second, in the bupivacaine-alone group, the increased basal rates required to achieve analgesia resulted in hypotension more frequently than in the bupivacaine/hydromorphone combination group, underscoring the benefit of the synergistic activity. Finally, in agreement with previous retrospective studies, the current data suggest that CPI of local anesthetic appears to provide acceptable analgesia for post thoracotomy pain. PMID- 22100215 TI - Enhancement of the detection limit for lateral flow immunoassays: evaluation and comparison of bioconjugates. AB - There is an increasing demand for convenient and accurate point-of-care tools that can detect and diagnose different stages of a disease in remote or impoverished settings. In recent years, lateral flow immunoassays (LFIA) have been indicated as a suitable medical diagnostic tool for these environments because they require little or no sample preparation, provide rapid and reliable results with no electronic components and thus can be manufactured at low costs and operated by unskilled personnel. However, even though they have been successfully applied to acute and chronic disease detection, LFIA based on gold nanoparticles, the standard marker, show serious limitations when high sensitivity is needed, such as early stage disease detection. Moreover, based on the lack of comparative information for label performance, significant optimization of the systems that are currently in use might be possible. To this end, in the presented work, we compare the detection limit between the four most used labels: colloidal-gold, silver enhanced gold, blue latex bead and carbon black nanoparticles. Preliminary results were obtained by using the biotin streptavidin coupling as a model system and showed that carbon black had a remarkably low detection limit of 0.01 MUg/mL in comparison to 0.1 MUg/mL, 1 MUg/mL and 1mg/mL for silver-coated gold nanoparticles, gold nanoparticles and polystyrene beads, respectively. Therefore, as a proof of concept, carbon black was used in a detection system for Dengue fever. This was achieved by immobilizing monoclonal antibodies for the nonstructural glycoprotein (NS1) of the Dengue virus to carbon black. We found that the colorimetric detection limit of 57 ng/mL for carbon black was ten times lower than the 575 ng/mL observed for standard gold nanoparticles; which makes it sensitive enough to diagnose a patient on the first days of infection. We therefore conclude that, careful screening of detection labels should be performed as a necessary step during LFIA development in order to enhance the detection limit in a final test system. PMID- 22100214 TI - Mismatch-mediated error prone repair at the immunoglobulin genes. AB - The generation of effective antibodies depends upon somatic hypermutation (SHM) and class-switch recombination (CSR) of antibody genes by activation induced cytidine deaminase (AID) and the subsequent recruitment of error prone base excision and mismatch repair. While AID initiates and is required for SHM, more than half of the base changes that accumulate in V regions are not due to the direct deamination of dC to dU by AID, but rather arise through the recruitment of the mismatch repair complex (MMR) to the U:G mismatch created by AID and the subsequent perversion of mismatch repair from a high fidelity process to one that is very error prone. In addition, the generation of double-strand breaks (DSBs) is essential during CSR, and the resolution of AID-generated mismatches by MMR to promote such DSBs is critical for the efficiency of the process. While a great deal has been learned about how AID and MMR cause hypermutations and DSBs, it is still unclear how the error prone aspect of these processes is largely restricted to antibody genes. The use of knockout models and mice expressing mismatch repair proteins with separation-of-function point mutations have been decisive in gaining a better understanding of the roles of each of the major MMR proteins and providing further insight into how mutation and repair are coordinated. Here, we review the cascade of MMR factors and repair signals that are diverted from their canonical error free role and hijacked by B cells to promote genetic diversification of the Ig locus. This error prone process involves AID as the inducer of enzymatically-mediated DNA mismatches, and a plethora of downstream MMR factors acting as sensors, adaptors and effectors of a complex and tightly regulated process from much of which is not yet well understood. PMID- 22100216 TI - Oral immunization using HgbA in a recombinant chancroid vaccine delivered by attenuated Salmonella typhimurium SL3261 in the temperature-dependent rabbit model. AB - Chancroid, a sexually transmitted genital ulcer disease caused by the Gram negative bacterium Haemophilus ducreyi, facilitates the acquisition and transmission of HIV. An effective vaccine against chancroid has not been developed. In this preliminary study, the gene encoding the H. ducreyi outer membrane hemoglobin receptor HgbA was cloned into the plasmid pTETnir15. The recombinant construct was introduced into the attenuated Salmonella typhimurium SL3261 strain and stable expression was induced in vitro under anaerobic conditions. The vaccine strain was delivered into the temperature-dependent rabbit model of chancroid by intragastric immunization as a single dose, or as three doses administered at two-weekly intervals. No specific antibody to HgbA was elicited after either dose schedule. Although the plasmid vector survived in vivo passage for up to 15 days following single oral challenge, HgbA expression was restricted to plasmid isolates recovered one day after immunization. Rabbits inoculated with the 3-dose booster regimen achieved no protective immunity from homologous challenge. These results emphasize that refinements in plasmid design to enhance a durable heterologous protein expression are necessary for the development of a live oral vaccine against chancroid. PMID- 22100217 TI - [Editorial]. PMID- 22100218 TI - [Upper gastrointestinal haemorrhage in patients over 80 years-old]. AB - OBJECTIVES: To evaluate the patient characteristics, outcome, and prognosis of upper gastrointestinal haemorrhage in the elderly. MATERIAL AND METHODS: A prospective study was conducted on 103 patients aged 80 years and over, admitted to a Gastrointestinal Bleeding Unit after an episode of upper gastrointestinal bleeding. We analysed the personal history, the characteristics of the bleeding event, and whether an urgent diagnostic or therapeutic endoscopy was performed, in order to identify clinical data and endoscopic findings that may have an influence on the outcome of the haemorrhage. RESULTS: The major cause of the haemorrhage was peptic ulcer in 65.1%, and 60.2% of patients were on chronic treatment with non-steroidal anti-inflammatory drugs. An urgent diagnostic endoscopy was performed in all of them, identifying the source of bleeding in 94.2%, and treatment was carried out on 28.2%. The likelihood of rebleeding was 8%, and 4.9% of patients underwent emergency surgery, with an overall mortality rate of 5.8%. CONCLUSIONS: The performance of urgent endoscopy and the application of endoscopic haemostasis are safe and effective in stopping upper gastrointestinal bleeding in the elderly. This has significantly reduced the need for emergency surgery, improving the survival of the bleeding elderly patient and preventing recurrent bleeding. PMID- 22100219 TI - [The bookmarks of life. Emotion as a tool for the diagnosis of Alzheimer's]. PMID- 22100220 TI - Enhanced magnetic separation and photocatalytic activity of nitrogen doped titania photocatalyst supported on strontium ferrite. AB - An enhanced ferromagnetic property, visible light active TiO(2) photocatalyst was successfully synthesized by supporting strontium ferrite (SrFe(12)O(19)) onto TiO(2) doped with nitrogen (N) and compared with N-doped TiO(2). The synthesized catalysts were further characterized with X-ray diffraction (XRD), transmission electron microscope (TEM), energy dispersive X-ray spectroscopy (EDS), BET surface area analysis, vibrating sample magnetometer (VSM), X-ray photon spectroscopy (XPS) and visible light spectroscopy analysis for their respective properties. The XRD and EDS revealed the structural and inorganic composition of N-TiO(2) supported on SrFe(12)O(19). The supported N-TiO(2) exhibited a strong ferromagnetic property with tremendous stability against magnetic property losses. It also resulted in reduced band gap (2.8 eV) and better visible light absorption between 400 and 800 nm compared to N-doped TiO(2). The photocatalytic activity was investigated with a recalcitrant phenolic compound namely 2,4 dichlorophenol (2,4-DCP) as a model pollutant under direct bright and diffuse sunlight exposure. A complete degradation of 2,4-DCP was achieved with an initial concentration of 50mg/L for both photocatalysts in 180 min and 270 min respectively under bright sunlight. Similarly the diffuse sunlight study resulted in complete degradation for supported N-TiO(2) and >85% degradation N-TiO(2), respectively. Finally the supported photocatalyst was separated under permanent magnetic field with a mass recovery ~ 98% for further reuse. PMID- 22100221 TI - A copper-catalyzed bioleaching process for enhancement of cobalt dissolution from spent lithium-ion batteries. AB - A copper-catalyzed bioleaching process was developed to recycle cobalt from spent lithium-ion batteries (mainly LiCoO(2)) in this paper. The influence of copper ions on bioleaching of LiCoO(2) by Acidithiobacillus ferrooxidans (A.f) was investigated. It was shown that almost all cobalt (99.9%) went into solution after being bioleached for 6 days in the presence of 0.75 g/L copper ions, while only 43.1% of cobalt dissolution was obtained after 10 days without copper ions. EDX, XRD and SEM analyses additionally confirmed that the cobalt dissolution from spent lithium-ion batteries could be improved in the presence of copper ions. The catalytic mechanism was investigated to explain the enhancement of cobalt dissolution by copper ions, in which LiCoO(2) underwent a cationic interchange reaction with copper ions to form CuCo(2)O(4) on the surface of the sample, which could be easily dissolved by Fe(3+). PMID- 22100222 TI - Sensitivity and selectivity determination of bisphenol A using SWCNT-CD conjugate modified glassy carbon electrode. AB - In this study, we demonstrated a highly sensitive electrochemical sensor for the determination of bisphenol A (BPA) in aqueous solution by using single-walled carbon nanotubes (SWCNTs)/beta-cyclodextrin (beta-CD) conjugate (SWCNT-CD) modified glassy carbon electrode (GCE). The cyclic voltammetry results show that the modified GCE exhibits strong catalytic activity toward the oxidation of BPA with a well-defined cyclic voltammetric peak at 0.543 V. The response current exhibits a linear range between 10.8 nM and 18.5 MUM with a high sensitivity (1256 MUA mM(-1)). The detection limit of BPA is 1.0 nM (S/N=3). The enhanced performance of the fabricated sensor can be attributed to the combination of the excellent electrocatalytic properties of SWCNTs and the molecular recognition ability of beta-CD. The sensor was successfully applied to determine BPA leached from real plastic samples with good recovery, ranging from 95% to 103%. PMID- 22100223 TI - Anodic oxidation of a biologically treated leachate on a boron-doped diamond anode. AB - In the present study, the anodic oxidation of a leachate from an intermunicipal sanitary landfill was evaluated using a boron-doped diamond anode as a possible post-treatment to the biological one, in order to diminish the remaining bio refractory organic matter. The influence of the dilution of the leachate sample and the applied current density on the performance of electrochemical oxidation was investigated. For the different assays performed, a comparison between the theoretical kinetic model for organic mineralization, proposed in the literature, and experimental data was done and the best correspondences were attained at lower applied current density for sample without dilution and at higher applied current density for the more diluted sample. However, the energetic most favourable treatment is attained for sample without dilution at very low current density. The DOC/COD ratio was also analysed and apparently, the mineralization of the organic matter improves with the dilution of the leachate samples. PMID- 22100224 TI - Cochlear implant outcomes in children with motor developmental delay. AB - INTRODUCTION: Multiple handicapped children and children with syndromes and conditions resulting additional disabilities such as cerebral palsy, global developmental delay and autistic spectrum disorder, are now not routinely precluded from receiving a cochlear implant. The primary focus of this study was to determine the effect of cochlear implants on the speech perception and intelligibility of deaf children with and without motor development delay. METHOD: In a cohort study, we compared cochlear implant outcomes in two groups of deaf children with or without motor developmental delay (MDD). Among 262 children with pre-lingual profound hearing loss, 28 (10%) had a motor delay based on Gross Motor Function Classification (GMFC). Children with severe motor delays (classification scale levels 4 and 5) and cognitive delays were excluded. All children completed the Categories of Auditory Perception Scales (CAP) and Speech Intelligibility Rating (SIR) prior to surgery and 24 months after the device was activated. RESULT: The mean age for the study population was 4.09 +/- 1.86 years. In all 262 patients the mean CAP score after surgery (5.38 +/- 0.043) had a marked difference in comparison with the mean score before surgery (0.482 +/- 0.018) (P=0.001). The mean CAP score after surgery for MDD children was 5.03, and was 5.77 for normal motor development children (NMD). The mean SIR score after surgery for MDD children was 2.53, and was 2.66 for NMD children. The final results of CAP and SIR did not have significant difference between NMD children versus MDD children (P>0.05). CONCLUSION: Regarding to the result, we concluded that children with hearing loss and concomitant MDD as an additional disabilities can benefit from cochlear implantation similar to those of NMD. PMID- 22100225 TI - Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells. AB - Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHSR), is thought to exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function such as cell proliferation, migration, survival and angiogenesis. However, the effect of ghrelin on angiogenesis and the corresponding mechanisms have not yet been extensively studied in cardiac microvascular endothelial cells (CMECs) isolated from left ventricular myocardium of adult Sprague-Dawley (SD) rats. In our study, we found that ghrelin and GHSR are constitutively expressed in CMECs. Ghrelin significantly increases CMECs proliferation, migration, and in vitro angiogenesis. The ghrelin-induced angiogenic process was accompanied by phosphorylation of ERK and Akt. MEK inhibitor PD98059 abolished ghrelin-induced phosphorylation of ERK, but had no effect on Akt phosphorylation. PI3K inhibitor LY294002 abolished ghrelin-induced phosphorylation of Akt, but had no effect on ERK phosphorylation. Ghrelin-induced angiogenesis was partially blocked by treatment with PD98059 or LY294002. In addition, this angiogenic effect was almost completely inhibited by PD98059+LY294002. Pretreatment with GHSR1a blocker [D-Lys3]-GHRP-6 abolished ghrelin-induced phosphorylation of ERK, Akt and in vitro angiogenesis. In conclusion, this is the first demonstration that ghrelin stimulates CMECs angiogenesis through GHSR1a-mediated MEK/ERK and PI3K/Akt signal pathways, indicating that two pathways are required for full angiogenic activity of ghrelin. This study suggests that ghrelin may play an important role in myocardial angiogenesis. PMID- 22100226 TI - Toxicity study of antimicrobial peptides from wild bee venom and their analogs toward mammalian normal and cancer cells. AB - Recently, we have isolated and characterized remarkable antimicrobial peptides (AMPs) from the venom reservoirs of wild bees. These peptides (melectin, lasioglossins, halictines and macropin) and their analogs display high antimicrobial activity against Gram-positive and -negative bacteria, antifungal activity and low or moderate hemolytic activity. Here we describe cytotoxicity of the above-mentioned AMPs and some of their analogs toward two normal cell lines (human umbilical vein endothelial cells, HUVEC, and rat intestinal epithelial cells, IEC) and three cancer cell lines (HeLa S3, CRC SW 480 and CCRF-CEM T). HeLa S3 cells were the most sensitive ones (concentration causing 50% cell death in the case of the most toxic analogs was 2.5-10 MUM) followed by CEM cells. For the other cell lines to be killed, the concentrations had to be four to twenty times higher. These results bring promising outlooks of finding medically applicable drugs on the basis of AMPs. Experiments using fluorescently labeled lasioglossin III (Fl-VNWKKILGKIIKVVK-NH(2)) as a tracer confirmed that the peptides entered the mammalian cells in higher quantities only after they reached the toxic concentration. After entering the cells, their concentration was the highest in the vicinity of the nucleus, in the nucleolus and in granules which were situated at very similar places as mitochondria. Experiments performed using cells with tetramethylrhodamine labeled mitochondria showed that mitochondria were fragmented and lost their membrane potential in parallel with the entrance of the peptides into the cell and the disturbance of the cell membrane. PMID- 22100227 TI - Berberine induces heme oxygenase-1 up-regulation through phosphatidylinositol 3 kinase/AKT and NF-E2-related factor-2 signaling pathway in astrocytes. AB - Our previous report has shown that berberine effectively inhibits LPS- and IFN gamma-induced neuroinflammation in microglia cells. Recently, we also reported that HO-1 (Heme oxygenase-1) may be a therapeutic target to regulate neuroinflammation in microglia cells. The present study examined the ability of berberine, the major constituents of Chinese herb Rhizoma coptidis, to induce expression of HO-1, and analyzed its signaling mechanism in rat brain astrocytes. HO-1 is known as an antioxidant enzyme which helps to protect against cellular damage and maintains tissue homeostasis. Here, we found that berberine increased HO-1 mRNA and protein expression concentration- and time-dependently. In addition, berberine-induced HO-1 expression was attenuated by PI 3-kinase (phosphatidylinositol 3-kinase) inhibitors LY294002 and wortmannin, and an AKT inhibitor. Treatment of astrocytes with berberine also induced p85 (PI 3-kinase) and AKT phospholation, and increased AKT kinase activity. Berberine also increased NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and increased Nrf2-DNA binding activity as determined by the EMSA (electrophoretic mobility shift assay). Moreover, berberine-induced increase of Nrf2-DNA binding activity was reduced by PI 3-kinase and AKT inhibitors. Berberine-increased HO-1 luciferase activity was also inhibited by co-transfection with dominant-negative (DN) mutants of p85 and AKT. Moreover, berberine-mediated increase of HO-1 transcriptional activity and protein expression were reduced by transfection with siRNA againt Nrf2. These findings suggest that berberine-increased HO-1 expression is mediated by Nrf2 activation through the PI 3-kinase/AKT pathway in astrocytes. Thus, berberine may be useful as a therapeutic agent for the treatment of neuroinflammation-associated disorders. PMID- 22100228 TI - Biphasic response of skeletal muscle mitochondria to chronic cardiac pressure overload - role of respiratory chain complex activity. AB - Pressure overload induced heart failure affects cardiac mitochondrial function and leads to decreased respiratory capacity during contractile dysfunction. A similar cardiac mitochondrial dysfunction has been demonstrated by studies which induce heart failure through myocardial infarction or pacing. These heart failure models differ in their loading conditions to the heart and show nevertheless the same cardiac mitochondrial changes. Based on these observations we speculated that a workload independent mechanism may be responsible for the impairment in mitochondrial function after pressure overload, which may then also affect the skeletal muscle. We aimed to characterize changes in mitochondrial function of skeletal muscle during the transition from pressure overload (PO) induced cardiac hypertrophy to chronic heart failure. PO by transverse aortic constriction caused compensated hypertrophy at 2 weeks, HF with normal ejection fraction (EF) at 6 and 10 weeks, and hypertrophy with reduced EF at 20 weeks. Cardiac output was normal at all investigated time points. PO did not cause skeletal muscle atrophy. Mitochondrial respiratory capacity in soleus and gastrocnemius muscles showed an early increase (up to 6 weeks) and a later decline (significant at 20 weeks). Respiratory chain complex activities responded to PO in a biphasic manner. At 2 weeks, activity of complexes I and II was increased. These changes pseudo normalized within the 6-10 week interval. At 20 weeks, all complexes showed reduced activities which coincided with clinical heart failure symptoms. However, both protein expression and supercomplex assembly (Blue-Native gel) remained normal. There were also no relevant changes in mRNA expression of genes involved in mitochondrial biogenesis. This temporal analysis reveals that mitochondrial function of skeletal muscle is changed early in the development of pressure overload induced heart failure without being directly influenced by an increased loading condition. The observed early increase and the later decline in respiratory capacity can be explained by concomitant activity changes of complex I and complex II and is not due to differences in gene expression or supercomplex assembly. PMID- 22100229 TI - Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction. AB - Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-beta signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-beta signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-beta signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling. PMID- 22100230 TI - Mechanism research on cellulose pyrolysis by Py-GC/MS and subsequent density functional theory studies. AB - The mechanism of fast pyrolysis of cellulose has been studied by using an analytical pyrolyzer coupled with a gas chromatography-mass spectrometry set-up (Py-GC/MS). The results showed that the main products comprised pyrans such as levoglucosan and levoglucosenone, furans such as furfural and 5-hydroxymethyl furfural, and linear small molecular chemicals such as acetaldehyde and 1-hydroxy 2-propanone. The compositions of products from fast pyrolysis of cellubiose and glucose were similar to that from cellulose, but with higher furan contents and lower pyran contents. Based on the experimental results, density functional theory (DFT) studies were carried out to deduce the pyrolysis mechanism of cellulose. The results showed the formation of 5-hydroxymethyl furfural from d glucopyranose unit to be easier than the formation of levoglucosan, in agreement with the experimental results. The deduced mechanism of reaction pathways in cellulose pyrolysis provides insight into the pyrolysis behavior of cellulose and allows modification of previously proposed related mechanisms. PMID- 22100231 TI - Rational approach to optimize cellulase mixtures for hydrolysis of regenerated cellulose containing residual ionic liquid. AB - For the efficient production of glucose for platform chemicals or biofuels, cellulosic biomass is pretreated and subsequently hydrolyzed with cellulases. Although ionic liquids (IL) are known to effectively pretreat cellulosic biomass, the hydrolysis of IL pretreated biomass has not been optimized so far. Here, we present a semi-empirical model to rationally optimize the hydrolysis of pretreated alpha-cellulose - regenerated from IL and containing residual IL from the pretreatment. First, the influence of the IL MMIM DMP on the individual cellulases endoglucanase I, cellobiohydrolase I and beta-glucosidase was investigated. Second, an enzyme loading-dependent model was developed to describe kinetics for the individual cellulases and cellulase mixtures. Third, this model was used to optimize the cellulase mixture for the efficient hydrolysis of regenerated cellulose containing residual IL. Finally, we could significantly increase the initial hydrolysis rate in 10% (v/v) MMIM DMP by 49% and the sugar yield by 10% points. PMID- 22100232 TI - Overexpression and characterization of a new organic solvent-tolerant esterase derived from soil metagenomic DNA. AB - In this study, an esterase, designated EstC23, was isolated from a soil metagenomic library. The protein was amenable to overexpression in Escherichia coli under control of the T7 promoter, resulting in expression of the active, soluble protein that constituted 30% of the total cell protein content. This enzyme showed optimal activity at 40 degrees C and retained about 50% maximal activity at 5-10 degrees C. EstC23 showed remarkable stability in up to 50% (v/v) benzene and alkanes (high logP solvents). When incubated for 7 days in the presence of 50% benzene or alkanes, the enzyme maintained its 2-3 fold elevated activity. The purified enzyme also cleaved sterically hindered esters of tertiary alcohols. These results indicate that EstC23 has potential for use in industrial processes. PMID- 22100233 TI - Production of xylooligosaccharides from corncob xylan by fungal xylanase and their utilization by probiotics. AB - The selective production of xylooligosaccharides (XOS) was carried out using partially purified xylanase from Aspergillus foetidus MTCC 4898. Corncob xylan was extracted using a mild alkali treatment which yielded 178.73+/-5.8 g of xylan/kg of corncobs. Partially purified beta-xylosidase free xylanase was found efficient in releasing xylooligosaccharides from corncob xylan. Maximum yield of xylooligosaccharides was 6.73+/-0.23 mg/ml after 8 h of reaction time using 20 U of xylanase at 45 degrees C. Purification of XOS was done using activated charcoal column chromatography. The purified XOS preparation contained mainly xylobiose and xylotriose. XOS mixture was found suitable for food industry looking at its high thermal stability at low pH. Prebiotic effect of XOS was evaluated by in vitro fermentation of XOS using known probiotic strains viz. Bifidobacterium adolescentis, Bifidobacterium bifidum, Lactobacillus fermentum, Lactobacillus acidophilus. The results of this study revealed better growth of Bifidobacterium spp. on XOS than Lactobacillus spp. PMID- 22100234 TI - Process design and economic analysis of a hypothetical bioethanol production plant using carob pod as feedstock. AB - A process for the production of ethanol from carob (Ceratonia siliqua) pods was designed and an economic analysis was carried out for a hypothetical plant. The plant was assumed to perform an aqueous extraction of sugars from the pods followed by fermentation and distillation to produce ethanol. The total fixed capital investment for a base case process with a capacity to transform 68,000 t/year carob pod was calculated as 39.61 millon euros (?) with a minimum bioethanol production cost of 0.51 ?/L and an internal rate of return of 7%. The plant was found to be profitable at carob pod prices lower than 0.188 ?/kg. An increase in the transformation capacity of the plant from 33,880 to 135,450 t/year was calculated to result in an increase in the internal rate of return from 5.50% to 13.61%. The obtained results show that carob pod is a promising alternative source for bioethanol production. PMID- 22100235 TI - Efficient asymmetric hydrolysis of styrene oxide catalyzed by Mung bean epoxide hydrolases in ionic liquid-based biphasic systems. AB - The asymmetric hydrolysis of styrene oxide to (R)-1-phenyl-1,2-ethanediol using Mung bean epoxide hydrolases was, for the first time, successfully conducted in an ionic liquid (IL)-containing biphasic system. Compared to aqueous monophasic system, IL-based biphasic systems could not only dissolve the substrate, but also effectively inhibit the non-enzymatic hydrolysis, and therefore markedly improve the reaction efficiency. Of all the tested ILs, the best results were observed in the biphasic system containing C(4)MIM.PF(6), which exhibited good biocompatibility with the enzyme and was an excellent solvent for the substrate. In the C(4)MIM.PF(6)/buffer biphasic system, it was found that the optimal volume ratio of IL to buffer, reaction temperature, buffer pH and substrate concentration were 1/6, 35 degrees C, 6.5 and 100 mM, respectively, under which the initial reaction rate, the yield and the product e.e. were 18.4 mM/h, 49.4% and 97.0%. The biocatalytic process was shown to be feasible on a 500-mL preparative scale. PMID- 22100236 TI - Enhanced nitrogen removal from sludge dewatering liquor by simultaneous primary sludge fermentation and nitrate reduction in batch and continuous reactors. AB - In this study, a novel denitrification reactor is used to treat sludge dewatering liquor, where the co-occurrence of sludge fermentation and nitrate reduction was obtained. The system showed an efficient and stable nitrogen removal performance. When the effluent recycle ratio was 200%, TN and NH(4)(+) removal efficiency was 99.6% and 83.5%, respectively. In addition, primary sludge could be well degraded in the novel system. Over 50% volatile suspended solid (VSS) of primary sludge was utilized, and the ratio of VSS/SS declined from 0.76 to 0.39. Further investigation with batch experiments revealed that, compared to conventional sludge fermentation, the integration of denitrification and fermentation was better at carbon production as well as the control of ammonium release. PMID- 22100237 TI - Empirical characterisation and mathematical modelling of settlement in composting batch reactors. AB - The settlement of organic matter during composting was measured at different levels during the active biodegradation phase in forced-aerated static reactors loaded with different mixtures of organic wastes. The temperature evolution and the concentration of oxygen and carbon dioxide were also recorded in the exhaust gases. Two two-parameter equations and their generalised three-parameter form were fitted to the experimental data and their capability to predict settlement as a function of time was discussed. The settlement field inside the reactors was successfully described with a linear profile. At any given time and vertical position, mass settlement was proportional to the initial height after reactor loading. Furthermore, a relationship linking settlement to biological activity was also proposed. Under all tested experimental conditions, settlement showed a clear correlation with the cumulative oxygen consumption that was modelled with a three parameter equation. PMID- 22100238 TI - Trace element requirements for stable food waste digestion at elevated ammonia concentrations. AB - The work investigated why anaerobic digesters treating food waste and operating at high ammonia concentrations suffer from propionic acid accumulation which may result in process failure. The results showed deficiency of selenium, essential for both propionate oxidation and syntrophic hydrogenotrophic methanogenesis, leads to this while supplementation allows operation at substantially higher organic loading rates (OLR). At high loadings cobalt also becomes limiting, due to its role either in acetate oxidation in a reverse Wood-Ljungdahl or in hydrogenotrophic methanogenesis. Population structure analysis using fluorescent in situ hybridization showed only hydrogenotrophic methanogens. Critical Se and Co concentrations were established as 0.16 and 0.22 mg kg(-1) fresh matter feed at moderate loading. At this dosage the OLR could be raised to 5 g VS l(-1) day( 1) giving specific and volumetric biogas productions of 0.75 m(3) kg(-1) VS(added) and 3.75 STP m(3) m(-3) day(-1), representing a significant increase in process performance and operational stability. PMID- 22100239 TI - Effect of lignin-derived and furan compounds found in lignocellulosic hydrolysates on biomethane production. AB - Hydrolysates resulting from the lignocellulosic biomass pretreatment in bioethanol production may be used to produce biogas. Such hydrolysates are rich in xylose but also contain lignin polymers or oligomers as well as phenolic and furan compounds, such as syringaldehyde, vanillin, HMF, furfural. The aim of this study was to investigate the impact of these byproducts on biomethane production from xylose. The anaerobic digestion of the byproducts alone was also investigated. No inhibition of the anaerobic digestion of xylose was observed and methane was obtained from furans: 430 mL CH(4)/g of furfural and 450 mL CH(4)/g of HMF; from phenolic compounds: 453 mL CH(4)/g of syringaldehyde and 105 mL CH(4)/g of vanillin; and, to a lesser extent, from lignin polymers: from 14 to 46 mL CH(4)/g MV. The use of different natural polymers (lignosulfonates, organosolv and kraft lignins) and synthetic dehydrogenative polymers showed that higher S/G ratios and lower molecular weights in lignin polymers led to greater methane production. PMID- 22100240 TI - Purification and characterization of haloalkaline thermoactive, solvent stable and SDS-induced protease from Bacillus sp.: a potential additive for laundry detergents. AB - An extracellular haloalkaline, thermoactive, solvent stable, SDS-induced serine protease was purified and characterized from an alkali-thermo tolerant strain Bacillus sp. SM2014 isolated from reverse osmosis reject. The enzyme was purified to homogeneity with recovery of 54.4% and purity fold of 64. The purified enzyme was composed of single polypeptide of molecular mass about 71 kDa. The enzyme showed optimum activity at alkaline pH 10 and temperature 60 degrees C. The km and Vmax for the enzyme was 0.57 mg/ml and 445.23 U/ml respectively. The enzyme showed novel catalytic ability at high pH (10), temperature (60 degrees C) and salinity (3M). Moreover, the stability of enzyme in organic solvents (50% v/v) of logP >= 2 signified the prospective of this enzyme for peptide synthesis. The compatibility of the enzyme with surfactants and various detergent matrices together with wash performance test confirmed its potential applicability in laundry industry. PMID- 22100241 TI - Preparation and heavy metal ions biosorption of graft copolymers from enzymatic hydrolysis lignin and amino acids. AB - Novel biosorbents, graft copolymers, were prepared via Mannich reaction from enzymatic hydrolysis lignin with glycine and cystine, respectively. The element content, FT-IR and fluorescence spectra, relative viscosity, and particle size of the copolymers were systematically investigated. Furthermore, effects of initial pH, ionic strength, temperature, contact time and initial metal ion concentration on the biosorption capacities of Cu(II) and Co(II) ions onto the copolymers were studied using batch sorption technique. It was found that the copolymers exhibited excellent biosorption characteristics for Cu(II) and Co(II) ions. The sorption kinetic data can be described well with a pseudo-second-order model, and the equilibrium data can be fitted well to the Langmuir and Freundlich isotherm for Cu(II) and Co(II) biosorption process, respectively. Surface complexation and ion-exchange modeling were performed to elucidate the biosorption mechanism involved because surfaces of the copolymers contained three main types of acid/base sites from the amino acid grafted copolymer units. PMID- 22100242 TI - Metabolic properties of a mixed culture of aerobic ammonia oxidizers and its optimal reaction conditions. AB - The aerobic ammonia oxidation is an important process for nitrogen removal from wastewater with high ammonia concentration. Here, we investigated the metabolic properties of a mixed culture of aerobic ammonia oxidizers and determined its optimal reaction conditions. The maximum specific rate of NO(2)(-)-N formation of the culture was 14.9 mg N mg(protein)(-1) d(-1). The ammonia oxidation capacity was positively correlated with the microbial biomass concentration. Haldane model showed that the half-saturation constant (K(s)) for NH(4)(+)-N of the culture was 78.5 mg L(-1), and the inhibition constant (K(i)) for NH(4)(+)-N was 393.4 mg L( 1). The acetic acid and beef extract had significant inhibitory effects on ammonia oxidation, while there was little effect of methanol and glucose on ammonia oxidation. Orthogonal experiments with range analysis, variance analysis, factor contribution analysis and response surface analysis confirmed the optimal reaction conditions for ammonia oxidation to be 30-32 degrees C, pH 7.8-8.0, and 150-200 mg L(-1) NH(4)(+)-N concentration. PMID- 22100243 TI - Increased blood mRNA expression of inflammatory and anti-fibrotic markers in dogs with congestive heart failure. AB - Inflammation and extracellular matrix (ECM) remodeling contribute to the development of congestive heart failure (CHF), but the pathogenesis is still incompletely understood. Therefore, whole blood samples from eight dogs without cardiac disease and eight dogs with CHF were investigated for mRNA expression of IL1beta, IL2, IL4, IL6, IL8, IL10, TNFalpha, IFNgamma, TGFbeta1-3, MMP1, -2, -3, 9 and TIMP1-4 using quantitative PCR. Dogs with CHF had significantly higher IL1beta (P=0.015), IL2 (P=0.043), MMP1 (P=0.031), TIMP3 (P=0.012) and lower TNFalpha (P<0.001), TGFbeta3 (P=0.006), TIMP1 (P=0.015) and TIMP2 (P=0.011) mRNA levels. Increased pro-inflammatory IL1beta and anti-fibrotic MMP1 and reduced pro fibrotic TGFbeta and TIMP1 and TIMP2 in dogs with CHF suggest progressive left ventricular remodeling. The reduction of TNFalpha and increase of immunomodulatory IL2 and TIMP3 might suggest control of the inflammatory response. A better understanding of inflammation and ECM remodeling in cardiac diseases may lead to novel treatment approaches. PMID- 22100244 TI - Virus-like particles: potential veterinary vaccine immunogens. AB - Virus-like particle (VLP) composed of outer shell but no genome of virus mimics the natural configuration of authentic virion and has no characteristics of self replication. A close resemblance to native viruses in molecular scaffolds and an absence of genomes make VLPs effectively elicit both humoral and cell-mediated immune responses even with no requirement of adjuvant for vaccines. As effective immunogens, characterized by high immunogenicity and safety, VLPs have been employed in production of human vaccines, such as the licensed vaccines of hepatitis B virus and human papillomavirus. However, there has been no report of licensed veterinary VLP vaccine worldwide as yet. Despite the wide application in vaccination, both the conventional inactivated and live attenuated vaccines for animals are subject to potential limitations due to incomplete inactivation and reversion to virulence. Therefore, those conventional vaccines may, to some extent, be replaced with the VLP-based vaccines conferring higher protection and safety to vaccinated animals. Here, we review the current status of VLPs as veterinary vaccines, and discuss the characteristics and problems associated with generating VLPs for different animal viruses. PMID- 22100245 TI - Myxoma virus induces apoptosis in cultured feline carcinoma cells. AB - There is growing interest in utilizing replicating oncolytic viruses as cancer therapeutics agents. The effectiveness of myxoma virus-induced oncolysis was evaluated in two feline cancer cell cultures. Although myxoma virus is a rabbit specific pathogen, protein expression driven by myxoma virus and production of infectious viral particles were detected. Cell death occurred in primary feline cancer cells within 48 h of inoculation with myxoma virus. Future studies to determine if other feline neoplasms are susceptible to myxoma virus infection are warranted. PMID- 22100246 TI - Association of herd BHV-1 seroprevalence with respiratory disease in youngstock in Estonian dairy cattle. AB - The associations between herd bovine herpesvirus 1 (BHV-1) seroprevalence, along with other infectious and farm management factors with bovine respiratory disease (BRD) in dairy calves and heifers, were investigated. Serum samples from 103 dairy cattle herds were analyzed for antibodies against BHV-1, bovine respiratory syncytial virus (BRSV), bovine viral diarrhea virus (BVDV), and Mycoplasma bovis (M. bovis). A questionnaire was used to record herd management practices. A high occurrence of respiratory disease in unweaned calves was associated with low to moderate and high prevalence of BHV-1 among cows (OR=14.8, p=0.005 and OR=19.2, p=0.002, respectively) and positive BVDV status of a herd (OR=5.1, p=0.02). The presence of BVDV in a herd was related to a high incidence of respiratory disease in heifers 3-16 months old (OR=4.3, p=0.027). Based on the results of multiple correspondence analysis, holding youngstock separately from cows until pregnancy, introducing new animals and the activities of on-farm employees may contribute to a higher incidence of BRD. PMID- 22100247 TI - Survival of Pochonia chlamydosporia in the gastrointestinal tract of experimentally treated dogs. AB - The predatory capacity of the nematophagous fungus Pochonia chlamydosporia (isolate VC4) after passage through the gastrointestinal tract of dogs was assessed in vivo against Toxocara canis eggs. Twelve dogs previously wormed were divided into two groups of six animals and caged. The treatments consisted of a fungus-treated group (VC4) and a control group without fungus. Each dog of the fungus-treated group received a single 4 g dose of mycelial mass of P. chlamydosporia (VC4). Fecal samples from animals of both groups (treated and control) were collected at five different times (6, 12, 24, 36, and 48 h) after fungal administration, and placed in Petri dishes. Each Petri dish of both groups for each studied time interval received approximately 1000 T. canis eggs. Thirty days after the fecal samples were collected, approximately one hundred eggs were removed from each Petri dish of each studied time interval and evaluated by light microscopy (LM) and scanning electron microscopy (SEM). Microscopy examination of plates inoculated with the fungus showed that the isolate VC4 was able to destroy the T. canis eggs with destruction percentages of 28.6% (6 h), 29.1% (12 h), 32.0% (24 h), 31.7% (36 h), and 37.2% (48 h). These results suggest that P. chlamydosporia can be used as a tool for the biological control of T. canis eggs in feces of contaminated dogs. PMID- 22100248 TI - The effects of feed restriction on physical activity, body weight, physiology, haematology and immunology in female mink. AB - The aim of the present study was to investigate if adult mink females characterised as having a high or low residual feed intake (RFI) differed in their response to feed restriction with regard to activity, body weight loss and physiological parameters. For RFI-High, the activity was higher prior to the expected feeding time both in the cases of restrictive and ad libitum feeding indicating a changed RFI-High feeding motivation and a higher risk of developing stereotypic activity. The body weight gain and the feed consumption were higher for RFI-High than for RFI-Low when feeding ad libitum indicating that RFI-High has a higher growth potential and/or a higher energy requirement than RFI-Low. Signs of immunosuppression were shown in connection with restrictive feeding compared to ad libitum feeding, and RFI-High females seemed to be more susceptible to immunosuppression than RFI-Low females. Based on the present results, mink characterised as RFI-Low would be preferable as breeders because they involve lower feed costs and seem to be less susceptible to immunosuppression. They also seem to have less risk of developing stereotypic activity, which is beneficial for the welfare. PMID- 22100249 TI - Echium oil reduces atherosclerosis in apoB100-only LDLrKO mice. AB - INTRODUCTION: The anti-atherogenic and hypotriglyceridemic properties of fish oil are attributed to its enrichment in eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Echium oil contains stearidonic acid (SDA; 18:4, n-3), which is metabolized to EPA in humans and mice, resulting in decreased plasma triglycerides. OBJECTIVE: We used apoB100 only, LDLrKO mice to investigate whether echium oil reduces atherosclerosis. METHODS: Mice were fed palm, echium, or fish oil-containing diets for 16 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. RESULTS: Compared to palm oil, echium oil feeding resulted in significantly less plasma triglyceride and cholesterol levels, and atherosclerosis, comparable to that of fish oil. CONCLUSION: This is the first report that echium oil is anti-atherogenic, suggesting that it may be a botanical alternative to fish oil for atheroprotection. PMID- 22100250 TI - Expression of fat mobilizing genes in human epicardial adipose tissue. AB - BACKGROUND: Epicardial adipose tissue (EAT) mass correlates with metabolic syndrome and coronary artery disease (CAD). However, little is known about the expression of genes involved in triglyceride (TG) storage and mobilization in EAT. We therefore analyzed the expression of genes involved in fat mobilization in EAT in comparison to subcutaneous abdominal adipose tissue (AAT) in CAD patients and in controls. METHODS: EAT and AAT were obtained during coronary artery bypass graft (CABG) surgery from 16 CAD patients and from 14 non-CAD patients presenting for valve surgery. The state of atherosclerosis was assessed by angiography. RNA from tissues were extracted, reversibly transcribed and quantified by real time polymerase chain reaction (RT-PCR). The following genes were analyzed: perilipin-1 and -5 (PLIN1, PLIN5), lipoprotein lipase (LPL), hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CIG-58), angiopoietin like protein 4 (ANGPTL4), in addition to interleukine-6 (IL-6), leptin (LEP) and adiponectin (ADPN). RESULTS: A significant expression of all listed genes could be observed in EAT. The relative expression pattern of the 10 genes in EAT was comparable to the expression in AAT, yet there was a significantly higher overall expression in AAT. The expression of the listed genes was not different between CAD patients and controls. CONCLUSION: It is suggested that the postulated difference in EAT volume between CAD patients and non-CAD patients is not caused by a differential mRNA expression of fat mobilizing genes. Further work on protein levels and enzyme activities will be necessary to get a complete picture. PMID- 22100251 TI - Commentary on the paper by Gustavsson et al. entitled 'Interaction of apolipoprotein E genotype with smoking and physical inactivity on coronary heart disease risk in men and women'. PMID- 22100252 TI - Expression of the aging gene p66Shc is increased in peripheral blood monocytes of patients with acute coronary syndrome but not with stable coronary artery disease. AB - OBJECTIVE: The interplay between oxidative stress and inflammation is crucial in the pathogenesis of atherosclerosis. The adaptor protein p66Shc is implicated in atherogenesis and oxidative stress related responses in animal models of diseases. However, its role in humans remains to be defined. In this study, we hypothesized that expression of p66Shc increases in peripheral blood monocytes of patients affected by acute coronary syndromes (ACS). METHODS: Male subjects aged 59+/-4 (mean+/-SD) years admitted for cardiac catheterization were subdivided in three groups: (a) no local stenosis for the control group, (b) at least one stenosis >=75% in either left, circumflex or right coronary artery for the coronary artery disease (CAD) group or (c) ST-elevation/non-ST-elevation myocardial infarction for the ACS group. Monocytes were isolated from whole blood and p66Shc RNA levels were determined by quantitative real time PCR. RESULTS: p66Shc RNA levels were increased in ACS patients as compared to CAD (p=0.007) and controls (p=0.0249). Furthermore, malondialdehyde (MDA) and C-reactive protein (CRP) were increased in plasma of ACS patients. Levels of MDA correlated positively to p66Shc (r=0.376, p=0.01). Our data demonstrate increased p66Shc levels in monocytes of ACS but not CAD patients. CONCLUSION: This study suggests an involvement of p66Shc in the transition of a stable CAD to an ACS patient. p66Shc was associated with states of increased oxidative stress. Further work is needed to understand whether p66Shc may represent a possible pharmacological target or whether it represents an interesting novel biomarker. PMID- 22100253 TI - Visit-to-visit variability in systolic blood pressure is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. AB - OBJECTIVE: Recent studies make remarks on the effect of variability in systolic blood pressure (SBP) on the development of cardiovascular disease. The aim of this study was to investigate the relationship between the variability in SBP and the degree of diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. METHODS: We measured SBP in 422 consecutive patients with type 2 diabetes at every visit during a year, and we calculated the coefficient of variation (CV) of SBP. Then, we evaluated relationships of variability of SBP to degree of urinary albumin excretion (UAE), which is a useful marker for cardiovascular disease as well as diabetic nephropathy, ankle-brachial index (ABI) and pulse wave velocity (PWV). RESULTS: CV of SBP positively correlated with logUAE (r=0.210, P<0.0001) or PWV (r=0.409, P<0.0001), whereas CV of SBP inversely correlated with ABI (r=-0.098, P=0.0463). Multiple regression analysis demonstrated that CV of SBP independently correlated with logUAE (beta=0.149, P=0.0072), PWV (beta=0.337, P<0.0001) or ABI (beta=-0.162, P=0.0101). CONCLUSIONS: Not only average SBP but also variability in SBP is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. PMID- 22100254 TI - Spatial analysis of binary health indicators with local smoothing techniques The Viadana study. AB - INTRODUCTION: When pollution data from a monitoring network is not available, mapping the spatial distribution of disease can be useful to identify populations at risk and to suggest a potential role for suspected emission sources. We aimed at obtaining a continuous spatial representation of the prevalence of symptoms that are potentially associated with the exposure to the pollutants emitted from the wood factories in the children who live in the district of Viadana (Northern Italy). METHODS: In 2006, all the parents of the children aged 3-14 years residing in the Viadana district (n = 3854), filled in a questionnaire on respiratory symptoms, irritation symptoms of the eyes and skin, use of health services. The children's residential addresses were also collected and geocoded. Generalized additive models and local weighted regression (LOWESS) were used to estimate the distribution of the symptoms, to test for spatial trends of the symptoms' prevalence and to control for potential confounders. Permutation tests were used to identify the areas of significantly increased risk ("hot spots"). RESULTS: The prevalence of respiratory symptoms, eye symptoms and the use of health services showed a statistically significant spatial variation (p < 0.05), but skin symptoms did not. Symptoms' prevalence was lower in the northern part of the district, where no wood factories were present, and it was higher in the southern part, where the two big chipboard industries were located. Hot spots were identified fairly near to one of the two chipboard industries in the district. CONCLUSIONS: The north-to-south trend in the prevalence of respiratory and eye symptoms, but not of skin symptoms, as well as the location of hot spots, are consistent with the potential exposure to air pollutants both emitted by the wood factories and related to traffic. In these "high risk areas" monitoring of pollution and preventive actions are clearly needed. PMID- 22100255 TI - Spatial trends of perfluorochemicals in harbor seals (Phoca vitulina) from Danish waters. AB - Spatial trends of concentrations of perfluorinated chemicals (PFCs) were investigated in harbour seal liver tissue from seven locations in Denmark, ranging from the Wadden Sea in the southern North Sea to the Western Baltic. All samples were collected during the phocine distemper epizootic in 2002 which provided access to a large number of comparable samples over a short time period. PFOS was dominating (mean: 92% of ?PFC) among the PFCs in the samples, followed by considerably lower concentrations of PFHxS (1.8%), PFDA (1.7%), PFNA (1.6%) PFUnA (1.5%), PFOA (0.9%) and PFOSA (0.5%). The concentrations of all the investigated compounds showed significant differences among the seven locations. PFOS showed the highest concentrations in the Wadden Sea, where high burdens have also been recorded in German seals. Most compounds showed a trend towards higher concentrations at one or both extremes of the geographic range. Two different patterns of relative PFC concentrations were detected; one in the inner Danish waters where PFOSA and PFUnA were more prevalent and another in the Wadden Sea and Limfjord where PFOA, PFHxS and PFNA were found in greater proportions. These patterns probably represent Baltic and North Sea contamination sources. PMID- 22100256 TI - The design, synthesis and biological evaluations of C-6 or C-7 substituted 2 hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus. AB - C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C 6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site. PMID- 22100257 TI - Efficient microwave-assisted synthesis, antibacterial activity and high fluorescence of 5 benzimidazolyl-2'-deoxyuridines. AB - A series of novel C-5 benzimidazolyl-2'-deoxyuridines was synthesized in good yields under solvent-free conditions and microwave irradiation from 5-formyl-2' deoxyuridine and arylenediamine derivatives in the presence of NaHSO(3) as catalyst. Their absorption and fluorescence spectra were measured. They showed intense fluorescence around 400-500nm with quantum yields between 0.3 and 0.5. All compounds studied in this work were screened for their antibacterial activities against a series of Gram positive and negative bacteria. The trifluoromethyl substituted benzimidazole derivatives showed some antibacterial activity. PMID- 22100258 TI - Bivalent molecular probes for dopamine D2-like receptors. AB - Merging two arylamidoalkyl substituted phenylpiperazines as prototypical recognition elements for dopamine D(2)-like receptors by oligoethylene glycol linkers led to a series of bivalent ligands. These dimers were investigated in comparison to their monomeric analogues for their dopamine D(2long), D(2short), D(3) and D(4) receptor binding. Radioligand binding experiments revealed strong bivalent effects for some para-substituted benzamide derivatives. For the D(3) subtype, the target compounds 32, 34 and 36 showed an up to 70-fold increase of affinity and a substantial enhancement of subtype selectivity when compared to the monovalent analogue 24. Analysis of the binding curves displayed Hill slopes very close to one indicating that the bivalent ligands displace 1equiv of radioligand. Obviously, the two pharmacophores occupy an orthosteric and an allosteric binding site rather than adopting a receptor-bridging binding mode. PMID- 22100259 TI - Synthetic studies of bi-fluorescence-labeled maltooligosaccharides as substrates for alpha-amylase on the basis of fluorescence resonance energy transfer (FRET). AB - A series of bi-fluorescence-labeled maltooligosaccharides that lead to fluorescence resonance energy transfer (FRET) was systematically synthesized. Effective FRETs were observed with all of the synthesized probes. Digestion of probes having tetra-, quintet-, hexa- or hepta-saccharidic chain lengths with human saliva alpha-amylase resulted in disappearance of FRET when an excitation wavelength of at 290nm was used followed by detection at ca. 520nm due to emission from the dansyl moiety. However, continuous FRET was observed when probes having di- or trisaccharidic chain lengths were used as substrates. In addition to the substrate characteristics based on saccharidic chain length, the reaction rates of digestion for the substrates by amylase were different and also depended on their saccharidic chain length. PMID- 22100260 TI - The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics. AB - This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published. PMID- 22100261 TI - Synthesis and biological evaluation of sialic acid derivatives containing a long hydrophobic chain at the anomeric position and their C-5 linked polymers as potent influenza virus inhibitors. AB - Conversions of the C-5 acetamide group in sialic acid into two kinds of C=C double bond substituents were accomplished under Shotten-Baumann conditions. The polymerizable glycomonomers also contain a hydrophobic chain or hydroxyl group at the anomeric position. Radical polymerizations of the fully protected glycomonomers were carried out with acryl amide in the presence of ammonium persulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TEMED), followed by deprotection to furnish water-soluble glycopolymers. The activities of the deprotected glycopolymers and glycomonomers against human influenza viruses (H1N1 and H3N2) and avian influenza virus (H5N3) were evaluated. Biological evaluations showed that the glycomonomers containing a long hydrophobic chain at the anomeric position had both hemagglutination and neuraminidase inhibitory activities. PMID- 22100263 TI - Waif1/5T4 inhibits Wnt/beta-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization. AB - Wnt proteins can activate distinct signaling pathways, but little is known about the mechanisms regulating pathway selection. Here we show that the metastasis associated transmembrane protein Wnt-activated inhibitory factor 1 (Waif1/5T4) interferes with Wnt/beta-catenin signaling and concomitantly activates noncanonical Wnt pathways. Waif1 inhibits beta-catenin signaling in zebrafish and Xenopus embryos as well as in mammalian cells, and zebrafish waif1a acts as a direct feedback inhibitor of wnt8-mediated mesoderm and neuroectoderm patterning during zebrafish gastrulation. Waif1a binds to the Wnt coreceptor LRP6 and inhibits Wnt-induced LRP6 internalization into endocytic vesicles, a process that is required for pathway activation. Thus, Waif1a modifies Wnt/beta-catenin signaling by regulating LRP6 subcellular localization. In addition, Waif1a enhances beta-catenin-independent Wnt signaling in zebrafish embryos and Xenopus explants by promoting a noncanonical function of Dickkopf1. These results suggest that Waif1 modulates pathway selection in Wnt-receiving cells. PMID- 22100262 TI - Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. AB - An effective bidirectional communication between an implantation-competent blastocyst and the receptive uterus is a prerequisite for mammalian reproduction. The blastocyst will implant only when this molecular cross-talk is established. Here we show that the muscle segment homeobox gene (Msh) family members Msx1 and Msx2, which are two highly conserved genes critical for epithelial-mesenchymal interactions during development, also play crucial roles in embryo implantation. Loss of Msx1/Msx2 expression correlates with altered uterine luminal epithelial cell polarity and affects E-cadherin/beta-catenin complex formation through the control of Wnt5a expression. Application of Wnt5a in vitro compromised blastocyst invasion and trophoblast outgrowth on cultured uterine epithelial cells. The finding that Msx1/Msx2 genes are critical for conferring uterine receptivity and readiness to implantation could have clinical significance, because compromised uterine receptivity is a major cause of pregnancy failure in IVF programs. PMID- 22100264 TI - DNA family shuffling within the chicken avidin protein family - A shortcut to more powerful protein tools. AB - Avidins represent an interesting group of proteins showing high structural similarity and ligand-binding properties but low similarity in primary structure. In this study, we show that it is possible to create functional chimeric proteins from the avidin protein family when applying DNA family shuffling to the genes of the avidin protein family: avidin, avidin related gene 2 and biotin-binding protein A. The novel chimeric proteins were selected by phage display biopanning against biotin, and the selected enriched proteins were characterized, displaying diverse features distinct from the parental genes, including binding to cysteine. PMID- 22100265 TI - Kinetic and stoichiometric characterization of a fixed biofilm reactor by pulse respirometry. AB - An in situ respirometric technique was applied to a sequential biofilm batch reactor treating a synthetic wastewater containing acetate. In this reactor, inoculated with mixed liquor from a wastewater plant, unglazed ceramic tiles were used as support media while maintaining complete mixing regime. A total of 8 kinetic and stoichiometric parameters were determined by in situ pulse respirometry; namely substrate oxidation yield, biomass growth yield, storage yield, storage growth yield, substrate affinity constant, storage affinity constant, storage kinetic constant and maximum oxygen uptake rate. Additionally, biofilm growth was determined from support media sampling showing that the colonization process occurred during the first 40 days, reaching an apparent steady-state afterward. Similarly, most of the stoichiometric and kinetic parameters were changing over time but reached steady values after day 40. During the experiment, the respirometric method allowed to quantify the amount of substrate directed to storage, which was significant, especially at substrate concentration superior to 30mg CODL(-1). The Activated Sludge Model 3 (ASM3), which is a model that takes into account substrate storage mechanisms, fitted well experimental data and allowed confirming that feast and famine cycles in SBR favor storage. These results also show that in situ pulse respirometry can be used for fixed-bed reactors characterization. PMID- 22100266 TI - Capacitive immunosensor for the detection of host cell proteins. AB - A new analysis for monitoring host cell proteins in preparations of transgenically produced protein pharmaceuticals is described. A capacitive biosensor with a very high sensitivity is used to monitor trace amounts of host cell proteins. The sensor consists of a gold electrode, the surface of which is well insulated and on which a preparation of a population of polyclonal antibodies raised against the complete protein set-up of the host cell are immobilized. Host cell proteins are present at very low concentrations during the production of a transgenic protein. The system studied here is a model system with an enzyme expressed in Escherichia coli (E. coli). Due to the high sensitivity, it may even be possible to dilute the samples to be analyzed, thereby reducing a negative influence from non-specific binding to the sensor surface. PMID- 22100267 TI - Synthetic scaffolds increased resveratrol biosynthesis in engineered yeast cells. AB - Resveratrol is a polyphenolic compound produced by a few higher plants when under attack by pathogens such as bacteria or fungi. Besides antioxidant benefits to humans, this health-promoting compound has been reported to extend longevity in yeasts, flies, worms, fishes and obesity mice. Here we utilized the synthetic scaffolds strategy to improve resveratrol production in Saccharomyces cerevisiae. We observed a 5.0-fold improvement over the non-scaffolded control, and a 2.7 fold increase over the previous reported with fusion protein. This work demonstrated the synthetic scaffolds can be used for the optimization of engineered metabolic pathway. PMID- 22100268 TI - Optimization of erythropoietin production with controlled glycosylation-PEGylated erythropoietin produced in glycoengineered Pichia pastoris. AB - Pichia pastoris is a methylotropic yeast that has gained great importance as an organism for protein expression in recent years. Here, we report the expression of recombinant human erythropoietin (rhEPO) in glycoengineered P. pastoris. We show that glycosylation fidelity is maintained in fermentation volumes spanning six orders of magnitude and that the protein can be purified to high homogeneity. In order to increase the half-life of rhEPO, the purified protein was coupled to polyethylene glycol (PEG) and then compared to the currently marketed erythropoiesis stimulating agent, Aranesp((r)) (darbepoetin). In in vitro cell proliferation assays the PEGylated protein was slightly, and the non-PEGylated protein was significantly more active than comparator. Pharmacodynamics as well as pharmacokinetic activity of PEGylated rhEPO in animals was comparable to that of Aranesp((r)). Taken together, our results show that glycoengineered P. pastoris is a suitable production host for rhEPO, yielding an active biologic that is comparable to those produced in current mammalian host systems. PMID- 22100269 TI - Development of a strong intracellular expression system for Bacillus subtilis by optimizing promoter elements. AB - Transcription efficiency of inducible promoters remains a bottleneck in recombinant protein production in Bacillus subtilis cells. Here, we present experimental data how to generate strong IPTG-inducible promoters by optimization of nucleotides at the conserved regions of the groESL promoter including the UP element, the -35, -15, -10 and the +1 region. Combination of these changes into one promoter enhanced the amount of recombinant proteins accumulating intracellularly up to about 30% of the total cellular protein. PMID- 22100270 TI - The welfare state and global health: Latin America, the Arab world and the politics of social class. PMID- 22100271 TI - [New channels of communication through social network: become a "friend" and a "follower" of Gaceta Sanitaria!]. PMID- 22100272 TI - The afterhyperpolarizing potential following a train of action potentials is suppressed in an acute epilepsy model in the rat Cornu Ammonis 1 area. AB - In hippocampal Cornu Ammonis 1 (CA1) neurons, a prolonged depolarization evokes a train of action potentials followed by a prominent afterhyperpolarizing potential (AHP), which critically dampens neuronal excitability. Because it is not known whether epileptiform activity alters the AHP and whether any alteration of the AHP is independent of inhibition, we acutely induced epileptiform activity by bath application of the GABA(A) receptor blocker gabazine (5 MUM) in the rat hippocampal slice preparation and studied its impact on the AHP using intracellular recordings. Following 10 min of gabazine wash-in, slices started to develop spontaneous epileptiform discharges. This disinhibition was accompanied by a significant shift of the resting membrane potential of CA1 neurons to more depolarized values. Prolonged depolarizations (600 ms) elicited a train of action potentials, the number of which was not different between baseline and gabazine treatment. However, the AHP following the train of action potentials was significantly reduced after 20 min of gabazine treatment. When the induction of epileptiform activity was prevented by co-application of 6-cyano-7 nitroquinoxaline-2,3-dione disodium (CNQX, 10 MUM) and D-(-)-2-amino-5 phosphonopentanoic acid (D-AP5, 50 MUM) to block alpha-amino-3-hydroxy-5 methylisoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors, respectively, the AHP was preserved despite of GABA(A) receptor inhibition suggesting that the epileptiform activity was required to suppress the AHP. Moreover, the AHP was also preserved when the slices were treated with the protein kinase blockers H-9 (100 MUM) and H-89 (1 MUM). These results demonstrate that the AHP following a train of action potentials is rapidly suppressed by acutely induced epileptiform activity due to a phosphorylation process-presumably involving protein kinase A. PMID- 22100273 TI - Distribution of dopamine D(2)-like receptors in the rat amygdala and their role in the modulation of unconditioned fear and anxiety. AB - Amygdaloid dopamine D(2) receptors play an important role in the modulation of fear/anxiety. Their topographical distribution within the amygdala is however unclear, and their role in unconditioned fear/anxiety remains largely unknown. The aim of this paper was to study the intra-amygdaloid distribution of D(2) receptors and to ascertain their role in unconditioned anxiety. Chemical anatomical studies in the rat, using D(2) and D(3)in situ hybridization, quantitative receptor autoradiography with either [(3)H]raclopride or [(125)I]sulpiride, and D(2)-like immunocytochemistry showed that the highest density of dopamine D(2) receptors is present in the central amygdaloid nucleus, particularly within its latero-capsular division, in which a D(2) but not a D(3) mRNA signal was observed. However, although at considerably reduced densities dopamine D(2) receptors were also found in other locations within the amygdala, including the basolateral nucleus. Behaviorally, the infusion of raclopride (0.75 4 MUg/side) in the area of the central amygdaloid nucleus resulted at low doses in the appearance of anxiogenic-like effects in the Shock-Probe Burying test, whereas no effects of raclopride treatment were found at any dose in the Elevated Plus-Maze and the Open-Field test. Our results indicate that amygdaloid dopamine D(2)-like receptors have a topographically differentiated distribution within the rat amygdala, the major location being in the central amygdaloid nucleus. D(2) like receptors play a role in the modulation of anxiety responses involving a potential differential function of D(2)-like receptors in the central amygdaloid nucleus versus the basolateral amygdaloid nucleus. PMID- 22100274 TI - Identification and functional characterization of polo-like kinase 2 autoregulatory sites. AB - Polo family kinases play important roles in cellular proliferation as well as neuronal synaptic plasticity. However, the posttranslational regulation of these kinases is not fully understood. Here, we identified several novel Plk2 phosphorylation sites stimulated by Plk2 itself. By site-directed mutagenesis, we uncovered three additional hyperactivating Plk2 mutations as well as a series of residues regulating Plk2 steady-state expression level. Because of the established role of Plk2 in homeostatic negative control of excitatory synaptic strength, these phosphorylation sites could play an important role in the rapid activation, expansion, and prolongation of Plk2 signaling in this process. PMID- 22100275 TI - WITHDRAWN: Upregulation of conventional protein kinase C phosphorylation and translocation in the rat nucleus accumbens following cocaine administration. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22100276 TI - From armchair to wheelchair: how patients with a locked-in syndrome integrate bodily changes in experienced identity. AB - Different sort of people are interested in personal identity. Philosophers frequently ask what it takes to remain oneself. Caregivers imagine their patients' experience. But both philosophers and caregivers think from the armchair: they can only make assumptions about what it would be like to wake up with massive bodily changes. Patients with a locked-in syndrome (LIS) suffer a full body paralysis without cognitive impairment. They can tell us what it is like. Forty-four chronic LIS patients and 20 age-matched healthy medical professionals answered a 15-items questionnaire targeting: (A) global evaluation of identity, (B) body representation and (C) experienced meaning in life. In patients, self-reported identity was correlated with B and C. Patients differed with controls in C. These results suggest that the paralyzed body remains a strong component of patients' experienced identity, that patients can adjust to objectives changes perceived as meaningful and that caregivers fail in predicting patients' experience. PMID- 22100277 TI - A simple and efficient protocol for the production of recombinant cathepsin V and other cysteine cathepsins in soluble form in Escherichia coli. AB - Cysteine cathepsins are major players in numerous physiologic and pathologic processes and important drug targets. Several different expression systems have been developed for the production of these enzymes. Here we describe a novel, simple and efficient protocol for the production of recombinant cathepsin V and other cysteine cathepsins. Recombinant procathepsin V was expressed in soluble form in the cytoplasm of Escherichia coli and purified in one step by immobilized nickel ion-affinity chromatography, yielding approximately 0.7 mg procathepsin V per liter bacterial culture. The recombinant proenzyme was then autocatalytically activated in vitro by incubation at pH 4.0 and 30 degrees C. The yield of proenzyme conversion was over 95% and the mature enzyme exhibited potent activity towards several commonly used synthetic substrates. The same protocol also proved successful in the production of several other cysteine procathepsins, such as cathepsin B, demonstrating that this procedure is widely applicable for the production of recombinant papain-like cysteine peptidases. PMID- 22100278 TI - Central-peripheral respiratory chemoreflex interaction in humans. AB - We investigated the interaction between the central and peripheral chemoreflexes in humans using a temporal separation technique in three tests. In two tests hyperventilation was used to reduce central P(CO)2 . In these tests the difference in the responses to the same step increases in P(CO)2 to 45 mmHg at normoxic and hypoxic O(2) tensions provided a measure of the response to isocapnic hypoxia at a low central P(CO)2. In a third test the response to a hypoxic step during sustained isocapnia at 45mmHg provided a measure of the response to isocapnic hypoxia at a high central P(CO)2. The responses to isocapnic hypoxia at high and low central P(CO)2were not significantly different, confirming the conclusion of previous studies that central and peripheral chemoreflex signals interact additively. This finding contrasts with those from recent animal experiments and emphasizes the need for caution when using animal experiments to make conclusions about the physiology of the respiratory chemoreflexes in humans. PMID- 22100279 TI - Community-onset bacteraemia caused by fluoroquinolone-resistant Klebsiella pneumoniae: clinical epidemiology and risk factors. PMID- 22100280 TI - Molecular characterisation of high-level ciprofloxacin-resistant Salmonella enterica with multiple antibiotic resistance and class 1 integrons isolated from imported foods. PMID- 22100281 TI - Synergistic activity of sulbactam combined with colistin against colistin resistant Acinetobacter baumannii. PMID- 22100282 TI - Hox genes from the parasitic flatworm Schistosoma japonicum. AB - Hox genes are characterized by a highly conserved peptide domain and contribute to antero-posterior axis patterning during embryogenesis. These genes have been widely studied in a variety of animal species due to their central role in evolutionary developmental biology. Based on the published genome assembly and unpublished re-sequencing project data, we present the first genome-wide characterization and comparative genomic analysis of the Hox gene family within Schistosoma japonicum. Eight Hox genes were identified and validated in our investigation. Phylogenetic analysis revealed that these genes are distributed among seven orthology groups of the Hox gene family. Our study further suggested that differences in the Lox5 gene copy number existed between the two closely related species, S. japonicum and Schistosoma mansoni. Semi-quantitative real time polymerase chain reaction experiments revealed that Lox5 and Hox4 gene expression was high in the schistosomulum stage, and all four genes investigated showed highest expression within the eggs. PMID- 22100283 TI - Preface. Introduction--microorganisms and the locomotor system. PMID- 22100284 TI - Arthritis after infection with Chikungunya virus. AB - Chikungunya virus (CHIKV) is an emerging alphavirus responsible for several infectious outbreaks in the world. After an acute stage of illness characterised by a fever-arthralgia syndrome and rash, joint disorders due to CHIKV infection can sometimes persist for several months or years. Chronic arthritis after this emerging disease is well documented, and similarities to rheumatoid arthritis have been described. Knowledge of the geographical epidemiology of CHIKV infection is crucial for better control of the disease. Thus, recent outbreaks have led to several studies, which have highlighted the need for a better understanding of the clinical features of Chikungunya (CHIK) and beginning knowledge of the pathophysiogenesis, which can lead to further research. PMID- 22100285 TI - Reactive arthritis. AB - Reactive arthritis (ReA) can be defined as the development of sterile inflammatory arthritis as a sequel to remote infection, often in the gastrointestinal or urogenital tract. Although no generally agreed-upon diagnostic criteria exist, the diagnosis is mainly clinical, and based on acute oligoarticular arthritis of larger joints developing within 2-4 weeks of the preceding infection. According to population-based studies, the annual incidence of ReA is 0.6-27/100,000. In addition to the typical clinical picture, the diagnosis of ReA relies on the diagnosis of the triggering infection. Human leucocyte antigen (HLA)-B27 should not be used as a diagnostic tool for a diagnosis of acute ReA. In the case of established ReA, prolonged treatment of Chlamydia-induced ReA may be of benefit, not only in the case of acute ReA but also in those with chronic ReA or spondylarthropathy with evidence of persisting chlamydia antigens in the body. In other forms of ReA, there is no confirmed evidence in favour of antibiotic therapy to shorten the duration of acute arthritis. The outcome and prognosis of ReA are best known for enteric ReA, whereas studies dealing with the long-term outcome of ReA attributable to Chlamydia trachomatis are lacking. PMID- 22100286 TI - Chlamydia-induced reactive arthritis: hidden in plain sight? AB - Reactive arthritis belongs to the group of arthritidies known as the spondyloarthritides. There are two main types of reactive arthritis: post venereal and post-enteric. Chlamydia trachomatis is felt to be the most common cause of reactive arthritis, in general. Until recently, even the terminology for the condition itself was unclear as multiple eponyms and names have been associated with reactive arthritis. In recent years, a great deal has been learnt about the epidemiology, pathophysiology and treatment of reactive arthritis and Chlamydia-induced reactive arthritis, specifically. Prospective epidemiologic data suggest that Chlamydia-induced reactive arthritis is underdiagnosed. Other truths being actively revealed include data suggesting that the pathogen itself (i.e., Chlamydia) might play an equally important role, or perhaps even more important, than the host with disease susceptibility; asymptomatic chlamydial infections might be a common cause of ReA and the two variants of reactive arthritis might respond differently to treatment in spite of the congruent clinical presentation. However, much about this syndrome remains shrouded in mystery. Data covered in this review suggest that Chlamydia-induced reactive arthritis might be a common condition that clinicians fail to recognise. An emphasis is placed on disease awareness since viable treatment options are emerging. PMID- 22100287 TI - Tuberculosis and other infections in the anti-tumour necrosis factor-alpha (anti TNF-alpha) era. AB - We review the global experience of infections in patients treated with tumour necrosis factor (TNF)-alpha inhibitors, which shows that the overall incidence of severe infections is at least doubled. In particular, this is true regarding tuberculosis. Screening and prophylactic measures have substantially reduced but not eliminated the risk. Recent improvements in immunologic testing for non Bacillus Calmette-Guerin (BCG)-related antigens allow more sensitive identification of latent tuberculosis and wider use of such methods holds promise as pre-treatment screening instruments. PMID- 22100288 TI - Behcet's syndrome and micro-organisms. AB - Behcet's syndrome (BS) is a multi-systemic vasculitis of unknown aetiology. More than one mechanism seems to be operative in the pathogenesis of Behcet's syndrome, including genetic and environmental factors, causing different manifestations of the syndrome. There are several clues to the role of environmental factors and especially micro-organisms in the pathogenesis. These include clinical findings such as a decrease in the frequency of a positive pathergy reaction with surgical cleaning of the skin before the procedure, the acne-arthritis association carrying similar features to acne-associated reactive arthritis, a higher rate of tonsillectomy, cold sores, late birth order, higher number of siblings, history of travel to countries with a high incidence of BS and earlier age at first sexual intercourse. Moreover, basic research on both viruses and bacteria suggests that micro-organisms may be playing a role, possibly through heat shock proteins and T-cell hypersensitivity. PMID- 22100289 TI - Septic arthritis. AB - This article presents a review of the current approach to diagnostic and therapeutic conditions of septic arthritis. Acute septic arthritis is an uncommon, but potentially fatal, emergency. Early diagnosis as well as prompt and effective treatment are essential to avoid either irreversible joint destruction or even death. The clinical features of this condition are different in neonates, children and adults. The definitive diagnosis of septic arthritis requires the direct demonstration of bacteria in synovial fluid or on positive culture of the pathogen. A combination of antibiotics and the prompt removal of purulent material from the affected joint constitutes the mainstay of successful treatment. In addition, this article discusses, in particular, prosthetic joint infection and gonococcal arthritis. PMID- 22100290 TI - The SAPHO syndrome--are microbes involved? AB - The syndrome of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) includes a rare group of chronic, relapsing, inflammatory osteoarticular disorders that is conventionally associated with manifestations in the skin. Diagnostic dilemmas can arise due to incomplete manifestations or confusion generated through mimicking of other conditions, such as osteomyelitis. The aetiology of this syndrome remains unclear, but probably involves genetic, immunological and infectious mechanisms. The possible pathogenetic role of infectious agents in genetically predisposed individuals, resulting in a 'reactive osteitis', has been suggested because microbes such as Propionibacterium acnes have been recovered from bone biopsy samples. However, this hypothesis has not been demonstrated as yet. Current knowledge with regard to treatment of this syndrome is based on results reported from small case studies and, thus, is still empiric. The use of antibiotics, instituted based on the isolation of Propionibacterium acnes, has been reported to show conflicting results. Promising results for potential future application have recently been reported for treatment of SAPHO with bisphosphonates and antagonists of tumour necrosis factor-alpha. This review aims to evaluate the existing knowledge on the SAPHO syndrome and to provide information on symptoms, diagnosis and treatment options for this disease. PMID- 22100291 TI - Ammonia transport by terrestrial and aquatic insects. AB - Ammonia, an end product from amino acid and nucleic acid metabolism, is highly toxic for most animals. This review will provide an update on nitrogen metabolism in terrestrial and aquatic insects with emphasis on ammonia generation and transport. Aspects that will be discussed include metabolic pathways of nitrogenous compounds, the origin of ammonia and other nitrogenous waste products, ammonia toxicity, putative ammonia transporters as well as ammonia transport processes known in insects. Ammonia transport mechanisms in the mosquito Aedes aegypti, the tobacco hornworm Manduca sexta and the locust Schistocerca gregaria will be discussed in detail while providing additional, novel data. PMID- 22100292 TI - The effect of Galleria mellonella apolipophorin III on yeasts and filamentous fungi. AB - Galleria mellonella apolipophorin III (apoLp-III) has been implicated in the innate immune response against bacterial infections. The protein binds components of bacterial cell wall and inhibits growth of selected Gram-positive and Gram negative bacteria. Interaction of apoLp-III with fungal beta-1,3-glucan suggests antifungal properties of the protein. In the present study, the effect of apoLp III on the growth, metabolic activity and cell surface characteristics of selected yeasts and filamentous fungi was investigated using light, confocal and atomic force microscopy. ApoLp-III bound to the cell surface of different yeasts and filamentous fungi as confirmed by immunoblotting with anti-apoLp-III antibodies. Incubation of the fungi in the presence of apoLp-III induced alterations in growth morphology. Candida albicans underwent transition from yeast-like to hyphal growth with formation of true hyphae, whereas Fusarium oxysporum hyphae exhibited decreased metabolic activity, increased vacuolization and appearance of numerous monophialids with microconidia. Atomic force microscopy imaging demonstrated evident alterations in the fungal cell surface after incubation with apoLp-III, suggesting that the protein affected the cell wall components. PMID- 22100293 TI - Vertebral brown tumors causing neurologic compromise. AB - OBJECTIVE: Brown tumors are nonneoplastic lesions that occur only in the setting of hyperparathyroidism. Although vertebral brown tumors are relatively rare pathologic entities, their incidence seems to be on the rise, as evidenced by multiple case reports published during the past four decades. An extensive review of these lesions is lacking in the literature. We present a case of paraparesis secondary to vertebral brown tumor followed by a detailed review of the literature. METHODS: We performed a review of the literature to locate all reported cases to date of vertebral brown tumors resulting in neurologic sequelae. In addition, we present the case of a 33-year-old female with end-stage renal disease and previous subtotal parathyroidectomy who presented with acute onset paraparesis from an expansile L1 brown tumor and was treated successfully by laminectomy and bracing. RESULTS: Thirty cases of vertebral brown tumor resulting in neurologic deficit were located in our literature search. Most occurred in women (63%), those aged 40 to 49 years (27%), and in the thoracic spine (57%). Lesions occurred roughly equally in primary (47%) and secondary (53%) hyperparathyroidism. Most patients demonstrated either symptomatic or radiographic improvement after neurosurgical intervention and/or subtotal or total parathyroidectomy. CONCLUSION: In patients presenting with a lytic vertebral lesion and known hyperparathyroidism or end-stage renal disease, brown tumor should be considered in the differential diagnosis. In select cases with minimal neurologic symptoms, parathyroidectomy may be warranted prior to neurosurgical intervention. PMID- 22100294 TI - Rvb2/reptin physically associates with telomerase in budding yeast. AB - Telomerase is a reverse transcriptase that maintains linear telomeres at a constant length. Here, we report that in the budding yeast Saccharomyces cerevisiae, Rvb2, a highly conserved member of the AAA+ family of ATPases, physically associates with telomerase/Est2 in vivo, both expressed from their endogenous promoter. Importantly, in genetic settings leading to a failure to recruit telomerase at telomeric ends, Rvb2 still associated with Est2. On the other hand, Rvb2 was present in immunoprecipitates of crosslinked telomeric chromatin even in the presumed absence of telomerase at the telomeres. Finally, we could also isolate RVB2 mutant alleles conferring slight, but stable, telomere shortening. PMID- 22100295 TI - Changes in cell migration of mesenchymal cells during osteogenic differentiation. AB - We showed that the migration, morphology and adhesiveness of undifferentiated mesenchymal cells dramatically changed during osteogenic differentiation. The migration of these cells was transiently upregulated early in osteogenic differentiation. At a later stage, migration was decreased but adhesiveness was increased. Furthermore, Cdc42 and Rac1 Rho-family small GTPases were activated at early stages of differentiation and the phosphorylation level of FAK decreased as differentiation progressed. We also showed cell migration was promoted by inhibition of the Rho-ROCK-myosin signaling. Finally, using a mouse model of ectopic bone formation, we confirmed that treatment with ROCK inhibitor, Y-27632 increased cell movement into bone formation sites, resulting in enhanced osteogenesis. These results provide a new insight into the link between cell migration and osteogenic differentiation. PMID- 22100296 TI - Protein kinase D regulates the human cardiac L-type voltage-gated calcium channel through serine 1884. AB - Protein kinase D (PKD) regulates the activity of the L-type calcium channel in rat ventricular cardiomyocytes. However, the functional target residues of PKD on the L-type calcium channel remain to be identified. Our aim was to identify the functional phosphorylation sites of PKD on the human L-type calcium channel. The pore subunit of the human CaV1.2 (hCaV1.2) was stably expressed in HEK293 cells. Both the expression of a dominant-negative mutant of PKD and the mutation of serine 1884 but not serine 1930, putative targets of PKD, strongly reduced L-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hCaV1.2 by PKD. PMID- 22100297 TI - Polysomy and p16 deletion by fluorescence in situ hybridization in the diagnosis of indeterminate biliary strictures. AB - BACKGROUND: The diagnosis of indeterminate biliary strictures is limited because of the low sensitivity of cytology. However, an accurate diagnosis of malignancy is critical in the management of patients with suspected biliary malignancy. Testing for chromosomal aneuploidy by fluorescence in situ hybridization (FISH) may increase the yield. OBJECTIVE: To evaluate the diagnostic accuracy of FISH in indeterminate biliary strictures and the additional value of including deletion of 9p21 (p16) in the diagnostic criteria of malignant biliary strictures. DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: This study involved 76 consecutive patients who were seen for the evaluation of indeterminate strictures at our institution. These patients were screened, and 50 patients with either a final pathologic diagnosis or >= 12 months' conclusive follow-up were included in the analysis. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, and area under the curve (AUC) analysis of cytology alone compared with the presence of FISH polysomy versus FISH polysomy and 9p21 deletion. RESULTS: The presence of increased copy numbers (polysomy) of chromosome 3, 7, or 17 by FISH increased the sensitivity of brush cytology from 21% to 58%, and when the presence of 9p21 deletion was included, the sensitivity increased to 89%. The specificity of FISH was 97% (vs 100% for cytology). The accuracy of cytology combined with FISH polysomy (AUC = 0.93) or p16 deletion was significantly greater than the accuracy of cytology alone (AUC 0.6; P < .001) or even cytology combined with FISH polysomy (AUC = 0.77; P <= .05). LIMITATIONS: Sample size. There is a relatively high incidence of malignant biliary strictures in the entire cohort but low incidence among primary sclerosing cholangitis patients, and the majority of cancers are cholangiocarcinomas (as opposed to pancreatic). CONCLUSION: FISH significantly improves the diagnostic accuracy of brush cytology in indeterminate biliary strictures. In our series, the addition of 9p21 deletion to FISH polysomy and cytology further improved sensitivity. This suggests that 9p21 deletion may be added to the diagnostic criteria in indeterminate strictures. PMID- 22100298 TI - Hemodynamic efficacy of the over-the-scope clip in an established porcine cadaveric model for spurting bleeding. AB - BACKGROUND: Clip application has been proven to be effective for endoscopic hemostasis. There are limited bench data on the efficacy of the over-the-scope clip (OTSC) for the treatment of spurting GI hemorrhage. We evaluated the hemodynamic efficacy of the OTSC in an established bleeding model. OBJECTIVE: To evaluate the hemodynamic efficacy of the OTSC in an established bleeding model. DESIGN: Prospective experimental trial with historical comparison. SETTING: We tested the OTSC prospectively in a validated bleeding model by using the compact Erlangen Active Simulator for Interventional Endoscopy equipped with an upper GI organ package. The artificial blood circulation system of the simulator was connected to an arterial pressure transducer. Two investigators with different endoscopic experience (4000 and 10,000 endoscopies performed) participated. Each investigator treated 16 bleeding sites in the simulator with the OTSC by using only suction (n = 8) and a novel retraction device to grasp tissue (n = 8). Systemic pressures were recorded 1 minute before, during, and 1 minute after clip application to objectify the effects of clipping on the vessel diameter. MAIN OUTCOME MEASUREMENTS: Mean and maximum reduction in vessel diameter. RESULTS: The application of the OTSC on the bleeding vessel led to a significant increase in systemic pressure (P < .001) and decreased vessel diameter (P < .001) independent of the endoscopic experience of the investigator. There was no difference in the decrease in vessel diameter based on the application technique (suction vs suction plus grasping). A historical comparison with our former trials demonstrated that the OTSC decreased the vessel diameter significantly more than other traditional endoclips. LIMITATIONS: Small sample size. CONCLUSIONS: We could demonstrate the efficacy of the OTSC with increased hemodynamic efficiency compared with other endoscopic clip devices tested previously. PMID- 22100299 TI - The appropriateness of colonoscopies at a teaching hospital: magnitude, associated factors, and comparison of EPAGE and EPAGE-II criteria. AB - BACKGROUND: The growing demand for colonoscopies and inappropriate colonoscopies have become a significant problem for health care. OBJECTIVES: To assess the appropriateness of colonoscopies and to analyze the association with some clinical and organizational factors. To compare the results of the European Panel of Appropriateness of Gastrointestinal Endoscopy (EPAGE) and the EPAGE-II criteria. DESIGN: Cross-sectional study. SETTING: Endoscopy unit of a teaching hospital in Spain. PATIENTS: Patients referred for colonoscopy, excluding urgent, therapeutic indications, and poor cleansing. MAIN OUTCOME MEASUREMENTS: Appropriateness of colonoscopies according to the EPAGE criteria. RESULTS: From 749 colonoscopies, 619 were included. Most patients were referred by gastroenterologists (66.1%) in an outpatient setting (80.6%). Hematochezia was the most frequent indication (31.5%) followed by colorectal cancer-related indications (27.3%); a clinically relevant diagnosis was established in 41%. Inappropriate use was higher with EPAGE (27.0%) than EPAGE-II (17.4%) criteria. Surveillance after colonic polypectomy and uncomplicated lower abdominal pain were the indications exhibiting higher inadequacy. Inappropriate use was less with older age, in hospitalized patients, with referrals from internal medicine, and in colonoscopies with clinically relevant diagnoses. Agreement between EPAGE and EPAGE-II was fair (weighted kappa = 0.31) but improved to moderate (simple kappa = 0.60) after grouping appropriate and uncertain levels. LIMITATIONS: The appropriateness criteria are based on panel opinions. Some patients (12%) could not be evaluated with the EPAGE criteria. CONCLUSIONS: Our study identifies substantial colonoscopy overuse, especially in tumor disease surveillance. The EPAGE-II criteria decrease the inappropriate rate and the possibility of overlooking potentially severe lesions. PMID- 22100300 TI - Early cholecystectomy and ERCP are associated with reduced readmissions for acute biliary pancreatitis: a nationwide, population-based study. AB - BACKGROUND: Cholecystectomy is recommended during hospitalizations for acute biliary pancreatitis (ABP). OBJECTIVE: We sought to assess the population-based effectiveness of index cholecystectomy by using nationwide data. DESIGN: Retrospective, cohort study. SETTING: All acute-care hospitals in Canada from 2007 to 2010. PATIENTS: This study involved patients admitted for ABP in the Canadian Institutes for Health Information hospital discharge database. INTERVENTION: Cholecystectomy and therapeutic ERCP during the index admission. MAIN OUTCOME MEASUREMENTS: Rate of hospital readmissions for ABP. RESULTS: Among 5646 patients with ABP, 32% underwent cholecystectomy and 22% ERCP during the index admissions. Patients admitted to hospitals in the highest quartile for cholecystectomy volume were more than 10-fold likely to undergo cholecystectomy during the index admission (adjusted odds ratio 11.0; 95% confidence interval [CI], 7.4-16.5). The 12-month readmission rate for ABP was lower with cholecystectomy (5.6% vs 14.0%; P < .0001) and therapeutic ERCP (5.1% vs 13.1%; P < .0001). After multivariate adjustment, lower readmission rates were independently associated with both cholecystectomy (adjusted hazard ratio [HR] 0.39; 95% CI, 0.32-0.48) and ERCP (adjusted HR 0.37; 95% CI, 0.29-0.50). After excluding early readmissions (within 28 days of discharge), the adjusted HR for cholecystectomy was 0.43 (95% CI, 0.34-0.57). The admitting hospital's cholecystectomy volume was inversely associated with 12-month readmission rates for ABP (quartile 1, 15.9%; quartile 2, 13.9%; quartile 3, 11.3%; quartile 4, 10.0%; P < .001). LIMITATIONS: The study was based on hospital administrative data. CONCLUSION: Cholecystectomy and ERCP during the index admission were associated with reduced readmission rates for ABP, providing population-based evidence to support consensus guidelines that recommend early biliary intervention. PMID- 22100302 TI - Hemostatic efficacy and clinical outcome of endoscopic treatment of Dieulafoy's lesions: comparison of endoscopic hemoclip placement and endoscopic band ligation. AB - BACKGROUND: The most suitable mechanical endoscopic hemostasis for a bleeding Dieulafoy's lesion (DL) is not yet well established. OBJECTIVE: To compare the hemostatic efficacy and clinical outcome of endoscopic hemoclip placement (EHP) and endoscopic band ligation (EBL). DESIGN: Retrospective, single-center study. SETTING: A tertiary-care referral university hospital. PATIENTS: Sixty-six patients who received mechanical endoscopic hemostasis for bleeding DLs. INTERVENTIONS: Endoscopic hemostasis. MAIN OUTCOME MEASUREMENT: Primary hemostasis and rebleeding rates. RESULTS: DLs accounted for 3.8% of cases of acute nonvariceal upper GI bleeding during the study period. Active bleeding from DLs was noted in 34 patients (51.5%). EHP and EBL were performed as a method of endoscopic hemostasis in 34 and 32 patients, respectively. There were no significant differences between the 2 groups with respect to baseline characteristics (except comorbidities) and endoscopic features of DLs. Primary hemostasis was achieved in all 66 patients (100%). There were 6 cases of recurrent bleeding: 5 (14.7%) and 1 (3.1%) in the EHP and EBL groups, respectively. Secondary hemostasis was achieved with endoscopic treatment and angiographic embolization in 5 patients and 1 patient, respectively, and no patients required surgery. The mean procedure time of endoscopic hemostasis was significantly longer in the EHP group (19.1 vs 11.5 minutes, P = .015). There was no bleeding-related mortality. LIMITATIONS: Retrospective analysis. CONCLUSIONS: Both EHP and EBL are suitable for the treatment of bleeding DLs. EBL can be used as an initial hemostatic method for bleeding DLs because of a favorable clinical outcome comparable to that with EHP and a shorter procedure time. PMID- 22100301 TI - Overutilization of endoscopic surveillance in nondysplastic Barrett's esophagus: a multicenter study. AB - BACKGROUND: Guidelines suggest that patients with nondysplastic Barrett's esophagus (BE) undergo endoscopic surveillance every 3 to 5 years, but actual use of surveillance endoscopy and the determinants of variation in surveillance intervals are not known. OBJECTIVE: To measure use of surveillance endoscopy and its variation in patients with nondysplastic BE. DESIGN: Multicenter, cross sectional study. SETTING: Three sites in Arizona, Minnesota, and North Carolina. PATIENTS: This study involved patients who had prevalent BE without a history of high-grade dysplasia or esophageal adenocarcinoma. INTERVENTION: Participants were given validated measures of quality of life, numeracy, and cancer risk perception, and the total number of prior endoscopic surveillance examinations was measured. MAIN OUTCOME MEASUREMENTS: Oversurveillance was defined as >1 surveillance examination per 3-year period. RESULTS: Among 235 patients with nondysplastic BE, 76% were male and 94% were white. The average (+/- standard deviation [SD]) duration of BE was 6.5 +/- 5.9 years. The mean (+/- SD) number of endoscopies per 3-year period was 2.7 +/- 2.6. Oversurveillance was present in 65% of participants, resulting in a mean of 2.3 excess endoscopies per patient. Neither numeracy skills nor patient perception of cancer risk were associated with oversurveillance. LIMITATIONS: Endoscopies were measured by patient report, which is subject to error. Results may be generalizable only to patients seen in academic centers. CONCLUSION: Most patients with nondysplastic BE had more surveillance endoscopic examinations than is recommended by published guidelines. Patient factors did not predict oversurveillance, indicating that other factors may influence decisions about the interval and frequency of surveillance examinations. PMID- 22100303 TI - Pharmacophore insights into rpoB gene mutations in Mycobacterium tuberculosis rifampicin resistant isolates. AB - This paper reports the susceptibility profile to rifabutin (RFB) 1 and six recently synthesized RFB analogs 3-8, of either rifampicin (RFP) susceptible Mycobacterium tuberculosis and resistant clinical isolates from two sources: Mexico and Brazil. Taking into account that about 95% of M. tuberculosis strains resistant to RFP present mutations in the rpoB gene, with some of these mutations being determinant also to RFB resistance, the RFB analogs were screened for activity against a set of known RFP susceptible and resistant strains. N'-Acetyl RFB 5 and N'-(undec-10"-enoyl)-RFB 8 showed the best results, in particular with mutations in the codon 516, 522 and 531 of the rpoB gene, and were therefore selected for in vivo assessment of their efficacy. Studies conducted with tuberculous Balb/C mice previously infected with Ser531Leu mutated clinical isolate, evidenced both 5 and 8 as promoters of a significant decrease on tubercle bacilli burden in lungs associated with lower tissue damage, thus confirming them as good leads for drug discovery. The SAR of the acylated compounds 5 and 8 envisaging the identification of pharmacophore features, highlights the importance of profiling more clearly the chemistry within the molecular aspects for elucidation of the mode of action of RFB and analogs, in relation to mutations in Multidrug-Resistant (MDR) strains. PMID- 22100304 TI - Inhibitors of membranous adenylyl cyclases. AB - Membranous adenylyl cyclases (mACs) constitute a family of nine isoforms with different expression patterns. Studies with mAC gene knockout mice provide evidence for the notion that AC isoforms play distinct (patho)physiological roles. Consequently, there is substantial interest in the development of isoform selective mAC inhibitors. Here, we review the current literature on mAC inhibitors. Structurally diverse inhibitors targeting the catalytic site and allosteric sites (e.g. the diterpene site) have been identified. The catalytic site of mACs accommodates both purine and pyrimidine nucleotides, with a hydrophobic pocket constituting a major affinity-conferring domain for substituents at the 2'- and 3'-O-ribosyl position of nucleotides. BODIPY forskolin stimulates ACs 1 and 5 but inhibits AC2. However, so far, no inhibitor has been examined at all mAC isoforms, and data obtained with mAC inhibitors in intact cells have not always been interpreted cautiously enough. Future strategies for the development of the mAC inhibitor field are discussed critically. PMID- 22100305 TI - Human leukocyte antigen epitope analysis to assess complement- and non-complement binding donor-specific antibody repertoire in a pediatric heart transplant recipient. AB - This case report summarizes the spectrum of anti-human leukocyte antigen (HLA) antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining antibody specificities against epitopes using various Luminex-based assays. PMID- 22100306 TI - Structure and kinetic stability of the p63 tetramerization domain. AB - The p53 family of transcription factors--comprising p53, p63 and p73--plays an important role in tumor prevention and development. Essential to their function is the formation of tetramers, allowing cooperative binding to their DNA response elements. We solved crystal structures of the human p63 tetramerization domain, showing that p63 forms a dimer of dimers with D2 symmetry composed of highly intertwined monomers. The primary dimers are formed via an intramolecular beta sheet and hydrophobic helix packing (H1), a hallmark of all p53 family members. Like p73, but unlike p53, p63 requires a second helix (H2) to stabilize the architecture of the tetramer. In order to investigate the impact of structural differences on tetramer stability, we measured the subunit exchange reaction of p53 family homotetramers by nanoflow electrospray mass spectrometry. There were differences in both the kinetics and the pattern of the exchange reaction, with the p53 and p63 tetramers exhibiting much faster exchange kinetics than p73. The structural similarity between p63 and p73 rationalizes previous observations that p63 and p73 form mixed tetramers, and the kinetic data reveal the dissociation of the p73 homotetramers as the rate-limiting step for heterotetramer formation. Differential stability of the tetramers may play an important role in the cross talk between different isoforms and regulation of p53, p63 and p73 function in the cell cycle. PMID- 22100307 TI - Transcription factor GATA-6 recruits PPARalpha to cooperatively activate Glut4 gene expression. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear hormone receptor that regulates energy metabolism, but its precise mechanisms remain unknown. Here, we demonstrate that the PPARalpha agonist fenofibrate activated expression of the glucose transporter Glut4. Moreover, PPARalpha was associated with the Glut4 promoter through GATA sites upon fenofibrate stimulation in cardiomyocytes. This occupancy is achieved through an interaction between amino acids 1-136 of PPARalpha with amino acids 276-443 of the cardiac transcription factor GATA-6. In addition, the interaction of PPARalpha with GATA-6 activated Glut4 gene expression, improved glucose consumption, and enhanced activity of mitochondrial citrate synthase in C2C12 myoblasts; both mutants of PPARalpha (1 101 aa) and GATA-6 (227-331 aa) were unable to cooperate in Glut4 activation. Thus, GATA-6 is an important component of the transcription network required for energy metabolism mediated by PPARalpha, and these findings provide a molecular basis for understanding the role of GATA-6 proteins in muscle development and disease. PMID- 22100308 TI - Adenine recognition is a key checkpoint in the energy release mechanism of phage T4 DNA packaging motor. AB - ATP is the source of energy for numerous biochemical reactions in all organisms. Tailed bacteriophages use ATP to drive powerful packaging machines that translocate viral DNA into a procapsid and compact it to near-crystalline density. Here we report that a complex network of interactions dictates adenine recognition and ATP hydrolysis in the pentameric phage T4 large "terminase" (gp17) motor. The network includes residues that form hydrogen bonds at the edges of the adenine ring (Q138 and Q143), base-stacking interactions at the plane of the ring (I127 and R140), and cross-talking bonds between adenine, triphosphate, and Walker A P-loop (Y142, Q143, and R140). These interactions are conserved in other translocases such as type I/type III restriction enzymes and SF1/SF2 helicases. Perturbation of any of these interactions, even the loss of a single hydrogen bond, leads to multiple defects in motor functions. Adenine recognition is therefore a key checkpoint that ensures efficient ATP firing only when the fuel molecule is precisely engaged with the motor. This may be a common feature in the energy release mechanism of ATP-driven molecular machines that carry out numerous biomolecular reactions in biological systems. PMID- 22100309 TI - Abnormal event-related potentials in young and middle-aged adults with the ApoE epsilon4 allele. AB - The largest genetic susceptibility factor for Alzheimer's disease is the Apolipoprotein E (ApoE) epsilon4 allele. Cognitive decline and olfactory impairment are greater in those positive for the epsilon4 allele. This study sought to determine if the olfactory event-related potential (OERP), compared to the visual ERP, would be sensitive to these subtle declines. Participants included 40 individuals from two age groups, half of each group were epsilon4 allele positive and half were epsilon4 negative. Visual ERPs did not demonstrate significant differences between ApoE groups. OERPs demonstrated robust age by ApoE interactions. P3 latencies were significantly longer in epsilon4 young and middle age participants. These findings suggest that very early olfactory and cognitive changes related to ApoE status are detectible via the OERP. PMID- 22100310 TI - The role of gender and organ specific autoimmunity. AB - Autoimmunity is influenced by multiple factors including gender and sex hormones. A definite female predominance is found in many autoimmune diseases. Gender is also associated with differences in clinical presentation, onset, progression and outcome of autoimmune diseases. Sex hormones might influence the target organ's vulnerability to an autoimmune response. Gender differences also exist in organ specific autoimmune diseases such as multiple sclerosis, Guillain-Barre syndrome, Crohn's disease and celiac disease. Nevertheless, other organ specific autoimmune diseases (i.e. ulcerative colitis) are seemingly characterized with similar prevalence in both males and females. The reason for gender differences in certain autoimmune diseases remains unknown, but may be attributed to sex hormone influence, fetal microchimerism, X chromosome inactivation, and X chromosome abnormalities. Sex hormones have been found to have immune modulating properties, as well as providing cellular protection following tissue damage in certain circumstances. Sex hormones also influence innate and adaptive immune cells, number of B and T cells, antigen presentation and cytokine secretion. Herein, we review the influence of gender on organ-specific autoimmune diseases affecting the heart, blood vessels, central nervous system and gastrointestinal tract. It appears that sex hormones may have a therapeutic potential in several autoimmune conditions, although further research is required before therapeutic recommendations can be made. PMID- 22100311 TI - Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases. AB - A folate receptor targeted didemnin B conjugate was synthesized using a hydrophilic peptide spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity and TNF-alpha inhibition in RAW264.7 macrophage-like cells exhibited IC(50)s of 13 and 5 nM, respectively. Folate didemnin B was found to be ~50-100 fold more potent than didemnin B itself. More importantly, activity of the prodrug was blocked by excess folic acid, demonstrating receptor-mediated cellular uptake of the conjugate. PMID- 22100312 TI - Indole RSK inhibitors. Part 1: discovery and initial SAR. AB - A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization. PMID- 22100313 TI - aza-Flavanones as potent cross-species microRNA inhibitors that arrest cell cycle. AB - aza-Flavanones have been identified as a new class of selective microRNA inhibitors. These compounds were found to arrest cell cycle via a novel cross species microRNA-dependent regulatory pathway interpreting an unexpected link between cell cycle arrest and microRNA mediated control in cancer. PMID- 22100314 TI - Novel 5- and 6-subtituted benzothiazoles with improved physicochemical properties: potent S1P1 agonists with in vivo lymphocyte-depleting activity. AB - An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity. PMID- 22100315 TI - Functional genetics. AB - How genetic variations mediate normal and abnormal biological function is a major issue in biology and medicine. The enormous number of genomic sequences, and their frequent and rare variations identified in humans, require efficient approaches aimed at dissecting functional correlates. In this review we will focus on the importance of the assessment of well-defined intermediate phenotypes, on the set up of transcriptomic approaches in diseased cells and on the modulation of expression by sequence variations modulating mRNA splicing or influencing protein multimerization. These information provide the molecular bases of associations discovered through genomic approaches, and might open new avenues toward the design of novel and specific diagnostic, prophylactic or therapeutic interventions. Taking into account our previous and current experimental activities we shall focus on a few examples and open issues in cardiovascular disorders, the main clinical topic of this short review. PMID- 22100316 TI - Sex-specific risk factors for recurrent venous thromboembolism. AB - BACKGROUND: Men have higher risk of recurrent venous thromboembolism (VTE) than women but this sex difference remains unexplained. In addition, whether men and women share same risk factors for recurrent VTE is unclear. METHODS: In a prospective cohort study, 583 patients (234 men and 349 women) aged 18 to 90, with a first idiopathic VTE, were followed for an average of 28 months. We assessed the association between baseline characteristics and VTE recurrence by gender. RESULTS: Recurrent VTE occurred in 38 women and 36 men (incidence=4.6% and 7.5% per year respectively; HR=1.6; 95% CI, 1.0-2.6). This relation between sex and recurrent VTE was more pronounced in patients younger than 50 years and in the presence of factor V Leiden (FVL) mutation. Multivariate analyses showed that obesity (HR, 2.8 (95% CI, 1.3-6.0)) and aging (HR, 1.3 (95% CI, 1.1-1.4) per 10 years increase) were related to an increased risk of recurrent VTE in women while FVL mutation (HR, 3.5 (95% CI, 1.5-8.1)) was a risk factor of recurrent VTE among men. CONCLUSION: Men and women do not share the same risk factors for recurrent VTE. Consequently, gender has to be taken into account to improve the risk stratification and prevention of VTE recurrence. PMID- 22100317 TI - The Mediterranean diet: the reasons for a success. AB - There is a substantial body of evidence linking Mediterranean Diet to cardiovascular risk reduction and prevention of the major chronic diseases. Nevertheless Mediterranean societies are rapidly withdrawing from this eating pattern orienting their food choices toward products typical of the Western diet pattern, which is rich in refined grains, animal fats, sugars, processed meat but are quite poor in legumes, cereals, fruits and vegetables. The reasons people keep on shifting from healthy to unhealthy dietary habits remain open to several interpretations. Social changes appear to have consistently contributed to radical reversal in dietary habits in European Mediterranean societies even though developing Countries are somewhat turning into westernized diets as well. Among possible causes, increasing prices of some of the major food items of Mediterranean pyramid seem to have led people to give up this eating pattern in favor of less expensive products which allow to save money but are definitively unhealthy. Many studies suggest that diet quality follows a socio-economic gradient highlighting how disadvantaged people present higher rates of obesity, diabetes, cardiovascular disease and some types of cancer. Recent studies have shown a linear relationship between food cost and adherence to eating patterns and obesity. In addition to financial crisis, during the last decades the Mediterranean Diet has been put on the spot because of its alcohol -in- moderation component. Does it make any sense to blame a whole philosophy, which turned out to have beneficial effects on human health, just because, in some Countries, there is a misuse of alcoholic beverages? PMID- 22100318 TI - Ultrastructural study of spermiogenesis and the spermatozoon of Cavisoma magnum (Southwell, 1927) (Acanthocephala, Palaeacanthocephala, Cavisomidae), from Siganus lineatus (Pisces, Teleostei, Siganidae) (Valenciennes, 1835) in New Caledonia. AB - This paper presents an ultrastructural study of Cavisoma magnum (Acanthocephala, Cavisomatidae) with a Transmission Electron Microscopy tool. This parasite of the fish Siganus lineatus is here reported for the first time from off New Caledonia, South Pacific. It is the first study describing the ultrastructure, spermiogenesis and spermatozoon of a species of the family Cavisomatidae. The young spermatid of C. magnum possesses a centriole constituted of doublets without a central element. After the elaboration of a flagellum of 9+2 pattern, the centriole migrates in a nuclear groove. Then the flagellum migration occurs and gives rise to a spermatozoon. The distribution and the size of the protein granules are reported and the posterior extremity appears like a chromatin lamina wave. Comparative ultrastructural data are presented on sperm and spermiogenesis of the Acanthocephala and Rotifers examined to date and the phylogenetic implications are discussed. PMID- 22100320 TI - Satoyoshi's syndrome related muscle spasms: functional study. AB - Satoyoshi syndrome is a rare disease presumed to be immunologically mediated, characterized by muscle spasms, alopecia and diarrhea. We describe the case of a female in whom the muscle spasms were the predominant feature and we analyze the changes in cortical and in spinal excitability under the paired pulses paradigm. Hyperexcitability was present in the H-reflex study, thus suggesting that the spinal cord is the structure most likely responsible for the spasms. This is the first reported case in Spain. PMID- 22100319 TI - Associations between inflammatory markers, candidate polymorphisms and physical performance in older Danish twins. AB - Inflammation may play an essential role in the decline of physical performance. In this study we investigated the associations between inflammatory markers, candidate polymorphisms and physical performance in elderly people. Plasma levels of TNF-alpha, IL-6, CRP, fibrinogen, sICAM-1 and candidate polymorphisms were measured in 600 twin individuals aged 73 years and older participating in the Longitudinal Study of Aging Danish Twins. Physical performance was assessed using a self-reported measure. The inclusion of twins allowed both traditional and within-twin-pair analysis which permitted control for shared environment and genetic factors. Higher levels of inflammatory markers were generally associated with a lower level of physical performance. The TNFalpha-238G/A polymorphism was significantly associated with physical performance in men, with A allele carriers having significantly better performance than GG homozygotes. However, this gene variation seems to have only a minor role in explaining the associations between the levels of inflammatory markers and physical performance. When using twin pair analysis to test whether genetic factors in general account for this association, results showed that the association between the level of fibrinogen and physical performance could be caused by genetic factors. Also the association between the level of TNF-alpha and physical performance in males could be caused by genetic factors. However, other gene variations than the candidate gene polymorphisms studied here seem to explain the major part of the genetic proportion of this association. PMID- 22100321 TI - [A rare case of neuropathic osteoarthropathy]. PMID- 22100322 TI - [Hematological side effects of natalizumab: Correlation with clinical outcome]. AB - INTRODUCTION: Natalizumab (NTZ) is a monoclonal antibody used in a single-drug regimen to treat active relapsing remitting multiple sclerosis. Safety data collected during the AFFIRM pivotal study and post marketing cohorts reported infusion-related and allergic reactions, with development of persistent anti-NTZ antibodies in 6% of patients. Occurrence of hematological side effects (HSE), such as hyperlymphocytosis (HL) and hypereosinophilia (HEo) have been described. To our knowledge, there is no study assessing neither incidence of HSE, nor their correlation with clinical outcome. The objective is to evaluate prospectively the incidence of HSE of NTZ and to search for correlations with clinical outcome. METHODS: Clinical (EDSS, relapse, tolerance) and biological assessments were performed before the first infusion and every month during the follow-up in all patients treated with NTZ between 2007 and 2010. Before starting NTZ, data were collected on prior history of allergy and previous disease-modifying treatments (DMT). Statistical analysis was performed to search for correlations between the occurrence of HSE and clinical outcome. RESULTS: The series included 66 patients (sex ratio: 1/2.8) followed for up to 17 months. Mean age was 39 (+/-SD) years. Mean EDSS score was 3.2 (+/-SD). Fifty-six percent of patients had DMT history with beta interferons (41%), glatiramer acetate (6%) and immunosuppressive drugs (cyclophosphamide, mitoxantrone) (9%). Annualized relapse rate during follow-up was 0.41. Infusion-related reactions were noted in 10% of patients. Two patients had allergic reactions and had stopped their infusions. HL developed in 48% of patients and HEo in 20%. Regarding age and medical or therapeutic history, no predictive factor of HSE occurrence could be identified. Incidence of infusion related side effects was higher in patients with HEo (38%) in comparison with patients without HEo (3.8%). Relapse rate during NTZ treatment was not significantly different between the different groups. CONCLUSION: This is the first prospective study assessing of HSE during NTZ treatment. There is a higher occurrence of intolerance reactions in patients with HEo. PMID- 22100323 TI - [DNA microarray analysis in nerve biopsies of patients with vasculitic neuropathy]. AB - DNA microarray analysis is a powerful tool for simultaneous analysis and comparison of gene products expressed in normal and diseased tissues. We used this technique to identify differentially expressed genes (DEGs) in nerve biopsy samples of vasculitic neuropathy (VAS) patients. We find novel previously uncharacterized genes of relevance to VAS pathogenesis. Genes upregulated in VAS include IGLJ3, IGHG3, IGKC, and IGL, which all function in B-cell selection or antigen recognition of B cells. Other upregulated genes are chemokines, such as CXCL9 and CCR2 and CX3CR1. Allograft inflammatory factor-1 (AIF-1), a modulator of immune response is upregulated in VAS. We demonstrate by immunolocalisation the expression of AIF-1 in vascular smooth muscle cells, suggesting a role for AIF-1 in vascular remodeling in VAS. Microarray-based analysis of human nerve biopsies shows distinct gene expression patterns in VAS. DEGs might provide clues to the pathogenesis of this condition and help define potential targets for therapeutics. PMID- 22100324 TI - [Original articles on axonal neuropathy in 2010]. AB - During 2010, 15 articles were published which focused on chronic sensorimotor axonal neuropathy; some will be discussed in this review. Clinical diagnosis from signs and symptoms seems to be excessively variable, often overestimating the incidence of diabetic sensorimotor polyneuropathy. Long-term use of Metformin is associated with malabsorption of vitamin B12. Metformin exposure may be a iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. The neuroprotective role of vitamin E against cisplatinperipheral neurotoxicity has been suggested by a phase III study. Metallosis after hip arthroplasty with a cobalt-chromium alloy prosthesis can cause progressive sensory disturbance, hearing loss and hypothyroidism. The effects of electrical stimulation on neuromuscular recovery after nerve crush injury in rats do not support a benefit of the tested protocol using electrical stimulation during the period of motor nerve recovery following injury. The rate of motor vehicle accidents in patients with neuropathy, based on surveys from 260 subjects, demonstrated that 40.6% were involved in traffic accidents. Accident frequency and discomfort with driving are higher in neuropathy patients compared to age matched national statistics. Peripheral neuropathy in primary (AL) amyloidosis may be the cause of stepwise progressive, multiple upper limb mononeuropathies. PMID- 22100325 TI - [Therapeutic advances in pharmaceutical treatment of neuropathic pain]. AB - Neuropathic pain is difficult to treat. Recommended first-line treatments include tricyclic antidepressants and alpha2delta agonists pregabalin and gabapentin for multiple neuropathic conditions, the antidepressants duloxetine and venlafaxine in diabetic painful neuropathies and lidocaine patches for postherapetic neuralgia. Therapeutic prospects include focal therapy with sustained analgesic efficacy (capsaicin patches, botulinum toxin), treatments acting on new targets (i.e., cytokine inhibitors, metabotropic glutamate inhibitors, TRPV1 antagonists). The methodology of clinical trials also tends to take better into account the symptomatic profiles of patients, which should contribute to better prediction or responders to treatment. PMID- 22100326 TI - [F-waves]. AB - F-waves result from the discharge of the motoneurons following their antidromic activation. The F-wave appears, as an indirect (the F-wave latency decreases when the stimulation site moves away from the muscular detection) and late response (occurring after the M response). In practice, the most useful parameter is the F wave minimal latency, provided that at least seven distinct F-waves are evoked. When the analysis is relative either to the controlateral side, or to a former examination, this parameter is one of most sensitive in electroneuromyography. F wave evocation implies conduction along the entire peripheral nervous system, and particularly its proximal part, which is not investigated by nervous trunks conduction velocity studies. Thus, F wave study is the most useful in plexopathies and polyradiculonevritis. In the early phase of Guillain-Barre syndrome, their absence may be the unique sign indicative of proximal conduction blocks. PMID- 22100327 TI - [Hereditary sensory and motor neuropathy and hereditary sensory and autonomic neuropathies: recent advances]. AB - This review summarizes the recent genetic advances in hereditary sensorimotor neuropathy also called Charcot-Marie-Tooth disease. The different new genes discovered in 2010 and their underlying phenotypes will be presented. PMID- 22100328 TI - Determination of sex from the metacarpals in a Thai population. AB - Determination of sex using metacarpals was carried out on a sample of 249 skeletons from a Thai population (154 males and 95 females), ranging in age from 19 to 93 years. Six measurements were taken on each metacarpal, namely maximum length, medio-lateral base width, antero-posterior base height, medio-lateral head width, antero-posterior head height and mid-shaft diameter. Binary logistic regression equations were calculated for determining sex from these measurements. All metacarpals from both sides produced at least one equation that correctly allocated the skeletons with 80% or greater accuracy. In a comparative test using only individuals with no missing measurements (n=196), the most accurate equations for each metacarpal on the right side had pooled allocation accuracies ranging from 85.2% to 89.3%, with the best equation based on three measurements from the 5th metacarpal. On the left side, the most accurate equations for each metacarpal ranged from 83.2% to 89.8% correct allocation, with the best equation based on three measurements of the 2nd metacarpal. When the allocation accuracy for each sex is considered in addition to the pooled accuracy, the best equations involve the same three measurements of the 5th metacarpal on the right side, but shift to three measurements of the first metacarpal on the left side, with a pooled accuracy of 88.3%. The results of this study suggest that metacarpals can be used quite reliably for sexing in forensic contexts in Thailand. PMID- 22100329 TI - miRNAs and related polymorphisms in rheumatoid arthritis susceptibility. AB - The epigenetic mechanisms in regulation of genes' expression seem to be another field of research that gains land in genetic association studies of rheumatoid arthritis (RA) susceptibility factors. Recently, a new class of molecules has been discovered, the microRNAs (miRNAs). miRNAs are related to post transcriptional regulation of genes' expression. Different expression patterns of mir-146a, miRNA-155, miRNA-124a, mir-203, mir-223, mir-346, mir-132, mir-363, mir 498, mir-15a, and mir-16 were documented in several tissue sample types of RA patients. The polymorphisms of these miRNAs and their gene targets, which previously have been associated with RA or other autoimmune diseases, are also reviewed. Finally, using web-based tools we propose polymorphisms of the discussed miRNAs and their gene-targets that worth to be studied for their role in RA predisposition. PMID- 22100330 TI - Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases. AB - The presence of anti-nuclear antibodies (ANA) is a hallmark of systemic autoimmune rheumatic diseases (SARD). The indirect immunofluorescence (IIF) assay on HEp-2 cells is a commonly used test for the detection of ANA and was recently recommended as the screening test of choice by a task force of the American College of Rheumatology. However, up to 20% of serum samples from healthy individuals (HI) have been reported to have a positive ANA test, the majority of which are directed to the dense fine speckles 70 (DFS70) antigen. Even more important, the DFS IIF pattern has been reported in 33% of ANA positive HI, but not in ANA positive SARD sera. Since the intended use of the ANA HEp-2 test is to aid in the diagnosis of SARD, the reporting of anti-DFS70 antibodies and their associated pattern (DFS) as a positive test, significantly reduces the specificity and the positive likelihood of the ANA test. This has significant implications for diagnostic algorithms involving the detection of ANA. We summarize the current knowledge of anti-DFS70 antibodies and their impact on ANA testing. We also suggest a test algorithm which considers the DFS pattern and the presence of anti-DFS70 antibodies. In addition, we describe a novel method based on immunoadsorption of anti-DFS70 antibodies, which increases the specificity of the ANA HEp-2 test for SARD and which has the potential to overcome a significant limitation of the ANA HEp-2 assay. PMID- 22100331 TI - Origin and plasticity of MHC I-associated self peptides. AB - Endogenous peptides presented by MHC I molecules represent the essence of self for CD8 T lymphocytes. These MHC I peptides (MIPs) regulate all key events that occur during the lifetime of CD8 T cells. CD8 T cells are selected on self-MIPs, sustained by self-MIPs, and activated in the presence of self-MIPs. Recently, large-scale mass spectrometry studies have revealed that the self-MIP repertoire is more complex and plastic than previously anticipated. The composition of the self-MIP repertoire varies from one cell type to another and can be perturbed by cell-intrinsic and -extrinsic factors including dysregulation of cellular metabolism and infection. The complexity and plasticity of the self-MIP repertoire represent a major challenge for the maintenance of self tolerance and can have pervasive effects on the global functioning of the immune system. PMID- 22100332 TI - Letter to the editor--atrial fibrillation: an inflammatory and autoimmune disorder. PMID- 22100333 TI - Variation of pain and vasomotor responses evoked by intramuscular infusion of hypertonic saline in human subjects: influence of gender and its potential neural mechanisms. AB - The aim of current study was to explore role of gender in pain and cutaneous vasomotor responses during the condition of intramuscular (i.m.) hypertonic (HT, 5.8%) saline induced muscle pain. In 20 healthy human subjects (10 females), 2 4.8ml of either HT or isotonic (IT, 0.9%) saline was infused into the left tibialis anterior muscle to elicit muscle pain, during which the intensity and distribution of pain together with skin vasomotor responses were investigated. Cutaneous blood flow was assessed using laser-Doppler flowmetry in 4 different skin areas: ipsilateral infusion area (5cm*5cm), ipsilateral referred pain area (5cm*10cm), contralateral area to the infusion site (5cm*5cm), and contralateral area to the referred pain site (5cm*10cm). Among the different i.m. infusions, 4.8ml HT saline evoked the highest pain intensity, the longest pain duration, and the largest pain distribution area in different subjects (P<0.001). Gender related differences in pain and skin vasomotor responses were observed following the i.m. HT, but not IT, saline infusion while women exhibited stronger pain intensity and duration (P<0.001), and more expressed vasomotor responses (P<0.05) at the infusion area and contralateral mirror site. Intramuscularly pre-treating the infusion area with 1ml of 2% lidocaine markedly reduced the muscle pain and blocked the increased skin blood flow in both men and women (P<0.05). However, post-treatment with lidocaine significantly reduced the pain intensity and the increased skin blood flow only in men, but not women. The data demonstrate that gender-associated difference exists in HT saline intramuscularly induced local muscle pain and vasomotor responses. Neural mechanisms underlying gender-related differences in vasomotor responses is significantly different, suggesting that local pre-treatment, but not post-treatment, with anesthetic may provide superior analgesia to block sex-associated difference in pain and vasomotor responses. PMID- 22100334 TI - Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats. AB - EGb761 is a standard extract of Ginkgo biloba, which is a kind of traditional Chinese herbs that has widely used in clinic treatment of stroke in China. However, its effects against ischemic stroke have not been evaluated comprehensively and its neuroprotective mechanism has not really been explored. In the present study, magnetic resonance diffusion-weighted imaging (DWI), neurological behavior and TTC staining were used to evaluate the therapeutic effect of EGb761 in rat ischemic models. Additionally, Western blot and immunohistochemistry were performed to measure the phosphorylations of cAMP response element binding protein (CREB) and Akt as well as the expression of brain-derived neurotrophic factor (BDNF) in rat brains. The results showed that Ginkgo biloba extract injection significantly increased the apparent diffusion coefficient (ADC) value and average diffusion coefficient (DCavg) value both in the peripheral zone and central zone, improved behavior scores, as well as enhanced the phosphorylations of AKT, CREB and the expression of BDNF in the brains. All these data demonstrate that EGb761 had significant therapeutic effects on ischemic stroke and it perhaps worked through activating the Akt-CREB BDNF pathway. PMID- 22100335 TI - Domain topology of nucleoporin Nup98 within the nuclear pore complex. AB - Nuclear pore complexes (NPCs) facilitate selective transport of macromolecules across the nuclear envelope in interphase eukaryotic cells. NPCs are composed of roughly 30 different proteins (nucleoporins) of which about one third are characterized by the presence of phenylalanine-glycine (FG) repeat domains that allow the association of soluble nuclear transport receptors with the NPC. Two types of FG (FG/FxFG and FG/GLFG) domains are found in nucleoporins and Nup98 is the sole vertebrate nucleoporin harboring the GLFG-type repeats. By immuno electron microscopy using isolated nuclei from Xenopus oocytes we show here the localization of distinct domains of Nup98. We examined the localization of the C- and N-terminal domain of Nup98 by immunogold-labeling using domain-specific antibodies against Nup98 and by expressing epitope tagged versions of Nup98. Our studies revealed that anchorage of Nup98 to NPCs through its C-terminal autoproteolytic domain occurs in the center of the NPC, whereas its N-terminal GLFG domain is more flexible and is detected at multiple locations within the NPC. Additionally, we have confirmed the central localization of Nup98 within the NPC using super resolution structured illumination fluorescence microscopy (SIM) to position Nup98 domains relative to markers of cytoplasmic filaments and the nuclear basket. Our data support the notion that Nup98 is a major determinant of the permeability barrier of NPCs. PMID- 22100336 TI - Regulation of alternative splicing within the supraspliceosome. AB - Alternative splicing is a fundamental feature in regulating the eukaryotic transcriptome, as ~95% of multi-exon human Pol II transcripts are subject to this process. Regulated splicing operates through the combinatorial interplay of positive and negative regulatory signals present in the pre-mRNA, which are recognized by trans-acting factors. All these RNA and protein components are assembled in a gigantic, 21 MDa, ribonucleoprotein splicing machine - the supraspliceosome. Because most alternatively spliced mRNA isoforms vary between different cell and tissue types, the ability to perform alternative splicing is expected to be an integral part of the supraspliceosome, which constitutes the splicing machine in vivo. Here we show that both the constitutively and alternatively spliced mRNAs of the endogenous human pol II transcripts: hnRNP A/B, survival of motor neuron (SMN) and ADAR2 are predominantly found in supraspliceosomes. This finding is consistent with our observations that the splicing regulators hnRNP G as well as all phosphorylated SR proteins are predominantly associated with supraspliceosomes. We further show that changes in alternative splicing of hnRNP A/B, affected by up regulation of SRSF5 (SRp40) or by treatment with C6-ceramide, occur within supraspliceosomes. These observations support the proposed role of the supraspliceosome in splicing regulation and alternative splicing. PMID- 22100337 TI - Fascin and VASP synergistically increase the Young's modulus of actin comet tails. AB - Cell motility is locally achieved by the interplay between lamellipodia and filopodia at the protrusion sites. The actin cytoskeleton rearranges from a highly branched short filamentous network to well aligned elongated bundles from lamellipodia to filopodia, respectively. This process is governed predominantly by actin binding proteins, VASP and fascin, at the leading edge of migratory cells. Here we use an Arp2/3-complex dependent bead motility assay to study the effect of fascin both on its own and in the presence of VASP. The Young's modulus of phalloidin stabilized comets grown in the presence of fascin increased linearly with concentration above a 0.5 MUM threshold. Inversely, the initial velocity of the comets decreased linearly with fascin concentration above the same threshold. Interestingly, VASP and fascin together increased the Young's modulus of the comets compared to those grown in the presence of only one of the two proteins. This effect was most remarkable at low concentration, below 0.5 and 0.15 MUM for fascin and VASP, respectively. Our results showed that fascin and VASP work cooperatively to enhance the Young's modulus of the actin network within the comets. PMID- 22100338 TI - Nuclear transport of baculovirus: revealing the nuclear pore complex passage. AB - Baculoviruses are one of the largest viruses that replicate in the nucleus of their host cells. During an infection the capsid, containing the DNA viral genome, is released into the cytoplasm and delivers the genome into the nucleus by a mechanism that is largely unknown. Here, we used capsids of the baculovirus Autographa californica multiple nucleopolyhedrovirus in combination with electron microscopy and discovered this capsid crosses the NPC and enters into the nucleus intact, where it releases its genome. To better illustrate the existence of this capsid through the NPC in its native conformation, we reconstructed the nuclear import event using electron tomography. In addition, using different experimental conditions, we were able to visualize the intact capsid interacting with NPC cytoplasmic filaments, as an initial docking site, and midway through the NPC. Our data suggests the NPC central channel undergoes large-scale rearrangements to allow translocation of the intact 250-nm long baculovirus capsid. We discuss our results in the light of the hypothetical models of NPC function. PMID- 22100339 TI - The effect of the G1888A mutation of subgenotype A1 of hepatitis B virus on the translation of the core protein. AB - A distinctive characteristic of subgenotype A1 of hepatitis B virus is G1888A in the precore region. This transition introduces an out-of-frame AUG, creating an overlapping upstream open reading frame (uORF), terminating five nucleotides downstream from the core AUG. This uORF can potentially be translated into a seven amino acid peptide. In addition to stabilizing the encapsidation signal by forming a base pair with T1871, this mutation may affect translation of the core protein. The aim of this study was to use reporter constructs to determine whether G1888A had any modulating effect on core protein translation. The complete core gene with part of the precore of subgenotype A1 was cloned into the amino terminal of a green fluorescent protein (GFP) plasmid. Core/GFP fusion protein expression was measured using flow cytometry following transfection of Huh 7 cells. The introduction of uORF resulted in an 18.75% reduction of core gene expression. When the suboptimal Kozak sequence of the 1888 AUG was replaced with an optimal one, this reduction was enhanced (64.84%). By increasing the distance between the stop of the overlapping uORF and the core AUG, by a minimum of 15 nucleotides, core/GFP expression was almost doubled, indicating that stalling of ribosomes at the stop of the uORF may be interfering with initiation at the core AUG through steric hindrance. Our findings indicate that the G1888A mutation, may interfere with initiation at the downstream 1901 core AUG, decreasing core protein translation. This decrease may account for the relatively low viral loads seen in individuals infected with subgenotype A1. PMID- 22100340 TI - Recent emergence of the Arctic rabies virus lineage. AB - The rabies viruses that circulate in Arctic countries and in much of northern and central Asia are phylogenetically closely related and collectively referred to as the Arctic/Arctic-like (AL) lineage. The emergence and spread of this lineage is of significant interest given that rabies remains a serious zoonotic disease in many parts of Asia, especially in India where the prevalence of dog rabies leads to frequent human exposures and deaths. Previous molecular epidemiological studies of rabies viruses in India identified the AL lineage as the type circulating across much of the country. To further explore the relationship of Indian and Arctic rabies viruses, a collection of samples recovered from Rajasthan state in northern India was characterised at the N gene locus. Combination of these data with a larger collection of samples from India, central/northern Asia and the Arctic has permitted detailed phylogenetic analysis of this viral lineage and estimation of its time-frame of emergence. These analyses suggest that most current Indian viruses emerged from a common progenitor within the last 40 years and that the entire Arctic/AL lineage emerged within the last 200 years, a time-frame in accord with historical records of the invasion of Canada by the Arctic clade. PMID- 22100341 TI - A nine-base nucleotide sequence in the porcine circovirus type 2 (PCV2) nucleocapsid gene determines viral replication and virulence. AB - Porcine circovirus type 2 (PCV2) was retrospectively identified by serology in swine populations as an asymptomatic infection at least 25 years prior to the first reported case of PCV2-associated postweaning multisystemic wasting syndrome (PMWS). To investigate the sudden emergence of PMWS, viral sequences were amplified from frozen archived (1970-1971) porcine tissues and the complete genome of archival PCV2 was determined. The ORF1 gene product (viral DNA replicase) was homologous to contemporary PCV2 ORF1. In ORF2 (viral nucleocapsid gene) archival PCV2, a consistent linear nine-base sequence difference at base positions 1331 through 1339 was observed. The deduced amino acid sequence from these base changes alters the nucleocapsid conformation within the second immunogenic epitope from a hydrophobic (contemporary PCV2) to a hydrophilic (archival PCV2) configuration. To test the hypothesis that archival PCV2 was avirulent, cloned engineered archival and contemporary PCV2 genomes were constructed wherein the ORF1 gene was identical in each clone and the ORF2 gene (nucleocapsid protein) was sequence-identical in both clones except for the nine base difference (bases 1331-1339), corresponding to archival and contemporary PCV2 viruses respectively. Clones were transfected into porcine kidney (PK) 15 cells and, after sequence confirmation, further passed in PK15 and 3D4/2 porcine alveolar macrophage cell cultures. Virulence trials in gnotobiotic piglets were conducted with cloned PCV2s. The data show that archival PCV2 is avirulent when compared to contemporary PCV2 and supports the hypothesis that the emergence of virulent contemporary PCV2 was a result of mutational events within this critical epitope after 1971. PMID- 22100342 TI - Molecular interactions of porcine circoviruses type 1 and type 2 with its host. AB - This review discusses the molecular interaction of proteins encoded by porcine circoviruses type 1 (PCV1) and type 2 (PCV2) with respect to the putative role for disease induction. Besides protein:protein interactions also proteins binding to PCV DNA are covered. Moreover, new approaches are considered which have been generated by genomic and proteomic techniques. PCV are still an enigma, when communication with the host and induction of disease are concerned. This is remarkably, since comparison of two viruses with a size of less than 2000 nts should easily identify the molecular trigger responsible for pathogenicity of PCV2. Since scientific life isn't all beer and skittles we have to accept that this conundrum may be solved only in a long time range. The good news is that some common themes become visible and that certain aspects of the cell life cycle have been identified to be involved in interaction with the pathogen. PMID- 22100343 TI - NAD(P)H oxidase-dependent intracellular and extracellular O2*- production in coronary arterial myocytes from CD38 knockout mice. AB - Activation of NAD(P)H oxidase has been reported to produce superoxide (O(2)(*-)) extracellularly as an autocrine/paracrine regulator or intracellularly as a signaling messenger in a variety of mammalian cells. However, it remains unknown how the activity of NAD(P)H oxidase is regulated in arterial myocytes. Recently, CD38-associated ADP-ribosylcyclase has been reported to use an NAD(P)H oxidase product, NAD(+) or NADP(+), to produce cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate, which mediates intracellular Ca(2+) signaling. This study was designed to test a hypothesis that the CD38/cADPR pathway as a downstream event exerts feedback regulatory action on the NAD(P)H oxidase activity in production of extra- or intracellular O(2)(*-) in mouse coronary arterial myocytes (CAMs). By fluorescence microscopic imaging, we simultaneously monitored extra- and intracellular O(2)(*-) production in wild type (CD38(+/+)) and CD38 knockout (CD38(-/-)) CAMs in response to oxotremorine (OXO), a muscarinic type 1 receptor agonist. It was found that CD38 deficiency prevented OXO-induced intracellular but not extracellular O(2)(*-) production in CAMs. Consistently, the OXO-induced intracellular O(2)(*-) production was markedly inhibited by CD38 shRNA or the CD38 inhibitor nicotinamide in CD38(+/+) CAMs. Further, Nox4 siRNA inhibited OXO-induced intracellular but not extracellular O(2)(*-) production, whereas Nox1 siRNA attenuated both intracellular and extracellular O(2)(*-) production in CD38(+/+) CAMs. Direct delivery of exogenous cADPR into CAMs markedly elevated intracellular Ca(2+) and O(2)(*-) production in CD38(-/-) CAMs. Functionally, CD38 deficiency or Nox1 siRNA and Nox4 siRNA prevented OXO-induced contraction in isolated perfused coronary arteries in CD38 WT mice. These results provide direct evidence that the CD38/cADPR pathway is an important controller of Nox4-mediated intracellular O(2)(*-) production and that CD38-dependent intracellular O(2)(*-) production is augmented in an autocrine manner by CD38-independent Nox1-derived extracellular O(2)(*-) production in CAMs. PMID- 22100344 TI - Critical review and perspective of macromolecularly imprinted polymers. AB - Molecular recognition is a fundamental and ubiquitous process that is the driving force behind life. Natural recognition elements - including antibodies, enzymes, nucleic acids, and cells - exploit non-covalent interactions to bind to their targets with exceptionally strong affinities. Due to this unparalleled proficiency, scientists have long sought to mimic natural recognition pathways. One promising approach is molecularly imprinted polymers (MIPs), which are fully synthetic systems formed via the crosslinking of organic polymers in the presence of a template molecule, which results in stereo-specific binding sites for this analyte of interest. Macromolecularly imprinted polymers, those synthesized in the presence of macromolecule templates (>1500 Da), are of particular importance because they open up the field for a whole new set of robust diagnostic tools. Although the specific recognition of small-molecular-weight analytes is now considered routine, extension of these efficacious procedures to the protein regime has, thus far, proved challenging. This paper reviews the main approaches employed, highlights studies of interest with an emphasis on recent work, and offers suggestions for future success in the field of macromolecularly imprinted polymers. PMID- 22100345 TI - A facile preparation of novel multifunctional vectors by non-covalent bonds for co-delivery of doxorubicin and gene. AB - In this study, novel multifunctional ternary complexes of biotinylated transferrin-avidin-biotin-poly(ethylene glycol)-poly(L-glutamate acid)/poly(2-(2 aminoethylamino) ethyl methacrylate)/doxorubicin-poly(L-aspartic acid)/pDNA (TAB/PIC-D/pDNA complexes) were prepared based on polyion complex micelles (PIC) and the avidin-biotin system, which aimed to target co-delivery of anti-cancer doxorubicin and gene. Cytotoxicity studies revealed that PIC-D could have anti tumor effect on HeLa cells and HepG2 cells; TAB coating could increase the biocompatibility of PIC-D/pDNA complexes and the targeting delivery efficiency of doxorubicin. TAB/PIC-D/pDNA complexes possessed higher transfection efficiency than the unmodified complexes in serum, and transferrin could enhance luciferase expression in HeLa cells and HepG2 cells. Furthermore, confocal laser scanning microscopy showed that doxorubicin and gene could be delivered into HepG2 cells simultaneously by TAB/PIC-D/pDNA complexes. The formation of the ternary complexes provides a facile approach to constructing a multifunctional delivery system for targeted co-delivery of anticancer drugs and gene. PMID- 22100346 TI - Controlled release of bone morphogenetic protein 2 and dexamethasone loaded in core-shell PLLACL-collagen fibers for use in bone tissue engineering. AB - Electrospun nanofibers mimic the native extracellular matrix of bone and have generated considerable interest in bone tissue regeneration. The aim of this study was to fabricate novel poly(l-lactide-co-caprolactone) (PLLACL), PLLACL/collagen nanofibers blended with bone morphogenetic protein 2 (BMP2) and dexamethasone (DEX) for controlled release during bone tissue engineering (BTE). The morphology, surface hydrophilicity, and mechanical properties of the PLLACL/collagen nanofibrous mats were analyzed by scanning electron microscopy and water contact angle and mechanical stability determination. The performance of the scaffolds was investigated in terms of the viability and morphology of human mesenchymal stromal cells (hMSC) on the nanofibrous mats. BMP2 and DEX were successfully incorporated into PLLACL/collagen nanofibers by means of blending or coaxial electrospinning and the PLLACL/collagen blended fibers proved useful for hMSC culture. Release of the two growth factors from PLLACL/collagen nanofibrous mats in vitro was investigated by UV spectrophotometry. The release profiles for core-shell nanofibers showed more controlled release of the growth factors compared with the blended electrospun fibers. The experimental results show that controlled release of BMP2 and DEX can induce hMSC to differentiate into osteogenic cells for bone tissue engineering. The results imply that PLLACL/collagen nanofibers encapsulating two drugs and/or proteins have great potential in bone tissue engineering. PMID- 22100347 TI - Fluorescence labeling of colloidal core-shell particles with defined isoelectric points for in vitro studies. AB - In the light of in vitro nanotoxicological studies fluorescence labeling has become standard for particle localization within the cell environment. However, fluorescent labeling is also known to significantly alter the particle surface chemistry and therefore potentially affect the outcome of cell studies. Hence, fluorescent labeling is ideally carried out without changing, for example, the isoelectric point. A simple and straightforward method for obtaining fluorescently labeled spherical metal oxide particles with well-defined isoelectric points and a narrow size distribution is presented in this study. Spherical amorphous silica (SiO2, 161 nm diameter) particles were used as the substrate material and were coated with silica, alumina (Al2O3), titania (TiO2), or zirconia (ZrO2) using sol-gel chemistry. Fluorescent labeling was achieved by directly embedding rhodamine 6G dye in the coating matrix without affecting the isoelectric point of the metal oxide coatings. The coating quality was confirmed by high resolution transmission electron microscopy, energy filtered transmission electron microscopy and electrochemical characterization. The coatings were proven to be stable for at least 240 h under different pH conditions. The well defined fluorescent particles can be directly used for biomedical investigations, e.g. elucidation of particle-cell interactions in vitro. PMID- 22100348 TI - A functional polymer designed for bone tissue engineering. AB - Most synthetic polymers lack biological and chemical functionalities. This lack of functionality restricts the polymer properties and prevents them from controlling specific cell-material interactions. Polymers with free functional groups allow facile modifications, which can be used to control the biointerface. Here we created a functionalizable polymer, poly(fumaroyl bioxirane) maleate (PFM), with three free functional groups--hydroxyl, carboxyl and alkenyl--for bone tissue engineering. PFM was readily synthesized in two steps. PFM showed strain-dependent moduli with mechanical strength approaching native bones. PFM supported the adhesion, spreading, proliferation, and maturity of rat calvarial osteoblasts. The alkaline phosphatase activity of osteoblasts on PFM was significantly higher than that on tissue-culture-treated polystyrene in vitro. The physical, mechanical, and biological properties of PFM can be modulated by various functionalizations to explore methods to improve bone tissue engineering and regenerative medicine in general. PMID- 22100349 TI - Abdominal pain and weight loss after adalimumab therapy. PMID- 22100350 TI - The use of Pap smear and its influencing factors among women with disabilities in Taiwan. AB - Cervical cancer is a prevalent cancer among Taiwanese women, and can be effectively cured if diagnosed early. Therefore, cervical cancer is worthy of preventive health screening. Due to physical and psychological barriers, patients with disability may be unable to express their physical complaints accurately, thus reducing their access to health care; some may not even receive proper preventive health care or medical treatment. This study investigates the utilization of Pap smear among women with disability in Taiwan and its influencing factors. With women aged 30 and over as the study subjects, this retrospective cohort study is conducted based on the database of the Ministry of the Interior, Taiwan, 2008, combined with information gathered between 2006 and 2008 regarding preventive health care and health insurance medical claims data from the Bureau f Health Promotion and the National Health Research Institutes, respectively. The frequency of Pap smears and the percentage differences of each variable are examined using the 2* tests to check for statistical significance. Finally, logistic regression analysis is used to examine the factors influencing the use of Pap smears. The results revealed that among disabled women aged 30 and over, the use of Pap smears was 7.71% in 2008. Disabled women with the following characteristics had lower use levels regarding Pap smears: greater age, residing in areas of higher urbanization, lower income, lower education levels, unmarried, not diagnosed with cancer, diagnosed with diabetes, and with severe disability levels. Disabled women with hearing impairments or mental retardation were possessed of the highest and lowest probabilities of using Pap smear, respectively. The recommendations of this study include: (1) provide physicians with a varying pricing scheme and incentives for Pap smear based on the type or severity of disability; (2) proactively encourage gynecologist and obstetricians to conduct regular and convenient Pap smear on disabled women; and (3) target disabled women in low usage groups, and improve their knowledge of Pap smear. PMID- 22100351 TI - Feasibility, reliability and validity of the Dutch translation of the Anxiety, Depression And Mood Scale in older adults with intellectual disabilities. AB - BACKGROUND: The informant-based Anxiety, Depression And Mood Scale was translated into Dutch and its feasibility, reliability and validity in older adults (aged >= 50 years) with intellectual disabilities (ID) was studied. METHOD: Test-retest (n = 93) and interrater reliability (n = 83), and convergent (n = 202 and n = 787), discriminant (n = 288) and criterion validity (n = 288) were studied. Convergent and criterion validity were studied for the Depressed mood and General anxiety subscales. Subgroups based on level of ID and autism have been made to study the criterion validity. Psychiatric diagnoses based on the PAS-ADD Interview were used as gold standard. RESULTS: All subscales had good internal consistency (alpha >= 0.80), excellent test-retest reliability (ICC >= 0.75) and good interrater reliability (ICC >= 0.74), except for the Social avoidance subscale (ICC = 0.57). The Depressed mood subscale showed low correlation (r = 0.44) with the self-report Inventory of Depressive Symptomatology, high correlation with the informant-report Signalizing Depression List for people with ID (r = 0.71) and no correlation with the PAS-ADD's sleep disorders subscale (r = 0.15). Its sensitivity ranged from 73 to 80%, and its specificity from 71 to 79%. The General anxiety subscale showed low correlation with the self-report scales: Glasgow Anxiety Scale (r= 0.37) and Hospital Anxiety and Depression Scale (r = 0.41), and no correlation with the sleep disorder subscale (r = 0.02). Its sensitivity ranged from 67 to 100%, and its specificity from 48 to 81%. CONCLUSIONS: The Dutch translation of the ADAMS is reliable and sufficiently valid to screen for anxiety and depression in older people with ID. PMID- 22100352 TI - Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner. AB - Sex differences exist in the hypertrophic response, cardiac remodeling, and transition to heart failure of hypertensive patients, and while some of these differences are likely influenced by estrogen, the genetic pathways downstream of estrogen that impact on cardioprotection have yet to be fully elucidated. We have previously shown that the cardioprotective effects of adrenomedullin (AM), an emerging clinical biomarker for cardiovascular disease severity, vary with sex in mouse models. AM signaling during cardiovascular stress is strongly modulated by receptor activity-modifying protein 3 (RAMP3) via its interaction with the G protein-coupled receptor calcitonin receptor-like receptor (CLR). Like AM, RAMP3 expression is potently regulated by estrogen, and so we sought to determine the consequences of genetic Ramp3 loss on cardiac adaptation to chronic hypertension, with a particular focus on characterizing potential sex differences. We generated and bred RAMP3(-/-) mice to RenTgMK mice that consistently display severe angiotensin II-mediated CV disease and compared CV disease progression in RenTgMK to that of RenTgMK:RAMP3(-/-) offspring. As expected, RAMP3 gene expression was higher in cardiovascular tissues of RenTgMK mice and more strongly up-regulated in female RenTgMK mice relative to wildtype controls. RAMP3 loss did not affect the development of hypertension or the presence and severity of perivascular and interstitial fibrosis in the left ventricle (LV). However, echocardiography revealed that while RenTgMK mice developed concentric cardiac hypertrophy with sustained systolic function, male RenTgMK:RAMP3(-/-) mice showed evidence of LV chamber dilatation and depressed systolic function, suggestive of cardiac decompensation. Consistent with these measures of heart failure, male RenTgMK:RAMP3(-/-) mice had increased cardiac apoptosis and elevated activation of Akt. These phenotypes were not present in female RenTgMK:RAMP3(-/-) mice. Collectively, these data demonstrate a sex-dependant, cardioprotective role of RAMP3 in the setting of chronic hypertension. PMID- 22100353 TI - Cannabis cue-elicited craving and the reward neurocircuitry. AB - Cue-elicited craving or the intense desire to consume a substance following exposure to a conditioned drug cue is one of the primary behavioral symptoms of substance use disorders (SUDs). While the concept of cue-elicited craving is well characterized in alcohol and other substances of abuse, only recently has it been described in cannabis. A review of the extant literature has established that cue elicited craving is a powerful reinforcer that contributes to drug-seeking for cannabis. Further, emergent research has begun to identify the neurobiological systems and neural mechanisms associated with this behavior. What research shows is that while theories of THC's effects on the dopaminergic-reward system remain divergent, cannabis cues elicit neural activation in the brain's reward network. PMID- 22100354 TI - Suppressed alpha oscillations predict intelligibility of speech and its acoustic details. AB - Modulations of human alpha oscillations (8-13 Hz) accompany many cognitive processes, but their functional role in auditory perception has proven elusive: Do oscillatory dynamics of alpha reflect acoustic details of the speech signal and are they indicative of comprehension success? Acoustically presented words were degraded in acoustic envelope and spectrum in an orthogonal design, and electroencephalogram responses in the frequency domain were analyzed in 24 participants, who rated word comprehensibility after each trial. First, the alpha power suppression during and after a degraded word depended monotonically on spectral and, to a lesser extent, envelope detail. The magnitude of this alpha suppression exhibited an additional and independent influence on later comprehension ratings. Second, source localization of alpha suppression yielded superior parietal, prefrontal, as well as anterior temporal brain areas. Third, multivariate classification of the time-frequency pattern across participants showed that patterns of late posterior alpha power allowed best for above-chance classification of word intelligibility. Results suggest that both magnitude and topography of late alpha suppression in response to single words can indicate a listener's sensitivity to acoustic features and the ability to comprehend speech under adverse listening conditions. PMID- 22100355 TI - The CONECSI trial: results of a randomized controlled trial of a multidisciplinary cognitive behavioral program for coping with chronic neuropathic pain after spinal cord injury. AB - Many people with spinal cord injury (SCI) rate chronic neuropathic pain as one of the most difficult problems to manage. The aim of the CONECSI (COping with NEuropathiC Spinal cord Injury pain) trial was to evaluate a multidisciplinary cognitive behavioral treatment program for persons with chronic neuropathic pain after SCI. The intervention consisted of educational, cognitive, and behavioral elements. A total of 61 people were randomized to either the intervention group or the waiting list control group in 4 Dutch rehabilitation centers. Primary outcomes were pain intensity and pain-related disability (Chronic Pain Grade questionnaire), and secondary outcomes were mood (Hospital Anxiety and Depression Scale), participation in activities (Utrecht Activities List), and life satisfaction (Life Satisfaction Questionnaire). Measurements were performed at baseline, and at 3, and 6 months follow-up. The primary statistical technique was random coefficient analysis. The analyses showed significant changes over time on both primary (t1-t2), and 2 out of 4 secondary outcomes (both t1-t2 and t1-t3). Significant intervention effects (Time*Group interactions) were found for anxiety and participation in activities, but not for the primary outcomes. Subsequent paired t tests showed significant changes in the intervention group that were not seen in the control group: decrease of pain intensity, pain-related disability, anxiety, and increase of participation in activities. This study implies that a multidisciplinary cognitive behavioral program might have beneficial effects on people with chronic neuropathic SCI pain. PMID- 22100356 TI - The role of co-morbidity in accumulating risk of chronic pain. PMID- 22100357 TI - Effect of intravenous tropisetron on modulation of pain and central hypersensitivity in chronic low back pain patients. AB - The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 +/- 14 years) and 15 men (aged 48 +/- 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity. PMID- 22100358 TI - Gender differences in outcomes of a multimodal pain management program. AB - Although gender differences in pain and analgesia are well known, it still remains unclear whether men and women vary in response to multimodal pain treatment. This study was conducted to investigate whether men and women exhibited different outcomes after an intensive multimodal pain treatment program. The daily outpatient program consisted of individual treatment as well as group therapy, with a total amount of therapy of 117.5h per patient. Overall, 496 patients (254 women) completed the multimodal program. Pretreatment parameters for pain, disability due to pain, pain duration, and pain chronicity stage, as well as age or psychiatric comorbidities, did not differ between genders. The average pain, measured with a Numeric Rating Scale, decreased after treatment of -1.54 (+/-1.96) with a large effect size (ES) of .911 for the total sample. However, there were considerable differences in the benefit for women ( 1.83+/-2.12; ES 1.045) compared with men (-1.23+/-1.74; ES .758). Consistently, women (ES .694) improved more in pain-related disabilities in daily life than men (ES .436). These distinctions are not due to differences in pain duration, received medication, psychiatric comorbidities, pain chronicity stage, or application for a disability pension. Therefore, gender differences not only refer to chronic pain prevalence, pain perception, or experimental pain measurement, but also seem to have a clinically relevant impact on the response to pain therapy. PMID- 22100359 TI - One man's risk factor is another man's outcome: difference in risk factor profiles for chronic postsurgical pain maintenance vs transition. PMID- 22100360 TI - Anatomy and physiology of cerebrospinal fluid. AB - The cerebrospinal fluid (CSF) is contained in the brain ventricles and the cranial and spinal subarachnoid spaces. The mean CSF volume is 150 ml, with 25 ml in the ventricles and 125 ml in subarachnoid spaces. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. CSF circulation from sites of secretion to sites of absorption largely depends on the arterial pulse wave. Additional factors such as respiratory waves, the subject's posture, jugular venous pressure and physical effort also modulate CSF flow dynamics and pressure. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. CSF is renewed about four times every 24 hours. Reduction of the CSF turnover rate during ageing leads to accumulation of catabolites in the brain and CSF that are also observed in certain neurodegenerative diseases. The CSF space is a dynamic pressure system. CSF pressure determines intracranial pressure with physiological values ranging between 3 and 4 mmHg before the age of one year, and between 10 and 15 mmHg in adults. Apart from its function of hydromechanical protection of the central nervous system, CSF also plays a prominent role in brain development and regulation of brain interstitial fluid homeostasis, which influences neuronal functioning. PMID- 22100361 TI - A rare complication of radiotherapy. PMID- 22100362 TI - Prognostic value of the status of resection margins after endoscopic laser cordectomy for T1a glottic carcinoma. AB - OBJECTIVES: The small size of endoscopic laser cordectomy (ELC) specimens frequently leads the histopathologist to assess excision margins as pathologic. The present study sought to assess the prognostic value of margin status in terms of overall and of recurrence-free survival in a population of T1a glottic carcinoma operated on by ELC. MATERIAL AND METHODS: Sixty-four records of T1a squamous-cell carcinoma treated between 1996 and 2006 were retrospectively analyzed. Overall and recurrence-free survival for the group with negative margins (group 1) and with positive margins (group 2) were analyzed following Kaplan-Meier. The influence of resection margin histologic status was assessed on Log Rank test. RESULTS: Six female and 58 male patients were included. Forty (62.5%) had negative margins (group 1) and 24 (37.5%) positive margins (group 2). Overall five-year survival was 97% (95% in group 1 and 100% in group 2). Five year recurrence-free survival was 94% (91.7% in group 1 and 95% in group 2). There was no significant difference in overall or recurrence-free survival according to resection margin histologic status. CONCLUSIONS: The present results show that margins considered positive after laser resection do not significantly impact carcinologic course, while still requiring close surveillance. The most generally recommended attitude is control endoscopy with biopsy at 10 weeks. PMID- 22100363 TI - Inhibitory control after traumatic brain injury in children. AB - Inhibitory control describes a number of distinct processes. Effortless inhibition refers to acts of control that are automatic and reflexive. Effortful inhibition refers to voluntary, goal-directed acts of control such as response flexibility, interference control, cancellation inhibition, and restraint inhibition. Disruptions to a number of inhibitory control processes occur as a consequence of childhood traumatic brain injury (TBI). This paper reviews the current knowledge of inhibition deficits following childhood TBI, and includes an overview of the inhibition construct and a discussion of the specific deficits shown by children and adolescents with TBI and the factors that mediate the expression of these deficits, including injury-related variables and the expression of pre- and post-injury attention-deficit/hyperactivity disorder. The review illustrates that inhibitory control processes differ in terms of measurement, assessment, and neurological underpinnings, and also that childhood TBI may selectively disrupt particular forms of inhibition. PMID- 22100364 TI - 10 years outcome from childhood traumatic brain injury. AB - Childhood traumatic brain injury (TBI) is a common, acquired disability, which has significant implications for subsequent development, and for later quality of life. To date few studies have documented outcomes in these children into adolescence, when academic, social and personal demands increase. The objective of this study was to document functional outcomes at 10 years post-injury, and to identify predictors of outcome including injury, socio-demographic and pre-injury characteristics. The study employed consecutive recruitment to a prospective, longitudinal study. Children with a diagnosis of TBI between 2 and 12 years were initially recruited and divided according to injury severity (mild, moderate, severe). The sample was reviewed at 10 years post-injury and intellectual, adaptive, executive and social domains were investigated. Results indicated that, at 10 years post child TBI, survivors' functional abilities fell overall within the low average to average range regardless of injury severity, suggesting no extreme impairments at a group level for any of the domains under investigation. Significant group differences were identified, though, for adaptive abilities and for speed of processing, with more severe injury associated with poorer performances in each instance. Further, a similar trend was identified for measures of intellectual ability and executive functions. Individual rates of impairment were considerably higher than population expectations across all severity groups for these domains. Although rates of social impairment were also elevated, they were less related to injury factors, suggesting that cognitive/adaptive outcomes and social consequences of TBI may have different bases. PMID- 22100365 TI - Inhibition of presynaptic Na(+)/K(+)-ATPase reduces readily releasable pool size at the avian end-bulb of Held synapse. AB - A glutamatergic end-bulb synapse in the avian nucleus magnocellularis relays temporal sound information from the auditory nerve. Here, we show that presynaptic Na(+)/K(+)-ATPase (NKA) activity at this synapse contributes to the maintenance of the readily releasable pool (RRP) of vesicles, thereby preserving synaptic strength. Whole-cell voltage clamp recordings were made from chick brainstem slices to examine the effects of NKA blocker dihydroouabain (DHO) on synaptic transmission. DHO suppressed the amplitude of EPSCs in a dose-dependent manner. This suppression was caused by a decrease in the number of neurotransmitter quanta released because DHO increased the coefficient of variation of EPSC amplitude and reduced the frequency but not the amplitude of miniature EPSCs. Cumulative plots of EPSC amplitude during a stimulus train revealed that DHO reduced the RRP size without affecting vesicular release probability. DHO did not affect [Ca(2+)](i)-dependent processes, such as the paired-pulse ratio or recovery time course from the paired-pulse depression, suggesting a minimal effect on Ca(2+) concentration in the presynaptic terminal. Using mathematical models of synaptic depression, we further demonstrated the contribution of RRP size to the synaptic strength during a high-frequency stimulus train to highlight the importance of presynaptic NKA in the auditory synapse. PMID- 22100366 TI - Cyclooxygenase-2 -765G>C polymorphism is associated with C-reactive protein levels in resistant smokers but not in chronic obstructive pulmonary disease patients. AB - We sought to investigate whether the serum concentrations of several inflammatory biomarkers are related to the cyclooxygenase-2 (COX2) -765G>C polymorphism in chronic obstructive pulmonary disease (COPD) and a control group of non-COPD smokers. Serum inflammatory markers (CRP, SAA, CXCL8, and sICAM-1) were measured by ELISA in 144 patients with COPD and in 55 control subjects. Genomic DNA was extracted from peripheral blood leukocytes, and the COX2 -765G>C (rs20417) polymorphism was genotyped. After adjustment for age and active smoking, CRP and SAA concentrations were associated with the COX2 polymorphism in controls (p=0.041 and 0.014, respectively) but not in COPD patients. The CXCL8 and sICAM-1 concentrations were not associated with the COX2 polymorphism for either cases or controls. The results of the present study indicate that there is a relationship between the COX2 -765G>C polymorphism and the concentrations of CRP and SAA in non-COPD smokers and that this relationship does not exist in COPD patients. PMID- 22100367 TI - Monitoring the hepatitis A virus in urban wastewater from Rio de Janeiro, Brazil. AB - Hepatitis A is a viral disease with a significant public health impact, especially in developing countries. Improvements in sewage services could prevent hepatitis A virus (HAV) dissemination into the environment and minimize the risk of infection. The aim of this study was to monitor HAV for one year in urban sewage samples from the largest wastewater treatment plant in Rio de Janeiro, Brazil, to assess environmental contamination with HAV and its dissemination after treatment by an activated sludge process. For this purpose, 48 samples (24 raw sewage samples and 24 treated effluent samples) were collected from August 2009 to July 2010 for HAV detection. Using quantitative real-time PCR 14 (58%) raw sewage samples were positive for HAV, and the highest viral genome loads were detected in the spring and summer. HAV was not detected in treated effluent samples, which suggests that the viral loads observed could be easily removed by the activated sludge process, thus preventing the dissemination of HAV into the environment. All of the HAV strains sequenced belonged to subgenotype IA, which clustered closely with Brazilian and Argentine HAV strains. These data demonstrate that environmental monitoring can be a useful tool in epidemiological studies. PMID- 22100368 TI - Prevalence and characteristics of paratracheal air cysts and their association with emphysema in a general population. AB - BACKGROUND: To evaluate the prevalence and characteristics of paratracheal air cysts and their association with emphysema and gender in a general population using low-dose computed tomography scanning of the chest. MATERIALS AND METHODS: We retrospectively enrolled a total of 924 patients (584 women, 340 men; mean age, 59.73 years; range, 37-89 years) who had received low-dose computed tomography scanning for health examination during the period January 1, 2010 to June 30, 2010. Computed tomographic images were evaluated for the presence of paratracheal air cysts. If paratracheal air cysts were identified, the lungs were reconstructed as a three-dimensional model on a commercial workstation. An emphysema index, an objective quantification of the extent of emphysematous changes on CT imaging, was defined as the percentage area of lung with attenuation values below -950 Hounsfield units. RESULTS: A total of 60 patients with paratracheal air cysts were included in this study (estimated prevalence, 6.5%; 12 men, 48 women; mean age, 59.85; range 45-89 years). Emphysema index differed significantly between genders (P<0.0001). The prevalence of paratracheal air cysts in men was significantly lower than that in women (P=0.005); however, the emphysema index in patients of both genders showed no evidence of emphysema. The majority (95%) of paratracheal air cysts were at the level of the seventh cervical to the second thoracic vertebrae. CONCLUSION: The presence of paratracheal air cysts is a common condition in general populations and should not be misdiagnosed as abnormal paratracheal free air. Paratracheal air cysts are more common in woman than in man. In our study, there is no patient with paratracheal air cysts has CT evidence of emphysema. PMID- 22100369 TI - Diffusion-weighted MRI versus transient elastography in quantification of liver fibrosis in patients with chronic cholestatic liver diseases. AB - PURPOSE: To evaluate the diagnostic value of diffusion-weighted magnetic resonance imaging (DWMRI) and transient elastography (TE) in quantification of liver fibrosis in patients with chronic cholestatic liver diseases. MATERIALS AND METHODS: Forty-five patients underwent DWMRI, TE, and liver biopsy for staging of liver fibrosis. Apparent diffusion coefficient (ADC) was calculated for six locations in the liver for combination of five diffusion sensitivity values b=0, 50, 200, 400 and 800 s/mm(2). A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of DWMRI and TE. Segmental ADC variations were evaluated by means of coefficient of variation. RESULTS: The mean ADCs (* 10(-3)mm(2)/s; b=0-800 s/mm(2)) were significantly different at stage F1 versus F >= 2 (p<0.05) and F2 versus F4. However, no significant difference was found between F2 and F3. For prediction of F >= 2 and F >= 3 areas under the ROC curves were 0.868 and 0.906 for DWMRI, and 0.966 and 0.960 for TE, respectively. The sensitivity and specificity were 90.9% and 89.3% for F >= 2 (ADC <= 1.65), and 92.3% and 92.1% for F >= 3 (ADC <= 1.63). Segmental ADC variation was lowest for F4 (CV=9.54 +/- 6.3%). CONCLUSION: DWMRI and TE could be used for assessment of liver fibrosis with TE having higher diagnostic accuracy and DWMRI providing insight into liver fibrosis distribution. PMID- 22100370 TI - Special section: Emerging clinical applications with 7 Tesla. Editorial. PMID- 22100371 TI - Effect of visual experience on structural organization of the human brain: a voxel based morphometric study using DARTEL. AB - OBJECTIVE: To investigate structural reorganization in the brain with differential visual experience using Voxel-Based Morphometry with Diffeomorphic Anatomic Registration Through Exponentiated Lie algebra algorithm (DARTEL) approach. MATERIALS AND METHODS: High resolution structural MR images were taken in fifteen normal sighted healthy controls, thirteen totally blind subjects and six partial blind subjects. The analysis was carried out using SPM8 software on MATLAB 7.6.0 platform. RESULTS: VBM study revealed gray matter volume atrophy in the cerebellum and left inferior parietal cortex in total blind subjects and in left inferior parietal cortex, right caudate nucleus, and left primary visual cortex in partial blind subjects as compared to controls. White matter volume loss was found in calcarine gyrus in total blind subjects and Thlamus somatosensory region in partially blind subjects as compared to controls. Besides, an increase in Gray Matter volume was also found in left middle occipital and middle frontal gyrus and right entorhinal cortex, and an increase in White Matter volume was found in superior frontal gyrus, left middle temporal gyrus and right Heschl's gyrus in totally blind subjects as compared to controls. Comparison between total and partial blind subjects revealed a greater Gray Matter volume in left cerebellum of partial blinds and left Brodmann area 18 of total blind subjects. CONCLUSION: Results suggest that, loss of vision at an early age can induce significant structural reorganization on account of the loss of visual input. These plastic changes are different in early onset of total blindness as compared to partial blindness. PMID- 22100372 TI - Inclusion of computed tomographic colonography on pre-operative CT for patients with colorectal cancer. AB - OBJECTIVES: To evaluate the impact of the inclusion of computed tomographic colonography (CTC) involving faecal tagging and no laxatives on the computed tomography (CT) study routinely used in staging patients with colorectal cancer. METHODS: CTC was performed on 25 patients who had a diagnosis of colorectal carcinoma, with pathological correlation. Researchers recorded the accuracy of the CTC for staging colorectal cancer, as well as any changes to the plans for surgery based on this exam. The patients' tolerance of the preparation required and the quality of the exams was also evaluated. RESULTS: All exams were well tolerated, and only one had unsatisfactory quality. CTC identified all the carcinomas and had an overall accuracy of 80%, 60.1% and 100% for the evaluation of tumour depth, lymph nodes and metastases respectively. CTC identified all polyps greater than 9 mm. Following CTC, changes to surgical plans were observed in 20.8% of the cases, all with incomplete optical colonoscopies. CONCLUSIONS: CTC proved useful for the pre-operative evaluation of patients with a diagnosis of colorectal carcinoma, affecting plans for surgery in a expressive number of patients with an incomplete colonoscopy. PMID- 22100373 TI - Advantages of high b-value diffusion-weighted imaging to diagnose pseudo responses in patients with recurrent glioma after bevacizumab treatment. AB - BACKGROUND: The diagnosis of pseudo-responses after bevacizumab treatment is difficult. Because diffusion-weighted imaging (DWI) is associated with cell density, it may facilitate the differentiation between true- and pseudo responses. Furthermore, as high b-value DWI is even more sensitive to diffusion, it has been reported to be diagnostically useful in various clinical settings. MATERIALS AND METHODS: Between September 2008 and May 2011, 10 patients (5 males, 5 females; age range 6-65 years) with recurrent glioma were treated with bevacizumab. All underwent pre- and post-treatment MRI including T2- or FLAIR imaging, post-gadolinium contrast T1-weighted imaging, and DWI with b-1000 and b 4000. Response rates were evaluated by MacDonald- and by response assessment in neuro-oncology working group (RANO) criteria. We also assessed the response rate by calculating the size of high intensity areas using high b-value diffusion weighted criteria. Prognostic factors were evaluated using Kaplan-Meier survival curves (log-rank test). RESULTS: It was easier to identify pseudo-responses with RANO- than MacDonald criteria, however the reduction of edema by bevacizumab rendered the early diagnosis of tumor progression difficult by RANO criteria. In some patients with recurrent glioma treated with bevacizumab, high b-value diffusion-weighted criteria did, while MacDonald- and RANO criteria did not identify pseudo-responses at an early point after the start of therapy. DISCUSSION AND CONCLUSION: High b-value DWI reflects cell density more accurately than regular b-value DWI. Our findings suggest that in patients with recurrent glioma, high b-value diffusion-weighted criteria are useful for the differentiation between pseudo- and true responses to treatment with bevacizumab. PMID- 22100374 TI - Characterisation of focal liver lesions with unenhanced and contrast enhanced low MI real time ultrasound: on-site unblinded versus off-site blinded reading. AB - OBJECTIVE: To compare on-site and blinded off-site reading of baseline ultrasound (US) and contrast enhanced ultrasound (CEUS) for classification and characterisation of focal liver lesions. MATERIALS AND METHODS: 99 patients (57 women and 42 men, age range 18-89 years, mean age: 59 years) with 53 malignant and 46 benign liver lesions were studied with unenhanced US followed by contrast enhanced US after injection of 2.4 ml SonoVue(r) (Bracco, Milano, Italy). Image interpretation was performed on-site with clinical information available by consensus of two readers and off-site by two independent blinded readers at two different centers. Comparison of pre and post contrast scans and of the different readers was performed. Reference examinations were histology, intraoperative US, MRI or CT. RESULTS: Sensitivity for malignancy improved from 81/89/66% (on site/off-site reader 1/2) before to 100/96/96% post contrast administration (p<0.05, except for reader 1). Specificity improved from 48/48/54% on baseline US to 89/80/76% on CEUS (p<0.05). Accuracy for specific lesion diagnosis was 62/59/50% pre and 90/77/72% post contrast (p<0.05). Classification and characterisation post contrast were mildly inferior for off-site reading. Agreement between on-site and off-site readers of unenhanced scans was fair (kappa=0.29-0.39) while it was good for CEUS (kappa=0.63-0.79). CONCLUSIONS: CEUS improves classification and characterisation of focal liver lesions and interobserver agreement compared to conventional US. Classification and characterisation post contrast were mildly but statistically significantly better for on-site than for off-site reading. PMID- 22100375 TI - Aortic stenosis and vascular calcifications in alkaptonuria. AB - Alkaptonuria is a rare metabolic disorder of tyrosine catabolism in which homogentisic acid (HGA) accumulates and is deposited throughout the spine, large joints, cardiovascular system, and various tissues throughout the body. In the cardiovascular system, pigment deposition has been described in the heart valves, endocardium, pericardium, aortic intima and coronary arteries. The prevalence of cardiovascular disease in patients with alkaptonuria varies in previous reports. We present a series of 76 consecutive adult patients with alkaptonuria who underwent transthoracic echocardiography between 2000 and 2009. A subgroup of 40 patients enrolled in a treatment study underwent non-contrast CT scans and these were assessed for vascular calcifications. Six of the 76 patients had aortic valve replacement. In the remaining 70 patients, 12 patients had aortic sclerosis and 7 patients had aortic stenosis. Unlike degenerative aortic valve disease, we found no correlation with standard cardiac risk factors. There was a modest association between the severity of aortic valve disease and joint involvement, however, we saw no correlation with urine HGA levels. Vascular calcifications were seen in the coronaries, cardiac valves, aortic root, descending aorta and iliac arteries. These findings suggest an important role for echocardiographic screening of alkaptonuria patients to detect valvular heart disease and cardiac CT to detect coronary artery calcifications. PMID- 22100376 TI - Three new arylnaphthalene lignans from Schisandra propinqua var. sinensis. AB - Three new arylnaphthalene lignans, named sinensisins A-C (1-3), together with three known compounds, were isolated from the aerial parts of Schisandra propinqua var. sinensis. Their structures were established by spectroscopic methods, and compound 1 exhibited weak anti-HIV-1 activity with an TI value of 6.7. PMID- 22100377 TI - Coincidence summing of X- and gamma rays of 75Se. AB - A study of coincidence summing of X- and gamma rays of (75)Se has been presented in this paper. The computation of the (75)Se spectra was performed by application of the previously published theory by Novkovic et al. The method enables the treatment of all possible single and sum peaks of (75)Se. The calculation gave the 419 decay path outcomes, resulting in 84 peak count rate equations and also the total count rate equation. By HPGe spectrometers with 15% and 18% relative efficiency, 20 and 30 peaks were recorded, respectively. Some simplification of the decay scheme was introduced and existing metastable level had to be treated separately. Nevertheless, the experimental values of the peak count rates were in good agreement with the theoretical evaluation. PMID- 22100378 TI - Organic scintillators response function modeling for Monte Carlo simulation of Time-of-Flight measurements. AB - In neutron Time-of-Flight (TOF) measurements performed with fast organic scintillation detectors, both pulse arrival time and amplitude are relevant. Monte Carlo simulation can be used to calculate the time-energy dependant neutron flux at the detector position. To convert the flux into a pulse height spectrum, one must calculate the detector response function for mono-energetic neutrons. MCNP can be used to design TOF systems, but standard MCNP versions cannot reliably calculate the energy deposited by fast neutrons in the detector since multiple scattering effects must be taken into account in an analog way, the individual recoil particles energy deposit being summed with the appropriate scintillation efficiency. In this paper, the energy response function of 2"*2" and 5"*5" liquid scintillation BC-501 A (Bicron) detectors to fast neutrons ranging from 20 keV to 5.0 MeV is computed with GEANT4 to be coupled with MCNPX through the "MCNP Output Data Analysis" software developed under ROOT (Carasco, 2010). PMID- 22100379 TI - [Antiphospholipid antibodies and haemostasis]. AB - The antiphospholipid syndrome is characterized by recurrent thrombosis and pregnancy morbidity in association with the persistent presence of autoantibodies called antiphospholipid antibodies. Antiphospholipids are a heterogeneous group of circulating autoantibodies associated with a risk of thrombosis and can paradoxically prolong in vitro the clotting times. In the past few years, significant improvement has been made in understanding the pathophysiologic mechanisms of the disease, thus raising the possibility of future predictive test for the risk of thrombosis. The aim of this review is to make an overview on how the antiphospholipids increase the risk of thrombosis and to provide an update of the laboratory diagnosis and the possible future therapies. PMID- 22100380 TI - Implicit and explicit attitudes toward self harm: support for a functional model. AB - BACKGROUND AND OBJECTIVES: Self harm is a serious public health problem worldwide. Implicit attitude measures offer a novel method of exploring associations with self harm (SH). Here we used implicit measures in order to (i) examine implicit evaluative and arousal associations with SH (ii) compare the discriminatory power of implicit and explicit attitude measures in a non-clinical sample at high risk of SH. METHODS: Two experiments using Go No-Go Association (GNAT) tasks designed to tap implicit attitudes toward SH in an undergraduate sample. RESULTS: In Study One logistic regression analysis demonstrated that explicit, rather than implicit measures successfully discriminated between SH cases and controls which contrasts with previous research. Faster reaction times were observed for negative implicit associations (SH and 'I dislike') compared to positive implicit associations (SH and 'I like') for both SH cases and controls. The SH group were faster to respond to arousal implicit associations compared to implicit sedation associations. Study Two extended this finding to demonstrate associations between evaluative/arousal GNATs and self-reported functions of SH. Internal motivations for self harmful behaviour were significantly related to an implicit sedation association with SH, whereas interpersonal motivations were associated with an implicit arousal association with SH. These findings are consonant with existing functional accounts of SH. LIMITATIONS: Longitudinal data is necessary to identify whether the attitudes assessed could predict future SH. CONCLUSIONS: The findings provide novel experimental support for the hypothesised role of automatic/affect regulation and social/interpersonal functions of SH. Implications for intervention are discussed. PMID- 22100381 TI - Comparative 2D-DIGE proteomic analysis of ovarian carcinoma cells: toward a reorientation of biosynthesis pathways associated with acquired platinum resistance. AB - Ovarian cancer is the fifth most frequent cause of cancer death in women. Emergence of chemoresistance in the course of treatments with platinum drugs is in part responsible for therapeutic failures. In order to improve the understanding of the complex mechanisms involved in acquired platinum chemoresistance, we decided to compare the basal protein expression profile of the platinum-sensitive cell line OAW42 and that of its resistant counterpart OAW42-R by a proteomic approach. Reversed-phase HPLC pre-fractionated extracts from both cell lines were subjected to 2D-DIGE coupled to mass spectrometry (MS). Forty eight differentially expressed proteins were identified, 39 being up regulated and 19 down-regulated in OAW42-R versus OAW42 cells. From the current knowledge on biological activities of most differentially expressed proteins, it can be inferred that the acquisition of resistance was associated with a global reorganization of biochemical pathways favoring the production of precursors for biosynthesis, and with the mobilization of macromolecule quality control mechanisms, preserving RNA and protein integrity under damage-inducing conditions. PMID- 22100382 TI - Cathepsin L of Triatoma brasiliensis (Reduviidae, Triatominae): sequence characterization, expression pattern and zymography. AB - Triatoma brasiliensis is considered one of the main vectors of Chagas disease commonly found in semi-arid areas of northeastern Brazil. These insects use proteases, such as carboxypeptidase B, aminopeptidases and different cathepsins for blood digestion. In the present study, two genes encoding cathepsin L from the midgut of T. brasiliensis were identified and characterized. Mature T. brasiliensis cathepsin L-like proteinases (TBCATL-1, TBCATL-2) showed a high level of identity to the cathepsin L-like proteinases of other insects, with highest similarity to Rhodnius prolixus. Both cathepsin L transcripts were highly abundant in the posterior midgut region, the main region of the blood digestion. Determination of the pH in the whole intestine of unfed T. brasiliensis revealed alkaline conditions in the anterior midgut region (stomach) and acidic conditions in the posterior midgut region (small intestine). Gelatine in-gel zymography showed the activity of at least four distinct proteinases in the small intestine and the cysteine proteinase inhibitors transepoxysuccinyl-l-leucylamido-(4 guanidino)butane (E-64) and cathepsin B inhibitor and N-(l-3-trans propylcarbamoyl-oxirane-2-carbonyl)-l-isoleucyl-l-proline (CA-074) were employed to characterize enzymatic activity. E-64 fully inhibited cysteine proteinase activity, whereas in the samples treated with CA-074 residual proteinase activity was detectable. Thus, proteolytic activity could at least partially be ascribed to cathepsin L. Western blot analysis using specific anti cathepsin L antibodies confirmed the presence of cathepsin L in the lumen of the small intestine of the insects. PMID- 22100383 TI - Transferrin gene expression in response to LPS challenge and heavy metal exposure in roughskin sculpin (Trachidermus fasciatus). AB - Transferrin plays an important role in immune response of vertebrates. In the present study, a transferrin cDNA with a partial 5' UTR of 7 bp and a complete 3' UTR of 345 bp was obtained from the liver of roughskin sculpin, Trachidermus fasciatus, which encodes a deduced 681 amino acid protein containing an N terminal signal peptide and two conserved lobes. In the N-terminal lobe, the anion-binding residue Arg was substituted with Lys, which represents a common feature in fish and implies a selective preference in the transferrin evolutionary process. In contrast to mammalian transferrin, the roughskin sculpin transferrin did not contain potential N-glycosylation sites, similar to those obtained in cyprinid fish, but not in salmonid fish. Quantitative real-time polymerase chain reaction demonstrated that the transferrin transcripts were abundant in the liver, but also significant in the brain, with a lesser expression in the other nine tissues. The temporal expression profiles were detected during the LPS challenge and heavy metal exposure experiment. Transferrin mRNA expression decreased in the liver in both experiments. Nevertheless, in the main immune organs (skin, blood, and spleen), transferrin mRNA expression was up-regulated significantly. These results suggest that transferrin is involved in the innate immune response of roughskin sculpin. PMID- 22100384 TI - In situ forming, metal-adhesive heparin hydrogel surfaces for blood-compatible coating. AB - Durable and blood-compatible coating of metallic biomaterials remains a major issue in biomedical fields despite its long history of development. In this study, in situ forming, metal-adhesive heparin hydrogels were developed to coat metallic substrates to enhance blood compatibility. The hydrogels are composed of metal-adhesive and enzyme-reactive amphiphilic block copolymer (Tetronic tyramine/dopamine; TTD) and enzyme-reactive heparin derivatives (heparin-tyramine or heparin-polyethylene glycol-tyramine), which are cross-linkable in situ via an enzyme reaction. The combinations of heparin and Tetronic formed hydrogels with relatively high mechanical strengths of 300-5000 Pa within several tens of seconds; this was also confirmed by observing a dried porous structure as coated on a metal surface. The introduction of dopamine to the hydrogel network enhanced the durability of the hydrogel layers coated on metal, such that more than 60% heparin remained for 7 days. Compared to bare metal surfaces, hydrogel-coated metal surfaces exhibited significantly enhanced blood compatibility. Reduced fibrinogen adsorption and platelet adhesion showed that blood compatibility was 3 5-fold-enhanced on coated hydrogel layers than on the bare metal surface. In conclusion, hydrogels containing heparin and dopamine prepared by enzyme reaction have the potential to be an alternative coating method for enhancing blood compatibility of metallic biomaterials. PMID- 22100385 TI - Poly(lactic acid)/N-maleoylchitosan core-shell capsules: preparation and drug release properties. AB - An oil in water interface radical polymerization was used to prepare felodipine loaded polymerized-N-maleoylchitosan (p-NMCS) and poly(lactic acid) (PLA)/p-NMCS capsules. Dynamic Light Scattering, Field Emission Scanning Electron Microscopy and Transmission Electron Microscope characterization revealed that both the p NMCS and PLA/p-NMCS microcapsules had a ~550 nm hydrodynamic diameter, regular spherical morphology and an obvious core-shell structure. The ratio of PLA to p NMCS in PLA/p-NMCS microcapsules was found affecting the drug loading content and entrapment efficiency. In vitro release kinetic results indicated that the p-NMCS microcapsules had a fast release rate comparing with that of the PLA/p-NMCS core shell microcapsules, suggesting the release mechanism of the p-NMCS microcapsules was a diffusion-driven process, while the release mechanism of the PLA/p-NMCS microcapsules with high ratio of PLA to p-NMCS (not less than 1/1) was a combined diffusion and degradation-driven process. PMID- 22100386 TI - Engineered cartilage via self-assembled hMSC sheets with incorporated biodegradable gelatin microspheres releasing transforming growth factor-beta1. AB - Self-assembling cell sheets have shown great potential for use in cartilage tissue engineering applications, as they provide an advantageous environment for the chondrogenic induction of human mesenchymal stem cells (hMSCs). We have engineered a system of self-assembled, microsphere-incorporated hMSC sheets capable of forming cartilage in the presence of exogenous transforming growth factor beta1 (TGF-beta1) or with TGF-beta1 released from incorporated microspheres. Gelatin microspheres with two different degrees of crosslinking were used to enable different cell-mediated microsphere degradation rates. Biochemical assays, histological and immunohistochemical analyses, and biomechanical testing were performed to determine biochemical composition, structure, and equilibrium modulus in unconfined compression after 3 weeks of culture. The inclusion of microspheres with or without loaded TGF-beta1 significantly increased sheet thickness and compressive equilibrium modulus, and enabled more uniform matrix deposition by comparison to control sheets without microspheres. Sheets incorporated with fast-degrading microspheres containing TGF beta1 produced significantly more GAG and GAG per DNA than all other groups tested and stained more intensely for type II collagen. These findings demonstrate improved cartilage formation in microsphere-incorporated cell sheets, and describe a tailorable system for the chondrogenic induction of hMSCs without necessitating culture in growth factor-containing medium. PMID- 22100387 TI - Hepatitis B virus envelope L protein-derived bio-nanocapsules: mechanisms of cellular attachment and entry into human hepatic cells. AB - A bio-nanocapsule (BNC) is a hollow nanoparticle consisting of an approximately 100-nm-diameter liposome with about 110 molecules of hepatitis B virus (HBV) surface antigen L protein embedded as a transmembrane protein. BNC can encapsulate various drugs and genes and deliver them specifically to human hepatic cells based on the ability of HBV to recognize human hepatocyte, which is integrated in the N-terminal region of L protein. However, it is elusive whether the cellular attachment and entry into hepatic cells of BNC utilize the early infection mechanism of HBV. In this study, we have found that while all human hepatic cells show distinct affinities for BNC compared to non-hepatic cells, primary hepatocytes shows the highest efficiency for cellular binding and incorporation of BNC. Amounts of BNCs bound weakly and strongly to cell membranes and those entered into the cells varied significantly depending on the types of human hepatic cells. The weak and strong binding modes of BNC are likely mediated through binding to two distinct HBV receptors (heparin-mediated low-affinity and unidentified high-affinity receptors), which play major roles in the early infection mechanism of HBV. The rates of cellular uptake of BNC are similar to those reported for HBV. The BNCs incorporated into the cells are swiftly sorted to either early endosomes or macropinosomes and then to late endosomes and/or lysosomes. These findings strongly suggest that BNC is bound to and incorporated into human hepatic cells according to the early infection mechanism of HBV. PMID- 22100388 TI - In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia. AB - Prognosis of patients with acute myeloid leukemia (AML) remains poor despite the use of first-line induction chemotherapy. Therefore, it is imperative to find effective treatment for AML patients. Safingol is a bioactive sphingolipid which has demonstrated promising in vitro anti-leukemic properties; however, translation into clinical use is hampered by its low water solubility and dose limiting hemolysis. The present study is the first to describe a rationally designed liposome formulation of safingol and demonstrate the anti-leukemic potential using a panel of human AML cell lines and patient samples as well as a human xenograft model in SCID mice. Encapsulation efficiency of safingol into liposomes was approximately 100%, and the release of drug followed square-root-of time release model. The presence of a transmembrane pH gradient completely abolished the biological activity of liposomal safingol. A positive zeta potential, which influenced cellular accumulation of liposomal safingol, was crucial to the anti-leukemic activity. Liposomal safingol was effective against a wide range of AML subtypes with minimal hemolytic toxicity, and was able to extend the median survival time of the U937-inoculated mice to 31 days as compared to 23 days by free drug. The increase in therapeutic efficacy could be related to the increase in systemic drug exposure as a result of liposome encapsulation. PMID- 22100389 TI - Dexamethasone-loaded peptide micelles for delivery of the heme oxygenase-1 gene to ischemic brain. AB - The R3V6 peptides, which are composed of a 3-arginine block and a 6-valine block, formed self-assembled micelles in aqueous solution. Dye quenching assays showed that a hydrophobic fluorescent dye, 5-dodecanoylaminofluorescein (DAF), interacted with and was loaded into the hydrophobic core of the micelles. In this study, dexamethasone-loaded R3V6 peptide micelles (R3V6-Dexa) were evaluated as a gene carrier. R3V6-Dexa had higher gene delivery efficiency in human embryonic kidney 293 cells compared to those of the R3V6 peptides and poly-L-lysine (PLL). Dexamethasone might stabilize the micelle structure of the R3V6 peptides by forming strong hydrophobic cores and enhanced the transfection efficiency. Furthermore, R3V6-Dexa reduced the expression of an inflammatory cytokine, interleukin-6 (IL-6), more efficiently in lipopolysaccharide (LPS)-induced Raw264.7 cells than did dexamethasone, suggesting that R3V6-Dexa is also a useful carrier for dexamethasone delivery. A focal brain ischemia-reperfusion model was produced by middle cerebral artery occlusion (MCAO). A heme oxygenase-1 (HO-1) expression plasmid DNA, pSV-HO-1, was delivered into the brain using R3V6-Dexa as a carrier. The pSV-HO-1/R3V6-Dexa complex was injected into the brain 1hr prior to MCAO. Twenty-four hours later, the HO-1 expression of the pSV-HO-1/R3V6-Dexa injection group was higher than those of the MCAO control, pbeta-Luc/R3V6-Dexa, and pSV-HO-1/PEI25k injection groups. In addition, the infarct size was reduced due to the delivery of pSV-HO-1/R3V6-Dexa complex. Therefore, R3V6-Dexa may be a useful carrier for HO-1 gene delivery and stroke gene therapy. PMID- 22100390 TI - Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis. AB - MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP. PMID- 22100391 TI - Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. AB - Specific outcomes upon activation of the c-Jun N-terminal kinase (JNK) pathway critically depend on the intensity and duration of signal transmission. Dual specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK. It has been shown that M3/6 itself is phosphorylated by JNK upon stimulation with arsenite, but the role of this phosphorylation has not been investigated. In this study, we mapped JNK induced phosphorylation sites on M3/6 using mass spectrometry. Phosphorylated residues Ser 515, Thr 518 and Ser 520 were identified and site-directed mutagenesis was employed to investigate their role. Upon arsenite stimulation, M3/6 mutated at these sites exhibited decreased phosphorylation compared to the wild-type protein. No difference was observed in terms of the enzyme's in vitro phosphatase activity, its substrate specificity towards JNK isoforms, its interactions with JNK and the scaffold family of JNK-interacting proteins (JIPs), its stability or its subcellular localization. Interestingly, expression of M3/6 phosphorylation mutants delayed the time-course of JNK phosphorylation and activation by arsenite. We propose that phosphorylation of the M3/6 phosphatase by JNK in response to stress stimuli results in attenuation of phosphatase activity and acceleration of JNK activation. PMID- 22100392 TI - MKP3 negatively modulates PDGF-induced Akt and Erk5 phosphorylation as well as chemotaxis. AB - MAP kinase phosphatase-3 (MKP3), also known as DUSP6 or Pyst1, is a dual specificity phosphatase considered to selectively dephosphorylate extracellular signal-regulated kinase 1/2 (Erk1/2). Here, we report that in NIH3T3 cells, MKP3 is induced in response to platelet-derived growth factor (PDGF)-BB treatment in an Erk1/2- and phosphatidylinositol 3-kinase (PI3K)-dependent manner, but independently of Erk5 expression. Silencing of MKP3 expression did not affect PDGF-BB-induced Erk1/2 or p38 phosphorylation; however, their basal level of phosphorylation was elevated. Furthermore, we found that PDGF-BB-mediated activation of Erk5 and Akt was enhanced when the MKP3 expression was reduced. Interfering with Mek1/2 or PI3K using the inhibitors CI-1040 and LY-294002, respectively, inhibited PDGF-BB-induced MKP3 expression. Functionally, we found that MKP3 silencing did not affect cell proliferation, but enhanced the chemotactic response toward PDGF-BB. Although both Akt and Erk5 have been linked to increased cell survival, downregulation of MKP3 did not alter the ability of PDGF-BB to protect NIH3T3 cells from starvation-induced apoptosis. However, we observed an increased apoptosis in untreated cells with reduced MKP3 expression. In summary, our data indicate that there is negative cross-talk between Erk1/2 and Erk5 that involves regulation of MKP3 expression, and that PI3K in addition to promoting Akt phosphorylation also negatively modulates Akt, through MKP3 expression. PMID- 22100393 TI - Posttraumatic growth in long term breast cancer survivors: relation to coping, social support and cognitive processing. AB - Post-traumatic growth (PTG) has rarely been studied in long term breast cancer survivors using open interviews. In order to address the issue of how women integrate PTG in their overall cancer experience, 28 open interviews concerning changes after cancer were carried out with 5- to 15-year survivors. The analysis of results, performed using Alceste software, revealed one thematic class of PTG which was specific to women with high coping and social support and active cognitive processing. PTG theme appeared most often as a conclusion of interviews rather than in response to the question about changes after cancer. PMID- 22100394 TI - UG repeats/TDP-43 interactions near 5' splice sites exert unpredictable effects on splicing modulation. AB - TDP-43 is a nuclear protein implicated in the pathogenesis of several neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration, with broad involvement in numerous stages of RNA processing ranging from transcription to translation. In diseased neurons, TDP-43 mostly aggregates in the cytoplasm, suggesting that a loss of protein function in the nucleus may play an important role in neurodegeneration. A better understanding of TDP-43 general nuclear functions is therefore an essential step to evaluate this possibility. Presently, the TDP-43 best-characterized functional property is its ability to modulate pre-mRNA splicing when binding in proximity of 3'SS acceptor sequences. In this work, using a variety of artificial and natural splicing substrates, we have investigated the effects of TDP-43 binding to UG repeats in the vicinity of 5'SS donor sequences. In general, our results show that UG repeats are not powerful splicing regulatory elements when located near to exonic 5'SS sequences. However, in cases like the BRCA1, ETF1, and RXRG genes, TDP-43 binding to natural UG-repeated sequences can act as either an activator or a suppressor of 5'SS recognition, depending on splice site strength and on the presence of additional splicing regulatory sequences. The results of this analysis suggest that a role of UG repeats/TDP-43 in 5'SS recognition may exists and may become critical in the presence of mutations that weaken the 5'SS. The general rule that can be drawn at the moment is that the importance of UG repeats near 5' splice sites should always be experimentally validated on a case by-case basis. PMID- 22100395 TI - ExbD mutants define initial stages in TonB energization. AB - Cytoplasmic membrane proteins ExbB and ExbD of the Escherichia coli TonB system couple cytoplasmic membrane protonmotive force (pmf) to TonB. TonB transmits this energy to high-affinity outer membrane active transporters. ExbD is proposed to catalyze TonB conformational changes during energy transduction. Here, the effect of ExbD mutants and changes in pmf on TonB proteinase K sensitivity in spheroplasts was examined. Spheroplasts supported the pmf-dependent formaldehyde cross-link between periplasmic domains of TonB and ExbD, indicating that they constituted a biologically relevant in vivo system to study changes in TonB proteinase K sensitivity. Three stages in TonB energization were identified. In Stage I, ExbD L123Q or TonB H20A prevented proper interaction between TonB and ExbD, rendering TonB sensitive to proteinase K. In Stage II, ExbD D25N supported conversion of TonB to a proteinase-K-resistant form, but not energization of TonB or formation of the pmf-dependent formaldehyde cross-link. Addition of protonophores had the same effect as ExbD D25N. This suggested the existence of a pmf-independent association between TonB and ExbD. TonB proceeded to Stage III when pmf was present, again becoming proteinase K sensitive, but now able to form the pmf-dependent cross-link to ExbD. Absence or presence of pmf toggled TonB between Stage II and Stage III conformations, which were also detected in wild type cells. ExbD also underwent pmf-dependent conformational changes that were interdependent with TonB. These observations supported the hypothesis that ExbD couples TonB to the pmf, with concomitant transitions of ExbD and TonB periplasmic domains from unenergized to energized heterodimers. PMID- 22100396 TI - Pharmacokinetic and toxicological data of spirolides after oral and intraperitoneal administration. AB - Spirolides are a kind of marine toxins included in the cyclic imine toxin group and produced by the dinoflagellate Alexandrium ostenfeldii. This study shows for the first time a complete and detailed description about the symptoms observed in mice when these toxins were intraperitoneal (i.p.) administered. It is also compared the i.p. toxicity of 13-desmethyl spirolide C (13-desMeC), 13,19 didesMeC (13,19-didesMeC) and 20-methyl spirolide G (20-Me-G) in experiments performed with highly purified toxins. The bioassay indicates that 13-desMeC and 13,19-didesMeC are extremely toxic compounds which have a LD(50) of 27.9MUg/kg and 32.2MUg/kg, respectively. However, when 20-MeG was i.p administrated with dose up 63.5MUg/kg, no deaths were recorded. In order to evaluate the oral toxicity, spirolides were administered by gastric intubation into mice. Then, samples of blood, urine and faeces were collected and analyzed by liquid chromatography-mass spectrometry tandem (LC-MS/MS) technique. Spirolides appear in blood at 15min and in urine after 1h of being toxin administered. In summary, in this paper, it is provided new data about the toxicity, absorption, and excretion of spirolides in mouse. So far, little information is available on this item but necessary for spirolide regulation in the European Union (EU). PMID- 22100397 TI - Polybrominated diphenyl ethers in food and human dietary exposure: a review of the recent scientific literature. AB - Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) used to protect people from fires by reducing the flammability of combustible materials. In recent years, PBDEs have become widespread environmental pollutants, while body burden in the general population has been increasing. A number of studies have shown that, as for other persistent organic pollutants, dietary intake is one of the main routes of human exposure to PBDEs. The most recent scientific literature concerning the levels of PBDEs in foodstuffs and the human dietary exposure to these BFRs are here reviewed. It has been noted that the available information on human total daily intake through food consumption is basically limited to a number of European countries, USA, China, and Japan. In spite of the considerable methodological differences among studies, the results show notable coincidences such as the important contribution to the sum of total PBDEs of some congeners such as BDEs 47, 49, 99 and 209, the comparatively high contribution of fish and seafood, and dairy products, and the probably limited human health risks derived from dietary exposure to PBDEs. Various issues directly related to human exposure to PBDEs through the diet still need investigation. PMID- 22100398 TI - The in vitro diagnosis of anthelmintic resistance in cyathostomins. AB - Cyathostomins are the primary parasitic pathogens of equids. For over 40 years, these nematodes have been controlled using broad spectrum anthelmintics. Three classes of anthelmintic are currently available for this use but, unfortunately, resistance to each of these has now been recorded in cyathostomin populations. As part of an optimal strategy to control cyathostomin infections in the field, it will be important to identify drug-resistant worms at as early a stage as possible. This objective needs to be supported by methodologies that will allow the accurate comparison of anthelmintic resistance in different nematode populations. At present, the faecal egg count reduction test is considered the most suitable method for initial screening for anthelmintic resistance in equine nematode populations. However, in its current state, this test lacks sensitivity. It is also costly and time-consuming to perform. Laboratory-based techniques, such as the egg hatch assay, larval development assay, larval migration inhibition assay and the larval feeding inhibition assay offer alternative options for assessing anthelmintic resistance in nematode populations. All of these tests have been investigated for their utility in measuring drug resistance in sheep nematode populations and some have proven useful. The egg hatch assay, larval development assay and larval migration inhibition assay have been investigated for use in measuring levels of drug resistance in equine nematode populations. However, at best, the results obtained thus far indicate that these tests require further refinement. PMID- 22100399 TI - Survival of a feline isolate of Tritrichomonas foetus in water, cat urine, cat food and cat litter. AB - Feline intestinal trichomoniasis caused by Tritrichomonas foetus is associated with large bowel diarrhea in cats from many parts of the world. It has long been recognized as an economically important sexually transmitted disease that causes early abortion in cattle. Isolates of T. foetus from cattle are infectious for the large intestine of cats and isolates of T. foetus from cats are infectious for the reproductive system of cattle. The parasite is maintained by fecal-oral transmission in cats. The present study was conducted to examine the survival of a feline isolate of T. foetus, AUTf-12, under various conditions that are relevant to fecal-oral transmission in cats. Trophozoites were grown in TYM medium and then exposed to water, cat urine, dry cat food, canned cat food, clumping cat litter, or filter paper for various lengths of time and then re cultured in TYM medium. Trophozoites survived exposure to distilled or tap water for 30 but not 60 min, while they survived for at least 180 min in urine. Trophozoites survived for 30 min on dry cat food but survived for 120-180 min in canned cat food. No survival of trophozoites was observed on cat litter but trophozoites survived for 15 min when placed on filter paper. Our results indicate that T. foetus can survive and be potentially infectious in water, urine, dry cat food and canned cat food. PMID- 22100400 TI - Back to the future. PMID- 22100401 TI - The generation of a reverse genetics system for Kyasanur Forest Disease Virus and the ability to antagonize the induction of the antiviral state in vitro. AB - Kyasanur Forest Disease Virus (KFDV) is a tick-borne, hemorrhagic fever-causing member of the Flaviviridae virus family. With infections annually ranging from 50 to 1000 people in south-west India and the lack of effective treatments, a better understanding of this virus is needed. The development of a reverse genetics system (RGS) for KFDV would provide the opportunity to address these issues. The KFDV genome sequence was elucidated and the RGS was created. Utilizing this system, live infectious KFDV particles were produced from mammalian cell culture, thereby validating the success of the RGS. Flaviviruses have the ability to suppress the type 1 interferon response and indications are that the non structural (NS) proteins serve this role. Using luciferase bioassays, the NS5 protein of KFDV was determined to be the primary antagonist of the IFN response when compared to the other NS proteins, specifically NS4B and NS4B-2k. Moreover, our results indicate that this is attributed to a region, beginning before and including the RNA-dependent RNA polymerase (RdRp). With evasion of the interferon response by KFDV established, the further implementation of the reverse genetics system will enable investigation into pathogenesis and disease progression of KFDV with respect to the innate immune response, at the IFN and the NS5 protein levels. PMID- 22100402 TI - Cell tropism and entry of porcine circovirus 2. AB - Porcine circovirus 2 (PCV2) may induce reproductive failure (return to oestrus, embryonic death, mummification, weak- and stillborn piglets) and postweaning multisystemic wasting syndrome (PMWS). Furthermore, it may modulate the immunity in such a way that it aggravates the outcome of many bacterial and viral infections. In the present paper, the cellular tropism and entry of PCV2 are described and linked with the pathological and clinical consequences. PMID- 22100403 TI - Enhancing sensitivity and precision on NIR reflectance determination of an API at low concentration: Application to an hormonal preparation. AB - The use of a mixed calibration sample set (intact production tablets and powdered doped samples used to enlarge calibration range) is a usual procedure for the NIR reflectance determination of the API content of a pharmaceutical solid preparation. However, the high difference in scattering properties and the intrinsic low sensitivity of NIR make difficult the achievement of a good precision when API is at a low mass proportion (~1%, w/w). The compression of the calibration powdered samples has been studied as a very simple procedure to enhance the sensitivity of NIR reflectance measurements and, consequently, to improve precision. Different pretreatments (SNV, 1D, 2D and their combinations) have been applied to reduce the spectral difference between powdered and compressed samples. Although none eliminates completely this difference, the combined pretreatment SNV+2D has proved to be the one with a better performance. Results obtained by using both calibration sample sets (powdered and compacted) in the quantification of estradiol valerate (VE, 2mg/tablet, ~1.6%, w/w) and medroxyprogesterone (MPA, 10mg, ~8%, w/w) in intact tablets of the hormonal preparation show that a slight but significant improvement in precision is obtained when using compacted samples for calibration. A HPLC procedure was developed to be used as reference method. PMID- 22100404 TI - Inaccurate data cannot be used as standards in pharmaceutical and biomedical analysis. PMID- 22100405 TI - Practice makes perfect-research makes perfect practice. PMID- 22100406 TI - Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. AB - The fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1. PMID- 22100408 TI - Old enzymes, new tricks: sirtuins are NAD(+)-dependent de-acylases. AB - Seven mammalian sirtuins are nicotinamide adenine dinucleotide (NAD)(+)-dependent deacetylases and are important modulators of energy metabolism and stress resistance. Two new studies by Du et al. (2011) and Peng et al. (2011) identify a new enzymatic activity for SIRT5, expanding the cellular repertoire of posttranslational modifications targeted by the sirtuins. PMID- 22100407 TI - NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. AB - Fasting-induced suppression of the hypothalamic-pituitary-thyroid (HPT) axis is an adaptive response to decrease energy expenditure during food deprivation. Previous studies demonstrate that leptin communicates nutritional status to the HPT axis through thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN) of the hypothalamus. Leptin targets TRH neurons either directly or indirectly via the arcuate nucleus through pro-opiomelanocortin (POMC) and agouti related peptide/neuropeptide Y (AgRP/NPY) neurons. To evaluate the role of these pathways in vivo, we developed double knockout mice that lack both the melanocortin 4 receptor (MC4R) and NPY. We show that NPY is required for fasting induced suppression of Trh expression in the PVN. However, both MC4R and NPY are required for activation of hepatic pathways that metabolize T(4) during the fasting response. Thus, these signaling pathways play a key role in the communication of fasting signals to reduce thyroid hormone levels both centrally and through a peripheral hepatic circuit. PMID- 22100409 TI - In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis. AB - The glutathione redox couple (GSH/GSSG) and hydrogen peroxide (H(2)O(2)) are central to redox homeostasis and redox signaling, yet their distribution within an organism is difficult to measure. Using genetically encoded redox probes in Drosophila, we establish quantitative in vivo mapping of the glutathione redox potential (E(GSH)) and H(2)O(2) in defined subcellular compartments (cytosol and mitochondria) across the whole animal during development and aging. A chemical strategy to trap the in vivo redox state of the transgenic biosensor during specimen dissection and fixation expands the scope of fluorescence redox imaging to include the deep tissues of the adult fly. We find that development and aging are associated with redox changes that are distinctly redox couple-, subcellular compartment-, and tissue-specific. Midgut enterocytes are identified as prominent sites of age-dependent cytosolic H(2)O(2) accumulation. A longer life span correlated with increased formation of oxidants in the gut, rather than a decrease. PMID- 22100410 TI - Proteomics analysis of aromatic catabolic pathways in thermophilic Geobacillus thermodenitrificans NG80-2. AB - Geobacillus thermodenitrificans NG80-2 is a crude oil-degrading thermophilic bacterium isolated from an oil reservoir in China. In this study, the gene clusters and pathways for the degradation of benzoate (via benzoyl-CoA), phenylacetate (via phenylacetyl-CoA), 4-hydroxyphenylacetate (via 3,4 dihydroxyphenylacetate) and anthranilate (via 3-hydroxyanthranilate) were confirmed using combined in silico analysis and proteomics approaches. It was observed that synthesis of the enzymes catalyzing initial activation, ring oxidation and ring cleavage reactions were generally induced specifically by their respective substrates, while many of the enzymes catalyzing downstream reactions exhibited broader substrate specificities. Novel genes encoding benzoyl CoA epoxidase and 3,4-dihydroxyphenylacetate 2,3-dioxygenase, and a paaX homologue that serves as a positive regulator of benzoate degradation were proposed. Downregulation of the glycolysis pathway, along with upregulation of the gluconeogenesis pathway and the glyoxylate bypass (phenylacetate) were detected in association with the utilization of the aromatics. This novel proteomics approach confirmed the presence of multiple metabolic pathways for aromatic compounds in NG80-2, which is highly advantageous to the survival of this thermophilic bacterium under reservoir conditions. PMID- 22100411 TI - Intersession reliability and concurrent validity of isometric endurance tests for the lateral trunk muscles. AB - CONTEXT: A torso-elevated side support (TESS) has previously been described for measuring endurance of the lateral trunk muscles. In some individuals, however, TESS performance may be hindered by upper extremity pain or fatigue. For this reason a novel test, the feet-elevated side-support test (FESS), was examined. OBJECTIVE: To determine intersession reliability of a FESS and a TESS on the left and right sides using a single examiner, to evaluate the relationship between tests, and to compare reasons for test termination. DESIGN: Nonexperimental prospective repeated measures. SETTING: University laboratory. PARTICIPANTS: A convenience sample of 60 healthy participants from a university community (17 men, 43 women; age 21.1 +/- 2.2 y; height 169.9 +/- 9.5 cm; weight 67.1 +/- 11.9 kg). RESULTS: Intraclass correlation coefficient between 3 testing sessions = .87 with right FESS, .86 with left FESS, .78 with right TESS, and .91 with left TESS. Pearson correlation coefficients ranged from .59 (between left FESS and left TESS in women) to .75 (between left FESS and left TESS in men). Upper extremity pain or fatigue was the reason given for test termination in 42.5% of participants during the TESS and 5.0% during the FESS (P = .000, Fisher exact test). CONCLUSIONS: FESS and TESS had comparable intersession reliability by the same evaluator. Moderate to high correlations were found between FESS and TESS scores, suggesting that the tests assess similar qualities. Far fewer participants terminated the FESS because of upper extremity pain or fatigue. Thus, the FESS may be a suitable alternative to the previously validated TESS, particularly for individuals with upper extremity pain or weakness. PMID- 22100412 TI - The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenome to an embryonic-like state. Vitamin C enhances the reprogramming process, but the underlying mechanisms are unclear. Here we show that the histone demethylases Jhdm1a/1b are key effectors of somatic cell reprogramming downstream of vitamin C. We first observed that vitamin C induces H3K36me2/3 demethylation in mouse embryonic fibroblasts in culture and during reprogramming. We then identified Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, as potent regulators of reprogramming through gain- and loss-of-function approaches. Furthermore, we found that Jhdm1b accelerates cell cycle progression and suppresses cell senescence during reprogramming by repressing the Ink4/Arf locus. Jhdm1b also cooperates with Oct4 to activate the microRNA cluster 302/367, an integral component of the pluripotency machinery. Our results therefore reveal a role for H3K36me2/3 in cell fate determination and establish a link between histone demethylases and vitamin-C-induced reprogramming. PMID- 22100413 TI - [Revisiting the dose-effect correlations in irradiated head and neck cancer using automatic segmentation tools of the dental structures, mandible and maxilla]. AB - PURPOSE: Manual delineation of dental structures is too time-consuming to be feasible in routine practice. Information on dose risk levels is crucial for dentists following irradiation of the head and neck to avoid postextraction osteoradionecrosis based on empirical dose-effects data established on bidimensional radiation therapy plans. MATERIAL AND METHODS: We present an automatic atlas-based segmentation framework of the dental structures, called Dentalmaps, constructed from a patient image-segmentation database. RESULTS: This framework is accurate (within 2 Gy accuracy) and relevant for the routine use. It has the potential to guide dental care in the context of new irradiation techniques. CONCLUSION: This tool provides a user-friendly interface for dentists and radiation oncologists in the context of irradiated head and neck cancer patients. It will likely improve the knowledge of dose-effect correlations for dental complications and osteoradionecrosis. PMID- 22100414 TI - Investigation of bone resorption within a cortical basic multicellular unit using a lattice-based computational model. AB - In this paper we develop a lattice-based computational model focused on bone resorption by osteoclasts in a single cortical basic multicellular unit (BMU). Our model takes into account the interaction of osteoclasts with the bone matrix, the interaction of osteoclasts with each other, the generation of osteoclasts from a growing blood vessel, and the renewal of osteoclast nuclei by cell fusion. All these features are shown to strongly influence the geometrical properties of the developing resorption cavity including its size, shape and progression rate, and are also shown to influence the distribution, resorption pattern and trajectories of individual osteoclasts within the BMU. We demonstrate that for certain parameter combinations, resorption cavity shapes can be recovered from the computational model that closely resemble resorption cavity shapes observed from microCT imaging of human cortical bone. PMID- 22100415 TI - [Acute renal failure and Plasmodium falciparum malaria: a case report]. AB - Malaria is an endemic disease caused by one of the several Plasmodium species. Severe malaria is mainly due to Plasmodium falciparum in highly endemic areas. Acute renal failure (ARF) is a criterion of malaria severity as defined by WHO. Often observed in adults, particularly in India and Southeast Asia, this complication remains a rare complication of malaria in children. We report a case of oliguric ARF that occurred in a 7-year-old girl a few days after the onset of fever. The vascular obstruction by parasitized erythrocytes often causing tubular necrosis is the primary mechanism of renal failure. As a possible diagnosis, hemolytic uremic syndrome, renal failure and quartan hemoglobinuric nephropathy are other possible causes of renal failure in malaria. Renal biopsy, which was not performed in our patient, would have been a great help, but was not available. The outcome was favorable with recovery of renal function after 3 weeks of diuretic therapy. This development is not always the rule and the prognosis depends on early diagnosis and treatment options. PMID- 22100416 TI - [Pseudostatus epilepticus: a severe complication of psychogenic nonepileptic seizures (PNES) in children]. AB - Psychogenic nonepileptic seizures are clinical events that mimic epileptic seizures but are not associated with electroencephalographic discharges. These seizures are seldom reported in children in the literature and could be misinterpreted as generalized tonicoclonic seizures. We report the case of a child, already treated for epilepsy, who presented at 8 years of age with several psychogenic seizures leading to pseudostatus epilepticus. After several hospitalizations, the diagnosis of pseudostatus was established on the basis of clinical semiology, lack of EEG abnormalities during the seizures, and a positive provocation maneuver, which elicited and blocked the manifestations. The clinical spectrum of psychogenic seizures is wide and it is particularly difficult to differentiate psychogenic seizures from epileptic seizures, especially when occurring in children, some of whom are already treated for epilepsy. Well described clinical features can suggest the diagnosis of psychogenic seizure. It is important and necessary to make the diagnosis as soon as possible in order to rapidly begin appropriate treatment including psychotherapy. In fact, the long term prognosis in children is better than in the adult population. Associated risk factors, such as anxiety as reported in the present case, have to be sought. Recognizing psychogenic seizures will thus avoid their fixation in the child's personality and the risk of inappropriate and escalating treatments leading to iatrogenic complications. PMID- 22100417 TI - Laboratory and field evaluations of the efficacy of a fast-killing baculovirus isolate from Spodoptera frugiperda. AB - Three biopesticide parameters were evaluated for a fast-killing isolate (3AP2) and a wild-type isolate (Sf3) of Spodoptera frugiperda multiple nucleopolyhedrovirus (SfMNPV). Both isolates were evaluated for virus production using in vivo methods, for speed of kill based on bioassay of applications to glasshouse-grown and field-grown plants, and for residual insecticidal activity of unformulated virus and an encapsulating formulation to provide UV protection. Two inoculation rates comparing relative in vivo production of the isolates demonstrated 3AP2 inoculated larvae were significantly smaller than Sf3 inoculated larvae at death. At the lower inoculation rate, Sf3 inoculated larvae produced approximately twofold more occlusion bodies as the 3AP2 inoculated larvae. A model system of applications to cabbage plants and a bioassay to observe mortality of neonate S. frugiperda (J.E. Smith) after feeding on samples of treated leaves was used to evaluate speed of kill and residual insecticidal activity. The LT(50) for the 3AP2 isolate was at least 30 h less than the LT(50) for the Sf3 isolate when applied to either glasshouse-grown or field-grown plants. The spray-dried lignin encapsulating formulation provided similar benefits to both virus isolates when exposed to simulated sunlight in the laboratory and to natural sunlight in the field. For treatment applications to field grown cabbage in June, the half-life for efficacy of unformulated virus was <7.5 h compared with a half-life of >26.7 h for encapsulated virus. These results demonstrate that improved technologies can be combined to address characteristics which otherwise can limit the commercial potential of microbial-based biological insecticides. PMID- 22100418 TI - Striatal topography of probability and magnitude information for decisions under uncertainty. AB - Most decisions involve some element of uncertainty. When the outcomes of these decisions have different likelihoods of occurrence, the decision-maker must consider both the magnitude of each outcome and the probability of its occurrence, but how do individual decision makers combine the two dimensions of magnitude and probability? Here, we approach the problem by separating in time the presentation of magnitude and probability information, and focus the analysis of fMRI activations on the first piece of information only. Thus, we are able to identify distinct neural circuits for the two dimensions without the confounding effect of divided attention or the cognitive operation of combining them. We find that magnitude information correlates with the size of the response of the ventral striatum while probability information correlates with the response in the dorsal striatum. The relative responsiveness of these two striatal regions correlates with the behavioral tendency to weight one more than the other. The results are consistent with a second-order process of information aggregation in which individuals make separate judgments for magnitude and probability and then integrate those judgments. PMID- 22100419 TI - Brain connectivity in psychiatric imaging genetics. AB - In the past decade, imaging genetics has evolved into a highly successful neuroimaging discipline with a variety of sophisticated research tools. To date, several neural systems mechanisms have been identified that mediate genetic risk for mental disorders linked to common candidate and genome-wide-supported variants. In particular, the examination of intermediate connectivity phenotypes has recently gained increasing popularity. This paper gives an overview of the scientific methods and evidence that link indices of neural network organization to the genetic susceptibility for mental illness with a focus on the effects of candidate genes and genome-wide supported risk variants on brain structure and function. PMID- 22100420 TI - Making research real: embedding a longitudinal study in a taught research course for undergraduate nursing students. AB - Learning how and why scholarly research underpins and informs professional nursing practice is a continual challenge for undergraduate nursing students. They find the language and methods of research to be unfamiliar and unsettling. The work of educators thus becomes the process of breaking down barriers to students' understanding of research processes and application. Such work is increasingly important in the current era of evidence based practice, where students must be competent in sourcing, critiquing and applying research to meet real clinical questions. In response, as lecturers who taught the course, Research for Health Professionals, we have reinvented how research is taught to second year undergraduate students. This article outlines our creative approach to facilitate students learning research theory and methodology by conducting a "real-life" research study in a local retirement community. PMID- 22100421 TI - Developing a pedagogy for nursing teaching-learning. AB - Each nurse educator's pedagogy underpins their understanding of and approach to teaching and learning, regardless of whether this has been reflected upon or articulated. In this paper, we overview factors and issues that should be considered when developing a teaching philosophy of nursing education and set out broad differences between traditional and contemporary pedagogic models and various ways of knowing. As values underpin any teaching framework these are considered in relation to pedagogies, epistemologies and their relevance to nursing practice. Key teacher roles and strategies that are congruent with a contemporary pedagogy for teaching nursing in the classroom or the clinical setting are also outlined. A premise for writing this paper was that clarifying one's own understandings of education and knowledge and the implicit values held within those terms and processes will contribute to greater self-awareness and more effective teaching of nursing. Education approaches underpinned by a sound teaching philosophy and framework can facilitate an educationally sound and positive experience for learners. PMID- 22100422 TI - Stochastic approximation to the T cell mediated specific response of the immune system. AB - We develop a stochastic model to study the specific response of the immune system. The model is based on the dynamical interaction between Regulatory and Effector CD4+ T cells in the presence of Antigen Presenting Cells inside a lymphatic node. At a mean field level the model predicts the existence of different regimes where active, tolerant, or cyclic immune responses are possible. To study the model beyond mean field and to understand the specific responses of the immune system we use the Linear Noise Approximation and show that fluctuations due to finite size effects may strongly alter the mean field scenario. Moreover, it was found that the existence of a certain characteristic frequency for the fluctuations. All the analytical predictions were compared with simulations using Gillespie's algorithm. PMID- 22100423 TI - A novel option in negative pressure wound therapy (NPWT) for chronic and acute wound care. AB - INTRODUCTION: Negative pressure wound therapy (NPWT) has become a widely accepted technique in treatment of all kinds of wounds. After a long period of clinical application of the V.A.C.TM system (KCI Inc., San Antonio, Texas, USA) a number of options for delivery of NPWT are now commercially available. An urgent need exists for evidence demonstrating clinical efficacy of these new devices to support clinicians regarding their choice of NPWT. METHODS: 42 patients with an acute or chronic wound were randomly assigned to either treatment by V.A.C.TM (group A) or therapy with an alternative newly available polyurethane foam-based NPWT system (RENASYS GOTM - F/P, Smith & Nephew GmbH) (group B). In both groups NPWT was applied after surgical debridement to prepare the wound bed for skin grafting. After skin grafting NPWT was applied additionally to secure skin grafts and improve grafts survival. Primary outcome measures were the time to complete healing (days) and duration of the NPWT application (days). Secondary outcome measures were the number of dressing changes and reported complications. In addition, we evaluated the cost-benefit in the clinical implementation. RESULTS: There were no significant differences comparing the investigated parameters between both groups. Especially average time to complete healing and average time NPWT was applied did not differ (p>0.05). No complications occurred in either group. By an almost identical supply agreement of both providers for our hospital RENASYSTM system appeared to be more cost-effective. CONCLUSION: After a long period of preserving a monopoly market position of the V.A.C.TM system, a new comparable option was successfully tested in this preliminary study. The polyurethane foam-based NPWT system (RENASYS GOTM - F/P, Smith & Nephew GmbH) is an efficient and cost-effective alternative NPWT system, which we effectively implemented in therapeutic management of different kinds of wounds. PMID- 22100424 TI - Perceptions of tap water temperatures, scald risk and prevention among parents and older people in social housing: a qualitative study. AB - BACKGROUND: Young children and older people are particularly vulnerable to tap water scalding. For children, there are also socio-economic inequalities in risk. Evidence suggests that reducing tap water temperatures in social (public) housing through 'passive' means is effective in reducing risk. However, little is known about parents' or older people's perceptions of scald risk and prevention. OBJECTIVES: This study aimed to document the views of parents and older residents in social housing in an inner-London borough about their tap water temperature, perceived scalding risk and scald prevention strategies. METHODS: Analysis of twenty in-depth interviews with 11 parents and 10 people aged 65 years or older. RESULTS: Tap water was described as very hot, but participants did not consider themselves at risk, viewing scald prevention as a personal responsibility achieved with a range of everyday, routine strategies. Very hot water was preferred for health- and convenience-related reasons. However, it was felt that others, particularly children, could be scalded, and some concern was expressed about the environmental and financial impacts of excessively hot water. CONCLUSIONS: Those seeking to introduce engineering-based scald prevention interventions in social housing should emphasise the potential environmental and financial impacts of water temperature reduction, in addition to promoting safety benefits for vulnerable others. PMID- 22100425 TI - The use of topical, un-buffered sodium hypochlorite in the management of burn wound infection. AB - BACKGROUND: Burn wound infections are a major cause of morbidity and mortality. The bactericidal action of sodium hypochlorite has been known for centuries and it has been in clinical practice for over 70 years. Whereas a buffered sodium hypochlorite solution is not universally available, an un-buffered solution is cheap and easy to prepare. AIM: The aim of this study was to determine the optimum concentration with regard to safety and efficacy, as well as shelf life of an un-buffered sodium hypochlorite solution for the topical management of burn wound infections. METHODS: Human fibroblasts were exposed to serial dilutions of un-buffered sodium hypochlorite solutions for 30 min and assessed for viability. Isolates of Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes were exposed to the same dilutions of un-buffered sodium hypochlorite to establish the minimum bactericidal concentration. The pH, osmolality and electrolyte concentrations were measured. These experiments were repeated with solution stored at room temperature for 6 consecutive days. RESULTS: 24% of fibroblasts were viable after exposure to a 0.025% solution and 98.9% with a 0.003% solution. The MBC for the P. aeruginosa isolates was 0.003%, for S. aureus was 0.006% and for S. pyogenes was 0.0015%. This remained constant for 6 consecutive days. The un-buffered 0.0025% solution has a pH of 10, an osmolality of 168 sodium concentration of 89 mmol/dl and chloride of 84 mmol/dl. This remained stable for 14 days. CONCLUSIONS: An un-buffered solution of sodium hypochlorite with a concentration of 0.006% would be suitable for the topical management of burn wound infections caused by common pathogens. It has a shelf life of at least 6 days. PMID- 22100426 TI - Pathogenic alteration in severe burn wounds. AB - The present study aims to define the trend of time related changes with local bacterial alteration of bacterial resistance in severe burns in our burn center during a 12-year period. Retrospective analysis of microbiological results on severely burned wounds between 1998 and 2009 was carried out. A study of 3615 microbial isolates was performed. Staphylococcus aureus was the most commonly isolated pathogen (38.2%) followed by A. baumannii (16.2%), Streptococcus viridans (11.4%), Pseudomonas aeruginosa (10.4%), coagulase-negative staphylococci (CNS, 9.2%). The species ratios of S. aureus and A. baumannii increased significantly from 1st to 8th week of hospitalization, while those of Streptococcus viridans, P. aeruginosa and coagulase-negative staphylococci decreased during the same period. Bacterial resistance rates were compared between the periods 1998-2003 and 2004-2009. Vancomycin remained as the most sensitive antibiotic in S. aureus including methicillin-resistant S. aureus (MRSA). It was very likely that the majority of infections caused by Streptococcus viridans, P. aeruginosa and coagulase-negative staphylococci occurred in the early stage of burn course and the majority of infections caused by A. baumannii occurred 4 weeks after admission. The use of different antibiotics was probably the major contributor to these trends. PMID- 22100427 TI - Community reintegration of sex offenders of children in new zealand. AB - Reintegration of offenders following incarceration is most successful if matched to the needs of offenders, victims, and the community. This study explored child sex offenders' expectations for and experiences of reintegration into the community. A longitudinal design was used in which semistructured interviews covered issues identified in the literature as being related to reintegration. Nine offenders were interviewed within 1 week prior to release, 3 months post release, and 6 months post release. Interviews were analysed using thematic analyses producing six key themes. The interviews revealed that most of the participants feared their release from prison into the community and once released struggled to live in society. Overall, reintegration planning was simplistic and aimed primarily to manage risk factors rather than promote reintegration. Those participants who reported most satisfaction with their adjustment following release had more comprehensive reintegration plans, which enabled them to visualise what life would be like after release. PMID- 22100428 TI - Recombinant expression, localization and in vitro inhibition of midgut cysteine peptidase (Sl-CathL) from sugarcane weevil, Sphenophorus levis. AB - A cDNA coding for a digestive cathepsin L, denominated Sl-CathL, was isolated from a cDNA library of Sphenophorus levis larvae, representing the most abundant EST (10.49%) responsible for proteolysis in the midgut. The open reading frame of 972 bp encodes a preproenzyme similar to midgut cathepsin L-like enzymes in other coleopterans. Recombinant Sl-CathL was expressed in Pichia pastoris, with molecular mass of about 42 kDa. The recombinant protein was catalytically activated at low pH and the mature enzyme of 39 kDa displayed thermal instability and maximal activity at 37 degrees C and pH 6.0. Immunocytochemical analysis revealed Sl-CathL production in the midgut epithelium and secretion from vesicles containing the enzyme into the gut lumen, confirming an important role for this enzyme in the digestion of the insect larvae. The expression profile identified by RT-PCR through the biological cycle indicates that Sl-CathL is mainly produced in larval stages, with peak expression in 30-day-old larvae. At this stage, the enzyme is 1250-fold more expressed than in the pupal fase, in which the lowest expression level is detected. This enzyme is also produced in the adult stage, albeit in lesser abundance, assuming the presence of a different array of enzymes in the digestive system of adults. Tissue-specific analysis revealed that Sl CathL mRNA synthesis occurs fundamentally in the larval midgut, thereby confirming its function as a digestive enzyme, as detected in immunolocalization assays. The catalytic efficiency of the purified recombinant enzyme was calculated using different substrates (Z-Leu-Arg-AMC, Z-Arg-Arg-AMC and Z-Phe-Arg AMC) and rSl-CathL exhibited hydrolysis preference for Z-Leu-Arg-AMC (k(cat)/K(m)=37.53 mMS(-1)), which is similar to other insect cathepsin L-like enzymes. rSl-CathL activity inhibition assays were performed using four recombinant sugarcane cystatins. rSl-CathL was strongly inhibited by recombinant cystatin CaneCPI-4 (K(i)=0.196 nM), indicating that this protease is a potential target for pest control. PMID- 22100429 TI - Recombinant production of cathelicidin-derived antimicrobial peptides in Escherichia coli using an inducible autocleaving enzyme tag. AB - Antimicrobial peptides (AMPs), such as the linear amphipathic cathelicidins, are produced widely in the natural world and are active against a broad range of pathogenic microorganisms. Their potential as a new range of antibiotics has prompted numerous studies of AMP structure and function. Most such studies are performed with chemically synthesised peptides, but a simple and rapid biosynthetic route would offer a more cost-effective alternative for the production of AMPs and analysis of their structure/function relationships. The cysteine protease domain (CPD) from Vibrio cholerae MARTX toxin possesses an autocleaving ability that is inducible by inositol hexakisphosphate (IP(6)). When coupled with a hexa-histidine tag and fused to the C-terminus of an AMP, this AMP CPD fusion may be expressed in Escherichia coli and purified using immobilized metal affinity chromatography. A brief on-column induction of cleavage liberates the AMP, and subsequent polishing using hydrophobic interaction resin allows for purification of the peptide within a day. We used this system to express and purify several 18-residue cathelicidin variants and tested their activity on E. coli, Pseudomonas putida, Bacillus subtilis and Candida albicans. This approach to linear AMP production may aid rapid construction and purification of structural variants for subsequent functional analysis. PMID- 22100430 TI - The lipidic extract of the seaweed Gracilariopsis longissima (Rhodophyta, Gracilariales): a potential resource for biotechnological purposes? AB - In recent years seaweeds increasingly attracted interest in the search for new drugs and have been shown to be a primary source of bioactive natural products including antibiotics. In the present investigation the antimicrobial activity of Gracilariopsis longissima lipidic extract was assayed and its chemical characterization was carried out by means of advanced analytical techniques such as gas-chromatography and multinuclear and multidimensional NMR spectroscopy. G. longissima lipidic extract showed an antibacterial activity against several Vibrio species. These results are interesting considering both the resistance against antibiotics developed by vibrios and the need to control fish and shellfish diseases due to vibriosis. Analysis of fatty acid methyl esters performed by gas-chromatography showed that palmitic acid methyl ester (16:0) was the predominant saturated fatty acid (42%), while, among monounsaturated fatty acids, oleic acid methyl ester (18:1) prevailed (8.5%). Because the palmitic acid represents the main component of fatty acids we hypothesized its involvement in the antibacterial activity observed. However, a pure sample of palmitic acid did not show an antibacterial activity. The fatty acid profile of G. longissima revealed also an interesting composition in polyunsaturated fatty acids and in particular the ratio of omega-3 to omega-6 fatty acids was >1 thus suggesting that this macroalga may be used as a natural source of omega3. Moreover, the (1)H NMR spectrum in CDCl(3) of algal lipid fraction shows the characteristic signals of saturated and unsaturated fatty acids as well as other metabolites. Interestingly, in the lipid extract the presence of polyhydroxybutyrate, a linear biodegradable and biocompatible polyester, was clearly identified by NMR spectroscopy. In conclusion, the lipidic extract of G. longissima on account of its antimicrobial activity, nutritional value and content in biodegradable and biocompatible polyester represents an interesting potential biotechnological resource. PMID- 22100431 TI - How to turn industrial biotechnology into reality. AB - The emerging bioeconomy is pulled by consumers asking for sustainable products and processes, governments enforcing climate protection and industries demanding feedstock flexibility and last but not least it is pushed by progress in basic and applied science. It will use renewable carbon sources not only from agri- and silviculture, but potentially also from industrial flue gases - for example, from power generation and steel production. Connecting such industries with the future bio-chemical industry results in a challenging new value chain which connects thus far separated industries. Realising this value chain needs disruptive technologies in providing sustainable carbon sources and transforming them into precursors for biochemical production up to consumer products. PMID- 22100432 TI - Fructo-oligosaccharides purification from a fermentative broth using an activated charcoal column. AB - In this study, a simple and efficient process to purify fructo-oligosaccharides (FOS) from a fermentative broth was proposed using a single activated charcoal column. The FOS adsorption onto the activated charcoal was modeled by a pseudo second order model. Several volumes and concentrations of water/ethanol were studied to optimize the selective desorption of sugars from the broth mixture at 25 degrees C. Mixtures containing 50.6% (w/w) of FOS (FOS content in the fermentative broth) were purified to 92.9% (w/w) with a FOS recovery of 74.5% (w/w). Moreover, with the proposed process, fractions with purity up to 97% (w/w) of FOS were obtained. This purification process was also found to be efficient in the desalting of the fermentative broth. PMID- 22100433 TI - Glucose-limited high cell density cultivations from small to pilot plant scale using an enzyme-controlled glucose delivery system. AB - The enzyme controlled substrate delivery cultivation technology EnBase((r)) Flo allows a fed-batch-like growth in batch cultures. It has been previously shown that this technology can be applied in small cultivation vessels such as micro- and deep well plates and also shake flasks. In these scales high cell densities and improved protein production for Escherichia coli cultures were demonstrated. This current study aims to evaluate the scalability of the controlled glucose release technique to pilot scale bioreactors. Throughout all scales, that is, deep well plates, 3 L bioreactor and 150 L bioreactor cultivations, the growth was very similar and the model protein, a recombinant alcohol dehydrogenase (ADH) was produced with a high yield in soluble form. Moreover, EnBase Flo also was successfully used as a controlled starter culture in high cell density fed-batch cultivations with external glucose feeding. Here the external feeding pump was started after overnight cultivation with EnBase Flo. Final optical densities in these cultivations reached 120 (corresponding to about 40 g L(-1) dry cell weight) and a high expression level of ADH was obtained. The EnBase cultivation technology ensures a controlled initial cultivation under fed-batch mode without the need for a feeding pump. Because of the linear cell growth under glucose limitation it provides optimal and robust starting conditions for traditional external feed-based processes. PMID- 22100434 TI - Involvement of gonadotropins in the induction of hypertrophy-hyperplasia in the interstitial tissues of ovaries in neonatally diethylstilbestrol-treated mice. AB - Neonatally diethylstilbestrol (DES) treatment causes hypertrophy-hyperplasia in the interstitial tissue of mouse ovaries. To understand the induction mechanism of the hypertrophy, mRNA expression involved in steroidogenesis in the ovary of neonatally DES-treated mice was examined. The expression of StAR and Cyp11a1 was significantly reduced while Cyp19 and Sf-1 were stimulated in the ovary of neonatally DES-treated 3-month-old mice. Expression of those genes was not different between DES- and oil-treated mice after the gonadotropins treatment. Lhb in the pituitary of 3-month-old neonatally DES-treated mice was significantly decreased. Finally, ovaries from DES-treated mice transplanted to neonatally oil treated hosts had developing follicles at several stages and corpora lutea, whereas grafted ovaries from neonatally oil-treated mice in 3-month-old neonatally DES-treated hosts showed lipid accumulation in the interstitial tissue. Thus, hypertrophy and accumulation of lipid droplets in interstitial cells of neonatally DES-treated mice is caused by impaired steroidogenesis due to the alterations of gonadotropins levels. PMID- 22100435 TI - Passive knee-extension test to measure hamstring tightness: influence of gravity correction. AB - CONTEXT: A passive knee-extension test has been shown to be a reliable method of assessing hamstring tightness, but this method does not take into account the potential effect of gravity on the tested leg. OBJECTIVE: To compare an original passive knee-extension test with 2 adapted methods including gravity's effect on the lower leg. DESIGN: Repeated measures. SETTING: Laboratory. PARTICIPANTS: 20 young track and field athletes (16.6 +/- 1.6 y, 177.6 +/- 9.2 cm, 75.9 +/- 24.8 kg). INTERVENTION: Each subject was tested in a randomized order with 3 different methods: In the original one (M1), passive knee angle was measured with a standard force of 68.7 N (7 kg) applied proximal to the lateral malleolus. The second (M2) and third (M3) methods took into account the relative lower-leg weight (measured respectively by handheld dynamometer and anthropometrical table) to individualize the force applied to assess passive knee angle. MAIN OUTCOME MEASURES: Passive knee angles measured with video-analysis software. RESULTS: No difference in mean individualized applied force was found between M2 and M3, so the authors assessed passive knee angle only with M2. The mean knee angle was different between M1 and M2 (68.8 +/- 12.4 vs 73.1 +/- 10.6, P < .001). Knee angles in M1 and M2 were correlated (r = .93, P < .001). CONCLUSIONS: Differences in knee angle were found between the original passive knee-extension test and a method with gravity correction. M2 is an improved version of the original method (M1) since it minimizes the effect of gravity. Therefore, we recommend using it rather than M1. PMID- 22100436 TI - The effect of surface conditioning on the bond strength of resin composite to amalgam. AB - OBJECTIVES: This study evaluated the effect of different surface conditioning methods on the tensile bond strength (TBS) and integrity of the amalgam-resin composite interface, using commercially available restoration repair systems. METHODS: One hundred and sixty Gamma 2 amalgam specimens were stored in artificial saliva for 2 weeks and then randomly assigned to one of the following conditioning groups (n=20/group): Group 1: air abrasion, alloy primer and 'Panavia 21', Group 2: air abrasion and 'Amalgambond Plus', Group 3: air abrasion and 'All-Bond 3', Group 4: diamond bur, alloy primer and 'Panavia 21', Group 5: diamond bur and 'Amalgambond Plus', Group 6: diamond bur and 'All-Bond 3', Group 7: silica coating technique, and Group 8: non-conditioned amalgam surfaces (control group). Subsequently, resin composite material was added to the substrate surfaces and the amalgam-resin composite specimens were subjected to TBS testing. Representative samples from the test groups were subjected to scanning electron microscopy and surface profilometry. The data was analysed statistically with one-way ANOVA and post hoc Tukey's tests (alpha=0.05). RESULTS: The mean TBS of amalgam-resin composite ranged between 1.34 and 5.13MPa and varied with the degree of amalgam surface roughness and the type of conditioning technique employed. Significantly highest TBS values (5.13+/ 0.96MPa) were obtained in Group 1 (p=0.013). CONCLUSION: Under the tested conditions, significantly greater tensile bond strength of resin composite to amalgam was achieved when the substrate surface was conditioned by air abrasion followed by the application of the Panavia 21 adhesive system. CLINICAL SIGNIFICANCE: Effecting a repair of an amalgam restoration with resin composite via the use of air abrasion and application of Panavia 21 would seem to enhance the integrity of the amalgam-resin composite interface. Clinical trials involving the implementation of this technique are indicated to determine the usefulness of this technique. PMID- 22100437 TI - Enzymatic measurement of phosphatidylserine in cultured cells. AB - Phosphatidylserine (PS) is a quantitatively minor membrane phospholipid involved in diverse cellular functions. In this study, we developed a new fluorometric method for measuring PS using combinations of specific enzymes and Amplex Red. The calibration curve for PS measurement was linear and hyperbolic at low (0-50 uM) and high (50-1000 uM) concentrations, respectively, and the detection limit was 5 uM (50 pmol in the reaction mixture). This assay quantified PS regardless of the chain length and the number of double bonds. We applied this new method to the determination of PS content in HEK293 cells, which was validated by a recovery study and comparison with TLC-phosphorus assay. We showed that the PS content was high in sparse cells. The overexpression of PS synthase 1 elevated not only the cellular PS content but also the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) contents, suggesting the conversion of PS into PE and the enhancement of PC production. This new assay for PS measurement is simple, specific, sensitive, and high throughput, and it will be useful to clarify the metabolism and biological functions of PS. PMID- 22100438 TI - Tat(48-60) peptide amino acid sequence is not unique in its cell penetrating properties and cell-surface glycosaminoglycans inhibit its cellular uptake. AB - Biomolecules and drug delivery agents, such as liposomes, are often delivered intracellularly with help of cell penetrating peptides (CPPs) and, in particular, Tat peptide. Tat peptide acts as a membrane shuttle; the structural determinants of transport and the manner by which the peptide crosses the lipid bilayer are, however, still unknown. The roles of direct membrane translocation, endocytosis and cell surface proteoglycans, in particular, remain elusive. Our study aimed to explore the relationship between structure and activity of Tat peptide and its uptake mechanism. For this purpose we introduced several modifications (e.g. lipophilic, aromatic, neutral and non-natural amino acids) into the original Tat sequence. We studied the interaction of the peptides with a model lipid membrane and with three cell lines, a phagocytic cell line (human retinal pigment epithelium cell line, ARPE-19), a non-phagocytic cell line (Chinese hamster ovary cells, CHO wt) and a mutant form of the latter cell line deficient in glycosaminoglycans chondroitin sulfate and heparan sulfate (CHO-pgsB 618). The amino acid residues introduced into the original sequence of Tat peptide failed to influence cellular uptake, indicating that the cationic charge alone may be responsible for translocation. Clear discrepancy between permeation activity of the peptides into cells and their interaction with lipid bilayers of liposomes indicated the limited value of the model membrane in predicting cellular peptide delivery. Cell uptake of Tat peptide was unspecific, took place either by phagocytosis or pinocytosis, and was inhibited by cell-surface glycosaminoglycans. The internalized peptides were localized in vesicles and unable to reach the cell nuclei. In conclusion, we show that Tat-related peptides enter cells on the basis of their cationic charge following different endocytosis pathways and that glycosaminoglycans on the cell surface negatively affect their uptake. This lack of specificity should be taken into account when exploiting Tat peptide as vehicle for intracellular delivery of biomacromolecules. PMID- 22100439 TI - Reductionism and complexity in nanoparticle-vectored drug targeting. AB - This paper briefly discusses reductionism as a process for dissecting the complexities of drug targeting mediated by nanoparticulate carriers. While reductionism has been said to have been a drawback to enhanced appreciation and understanding of complex biological systems, it is concluded here that the dissection of the individual stages of the procession from injection to final destination in specific targets in a living complex organism is essential. It should allow a decrease in the empiricism from laudable and inventive efforts to achieve high levels of drug delivery to specific diseased targets such as tumours. At the stage of development of the field there have perhaps been fewer than desirable detailed experimental or theoretical investigations of these individual stages. However, there are frequently analogies in the literature from which to draw at least tentative conclusions about the physics, physical chemistry and biology which underpin the processes involved. PMID- 22100440 TI - A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis - Insight into the observed synergism. AB - The synergism between low-frequency sonophoresis (LFS) and chemical penetration enhancers (CPEs), especially surfactants, in transdermal enhancement has been investigated extensively since this phenomenon was first observed over a decade ago. In spite of the identifying that the origin of this synergism is the increased penetration and subsequent dispersion of CPEs in the skin in response to LFS treatment, to date, no mechanism has been directly proposed to explain how LFS induces the observed increased transport of CPEs. In this study, we propose a plausible physical mechanism by which the transport of all CPEs is expected to have significantly increased flux into the localized-transport regions (LTRs) of LFS-treated skin. Specifically, the collapse of acoustic cavitation microjets within LTRs induces a convective flux. In addition, because amphiphilic molecules preferentially adsorb onto the gas/water interface of cavitation bubbles, amphiphiles have an additional adsorptive flux. In this sense, the cavitation bubbles effectively act as carriers for amphiphilic molecules, delivering surfactants directly into the skin when they collapse at the skin surface as cavitation microjets. The flux equations derived for CPE delivery into the LTRs and non-LTRs during LFS treatment, compared to that for untreated skin, explain why the transport of all CPEs, and to an even greater extent amphiphilic CPEs, is increased during LFS treatment. The flux model is tested with a non-amphiphilic CPE (propylene glycol) and both nonionic and ionic amphiphilic CPEs (octyl glucoside and sodium lauryl sulfate, respectively), by measuring the flux of each CPE into untreated skin and the LTRs and non-LTRs of LFS-treated skin. The resulting data shows very good agreement with the proposed flux model. PMID- 22100441 TI - Versatile cationic lipids for siRNA delivery. AB - Exploitation of the RNA interference (RNAi) pathway offers the promise of new and effective therapies for a wide variety of diseases. Clinical development of new drugs based on this platform technology is still limited, however, by a lack of safe and efficient delivery systems. Here we report the development of a class of structurally versatile cationic lipopolyamines designed specifically for delivery of siRNA which show high levels of target transcript knockdown in a range of cell types in vitro. A primary benefit of these lipids is the ease with which they may be covalently modified by the addition of functional molecules. For in vivo applications one of the core lipids (Staramine) was modified with methoxypolyethylene glycols (mPEGs) of varying lengths. Upon systemic administration, PEGylated Staramine nanoparticles containing siRNA targeting the caveolin-1 (Cav-1) transcript caused a reduction of the Cav-1 transcript of up to 60%, depending on the mPEG length, specifically in lung tissue after 48h compared to treatment with non-silencing siRNA. In addition, modification with mPEG reduced toxicity associated with intravenous administration. The ability to produce a high level of target gene knockdown in the lung with minimal toxicity demonstrates the potential of these lipopolyamines for use in developing RNAi therapeutics for pulmonary disease. PMID- 22100442 TI - Outcome of laparoscopic repair of ureteral injury: follow-up of twelve cases. AB - STUDY OBJECTIVE: To review the feasibility of laparoscopic repair in cases of ureteral injuries occurring during gynecologic laparoscopy. DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: Institution-specific retrospective review of data from a tertiary referral medical center. PATIENTS: Patients suffering from iatrogenic ureteral injuries diagnosed during or after surgery, and cases with deliberate ureteral resection and repair because of underlying disease. MEASUREMENTS AND MAIN RESULTS: We conducted a retrospective review of all (10 345) laparoscopic gynecologic surgeries performed in our institute between February 2004 and November 2008. Twelve cases (median: 45.5 years, range: 27-63) of ureter transections were diagnosed and repaired laparoscopically by endoscopists. Of these, 10 had previous surgeries, pelvic adhesions, or a large pelvic-abdominal mass. One patient had undergone a segmental resection and laparoscopic ureteroureterostomy for deep infiltrative endometriosis. Of the remaining 11 iatrogenic ureteral transections, 10 were repaired via laparoscopic ureteroureterostomy, whereas 1 had undergone a laparoscopic ureteroneocystostomy. One injury was recognized on the second postoperative day, but intraoperative recognition was attained in 11 cases. The median duration of double J stenting was 73 days. Three patients had development of strictures (between 42 and 79 days after surgery) treated with restenting, but 1 had to undergo an ureteroneocystostomy for ureter disruption when trying to restent. One patient had development of leakage of the anastomotic site but recovered with a change of the double J stent. Only 1 case required another laparotomy for ureteroneocystostomy. Laparoscopic primary repair of ureteral injury was successful for 11 of 12 patients. All the patients were well and symptom free at the conclusion of the study period. CONCLUSION: Early recognition and treatment of ureteral injuries are important to prevent morbidity. Laparoscopic ureteroureterostomy could be considered in transections of the ureter where technical expertise is available. To the best of our knowledge, this is the largest series, to date, of ureteral repairs via laparoscopy. PMID- 22100443 TI - Cost analysis of abdominal, laparoscopic, and robotic-assisted myomectomies. AB - STUDY OBJECTIVE: To perform a cost-minimization analysis of abdominal, traditional laparoscopic and robotic-assisted myomectomy. DESIGN: Cost analysis (Canadian Task Force Classification III). SETTING: Academic medical center. PATIENTS: Women undergoing myomectomy by various surgical approaches. INTERVENTIONS: We developed a decision model to compare the costs ($2009) of different approaches to myomectomy from a healthcare system perspective. The model included operative time, conversion risk, transfusion risk, and length of stay (LOS) for each modality. Baseline estimates and ranges were based on reported values extracted from existing literature. We analyzed two different models: #1) Existing Robot model and #2) Robot Purchase model. MEASUREMENTS AND MAIN RESULTS: In the baseline analysis for the Existing Robot model, abdominal myomectomy (AM) was the least expensive at $4937 compared with laparoscopic myomectomy (LM) at $6219 and robotic-assisted laparoscopic myomectomy (RM) at $7299. The abdominal route remained the least expensive when varying all parameters and costs except for two cases in which LM became least expensive: 1) If AM length of stay was greater than 4.6 days, and 2) If the surgeon's fee for AM was greater than $2410. When comparing LM to RM, the cost of RM was consistently higher unless the robotic disposable equipment costs were less than $1400. In the Robot Purchase model, only the RM costs increased while AM and LM costs remained the same. CONCLUSION: In this cost-minimization analysis, abdominal myomectomy is the least expensive approach when compared to laparoscopy and robotic-assisted laparoscopy. PMID- 22100444 TI - Polaprezinc prevents ongoing thioacetamide-induced liver fibrosis in rats. AB - AIMS: Cirrhotic patients commonly have a liver zinc deficiency, which may aggravate liver fibrosis due to the lack of antioxidative effects of zinc. This study examined the ability of polaprezinc, N-(3-aminopropionyl)-l-histidinato zinc, to prevent fibrosis in a rat model of thioacetamide (TAA)-induced hepatic fibrosis. MAIN METHODS: Liver cirrhosis was induced by orally administering TAA for 20 weeks. The rats were cotreated with one of the following for the last 10 weeks of TAA treatment: (1) polaprezinc (50 or 200mg/kg/day); (2) l-carnosine (155 mg/kg/day), which contained equal amounts of l-carnosine as 200mg/kg/day polaprezinc; (3) zinc sulfate (112 mg/kg/day) or (4) zinc-l-aspartic complex (317.8 mg/kg/day). Both zinc supplementations contained equal amounts of zinc as high-dose polaprezinc. KEY FINDINGS: Hepatic zinc levels fell significantly in rats treated with TAA for 20 weeks. Cotreating with high-dose polaprezinc and zinc-l-aspartic complex for 10 weeks prevented hepatic zinc loss. Hepatic hydroxyproline and tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly higher in rats treated with TAA for 20 weeks than 10 weeks, whereas polaprezinc prevented changes in these fibrosis markers and reduced hepatic transforming growth factor-beta1 protein concentration, macroscopic and histologic changes. TAA caused oxidative stress-related changes in the liver that were prevented by high-dose polaprezinc and partially by zinc-l-aspartic complex. Treatment with l-carnosine, low-dose polaprezinc or zinc sulfate for 10 weeks did not affect liver fibrosis progression or oxidative stress-related changes. SIGNIFICANCE: Polaprezinc may prevent ongoing fibrosis by preventing zinc depletion, oxidative stress and fibrosis markers in cirrhotic livers. PMID- 22100445 TI - Loss of activity-dependent Arc gene expression in the retrosplenial cortex after hippocampal inactivation: interaction in a higher-order memory circuit. AB - The rodent hippocampus is well known for its role in spatial navigation and memory, and recent evidence points to the retrosplenial cortex (RSC) as another element of a higher order spatial and mnemonic circuit. However, the functional interplay between hippocampus and RSC during spatial navigation remains poorly understood. To investigate this interaction, we examined cell activity in the RSC during spatial navigation in the water maze before and after acute hippocampal inactivation using expression of two immediate-early genes (IEGs), Arc and Homer 1a (H1a). Adult male rats were trained in a spatial water maze task for 4 days. On day 5, the rats received two testing/training sessions separated by 20 min. Eight minutes before the second session, different groups of rats received bilateral intrahippocampal infusion of tetrodotoxin (TTX), muscimol (MUS), or vehicle. Another group of rats (uni-TTX) received infusion of TTX in one hippocampus and vehicle in the other. Signals from Arc and H1a RNA probes correspond to the post- and pre-infusion sessions, respectively. Bilateral TTX and MUS impaired spatial memory, as expected, and decreased Arc expression in CA1 of hippocampus. Importantly, bilateral inactivation of hippocampus resulted in loss of behavior-induced Arc expression in RSC. Despite a lateralized effect in CA1, Arc expression was equivalently and bilaterally decreased in RSC of uni-TTX rats, consistent with a network level interaction between hippocampus and RSC. We conclude that the loss of hippocampal input alters activity of RSC neurons and compromises their ability to engage plastic processes dependent on IEG expression. PMID- 22100446 TI - Socio-demographics and the development of malaria elimination strategies in the low transmission setting. AB - This analysis presents a comprehensive description of malaria burden and risk factors in Peruvian Amazon villages where malaria transmission is hypoendemic. More than 9000 subjects were studied in contrasting village settings within the Department of Loreto, Peru, where most malaria occurs in the country. Plasmodium vivax is responsible for more than 75% of malaria cases; severe disease from any form of malaria is uncommon and death rare. The association between lifetime malaria episodes and individual and household covariates was studied using polychotomous logistic regression analysis, assessing effects on odds of some vs. no lifetime malaria episodes. Malaria morbidity during lifetime was strongly associated with age, logging, farming, travel history, and living with a logger or agriculturist. Select groups of adults, particularly loggers and agriculturists acquire multiple malaria infections in transmission settings outside of the main domicile, and may be mobile human reservoirs by which malaria parasites move within and between micro-regions within malaria endemic settings. For example, such individuals might well be reservoirs of transmission by introducing or reintroducing malaria into their home villages and their own households, depending on vector ecology and the local village setting. Therefore, socio-demographic studies can identify people with the epidemiological characteristic of transmission risk, and these individuals would be prime targets against which to deploy transmission blocking strategies along with insecticide treated bednets and chemoprophylaxis. PMID- 22100447 TI - Protein hot spots: the islands of stability. AB - Understanding the structural basis of protein-protein interactions (PPIs) may shed light on the organization and functioning of signal transduction and metabolic networks and may assist in structure-based design of ligands (drugs) targeting protein-protein interfaces. The residues at the bimolecular interface, designated as the hot spots, contribute most of the free binding energy of PPI. To date, there is no conclusive atomistic explanation for the unique functional properties of the hot spots. We hypothesized that backbone compliance may play a role in protein-protein recognition and in the mechanism of binding of small molecule compounds to protein surfaces. We used a steered molecular dynamics simulation to explore the compliance properties of the backbone of surface exposed residues in several model proteins: interleukin-2, mouse double minute protein 2 and proliferating cell nuclear antigen. We demonstrated that protein surfaces exhibit distinct patterns in which highly immobile residues form defined clusters ("stability patches") alternating with areas of moderate to high mobility. These "stability patches" tend to localize in functionally important regions involved in protein-protein recognition. We propose a mechanism by which the distinct structural organization of the hot spots may contribute to their role in mediating PPI and facilitating binding of structurally diverse small molecule compounds to protein surfaces. PMID- 22100448 TI - A Bayesian view on cryo-EM structure determination. AB - Three-dimensional (3D) structure determination by single-particle analysis of cryo-electron microscopy (cryo-EM) images requires many parameters to be determined from extremely noisy data. This makes the method prone to overfitting, that is, when structures describe noise rather than signal, in particular near their resolution limit where noise levels are highest. Cryo-EM structures are typically filtered using ad hoc procedures to prevent overfitting, but the tuning of arbitrary parameters may lead to subjectivity in the results. I describe a Bayesian interpretation of cryo-EM structure determination, where smoothness in the reconstructed density is imposed through a Gaussian prior in the Fourier domain. The statistical framework dictates how data and prior knowledge should be combined, so that the optimal 3D linear filter is obtained without the need for arbitrariness and objective resolution estimates may be obtained. Application to experimental data indicates that the statistical approach yields more reliable structures than existing methods and is capable of detecting smaller classes in data sets that contain multiple different structures. PMID- 22100449 TI - Crystal structure of Sol I 2: a major allergen from fire ant venom. AB - Sol i 2 is a potent allergen from the venom of red imported fire ant, which contains allergens Sol i 1, Sol i 2, Sol i 3, and Sol i 4 that are known to be powerful triggers of anaphylaxis. Sol i 2 causes IgE antibody production in about one-third of individuals stung by fire ants. Baculovirus recombinant dimeric Sol i 2 was crystallized as a native and selenomethionyl-derivatized protein, and its structure has been determined by single-wavelength anomalous dispersion at 2.6 A resolution. The overall fold of each subunit consists of five helices that enclose a central hydrophobic cavity. The structure is stabilized by three intramolecular disulfide bridges and one intermolecular disulfide bridge. The nearest structural homologue is the sequence-unrelated odorant binding protein and pheromone binding protein LUSH of the fruit fly Drosophila, which may suggest a similar biological function. To test this hypothesis, we measured the reversible binding of various pheromones, plant odorants, and other ligands to Sol i 2 by the changes in N-phenyl-1-naphthylamine fluorescence emission upon binding of ligands that compete with N-phenyl-1-naphthylamine. The highest binding affinity was observed for hydrophobic ligands such as aphid alarm pheromone (E)-beta-farnesene, analogs of ant alarm pheromones, and plant volatiles decane, undecane, and beta-caryophyllene. Conceivably, Sol i 2 may play a role in capturing and/or transporting small hydrophobic ligands such as pheromones, odors, fatty acids, or short-living hydrophobic primers. Molecular surface analysis, in combination with sequence alignment, can explain the serological cross-reactivity observed between some ant species. PMID- 22100450 TI - UHRF1 double tudor domain and the adjacent PHD finger act together to recognize K9me3-containing histone H3 tail. AB - Human multi-domain-containing protein UHRF1 has recently been extensively characterized as a key epigenetic regulator for maintaining DNA methylation patterns. UHRF1 SRA domain preferentially binds to hemimethylated CpG sites, and double Tudor domain has been implicated in recognizing H3K9me3 mark, but the role of the adjacent PHD finger remains unclear. Here, we report the high-resolution crystal structure of UHRF1 PHD finger in complex with N-terminal tail of histone H3. We found that the preceding zinc-Cys4 knuckle is indispensable for the PHD finger of UHRF1 to recognize the first four unmodified residues of histone H3 N terminal tail. Quantitative binding studies indicated that UHRF1 PHD finger (including the preceding zinc-Cys4 knuckle) acts together with the adjacent double Tudor domain to specifically recognize the H3K9me3 mark. Combinatorial recognition of H3K9me3-containing histone H3 tail by UHRF1 PHD finger and double Tudor domain may play a role in establishing and maintaining histone H3K9 methylation patterns during the cell cycle. PMID- 22100451 TI - Crystallographic evidence for a domain motion in rat nucleoside triphosphate diphosphohydrolase (NTPDase) 1. AB - Nucleoside triphosphate diphosphohydrolases (NTPDases) are a physiologically important class of membrane-bound ectonucleotidases responsible for the regulation of extracellular levels of nucleotides. CD39 or NTPDase1 is the dominant NTPDase of the vasculature. By hydrolyzing proinflammatory ATP and platelet-activating ADP to AMP, it blocks platelet aggregation and supports blood flow. Thus, great interest exists in understanding the structure and dynamics of this prototype member of the eukaryotic NTPDase family. Here, we report the crystal structure of a variant of soluble NTPDase1 lacking a putative membrane interaction loop identified between the two lobes of the catalytic domain. ATPase and ADPase activities of this variant are determined via a newly established kinetic isothermal titration calorimetry assay and compared to that of the soluble NTPDase1 variant characterized previously. Complex structures with decavanadate and heptamolybdate show that both polyoxometallates bind electrostatically to a loop that is involved in binding of the nucleobase. In addition, a comparison of the domain orientations of the four independent proteins in the crystal asymmetric unit provides the first direct experimental evidence for a domain motion of NTPDases. An interdomain rotation angle of up to 7.4 degrees affects the active site cleft between the two lobes of the protein. Comparison with a previously solved bacterial NTPDase structure indicates that the domains may undergo relative rotational movements of more than 20 degrees . Our data support the idea that the influence of transmembrane helix dynamics on activity is achieved by coupling to a domain motion. PMID- 22100452 TI - Structural basis for activation of calcineurin by calmodulin. AB - The highly conserved phosphatase calcineurin (CaN) plays vital roles in numerous processes including T-cell activation, development and function of the central nervous system, and cardiac growth. It is activated by the calcium sensor calmodulin (CaM). CaM binds to a regulatory domain (RD) within CaN, causing a conformational change that displaces an autoinhibitory domain (AID) from the active site, resulting in activation of the phosphatase. This is the same general mechanism by which CaM activates CaM-dependent protein kinases. Previously published data have hinted that the RD of CaN is intrinsically disordered. In this work, we demonstrate that the RD is unstructured and that it folds upon binding CaM, ousting the AID from the catalytic site. The RD is 95 residues long, with the AID attached to its C-terminal end and the 24-residue CaM binding region toward the N-terminal end. This is unlike the CaM-dependent protein kinases that have CaM binding sites and AIDs immediately adjacent in sequence. Our data demonstrate that not only does the CaM binding region folds but also an ~25- to 30-residue region between it and the AID folds, resulting in over half of the RD adopting alpha-helical structure. This appears to be the first observation of CaM inducing folding of this scale outside of its binding site on a target protein. PMID- 22100453 TI - Altered strand transfer activity of a multiple-drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutant with a dipeptide fingers domain insertion. AB - Prolonged highly active anti-retroviral therapy with multiple nucleoside reverse transcriptase inhibitors for the treatment of patients infected with human immunodeficiency virus type 1 (HIV-1) can induce the development of an HIV-1 reverse transcriptase (RT) harboring a dipeptide insertion at the RT fingers domain with a background thymidine analog mutation. This mutation renders viral resistance to multiple nucleoside reverse transcriptase inhibitors. We investigated the effect of the dipeptide fingers domain insertion mutation on strand transfer activity using two clinical RT variants isolated during the pre treatment and post-treatment of an infected patient, termed pre-drug RT without dipeptide insertion and post-drug RT with Ser-Gly insertion, respectively. First, the post-drug RT displayed elevated strand transfer activity compared to the pre drug RT, with two different RNA templates. Second, the post-drug RT exhibited less RNA template degradation than the pre-drug RT but higher polymerization dependent RNase H activity. Third, the post-drug RT had a faster association rate (k(on)) for template binding and a lower equilibrium binding constant K(d) for the template, leading to a template binding affinity tighter than that of the pre drug RT. The k(off) values for the pre-drug RT and the post-drug RT were similar. Finally, the removal of the dipeptide insertion from the post-drug RT abolished the elevated strand transfer activity and RNase H activity, in addition to the loss of azidothymidine resistance. These biochemical data suggest that the dipeptide insertion elevates strand transfer activity by increasing the interaction of the RT with the RNA donor template, promoting cleavage that generates more invasion sites for the acceptor template during DNA synthesis. PMID- 22100454 TI - Oral granuloma formation after injection of cosmetic filler. AB - The increased use of orofacial fillers in cosmetic procedures has led to new diagnostic challenges for dentists and oral pathologists. Here, we describe a case with multiple oral foreign body granulomas, which were formed after a polymethylmetacrylate injection for cosmetic purposes. PMID- 22100455 TI - Changes in cortical activation in craniomandibular disorders during splint therapy - a single subject fMRI study. AB - There is some controversial discussion within the therapy of craniomandibular disorders (CMDs) about the mode of action of occlusal splints. Here we present a case report on one CMD-patient measuring cerebral activation changes with functional magnetic resonance imaging (fMRI) before and after therapy with a stabilization splint. Wearing the Michigan splint for 11 nights and partially days resulted in substantial pain relief and changes in occlusal movement performance. Cerebral activation during occlusion was decreased after therapy (PRE-POST) in bilateral sensorimotor regions but also additional areas such as left posterior insula, right superior temporal cortex and bilateral occipital lobe. During the first usage of the splint in the scanner (PRE) increased activation in the left dorsolateral prefrontal lobe (BA 9) was observed. After splint training occlusion with the splint compared to without a splint increasingly involved the left superior parietal lobe (BA 7, POST). Whereas BA 9 might be associated with increasing working memory load due to the manipulation with an unusual object, the BA 7 activation in the POST session might document increased sensorimotor interaction after getting used to the splint. Our findings indicate that wearing an occlusion splint triggers activation in parietal sensorimotor integration areas, also observed after long periods of sensorimotor training. These additional recourses might improve coordination and physiological handling of the masticatory system. PMID- 22100456 TI - A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: rationale and recommendations for implementation. PMID- 22100457 TI - Fluoxetine has neuroprotective effects after cardiac arrest and cardiopulmonary resuscitation in mouse. AB - AIMS: Fluoxetine, a selective serotonin reuptake inhibitor, is protective in a rat focal ischaemia model via anti-inflammatory mechanisms. Cardiac arrest and cardiopulmonary resuscitation (CA/CPR) were performed in mice to test the hypothesis that fluoxetine protects the brain following global cerebral ischaemia, even when administered after an insult. METHODS: Global cerebral ischaemia was induced with 8 min CA/CPR in C57BL/6 male mice. Thirty minutes after recovery of spontaneous circulation, the mice were randomly assigned into 3 groups and administered fluoxetine; fluoxetine (5 mg/kg: n=15, 10 mg/kg: n=15) or vehicle (NaCl: n=15). Three days after CA/CPR, sensorimotor evaluations were conducted and brains were removed for histological evaluation of the hippocampus and caudate putamen. RESULTS: Analysis of histological damage 72 h after resuscitation revealed that low dose fluoxetine (5 mg/kg) did not protect, while high dose (10 mg/kg) fluoxetine protected neurons in the caudate putamen. In contrast, there were no protective effects in the hippocampus at either dose. In agreement with histological observations of neuronal damage in the caudate putamen, high dose fluoxetine decreased sensorimotor deficits following CA/CPR compared to vehicle-treated animals. CONCLUSIONS: Our data showed that 10mg/kg fluoxetine administered following global cerebral ischaemia decreases neuronal damage. Although long-term neuroprotection needs further study, the results of our study suggest that fluoxetine may have therapeutic potential when administered after global cerebral ischaemia, cardiac arrest and cardiopulmonary resuscitation. PMID- 22100458 TI - Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. AB - Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity. PMID- 22100459 TI - Floral reversion mechanism in longan (Dimocarpus longan Lour.) revealed by proteomic and anatomic analyses. AB - Two-dimensional gel electrophoresis (2-DE) was used to analyze the proteins related to floral reversion in Dimocarpus longan Lour. Proteins were extracted from buds undergoing the normal process of flowering and from those undergoing floral reversion in three developing stages in D. longan. Differentially expressed proteins were identified from the gels after 2-DE analysis, which were confirmed using matrix-assisted laser desorption/ionization-time of flying-mass spectroscopy and protein database search. A total of 39 proteins, including 18 up regulated and 21 down-regulated proteins, were classified into different categories, such as energy and substance metabolism, protein translation, secondary metabolism, phytohormone, cytoskeleton structure, regulation, and stress tolerance. Among these, the largest functional class was associated with primary metabolism. Down-regulated proteins were involved in photosynthesis, transcription, and translation, whereas up-regulated proteins were involved in respiration. Decreased flavonoid synthesis and up-regulated GA20ox might be involved in the floral reversion process. Up-regulated 14-3-3 proteins played a role in the regulation of floral reversion in D. longan by responding to abiotic stress. Observations via transmission electron microscopy revealed the ultrastructure changes in shedding buds undergoing floral reversion. Overall, the results provided insights into the molecular basis for the floral reversion mechanism in D. longan. PMID- 22100460 TI - Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury. AB - Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-beta mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation. PMID- 22100461 TI - Multiple regulatory roles of the carboxy terminus of Ste2p a yeast GPCR. AB - Signaling and internalization of Ste2p, a model G protein-coupled receptor (GPCR) from the yeast Saccharomyces cerevisiae, are reported to be regulated by phosphorylation status of serine (S) and threonine (T) residues located in the cytoplasmic C-terminus. Although the functional roles of S/T residues located in certain C-terminus regions are relatively well characterized, systemic analyses have not been conducted for all the S/T residues that are spread throughout the C terminus. A point mutation to alanine was introduced into the S/T residues located within three intracellular loops and the C-terminus individually or in combination. A series of functional assays such as internalization, FUS1-lacZ induction, and growth arrest were conducted in comparison between WT- and mutant Ste2p. The Ste2p in which all S/T residues in the C-terminus were mutated to alanine was more sensitive to alpha-factor, suggesting that phosphorylation in the C-terminus exerts negative regulatory activities on the Ste2p signaling. C terminal S/T residues proximal to the seventh transmembrane domain were important for ligand-induced G protein coupling but not for receptor internalization. Sites on the central region of the C-terminus regulated both constitutive and ligand induced internalization. Residues on the distal part were important for constitutive desensitization and modulated the G protein signaling mediated through the proximal part of the C-terminus. This study demonstrated that the C terminus contains multiple functional domains with differential and interdependent roles in regulating Ste2p function in which the S/T residues located in each domain play critical roles. PMID- 22100462 TI - The effect of traditional bridging or suspension-exercise bridging on lateral abdominal thickness in individuals with low back pain. AB - CONTEXT: Individuals with low back pain (LBP) are thought to benefit from interventions that improve motor control of the lumbopelvic region. It is unknown if therapeutic exercise can acutely facilitate activation of lateral abdominal musculature. OBJECTIVE: To investigate the ability of 2 types of bridging exercise progressions to facilitate lateral abdominal muscles during an abdominal drawing-in maneuver (ADIM) in individuals with LBP. DESIGN: Randomized control trial. SETTING: University research laboratory. PARTICIPANTS: 51 adults (mean +/- SD age 23.1 +/- 6.0 y, height 173.6 +/- 10.5 cm, mass 74.7 +/- 14.5 kg, and 64.7% female) with LBP. All participants met 3 of 4 criteria for stabilization classification LBP or at least 6 best-fit criteria for stabilization classification. INTERVENTIONS: Participants were randomly assigned to either traditional-bridge progression or suspension-exercise-bridge progression, each with 4 levels of progressive difficulty. They performed 5 repetitions at each level and were progressed based on specific criteria. MAIN OUTCOME MEASURES: Muscle thickness of the external oblique (EO), internal oblique (IO), and transversus abdominis (TrA) was measured during an ADIM using ultrasound imaging preintervention and postintervention. A contraction ratio (contracted thickness:resting thickness) of the EO, IO, and TrA was used to quantify changes in muscle thickness. RESULTS: There was not a significant increase in EO (F1,47 = 0.44, P = .51) or IO (F1,47 = .30, P = .59) contraction ratios after the exercise progression. There was a significant (F1,47 = 4.05, P = .05) group-by-time interaction wherein the traditional-bridge progression (pre = 1.55 +/- 0.22; post = 1.65 +/- 0.21) resulted in greater (P = .03) TrA contraction ratio after exercise than the suspension-exercise-bridge progression (pre = 1.61 +/- 0.31; post = 1.58 +/- 0.28). CONCLUSION: A single exercise progression did not acutely improve muscle thickness of the EO and IO. The magnitude of change in TrA muscle thickness after the traditional-bridging progression was less than the minimal detectable change, thus not clinically significant. PMID- 22100463 TI - Incidence of tricyclic antidepressant-like complications after cyclobenzaprine overdose. PMID- 22100464 TI - Pulmonary cavitation in a patient presenting with nonspecific complaints. AB - Most commonly, patients with pulmonary embolism present with dyspnea, chest pain, and/or tachypnea to the emergency department (ED). The presence of multiple suggestive symptoms, especially when severe, significantly reduces delay in diagnosis. We report a case of an 86-year-old patient presenting to the ED with nonspecific complaints: she claimed to feel lethargic and "reluctant to prepare meals." She did not complain of either dyspnea or chest pain. As underlying cause, an intrapulmonary cavitation with pulmonary embolism was found. The combination of absence of specific symptoms regarding pulmonary embolism and radiologic findings of an obstructed pulmonary artery supplying the cavitary lung segment is rare. Common etiologies of cavitary lung processes are discussed, and risk factors of pulmonary infarction are highlighted. PMID- 22100465 TI - Too good to be true? Our experience with the Cunningham method of dislocated shoulder reduction. PMID- 22100466 TI - The impact of an ED-only full-capacity protocol. AB - OBJECTIVE: The objective of this study was to assess the impact of an emergency department (ED)-only full-capacity protocol and diversion, controlling for patient volumes and other potential confounding factors. METHODS: This was a preintervention and postintervention cohort study using data 12 months before and 12 months after the implementation of the protocol. During the implementation period, attending physicians and charge nurses were educated with clear and simple figures on the criteria for the initiation of the new protocol. A multiple logistic regression model was used to compare ambulance diversion between the 2 periods. RESULTS: The proportion of days when the ED went on diversion at least once during a 24-hour period was 60.4% during the preimplementation period and 20% in the postimplementation periods (P < .001). In the multivariate logistic regression model, the use of the new protocol was significantly associated with decreased odds of diversion rate in the postimplementation period (odds ratio, 0.32; 95% confidence interval, 0.21-0.48). CONCLUSION: Our predivert/full capacity protocol is a simple and generalizable strategy that can be implemented within the boundaries of the ED and is significantly associated with a decreased diversion rate. PMID- 22100467 TI - Cardiovascular emergencies related to the Xynthia storm. PMID- 22100468 TI - The effect of bedside ultrasound on diagnosis and management of soft tissue infections in a pediatric ED. AB - BACKGROUND: Presentation of skin and soft tissue infections (SSTIs) to the pediatric emergency department (PED) has increased. Physical examination alone can be inadequate in differentiating cellulitis from an abscess. The purposes of this study were to determine the effect of bedside ultrasound (US) in improving diagnostic accuracy for SSTIs in the PED and to evaluate its effect on the management of patients with SSTIs. METHODS: We conducted a prospective study of a convenience sample of children who presented to an inner-city PED with signs and symptoms of SSTI. The treating physician's pretest opinions regarding the need for incision and drainage and procedural sedation were collected. A bedside US was performed by trained PED physicians to evaluate for cellulitis vs abscess. The treating physician was made aware of the US findings, and the effect on management was recorded. RESULTS: Sixty-five patients were enrolled, of whom 47 had US-proven abscess and 18 had cellulitis. The sensitivity of US for detection of abscess was 97.5% (95% confidence interval [CI], 90.1%-99.5%), and the specificity was 69.2% (95% CI, 57.8-72.4%). In comparison, the sensitivity for physical examination alone for detection of abscess was 78.7% (95% CI, 71.4% 84.4%), and the specificity was 66.7% (95% CI, 47.6-81.6%). Ultrasound disagreed with clinical examination and changed management in 9 (13.8%) of 65 patients. CONCLUSIONS: Emergency department bedside US improves accuracy in diagnosis of SSTIs. Bedside US changes management in a small but significant number of patients with SSTIs. PMID- 22100469 TI - Small-volume resuscitation from hemorrhagic shock with polymerized human serum albumin. AB - Human serum albumin (HSA) is used as a plasma expander; however, albumin is readily eliminated from the intravascular space. The objective of this study was to establish the effects of various-sized polymerized HSAs (PolyHSAs) during small-volume resuscitation from hemorrhagic shock on systemic parameters, microvascular hemodynamics, and functional capillary density in the hamster window chamber model. Polymerized HSA size was controlled by varying the cross link density (ie, molar ratio of glutaraldehyde to HSA). Hemorrhage was induced by controlled arterial bleeding of 50% of the animal's blood volume (BV), and hypovolemic shock was maintained for 1 hour. Resuscitation was implemented in 2 phases, first, by infusion of 3.5% of the BV of hypertonic saline (7.5% NaCl) then followed by infusion of 10% of the BV of each PolyHSA. Resuscitation provided rapid recovery of blood pressure, blood gas parameters, and microvascular perfusion. Polymerized HSA at a glutaraldehyde-to-HSA molar ratio of 60:1 (PolyHSA(60:1)) provided superior recovery of blood pressure, microvascular blood flow, and functional capillary density, and acid-base balance, with sustained volume expansion in relation to the volume infused. The high molecular weight of PolyHSA(60:1) increased the hydrodynamic radius and solution viscosity. Pharmacokinetic analysis of PolyHSA(60:1) indicates reduced clearance and increased circulatory half-life compared with monomeric HSA and other PolyHSA formulations. In conclusion, HSA molecular size and solution viscosity affect central hemodynamics, microvascular blood flow, volume expansion, and circulation persistence during small-volume resuscitation from hemorrhagic shock. In addition, PolyHSA can be an alternative to HSA in pathophysiological situations with compromised vascular permeability. PMID- 22100470 TI - Prevalence of validated risk factors for developing atrial fibrillation--can we identify high-risk ED patients? AB - OBJECTIVE: The aim of this study was to investigate whether emergency department (ED) patients who were newly diagnosed with atrial fibrillation (AF) displayed risk factors for incident AF on prior ED visits. METHODS: This was a secondary analysis of a retrospective cohort study of ED patients with symptomatic AF at a tertiary referral center. We selected patients who were newly diagnosed with AF between July 1, 2005, and August 31, 2008, and had at least 1 ED visit before their diagnosis. We calculated the Framingham Heart Study AF risk score for each visit by documenting the presence of the risk factors (age, sex, body mass index, systolic blood pressure, hypertension treatment, PR interval, and ages of clinically significant cardiac murmur and heart failure diagnosis). RESULTS: Of the 296 patients newly diagnosed with AF, 115 (39%) had at least 1 prior ED visit resulting in 454 ED visits for analysis. The median time from first to last visit was 4 years (interquartile range [IQR], 2.1-5.9). The median age was 66 years (IQR, 49-79 years). Home medications included antihypertensives in 81% of visits, and 60% of visits with available electrocardiograms had a PR interval of 160 milliseconds or more. Heart failure history was reported in 23% of visits. The median AF risk score was 8 (IQR, 4-10) corresponding to a 16% 10-year predicted risk. CONCLUSIONS: Nearly 40% of patients diagnosed with new AF had previous ED visits and displayed validated risk factors for incident AF. The ED provides an opportunity to identify and educate these patients as well as refer them for primary prevention interventions. PMID- 22100471 TI - A "summertime differential diagnosis" of elevated cardiac troponin. PMID- 22100472 TI - Effects of terlipressin in a rat model of severe uncontrolled hemorrhage via liver injury. AB - BACKGROUND: Animal experiments and clinical studies have shown that vasopressin infusion in cases of uncontrolled hemorrhagic shock is a promising treatment. However, there are only a few studies regarding the application of terlipressin in hemorrhagic cases. This study was designed to evaluate the effects of terlipressin vs controlled fluid resuscitation on hemodynamic variables and abdominal bleeding in a rat model of uncontrolled hemorrhage via liver injury. METHODS: A total of 21 average weight 250 +/- 30 g Wistar rats were used. A midline celiotomy was performed, and approximately 65% of the median and left lateral lobes were removed with sharp dissection. After creation of the liver injury, rats were randomized into 1 of 3 resuscitation groups, the control group, Lactated Ringer's (LR) group, and terlipressin group, with 7 rats in each group. Blood samples were taken from rats for arterial blood gas analysis. At the end of the experiments, free intraperitoneal blood was collected on preweighed pieces of cotton, and the amount of free blood was determined by the difference in wet and dry weights. RESULTS: In response to resuscitation, the terlipressin group demonstrated a significant elevation in mean arterial pressure (MAP). Blood loss was greater in the LR group compared with the control group (12.8 +/- 1.9 mL vs 8.2 +/- 0.7 mL, P < .05). At the end of the experiments, 5 rats in the control group, 5 in the LR group, and 2 in the terlipressin group died. The average survival rates were 28.6%, 28.6%, and 71.4%, respectively. CONCLUSIONS: Compared with the control group, intravenous terlipressin bolus after liver injury contributed to an increase in MAP and survival rates without increasing abdominal bleeding. PMID- 22100473 TI - The use of mechanical ventilation in the ED. AB - OBJECTIVES: Although EDs are responsible for the initial care of critically ill patients and the amount of critical care provided in the ED is increasing, there are few data examining mechanical ventilation (MV) in the ED. In addition, characteristics of ED-based ventilation may affect planning for ventilator shortages during pandemic influenza or bioterrorist events. The study examined the epidemiology of MV in US EDs, including demographic, clinical, and hospital characteristics; indications for MV; ED length of stay (LOS); and in-hospital mortality. METHODS: This study was a retrospective review of the 1993 to 2007 National Hospital Ambulatory Medical Care Survey ED data sets. Ventilated patients were compared with ED patients admitted to the intensive care unit (ICU) and to all other ED visits. RESULTS: There were 3.6 million ED MV visits (95% confidence interval [CI], 3.2-4.0 million) over the study period. Sex, age, race, and payment source were similar for mechanically ventilated and ICU patients (P > .05 for all). Approximately 12.5% of ventilated patients underwent cardiopulmonary resuscitation compared with 1.7% of ICU admissions and 0.2% of all other ED visits (P < .0001). Accordingly, in-hospital mortality was significantly higher for ventilated patients (24%; 95% CI, 13.1%-34.9%) than both comparison groups (9.3% and 2.5%, respectively). Median LOS for ventilated patients was 197 minutes (interquartile range, 112-313 minutes) compared with 224 minutes for ICU admissions and 140 minutes for all other ED visits. CONCLUSIONS: Patients undergoing ED MV have particularly high in-hospital mortality rates, but their ED LOS is sufficient for implementation of evidence-based ventilator interventions. PMID- 22100474 TI - Should creatine kinase-MB index be eliminated in patients with indeterminate troponins in the ED? AB - OBJECTIVES: The objective of this study is to determine whether creatine kinase MB (CK-MB) index (CK-MBi) is useful in the evaluation of acute myocardial infarction (AMI) in patients with indeterminate troponin (Tn) in the emergency department (ED). METHODS: A retrospective cohort study was conducted of patients at an urban academic ED with over 55 000 annual visits who underwent Tn T (Roche, Indianapolis, IN) and CK-MB testing. One year of ED patients who had Tn testing were identified, and their corresponding CK-MBi was examined to find patients with indeterminate Tn (0.01-0.09) and positive CK-MBi (>6.0). Subsequent cardiac enzymes and hospital course were reviewed to identify patients diagnosed with AMI. A 95% confidence interval around point estimates were used in data analysis. RESULTS: Over 1 year, 11 718 initial Tn were identified. Indeterminate Tn was seen in 2512 cases. Of these, 28 had positive CK-MBi. Of the 28, 5 were judged by treating physicians to be having AMI and underwent cardiac catheterization. Of the 5 patients, 4 had subsequent positive Tns on serial enzyme testing. One of the patients thought to be having AMI had no coronary artery disease on catheterization. The rate of true positive CK-MBi with indeterminate Tn was 0.16% (95% confidence interval, 0.04%-0.41%). CONCLUSION: Initial results identify rare cases of AMI where CK-MBi is positive in the setting of indeterminate Tn. However, most patients with indeterminate Tn and positive CK-MBi were not judged to be having AMI. In most cases, CK-MBi is not positive with indeterminate Tn and when positive more commonly confuses the picture. This suggests CK-MBi could be eliminated in patients with indeterminate Tns. PMID- 22100475 TI - Severe hypercalcemia in nonobstructive pyelonephritis with acute renal failure: hit or miss? AB - Severe hypercalcemia in the course of renal failure is quite unusual. If unrecognized, irreversible inexorable attrition of renal function takes place, carrying a substantial morbidity and mortality. In particular, acute nonobstructive pyelonephritis is barely considered in the primary differential diagnosis of renal failure. Without urinary obstruction, kidney hypoperfusion, or exposure to nephrotoxic agents, a significant decline in glomerular filtration rate generally does not occur. We report a case with severe hypercalcemia after acute renal failure caused by fulminating bacterial pyelonephritis. To obviate unnecessary intervention, preserve organ function, and achieve better outcomes, clinicians should not miss this entity. PMID- 22100476 TI - Acute kidney injury from bilateral ureteral calcium stones in the setting of primary hyperparathyroidism. PMID- 22100477 TI - An unusual presentation of bee sting: subarachnoid hemorrhagia. AB - A person consists of a variety of immune reactions as a result of bee stings, depending on his/her immunologic structure. A 49-year-old male patient was brought to the emergency department because of generalized tonic clonic seizure and loss of consciousness after an hour of wild bee bite from the anterior abdomen in a rural area. After cardiopulmonary resuscitation, he was admitted to intensive care unit. Although cranial computed tomography taken in the emergency department was normal, control cranial computed tomography at the 36th hour after admission was consisted with subarachnoid hemorrhagia (SAH). The patient was diagnosed as SAH due to exposure to bee stings. The patient was treated for a month in an intensive care unit and discharged in a vegetative state. We present and discuss the case that had epileptic seizures and SAH after a bee bite, with the review of the literature. PMID- 22100478 TI - Icatibant: a novel approach to the treatment of angioedema related to the use of angiotensin-converting enzyme inhibitors. AB - Angioedema related to the use of angiotensin-converting enzyme inhibitors (AE ACEi) has, so far, been treated with antiallergic drugs with questionable results. Because angioedema in this setting is likely related to increased levels of bradikinin, we decided to use icatibant, a bradikinin receptor antagonist licensed for use in hereditary angioedema, in a patient with AE-ACEi. In the same patient, the time to resolution of the angioedema during previous attacks was about 2 days when classic antiallergic drug regimens were used; when icatibant was used, this time shortened to 10 hours. Icatibant is a promising drug in the treatment of AE-ACEi. PMID- 22100479 TI - Heart blockage in a patient with cavitary lung lesions. AB - Cavitary lesions on a chest radiograph can be the manifestations of various diseases. The etiologies include abscess, mycobacterial infections, fungal infections, parasite infection, cavitary tumors, septic pulmonary embolism and vasculitis. While in comparison with the causes that could simultaneously develop a complete heart block, the differential diagnosis is limited. A 43-year-old man presented to the emergency department with a two-week history of dry cough, chest tightness and presyncopal symptoms.A chest radiograph showed patchy opacities in both lower lungs. A computed tomography of the chest revealed cavitary lesions bilaterally. The electrocardiogram showed a complete atrioventricular block. He was later diagnosed with Wegener's granulomatosis that involved nose, lung and heart. Cardiac involvements are not rare in Wegener's granulomatosis, but are not usually clinically apparent. A complete atrioventricular block is a rare but treatable manifestation of cardiac involvement usually indicating early active systemic disease. Patients presenting with cardiac abnormalities and evidence of systemic inflammation should be screened for Wegener's by history, radiographic and laboratory assessment. PMID- 22100480 TI - A novel approach to confirming nasogastric tube placement in the ED. AB - We present a case of 2-dimensional ultrasound-assisted confirmation of nasogastric tube (NGT) placement using both soft tissue neck and epigastric sonographic imaging. Given our findings and review of the literature, we suggest that bedside ultrasound evaluation of NGT placement is a straightforward, rapid, and novel alternative method to the "gold standard" of a portable chest radiograph in the emergency department (ED). PMID- 22100481 TI - Spontaneous tension pneumothorax and CO2 narcosis in a near fatal episode of chronic obstructive pulmonary disease exacerbation. AB - Exacerbation of chronic obstructive pulmonary disease (COPD) is a disease pattern frequently seen in emergency medical services and intensive care units. Usually, exacerbations of COPD are of infectious origin, and an acute vital threat may take several days to develop. Tension pneumothorax in patients with COPD is a rare and often unexpected cause of acute vital threat. To the best of our knowledge, this is a unique case of CO2 narcosis after spontaneous tension pneumothorax in a patient with COPD. We describe the rapid development of respiratory insufficiency and near fatal pulmonary failure in a 65-year-old female patient with COPD due to spontaneous tension pneumothorax. The patient was in respiratory failure and comatose upon arrival of the emergency service. Before mechanical ventilation, coma could be confirmed to be due to CO2 narcosis caused by exorbitant arterial hypercapnia (PCO2, 193 mm Hg). Pneumothorax was diagnosed in the hospital by chest x-ray and resolved after pleural drainage. The patient could be extubated early and discharged without sequelae. In conclusion, we want to report the occurrence of a tension pneumothorax as an important and potentially overseen condition in patients with COPD with acute respiratory failure. PMID- 22100482 TI - Comparison of conservative management and laparotomy in the management of stable patients with abdominal stab wound. AB - INTRODUCTION: The management of the hemodynamically stable patients with penetrating abdominal stab wounds is a problematic issue among trauma surgeons. METHODS: In a retrospective study, we analyzed stable patients with anterior abdominal stab wound from August 2009 to 2010. The patients who were hemodynamically unstable or had developed peritonitis were excluded. In our center, the patients are treated through conservative or operative management depending on the protocol of management of the stable penetrating abdominal stab wound in our center. We compared the effectiveness, mean duration of hospital admission, and the time of starting diet in 2 groups. RESULTS: There were 99 cases including 47 patients in the conservative group and 52 in the laparotomy group. The laparotomy was negative in 73% and positive in 27% of the patients. In the conservative group, all the patients remained asymptomatic and stable except for 6 patients who needed subsequent laparotomy. The maximum period between admission and delayed laparotomy in these 6 patients was 17 hours. The mean length of hospital stay and the time of starting diet were 70.4 vs 43 hours and 42.3 vs 30.6 hours in the operative group and conservative group, respectively. P < .05 was considered significant. CONCLUSION: Our study showed that conservative management of asymptomatic and stable patients with anterior abdominal stab wound with physical examination can decrease the rate of normal laparotomy and the length of hospitalization and help to start diet earlier. This study made this hypothesis that after 17 hours of observation, diet can be started for the stable asymptomatic patients. PMID- 22100483 TI - The critical care literature 2010. PMID- 22100484 TI - Does primary stroke center certification change ED diagnosis, utilization, and disposition of patients with acute stroke? AB - BACKGROUND AND PURPOSE: We examined the impact of primary stroke center (PSC) certification on emergency department (ED) use and outcomes within an integrated delivery system in which EDs underwent staggered certification. METHODS: A retrospective cohort study of 30,461 patients seen in 17 integrated delivery system EDs with a primary diagnosis of transient ischemic attack (TIA), intracranial hemorrhage, or ischemic stroke between 2005 and 2008 was conducted. We compared ED stroke patient visits across hospitals for (1) temporal trends and (2) pre- and post-PSC certification-using logistic and linear regression models to adjust for comorbidities, patient characteristics, and calendar time, to examine major outcomes (ED throughput time, hospital admission, radiographic imaging utilization and throughput, and mortality) across certification stages. RESULTS: There were 15,687 precertification ED visits and 11,040 postcertification visits. Primary stroke center certification was associated with significant changes in care processes associated with PSC certification process, including (1) ED throughput for patients with intracranial hemorrhage (55 minutes faster), (2) increased utilization of cranial magnetic resonance imaging for patients with ischemic stroke (odds ratio, 1.88; 95% confidence interval, 1.36 2.60), and (3) decrease in time to radiographic imaging for most modalities, including cranial computed tomography done within 6 hours of ED arrival (TIA: 12 minutes faster, ischemic stroke: 11 minutes faster), magnetic resonance imaging for patients with ischemic stroke (197 minutes faster), and carotid Doppler sonography for TIA patients (138 minutes faster). There were no significant changes in survival. CONCLUSIONS: Stroke center certification was associated with significant changes in ED admission and radiographic utilization patterns, without measurable improvements in survival. PMID- 22100485 TI - ST elevation in inferior derivation, coronary ectasia, and slow coronary flow following ceftriaxone use. AB - A 24-year-old male patient presented with acute coronary syndrome with ST elevation following an allergic reaction to ceftriaxone. A coronary angiogram revealed ectasia and slow coronary flow in the right coronary artery, whereas the left coronary system was found to be normal. The patient was transferred to the coronary intensive care unit and given steroids, antihistamines, acetylsalicylic acid, clopidogrel, low-molecular weight heparin, and diltiazem. In this case study, we presented acute coronary events following an allergic reaction to ceftriaxone. PMID- 22100486 TI - Both the unique and repeat regions of the Porphyromonas gingivalis hemagglutin A are involved in adhesion and invasion of host cells. AB - Porphyromonas gingivalis is one of the major etiologic agents of adult periodontitis and has been associated with cardiovascular diseases. It expresses multiple hemagglutinins that are significant virulence factors and play an important role in bacterial attachment and invasion of host cells. The objective of this study was to determine the impact of P. gingivalis hemagglutinin A (HagA) on the attachment to and invasion of human coronary artery endothelial cells (HCAEC) and gingival epithelial cells (GEC). Bacterial strains expressing the HagA protein (or subunits), including Escherichia coli carrying plasmid pEKS5, E. coli carrying plasmid ST2, and Salmonella enterica serovar Typhimurium with plasmid pNM1.1 were used in this study. The strains were tested for their ability to attach to and invade HCAEC and GEC using antibiotic protection assays. In addition, the unique 5' N-terminal non-repeated segment of HagA was purified in recombinant form and a monoclonal antibody was created against the polypeptide. The monoclonal antibody against the unique portion of HagA was tested for inhibitory activity in these assays. The attachment of both E. coli strains expressing HagA fragment to host cells was significantly increased compared to their respective controls. However, they did not invade GEC or HCAEC. Interestingly, HagA expression in the Salmonella strain increased both adherence to and invasion of HCAEC, which may be due to the presence of the entire hagA ORF. A monoclonal antibody against the unique 5' N-terminal portion of HagA reduced invasion. Further experiments are needed to determine the role of the unique and the repeat segments of P. gingivalis HagA. PMID- 22100487 TI - Relationships between tea and other beverage consumption to work performance and mood. AB - The aim of this research was to examine relationships between tea, coffee and other beverage consumption and associates of work performance and mood among individuals in relatively stressful and cognitively demanding work-place settings. Using a naturalistic, cross-sectional study design, 95 professional and academic staff logged their beverage intake and completed self-reports of associates of work performance (fatigue/exhaustion, mindfulness, work engagement), subjective work performance, mood, work-related strain and recovery four times daily during ten working days. Data were analysed using multilevel modelling in keeping with the hierarchical structure of the data. Tea consumption was associated with increased perceived work performance and reduced tiredness, especially when consumed without milk or sugar. Consumption of non-caffeinated beverages was associated with increased relaxation and recovery from work. In contrast, tea and other caffeinated beverages were found to enhance the negative effects of evening recovery and morning mood on mindfulness during the day. The findings suggest that beverage intake may have a role in optimising work-related psychological states and performance. PMID- 22100488 TI - T-cell movement on the reticular network. AB - The idea that the apparently random motion of T cells in lymph nodes is a result of movement on a reticular network (RN) has received support from dynamic imaging experiments and theoretical studies. We present a mathematical representation of the RN consisting of edges connecting vertices that are randomly distributed in three-dimensional space, and models of lymphocyte movement on such networks including constant speed motion along edges and Brownian motion, not in three dimensions, but only along edges. The simplest model, in which a cell moves with a constant speed along edges, is consistent with mean-squared displacement proportional to time over intervals long enough to include several changes of direction. A non-random distribution of turning angles is one consequence of motion on a preformed network. Confining cell movement to a network does not, in itself, increase the frequency of cell-cell encounters. PMID- 22100489 TI - Dynamic modelling of cell death during biofilm development. AB - Biofilms are currently recognised as the predominant bacterial life-style and it has been suggested that biofilm development is influenced by a number of different processes such as adhesion, detachment, mass transport, quorum sensing, cell death and active dispersal. One of the least understood processes and its effects on biofilm development is cell death. However, experimental studies suggest that bacterial death is an important process during biofilm development and many studies show a relationship between cell death and dispersal in microbial biofilms. We present a model of the process of cell death during biofilm development, with a particular focus on the spatial localisation of cell death or cell damage. Three rules governing cell death or cell damage were evaluated which compared the effects of starvation, damage accumulation, and viability during biofilm development and were also used to design laboratory based experiments to test the model. Results from model simulations show that actively growing biofilms develop steep nutrient gradients within the interior of the biofilm that affect neighbouring microcolonies resulting in cell death and detachment. Two of the rules indicated that high substrate concentrations lead to accelerated cell death, in contrast to the third rule, based on the accumulation of damage, which predicted earlier cell death for biofilms grown with low substrate concentrations. Comparison of the modelling results with experimental results suggests that cell death is favoured under low nutrient conditions and that the accumulation of damage may be the main cause of cell death during biofilm development. PMID- 22100490 TI - The effects of transrectal radiofrequency hyperthermia on patients with chronic prostatitis and the changes of MDA, NO, SOD, and Zn levels in pretreatment and posttreatment. AB - OBJECTIVE: To assess the effect of transrectal radiofrequency hyperthermia (TRFH) in 159 patients with chronic prostatitis (CP) and explore the changes of reactive oxygen species in CP patients pretreatment and posttreatment. METHODS: Patients diagnosed with CP were randomized to 6 weeks of tamsulosin plus clarithromycin, TRFH, or TRFH with tamsulosin plus clarithromycin group. The primary outcome measure was evaluated by the National Institutes of Health Chronic Prostatitis Symptom Index. Malondiadehyde (MDA), superoxide dismutase (SOD), and nitrogen monoxide (NO) were measured by biochemical assay. Zinc (Zn) content was assayed by atomical spectrophotography. RESULTS: All 105 patients in the TRFH or TRFH with tamsulosin plus clarithromycin group showed statistically significant improvement of pain, quality of life, and micturition domains compared with the tamsulosin plus clarithromycin group. Regardless of type IIIa or type IIIb CP, there was a significant improvement in the TRFH or TRFH with tamsulosin plus clarithromycin group compared with tamsulosin plus clarithromycin group (P<.05). Compared with pretreatment, MDA, NO, and Zn were decreased in type II and IIIa, whereas SOD was only increased significantly in type II (P<.05). CONCLUSION: Our study reveals TRFH as an effective therapy option for CP, especially type IIIa or type IIIb CP. The results of TRFH with tamsulosin plus clarithromycin group was superior to the TRFH group or the tamsulosin plus clarithromycin group alone. In comparison with pretreatment, differences in reactive oxygen species levels and Zn in CP patients suggest that these factors could be used as a biomarker to evaluate the symptoms of CP and the effects of treatment. PMID- 22100492 TI - Differential effects of the particle core and organic extract of diesel exhaust particles. AB - Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been associated with lung disease and induction of pro-inflammatory mediators and CYP1A1 expression. The aim of this study was to further characterise DEP-components accounting for these effects. Human bronchial epithelial cells (BEAS-2B) were exposed to either native DEPs, or corresponding methanol DEP-extract or residual DEPs, and investigated with respect to cytotoxicity and expression and release of multiple inflammation related mediators. Both native DEPs and DEP-extract, but not residual DEPs, induced marked mRNA expression of COX-2, IL-6 and IL-8, as well as cytotoxicity and release of IL-6. However, CYP1A1 was primarily induced by the native and residual DEPs. Overall, the results of near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and gas chromatography with mass spectrometry (GC/MS) analysis of DEP-extracts indicated that the majority of the analysed PAHs and PAH derivatives were extracted from the particles, but that certain PAH-derivatives, probably their carboxylic isomers, tended to be retained on the residual DEPs. Moreover, it appeared that certain components of the methanol extract may suppress CYP1A1 expression. These results provide insight into how different components of the complex DEP-mixture may be differently involved in DEP-induced pro-inflammatory responses and underscore the importance of identifying and clarifying the roles of active DEP-components in relation to different biological effects. PMID- 22100491 TI - Hypoxia induces angiogenic factors in brain microvascular endothelial cells. AB - Hypoxia is increasingly recognized as an important contributing factor to the development of brain diseases such as Alzheimer's disease (AD). In the periphery, hypoxia is a powerful regulator of angiogenesis. However, vascular endothelial cells are remarkably heterogeneous and little is known about how brain endothelial cells respond to hypoxic challenge. The objective of this study is to characterize the effect of hypoxic challenge on the angiogenic response of cultured brain-derived microvascular endothelial cells. Brain endothelial cell cultures were initiated from isolated rat brain microvessels and subjected to hypoxia (1% O(2)) for various time periods. The results showed that hypoxia induced rapid (<= 0.5h) expression of hypoxia-inducible factor 1alpha (HIF 1alpha) and that cell viability, assessed by MTT assay, was unaffected within the first 8h. Examination of brain endothelial cell cultures for pro- and anti angiogenic proteins by western blot, RT-PCR and ELISA revealed that within 0.5 to 2h of hypoxia levels of vascular endothelial growth factor and endothelin-1 mRNA and protein were elevated. The expression of heme oxygenase-1 also increased but only after 8h of hypoxia. In contrast, similar hypoxia exposure evoked a decrease in endothelial nitric oxide synthase and thrombospondin-2 levels. Exposure of brain endothelial cell cultures to hypoxia resulted in a significant (p<0.001) decrease (94%) in tube length, an in vitro index of angiogenesis, compared to control cultures. The data indicate that, despite a shift toward a pro-angiogenic phenotype, hypoxia inhibited vessel formation in brain endothelial cells. These results suggest that in brain endothelial cells expression of angiogenic factors is not sufficient for the development of new vessels. Further work is needed to determine what factors/conditions prevent hypoxia-induced angiogenic changes from culminating in the formation of new brain blood vessels and what role this may play in the pathologic changes observed in AD and other diseases characterized by cerebral hypoxia. PMID- 22100493 TI - Fluorescence in situ hybridization using bacterial artificial chromosome (BAC) clones for the analysis of chromosome rearrangement in Chinese hamster ovary cells. AB - Chromosome identification using Chinese hamster ovary (CHO) genomic bacterial artificial chromosome (BAC) clones has the potential to contribute to the analysis and understanding of chromosomal instability of CHO cell lines and to improve our understanding of chromosome organization during the establishment of recombinant CHO cells. Fluorescence in situ hybridization imaging using BAC clones as probes (BAC-FISH) can provide valuable information for the identification of chromosomes. In this study, we identified chromosomes and analyzed the chromosome rearrangement in CHO cells using BAC-FISH methods. PMID- 22100494 TI - Clonal plasma cell pathophysiology and clinical features of disease are linked to clonal plasma cell expression of cyclin D1 in systemic light-chain amyloidosis. AB - BACKGROUND: Overexpression of cyclin D1 (CCND1) in the clonal plasma cells (PCs) of patients with systemic light chain amyloidosis (AL) has been shown to occur even in cases without t(11;14). Associations between CCND1 expression and the clonal PC disease that underlies AL and the clinical features that characterize AL have not been systematically evaluated. PATIENTS AND METHODS: To assess the significance of CCND1 expression in the pathophysiology of the clonal PC in AL, we evaluated CD138+ marrow PC from 16 newly diagnosed untreated patients by gene expression profiling (GEP) and performed a supervised analysis comparing clones that overexpressed CCND1 with those that did not. To assess the significance of CCND1 expression with respect to the clinical features of AL, we developed and validated a real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) method for quantitating expression of CCND1 in the CD138+ marrow PC cells from 53 newly diagnosed cases of AL. RESULTS: In the analysis of GEP data, clones that overexpressed CCND1 also expressed significantly higher levels of endoplasmic reticulum protein processing genes such as SEL1L, Sec63, and PDIA6. In the analysis of RT-qPCR data, patients whose clones overexpressed CCND1 more often made only free light chains and fewer intact M-proteins, and also had a lower response rate to initial therapy. In multivariate analysis, CCND1 expression was an independent baseline predictor of survival in AL. CONCLUSION: CCND1 expression is a feature of the clonal PC disease in AL that merits prospective evaluation. PMID- 22100495 TI - P-21 activated kinase 1 knockdown inhibits beta-catenin signalling and blocks colorectal cancer growth. AB - The p21-activated kinase 1 (PAK1) plays important roles in cell growth, motility, and transformation. The aims of this study were to delineate the signalling mechanisms downstream of PAK1, and to investigate the importance of PAK1 for colorectal cancer (CRC) growth and metastasis in vivo. PAK1 knockdown in human CRC cell lines inhibited beta-catenin expression, beta-catenin/TCF4 transcriptional activity, and the expression of c-Myc. In mouse models PAK1 knockdown suppressed the growth and metastasis of human CRC cells by decreasing proliferation and increasing apoptosis. Our findings demonstrate for the first time the crucial role of PAK1 in CRC progression in vivo. PMID- 22100496 TI - TRIAD III: nationwide assessment of living wills and do not resuscitate orders. AB - BACKGROUND: Concern exists that living wills are misinterpreted and may result in compromised patient safety. OBJECTIVE: To determine whether adding code status to a living will improves understanding and treatment decisions. METHODS: An Internet survey was conducted of General Surgery, and Family, Internal, and Emergency Medicine residencies between May and December 2009. The survey posed a fictitious living will with and without additional clarification in the form of code status. An emergent patient care scenario was then presented that included medical history and signs/symptoms. Respondents were asked to assign a code status and choose appropriate intervention. Questions were formatted as dichotomous responses. Correct response rate was based on legal statute. Significance of changes in response due to the addition of either clinical context (past medical history/signs/symptoms) or code status was assessed by contingency table analysis. RESULTS: Seven hundred sixty-eight faculty and residents at accredited training centers in 34 states responded. At baseline, 22% denoted "full code" as the code status for a typical living will, and 36% equated "full care" with a code status DNR. Adding clinical context improved correct responses by 21%. Specifying code status further improved correct interpretation by 28% to 34%. Treatment decisions were either improved 12-17% by adding code status ("Full Code," "Hospice Care") or worsened 22% ("DNR"). CONCLUSION: Misunderstanding of advance directives is a nationwide problem. Addition of code status may help to resolve the problem. Further research is required to ensure safety, understanding, and appropriate care to patients. PMID- 22100497 TI - Corneal ulcer associated with pepper spray exposure during military training. PMID- 22100498 TI - Temporary vision improvement and pain relief after insect sting. PMID- 22100499 TI - Effect of zinc supplementation on glutathione peroxidase activity and selenium concentration in the serum, liver and kidney of rats chronically exposed to cadmium. AB - It was investigated whether the ability of zinc (Zn) to prevent cadmium (Cd) induced lipid peroxidation may be connected with its impact on glutathione peroxidase (GPx) activity and selenium (Se) concentration. GPx and Se were determined in the serum, liver and kidney of the rats that received Cd (5 or 50 mg/L) or/and Zn (30 mg/L) in drinking water for 6 months in whose the protective Zn impact was noted (Rogalska J, Brzoska MM, Roszczenko A, Moniuszko-Jakoniuk J. Enhanced zinc consumption prevents cadmium-induced alterations in lipid metabolism in male rats. Chem Biol Interact 2009;177:142-52). Moreover, dependences between these parameters, and indices of lipid peroxidation (F(2) isoprostane, lipid peroxides, oxidized low density lipoprotein cholesterol) as well as concentrations of Cd and Zn were estimated. The supplementation with Zn during the exposure to 5 mg Cd/L entirely antagonized the Cd-induced increase in GPx activity and Se concentration in the liver and kidney, but not in the serum. Zn administration during the treatment with 50 mg Cd/L totally or partially prevented from the Cd-caused decrease in GPx activity and Se concentration in the serum, liver and kidney. At the higher level of Cd exposure, GPx activity in the serum and tissues positively correlated with Se concentration. Moreover, numerous correlations were noted between GPx and/or Se and the indices of lipid peroxidation. The results indicate that the protective impact of Zn against the Cd-induced lipid peroxidation during the relatively high exposure might be connected with its beneficial influence on Se concentration and GPx activity in the serum and tissues, whereas this bioelement influence at the moderate exposure seems to be independent of GPx and Se. PMID- 22100500 TI - The relative contributions of propulsive forces and receptor-ligand binding forces during early contact between spermatozoa and zona pellucida of oocytes. AB - When reaching the zona pellucida (ZP) of the oocyte, spermatozoa apply propulsive forces produced by the motion of their flagella, which push against the ZP and theoretically should contribute to their penetration into the ZP. Additionally, specific receptors on the spermatozoon head bind to ZP3 ligands located on the surface of the ZP, which locks the sperm's head onto the oocyte. Both mechanisms are important cofactors in the initial sperm penetration into the ZP, which is required for successful fertilization of the oocyte, but it is unclear which forces-mechanical thrust or biochemical binding-are more influential at this stage. To address this question, we developed a biomechanical sperm-oocyte contact model, which is based on the Johnson-Kendall-Roberts model adopted from the contact mechanics theory. The modeling predicted that during the early stage of penetration into the ZP, biochemical binding forces acting on spermatozoa, which are swimming at a (normal) velocity of 100MUm/s are ~4.2-times to ~16.7 times less than the mechanically-generated propulsive forces. In a simulated pathology of a low number of properly functioning receptors (50 out of 300receptors/MUm(2)), the biochemical binding forces are ~63-times less than the propulsive forces for the normally swimming sperm. It is suggested that such dominance of the propulsive forces over the biochemical binding forces can prevent efficient binding of spermatozoa to the ZP of the oocyte due to continuous movement of the sperm (which is not necessarily perpendicular to the ZP surface, and can cause sliding of sperm over the ZP). Thus, our theoretical analysis indicates that a sufficiently large density of receptors to ZP3 ligands on the sperm head is critical at the stage of early sperm-oocyte contact, in order to allow an efficient acrosome reaction to follow, so that the spermatozoon can start penetrating into the ZP. PMID- 22100501 TI - Kinetic behavior of the general modifier mechanism of Botts and Morales with non equilibrium binding. AB - In this paper, we perform a complete analysis of the kinetic behavior of the general modifier mechanism of Botts and Morales in both equilibrium steady states and non-equilibrium steady states (NESS). Enlightened by the non-equilibrium theory of Markov chains, we introduce the net flux into discussion and acquire an expression of the rate of product formation in NESS, which has clear biophysical significance. Up till now, it is a general belief that being an activator or an inhibitor is an intrinsic property of the modifier. However, we reveal that this traditional point of view is based on the equilibrium assumption. A modifier may no longer be an overall activator or inhibitor when the reaction system is not in equilibrium. Based on the regulation of enzyme activity by the modifier concentration, we classify the kinetic behavior of the modifier into three categories, which are named hyperbolic behavior, bell-shaped behavior, and switching behavior, respectively. We show that the switching phenomenon, in which a modifier may convert between an activator and an inhibitor when the modifier concentration varies, occurs only in NESS. Effects of drugs on the Pgp ATPase activity, where drugs may convert from activators to inhibitors with the increase of the drug concentration, are taken as a typical example to demonstrate the occurrence of the switching phenomenon. PMID- 22100503 TI - Effect of static foot alignment on plantar-pressure measures during running. AB - CONTEXT: Altered foot dynamics due to malalignment of the foot may change plantar pressure properties, resulting in various kinds of overuse injuries. OBJECTIVE: To assess the effect of foot characteristics on plantar-pressure-related measures such as maximum pressure, maximum pressure-time, and pressure-time integral underneath the medial aspect of the foot during running. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: 8 men and 17 women. MAIN OUTCOME MEASURES: Static non-weight-bearing rear-foot and forefoot alignment and navicular drop were measured. Plantar-pressure data were collected while subjects jogged at 2.6 m/s on a treadmill. Maximum pressure, time to maximum pressure, and pressure-time integral of the medial side of the foot were extracted for data analysis. Multiple-regression analysis was used to examine the effect of arch height and rear-foot and forefoot alignment on maximum pressure and pressure-time integral in the medial side of the foot. RESULTS: In the medial rear-foot and midfoot regions, only rear-foot alignment had a significant effect on the variance of maximum pressure and pressure-time integral. There were no significant difference effects in the medial forefoot region. CONCLUSION: Rear-foot alignment was found to be a significant predictor of maximum plantar pressure and pressure-time integral in the medial rear-foot and midfoot regions. This indicates that control of rear-foot alignment may help decrease plantar pressure on the medial region of the foot, which may potentially prevent injuries associated with excessive rear foot eversion. PMID- 22100502 TI - PGC-1alpha at the intersection of bioenergetics regulation and neuron function: from Huntington's disease to Parkinson's disease and beyond. AB - Neurons are specialized cells with unique features, including a constant high demand for energy. Mitochondria satisfy this constant demand, and are emerging as a central target for dysfunction in neurodegenerative disorders, such as Huntington's disease (HD) and Parkinson's disease. PPARgamma co-activator-1alpha (PGC-1alpha) is a transcription co-activator for nuclear receptors such as the PPARs, and thereby coordinates a number of gene expression programs to promote mitochondrial biogenesis and oxidative phosphorylation. Studies of PGC-1alpha knock-out mice have yielded important insights into the role of PGC-1alpha in normal nervous system function and potentially neurological disease. HD is caused by a polyglutamine repeat expansion in the huntingtin protein, and decades of work have established mitochondrial dysfunction as a key feature of HD pathogenesis. However, after the discovery of the HD gene, numerous reports produced strong evidence for altered transcription in HD. In 2006, a series of studies revealed that PGC-1alpha transcription interference contributes to HD neurodegeneration, linking the nuclear transcriptionopathy with the mitochondrial dysfunction. Subsequent work has strengthened this view, and further extended the role of PGC-1alpha within the CNS. Within the last year, studies of Parkinson's disease, another involuntary movement disorder long associated with mitochondrial dysfunction, have shown that PGC-1alpha dysregulation is contributing to its pathogenesis. As PGC-1alpha is likely also important for aging, a process with considerable relevance to neuron function, translational studies aimed at developing therapies based upon the PGC-1alpha pathway as a high priority target are underway. PMID- 22100504 TI - Disruption of alternative NAD(P)H dehydrogenases leads to decreased mitochondrial ROS in Neurospora crassa. AB - Mitochondria are a main providers of high levels of energy, but also a major source of reactive oxygen species (ROS) during normal oxidative metabolism. The involvement of Neurospora crassa alternative NAD(P)H dehydrogenases in mitochondrial ROS production was evaluated. The growth responses of a series of respiratory mutants to several stress conditions revealed that disrupting alternative dehydrogenases leads to an increased tolerance to the redox cycler paraquat, with a mutant devoid of the external NDE1 and NDE2 enzymes being significantly more resistant. The nde1nde2 mutant mitochondria show a significant decrease in ROS generation in the presence and absence of paraquat, regardless of the respiratory substrate used, and an intrinsic increase in catalase activity. Analysis of ROS production by a complex I mutant (nuo51) indicates that, as in other organisms, paraquat-derived ROS in Neurospora mitochondria occur mainly at the level of complex I. We propose that disruption of the external NAD(P)H dehydrogenases NDE1 and NDE2 leads to a synergistic effect diminishing ROS generation by the mitochondrial respiratory chain. This, in addition to a robust increase in scavenging capacity, provides the mutant strain with an improved ability to withstand paraquat treatment. PMID- 22100506 TI - Evaluating educational media using traditional folk songs ('lam') in Laos: a health message combined with oral tradition. AB - In the Lao People's Democratic Republic (Laos), health education is clearly a core aspect of the health service and is vital in improving people's lives through good health. However, there are many obstacles to conducting effective health education. The development of effective educational media is one solution to these problems. In Laos, traditional folk songs (lam) are preserved as part of the local communication media, and recently this communication medium has been used for health education. The aim of this study is to evaluate the effectiveness of educational media using lam. For this purpose, we conducted focus group discussions with 48 participants. The reactions of the participants towards a lam, developed for preventing HIV/AIDS, were analysed using the KJ (Kawakita Jiro) method. The analysis showed there were eight areas of concern: (1) interest in a lam talking about HIV/AIDS; (2) knowledge and perception related to HIV infection routes; (3) expressing a willingness for preventing HIV/AIDS; (4) togetherness with people living with HIV/AIDS; (5) HIV/AIDS education for children; (6) improving educational methods; (7) characteristics and effectiveness of the lam and (8) song preferences. The reactions of the participants, such as gaining knowledge and expressing individual attitudes and community actions for preventing HIV/AIDS, were promoted by the characteristics and effectiveness of the lam such as oral tradition, artistry and cultural values. In particular, the oral tradition represented by lam is useful for the Lao people in memorizing and communicating information. PMID- 22100505 TI - Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. AB - 17-Allylamino-17-demethoxygeldanamycin (17AAG) is an experimental chemotherapeutic agent believed to form free radicals in vivo, and cancer cell resistance to 17AAG is believed to be a thiol-dependent process. Inhibitors of thiol-dependent hydroperoxide metabolism [L-buthionine-S,R-sulfoximine (BSO) and auranofin] were combined with the glucose metabolism inhibitor 2-deoxy-d-glucose (2DG) to determine if 17AAG-mediated cancer cell killing could be enhanced. When 2DG (20mM, 24h), BSO (1mM, 24h), and auranofin (500nM, 3h) were combined with 17AAG, cell killing was significantly enhanced in three human cancer cell lines (PC-3, SUM159, MDA-MB-231). Furthermore, the toxicity of this drug combination was significantly greater in SUM159 human breast cancer cells, relative to HMEC normal human breast epithelial cells. Increases in toxicity seen with this drug combination also correlated with increased glutathione (GSH) and thioredoxin (Trx) oxidation and depletion. Furthermore, treatment with the thiol antioxidant NAC (15mM, 24h) was able to significantly protect from drug-induced toxicity and ameliorate GSH oxidation, Trx oxidation, and Trx depletion. These data strongly support the hypothesis that simultaneous inhibition of GSH- and Trx-dependent metabolism is necessary to sensitize human breast and prostate cancer cells to 2DG+17AAG-mediated killing via enhancement of thiol-dependent oxidative stress. These results suggest that simultaneous targeting of both GSH and Trx metabolism could represent an effective strategy for chemosensitization in human cancer cells. PMID- 22100507 TI - Relationship between placental expression of the imprinted PHLDA2 gene, intrauterine skeletal growth and childhood bone mass. AB - Alterations in expression of the imprinted gene PHLDA2 are linked to low birth weight in both humans and the mouse. However birth weight is a summary measure of fetal growth and provides little information on the growth rate of the fetus in early and late pregnancy. To examine the relation of PHLDA2 expression with rates of fetal growth and explore associations with the infant's body composition in early childhood, we measured PHLDA2 mRNA levels in the term placenta of 102 infants whose mothers were participating in the Southampton Women's Survey (SWS). Higher PHLDA2 expression was associated with a lower fetal femur growth velocity between 19 and 34 weeks gestation. In addition, higher placental PHLDA2 gene expression was associated with a lower child's bone mineral content at four years of age, measured using dual-energy X-ray absorptiometry. The results suggest that placental PHLDA2 may provide a biomarker for suboptimal skeletal growth in pregnancies uncomplicated by overt fetal growth restriction. PMID- 22100508 TI - AMP-activated protein kinase regulates PDGF-BB-stimulated interleukin-6 synthesis in osteoblasts: involvement of mitogen-activated protein kinases. AB - AIM: We have previously reported that platelet-derived growth factor (PDGF)-BB stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells, and that the activation of p44/p42 mitogen activated protein (MAP) kinase, p38MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is implicated in the IL-6 synthesis. In the present study,we investigated the involvement of AMP-activated protein kinase (AMPK), a regulator of energy metabolism, in the PDGF-BB-stimulated IL-6 synthesis in MC3T3-E1 cells. MAIN METHODS: The levels of IL-6 were measured by ELISA. The phosphorylation of each protein kinases was analyzed by Western blotting. The mRNA levels of IL-6 were determined by real-time RT-PCR. KEY FINDINGS: PDGF-BB time-dependently induced the phosphorylation of AMPK. Compound C, an inhibitor of AMPK, which reduced PDGF-BB-induced acetyl-CoA carboxylase phosphorylation, dose-dependently suppressed the PDGF-BB-stimulated IL-6 release. In addition, the PDGF-BB-stimulated IL-6 release in human osteoblasts was also inhibited by compound C. The mRNA expression of IL-6 induced by PDGF-BB was markedly reduced by compound C. The PDGF-BB-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK was inhibited by compound C. SIGNIFICANCE: These results strongly suggest that AMPK positively regulates PDGF BB-stimulated IL-6 synthesis via the MAP kinases in osteoblasts. PMID- 22100509 TI - Effects of Kupffer cell blockade on the hepatic expression of metallothionein and heme oxygenase genes in endotoxemic rats with obstructive jaundice. AB - AIMS: Heme oxygenase (HO) and metallothionein (MT) genes are rapidly upregulated in the liver by pro-inflammatory cytokines and/or endotoxin as protection against cellular stress and inflammation. Gadolinium chloride (GdCl3)-induced Kupffer cell blockade has beneficial consequences in endotoxemia following bile duct ligation. Herein we further characterized the effects of Kupffer cell inhibition on the activation of the antioxidant defense system (HO and MT gene expressions, and antioxidant enzyme activities) in response to endotoxemia and obstructive jaundice. MAIN METHODS: The isoform-specific expression of MT and HO genes was assessed (RT-PCR) in rat livers following 3-day bile duct ligation, 2-h lipopolysaccharide treatment (1mg/kg) or their combination, with or without GdCl3 pretreatment (10 mg/kg, 24h before endotoxin). Lipid peroxidation, DNA damage and hepatic antioxidant enzyme activities were also assessed. KEY FINDINGS: All these challenges induced similar extents of DNA damage, whereas the lipid peroxidation increased only when endotoxemia was combined with biliary obstruction. The MT and HO mRNA levels displayed isoform-specific changes: those of MT-1 and HO-2 did not change appreciably, whereas those of MT-2 and HO-1 increased significantly in 2-h endotoxemia, with or without obstructive jaundice. Among the enzymes reflecting the endogenous protective mechanisms, the catalase and copper/zinc-superoxide dismutase levels decreased, while that of Mn-SOD slightly increased. Interestingly, GdCl3 alone induced lipid peroxidation, DNA damage and MT-2 expression. In response to GdCl3, HO-1 induction was significantly lower in each model. SIGNIFICANCE: Despite its moderate hepatocellular toxicity, the ameliorated stress-induced hepatic reactions provided by GdCl3 may contribute to its protective effects. PMID- 22100510 TI - Structural and histomorphometric evaluations of ferutinin effects on the uterus of ovariectomized rats during osteoporosis treatment. AB - AIMS: The effects of chronic administration of Ferutinin (phytoestrogen found in the plants of genus Ferula), compared with those elicited by estradiol benzoate, were evaluated, following ovariectomy, on the uterus of ovariectomized rats as regard weight, size, structure and histomorphometry. MAIN METHODS: The experimental study included 40 female Sprague-Dawley rats, assigned to two different protocols, i.e. preventive and recovering. In the preventive protocol, ferutinin (2mg/kg/day) was orally administered for 30days, starting from the day after ovariectomy; in the recovering protocol, ferutinin was administered, at the same dosage, for 30days starting from the 60th day after ovariectomy, when osteoporosis was clearly established. Its effects were compared with those of estradiol benzoate (1.5MUg per rat twice a week, subcutaneously injected) vs. vehicle-treated ovariectomized controls and vehicle-treated sham-operated controls. Uteri were removed, weighed and analysed under both the structural and histomorphometrical points of view. KEY FINDINGS: Our data show that ferutinin acts, similarly to estradiol benzoate, on the uterus stimulating endometrial and myometrial hypertrophy; this notwithstanding, the phytoestrogen ferutinin, in contrast to estrogen treatment, appears to increase apoptosis in uterine luminal and glandular epithelia. SIGNIFICANCE: Ferutinin, used in osteoporosis treatment primarily for bone mass recovering, seems in line with an eventual protective function against uterine carcinoma, unlike estrogens so far employed in hormone replacement therapy (HRT). PMID- 22100511 TI - The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment. AB - AIMS: Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11 dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. MAIN METHODS: Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneously (s.c.) twice per day for 9 days to male Sprague-Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [(35)S]GTPgammaS binding to the MOR and DOR. KEY FINDINGS: Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [(35)S]GTPgammaS binding in the membranes of HEK293 cells expressing either the MOR or the DOR. SIGNIFICANCE: LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR. PMID- 22100512 TI - Effects of zinc and manganese on advanced glycation end products (AGEs) formation and AGEs-mediated endothelial cell dysfunction. AB - AIMS: The present study investigated the effects of ZnCl2 and MnCl2 supplementations on advanced glycation end products (AGEs) formation and AGEs mediated endothelial cell dysfunction. MAIN METHODS: Fluorescence detection was used to monitor the Maillard reaction. Inductively coupled plasma optical emission spectroscopy was used to test cellular zinc and manganese levels. Real time reverse transcription polymerase chain reaction and western blot were used to analyze the expression of endothelial nitric oxide synthase (eNOS), nuclear transcription factor kappa B (NF-kappaB), and receptor for AGEs (RAGE). Intracellular reactive oxygen species (ROS) and nitric oxide (NO) production, NOS activity were determined by fluorescent probe assay, superoxide dismutase (SOD) activity was determined by water soluble tetrazolium salt assay. KEY FINDINGS: MnCl2 showed excellent inhibitory effect on AGEs formation. Primary cultured bovine aortic endothelial cells (BAECs) were exposed to AGEs for 30 min, followed by trace element treatments. Cell viability and the zinc levels declined due to AGEs exposure, which were improved with the supplementations of ZnCl2 and MnCl2. Furthermore, ZnCl2 supplementation effectively enhanced intracellular NO production, elevated eNOS expression and enzymatic activity, and down-regulated NF-kappaB activation and RAGE expression. MnCl2 dose-dependently impaired ROS formation, down-regulated NF-kappaB protein expression and nuclear translocation, as well as restored Mn-SOD enzymatic capability. SIGNIFICANCE: Our findings suggested that trace elements relevant to diabetic, such as zinc and manganese played different roles in the formation of AGEs. Both the elements benefited the AGEs-injured BAECs through different mechanisms. PMID- 22100513 TI - Gene delivery system involving Bubble liposomes and ultrasound for the efficient in vivo delivery of genes into mouse tongue tissue. AB - Oral squamous cell carcinoma is the most common type of head and neck cancer. Recently, efficient, easy, and minimally invasive gene delivery methods are expected to be developed as cancer gene therapies. However, the optimal method for delivering therapeutic genes into oral tissue for cancer treatment has not been elucidated. Therefore, we hypothesized that the tongue is a good target tissue for gene delivery with Bubble liposomes and ultrasound. To assess this, we attempted to deliver a mixture of plasmid DNA encoding a luciferase or enhanced green fluorescent protein, and Bubble liposomes into murine tongue with or without ultrasound exposure. The ultrasound conditions were 1 MHz, 2 W/cm(2), 60s, and duty cycle: 50%. The time-course of gene expression in the tongue was investigated with a luciferase assay and fluorescent microscopy. Luciferase expression was significantly increased in tongue transfected using Bubble liposomes and ultrasound compared with that of the tongue untreated with ultrasound, and this high level of luciferase activity was maintained for 2 weeks. From these results, Bubble liposomes can be used in combination with ultrasound to efficiently deliver plasmid DNA into the tongue in vivo. This technique is a highly promising approach for gene delivery into oral tissue. PMID- 22100514 TI - The solid-state characterization of fusidic acid. AB - PURPOSE: The aim of this work was to characterize the solid-state properties of fusidic acid (FA). METHODS: Solid forms of FA were prepared by solvent-mediated polymorphic transformation of commercial FA (Form III) in acetonitrile (ACN), and methanol:H(2)O (50:50), or generated by solvent recrystallization from dichloromethane (DCM). Polymorphs were characterized using, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), polarizing hot stage microscopy (HSM), and intrinsic dissolution rate (IDR). RESULTS: Slurrying commercial FA (Form III) in methanol:H(2)O (50:50), yielded a metastable form (Form IV). This metastable form converts to Form I or back to Form III in ACN and H(2)O, respectively, and Form II upon recrystallization from DCM. IDR of Form IV was 0.092 mg/min/cm(2), and was statistically different (p<0.05) from the IDR of Forms I, II, and III, with IDR of 0.053, 0.043, and 0.045mg/min/cm(2), respectively. The amorphous FA had an IDR of 0.125 mg/min/cm(2), and was significantly higher (p<0.05) than any other solid form. There were no statistical differences in the IDR of Form I, II, or III. CONCLUSIONS: This work provides evidence for the existence of two previously unreported polymorphic forms of FA (Forms II and IV) and an amorphate. PMID- 22100515 TI - Efficient systemic delivery of siRNA to the mouse liver by pegylated lipopolymer. AB - Short interfering RNA (siRNA) drugs have entered clinical trials in various disease areas. However, systemic use of siRNA drugs faces a challenge of tissue in-specificity and membrane impenetrability. In this study, we hypothesized that the combined of lipidic molecules with a pegylated cationic polymer through random polymerization of Micheal reaction could enhance the hepatocyte's preferential uptake and improve membrane penetrability. We reported the efficacy of in vitro knockdown of apoB mRNA in HepG2 cell line and in vivo knockdown of the liver apoB mRNA using a pegylated lipopolymer-siapoB complex. Results show that apoB mRNA in the nu/nu and C57BL/6 black mice was knockdown to ~60-80%, up to 2 weeks, at low doses of 1.0-2.5 mg/kg of siRNA. The finding sets a new stage for further developments for apoB siRNA therapeutics. PMID- 22100516 TI - Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials--a comparison with inverse gas chromatography. AB - This study investigates the impact of micronization on the measured surface energy characteristics of an active pharmaceutical ingredient (API), ibipinabant, by inverse gas chromatography (IGC) using both a fixed probe concentration, commonly used in standard IGC methods, and a fixed probe surface coverage approach applied by the surface energy analyzer (SEA), a next generation IGC system. The IGC measurements indicate an initial increase in surface energy, going from un-micronized to micronized, followed by a reduction in surface energy with increasing micronization extent. This was attributable to the change in the retention behaviour of the dispersive probes as a consequence of the change in the probe surface coverage rather than a change in the actual surface energy of the materials being analysed. It was observed in the SEA data that micronization leads to an increase in the measured dispersive surface energy of the drug substance with increasing micronization extent. The increase in surface energy is primarily due to the generation of new, higher energy interaction sites, although a small additional increase is also observed which is related to the increase in the number and distribution of high energy sites. The results demonstrate that in order to obtain comparable surface energetic data between batches with varied surface area, and presumably between different materials, results should be obtained at a specific, and constant, probe surface coverage. PMID- 22100517 TI - Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis. AB - Different destructive and nondestructive analytical methods, namely powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Raman and near infrared (NIR) spectroscopy and imaging, to detect and characterize tacrolimus trace crystallinity in an amorphous solid dispersion (SD) using chemometric analysis were developed. The SD was spiked with different percentages of the crystalline drug to construct an array of SDs with different crystallinity percentages. Partial least square (PLS) regression analysis was employed to compare the performance of the calibration models created using these analytical methods. The obtained results indicated a significant interaction between tacrolimus and the employed polymer and a drug dissolution dependency on the crystalline fraction within the SDs. Using two PLS factors, these analytical methods were ranked according to its specificity to detect the trace crystallinity of SDs as NIR>PXRD>Raman>DSC. Through the application of PLS, root mean-squared error of calibration values of 2.91%, 5.36%, 7.07% and 11.58% were calculated for the calibration models constructed by NIR, PXRD, Raman and DSC, respectively. Having a prediction error of 2.1% and a correlation coefficient of 0.99, it is demonstrated that combined NIR imaging and chemometric analysis outperformed the other methods in detecting trace crystallinity in tacrolimus amorphous systems. The spatial distributions of amorphous and crystalline drug were also obtained in order to allow for studying the crystallization dissemination in the solid dispersions. Consequently, NIR and NIR imaging coupled with chemometry was shown to be a powerful tool for the prediction of drug crystallinity within SDs. PMID- 22100518 TI - Identification and characterization of antimicrobial peptides from skin of Amolops ricketti (Anura: Ranidae). AB - As one of large amphibian group, there are a total of 45 species of Amolops in the world. However, the antimicrobial peptides (AMPs) existing in this genus has not been extensively studied. In this study, cDNAs encoding five novel AMP precursors were cloned by screening the skin-derived cDNA library of Amolops ricketti, a frog species that exists in southern and western parts of China. Protein sequence analysis led to the identification of five deduced peptides, three belonging to the brevinin-1 family and two belonging to the brevinin-2 family of amphibian AMPs. Thus, they were named as brevinin-1RTa (FLPLLAGVVANFLPQIICKIARKC), brevinin-1RTb (FLGSLLGLVGKVVPTLFCKISKKC), brevinin 1RTc (FLGSLLGLVGKIVPTLICKISKKC), brevinin-2RTa (GLMSTLKDFGKTAAKEIAQSLLSTASCKLAKTC), and brevinin-2RTb (GILDTLKEFGKTAAKGIAQSLLSTASCKLAKTC), respectively. The purification of brevinin 1RTa, brevinin-1RTb, and brevinin-2RTb was carried out by RP-HPLC, and confirmed by the LC-MS/MS-based proteomics approach. All of the peptides displayed different antimicrobial potency against a variety of microorganisms. In addition, brevinin-2RTa and brevinin-2RTb were found to have relatively low hemolytic activity (>400MUg/ml) against mammalian red blood cells in vitro, which could potentially be as candidates for developing novel anti-infection agents. PMID- 22100519 TI - Purification and characterization of a novel angiotensin-I converting enzyme (ACE) inhibitory peptide derived from enzymatic hydrolysate of grass carp protein. AB - Peptides inhibiting angiotensin-I converting enzyme (ACE, EC. 3.4.15.1) are possible cures of hypertension. Food-derived ACE-inhibitory peptides are particularly attractive because of reduced side effects. Previously, we reported ACE-inhibitory activity of grass carp protein hydrolysates. In this work, we report steps for purifying the ACE-inhibitory peptide from the hydrolysate and its biochemical properties. Following steps of ultrafiltration, macroporous adsorption resin, and two steps of reversed phase high performance liquid chromatography (RE-HPLC), a single Val-Ala-Pro (VAP) tripeptide was identified. The tripeptide with excellent ACE-inhibitory activity (IC(50) value of 0.00534 mg/mL) was a competitive ACE inhibitor and stable against both ACE and gastrointestinal enzymes of pepsin and chymotrypsin. This is the first report of food-derived VAP. The identified unique biochemical properties of VAP may enable the application of grass carp protein hydrolysates as a functional food for treatments of hypertension. The developed purification conditions also allow the production of VAP for pharmaceutical applications. PMID- 22100520 TI - Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity. AB - Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n=17) or steatosis alone (n=18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M(1)dG adducts. No differences in M(1)dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation (gammaH2AX). This reduction in gammaH2AX formation in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease. PMID- 22100521 TI - Haploinsufficiency and telomere length homeostasis. AB - In humans, autosomal dominant or X-linked disease can arise through a phenomenon termed haploinsufficiency, where one remaining wild-type allele is insufficient for function. In model organisms, the impact of heterozygosity can be tested directly with engineered mutant alleles or in a hemizygous state where the expression of one allele is abrogated completely. This review will focus on haploinsufficiency as it relates to telomerase and telomere length maintenance and, citing selected examples in various model organisms, it will discuss how the problem of gene dosage relates to telomere function in normal and diseased states. PMID- 22100522 TI - 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. AB - CYP24A1 is the cytochrome P450 component of the 25-hydroxyvitamin D(3)-24 hydroxylase enzyme that catalyzes the conversion of 25-hydroxyvitamin D(3) (25-OH D(3)) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) into 24-hydroxylated products, which constitute the degradation of the vitamin D molecule. This review focuses on recent data in the CYP24A1 field, including biochemical, physiological and clinical developments. Notable among these are: the first crystal structure for rat CYP24A1; mutagenesis studies which change the regioselectivity of the enzyme; and the finding that natural inactivating mutations of CYP24A1 cause the genetic disease idiopathic infantile hypercalcemia (IIH). The review also discusses the emerging correlation between rising serum phosphate/FGF-23 levels and increased CYP24A1 expression in chronic kidney disease, which in turn underlies accelerated degradation of both serum 25-OH-D(3) and 1,25-(OH)(2)D(3) in this condition. This review concludes by evaluating the potential clinical utility of blocking this enzyme with CYP24A1 inhibitors in various disease states. PMID- 22100523 TI - Body mass index in Parkinson's disease: a meta-analysis. AB - Prior work suggested that patients with Parkinson's disease (PD) have a lower Body Mass Index (BMI) than controls, but evidence is inconclusive. We therefore conducted a meta-analysis on BMI in PD. We searched MEDLINE, EMBASE, Cinahl and Scopus to identify cohort studies on BMI in PD, published before February 2011. Studies that reported mean BMI for PD patients and healthy controls were eligible. Twelve studies were included, with a total of 871 patients and 736 controls (in three studies controls consisted of subjects from other published studies). Our primary aim was to assess differences in BMI between patients and controls; this was analyzed with random effects meta-analysis. Our secondary aim was to evaluate the relation with disease severity (Hoehn and Yahr stage) and disease duration, using random effects meta-regression. PD patients had a significantly lower BMI than controls (overall effect 1.73, 95% CI 1.11-2.35, P<0.001). Pooled data of seven studies showed that patients with Hoehn and Yahr stage 3 had a lower BMI than patients with stage 2 (3.9, 95% CI 0.1-7.7, P<0.05). Disease duration was not associated with BMI. Because a low body weight is associated with negative health effects and a poorer prognosis, monitoring weight and nutritional status should be part of PD management. PMID- 22100524 TI - Expression of a biologically-active conotoxin PrIIIE in Escherichia coli. AB - Conotoxin PrIIIE is a 22-amino acid peptide containing three disulfide bonds isolated from the venom of Conus parius Reeve. It is a non-competitive antagonist of the mammalian muscle nicotinic acetylcholine receptor (nAChR). We fused the PrIIIE to small ubiquitin-like modifier (SUMO) and expressed the fusion protein in an Escherichia coli strain with an oxidizing cytoplasm. We purified the fusion protein by immobilized metal affinity chromatography and further purified PrIIIE from cleaved SUMO using cation exchange chromatography. The yield of peptide was 1.5mg/L of culture. The recombinant peptide is functional, as demonstrated by two electrode voltage clamp experiments. This system may prove valuable for future structure-function studies. PMID- 22100525 TI - RNA secondary structure and in vitro translation efficiency. AB - Cell-free protein synthesis is a promising technology featuring many advantages compared to in vivo expression techniques. However, most proteins are still synthesized in vivo due to relatively low protein yields commonly achieved in vitro, especially in the batch mode of reaction. In Escherichia coli S30 extract based cell-free systems protein yields are supposed to be partially limited by a secondary structure formation of the mRNA. In this study we checked promising members of various classes of RNA chaperones and several different RNA helicases on their ability to enhance in vitro translation. The data clearly show that the addition of none of these factors provides a general solution to the problem. However, protein yields can be increased in presence of a microRNA hybridizing with the 5' untranslated region of mRNAs, possibly by inducing structural changes improving accessibility of the Shine Dalgarno sequence for the ribosomes. PMID- 22100526 TI - Expression and immunoaffinity purification of recombinant dengue virus 2 NS1 protein as a cleavable SUMOstar fusion. AB - Dengue virus (DENV) encoded nonstructural one (NS1) is a 352 amino acid protein that exists in multiple oligomeric states and is conserved within the flavivirus family. Although NS1 has been heavily researched for its diagnostic utility, there is a gap in the understanding of its role in a range of viral processes, including replication and development of clinical pathologies such as vascular leakage. Many of these functions involve unknown interactions with viral and host proteins. This study describes the generation of a mouse monoclonal antibody (mAb 56.2) that reacts with NS1 from DENV1 and 2, and the expression of recombinant SUMOstar-tagged DENV2 NS1 (DENV2 S*-NS1) in baculovirus. This is the first time dengue NS1 has been produced as a SUMOstar fusion with the S*-tag increasing protein solubility and secretion compared with a non-S*-tagged NS1 construct. The protein was readily purified using a mAb 56.2 immunoaffinity column and untagged NS1 was obtained by treatment with tobacco etch virus protease to remove the S* tag. Size exclusion chromatography and glycosylation assays showed that both secreted S*-NS1, and cleaved NS1, are hexameric and glycosylated, and will be useful tools in elucidating dengue NS1 protein interactions and functions. PMID- 22100527 TI - Expression, purification and some properties of fluorescent chimeras of human small heat shock proteins. AB - Small heat shock proteins (sHsp) are ubiquitously expressed in all human tissues and have an important housekeeping role in preventing the accumulation of aggregates of improperly folded or denatured proteins. They also participate in the regulation of the cytoskeleton, proliferation, apoptosis and many other vital processes. Fluorescent chimeras composed of sHsp and enhanced fluorescent proteins have been used to determine the intracellular locations of small heat shock proteins and to analyse the hetero-oligomeric complexes formed by different sHsp. However, the biochemical properties and chaperone-like activities of these chimeras have not been investigated. To determine the properties of these chimeras, we fused enhanced yellow and cyan fluorescent proteins (EYFP and ECFP) to the N-termini of four ubiquitously expressed human small heat shock proteins: HspB1, HspB5, HspB6, and HspB8. The eight fluorescent chimeras of small heat shock proteins and isolated fluorescent proteins were expressed in Escherichia coli. The chimeric proteins were isolated and purified via ammonium sulphate fractionation, ion exchange and size-exclusion chromatography. This method provided 20-100 mg of fluorescent chimeras from 1L of bacterial culture. The spectral properties of the chimeras were similar to those of the isolated fluorescent proteins. The fusion of fluorescent proteins to HspB6 and HspB8, which typically form dimers, did not affect their quaternary structures. Oligomers of the fluorescent chimeras of HspB1 and HspB5 were less stable and contained fewer subunits than oligomers formed by the wild-type proteins. Fusion with EYFP decreased the chaperone-like activity of HspB5 and HspB6 whereas fusion with ECFP increased chaperone-like activity. All fluorescent chimeras of HspB1 and HspB8 had higher chaperone-like activity than the wild-type proteins. Thus, although fluorescent chimeras are useful for many purposes, the fluorescent proteins used to form these chimeras may affect certain important properties of sHsp. PMID- 22100528 TI - Isothermal microcalorimetry for quantifying amorphous content in processed pharmaceuticals. AB - Many processing steps can result in generation of partially amorphous materials. While the fraction of disorder may be low (typically up to 5% w/w) its location primarily on particle surfaces means its effects might be significant, especially in regard to powder flow and force of adhesion. Quantification of small amorphous contents is thus becoming an important part of product development. Isothermal microcalorimetry can be used as an assay for amorphous content by controlling the relative humidity or relative vapour pressure in the sample ampoule. The technique is very sensitive (typically detecting less than 1% w/w amorphous content) and universally applicable to pharmaceutical powders. However method design and data interpretation are critical factors in successful assay design. This article discusses methods and techniques and reviews current pharmaceutical applications to aid assay design. PMID- 22100529 TI - The phosphoglucan phosphatase like sex Four2 dephosphorylates starch at the C3 position in Arabidopsis. AB - Starch contains phosphate covalently bound to the C6-position (70 to 80% of total bound phosphate) and the C3-position (20 to 30%) of the glucosyl residues of the amylopectin fraction. In plants, the transient phosphorylation of starch renders the granule surface more accessible to glucan hydrolyzing enzymes and is required for proper starch degradation. Phosphate also confers desired properties to starch-derived pastes for industrial applications. In Arabidopsis thaliana, the removal of phosphate by the glucan phosphatase Starch Excess4 (SEX4) is essential for starch breakdown. We identified a homolog of SEX4, LSF2 (Like Sex Four2), as a novel enzyme involved in starch metabolism in Arabidopsis chloroplasts. Unlike SEX4, LSF2 does not have a carbohydrate binding module. Nevertheless, it binds to starch and specifically hydrolyzes phosphate from the C3-position. As a consequence, lsf2 mutant starch has elevated levels of C3-bound phosphate. SEX4 can release phosphate from both the C6- and the C3-positions, resulting in partial functional overlap with LSF2. However, compared with sex4 single mutants, the lsf2 sex4 double mutants have a more severe starch-excess phenotype, impaired growth, and a further change in the proportion of C3- and C6-bound phosphate. These findings significantly advance our understanding of the metabolism of phosphate in starch and provide innovative options for tailoring novel starches with improved functionality for industry. PMID- 22100530 TI - Dynamic-position-sense impairment's independence of perceived knee function in women with ACL reconstruction. AB - CONTEXT: There is conflicting evidence in the literature regarding whether women with anterior cruciate ligament reconstruction (ACLR) demonstrate impaired proprioception. This study examined dynamic-position-sense accuracy and central nervous-system (CNS) processing time between those with and without long-term ACLR. OBJECTIVE: To compare proprioception of knee movement in women with ACLR and healthy controls. DESIGN: Cross-sectional. SETTING: Human neuromuscular performance laboratory. PARTICIPANTS: 11 women (age 22.64 +/- 2.4 y) with ACLR (1.6-5.8 y postsurgery) and 20 women without (age 24.05 +/- 1.4 y). INTERVENTIONS: The authors evaluated subjects using 3 methods to assess position sense. During knee flexion at pseudorandomly selected speeds (40 degrees , 60 degrees , 80 degrees , 90 degrees , and 100 degrees /s), subjects indicated with their index finger when their knee reached a predetermined target angle (50 degrees ). Accuracy was calculated as an error score. CNS processing time was computed using the time to detect movement and the minimum time of angle indication. Passive and active joint-position sense were also determined at a slow velocity (3 degrees /s) from various knee-joint starting angles. MAIN OUTCOME MEASUREMENTS: Absolute and constant error of target angle, indication accuracy, CNS processing time, and perceived function. RESULTS: Both subject groups showed similar levels of error during dynamic-position-sense testing, despite continued differences in perceived knee function. Estimated CNS processing time was 260 ms for both groups. Joint-position sense during slow active or passive movement did not differ between cohorts. CONCLUSIONS: Control and ACLR subjects demonstrated similar dynamic, passive, and active joint position-sense error and CNS processing speed even though ACLR subjects reported greater impairment of function. The impairment of proprioception is independent of post-ACLR perception of function. PMID- 22100531 TI - Antioxidant and antifungal potential of methanol extracts of Phellinus spp. from Sonora, Mexico. AB - BACKGROUND: Among the potential natural sources of bioactive compounds, those of the macroscopic fungi Phellinus spp. have been identified by previous researches. Phenolic compounds are among the major antioxidant and antimicrobial contributors due to their bioactive properties. AIMS: The goal of this study was to determine the total phenolic and flavonoid contents, and its relation with the antioxidant and antifungal activity of methanolic extracts of Phellinus gilvus, Phellinus rimosus and Phellinus badius, respectively. METHODS: The collected and identified organisms of Phellinus spp. were treated with methanol and the generated aqueous extract was analyzed to quantified total phenolic compounds, total flavonoids, radical scavenging activity against DPPH, trolox equivalent antioxidant capacity, and oxygen absorbance capacity. The antifungal property of the extracts was evaluated against Alternaria alternata. RESULTS: The content of phenolic compounds was of 49.31, 46.51 and 44.7 mg of gallic acid equivalents/g, for P. gilvus, P. rimosus and P. badius, respectively. The total flavonoid content followed the same pattern with values of 30.58, 28, and 26.48 mg of quercetin equivalents/g for P. gilvus, P. rimosus and P. badius, respectively. The variation on the content of phenolic components was reflected on the antioxidant activity of every organism. The antioxidant activity ranked as follows: P. gilvus>P. rimosus>P. badius. The antifungal effect of the different extracts against A. alternata showed a significant effect, all of them, inhibiting the growth of this pathogen. CONCLUSIONS: P. gilvus showed the best potential to inactivate free radicals, being all the tested fungi effective to inhibit A. alternata growth. PMID- 22100532 TI - Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia-reperfusion injury in a swine hemorrhagic shock model. AB - BACKGROUND: Vascular endothelial cells serve as the first line of defense for end organs after ischemia and reperfusion injuries. The full etiology of this dysfunction is poorly understood, and valproic acid (VPA) has proven to be beneficial after traumatic injury. The purpose of this study was to determine the mechanism of action through which VPA exerts its beneficial effects. METHODS: Sixteen Yorkshire swine underwent a standardized protocol for an ischemia reperfusion injury through hemorrhage and a supraceliac cross-clamp with ensuing 6-hour resuscitation. The experimental swine (n = 6), received VPA at cross-clamp application and were compared with a sham (n = 5) and injury-control models (n = 5). Aortic endothelium was harvested, and microarray analysis was performed along with a functional clustering analysis with gene transcript validation using relative quantitative polymerase chain reaction. RESULTS: Clinical comparison of experimental swine matched for sex, weight, and length demonstrated that VPA significantly decreased resuscitative requirements, with improved hemodynamics and physiologic laboratory measurements. Six transcript profiles from the VPA treatment were compared with the 1536 gene transcripts (529 up and 1007 down) from sham and injury-control swine. Microarray analysis and a Database for Annotation, Visualization and Integrated Discovery functional pathway analysis approach identified biologic processes associated with pathologic vascular endothelial function, specifically through functional cluster pathways involving apoptosis/cell death and angiogenesis/vascular development, with five specific genes (THBS1, TNFRSF12A, ANGPTL4, RHOB, and RTN4) identified as members of both functional clusters. This study also examined gene expression of transforming growth factor (TGF)-beta (TGF-beta1, TGF-beta2, and TGF-beta-releasing thrombospondin 1 [THBS1]) and genes expressing vascular endothelial growth factor (VEGF) C, VEGFD, and VEGFR1 and found that these genes were involved in the endothelial functional preservation associated with VPA administration. CONCLUSIONS: VPA minimized pathologic endothelial cell function through the TGF beta and VEGF functional pathways. This study also implicates that integrated functional modeling and analysis will enable advancements in endothelial dysfunction using a systems biology approach. PMID- 22100533 TI - Thyroid surgery in the UK and on board the Mercy Ships. AB - Diseases of the thyroid are common in the developed and developing world. We retrospectively compared surgical pathologies, types of thyroidectomy, and postoperative complications between 2 case series, one from the Mercy Ships in West Africa with 87 patients, and the other from London in the United Kingdom with 120 patients. In both, the most common operation was hemithyroidectomy, and nodular hyperplasia was the most common disease. The postoperative complication rate of sero-haematoma was comparable with large international series. PMID- 22100534 TI - Analyses of regional-average activation and multivoxel pattern information tell complementary stories. AB - Multivariate pattern analysis (MVPA) has recently received increasing attention in functional neuroimaging due to its ability to decode mental states from fMRI signals. However, questions remain regarding both the empirical and conceptual relationships between results from MVPA and standard univariate analyses. In the current study, whole-brain univariate and searchlight MVPAs of parametric manipulations of monetary gain and loss in a decision making task (Tom et al., 2007) were compared to identify the differences in the results across these methods and the implications for understanding the underlying mental processes. The MVPA and univariate results did identify some overlapping regions in whole brain analyses. However, an analysis of consistency revealed that in many regions the effect size estimates obtained from MVPA and univariate analysis were uncorrelated. Moreover, comparison of sensitivity showed a general trend towards greater sensitivity to task manipulations by MVPA compared to univariate analysis. These results demonstrate that MVPA methods may provide a different view of the functional organization of mental processing compared to univariate analysis, wherein MVPA is more sensitive to distributed coding of information whereas univariate analysis is more sensitive to global engagement in ongoing tasks. The results also highlight the need for better ways to integrate these methods. PMID- 22100535 TI - Direct medical costs of COPD--an excess cost approach based on two population based studies. AB - AIM: While it is known that severe COPD has substantial economic consequences, evidence on resource use and costs in mild disease is scarce. The objective of this study was to investigate excess costs of early stages of COPD. METHODS: Using data from two population-based studies in Southern Germany, current GOLD criteria were applied to pre-bronchodilator spirometry for COPD diagnosis and staging in 2255 participants aged 41 to 89. Utilization of physician visits, hospital stays and medication was compared between participants with COPD stage I, stage II+ (II or higher) and controls. Costs per year were calculated by applying national unit costs. In controlling for confounders, two-part generalized regression analyses were used to account for the skewed distribution of costs and the high proportion of subjects without costs. RESULTS: Utilization in all categories was significantly higher in COPD patients than in controls. After adjusting for confounders, these differences remained present in physician visits and medication, but not in hospital days. Adjusted annual costs did not differ between stage I (? 1830) and controls (? 1822), but increased by about 54% to ? 2812 in stage II+. CONCLUSION: The finding that utilization and costs are considerably higher in moderate but not in mild COPD highlights the economic importance of prevention and of interventions aiming at early diagnosis and delayed disease progression. PMID- 22100536 TI - Cause-specific mortality adjudication in the UPLIFT(r) COPD trial: findings and recommendations. AB - Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT(r)) trial, a mortality adjudication committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data. PMID- 22100537 TI - The active cycle of breathing technique: a systematic review and meta-analysis. AB - QUESTION: What is the best available research evidence (volume, quality, consistency, generalisability) for the active cycle of breathing technique (ACBT)? DESIGN: Systematic review with meta-analysis. PARTICIPANTS: Participants with respiratory conditions characterised by chronic sputum production. INTERVENTION: The active cycle of breathing or forced expiratory technique. COMPARATOR: All comparators including control conditions. OUTCOME MEASURES: All outcomes providing continuous data. RESULTS: Twenty-four studies were included. Ten comparators were identified with the most common being conventional chest physiotherapy, positive expiratory pressure and a control. The outcomes most frequently assessed were sputum wet weight (n = 17), forced vital capacity (n = 12) and forced expiratory volume in 1 s (n = 12). Meta-analysis was completed on the primary outcome of sputum wet weight. The standardised mean difference (SMD, random effects) showed an increase in sputum wet weight during and up to 1 h post ACBT compared to conventional physiotherapy (SMD 0.32, 95%CI 0.05-0.59), external oscillatory devices (0.75, 0.48-1.02), and control (0.24, 0.02-0.46). CONCLUSION: The overall body of evidence was classified as good (good volume, quality and consistency, excellent generalisability). High level, variable risk of bias research evidence favours ACBT over most alternatives for short-term improvements in secretion clearance. PMID- 22100538 TI - Surfactant protein A and albumin in particles in exhaled air. AB - In this study we test the hypothesis that endogenous particles in exhaled air (PEx), non-invasively sampled from lower airways, are well suited for the analysis of respiratory tract lining fluid (RTLF) proteins, i.e., surfactant protein A (SP-A) and albumin. Ten healthy volunteers were included in the study and participated in two sampling sessions. Blood, exhaled breath condensate (EBC) and PEx were collected at each session. 100 L of breath were collected for each exhaled sample. Serum and exhaled samples were analyzed for SP-A using an in house ELISA. Albumin was analyzed in exhaled samples using a commercial ELISA kit. SP-A detection rates were 100%, 21%, and 89% for PEx, EBC and serum, respectively. Albumin was detected in PEx, but not in EBC. SP-A measurements in PEx showed good repeatability with an intra-individual coefficient of variation of 13%. Both SP-A and albumin showed significant correlation to mass of PEx (r(s) = 0.93, p < 0.001 and r(s) = 0.86, p = 0.003, respectively). Sampling and analysis of PEx is a valid non-invasive method to monitor RTLF proteins sampled from the lower respiratory tract, as demonstrated here by example of SP-A and albumin analysis. PMID- 22100539 TI - Dynamic hyperinflation during exercise in patients with precapillary pulmonary hypertension. AB - BACKGROUND: Patients with pulmonary arterial hypertension often present with a mild obstructive lung pattern, however, the functional consequences are not known. METHODS: We analysed flow volume loops during exercise in 61 patients with precapillary pulmonary hypertension (PH) (age 55 +/- 14 years) in comparison with 21 patients with COPD (60 +/- 12 years), 39 patients with pulmonary fibrosis (58 +/- 11 years) and 38 healthy controls (HC) (39 +/- 15 years). Inspiratory capacity (IC) was measured at rest, and during maximum exercise (max). RESULTS: HC exhibited a stable IC of 3.0 +/- 0.9 l at rest, and at max. A reduction in IC of 2.6 +/- 0.8 l at rest to 2.0 +/- 0.7 l at max was observed in patients with COPD. Patients with PH exhibited a significant reduction in IC from 2.3 +/- 0.6 l at rest to 2.1 +/- 0.6 l at max, while patients with pulmonary fibrosis exhibited a stable IC of 1.8 +/- 0.6 at rest and 1.7 +/- 0.6 l at max. In patients with PH, a weak negative correlation was drawn between the change in IC (%) and peak VO2 (r = -0.29, p = 0.01), as well as with PVR (r = -0.27, p = 0.02). CONCLUSION: Patients with PH demonstrate a characteristic change in IC during exercise, which might contribute to impaired exercise tolerance. PMID- 22100540 TI - Detection and quantification of schistosome DNA in freshwater snails using either fluorescent probes in real-time PCR or oligochromatographic dipstick assays targeting the ribosomal intergenic spacer. AB - Several DNA probes were designed for use in real-time polymerase chain reaction (PCR) assays to target sequence variation within the ribosomal intergenic spacer (IGS) of schistosomes. A sub-section of the IGS (~300bp) was amplified, with cross-specific primers, after which group-specific fluorescent, locked nucleic acid probes were assessed for their ability to differentiate and quantify DNA from Schistosoma haematobium and Schistosoma mansoni group parasites. A number of fluorescent probe candidates were screened and validated against genomic DNA from adult schistosome worms and laboratory infected freshwater snails. Two fluorescent, locked nucleic acid probes ShaemLNA5 and SmanLNA2, of 20-26bp in length, were identified and found to be effective in providing evidence of infection in field-collected snails. To adapt these real-time PCR assays for more resource-poor laboratory settings, a PCR-restriction fragment length polymorphism (RFLP) assay was developed and primer/probe combinations were modified for use in oligochromatography, a DNA 'dipstick' technology. An appropriate dipstick was developed, inclusive of internal amplification and amplicon migration controls that could be of particular importance for assessing schistosome transmission dynamics. These assays and tools also have future potential for use in detection of schistosome infections in humans and livestock. PMID- 22100541 TI - Heterochromatin influences the secondary metabolite profile in the plant pathogen Fusarium graminearum. AB - Chromatin modifications and heterochromatic marks have been shown to be involved in the regulation of secondary metabolism gene clusters in the fungal model system Aspergillus nidulans. We examine here the role of HEP1, the heterochromatin protein homolog of Fusarium graminearum, for the production of secondary metabolites. Deletion of Hep1 in a PH-1 background strongly influences expression of genes required for the production of aurofusarin and the main tricothecene metabolite DON. In the Hep1 deletion strains AUR genes are highly up regulated and aurofusarin production is greatly enhanced suggesting a repressive role for heterochromatin on gene expression of this cluster. Unexpectedly, gene expression and metabolites are lower for the trichothecene cluster suggesting a positive function of Hep1 for DON biosynthesis. However, analysis of histone modifications in chromatin of AUR and DON gene promoters reveals that in both gene clusters the H3K9me3 heterochromatic mark is strongly reduced in the Hep1 deletion strain. This, and the finding that a DON-cluster flanking gene is up regulated, suggests that the DON biosynthetic cluster is repressed by HEP1 directly and indirectly. Results from this study point to a conserved mode of secondary metabolite (SM) biosynthesis regulation in fungi by chromatin modifications and the formation of facultative heterochromatin. PMID- 22100542 TI - Prescription medication use among normal weight, overweight, and obese adults, United States, 2005-2008. AB - PURPOSE: We sought to describe differences between normal weight, overweight, and obese adults in use of specific prescription medication classes. METHODS: Cross sectional analysis of prescription medication use among 9789 adults in the National Health and Nutrition Examination Survey, a nationally representative sample of the United States. RESULTS: In 2005-2008, 56.4% (95% confidence interval [CI], 54.6-58.3) of adults used 1+ prescription medication. Approximately one-quarter of adults used a hypertension medication (26.1%; 95% CI, 24.5%-27.8%). The use of hypertension medications increased with increasing weight status (normal weight: 17.2%; 95% CI, 15.6%-18.8%; overweight: 24.5%, 95% CI, 22.6%-26.4%; and obese: 35.1%, 95% CI, 32.8%-37.4%). Similarly, lipid lowering, analgesic, antidepressant, proton pump inhibitors, thyroid, diabetes, and bronchodilator medication use was greater among obese compared with normal weight adults (each p < .01). Among adults 65+ years, 72% (95% CI, 68.2%-75.8%) of men and 67.7% (95% CI, 64.3%-71.2%) of women used a hypertension medication and a majority of men (51.2%, 95% CI, 48.4%-54%) and 40.3% (95% CI, 36.8%-43.8%) of women used lipid lowering medications; the use of both was greater among obese adults compared to normal weight adults (both p < .01). CONCLUSIONS: Obese adults in the United States use several prescription medication classes more frequently, than normal weight adults, including hypertension, lipid-lowering, and diabetes medications. PMID- 22100543 TI - Change of sex gaps in total and cause-specific mortality over the life span in the United States. AB - PURPOSE: Previous research has led to the expectation that the gap in mortality between sexes narrows in older ages as sex differences in fecundity decrease. However, the patterns and explanations of variations in sex disparities in mortality across the life span and underlying causes of death are not well understood. We conducted a population-based study to further test this hypothesis. METHODS: By using a nationally representative sample of adults (N = 25,254) with mortality follow-ups for 18 years, we modeled age variations in sex differences in risks of mortality from leading causes of death. RESULTS: Male excesses in mortality decrease at older ages significantly for some but not all causes. Differential exposures to social, physiological, and morbidity risk factors account for the late life reductions of the sex mortality gaps completely in circulatory diseases, partially or minimally in the other causes of death. Social status and relationship are more important risk factors for mortality in younger ages, health behaviors are significant for all ages, and physiological dysregulation is more predictive of mortality in older ages. CONCLUSIONS: Sex differences in the risk of mortality have strong age variations and are cause specific. Additional studies of age acceleration of cancer mortality risk are needed. PMID- 22100544 TI - LARG links histamine-H1-receptor-activated Gq to Rho-GTPase-dependent signaling pathways. AB - Activation of heterotrimeric G proteins, such as G(12/13) and G(q), by cell surface receptors is coupled to the regulation of numerous cellular functions controlled by activated Rho GTPases. Previous studies have implicated the Rho guanine nucleotide exchange factor (RhoGEF) leukemia-associated RhoGEF (LARG) as a regulatory protein receiving stimulatory inputs from activated Galpha(12/13) and Galpha(q). However, the molecular mechanisms of the Galpha(q)-mediated LARG activation are not fully understood and the structural elements of LARG involved in this process have remained unclear. In the present work, the specific coupling of the histamine H1 receptor (HRH1) exogenously expressed in COS-7 cells to G(q), but not to G(12/13), was used to conduct a detailed analysis of receptor- and Galpha(q)-mediated LARG activation and to define its structural requirements. The results show that HRH1-mediated activation of the strictly Rho-dependent transcriptional activity of serum response factor requires the PDZ domain of LARG and can be mimicked by activated Galpha(q)(Q209L). The functional interaction between activated Galpha(q) and LARG requires no more than the catalytic DH-PH tandem of LARG, and is independent of PLCbeta activation and distinct from the mechanisms of Galpha(q)-mediated p63RhoGEF and PLCbeta(3) activation. Activated Galpha(q) physically interacts with the relevant portions of LARG in COS-7 cells and histamine causes activation of LARG in native HeLa cells endogenously expressing HRH1, G(q), and LARG. This work is the first positive demonstration of a stimulatory effect of LARG on the ability of a strictly G(q)-coupled receptor to cause activation of a Rho-GTPase-dependent signaling pathway. PMID- 22100545 TI - Microbial control of malaria: biological warfare against the parasite and its vector. AB - Microbial applications in malaria transmission control have drawn global attention. Mosquito midgut microbiota can modulate vector immunity and block Plasmodium development. Paratransgenic manipulation of bacterial symbionts and Wolbachia can affect reproductive characteristics of mosquitoes. Bacillus-based biolarvicides can control mosquito larvae in different breeding habitats, but their effectiveness differs according to the type of formulation applied, and the physical and ecological conditions of the environment. Entomopathogenic fungi show promise as effective and evolution-proof agents against adult mosquitoes. In addition, transgenic fungi can express anti-plasmodial effector molecules that can target the parasite inside its vector. Despite showing effectiveness in domestic environments as well as against insecticide-resistant mosquitoes, claims towards their deployability in the field and their possible use in integrated vector management programmes have yet to be investigated. Viral pathogens show efficacy in the interruption of sporogonic development of the parasite, and protozoal pathogens exert direct pathogenic potential on larvae and adults with substantial effects on mosquito longevity and fecundity. However, the technology required for their isolation and maintenance impedes their field application. Many agents show promising findings; however, the question remains about the epidemiologic reality of these approaches because even those that have been tried under field conditions still have certain limitations. This review addresses aspects of the microbial control of malaria between proof-of-concept and epidemiologic reality. PMID- 22100547 TI - The substance use profile of Canadian youth: exploring the prevalence of alcohol, drug and tobacco use by gender and grade. AB - The current study examined the prevalence of alcohol, tobacco and drug use and comorbid use of these substances among 45,425 students in grades 7 to 12 as part of the 2008-09 Canadian Youth Smoking Survey. The results of this paper suggest that alcohol, tobacco, marijuana and illicit drugs are currently used by a substantial number of youth in Canada, and that comorbid use is also very widespread among users. Alcohol was the most prevalent substance used by youth and it was rare to find youth who had used tobacco or drugs without also currently using alcohol. By grade 12, the majority of students were current users of alcohol, tobacco or drugs. Future research should consider developing a better understanding of how to prevent substance use among this population. PMID- 22100546 TI - Malaria elimination in Malawi: research needs in highly endemic, poverty-stricken contexts. AB - Malaria control in the impoverished, highly endemic settings of sub-Saharan Africa remains a major public health challenge. Successes have been achieved only where sustained, concerted, multi-pronged interventions have been instituted. As one of the world's poorest countries, Malawi experiences malaria incidence rates that have remained high despite a decade of gradually expanding and more intensive prevention efforts. The Malawi International Center for Excellence in Malaria Research (ICEMR) is beginning work to augment the knowledge base for reducing Plasmodium transmission and malaria morbidity and mortality. Among ICEMR goals, we intend to better assess patterns of infection and disease, and analyze transmission by Anopheles vector species in both urban and rural ecological settings. We will evaluate parasite population genetics and dynamics, transmission intensities and vector ecologies, social and environmental determinants of disease patterns and risk, and human-vector-parasite dynamics. Such context-specific information will help to focus appropriate prevention and treatment activities on efforts to control malaria in Malawi. In zones of intense and stable transmission, like Malawi, elimination poses particularly thorny challenges - and these challengers are different from those of traditional control and prevention activities. Working toward elimination will require knowledge of how various interventions impact on transmission as it approaches very low levels. At present, Malawi is faced with immediate, context-specific problems of scaling-up prevention and control activities simply to begin reducing infection and disease to tolerable levels. The research required to support these objectives is critically evaluated here. PMID- 22100548 TI - Concurrent heroin use among methadone maintenance clients in China. AB - BACKGROUND: The study examined concurrent illicit heroin use among methadone maintenance clients in China and its association with clients' demographic characteristics, treatment experience, and personal social network. METHODS: Face to-face surveys were conducted with 178 clients randomly recruited from six methadone maintenance treatment (MMT) clinics in Sichuan, China. Concurrent heroin use was measured based on self-report of heroin use during the past 30 days and a confirmatory urine morphine test. The participants' demographic characteristics and treatment factors were measured and examined. The drug use status of their family members and friends was also assessed. RESULTS: A total of 80 participants (44.9%) who either reported illicit heroin use in the past 30 days or had a positive urine test were defined as using heroin concurrently. Having drug-using friends was significantly associated with increased concurrent heroin use. Longer length of treatment (2 years or longer) was associated with increased concurrent heroin use. Among those who had both drug-using family members and friends, more women (71.4%) than men (50.0%) used heroin. For those who had no drug-using family members or friends, more men (34.8%) than women (20.8%) used heroin. DISCUSSION: Study findings indicate an urgent need to address concurrent illicit heroin use among MMT clients. Further examination of the influence of social networks on concurrent drug abuse behavior is encouraged. Results also highlight the importance of understanding gender differences in treatment seeking and behavioral changes, which is crucial to the development of gender-specific treatment strategies. PMID- 22100549 TI - High-performance liquid chromatography analysis of a novel small-molecule, anti cancer drug, Palomid 529, in human and mouse plasma and in mouse tissue homogenates. AB - Palomid 529 (8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy) benzo[c]chromen-6-one), is a novel non-steroidal small-molecule drug, which inhibits both mTORC1 and mTORC2 assembly, and elicits both anti-angiogenic and direct anti-tumor effects in vivo. We have developed and validated a sensitive and selective method for the quantification of Palomid 529 in human and mouse plasma and in a range of mouse tissue samples. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether yielding a recovery of >75%. Palomid 529 and the internal standard Palomid 545 were separated using a GraceSmart RP18 column (2.1 mm * 150 mm) packed with 5 MUm C-18 material and a mobile phase comprised of 50% (v/v) acetonitrile and 50% (v/v) water delivered at a flow rate of 0.2 ml/min, and were detected by UV absorbance at a wavelength of 315 nm. Within the linear range of the calibration curve (10-10,000 ng/ml), acceptable accuracy and precision was achieved for all tested matrices. The validation results show that the method was selective and reproducible. Palomid 529 was stable in plasma upon 3 repeated freeze-thaw cycles and during storage for up to 24h at ambient temperature. However, pre-treated samples waiting for HPLC analyses need to be kept under dimmed light conditions at ambient temperature since a significant degradation of both Palomid 529 and Palomid 545 was observed when exposed to light. A pilot pharmacokinetic study in mice demonstrated the applicability of this method for pharmacokinetic purposes. Even at a low dose of 5.4 mg/kg this assay was still sensitive enough to determine the drug concentration in plasma samples obtained up to 24h after administration. PMID- 22100550 TI - Purification of lipase produced by a new source of Bacillus in submerged fermentation using an aqueous two-phase system. AB - This work discusses the application of an aqueous two-phase system for the purification of lipases produced by Bacillus sp. ITP-001 using polyethylene glycol (PEG) and potassium phosphate. In the first step, the protein content was precipitated with ammonium sulphate (80% saturation). The enzyme remained in the aqueous solution and was dialyzed against ultra-pure water for 18 h and used to prepare an aqueous two-phase system (PEG/potassium phosphate). The use of different molecular weights of PEG to purify the lipase was investigated; the best purification factor (PF) was obtained using PEG 20,000g/mol, however PEG 8000 was used in the next tests due to lower viscosity. The influence of PEG and potassium phosphate concentrations on the enzyme purification was then studied: the highest FP was obtained with 20% of PEG and 18% of potassium phosphate. NaCl was added to increase the hydrophobicity between the phases, and also increased the purification factor. The pH value and temperature affected the enzyme partitioning, with the best purifying conditions achieved at pH 6.0 and 4 degrees C. The molecular mass of the purified enzyme was determined to be approximately 54 kDa by SDS-PAGE. According to the results the best combination for purifying the enzyme is PEG 8000g/mol and potassium phosphate (20/18%) with 6% of NaCl at pH 6.0 and 4 degrees C (201.53 fold). The partitioning process of lipase is governed by the entropy contribution. PMID- 22100551 TI - Evaluation of the performance of protein separation in figure-8 centrifugal counter-current chromatography. AB - The performance of protein separation using the figure-8 column configuration in centrifugal counter-current chromatography was investigated under various flow rates and revolution speeds. The separation was performed with a two-phase solvent system composed of polyethylene glycol 1000/potassium phosphate each at 12.5% (w/w) in water and with lysozyme and myoglobin as test samples. In order to improve tracing of the elution curve, a hollow fiber membrane dialyzer was inserted at the inlet of the UV detector. The results showed that the retention of stationary phase (Sf) and resolution (Rs) increased with decreased flow rate and increased revolution speed. The highest Rs of approximately 1 was obtained at a flow rate of 0.01 mL/min under a revolution speed of 1200 rpm with a 3.4 mL capacity column. PMID- 22100552 TI - A rapid and sensitive method for the analysis of brain monoamine neurotransmitters using ultra-fast liquid chromatography coupled to electrochemical detection. AB - Electrochemical detection is often used to detect catecholamines and indolamines in brain samples that have been separated by conventional reverse-phase high performance liquid chromatography (HPLC). This paper presents the transfer of an existing chromatographic method for the determination of monoamines in brain tissues using 5 MUm granulometry HPLC columns to columns with a particle diameter less than 3 MUm. Several parameters (repeatability, linearity, accuracy, limit of detection, and stability of samples) for this new ultrafast high performance liquid chromatography (UHPLC) method were examined after optimization of the analytical conditions. The separation of seven compounds, noradrenaline, dopamine and three of its metabolites, dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxytyramine, and serotonin and its metabolite, 5-hydroxyindole-3-acetic acid was analyzed using this UHPLC-electrochemical detection method. The final method, which was applied to brain tissue extracts from mice, rats, and cats, decreased analysis time by a factor of 4 compared to HPLC, while guaranteeing good analytical performance. PMID- 22100553 TI - Simple and rapid determination of thiol compounds by HPLC and fluorescence detection with 1,3,5,7-tetramethyl-8-phenyl-(2-maleimide) difluoroboradiaza-s indacene. AB - A rapid and simple background-free high-performance liquid chromatographic (HPLC) approach has been developed for simultaneously determining free thiol compounds including coenzyme A (CoA), cysteine (Cys), glutathione (GSH) and N-acetyl cysteine (NAC) in biological samples by using 1,3,5,7-tetramethyl-8-phenyl-(2 maleimide) difluoroboradiaza-s-indacene (TMPAB-o-M) as fluorogenic reagent. After derivatization under physiological conditions within 6 min, baseline separation was finished in just 6 min using isocratic elution with reversed-phase HPLC and fluorescence detection. Excellent linearity was observed for all analytes over their concentration ranges of 1-500 nM and detection limits ranging 0.13 nM for CoA to 0.25 nM for Cys (S/N=3) were achieved. The utility of the proposed method has been validated by measuring thiol compounds mentioned above in tissue, fluid and cell samples. The results indicated that this approach was well suited for high-throughput quantitative determination of thiols and study of the physiological role of them. PMID- 22100554 TI - Protein characterization by LC-MS/MS may be required for the DNA identification of a fusion hemoglobin: the example of Hb P-Nilotic. AB - DNA analysis is currently the easiest way to identify a hemoglobin variant in most cases. Nevertheless, in case of complex gene rearrangements, mass spectrometry studies may be required to orientate the DNA diagnosis. The present report shows the use of mass spectrometry techniques prior to DNA analysis for the identification of the rare P-Nilotic fusion hemoglobin. Complete protein analysis is performed by liquid chromatography-tandem mass spectrometry on the abnormal globin chain isolated by reversed-phase liquid chromatography. PMID- 22100555 TI - Successful and cost-efficient replacement of immunoassays by tandem mass spectrometry for the quantification of immunosuppressants in the clinical laboratory. AB - The purpose of this paper is to describe the implantation of mass spectrometry in replacement of immunoassays for the measurement of immunosuppressant drugs in the clinical setting, from scientific and financial perspectives. A straightforward, rapid, and economical method was developed for the simultaneous quantification of tacrolimus, sirolimus, and cyclosporine. Following a simple protein precipitation step, supernatants are injected on a small C(18) guard cartridge and gradient elution of the immunosuppressants is performed in a total chromatographic run time of 2.25 min. Sodium adducts of the compounds and internal standards are quantified by electrospray tandem mass spectrometry. The method shows inter-assay impression of less than 10-15% for all compounds with good extraction efficiency (89-104%) and minimal matrix effects, except for sirolimus where ion suppression is more pronounced. The method correlates well with chemiluminescent microparticle immunoassays (on the Abbott Architect analyzer), although the immunoassay results are significantly higher than those obtained by HPLC-MS/MS. The transition from immunoassays to mass spectrometry was well received by the laboratory staff, and significant reductions in reagent costs have been realized (>$250,000 CAD per year). With these savings, the purchase and installation of two complete HPLC-MS/MS systems was completely financed in less than three years. PMID- 22100556 TI - Biomimetic affinity purification of Candida antarctica lipase B. AB - Candida antarctica lipase B (CalB) is one of the most widely used biocatalysts in organic synthesis. The traditional method for purification of CalB is a multi step, high cost and low recovery procedure. Biomimetic affinity purification had high efficiency purification. We selected 298 ligand columns from a 700-member library of synthetic ligands to screen Pichia pastoris protein extract. Of the 298, three columns (named as A9-14, A9-10, and A11-33) had one-step purification effect, and A9-14 of these affinity ligands, had both high purification and recovery. The one-step recovery of CalB reached 73% and the purification reached 91% upon purification. The active groups of A9-14 were cyclohexylamine and propenylamine. Furthermore, both A9-14 and A9-10 had the same R1 active group of cyclohexylamine which might act the main binding role for CalB. The synthetic ligand A9-14 had a binding capacity of 0.4 mg/mL and had no negative effects on its hydrolytic activity. Unlike a natural affinity ligand, this synthetic ligand is highly stable to resist 1M NaOH, and thus has great potential for industrial scale production of CalB. PMID- 22100557 TI - Simplified absolute metabolite quantification by gas chromatography-isotope dilution mass spectrometry on the basis of commercially available source material. AB - In the field of metabolomics, GC-MS has rather established itself as a tool for semi-quantitative strategies like metabolic fingerprinting or metabolic profiling. Absolute quantification of intra- or extracellular metabolites is nowadays mostly accomplished by application of diverse LC-MS techniques. Only few groups have so far adopted GC-MS technology for this exceptionally challenging task. Besides numerous and deeply investigated problems related to sample generation, the pronounced matrix effects in biological samples have led to the almost mandatory application of isotope dilution mass spectrometry (IDMS) for the accurate determination of absolute metabolite concentrations. Nevertheless, access to stable isotope labeled internal standards (ILIS), which are in many cases commercially unavailable, is quite laborious and very expensive. Here we present an improved and simplified gas chromatography-isotope dilution mass spectrometry (GC-IDMS) protocol for the absolute determination of intra- and extracellular metabolite levels. Commercially available (13)C-labeled algal cells were used as a convenient source for the preparation of internal standards. Advantages as well as limitations of the described method are discussed. PMID- 22100558 TI - Quantification of bioactive sphingo- and glycerophospholipid species by electrospray ionization tandem mass spectrometry in blood. AB - Bioactive glycerophospho- and sphingolipids species are involved in the regulation of numerous biological processes and implicated in the pathophysiology of various diseases. Here we review electrospray ionization tandem mass spectrometric (ESI-MS/MS) methods for the analysis of these bioactive lipid species in blood including lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), bis(monoacylglycero)phosphate (BMP), ceramide (Cer), sphingosine-1 phosphate (S1P) and sphingosylphosphorylcholine (SPC). Beside direct tandem mass spectrometric and liquid chromatography coupled approaches, we present an overview of concentrations of these bioactive lipids in plasma. The analytical strategies are discussed together with aspects of sample preparation, quantification and sample stability. PMID- 22100559 TI - High-performance liquid chromatographic determination of tiapride and its phase I metabolite in blood plasma using tandem UV photodiode-array and fluorescence detection. AB - New bioanalytical SPE-HPLC-PDA-FL method for the determination of the neuroleptic drug tiapride and its N-desethyl metabolite was developed, validated and applied to xenobiochemical and pharmacokinetic studies in humans and animals. The sample preparation process involved solid-phase extraction of diluted plasma spiked with sulpiride (an internal standard) using SPE cartridges DSC-PH Supelco, USA. Chromatographic separation of the extracts was performed on a Discovery HS F5 250 mm * 4 mm (Supelco) column containing pentafluorophenylpropylsilyl silica gel. Mobile phase (acetonitrile-0.01 M phosphate buffer pH=3, flow rate 1 ml min(-1)) in the gradient mode was employed in the HPLC analysis. Tandem UV photodiode array->fluorescence detection was used for the determination of the analytes. Low concentrations of tiapride and N-desethyl tiapride were determined using a more selective fluorescence detector (lambda(exc.)/lambda(emiss.)=232 nm/334 nm), high concentrations (500-6000 pmol ml(-1)) using a UV PDA detector at 212 nm with a linear response. Each HPLC run lasted 15 min. Lower limits of quantification (LLOQ) for tiapride (N-desethyl tiapride) were found to be 8.24 pmol ml(-1) (10.11 pmol ml(-1)). The recoveries of tiapride ranged from 89.3 to 94.3%, 81.7 to 86.8% for internal standard sulpiride and 90.9 to 91.8% for N-desethyl tiapride. PMID- 22100560 TI - Relative magnitude of vascular reactivity in the major arterioles of the retina. AB - The relative magnitude of vascular reactivity to inhaled gas stimuli in the major retinal arterioles has not been systematically investigated. The purpose of this study was to compare the magnitude of retinal vascular reactivity in response to inhaled gas provocation at equivalent measurement sites in the superior-, and inferior-, temporal retinal arterioles (STA, ITA). One randomly selected eye of each of 17 healthy volunteers (age 24.4 +/- 4.7) was prospectively enrolled. Volunteers were connected to a sequential gas delivery circuit and a computer controlled gas blender (RespirActTM, Thornhill Research Inc., Canada) and underwent an isocapnic hyperoxic challenge i.e. P(ET)O(2) of 500 mm Hg with P(ET)CO(2) maintained at 38 mm Hg during baseline and hyperoxia. Four retinal hemodynamic measurements were acquired using bi-directional laser Doppler velocimetry and simultaneous vessel densitometry (Canon Laser Blood Flowmeter, CLBF-100, Japan) at equivalent positions on the STA and ITA. Statistical analysis was performed using linear mixed-effect models. During the hyperoxic phase, the vessel diameter (STA p=0.004; ITA p=0.003), blood velocity (STA p<0.001; ITA p<0.001) and flow (STA p<0.001; ITA p<0.001) decreased in both the STA and the ITA relative to baseline. The diameter, velocity and flow were equivalent between STA and ITA at baseline and during hyperoxia; and their magnitude of change remained comparable with hyperoxia (p>0.05). The magnitude of retinal arteriolar vascular reactivity in response to isocapnic hyperoxic inhaled gas challenge was not significantly different between the STA and ITA. However, the correlation analysis did not reveal a significant relationship between the percentage changes in diameter, velocity and flow of the STA and ITA and did not demonstrate equal responses from the STA and ITA to gas provocation. PMID- 22100561 TI - Spatio-temporal variations in cell-free layer formation near bifurcations of small arterioles. AB - Blood flow partitioning at an arteriolar bifurcation could lead to spatio temporal variations in cell-free layer formation in the upstream and downstream vessels of the bifurcation. To investigate this effect, we quantitatively analyzed characteristics of the cell-free layer in the vicinity of an arteriolar bifurcation in the rat cremaster muscle in normal physiological flow conditions. To simulate hemorheological relevance to humans, red blood cell aggregation was elevated by infusion of Dextran 500 to levels seen in humans in normal states. Spatial variations of the layer width were observed in both the parent and larger daughter vessels. A more pronounced attenuation of the layer width was generally observed in the parent vessel at its wall adjacent to the side branch than at its opposite wall. A thicker layer width was consistently found at the opposite than adjacent wall of the larger daughter vessel. Accordingly, large asymmetries of the layer widths could be developed on opposite sides of the larger daughter vessel, which were significantly greater (P<0.01) than those observed in the parent vessel. A positive correlation was generally observed between mean layer widths in the downstream vessel and on the side of the parent vessel from which bulk of the flow enters the downstream vessel. The fraction of the downstream layer formation constituted by the side branch decreased with increasing flow fraction in this vessel. These findings confirmed the modulation of the cell-free layer formation near an arteriolar bifurcation, implicated by flow separation at the bifurcation. PMID- 22100562 TI - Antioxidant and anti-inflammatory properties of Capsicum baccatum: from traditional use to scientific approach. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Peppers from Capsicum species (Solanaceae) are native to Central and South America, and are commonly used as food and also for a broad variety of medicinal applications. AIM OF THE STUDY: The red pepper Capsicum baccatum var. pendulum is widely consumed in Brazil, but there are few reports in the literature of studies on its chemical composition and biological properties. In this study the antioxidant and anti-inflammatory activities of Capsicum baccatum were evaluated and the total phenolic compounds and flavonoid contents were determined. MATERIALS AND METHODS: The antioxidant property was assayed by scavenging abilities using DPPH and the anti-inflammatory activity was tested through the carrageenan-induced pleurisy model in mice. The total phenolic compounds and flavonoid contents were determined spectrophotometrically. RESULTS: The ethanolic and butanol extracts (200mg/kg, p.o.) presented a significant anti inflammatory activity toward carrageenan-induced pleurisy model in mice in comparison to dexamethasone (0.5mg/kg, s.c.). Among the parameters evaluated, the treatment with these samples inhibited leukocyte migration and reduced the formation of exudate. The contents of flavonoids and total phenolic compounds could be correlated with the antioxidant and anti-inflammatory activities observed for Capsicum baccatum. CONCLUSIONS: Our findings suggest that Capsicum baccatum contains potential antioxidant and anti-inflammatory compounds which could be tested as drug candidates against oxidative and inflammation-related pathological processes in medicinal chemistry studies. PMID- 22100563 TI - Trillin, a steroidal saponin isolated from the rhizomes of Dioscorea nipponica, exerts protective effects against hyperlipidemia and oxidative stress. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Numerous efforts have been conducted in searching for effective agents against cardiovascular diseases, in particular from herbal medicines. The rhizome of Dioscorea nipponica (Dioscoreae Nipponicae Rhizoma) is a traditional Chinese herb being prescribed to improve the blood circulation. Here, we identified a steroidal saponin trillin from Dioscorea nipponica, which showed robust anti-hyperlipidemic effects. MATERIALS AND METHODS: Rats were induced for hyperlipidemia and subjected to the drug treatment. The anti hyperlipidemic effects of trillin were evaluated by different biochemical assays. RESULTS: In hyperlipidemic rat model, fed with high-fat diet, the blood levels of cholesterol, triglyceride, low density lipoprotein (LDL) and high density lipoprotein (HDL) were increased. The intra-peritoneal administration of trillin into those rats significantly improved the bleeding and blood coagulation time, and in parallel the treatment restored the levels of cholesterol, glyceride, LDL and HDL back to the normal condition. In addition, the administration of trillin in rats exerted beneficial effects in improving the levels of lipid peroxidation and superoxide dismutase activity. CONCLUSION: This was the first time to reveal the anti-hyperlipidemic and anti-oxidative effects of trillin. These results would be important in developing food supplements for health improvements and therapeutic drugs against hyperlipidemia and cardiovascular diseases in future. PMID- 22100564 TI - Mechanisms of action underlying the gastric antiulcer activity of the Rhizophora mangle L. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizophora mangle, the red mangrove, has long been known as a traditional antiulcer medicine. The present work evaluated the mechanisms of action involved in the anti-ulcer properties of the Rhizophora mangle bark extracts. MATERIALS AND METHODS: Gastroprotection of Rhizophora mangle was evaluated in rodent experimental models (ethanol). To elucidate the mechanisms of action the antisecretory action and involvement of NO, SH, mucus and PGE(2) were evaluated. The acetic acid-induced gastric ulcer model, Western blotting assay (COX-1, COX-2 and EGF) and immunohistochemical localization of HSP 70, PCNA and COX-2 were also used to evaluate the Rhizophora mangle healing properties. RESULTS: Results showed that Rhizophora mangle bark crude extract (CE), as well as ethyl acetate (EtOAc) and butanolic fractions (BuOH) provided significant gastroprotection at all the tested doses. Thereby, the following protocols were performed using the lowest dose capable of producing the most effective gastroprotection, which was the BuOH 0.5mg/kg (P<0.001). Several mechanisms are involved in the antiulcer activity of Rhizophora mangle, such as, participation of NO, SH and mucus. The enhancement of PGE(2) levels and the upregulation of COX-2 and EGF seem to be directly linked to the antisecretory, cytoprotective and healing effects of BuOH. HSP-70 and PCNA are also involved in this cicatrisation process. No sign of toxicity was observed in this study, considering the analyzed parameters. CONCLUSION: Our study reinforces its traditional medicinal use. Considering that the current therapies are based on the use of antisecretory or cytoprotective drugs, the Rhizophora mangle arises as a promising alternative antiulcer therapy. PMID- 22100565 TI - Protective action of mithramycin against neurodegeneration and impairment of synaptic plasticity in the hippocampal CA1 area after transient global ischemia. AB - Mithramycin A (MTM) is an antibiotic used for the treatment of hypercalcemia and several types of cancer. We have reported previously that MTM protects against endoplasmic reticulum (ER) stress-induced neuronal death in organotypic hippocampal slice cultures. In the present study, the neuroprotective effect of MTM against ischemia/reperfusion-induced neuronal injury was evaluated in the hippocampus in mice. Neuronal damage was apparent in area CA1 of the hippocampus after transient global ischemia/reperfusion. The expression of C/EBP homologous protein (CHOP), a key transcription factor for ER stress-induced neuronal death, showed a pronounced increase in area CA1 in these mice. Treatment of the mice with MTM significantly decreased both the number of neurons stained with Fluoro Jade B and the level of CHOP expression in the hippocampus. MTM did not affect the increase of 78-kDa glucose-regulated protein induced by ischemia/reperfusion. MTM also restored the ischemia/reperfusion-induced impairment of long-term potentiation in the hippocampus, without any change in paired pulse facilitation. These results suggest that administration of MTM protects hippocampal neurons against injury induced by transient global ischemia/reperfusion through attenuation of ER stress-associated signals, and ameliorates neuronal injury induced by ischemia/reperfusion in the hippocampus. PMID- 22100567 TI - Neurological complications of acute liver failure: pathophysiological basis of current management and emerging therapies. AB - One of the major causes of mortality in patients with acute liver failure (ALF) is the development of hepatic encephalopathy (HE) which is associated with increased intracranial pressure (ICP). High ammonia levels, increased cerebral blood flow and increased inflammatory response have been identified as major contributors to the development of HE and the related brain swelling. The general principles of the management of patients with ALF are straightforward. They include identifying the insult causing hepatic injury, providing organ systems support to optimize the patient's physical condition, anticipation and prevention of development of complications. Increasing insights into the pathophysiological mechanisms of ALF are contributing to better therapies. For instance, the evident role of cerebral hyperemia in the pathogenesis of increased ICP has led to a re evaluation of established therapies such as hyperventilation, N-acetylcysteine, thiopentone sodium and propofol. The role of systemic inflammatory response in the pathogenesis of increased ICP has also gained importance supporting the concept that antibiotics given prophylactically reduce the risk of developing sepsis during the course of illness. Moderate hypothermia has also been established as a therapy able to reduce ICP in patients with uncontrolled intracranial hypertension and to prevent increases in ICP during orthopic liver transplantation. Ornithine phenylacetate, a new drug in the treatment of liver failure, and liver replacement therapies are still being investigated both experimentally and clinically. Despite many advances in the understanding of the pathophysiological basis and the management of intracranial hypertension in ALF, more clinical trials should be conducted to determine the best therapeutic management for this difficult clinical event. PMID- 22100566 TI - Blood-brain barrier in acute liver failure. AB - Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF. PMID- 22100568 TI - Pathological alterations of astrocytes in stroke-prone spontaneously hypertensive rats under ischemic conditions. AB - Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. We showed the vulnerability of neuronal cells of SHRSP/Izm rats. Furthermore, we analyzed the characteristics of SHRSP/Izm astrocytes during a stroke. It is known that the proliferating ability of SHRSP/Izm astrocytes is significantly enhanced compared with those in the normotensive Wistar Kyoto rats (WKY/Izm) strain. Conversely, the ability of SHRSP/Izm astrocytes to form tight junctions (TJ) was attenuated compared with astrocytes from WKY/Izm rats. During the stress of hypoxia and reoxygenation (H/R), lactate production, an energy source for neuronal cells, decreased in SHRSP/Izm astrocytes in comparison with the WKY/Izm strain. Moreover, during H/R, SHRSP/Izm astrocytes decreased their production of glial cell line-derived neurotrophic factor (GDNF) in comparison with WKY/Izm astrocytes. Furthermore, SHRSP/Izm rats decreased production of l-serine, compared with WKY/Izm rats following nitric oxide (NO) stimulation. Additionally, in H/R, astrocytes of SHRSP/Izm rats expressed adhesion molecules such as VCAM-1 at higher levels. It is possible that all of these differences between SHRSP/Izm and WKY/Izm astrocytes are not associated with the neurological disorders in SHRSP/Izm. However, attenuated production of lactate and reduced GDNF production in astrocytes may reduce required energy levels and weaken the nutritional status of SHRSP/Ism neuronal cells. We suggest that the attenuation of astrocytes' functions accelerates neuronal cell death during stroke, and may contribute to the development of strokes in SHRSP/Izm. In this review, we summarize the altered properties of SHRSP/Izm astrocytes during a stroke. PMID- 22100569 TI - Sources of parental burden in a UK sample of first-generation North Indian Punjabi Sikhs and their white British counterparts. AB - OBJECTIVE: The correlates of parental burden in schizophrenia may differ between ethnic groups, but few studies have examined this in a UK setting. Our aim was to identify the correlates of burden in a UK sample of first-generation North Indian Punjabi Sikh parents and their white British counterparts. METHOD: Test the association of burden with a series of clinical, social and service use variables and control for potential confounding factors in a model predicting drivers of burden in a combined sample of the above. RESULTS: The strongest correlates of burden were patient symptoms and parental distress. Differences in correlates of burden between the groups emerged when individual components of service use and parental social network were tested. The group comparisons also revealed differences in expressed emotion (EE) and social networks. CONCLUSION: The similarities in sources of burden between the groups could be explained by a commonality of sociocultural and economic experience, resulting from the successful acculturation and affluence of this British Sikh group. The differences between the groups may be related to enduring cultural factors such as kin support, since larger family groups were associated with low burden in the British Sikh group. The nature of EE in this British Sikh group may explain why it was not associated with burden in this sample. PMID- 22100570 TI - Burden of informal care giving to patients with psychoses: a descriptive and methodological study. AB - BACKGROUND: There is a lack of studies of the size of burden associated with informal care giving in psychosis. AIMS: To evaluate the objective and subjective burden of informal care giving to patients with psychoses, and to compare a diary and recall method for assessments of objective burden. METHOD: Patients and their informal caregivers were recruited from nine Swedish psychiatric outpatient centres. Subjective burden was assessed at inclusion using the CarerQoL and COPE index scales. The objective burden (time and money spent) was assessed by the caregivers daily using diaries over four weeks and by recall at the end of weeks 1 and 2. RESULTS: One-hundred and seven patients (53% females; mean age 43 +/- 11) and 118 informal caregivers (67%; 58 +/- 15 years) were recruited. Informal caregivers spent 22.5 hours/week and about 14% of their gross income on care related activities. The time spent was underestimated by two to 20 hours when assessed by recall than by daily diary records. The most prominent aspects of the subjective burden were mental problems. CONCLUSION: Despite a substantial amount of time and money spent on care giving, the informal caregivers perceived the mental aspects of burden as the most troublesome. The informal caregiver burden is considerable and should be taken into account when evaluating effects of health care provided to patients with psychoses. PMID- 22100571 TI - The use of positron emission tomography in the diagnosis of pacemaker related infection. PMID- 22100572 TI - Association between seasonal influenza vaccination in 2008-2009 and pandemic influenza A (H1N1) 2009 infection among school students from Kobe, Japan, April June 2009. AB - We assessed the effect of seasonal trivalent inactivated influenza vaccination (TIV) on pandemic influenza 2009 (pH1N1)-related illness from April to June 2009 among 2849 students (aged 12-18 years). TIV was associated with an increase in the frequency of pH1N1-related illness among subjects (adjusted odds ratio, 1.47; 95% confidence interval, 1.14-1.89). TIV during the 2008-2009 season increased the risk of pH1N1-related illness from April to June 2009. PMID- 22100573 TI - Risk of community-acquired pneumonia in veteran patients to whom proton pump inhibitors were dispensed. AB - BACKGROUND: Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. METHODS: From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. RESULTS: Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. CONCLUSIONS: Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations. PMID- 22100574 TI - Listeria monocytogenes-associated joint and bone infections: a study of 43 consecutive cases. AB - BACKGROUND: Little is known about Listeria monocytogenes-associated bone and joint infections. Only case reports of this infection have been published. METHODS: Retrospective study of culture-proven bone and joint cases reported to the French National Reference Center for Listeria from 1992 to 2010. RESULTS: Forty-three patients were studied: 61% were men, and the median age was 72 (range, 16-89); 24 patients exhibited comorbidities (56%). Thirty-six patients (84%) had orthopedic implant devices: prosthetic joints (n = 34) or internal fixation (n = 2); the median time after insertion was 9 years (0.1-22). Subacute infection was more frequent (median, 4 weeks [range, 2-100], 74%) than acute infection (<7 days, 23%), with nonspecific clinical features; 45% of patients had no fever. Blood cultures were positive in 3 of 19 cases. Isolate polymerase chain reaction genogrouping revealed 4 patterns: IVb (21 of 42, 50%), IIa (17 of 42, 40%), IIb (2 of 42, 5%), and IIc (2 of 42, 5%). Five groups of strains with similar pulsotype patterns were identified without an epidemiological link. Antibiotics, primarily amoxicillin (80%) with aminoglycosides (48%), were prescribed for a median duration of 15 weeks (range, 2-88). Eighteen patients (50%) underwent prosthesis replacement; all were successful after median follow up of 10 months (range, 1-75). Five of 13 patients for whom material was not removed had protracted infection despite prolonged antibiotherapy; 3 of these patients later underwent prosthesis replacement with sustained recovery. CONCLUSIONS: Osteoarticular listeriosis primarily involves prosthetic joints and occurs in immunocompromised patients. It requires intensive treatment with antibiotherapy and usually requires implant removal or replacement for cure. PMID- 22100575 TI - High-dose daptomycin for cardiac implantable electronic device-related infective endocarditis. AB - BACKGROUND: Cardiac implantable electronic device (CIED)-related endocarditis is a growing challenge because of increasing incidence and significant mortality. Current treatment is based on complete hardware removal coupled with long-term administration of effective and safe antimicrobials. Daptomycin at the dose of 6 mg/kg/day has been found to be effective in staphylococcal endocarditis, but limited data exist on CIED endocarditis. Moreover, whether higher doses could be more effective but equally safe in this setting is currently unknown. METHODS: We report here our experience with high-dose daptomycin in the treatment of 25 cases of CIED endocarditis due to staphylococci. RESULTS: Patients were mostly elderly and male, with large lead vegetations and severe comorbidities. Pathogens were Staphylococcus epidermidis (56%), Staphylococcus aureus (28%), and other coagulase-negative staphylococci (16%). Only 4 patients (16%) had a normal pretreatment renal function. The median daptomycin daily dose was 8.3 mg/kg (range, 6.4-10.7). Daptomycin was administered for a median of 20 days (range, 8 52). Percutaneous lead extraction was performed in 88% of patients. Two patients (8%) failed to clear bacteremia. The overall clinical success of treatment was 80%, whereas a complete microbiological success was observed in 92% of patients. Creatine phosphokinase values were monitored and increased above normal in 5 cases (20%). No serious adverse event related to high-dose daptomycin was observed and no patient required discontinuation because of muscle toxicity. CONCLUSIONS: Our experience suggests that high-dose daptomycin may be a safe therapeutic option in staphylococcal CIED endocarditis and may be associated with high microbiological responses and clinical success. PMID- 22100576 TI - Interactions between buprenorphine and the protease inhibitors darunavir ritonavir and fosamprenavir-ritonavir. AB - BACKGROUND: This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir ritonavir. METHODS: The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine. RESULTS: There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3 glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine. CONCLUSIONS: Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease. PMID- 22100577 TI - Cranberry juice for the prevention of recurrences of urinary tract infections in children: a randomized placebo-controlled trial. AB - BACKGROUND: Cranberry juice prevents recurrences of urinary tract infections (UTIs) in adult women. The objective of this study was to evaluate whether cranberry juice is effective in preventing UTI recurrences in children. METHODS: A double-blind randomized placebo-controlled trial was performed in 7 hospitals in Finland. A total of 263 children treated for UTI were randomized to receive either cranberry juice (n = 129) or placebo (n = 134) for 6 months. Eight children were omitted because of protocol violations, leaving 255 children for the final analyses. The children were monitored for 1 year, and their recurrent UTIs were recorded. RESULTS: Twenty children (16%) in the cranberry group and 28 (22%) in the placebo group had at least 1 recurrent UTI (difference, -6%; 95% confidence interval [CI], -16 to 4%; P = .21). There were no differences in timing between these first recurrences (P = .32). Episodes of UTI totaled 27 and 47 in the cranberry and placebo groups, respectively, and the UTI incidence density per person-year at risk was 0.16 episodes lower in the cranberry group (95% CI, -.31 to -.01; P = .035). The children in the cranberry group had significantly fewer days on antimicrobials (-6 days per patient-year; 95% CI, -7 to -5; P < .001). CONCLUSIONS: The intervention did not significantly reduce the number of children who experienced a recurrence of UTI, but it was effective in reducing the actual number of recurrences and related antimicrobial use. PMID- 22100578 TI - Association of IL-10-promoter genetic variants with the rate of CD4 T-cell loss, IL-10 plasma levels, and breadth of cytotoxic T-cell lymphocyte response during chronic HIV-1 infection. AB - BACKGROUND: Interleukin-10 (IL-10) is a potent immunoregulatory cytokine. IL-10 promoter polymorphisms have been shown to affect human immunodeficiency virus type 1 (HIV-1) clinical outcomes but the underlying mechanisms are poorly understood. METHODS: We investigated the relationship between IL-10-promoter variants, plasma cytokine levels, immune responses and markers of disease outcome in antiretroviral-naive HIV-1 chronically infected individuals from South Africa. Two IL-10-promoter single nucleotide polymorphisms (SNPs) were genotyped in 451 participants. Baseline plasma levels of select cytokines were measured for 112 individuals. Viral load, CD4(+) T-cell counts and HIV-1-specific interferon-gamma CD8(+) T-cell immune responses were measured at baseline. CD4(+) T-cell counts were measured longitudinally and rates of CD4(+) T-cell decline computed for 300 study subjects. RESULTS: The minor IL-10-1082G and -592A variants occurred at frequencies of 0.31 and 0.34, respectively. The -592AA genotype associated significantly with attenuated loss of CD4(+) T cells (P = .0496). Individuals possessing -1082GG had significantly higher IL-10 levels compared to -1082AA/AG (P = .0006). The -592AA genotype was associated with greater breadth of virus specific CD8(+) T-cell responses compared to CC and CA (P = .002 and .004 respectively). CONCLUSIONS: IL-10-promoter variants may influence the rate of HIV 1 disease progression by regulating IL-10 levels and the breadth of CD8(+) T-cell immune responses. PMID- 22100580 TI - StatBite: Prostate cancer U.S. mortality rate 2000-2008. PMID- 22100581 TI - Vitamin E and prostate cancer: research focus turns to biologic mechanisms. PMID- 22100582 TI - Targeting advanced prostate cancer. PMID- 22100583 TI - Large-scale genome projects enter the clinic on both sides of the Atlantic. PMID- 22100584 TI - 9/11 study on cancer risk may be premature. PMID- 22100585 TI - Radiation example and cancer: the Japanese example. PMID- 22100586 TI - Genetic parameters for production traits in New Zealand dual-purpose sheep, with an emphasis on dagginess. AB - Genetic and phenotypic parameters were estimated for production and disease traits (including dagginess) from about 2 million pedigree-recorded animals born between 1990 and 2008 in New Zealand dual-purpose ram breeding flocks. This is the most comprehensive study of genetic parameter estimates for the New Zealand sheep industry to date and includes estimates that have not previously been reported. Estimates of heritability were moderate for BW at 8 mo (LW8), fleece weight at 12 mo (FW12), dagginess score at 3 and 8 mo (DAG3, DAG8; 0.31 to 0.37), typical for weaning weight (WWT), fecal egg count in summer (FEC1) and autumn (FEC2), and analogous Nematodirus counts (NEM1, NEM2; 0.17 to 0.21), and low for number of lambs born to ewes (NLB; 0.09). The genetic correlations among production traits, WWT, LW8, and FW12, were positive and moderate to high. Correlations of DAG3 and DAG8 with production and disease traits were low and mostly negative. The NLB had low, but typically positive, correlations with other traits. Disease traits also had low, but positive, correlations with production traits (WWT, LW8, and FW12), and were highly correlated among themselves. In general, the heritability estimate for BW and dagginess were greater than what is currently used in the New Zealand genetic evaluation service (Sheep Improvement Limited), and the availability of accurate estimates for dagginess plus parasite resistance and their genetic correlations with production traits will enable more accurate breeding values to be estimated for New Zealand sheep. PMID- 22100587 TI - The effects of different environmental conditions on thermoregulation and clinical and hematological variables in long-distance road-transported calves. AB - The aim of this study was to investigate the effects of long-distance road transport (19 h, from Poland to Italy) during 2 seasons (summer vs. winter) on clinical and hematological variables in calves. The environmental temperature range that could compromise the thermoregulation system (thermal stress) of the calves was tested. For the 7 Holstein calves in each transport, the BW and rectal temperature (RT) were measured, and blood samples were collected at the farm of origin, before loading at the transit center (T2), after unloading at the farm of destination (T3), and 1, 2, 3, and 4 d after arrival. The body temperature (BT) and heart rate (HR) were continuously monitored from T2 to T3. The data were statistically analyzed according to a mixed model that considered the fixed effects of transport (repeated measurements), season of journey, and their interaction. Within the observed temperature-humidity index (THI) range (30 to 80), effective thermoregulation allowed the calves to maintain their BT with small physiologic changes to prevent thermal stress, particularly in the summer. With no seasonal differences, the HR was greater at loading than unloading (120 vs. 115 beats per min; P = 0.012). As for the transport effect, the BW was less (P < 0.001) after unloading, and the RT was greater (P = 0.004). This effect was more marked in summer. The hematological variables indicated a moderate effect of transport on the hydration condition, reactive and muscular systems, and metabolism, although hematocrit (P = 0.004), erythrocytes, cortisol, NEFA, beta hydroxybutyrate, lactate, creatine kinase, lactate dehydrogenase, and aspartate aminotransferase activity (P < 0.001), and total protein (P = 0.007) were greater after unloading. This was confirmed by a moderate decrease in total leukocytes (P = 0.031) and glucose concentration (P = 0.002). The changes in the clinical variables were similar for both seasons even though in the summer, hematocrit (P < 0.001), urea (P = 0.008), and total protein (P = 0.010) increased and glucose concentration (P = 0.038) decreased. In conclusion, the data did not show a pronounced effect attributable to the season of the journey. Long-distance road transport leads to notable changes in clinical and hematological variables at the end of the journey. However, these variables remained within their physiological ranges and returned to basal values within a few days after the journey. PMID- 22100588 TI - Genetic basis of semen traits and their relationship with growth rate in rabbits. AB - This work aims to estimate the genetic parameters of seminal and production traits in a paternal line of rabbits selected for ADG during the fattening period. The considered traits were male libido (Lib) defined as successful mounting of an artificial vagina; presence of urine (Ur) and calcium carbonate deposits (Ca) in the ejaculate; semen pH; individual sperm motility (IM); the suitability for AI of the ejaculate (Sui), which involves the subjective combination of several quality traits; the average ejaculate volume (Vol); sperm concentration (Conc); and the average sperm production per ejaculate (Prod = Vol * Conc). The genetic relationship between all of these traits with ADG is also provided. Male libido and seminal data came either from routine evaluations of the ejaculates in an AI center or from 2 experiments in which bucks from the same population were used. Two consecutive ejaculates per male and per week were collected, leaving 7 d within weekly collections. A linear tri-trait model was used to analyze Conc, Vol, and ADG, whereas linear and threshold-linear 2-trait models were used to analyze male libido and the remaining seminal traits with ADG. A Bayesian approach was adopted for inference. Approximately 38% of ejaculates were rejected for AI primarily due to low IM scores. Variables related to the quality of the ejaculate (Ur, Ca, pH, IM, Sui) and Lib were found to be lowly heritable (h(2) ranged from 0.04 to 0.11), but repeatable. This indicates performance of bucks for seminal quality traits and libido in AI centers would be more strongly affected by management practices rather than genetic selection. Semen production traits exhibited moderate values of h(2) (0.22, 0.27, and 0.23 for Conc, Vol, and Prod, respectively), suggesting the possibility of effective selection for these traits. A moderate to high negative genetic correlation (r(g); posterior mean; highest posterior density at 95%, HPD(95%)) was estimated between Conc and Vol (-0.53, HPD(95%) = -0.76, -0.27). The ADG was estimated to have an h(2) of 0.16, to have a low, positive r(g) with Conc (0.21, HPD(95%) = 0.03, 0.48), to have a low, negative r(g) with Vol (-0.19, HPD(95%) = -0.47, 0.08), and to be genetically uncorrelated with all remaining traits analyzed. Therefore, selection for increasing ADG in paternal lines is expected to have no detrimental effects on Ur, Ca, pH, IM, Sui, and Lib and little to no effect on Conc, Vol, and Prod. PMID- 22100589 TI - Effects of graded levels of microbial phytase on the standardized total tract digestibility of phosphorus in corn and corn coproducts fed to pigs. AB - An experiment was conducted to determine the influence of adding graded levels of microbial phytase to corn, distillers dried grains with solubles (DDGS), high protein distillers dried grains (HP-DDG), and corn germ on the standardized total tract digestibility (STTD) of P. A second objective was to develop regression equations to predict the response of adding phytase to each of these ingredients. Four corn-based diets, 4 DDGS-based diets, 4 HP-DDG-based diets, and 4 corn germ based diets were formulated. The 4 diets with each ingredient were formulated to contain 0, 500, 1,000, or 1,500 phytase units (FTU)/kg. A P-free diet was also formulated to determine basal endogenous losses of P. A total of 102 pigs (initial BW: 18.2 +/- 2.1 kg) were individually housed in metabolism cages equipped with a feeder, a nipple drinker, and a screen floor that allowed for total collection of feces. Pigs were allotted to the 17 diets in a randomized complete block design with 6 replicate pigs per diet. Pigs were fed their respective diets for 12 d, and feces were collected quantitatively from d 6 to 11. Supplementation with 500, 1,000, or 1,500 FTU of microbial phytase/kg increased (linear, P < 0.01; quadratic, P < 0.05) the STTD of P in corn from 40.9 to 67.5, 64.5, and 74.9%, respectively, tended to increase (linear, P = 0.07) the STTD of P in DDGS from 76.9 to 82.9, 82.5, and 83.0%, respectively, increased (linear, P < 0.01; quadratic, P < 0.05) the STTD of P in HP-DDG from 77.1 to 88.0, 84.1, and 86.9%, respectively, and increased (linear and quadratic, P < 0.01) the STTD of P in corn germ from 40.7 to 59.0, 64.4, and 63.2%, respectively. Regression equations were developed to calculate the STTD of P in corn and corn germ, and R(2) values were 0.63 and 0.79, respectively. However, for DDGS and HP-DDG, the R(2) values were only 0.20 and 0.36, respectively, and these equations were, therefore, not considered adequate to predict the STTD of P. In conclusion, the increase in the STTD of P in corn and corn germ that is a result of microbial phytase can be predicted by regression equations, but microbial phytase has much less of an effect on the STTD of P in DDGS and HP-DDG and responses to addition of graded levels of phytase to these ingredients can, therefore, not be accurately predicted by regression equations. PMID- 22100590 TI - Triennial Lactation Symposium: Bovine mammary epithelial cell lineages and parenchymal development. AB - Mammary development proceeds from an aggregation of cells in the ventral ectoderm to the establishment of an elaborate tree of alveoli, ducts, and cisternae. However, despite abundant data on endocrine regulation of ruminant mammary growth, we know comparatively little about cell lineages, expression of differentiation markers, and plasticity in mammary cell phenotype. Histologic analyses have revealed cell populations with distinct histochemical profiles, but functional assessment of cell populations during development has been limited to analysis of proliferation and frequency estimations of morphotypes. The lack of transplantation models, limited availability of validated antibodies with reactivity to bovine antigens, and similar technical challenges have generally hindered the pace of discovery, but the application of new technologies such as laser microdissection, transcriptional profiling, and multispectral image analysis are yielding important clues into bovine mammary cell ontogeny and developmental regulation. Our analyses have shown that prepubertal ovariectomy affects epithelial architecture, increases the proportion of cells expressing the estrogen receptor, and increases myoepithelial cell development, all concomitant with a dramatic reduction in the mass of parenchymal tissue. Our observations point to a dual role for ovarian secretions in the control of not only the rate of epithelial development, but also the nature of the parenchymal development. The balance of stimulus and inhibition pathways cooperatively regulates mammary growth. The increased reliance on objective staining analyses and quantitative approaches will ensure broader repeatability, application, and extension of the findings regarding the impact of the ovary and other regulatory entities and factors. Advances in understanding the ontogeny of mammary epithelial cells, coupled with established and increasing knowledge of endocrine factors affecting mammary development, may yield intervention strategies to improve dairy profitability. PMID- 22100591 TI - Wheat distillers grains in feedlot cattle diets: feeding behavior, growth performance, carcass characteristics, and blood metabolites. AB - A study was conducted to evaluate feed intake, ADG, carcass quality, eating behavior, and blood metabolites in feedlot beef steers fed diets that varied in proportion of wheat dried distillers grains with solubles (DDGS) replacing barley grain or barley silage. Two hundred crossbred steers (BW = 489 +/- 30 kg) were blocked by BW and randomly allotted to 20 pens (5 pens per treatment). Steers were fed 1 of 4 diets: control without DDGS (CON), 25% (25DDGS), 30% (30DDGS), or 35% (35DDGS) wheat DDGS (DM basis). The CON diet consisted of 15% barley silage and 85% barley-based concentrate; the 3 wheat DDGS diets were formulated by substituting 20% barley grain and 5, 10, or 15% silage, respectively, with 25, 30, or 35% wheat DDGS so that the 35DDGS diet contained no silage. The diets were formulated such that wheat DDGS was substituted for both barley grain and barley silage to evaluate whether wheat DDGS can be fed as a source of both energy and fiber in feedlot finishing diets. Dry matter intake of steers fed 25DDGS was greater (P < 0.01), but final BW, ADG, and G:F were not different compared with steers fed CON diet. Carcass characteristics and liver abscess score were not different between CON and 25DDGS. Steers fed 25DDGS had longer eating time (min/d; P < 0.01), greater meal frequency (P < 0.04), but a slower eating rate (P < 0.04). Replacing barley silage with increasing amounts of wheat DDGS (from 25DDGS to 35DDGS) linearly reduced (P < 0.01) DMI. Final BW, ADG, and G:F were not affected by increasing amounts of wheat DDGS. Carcass traits were not different, whereas liver abscess scores linearly (P < 0.01) increased as more barley silage was replaced by wheat DDGS. Eating time (min/d) and duration of each meal linearly (P < 0.02) decreased, whereas eating rate (min/g of DM) linearly (P < 0.01) increased with increasing replacement of barley silage. Blood urea N was doubled (P < 0.01) compared with CON by inclusion of wheat DDGS. Results indicate that wheat DDGS can be used effectively in feedlot diets, decreasing the need for barley grain or silage without negatively affecting growth performance and carcass characteristics. A reduction in the amount of roughage required to maintain growth performance is a potential advantage in feedlot operations because forage is costly and often of limited availability. Thus, DDGS can be a possible alternative as long as they are available and cost effective; however, increased incidence of liver abscess and increased N content of manure need to be considered when greater amounts of wheat DDGS are included in finishing diets. PMID- 22100592 TI - Relationship of polymorphisms within metabolic genes and carcass traits in crossbred beef cattle. AB - Feed intake has been shown to alter neurological signaling related to feeding behavior and subsequent activation of adipogenic mechanisms. Fat characteristics are pivotal for carcass and meat quality, including marbling score, flavor, and tenderness. The objective of this study was to establish the association of SNP, from genes functionally related to fat metabolism and obesity, with growth, fat, and carcass traits in steers. A total of 33 informative SNP from candidate genes [cocaine- and amphetamine-regulated transcript (CART), DNA-protein kinase (DNA PK), fatty acid synthase (FASN), and fat mass and obesity associated (FTO)] were used to genotype crossbred steers (n = 620), and associations with growth and carcass traits were assessed. Five markers within the DNA-PK gene were associated (P < 0.05) with fat thickness. One of these SNP was also associated (P < 0.05) with percent choice, yield grade, and retail product yield. Additionally, 2 unique DNA-PK SNP were associated (P < 0.05) with marbling score. Three haplotypes were observed using these SNP and were significantly (P = 0.0014) associated with marbling score. Slaughter weight, ADG, and HCW were associated (P < 0.05) with SNP from CART, FTO, and FASN. Data from this study indicate that polymorphisms within candidate genes have an indirect relationship with lipogenesis. Replication of these results within other populations will be necessary to establish if these markers will be successful as predictors of fatness components and carcass traits in cattle. PMID- 22100593 TI - Nonruminant Nutrition Symposium: The role of glucagon-like peptide-2 in controlling intestinal function in human infants: regulator or bystander? AB - The regulation of nutrient absorptive capacity is a critical factor in the normal growth and development of infants of all species. In human infants this is a common problem after surgical resection; the process of adaptation or upregulation of nutrient transport capacity is the physiologic process, which allows patients to transition to enteral feeding. The specific mechanisms that control this are still relatively poorly understood but are likely relevant for most mammals with an ontogeny of intestinal function related to the weaning process. Many actions of the entero-endocrine hormone glucagon-like peptide (GLP) 2 indicate that it may be a key factor in regulating physiologic intestinal development, nutrient absorptive capacity, and the process of adaptative upregulation of nutrient absorption after resection. This article will review the biology of GLP-2, which is preserved across a broad range of species. This will include the production of GLP-2 in the L cell, the regulation of GLP-2 release, and the mechanism of action. The GLP-2 receptor is specifically located on enteric neurons and pericryptal myofibroblast; thus, effects on the intestinal mucosa involve a second messenger. We will review the functioning of this system in the developing human infant and the role of GLP-2 in the regulation of adaptation, with the general implications for nutrient absorption in animals and humans. PMID- 22100595 TI - Nonruminant Nutrition Symposium: Neurogastroenterology and food allergies. AB - Neurogastroenterology is a subspecialty encompassing relations of the nervous system to the gastrointestinal tract. The central concept is emergence of whole organ behavior from coordinated activity of the musculature, mucosal epithelium, and blood vasculature. Behavior of each effector is determined by the enteric nervous system (ENS). The ENS is a minibrain positioned close to the effectors it controls. The ENS neurophysiology is in the framework of neurogastroenterology. The digestive tract is recognized as the largest lymphoid organ in the body with a unique complement of mast cells. In its position at the "dirtiest" of interfaces between the body and outside world, the mucosal immune system encounters food antigens, bacteria, parasites, viruses, and toxins. Epithelial barriers are insufficient to exclude fully the antigenic load, thereby allowing chronic challenges to the immune system. Observations in antigen-sensitized animals document direct communication between the mucosal immune system and ENS. Communication is functional and results in adaptive responses to circumstances within the lumen that are threatening to the functional integrity of the whole animal. Communication is paracrine and incorporates specialized sensing functions of mast cells for specific antigens together with the capacity of the ENS for intelligent interpretation of the signals. Immuno-neural integration progresses sequentially, beginning with immune detection, followed by signal transfer to the ENS, followed by neural interpretation and then selection of a neural program with coordinated mucosal secretion and a propulsive motor event that quickly clears the threat from the intestinal lumen. Operation of the defense program evokes symptoms of cramping abdominal pain, fecal urgency, and acute watery diarrhea. Investigative approaches to immuno-ENS interactions merge the disciplines of mucosal immunology and ENS neurophysiology into the realm of neurogastroenterology. PMID- 22100594 TI - Meat Science and Muscle Biology Symposium: stem cell niche and postnatal muscle growth. AB - Stem cell niche plays a critical role in regulating the behavior and function of adult stem cells that underlie tissue growth, maintenance, and regeneration. In the skeletal muscle, stem cells, called satellite cells, contribute to postnatal muscle growth and hypertrophy, and thus, meat production in agricultural animals. Satellite cells are located adjacent to mature muscle fibers underneath a sheath of basal lamina. Microenvironmental signals from extracellular matrix mediated by the basal lamina and from the host myofiber both impinge on satellite cells to regulate their activity. Furthermore, several types of muscle interstitial cells, including intramuscular preadipocytes and connective tissue fibroblasts, have recently been shown to interact with satellite cells and actively regulate the growth and regeneration of postnatal skeletal muscles. From this regard, interstitial adipogenic cells are not only important for marbling and meat quality, but also represent an additional cellular component of the satellite cell niche. At the molecular level, these interstitial cells may interact with satellite cells through cell surface ligands, such as delta-like 1 homolog (Dlk1) protein whose overexpression is thought to be responsible for muscle hypertrophy in callipyge sheep. In fact, extracellular Dlk1 protein has been shown to promote the myogenic differentiation of satellite cells. Understanding the cellular and molecular mechanisms within the stem cell niche that regulate satellite cell differentiation and maintain muscle homeostasis may lead to promising approaches to optimizing muscle growth and composition, thus improving meat production and quality. PMID- 22100596 TI - Correlated responses in sow appetite, residual feed intake, body composition, and reproduction after divergent selection for residual feed intake in the growing pig. AB - Residual feed intake (RFI) has been explored as an alternative selection criterion to feed conversion ratio to capture the fraction of feed intake not explained by expected production and maintenance requirements. Selection experiments have found that low RFI in the growing pig is genetically correlated with reduced fatness and feed intake. Selection for feed conversion ratio also reduces sow appetite and fatness, which, together with increased prolificacy, has been seen as a hindrance for sow lifetime performance. The aims of our study were to derive equations for sow RFI during lactation (SRFI) and to evaluate the effect of selection for RFI during growth on sow traits during lactation. Data were obtained on 2 divergent lines selected for 7 generations for low and high RFI during growth in purebred Large Whites. The RFI was measured on candidates for selection (1,065 pigs), and sow performance data were available for 480 sows having from 1 to 3 parities (1,071 parities). Traits measured were sow daily feed intake (SDFI); sow BW and body composition before farrowing and at weaning (28.4 +/- 1.7d); number of piglets born total, born alive, and surviving at weaning; and litter weight, average piglet BW, and within-litter SD of piglet BW at birth, 21 d of age (when creep feeding was available), and weaning. Sow RFI was defined as the difference between observed SDFI and SDFI predicted for sow maintenance and production. Daily production requirements were quantified by litter size and daily litter BW gain as well as daily changes in sow body reserves. The SRFI represented 24% of the phenotypic variability of SDFI. Heritability estimates for RFI and SRFI were both 0.14. The genetic correlation between RFI and SRFI was 0.29 +/- 0.23. Genetic correlations of RFI with sow traits were low to moderate, consistent with responses to selection; selection for low RFI during growth reduced SDFI and increased number of piglets and litter growth, but also increased mobilization of body reserves. No effect on rebreeding performance was found. Metabolic changes previously observed during growth in response to selection might explain part of the better efficiency of the low-RFI sows, decreasing basal metabolism and favoring rapid allocation of resources to lactation. We propose to consider SRFI as an alternative to SDFI to select for efficient sows with reduced input demands during lactation. PMID- 22100597 TI - Blood variables and body weight gain on the first day of life in crossbred pigs and importance for survival. AB - Improving survival is a continuous objective in swine breeding. The aim of this study was to record 22 blood variables and BW gain on the first day of life in Landrace-Yorkshire-Duroc crossbred piglets and to find associations between these variables and survival at weaning. All live piglets from 18 litters were weighed and blood sampled at birth and on d 1 and were monitored to weaning at the age of 5 wk. A total of 261 piglets were born, of which 8.8% were stillborn. Additionally, 15.1% died before weaning. The blood variables glucose, immunoglobulins, and white blood cells increased from birth to d 1 (P < 0.001), whereas alpha(1)- and beta(1)-globulin, red blood cells, hemoglobin, and hematocrit decreased (P < 0.001). At birth, concentrations of lactate (P = 0.004), pH (P = 0.007), red blood cells (P = 0.017), hemoglobin (P = 0.018), and hematocrit (P = 0.052) were associated with survival to weaning. Also, concentrations of lactate increased (P = 0.030) and pH decreased (P < 0.001) when piglets were born in the last third of a litter. On d 1, concentrations of glucose (P = 0.015), hemoglobin (P = 0.025), and BW gain (P = 0.001) were all decreased in piglets that did not survive to weaning. Body weight gain also decreased (P = 0.005) when piglets were born in the last third of a litter. Concentrations of IgG on d 1 was not associated with survival at weaning (P = 0.230) but decreased (P < 0.001) when piglets were born in the last third of a litter. We conclude that several blood variables recorded at birth and on d 1 and BW gain on d 1 were highly associated with survival at weaning and that piglets born in the last third of the litter had less favorable vitality. PMID- 22100598 TI - Breeding and Genetics Symposium: really big data: processing and analysis of very large data sets. AB - Modern animal breeding data sets are large and getting larger, due in part to recent availability of high-density SNP arrays and cheap sequencing technology. High-performance computing methods for efficient data warehousing and analysis are under development. Financial and security considerations are important when using shared clusters. Sound software engineering practices are needed, and it is better to use existing solutions when possible. Storage requirements for genotypes are modest, although full-sequence data will require greater storage capacity. Storage requirements for intermediate and results files for genetic evaluations are much greater, particularly when multiple runs must be stored for research and validation studies. The greatest gains in accuracy from genomic selection have been realized for traits of low heritability, and there is increasing interest in new health and management traits. The collection of sufficient phenotypes to produce accurate evaluations may take many years, and high-reliability proofs for older bulls are needed to estimate marker effects. Data mining algorithms applied to large data sets may help identify unexpected relationships in the data, and improved visualization tools will provide insights. Genomic selection using large data requires a lot of computing power, particularly when large fractions of the population are genotyped. Theoretical improvements have made possible the inversion of large numerator relationship matrices, permitted the solving of large systems of equations, and produced fast algorithms for variance component estimation. Recent work shows that single-step approaches combining BLUP with a genomic relationship (G) matrix have similar computational requirements to traditional BLUP, and the limiting factor is the construction and inversion of G for many genotypes. A naive algorithm for creating G for 14,000 individuals required almost 24 h to run, but custom libraries and parallel computing reduced that to 15 m. Large data sets also create challenges for the delivery of genetic evaluations that must be overcome in a way that does not disrupt the transition from conventional to genomic evaluations. Processing time is important, especially as real-time systems for on farm decisions are developed. The ultimate value of these systems is to decrease time-to-results in research, increase accuracy in genomic evaluations, and accelerate rates of genetic improvement. PMID- 22100599 TI - Genome-wide association studies of female reproduction in tropically adapted beef cattle. AB - The genetics of reproduction is poorly understood because the heritabilities of traits currently recorded are low. To elucidate the genetics underlying reproduction in beef cattle, we performed a genome-wide association study using the bovine SNP50 chip in 2 tropically adapted beef cattle breeds, Brahman and Tropical Composite. Here we present the results for 3 female reproduction traits: 1) age at puberty, defined as age in days at first observed corpus luteum (CL) after frequent ovarian ultrasound scans (AGECL); 2) the postpartum anestrous interval, measured as the number of days from calving to first ovulation postpartum (first rebreeding interval, PPAI); and 3) the occurrence of the first postpartum ovulation before weaning in the first rebreeding period (PW), defined from PPAI. In addition, correlated traits such as BW, height, serum IGF1 concentration, condition score, and fatness were also examined. In the Brahman and Tropical Composite cattle, 169 [false positive rate (FPR) = 0.262] and 84 (FPR = 0.581) SNP, respectively, were significant (P < 0.001) for AGECL. In Brahman, 41% of these significant markers mapped to a single chromosomal region on BTA14. In Tropical Composites, 16% of these significant markers were located on BTA5. For PPAI, 66 (FPR = 0.67) and 113 (FPR = 0.432) SNP were significant (P < 0.001) in Brahman and Tropical Composite, respectively, whereas for PW, 68 (FPR = 0.64) and 113 (FPR = 0.432) SNP were significant (P < 0.01). In Tropical Composites, the largest concentration of PPAI markers were located on BTA5 [19% (PPAI) and 23% (PW)], and BTA16 [17% (PPAI) and 18% (PW)]. In Brahman cattle, the largest concentration of markers for postpartum anestrus was located on BTA3 (14% for PPAI and PW) and BTA14 (17% PPAI). Very few of the significant markers for female reproduction traits for the Brahman and Tropical Composite breeds were located in the same chromosomal regions. However, fatness and BW traits as well as serum IGF1 concentration were found to be associated with similar genome regions within and between breeds. Clusters of SNP associated with multiple traits were located on BTA14 in Brahman and BTA5 in Tropical Composites. PMID- 22100600 TI - Growth hormone stimulates protein synthesis in bovine skeletal muscle cells without altering insulin-like growth factor-I mRNA expression. AB - Growth hormone is a major stimulator of skeletal muscle growth in animals, including cattle. In this study, we determined whether GH stimulates skeletal muscle growth in cattle by direct stimulation of proliferation or fusion of myoblasts, by direct stimulation of protein synthesis, or by direct inhibition of protein degradation in myotubes. We also determined whether these direct effects of GH are mediated by IGF-I produced by myoblasts or myotubes. Satellite cells were isolated from cattle skeletal muscle and were allowed to proliferate as myoblasts or induced to fuse into myotubes in culture. Growth hormone at 10 and 100 ng/mL increased protein synthesis in myotubes (P < 0.05), but had no effect on protein degradation in myotubes or proliferation of myoblasts (P > 0.05). Insulin-like growth factor-I at 50 and 500 ng/mL stimulated protein synthesis (P < 0.01), and this effect of IGF-I was much greater than that of GH (P < 0.05). Besides stimulating protein synthesis, IGF-I at 50 and 500 ng/mL also inhibited protein degradation in myotubes (P < 0.01), and IGF-I at 500 ng/mL stimulated proliferation of myoblasts (P < 0.05). Neither GH nor IGF-I had effects on fusion of myoblasts into myotubes (P > 0.1). These data indicate that GH and IGF-I have largely different direct effects on bovine muscle cells. Growth hormone at 10 and 100 ng/mL had no effect on IGF-I mRNA expression in either myoblasts or myotubes (P > 0.1). This lack of effect was not because the cultured myoblasts or myotubes were not responsive to GH; GH receptor mRNA was detectable in them and the expression of the cytokine-inducible SH2-containing protein (CISH) gene, a well established GH target gene, was increased by GH in bovine myoblasts (P < 0.05). Overall, the data suggest that GH stimulates skeletal muscle growth in cattle in part through stimulation of protein synthesis in the muscle and that this stimulation is not mediated through increased IGF-I mRNA expression in the muscle. PMID- 22100601 TI - Mechanism of structural transformations induced by antimicrobial peptides in lipid membranes. AB - It has long been suggested that pore formation is responsible for the increase in membrane permeability by antimicrobial peptides (AMPs). To better understand the mechanism of AMP activity, the disruption of model membrane by protegrin-1 (PG 1), a cationic antimicrobial peptide, was studied using atomic force microscopy. We present here the direct visualization of the full range of structural transformations in supported lipid bilayer patches induced by PG-1 on zwitterionic 1,2-dimyristoyl-snglycero-phospho-choline (DMPC) membranes. When PG 1 is added to DMPC, the peptide first induces edge instability at low concentrations, then pore-like surface defects at intermediate concentrations, and finally wormlike structures with a specific length scale at high concentrations. The formation of these structures can be understood using a mesophase framework of a binary mixture of lipids and peptides, where PG-1 acts as a line-active agent. Atomistic molecular dynamics simulations on lipid bilayer ribbons with PG-1 molecules placed at the edge or interior positions are carried out to calculate the effect of PG-1 in reducing line tension. Further investigation of the placement of PG-1 and its association with defects in the bilayer is carried out using unbiased assembly of a PG-1 containing bilayer from a random mixture of PG-1, DMPC, and water. A generalized model of AMP induced structural transformations is also presented in this work. This article is part of a Special Issue entitled: Membrane protein structure and function. PMID- 22100602 TI - Mechanisms for quality control of misfolded transmembrane proteins. AB - To prevent the accumulation of misfolded and aggregated proteins, the cell has developed a complex network of cellular quality control (QC) systems to recognize misfolded proteins and facilitate their refolding or degradation. The cell faces numerous obstacles when performing quality control on transmembrane proteins. Transmembrane proteins have domains on both sides of a membrane and QC systems in distinct compartments must coordinate to monitor the folding status of the protein. Additionally, transmembrane domains can have very complex organization and QC systems must be able to monitor the assembly of transmembrane domains in the membrane. In this review, we will discuss the QC systems involved in repair and degradation of misfolded transmembrane proteins. Also, we will elaborate on the factors that recognize folding defects of transmembrane domains and what happens when misfolded transmembrane proteins escape QC and aggregate. This article is part of a Special Issue entitled: Protein Folding in Membranes. PMID- 22100603 TI - Na-glutamine co-transporters B(0)AT1 in villus and SN2 in crypts are differentially altered in chronically inflamed rabbit intestine. AB - Glutamine is a major nutrient utilized by the intestinal epithelium and is primarily assimilated via Na-glutamine co-transport (NGcT) on the brush border membrane (BBM) of enterocytes. Recently we reported that B(0)AT1 (SLC6A19) mediates glutamine absorption in villus while SN2 (SLC38A5) does the same in crypt cells. However, how B(0)AT1 and SN2 are affected during intestinal inflammation is unknown. In the present study it was shown that during chronic enteritis NGcT was inhibited in villus cells, however, it was stimulated in crypt cells. Our studies also demonstrated that the mechanism of inhibition of NGcT during chronic enteritis was secondary to a reduction in the number of B(0)AT1 co transporters in the villus cell BBM without a change in the affinity of the co transporter. In contrast, stimulation of NGcT in crypt cells was secondary to an increase in the affinity of SN2 for glutamine without an alteration in the number of co-transporters. Thus, glutamine assimilation which occurs via distinct transporters in crypt and villus cells is altered in the chronically inflamed intestine. PMID- 22100604 TI - Effects of active and passive tobacco cigarette smoking on heart rate variability. AB - Given the widespread incidence of smoking as well as its deleterious health effects, it is crucial to examine practical and cost effective prognostic markers assessing its health impact. Heart rate variability (HRV) is a straightforward and cost effective technique to foresee health problems of cardiovascular nature and may be used to predict in advance smoking-induced health effects. In this review we evaluate the existing biological evidence regarding the effects of smoking on HRV and their associated cardiovascular consequences. In addition, we summarize fundamental information on the various HRV indicators and their diagnostic significance in relation to heart failure. An in depth analysis of the various HRV indices characterizing changes in the activation of the autonomic nervous system is provided together with a critical evaluation of all evidence published to date on the influence of chronic and acute active and passive smoking on HRV. Overall, the vast majority of published evidence suggests that acute and chronic active and passive smoking generate marked disruptions in the normal autonomic nervous system functioning characterized by increased sympathetic drive and reduced HRV and parasympathetic modulation. The proposed mechanisms that may generate this smoke-induced HRV reduction as well as its clinical implications are thoroughly evaluated. PMID- 22100605 TI - Superficial calcified nodules and post-stenting micro-dissections imaged through 3-dimensional optical coherence tomography. PMID- 22100606 TI - Effects of Omega-3 fatty acids on endothelial function, arterial wall properties, inflammatory and fibrinolytic status in smokers: a cross over study. AB - BACKGROUND: Smoking is associated with endothelial dysfunction and arterial stiffness. Supplementation of Omega-3 PUFAs is associated with better prognosis. Aim of this study was to evaluate the effects of Omega-3 polyunsaturated fatty acids (PUFAs) supplementation on smoking-induced impairment of arterial function. METHODS: We studied the effect of a 12 weeks oral treatment with 2gr/day of Omega 3 PUFAs in 20 healthy smokers on three occasions (day 0:baseline, day 28 and day 84). The study was carried out on two separate arms (Omega-3 fatty acids and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm), immediately and 20min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Circulating levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared with placebo, Omega-3 PUFAs treatment resulted in a significant improvement in pSm values of FMD (p<0.05), AIx (p<0.001) and PWV (p<0.01). Although, acute cigarette smoking decreased FMD and caused an increase in AIx and PWV, Omega-3 PUFAs treatment blunted the acute smoking-induced impairment of FMD (p<0.001), AIx (p<0.05) and PWV (p<0.05) and significantly decreased levels of TNFalpha (p<0.05) and IL-6 (p=0.01) and increased levels of PAI-1 (p=0.05). CONCLUSIONS: Omega-3 PUFAs improved endothelial function and the elastic properties of the arterial tree in healthy smokers, with a parallel anti-inflammatory effect. PMID- 22100607 TI - Inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by chlorpyrifos oxon, paraoxon and methyl paraoxon. AB - Oxons are the bioactivated metabolites of organophosphorus insecticides formed via cytochrome P450 monooxygenase-catalyzed desulfuration of the parent compound. Oxons react covalently with the active site serine residue of serine hydrolases, thereby inactivating the enzyme. A number of serine hydrolases other than acetylcholinesterase, the canonical target of oxons, have been reported to react with and be inhibited by oxons. These off-target serine hydrolases include carboxylesterase 1 (CES1), CES2, and monoacylglycerol lipase. Carboxylesterases (CES, EC 3.1.1.1) metabolize a number of xenobiotic and endobiotic compounds containing ester, amide, and thioester bonds and are important in the metabolism of many pharmaceuticals. Monoglyceride lipase (MGL, EC 3.1.1.23) hydrolyzes monoglycerides including the endocannabinoid, 2-arachidonoylglycerol (2-AG). The physiological consequences and toxicity related to the inhibition of off-target serine hydrolases by oxons due to chronic, low level environmental exposures are poorly understood. Here, we determined the potency of inhibition (IC(50) values; 15 min preincubation, enzyme and inhibitor) of recombinant CES1, CES2, and MGL by chlorpyrifos oxon, paraoxon and methyl paraoxon. The order of potency for these three oxons with CES1, CES2, and MGL was chlorpyrifos oxon>paraoxon>methyl paraoxon, although the difference in potency for chlorpyrifos oxon with CES1 and CES2 did not reach statistical significance. We also determined the bimolecular rate constants (k(inact)/K(I)) for the covalent reaction of chlorpyrifos oxon, paraoxon and methyl paraoxon with CES1 and CES2. Consistent with the results for the IC(50) values, the order of reactivity for each of the three oxons with CES1 and CES2 was chlorpyrifos oxon>paraoxon>methyl paraoxon. The bimolecular rate constant for the reaction of chlorpyrifos oxon with MGL was also determined and was less than the values determined for chlorpyrifos oxon with CES1 and CES2 respectively. Together, the results define the kinetics of inhibition of three important hydrolytic enzymes by activated metabolites of widely used agrochemicals. PMID- 22100608 TI - Identification of early target genes of aflatoxin B1 in human hepatocytes, inter individual variability and comparison with other genotoxic compounds. AB - Gene expression profiling has recently emerged as a promising approach to identify early target genes and discriminate genotoxic carcinogens from non genotoxic carcinogens and non-carcinogens. However, early gene changes induced by genotoxic compounds in human liver remain largely unknown. Primary human hepatocytes and differentiated HepaRG cells were exposed to aflatoxin B1 (AFB1) that induces DNA damage following enzyme-mediated bioactivation. Gene expression profile changes induced by a 24h exposure of these hepatocyte models to 0.05 and 0.25MUM AFB1 were analyzed by using oligonucleotide pangenomic microarrays. The main altered signaling pathway was the p53 pathway and related functions such as cell cycle, apoptosis and DNA repair. Direct involvement of the p53 protein in response to AFB1 was verified by using siRNA directed against p53. Among the 83 well-annotated genes commonly modulated in two pools of three human hepatocyte populations and HepaRG cells, several genes were identified as altered by AFB1 for the first time. In addition, a subset of 10 AFB1-altered genes, selected upon basis of their function or tumor suppressor role, was tested in four human hepatocyte populations and in response to other chemicals. Although they exhibited large variable inter-donor fold-changes, several of these genes, particularly FHIT, BCAS3 and SMYD3, were found to be altered by various direct and other indirect genotoxic compounds and unaffected by non-genotoxic compounds. Overall, this comprehensive analysis of early gene expression changes induced by AFB1 in human hepatocytes identified a gene subset that included several genes representing potential biomarkers of genotoxic compounds. PMID- 22100609 TI - Tumor necrosis factor -308 and lymphotoxin +252 polymorphisms in Mexican children with Kawasaki disease and coronary aneurysms. AB - BACKGROUND AND AIMS: The Mexican population has a distinct capacity for the expression of tumor necrosis factor (TNF), a cytokine that plays a cardinal role in Kawasaki disease (KD), particularly in those who develop coronary aneurysms. It is important to identify, in Mexican pediatric patients, the association of the frequency of TNF. This study determined the association of TNF -308 and lymphotoxin-alpha (LTA) +252 polymorphisms in Mexican pediatric patients with KD and coronary aneurysms (CA). METHODS: We conducted a cross-sectional, analytical study in 48 children with KD, 22 with CA. Control samples were obtained from 61 aged-matched children. We took a peripheral blood sample and extracted genomic DNA from all children participating in the study. Using restriction factor length polymorphism-polymerase chain reaction (RFLP-PCR), we performed determination of TNF -308 and LTA +252. RESULTS: There was no difference in frequency between the study groups for genotype LTA +252 (OR 0.37, 95% CI, 0.06-2, p = 0.44) or between groups for KD with or without coronary aneurysms for both polymorphisms. In subjects with KD, we did not observe the heterozygous genotype of TNF -308, the difference being significant (OR 12, 95% CI, 4.8-30.4, p = 0.0001) using the chi(2) test with the continuity correction on comparison with the control group. CONCLUSIONS: Comparative analysis by group did not show a significant difference in the frequency of the alleles and genotypes between KD with CA vs. KD without CA vs. controls, for both TNF -308 and LTA +252. PMID- 22100610 TI - Elevated serum levels of advanced glycation end products and their monocyte receptors in patients with type 2 diabetes. AB - BACKGROUND AND AIMS: Animal experiments showed that interaction between advanced glycation end products (AGE) and their receptors (RAGE) play an important role in the pathogenesis of diabetic complications. Soluble RAGE (sRAGE) can function as a decoy for RAGE ligands. The present study aimed to examine the levels of AGEs, RAGE and sRAGE in patients with type 2 diabetes (T2D). METHODS: RAGE gene expression was determined by real-time PCR in 50 patients with T2D (27 men, mean age 52 +/- 7.7 years) and 50 age-matched controls without T2D. Serum AGEs and sRAGEs were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum level of AGEs was increased in patients with T2D (10.35 +/- 2.27 MUg/mL vs.7.69 +/- 0.56 MUg/mL, p <0.05). sRAGE was decreased in patients with T2D (573.6 +/- 172.5 pg/mL vs. 603.4 +/- 120.8 pg/mL p <0.01). RAGE gene expression was higher in T2D than in controls (p <0.01). There was an association between monocyte RAGE and serum levels of AGEs in both T2D patients (r = 0.29, p = 0.03) and controls (r = 0.31, p = 0.02). Serum AGEs correlated with homeostasis model assessment of insulin resistance (HOMA-IR) in both patients with T2D (r = 0.322, p = 0.004) and controls (r = 0.281, p = 0.003). CONCLUSIONS: Serum AGEs and monocyte RAGE expression are increased in patients with T2D, whereas serum sRAGE is decreased. Pharmacological intervention on serum AGEs and sRAGE may be a potential therapy for diabetes. PMID- 22100611 TI - Assessing the influence of indoor exposure to "outdoor ozone" on the relationship between ozone and short-term mortality in U.S. communities. AB - BACKGROUND: City-to-city differences have been reported for the increase in short term mortality associated with a given increase in ozone concentration (ozone mortality coefficient). Although ozone concentrations are monitored at central outdoor locations, a large fraction of total ozone exposure occurs indoors. OBJECTIVES: To clarify the influence of indoor exposure to ozone of outdoor origin on short-term mortality, we conducted an analysis to determine whether variation in ozone mortality coefficients among U.S. cities might be partly explained by differences in total ozone exposure (from both outdoor and indoor exposures) resulting from the same outdoor ozone concentration. METHODS: We estimated average annual air change rates (the overall rate at which indoor air is replaced with outdoor air) and used these to estimate the change in total ozone exposure per unit change in outdoor ozone exposure (ozone exposure coefficient) for 18 cities that had been included in the National Morbidity and Mortality Air Pollution Study (NMMAPS). We then examined associations between both parameters and published ozone mortality coefficients. RESULTS: For the 18 targeted NMMAPS cities, the association between ozone mortality coefficients and ozone exposure coefficients was strong (1-hr ozone metric: R2 = 0.58, p < 0.001; 8-hr ozone: R2 = 0.56, p < 0.001; 24-hr ozone: R2 = 0.48, p = 0.001). When extended to another 72 NMMAPS cities, the associations remained strong (R2 = 0.47 0.63; p < 0.001). CONCLUSIONS: Differences in ozone mortality coefficients among cities appear to partially reflect differences in total ozone exposure resulting from differences in the amount of outdoor ozone that is transported indoors. PMID- 22100612 TI - Identification of alpha1-antitrypsin as a positive acute phase protein in ayu (Plecoglossus altivelis) associated with Listonella anguillarum infection. AB - alpha1-Antitrypsin (AAT) is implicated in the regulation of a variety of mammalian immune responses and was recently identified as a major serpin in blood plasma of some fish. However, AAT expression following bacterial infection in fish has not been well described. In this study, we cloned the full-length ayu (Plecoglossus altivelis) AAT gene cDNA. It contained a 1368-bp coding region, which encodes a 19-amino acids (aa) signal peptide and a 437-aa mature AAT containing the serpin's signature sequence ((427)LKFDRPFMMLV(437)). PNGase F digestion confirmed that the higher molecular mass of the serum AAT was caused by N-glycosylation. Phylogenetic analysis indicated that ayu AAT was closest to that of green spotted pufferfish. AAT transcripts were present in a variety of tissues, with the highest level in the liver. The real-time quantitative PCR data showed that AAT transcripts dramatically increased in various ayu tissues after Listonella anguillarum infection. Western blot analysis revealed that the serum AAT protein level significantly increased in response to inflammation, but displayed no significant changes after cadmium exposure or salinity challenge. This work represents the first report that identifies AAT as a positive acute phase protein in ayu fish associated with bacterial infection, suggesting that it might play a role in fish innate immunity. PMID- 22100613 TI - A sequential study of incomplete Freund's adjuvant-induced peritonitis in Atlantic cod. AB - Development of diagnostic and prophylactic methodologies is dependent on knowledge of the host's defence system and reaction to different vaccine adjuvants. Here we present a sequential morphological study of peritonitis and inflammatory cell processing of incomplete Freund's adjuvant (IFA) in intraperitoneally injected Atlantic cod. The peritoneal tissue responses were characterised using necropsy, histology and electron microscopy. An extensive inflammatory response as characterised by leukocyte morphology and contents of enzymes, presence of apoptotic cells and IFN-gamma-expressing cells was observed. Three days post injection, IFA droplets were surrounded by different types of inflammatory cells and two different patterns could be discerned. The first was characterised by flattened and concentrically arranged interdigitating cells connected by desmosomes and with macrophage-like cells (MLCs) predominant in the periphery. The second type possessed four stratified layers with an inner layer containing many apoptotic MLCs; a second layer containing flattened and shrunken cells and outer layers comprising moderately flattened cells and an outermost layer of mononuclear cells expressing IFN-gamma. Oil was detected both inside and outside MLCs. The two types of processes, of which the second was clearly stratified, were similar to those observed in other teleosts, indicating a variety of reaction modes or alternatively sequential process development. The numerous dead MLCs contributed to inflammation. PMID- 22100614 TI - Studying mitochondrial Ca(2+) uptake - a revisit. AB - Mitochondrial Ca(2+) sequestration is a well-known process that is involved in various physiological and pathological mechanisms. Using isolated suspended mitochondria one unique mitochondrial Ca(2+) uniporter was considered to account ubiquitously for the transfer of Ca(2+) into these organelles. However, by applying alternative techniques for measuring mitochondrial Ca(2+) uptake evidences for molecularly distinct mitochondrial Ca(2+) carriers accumulated recently. Herein we compared different methodical approaches of studying mitochondrial Ca(2+) uptake. Patch clamp technique on mitoplasts from endothelial and HeLa cells revealed the existence of three and two mitoplast Ca(2+) currents (I(CaMito)), respectively. According to their conductance, these channels were named small (s-), intermediate (i-), large (l-) and extra-large (xl-) mitoplast Ca(2+) currents (MCC). i-MCC was found in mitoplasts of both cell types whereas s MCC and l-MCC or xl-MCC were/was exclusively found in mitoplasts from endothelial cells or HeLa cells. The comparison of mitochondrial Ca(2+) signals, measured either indirectly by sensing extra-mitochondrial Ca(2+) or directly by recording changes of the matrix Ca(2+), showed different Ca(2+) sensitivities of the distinct mitochondrial Ca(2+) uptake routes. Subpopulations of mitochondria with different Ca(2+) uptake capacities in intact endothelial cells could be identified using Rhod-2/AM. In contrast, cells expressing mitochondrial targeted pericam or cameleon (4mtD3cpv) showed homogeneous mitochondrial Ca(2+) signals in response to cell stimulation. The comparison of different experimental approaches and protocols using isolated organelles, permeabilized and intact cells, pointed to cell-type specific and versatile pathways for mitochondrial Ca(2+) uptake. Moreover, this work highlights the necessity of the utilization of multiple technical approaches to study the complexity of mitochondrial Ca(2+) homeostasis. PMID- 22100615 TI - Animal models of adrenocortical tumorigenesis. AB - Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species - mouse, ferret, and dog - are reviewed, and their relevance to adrenocortical tumors in humans is discussed. PMID- 22100616 TI - Parasites modify sub-cellular partitioning of metals in the gut of fish. AB - Infestation of fish by parasites may influence metal accumulation patterns in the host. However, the subcellular mechanisms of these processes have rarely been studied. Therefore, this study determined how a cyprinid fish (Rastrineobola argentea) partitioned four metals (Cd, Cr, Zn and Cu) in the subcellular fractions of the gut in presence of an endoparasite (Ligula intestinalis). The fish were sampled along four sites in Lake Victoria, Kenya differing in metal contamination. Accumulation of Cd, Cr and Zn was higher in the whole body and in the gut of parasitized fish compared to non-parasitized fish, while Cu was depleted in parasitized fish. Generally, for both non-parasitized and parasitized fish, Cd, Cr and Zn partitioned in the cytosolic fractions and Cu in the particulate fraction. Metal concentrations in organelles within the particulate fractions of the non-parasitized fish were statistically similar except for Cd in the lysosome, while in the parasitized fish, Cd, Cr and Zn were accumulated more by the lysosome and microsomes. In the cytosolic fractions, the non-parasitized fish accumulated Cd, Cr and Zn in the heat stable proteins (HSP), while in the parasitized fish the metals were accumulated in the heat denatured proteins (HDP). On the contrary, Cu accumulated in the HSP in parasitized fish. The present study revealed specific binding of metals to potentially sensitive sub cellular fractions in fish in the presence of parasites, suggesting interference with metal detoxification, and potentially affecting the health status of fish hosts in Lake Victoria. PMID- 22100617 TI - Effect of limiting ankle-dorsiflexion range of motion on lower extremity kinematics and muscle-activation patterns during a squat. AB - CONTEXT: Limitations in gastrocnemius/soleus flexibility that restrict ankle dorsiflexion during dynamic tasks have been reported in individuals with patellofemoral pain (PFP) and are theorized to play a role in its development. OBJECTIVE: To determine the effect of restricted ankle-dorsiflexion range of motion (ROM) on lower extremity kinematics and muscle activity (EMG) during a squat. The authors hypothesized that restricted ankle-dorsiflexion ROM would alter knee kinematics and lower extremity EMG during a squat. DESIGN: Cross sectional. PARTICIPANTS: 30 healthy, recreationally active individuals without a history of lower extremity injury. INTERVENTIONS: Each participant performed 7 trials of a double-leg squat under 2 conditions: a no-wedge condition (NW) with the foot flat on the floor and a wedge condition (W) with a 12 degrees forefoot angle to simulate reduced plantar-flexor flexibility. MAIN OUTCOME MEASURES: 3 dimensional hip and knee kinematics, medial knee displacement (MKD), and ankle dorsiflexion angle. EMG of vastus medialis oblique (VMO), vastus lateralis (VL), lateral gastrocnemius (LG), and soleus (SOL). One-way repeated-measures ANOVAs were performed to determine differences between the W and NW conditions. RESULTS: Compared with the NW condition, the wedge produced decreased peak knee flexion (P < .001, effect size [ES] = 0.81) and knee-flexion excursion (P < .001, ES = 0.82) while producing increased peak ankle dorsiflexion (P = .006, ES = 0.31), ankle dorsiflexion excursion (P < .001, ES = 0.31), peak knee-valgus angle (P = .02, ES = 0.21), and MKD (P < .001, ES = 2.92). During the W condition, VL (P = 0.002, ES = 0.33) and VMO (P = .049, ES = 0.20) activity decreased while soleus activity increased (P = .03, ES = 0.64) compared with the NW condition. No changes were seen in hip kinematics (P > .05). CONCLUSIONS: Altering ankle-dorsiflexion starting position during a double-leg squat resulted in increased knee valgus and MKD, as well as decreased quadriceps activation and increased soleus activation. These changes are similar to those seen in people with PFP. PMID- 22100618 TI - Childbirth experience according to a group of Brazilian primiparas. AB - OBJECTIVE: to understand the meaning of the childbirth experience for Brazilian primiparas in the postpartum period. DESIGN: a qualitative approach using semi structured interviews. Content analysis was used to derive the two themes that emerged from the discourses. SETTING: participants were recruited at four primary level health-care units in Ribeirao Preto, Brazil. After providing written informed consent, an appointment was made for an interview at the participants' homes. PARTICIPANTS: 20 primiparas in the postpartum period, aged 15-26 years old, who attended the health-care units to vaccinate their infants and test for phenylketonuria. FINDINGS: two thematic categories emerged from the interviews: the meaning attributed to childbirth (with four subcategories) and perceptions of care. Among the participants, the childbirth experience was marked by the 'fear of death' and 'losing the child'. The pain of giving birth was expected, and the moment of childbirth was associated with pain of high intensity. KEY CONCLUSIONS: childbirth is considered synonymous with physical and emotional suffering, pain, fear and risk of death. IMPLICATIONS FOR PRACTICE: this research indicates the need to break the current mechanistic model of care on which health professionals' actions are based. Care during childbirth must be guided by the foundation that women are the subjects of childbirth actions, in an attempt to emphasise actions that grant them with the autonomy and empowerment needed to experience the situation. PMID- 22100619 TI - Identification of protein nitrosothiols using phosphine-mediated selective reduction. AB - Regulation of protein function by S-nitrosation of critical cysteines is known to be an important mechanism for nitric oxide signaling. Evidence for this comes from several different experimental approaches including the ascorbate-based biotin switch method. However technical problems with specificity and sensitivity of ascorbate reduction of S-nitrosothiols limit its usefulness and reliability. In the current study we report the use of triphenylphosphine ester derivatives to selectively reduce SNO bonds in proteins. After triphenylphosphine ester reduction, thiols were tagged with biotin or fluorescently labeled maleimide reagents. Importantly we demonstrate that these compounds are specific reductants of SNO in complex biological samples and do not reduce protein disulfides or protein thiols modified by hydrogen peroxide. Reduction proceeds efficiently in cell extracts and in whole fixed cells. Application of this approach allowed us to demonstrate S-nitrosation of specific cellular proteins, label S nitrosoproteins in whole fixed cells (especially the nuclear compartment) and demonstrate S-nitrosoprotein formation in cells expressing inducible nitric oxide synthase. PMID- 22100620 TI - Calreticulin Transacetylase mediated activation of human platelet nitric oxide synthase by acetyl group donor compounds. AB - Polyphenols have attracted immense interest because of their diverse biological and pharmacological activities. Surprisingly, not much is documented about the biological activities of acetoxy derivatives of polyphenol called polyphenolic acetates (PA). In our previous reports, we have conclusively established the Calreticulin Transacetylase (CRTAase) catalyzed activation of neuronal nitric oxide synthase (nNOS) and tumor necrosis factor-alpha (TNF-alpha) induced nitric oxide synthase (iNOS) by PA. In the present work, specificity of CRTAase to various classes of PA was characterized in human platelet. The effect of PA, on platelet NOS and intracellular cyclic guanosine monophosphate (cGMP), and adenosine diphosphate (ADP)-induced platelet aggregation were studied in an elaborated manner. Platelet CRTAase exhibited differential specificities to polyphenolic acetates upon incubation with l-arginine leading to activation of NOS. The intraplatelet generation of NO was studied by flowcytometry using DCFH DA. The differential specificities of CRTAase to PA were found to positively correlate with increased production of NO upon incubation of PRP with PA and l arginine. Further, the inhibitory effect of l-NAME on PA induced NO formation in platelets substantiated the CRTAase catalyzed activation of NOS. The real-time RT PCR profile of NOS isoforms confirmed the preponderance of eNOS over iNOS in human platelets on treatment with PA. Western blot analysis also reiterated the differential pattern of acetylation of eNOS by PA. PA were also found effective in increasing the intraplatelet cGMP levels and inhibiting ADP-induced platelet aggregation. It is worth mentioning that the effects of PA were found to be in tune with the specificities of platelet CRTAase to PA as the substrates. PMID- 22100622 TI - Intrahospital transport of critically ill patients (excluding newborns). PMID- 22100623 TI - [Intra-hospital transport: from aeronautic to medicine]. PMID- 22100624 TI - Screening based on risk for colorectal cancer is the most cost-effective approach. AB - BACKGROUND & AIMS: Performing single endoscopic examinations or selective screening based on risk might be more practical than recommended screening strategies for colorectal cancer (CRC). We investigated the cost effectiveness of these strategies, under real-life conditions of suboptimal compliance, and the societal cost perspective. METHODS: We used Markov modeling to analyze data from 787,000 individuals in Singapore, aged 50 to 75 years, with an age-standardized rate of CRC of 30 to 40/100,000 in 2009. Potential outcomes, incremental cost effectiveness ratio, and net health benefit were compared between single sigmoidoscopy or colonoscopy and current recommended screening strategies, and also with a strategy of selective screening based on risk of CRC. RESULTS: Performing single sigmoidoscopies on individuals when they are 60 years old was the cheapest screening strategy; it would reduce CRC incidence by 19% and mortality by 16%, compared with no screening. A single colonoscopy is less cost effective than a single sigmoidoscopy, unless the proportion of right-sided lesions exceeds 65%. The fecal occult blood test (iFOBT) had the lowest incremental cost-effectiveness ratio when all strategies were compared with no screening; iFOBT and colonoscopic examinations every 10 years each had extended dominance over other strategies. Screening subjects 50 to 60 years old by iFOBT and subjects 60 to 72 years old with colonoscopies every 10 years was the most cost-effective strategy (US$25,000/quality-adjusted life-years). Risk for CRC, adherence, and cost of colonoscopy were the main determinants of cost effectiveness, based on sensitivity analysis. CONCLUSIONS: Markov modeling analysis indicates that selectively screening individuals for CRC based on risk is the most cost-effective approach; it limits the cost and number of colonoscopies needed and significantly reduces CRC mortality. PMID- 22100625 TI - Optimizing reliability and sensitivity of Semmes-Weinstein monofilaments for establishing point tactile thresholds. AB - Semmes-Weinstein monofilaments (SWM) are widely used to assess tactile point pressure sensitivity. However, the reliability of SWMs has been questioned, standardization of stimulus presentation procedures is lacking, and the sensitivity measure is commonly confounded by the response criterion. This study sought to assess the reliability of two versions of a forced-choice single staircase SWM test with the goal of optimizing test reliability with a minimum number of test trials. Test-retest and intra-test reliability coefficients for SWM threshold values from the plantar halluces of 24 normal subjects were obtained using two versions of a forced-choice single-staircase procedure. One version followed a two-down one-up rule (2D) and the other a three-down one-up rule (3D). The 3D procedure was significantly more reliable than the 2D procedure for all sequential combinations of reversal pairs. A total of four 3D reversal pairs (i.e., eight reversals) were sufficient to achieve test-retest and intra test reliability coefficients>0.90. High reliability with the minimum number of trials was obtained by calculating the threshold as the mean of eight reversals (test-retest r=0.93, p<0.001; Sessions 1 and 2 intra-test rs=0.87 and 0.92; ps<0.001). Identical median detection thresholds were noted for the two repeated test sessions (5.1g/mm(2)). The threshold values correlated with subject age despite the small range of ages tested, suggesting high sensitivity (Sessions 1 and 2 rs=0.61 and 0.63, ps<0.001). This study demonstrates that SWMs provide highly reliable and sensitive point pressure thresholds with very few trials when an appropriate psychophysical paradigm is employed. The brief forced-choice procedure described herein could serve as a basis for standardizing SWM stimulus presentation methods. PMID- 22100626 TI - Flavor and feeding: introduction to an international conference. AB - This submission is just the introductory piece for the special issue. It does not seem that an abstract is warranted. PMID- 22100627 TI - Interactions between salivary cortisol and alpha-amylase as predictors of children's cognitive functioning and academic performance. AB - We examined relations between salivary cortisol, alpha-amylase (sAA), and children's cognitive and academic functioning. Of interest were curvilinear and interactive effects of these salivary measures on cognitive and academic performance. Data were based on a sample of 28 boys and 36 girls (ages 8 and 9) in the Southeastern U.S.A. Children provided resting afternoon saliva samples. Children completed standardized tests of Intellectual Ability and schools provided academic achievement information. Regression analyses demonstrated significant curvilinear relations and interactions between cortisol and sAA in the prediction of child functioning. Contrary to current models of interactions among biological systems, findings indicated some of the highest and lowest scores were predicted at moderate levels of physiological arousal. For example, children with moderate sAA and either higher or lower cortisol had low predicted scores for Reading Ability. Children with moderate cortisol and lower sAA had the highest predicted scores for Intellectual Ability. Findings suggest that the study of interactions between biological stress response systems should not be based on models of rectilinear interactions. PMID- 22100628 TI - Neuroscience and eating disorders: the allocentric lock hypothesis. AB - Evidence from psychology and neuroscience indicates that our spatial experience, including the bodily one, involves the integration of different sensory inputs within two different reference frames egocentric (body as reference of first person experience) and allocentric (body as object in the physical world). Even if functional relations between these two frames are usually limited, they influence each other during the interaction between long- and short-term memory processes in spatial cognition. If, for some reasons, this process is impaired, the egocentric sensory inputs are no more able to update the contents of the allocentric representation of the body: the subject is locked to it. In the presented perspective, subjects with eating disorders are locked to an allocentric representation of their body, stored in long-term memory (allocentric lock). A significant role in the locking may be played by the medial temporal lobe, and in particular by the connection between the hippocampal complex and amygdala. The differences between exogenous and endogenous causes of the lock may also explain the difference between bulimia nervosa and anorexia nervosa. PMID- 22100629 TI - Extension of bladder-based organ regeneration platform for tissue engineering of esophagus. AB - Recent successes in regenerative medicine and tissue engineering of bladder and bladder-like neo-organs have leveraged regenerative constructs composed of a biodegradable scaffold seeded with a population of smooth muscle cells. We have shown that such smooth muscle cells are isolatable from adipose and other sources alternate to the primary organ. We hypothesize that this regenerative platform is not limited to regeneration of bladder and bladder-like neo-organs, but rather represents a foundational technology platform broadly applicable for regeneration of laminarly organized hollow organs. Using esophagus as an illustrative example in support of this hypothesis, we demonstrate that patch constructs composed of adipose-derived smooth muscle cells seeded on a biodegradable matrix catalyze complete regeneration of the esophageal wall in a rodent model of esophageal injury. By implication, such regenerative constructs may potentially be used to mediate the regeneration of any laminarly organized tubular organ. PMID- 22100630 TI - Soluble triggering receptor expressed on myeloid cells-1 as a new therapeutic molecule in rheumatoid arthritis. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface receptor that is expressed mainly on monocytes and neutrophils, and plays an important role as an amplifier of inflammatory response in acute and chronic inflammatory conditions. Recent studies suggested that TREM 1 contributes to the pathogenesis of rheumatoid arthritis (RA) and therefore TREM 1 could be a new therapeutic target in RA. In addition to its membrane-bound form, a soluble form of TREM-1 (sTREM-1) exists that is liberated by the proteolytic cleavage of membrane-bound form. This soluble form works as decoy receptor to prevent the binding of its ligand to membrane-bound TREM-1 and to inhibit the effect of TREM-1 activation. Proteolytic cleavage of TNF receptor (TNFR) has been reported and soluble TNFR are capable of binding and neutralizing TNF, thus working as natural TNF antagonist. Currently, etanercept, a soluble TNF receptor fusion protein has been widely used to treat RA. In this report, we suggest that sTREM-1 can be used as a new therapeutic molecule in RA. PMID- 22100631 TI - Alcohol intake and folate antagonism via CYP2E1 and ALDH1: effects on oral carcinogenesis. AB - The interaction of folate and alcohol consumption has been shown to have an antagonistic effect on the risk of oral cancer. Studies have demonstrated that increased intake of folate decreases the risk of oral cancer, while greater alcohol consumption has an opposite effect. However, what is poorly understood is the biological interaction of these two dietary factors in relation to carcinogenesis. We hypothesize that cytochrome P450 2E1 (CYP2E1) and the family of aldehyde dehydrogenase 1 (ALDH1) enzymes may play a causal role in the occurrence of oral cancer. Chronic and high alcohol use has been implicated in the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a known carcinogen. As the first metabolite of ethanol, it has been shown to interfere with DNA methylation, synthesis and repair, as well as bind to protein and DNA to form stable adducts, which lead to the eventual formation of damaged DNA and cell proliferation. Studies using liver cells have demonstrated that S adenosyl methionine (SAM), which is a product of folate metabolism, regulates the expression and catalytic activity of CYP2E1. Our first hypothesis is that as increased levels of folate lead to higher concentrations of SAM, SAM antagonizes the expression of CYP2E1, which results in decreased conversion of ethanol into acetaldehyde. Thus, the lower levels of acetaldehyde may lower risk of oral cancer. There are also two enzymes within the ALDH1 family that play an important role both in ethanol metabolism and the folate one-carbon pathway. The first, ALDH1A1, converts acetaldehyde into its non-carcinogenic byproduct, acetate, as part of the second step in the ethanol metabolism pathway. The second, ALDH1L1, also known as FDH, is required for DNA nucleotide biosynthesis, and is upregulated at high concentrations of folate. ALDH1L1 appears to be a chief regulator of cellular metabolism as it is strongly downregulated at certain physiological and pathological conditions, while its upregulation can produce drastic antiproliferative effects. ALDH1 has three known response elements that regulate gene expression (NF-Y, C/EBPbeta, and RARalpha). Our second hypothesis is that folate interacts with one of these response elements to upregulate ALDH1A1 and ALDH1L1 expression in order to decrease acetaldehyde concentrations and promote DNA stability, thereby decreasing cancer susceptibility. Conducting future metabolic and biochemical human studies in order to understand this biological mechanism will serve to support evidence from epidemiologic studies, and ultimately promote the intake of folate to at-risk populations. PMID- 22100632 TI - Hypothesis: Low frequency heart rate variability (LF-HRV) is an input for undisclosed yet biological adaptive control, governing the cardiovascular regulations to assure optimal functioning. AB - Cardiovascular regulation is considered today as having three levels: autoregulations, neural regulations and hormonal regulations. We hypothesize that the cardiovascular regulation has an additional (fourth) control level which is outer, hierarchical (adaptive) loop where LF-HRV amplitude serves as a reference input which the neural cardiovascular center detects and responses in order to maintain LF-HRV around some prescribed level. Supporting evidences: LF-HRV absence during artificial cardiac pacing may be associated with "pacemaker syndrome" which had not been sufficiently understood regardless of apparently unimpaired cardiovascular performance. The hypothesis may provide an essential basis for understanding several cardiovascular morbidities and insight toward diagnostic measures and treatments (including but not limited to adding variability to the pulse generator of artificial pacemakers to eliminate "pace maker syndrome"). PMID- 22100633 TI - Primary care is the best place to care for drug users. PMID- 22100634 TI - Random phage-epitope library based identification of a peptide antagonist of Mac 1 beta2 integrin ligand binding. AB - The leukocyte beta2 integrin Mac-1 (CD11b/CD18) plays a pivotal role in inflammation and host defense. To develop peptide antagonists selectively inhibiting the function of Mac-1, we used a random constrained 6-mer (cys-6aa cys) peptide library to map the structural features of CD11b, by determining the epitope of neutralizing monoclonal antibody mAb 44a (anti-CD11b). We have used a stringent phage display strategy, which resulted in the identification of one disulfide C-RLKEKH-C constrained peptide by direct biopanning of library on decreasing amounts of purified mAb 44a. The selected peptide mimics a discontinuous epitope, a peculiar shape on the CD11b-I-domain surface. Competitive ELISA experiments with different Mac-1 ligands showed that C-RLKEKH-C is able to bind to fibrinogen, iC3b, and C1q. Furthermore, the monomeric circular peptide C-RLKEKH-C, was effective in blocking the interaction between (125)I fibrinogen and Mac-1 (IC(50)=3.35+/-0.1*10(-6)M), and inhibited the adhesion of human neutrophils to fibrinogen and iC3b. These data provide information about the relative location of amino acids on the I-domain surface using mAb 44a imprint of the CD11b protein. The derived mimotope may help in the design of future anti-inflammatory therapeutic agents that can act as specific therapeutic agents targeting PMNs mediated inflammation. PMID- 22100635 TI - Identification and characterization of Borrelia antigens as potential vaccine candidates against Lyme borreliosis. AB - The three Borrelia species, Borrelia afzelii, Borrelia burgdorferi and Borrelia garinii are the main species causing the most common tick-borne zoonosis, Lyme borreliosis. By applying a genomic approach relying on human antibodies we have identified 122 antigenic Borrelia proteins associated with Lyme borreliosis, including already known and published protective antigens. The heterogeneity of the Borrelia species causing Lyme borreliosis makes the search for conserved antigens providing broad protection challenging. Using several in vitro assays we narrowed down the selection to 15 vaccine candidates. These antigens were further analyzed for antigenicity and cross-reactivity using sera from mice infected with the three pathogenic Borrelia species. All antigens analyzed showed a high degree of cross-reactivity between the three Borrelia species, essential for providing cross-protection. We also investigated whether mice infected with B. afzelii through tick exposure are primed to mount cytokine responses. For a selection of these antigens, we observed preferentially a pro-inflammatory response in C3H/HeN mice, while in contrast also a type 2 T cell response was seen in the Borrelia resistant mouse strain BALB/c. Thus, antigens mounting a type 2 or mixed type 2/type 1 T cell response might be preferred vaccine candidates for evaluation in animal models of Lyme borreliosis. PMID- 22100636 TI - Vaccine effectiveness in preventing influenza hospitalizations in Navarre, Spain, 2010-2011: cohort and case-control study. AB - We evaluated the 2010-2011 seasonal influenza vaccine effectiveness in preventing hospitalizations. Using healthcare databases we defined the target population for vaccination in Navarre, Spain, consisting of 217,320 people with major chronic conditions or aged 60 years and older. All hospitalized patients with influenza like illness (ILI) were swabbed for influenza testing. A total of 269 patients with ILI were hospitalized and 61 of them were found positive for influenza virus: 58 for A(H1N1)2009 and 3 for B virus. The incidence rates of hospitalization with laboratory-confirmed influenza were compared by vaccination status. In the Cox regression model adjusted for sex, age, children in the household, urban/rural residence, comorbidity, pandemic vaccination, pneumococcal vaccination, outpatient visits and hospitalization in the previous year, the seasonal vaccine effectiveness was 58% (95% CI: 16-79%). The nested test-negative case-control analysis gave an adjusted estimate of 59% (95% CI: 4-83%). These results suggest a moderate effect of the 2010-2011 seasonal influenza vaccine in preventing hospitalization in a risk population. The close estimates obtained in the cohort and the test-negative case-control analyses suggest good control of biases. PMID- 22100637 TI - Devices for intradermal vaccination. AB - New insights in vaccine development, the need for safe, economic and efficient vaccine administration and the increasing mechanistic knowledge of immune responses induced by targeting the intradermal layers of the skin have all driven the engineering of devices for intradermal vaccination. In this review we highlight different delivery devices that make the epidermal and dermal layers of the skin accessible for vaccine administration. Depending on the device the desired vaccine can be applied either as a liquid formulation or as solid, powdered vaccine particles. The process of intradermal injection employs micron sized needles that are inserted 1.5mm perpendicularly into the skin, and which inject approximately 100-200MUl of a liquid vaccine formulation into the dermal skin layers. Tattoo devices, on the other hand, can be used to deliver liquid vaccine formulations into the dermal layer of the skin by the use of oscillating needles. Microneedle arrays are made of vaccine-coated solid microneedles or biodegradable microneedles. These are inserted into the dermal layers of the skin where either the vaccine coating is dissolved, or the microneedle itself dissolves in place. Jet-injectors operate by generating a high pressured stream, which flushes the liquid vaccine formulation into the deeper skin layers. Delivery devices using liquid vaccine formulations are advantageous, as established vaccine formulations can be used as provided without the need for reformulation. However, approaches that deliver vaccines in a solid form may also prove to be promising. One such method is the ballistic approach, in which solid vaccine particles or vaccine-coated gold particles are accelerated towards the skin by needle-free devices, so that the particles are deposited in the epidermal and dermal layers of the skin. These various delivery devices are explored in this review with regard to their delivery mechanism and ease of handling, their efficacy in clinical trials and their suitability for practical use. PMID- 22100638 TI - PLGA/PLA micro- and nanoparticle formulations serve as antigen depots and induce elevated humoral responses after immunization of Atlantic salmon (Salmo salar L.). AB - Novel vaccine delivery systems are highly needed to improve the salmon aquaculture industry. Although particles of biocompatible polymers such as poly(lactic-co-glycolic) acid (PLGA) have long been considered promising candidates for delivery of immunogenic compounds, few studies have addressed their use as vaccine carriers in Atlantic salmon (Salmo salar L.). Investigating their ability to retain/depot antigen and induce time and dosage dependent adaptive humoral responses to immunization, we here present a basic study of the adjuvantic properties PLGA and PLA particles may have in salmon vaccines. A model antigen (human gamma globulin, HGG) was co-encapsulated with beta-glucan in nanoparticles (<1000nm) and microparticles (~8MUm) of different chemical compositions. Atlantic salmon were immunized with (a) PLGA or PLA particle entrapped antigen (12 different treatment groups), (b) antigen and beta-glucan in PBS, (c) an oil-based formulation or (d) nanoparticles (NPs) or microparticles (MPs) combined with the oil-adjuvanted formulation. ELISA analysis showed that NPs and MPs were capable of inducing elevated antibody responses at day 60 and 75 post immunization, but the antibody levels were reduced at day 90 and 120. In contrast, oil-based formulations, either alone or in combination with NPs or MPs resulted in strong antibody responses at all sampling time points. Comparable dosage dependent increase in antibody responses was observed when administering antigen with beta-glucan either in PBS, entrapped in NPs or MPs, or in an oil adjuvanted formulation. However, as the antigen doses were increased, MPs and the oil-based formulation gave the strongest responses. Antigen presence in the blood, organ package/injection site, kidney, carcass and the whole body was quantified by radiotracing of I(125)-labelled HGG at day 7 and 36 post immunization. At both sampling time points, the highest radioactivity levels were measured from the whole-body and organ package/injection site in groups injected with MPs and oil-based formulations, indicating that these formulations resulted in superior antigen retention. Interestingly, NPs were found to accumulate in the kidney, a result that corroborated with in vitro uptake of NPs in a DC/Mphi-like cell line from Atlantic salmon. PMID- 22100639 TI - Telomeres and disease: an overview. PMID- 22100640 TI - [Chronobiological aspects of obesity and metabolic syndrome]. AB - Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed. PMID- 22100641 TI - Age-related loss of cardiac preconditioning: impact of protein kinase A. AB - Helium induces preconditioning (He-PC) by mitochondrial calcium-sensitive potassium (mK(Ca)) channel-activation, but this effect is lost in the aged myocardium. Both, the upstream signalling pathway of He-PC and the underlying mechanisms for an age-related loss of preconditioning are unknown. A possible candidate as upstream regulator of mK(Ca) channels is protein kinase A (PKA). We investigated whether 1) regulation of PKA is involved in He-PC and 2) regulation of PKA is age-dependent. Young (2-3 months) and aged (22-24 months) Wistar rats were randomised to eight groups (each n=8). All animals underwent 25 min regional myocardial ischemia and 120 min reperfusion. Control (Con, Age Con) animals were not further treated. Young rats inhaled 70% helium for 3*5 min (He-PC). The PKA blocker H-89 (10 MUg/kg) was administered with and without helium (He-PC+H-89, H 89). Furthermore, we tested the effect of direct activation of mK(Ca) channels with NS1619. The adenylyl cyclase activator forskolin (For) was administered in young (300 MUg/kg) and aged animals (300 and 1000 MUg/kg). He-PC reduced infarct size from 60+/-4% (Con) to 37+/-10% (p<0.05). Infarct size reduction was completely abolished by H-89 (58+/-5%; p<0.05), but H-89 alone had no effect (57+/-2%). NS1619 reduced infarct size in the same concentration in both, young and aged rats (35+/-6%; p<0.05 vs. Con and 34+/-8%; p<0.05 vs. Age Con). Forskolin in a concentration of 300 MUg/kg reduced infarct size in young (37+/ 6%; p<0.05) but not in aged rats (48+/-13%; n.s.). In contrast, 1000 MUg/kg Forskolin reduced infarct size also in aged rats (28+/-3%; p<0.05). He-PC is mediated by activation of PKA. Alterations in PKA regulation might be an underlying mechanism for the age-dependent loss of preconditioning. PMID- 22100643 TI - Grid cells use HCN1 channels for spatial scaling. AB - Entorhinal grid cells have periodic, hexagonally patterned firing locations that scale up progressively along the dorsal-ventral axis of medial entorhinal cortex. This topographic expansion corresponds with parallel changes in cellular properties dependent on the hyperpolarization-activated cation current (Ih), which is conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. To test the hypothesis that grid scale is determined by Ih, we recorded grid cells in mice with forebrain-specific knockout of HCN1. We find that, although the dorsal-ventral gradient of the grid pattern was preserved in HCN1 knockout mice, the size and spacing of the grid fields, as well as the period of the accompanying theta modulation, was expanded at all dorsal-ventral levels. There was no change in theta modulation of simultaneously recorded entorhinal interneurons. These observations raise the possibility that, during self-motion based navigation, Ih contributes to the gain of the transformation from movement signals to spatial firing fields. PMID- 22100642 TI - Ischemic preconditioning: the role of mitochondria and aging. AB - Aging represents a triple threat for myocardial infarction (MI). Not only does the incidence of MI increase with age, but the heart becomes more susceptible to MI induced damage and protective interventions such as ischemic preconditioning (IPC) become less effective. Therefore, any rational therapeutic strategy must be built around the ability to combat the detrimental effects of ischemia in aged individuals. To accomplish this, we need to develop a better understanding of how ischemic damage, protection, and aging are linked. In this regard, mitochondria have emerged as a common theme. First, mitochondria contribute to cell damage during ischemia-reperfusion (IR) and are central to cell death. Second, the protective signaling pathways activated by IPC converge on mitochondria, and the opening of mitochondrial ion channels alone is sufficient to elicit protection. Finally, mitochondria clearly influence the aging process, and specific defects in mitochondrial activity are associated with age-related functional decline. This review will summarize the effects of aging on myocardial IR injury and discuss relevant and emerging strategies to protect against MI with an emphasis on mitochondrial function. PMID- 22100644 TI - No primexine and plasma membrane undulation is essential for primexine deposition and plasma membrane undulation during microsporogenesis in Arabidopsis. AB - Primexine deposition and plasma membrane undulation are the initial steps of pollen wall formation. However, little is known about the genes involved in this important biological process. Here, we report a novel gene, NO PRIMEXINE AND PLASMA MEMBRANE UNDULATION (NPU), which functions in the early stage of pollen wall development in Arabidopsis (Arabidopsis thaliana). Loss of NPU function causes male sterility due to a defect in callose synthesis and sporopollenin deposition, resulting in disrupted pollen in npu mutants. Transmission electronic microscopy observation demonstrated that primexine deposition and plasma membrane undulation are completely absent in the npu mutants. NPU encodes a membrane protein with two transmembrane domains and one intracellular domain. In situ hybridization analysis revealed that NPU is strongly expressed in microspores and the tapetum during the tetrad stage. All these results together indicate that NPU plays a vital role in primexine deposition and plasma membrane undulation during early pollen wall development. PMID- 22100645 TI - Bipartite promoter element required for auxin response. AB - Multiple mechanisms have been described for coordination of responses to the plant hormones auxin and brassinosteroids (Zhang et al., 2009). One unexplained phenomenon is the reliance of the auxin transcriptional response on a functional brassinosteroid pathway. In this study, we used luciferase reporters to interrogate the promoter of SMALL AUXIN-UP RNA15 (SAUR15), a well-characterized auxin and brassinosteroid early response gene in Arabidopsis (Arabidopsis thaliana). After identifying a minimal region sufficient for auxin response, we targeted predicted cis-regulatory elements contained within this sequence and found a critical subset required for hormone response. Specifically, reporter sensitivity to auxin treatment required two elements: a Hormone Up at Dawn (HUD) type E-box and an AuxRE-related TGTCT element. Reporter response to brassinosteroid treatment relied on the same two elements. Consistent with these findings, the transcription factors BRASSINOSTEROID INSENSITIVE1-EMS SUPPESSOR1 and MONOPTEROS (MP)/ AUXIN RESPONSE FACTOR5 (ARF5) showed enhanced binding to the critical promoter region containing these elements. Treatment with auxin or brassinosteroids could enhance binding of either transcription factor, and brassinosteroid enhancement of MP/ARF5 binding required an intact HUD element. Conservation of clustered HUD elements and AuxRE-related sequences in promoters of putative SAUR15 orthologs in a number of flowering plant species, in combination with evidence for statistically significant clustering of these elements across all Arabidopsis promoters, provided further evidence of the functional importance of coordinated transcription factor binding. PMID- 22100646 TI - Involvement of the mitochondrial compartment in human NCL fibroblasts. AB - Neuronal ceroid lipofuscinosis (NCL) are a group of progressive neurodegenerative disorders of childhood, characterized by the endo-lysosomal storage of autofluorescent material. Impaired mitochondrial function is often associated with neurodegeneration, possibly related to the apoptotic cascade. In this study we investigated the possible effects of lysosomal accumulation on the mitochondrial compartment in the fibroblasts of two NCL forms, CLN1 and CLN6. Fragmented mitochondrial reticulum was observed in all cells by using the intravital fluorescent marker Mitotracker, mainly in the perinuclear region. This was also associated with intense signal from the lysosomal markers Lysotracker and LAMP2. Likewise, mitochondria appeared to be reduced in number and shifted to the cell periphery by electron microscopy; moreover the mitochondrial markers VDCA and COX IV were reduced following quantitative Western blot analysis. Whilst there was no evidence of increased cell death under basal condition, we observed a significant increase in apoptotic nuclei following Staurosporine treatment in CLN1 cells only. In conclusion, the mitochondrial compartment is affected in NCL fibroblasts invitro, and CLN1 cells seem to be more vulnerable to the negative effects of stressed mitochondrial membrane than CLN6 cells. PMID- 22100647 TI - Two amino acids in each of D1 and D2 dopamine receptor cytoplasmic regions are involved in D1-D2 heteromer formation. AB - D(1) and D(2) dopamine receptors exist as heteromers in cells and brain tissue and are dynamically regulated and separated by agonist concentrations at the cell surface. We determined that these receptor pairs interact primarily through discrete amino acids in the cytoplasmic regions of each receptor, with no evidence of any D(1)-D(2) receptor transmembrane interaction found. Specifically involved in heteromer formation we identified, in intracellular loop 3 of the D(2) receptor, two adjacent arginine residues. Substitution of one of the arginine pair prevented heteromer formation. Also involved in heteromer formation we identified, in the carboxyl tail of the D(1) receptor, two adjacent glutamic acid residues. Substitution of one of the glutamic acid pair prevented heteromer formation. These amino acid pairs in D(1) and D(2) receptors are oppositely charged, and presumably interact directly by electrostatic interactions. PMID- 22100648 TI - Rickettsia conorii infection stimulates the expression of ISG15 and ISG15 protease UBP43 in human microvascular endothelial cells. AB - Rickettsia conorii, an obligate intracellular bacterium and the causative agent of Mediterranean spotted fever, preferentially infects microvascular endothelial cells of the mammalian hosts leading to onset of innate immune responses, characterized by the activation of intracellular signaling mechanisms, release of pro-inflammatory cytokines and chemokines, and killing of intracellular rickettsiae. Our recent studies have shown that interferon (IFN)-beta, a cytokine traditionally considered to be involved in antiviral immunity, plays an important role in the autocrine/paracrine regulation of host defense mechanisms and control of R. conorii growth in the host endothelial cells. Here, we show that R. conorii infection induces the expression of ISG15 (an interferon-stimulated gene coding a protein of 17kD) and UBP43 (an ISG15-specific protease) at the levels of mRNA and protein and report the evidence of ISGylation of as yet unidentified target proteins in cultured human microvascular endothelium. Infection-induced expression of ISG15 and UBP43 requires intracellular replication of rickettsiae and production of IFN-beta, because treatment with tetracycline and presence of an antibody capable of neutralizing IFN-beta activity resulted in near complete attenuation of both responses. Inhibition of R. conorii-induced ISG15 by RNA interference results in significant increase in the extent of rickettsial replication, whereas UBP43 knockdown yields a reciprocal inhibitory effect. In tandem, these results demonstrate the stimulation of interferon-beta-mediated innate immune mechanisms capable of perturbing the growth and replication of pathogenic rickettsiae and provide first evidence for ISG15-mediated post translational modification of host cellular proteins during infection with an intracellular bacterium. PMID- 22100649 TI - Dynamic behavior of small heat shock protein inhibition on amyloid fibrillization of a small peptide (SSTSAA) from RNase A. AB - Small heat shock proteins, a class of molecular chaperones, are reported to inhibit amyloid fibril formation in vitro, while the mechanism of inhibition remains unknown. In the present study, we investigated the mechanism by which Mj HSP16.5 inhibits amyloid fibril formation of a small peptide (SSTSAA) from RNase A. A model peptide (dansyl-SSTSAA-W) was designed by introducing a pair of fluorescence resonance energy transfer (FRET) probes into the peptide, allowing for the monitoring of fibril formation by this experimental model. Mj HSP16.5 completely inhibited fibril formation of the model peptide at a molar ratio of 1:120. The dynamic process of fibril formation, revealed by FRET, circular dichroism, and electron microscopy, showed a lag phase of about 2 h followed by a fast growth period. The effect of Mj HSP16.5 on amyloid fibril formation was investigated by adding it into the incubation solution during different growth phases. Adding Mj HSP16.5 to the incubating peptide before or during the lag phase completely inhibited fibril formation. However, introducing Mj HSP16.5 after the lag phase only slowed down the fibril formation process by adhering to the already formed fibrils. These findings provide insight into the inhibitory roles of small heat shock proteins on amyloid fibril formation at the molecular level. PMID- 22100650 TI - Structure and dimerization of translation initiation factor aIF5B in solution. AB - Translation initiation factor 5B (IF5B) is required for initiation of protein synthesis. The solution structure of archaeal IF5B (aIF5B) was analysed by small angle X-ray scattering (SAXS) and dynamic light scattering (DLS) and was indicated to be in both monomeric and dimeric form. Sedimentation equilibrium (SE) analytical ultracentrifugation (AUC) of aIF5B indicated that aIF5B forms irreversible dimers in solution but only to a maximum of 5.0-6.8% dimer. Sedimentation velocity (SV) AUC at higher speed also indicated the presence of two species, and the sedimentation coefficients s(20,w)(0) were determined to be 3.64 and 5.51+/-0.29 S for monomer and dimer, respectively. The atomic resolution (crystallographic) structure of aIF5B (Roll-Mecak et al. [6]) was used to model monomer and dimer, and theoretical sedimentation coefficients for these models were computed (3.89 and 5.63 S, respectively) in good agreement with the sedimentation coefficients obtained from SV analysis. Thus, the structure of aIF5B in solution must be very similar to the atomic resolution structure of aIF5B. SAXS data were acquired in the same buffer with the addition of 2% glycerol to inhibit dimerization, and the resultant monomeric aIF5B in solution did indeed adopt a structure very similar to the one reported earlier for the protein in crystalline form. The p(r) function indicated an elongated conformation supported by a radius of gyration of 37.5+/-0.2 A and a maximum dimension of ~130 A. The effects of glycerol on the formation of dimers are discussed. This new model of aIF5B in solution shows that there are universal structural differences between aIF5B and the homologous protein IF2 from Escherichia coli. PMID- 22100651 TI - New phenotypic aspects of the decidual spiral artery wall during early post implantation mouse pregnancy. AB - During pregnancy the walls of decidual spiral arteries (SAs) undergo clinically important structural modifications crucial for embryo survival/growth and maternal health. However, the mechanisms of SA remodeling (SAR) are poorly understood. Although an important prerequisite to this understanding is knowledge about the phenotype of SA muscular wall prior to and during the beginning of mouse SAR, this remains largely unexplored and was the main aim of this work. Using histological and immunohistochemical techniques, this study shows for the first time that during early mouse gestation, from embryonic day 7.5 (E7.5) to E10.5, the decidual SA muscular coat is not a homogeneous structure, but consists of two concentric layers. The first is a largely one cell-thick sub-endothelial layer of contractile mural cells (positive for alpha-smooth muscle actin, calponin and SM22alpha) with pericyte characteristics (NG2 positive). The second layer is thicker, and evidence is presented that it may be of the synthetic/proliferative smooth muscle phenotype, based on absence (alpha-smooth muscle actin and calponin) or weak (SM22alpha) expression of contractile mural cell markers, and presence of synthetic smooth muscle characteristics (expression of non-muscle Myosin heavy chain-IIA and of the cell proliferation marker PCNA). Importantly, immunohistochemistry and morphometrics showed that the contractile mural cell layer although prominent at E7.5-E8.5, becomes drastically reduced by E10.5 and is undetectable by E12.5. In conclusion, this study reveals novel aspects of the decidual SA muscular coat phenotype prior to and during early SAR that may have important implications for understanding the mechanisms of SAR. PMID- 22100652 TI - Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea. AB - The mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac mesodermal induction in undifferentiated cells independently of cell proliferation. This analysis suggests that IGF-1Ea may be a good candidate to improve both in vitro production of cardiomyocytes from pluripotent stem cells and in vivo activation of the differentiation program of cardiac progenitor cells. PMID- 22100653 TI - Suppression of phospholipase Cgamma1 phosphorylation by cinnamaldehyde inhibits antigen-induced extracellular calcium influx and degranulation in mucosal mast cells. AB - Antigen-IgE-mediated mucosal mast-cell activation is critical in the development of food allergies. Cinnamaldehyde, a major constituent of Cinnamomi cortex, dose dependently inhibited the antigen-IgE-induced degranulation of mucosal-type bone marrow derived mast cells (mBMMCs) and RBL-2H3 cells. Cinnamaldehyde also suppressed the elevation of the intracellular Ca(2+) level that is induced by the extracellular Ca(2+) influx in antigen-IgE-stimulated mBMMCs. Furthermore, tyrosine phosphorylation of phospholipase C (PLC) gamma1, which is a crucial activation switch for the intracellular Ca(2+) mobilization in mast cells, was attenuated by cinnamaldehyde. Together, our results demonstrated that cinnamaldehyde suppressed the intracellular Ca(2+) mobilization and the degranulation of mucosal mast cells by inhibiting the activity of the IgE receptor-PLCgamma-Ca(2+) influx pathway. These findings suggest that cinnamaldehyde may have therapeutic potential in mucosal mast cell-related allergic diseases, such as food allergies. PMID- 22100654 TI - Comparison of anisotropic aperture based intensity modulated radiotherapy with 3D conformal radiotherapy for the treatment of large lung tumors. AB - PURPOSE/OBJECTIVE(S): IMRT allows dose escalation for large lung tumors, but respiratory motion may compromise delivery. A treatment plan that modulates fluence predominantly in the transversal direction and leaves the fluence identical in the direction of the breathing motion may reduce this problem. MATERIALS/METHODS: Planning-CT-datasets of 20 patients with Stage I-IV non small cell lung cancer (NSCLC) formed the basis of this study. A total of two IMRT plans and one 3D plan were created for each patient. Prescription dose was 60 Gy to the CTV and 70 Gy to the GTV. For the 3D plans an energy of 18 MV photons was used. IMRT plans were calculated for 6 MV photons with 13 coplanar and with 17 noncoplanar beams. Robustness of the used method of anisotropic modulation toward breathing motion was tested in a 13-field IMRT plan. RESULTS: As a consequence of identical prescription doses, mean target doses were similar for 3D and IMRT. Differences between 3D and 13- and 17-field IMRT were significant for CTV Dmin (43 Gy vs. 49.1 Gy vs. 48.6 Gy; p<0.001) and CTV D(95) (53.2 Gy vs. 55.0 Gy vs. 55.4 Gy; p=0.001). The D(mean) of the contralateral lung was significantly lower in the 17-field plans (17-field IMRT vs. 13- vs. 3D: 12.5 Gy vs. 14.8 Gy vs. 15.8 Gy: p<0.05). The spinal cord dose limit of 50 Gy was always respected in IMRT plans and only in 17 of 20 3D-plans. Heart D(max) was only marginally reduced with IMRT (3D vs. 13- vs. 17-field IMRT: 38.2 Gy vs. 36.8 Gy vs. 37.8 Gy). Simulated breathing motion caused only minor changes in the IMRT dose distribution (~0.5-1 Gy). CONCLUSIONS: Anisotropic modulation of IMRT improves dose delivery over 3D-RT and renders IMRT plans robust toward breathing induced organ motion, effectively preventing interplay effects. PMID- 22100655 TI - Combined treatment of the immunoconjugate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo. AB - BACKGROUND AND PURPOSE: To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone. MATERIAL AND METHODS: For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 MUg/kg DM1 and 100 MUg/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels). RESULTS: BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response. CONCLUSION: Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity. PMID- 22100656 TI - Clinical comparison of positional accuracy and stability between dedicated versus conventional masks for immobilization in cranial stereotactic radiotherapy using 6-degree-of-freedom image guidance system-integrated platform. AB - PURPOSE: To compare the positioning accuracy and stability of two distinct noninvasive immobilization devices, a dedicated (D-) and conventional (C-) mask, and to evaluate the applicability of a 6-degrees-of-freedom (6D) correction, especially to the C-mask, based on our initial experience with cranial stereotactic radiotherapy (SRT) using ExacTrac (ET)/Robotics integrated into the Novalis Tx platform. MATERIALS AND METHODS: The D- and C-masks were the BrainLAB frameless mask system and a general thermoplastic mask used for conventional radiotherapy such as whole brain irradiation, respectively. A total of 148 fractions in 71 patients and 125 fractions in 20 patients were analyzed for the D and C-masks, respectively. For the C-mask, 3D correction was applied to the initial 10 patients, and thereafter, 6D correction was adopted. The 6D residual errors (REs) in the initial setup, after correction (pre-treatment), and during post-treatment were measured and compared. RESULTS: The D-mask provided no significant benefit for initial setup. The post-treatment median 3D vector displacements (interquatile range) were 0.38 mm (0.22, 0.60) and 0.74 mm (0.49, 1.04) for the D- and C-masks, respectively (p<0.001). The post-treatment maximal translational REs were within 1 mm and 2 mm for the D- and C-masks, respectively, and notably within 1.5 mm for the C-mask with 6D correction. The pre-treatment 3D vector displacements were significantly correlated with those for post-treatment in both masks. CONCLUSIONS: The D-mask confers positional stability acceptable for SRT. For the C-mask, 6D correction is also recommended, and an additional setup margin of 0.5 mm to that for the D-mask would be sufficient. The tolerance levels for the pre-treatment REs should similarly be set as small as possible for both systems. PMID- 22100657 TI - Mediastinal lymph nodes staging by 18F-FDG PET/CT for early stage non-small cell lung cancer: a multicenter study. AB - PURPOSE: Accurate staging of mediastinal lymph nodes metastases is critical for determining the application of stereotactic body radiation therapy (SBRT) for patients with early stage non-small cell lung cancer (NSCLC). In this multicenter study the accuracy of (18)F-FDG PET/CT to detect lymph node metastases was evaluated for early stage NSCLC. MATERIALS AND METHODS: The data from the patients with stage1 NSCLC who received preoperative (18)F-FDG PET/CT staging and radical surgery was retrospectively reviewed of five centers from February 2004 to August 2010. The lymph node metastases were confirmed histopathologically after radical surgery. And the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for PET/CT staging. RESULTS: Two hundred patients were enrolled. The sensitivity, specificity, accuracy, PPV and NPV for lymph node metastases on PET/CT were 44%, 83%, 78%, 29% and 91%, respectively. There were eight and 19 cases positive for lymph node metastases with central (n=62) and peripheral (n=138) NSCLC (P>0.05), respectively. CONCLUSION: (18)F-FDG PET/CT was specific in N(0) staging for T(1 2) NSCLC. The NPV was about 91% in clinical N(0) patients, suggested that (18)F FDG PET/CT may help to accurately stage N(0) patients and thus identify patients for SBRT. PMID- 22100658 TI - Genetic variants in TGFbeta-1 and PAI-1 as possible risk factors for cardiovascular disease after radiotherapy for breast cancer. AB - BACKGROUND AND PURPOSE: It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFbeta pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFbeta1 29C>T and PAI-1 5G>4G, on CVD incidence. MATERIALS AND METHODS: This retrospective cohort study included 422 10-year breast cancer survivors, aged <50 years at diagnosis, treated between 1977 and 1995. We collected information on treatment, oncological follow-up, CVD, CVD risk factors and genotypes. RESULTS: During a mean follow-up of 19.4 years, 61 patients developed CVD. Internal mammary chain (IMC) irradiation, exposing a part of the heart to radiation, was associated with a hazard ratio of 2.36 (95% CI: 1.27-4.37, p=0.01) compared to no IMC irradiation. Compared to the C/C+C/T genotype, the T/T genotype of the TGFbeta1 polymorphism was associated with hazard ratios of 1.79 (0.99-3.26, p=0.06) and 1.74 (0.90-3.34, p=0.10) in the total and IMC-irradiated group, respectively. We found no evidence for an association between PAI-1 5G>4G and CVD risk. CONCLUSION: Our study suggests there might be an association between the TGFbeta1 29C>T polymorphism and CVD risk in long-term breast cancer survivors. PMID- 22100659 TI - Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective population-based study. AB - BACKGROUND: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. METHODS: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. RESULTS: Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2 year survival that was not reached and 66.7%, respectively (p=0.004). CONCLUSIONS: The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy. PMID- 22100660 TI - Functional food and satiety. Impact of a satiating context effect on appetite control of non-obese men. AB - The aim of this study was to verify if the addition of satiating nutrients and a satiating context effect could influence appetite sensations, spontaneous energy intake and food appreciation under conditions of standardized energy density of a meal. Eighteen non-obese men were submitted to a control, a satiating, and a context effect condition composed of a standardized breakfast and an ad libitum test lunch (macaroni entree plus chocolate cake). The satiating macaroni contained more proteins, unsaturated fats, fibres and calcium than the control macaroni despite similar energy density, appearance and palatability. In the context effect condition, participants believed they were eating "a highly satiating macaroni", but were served the control macaroni. Appreciation of the macaronis, quantities of macaroni and cake consumed and 4-h satiating potential were measured for each condition. Quantities of macaroni and dessert consumed did not differ between conditions. Satiating potential was greater for the context effect meal compared to the control and/or the satiating meals up to 4h after its consumption. The context effect macaroni obtained higher appreciation rates than the control and the satiating macaronis. The context effect may positively influence the appreciation toward a meal and contribute to increase its satiety potential for many hours. PMID- 22100661 TI - Deletion of the adenosine A(2A) receptor in mice enhances spinal cord neurochemical responses to an inflammatory nociceptive stimulus. AB - Knockout mice lacking the adenosine A(2A) receptor are less sensitive to nociceptive stimuli, and this may be due to the presence of pronociceptive A(2A) receptors on sensory nerves. In support of this hypothesis, we have recently shown that in A(2A) receptor knockout mice there are marked reductions in the changes of two markers of spinal cord neuronal activity, [(3)H]MK801 binding to NMDA receptors and uptake of [(14)C]-2-deoxyglucose, in response to formalin injection. We now report that following a more prolonged inflammatory stimulus, consisting of intraplantar injections of PGE(2) and paw pressure, there was in contrast an increase in [(3)H]MK801 binding and [(14)C]-2-deoxyglucose uptake in the spinal cords of the A(2A) receptor knockout mice which was much greater than in the wild-type mice. This increase suggests that when there is a pronounced inflammatory component to the stimulus, loss of inhibitory A(2A) receptors on inflammatory cells outweighs the loss of pronociceptive A(2A) receptors on peripheral nerves so that overall there is an increase in nociceptive signalling. This implies that although A(2A) antagonists have antinociceptive effects they may have only limited use as analgesics in chronic inflammatory pain. PMID- 22100662 TI - GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant. AB - Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimer's Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1 1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin 1beta activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk. PMID- 22100663 TI - Adaptive Kalman filtering for real-time mapping of the visual field. AB - This paper demonstrates the feasibility of real-time mapping of the visual field for clinical applications. Specifically, three aspects of this problem were considered: (1) experimental design, (2) statistical analysis, and (3) display of results. Proper experimental design is essential to achieving a successful outcome, particularly for real-time applications. A random-block experimental design was shown to have less sensitivity to measurement noise, as well as greater robustness to error in modeling of the hemodynamic impulse response function (IRF) and greater flexibility than common alternatives. In addition, random encoding of the visual field allows for the detection of voxels that are responsive to multiple, not necessarily contiguous, regions of the visual field. Due to its recursive nature, the Kalman filter is ideally suited for real-time statistical analysis of visual field mapping data. An important feature of the Kalman filter is that it can be used for nonstationary time series analysis. The capability of the Kalman filter to adapt, in real time, to abrupt changes in the baseline arising from subject motion inside the scanner and other external system disturbances is important for the success of clinical applications. The clinician needs real-time information to evaluate the success or failure of the imaging run and to decide whether to extend, modify, or terminate the run. Accordingly, the analytical software provides real-time displays of (1) brain activation maps for each stimulus segment, (2) voxel-wise spatial tuning profiles, (3) time plots of the variability of response parameters, and (4) time plots of activated volume. PMID- 22100664 TI - Linking white matter tracts to associated cortical grey matter: a tract extension methodology. AB - Quantitative diffusion analysis of white matter (WM) tracts has been utilised in many diseases for determining damage to, and changes in, WM tracts throughout the brain. However, there are limited studies investigating associations between quantitative measures in WM tracts and anatomically linked grey matter (GM), due to the difficulty in determining GM regions connected with a given WM tract. This work describes a straightforward method for extending a WM tract through GM based on geometry. The tract is extended by following a straight line from each point on the tract boundary to the outer boundary of the cortex. A comparison between a multiplanar 2D approach and a 3D method was made. This study also tested an analysis pipeline from tracking WM tracts to quantifying magnetisation transfer ratios (MTR) in the associated cortical GM, and assessed the applicability of the method to healthy control subjects. Tract and associated cortical volumes and MTR values for the cortico-spinal tracts, genu and body of the corpus callosum were extracted; the between-subjects standard deviation was calculated. It was found that a multiplanar 2D approach produced a more anatomically plausible volume of GM than a 3D approach, at the expense of possible overestimation of the GM volume. The between-subjects standard deviation of the tract specific quantitative measurements (from both the WM and GM masks) ranged between 1.2 and 7.3% for the MTR measures, and between 10 and 45% for the absolute volume measures. The results show that the method can be used to produce anatomically plausible extensions of the WM tracts through the GM, and regions defined in this way yield reliable estimates of the MTR from the regions. PMID- 22100665 TI - The ADNI Publication Policy: commensurate recognition of critical contributors who are not authors. AB - An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities. PMID- 22100666 TI - Aging-kb: a knowledge base for the study of the aging process. AB - As the science of the aging process moves forward, a recurring challenge is the integration of multiple types of data and information with classical aging theory while disseminating that information to the scientific community. Here we present AGING-kb, a public knowledge base with the goal of conceptualizing and presenting fundamental aspects of the study of the aging process. Aging-kb has two interconnected parts, the Aging-kb tree and the Aging Wiki. The Aging-kb tree is a simple intuitive dynamic tree hierarchy of terms describing the field of aging from the general to the specific. This enables the user to see relationships between areas of aging research in a logical comparative fashion. The second part is a specialized Aging Wiki which allows expert definition, description, supporting information, and documentation of each aging keyword term found in the Aging-kb tree. The Aging Wiki allows community participation in describing and defining concepts and terms in the Wiki format. This aging knowledge base provides a simple intuitive interface to the complexities of aging. PMID- 22100667 TI - Chloroviruses: not your everyday plant virus. AB - Viruses infecting higher plants are among the smallest viruses known and typically have four to ten protein-encoding genes. By contrast, many viruses that infect algae (classified in the virus family Phycodnaviridae) are among the largest viruses found to date and have up to 600 protein-encoding genes. This brief review focuses on one group of plaque-forming phycodnaviruses that infect unicellular chlorella-like green algae. The prototype chlorovirus PBCV-1 has more than 400 protein-encoding genes and 11 tRNA genes. About 40% of the PBCV-1 encoded proteins resemble proteins of known function including many that are completely unexpected for a virus. In many respects, chlorovirus infection resembles bacterial infection by tailed bacteriophages. PMID- 22100669 TI - Assimilating the current clinical data of fully bioabsorbable stents. PMID- 22100670 TI - Ten-year follow-up of the IGAKI-TAMAI stent. A posthumous tribute to the scientific work of Dr. Hideo Tamai. PMID- 22100668 TI - A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. AB - BACKGROUND: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. METHODS AND RESULTS: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. CONCLUSIONS: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes. PMID- 22100671 TI - Design principles and performance of bioresorbable polymeric vascular scaffolds. AB - AIMS: Bioresorbable polymeric vascular scaffolds may spawn a fourth revolution in percutaneous coronary intervention (PCI) and a novel treatment termed vascular restoration therapy. The principal design considerations for bioresorbable scaffolds are discussed in the context of physiological behaviour using the Bioabsorbable Vascular Solutions (BVS) ABSORB Cohort B scaffold (Abbott Vascular) as an example. METHODS AND RESULTS: The lifecycle of a bioresorbable scaffold is divided into three phases: (1) revascularisation; (2) restoration; and (3) resorption. In the revascularisation phase spanning the first three months after intervention, the bioresorbable scaffold should perform comparably to metallic drug-eluting stents (DES) in terms of deliverability, radial strength, recoil, and neointimal thickening. The ensuing restoration phase is characterised by gradual erosion of radial strength and a loss of structural continuity, where the time scale at which each occurs is related to the hydrolytic degradation rate of the polymer. Natural vasomotion in response to external stimuli is theoretically possible at the end of this phase. Finally, in the resorption phase, the passive implant is systematically resorbed and processed by the body. CONCLUSIONS: Limited clinical data speak to the potential of bioresorbable scaffolds as a new therapy, and future studies will prove critical to inspiring a fourth revolution in PCI. PMID- 22100672 TI - ABC's of bioabsorption: application of lactide based polymers in fully resorbable cardiovascular stents. AB - Lactide based polymers present a promising class of materials for successful development of fully resorbable stents, thus helping to bring the concept of vascular restoration therapies to life. Not only can these polymers be perfectly tuned to fulfil technical requirements for a fully resorbable stent, they have been proven to be safe materials with a long track record of in vivo biocompatibility in a broad range of medical and pharmaceutical fields. They have a strong regulatory history as well. The polymers degrade through hydrolysis, and are eliminated by the human body through natural pathways via the Krebs cycle. The polymers can perform a temporary mechanical function, allowing the tissue to heal and resume its original function before the implant looses its mechanical integrity. The mechanical performance of the stent can be achieved through stent design and manufacturing methods, as well as tailoring the properties of the polymer itself. The resorption time of cardiovascular stents based on these polymers can be tuned -from a polymer perspective- by tailoring the molecular weight, the crystallinity and the hydrophilicity of the polymer. Drug eluting coatings for resorbable stents can be developed from the same family of polymers, tailoring the composition to the desired controlled release of the applicable drug. To successfully develop resorbable cardiovascular devices an interdisciplinary approach is needed, bringing together polymer chemists and engineers and connecting them with medical device and clinical experts. PMID- 22100673 TI - The bioabsorption process: tissue and cellular mechanisms and outcomes. PMID- 22100674 TI - Coating bioabsorption and chronic bare metal scaffolding versus fully bioabsorbable stent. AB - Advances in coronary stent technology, including refinement of the stent alloy, strut thickness, stent geometry, passive coating, and drug elution, have dramatically enhanced the safety and efficacy of percutaneous coronary intervention (PCI) with stenting. Stents are currently used in over 90% of coronary interventions and the use of drug-eluting stents (DES) has been disseminated to more complex lesion subsets such as total occlusions, long lesions, bifurcation lesions, and for patients with acute myocardial infarction. DES continue to demonstrate reduction in restenosis and the need for repeat revascularisation but are associated with delayed healing and re endothelialisation, which have led to an increased rates of late stent thrombosis, dependency on prolonged dual antiplatelet therapy, impaired in-vessel reactivity, and chronic inflammation. As scientists and clinicians better understand the mechanism for late restenosis and stent thrombosis, a variety of solutions in regard to stent technology have been proposed, including stent coating, polymer bioabsorption, and fully biodegradable stents. Bare metal stents were improved by the reduction of strut thickness, changes in stent geometry, and the addition of passive coating, which lead to improvements in efficacy and reduction of restenosis. In addition, there is continued improvement in the polymer technology for DES, including new biocompatible, thinner durable polymers, and bioabsorbable polymers that completely bioabsorb within 3-12 months after stent implantation. These features potentially minimise the chronic inflammatory response and late stent thrombosis. Finally, fully bioabsorbable stents, both polymeric and metallic, continue to be developed in order to eliminate any late stenting effects and potentially may enable complete vessel restoration. This manuscript will discuss the wide variety of new stent technologies and compare and contrast durable metallic and polymeric stents to current biodegradable stent technology. PMID- 22100675 TI - Late loss in a disappearing frame of reference: is it still applicable to fully absorbable scaffolds? AB - Bioabsorbable stents are an important advancement in stent technology providing a temporary scaffold and may be augmented with drugs to suppress neointimal hyperplasia.Though changes are being made to the design of the stents, to ensure similar rates of acute recoil, residual stenosis postintervention remains higher when compared to contemporary durable stents. In order to achieve similar clinical restenosis outcomes, bioabsorbable stents must first show similar MLD or percent diameter stenosis at follow-up to drug-eluting stents.While variable different acute gain and post-procedure MLD for bioabsorbable stents make late lumen loss a poor marker for restenosis probability by itself, late loss can be an informative metric for neointimal hyperplasia over time in these stents.Metrics which are independent of acute gain such as minimal luminal diameter and percentage diameter stenosis may make better surrogates for restenosis (Table 1). Moreover, remodelling over time requires measurement of the vessel and lumen diameters in later follow-up. Since the natural history of the vascular response to bioabsorbable stents is in its infancy of investigation, follow-up of these stents at least beyond the duration of polymer is prudent. Finally, given a disappearing frame of reference, both careful angiographic and intravascular ultrasound assessments are helpful to delineate the varying contributions of recoil, remodelling, and neointima formation. PMID- 22100676 TI - Vascular restoration therapy: what should the clinical and angiographic measures for success be? PMID- 22100677 TI - Engineering a bioresorbable stent: REVA programme update. PMID- 22100678 TI - Novel fully bioabsorbable salicylate-based sirolimus-eluting stent. AB - AIMS: The concept of fully biodegradable stents has emerged as an attractive alternative to current permanent metallic stents, mainly as a potential solution to avoid late stent thrombotic events. We sought to evaluate a novel, fully bioabsorbable sirolimus-eluting stent (SES) synthesised entirely from a unique salicylic-acid polymer, in a clinically relevant animal model. METHODS AND RESULTS: Fully biodegradable balloon-expandable stents (n=45) were implanted in a porcine coronary arteries using quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) to optimise stent apposition. Dose density of sirolimus was 8.3 ug/mm of stent length with in vitro studies demonstrating elution over 30 days and complete stent degradation over 12 months. Animals were terminated at 7, 14, 30, 90, and 180 days for complete histological analysis. Optical coherence tomography (OCT) was also performed for the 90- and 180-days samples. All stents were deployed successfully without notable mechanical difficulties. Angiographic diameter stenosis (DS) was 20+/-16%, 24+/-4%, and 23+/ 17%, at one, three, and six months, respectively. In parallel, IVUS showed good stent apposition with DS of 21+/-9%, 25+/-7%, and 18+/-3%; and area stenosis (AS) of 35+/-13%, 33+/-7%, and 32+/-4% at one, three, and six months,respectively. OCT further demonstrated good stent apposition with DS of 28+/-7% and 20+/-6%, and AS of 37+/-10% and 33+/-13% at three and six months, respectively. OCT showed reduction of stent thickness by 23% from three to six months. Histologic analysis confirmed these in vivo findings and revealed a favourable healing process of absorbable stent incorporation into the arterial wall, without excessive thrombotic or inflammatory reactions. CONCLUSIONS: This study shows favourable vascular compatibility and efficacy for a novel fully bioabsorbable salicylate based SES. This device has good mechanical performance during deployment and stays well-apposed to the vessel wall at long-term follow-up. These initial results are highly encouraging and support progress into more extensive preclinical studies as well as early clinical testing. PMID- 22100679 TI - OrbusNeich fully absorbable coronary stent platform incorporating dual partitioned coatings. AB - The field of stent based tissue engineering continues to revolutionise modern medicine by designing novel materials to restore vascular tissue function. Accordingly, the following discussion examines a novel, absorbable, polymeric scaffold engineered in combination with dual therapeutic coating, enabling locally administered temporary scaffolding in the coronary arteries for long term vascular patency and repair. This coronary stent platform consists of an absorbable polymeric material stent structure that incorporates a dual partitioned coating, by means of pro-healing EPC (endothelial progenitor cell) capture technology allowing for rapid endothelial coverage, and an absorbable polymer matrix with sustained elution of sirolimus, a drug controlling neointimal proliferation. This paper provides a brief overview of the various innovations developed by OrbusNeich to create this fully absorbable coronary device platform. PMID- 22100680 TI - Vascular restoration therapy: the fourth revolution in interventional cardiology and the ultimate "rosy" prophecy. PMID- 22100681 TI - Challenges related to development of bioabsorbable vascular stents. AB - Vascular stents have revolutionised the field of interventional cardiology. Once an artery has healed, however, stents are no longer thought to serve a functional role. Bioabsorbable stents would be preferred to permanent implants if they maintain arterial architecture, minimise device/host interactions, and reduce the need for long-term anticoagulation therapy. Technical challenges to develop and commercialise a successful bioabsorbable stent relate to identification of materials and stent designs capable of balancing acute and chronic mechanical properties, degradation time, and biocompatibility. Successful programs will be ones that achieve these requirements with uncompromised product deliverability, efficacy and safety. Many materials currently proposed for use in bioabsorbable stents take longer than 24 months to degrade and so may not meet these criteria. We describe here the Medtronic CardioVascular bioabsorbable program which focuses on developing a degradable stent for superficial femoral arteries that targets degradation in less than 12 months. PMID- 22100682 TI - Elixir Medical's bioresorbable drug eluting stent (BDES) programme: an overview. PMID- 22100683 TI - A.R.T.: concept of a bioresorbable stent without drug elution. PMID- 22100684 TI - NEVOTM: a new generation of sirolimus-eluting coronary stent. PMID- 22100685 TI - Bioabsorbable polymers in medicine: an overview. AB - Today the domains of life-respecting, degradable therapeutic materials and devices are among the most attractive areas in polymer science. Increasing attention is being paid to polymeric compounds that can be bioresorbable, i.e., degradable and ideally excreted or bio-assimilated - suitable to treat human diseases or trauma that require therapeutic assistance for a limited period of time, namely the healing period. Basically, biopolymers are of interest because of their inherent biodegradability. However, other characteristics limit their applications in the human body. Artificial polymers, i.e., polymers of non natural origin, can be degradable in vivo and thus serve in time-limited biomedical or pharmacological therapy. The potential of these degradable polymers is discussed with respect to bioresorbability, with a special attention to polymers of the poly (alpha-hydroxy acid) type. PMID- 22100686 TI - Current state of the absorbable metallic (magnesium) stent. AB - BIOTRONIK's absorbable metal stent technology is based ona magnesium alloy that offers superior stent mechanics and biocompatibility. The first generation (AMS 1) showed promising results regarding mechanical properties as well as feasibility and safety in several human applications (150 cases). The second generation (AMS-2.1) shows improved scaffolding and efficacy in animals due to a more slowly degrading magnesium alloy and an optimised stent design. The preclinical results of the drug-eluting AMS-3 are encouraging and the clinical investigational program will resume in 2010. PMID- 22100687 TI - Everolimus-eluting bioabsorbable stent--Abbot Vascular programme. PMID- 22100688 TI - Are some individuals diagnosed with ADHD prone to alcohol abuse? Consideration of two possible mediating factors for this susceptibility. AB - Some studies conducted on ADHD have found a statistically significant relationship between those diagnosed with the disorder and a higher susceptibility to abuse alcohol. However, other studies have found no such correlation, or have found this to be true of only a nonstatistically significant subset of the population of individuals with ADHD. This research found an answer to what may be causing these discrepancies in findings. Various studies on ADHD have discovered both biological and cognitive differences in some individuals with ADHD that may be responsible for this predisposition toward alcohol abuse found in a subset of the ADHD population. It is proposed that those individuals diagnosed with ADHD who also have a mutation in the dopamine receptor D4 (DRD4) and who possess a deficiency in functionality of the prefrontal area of the brain designed for planning and reasoning may be more likely to develop alcohol abuse. PMID- 22100689 TI - Screening for ADHD in an adult social phobia sample. AB - OBJECTIVE: Recent studies have suggested a link between a primary anxiety disorder and ADHD. METHOD: A total of 39 participants with a primary diagnosis of social phobia were compared with 178 patients with ADHD and 88 patients with other psychiatric disorders on measures for childhood and adult ADHD (the Wender Utah Rating Scale and the Adult ADHD Self-Report Scale). RESULTS: Childhood symptoms of ADHD were reported by 7.8% of the social phobia participants, and 5.1% scored within the range of adult ADHD. The social phobia group reported significantly fewer ADHD symptoms than both of the comparison groups, who frequently reported social anxiety. CONCLUSION: Participants with social phobia recruited from the general population are less likely to suffer from ADHD. In contrast, patients with ADHD and patients with other psychiatric disorders appear to be likely to suffer from social anxiety. PMID- 22100690 TI - Conceptual structure of the symptoms of adult ADHD according to the DSM-IV and retrospective Wender-Utah criteria. AB - OBJECTIVE: Adult Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and retrospective childhood Wender-Utah ADHD criteria are implemented in self-report measures to assess adult ADHD and its required onset in childhood. Yet their dimensional structure and relationship to adult ADHD depressivity is still at debate. Therefore, both aspects were investigated, applying two respective German instruments (ADHD-Self-Report [ADHD-SR] and Wender Utah Rating Scale-German [WURS-G]) to two student samples. METHOD: ADHD-SR and WURS-G dimensions were identified by nonlinear confirmatory factor analyses, and their interrelations and relationship with adult depressivity were identified by structural equation modeling. RESULTS: Adult ADHD-SR symptoms were organized into inattention, hyperactivity, and impulsivity, and WURS-G symptoms were organized into inattention/hyperactivity, affect lability, depressivity, and conduct problems. Yet only the first two WURS factors directly affected adult ADHD facets, though childhood depressivity influenced them indirectly via adult depressivity. CONCLUSION: Only criteria of the first two WURS factors can be considered valid childhood ADHD indicators. Thus, only they should be used as an aid in the retrospective assessment of ADHD symptoms. PMID- 22100691 TI - Oppositional defiant disorder in adults with ADHD. AB - OBJECTIVE: Oppositional defiant disorder (ODD) is the most common comorbid condition in childhood ADHD. This trial was prospectively designed to explore ODD symptoms in ADHD adults. METHOD: A total of 86 patients in this placebo controlled, double-blind trial of methylphenidate transdermal system (MTS) were categorized based on the presence of ODD symptoms in childhood and adulthood, and then were compared for baseline and outcome differences. RESULTS: In all, 42% met Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria for ODD as adults and were significantly more impaired on measures of ADHD, personality disorder, and substance abuse and 27% had childhood ODD that had resolved. Childhood and adult ODD symptoms were significantly correlated. ODD and ADHD symptoms improved significantly with MTS (p < .001), and the most consistently significant results were found in participants with adult ODD. CONCLUSION: A total of 69% met criteria for ODD as children and/or adults. Understanding how ODD interacts with ADHD to impact personality disorder, substance abuse, and treatment response has important clinical, social, and theoretical implications. PMID- 22100692 TI - Second malignancies among Waldenstrom macroglobulinemia patients: small samples and sparse data. PMID- 22100693 TI - Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma. AB - BACKGROUND: Immunohistochemistry has been proposed as a specific and sensitive method to identify EGFR mutations or ALK rearrangements in lung tumours. PATIENTS AND METHODS: We assessed EGFR and KRAS by direct sequencing in 154 patients with lung adenocarcinoma. ALK rearrangements were assayed by FISH and RT-PCR. Immunohistochemistry was carried out and evaluated closely following published methods using recommended monoclonal rabbit or mouse antibodies. RESULTS: Thirteen of 36 exon 19 EGFR-mutated tumours (36%)-including 12 of 22 with p.Glu746_Ala750del (55%)-were positive with the 6B6 antibody that was raised against p.Glu746_Ala750del. One hundred eleven of 114 EGFR exon 19 wild-type tumours (97%) were negative with 6B6. Four of 21 exon 21 EGFR-mutated tumours (19%)-including 4 of 17 with p.Leu858Arg (24%)-were positive with the 43B2 antibody that was raised against p.Leu858Arg. One hundred twenty-two of 124 (98%) EGFR exon 21 wild-type tumours were negative with 43B2. Two of four ALK rearrangements-including two of three with ELM4-ALK fusion transcripts-were identified with the 5A4 antibody. Eleven of 13 tumours without ALK rearrangement (85%) were negative with 5A4. CONCLUSIONS: Immunohistochemistry is a specific means for identification of EGFR mutations and ALK rearrangements. It suffers, however, from poor sensitivity. PMID- 22100695 TI - Dissecting responsive phenotypes through cytokine and angiogenic factor analysis. PMID- 22100694 TI - Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort. AB - BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings. PMID- 22100700 TI - An exploration of athletes' views on their adherence to physiotherapy rehabilitation after sport injury. AB - OBJECTIVE: To explore athletes' perceptions of the factors that they feel may affect their adherence to a physiotherapy intervention. DESIGN: A qualitative design using semistructured interviews. SETTING: Participants were interviewed at home or their athletic club. PARTICIPANTS: 8 participants, 5 men and 3 women with a mean age of 30.4 y. RESULTS: Thematic analysis revealed 2 main categories of themes. The first relates to the athlete's perceptions of factors affecting his or her own adherence, with themes including the impact of injury, justification of adherence, and strategies used by the patient. The second relates to perceptions of the physiotherapist's impact on adherence, with themes relating to characteristics of and strategies used by the physiotherapist. CONCLUSIONS: Findings demonstrate the importance of exploring patients' perceptions of adherence. A number of factors that affect adherence are identified, and strategies that may enhance adherence suggested. PMID- 22100701 TI - TBNA or EBUS-TBNA? That is the question. PMID- 22100702 TI - Temporal fatty acid dynamics of the octocoral Veretillum cynomorium. AB - The objectives of the present work were to investigate the temporal variation in the fatty acid (FA) composition of the octocoral Veretillum cynomorium, examine the effects of reproduction and environmental factors on FA variation, and establish a chemotaxonomic identification for this species. Mean oocyte size frequency distributions showed that the majority of the oocytes had an intermediate size (Group II) before spawning (April and June). The late vitellogenic oocytes (Group III) became absent in August and October and, during this post-spawning period, oocytes were primarily of small size (Group I). Most of the major FA, 16:0, 18:0, 20:4n-6, 20:5n-3, and the tetracosapolyenoic fatty acid (TPA), 24:6n-3, varied significantly throughout the year (p<0.01), with two peaks in August/October and February. The boost in early oogenesis, also associated with warmer temperatures, seemed to be responsible for the observed increase in FA content between June and August. The highest values of FA content were observed in February when intermediate oogenesis (Group II) was at its peak and there were considerable levels of available food in the environment. Also, the increase in food availability seemed to trigger the final stages of gametogenesis. The high quantity of 18:1n-7, odd-numbered and branched FAs, suggested the presence of a dynamic bacterial community in V. cynomorium, probably as an adaptive response to the lack of symbiotic microalgae. Although the presence of TPAs is the main feature distinguishing octocorals from other coral species, here we showed that there was no single FA clearly dominating the FA composition of V. cynomorium throughout the year. Instead, four main FAs share similar concentrations: 16:0, 20:4n-6, 20:5n-3 and 24:6n-3. The predominance of these four FAs combined with the higher amount of 24:6n-3 when compared to 24:5n 6 may serve as a chemotaxonomic feature to distinguish this octocoral species (or genus). PMID- 22100703 TI - Characterization of the binding sites for the interactions between FKBP12 and intracellular calcium release channels. AB - FKBP12, an FK506 binding protein, interacts with type 1 ryanodine receptor (RyR1) and modulates its calcium channel activity. However, there are many opposing reports of FKBP12's interaction with other related calcium channels, such as type 1 IP(3) receptor and type 3 ryanodine receptor (IP(3)R1 and RyR3). In addition, the involvement of the prolyl-dipeptide motif in the calcium channels and the corresponding binding residues in FKBP12 remain controversial. Through pulldown assays with recombinant proteins, we provide biochemical evidence of the interaction between FKBP12 and RyR1, RyR3 and IP(3)R1. Using NMR chemical shift mapping, we show that the important binding residues in FKBP12 are located in its hydrophobic FK506 binding region. Consistently, we demonstrate that FK506 can competitively inhibit the interaction between FKBP12 and the dipeptide motifs of the calcium channels. We believe our results shed lights on the binding mechanism of calcium channel-FKBP12 interaction. PMID- 22100704 TI - Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: purine nucleosides are alternative energy sources in LLC PK1 cells during hypoxia. AB - Acute tubular necrosis is a clinical problem that lacks specific therapy and is characterized by high mortality rate. The ischemic renal injury affects the proximal tubule cells causing dysfunction and cell death after severe hypoperfusion. We utilized a cell-based screening approach in a hypoxia reoxygenation model of tubular injury to search for cytoprotective action using a library of pharmacologically active compounds. Oxygen-glucose deprivation (OGD) induced ATP depletion, suppressed aerobic and anaerobic metabolism, increased the permeability of the monolayer, caused poly(ADP-ribose) polymerase cleavage and caspase-dependent cell death. The only compound that proved cytoprotective either applied prior to the hypoxia induction or during the reoxygenation was adenosine. The protective effect of adenosine required the coordinated actions of adenosine deaminase and adenosine kinase, but did not requisite the purine receptors. Adenosine and inosine better preserved the cellular ATP content during ischemia than equimolar amount of glucose, and accelerated the restoration of the cellular ATP pool following the OGD. Our results suggest that radical changes occur in the cellular metabolism to respond to the energy demand during and following hypoxia, which include the use of nucleosides as an essential energy source. Thus purine nucleoside supplementation holds promise in the treatment of acute renal failure. PMID- 22100705 TI - Functional processing of nuclear Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP-N): evidence for a critical role of proteolytic processing in the regulation of its catalytic activity, subcellular localization and substrate targeting in vivo. AB - Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) and its nuclear homolog CaMKP-N are Ser/Thr protein phosphatases that belong to the PPM family. These phosphatases are highly specific for multifunctional CaM kinases and negatively regulate their activities. CaMKP-N is only expressed in the brain and specifically localized in the nucleus. In this study, we found that zebrafish CaMKP-N (zCaMKP-N) underwent proteolytic processing in both the zebrafish brain and Neuro2a cells. In Neuro2a cells, the proteolytic processing was effectively inhibited by the proteasome inhibitors MG-132, Epoxomicin, and Lactacystin, suggesting that the ubiquitin-proteasome pathway was involved in this processing. Using MG-132, we found that the proteolytic processing changed the subcellular localization of zCaMKP-N from the nucleus to the cytosol. Accompanying this change, the cellular targets of zCaMKP-N in Neuro2a cells were significantly altered. Furthermore, we obtained evidence that the zCaMKP-N activity was markedly activated when the C-terminal domain was removed by the processing. Thus, the proteolytic processing of zCaMKP-N at the C-terminal region regulates its catalytic activity, subcellular localization and substrate targeting in vivo. PMID- 22100706 TI - Synthesis and characterization of (+/-)-13-hydroxy-3,11-diaza steroids. AB - An efficient strategy for introducing a nitrogen atom in positions 3 and 11 of the steroidal skeleton, which are key positions for biological purposes, is described. This procedure involves an intramolecular Diels-Alder cycloaddition of o-quinodimethanes which are generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien 7-one. The characteristic (1)H and (13)C NMR spectroscopic features of the synthesized compounds are reported. PMID- 22100707 TI - [Letter on the article: "classifications and definitions of adverse events in primary care: a systematic review"]. PMID- 22100708 TI - [Appendicular mucocele and endocrine tumor]. PMID- 22100709 TI - Gap junctions and arrhythmogenic cardiomyopathy. PMID- 22100711 TI - Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. AB - BACKGROUND: Reduced expression of connexin43 (Cx43) and sodium channel (Nav1.5) and increased expression of collagen (fibrosis) are important determinants of impulse conduction in the heart. OBJECTIVE: To study the importance and interaction of these factors at very low Cx43 expression, inducible Cx43 knockout mice with and without inducible ventricular tachycardia (VT) were compared through electrophysiology and immunohistochemistry. METHODS: Cx43(CreER(T)/fl) mice were induced with tamoxifen and killed after 2 weeks. Epicardial activation mapping was performed on Langendorff-perfused hearts, and arrhythmia vulnerability was tested. Mice were divided into arrhythmogenic (VT+; n = 13) and nonarrhythmogenic (VT-; n = 10) animals, and heart tissue was analyzed for Cx43, Nav1.5, and fibrosis. RESULTS: VT+ mice had decreased Cx43 expression with increased global, but not local, heterogeneity of Cx43 than did VT- mice. Nav1.5 immunoreactive protein expression was lower in VT+ than in VT- mice, specifically at sites devoid of Cx43. Levels of fibrosis were similar between VT- and VT+ mice. QRS duration was increased and epicardial activation was more dispersed in VT+ mice than in VT- mice. The effective refractory period was similar between the 2 groups. Premature stimulation resulted in a more severe conduction slowing in VT+ than in VT- hearts in the right ventricle. Separate patch-clamp experiments in isolated rat ventricular myocytes confirmed that the loss of Cx43 expression correlated with the decreased sodium current amplitude. CONCLUSIONS: Global heterogeneity in Cx43 expression and concomitant heterogeneous downregulation of sodium-channel protein expression and sodium current leads to slowed and dispersed conduction, which sensitizes the heart for ventricular arrhythmias. PMID- 22100712 TI - Letter to the editor--retaining vascular access during lead replacement. PMID- 22100713 TI - High pressure effect on the color of minced cured restructured ham at different levels of drying, pH, and NaCl. AB - Color changes of minced cured restructured ham was studied considering the effects of high pressure (HP) treatment (600MPa, 13 degrees C, 5min), raw meat pH(24) (low, normal, high), salt content (15, 30g/kg), and drying (20%, 50% weight loss). Raw hams were selected based on pH(24) in Semimembranosus, mixed with additives, frozen, sliced, and dried using the Quick-Dry-Slice(r) process. Meat color (CIE 1976 L*a*b*) and reflectance spectra were measured before and after HP treatment. HP significantly increased L*, decreased a*, and decreased b* for restructured ham dried to 20% weight loss, regardless of salt content and pH(24). L* and a* were best preserved in high pH/high salt restructured ham. HP had no effect on the color of restructured ham dried to 50% weight loss. HP had no effect on the shape of reflectance curves, indicating that the pigment responsible for minced cured restructured ham color did not change due to HP. PMID- 22100714 TI - Rapid detection of radiation-induced hydrocarbons in cooked ham. AB - Solid phase microextraction (SPME) coupled with either gas chromatography ionization flame detector (CG-FID) or multidimensional gas chromatography-mass spectrometry (MDGC-MS) was evaluated for its ability to detect volatile hydrocarbons produced during the irradiation of cooked ham. The chromatogram of an irradiated sample obtained using GC-FID showed a complex pattern of peaks, with several co-eluting peaks superimposed, indicating that the method was unlikely to resolve adequately the volatile hydrocarbons formed during irradiation. Using SPME-MDGC-MS 1-tetradecene (C(1-14:1)), n-pentadecane (C(15:0)), 1-hexadecene (C(1-16:1)), n-heptadecane (C(17:0)) and 8-heptadecene (C(8-17:1)) were detected in cooked ham irradiated at 0.5, 2, 4 and 8kGy. This method allows the detection of most n-alkanes and n-alkenes produced during the irradiation of the majority of fatty acids in cooked ham, namely oleic acid, stearic acid and palmitic acid. SPME is rapid and inexpensive and does not require organic solvents. The proposed SPME-MDGC-MS method allows the determination of radiolytic markers in cooked ham in less than 115min. PMID- 22100715 TI - Ammonia-containing dimethyl sulfoxide: an improved solvent for the dissolution of formazan crystals in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. AB - To reduce interference with the dissolution of formazan crystals in the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, we conducted a systematic investigation to study the effects of various buffers, HCl, NaOH, and ammonia. As a result, we identified an improved solvent, alkaline dimethyl sulfoxide (DMSO) containing 8 to 800 mM ammonia, which could dissolve formazan crystals in approximately 10 min so as to give a stable spectrum by eliminating buffering effects of the residual medium. PMID- 22100716 TI - Comparisons of four categories of waste recycling in China's paper industry based on physical input-output life-cycle assessment model. AB - Waste recycling for paper production is an important component of waste management. This study constructs a physical input-output life-cycle assessment (PIO-LCA) model. The PIO-LCA model is used to investigate environmental impacts of four categories of waste recycling in China's paper industry: crop straws, bagasse, textile wastes and scrap paper. Crop straw recycling and wood utilization for paper production have small total intensity of environmental impacts. Moreover, environmental impacts reduction of crop straw recycling and wood utilization benefits the most from technology development. Thus, using crop straws and wood (including wood wastes) for paper production should be promoted. Technology development has small effects on environmental impacts reduction of bagasse recycling, textile waste recycling and scrap paper recycling. In addition, bagasse recycling and textile waste recycling have big total intensity of environmental impacts. Thus, the development of bagasse recycling and textile waste recycling should be properly limited. Other pathways for reusing bagasse and textile wastes should be explored and evaluated. Moreover, imports of scrap paper should be encouraged to reduce large indirect impacts of scrap paper recycling on domestic environment. PMID- 22100717 TI - P53 mediates estradiol induced activation of apoptosis and DNA repair in non malignant colonocytes. AB - Clinical and animal studies have shown a strong link between estrogen status in women and decreased risk of colon cancer. However, little research has been done into the mechanism of protection that estrogen provides. Our laboratory has demonstrated that estradiol (E2) inhibits the development of pre-neoplastic lesions through an estrogen receptor beta (ERbeta) mediated mechanism in mice. Our data also suggest that the primary protective role of E2 treatment is increased apoptosis in non-malignant colonocytes that are damaged and at risk of becoming cancerous. The p53 protein plays a crucial role in the cellular response to stress by inducing cell cycle arrest, DNA repair mechanisms, and/or apoptosis. Due to the observed induction of apoptosis in response to E2, we are investigating the role of p53 in this chemo-protective mechanism. E2 suppressed growth of young adult mouse colonocytes (YAMCs) by inducing apoptosis and these physiological responses were completely lost in YAMCs lacking a functional p53 protein. Western blot analysis demonstrated increases in p53 protein levels in YAMCs after treatment with E2 likely due to protein stabilization. E2 was shown to enhance the transcriptional activity of p53, resulting in up-regulation of pro apoptotic p53 target genes (Bax, Noxa, and PUMA). Finally, repair of DNA double stranded breaks was shown to be increased by E2 treatment. Collectively, these data are the first to demonstrate that p53 is a primary mediator of the protective actions of E2 in the colon. PMID- 22100718 TI - Acute and 28-day repeated dose toxicology studies in mice with aryloxyalkanoate dioxygenase (AAD-1) protein expressed in 2,4-D tolerant DAS-40278-9 maize. AB - DAS-40278-9 maize (corn) plants have been genetically modified by the insertion of the aad-1 gene (aryloxyalkanoate dioxygenase), which confers tolerance to 2,4 dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) acetyl coenzyme A carboxylase (ACCase) inhibitors ("fop" herbicides) to enable the effective use of these herbicides on maize. The aad-1 gene, derived from Sphingobium herbicidovorans, encodes the aryloxyalkanoate dioxygenase (AAD-1) enzyme. As part of the safety assessment of the AAD-1 protein expressed in maize, acute and repeated dose mammalian toxicology studies were conducted. AAD-1 protein (heterologously produced) was orally administered to mice at a dose of 2000mg/kg, and no acute lethality or adverse effects were observed. Similarly, no adverse effects were observed in mice in a 28-day repeated-dose dietary toxicity study that incorporated the AAD-1 protein into diets at concentrations up to 1000 fold greater than the highest estimate of human exposure to maize. These results support the conclusion that the AAD-1 protein, as expressed in biotechnology derived DAS-40278-9 maize, represents a negligible risk to human health. PMID- 22100719 TI - Individuals with non-specific low back pain use a trunk stiffening strategy to maintain upright posture. AB - There is increasing evidence that individuals with non-specific low back pain (LBP) have altered movement coordination. However, the relationship of this neuromotor impairment to recurrent pain episodes is unknown. To assess coordination while minimizing the confounding influences of pain we characterized automatic postural responses to multi-directional support surface translations in individuals with a history of LBP who were not in an active episode of their pain. Twenty subjects with and 21 subjects without non-specific LBP stood on a platform that was translated unexpectedly in 12 directions. Net joint torques of the ankles, knees, hips, and trunk in the frontal and sagittal planes as well as surface electromyographs of 12 lower leg and trunk muscles were compared across perturbation directions to determine if individuals with LBP responded using a trunk stiffening strategy. Individuals with LBP demonstrated reduced peak trunk torques, and enhanced activation of the trunk and ankle muscle responses following perturbations. These results suggest that individuals with LBP use a strategy of trunk stiffening achieved through co-activation of trunk musculature, aided by enhanced distal responses, to respond to unexpected support surface perturbations. Notably, these neuromotor alterations persisted between active pain periods and could represent either movement patterns that have developed in response to pain or could reflect underlying impairments that may contribute to recurrent episodes of LBP. PMID- 22100720 TI - The spectral content of postural sway during quiet stance: influences of age, vision and somatosensory inputs. AB - Maintenance of human upright stance requires the acquisition and integration of sensory inputs. Conventional measures of sway have had success in identifying age and some disease-related changes, but remain unable to address the complexities and dynamics associated with postural control. We investigated the effects of vision, surface compliance, age, and gender on the spectral content of center of pressure (COP) time series. Sixteen healthy young (age 18-24) and older participants (age 55-65) performed trials of quiet, upright stance under different vision (eyes open vs. closed) and surface (hard vs. compliant) conditions. Spectral analyses were conducted to describe COP mean normalized power in discretized bands. Effects of the two sensory modalities and age were distinct in the antero-posterior and medio-lateral directions, and a reorganization of spectral content was evident with increasing task difficulty (eyes open vs. closed and hard vs. compliant surface) and among older adults. These results indicate that vision and surface compliance are predominantly associated with responses from musculature associated with antero-posterior and medio-lateral directions of sway, respectively. Finally, distinguishing between the contributions of different afferent systems to the postural control system using the spectral content of sway bi-directionally may help in diagnosing individuals with balance impairments. PMID- 22100721 TI - Visual body recognition in a prosopagnosic patient. AB - Conspicuous deficits in face recognition characterize prosopagnosia. Information on whether agnosic deficits may extend to non-facial body parts is lacking. Here we report the neuropsychological description of FM, a patient affected by a complete deficit in face recognition in the presence of mild clinical signs of visual object agnosia. His deficit involves both overt and covert recognition of faces (i.e. recognition of familiar faces, but also categorization of faces for gender or age) as well as the visual mental imagery of faces. By means of a series of matching-to-sample tasks we investigated: (i) a possible association between prosopagnosia and disorders in visual body perception; (ii) the effect of the emotional content of stimuli on the visual discrimination of faces, bodies and objects; (iii) the existence of a dissociation between identity recognition and the emotional discrimination of faces and bodies. Our results document, for the first time, the co-occurrence of body agnosia, i.e. the visual inability to discriminate body forms and body actions, and prosopagnosia. Moreover, the results show better performance in the discrimination of emotional face and body expressions with respect to body identity and neutral actions. Since FM's lesions involve bilateral fusiform areas, it is unlikely that the amygdala-temporal projections explain the relative sparing of emotion discrimination performance. Indeed, the emotional content of the stimuli did not improve the discrimination of their identity. The results hint at the existence of two segregated brain networks involved in identity and emotional discrimination that are at least partially shared by face and body processing. PMID- 22100722 TI - High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma. AB - INTRODUCTION: Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. PATIENTS AND METHODS: A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n=7) and purine nucleotide analogues (n=6). RESULTS: Median follow-up was 8.7 (1 97) months. Surgery was required in 10 patients (66%) for intestinal complications (n=7) or elective small bowel resection (n=3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan-Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p=0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. CONCLUSION: Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy. PMID- 22100723 TI - Chronic rectal ulcer as result of combined mucosal toxicity of NSAID, argon plasma coagulation and radiotherapy. PMID- 22100724 TI - Prenatal pesticide exposure linked to lower IQ in children. PMID- 22100725 TI - Maturation affects fluoride uptake by glass-ionomer dental cements. AB - OBJECTIVES: Four commercial glass-ionomer cements have been studied for their ability to take up fluoride from aqueous solution following variable maturation times in the dry at 37 degrees C. METHODS: Sets of five specimens of four different materials were cured for times of 10 min, 24 h and 1 month, then transferred to a neutral solution of NaF at approximately 1000 ppm in fluoride. Fluoride concentration was then measured at regular time intervals up to 1 month using a fluoride ion selective electrode. RESULTS: Specimens cured for 1 month showed little or no uptake over 24 h, specimens cured for 24 h showed fluctuating uptake over time, and specimens cured for 10 min showed the greatest fluoride uptake. For the latter specimens, simple kinetic models were found to apply in two cases (pseudo-first order and pseudo-second order for Chemflex and Ketac Molar Quick respectively). SIGNIFICANCE: The ability to take up fluoride has been shown to decline with age of cement which suggests that in clinical use glass ionomers may become less effective at undergoing fluoride recharge than has been previously assumed. PMID- 22100726 TI - Schisandrin B suppresses TGFbeta1 signaling by inhibiting Smad2/3 and MAPK pathways. AB - TGFbeta1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Schisandra chinensis (S. chinensis), which is used as an oriental herbal medicine, is effective in the treatment of vascular injuries that cause aberrant TGFbeta1 signaling. In this study, we investigated whether S. chinensis extract and its active ingredients inhibit TGFbeta1 signaling in A7r5 vascular smooth muscle cells. We found that S. chinensis extract suppressed TGFbeta1 signaling via inhibition of Smad2/3 phosphorylation and nuclear translocation. Among the active ingredients of S. chinensis extract, schisandrin B (SchB) most potently inhibited TGFbeta1 signaling. SchB inhibited sustained phosphorylation and nuclear translocation of Smad2/3. Moreover, SchB suppressed TGFbeta1-induced phosphorylation of p38 and JNK, which contributed to Smad2/3 inactivation. The present study is the first to demonstrate that S. chinensis extract and SchB inhibit TGFbeta1 signaling. Our results may help future investigations to understand vascular fibrosis pathogenesis and to develop novel therapeutic strategies for treatment of vascular fibrotic diseases. PMID- 22100727 TI - The genetics of calcium signaling in Drosophila melanogaster. AB - BACKGROUND: Genetic screens for behavioral and physiological defects in Drosophila melanogaster, helped identify several components of calcium signaling of which some, like the Trps, were novel. For genes initially identified in vertebrates, reverse genetic methods have allowed functional studies at the cellular and systemic levels. SCOPE OF REVIEW: The aim of this review is to explain how various genetic methods available in Drosophila have been used to place different arms of Ca2+ signaling in the context of organismal development, physiology and behavior. MAJOR CONCLUSION: Mutants generated in genes encoding a range of Ca2+ transport systems, binding proteins and enzymes affect multiple aspects of neuronal and muscle physiology. Some also affect the maintenance of ionic balance and excretion from malpighian tubules and innate immune responses in macrophages. Aspects of neuronal physiology affected include synaptic growth and plasticity, sensory transduction, flight circuit development and function. Genetic interaction screens have shown that mechanisms of maintaining Ca2+ homeostasis in Drosophila are cell specific and require a synergistic interplay between different intracellular and plasma membrane Ca2+ signaling molecules. GENERAL SIGNIFICANCE: Insights gained through genetic studies of conserved Ca2+ signaling pathways have helped understand multiple aspects of fly physiology. The similarities between mutant phenotypes of Ca2+ signaling genes in Drosophila with certain human disease conditions, especially where homologous genes are causative factors, are likely to aid in the discovery of underlying disease mechanisms and help develop novel therapeutic strategies. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling. PMID- 22100728 TI - The effects of a controlled energy storage and return prototype prosthetic foot on transtibial amputee ambulation. AB - The lack of functional ankle musculature in lower limb amputees contributes to the reduced prosthetic ankle push-off, compensations at other joints and more energetically costly gait commonly observed in comparison to non-amputees. A variety of energy storing and return prosthetic feet have been developed to address these issues but have not been shown to sufficiently improve amputee biomechanics and energetic cost, perhaps because the timing and magnitude of energy return is not controlled. The goal of this study was to examine how a prototype microprocessor-controlled prosthetic foot designed to store some of the energy during loading and return it during push-off affects amputee gait. Unilateral transtibial amputees wore the Controlled Energy Storage and Return prosthetic foot (CESR), a conventional foot (CONV), and their previously prescribed foot (PRES) in random order. Three-dimensional gait analysis and net oxygen consumption were collected as participants walked at constant speed. The CESR foot demonstrated increased energy storage during early stance, increased prosthetic foot peak push-off power and work, increased prosthetic limb center of mass (COM) push-off work and decreased intact limb COM collision work compared to CONV and PRES. The biological contribution of the positive COM work for CESR was reduced compared to CONV and PRES. However, the net metabolic cost for CESR did not change compared to CONV and increased compared to PRES, which may partially reflect the greater weight, lack of individualized size and stiffness and relatively less familiarity for CESR and CONV. Controlled energy storage and return enhanced prosthetic push-off, but requires further design modifications to improve amputee walking economy. PMID- 22100729 TI - Phylogenetic relationships of living and recently extinct bandicoots based on nuclear and mitochondrial DNA sequences. AB - Bandicoots (Peramelemorphia) are a major order of australidelphian marsupials, which despite a fossil record spanning at least the past 25 million years and a pandemic Australasian range, remain poorly understood in terms of their evolutionary relationships. Many living peramelemorphians are critically endangered, making this group an important focus for biological and conservation research. To establish a phylogenetic framework for the group, we compiled a concatenated alignment of nuclear and mitochondrial DNA sequences, comprising representatives of most living and recently extinct species. Our analysis confirmed the currently recognised deep split between Macrotis (Thylacomyidae), Chaeropus (Chaeropodidae) and all other living bandicoots (Peramelidae). The mainly New Guinean rainforest peramelids were returned as the sister clade of Australian dry-country species. The wholly New Guinean Peroryctinae was sister to Echymiperinae. The poorly known and perhaps recently extinct Seram Bandicoot (Rhynchomeles) is sister to Echymipera. Estimates of divergence times from relaxed-clock Bayesian methods suggest that living bandicoots originated in the late Oligocene or early Miocene, much earlier than currently thought based on fossils. Subsequent radiations within Peramelemorphia probably took place on the Australian mainland during the Miocene, with diversification of rainforest taxa on the newly emergent New Guinean landmasses through the middle-late Miocene and complete establishment of modern lineages by the early Pliocene. PMID- 22100730 TI - Plasma C-type natriuretic peptide levels in healthy children. AB - C-type natriuretic peptide (CNP) is assuming increasing importance in cardiovascular disease, and in adults its plasma levels are related to clinical and functional disease severity. Data are scarce regarding the reference values for CNP in infancy. Aim of this study was to assess the reference intervals for CNP in human healthy newborns and infants. Plasma CNP was measured in 121 healthy children divided into: 41 newborns (age 0-3 days), 24 newborns (4-30 days), 22 infants (1-12 months) and 32 children (1-12 years). A group of 32 healthy adult subjects (age 64 +/- 1 years) was also studied. CNP was measured by a specific radioimmunoassay. Between- and within-assay variability resulted <= 30 and 20%, respectively and analytical sensitivity 0.77 +/- 0.05 pg/tube. Plasma CNP resulted significantly higher in children than in adult subjects (13.6 +/- 1.2 pg/ml vs. 7.4 +/- 1.0 pg/ml, p=0.030). When the results were analyzed as a function of the age the reference intervals for plasma CNP resulted: 11.6 +/- 2.1 pg/ml for newborns (0-3 days), 16.4 +/- 3.7 pg/ml for newborns (4-30 days), 15.4 +/- 2.7 pg/ml for infants (1-12 months), 13.6 +/- 2.3 pg/ml for children (1-12 years) [p=0.01 newborns (4-30 days) vs. adults; p=0.03 infants (1-12 months) vs. adults]. CNP showed the highest concentrations after 12h of life with a peak between 4 and 5 days of life and with a progressive decline afterwards. According to these data at least five different reference intervals for CNP determinations should be used. These observations may be helpful for future clinical application of CNP in human children. PMID- 22100731 TI - An evolutionary comparison of leucine-rich repeat containing G protein-coupled receptors reveals a novel LGR subtype. AB - Leucine-rich repeat containing G protein-coupled receptors or LGRs are receptors with important functions in development and reproduction. Belonging to this evolutionarily conserved group of receptors are the well-studied glycoprotein hormone receptors and relaxin receptors in mammals, as well as the bursicon receptor, which triggers cuticle hardening and tanning in freshly enclosed insects. In this study, the numerous LGR sequences in different animal phyla are analyzed and compared. Based on these data a phylogenetic tree was generated. This information sheds new light on structural and evolutionary aspects regarding this receptor group. Apart from vertebrates and insects, LGRs are also present in early chordates (Urochordata, Cephalochordata and Hyperoartia) and other arthropods (Arachnida and Branchiopoda) as well as in Mollusca, Echinodermata, Hemichordata, Nematoda, and even in ancient animal life forms, such as Cnidaria and Placozoa. Three distinct types of LGR exist, distinguishable by their number of leucine-rich repeats (LRRs), their type-specific hinge region and the presence or absence of an LDLa motif. Type C LGRs containing only one LDLa (C1 subtype) appear to be present in nearly all animal phyla. We here describe a second subtype, C2, containing multiple LDLa motifs, which was discovered in echinoderms, mollusks and in one insect species (Pediculus humanis corporis). In addition, eight putative LGRs can be predicted from the genome data of the placozoan species Trichoplax adhaerens. They may represent an ancient form of the LGRs, however, more genomic data will be required to confirm this hypothesis. PMID- 22100732 TI - Testing a portable Raman instrument: the detection of biomarkers in gypsum powdered matrix under gypsum crystals. AB - In this study the possibility to detect biomarkers in experimentally prepared evaporitic matrices using a portable Raman instrument was estimated. Testing of the instrument was carried-out under the Alpine conditions outdoors at a low ambient temperature of -10 degrees C and at an altitude of 2860 m (Pitztal, Austria). Amino acids glycine and l-alanine, nucleo bases thymine and adenine, and metabolite urea were the organics mixed with gypsum powder. In this step it was shown that portable Raman spectroscopic instrumentation is capable of detecting biomarkers in complex samples in a host geological matrix. Such detection is possible even when the laser beam was focussed through the gypsum crystals 3-9 mm thick. For exobiology areas, this is an important fact, because life and/or related biomolecules are likely to be found in cavities under the surface of partially transparent evaporitic minerals that provide them a shelter from the hostile surrounding environment. For influencing the intensity of Raman bands the thickness of covering crystals is not as important as is the actual concentration of the biomarkers. This work and similar experiments serve for better evaluation of Raman spectroscopy as a method for future planetary exploration mission adoption. PMID- 22100733 TI - New 1,2,4-triazole-based azo-azomethine dyes. Part I: synthesis, characterization and spectroscopic studies. AB - Four new 1,2,4-triazole-based azo-azomethine dyes were synthesized via condensation of 3,5-diamino-1,2,4-triazole with azo-coupled o-vanillin precursors. The prepared dyes were characterized by IR, UV-vis and (1)H NMR spectroscopic methods as well as elemental analyses. Thermal properties of the prepared dyes were examined by thermogravimetric analysis. Results indicated that the framework of the dyes was stable up to 225 degrees C. Also, the influence of various factors including time and mixed DMSO/EtOH solution on UV-vis spectra of the dyes were investigated. PMID- 22100734 TI - Socio-demographic and medical correlates of the use of biologically based complementary and alternative medicines amongst recent Australian cancer survivors. AB - OBJECTIVE: Describe the socio-demographic/medical correlates of the use of biologically based complementary and alternative medicines (BBCAM) amongst a heterogeneous sample of recent cancer survivors. METHOD: Cross-sectional analysis was undertaken on the baseline data of a population-based longitudinal study conducted in New South Wales and Victoria, Australia (2006-2008) of cancer survivors 6 months post diagnosis. Participants (n=1323) completed a self-report survey assessing socio-demographic/medical characteristics and use of BBCAM (dietary supplements or vitamins, herbal treatments, and special diets). RESULTS: Twenty-seven percent of respondents (n=349) reported using at least one BBCAM to help manage their cancer and related symptoms. Nutritional supplements and vitamins were the most commonly reported BBCAM (23%). Correlates of BBCAM use included cancer type (bowel [OR=3.3; CI:1.8-5.9], breast [OR=2.4; CI:1.4-4.1], head and neck [OR=3.8; CI: 2.0-7.2], haematological [OR=2.0; CI: 1.1-3.7], prostate [OR=1.8; CI: 1.0-3.9] versus melanoma), education level (university degree [OR=1.6; CI:1.1-2.3] versus secondary school) and treatment types (chemotherapy [OR=2.0; CI:1.4-2.7] versus not, bone marrow/stem cell transplant/immunotherapy [OR=2.3; CI:1.2-4.4] versus not). CONCLUSION: Providers should openly discuss the use of complementary and alternative therapies with all cancer patients, and given potential safety concerns, be proactive in exploring BBCAM use among the subgroups of survivors identified in this study. PMID- 22100735 TI - Assessing ADHD in Latino families: evidence for moving beyond symptomatology. AB - OBJECTIVE: In an effort to combat the mental health disparities that exist among Latinos, the current study aimed to add to our knowledge related to culturally appropriate assessments for Latino children presenting with ADHD. METHOD: As part of a larger study, a community sample of 68 Spanish-speaking, Latino parents completed the Spanish translation of the Disruptive Behavior Disorders Rating Scale (DBD-S), a commonly used, parent-report measure of ADHD. RESULTS: Results suggest that although both the Inattentive and Hyperactive/Impulsive subscales of the DBD-S are psychometrically sound, the Hyperactive/Impulsive subscale may not be culturally appropriate with some Latino families, particularly those who are less acculturated. This was further supported by preliminary evidence suggesting that this subscale also was not diagnostically useful with the current, community sample. CONCLUSION: The potential problems associated with the overemphasis on symptomatology when working with Latino families, the importance of examining functional impairment as part of a culturally appropriate assessment, and the need to replicate the current findings with a clinical sample are discussed. PMID- 22100736 TI - Magneto-optical contrast in liquid-state optically detected NMR spectroscopy. AB - We use optical Faraday rotation (OFR) to probe nuclear spins in real time at high magnetic field in a range of diamagnetic sample fluids. Comparison of OFR detected NMR spectra reveals a correlation between the relative signal amplitude and the fluid Verdet constant, which we interpret as a manifestation of the variable detuning between the probe beam and the sample optical transitions. The analysis of chemical-shift-resolved, optically detected spectra allows us to set constraints on the relative amplitudes of hyperfine coupling constants, both for protons at chemically distinct sites and other lower-gyromagnetic-ratio nuclei including carbon, fluorine, and phosphorous. By considering a model binary mixture we observe a complex dependence of the optical response on the relative concentration, suggesting that the present approach is sensitive to the solvent solute dynamics in ways complementary to those known in inductive NMR. Extension of these experiments may find application in solvent suppression protocols, sensitivity-enhanced NMR of metalloproteins in solution, the investigation of solvent-solute interactions, or the characterization of molecular orbitals in diamagnetic systems. PMID- 22100738 TI - Eugene Patrick Kennedy, 1919-2011. PMID- 22100737 TI - Comparative analysis of a large dataset indicates that internal transcribed spacer (ITS) should be incorporated into the core barcode for seed plants. AB - A two-marker combination of plastid rbcL and matK has previously been recommended as the core plant barcode, to be supplemented with additional markers such as plastid trnH-psbA and nuclear ribosomal internal transcribed spacer (ITS). To assess the effectiveness and universality of these barcode markers in seed plants, we sampled 6,286 individuals representing 1,757 species in 141 genera of 75 families (42 orders) by using four different methods of data analysis. These analyses indicate that (i) the three plastid markers showed high levels of universality (87.1-92.7%), whereas ITS performed relatively well (79%) in angiosperms but not so well in gymnosperms; (ii) in taxonomic groups for which direct sequencing of the marker is possible, ITS showed the highest discriminatory power of the four markers, and a combination of ITS and any plastid DNA marker was able to discriminate 69.9-79.1% of species, compared with only 49.7% with rbcL + matK; and (iii) where multiple individuals of a single species were tested, ascriptions based on ITS and plastid DNA barcodes were incongruent in some samples for 45.2% of the sampled genera (for genera with more than one species sampled). This finding highlights the importance of both sampling multiple individuals and using markers with different modes of inheritance. In cases where it is difficult to amplify and directly sequence ITS in its entirety, just using ITS2 is a useful backup because it is easier to amplify and sequence this subset of the marker. We therefore propose that ITS/ITS2 should be incorporated into the core barcode for seed plants. PMID- 22100739 TI - What are the main research findings during the last 5 years that have changed my clinical practice in diabetes medicine? AB - The world of childhood diabetes has seen more changes in clinical care being introduced in recent years than many subspecialty areas of clinical practice. This review identifies some of the key underlying evidence and considers the implications for clinical teams that personal experience of these developments has highlighted. PMID- 22100740 TI - Why do children hospitalised with pneumonia not receive antibiotics in primary care? AB - BACKGROUND: Although antibiotics are recommended for the primary care management of community-acquired pneumonia, a recent UK study reported that most children admitted to hospital had not received antibiotics. OBJECTIVE: To describe primary care antibiotic use for children subsequently hospitalised with community acquired pneumonia. DESIGN/METHODS: A case series of 280 children <5 years old hospitalised with pneumonia in Auckland, New Zealand. Pneumonia was defined as an acute illness with cough or respiratory distress, the presence of tachypnoea or indrawing and an abnormal chest radiograph. Receipt of antibiotics was determined by parental report and medical record review. RESULTS: Fewer than half (108, 39%) of the children had received an antibiotic before hospital admission. For 60 children (21%) there had been no opportunity to prescribe because the illness evolved rapidly, resulting in early hospital admission. For the remaining 112 children (40%) an opportunity to receive antibiotics was missed. The parent failed to obtain the antibiotic prescribed for 23 children (21% of 112), but in 24 children (21%) pneumonia was diagnosed but no antibiotic prescribed and in a further 28 children (25%) the diagnosis was not made despite parental report of symptoms suggesting pneumonia. Missed opportunities to prescribe were not associated with increased overall severity of symptoms at hospital presentation but were associated with an increased risk of: focal chest radiological abnormalities (rate ratio (RR)=2.14; 95% CI 1.49 to 2.83), peripheral leucocytosis >15*10(9)/l (RR=2.29; 95% CI 1.61 to 2.98) and bacteraemia (RR=6.68, 95% CI 1.08 to 58.44). CONCLUSIONS: Young children with community-acquired pneumonia may not receive an antibiotic before hospital admission because the illness evolves rapidly or the prescribed medicine is not given by parents. However, missed opportunities for appropriate antibiotic prescribing by health professionals in primary care appear to be common. PMID- 22100741 TI - Pilot study of vapotherm oxygen delivery in moderately severe bronchiolitis. PMID- 22100742 TI - Tinnitus and hearing in 7-year-old children. AB - BACKGROUND: Tinnitus occurs with or without prior noise exposure (noise-induced tinnitus (NIT) and spontaneous tinnitus (ST)), and is considered a symptom related to permanent hearing impairment (HI) or temporary hearing threshold shift (TTS). OBJECTIVE: To carry out a cross-sectional interview study on TTS, ST and NIT during a standard audiometric screening of 756 7-year-old children in Gothenburg. RESULTS: 41% out of 756 children reported either NIT or ST on several occasions, 17% reported recurrent TTS and 7% failed the audiometry screening. The probability of ST was 27% for children with no HI or TTS (OR=1.23 (95% CI 1.12 to 1.34)) but 63% (OR=1.16 (95% CI 1.02 to 1.33)) if exhibiting both HI and TTS. CONCLUSION: This study confirms an increased occurrence of spontaneous tinnitus in children with TTS or HI and in children with both TTS and HI, in particular, but also in children with normal hearing. Possibly, tinnitus in young children correlates with stress as in adolescents and adults. PMID- 22100743 TI - Attentional bias towards pain-related information in chronic pain; a meta analysis of visual-probe investigations. AB - Research investigating the presence of attentional bias in chronic pain has produced mixed results. The purpose of this review is to summarise former research using the visual-probe task to explore attentional bias in pain populations, and meta-analyse the results of controlled investigations comparing individuals with chronic pain to healthy controls. Ten eligible studies were included in this analysis (chronic pain n=515, control n=314). Overall, individuals with chronic pain were found to show significantly greater bias towards pain-related information compared to controls, with an effect size of .36 (Hedges' adjusted g). The time-course of attentional bias was also explored, with evidence found for significant bias during stages of initial orienting of attention (effect size .29) and maintained attention (effect size .42). Bias therefore appears more pronounced during later stages of attention, possibly arising from processes of rumination. It is important for future research to fully explore the role attentional bias plays in the causation and maintenance of chronic pain, and the potential consequences bias may have upon quality of life. PMID- 22100744 TI - Tendon structure's lack of relation to clinical outcome after eccentric exercises in chronic midportion Achilles tendinopathy. AB - CONTEXT: Chronic midportion Achilles tendinopathy is a common and hard-to-treat disorder characterized by degenerative changes of the tendon matrix. Ultrasonographic tissue characterization (UTC) was successfully used to quantify structural human Achilles tendon changes. This novel and reliable technique could be used in follow-up studies to relate tendon structure to symptoms. OBJECTIVE: To quantify structural tendon changes and assess clinical change in patients with tendinopathy. DESIGN: Prospective observational study. SETTING: Orthopedic department in a university medical center. PATIENTS: 23 patients with chronic midportion Achilles tendinopathy. INTERVENTION: The patients performed a 16-wk home-based eccentric exercise program. An experienced researcher performed the ultrasonographic data collection with the UTC procedure. These data were assessed by a blinded observer. The severity of symptoms was established with the validated Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire. MAIN OUTCOME MEASURES: UTC was performed to quantify tendon structure through measuring the proportion of 4 echo types. Echo types I and II represent more or less organized tendon bundles, and echo types III and IV represent disintegrated tendon structure. On the VISA-A, the total possible score is divided by 100 for a percentage score, with a perfect score of 100. Follow-up was at 2, 8, 16, and 24 wk. RESULTS: The mean percentage of echo types I and II changed by 0.3% after 24 wk (P = .92, 95% CI -5.8 to 5.3). The mean VISA-A score increased slightly but significantly by 11.3 points after 24 wk (P = .01, 95% CI 2.6-20.0). An increased VISA-A score was not correlated with an increased percentage of echo types I and II (P = .94, r = -.02), and the baseline percentage of echo types I and II did not correlate with an increased VISA-A score (P = .74, r = .07). CONCLUSIONS: There is no short-term increase in organized tendon structure after eccentric exercises. Tendon structure is not related to symptom severity and cannot be used as a predictor of clinical outcome. PMID- 22100745 TI - Epoxyeicosatrienoic acids and heme oxygenase-1 interaction attenuates diabetes and metabolic syndrome complications. AB - MSCs are considered to be the natural precursors to adipocyte development through the process of adipogenesis. A link has been established between decreased protective effects of EETs or HO-1 and their interaction in metabolic syndrome. Decreases in HO-1 or EET were associated with an increase in adipocyte stem cell differentiation and increased levels of inflammatory cytokines. EET agonist (AKR I-27-28) inhibited MSC-derived adipocytes and decreased the levels of inflammatory cytokines. We further describe the role of CYP-epoxygenase expression, HO expression, and circulating cytokine levels in an obese mouse, ob/ob(-/-) mouse model. Ex vivo measurements of EET expression within MSCs derived from ob/ob(-/-) showed decreased levels of EETs that were increased by HO induction. This review demonstrates that suppression of HO and EET systems exist in MSCs prior to the development of adipocyte dysfunction. Further, adipocyte dysfunction can be ameliorated by induction of HO-1 and CYP-epoxygenase, i.e. EET. PMID- 22100746 TI - VDAC inhibition by tubulin and its physiological implications. AB - Regulation of mitochondrial outer membrane (MOM) permeability has dual importance: in normal metabolite and energy exchange between mitochondria and cytoplasm, and thus in control of respiration, and in apoptosis by release of apoptogenic factors into the cytosol. However, the mechanism of this regulation involving the voltage-dependent anion channel (VDAC), the major channel of MOM, remains controversial. For example, one of the long-standing puzzles was that in permeabilized cells, adenine nucleotide translocase is less accessible to cytosolic ADP than in isolated mitochondria. Still another puzzle was that, according to channel-reconstitution experiments, voltage regulation of VDAC is limited to potentials exceeding 30mV, which are believed to be much too high for MOM. We have solved these puzzles and uncovered multiple new functional links by identifying a missing player in the regulation of VDAC and, hence, MOM permeability - the cytoskeletal protein tubulin. We have shown that, depending on VDAC phosphorylation state and applied voltage, nanomolar to micromolar concentrations of dimeric tubulin induce functionally important reversible blockage of VDAC reconstituted into planar phospholipid membranes. The voltage sensitivity of the blockage equilibrium is truly remarkable. It is described by an effective "gating charge" of more than ten elementary charges, thus making the blockage reaction as responsive to the applied voltage as the most voltage sensitive channels of electrophysiology are. Analysis of the tubulin-blocked state demonstrated that although this state is still able to conduct small ions, it is impermeable to ATP and other multi-charged anions because of the reduced aperture and inversed selectivity. The findings, obtained in a channel reconstitution assay, were supported by experiments with isolated mitochondria and human hepatoma cells. Taken together, these results suggest a previously unknown mechanism of regulation of mitochondrial energetics, governed by VDAC interaction with tubulin at the mitochondria-cytosol interface. Immediate physiological implications include new insights into serine/threonine kinase signaling pathways, Ca(2+) homeostasis, and cytoskeleton/microtubule activity in health and disease, especially in the case of the highly dynamic microtubule network which is characteristic of cancerogenesis and cell proliferation. In the present review, we speculate how these findings may help to identify new mechanisms of mitochondria-associated action of chemotherapeutic microtubule targeting drugs, and also to understand why and how cancer cells preferentially use inefficient glycolysis rather than oxidative phosphorylation (Warburg effect). This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. PMID- 22100747 TI - Structural investigation of the transmembrane C domain of the mannitol permease from Escherichia coli using 5-FTrp fluorescence spectroscopy. AB - The mannitol transporter EII(mtl) from Escherichia coli is responsible for the uptake of mannitol over the inner membrane and its concomitant phosphorylation. EII(mtl) is functional as a dimer and its membrane-embedded C domain, IIC(mtl), harbors one high affinity mannitol binding site. To characterize this domain in more detail the microenvironments of thirteen residue positions were explored by 5-fluorotryptophan (5-FTrp) fluorescence spectroscopy. Because of the simpler photophysics of 5-FTrp compared to Trp, one can distinguish between the two 5 FTrp probes present in dimeric IIC(mtl). At many labeled positions, the microenvironment of the 5-FTrps in the two protomers differs. Spectroscopic properties of three mutants labeled at positions 198, 251, and 260 show that two conserved motifs (Asn194-His195 and Gly254-Ile255-His256-Glu257) are located in well-structured parts of IIC(mtl). Mannitol binding has a large impact on the structure around position 198, while only minor changes are induced at positions 251 and 260. Phosphorylation of the cytoplasmic B domain of EII(mtl) is sensed by 5-FTrp at positions 30, 42, 251 and 260. We conclude that many parts of the IIC(mtl) structure are involved in the sugar translocation. The structure of EII(mtl), as investigated in this work, differs from the recently solved structure of a IIC protein transporting diacetylchitobiose, ChbC, and also belonging to the glucose superfamily of EII sugar transporters. In EII(mtl), the sugar binding site is more close to the periplasmic face and the structure of the 2 protomers in the dimer is different, while both protomers in the ChbC dimer are essentially the same. PMID- 22100748 TI - Listeria monocytogenes cell wall constituents exert a charge effect on electroporation threshold. AB - Genetically engineered cells with mutations of relevance to electroporation, cell membrane permeabilization by electric pulses, can become a promising new tool for fundamental research on this important biotechnology. Listeria monocytogenes mutants lacking DltA or MprF and assayed for sensitivity to the cathelicidin like anti-microbial cationic peptide (mCRAMP), were developed to study the effect of cell wall charge on electroporation. Working in the irreversible electroporation regime (IRE), we found that application of a sequence of 50 pulses, each 50MUs duration, 12.5kV/cm field, delivered at 2Hz led to 2.67+/-0.29 log reduction in wild-type L. monocytogenes, log 2.60+/-0.19 in the MprF-minus mutant, and log 1.33+/-0.13 in the DltA-minus mutant. The experimental observation that the DltA minus mutant was highly susceptible to cationic mCRAMP and resistant to IRE suggests that the charge on the bacterial cell wall affects electroporation and shows that this approach may be promising for fundamental studies on electroporation. PMID- 22100749 TI - Tumor-to-tumor metastasis: case report of a pulmonary adenocarcinoma metastatic to a clear cell renal cell carcinoma. AB - Tumor-to-tumor metastasis is a very rare event. The recipient tumor may be benign or malignant. Renal cell carcinoma is the most common tumor recipient of metastasis while lung carcinoma is the most common donor tumor. We report a 57 year-old Caucasian male who presented with chest pain. On PET CT Scan, he was also found to have a large renal mass for which he underwent left nephrectomy. On histology of the renal mass, the tumor was a conventional renal cell carcinoma with areas of metastatic non-small cell lung carcinoma. The two components had a distinctive morphology which was confirmed on subsequent immunohistochemistry. The physiopathological mechanisms making clear cell renal cell carcinoma an avid recipient of a metastatic carcinoma have been speculated upon, but are still unknown. PMID- 22100750 TI - [NT-proBNP for risk stratification of pulmonary embolism]. AB - INTRODUCTION: Pulmonary embolism (PE) is an entity with high mortality and morbidity, in which risk stratification for adverse events is essential. N terminal brain natriuretic peptide (NT-proBNP), a right ventricular dysfunction marker, may be useful in assessing the short-term prognosis of patients with PE. AIMS: To characterize a sample of patients hospitalized with PE according to NT proBNP level at hospital admission and to assess the impact of this biomarker on short-term evolution. METHODS: We performed a retrospective analysis of consecutive patients admitted with PE over a period of 3.5 years. Based on the median NT-proBNP at hospital admission, patients were divided into two groups (Group 1: NT-proBNP= median). The two groups were compared in terms of demographic characteristics, personal history, clinical presentation, laboratory, electrocardiographic and echocardiographic data, drug therapy, in-hospital course (catecholamine support, invasive ventilation and in hospital death and the combined endpoint of these events) and 30-day all-cause mortality. A receiver operating characteristic (ROC) curve was constructed to determine the discriminatory power and cut-off value of NT-proBNP for 30-day all cause mortality. RESULTS: Ninety-one patients, mean age 69+/-16.4 years (51.6% aged >=75 years), 53.8% male, were analyzed. Of the total sample, 41.8% had no etiological or predisposing factors for PE and most (84.6%) were stratified as intermediate-risk PE. Median NT-proBNP was 2440 pg/ml. Patients in Group 2 were significantly older (74.8+/-13.2 vs. 62.8+/-17.2 years, p=0.003) and more had a history of heart failure (35.5% vs. 3.3%, p=0.002) and chronic kidney disease (32.3% vs. 6.7%, p=0.012). They had more tachypnea on initial clinical evaluation (74.2% vs. 44.8, p=0.02), less chest pain (16.1% vs. 46.7%, p=0.01) and higher creatininemia (1.7+/-0.9 vs. 1.1+/-0.5mg/dl, p=0.004). Group 2 also more frequently had right chamber dilatation (85.7% vs. 56.7%, p=0.015) and lower left ventricular ejection fraction (56.4+/-17.6% vs. 66.2+/-13.5%, p=0.036) on echocardiography. There were no significant differences in drug therapy between the two groups. Regarding the studied endpoints, Group 2 patients needed more catecholamine support (25.8% vs. 6.7%, p=0.044), had higher in-hospital mortality (16.1% vs. 0.0%, p=0.022) and more frequently had the combined endpoint (32.3% vs. 10.0%, p=0.034). All-cause mortality at 30 days was seen only in Group 2 patients (24.1% vs. 0.0%, p=0.034). By ROC curve analysis, NT-proBNP had excellent discriminatory power for this event, with an area under the curve of 0.848. The best NT-proBNP cut-off value was 4740 pg/ml. CONCLUSION: Elevated NT proBNP levels identified PE patients with worse short-term prognosis, and showed excellent power to predict 30-day all-cause mortality. The results of this study may have important clinical implications. The inclusion of NT-proBNP measurement in the initial evaluation of patients with PE can add valuable prognostic information. PMID- 22100751 TI - [Twiddler syndrome in a pediatric patient]. PMID- 22100752 TI - The mapping of epistatic effects onto a genealogical tree in haploid populations. AB - In this paper we present a model that maps epistatic effects onto a genealogical tree for a haploid population. Prior work has demonstrated that genealogical structure causes the genotypic values of individuals to covary. Our results indicate that epistasis can reduce genotypic covariance that is caused by genealogical structure. Genotypic effects (both additive and epistatic) occur along the branches of a genealogical tree, from the base of the tree to its tips. Epistasis reduces genotypic covariance because there is a reweighting of the contribution of branches to the states of genotypes compared to the additive case. Branches near the tips of a genealogical tree contribute proportionally more genetic effects with epistasis than without epistasis. Epistatic effects are most numerous at basal positions in a genealogical tree when a population is constant in size and experiencing no selection, optimizing selection, diversifying selection or directional selection, indicating that epistatic effects are typically old. For a population that is growing in size, epistatic effects are most numerous at midpoints in a genealogical tree, indicating epistatic effects are of moderate age. Our results are important in that they suggest epistatic effects may typically explain deep (old) divergences and broad patterns of divergence that exist in populations, except in growing populations. In a growing population, epistatic effects may cause more within group divergence higher up in a tree and less between group divergence that is deep in a tree. The distribution of the number of epistatic effects and the expected variance and covariance in the number of epistatic effects is also provided assuming neutrality. PMID- 22100753 TI - Bioactive silica-based nanoparticles stimulate bone-forming osteoblasts, suppress bone-resorbing osteoclasts, and enhance bone mineral density in vivo. AB - Bone is a dynamic tissue that undergoes renewal throughout life in a process whereby osteoclasts resorb worn bone and osteoblasts synthesize new bone. Imbalances in bone turnover lead to bone loss and development of osteoporosis and ultimately fracture, a debilitating condition with high morbidity and mortality. Silica is a ubiquitous biocontaminant that is considered to have high biocompatibility. The authors report that silica nanoparticles (NPs) mediate potent inhibitory effects on osteoclasts and stimulatory effects on osteoblasts in vitro. The mechanism of bioactivity is a consequence of an intrinsic capacity to antagonize activation of NF-kappaB, a signal transduction pathway required for osteoclastic bone resorption but inhibitory to osteoblastic bone formation. We further demonstrate that silica NPs promote a significant enhancement of bone mineral density (BMD) in mice in vivo, providing a proof of principle for the potential application of silica NPs as a pharmacological agent to enhance BMD and protect against bone fracture. PMID- 22100754 TI - Lapatinib/Paclitaxel polyelectrolyte nanocapsules for overcoming multidrug resistance in ovarian cancer. AB - The sonication-assisted layer-by-layer (SLBL) technology was developed to combine necessary factors for an efficient drug-delivery system: (i) control of nanocolloid size within 100 - 300 nm, (ii) high drug content (70% wt), (iii) shell biocompatibility and biodegradability, (iv) sustained controlled release, and (v) multidrug-loaded system. Stable nanocolloids of Paclitaxel (PTX) and lapatinib were prepared by the SLBL method. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, lapatinib/PTX nanocolloids mediated an enhanced cell growth inhibition in comparison with the PTX-only treatment. A series of in vitro cell assays were used to test the efficacy of these formulations. The small size and functional versatility of these nanoparticles, combined with their ability to incorporate various drugs, indicates that lapatinib/PTX nanocolloids may have in vivo therapeutic applications. PMID- 22100755 TI - Double-walled carbon nanotubes trigger IL-1beta release in human monocytes through Nlrp3 inflammasome activation. AB - Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Toll-like receptor agonists to enhance IL-1beta release in human monocytes. We show that DWCNTs-induced IL-1beta secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1beta secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. PMID- 22100756 TI - Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid. AB - A drug carrier based on glycyrrhetinic acid-modified sulfated chitosan (GA-SCTS) was synthesized. The glycyrrhetinic acid (GA) acted as both a hydrophobic group and a liver-targeting ligand. The GA-SCTS micelles displayed rapid and significant ability to target the liver in vivo. The IC(50) for doxorubicin (DOX) loaded GA-SCTS micelles (DOX/SA-SCTS micelles) against HepG2 cells was 54.7 ng/mL, which was extremely lower than the amount of no-GA-modified DOX-loaded micelles. In addition, DOX/SA-SCTS micelles could target specifically the liver cancer cells. They had higher affinity for the liver cancer cells (HepG2 cells) than for the normal liver cells (Chang liver cells). There was nearly 2.18-fold improvement in uptake of the DOX/SA-SCTS micelles by HepG2 cells than that by Chang liver cells. These results indicate that GA-SCTS is not only an excellent carrier for drugs, but also a potential vehicle for liver-cancer targeting. PMID- 22100757 TI - Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobe. AB - Specific bioprobes for single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have enormous potential for use in cancer imaging in near-future clinical settings. The authors describe the development of dual modality molecular imaging bioprobes, in the form of magnetic nanoparticles (NPs) conjugated to antibodies, for SPECT and MRI of mesothelin-expressing cancers. The bioprobes were developed by conjugating (111)In labeled antimesothelin antibody mAbMB to superparamagnetic iron oxide NPs. Our experimental findings provide evidence that such bioprobes retain their magnetic properties as well as the ability to specifically localize in mesothelin expressing tumors. It is anticipated that combining SPECT with MR will help obtain both functional and anatomical imaging information with high signal sensitivity and contrast, thereby providing a powerful diagnostic tool for early diagnosis and treatment planning of mesothelin-expressing cancers. PMID- 22100758 TI - Photothermal release of small molecules from gold nanoparticles in live cells. AB - The ability of gold (Au) nanoparticles (NPs) to generate heat efficiently by absorbing visible and near-infrared (NIR) light holds great promise as a means to trigger chemical and biochemical events near the NPs. Previous demonstrations show that pulsed laser irradiation can selectively elicit the release of a fluorescent dye covalently anchored to the NP surface through a heat-labile linker without measurably changing the temperature of the surroundings. This article reports that the authors demonstrate the biological efficacy of this approach to photodelivery by showing that the decorated Au NPs are rapidly internalized by cells, are stable under physiological conditions, are nontoxic, and exhibit nonlethal photorelease following exposure to pulsed laser radiation. These observations, further supported by the versatility of our delivery motif, reaffirm the potential for further development of nonlethal photothermal therapeutics and their future relevance to such fields as gene therapy and stem cell differentiation. PMID- 22100759 TI - Contrasting effects of selenite and tellurite on lipoamide dehydrogenase activity suggest a different biological behaviour of the two chalcogens. AB - The effects of selenite and tellurite on the mammalian enzyme lipoamide dehydrogenase were compared. Selenite acts as a substrate of lipoamide dehydrogenase in a process requiring the presence of lipoamide. In contrast, tellurite is a potent inhibitor, effective in the low micromolar range. The inhibitory effect of tellurite on lipoamide dehydrogenase is partially reverted by dithiothreitol indicating the participation of the thiol groups of the enzyme. Tellurite, but not selenite, stimulates the diaphorase activity of lipoamide dehydrogenase. In a mitochondrial matrix protein preparation, which contains lipoamide dehydrogenase, an inhibitory action similar to that observed on the purified enzyme was also elicited by tellurite. Human embryonic kidney cells (HEK 293 T) treated with tellurite show a partial inhibition of lipoamide dehydrogenase. In addition to the toxicological implications of tellurium compounds, the reported results suggest that tellurite and its derivatives can be used as potential tools for studying biochemical reactions. PMID- 22100760 TI - Sera from neuromyelitis optica patients disrupt the blood-brain barrier. AB - OBJECTIVE: In neuromyelitis optica (NMO), the destruction of the blood-brain barrier (BBB) has been considered to be the first step of the disease process. It is unclear whether sera from patients with NMO can open the BBB, and which component of patient sera is most important for this disruption. METHODS: The effects of sera from antiaquaporin4 (AQP4) antibody positive NMO patients, multiple sclerosis patients and control subjects were evaluated for expression of tight junction proteins and for transendothelial electrical resistance (TEER) of human brain microvascular endothelial cells (BMECs). Whether antibodies against human BMECs as well as anti-AQP4 antibodies exist in NMO sera was also examined using western blot analysis. RESULTS: Expression of tight junction proteins and TEER in BMECs was significantly decreased after exposure to NMO sera. However, this effect was reversed after application of an antivascular endothelial growth factor (VEGF) neutralising antibody. Antibodies against BMECs other than anti AQP4 antibodies were found in the sera of NMO patients whereas no specific bands were detected in the sera of healthy and neurological controls. These antibodies apparently disrupt the BBB by increasing the autocrine secretion of VEGF by BMECs themselves. Absorption of the anti-AQP4 antibody by AQP4 transfected astrocytes reduced AQP4 antibody titres but was not associated with a reduction in BBB disruption. CONCLUSIONS: Sera from NMO patients reduce expression of tight junction proteins and disrupt the BBB. Autoantibodies against BMECs other than anti-AQP4 antibodies may disrupt the BBB through upregulation of VEGF in BMECs. PMID- 22100761 TI - The split hand syndrome in amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS), hand muscle wasting preferentially affects the 'thenar (lateral) hand', including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the hypothenar muscles (the abductor digiti minimi (ADM)). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the 'split hand' and is rarely seen in diseases other than ALS. The muscles involved in the split hand are innervated through the same spinal segments (C8 and T1), and FDI and ADM, which are differentially affected, are both ulnar nerve innervated. The physiological mechanisms underlying the split hand in ALS are incompletely understood but both cortical and spinal/peripheral mechanisms are probably involved. Motor potentials evoked by magnetic stimulation are significantly smaller when recorded from the thenar complex, compared with the hypothenar muscles, supporting a cortical mechanism. But peripheral axonal excitability studies have suggested that APB/FDI motor axons have more prominent persistent sodium currents than ADM axons, leading to higher axonal excitability and thereby more ready degeneration. Pincer or precision grip is vital to human hand function, and frequent use of thenar complex muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motoneurons innervating the APB and FDI. The split hand is a useful diagnostic sign in early ALS, and recent objective studies indicate that the sign has a high degree of specificity. PMID- 22100762 TI - Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network. AB - The spinocerebellar ataxia type 7 (SCA7) gene product, Ataxin-7 (ATXN7), localizes to the nucleus and has been shown to function as a component of the TATA-binding protein-free TAF-containing-SPT3-TAF9-GCN5-acetyltransferase transcription complex, although cytoplasmic localization of ATXN7 in affected neurons of human SCA7 patients has also been detected. Here, we define a physiological function for cytoplasmic ATXN7. Live imaging reveals that the intracellular distribution of ATXN7 dynamically changes and that ATXN7 distribution frequently shifts from the nucleus to the cytoplasm. Immunocytochemistry and immunoprecipitation demonstrate that cytoplasmic ATXN7 associates with microtubules (MTs), and expression of ATXN7 stabilizes MTs against nocodazole treatment, while ATXN7 knockdown enhances MT degradation. Interestingly, normal and mutant ATXN7 similarly associate with and equally stabilize MTs. Taken together, these findings provide a novel physiological function of ATXN7 in the regulation of cytoskeletal dynamics, and suggest that abnormal cytoskeletal regulation may contribute to SCA7 disease pathology. PMID- 22100763 TI - Cellular prion protein is essential for oligomeric amyloid-beta-induced neuronal cell death. AB - In Alzheimer disease (AD), amyloid-beta (Abeta) oligomer is suggested to play a critical role in imitating neurodegeneration, although its pathogenic mechanism remains to be determined. Recently, the cellular prion protein (PrP(C)) has been reported to be an essential co-factor in mediating the neurotoxic effect of Abeta oligomer. However, these previous studies focused on the synaptic plasticity in either the presence or the absence of PrP(C) and no study to date has reported whether PrP(C) is required for the neuronal cell death, the most critical element of neurodegeneration in AD. Here, we show that Prnp(-/-) mice are resistant to the neurotoxic effect of Abeta oligomer in vivo and in vitro. Furthermore, application of an anti-PrP(C) antibody or PrP(C) peptide prevents Abeta oligomer induced neurotoxicity. These findings are the first to demonstrate that PrP(C) is required for Abeta oligomer-induced neuronal cell death, the pathology essential to cognitive loss. PMID- 22100764 TI - Pd nanoparticle assemblies--as the substitute of HRP, in their biosensing applications for H2O2 and glucose. AB - The spherical porous Pd nanoparticle assemblies (NPAs) have been successfully synthesized by starch-assisted chemical reduction of Pd(II) species at room temperature. Such Pd NPAs are not simply used to enlarge the surface area and to promote the electron transfer. They also catalyze the reduction of H(2)O(2) which are regarded as horseradish peroxidase (HRP) substitutes in electron transfer process. By using them as electrocatalysts, as low as 6.8*10(-7) M H(2)O(2) can be detected with a linear range from 1.0*10(-6) to 8.2*10(-4) M. Moreover, through co-immobilization of such Pd NPAs and glucose oxidase (GOx), a sensitive and selective glucose biosensor is developed. The detection principle lies on measuring the increase of cathodic current by co-reduction of dissolved oxygen and the in situ generated H(2)O(2) during the enzymatic reaction. Under optimal conditions, the detection limit is down to 6.1*10(-6) M with a very wide linear range from 4.0*10(-5) to 2.2*10(-2) M. The proposed biosensor shows a fast response, good stability, high selectivity and reproducibility of serum glucose level. It provides a promising strategy to construct fast, sensitive, stable and anti-interferential amperometric biosensors for early diagnosis and prevention of diabetes. PMID- 22100765 TI - Highly sensitive protein kinase activity assay based on electrochemiluminescence nanoprobes. AB - Herein, we describe a novel electrochemiluminescence (ECL) biosensor for protein kinase activities and inhibition monitoring based on the magnetic beads (MB) technology and signal enhancement of gold nanoparticles (GNP). In this design, ECL nanoprobes were prepared by conjugating GNP with phosphorylated DNA capture probes and tris-(2,2'-bipyridyl) ruthenium (TBR)-cysteamine. Zirconium cations, a specific bridging agent, mediate the linkage between biotin modified phosphorylated peptides and ECL nanoprobes. The complexes were then captured and enriched on the electrode surface by streptavidin-coated MB for ECL reaction. To confirm the feasibility of this biosensor, we employed protein kinase A (PKA) as the model kinase to validate the assay and a satisfactory detection limit of 0.005 U/mL was achieved. The combination of ECL and GNP lays a solid foundation for highly sensitive assay, meanwhile, the coupling of MB surfaces used for separation and capture with unmodified ECL electrode detection results in a greatly simplified and reusable protocol. Thus, our biosensor offers great promise for a highly sensitive and simple assay for protein kinase activity. Furthermore, the inhibition of PKA activity was monitored on the basis of the ECL signals change in response to the concentration of PKA inhibitor. PMID- 22100766 TI - An electrochemical aptasensor based on enzyme linked aptamer assay. AB - An aptamer is an artificial functional oligonucleic acid, which can interact with its target molecule with high affinity and specificity. Enzyme linked aptamer assay (ELAA) is developed to detect cocaine using aptamer fragment/cocaine configuration based on the affinity interaction between aptamer fragments with cocaine. The aptasensor was constructed by cleaving anticocaine aptamer into two fragments: one was assembled on a gold electrode surface, while the other was modified with biotin at 3'-end, which could be further labelled with streptavidin horseradish peroxidase (SA-HRP). Upon binding with cocaine, the HRP-labelled aptamer fragment/cocaine complex formed on the electrode would increase the reduction current of hydroquinone (HQ) in the presence of H(2)O(2). The sensitivity and the specificity of the proposed electrochemical aptasensor were investigated by differential pulse voltammetry (DPV). The results indicated that the DPV signal change could be used to sensitively detect cocaine with the dynamic range from 0.1 MUM to 50 MUM and the detection limit down to 20 nM (S/N=3). The proposed aptasensor has the advantages of high sensitivity and low background current. Furthermore, a new configuration for ELAA requiring only a single aptamer sequence is constructed, which can be generalized for detecting different kinds of targets by cleaving the aptamers into two suitable segments. PMID- 22100767 TI - Semantic combinatorial processing of non-anomalous expressions. AB - In this study, semantic meaning composition is investigated focusing on the ERP correlates of reading of minimal Spanish noun-adjective pairs. Comprehending these constructs requires combining the concepts expressed by nouns with the--not contextually expected--semantic feature expressed by the adjectives. Previous studies have mainly focused on the processing of either semantic anomalies or contextually expected target words; we focus on the comprehension of more natural expressions, manipulating the typicality of the noun-adjective relation. In two different ERP experiments, compared to neutral pairs (monstruo solitario, lonely monster), only anomalous adjectives (monstruo geografico, geographic monster) elicited increased N400, the effect classically associated with lexical/semantic processing. Low-typicality adjectives that apparently contrasted with the inherent prototypical features associated with the noun (monstruo hermoso, lovely monster) elicited a long-lasting frontal late positive effect (LPC, 550-750 ms) in Experiment 1; high-typicality adjectives that expressed redundant information (monstruo horrible, horrible monster) elicited a similar, but shorter, positivity (550-650 ms) in Experiment 2. These findings suggest that the combination of non anomalous noun-adjective pairs involves additional neurocognitive resources to the ones represented by the N400. Correlation analyses indicate that the LPC is associated with a meta-linguistic analysis of the expressions: a significant inverse correlation was found between the stimuli's naturality and the amplitude of the LPC. PMID- 22100768 TI - Pleasant human touch is represented in pregenual anterior cingulate cortex. AB - Touch massage (TM) is a form of pleasant touch stimulation used as treatment in clinical settings and found to improve well-being and decrease anxiety, stress, and pain. Emotional responses reported during and after TM have been studied, but the underlying mechanisms are still largely unexplored. In this study, we used functional magnetic resonance (fMRI) to test the hypothesis that the combination of human touch (i.e. skin-to-skin contact) with movement is eliciting a specific response in brain areas coding for pleasant sensations. The design included four different touch conditions; human touch with or without movement and rubber glove with or without movement. Force (2.5 N) and velocity (1.5 cm/s) were held constant across conditions. The pleasantness of the four different touch stimulations was rated on a visual analog scale (VAS-scale) and human touch was rated as most pleasant, particularly in combination with movement. The fMRI results revealed that TM stimulation most strongly activated the pregenual anterior cingulate cortex (pgACC). These results are consistent with findings showing pgACC activation during various rewarding pleasant stimulations. This area is also known to be activated by both opioid analgesia and placebo. Together with these prior results, our finding furthers the understanding of the basis for positive TM treatment effects. PMID- 22100769 TI - Evoked traveling alpha waves predict visual-semantic categorization-speed. AB - In the present study we have tested the hypothesis that evoked traveling alpha waves are behaviorally significant. The results of a visual-semantic categorization task show that three early ERP components including the P1-N1 complex had a dominant frequency characteristic in the alpha range and behaved like traveling waves do. They exhibited a traveling direction from midline occipital to right lateral parietal sites. Phase analyses revealed that this traveling behavior of ERP components could be explained by phase-delays in the alpha but not theta and beta frequency range. Most importantly, we found that the speed of the traveling alpha wave was significantly and negatively correlated with reaction time indicating that slow traveling speed was associated with fast picture-categorization. We conclude that evoked alpha oscillations are functionally associated with early access to visual-semantic information and generate--or at least modulate--the early waveforms of the visual ERP. PMID- 22100770 TI - A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch. AB - Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch. PMID- 22100771 TI - The variation of function across the human insula mirrors its patterns of structural connectivity: evidence from in vivo probabilistic tractography. AB - The human insula is a functionally complex yet poorly understood region of the cortex, implicated in a wide range of cognitive, motor, emotion and somatosensory activity. To elucidate the functional role of the insula, the current study used in vivo probabilistic tractography to map the structural connectivity of seven anatomically-defined insular subregions. The connectivity patterns identified reveal two complementary insular networks connected via a dual route architecture, and provide key insights about the neural basis of the numerous functions ascribed to this area. Specifically, anterior-most insular regions were associated with a ventrally-based network involving orbital/inferior frontal and anterior/polar temporal regions, forming part of a key emotional salience and cognitive control network associated with the implementation of goal-directed behavior. The posterior and dorsal-middle insular regions were associated with a network focused on posterior and (to a lesser extent) anterior temporal regions via both dorsal and ventral pathways. This is consistent with the involvement of the insula in sound-to-speech transformations, with an implicated role in the temporal resolution, sequencing, and feedback processes crucial for auditory and motor processing, and the monitoring and adjustment of expressive performance. PMID- 22100772 TI - When do you grasp the idea? MEG evidence for instantaneous idiom understanding. AB - We investigated the time-course of cortical activation during comprehension of literal and idiomatic sentences using MEG and anatomically guided distributed source analysis. Previous fMRI work had shown that the comprehension of sentences including action-related words elicits somatotopic semantic activation along the motor strip, reflecting meaning aspects of constituent words. Furthermore, idioms more strongly activated temporal pole and prefrontal cortex than literal sentences. Here we show that, compared to literal sentences, processing of idioms in a silent reading task modulates anterior fronto-temporal activity very early on, already 150-250 ms after the sentences' critical disambiguating words ("kick the habit"). In parallel, the meaning of action words embedded in sentences is reflected by somatotopic activation of precentral motor systems. As neural reflections of constituent parts of idiomatic sentences are manifest at the same early latencies as brain indexes of idiomatic vs. literal meaning processing, we suggest that within 1/4 of a second, compositional and abstract context-driven semantic processes in parallel contribute to the understanding of idiom meaning. PMID- 22100773 TI - 3D statistical parametric mapping of quiet sleep EEG in the first year of life. AB - This paper extends previously developed 3D SPM for Electrophysiological Source Imaging (Bosch et al., 2001) for neonate EEG. It builds on a prior paper by our group that established age dependent means and standard deviations for the scalp EEG Broad Band Spectral Parameters of children in the first year of life. We now present developmental equations for the narrow band log spectral power of EEG sources, obtained from a sample of 93 normal neonates from age 1 to 10 months in quiet sleep. The main finding from these regressions is that EEG power from 0.78 to 7.5 Hz decreases with age and also for 45-50 Hz. By contrast, there is an increase with age in the frequency band of 19-32 Hz localized to parietal, temporal and occipital areas. Deviations from the norm were analyzed for normal neonates and 17 with brain damage. The diagnostic accuracy (measured by the area under the ROC curve) of EEG source SPM is 0.80, 0.69 for average reference scalp EEG SPM, and 0.48 for Laplacian EEG SPM. This superior performance of 3D SPM over scalp qEEG suggests that it might be a promising approach for the evaluation of brain damage in the first year of life. PMID- 22100774 TI - Assessment of a prototype computer colour matching system to reproduce natural tooth colour on ceramic restorations. AB - OBJECTIVES: The aim of this study was to assess the accuracy of a prototype computer colour matching (CCM) system for dental ceramics targeting the colour of natural maxillary central incisors employing a dental spectrophotometer and the Kubelka-Munk theory. METHODS: Seventeen human volunteers with natural intact maxillary central incisors were selected to participate in this study. One central incisor from each subject was measured in the body region by a spectrophotometer and the reflectance values were used by the CCM system in order to generate a prescription for a ceramic mixture to reproduce the target tooth's colour. Ceramic discs were fabricated based on these prescriptions and layered on a zirconia ceramic core material of a specified colour. The colour match of each two-layered specimen to the target natural tooth was assessed by CIELAB colour coordinates (DeltaE(*), DeltaL(*), Deltaa(*) and Deltab(*)). RESULTS: The average colour difference DeltaE(*) value was 2.58+/-84 for the ceramic specimen-natural tooth (CS-NT) pairs. DeltaL(*) values ranged from 0.17 to 2.71, Deltaa(*) values ranged from -1.70 to 0.61, and Deltab(*) values ranged from -1.48 to 3.81. There was a moderate inverse correlation (R=-0.44, p-value=0.0721) between L(*) values for natural target teeth and DeltaE(*) values; no such correlation was found for a(*) and b(*) values. CONCLUSION: The newly developed prototype CCM system has the potential to be used as an efficient tool in the reproduction of natural tooth colour. PMID- 22100775 TI - Effect of hemodialysis and diet on the exhaled breath methanol concentration in patients with ESRD. AB - OBJECTIVES: End-stage renal disease (ESRD) causes accumulation of nitrogenous waste products and acid-base, mineral, fluid, and electrolyte disorders, which are partially corrected by hemodialysis (HD). While the effects of ESRD and dialysis on body fluid composition are well known, the effects on composition of expired breath are uncertain. Methanol is produced from unabsorbable complex carbohydrates by the colonic microbiome. Dietary restrictions of fruits and vegetables aimed at limiting potassium intake lower the intake of dietary fibers; the reduced fiber intake can in turn reduce production of methanol and its appearance in the exhaled breath. In this study, we investigated the inter- and intradialytic changes in the breath methanol levels. DESIGN AND METHOD: Ten ESRD patients were studied during HD procedures at 3- and 2-day interdialytic intervals. On each occasion, 20 exhaled breath and room air samples were collected using evacuated canisters. Ten age-matched normal subjects served as controls. The samples were analyzed on a unique 6-column/detector gas chromatography system. RESULTS: Seven ESRD patients consuming renal diet had lower methanol concentration (90 +/- 29 ppbv) than the 3 patients consuming high fiber diet (340 +/- 48 ppbv, P <= .0006) and the 10 controls consuming unrestricted diets (202 +/- 80 ppbv, P <= .001). HD significantly lowered breath methanol (60% +/- 12%), paralleling the fall in serum urea concentration (70% +/- 6%). The predialysis methanol concentration was slightly higher at 3-day than the 2-day interdialytic intervals. CONCLUSION: Dietary restriction of fruits and vegetables lowers methanol production by the gut microbial flora in ESRD patients. Perhaps, methanol is a reliable breath biomarker to monitor individuals' daily fiber intake. Breath methanol is dramatically reduced by HD, reflecting its efficient removal. PMID- 22100776 TI - The presence and activity of progesterone in the plant kingdom. AB - Steroids are present in living organisms as one of the most essential groups of compounds. Continuous research has led to new discoveries and the revision of existing information concerning the occurrence and the role of steroids, both in animals and plants. This article will focus on reviewing the literature studying progesterone in the plant kingdom, including its discovery, its occurrence in different plant species as well as its biological activity and molecular basis of action. This review will present and discuss the current data in addition to introducing potential directions for further research on the subject of progesterone in plants. PMID- 22100777 TI - [Acute genital ulcer unrelated to a sexually transmitted disease]. PMID- 22100778 TI - [Experience in the diagnosis of hepatitis E in a tropical infectious diseases unit]. AB - The hepatitis E virus (HEV) is endemic in some developing countries. It produces acute hepatitis in sporadic cases or epidemics. The main transmission route is faecal-oral by contaminated waters. In developed countries the cases described are more and more frequent, mainly due to population movement (travellers, immigrants, international adoptions), although there have also been increases in the local population. We currently have serological and molecular techniques for the diagnosis of this infection. We describe the experience in the diagnosis of the infection by HEV in a Paediatric Tropical Infectious Diseases Unit in Madrid. PMID- 22100779 TI - [Left ventricular characteristics in obesity and hypertension]. PMID- 22100780 TI - [Tripeptidyl peptidase 1 in patients with late infantile neuronal ceroid lipofuscinosis]. AB - INTRODUCTION: Neuronal ceroid lipofuscinoses are a group of inherited autosomal recessive lysosomal diseases, most commonly found in infancy. These are neuropathologically characterised by accumulation of an autofluorescent lipopigment in neurons and other cells. This condition is clinically characterised by loss of motor and cognitive skills, lack of motor coordination, ataxia, progressive visual impairment, behavioural changes; seizures of difficult to manage seizures, particularly myoclonic, and premature death. Ten clinical forms have been described, one of which is late infantile where clinical signs begin between two and four years. The gene responsible for this disease is located at 11p15 locus, and the enzyme encoded by this gene is the tripeptidyl peptidase 1. PATIENTS AND METHODS: We standardised the technique for the enzymatic diagnosis of late infantile neuronal ceroid lipofuscinoses from dried blood on filter paper card in 76 healthy individuals adults and children in order to establish a normal range in the Venezuelan population. The tripeptidyl peptidase activity was also determined in 9 patients with a clinical diagnosis of late infantile neuronal ceroid lipofuscinoses. RESULTS: Six of the samples showed activity lower than the lowest control value (0.11 to 0.45 nmol/spot) from healthy controls of infantile age, confirming the enzymatic diagnosis. Three of the 14 parent samples analysed showed values in the heterozygote ranges. CONCLUSIONS: The enzymatic diagnosis of late infantile neuronal ceroid lipofuscinoses from dried blood on filter paper card is a rapid, easier, less expensive and accurate molecular diagnosis tool. PMID- 22100781 TI - [The course of attention deficit/hyperactivity disorder in an outpatient sample]. AB - INTRODUCTION: Attention Deficit Hyperactivity Disorder may be a disorder of with a poor prognosis and more so when associated with psychosocial risk factors. The aim of this study is to identify clinical and psychosocial risk factors associated with poor prognosis of this disorder. PATIENTS AND METHODS: In a sample of 88 patients was followed up at our Child and Adolescent Mental Health Centres for two or more years. We classified subjects using the Clinical Global Impression Scale of Improvement following the clinical course in three categories (improved, worsened and unchanged). We performed bivariate and univariate logistic regressions to study the association between the variables and outcome. RESULTS: Worsened and unchanged groups (30% of the sample) had more psychiatric comorbidity, a higher percentage of individuals with no drug treatment, and presence of the following social risk factors: inadequate parenting, adverse social and family environment and psychosocial stress. The highest degree of association is related to the absence of drug treatment (OR=15.8, 95% CI 2.71 to 92.19, P=.002) and the presence of two comorbidities (OR=4.8, 95% CI 1.02 to 22.64, P=.047). CONCLUSIONS: In our sample of ADHD outpatients, there was a subgroup that was unchanged or worsened. Drug therapy, psychological treatment, detection and clinical management of comorbidity and some of the psychosocial risk factors can influence the course and outcome of ADHD and therefore the standard treatment of these patients needs to be considered. PMID- 22100782 TI - Identification of the couple GSK3alpha/c-Myc as a new regulator of hexokinase II in benzo[a]pyrene-induced apoptosis. AB - The early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from the mitochondria. Cancer cells often have an anomalous cell energy metabolism; since HKII dysfunction regulates B[a]P-induced apoptosis in F258 cells, but may also alter cell energy metabolism, HKII release from the mitochondria may represent an important B[a]P-related carcinogenic issue. Thus in the present study, we aimed at deciphering the mechanisms underlying HKII dysfunction upon B[a]P exposure. We show that while glycogen synthase kinase 3 beta (GSK3beta) regulated the expression of HKII at the transcriptional level, glycogen synthase kinase 3 alpha (GSK3alpha) was involved in B[a]P-induced apoptosis via a decrease in c-Myc expression. The reduced level of c-Myc caused the relocation of HKII from the mitochondria to the cytosol, thereby being involved in the formation of reactive oxygen species and apoptosis. In conclusion, we show that the couple GSK3alpha/c-Myc plays a key role in B[a]P induced early apoptotic cell signaling via HKII dysfunction. PMID- 22100783 TI - Inheritable stimulatory effects of caffeine on steroidogenic acute regulatory protein expression and cortisol production in human adrenocortical cells. AB - Caffeine is the most widely consumed psychoactive substance in the world. It can elevate the level of glucocorticoid which is involved in metabolism regulation, stress response, and immune function. However, the specific mechanism has yet to be elucidated. Glucocorticoid is steroid hormone synthesized in adrenal cortex and the key rate-limiting step in its biosynthesis is mediated by steroidogenic acute regulatory protein (StAR). This study was designed to investigate the direct effects and inheritable epigenetic mechanisms of caffeine on cortisol production and StAR expression in human adrenocortical cells. The human adrenocortical cell line NCI-H295A was cultured with 0.4-40MUM caffeine. There was a significant increase of the cortisol production in cells. In both acutely and chronically caffeine-treated cell groups, mRNA and protein expressions of StAR were stimulated in a dose-dependent manner. DNA methylation detection via bisulfite-sequencing PCR (BSP) uncovered a single site CpG demethylation at nt 682 within the StAR promoter region. Then we investigated how long the increased StAR expression and the single CpG demethylation could last. The caffeine was withdrawn after 48h of treatment and then the cells were continually subcultured for up to 5 and 10 passages, respectively. The results showed that the StAR expression at post-caffeine passage 10 still increased, as compared with that in the control. The caffeine-induced demethylation at nt -682 in StAR promoter underwent a similar time course as StAR expression does. The present study reveals the direct effect and possible inheritable epigenetic mechanism of caffeine on steroidogenesis in human adrenocortical cells and has implications for our understanding of the consumption of caffeine. PMID- 22100784 TI - Birds of an ethnic feather? Ethnic identity homophily among college-age friends. AB - This study assessed the degree to which pairs of friends report similar levels of ethnic identity. College-age friends (n=107 pairs; N=214 overall) completed measures of ethnic identity exploration and commitment, identity synthesis, relationship closeness, and frequency of talking to friends and family about ethnicity-related issues. Participants were ethnically-diverse and constituted three types of dyads: both ethnic minorities (n=51), both White (n=24), or mixed ethnic minority and White (n=32). Overall, friends reported similar levels of ethnic identity exploration and commitment. The ethnic composition of the pair moderated similarity, with ethnic minority pairs showing greater similarity than the White and mixed pairs. Frequency of ethnicity-related discussions with friends and family, but not relationship closeness, mediated the observed similarity for ethnic minority pairs. These findings suggest a level of ethnic identity homophily between ethnic minority friends that can be explained by interactional mechanisms. PMID- 22100785 TI - Spatial characterization of the motor neuron columns supplying the rat forelimb. AB - Rats can generate a rich array of forepaw and forelimb movements that are similar, although not as complex, to those produced by human and non-human primates. When reaching for food for instance, rats display skilled movements of the forelimb and the paw, therefore, making them attractive models to validate strategies aimed at the recovery of fine motor control. Surprisingly however, few anatomical studies have been performed on the central control of forelimb movements in the rat. The current series of experiments examined the details of the segmental arrangement of motor neurons that supply the rat forelimb. The distribution of motor end plates across the rat forelimb was first visualized by means of acetylcholinesterase histochemistry, and this information was used to create a motor end plate map of the forelimb muscles. This map was subsequently used as a guide for multiple injections of retrograde tracers along the motor end plate regions of 11 forelimb muscles. The entire cervical region of the spinal cord was subsequently analyzed under epifluorescence. This tract-tracing analysis confirmed that motor neurons innervating the rat forelimb are arranged in columns within the cervical segments of the spinal cord. This anatomical investigation also supports the previous observation that, although discrete, some of the motor neuron columns lying in the cervical aspect of the rat spinal cord are inter mingled. The length of these columns, and hence the overlap between them, appears to be greater than previously reported, particularly within the uppermost segments of the brachial plexus. PMID- 22100786 TI - Serotonin 5-HT(1A) receptor binding sites in the brain of the pigeon (Columba livia). AB - Present knowledge about the serotonergic system in birdbrains is very limited, although the pigeon was used as an animal model in various studies focused on the behavioral effects of serotonergic transmission. In the mammalian brain the 5 HT(1A) receptor is the most widespread serotonin receptor type, and is involved in various functions. Less is known about the distribution of 5-HT(1A) receptors in the avian species. Therefore, we analyzed serotonin 5-HT(1A) receptor binding sites in the pigeon brain using quantitative in vitro receptor autoradiography with the selective radioligand [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H] 8-OH-DPAT). The receptor is differentially distributed throughout the pigeon brain. High levels of 5-HT(1A) receptors are found in the nucleus pretectalis (PT). Moderate densities were detected in the tectum, as well as in the telencephalic nidopallium and hyperpallium. Very low levels were found in the hippocampal formation, the amygdaloid complex, the basal ganglia, and several thalamic nuclei. Furthermore, local variations in 5-HT(1A) receptor densities support the concept of further subdivisions of the entopallium. The regional distribution patterns of 5-HT(1A) receptors mostly display a similar distribution as found in homologue brain structures of mammals. PMID- 22100787 TI - Food odor, visual danger stimulus, and retrieval of an aversive memory trigger heat shock protein HSP70 expression in the olfactory lobe of the crab Chasmagnathus granulatus. AB - Although some of the neuronal substrates that support memory process have been shown in optic ganglia, the brain areas activated by memory process are still unknown in crustaceans. Heat shock proteins (HSPs) are synthesized in the CNS not only in response to traumas but also after changes in metabolic activity triggered by the processing of different types of sensory information. Indeed, the expression of citosolic/nuclear forms of HSP70 (HSC/HSP70) has been repeatedly used as a marker for increases in neural metabolic activity in several processes, including psychophysiological stress, fear conditioning, and spatial learning in vertebrates. Previously, we have shown that, in the crab Chasmagnathus, two different environmental challenges, water deprivation and heat shock, trigger a rise in the number of glomeruli of the olfactory lobes (OLs) expressing HSC/HSP70. In this study, we initially performed a morphometric analysis and identified a total of 154 glomeruli in each OL of Chasmagnathus. Here, we found that crabs exposed to food odor stimuli also showed a significant rise in the number of olfactory glomeruli expressing HSC/HSP70. In the crab Chasmagnathus, a powerful memory paradigm based on a change in its defensive strategy against a visual danger stimulus (VDS) has been extensively studied. Remarkably, the iterative presentation of a VDS caused an increase as well. This increase was triggered in animals visually stimulated using protocols that either build up a long-term memory or generate only short-term habituation. Besides, memory reactivation was sufficient to trigger the increase in HSC/HSP70 expression in the OL. Present and previous results strongly suggest that, directly or indirectly, an increase in arousal is a sufficient condition to bring about an increase in HSC/HSP70 expression in the OL of Chasmagnathus. PMID- 22100788 TI - Bactericidal effect of supercritical N2O on Staphylococcus aureus and Escherichia coli. AB - The aim of this study is to investigate the bactericidal effect of supercritical nitrous oxide (SC N(2)O) on both typical Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli while varying the operating conditions including the suspending medium (nutrient broth, phosphate buffered saline, phosphate buffer, phosphate buffer containing oleic acid), pressure, temperature, mixing intensity, and working volume (the ratio of the sample volume to the reactor volume). Approximately 7 log of both S. aureus and E. coli by SC N(2)O (10 MPa, 37 degrees C, 10% working volume, and 600 rpm) were completely inactivated within 20 min, although S. aureus exhibited relatively low sensitivity to SC N(2)O compared to E. coli. The bactericidal efficiency was not adversely affected by varying the suspending medium and the presence of oleic acid enhanced the inactivation. The mixing intensity, which is presumed to be associated with the increasing frequency of bacteria cells in contact with SC N(2)O as a result of the fast mass transfer of N(2)O molecules into the water layer containing the microbe, significantly affected the bactericidal activity, which was also supported by the % volume expansion of the aqueous phase. On the other hand, the other parameters (pressure, temperature, and working volume) appeared to moderately affect the bactericidal efficiency as long as the SC condition was maintained. This study reports that SC N(2)O technology can be effectively employed as an alternative for SC CO(2) sterilization technique in order to control bacteria in food which contains nutrients or fat in highly phosphate buffered conditions. PMID- 22100789 TI - Antifungal activity by vapor contact of essential oils added to amaranth, chitosan, or starch edible films. AB - Antimicrobial agents can be incorporated into edible films to provide microbiological stability, since films can be used as carriers of a variety of additives to extend product shelf life and reduce the risk of microbial growth on food surfaces. Addition of antimicrobial agents to edible films offers advantages such as the use of small antimicrobial concentrations and low diffusion rates. The aim of this study was to evaluate inhibition by vapor contact of Aspergillus niger and Penicillium digitatum by selected concentrations of Mexican oregano (Lippia berlandieri Schauer), cinnamon (Cinnamomum verum) or lemongrass (Cymbopogon citratus) essential oils (EOs) added to amaranth, chitosan, or starch edible films. Essential oils were characterized by gas chromatography-mass spectrometry (GC/MS) analysis. Amaranth, chitosan and starch edible films were formulated with essential oil concentrations of 0.00, 0.25, 0.50, 0.75, 1.00, 2.00, or 4.00%. Antifungal activity was evaluated by determining the mold radial growth on agar media inoculated with A. niger and P. digitatum after exposure to vapors arising from essential oils added to amaranth, chitosan or starch films using the inverted lid technique. The modified Gompertz model adequately described mold growth curves (mean coefficient of determination 0.991 +/- 0.05). Chitosan films exhibited better antifungal effectiveness (inhibition of A. niger with 0.25% of Mexican oregano and cinnamon EO; inhibition of P. digitatum with 0.50% EOs) than amaranth films (2.00 and 4.00% of cinnamon and Mexican oregano EO were needed to inhibit the studied molds, respectively). For chitosan and amaranth films a significant increase (p<0.05) of lag phase was observed among film concentrations while a significant decrease (p<0.05) of maximum specific growth was determined. Chitosan edible films incorporating Mexican oregano or cinnamon essential oil could improve the quality of foods by the action of the volatile compounds on surface growth of molds. PMID- 22100790 TI - Novel chemobiosynthetic approach for exclusive production of FK506. AB - FK506, a widely used immunosuppressant, is produced by industrial fermentation processes using various Streptomyces species. Independently of the strain, structurally related compound FK520 is co-produced, resulting in complex and costly isolation procedures. In this paper, we report a chemobiosynthetic approach for exclusive biosynthesis of FK506. This approach is based on the Streptomyces tsukubaensis strain with inactivated allR gene, a homologue of crotonyl-CoA carboxylase/reductase, encoded in the FK506 biosynthetic cluster. This strain produces neither FK506 nor FK520; however, if allylmalonyl-S-N acetylcysteamine precursor is added to cultivation broth, the production of FK506 is reestablished without FK506-related by-products. Using a combination of metabolic engineering and chemobiosynthetic approach, we achieved exclusive production of FK506, representing a significant step towards development of an advanced industrial bioprocess. PMID- 22100791 TI - Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: a whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer's disease patients. AB - One of the major pathological landmarks of Alzheimer's disease and other neurodegenerative diseases is the presence of amyloid deposits in the brain. The early non-invasive visualization of amyloid is a major objective of recent diagnostic neuroimaging approaches, including positron emission tomography (PET), with an eye on follow-up of disease progression and/or therapy efficacy. The development of molecular imaging biomarkers with binding affinity to amyloid in the brain is therefore in the forefront of imaging biomarker and radiochemistry research. Recently, a dodecamer peptide (amino acid sequence=QSHYRHISPAQV; denominated D1 or ACI-80) was identified as a prospective ligand candidate, binding with high ex vivo affinity to L-Abeta-amyloid (K(d): 0.4 MUM). In order to assess the ligand's capacity to visualize amyloid in Alzheimer's disease (AD), two (125)I labeled and three (18)F labeled analogues of the peptide were synthesized and tested in post mortem human autoradiography experiments using whole hemisphere brain slices obtained from deceased AD patients and age matched control subjects. The (18)F-labeled radioligands showed more promising visualization capacity of amyloid that the (125)I-labeled radioligands. In the case of each (18)F radioligands the grey matter uptake in the AD brains was significantly higher than that in control brains. Furthermore, the grey matter: white matter uptake ratio was over ~2, the difference being significant for each (18)F-radioligands. The regional distribution of the uptake of the various radioligands systematically shows a congruent pattern between the high uptake regions and spots in the autoradiographic images and the disease specific signals obtained in adjacent or identical brain slices labeled with histological, immunohistochemical or autoradiographic stains for amyloid deposits or activated astrocytes. The present data, using post mortem human brain autoradiography in whole hemisphere human brains obtained from deceased AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the (18)F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies. PMID- 22100792 TI - Human matrix metalloproteinases: an ubiquitarian class of enzymes involved in several pathological processes. AB - Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes. PMID- 22100793 TI - Impact of length or relevance of questionnaires on attrition in online trials: randomized controlled trial. AB - BACKGROUND: There has been limited study of factors influencing response rates and attrition in online research. Online experiments were nested within the pilot (study 1, n = 3780) and main trial (study 2, n = 2667) phases of an evaluation of a Web-based intervention for hazardous drinkers: the Down Your Drink randomized controlled trial (DYD-RCT). OBJECTIVES: The objective was to determine whether differences in the length and relevance of questionnaires can impact upon loss to follow-up in online trials. METHODS: A randomized controlled trial design was used. All participants who consented to enter DYD-RCT and completed the primary outcome questionnaires were randomized to complete one of four secondary outcome questionnaires at baseline and at follow-up. These questionnaires varied in length (additional 23 or 34 versus 10 items) and relevance (alcohol problems versus mental health). The outcome measure was the proportion of participants who completed follow-up at each of two follow-up intervals: study 1 after 1 and 3 months and study 2 after 3 and 12 months. RESULTS: At all four follow-up intervals there were no significant effects of additional questionnaire length on follow-up. Randomization to the less relevant questionnaire resulted in significantly lower rates of follow-up in two of the four assessments made (absolute difference of 4%, 95% confidence interval [CI] 0%-8%, in both study 1 after 1 month and in study 2 after 12 months). A post hoc pooled analysis across all four follow-up intervals found this effect of marginal statistical significance (unadjusted difference, 3%, range 1%-5%, P = .01; difference adjusted for prespecified covariates, 3%, range 0%-5%, P = .05). CONCLUSIONS: Apparently minor differences in study design decisions may have a measurable impact on attrition in trials. Further investigation is warranted of the impact of the relevance of outcome measures on follow-up rates and, more broadly, of the consequences of what we ask participants to do when we invite them to take part in research studies. TRIAL REGISTRATION: ISRCTN Register 31070347; http://www.controlled-trials.com/ISRCTN31070347/31070347 Archived by WebCite at (http://www.webcitation.org/62cpeyYaY). PMID- 22100794 TI - [The role of HLA-E polymorphism in immunological response]. AB - The HLA-E protein is one of the most extensively studied MHC class Ib antigens and the least polymorphic one compared to other MHC class I molecules. In the human population there have been reported just ten alleles encoding three different peptides. Only two of these alleles, namely HLA-E*0101 and HLA-E*0103, are widely distributed (around 50% each). The proteins encoded by these alleles differ from each other in one amino acid at position 107. In HLA-E*0101 it is arginine and in HLA-E*0103 it is glycine. The difference between these proteins manifests itself in surface expression levels, affinities to leader peptides and thermal stabilities of their complexes. The HLA-E molecule is a ligand for CD94/NKG2 receptors on NK cells and TCR receptors on NK-CTL (NK-cytotoxic T lymphocyte) cells, so it plays a double role in both innate and adaptive immunity. This paper reviews the knowledge on the role of the HLA-E molecule in the immunological response. Aspects related to polymorphism of the HLA-E gene and the course of several diseases including type I diabetes, ankylosing spondylitis, HCV and HIV infections, nasopharyngeal cancer and recurrent spontaneous abortions, as well as the outcome of hematopoietic stem cell transplantation, are presented and discussed in more detail. PMID- 22100795 TI - [Pathophysiological consequences of hemolysis. Role of cell-free hemoglobin]. AB - Abundant hemolysis is associated with a number of inherent and acquired diseases including sickle-cell disease (SCD), polycythemia, paroxysmal nocturnal hemoglobinuria (PNH) and drug-induced hemolytic anemia. Despite different etiopathology of hemolytic diseases, many concomitant symptoms are comparable and include e.g. hypertension, hemoglobinuria and hypercoagulation state. Studies in the last years have shown a growing list of mechanisms lying at the basis of those symptoms, in particular irreversible reaction between cell-free hemoglobin (Hb) and nitric oxide (NO) - endogenous vasorelaxant and anti-thrombotic agent. Saturation of protective physiological cell-free Hb-scavenging mechanisms results in accumulation of Hb in plasma and hemoglobinemia. Extensive hemoglobinemia subsequently leads to hemoglobinuria, which may cause kidney damage and development of Fanconi syndrome. A severe problem in patients with SCD and PNH is pulmonary and systemic hypertension. It may lead to circulation failure, including stroke, and it is related to abolition of NO bioavailability for vascular smooth muscle cells. Thrombotic events are the major cause of death in SCD and PNH. It ensues from lack of platelet inhibition evoked by Hb-mediated NO scavenging. A serious complication that affects patients with excessive hemolysis is erectile dysfunction. Also direct cytotoxic, prooxidant and proinflammatory effects of cell-free hemoglobin and heme compose the clinical picture of hemolytic diseases. The pathophysiological role of plasma Hb, mechanisms of its elimination, and direct and indirect (via NO scavenging) deleterious effects of cell-free Hb are presented in detail in this review. Understanding the critical role of hemolysis and cell-free Hb is important in the perspective of treating patients with hemolytic diseases and to design new effective therapies in future. PMID- 22100796 TI - [Antioxidant enzymosomes - properties and application]. AB - The application of catalase and superoxide dismutase in daily practice encounters many difficulties connected first of all with their loss of activity, and even with their degradation. Both enzymes, catalase and superoxide dismutase, practically do not penetrate biological membranes, which limits or even makes impossible their protective activity directed against ROS. However, the penetration of the membranous barrier becomes possible after the location of the enzymes in lipidic structures. One of the technologies of stabilization of the activity of enzymes consists in closing them in a liposome structure. The incorporation of the enzymes into a closed, such as liposome, structure or into their lipid bilayer screens and simultaneously protects them against degradation which they would undergo during use in the unshaded form. Concurrently it extends their half life and also increases their activity and stability. The structure in which an enzyme is enclosed in a liposome is called an enzymosome. PMID- 22100797 TI - [Carnitine: function, metabolism and value in hepatic failure during chronic alcohol intoxication]. AB - Alcoholism is one of the most frequent dependences among people, leading to damage of the liver and death of the person. Chronic alcohol consumption decreases fatty acid oxidation by interfering with carnitine metabolism and citric acid cycle activity. Block in activity of the citric acid cycle caused by alcohol and its metabolites is partially compensated by increased ketone body production, which results in ketosis. Chronic administration of alcohol induces liver injury, inflammation, cirrhosis, focal necrosis and steatosis. L carnitine (L-3-hydroxy-4-N, N, N-trimethylaminebutyric acid) is an essential factor in fatty acid metabolism, which plays a major role in transport of activated long-chain fatty acids to sites of beta-oxidation in mitochondria. Carnitine also stabilizes cell membranes by removing long-chain acyl-CoA and excess of the acyl group from the body. L-carnitine can be a useful and safe drug in the liver pathology induced by chronic ethanol exposure. PMID- 22100798 TI - A rare variant route of the ulnar artery does not contraindicate the creation of a fistula in the wrist of a diabetic patient with end-stage renal disease. AB - A superficial variant route of the ulnar artery is a rare variation of the arterial system of the wrist. The route of the arteries in that region is extremely important for patients with end-stage renal disease due to the necessity to create an arteriovenous fistula for hemodialysis. It is thought that the vascular access is too often achieved by catheters or vascular prostheses because of that each possibility to create a fistula in the wrist region should be utilized. In our patient a rare variant route of the ulnar artery was observed in the wrist region. Instead of a deep route between the muscles the artery did not only run superficially, but, also untypically, first laterally and then medially. A variation of the ulnar artery's route may evoke a fear of hand ischemia after creation arteriovenous fistula for hemodialysis. The fear may be connected with blood supply throw the palmar arch which is created by radial and ulnar artery. This fear of the doctor may result in avoiding the attempt to create an arteriovenous fistula on the wrist. The authors demonstrate that the variant route of the ulnar artery is not a contraindication to the creation of a fistula on the wrist using the radial artery because of a fear of hand ischemia. PMID- 22100799 TI - Circadian concentrations of free testosterone, selected markers of bone metabolism, osteoprotegerin and its ligand sRANKL in obese postmenopausal women. AB - BACKGROUND: It has been suggested that increased testosterone secretion in postmenopausal obese women might have some protective effect on bone tissue; the association might be significantly influenced by the RANKL/RANK/OPG system. AIM: The aim of the study was to determine whether postmenopausal obese women showed any relationship between the pattern of adipose tissue distribution, circadian free testosterone (FT) concentrations and bone metabolism (as assessed based on circadian osteocalcin [OC] and C-terminal telopeptide [CTx] levels), and to establish whether osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) might play a role in the relationship. MATERIAL/METHODS: FT, OC, CTx, OPG and soluble RANKL (sRANKL) levels were determined by ELISA in serum samples collected every three hours for 24 hours from 47 postmenopausal women (12 with gynoid obesity [GO], 17 with android obesity [AO], and 18 healthy individuals). RESULTS: Obese women demonstrated an adipose tissue distribution dependent increase in mean circadian FT levels and a decrease in mean circadian OC, CTx, OPG and sRANKL compared to control participants. In GO subjects, these changes were accompanied by smaller FT amplitudes, suppression of the circadian rhythms of bone markers and OPG, and a shift of sRANKL rhythm acrophase, whereas AO subjects showed a decrease in bone marker amplitudes and suppression of OPG and sRANKL rhythms. In comparison with the controls, significant adipose tissue distribution-dependent changes were found in the correlations between FT and bone markers, FT and OPG, OC and CTx, OPG and sRANKL, CTx and OPG, and CTx and sRANKL. Compared to GO participants, those with AO had higher coefficients of correlations between mean circadian FT and OC as well as between OC and CTx, and lower in the case of FT and sRANKL as well as CTx and OPG and CTx and sRANKL. DISCUSSION/CONCLUSIONS: Postmenopausal obesity results in adipose tissue distribution-dependent alterations in circadian FT levels accompanied by suppression of bone metabolism and a decline in circadian variations of the osteokines under investigation, especially sRANKL. Increased FT secretion in postmenopausal women might exert a protective effect on bone tissue, most likely via a shift in the OPG/RANKL ratio that tilts the balance toward a functional excess of OPG. PMID- 22100800 TI - [Renal catabolism of albumin - current views and controversies]. AB - Albumin is the main protein of blood plasma, lymph, cerebrospinal fluid and interstitial fluid. The protein assists in many important body functions, including maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver as well as in the kidney tubular epithelium. Renal catabolism of albumin consists of glomerular filtration and tubular reabsorption. The tubular processes include endocytosis via the multiligand scavenger receptor tandem megalin and cubilin-amnionless complex. Possible ways of further catabolism of this protein are lysosomal proteolysis to amino acids and short peptides, recycling of degradation products into the bloodstream and tubular lumen or transcytosis of whole molecules. The article discusses the molecular aspects of these processes and presents the controversies arising in the light of the last decade of research. PMID- 22100801 TI - [Can drugs used in type 2 diabetes therapy induce acute pancreatitis?]. AB - The increased number of subjects with type 2 diabetes and putting into clinical practice further new hypoglycemic agents and also aspiring to achieve the bettest glycemic control using a few medications may cause that undesirable actions of these agents may be observed more frequently. One undesirable effect of hypoglycemic drugs is acute pancreatitis; therefore the aim of the present paper is to review data concerning the development of this complication during type 2 diabetes pharmacotherapy. PMID- 22100802 TI - [Current views on etiopathogenesis of systemic lupus erythematosus]. AB - The article is a review of information concerning etiopathogenesis of systemic lupus erythematosus (SLE). Due to the risk of serious complications, including death, the clarification of etiology could result in substantial improvement or even complete cure of the disease. Progress in scientific research of observed disorder mechanisms together with implementation of appropriate therapies contributed to a higher detection rate, improved course and decreased mortality in SLE. However, there are still many doubts, which legitimate the need of further research. A significant role in development of the disease and further exacerbations is played by environmental factors. Therefore, decreased exposure to UV light, female sex hormone and microbial antigens is associated with improved course and decreased frequency of exacerbations. Less is known about the genetic basis of SLE, which results from a multigene disease background and complex hereditary mechanisms. It is estimated that the disease may be conditioned by around 100 genes, that only in part are functionally determined. Only part of them is already functionally characterized. The role played by most of them is still unknown. Research currently being conducted is aimed at detecting genetic polymorphism in large and genetically diverse populations. It will allow evaluation of the role of a particular gene in protein biosynthesis, which is responsible for development of regulatory process disturbances, commonly observed in the course of SLE. The article presents current directions of research and the latest advances in epidemiology as well as environmental and genetic risk factors of SLE. PMID- 22100803 TI - [Rho proteins - the key regulators of cytoskeleton in the progression of mitosis and cytokinesis]. AB - The Rho proteins are members of the Ras superfamily of small GTPases. They are thought to be crucial regulators of multiple signal transduction pathways that influence a wide range of cellular functions, including migration, membrane trafficking, adhesion, polarity and cell shape changes. Thanks to their ability to control the assembly and organization of the actin and microtubule cytoskeletons, Rho GTPases are known to regulate mitosis and cytokinesis progression. These proteins are required for formation and rigidity of the cortex during mitotic cell rounding, mitotic spindle formation and attachment of the spindle microtubules to the kinetochore. In addition, during cytokinesis, they are involved in promoting division plane determination, contractile ring and cleavage furrow formation and abscission. They are also known as regulators of cell cycle progression at the G1/S and G2/M transition. Thus, the signal transduction pathways in which Rho proteins participate, appear to connect dynamics of actin and microtubule cytoskeletons to cell cycle progression. We review the current state of knowledge concerning the molecular mechanisms by which Rho GTPase signaling regulates remodeling of actin and microtubule cytoskeletons in order to control cell division progression. PMID- 22100804 TI - Diagnostic accuracy of computer-assisted electrocardiography in the diagnosis of left ventricular hypertrophy in left bundle branch block. AB - INTRODUCTION AND OBJECTIVES: Left ventricular hypertrophy has important prognostic implications. Although electrocardiography is the technique most often recommended in the diagnosis of hypertrophy, its diagnostic accuracy is hampered in the presence of a left bundle branch block. METHODS: In 1875 consecutive patients (56+/-16 years) undergoing studies to rule out heart disease and/or hypertension, 2-dimensional echocardiography and electrocardiography were performed simultaneously in an outpatient clinic. Digitized electrocardiograms were interpreted using an online computer-assisted platform (ELECTROPRES). Sensitivity, specificity, likelihood ratios, and predictive values of standard electrocardiographic criteria and of some diagnostic algorithms for left ventricular hypertrophy were determined and compared with the findings in patients with neither left bundle branch block nor myocardial infarction. RESULTS: Left bundle branch block was present in 233 (12%) patients. Left ventricular hypertrophy was detected more frequently in patients with left bundle branch block (60% vs 31%). In patients with left bundle branch block, sensitivities were low but similar to those observed in patients without it, and ranged from 6.4% to 70.9%, whereas specificities were high, ranging from 57.6% to 100%. Positive likelihood ratios ranged from 1.33 to 4.94, and negative likelihood ratios from 0.50 to 0.98. Diagnostic algorithms, voltage-duration products, and certain compound criteria had the best sensitivities. CONCLUSIONS: Left ventricular hypertrophy can be diagnosed in the presence of left bundle branch block with an accuracy at least similar to that observed in patients without this conduction defect. Computer-assisted interpretation of the electrocardiogram may be useful in the diagnosis of left ventricular hypertrophy as it enables the implementation of more accurate algorithms. PMID- 22100805 TI - Further improvement in quantifying male fetal DNA in maternal plasma. AB - BACKGROUND: Cell-free fetal DNA (cffDNA) in maternal plasma can be clinically useful for detecting prenatal disorders and pregnancy monitoring. More sensitive, specific, and quantitative detection of cffDNA in maternal plasma may expand the clinical utility of such measurements. METHODS: We developed a quantitative real time PCR (qPCR) assay [Y chromosome repetitive sequence (YRS) assay] based on a highly repetitive short sequence specific for the Y chromosome. Both standard qPCR and digital qPCR were performed to compare the sensitivity and specificity of this new assay against already established male DNA-specific assays. RESULTS: The YRS assay was at least 10-fold more sensitive than the currently most sensitive DYS14 assay. The YRS assay was able to detect 0.5 genome equivalents (GE) per PCR reaction when fetal DNA was present at 0.2% of the total DNA. The background noise for the YRS assay was much lower than for the DYS14 assay in analyses of plasma samples from pregnancies with female fetuses. CONCLUSIONS: The YRS assay is a substantial improvement for quantifying rare male fetal DNA in maternal plasma. The higher sensitivity and specificity may expand the clinical and research utility of cffDNA. PMID- 22100806 TI - Troponin T measurements by high-sensitivity vs conventional assays for risk stratification in acute dyspnea. AB - BACKGROUND: Cardiac troponin T measured by a high-sensitivity assay (hs-cTnT) recently proved to be of prognostic value in several populations. The hs-cTnT assay may also improve risk stratification in acute dyspnea. METHODS: We prospectively studied the prognostic value of hs-cTnT in 678 consecutive patients presenting to the emergency department with acute dyspnea. On the basis of conventional cardiac troponin T assay (cTnT) and hs-cTnT assay measurements, patients were divided into 3 categories: (1) neither assay increased (cTnT<0.03 MUg/L, hs-cTnT<0.016 MUg/L), (2) only hs-cTnT increased>=0.016 MUg/L (cTnT<0.03 MUg/L), and (3) both assays increased (cTnT>=0.03 MUg/L, hs-cTnT>=0.016 MUg/L). Moreover, the prognostic value of hs-cTnT was investigated if cTnT was not detectable (<0.01). RESULTS: One hundred seventy-two patients were in the lowest, 282 patients in the middle, and 223 patients in the highest troponin category. Patients in the second and third categories had significantly higher mortality compared to those in the first category (90-day mortality rate 2%, 10%, and 26% in groups 1, 2, and 3, respectively, P<0.001; 1-year mortality rate 9%, 21%, and 39%, P<0.001). Importantly, in patients with undetectable cTnT (n=347, 51%), increased hs-cTnT indicated worse outcome [90-day mortality, odds ratio 4.26 (95% CI 1.19-15.21); 1-year mortality, hazard ratio 2.27 (1.19-4.36), P=0.013], whereas N-terminal pro-brain-type natriuretic peptide (NT-proBNP) was not predictive of short-term outcome. CONCLUSIONS: hs-cTnT is associated with mortality in patients presenting with acute dyspnea. hs-cTnT concentrations provide additional prognostic information to cTnT and NT-proBNP testing in patients with cTnT concentrations below the detection limit. In particular, the hs-cTnT cutoff of 0.016 MUg/L enables identification of low-risk patients. PMID- 22100807 TI - Next steps in cardiovascular disease genomic research--sequencing, epigenetics, and transcriptomics. AB - BACKGROUND: Genomic research in cardiovascular disease (CVD) has progressed rapidly over the last 5 years. In most cases, however, these groundbreaking observations have not yet been accompanied by clinically applicable tools for risk prediction, diagnosis, or therapeutic interventions. CONTENT: We reviewed the scientific literature published in English for novel methods and promising genomic targets that would permit large-scale screening and follow-up of recent genomic findings for CVD. We anticipate that advances in 3 key areas will be critical for the success of these projects. First, exome-centered and whole genome next-generation sequencing will identify rare and novel genetic variants associated with CVD and its risk factors. Improvements in methods will also greatly advance the field of epigenetics and gene expression in humans. Second, research is increasingly acknowledging that static DNA sequence variation explains only a fraction of the inherited phenotype. Therefore, we expect that multiple epigenetic and gene expression signatures will be related to CVD in experimental and clinical settings. Leveraging existing large-scale consortia and clinical biobanks in combination with electronic health records holds promise for integrating epidemiological and clinical genomics data. Finally, a systems biology approach will be needed to integrate the accumulated multidimensional data. SUMMARY: Novel methods in sequencing, epigenetics, and transcriptomics, plus unprecedented large-scale cooperative efforts, promise to generate insights into the complexity of CVD. The rapid accumulation and integration of knowledge will shed light on a considerable proportion of the missing heritability for CVD. PMID- 22100808 TI - Influence of population selection on the 99th percentile reference value for cardiac troponin assays. AB - OBJECTIVE: We sought to determine the effect of patient selection on the 99th reference percentile of 2 sensitive and 1 high-sensitivity (hs) cardiac troponin assays in a well-defined reference population. METHODS: Individuals>45 years old were randomly selected from 7 representative local community practices. Detailed information regarding the participants was collected via questionnaires. The healthy reference population was defined as individuals who had no history of vascular disease, hypertension, or heavy alcohol intake; were not receiving cardiac medication; and had blood pressure<140/90 mmHg, fasting blood glucose<110 mg/dL (approximately 6 mmol/L), estimated creatinine clearance>60 mL.min( 1).(1.73 m2)(-1), and normal cardiac function according to results of echocardiography. Samples were stored at -70 degrees C until analysis for cardiac troponin I (cTnI) and cardiac troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide. RESULTS: Application of progressively more stringent population selection strategies to the initial baseline population of 545 participants until the only individuals who remained were completely healthy according to the study criteria reduced the number of outliers seen and led to a progressive decrease in the 99th-percentile value obtained for the Roche hs-cTnT assay and the sensitive Beckman cTnI assay but not for the sensitive Siemens Ultra cTnI assay. Furthermore, a sex difference found in the baseline population for the hs-cTnT (P=0.0018) and Beckman cTnI assays (P<0.0001) progressively decreased with more stringent population selection criteria. CONCLUSIONS: The reference population selection strategy significantly influenced the 99th percentile reference values determined for troponin assays and the observed sex differences in troponin concentrations. PMID- 22100809 TI - Regulation of miR-200c by nuclear receptors PPARalpha, LRH-1 and SHP. AB - We investigated regulation of miR-200c expression by nuclear receptors. Ectopic expression of miR-200c inhibited MHCC97H cell migration, which was abrogated by the synergistic effects of PPARalpha and LRH-1 siRNAs. The expression of miR-200c was decreased by PPARalpha/LRH-1 siRNAs and increased by SHP siRNAs, and overexpression of the receptors reversed the effects of their respective siRNAs. SHP siRNAs also drastically enhanced the ability of the LRH-1 agonist RJW100 to induce miR-200c and downregulate ZEB1 and ZEB2 proteins. Co-expression of PPARalpha and LRH-1 moderately transactivated the miR-200c promoter, which was repressed by SHP co-expression. RJW100 caused strong activation of the miR-200c promoter. This is the first report to demonstrate that miR-200c expression is controlled by nuclear receptors. PMID- 22100810 TI - Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage. AB - The expansion of a CAG trinucleotide repeat (TNR) sequence has been linked to several neurological disorders, for example, Huntington's disease (HD). In HD, healthy individuals have 5-35 CAG repeats. Those with 36-39 repeats have the premutation allele, which is known to be prone to expansion. In the disease state, greater than 40 repeats are present. Interestingly, the formation of non-B DNA conformations by the TNR sequence is proposed to contribute to the expansion. Here we provide the first structural and thermodynamic analysis of a premutation length TNR sequence. Using chemical probes of nucleobase accessibility, we found that similar to (CAG)(10), the premutation length sequence (CAG)(36) forms a stem loop hairpin and contains a hot spot for DNA damage. Additionally, calorimetric analysis of a series of (CAG)(n) sequences, that includes repeat tracts in both the healthy and premutation ranges, reveal that thermodynamic stability increases linearly with the number of repeats. Based on these data, we propose that while non-B conformations can be formed by TNR tracts found in both the healthy and premutation allele, only sequences containing at least 36 repeats have sufficient thermodynamic stability to contribute to expansion. PMID- 22100811 TI - A novel mechanism for an old drug: amphotericin B in the treatment of visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is caused by various species of the genus Leishmania. Internalization of Leishmania into host cells is facilitated by a large number of receptors, and therefore no panacea is available for the treatment of leishmaniasis. We previously demonstrated the requirement of host membrane cholesterol in the entry of Leishmania into macrophages by cholesterol depletion using methyl-beta-cyclodextrin (MbetaCD). We recently showed that leishmanial infection is inhibited upon sequestration of host membrane cholesterol using amphotericin B (AmB), considered as the best existing drug against VL. The reason for the antileishmanial activity of AmB is generally believed to be its ability to bind ergosterol in parasite membranes. Our recent results offer the opportunity to reexamine the mechanism behind the effectiveness of current AmB based therapeutic strategies to treat leishmaniasis. We propose here a novel mechanism in which the effectiveness of AmB treatment could be partly based on its ability to sequester cholesterol in the host membrane, thereby abrogating macrophage-parasite interaction. PMID- 22100812 TI - Newly identified essential amino acid residues affecting Delta8-sphingolipid desaturase activity revealed by site-directed mutagenesis. AB - In order to identify amino acid residues crucial for the enzymatic activity of Delta(8)-sphingolipid desaturases, a sequence comparison was performed among Delta(8)-sphingolipid desaturases and Delta(6)-fatty acid desaturases from various plants. In addition to the known conserved cytb(5) (cytochrome b(5)) HPGG motif and three conserved histidine boxes, they share additional 15 completely conserved residues. A series of site-directed mutants were generated using our previously isolated Delta(8)-sphingolipid desaturase gene from Brassica rapa to evaluate the importance of these residues to the enzyme function. The mutants were functionally characterized by heterologous expression in yeast, allowing the identification of the products of the enzymes. The results revealed that residues H63, N203, D208, D210, and G368 were obligatorily required for the enzymatic activity, and substitution of the residues F59, W190, W345, L369 and Q372 markedly decreased the enzyme activity. Among them, replacement of the residues W190, L369 and Q372 also has significant influence on the ratio of the two enzyme products. Information obtained in this work provides the molecular basis for the Delta(8)-sphingolipid desaturase activity and aids in our understanding of the structure-function relationships of the membrane-bound desaturases. PMID- 22100813 TI - Structural properties of 6 forearm ligaments. AB - PURPOSE: To first determine the structural properties of 6 forearm ligaments and then to create linear and nonlinear analytical models of each ligament from these properties. METHODS: We nondestructively tested the annular ligament, dorsal and palmar radioulnar ligaments, and the distal, central, and proximal bands of the interosseous ligament from 7 fresh cadaver forearms in a servohydraulic testing apparatus. We performed testing with the bone-ligament-bone constructs positioned corresponding to neutral forearm rotation as well as in 45 degrees of supination and 45 degrees of pronation. Based on a mechanical creep test of each ligament, we computed a linear and nonlinear ligament stiffness value for each ligament. We then compared these computed analytical responses to loading with loading data when each ligament was tested at 1.0 and 0.05 mm/s. We analyzed differences among ligaments and forearm positions using 1-way and 2-way analyses of variance. RESULTS: The stiffnesses for the distal band and the dorsal radioulnar ligament were statistically less when the constructs were positioned in supination compared with neutral forearm rotation. At all forearm positions, the linear stiffness of the central band was greater than that for the distal band of the interosseous ligament, the proximal band of the interosseous ligament, and the dorsal radioulnar and palmar radioulnar ligaments. In neutral forearm rotation, the linear stiffness of the central band was statistically greater than the annular ligament. The experimental loading behavior of each ligament was better modeled by a nonlinear stiffness than a linear one. CONCLUSIONS: The central band of the interosseous membrane is the stiffest stabilizing structure of the forearm. Any structure used to replace the central band or other forearm ligaments should demonstrate a nonlinear response to loading. CLINICAL RELEVANCE: In considering a reconstruction for the forearm, the graft used should have a nonlinear response to loading and be one that is similar to the normal, original ligament. PMID- 22100814 TI - Co-learning analysis of two perceptual learning tasks with identical input stimuli supports the reweighting hypothesis. AB - Perceptual learning, even when it exhibits significant specificity to basic stimulus features such as retinal location or spatial frequency, may cause discrimination performance to improve either through enhancement of early sensory representations or through selective re-weighting of connections from the sensory representations to specific responses, or both. For most experiments in the literature, the two forms of plasticity make similar predictions (Dosher & Lu, 2009; Petrov, Dosher, & Lu, 2005). The strongest test of the two hypotheses must use training and transfer tasks that rely on the same sensory representation with different task-dependent decision structures. If training changes sensory representations, transfer (or interference) must occur since the (changed) sensory representations are common. If instead training re-weights a separate set of task connections to decision, then performance in the two tasks may still be independent. Here, we performed a co-learning analysis of two perceptual learning tasks based on identical input stimuli, following a very interesting study of Fahle and Morgan (1996) who used nearly identical input stimuli (a three dot pattern) in training bisection and vernier tasks. Two important modifications were made: (1) identical input stimuli were used in the two tasks, and (2) subjects practiced both tasks in multiple alternating blocks (800 trials/block). Two groups of subjects with counter-balanced order of training participated in the experiments. We found significant and independent learning of the two tasks. The pattern of results is consistent with the reweighting hypothesis of perceptual learning. PMID- 22100815 TI - Total ocular, anterior corneal and lenticular higher order aberrations in hyperopic, myopic and emmetropic eyes. AB - Total ocular higher order aberrations and corneal topography of myopic, emmetropic and hyperopic eyes of 675 adolescents (16.9 +/- 0.7 years) were measured after cycloplegia using COAS aberrometer and Medmont videokeratoscope. Corneal higher order aberrations were computed from the corneal topography maps and lenticular (internal) higher order aberrations derived by subtraction of corneal aberrations from total ocular aberrations. Aberrations were measured for a pupil diameter of 5mm. Multivariate analysis of variance followed by multiple regression analysis found significant difference in the fourth order aberrations (SA RMS, primary spherical aberration coefficient) between the refractive error groups. Hyperopic eyes (+0.083 +/- 0.05 MUm) had more positive total ocular primary spherical aberration compared to emmetropic (+0.036 +/- 0.04 MUm) and myopic eyes (low myopia=+0.038 +/- 0.05 MUm, moderate myopia=+0.026 +/- 0.06 MUm) (p<0.05). No difference was observed for the anterior corneal spherical aberration. Significantly less negative lenticular spherical aberration was observed for the hyperopic eyes (-0.038 +/- 0.05 MUm) than myopic (low myopia= 0.088 +/- 0.04 MUm, moderate myopia=-0.095 +/- 0.05 MUm) and emmetropic eyes ( 0.081 +/- 0.04 MUm) (p<0.05). These findings suggest the existence of differences in the characteristics of the crystalline lens (asphericity, curvature and gradient refractive index) of hyperopic eyes versus other eyes. PMID- 22100816 TI - Collision avoidance in persons with homonymous visual field defects under virtual reality conditions. AB - The aim of the present study was to examine the effect of homonymous visual field defects (HVFDs) on collision avoidance of dynamic obstacles at an intersection under virtual reality (VR) conditions. Overall performance was quantitatively assessed as the number of collisions at a virtual intersection at two difficulty levels. HVFDs were assessed by binocular semi-automated kinetic perimetry within the 90 degrees visual field, stimulus III4e and the area of sparing within the affected hemifield (A-SPAR in deg(2)) was calculated. The effect of A-SPAR, age, gender, side of brain lesion, time since brain lesion and presence of macular sparing on the number of collisions, as well as performance over time were investigated. Thirty patients (10 female, 20 male, age range: 19-71 years) with HVFDs due to unilateral vascular brain lesions and 30 group-age-matched subjects with normal visual fields were examined. The mean number of collisions was higher for patients and in the more difficult level they experienced more collisions with vehicles approaching from the blind side than the seeing side. Lower A-SPAR and increasing age were associated with decreasing performance. However, in agreement with previous studies, wide variability in performance among patients with identical visual field defects was observed and performance of some patients was similar to that of normal subjects. Both patients and healthy subjects displayed equal improvement of performance over time in the more difficult level. In conclusion, our results suggest that visual-field related parameters per se are inadequate in predicting successful collision avoidance. Individualized approaches which also consider compensatory strategies by means of eye and head movements should be introduced. PMID- 22100817 TI - Spatial characteristics of motion-sensitive mechanisms change with age and stimulus spatial frequency. AB - Contrast-dependent interactions between classical (CRF) and non-classical regions (nCRF) of visual neuron receptive fields are well documented in primate visual cortex. Physiological models that describe CRF and nCRF interactions in single neurons have recently been applied to psychophysical measures of spatial summation and suppression in motion perception of young adults (Tadin & Lappin, 2005). We wished to determine whether such models could account for the reduction in spatial suppression that occurs in normal aging (Betts et al., 2005). We applied three models to duration thresholds obtained in a simple motion discrimination task using drifting Gabor stimuli that ranged in spatial frequency from 0.5 to 4c/deg. We found that a model in which the center CRF and surrounding nCRF are represented as spatially-overlapping excitatory and inhibitory 2D Gaussians with independent contrast response functions, which we call the Gain model, could account for the effects of aging simply by increasing the spatial extent of the CRF. Two additional models were evaluated. The Size model, which varied the size of the CRF as a function of contrast, produced CRF and nCRF size constants that departed significantly from physiological estimates of receptive field sizes. The Drive model, which yoked the activation of the suppressive nCRF to the CRF response, yielded reasonable fits to the data and suggested an age related decline in the strength of suppression from the nCRF. However, the Drive model estimated the CRF size parameter to be equal to, or even slightly larger than, the nCRF size parameter, which is inconsistent with the physiological literature. Our findings therefore suggest that the Gain model provides the most plausible estimates of receptive field sizes. Based on this model, age-related increases in the size of central excitatory receptive fields relative to the inhibitory surrounds may contribute to behavioral measures of reduced spatial suppression found in older observers. PMID- 22100818 TI - Grant writing: tips and pointers from a personal perspective. PMID- 22100819 TI - Quantifying human eosinophils using three-dimensional volumetric images collected with multiphoton fluorescence microscopy. PMID- 22100820 TI - Allosteric interactions and proton conducting pathways in proton pumping aa(3) oxidases: heme a as a key coupling element. AB - In this paper allosteric interactions in protonmotive heme aa(3) terminal oxidases of the respiratory chain are dealt with. The different lines of evidence supporting the key role of H(+)/e(-) coupling (redox Bohr effect) at the low spin heme a in the proton pump of the bovine oxidase are summarized. Results are presented showing that the I-R54M mutation in P. denitrificans aa(3) oxidase, which decreases by more than 200mV the E(m) of heme a, inhibits proton pumping. Mutational amino acid replacement in proton channels, at the negative (N) side of membrane-inserted prokaryotic aa(3) oxidases, as well as Zn(2+) binding at this site in the bovine oxidase, uncouples proton pumping. This effect appears to result from alteration of the structural/functional device, closer to the positive, opposite (P) surface, which separates pumped protons from those consumed in the reduction of O(2) to 2 H(2)O. PMID- 22100821 TI - Increased anaesthetic workload associated with increased maternal age. PMID- 22100822 TI - Reduction in spinal-induced hypotension with ondansetron in parturients undergoing caesarean section: a double-blind randomised, placebo-controlled study. AB - BACKGROUND: Subarachnoid block is the preferred method of anaesthesia for caesarean section, but is associated with hypotension and bradycardia, which may be deleterious to both parturient and baby. Animal studies suggest that in the presence of decreased blood volume, 5-HT may be an important factor inducing the Bezold Jarisch reflex via 5-HT3 receptors located in intracardiac vagal nerve endings. In this study, we evaluated the effect of ondansetron, as a 5-HT3 receptor antagonist, on the haemodynamic response following subarachnoid block in parturients undergoing elective caesarean section. METHODS: Fifty-two parturients scheduled for elective caesarean section were randomly allocated into two groups. Before induction of spinal anaesthesia Group O (n=26) received intravenous ondansetron 4 mg; Group S (n=26) received normal saline. Blood pressure, heart rate and vasopressor requirements were assessed. RESULTS: Decreases in mean arterial pressure were significantly lower in Group O than Group S from 14 min until 35 min. Patients in Group O required significantly less vasopressor (P=0.009) and had significantly lower incidences of nausea and vomiting (P=0.049). CONCLUSION: Ondansetron 4 mg, given intravenously 5 min before subarachnoid block reduced hypotension and vasopressor use in parturients undergoing elective caesarean section. PMID- 22100823 TI - Intrathecal fentanyl added to bupivacaine and morphine for cesarean delivery may induce a subtle acute opioid tolerance. AB - BACKGROUND: Previous studies have demonstrated that the addition of intrathecal fentanyl to a spinal anesthetic for cesarean delivery improves intraoperative analgesia. However, intrathecal fentanyl may induce acute tolerance to opioids. The objective of this study was to investigate whether the addition of intrathecal fentanyl to spinal anesthesia with intrathecal morphine increases postoperative analgesic requirements and pain scores. METHODS: In this randomized, double-blinded study, 40 women having elective cesarean delivery were enrolled. Patients received spinal anesthesia with hyperbaric bupivacaine 12 mg, morphine 200 MUg, and fentanyl 0, 5, 10 or 25 MUg. Each patient received intravenous patient-controlled analgesia morphine for 24h postoperatively. Outcome measures included postoperative morphine usage and pain scores, as well as intraoperative pain, nausea, hypotension and vasopressor use. RESULTS: Total morphine use over the 24-h post-spinal study period was similar among the study groups (P=0.129). Postoperative pain scores were higher in patients receiving fentanyl 5, 10 and 25 MUg compared to fentanyl 0 MUg control group (P=0.003). CONCLUSIONS: The study results suggest that intrathecal fentanyl may induce acute tolerance to intrathecal morphine. However, because there was no difference in postoperative analgesia requirement and the difference in pain scores was small, the clinical significance of this finding is uncertain. PMID- 22100824 TI - Molecular phylogeny of the New World bloodfeeding leeches of the genus Haementeria and reconsideration of the biannulate genus Oligobdella. AB - The phylogenetic relationships of species of the New World bloodfeeding genus Haementeria were investigated for the first time. The analysis included five molecular markers. The mitochondrial COI, 12S and ND1 as well as the nuclear 28S and ITS. The evolutionary history of the group was investigated through Maximum Parsimony and Bayesian Inference. Both phylogenetic methods resulted in highly congruent hypotheses. The correlation between the phylogeny and morphological traits such as eyespot number, annulation, Lang's organs, salivary glands, bacteriomes and reproductive organs is discussed. Restricted to Haementeria are Lang's organs, spherical bacteriomes and ovaries forming an anterior ring around the ventral nerve cord. In addition, Oligobdella brasilensis was formally transferred to Haementeria, providing additional arguments for the disposal of the genus Oligobdella. Haementeria gracilis is shown to be just a junior synonym of Haementeria depressa as suggested by previous authors. Finally, the geographical distribution of species of Haementeria was compared with that of other non-leech and leech taxa. Multiple events of South-North American interchange were proposed to explain the current geographical distribution of the species of Haementeria. PMID- 22100825 TI - Dating cryptodiran nodes: origin and diversification of the turtle superfamily Testudinoidea. AB - The superfamily Testudinoidea is the most diverse and widely distributed clade of extant turtles. Surprisingly, despite an extensive fossil record, and increasing amount of molecular data available, the temporal origin of this group is still largely unknown. To address this issue, we used a comprehensive molecular dataset to perform phylogenetic and molecular dating analyses, as well as seven fossil constraints to calibrate the ages of the nodes in the phylogeny. The molecular dataset includes the complete mitochondrial genomes of 37 turtle species, including newly sequenced mitochondrial genomes of Phrynops hilarii, Emys orbicularis, Rhinoclemmys punctularia, and Chelonoidis nigra, and four nuclear markers. Our results revealed that the earliest divergences within crown testudinoids occurred around 95.0 Mya, in the early Late Cretaceous, earlier than previously reported, raising new questions about the historical biogeography of this group. PMID- 22100826 TI - The frog trefoil factor Bm-TFF2 activates human platelets via Gq and G12/13 signaling pathway. AB - Bm-TFF2 is an amphibian trefoil factor purified from the Bombina maxima skin secretion that is highly toxic to mammals. We previously reported that Bm-TFF2 activates human platelets via protease-activated receptor 1. In this study, for a better understanding of platelet activation induced by Bm-TFF2, we used affinity chromatography and pharmacological inhibitors to investigate the downstream signaling pathway. Using Bm-TFF2-affinity chromatography, Gq was specifically eluted from the Bm-TFF2-coulped column. Pharmacological inhibitors such as U73122, Xestospongin C, BAPTA-AM and Go6976 can significantly inhibit Bm-TFF2 induced platelet aggregation. These results suggested that Gq activation and the downstream PLCbeta-IP3 receptor-cytoplasmic Ca(2+)-PKC signaling pathway is crucial for Bm-TFF2 to stimulate platelet aggregation. Furthermore, Bm-TFF2 induced strong platelet shape change at the concentrations of 5nM, in which the Ca(2+) mobilization of the platelets stimulated was not detectable. The p160(ROCK) inhibitorY27632 totally inhibited the shape change, indicating that Bm TFF2 may activate the G12/13 pathway which leads to the activation of RhoA p160(ROCK). In conclusion, Bm-TFF2 induced platelet activation mainly via the Gq and G12/13 signaling pathway. This study on the signaling pathway of Bm-TFF2 stimulation may help us understand the toxicity of B. maxima skin secretion to the human platelets. PMID- 22100827 TI - Balloon test occlusion with the Doppler velocity guidewire. AB - Transcranial Doppler ultrasonography is the most commonly used method of cerebrovascular blood flow velocity measurement, but it is subject to certain technical and anatomic limitations. The Doppler velocity guidewire measures blood flow velocity within any vessel during cerebral angiography, overcoming these limitations. We report the first use of this guidewire in the measurement of blood flow velocity during balloon test occlusion, with results similar to simultaneously measured transcranial Doppler ultrasonography. Velocity measurement by Doppler guidewire could be useful in balloon test occlusion for vertebrobasilar circulation, where transcranial Doppler ultrasonography is limited, and provide anatomically specific blood flow velocity measurements in the diagnosis and treatment of stroke and other cerebrovascular diseases. PMID- 22100828 TI - Anemia is associated with poor outcomes in patients with less severe ischemic stroke. AB - Anemia is a known predictor of in-hospital mortality among patients with such vascular conditions as acute myocardial infarction, congestive heart failure, and chronic kidney disease. The role of anemia in patients with acute ischemic stroke is less well understood. We sought to examine the association between anemia at hospital admission and the combined outcome of in-hospital mortality and discharge to hospice in patients with acute ischemic stroke. We evaluated data from a retrospective cohort of consecutive ischemic stroke patients presenting within 48 hours of symptom onset at 5 hospitals between 1998 and 2003. Anemia was defined as an admission hematocrit value of <30%. Less severe stroke was defined as an admission National Institutes of Health Stroke Scale score of <10. The outcome was the combined endpoint of in-hospital mortality or discharge to hospice. Among 1306 patients with stroke, anemia was present on admission in 6.4%, and the combined outcome of death or discharge to hospice was present in 10.1%. Anemia was not associated with outcome in patients with severe stroke (anemia, 17.2% [5 of 29] vs no anemia, 28,4% [98 of 345]; P = .20), but was associated with outcome in patients with less severe stroke (anemia, 13.0% [7 of 54] vs no anemia, 2.5% [22 of 878]; P < .0001). After adjustment for stroke severity, admission anemia was independently associated with outcome in patients with less severe stroke (adjusted odds ratio, 4.17; 95% confidence interval, 1.47 11.90), but not in patients with more severe strokes (adjusted odds ratio, 0.82; 95% confidence interval, 0.30-2.22). Our data indicate that anemia is associated with in-hospital mortality or discharge to hospice in patients with less severe ischemic stroke. PMID- 22100829 TI - Factor V leiden and ischemic stroke risk: the Genetics of Early Onset Stroke (GEOS) study. AB - BACKGROUND: Factor V Leiden (FVL) has been associated with ischemic stroke in children but not in adults. Although the FVL mutation is associated with increased risk for venous thrombosis, its association with ischemic stroke in young adults remains uncertain. Therefore, we examined the association between FVL and ischemic stroke in participants of the Genetics of Early Onset Stroke (GEOS) study. METHODS: A population-based case control study identified 354 women and 476 men 15 to 49 years of age with first-ever ischemic stroke and 907 controls. Participant-specific data included vascular risk factors, FVL genotype and, for cases, the ischemic stroke subtype by modified Trial of ORG 10172 in Acute Stroke criteria. Logistic regression was used to calculate odds ratios for the entire population and for subgroups stratified by risk factors and ischemic stroke subtype. RESULTS: The frequency of the FVL mutation was similar between ischemic stroke patients (3.6%; 95% confidence interval [CI] 2.5%-5.1%) and nonstroke controls (3.8%; 95% CI 2.7%-5.2%). This frequency did not change significantly when cases were restricted to patients with stroke of undetermined etiology (4.1%; 95% CI 2.6%-6.4%). CONCLUSIONS: Among young adults, we found no evidence for an association between FVL and either all ischemic stroke or the subgroup with stroke of undetermined etiology. PMID- 22100830 TI - Developmental studies on the Sigma and Delta-1 glutathione transferases of Lucilia cuprina. AB - The glutathione transferases (GSTs) are a large group of enzymes having both detoxication roles and specialist metabolic functions. The present work represents an initial approach to identifying some of these roles by examining the variation of specific members of the family under differing conditions. The GSTs from Lucilia cuprina have been partially purified, members of two families being isolated, by the use of glutathione immobilised on epichlorhydrin-activated Sepharose 6B. The GSTs were separated by 2D SDS-PAGE and characterised by MALDI TOF analysis of tryptic peptides. The mass fragments were then matched against the corresponding Drosophila melanogaster and Musca domestica sequences. GSTs were identified as coming from only the Sigma and Delta classes. The multiple Delta zones appear all to be derived from the Lucilia GSTD1 isoform. The distribution of these GST proteins has been studied during different developmental stages of the insect. Delta isoforms were present in all developmental stages of L. cuprina. The Sigma GST was not detectable in the egg, was just detectable in the larval and pupal stages and was the major GST isolated in the adult. Sigma and Delta isoforms were both found in all body segments of the insect. Both isoforms appear to undergo extensive post-translational modification. Activities of the two types of protein with model substrates have been determined. PMID- 22100831 TI - Introduction to Special Section on HIV/AIDS and Substance Use in the Caribbean (Part 2): The Influence of Mobility and Environmental Conditions. PMID- 22100832 TI - Carotid intima media thickness is related positively to plasma pre beta-high density lipoproteins in non-diabetic subjects. AB - BACKGROUND: Lipid-poor or lipid-free high density lipoprotein (HDL) particles, designated pre beta-HDL, stimulate removal of cell-derived cholesterol to the extracellular compartment, which is an initial step in the reverse cholesterol transport pathway. Pre beta-HDL levels may be elevated in subjects with established cardiovascular disease. We determined the relationship of carotid intima media thickness (IMT), a marker of subclinical atherosclerosis, with pre beta-HDL in subjects without clinically manifest cardiovascular disease. METHODS: IMT and plasma pre beta-HDL, assayed by crossed immuno-electrophoresis, were determined in 70 non-diabetic subjects (aged 56+/-9 years; non-smokers only; 27 women). RESULTS: IMT was correlated positively with pre beta-HDL, both expressed as plasma apolipoprotein (apo) A-I concentration (r=0.271, p=0.023) and as% of apo A-I (r=0.341, p=0.004). In contrast, IMT was correlated inversely with HDL cholesterol (r=-0.253, p=0.035). IMT was also related positively to pre beta-HDL after adjustment for age, sex, systolic blood pressure (in apoA-I concentration, beta=0.203, p=0.043; in% of plasma apoA-I, beta=0.235, p=0.023). IMT remained associated with pre beta-HDL after additional adjustment for either body mass index, plasma glucose, cholesterol, triglycerides, HDL cholesterol, apoA-I and apoB. CONCLUSION: Subclinical atherosclerosis may relate to higher plasma pre beta-HDL independently of apoA-I and HDL cholesterol levels. PMID- 22100833 TI - The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity. AB - The indigenous microbiota impact mucosal, as well as systemic, immune responses, but whether the microbiota are involved in stressor-induced immunomodulation has not been thoroughly tested. A well characterized murine stressor, called social disruption (SDR), was used to study whether the microbiota are involved in stressor-induced enhancement of macrophage reactivity. Exposure to the SDR Stressor enhanced the ability of splenic macrophages to produce microbicidal mediators (e.g., inducible nitric oxide synthase (iNOS), superoxide anion, and peroxynitrite) and to kill target Escherichia coli. Exposure to the SDR Stressor also increased cytokine production by LPS-stimulated splenic macrophages. These effects, however, were impacted by the microbiota. Microbicidal activity and cytokine mRNA in splenic macrophages from Swiss Webster germfree mice that lack any commensal microbiota were not enhanced by exposure to the SDR Stressor. However, when germfree mice were conventionalized by colonizing them with microbiota from CD1 conventional donor mice, exposure to the SDR Stressor again increased microbicidal activity and cytokine mRNA. In follow-up experiments, immunocompetent conventional CD1 mice were treated with a cocktail of antibiotics to disrupt the intestinal microbiota. While exposure to the SDR Stressor-enhanced splenic macrophage microbicidal activity and cytokine production in vehicle treated mice, treatment with antibiotics attenuated the SDR Stressor-induced increases in splenic macrophage reactivity. Treatment with antibiotics also prevented the stressor-induced increase in circulating levels of bacterial peptidoglycan, suggesting that translocation of microbiota-derived peptidoglycan into the body primes the innate immune system for enhanced activity. This study demonstrates that the microbiota play a crucial role in stressor-induced immunoenhancement. PMID- 22100834 TI - Sign-dependent changes in retinal electrical activity with positive and negative defocus in the human eye. AB - The purpose of this study was to investigate the effect of optical defocus on changes of electrical response as a function of retinal region. Twenty-three subjects (aged 19-25 year) with normal ocular health were recruited for global flash multifocal electroretinogram (mfERG) recordings under control (fully corrected) condition, and short-term positive defocus (+2D and +4D) and negative defocus (-2D and -4D) conditions. The amplitudes and implicit times of direct (DC) and induced (IC) components of mfERG responses were pooled into six concentric rings for analyses. The mfERG responses demonstrated more significant changes in amplitude in paracentral retinal regions than in the central regions under defocused conditions. The paracentral DC amplitude showed a significant reduction under negative defocus conditions. In contrast, the paracentral IC amplitude showed a significant increment under positive defocus conditions. Interestingly, the central IC response showed significant reduction in amplitude only to negative defocus, while increasing its amplitude to positive defocus. However, the DC and IC implicit times were virtually unaffected under defocused conditions. Our findings suggest that human retina is able to differentiate defocused signals and to identify positive and negative defocus. It shows that paracentral retina reacts more vigorously to optical defocus than does central retina. PMID- 22100835 TI - Gaussian wavelet transform and classifier to reliably estimate latency of multifocal visual evoked potentials (mfVEP). AB - This paper describes a method to reliably estimate latency of multifocal visual evoked potential (mfVEP) and a classifier to automatically separate reliable mfVEP traces from noisy traces. We also investigated which mfVEP peaks have reproducible latency across recording sessions. The proposed method performs cross-correlation between mfVEP traces and second order Gaussian wavelet kernels and measures the timing of the resulting peaks. These peak times offset by the wavelet kernel's peak time represents the mfVEP latency. The classifier algorithm performs an exhaustive series of leave-one-out classifications to find the champion mfVEP features which are most frequently selected to infer reliable traces from noisy traces. Monopolar mfVEP recording was performed on 10 subjects using the Accumap1TM system. Pattern-reversal protocol was used with 24 sectors and eccentricity upto 33 degrees . A bipolar channel was recorded at midline with electrodes placed above and below the inion. The largest mfVEP peak and the immediate peak prior had the smallest latency variability across recording sessions, about +/-2ms. The optimal classifier selected three champion features, namely, signal-to-noise ratio, the signal's peak magnitude response from 5 to 15Hz and the peak-to-peak amplitude of the trace between 70 and 250 ms. The classifier algorithm can separate reliable and noisy traces with a high success rate, typically 93%. PMID- 22100836 TI - Compositional analysis and in vivo anti-diabetic activity of wild Algerian Marrubium vulgare L. infusion. AB - Marrubium vulgare (Lamiaceae) is a plant traditionally used for the treatment of diabetes in Algeria. Compositional analysis of the aqueous infusion revealed the presence of fifteen metabolites, all belonging to the class of polyphenols. Particularly, seven flavonoids have been detected, together with 5-caffeoylquinic (chlorogenic) acid in small amounts; the extract is dominated by the presence of a series of complex molecules, characterized as verbascoside (acteoside) derivatives. Concerning the anti-diabetic effectiveness a series of in vivo experiments were carried out on albinos Wistar rats. Diabetes was induced in the animals by intra-peritoneal injection of alloxane; they were treated twice a day with aqueous extract from aerial part infusion (100, 200 and 300 mg/kg body weight) and glibenclamide (5mg/kg body weight) for 15 days. Oral administration of 200 and 300 mg/kg body weight of aqueous extract the Marrubium vulgare induced an significant effect antidiabetic and antihyperlipidemic (dose-dependent effect). A decrease in blood glucose by 50% for the dose 100 mg/kg and more than 60% for doses 200 and 300 mg/kg, as well as a significant lowering of total lipids, triglycerides, and total cholesterol levels in treated animals, compared with diabetic controls group (p<0.001), have been observed. Glibenclamide was used as reference and showed similar effects. PMID- 22100837 TI - A cytotoxic 4alpha-methyl steroid from the aerial parts of Cimicifuga foetida L. AB - A new 4alpha-methyl sterol, cimisterol A (1), together with five known compounds (2-6), were isolated from the aerial parts of Cimicifuga foetida L. The new compound's structure was determined with the help of extensive 1D and 2D NMR spectroscopy. Compound 1 exhibited broad-spectrum and potent cytotoxic activities against human HL-60, Jurkat, K562, U937, HepG-2, and SGC-7091 cell lines, with IC(50) values of 7.23, 2.89, 6.88, 3.38, 4.21, and 4.89 MUM, respectively. Compound 3 showed moderate to weak activities to all cell lines, except for SGC 7091, having IC(50) values ranging from 13.37 to 17.72 MUM. This is the first time a cytotoxic 4alpha-methyl sterol constituent was discovered from Cimicifuga spp. PMID- 22100838 TI - Revision of FIGO surgical staging in 2009 for endometrial cancer validates to improve risk stratification. AB - OBJECTIVE: Correct staging is a cornerstone in cancer treatment. The FIGO surgical staging for endometrial cancer was revised in 2009. We have evaluated if the revision improved stratification with respect to prognosis in a large prospective multicenter setting. METHODS: 1268 endometrial cancer patients have been prospectively recruited in the MoMaTEC study for the investigation of clinical and histopathological data. RESULTS: Restaging from FIGO 88 to FIGO 09 criteria increased the number of stage I cases from 932 to 979. The majority of the non-endometrioid tumors, down-staged to FIGO 09 stage I, were of serous histology. One third of the patients classified as stage II tumors based on FIGO 88 criteria (FIGO88 IIA) were down-staged to FIGO 09 IA (53%) and FIGO 09 IB (47%). The histological subtype for these cases was mainly endometrioid (86.1%) and high/intermediate grade (77.7%). Patients with FIGO 88 stages IA, IB, IIA and IIIA with positive cytology only, showed similar survival. In Cox multivariate survival analysis adjusting for histopathological variables we found that the revised FIGO 09 criteria improved prognostication. For FIGO stage I patients the adjusted HR was 3.9 (p=0.01, CI 1.35-11.36) for FIGO IB compared to FIGO IA. The independent prognostic impact for the FIGO 09 staging was also confirmed in a subset analysis of patients not subjected to lymphadenectomy and for the endometrioid subgroup. CONCLUSIONS: The FIGO 2009 staging system has improved prediction of prognosis, and is less complex, compared to earlier versions. Careful assessment of myometrial invasion seems particularly important for patients not subjected to lymphadenectomy. PMID- 22100839 TI - Distribution of MICA haplotypes in a Chinese Han population. AB - The MICA gene encodes nonclassical major histocompatibility complex class I molecules, centromeric to HLA-B and telomeric to HLA-DRB1. The MICA genes are polymorphic. The immune response against MICA may correlate with a decrease in graft survival after transplantation. However, data on the frequency of MICA polymorphisms in different populations are limited. In this study, we determined MICA allelic frequencies in a Han population living in Guangdong Province in south China. A total of 15 MICA alleles were identified using sequence-based typing. The most frequent allele was MICA*010 (22.22%), followed by MICA*002:01(18.56%), MICA*008:01(16.32%), and MICA*019(14.93%). The MICA null gene (MICA*Del) exhibited a frequency of 1.743% in this population. MICA and HLA, MICA-HLA-B, and MICA-HLA-A/HLA-B/HLA-DRB1 haplotype frequencies were estimated. The most common 2-, 3- and 4-locus haplotypes were HLA-B*40:01-MICA*008:01 (13.70%), HLA-A*11:01-B*40:01-MICA*008:01(8.25%), and HLA-A*33:03-B*58:01 DRB1*03:01-MICA*002:01(5.22%). A new MICA allele, MICA*061, was identified and appears to be evolutionarily related to MICA*012:01. This study provides high resolution information on the distribution of haplotypes with MICA, HLA-A, HLA-B, and HLA-DRB1 in China. This information should help determine the mechanisms underlying diseases and allotransplant rejection associated with MICA polymorphisms in the southern Chinese Han population. PMID- 22100840 TI - Combined stimulation of glucagon-like peptide-1 receptor and inhibition of cannabinoid CB1 receptor act synergistically to reduce food intake and body weight in the rat. AB - Pharmacological activation of the glucagon-like peptide-1 (GLP-1) receptor and inhibition of the cannabinoid CB1 receptor were found to reduce food intake and body weight in humans and animals. Since earlier studies revealed that endocannabinoids may interact with other neurotransmitters to affect feeding behavior, we have examined whether a stable GLP-1 agonist, exendin-4 and a CB1 receptor antagonist, AM 251, may reciprocally enhance their inhibitory effects on food consumption in the rat. Additionally, we have tested whether the blockade of the GLP-1 receptor by exendin (9-39) modifies AM 251-dependent effects on energy balance. In a dose-response study, male Wistar rats were injected intraperitoneally with either 1.5-6.0 MUg/kg exendin-4, 0.5-2 mg/kg AM 251, 80 320 MUg/kg exendin (9-39) or their vehicle and the daily food and water intake as well as body weight changes were monitored two days before and two days after the injection. Exendin-4 at a dose of 3.0 and 6.0 MUg/kg and AM 251 at a dose 2 mg/kg decreased significantly 24-hour food intake and body weight. Therefore, in the next study, the effects of lower doses of exendin-4 (1.5 MUg/kg) and AM 251 (1.0 mg/kg) administered alone or together on food consumption were compared. As opposed to being injected alone, the co-administration of the two resulted in a marked decrease in both daily food intake and body weight. Exendin (9-39) did not modify the suppressory effect of the highest AM 251 dose on food consumption. Apparently, the effect of AM 251 on the appetite is not mediated by GLP-1. The concomitant stimulation of GLP-1 receptor and blockade of CB1 receptor, however, may act synergistically to inhibit appetite in the rat. PMID- 22100841 TI - Angiotensinogen and angiotensin-converting enzyme mRNA decrease and AT1 receptor mRNA and protein increase in epididymal fat tissue accompany age-induced elevation of adiposity and reductions in expression of GLUT4 and peroxisome proliferator-activated receptor (PPARgamma). AB - Elevated adiposity is one of the accompanying features of increased age in humans and animals. Angiotensin II (Ang II) is considered as growth promoting peptide to be involved in hypertrophic enlargement of adipose tissue. However, systemic renin-angiotensin system (RAS) seems to decrease with increased age of rats. Local adipose tissue RAS might be independent of the systemic one. Therefore we performed a comprehensive study using rats with increased age from 9 to 26 weeks and evaluated angiotensinogen, angiotensin-converting enzyme (ACE) and AT(1) receptor mRNA in epididymal adipose tissue by RT-PCR. In addition, we determined AT(1) receptor protein by Western blotting and Ang II binding. These RAS parameters were correlated with expression of selected adiposity-dependent proteins such as leptin, adiponectin, insulin-dependent glucose transporter (GLUT4) and PPARgamma. Angiotensinogen and ACE expression decreased with increased age and adiposity. On the contrary, AT(1) receptor mRNA and protein was significantly elevated in 26-week-old rats though the Ang II binding was not different between 9 and 26-week-old animals. These results suggest dynamic adaptation of local adipose tissue RAS components to increased age and adiposity most likely by decreasing local Ang II formation which is thereafter compensated by increased expression of AT(1) receptor. However, this increase in AT(1) receptor mRNA and protein is not reflected in increased receptor binding. We believe that this complex regulation of adipose tissue RAS slows down the negative age and adiposity related changes in adipose tissue leptin, adiponectin, GLUT4 and PPARgamma. PMID- 22100842 TI - Paramount levels of ergothioneine transporter SLC22A4 mRNA in boar seminal vesicles and cross-species analysis of ergothioneine and glutathione in seminal plasma. AB - Ergothioneine (ET) is a unique natural antioxidant which mammalia acquire exclusively from their food. Recently, we have discovered an ET transporter (ETT; gene symbol SLC22A4). The existence of a specific transporter suggests a beneficial role for ET; however, the precise physiological purpose of ET is still unclear. A conspicuous site of high extracellular ET accumulation is boar seminal plasma. Here, we have investigated whether ETT is responsible for specific accumulation of ET in the boar reproductive tract. The putative ETT from pig (ETTp) was cloned and validated by functional expression in 293 cells. The highest levels of ETTp mRNA were detected by real-time RT-PCR in seminal vesicles, eye, and kidney; much less was present in bulbourethral gland, testis, and prostate. By contrast, there was virtually no ETT mRNA in rat seminal vesicles. ET content in boar reproductive tissues, determined by LC-MS/MS, closely matched the ETT expression profile. Thus, strong and specific expression of ETTp in boar seminal vesicles explains high accumulation of ET in this gland and hence also in seminal plasma. Previous reports suggest that the glutathione (GSH) content of seminal plasma correlates directly with ET content; however, a comprehensive analysis across several species is not available. We have measured ET and GSH in seminal plasma from human, boar, bull, stallion, and rabbit by LC MS/MS. GSH levels in seminal plasma do not correlate with ET levels. This suggests that the function of ET, at least in this extracellular context, does not depend on redox cycling with GSH. PMID- 22100843 TI - Melatonin and succinate reduce rat liver mitochondrial dysfunction in diabetes. AB - Mitochondrial dysfunction and an increase in mitochondrial reactive oxygen species in response to hyperglycemia during diabetes lead to pathological consequences of hyperglycemia. The aim of the present work was to investigate the role of a specific functional damage in rat liver mitochondria during diabetes as well as to evaluate the possibility of metabolic and antioxidative correction of mitochondrial disorders by pharmacological doses of succinate and melatonin. In rat liver mitochondria, streptozotocin-induced diabetes was accompanied by marked impairments of metabolism: we observed a significant activation of alpha ketoglutarate dehydrogenase (by 60%, p<0.05) and a damage of the respiratory function. In diabetic animals, melatonin (10 mg/kg b.w., 30 days) or succinate (50 mg/kg b.w., 30 days) reversed the oxygen consumption rate V(3) and the acceptor control ratio to those in nondiabetic animals. Melatonin enhanced the inhibited activity of catalase in the cytoplasm of liver cells and prevented mitochondrial glutathione-S-transferase inhibition while succinate administration prevented alpha-ketoglutarate dehydrogenase activation. The mitochondria dysfunction associated with diabetes was partially remedied by succinate or melatonin administration. Thus, these molecules may have benefits for the treatment of diabetes. The protective mechanism may be related to improvements in mitochondrial physiology and the antioxidative status of cells. PMID- 22100844 TI - Effects of peripherally and centrally applied ghrelin in the pathogenesis of ischemia-reperfusion induced injury of the small intestine. AB - Ghrelin is an important hormone involved in the control of the human appetite center. Recently, protective properties of this hormone have been recognized in various models of impairment of the gastric mucosa, including stress, ischemia and reperfusion (I/R). Ghrelin is predominantly secreted by the gastric mucosa of stomach, but there are other sources of ghrelin, for example in the hypothalamus and various parts of the central nervous system (CNS) that should be taken into consideration. This hormone exerts biological effects via the activation of growth hormone secretagogue receptor (GHSR), the presence of which was confirmed in different parts of the gastrointestinal (GI) tract and midbrain structures. Although substantial evidence of the divergent biological effects of ghrelin and the mechanism of its action has been emphasized, the precise mechanisms of ghrelin which affords GI protection is still unclear. Particularly, there is a sparse amount of evidence concerning its action on the GI system. The major aim of the present study was to evaluate the importance of peripherally and centrally administered ghrelin at different times of the ischemia and reperfusion (I/R period in the modulation of resistance of the intestinal mucosa to the injury induced by ischemia and subsequent reperfusion. Secondly, we wanted to evaluate the possible mechanism of the action of ghrelin with a particular focus on its influence on the intestinal blood flow. Male Wistar rats were divided into 4 series (A-D) of the experimental groups (n=7). In series A the importance of peripherally administered ghrelin at different time of I/R period was studied. In series B the importance of centrally administered ghrelin at different time of I/R period was evaluated. In series C and D, the mechanisms of peripherally and centrally administered hormone were examined, respectively. Two models of the I/R period were selected: short lasting (30/60 min) and long lasting (60/120 min). The following drugs were used: ghrelin (50 MUg/kg i.p. or 1 nmol in 10 MUl i.c.v.), 6 hydroxy dopamine (50 mg/kg i.p.), nadolol (0.5 mg/kg i.p.), calcitonin gene related peptide fragment (CGRP(8-37), 100 MUg /kg i.p.), capsaicin (5-10 mg/100 ml solution s.c.). The mesenteric blood flow (MBF-ml/min), the intestinal microcirculatory blood flow (LDBF-PU), the arterio-venous oxygen difference (AVO(2)-ml/O(2)/100 ml blood), and the intestinal oxygen uptake (VO(2)) in ml O(2)/min were measured. Mucosal impairment was assessed planimetrically with the use of a digital photo analyzer (LA) and histologically with the use of the six point Park/Chiu scale. Peripheral administration of ghrelin evoked marked increase of MBF and LDBF by 42% and 48%, respectively, with significant reduction of LA by 38%. When ghrelin was administered at the beginning of the reperfusion period during the short I/R period or prior to the long lasting I/R period, the vascular reactions and protective effects were reduced, but not completely abolished. The central administration of ghrelin before the short I/R period significantly increased the MBF and LDBF by about 32% and 35%, respectively, as well as LA reduction by about 20% in comparison to the control group. However, when ghrelin was administered prior to the long I/R period or after the onset of completed ischemia, neither vascular nor protective effects were noticed. Sensory denervation and the blockade of the CGRP1 receptors totally blocked the protective and hyperemic effects of the peripherally administered ghrelin. Selective blockade of the adrenergic system or blunting of the vagal nerves (vagotomy) significantly but not totally eliminated the effects of centrally applied ghrelin, which were abolished when both adrenergic and parasympathetic pathways were ablated. These results indicate that ghrelin applied centrally or peripherally markedly increases resistance of the intestinal tissue during the I/R period induced mucosal and hyperemic impairment evoked by I/R. Ghrelin is an important mediator of the increase in the intestinal microcirculation and elevation of the intestinal metabolism, which seems to be, at least in part, responsible for the observed protection of the intestine subjected to I/R. Impairment of this microvasculature response due to I/R seems to be responsible for a markedly observed weaker effect of ghrelin when this hormone was administered after the ischemic period. The lack of a protective effect observed after central administration of this peptide against a long lasting I/R period is probably due to damage of neural pathways caused by I/R. Finally, the peripheral activity of ghrelin in the intestine is mediated by the sensory neurons with a prominent role of CGRP released from their endings. However, this peripheral action of ghrelin depends upon the proper functioning of both the sympathetic and parasympathetic system. PMID- 22100845 TI - Role of macrophage colony-stimulating factor (M-CSF)-dependent macrophages in gastric ulcer healing in mice. AB - We examined the role of macrophage colony-stimulating factor (M-CSF)-dependent macrophages in the healing of gastric ulcers in mice. Male M-CSF-deficient (op/op) and M-CSF-expressing heterozygote (+/?) mice were used. Gastric ulcers were induced by thermal cauterization under ether anesthesia, and healing was observed for 14 days after ulceration. The numbers of macrophages and microvessels in the gastric mucosa were determined immunohistochemically with anti-CD68 and anti-CD31 antibodies, respectively. Expression of tumor necrosis factor (TNF)-alpha, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF) mRNA was determined via real-time reverse transcription-polymerase chain reaction (RT-PCR), and the mucosal content of prostaglandin (PG) E(2) was determined via enzyme immunoassay on day 10 after ulceration. The healing of gastric ulcers was significantly delayed in op/op mice compared with +/? mice. Further, significantly fewer macrophages were observed in the normal gastric mucosa of op/op mice than in +/? mice. Ulcer induction caused a marked accumulation of macrophages around the ulcer base in +/? mice, but this response was attenuated in op/op mice. The mucosal PGE(2) content as well as the expression of COX-2, VEGF, and TNF-alpha mRNA were all upregulated in the ulcerated area of +/? mice but significantly suppressed in op/op mice. The degree of vascularization in the ulcerated area was significantly lower in op/op mice than in +/? mice. Taken together, these results suggest that M-CSF-dependent macrophages play an important role in the healing of gastric ulcers, and that this action may be associated with angiogenesis promoted by upregulation of COX 2/PGE(2) production. PMID- 22100846 TI - Lipid rafts mediate epigallocatechin-3-gallate- and green tea extract-dependent viability of human colon adenocarcinoma COLO 205 cells; clusterin affects lipid rafts-associated signaling pathways. AB - Epigallocatechin-3-gallate (EGCG) is an important bioactive constituent of green tea extract (GTE) that was widely believed to reduce proliferation of many cancer cell lines. The purpose of this study was to verify the possible pro-apoptotic action of GTE/EGCG in human colon adenocarcinoma COLO 205 cells. The effect of EGCG/GTE treatments on cell viability was studied using methyl thiazolyl tetrazolium (MTT) assay. Cell proliferation was assessed with crystal violet staining, whereas protein expression levels were evaluated by western blotting followed by densitometric analysis. Obtained results were analyzed statistically. Surprisingly, EGCG/GTE dose-dependently up-regulated COLO 205 cells viability and proliferation. Observed effects were mediated by lipid rafts, as cholesterol depletion significantly prevented EGCG/GTE-dependent cell survival. Furthermore, treatment of COLO 205 cells with EGCG/GTE resulted in activation of MEK/ERK1/2, but not Akt1/2/GSK-3beta signaling pathway. The presence of MEK inhibitor - PD98059 but not PI3-K inhibitor - LY294002, both reduced EGCG/GTE-induced ERK1/2 activation and the proliferative effect of catechins. Furthermore, EGCG/GTE stimulated secretory clusterin (sClu) expression level, which underwent complex control through lipid rafts/PKC/Wnt/beta-catenin system. Our studies demonstrated that EGCG and GTE stimulate cell survival and proliferation of COLO 205 cells in a lipid rafts-dependent manner via at least MEK/ERK1/2 signaling pathway. Furthermore, EGCG/GTE mediated positive effects on viability and mitogenicity of COLO 205, while suppression of beta-catenin activity was positively correlated with sClu clusterin expression. PMID- 22100847 TI - The expression of genes encoding opioid precursors and the influence of opioid receptor agonists on steroidogenesis in porcine adrenocortical cells in vitro. AB - Endogenous opioid peptides are involved in the regulation of the HPA-axis function and stress response mechanism. However, there is a scarcity of data on opioid involvement in the regulation of the adrenocortical endocrine function. This study was performed to: 1) establish the expression of proenkephalin, POMC and prodynorphin genes in the porcine adrenal cortex and test in vitro the influence of ACTH, angiotensin II, CRH and epinephrine on this expression, and 2) determine the effects of opioid receptor agonists on basal and ACTH- or angiotensin II-affected secretion of cortisol, aldosterone and progesterone by the cultured adrenocortical cells. Our experiment has demonstrated the presence of mRNAs for opioid precursors in cells isolated from the adrenal cortex and the significant effects of ACTH and angiotensin II, but not CRH or epinephrine, on adrenocortical transcription of the analyzed genes. Angiotensin II reduced the expression of the POMC gene but stimulated that of prodynorphin. In turn, ACTH decreased the transcription of prodynorphin. The study has also demonstrated the effects of selective opioid receptor agonists - DPLPE (delta), FK33-824 (mu) and U50,488 (kappa) - on adrenal steroidogenesis in pigs. Basal secretion of cortisol was enhanced after the activation of mu or kappa receptors, whereas ACTH stimulated cortisol output was increased only by the mu receptor agonist. Angiotensin II-treated cells significantly decreased aldosterone secretion in the presence of the kappa receptor agonist. The present results suggest that opioid peptides are synthesized in the porcine adrenal cortex, indicating their involvement in the regulation of adrenal steroidogenesis through autocrine and/or paracrine interactions. PMID- 22100848 TI - The measurement of leukotrienes in urine as diagnostic option in systemic mastocytosis. AB - Clinical symptoms of patients with mastocytosis may include skin reactions, but also gastrointestinal symptoms with hyperacidity and dysmotility (e.g. ulcer, diarrhea, pain). They are mostly caused by mediators derived from activated mast cells. In order to investigate the impact of leukotrienes on the clinical symptoms excretion of leukotriene B4 (LTB4) and leukotrienes C4-D4-E4 (cysteinyl leukotrienes) into urine was studied in 9 patients with indolent systemic mastocytosis divided into a group with high and low intensity of symptoms and in 11 healthy volunteers. Leukotriene excretion was determined by ELISA and correlated with methylhistamine excretion. Patients with systemic mastocytosis with high and low intense symptoms showed significantly higher urinary excretion of cysteinyl-leukotrienes than controls. There was a positive correlation of cysteinyl-leukotriene excretion and urinary methylhistamine excretion. LTB4 excretion was also significantly increased in patients with systemic mastocytosis compared to healthy volunteers. No correlation of urinary LTB4 excretion with urinary methylhistamine was observed. The present study demonstrates that urinary excretion of LTB4 and cysteinyl-leukotrienes LTC4-D4-E4 is clearly enhanced in indolent systemic mastocytosis Hence, determination of leukotriene excretion into urine can be used as a tool in the diagnostic and in the therapeutic monitoring of systemic mastocytosis. PMID- 22100849 TI - Expression of N-methyl-D-aspartate (R)(GluN2B) - subunits in the brain structures of rats selected for low and high anxiety. AB - In this paper, we studied differences in the density of N-methyl-D-aspartate (NMDA) receptor GluN2B subunits in the brains of low (LR) and high (HR) anxiety rats subjected to extinction trials and re-learning of a conditioned fear response, modeling a natural course of anxiety disorders. Classifications of animals as LR or HR was determined by fear-induced freezing responses in the contextual fear test. Increased basal concentrations of GluN2B subunits were observed in the amygdala of HR rats as compared to the unconditioned control group by Western blot analysis. Re-exposure of HR animals to the fear-conditioned context resulted in elevated concentrations of GluN2B subunits in the amygdala, hippocampus and the prefrontal cortex compared to LR rats as well as in the hippocampus and prefrontal cortex vs. the control group. In addition, it was shown that re-test of a conditioned fear increased the number of cells expressing GluN2B subunits in the basolateral amygdala, dentate gyrus of the hippocampus and secondary motor cortex (M2) in the HR group relative to the LR group. Together, these data suggest that animals that are more anxious have altered patterns of GluN2B subunit expression in the frontal cortex and limbic structures, which control emotional behaviour. PMID- 22100850 TI - Complex estrogenic regulation of catechol-O-methyltransferase (COMT) in rats. AB - Catechol-O-methyltransferase (COMT) activity depends on gender, age and physiological status suggesting that estrogen may regulate COMT activity. In fact, estrogens down-regulate the function of COMT promoters in cell cultures. On the other hand, COMT may play an important role in estrogen-induced cancers due to its ability to inactivate estrogen metabolites and thereby lowering the levels of these potential carcinogens. In this study, we explored the effect of estrogen on COMT activity in vivo in rats. Male and female Wistar rats received 14-day treatments with either estradiol (100 MUg/kg/day; s.c.) or tamoxifen (500 MUg/kg/day; s.c.), respectively; in addition ovariectomized rats were studied. COMT activity and COMT protein expression were measured from various brain- and peripheral tissues. Although we found a regulatory function of estrogen, its effects were sex and tissue dependent. Antagonizing the effects of estrogen via tamoxifen increased COMT protein expression in several central and peripheral tissues. However, amounts of COMT protein and COMT activities did not always match. Generally, COMT activities were quite resistant to the effects of tamoxifen and estradiol. Estradiol, unexpectedly, doubled the amount of COMT protein in the prostate but exhibited down-regulatory function in the prefrontal cortex and kidneys. Ovariectomy by itself, however, had only minor effects on COMT activity and expression. It is noteworthy that the estrogen down-regulation and tamoxifen up-regulation of COMT were best substantiated in the prefrontal cortex and kidneys where COMT is physiologically important for dopamine metabolism. PMID- 22100851 TI - Aspirin's ability to induce intestinal injury in rats is dependent on bile and can be reversed if pre-associated with phosphatidylcholine. AB - Clinical evidence suggests that aspirin and particularly enteric-coated aspirin induce significant injury to the lower gut. We have reported that NSAID injury to the small bowel is exacerbated by bile acids and that phosphatidylcholine (PC) can protect against this damage. Using a recently described method, we intra duodenally administered either: saline, aspirin or aspirin pre-associated with PC. The rats were euthanized 90 minutes later at which time we assessed: tissue injury morphologically, vascular permeability with i.v. administered Evan's blue and intestinal bleeding by measuring luminal hemoglobin. In a separate experiment, aspirin-induced injury was studied in rats whose bile duct was ligated either alone or in the presence of rat bile (collected from donor animals). Intra-duodenal administration of aspirin induced mucosal injury (observed histologically), an increase in vascular permeability and blood loss into the intestinal lumen, all of which could be attenuated if the NSAID was pre associated with PC. Furthermore, using 100 mg/kg dose of aspirin it was determined that bile duct ligation (BDL) significantly reduced aspirin-induced intestinal bleeding which was not different from control rats. Lastly, it was determined that intestinal bleeding was significantly increased in rats with BDL if the aspirin was administered in rodent bile. Aspirin-induced intestinal injury and bleeding in the rat is dependent on the presence of luminal bile, which is likely attributable to it's constituent bile acids. Pre-association of aspirin with PC provides a novel therapeutic approach to significantly reduce aspirin induced small intestinal injury and bleeding, as may occur with enteric-coated aspirin. PMID- 22100853 TI - One more reason to fund the Global Fund. PMID- 22100852 TI - Caveolin-1, cellular senescence and age-related diseases. AB - According to the "free radical theory" of aging, normal aging occurs as the result of tissue damages inflicted by reactive oxygen species (ROS) when ROS production exceeds the antioxidant capacity of the cell. ROS induce cellular dysfunctions such as stress-induced premature senescence (SIPS), which is believed to contribute to normal organismal aging and play a role in age-related diseases. Consistent with this hypothesis, increased oxidative damage of DNA, proteins, and lipids have been reported in aged animals and senescent cells accumulate in vivo with advancing age. Caveolin-1 acts as a scaffolding protein that concentrates and functionally regulates signaling molecules. Recently, great progress has been made toward understanding of the role of caveolin-1 in stress induced premature senescence. Data show that caveolin-mediated signaling may contribute to explain, at the molecular level, how oxidative stress promotes the deleterious effects of cellular senescence such as aging and age-related diseases. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of SIPS and their relevance to the biology of aging. PMID- 22100854 TI - Chikungunya: a re-emerging virus. AB - In the past decade, chikungunya--a virus transmitted by Aedes spp mosquitoes--has re-emerged in Africa, southern and southeastern Asia, and the Indian Ocean Islands as the cause of large outbreaks of human disease. The disease is characterised by fever, headache, myalgia, rash, and both acute and persistent arthralgia. The disease can cause severe morbidity and, since 2005, fatality. The virus is endemic to tropical regions, but the spread of Aedes albopictus into Europe and the Americas coupled with high viraemia in infected travellers returning from endemic areas increases the risk that this virus could establish itself in new endemic regions. This Seminar focuses on the re-emergence of this disease, the clinical manifestations, pathogenesis of virus-induced arthralgia, diagnostic techniques, and various treatment modalities. PMID- 22100855 TI - A stray bullet in the brain. PMID- 22100856 TI - Monitoring the variation in myocardial function with the Doppler-derived myocardial performance index during aortic cross-clamping. AB - OBJECTIVES: To investigate the effects of acute elevation in afterload on global (systolic and diastolic) myocardial function by performing serial intraoperative transesophageal echocardiograms during and after cross-clamp application on patients undergoing elective abdominal aortic aneurysm (AAA) surgery. DESIGN: A prospective observational study. SETTING: A tertiary care university hospital. PARTICIPANTS: Patients undergoing elective AAA repair under general anesthesia (GA). INTERVENTION: The use of perioperative transesophageal echocardiography to calculate a tissue Doppler-derived myocardial performance index (MPI) during different stages of the surgery. MEASUREMENT AND RESULTS: Twenty consecutive patients scheduled for suprarenal AAA repair under GA were included in the study. Perioperative transesophageal echocardiography was performed after the induction of GA. MPI was calculated with Doppler tissue imaging as the sum of isovolumetric contraction and relaxation times divided by the ejection time before cross clamping of the aorta and then 2, 10, and 20 minutes after cross-clamp application. A final MPI was measured after unclamping of the aorta. As compared with baseline, cross-clamp application initially worsened MPI within 2 minutes and then MPI improved to baseline after 10 minutes of cross-clamp application. The MPI improved significantly after unclamping of the aorta. CONCLUSIONS: The authors observed a temporal variation in global myocardial function after the application of a cross-clamp in the suprarenal position. There was transient deterioration of global myocardial function (the prolongation of MPI) 2 minutes after cross-clamp application, which improved within 10 minutes. Myocardial function returned to baseline after unclamping the aorta. PMID- 22100857 TI - Increased chest tube drainage is independently associated with adverse outcome after cardiac surgery. AB - OBJECTIVE: To investigate the clinical relevance of specific volume criteria for hemorrhage in a patient population undergoing cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A retrospective analysis; postoperative hemorrhage was defined by a fixed set of criteria >=200 mL/h in any 1 hour or part thereof, or (2) >=2 mL/kg/h for 2 consecutive hours in the first 6 hours after surgery. Classification and regression tree (CART) analysis were used to validate the results of the specific volume criteria. Multivariate regression analysis was applied to investigate the association of specific volume criteria for hemorrhage with clinical outcomes. SETTING: A university hospital. PARTICIPANTS: All adult cardiac surgery patients undergoing surgery with CPB at the authors' center in 2006. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 1,188 patients underwent cardiac surgery, and 76 patients (6.4%) experienced postoperative hemorrhage according to the fixed criteria for blood loss. Blood loss as measured by these criteria was associated with a higher 30 day mortality (odds ratio [OR] = 2.9, p < 0.001), incidence of stroke (OR = 3.3, p = 0.0033), re-exploration (OR = 103.655, p < 0.0001), intensive care unit stay >72 hours (OR = 1.3, p < 0.0001), and mechanical ventilation >24 hours (OR = 3.4, p = 0.0002). The clinical relevance of these criteria is supported by CART analysis. CONCLUSIONS: Postoperative hemorrhage (drainage loss) exceeding 200 mL/h in 1 hour or 2 mL/kg for 2 consecutive hours occurring within 6 hours after cardiac surgery is associated with higher 30-day mortality and other postoperative complications. Further research is needed to validate these results. PMID- 22100858 TI - The EuroSCORE in western Denmark: a population-based study. AB - OBJECTIVE: The present study aimed to examine the predictive performance of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) in a large cohort of patients undergoing cardiac surgery from 1999 through 2010 because methodologic shortcomings have hampered many previous studies questioning its predictive performance. DESIGN: Population-based prospectively registered data. SETTING: The Western Denmark Heart Registry, a multi-institutional registry. PARTICIPANTS: Twenty-one thousand six hundred sixty-four patients. INTERVENTIONS: On-pump cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The predictive ability of the logistic EuroSCORE was assessed using the area under the curve (AUC) for the discrimination test, the Hosmer-Lemeshow (HL) calibration test, and the mean estimated-to-observed mortality ratio (E/O). The overall AUC was 0.79 (95% confidence interval [CI] 0.77-0.81; HL test, p < 0.01; E/O 1.9). For coronary artery bypass grafting, the AUC was 0.78 (95% CI 0.75-0.81; HL test, p < 0.01; E/O 2.3). For coronary artery bypass grafting plus valve replacement, the AUC was 0.69 (95% CI 0.65-0.73; HL test, p = 0.02; E/O 1.5). For aortic valve replacement, the AUC was 0.76 (95% CI 0.72-0.80; HL test, p < 0.01; E/O 2.5). The overall and procedural specific E/O ratios tended to increase from 1999 to 2010. Mortality was overestimated across all levels of estimated risk, and in low-to medium-risk patients, this overestimation increased most notably with time. CONCLUSIONS: The EuroSCORE provides moderate-to-good discrimination and poor calibration. Despite substantial changes in risk factors during the study period, the EuroSCORE consistently overestimated 30-day mortality independent of the preoperative risk level and surgical procedure performed, indicating improved quality of surgery and patient care. PMID- 22100859 TI - Continuous theta-burst rTMS over primary somatosensory cortex modulates tactile perception on the hand. AB - OBJECTIVE: Theta-burst stimulation (TBS) over the primary somatosensory cortex (SI) alters cortical excitability, and in its intermittent form (iTBS) improves tactile spatial acuity. The effects of continuous TBS (cTBS) on tactile acuity remain unknown. The present study examined the influence of cTBS over SI on temporal and spatial tactile acuity on the contralateral hand. METHODS: In separate experiments, temporal discrimination threshold (TDT) and spatial amplitude discrimination threshold (SDT) were obtained from the right hand before and for up to 34 min following real and sham cTBS (600 pulses) over left hemisphere SI. RESULTS: CTBS reduced temporal and spatial tactile acuity for up to 18 min following real cTBS. Tactile acuity was unaltered in the groups receiving sham cTBS. CONCLUSIONS: CTBS over SI impairs both temporal and spatial domains of tactile acuity for a similar duration. SIGNIFICANCE: CTBS over SI appears to decrease neural activity within targeted cortex and has potential utility in reducing excessive sensory processing. PMID- 22100860 TI - Density spectral array analysis of SREDA during EEG-video monitoring. AB - OBJECTIVE: To report the temporal pattern of subclinical rhythmic electrographic discharge of adults (SREDA) and its response to lorazepam during EEG-video monitoring. METHODS: We recorded EEG-video for 3 days in a patient with SREDA, who was previously misdiagnosed with generalized epilepsy. Because SREDA had a very prominent signature on density spectral array (DSA), we used DSA to study the pattern of SREDA over the diurnal cycle, and the response to intravenous lorazepam. RESULTS: SREDA occurred in both waking and sleep, but tended to occur in single bursts in waking and in longer clusters during sleep. Lorazepam suppressed SREDA. CONCLUSIONS: The temporal pattern of SREDA varies during the sleep-wake cycle. Lorazepam appears to suppress SREDA. SIGNIFICANCE: Response to lorazepam cannot distinguish SREDA from electrographic seizure activity. PMID- 22100861 TI - Clinical neurophysiology and immunology of E-C coupling of muscle. PMID- 22100862 TI - [Endocavitary surgical procedures, an alternative to myomectomy in patients with symptomatic fibroids]. AB - Endometrial ablation can be used in heavy menstrual bleeding due to symptomatic submucosal myomas in women without desire of pregnancy. Those methods used alone, lead to an improvement on bleeding but results are not as good as in women without myomas. They can be associated with hysteroscopic myomectomy and, then, the results on bleeding are better than myomectomy alone. Second generation endometrial ablation methods must be used preferentially as they present less surgical complications than first generation methods. As the pregnancies that may occur after endometrial ablation have high risk of complications, a contraceptive mean is highly recommended after surgery. Transcervical sterilisation by intratubal insert (Essure) can also be proposed, but for women with Essure placed before endometrial ablation, only Thermachoice and bipolar resection have proven their safety. Finally, economical outcomes of endometrial ablation in myomas haven't been assessed yet. PMID- 22100863 TI - [Prolonged pregnancy term and beyond - introduction]. PMID- 22100864 TI - Proteomics/diagnosis of chorioamnionitis and of relationships with the fetal exposome. AB - Proteomics, a relatively young science, originally emerged as a complement to genomics research. By definition, the goal of proteomics is to provide a snapshot of all the proteins within an organism, tissue or biological sample at a given moment. Proteomics has the ability to single out one or more proteins (biomarkers) that change consistently in affected subjects as compared to those disease-free. From a proteomics perspective, chorioamnionitis poses both challenges and opportunities. Challenges relate to the dynamic course of the inflammatory process, and compartmentalization of the gestational sac in relation to the maternal compartment. An inability to evaluate the amniotic fluid non invasively and repeatedly for meaningful changes in its proteome, and lack of a true gold standard for diagnosis of inflammation and/or infection, represent additional challenges. On the other hand, the unbiased and holistic nature of proteomics offers a real opportunity to improve the current diagnostic and prognostic algorithms for chorioamnionitis. Even at this current stage there are reasons to believe that proteomic biomarkers will improve the understanding of how chorioamnionitis programs or affects the fetus in utero, thus defining its exposome (sum of interactions between genetic make-up of the fetus and the intrauterine environment) of pregnancies affected by infection and/or inflammation. This review summarizes the results of proteomics studies that have aimed or reached these goals. PMID- 22100865 TI - Time-resolved EPR immersion depth studies of a transmembrane peptide incorporated into bicelles. AB - The reduction in EPR signal intensity of nitroxide spin-labels by ascorbic acid has been measured as a function of time to investigate the immersion depth of the spin-labeled M2delta AChR peptide incorporated into a bicelle system utilizing EPR spectroscopy. The corresponding decay curves of n-DSA (n=5, 7, 12, and 16) EPR signals have been used to (1) calibrate the depth of the bicelle membrane and (2) establish a calibration curve for measuring the depth of spin-labeled transmembrane peptides. The kinetic EPR data of CLS, n-DSA (n=5, 7, 12, and 16), and M2delta AChR peptide spin-labeled at Glu-1 and Ala-12 revealed excellent exponential and linear fits. For a model M2delta AChR peptide, the depth of immersion was calculated to be 5.8A and 3A for Glu-1, and 21.7A and 19A for Ala 12 in the gel-phase (298K) and L(alpha)-phases (318K), respectively. The immersion depth values are consistent with the pitch of an alpha-helix and the structural model of M2delta AChR incorporated into the bicelle system is in a good agreement with previous studies. Therefore, this EPR time-resolved kinetic technique provides a new reliable method to determine the immersion depth of membrane-bound peptides, as well as, explore the structural characteristics of the M2delta AChR peptide. PMID- 22100867 TI - Folding and stability of membrane transport proteins in vitro. AB - Transmembrane transporters are responsible for maintaining a correct internal cellular environment. The inherent flexibility of transporters together with their hydrophobic environment means that they are challenging to study in vitro, but recently significant progress been made. This review will focus on in vitro stability and folding studies of transmembrane alpha helical transporters, including reversible folding systems and thermal denaturation. The successful re assembly of a small number of ATP binding cassette transporters is also described as this is a significant step forward in terms of understanding the folding and assembly of these more complex, multi-subunit proteins. The studies on transporters discussed here represent substantial advances for membrane protein studies as well as for research into protein folding. The work demonstrates that large flexible hydrophobic proteins are within reach of in vitro folding studies, thus holding promise for furthering knowledge on the structure, function and biogenesis of ubiquitous membrane transporter families. This article is part of a Special Issue entitled: Protein Folding in Membranes. PMID- 22100866 TI - Does the voltage dependent anion channel modulate cardiac ischemia-reperfusion injury? AB - The voltage dependent anion channel (VDAC) provides exchange of metabolites, anions, and cations across the outer mitochondrial membrane. VDAC provides substrates and adenine nucleotides necessary for electron transport and therefore plays a key role in regulating mitochondrial bioenergetics. VDAC has also been suggested to regulate the response to cell death signaling. Emerging data show that VDAC is regulated by protein-protein interactions as well as by post translational modifications. This review will focus on the regulation of VDAC and its potential role in regulating cell death in cardiac ischemia-reperfusion. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism. PMID- 22100868 TI - WITHDRAWN: Preparation and characterization of silica gel/chitosan composite for the removal of Cu(II) and Pb(II). AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22100869 TI - Corn porous starch: preparation, characterization and adsorption property. AB - This study was carried out to develop a new type of modified starch based on alpha-amylase and glucoamylase. The structural and chemical characteristics of the porous starch were determined by Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The potential application of the porous starch as an adsorbent was evaluated using methyl violet as an adsorbed model. The adsorption capacity was optimized by investigating the reaction factors, including the mass ratio of alpha-amylase to glucoamylase (m(alpha amylase)/m(glucoamylase)), the mass ratio of total amount of enzymes to starch (m(enzyme)/m(St)), the ratio of liquid volume to starch mass (V(H2O)/M(St)), pH value of the reaction solution, enzymatic reaction temperature, and enzymatic reaction time. The hydrolysis ratio of each sample was also determined to investigate the effect of different reaction conditions on the hydrolysis degree. The results suggest that the porous starch has a more excellent adsorption capacity than the native starch, and may be expected to have wide potential applications in many fields. PMID- 22100870 TI - Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling. AB - We previously demonstrated that the widely used immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (FK506), independent of immunophilin binding, can activate profibrogenic transforming growth factor beta (TGFbeta)/Smad signaling cascades in rat renal mesangial cells (MC). Here we report that both peptidyl-prolyl cis/trans isomerase (PPIase) inhibitors activate the extracellular-signaling regulated kinase (ERK) a member of the mitogen activated protein kinase (MAPK) and induce a rapid and transient increase in ERK phosphorylation. The MEK inhibitor U0126, the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), a cell-permeant superoxide dismutase (SOD) and stigmatellin, an inhibitor of mitochondrial cytochrome bc1 complex strongly attenuated the increase in ERK1/2 phosphorylation triggered by PPIase inhibitors. Moreover, neutralizing antibodies against heparin binding-epidermal growth factor (HB-EGF), and inhibition of the EGF receptor by either small interfering (si)RNA or AG1478, demonstrate that ERK activation by both PPIase inhibitors is mediated via HB-EGF-induced EGF receptor (EGFR) tyrosine kinase activation. The strong inhibitory effects achieved by GM6001 and TAPI-2 furthermore implicate the involvement of a desintegrin and metalloproteinase 17 (ADAM17). Concomitantly, the PPIase inhibitor-induced ADAM17 secretase activity was significantly reduced by SOD and stigmatellin thus suggesting that mitochondrial ROS play a primary role in PPIase inhibitor-induced and ADAM17-mediated HB-EGF shedding. Functionally, both immunosuppressants caused a strong increase in MC proliferation which was similarly impeded when cells were treated in the presence of NAC, TAPI-2 or AG1478, respectively. Our data suggest that CsA and FK506, via ROS-dependent and ADAM17-catalyzed HB-EGF shedding induce the mitogenic ERK1/2 signaling cascade in renal MC. PMID- 22100871 TI - Identifiability and online estimation of diagnostic parameters with in the glucose insulin homeostasis. AB - Today, diagnostic decisions about pre-diabetes or diabetes are made using static threshold rules for the measured plasma glucose. In order to develop an alternative diagnostic approach, dynamic models as the Minimal Model may be deployed. We present a novel method to analyze the identifiability of model parameters based on the interpretation of the empirical observability Gramian. This allows a unifying view of both, the observability of the system's states (with dynamics) and the identifiability of the system's parameters (without dynamics). We give an iterative algorithm, in order to find an optimized set of states and parameters to be estimated. For this set, estimation results using an Unscented Kalman Filter (UKF) are presented. Two parameters are of special interest for diagnostic purposes: the glucose effectiveness S(G) characterizes the ability of plasma glucose clearance, and the insulin sensitivity S(I) quantifies the impact from the plasma insulin to the interstitial insulin subsystem. Applying the identifiability analysis to the trajectories of the insulin glucose system during an intravenous glucose tolerance test (IVGTT) shows the following result: (1) if only plasma glucose G(t) is measured, plasma insulin I(t) and S(G) can be estimated, but not S(I). (2) If plasma insulin I(t) is captured additionally, identifiability is improved significantly such that up to four model parameters can be estimated including S(I). (3) The situation of the first case can be improved, if a controlled external dosage of insulin is applied. Then, parameters of the insulin subsystem can be identified approximately from measurement of plasma glucose G(t) only. PMID- 22100872 TI - Symmetrizing object and meta levels organizes thinking. AB - We present a single non-cellular finite automaton model first shown to exhibit self-organizing behavior with intermittency and criticality, through a self referential process. We propose a method to make self-referential contradiction a dynamic process of interaction with the selves in first person and third person description. The process represents thinking as inner dialogue with the self in second person. The dynamic effect of the rewrite shows characters proper to internal measurement, disequilibration by equilibration and transfer of inconsistency to the neighborhood by local resolution of the inconsistency. As the result, the advent of contradiction is postponed by the rewrite. The duality of internal measurement subject prevents inner dialogue in second person from lapsing into monologue. Criticality of thinking process is expressed. A probabilistic interpretation of non-determinacy weakening oracle is the key. PMID- 22100873 TI - On the origin of three base periodicity in genomes. AB - Genomes of almost all organisms have been found to exhibit several periodicities, the most prominent one is the three base periodicity. It is more pronounced in the gene coding regions and has been exploited to identify the segments of a genome that code for a protein. The reason for this three base periodicity in the gene-coding region has been attributed to inhomogeneous nucleotide compositions in the three codon positions. However, this reason cannot explain the three base periodicity present at the level of the whole genome where the codon concept is not applicable. Even though the distribution of each nucleotide is uniform at the positions 0(mod 3), 1(mod 3) and 2(mod 3) when the whole genome data is considered, our analysis reveals that the three base periodicity is arising because of higher correlations among the nucleotides separated by three bases. PMID- 22100874 TI - Neurobiology of disease. PMID- 22100875 TI - Molecular mechanisms of Streptococcus dysgalactiae subsp equisimilis enabling intravascular persistence. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE) can cause recurrent bacteremic infection. We have characterized novel virulence properties of an SDSE isolate of type stG485.0 that caused severe sepsis three times in a patient despite that he had opsonizing antibodies to the isolate. An infected aortic aneurysm was suspected to be the focus for the persisting bacteria. For the first time we show that this SDSE isolate, as well as other invasive SDSE isolates, aggregate human platelets and efficiently internalize into human endothelial cells. These properties may aid SDSE to persist and could explain the tendency of SDSE to cause recurrent bacteremia. PMID- 22100876 TI - XCL1 and XCR1 in the immune system. AB - XCL1, a C class chemokine also known as lymphotactin, is produced by T, NK, and NKT cells during infectious and inflammatory responses, whereas XCR1, the receptor of XCL1, is expressed by a dendritic cell subpopulation. The XCL1-XCR1 axis plays an important role in dendritic-cell-mediated cytotoxic immune response. It has been also shown that XCL1 and XCR1 are constitutively expressed in the thymus and regulate the thymic establishment of self-tolerance and the generation of regulatory T cells. This review summarizes the expression and function of XCL1 and XCR1 in the immune system. PMID- 22100877 TI - Depletion of pro-inflammatory CD161(+) double negative (CD3(+)CD4(-)CD8(-)) T cells in AIDS patients is ameliorated by expansion of the gammadelta T cell population. AB - In this present investigation, flow cytometry was utilized to evaluate 13 healthy controls and 31 HIV-1 infected patients who had advanced to the AIDS stage of infection (CD4 count below 200 cells/mm(3)), for the expression of CD161 on CD3(+) double negative (DN) (CD3(+)CD4(-)CD8(-)) T cells, CD4(+) T cells, CD8(+) T cells and gammadelta T cells. The observed depletion of CD161(+) T cells from peripheral circulation was due primarily to the loss of CD4(+)CD161(+) T cells; as these cells represented 8.67+/-0.74% of the total healthy control peripheral T cell population, while the CD4(+)CD161(+) T cells of the AIDS group represented only 3.35+/-0.41% (p=<0.0001) of the total peripheral T cell population. We have also shown here that the DN T cell population was more than doubled in the AIDS group, with the DN T cell population expanding from 3.29+/-0.45% of the healthy control peripheral T cell population to 8.64+/-1.16% (p=0.0001) of the AIDS group peripheral T cell population. By evaluating the expression of CD161 on the surface of the DN T cells we showed that within the healthy control group, 47.4+/ 4.99% of the DN T cells were positive for the expression of CD161, while only 26.4+/-3.54% (p=0.002) of the AIDS group's DN T cells expressed CD161. Despite CD161 expression being halved on the DN T cells of the AIDS group, when we compared the total peripheral T cell percentage of CD161(+) DN T cells between the healthy control group and the AIDS group, there was no statistical difference. Even though only 26.4% DN T cells within the AIDS group were positive for CD161(+), the overall DN T cell population had expanded to such an extent that there was no statistical difference between the groups with regard to CD161(+) DN T cells as a percentage of the total peripheral T cell population. Furthermore, we showed that within the DN T cell population, there was an approximate 2:1 ratio of gammadelta to alphabeta T cells, and this ratio was maintained in both the healthy control group and the AIDS group. While evaluating gammadelta T cells we also discovered that CD8(+) gammadelta T cells were expanded from 0.62+/-.09% of the healthy control peripheral T cell population to 5.01+/-.88% (p=<0.0001) of the peripheral T cell population of the AIDS group; and that this population of CD8(+) gammadelta T cells underwent the same reduction in percentage of cells expressing CD161(+), further demonstrated that the phenomenon of CD161(+) percentage reduction and compensatory increase in total cell population was affecting the entire circulating gammadelta T cell population. PMID- 22100878 TI - Labeling surface epitopes to identify Cryptosporidium life stages using a scanning electron microscopy-based immunogold approach. AB - The Apicomplexan parasite Cryptosporidium parvum is responsible for the widespread disease cryptosporidiosis, in both humans and livestock. The nature of C. parvum infection is far from understood and many questions remain in regard to host-parasite interactions, limiting successful treatment of the disease. To definitively identify a range of C. parvum stages in cell culture and to begin to investigate host cell interactions in some of the lesser known life stages, we have utilized a combined scanning electron microscopy and immunolabeling approach, correlating high resolution microstructural information with definitive immunogold labeling of Cryptosporidium stages. Several life cycle stages, including oocysts, merozoites I, trophozoites, gamonts and microgametocytes, were successfully immunolabeled in an in vitro model system. Developing oocysts were clearly immunolabeled, but this did not persist once excystation had occurred. Immunolabeling visualized on the host cell surface adjacent to invasive merozoites is likely to be indicative of receptor shedding, with merozoites also initiating host responses that manifested as abnormal microvilli on the host cell surface. Small sub-micron stages such as microgametocytes, which were impossible to identify as single entities without immunolabeling, were readily visualized and observed to attach to host cells via novel membranous projections. Epicellular parasites also expressed Cryptosporidium-derived epitopes within their encapsulating membrane. These data have allowed us to confidently identify a variety of C. parvum stages in cell culture at high resolution. With this, we provide new insight into C. parvum - host cell interactions and highlight future opportunities for investigating and targeting receptor-mediated interactions between Cryptosporidium life cycle stages and host cells. PMID- 22100879 TI - The expression of CD25, CD11b, SWC1, SWC7, MHC-II, and family of CD45 molecules can be used to characterize different stages of gammadelta T lymphocytes in pigs. AB - The expression of selected molecules was chosen to study porcine gammadelta lymphocytes and their CD2/CD8 subsets in different lymphoid organs in vivo and in vitro. Results indicate that many gammadelta T cells can constitutively express CD25 and MHC-II and that the frequency of gammadelta T cells positive for CD25, CD11b, SWC1 and SWC7 can be increased by stimulation. A diversified TCRdelta repertoire was found inside CD25(+), CD11b(+), SWC1(-) and CD45RA(-) cells. Ontogenetic studies revealed various age and/or colonization dependency for expression of all studied molecules except of SWC7. Findings generally indicate that CD25 represent an activation molecule that probably marks a functionally distinct subsets, expression of CD11b is perhaps connected to early functions of naive gammadelta T cells in the periphery, SWC1 is lineage specific marker, SWC7 may represent an activation molecule with intrinsic or transient expression, and the expression of CD45RA/RC most likely defines naive and terminally differentiated cells. PMID- 22100880 TI - Genome-based phylogeny of dsDNA viruses by a novel alignment-free method. AB - Sequence alignment is not directly applicable to whole genome phylogeny since several events such as rearrangements make full length alignments impossible. Here, a novel alignment-free method derived from the standpoint of information theory is proposed and used to construct the whole-genome phylogeny for a population of viruses from 13 viral families comprising 218 dsDNA viruses. The method is based on information correlation (IC) and partial information correlation (PIC). We observe that (i) the IC-PIC tree segregates the population into clades, the membership of each is remarkably consistent with biologist's systematics only with little exceptions; (ii) the IC-PIC tree reveals potential evolutionary relationships among some viral families; and (iii) the IC-PIC tree predicts the taxonomic positions of certain "unclassified" viruses. Our approach provides a new way for recovering the phylogeny of viruses, and has practical applications in developing alignment-free methods for sequence classification. PMID- 22100881 TI - Para-NO-aspirin inhibits NF-kappaB and induces apoptosis in B-cell progenitor acute lymphoblastic leukemia. AB - Although patients with acute lymphoblastic leukemia (ALL) usually achieve complete remission, disease relapse is common and difficult to treat. Para-NO aspirin (para-NO-ASA) is a novel drug with demonstrated efficacy against a number of solid tumors and most recently chronic lymphocytic leukemia. In this study, we used ALL cell lines to assess the effects on cell viability by flow cytometry and investigated the mechanism of cell death using chemical inhibitors of key molecules and assessed the effects by flow cytometry, electrophoretic mobility shift assay, Western blotting, and quantitative reverse transcription polymerase chain reaction. Para-NO-ASA induced cell death in the pre-B ALL cell lines in association with increased reactive oxygen species, and suppression of nuclear factor-kappaB (NF-kappaB) activity. Chemical inhibitors of NF-kappaB similarly induced apoptosis in ALL cells, suggesting a role for suppression of NF-kappaB in para-NO-ASA-induced cell death. Modulation of NF-kappaB was not via regulation of IkappaB but potentially through suppression of ROCK1 and loss of reduced glutathione. Our results demonstrate that para-NO-ASA potently induces apoptosis in B-lineage ALL cells via a reactive oxygen species-dependent mechanism that is associated with suppression of NF-kappaB activity. PMID- 22100882 TI - Roles for nucleotide phosphatases in sulfate assimilation and skeletal disease. PMID- 22100883 TI - Dysregulation of laminins in intestinal inflammation. AB - Laminins are structural components of basement membranes that regulate and control many cellular functions. Changes in basement membrane composition play significant roles in etiology of diseases. Inflammatory bowel diseases are conditions that lead to defects in the mucosal barrier which includes the basement membrane underlying the epithelium. This review will summarize the main findings related to the involvement of laminins and of the laminin-binding receptors in inflammatory conditions such as Crohn's disease and ulcerative colitis. We will review the current literature devoted to studies in humans (immunolocalisation, genetic factors, microarray data), as well as experimental cell models that show that laminins contribute to the inflammation process probably linked to the deregulation of proinflammatory cytokines. PMID- 22100884 TI - Development of immunization trials against Klebsiella pneumoniae. AB - Klebsiella pneumoniae is the most common cause of nosocomial respiratory tract and premature intensive care infections, and the second most frequent cause of Gram-negative bacteraemia and urinary tract infections. Drug resistant isolates remain an important hospital-acquired bacterial pathogen, add significantly to hospital stays, and are especially problematic in high impact medical areas such as intensive care units. Many investigations worldwide proved the increasing resistance of such pathogen, resulting in an average rate of 1.63 outbreak every year. A variety of preventive measures were applied to reduce such incidences. Immunotherapy and passive immunization researches as well found their way to the treatment of Klebsiella. During the last 40 years, many trials for constructing effective vaccines were followed. This up-to-date review classifies such trials and documents them in a progressive way. A following comment discusses each group benefits and defects. PMID- 22100885 TI - A single amino acid change in the Plasmodium falciparum RH5 (PfRH5) human RBC binding sequence modifies its structure and determines species-specific binding activity. AB - Identifying the ligands or regions derived from them which parasites use to invade their target cells has proved to be an excellent strategy for identifying targets for vaccine development. Members of the reticulocyte-binding homologue family (PfRH), including RH5, have been implicated in invasion as adhesins binding to specific receptors on erythrocyte surface. The regions mediating PfRH5 RBC specific interactions have been identified here by fine mapping the whole PfRH5 protein sequence. These regions, called high activity binding peptides (HABPs), bind to a receptor which is sensitive to trypsin treatment and inhibit merozoite invasion of RBCs by up to 80%, as has been found for HABP 36727. Our results show that a single amino acid change in the HABP 36727 sequence modifies a peptide's 3D structure, thereby resulting in a loss of specific binding to human RBCs and its inhibition ability, while binding to Aotus RBC remains unmodified. Such invasion differences and binding ability produced by replacing a single amino acid in an essential molecule, such as PfRH5, highlight the inherent difficulties associated with developing a fully effective vaccine against malaria. PMID- 22100886 TI - Intradermal fractional dose inactivated polio vaccine: a review of the literature. AB - Oral polio vaccine (OPV) will likely be insufficient to completely eradicate polio due to its propensity to mutate into neurovirulent forms and its inability to produce adequate immunity in certain areas of the world. Inactivated polio vaccine (IPV), a killed vaccine which therefore cannot mutate, may be more effective than OPV in certain populations, and will likely be required for global polio eradication. However, the high cost of IPV is prohibitive in many areas of the world. Intradermal administration has the potential to lower the dose, and thus the cost, of IPV. This article reviews the clinical studies to date on intradermal fractional dose polio vaccination. We conclude that intradermal IPV vaccination shows potential as a means to reduce the cost and increase the ease of administration of IPV, but that additional research is needed to determine the optimal fractional dose, timing, and role of adjuvants in intradermal IPV vaccination as well as the clinical significance of different antibody titers above the threshold for seroconversion. PMID- 22100887 TI - Reproducibility of serology assays for pandemic influenza H1N1: collaborative study to evaluate a candidate WHO International Standard. AB - Haemagglutination-inhibition (HI) and virus neutralisation (VN) assays are used to evaluate immunogenicity of pandemic H1N1 vaccines; however these bioassays are poorly standardised leading to inter-laboratory variation. A candidate International Standard (IS) for antibody to H1N1 pdm virus (09/194) was prepared from pooled sera of subjects who had either recovered from H1N1 pdm infection or who had been immunised with an adjuvanted subunit vaccine prepared from reassortant virus NYMC X-179A (derived from A/California/7/2009 virus). Ten laboratories from seven countries tested the candidate IS, 09/194 and a panel of human sera by HI and VN using the A/California/7/2009 virus (six laboratories) and/or the reassortant virus NYMC X-179A (ten laboratories). As expected, the inter-laboratory variability for HI and VN assay results was high. For results of antibody tests to NYMC X-179A, the % geometric coefficient of variation (%GCV) for 09/194 between laboratories was 83% for HI and 192% for VN. For tests of all sera, the median %GCV ranged from 95 to 345% for HI (80-fold variation) and 204 to 383% for VN (109-fold variation), but for the titres relative to 09/194 the median %GCV was much reduced (HI 34-231%; VN 44-214%). For tests of antibody to the A/California/7/2009 wild type virus there were similar reductions in %GCV when 09/194 was used. These results suggest that 09/194 will be of use to standardise assays of antibody to A/California/7/2009 vaccine and 09/194 has now been established by WHO as an IS for antibody to A/California/7/2009 with an assigned potency of 1300 IU per ml. PMID- 22100888 TI - Mechanisms underlying allergy vaccination with recombinant hypoallergenic allergen derivatives. AB - Hundred years ago therapeutic vaccination with allergen-containing extracts has been introduced as a clinically effective, disease-modifying, allergen-specific and long-lasting form of therapy for allergy, a hypersensitivity disease affecting more than 25% of the population. Today, the structures of most of the disease-causing allergens have been elucidated and recombinant hypoallergenic allergen derivatives with reduced allergenic activity have been engineered to reduce side effects during allergen-specific immunotherapy (SIT). These recombinant hypoallergens have been characterized in vitro, in experimental animal models and in clinical trials in allergic patients. This review provides a summary of the molecular, immunological and preclinical evaluation criteria applied for this new generation of allergy vaccines. Furthermore, we summarize the mechanisms underlying SIT with recombinant hypoallergens which are thought to be responsible for their therapeutic effect. PMID- 22100889 TI - A novel combined adjuvant for nasal delivery elicits mucosal immunity to influenza in aging. AB - Since a combination of flt3 ligand plasmid (pFL) and CpG-oligodeoxynucleotides (ODN)(3) as a dendritic cell (DC)-targeting double mucosal adjuvant elicited ovalbumin-specific secretory IgA (S-IgA) antibody (Ab) responses, we examined whether this double adjuvant could induce influenza-specific protective immunity in aged mice. A double adjuvant plus A/Puerto Rico/8/34 (PR8) hemagglutinin (HA) induced increased numbers of CD11b(+) CD11c(+) DCs and both CD4(+) Th1- and Th2 type responses in the nasopharyngeal-associated lymphoreticular tissue, nasal passages and cervical lymph nodes. Further, increased levels of PR8 HA-specific S IgA Ab responses were detected in the upper respiratory tact (URT) of aged and young adult mice given nasal PR8 HA with this double adjuvant. Thus, when mice were challenged with PR8 virus via the nasal route, both aged and young adult mice given nasal vaccine exhibited complete protection. Further, IgA-deficient mice nasally immunized with a double adjuvant influenza vaccine failed to provide protection against PR8 challenge. These results indicate that a nasal double adjuvant successfully induces PR8 HA-specific IgA Ab responses in both young adult and aged mice, which are essential for the prevention of influenza infection in the murine URT. PMID- 22100890 TI - Measurement of antibody responses to Modified Vaccinia virus Ankara (MVA) and Dryvax((r)) using proteome microarrays and development of recombinant protein ELISAs. AB - Modified Vaccinia virus Ankara (MVA) is an attenuated strain of vaccinia virus that is being considered as a safer alternative to replicating vaccinia vaccine strains such as Dryvax((r)) and ACAM2000. Its excellent safety profile and large genome also make it an attractive vector for the delivery of heterologous genes from other pathogens. MVA was attenuated by prolonged passage through chick embryonic fibroblasts in vitro. In human and most mammalian cells, production of infectious progeny is aborted in the late stage of infection. Despite this, MVA provides high-level gene expression and is immunogenic in humans and other animals. A key issue for vaccine developers is the ability to be able to monitor an immune response to MVA in both vaccinia naive and previously vaccinated individuals. To this end we have used antibody profiling by proteome microarray to compare profiles before and after MVA and Dryvax vaccination to identify candidate serodiagnostic antigens. Six antigens with diagnostic utility, comprising three membrane and three non-membrane proteins from the intracellular mature virion, were purified and evaluated in ELISAs. The membrane protein WR113/D8L provided the best sensitivity and specificity of the six antigens tested for monitoring both MVA and Dryvax vaccination, whereas the A-type inclusion protein homolog, WR148, provided the best discrimination. The ratio of responses to membrane protein WR132/A13L and core protein WR070/I1L also provided good discrimination between primary and secondary responses to Dryvax, whereas membrane protein WR101/H3L and virion assembly protein WR118/D13L together provided the best sensitivity for detecting antibody in previously vaccinated individuals. These data will aid the development novel MVA-based vaccines. PMID- 22100891 TI - HIV vaccine development: challenges and opportunities towards solving the HIV vaccine-neutralizing antibody problem. AB - Recent advances in HIV vaccine development have created a renaissance in the search for a safe and effective HIV vaccine. These advances include the first demonstration in human clinical trials of a vaccine candidate that provided modest levels of protection from HIV infection; a series of candidates entering into clinical trials with an improved profile of protection against SIV in non human primate studies, and the identification from HIV infected individuals of new broad and potent monoclonal antibodies against HIV that target conserved, vulnerable regions of the HIV envelope glycoprotein spike. The major challenge for successful HIV vaccine development rests on overcoming the unprecedented hyper-variability of HIV, which likely will require induction of broadly protective neutralizing antibodies to prevent HIV infection, and broad and robust cellular immune responses to control HIV infection. This presentation will review the challenges and opportunities for development of vaccine candidates capable of eliciting broadly neutralizing antibodies against HIV. PMID- 22100892 TI - Serotype changes in adult invasive pneumococcal infections in Portugal did not reduce the high fraction of potentially vaccine preventable infections. AB - We determined the serotype and antimicrobial susceptibility of 1100 isolates responsible for adult invasive pneumococcal infections (IPD) in Portugal between 2006 and 2008. Serotypes 3 (13%), 1 (12%), 7F (11%), 19A (10%) and 14 (7%) were the most frequent causes of IPD and the two later serotypes accounted for the majority of erythromycin and penicillin nonsusceptible isolates. Serotype 1 was associated with younger adults whereas serotype 3 was associated with older adults. Despite the availability of the 23-valent polysaccharide vaccine (PPV23) in Portugal since 1996, the proportion of PPV23 preventable IPD remained stable and above 80%. Comparing with previous data from Portugal, we showed a continued decline of the serotypes included in the 7-valent conjugate vaccine (PCV7) in adult IPD and a rise of serotypes included in the 13-valent conjugate vaccine, increasing its potential coverage of adult IPD to 70% in 2008. Penicillin non susceptibility remained stable (17%) whereas erythromycin resistance (18%) has continued to rise in the post-PCV7 years. PMID- 22100893 TI - Estimating pandemic vaccine effectiveness in two Italian regions using the screening method, 2009-2010. AB - The objective of this study, conducted within the I-MOVE project, was to estimate pandemic VE against laboratory confirmed cases in two Italian regions using the screening method. We calculated vaccine coverage using the number of first doses of pandemic vaccine administered and demographic data. A case was defined as a patient who was swabbed from week 44 of 2009 to week 3 of 2010 and who tested positive for A/H1N1v using RT-PCR. A case was considered vaccinated against influenza A/H1N1v if she/he had received one dose of the vaccine more than 14 days before swabbing. We used Farrington's method to build the confidence intervals. We included in the analysis 755 confirmed A/H1N1v cases. The median age of cases was 24 years (range 0-89). One case (0.1%) had received one dose of vaccine more than 14 days after swabbing. The overall crude estimated VE was 92.4% (95% CI: 46.3-98.9). It suggests that the pandemic vaccine offered good protection against medically attended laboratory-confirmed A/H1N1v. PMID- 22100894 TI - Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1. AB - Earlier studies demonstrated the involvement of the p300 histone acetyltransferase in Notch signaling but the precise mechanisms by which p300 might modulate Notch function remains to be investigated. In this study, we show that p300 acetylates Notch1 ICD in cell culture assay and in vitro, and conserved lysines located within the Notch C-terminal nuclear localization signal are essential for Notch acetylation. MAML1 and CSL, which are components of the Notch transcription complex, enhance Notch acetylation and we suggest that MAML1 increases Notch acetylation by potentiating p300 autoacetylation. Furthermore, MAML1-dependent acetylation of Notch1 ICD by p300 decreases the ubiquitination of Notch1 ICD in cellular assays. CDK8 has been shown to target Notch1 for ubiquitination and proteosomal degradation. We show that CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. Therefore, we speculate that acetylation of Notch1 might be a mechanism to regulate Notch activity by interfering with ubiquitin-dependent pathways. PMID- 22100895 TI - A simple method for preventing pharyngocutaneous fistula after pharyngolaryngectomy using a mesenteric turnover flap. PMID- 22100896 TI - Soluble CD40 ligand, soluble P-selectin and von Willebrand factor levels in subjects with prediabetes: the impact of metabolic syndrome. AB - OBJECTIVES: The data regarding circulating levels of markers of platelet activation and endothelial function in people with prediabetes are scant. The aim of the present study was to search blood levels of soluble CD40 ligand (sCD40L), soluble P-selectin (sP-sel) and von Willebrand Factor (vWF) in subjects with prediabetes, along with the effects of the metabolic syndrome (MetS) on these markers. DESIGN AND METHODS: A total of 77 prediabetic individuals and 81 age, sex and body mass index matched healthy subjects with normal glucose tolerance (NGT) were prospectively analyzed. Anthropometric parameters, fasting plasma glucose, blood d lipid profiles and insulin resistance indexes were determined. Plasma sCD40L, sP-sel and vWF levels were measured by ELISA. RESULTS: sCD40L, sP sel and vWF levels in the prediabetic group were similar to those in the controls. However, prediabetic subjects with the MetS had significantly higher level of sCD40L compared to those without MetS. Moreover, sCD40L level correlated significantly with waist circumference, systolic blood pressure and HDL cholesterol level in the patient group. CONCLUSION: These data imply that MetS may contribute, at least in part, to the mechanism of platelet activation and endothelial dysfunction in people with prediabetes. PMID- 22100897 TI - Pitfalls in the determination of human acylated ghrelin plasma concentrations using a double antibody enzyme immunometric assay. AB - OBJECTIVES: To investigate the effect of hemolysis and protease inhibitors on acylated ghrelin (AG) concentrations measured with a double antibody enzyme immunometric assay that uses an acetylcholinesterase (AChE)-Fab' conjugate. DESIGN AND METHODS: Samples were hemolysed or treated with PHMB (p hydroxymercuribenzoate), PMSF (phenylmethanesulfonylfluoride) or AEBSF (4-(2 Aminoethyl) benzenesulfonyl fluoride) to prevent AG degradation. RESULTS: Hemolysis decreased AG concentrations. PHMB or PMSF did not affect the assay. The standard curve was abolished by AEBSF but rescued by addition of a washing step prior to the AChE-Fab' conjugate. CONCLUSIONS: Hemolysis and AEBSF may affect AG determination. PMID- 22100898 TI - Organization of the capsule biosynthesis gene locus of the oral streptococcus Streptococcus anginosus. AB - The capsular polysaccharide (CPS) of the important oral streptococcus Streptococcus anginosus, which causes endocarditis, and the genes for its synthesis have not been clarified. In this study, we investigated the gene locus required for CPS synthesis in S. anginosus. Southern hybridization using the cpsE gene of the well-characterized bacterium S. agalactiae revealed that there is a similar gene in the genome of S. anginosus. By using the colony hybridization technique and inverse PCR, we isolated the CPS synthesis (cps) genes of S. anginosus. This gene cluster consisted of genes containing typical regulatory genes, cpsA-D, and glycosyltransferase genes coding for glucose, rhamnose, N acetylgalactosamine, and galactofuranose transferases. Furthermore, we confirmed that the cps locus is required for CPS synthesis using a mutant strain with a defective cpsE gene. The cps cluster was found to be located downstream the nrdG gene, which encodes ribonucleoside triphosphate reductase activator, as is the case in other oral streptococci such as S. gordonii and S. sanguinis. However, the location of the gene cluster was different from those of S. pneumonia and S. agalactiae. PMID- 22100899 TI - Application of supercritical fluid chromatography/mass spectrometry to lipid profiling of soybean. AB - A metabolomics technology for lipid profiling based on supercritical fluid chromatography (SFC) coupled with mass spectrometry (MS) was applied to analyze lipids of soybean. Principal component analysis (PCA) was used to discriminate twelve soybean cultivars according to their suitability for different processed foods such as natto, tofu, edamame, and nimame. By PCA assay, triacylglycerol (TAG) was found as the main variable for discrimination of soybean cultivars. Therefore, a high-throughput and high-resolution TAG profiling method by SFC/MS was developed to more effective discrimination. By investigating several columns, three Chromolith Performance RP-18e columns connected in series were chosen as the most effective column for TAG profiling. Diverse TAGs were separated effectively for 8 min without purification. Additionally, each TAG was identified successfully by the programmed cone voltage fragmentation even without MS/MS analysis and any standard sample. PMID- 22100900 TI - On-line carbon balance of yeast fermentations using miniaturized optical sensors. AB - Monitoring of microbiological processes using optical sensors and spectrometers has gained in importance over the past few years due to its advantage in enabling non-invasive on-line analysis. Near-infrared (NIR) and mid-infrared (MIR) spectrometer set-ups in combination with multivariate calibrations have already been successfully employed for the simultaneous determination of different metabolites in microbiological processes. Photometric sensors, in addition to their low price compared to spectrometer set-ups, have the advantage of being compact and are easy to calibrate and operate. In this work, the detection of ethanol and CO(2) in the exhaust gas during aerobic yeast fermentation was performed by two photometric gas analyzers, and dry yeast biomass was monitored using a fiber optic backscatter set-up. The optical sensors could be easily fitted to the bioreactor and exhibited high robustness during measuring. The ethanol content of the fermentation broth was monitored on-line by measuring the ethanol concentration in the fermentation exhaust and applying a conversion factor. The vapor/liquid equilibrium and the associated conversion factor strongly depend on the process parameter temperature but not on aeration and stirring rate. Dry yeast biomass was determined in-line by a backscattering signal applying a linear calibration. An on-line balance with a recovery rate of 95-97% for carbon was achieved with the use of three optical sensors (two infrared gas analyzers and one fiber optic backscatter set-up). PMID- 22100902 TI - Aquaporin-4 expression in primary human central nervous system lymphomas correlates with tumour cell proliferation and phenotypic heterogeneity of the vessel wall. AB - No literature data are available concerning the expression of aquaporin-4 in primary central nervous system lymphomas and the relationship between aquaporin-4 expression and the morphological characteristics of blood vessels. Here, we have investigated this relationship in 24 human diffuse large B-cell primary central nervous system lymphomas by means of immunocytochemistry and confocal laser microscopy. Results have shown that: (i) a high aquaporin-4 expression correlated with a high Ki-67 index and aquaporin-4 marked tumour and endothelial cells in cytoplasm and plasma membranes, while aquaporin-4 expression was low in tumour areas with a low Ki-67 index where few tumour cells were positive to aquaporin-4, and endothelial cells showed aquaporin-4 expression on their abluminal side. (ii) Different type of cells participated in vessels formation: CD20(+) tumour cells and factor VIII(+) endothelial cells; aquaporin-4(+) tumour cells and CD31(+) endothelial cells; CD20(+) and aquaporin-4(+) tumour cells; glial fibrillary acidid protein(+) endothelial cells surrounded by glial fibrillary acidic protein(+) tumour cells. Overall, these data suggest the importance of aquaporin 4 in primary central nervous system lymphomas due to its involvement in cerebral oedema formation and resolution and tumour cell migratory activity, and have documented that tumour microvasculature in lymphomas is extremely heterogeneous, confirming the importance of neoangiogenesis in the pathogenesis of lymphomas. PMID- 22100903 TI - Body mass index does not influence post-treatment survival in early stage endometrial cancer: results from the MRC ASTEC trial. AB - Body mass index (BMI) is a major risk factor for endometrial cancer incidence but its impact on post-treatment survival is unclear. We investigated the relationships of BMI (categorised using the WHO definitions) with clinico pathological characteristics and outcome in women treated within the MRC ASTEC randomised trial, which provides data from patients who received standardised allocated treatments and therefore reduces biases. The impact of BMI on both recurrence-free survival (RFS) and overall survival (OS) was analysed using the Cox regression models. An apriori framework of evaluating potential biases was explored. From 1408 participants, there were 1070 women with determinable BMI (median=29.1 kg/m(2)). Histological types were endometrioid (type 1) in 893 and non-endometrioid (type 2) in 146 women; the proportion of the latter decreasing with increasing BMI (8% versus 19% for obese III WHO category versus normal weight, p(trend)=0.003). For type 1 carcinomas, increasing BMI was associated with less aggressive histopathological features (depth of invasion, p=0.006; tumour grade, p=0.015). With a median follow-up of 34.3 months, there was no influence of BMI on RFS - adjusted HRs per 5 kg/m(2) were 0.98 (95% CI 0.86, 1.13) and 0.95 (0.74, 1.24), for type 1 and 2 carcinomas; and no influence on OS adjusted HRs per 5 kg/m(2) were 0.96 (0.81, 1.14) and 0.92 (0.70, 1.23), respectively. These findings demonstrate an important principle: that an established link between an exposure (here, obesity) and increased incident cancer risk, does not necessarily translate into an inferior outcome following treatment for that cancer. PMID- 22100904 TI - The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta analysis of randomised controlled trials. AB - BACKGROUND: The effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomised controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy. METHODS: We searched PubMed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992-2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004-2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end-points were the disease free survival (DFS). Secondary end-points were overall survival (OS), distant or loco-regional recurrence free survival and bone metastasis free survival. FINDINGS: Compared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival, disease free survival, bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (relative risk (RR) = 0.763, 95% confidence interval (CI) 0.658 0.884, p < 0.001) and reduce the risk of distant (RR = 0.744, 95%CI 0.611-0.906, p = 0.003) and locoregional recurrence (RR = 0.508, 95%CI 0.340-0.760, p = 0.001). INTERPRETATION: Adjuvant zoledronic acid did not significantly improve the prognosis of breast cancer patients. Due to the highly variable definitions of menopause utilised in different studies, we hypothesise that zoledronic acid may have a potential effect on postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal counterparts, differing disease stages and various pathological types of breast cancer. PMID- 22100905 TI - Scoring to predict the possibility of upgrades to malignancy in atypical ductal hyperplasia diagnosed by an 11-gauge vacuum-assisted biopsy device: an external validation study. AB - BACKGROUND: Ko's scoring system was developed to predict malignancy upgrades in patients diagnosed with atypical ductal hyperplasia by core needle biopsy. The Ko algorithm was able to identify a subset of patients who were eligible for exclusively clinical follow-up. The current study statistically investigated the patient outcomes to determine whether this scoring system could be translated and used safely in clinical practice. METHODS: We tested the statistical performance of the Ko scoring system against an external independent multicentre population. One hundred and seven cases of atypical ductal hyperplasia diagnosed by an 11 gauge biopsy needle were available for inclusion in this study. The discrimination, calibration and clinical utility of the scoring system were quantified. In addition, we tested the underestimation rate, sensitivity, specificity, and positive and negative predictive values according to the score threshold. RESULTS: The overall underestimation rate was 19% (20/107). The area under the receiver operating characteristic curve for the logistic regression model was 0.51 (95% confidence interval: 0.47-0.53). The model was not well calibrated. The lowest predicted underestimation rate was 11%. The sensitivity, specificity, positive predictive value, and negative predictive values were 90%, 22%, 20%, and 89%, respectively, according to the most accurate threshold proposed in the original study. CONCLUSION: The scoring system was not sufficiently accurate to safely define a subset of patients who would be eligible for follow-up only and no additional treatment. These results demonstrate a lack of reproducibility in an external population. A multidisciplinary approach that correlates clinicopathological and mammographic features should be recommended for the management of these patients. PMID- 22100906 TI - Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. AB - BACKGROUND: Annualised figures show an up to 7-fold higher incidence of vascular thromboembolism (VTE) in patients with advanced pancreatic cancer (APC) compared to other common malignancies. Concurrent VTE has been shown to confer a worse overall prognosis in APC. METHODS: One hundred and twenty three APC patients were randomised to receive either gemcitabine 1000 mg/m(2) or the same with weight adjusted dalteparin (WAD) for 12 weeks. Primary end-point was the reduction of all-type VTE during the study period. NCT00462852, ISRCTN: 76464767. FINDINGS: The incidence of all-type VTE during the WAD treatment period (<100 days from randomisation) was reduced from 23% to 3.4% (p = 0.002), with a risk ratio (RR)of 0.145, 95% confidence interval (CI) (0.035-0.612) and an 85% risk reduction. All type VTE throughout the whole follow-up period was reduced from 28% to 12% (p = 0.039), RR = 0.419, 95% CI (0.187-0.935) and a 58% risk reduction. Lethal VTE <100 days was seen only in the control arm, 8.3% compared to 0% (p = 0.057), RR = 0.092, 95% CI (0.005-1.635). INTERPRETATION: Weight adjusted dalteparin used as primary prophylaxis for 12 weeks is safe and produces a highly significant reduction of all-type VTE during the prophylaxis period. The benefit is maintained after dalteparin withdrawal although decreases with time. PMID- 22100907 TI - Purification and inflammatory edema induced by two PLA2 (Anch TX-I and Anch TX II) from sea anemone Anthothoe chilensis (Actiniaria: Sagartiidae). AB - The Anch TX-I and II PLA(2) were purified from Anthothoe chilensis (Lesson, 1830) from the extract of the anemone after only two chromatographic step using molecular exclusion chromatography (Sephadex G-75) and reverse phase HPLC on MU Bondapak C18 column. Both PLA(2) showed a molecular mass of ~14kDa determined by MALDI-TOF mass spectrometry and showed a high catalytic activity (data not showed). Although homologous with mammalian or snake venom group I PLA(2)s, Anch TX-I and II is sufficiently structurally different for the question of its placement into the existing PLA(2) classification scheme to arise. In addition, Anch TX-I and II, despite possessing many common structural features, also differ in some important structural properties. The amino acid sequence of both PLA(2) (Anch TX-I and III) showed high amino acid sequence identity with PLA(2)Rhopilema nomadica and Bunodosoma caissarum Cnidaria and PLA(2) of group III protein isolated from the Mexican lizard Heloderma horridum horridum and Heloderma suspectum. In addition, Anch TX-I and Anch TX-II showed high amino acid sequence identity with PLA(2) from group III also showed significant overall homology to bee Apis dorsata, Bombus terrestris and Bombus pennsylvanicus and PLA(2). We also investigated the in vivo edematogenic activity of Anch TX-I and Anch TX-II in a model of paw and skin edema in rats and observed that both are able to induce dose-dependent edema. PMID- 22100908 TI - Transient hypermutability, chromothripsis and replication-based mechanisms in the generation of concurrent clustered mutations. AB - Clustered mutations may be broadly defined as the presence of two or more mutations within a spatially localized genomic region on a single chromosome. Known instances vary in terms of both the number and type of the component mutations, ranging from two closely spaced point mutations to tens or even hundreds of genomic rearrangements. Although clustered mutations can represent the observable net result of independent lesions sequentially acquired over multiple cell cycles, they can also be generated in a simultaneous or quasi simultaneous manner within a single cell cycle. This review focuses on those mechanisms known to underlie the latter type. Both gene conversion and transient hypermutability are capable of generating closely spaced multiple mutations. However, a recently described phenomenon in human cancer cells, known as 'chromothripsis', has provided convincing evidence that tens to hundreds of genomic rearrangements can sometimes be generated simultaneously via a single catastrophic event. The distinctive genomic features observed in the derivative chromosomes, together with the highly characteristic junction sequences, point to non-homologous end joining (NHEJ) as being the likely underlying mutational mechanism. By contrast, replication-based mechanisms such as microhomology mediated break-induced replication (MMBIR) which involves serial replication slippage or serial template switching probably account for those complex genomic rearrangements that comprise multiple duplications and/or triplications. PMID- 22100909 TI - Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism. AB - Multiple studies converge to implicate alterations of the hippocampus and amygdala in the pathology of autism. We have previously reported anatomical alterations of the meninges, vasculature and fractones, the specialized extracellular matrix (ECM) of the subventricular zone, in the forebrain of adult BTBR T+ tf/J mice, animal model for autism. Here, we used bisbenzidine cell nucleus staining and dual immunofluorescence histochemistry for laminin and N sulfated heparan sulfate proteoglycans (NS-HSPG) to examine a series of brain sections containing the amygdala and hippocampus in the adult BTBR T+ tf/j mouse. We observed an excessive separation of the two hippocampi, a modified trajectory of the meninges leading to a shrunken choroid plexus in the lateral ventricle, a shorter granular layer of the dentate gyrus, and a reduced size of the amygdala nuclei. The lateral ventricle near the amygdala, and the third ventricle were shrunken. The number and size of fractones, and their immunoreactivity for NS HSPG, were reduced throughout the third and lateral ventricles walls. Enlarged blood vessels were found at the endopiriform cortex/amygdala interface. These results show anatomical alterations of the hippocampal/amygdala that are associated with defects of the choroid plexus/ventricular system and the ECM in the BTBR T+ TF/J mouse. Similar alterations of the hippocampus/amygdala axis in humans with autism to these observed in BTBR T+ tf/J mice make this animal model highly valuable for the study of autism. Moreover, the meningo/vascular and ECM alterations in BTBR T+ Tf/J mice suggest a possible role of the brain connective tissue in autism. PMID- 22100910 TI - Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite. AB - The recent recognition of Plasmodium falciparum Hsp90 (PfHsp90) as a promising anti-malaria drug target has sparked interest in identifying factors that regulate its function and drug-interaction. Co-chaperones are well-known regulators of Hsp90's chaperone function, and certain members have been implicated in conferring protection against lethal cellular effects of Hsp90 specific inhibitors. In this context, studies on PfHsp90's co-chaperones are imperative to gain insight into the regulation of the chaperone in the malaria parasite. In this study, a putative co-chaperone P. falciparum Aha1 (PfAha1) was identified and investigated for its interaction and regulation of PfHsp90. A previous genome-wide yeast two-hybrid study failed to identify PfAha1's association with PfHsp90, which prompted us to use a directed assay to investigate their interaction. PfAha1 was shown to interact with PfHsp90 via the in vivo split-ubiquitin assay and the association was confirmed in vitro by GST pull-down experiments. The GST pull-down assay further revealed PfAha1's interaction with PfHsp90 to be dependent on MgCl(2) and ATP, and was competed by co-chaperone Pfp23 that binds PfHsp90 under the same condition. In addition, the PfHsp90-PfAha1 complex was found to be sensitive to disruption by high salt, indicating a polar interaction between them. Using bio-computational modelling coupled with site-directed mutagenesis, the polar residue N108 in PfAha1 was found to be strategically located and essential for PfHsp90 interaction. The functional significance of PfAha1's interaction was clearly that of exerting a stimulatory effect on the ATPase activity of PfHsp90, likely to be essential for promoting the activation of PfHsp90's client proteins. PMID- 22100911 TI - Toll-like receptors 2 and 4 mediate the capacity of mesenchymal stromal cells to support the proliferation and differentiation of CD34+ cells. AB - Bone marrow derived-mesenchymal stromal cells (BM-MSCs) are multipotent, nonhematopoietic progenitors in a hematopoietic microenvironment and indispensable for regulating hematopoiesis. Several studies have reported that toll-like receptors (TLRs) are expressed in mesenchymal stromal cells (MSCs) to modulate their biological functions. In this study, we investigated the possible role(s) of TLRs in mediating the hematopoiesis-supporting role of human BM-MSCs. Human BM-MSCs were analyzed for mRNA expression of TLR1-10 by reverse transcription-polymerase chain reaction. TLR1-6, but not TLR7-10 were expressed by BM-MSCs. The protein expression of TLR2 and TLR4 was also confirmed by flow cytometry. We further explored the role of TLR2 and TLR4 in mediating the capacity of BM-MSCs to support the proliferation and differentiation of CD34(+) hematopoietic stem/progenitor cells obtained from cord blood. BM-MSCs increased proliferation of CD34(+) cells and promoted the differentiation towards the myeloid lineage 7 or 14days after co-culture, as well as colony formation by those cells and the production of interleukin 1 (IL-1), IL-8, IL-11, stem cell factor (SCF), granulocyte colony-stimulating factor (CSF), macrophage CSF and granulocyte-macrophage CSF, if MSCs had been stimulated with TLR2 agonist (PAM(3)CSK(4)) or TLR4 agonist (LPS). Interestingly, although these effects were elevated in a different degree, a synergistic effect was not observed in BM-MSCs co-stimulated with PAM(3)CSK(4) and LPS. Together, our findings suggest that TLR2 and TLR4 signaling may indirectly regulate hematopoiesis by modulating BM-MSCs' functions. The increased hematopoietic proliferation and differentiation could be mediated, at least in part, by augmented hematopoiesis-related cytokine production of BM-MSCs. PMID- 22100912 TI - The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells. AB - There is a growing evidence that the human homologue of the Drosophila headcase (HECA) plays an important role in human carcinogenesis. So far specific protein interaction partners and affected signaling pathways of HECA are still elusive. In a recent study we showed that HECA overexpression in oral squamous-cell carcinoma (OSCC) keratinocytes has tumor suppressive effects resulting in a recuperation of cell cycle control concerning the entry and progression of S phase, G2- and M-phase. Currently, quantitative RT-PCR and immunohistochemical analysis of primary tumor tissue from OSCC patients demonstrate that HECA expression is markedly decreased compared to normal control patients with abundant HECA expression. Additionally, there is nearly no HECA expression in OSCC metastases. Here, we show that HECA expression is negatively controlled by the Wnt-pathway and TCF4, a Wnt related transcription factor, binds to the HECA promoter. Furthermore, immunocytochemistry reveals colocalization of HECA with the cyclin dependent kinase CDK9. Immunoprecipitation experiments and proximity ligation assays further reveal an interaction of HECA with CDK2, CDK9, Cyclin A and Cyclin K, a direct transcriptional target of the p53 tumor suppressor. Silencing HECA in OSCC cell lines leads to a significant increase of cell division and a markedly increased resistance against the chemotherapeutic cisplatin. On the contrary, HECA overexpressing OSCC cell lines show decreased resistance of OSCC cells against cisplatin. Therefore, HECA could be considered as future therapeutic agent against Wnt-dependent tumor progression. PMID- 22100913 TI - Trends in utilization of management strategies for newly diagnosed atrial fibrillation patients in the United States: 1999 to 2008. AB - OBJECTIVE: To describe the trend in atrial fibrillation (AF) treatment strategies in newly diagnosed AF patients between 1999 and 2008. METHODS: The study was a retrospective cohort study of commercial health plans claims data. Newly diagnosed adult AF patients with >=1 claim for an AF-related intervention within 12 months of diagnosis were identified. Based on initial treatment, patients were classified into pharmacotherapy or nonpharmacotherapy groups. Pharmacotherapy group was subcategorized into rate-control or rhythm-control groups. Linear regression to assess linear trend and multinomial logistic regression to evaluate factors associated with treatment choice were conducted. RESULTS: Three thousand ninety-four newly diagnosed AF patients were identified. Eighty percent of these patients were initiated on pharmacotherapy with the majority (84%) receiving rate control medications only. Relative distribution of the 3 treatment groups remained similar over the study period. However, within the rate-control group, the use of beta blockers increased significantly (P < .001). Treatment with nonpharmacotherapy over rate-control medications was higher in males but lower in patients aged >=80 (relative risk ratio [RRR]: 1.67, 95% confidence interval [CI]: 1.27-2.20 and RRR: 0.48, 95% CI: 0.30-0.77, respectively). Having stroke and congestive heart failure significantly affected the treatment choice between nonpharmacotherapy and rate-control medications. CONCLUSION: Medication therapy, especially rate-control strategies, remains the preferred initial therapy of choice. PMID- 22100914 TI - Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL. AB - Patients with MCPH (autosomal recessive primary microcephaly) exhibit impaired brain development, presumably due to the compromised function of neuronal progenitors. Seven MCPH loci have been identified, including one that encodes centrosome protein 4.1 associated protein (CPAP; also known as centromere protein J, CENPJ). CPAP is a large coiled-coil protein enriched at the centrosome, a structure that comprises two centrioles and surrounding pericentriolar material (PCM). CPAP depletion impairs centriole formation, whereas CPAP overexpression results in overly long centrioles. The mechanisms by which CPAP MCPH patient mutations affect brain development are not clear. Here, we identify CPAP protein domains crucial for its centriolar localization, as well as for the elongation and the formation of centrioles. Furthermore, we demonstrate that conditions that resemble CPAP MCPH patient mutations compromise centriole formation in tissue culture cells. Using adhesive micropatterns, we reveal that such defects correlate with a randomization of spindle position. Moreover, we demonstrate that the MCPH protein SCL/TAL1 interrupting locus (STIL) is also essential for centriole formation and for proper spindle position. Our findings are compatible with the notion that mutations in CPAP and STIL cause MCPH because of aberrant spindle positioning in progenitor cells during brain development. PMID- 22100915 TI - NEK7 is essential for centriole duplication and centrosomal accumulation of pericentriolar material proteins in interphase cells. AB - The centrosomes in dividing cells follow a series of cyclical events of duplication and separation, which are tightly linked to the cell cycle. Serine/threonine-protein kinase NEK7 (NEK7) is a centrosomal kinase that is required for proper spindle formation during mitosis. In this study, we observed that centriole duplication was inhibited in NEK7-depleted cells. Ectopic expression of centrosome-directed NEK7 led to the formation of extra centrioles in a kinase-activity-dependent manner. We also observed extra centriole formation in centrosome-directed NEK6-expressing cells, suggesting that NEK6 and NEK7 might share biological activities that induce centriole duplication. The centrosomal pericentriolar material (PCM) proteins were significantly reduced in NEK7 depleted cells. The PCM proteins in NEK7-depleted cells did not accumulate at the centrosomes, even if the cells exited mitosis and progressed to the G2 phase. These results revealed that NEK7 is essential for PCM accumulation in a cell cycle stage-specific manner. Furthermore, HeLa cells depleted of NEK7 during S phase retained a higher quantity of PCM proteins and exhibited a less severe mitotic phenotype. On the basis of these results, we propose that NEK7 is involved in the recruitment of PCM proteins, which are necessary for both centriole duplication and spindle pole formation. Our study revealed that NEK7 activity is required for centrosome cycle progression not only at M phase, but also at G1 phase. PMID- 22100916 TI - Dynamics of CENP-N kinetochore binding during the cell cycle. AB - Accurate chromosome segregation requires the assembly of kinetochores, multiprotein complexes that assemble on the centromere of each sister chromatid. A key step in this process involves binding of the constitutive centromere associated network (CCAN) to CENP-A, the histone H3 variant that constitutes centromeric nucleosomes. This network is proposed to operate as a persistent structural scaffold for assembly of the outer kinetochore during mitosis. Here, we show by fluorescence resonance energy transfer (FRET) that the N-terminus of CENP-N lies in close proximity to the N-terminus of CENP-A in vivo, consistent with in vitro data showing direct binding of CENP-N to CENP-A. Furthermore, we demonstrate in living cells that CENP-N is bound to kinetochores during S phase and G2, but is largely absent from kinetochores during mitosis and G1. By measuring the dynamics of kinetochore binding, we reveal that CENP-N undergoes rapid exchange in G1 until the middle of S phase when it becomes stably associated with kinetochores. The majority of CENP-N is loaded during S phase and dissociates again during G2. We propose a model in which CENP-N functions as a fidelity factor during centromeric replication and reveal that the CCAN network is considerably more dynamic than previously appreciated. PMID- 22100917 TI - A dominant-negative form of POM121 binds chromatin and disrupts the two separate modes of nuclear pore assembly. AB - Nuclear pore complexes (NPCs) are formed during two separate stages of the metazoan cell cycle. They are assembled into the re-forming nuclear envelope (NE) at the exit from mitosis and into an intact, expanding NE during interphase. Here, we show that a soluble internal fragment of the membrane nucleoporin POM121 has a dominant-negative effect on both modes of assembly in a cell-free reconstitution system. The soluble POM121 fragment binds chromatin at sites that are distinct from ELYS-Nup107-160 'seeding' sites and prevents membrane enclosure and NPC formation. Importin-beta negatively regulates chromatin binding by the POM121 fragment through a conserved NLS motif and is also shown to affect the recruitment of the endogenous membrane protein to chromatin in the full assembly system. When an intact NE is present before the addition of the dominant-negative fragment, NPCs are inserted into the NE but membrane expansion is inhibited. This results in densely packed NPCs with no intervening membrane patches, as visualized by scanning electron microscopy. We conclude that POM121 plays an important role in both modes of assembly and links nuclear membrane formation and expansion to nuclear pore biogenesis. PMID- 22100918 TI - RanGTP is required for meiotic spindle organization and the initiation of embryonic development in Drosophila. AB - RanGTP is important for chromosome-dependent spindle assembly in Xenopus extracts. Here we report on experiments to determine the role of the Ran pathway on microtubule dynamics in Drosophila oocytes and embryos. Females expressing a dominant-negative form of Ran have fertility defects, suggesting that RanGTP is required for normal fertility. This is not, however, because of a defect in acentrosomal meiotic spindle assembly. Therefore, RanGTP does not appear to be essential or sufficient for the formation of the acentrosomal spindle. Instead, the most important function of the Ran pathway in spindle assembly appears to be in the tapering of microtubules at the spindle poles, which might be through regulation of proteins such as TACC and the HURP homolog, Mars. One consequence of this spindle organization defect is an increase in the nondisjunction of achiasmate chromosomes. However, the meiotic defects are not severe enough to cause the decreased fertility. Reductions in fertility occur because RanGTP has a role in microtubule assembly that is not directly nucleated by the chromosomes. This includes microtubules nucleated from the sperm aster, which are required for pronuclear fusion. We propose that following nuclear envelope breakdown, RanGTP is released from the nucleus and creates a cytoplasm that is activated for assembling microtubules, which is important for processes such as pronuclear fusion. Around the chromosomes, however, RanGTP might be redundant with other factors such as the chromosome passenger complex. PMID- 22100919 TI - Rab28 function in trypanosomes: interactions with retromer and ESCRT pathways. AB - Early endosomal cargo is typically targeted to either a degradative or recycling pathway. Despite established functions for the retromer and ESCRT complexes at late endosomes/multivesicular bodies, the mechanisms integrating and coordinating these functions remain largely unknown. Rab family GTPases are key membrane trafficking organizers and could contribute. Here, in the unicellular organism Trypanosoma brucei, we demonstrate that Rab28 locates to the endosomal pathway and partially colocalizes with Vps23, an ESCRT I component. Rab28 is required for turnover of endocytosed proteins and for lysosomal delivery of protein cargo. Using RNA interference we find that in Rab28-depleted cells, protein levels of ESCRT I (Vps23/28) and retromer (Vps26) are also decreased, suggesting that Rab28 is an important regulator of these factors. We suggest that Rab28 coordinates the activity of retromer-dependent trafficking and ESCRT-mediated degradative pathways. PMID- 22100920 TI - p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit. AB - Accurate chromosome segregation requires the spindle assembly checkpoint to be active at the onset of mitosis, before being silenced following chromosome alignment. p31(comet) is a checkpoint antagonist in that its inhibition delays mitotic exit, whereas its overexpression overrides the checkpoint. How exactly p31(comet) antagonises the checkpoint is unclear. A prevalent model is that p31(comet) acts as a 'cap' by inhibiting recruitment of the open conformation form of Mad2 (O-Mad2) to the kinetochore-bound complex of Mad1-C-Mad2 (closed conformation Mad2), an essential step that is required for checkpoint activation. Here, we show that although p31(comet) localises to kinetochores in mitosis, modulation of its activity has no effect on recruitment of O-Mad2 to kinetochores. Rather, our observations support a checkpoint-silencing role for p31(comet) downstream of kinetochores. We show that p31(comet) binds Mad2 when it is bound to the mitotic checkpoint complex (MCC) components BubR1 and Cdc20. Furthermore, RNAi-mediated inhibition of p31(comet) results in more Mad2 bound to BubR1-Cdc20, and conversely, overexpression of p31(comet) results in less Mad2 bound to BubR1-Cdc20. Addition of recombinant p31(comet) to checkpoint-arrested extracts removes Mad2 from the MCC, whereas a p31(comet) mutant that cannot bind Mad2 has no effect. Significantly, expression of a Mad2 mutant that cannot bind p31(comet) prolongs the metaphase to anaphase transition. Taken together, our data support the notion that p31(comet) negatively regulates the spindle assembly checkpoint by extracting Mad2 from the MCC. PMID- 22100921 TI - MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination. AB - Signaling through cyclic AMP (cAMP) has been implicated in the regulation of Schwann cell (SC) proliferation and differentiation. In quiescent SCs, elevation of cAMP promotes the expression of proteins associated with myelination such as Krox-20 and P0, and downregulation of markers associated with the non-myelinating SC phenotype. We have previously shown that the motor protein myosin II is required for the establishment of normal SC-axon interactions, differentiation and myelination, however, the mechanisms behind these effects are unknown. Here we report that the levels and activity of myosin light chain kinase (MLCK), an enzyme that regulates MLC phosphorylation in non-muscle cells, are dramatically downregulated in SCs after cAMP treatment, in a similar pattern to that of c-Jun, a known inhibitor of myelination. Knockdown of MLCK in SCs mimics the effect of cAMP elevation, inducing plasma membrane expansion and expression of Krox-20 and myelin proteins. Despite activation of myelin gene transcription these cells fail to make compact myelin when placed in contact with axons. Our data indicate that myosin II activity is differentially regulated at various stages during myelination and that in the absence of MLCK the processes of SC differentiation and compact myelin assembly are uncoupled. PMID- 22100922 TI - A role for seipin in lipid droplet dynamics and inheritance in yeast. AB - Malfunctions of processes involved in cellular lipid storage and mobilization induce the pathogenesis of prevalent human diseases such as obesity, type 2 diabetes and atherosclerosis. Lipid droplets are the main lipid storage depots for neutral lipids in eukaryotic cells, and as such fulfil an essential function to balance cellular lipid metabolism and energy homeostasis. Despite significant progress in identifying key metabolic enzymes involved in lipid storage and their regulation in various model organisms, some fundamental questions as to the biogenesis, subcellular distribution and inheritance of lipid droplets are as yet unsolved. In this study, we applied a set of imaging techniques such as high resolution four-dimensional (4D) live-cell imaging, quantitative microscopy, transmission electron microscopy and electron tomography to gain insight into the spatio-temporal organization of lipid droplets during cellular growth in the yeast Saccharomyces cerevisiae. This analysis revealed a high level of organization of the subcellular positioning of lipid droplets in individual cells, their directed migration towards the cellular periphery and a coordinated transfer of a subpopulation of lipid droplets into daughter cells during cell division. Lipid droplets appear to remain associated with ER membranes during cellular growth independently of their size and subcellular localization. Deletion of FLD1, the functional orthologue of the human BSCL2 gene encoding seipin, leads to impaired dynamics of yeast lipid droplets and defective lipolysis, which might be due to aberrant ER structures in these mutants. Our data suggest a role for yeast seipin as a scaffolding protein that is required for the dynamics of a specific subdomain of the ER, and provide a new aspect for the interpretation of abnormal lipid droplets phenotypes in yeast mutants lacking seipin. PMID- 22100923 TI - Force- and Ca2+-dependent internalization of integrins in cultured endothelial cells. AB - The effects of mechanical force applied to the integrin clusters at focal contacts were examined in cultured human umbilical vein endothelial cells. When a fibronectin-coated glass bead was attached to the apical cell surface, focal contacts formed beneath the bead that became linked to focal contacts at the basal cell membrane by actin stress fibers in 5 minutes. Integrin dynamics at the basal focal contacts were monitored in live cells in response to a localized mechanical stimulus generated by displacing the glass bead. Traction force transmitted to the basal focal contacts through the stress fibers was monitored by measuring the deformation of the polyacrylamide gel substratum. The force declined in a few seconds, probably owing to decreases in the elastic modulus of the stress fibers. This transient mechanical stimulus caused the dephosphorylation of paxillin and disassembly of integrin clusters at the basal cell membrane in 20 minutes. The disassembly was mediated mainly by clathrin dependent endocytosis of integrins. The integrin internalization was inhibited in Ca(2+)- and K(+)-free solution, and by phenylarsine oxide, a phosphatase inhibitor. These results suggest that a transient mechanical stimulus applied to focal contacts induces Ca(2+)-dependent dephosphorylation of some proteins, including paxillin, and facilitates clathrin-dependent endocytosis of integrins. PMID- 22100925 TI - Aortic valve replacement with smaller valve size. AB - The occurrence of prosthesis-patient mismatch after aortic valve replacement with a small valve size was evaluated in 249 patients, focusing on echocardiographic data. Aortic valve pathology included regurgitation in 174 patients and stenosis in 75. Echocardiography was performed in the early and late postoperative periods. A projected effective orifice area index < 0.85 cm(2).m(-2) was noted in 56 patients; values >= 0.85 cm(2).m(-2) were found in 128. Postoperative changes in ejection fraction, left ventricular mass regression, and peak transprosthetic gradient were similar in both groups. Small prostheses (<= 19 mm) were used in 43 patients who had significantly higher postoperative transprosthetic gradients in both the early and late periods, compared to those with larger prostheses. Our findings show that the occurrence of prosthesis-patient mismatch after aortic valve replacement is rare. Left ventricular mass regression occurred in most patients, with acceptable transprosthetic gradients. PMID- 22100926 TI - Ruptured sinus of Valsalva aneurysm: 10-year Indian surgical experience. AB - Sinus of Valsalva aneurysm is a rare anomaly with a higher incidence in Eastern than Western populations. Recent improvements in diagnostic techniques have resulted in more patients undergoing surgical repair. Uncorrected, the intracardiac shunts and frequently associated cardiac lesions cause a preventable deterioration in heart function. We retrospectively analyzed the data of 33 patients who underwent repair of ruptured sinus of Valsalva aneurysm from May 2000 to January 2010. The aneurysms originated from the right coronary sinus in 24 patients and from the noncoronary sinus in 9, and ruptured into the right ventricle in 21, right atrium in 10, and left ventricle in 2. Operative procedures included simple plication (1), patch repair (32), and aortic valve replacement (10). There were 3 early deaths. The 30 survivors were followed up for 5.4 +/- 2.6 years; all had an improvement in functional class, with superior results in those with no aortic regurgitation. Surgical treatment of ruptured sinus of Valsalva aneurysm has an acceptably low operative risk and good long term symptom-freedom survival. An early aggressive approach is recommended to prevent worsening symptoms and more extensive disease. PMID- 22100927 TI - Computed tomographic angiography in tetralogy of Fallot. AB - Echocardiography is often inadequate for imaging tetralogy of Fallot, prompting cineangiography. This study prospectively evaluated multidetector computed tomographic angiography for preoperative evaluation of tetralogy of Fallot in 112 consecutive patients. Forty-eight had nonconfluent or hypoplastic pulmonary arteries (mean z-score, -2; range, -11.1-0.13) permitting only palliative or no surgery; 64 had adequate pulmonary artery anatomy (mean z-score, 0.59; range, 2.53-3.4) allowing total repair. The surgical data of 50 patients who underwent total correction were compared with transthoracic echocardiography and multidetector computed tomographic angiography findings. Multidetector computed tomographic angiography tended to reveal unsuspected collaterals and coronary abnormalities besides outlining the right ventricular outflow tract and pulmonary artery branches. The branch pulmonary artery diameter z-score was the most important determinant of surgical strategy, with the worst figures being associated with no surgical options or palliative surgery, and the best figures leading to corrective surgery. The mean radiation dose was 3.45 mSv. Multidetector computed tomographic angiography is a powerful supplement to echocardiography in the preoperative evaluation of tetralogy of Fallot. PMID- 22100928 TI - Association between body mass index and outcome of coronary artery bypass. AB - Studies have shown disparate findings regarding body mass index and outcomes after coronary artery bypass. We analyzed body mass index and other clinical variables that might predict morbidity and mortality after primary isolated coronary artery bypass. Data on 4,425 patients (79% men) were reviewed retrospectively. They were classified as underweight (1.6%), normal weight (65%), obese (32%), and morbidly obese (1.4%) according to body mass index <20, 20-29, 30-39, and >40 kg.m(-2), respectively. Multiple logistic regression was used for correlates of 30-day outcome. Cox regression was used for predictors of late outcome in underweight and morbidly obese patients. There were 45 (1%) deaths and 234 (5%) cases of morbidity within 30 days. Independent correlates of 30-day morbidity were smoking, logistic EuroSCORE, blood and blood product transfusions. Correlates of 30-day mortality were logistic EuroSCORE and blood transfusion. The only independent predictor of late death in underweight and morbidly obese patients was preoperative arrhythmia. Body mass index was not a predictor of 30 day morbidity or mortality. The 1-, 3-, and 7-year survival rates were not significantly different between underweight and morbidly obese patients. Body mass index did not affect short-term outcomes after primary coronary artery bypass grafting. PMID- 22100929 TI - Effect of right ventricular pacing site on QRS width. AB - To assess the effect of various right ventricular pacing sites on QRS duration, we enrolled 50 patients (mean age, 64 +/- 13 years; 36 men); 16 had bradycardia and 34 had tachycardia. The right ventricle was arbitrarily divided into 5 sections: high and low right ventricular outflow tract, mid septum, low septum, and apex. Right ventricular pacing was performed using an electrode catheter at each of the 5 sites. QRS duration was 162 +/- 20 ms during high right ventricular outflow tract pacing, 143 +/- 17 ms during low right ventricular outflow tract pacing, 151 +/- 20 ms during mid-septal pacing, 163 +/- 16 ms during low-septal pacing, and 167 +/- 18 ms during apical pacing. Paced QRS duration was shorter during low right ventricular outflow tract and mid-septal pacing compared to apical pacing in 34 patients. There was a difference of 10 ms or less in the paced QRS duration between these pacing sites in the other 16 patients. QRS duration was shortest when the septum was paced in the right ventricle. However, QRS duration was similar during pacing in the septum and the apex in 32% of patients. PMID- 22100930 TI - Pneumocephalus and pneumococcal meningitis after thoracic surgery. AB - A 62-year-old man with adenocarcinoma underwent complete resection with a right upper lobectomy and en-bloc resection of the chest wall, with metallic clips applied to the vertebral nerve roots. A sudden deterioration in neurological status occurred due to pneumocephalus and ascending bacterial meningitis resulting from a subarachnoid-pleural fistula. The neurological status normalized after thoracoplasty and ceftriaxone treatment. PMID- 22100931 TI - An unusual case of left chest stab wound. AB - A 72-year-old man was admitted with one blade of a huge pair of shears in his left thorax. His hemodynamics deteriorated due to life-threatening vascular lesions. An urgent thoracotomy revealed several injuries to the intercostal vessels and left apical inferior lung lobe. The blade tip was stuck in the posterior chest wall, 2 cm adjacent to the descending aorta. The blade was removed, the lung was sutured, and the patient made a good recovery. PMID- 22100932 TI - Aortoesophageal fistula after thoracic stent grafting. AB - Aortoesophageal fistula after thoracic stent grafting is rare and usually fatal. A 66-year-old woman developed an aortoesophageal fistula 1 month after endovascular stent grafting of the thoracic aorta for a complicated type B dissection. She had a fatal episode of massive bleeding before she could be treated. The limited treatment options are discussed. PMID- 22100933 TI - Preoperative embolization of aberrant systemic artery in sequestration of lung. AB - A 40-year-old man presented with left lower lobe pneumonia that failed to resolve on antibiotic therapy. Computed tomography revealed intralobar sequestration of the left lower lobe supplied by a large artery from the descending aorta. The aberrant artery was embolized using polyvinyl alcohol particles. The sequestered tissue was resected 3 weeks later. Identification and control of the aberrant artery is essential to avoid inadvertent injury and massive hemorrhage. PMID- 22100934 TI - Ectopic hepatocellular carcinomas developed in the chest wall and skull. AB - A 68-year-old man presented with a suppurating mass on his skull and a palpable mass on his right upper thoracic wall. Computed tomography revealed a round mass, 70 mm in diameter, invading the right pleural cavity, and a second tumor infiltrating the skull through the left parietal bone. Both masses were resected simultaneously. Histopathology showed that both tumors were hepatocellular carcinomas. PMID- 22100935 TI - Right atrial thrombus migrating to the superior vena cava during surgery. AB - Free-floating right heart thrombi are extremely mobile structures that carry a very high mortality rate. We describe a case of pulmonary embolism with a free floating right heart thrombus that migrated to the superior vena cava during the institution of cardiopulmonary bypass. PMID- 22100936 TI - Simplified closure of ministernotomy using thermoreactive sternal clips. AB - An increasing number of aortic valve replacements are performed through a ministernotomy. Due to the small incision and partial fixation of the caudal sternum, the traditional wire closure can be complicated and even harmful to the surrounding tissue. In such cases, we recommend the use of nitinol clips for sternal closure. This technique, which we have used in 48 patients, is simple, safe, and fast, and results in excellent outcomes. PMID- 22100937 TI - Pulmonary arteriovenous malformation in Osler-Weber-Rendu syndrome. PMID- 22100938 TI - End-systolic murmur due to membranous interventricular septal aneurysm. PMID- 22100939 TI - Lung cancer in the native lung after single-lung transplantation. PMID- 22100940 TI - Complete bronchial obstruction without distal lung atelectasis. PMID- 22100942 TI - Ptosis. PMID- 22100943 TI - Tardive movement disorders: a practical approach. PMID- 22100944 TI - CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. PMID- 22100945 TI - An unusual cause of carpal tunnel syndrome. PMID- 22100946 TI - Seronegative limbic encephalitis: case report, literature review and proposed treatment algorithm. PMID- 22100947 TI - Simple dramatic research. PMID- 22100948 TI - Gesundheit! Sneezing, paraesthesiae and ataxia in a 35-year-old man. PMID- 22100949 TI - Ignorant of ignorance? PMID- 22100950 TI - General paralysis of the insane. PMID- 22100951 TI - It's just petit mal: she'll grow out of it. PMID- 22100952 TI - Stroke thrombolysis in Mombasa--an outreach service. PMID- 22100953 TI - Soduko. PMID- 22100954 TI - How healthy is UK neurology? A personal perspective. PMID- 22100955 TI - MS: the big knit. PMID- 22100956 TI - Neurologists 'suited and booted' and not a desk in sight. PMID- 22100957 TI - Who is really the world's best known neurologist? PMID- 22100958 TI - The world's most famous neurologist? A rapid response. PMID- 22100959 TI - Urinary F2-isoprostanes as a biomarker of reduced risk of type 2 diabetes. AB - OBJECTIVE: We have previously reported evidence of an inverse association between a urinary F(2)-isoprostane and type 2 diabetes risk in a pilot case-control study nested within the Insulin Resistance Atherosclerosis Study (IRAS). Here, we report the results from the study extended to the entire IRAS cohort. RESEARCH DESIGN AND METHODS: This prospective study included 138 incident type 2 diabetes case and 714 noncase subjects. Four F(2)-isoprostanes (iPF2alpha-III; 2,3-dinor iPF2alpha-III; iPF2alpha-VI; and 8,12-iso-iPF2alpha-VI) were assayed in baseline urine samples using liquid chromatography-tandem mass spectrometry. RESULTS: Three F(2)-isoprostanes showed significant inverse associations with type 2 diabetes risk: the adjusted odds ratios were 0.52 (95% CI 0.39-0.67), 0.56 (0.42 0.73), 0.62 (0.48-0.79), and 0.91 (0.72-1.12) for iPF2alpha-III; 2,3-dinor iPF2alpha-III; iPF2alpha-VI; and 8,12-iso-iPF2alpha-VI, respectively. CONCLUSIONS: Our findings indicate that urinary F(2)-isoprostanes are inversely associated with type 2 diabetes risk beyond the traditional risk factors and may be useful in identifying high-risk populations. PMID- 22100960 TI - Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. AB - OBJECTIVE: Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives. RESEARCH DESIGN AND METHODS: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. RESULTS: Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives. CONCLUSIONS: In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated. PMID- 22100961 TI - A prospective study of the associations between treated diabetes and cancer outcomes. AB - OBJECTIVE: To quantify the association of treated diabetes with cancer incidence and cancer mortality as well as cancer case fatality and all-cause mortality in adults who subsequently develop cancer and to calculate attributable fractions due to diabetes on various cancer outcomes. RESEARCH DESIGN AND METHODS: Prospective data on 599 diabetic and 17,681 nondiabetic adults from the CLUE II (Give Us a Clue to Cancer and Heart Disease) cohort in Washington County, Maryland, were analyzed. Diabetes was defined by self-reported use of diabetes medications at baseline. Cancer incidence was ascertained using county and state cancer registries. Mortality data were obtained from death certificates. RESULTS: From 1989 to 2006, 116 diabetic and 2,365 nondiabetic adults developed cancer, corresponding to age-adjusted incidence of 13.25 and 10.58 per 1,000 person years, respectively. Adjusting for age, sex, education, BMI, smoking, hypertension treatment, and high cholesterol treatment using Cox proportional hazards regression, diabetes was associated with a higher risk of incident cancer (hazard ratio 1.22 [95% CI 0.98-1.53]) and cancer mortality (1.36 [1.02-1.81]). In individuals who developed cancer, adults with diabetes had a higher risk of cancer case fatality (1.34 [1.002-1.79]) and all-cause mortality (1.61 [1.29 2.01]). For colorectal, breast, and prostate cancers, the attributable fractions resulting from diabetes were larger for cancer fatality and mortality than cancer incidence. CONCLUSIONS: In this prospective cohort, diabetes appears to exert a greater influence downstream on the risk of mortality in people with cancer than on upstream risk of incident cancer. PMID- 22100962 TI - Overwhelmed patients: a videographic analysis of how patients with type 2 diabetes and clinicians articulate and address treatment burden during clinical encounters. AB - OBJECTIVE: Patients with diabetes may experience high burden of treatment (BOT), including treatment-related effects and self-care demands. We examined whether patients with type 2 diabetes and their clinicians discuss BOT, the characteristics of their discussions, and their attempts to address BOT during visits. RESEARCH DESIGN AND METHODS: Two coders independently reviewed videos of 46 primary care visits obtained during a practice-based trial and identified utterances concerning BOT, classifying them by topic and by whether BOT was addressed (i.e., whether statements emerged aimed at alleviating BOT). RESULTS: Of the 46 visits, 43 (93.5%) contained BOT discussions. Both coders identified 83 discussions: 12 involving monitoring, 28 treatment administration, 19 access, and 24 treatment effects. BOT was unambiguously addressed only 30% of the time. CONCLUSIONS: BOT discussions usually arise during visits but rarely beget problem solving efforts. These discussions represent missed opportunities for reducing treatment-related disruptions in the lives of patients with diabetes, which may affect adherence and well-being. PMID- 22100963 TI - Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. AB - OBJECTIVE: To determine whether short-time, real-time continuous glucose monitoring (RT-CGM) has long-term salutary glycemic effects in patients with type 2 diabetes who are not on prandial insulin. RESEARCH DESIGN AND METHODS: This was a randomized controlled trial of 100 adults with type 2 diabetes who were not on prandial insulin. This study compared the effects of 12 weeks of intermittent RT CGM with self-monitoring of blood glucose (SMBG) on glycemic control over a 40 week follow-up period. Subjects received diabetes care from their regular provider without therapeutic intervention from the study team. RESULTS: There was a significant difference in A1C at the end of the 3-month active intervention that was sustained during the follow-up period. The mean, unadjusted A1C decreased by 1.0, 1.2, 0.8, and 0.8% in the RT-CGM group vs. 0.5, 0.5, 0.5, and 0.2% in the SMBG group at 12, 24, 38, and 52 weeks, respectively (P = 0.04). There was a significantly greater decline in A1C over the course of the study for the RT-CGM group than for the SMBG group, after adjusting for covariates (P < 0.0001). The subjects who used RT-CGM per protocol (>=48 days) improved the most (P < 0.0001). The improvement in the RT-CGM group occurred without a greater intensification of medication compared with those in the SMBG group. CONCLUSIONS: Subjects with type 2 diabetes not on prandial insulin who used RT-CGM intermittently for 12 weeks significantly improved glycemic control at 12 weeks and sustained the improvement without RT-CGM during the 40-week follow-up period, compared with those who used only SMBG. PMID- 22100964 TI - Explaining the increase of diabetes prevalence and plasma glucose in Mauritius. AB - OBJECTIVE: Secular trends in the epidemiology of diabetes are best described by studying the same population over time, but few such studies exist. Using surveys from Mauritius in 1987 and 2009, we examined 1) the change in the prevalence of diabetes, 2) the extent to which changes in traditional diabetes risk factors explained the increase, and 3) the change in the distribution of plasma glucose levels over time. RESEARCH DESIGN AND METHODS: Independent population-based surveys were undertaken in Mauritius in 1987 and 2009 using similar methodology in adults aged 20-74 years. Physical measurements and fasting blood samples were taken, and an oral glucose tolerance test was performed at both surveys. RESULTS: The age-standardized prevalence of diabetes in 2009 was 22.3% (95% CI 20.0-24.6) among men and 20.2% (18.3-22.3) among women, representing an increase since 1987 of 64 and 62% among men and women, respectively. Concurrent changes in the distribution of age, ethnicity, waist circumference, BMI, physical activity, smoking, family history of diabetes, and hypertension explained more of the increase in the prevalence of diabetes in men than in women. Increases in plasma glucose (especially fasting glucose) were seen across the population but were greater at the upper levels. CONCLUSIONS: In Mauritius, there has been a marked increase in diabetes prevalence over 22 years. This mainly results from changes in traditional risk factors, leading to population-wide increases in plasma glucose levels. Interventions to control this escalation of diabetes should focus on population-wide strategies. PMID- 22100965 TI - High plasma 5-hydroxyindole-3-acetic acid concentrations in subjects with metabolic syndrome. AB - OBJECTIVE: Serotonin mediates vasoconstriction and induces the activation of platelets, which may promote atherosclerosis. The aim of this study was to investigate whether plasma 5-hydroxyindole-3-acetic acid (5-HIAA; a derivative end product of serotonin) concentrations are high in subjects with metabolic syndrome (MetS) and to investigate the relationship between plasma 5-HIAA concentrations and clinical and biochemical metabolic parameters. RESEARCH DESIGN AND METHODS: Plasma 5-HIAA concentrations were measured in 311 subjects (152 men and 159 women) recruited from the Oike Clinic, which provides regular health check-ups for employees. We evaluated the relationship between plasma 5-HIAA concentrations and clinical and biochemical metabolic parameters, including waist circumference, serum lipid concentrations, fasting plasma glucose, or blood pressure. RESULTS: Plasma 5-HIAA concentrations were higher in subjects with MetS than in those without, in both men (6.5 +/- 4.4 vs. 4.9 +/- 1.3 ng/mL, P < 0.005) and women (7.9 +/- 6.5 vs. 5.2 +/- 1.6 ng/mL, P < 0.005). In men, fasting plasma glucose (r = 0.197, P = 0.0146) was positively correlated, whereas HDL cholesterol (r = -0.217, P = 0.0071) was negatively correlated, with logarithmic (log) (plasma 5-HIAA concentrations). In women, triglycerides (r = 0.252, P = 0.0013) and fasting plasma glucose (r = 0.344, P < 0.0001) were positively correlated, whereas HDL cholesterol (r = -0.328, P < 0.0001) was negatively correlated, with log (5-HIAA concentrations). Furthermore, log (plasma 5-HIAA concentrations) were higher in subjects with more components of MetS. CONCLUSIONS: Plasma 5-HIAA concentrations are high in subjects with MetS, suggesting the potential importance of serotonin in the development of cardiovascular disease in MetS. PMID- 22100966 TI - Assessment of the medial dorsal cutaneous, dorsal sural, and medial plantar nerves in impaired glucose tolerance and diabetic patients with normal sural and superficial peroneal nerve responses. AB - OBJECTIVE: This study evaluated the nerve conduction study (NCS) parameters of the most distal sensory nerves of the lower extremities-namely, the medial dorsal cutaneous (MDC), dorsal sural (DS), and medial plantar (MP) nerves-in diabetic (DM) and impaired glucose tolerance (IGT) patients who displayed normal findings on their routine NCSs. RESEARCH DESIGN AND METHODS: Standard NCSs were performed on healthy control (HC), DM, and IGT groups (N = 147). The bilateral NCS parameters of the MDC, DS, and MP nerves were investigated. The Toronto Clinical Scoring System (TCSS) was assessed for the DM and IGT groups. RESULTS: The mean TCSS scores of the IGT and DM groups were 2.5 +/- 2.3 and 2.8 +/- 2.2, respectively. No significant differences between the two groups were observed. After adjustment of age and BMI, the DM group showed significant NCS differences in DS and MDC nerves compared with the HC group (P < 0.05). These differences were also exhibited in the left DS of the IGT group (P = 0.0003). More advanced NCS findings were observed in the DM group. Bilateral abnormal NCS responses in these distal sensory nerves were found in 40 and 16% of DM and IGT patients, respectively. CONCLUSIONS: These results showed that the simultaneous assessment of the most distal sensory nerves allowed the detection of early NCS changes in the IGT and DM groups, even when the routine NCS showed normal findings. PMID- 22100967 TI - Processed and unprocessed red meat consumption and incident type 2 diabetes among French women. AB - OBJECTIVE: To evaluate the relation of processed and unprocessed red meat and incident type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a prospective study among 66,118 disease-free French women with dietary information from a validated questionnaire. Between 1993 and 2007, we identified 1,369 cases of incident diabetes. Multivariate analyses were adjusted for age, education, region, smoking, BMI, hypertension, hypercholesterolemia, physical activity, parental history of diabetes, menopause, hormone replacement therapy, alcohol, calories, n-3 fatty acids, carbohydrates, coffee, fiber, and fruits and vegetables. RESULTS: Comparing the highest category of processed meat intake, >=5 servings/week (median, 48 g/day), to the lowest, <1 serving/week (median, 5 g/day), processed meat was significantly associated with incident diabetes (hazard ratio 1.30 [95% CI 1.07-1.59], P trend = 0.0007; for 1 serving/day, 1.29 [1.14-1.45]). Unprocessed red meat was not associated with diabetes. CONCLUSIONS: In this large prospective cohort of French women, a direct association was observed only for processed red meat and type 2 diabetes. PMID- 22100968 TI - Size at birth, weight gain in infancy and childhood, and adult diabetes risk in five low- or middle-income country birth cohorts. AB - OBJECTIVE: We examined associations of birth weight and weight gain in infancy and early childhood with type 2 diabetes (DM) risk in five cohorts from low- and middle-income countries. RESEARCH DESIGN AND METHODS: Participants were 6,511 young adults from Brazil, Guatemala, India, the Philippines, and South Africa. Exposures were weight at birth, at 24 and 48 months, and adult weight, and conditional weight gain (CWG, deviation from expected weight gain) between these ages. Outcomes were adult fasting glucose, impaired fasting glucose or DM (IFG/DM), and insulin resistance homeostasis model assessment (IR-HOMA, three cohorts). RESULTS: Birth weight was inversely associated with adult glucose and risk of IFG/DM (odds ratio 0.91[95% CI 0.84-0.99] per SD). Weight at 24 and 48 months and CWG 0-24 and 24-48 months were unrelated to glucose and IFG/DM; however, CWG 48 months-adulthood was positively related to IFG/DM (1.32 [1.22 1.43] per SD). After adjusting for adult waist circumference, birth weight, weight at 24 and 48 months and CWG 0-24 months were inversely associated with glucose and IFG/DM. Birth weight was unrelated to IR-HOMA, whereas greater CWG at 0-24 and 24-48 months and 48 months-adulthood predicted higher IR-HOMA (all P < 0.001). After adjusting for adult waist circumference, birth weight was inversely related to IR-HOMA. CONCLUSIONS: Lower birth weight and accelerated weight gain after 48 months are risk factors for adult glucose intolerance. Accelerated weight gain between 0 and 24 months did not predict glucose intolerance but did predict higher insulin resistance. PMID- 22100969 TI - Detection of inadequate effort on neuropsychological testing: a meta-analytic update and extension. AB - The present meta-analysis provides the first meta-analysis of research on stand alone neurocognitive feigning tests since publication of the preceding paper by Vickery, Berry, Inman, Harris & Orey (2001). Studies of dedicated neurocognitive feigning test performances in adults appearing in published or unpublished (theses and dissertations) sources through October 2010 were reviewed and subjected to stringent inclusion criteria to maximize the validity of results. Neurocognitive feigning tests were included only if at least three contrasts of criterion-supported honest patient groups and feigners were available. Tests that met criteria for review included the Victoria Symptom Validity Test, used as an anchor to compare Vickery and colleagues' results; Test of Memory Malingering, Word Memory Test, Letter Memory Test, and Medical Symptom Validity Test. Effect sizes and test parameters at published cut scores were compiled and compared. Results reflected large effect sizes for all measures (mean d = 1.55, 95% confidence interval [CI] = 1.48-1.63). Mean specificity was 0.90 (95% CI = 0.85 0.94). Mean sensitivity was 0.69 (95% CI = 0.63-0.75). Several moderators of effect size were identified, with certain manipulations resulting in a weakening of effect size. Unexpectedly, warning simulators to feign believably increased effect sizes. PMID- 22100972 TI - Mitochondrial fission in endothelial cells after simulated ischemia/reperfusion: role of nitric oxide and reactive oxygen species. AB - Ischemia (I)/reperfusion (RP)-induced endothelial cell (EC) injury is thought to be due to mitochondrial reactive oxygen species (mtROS) production. MtROS have been implicated in mitochondrial fission. We determined whether cultured EC exposure to simulated I/RP causes morphological changes in the mitochondrial network and the mechanisms behind those changes. Because shear stress results in nitric oxide (NO)-mediated endothelial mtROS generation, we simulated I/RP as hypoxia (H) followed by oxygenated flow over the ECs (shear stress of 10dyn/cm(2)). By exposing ECs to shear stress, H, H/reoxygenation (RO), or simulated I/RP and employing MitoTracker staining, we assessed the differential effects of changes in mechanical forces and/or O(2) levels on the mitochondrial network. Static or sheared ECs maintained their mitochondrial network. H- or H/RO exposed ECs underwent changes, but mitochondrial fission was significantly less compared to that in ECs exposed to I/RP. I/RP-induced fission was partially inhibited by antioxidants, a NO synthase inhibitor, or an inhibitor of the fission protein dynamin-related protein 1 (Drp1) and was accompanied by Drp1 oligomerization and phosphorylation (Ser616). Hence, shear-induced NO, ROS (including mtROS), and Drp1 activation are responsible for mitochondrial fission in I/RP-exposed ECs, and excessive fission may be an underlying cause of EC dysfunction in postischemic hearts. PMID- 22100973 TI - 8-Oxoguanine-DNA glycosylase 1 deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice. AB - 8-Oxoguanine-DNA glycosylase (OGG-1) is a base excision DNA repair enzyme; however, its function in modulating allergic diseases remains undefined. Using OGG-1 knockout (KO) mice, we show that this protein affects allergic airway inflammation after sensitization and challenge by ovalbumin(OVA). OGG-1 KO mice exhibited less inflammatory cell infiltration and reduced oxidative stress in the lungs after OVA challenge compared to WT mice. The KO phenotype included decreased IL-4, IL-6, IL-10, and IL-17 in lung tissues. In addition, OGG-1 KO mice showed decreased expression and phosphorylation of STAT6 as well as NF kappaB. Down-regulation of OGG-1 by siRNA lowered ROS and IL-4 levels but increased IFN-gamma production in cultured epithelial cells after exposure to house dust mite extracts. OGG-1 may affect the levels of oxidative stress and proinflammatory cytokines during asthmatic conditions. OGG-1 deficiency negatively regulates allergen-induced airway inflammatory response. PMID- 22100974 TI - Construction of a novel sacB-based system for marker-free gene deletion in Corynebacterium glutamicum. AB - Bacillus subtilis sacB gene with its 463bp upstream region including its native promoter has been used for marker-free gene deletion in Corynebacterium glutamicum, but the role of this upstream region is not clear. In this study, it was demonstrated that the upstream region of sacB failed to efficiently promote its expression in C. glutamicum, and the native promoter of sacB is weak in C. glutamicum. The expression level of sacB under its native promoter in C. glutamicum is not high enough for cells to confer sucrose sensitivity. Therefore, a new promoter PlacM and a novel vector pDXW-3 were constructed. PlacM is 18 times stronger than the native promoter of sacB in C. glutamicum. The pDXW-3 contains B. subtilissacB with the PlacM fused at the 5'-end, a general Escherichia coli replicon oriE for easy cloning, a kanamycin resistance marker for selection, and a multiple unique restriction sites for XhoI, NotI, EagI, SalI, SacI, BamHI, and NheI, respectively. By using pDXW-3, the aceE gene in the chromosome of C. glutamicum was deleted. This sacB-based system should facilitate gene disruption and allelic exchange by homologous recombination in many bacteria. PMID- 22100975 TI - A multilevel meta-analysis of single-case and small-n research on interventions for reducing challenging behavior in persons with intellectual disabilities. AB - The effectiveness of different interventions for challenging behavior (CB) in persons with intellectual disabilities (ID) was reviewed by means of a two-phase study. First, a systematic review of 137 meta-analyses and reviews on group-study interventions for CB in persons with ID was conducted. Based on this review, hypotheses concerning the effectiveness of divergent interventions for CB and concerning the impact of variables moderating treatment effectiveness were systematically generated. Second, these hypotheses were tested by means of a multilevel meta-analysis of single-case and small-n research. Two hundred and eighty-five studies reporting on 598 individuals were examined. The average treatment effect was large and statistically significant. However, this effect varied significantly over the included studies and participants. Compared to the meta-analyses and reviews focusing on group-studies in this research domain, the results of the present multilevel meta-analysis of single-case and small-n intervention research provided more detailed knowledge on which specific CB and intervention components moderate the interventions' effectiveness. PMID- 22100976 TI - An investigation into water interactions with amorphous and milled salbutamol sulphate: the development of predictive models for uptake and recrystallization. AB - An investigation into the effect of water uptake on the glass transition of spray dried and milled salbutamol sulphate has been performed, with a particular view to exploring how the water uptake, T(g) value and recrystallization behaviour correlate. Samples of milled and spray dried drug were stored under controlled humidity conditions and the T(g) measured as a function of time. The T(g) was measured using modulated temperature differential scanning calorimetry (MTDSC) while the water content was measured using thermogravimetric analysis (TGA). A correlation was found between time of storage, water content and T(g) in that the samples showed time dependent equilibration with the storage environment (either gaining or losing water depending on the RH). The relationship between water content and stability, based on the concept of T(g) lowering, was modelled using the semi-empirical approach of Royall et al. (1999) as well as a derivation of the Kwei equation which allowed the interaction between the water and substrate to be accounted for. A method for predicting stability based on two simple DSC runs is proposed. In addition, we discuss the observation of a double glass transition for the spray dried samples. PMID- 22100977 TI - The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults. AB - INTRODUCTION: Diabetes is a major cause of morbidity and mortality and its global prevalence is growing rapidly. A simple and robust approach to estimate the prevalence of diabetes is essential for governments to set priorities on how to meet the challenges of the disease. The International Diabetes Federation has developed a methodology for generating country-level estimates of diabetes prevalence in adults (20-79 years). METHODS: Using country-level data sources from peer-reviewed studies, national health statistics reports, commissioned studies on diabetes prevalence, and unpublished data obtained through personal communication, we use logistic regression to generate estimates of the prevalence of diabetes. An approach matching countries on ethnicity, geography, and income group is used to fill in gaps where original data sources are not available. The methodology also uses changes in urbanization and population to generate estimates and projections on the prevalence of diabetes in adults. CONCLUSION: Diabetes prevalence estimates are very sensitive to the data from which they are derived. The revised IDF methodology for estimating diabetes prevalence is a transparent, reproducible approach that will be updated annually. It takes data driven approaches to filling in gaps where data are not available and where assumptions have to be made. It uses a qualification system to rank data sources so that only the highest quality data are used. PMID- 22100978 TI - The triterpenoid CDDO-Me promotes hematopoietic progenitor expansion and myelopoiesis in mice. AB - The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, because of its inhibition of NF-kappaB. We have previously demonstrated protection from acute graft-versus-host disease after CDDO-Me administration in an allogeneic bone marrow transplantation model. In the current study, we observed that CDDO-Me promoted myelopoiesis in both naive and transplanted mice. This effect was dose dependent, as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (granulocyte macrophage colony-forming unit, BFU-E) were promoted by CDDO-Me. We then compared the effects with granulocyte colony-stimulating factor, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood, and bone marrow, granulocyte colony-stimulating factor only induced granulocyte macrophage colony forming unit precursors in the spleen, while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total-body irradiation, mice pretreated with CDDO-Me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic bone marrow transplantation. Combined, these data suggest that CDDO-Me may be of use posttransplantation to accelerate myeloid recovery in addition to the prevention of graft-versus-host disease. PMID- 22100979 TI - NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: persistent immune deficiency in pediatric transplant survivors. AB - Defective immune reconstitution is a major barrier to successful hematopoietic cell transplantation (HCT), and has important implications in the pediatric population. There are many factors that affect immune recovery, including stem cell source and graft-versus-host disease (GVHD). Complete assessment of immune recovery, including T and B lymphocyte evaluation, innate immunity, and response to neoantigens, may provide insight as to infection risk and optimal time for immunizations. The increasing use of cord blood grafts requires additional study regarding early reconstitution and impact upon survival. Immunization schedules may require modification based upon stem cell source and immune reconstitution, and this is of particular importance as many children have been incompletely immunized, or not at all, before school entry. Additional studies are needed in children post-HCT to evaluate the impact of differing stem cell sources upon immune reconstitution, infectious risks, and immunization responses. PMID- 22100980 TI - Antifungal property of quaternized chitosan and its derivatives. AB - Five water-soluble chitosan derivatives were carried out by quaternizing either iodomethane or N-(3-chloro-2-hydroxypropyl) trimethylammonium chloride (Quat188) as a quaternizing agent under basic condition. The degree of quaternization (DQ) ranged between 28+/-2% and 90+/-2%. The antifungal activity was evaluated by using disc diffusion method, minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) methods against Trichophyton rubrum (T. rubrum), Trichophyton mentagrophyte (T. mentagrophyte), and Microsporum gypseum (M. gypseum) at pH 7.2. All quaternized chitosans and its derivatives showed more effective against T. rubrum than M. gypseum and T. mentagrophyte. The MIC and MFC values were found to range between 125-1000 MUg/mL and 500-4000 MUg/mL, respectively against all fungi. Our results indicated that the quaternized N-(4 N,N-dimethylaminocinnamyl) chitosan chloride showed highest antifungal activity against T. rubrum and M. gypseum compared to other quaternized chitosan derivatives. The antifungal activity tended to increase with an increase in molecular weight, degree of quaternization and hydrophobic moiety against T. rubrum. However, the antifungal activity was depended on type of fungal as well as chemical structure of the quaternized chitosan derivatives. PMID- 22100981 TI - The effect of upstream platelet-fibrinogen interactions on downstream adhesion and activation. AB - Circulating activated platelets roll and make transient contacts before ultimately adhering to a substrate. However, despite the dynamic nature of platelet adhesion, most in vitro adhesion and activation studies have focused on establishing local cause and effect relationships. Here, we determined the effect of exposing platelets to immobilized upstream human fibrinogen on downstream adhesion and activation. Microcontact printing was used to prepare substrates that contained well defined fibrinogen priming regions. Washed platelets were perfused over the substrates and adhesion and activation in a downstream capture region were compared with samples that did not contain a fibrinogen priming region. It was found that samples containing an upstream priming region resulted in higher adhesion, platelet spreading areas and aggregation than samples that lacked the priming region. Also, when the priming region was selectively blocked with a polyclonal anti-fibrinogen antibody, the platelet response was attenuated. To characterize this phenomenon further, flow cytometry was used to assess bulk platelet activation following fibrinogen priming. The expression of two activation markers, PAC-1 and P-selectin were quantified. Expression of both activation markers was found to be higher after perfusion over fibrinogen versus albumin-coated substrates. PMID- 22100982 TI - Inducing alignment in astrocyte tissue constructs by surface ligands patterned on biomaterials. AB - Planar substrates with patterned ligands were used to induce astrocyte alignment whereas substrates with uniform fields of ligand were used to produce random cell orientation. DRG neurons plated on top of oriented astrocyte monolayers exhibited directional outgrowth along aligned astrocytes, demonstrating that purely biological cues provided by the oriented astrocytes were sufficient to provide guidance cues. Antibody blocking studies demonstrated that astrocyte associated FN played a major mechanistic role in directing engineered neurite extension. Our results show that nanometer level surface cues are sufficient to direct nerve outgrowth through an intervening organized astrocyte cell layer. In other studies, we showed that patterned ligands were able to transmit organization cues through multiple cell layers to control the overall alignment of an astrocyte tissue construct, demonstrating how natural scar tissue may develop in situ into potent barriers. In such constructs the spatial organization of astrocyte derived FN maintained its organizational anisotropy throughout the thickness of multilayered astrocyte constructs. These in vitro studies suggest possible roles for such constructs as bridging substrates for neuroregenerative applications. PMID- 22100983 TI - ICP-MS analysis of lanthanide-doped nanoparticles as a non-radiative, multiplex approach to quantify biodistribution and blood clearance. AB - Recent advances in material science and chemistry have led to the development of nanoparticles with diverse physicochemical properties, e.g. size, charge, shape, and surface chemistry. Evaluating which physicochemical properties are best for imaging and therapeutic studies is challenging not only because of the multitude of samples to evaluate, but also because of the large experimental variability associated with in vivo studies (e.g. differences in tumor size, injected dose, subject weight, etc.). To address this issue, we have developed a lanthanide doped nanoparticle system and analytical method that allows for the quantitative comparison of multiple nanoparticle compositions simultaneously. Specifically, superparamagnetic iron oxide (SPIO) with a range of different sizes and charges were synthesized, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy (ICP-MS) was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood samples and the resected tumor and organs. The method proved generalizable to other nanoparticle platforms, including dendrimers, liposomes, and polymersomes. This approach provides a simple, cost-effective, and non-radiative method to quantitatively compare tumor localization, biodistribution, and blood clearance of more than 10 nanoparticle compositions simultaneously, removing subject-to-subject variability. PMID- 22100984 TI - Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors. AB - Aurora kinases are a family of mitotic kinases that play important roles in the tumorigenesis of a variety of cancers including pancreatic cancer. A number of Aurora kinase inhibitors (AKIs) are currently being tested in preclinical and clinical settings as anti-cancer therapies. However, the antitumor activity of AKIs in clinical trials has been modest. In order to improve the antitumor activity of AKIs in pancreatic cancer, we utilized a kinome focused RNAi screen to identify genes that, when silenced, would sensitize pancreatic cancer cells to AKI treatment. A total of 17 kinase genes were identified and confirmed as positive hits. One of the hits was the platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), which has been shown to be overexpressed in pancreatic cancer cells and tumor tissues. Imatinib, a PDGFR inhibitor, significantly enhanced the anti-proliferative effect of ZM447439, an Aurora B specific inhibitor, and PHA-739358, a pan-Aurora kinase inhibitor. Further studies showed that imatinib augmented the induction of G2/M cell cycle arrest and apoptosis by PHA-739358. These findings indicate that PDGFRA is a potential mediator of AKI sensitivity in pancreatic cancer cells. PMID- 22100985 TI - Role of the endogenous elastase inhibitor, elafin, in cardiovascular injury: from epithelium to endothelium. AB - Neutrophils and neutrophil-derived elastases play a major role in the regulation of vascular injury and inflammation, such as ischemia-reperfusion injury. Elafin is an endogenous inhibitor of neutrophil-derived elastases with numerous anti inflammatory functions that include modulation of inflammatory cytokine release as well as innate and adaptive immunity. It is produced by epithelial tissues including the skin and respiratory system that have adapted to respond to the microbial and chemical insults that lead to inflammation. The production of peptides like elafin with multi-faceted anti-inflammatory activity is an important part of this adaptation. Although not directly expressed within the cardiovascular system itself, pre-clinical studies have suggested therapeutic benefit of elafin in cardiovascular disease. The aim of this review is to highlight the role of neutrophil-derived elastases in vascular inflammation and injury. We will discuss the beneficial effects of elafin inhibition of neutrophil elastase and its extended anti-inflammatory activity in pre-clinical models of inflammatory vascular injury. PMID- 22100986 TI - Structurally distinct nicotine immunogens elicit antibodies with non-overlapping specificities. AB - Nicotine conjugate vaccine efficacy is limited by the concentration of nicotine specific antibodies that can be reliably generated in serum. Previous studies suggest that the concurrent use of 2 structurally distinct nicotine immunogens in rats can generate additive antibody responses by stimulating distinct B cell populations. In the current study we investigated whether it is possible to identify a third immunologically distinct nicotine immunogen. The new 1'-SNic immunogen (2S)-N,N'-(disulfanediyldiethane-2,1-diyl)bis[4-(2-pyridin-3 ylpyrrolidin-1-yl)butanamide] conjugated to keyhole limpet hemocyanin (KLH) differed from the existing immunogens 3'-AmNic-rEPA and 6-CMUNic-BSA in linker position, linker composition, conjugation chemistry, and carrier protein. Vaccination of rats with 1'-SNic-KLH elicited high concentrations of high affinity nicotine-specific antibodies. The antibodies produced in response to 1' SNic-KLH did not appreciably cross-react in ELISA with either 3'-AmNic-rEPA or 6 CMUNic-BSA or vice versa, showing that the B cell populations activated by each of these nicotine immunogens were non-overlapping and distinct. Nicotine retention in serum was increased and nicotine distribution to brain substantially reduced in rats vaccinated with 1'-SNic-KLH compared to controls. Effects of 1' SNic-KLH on nicotine distribution were comparable to those of 3'-AmNic-rEPA which has progressed to late stage clinical trials as an adjunct to smoking cessation. These data show that it is possible to design multiple immunogens from a small molecule such as nicotine which elicit independent immune responses. This approach could be applicable to other addiction vaccines or small molecule targets as well. PMID- 22100987 TI - Stable expression of lipocalin-type prostaglandin D synthase in cultured preadipocytes impairs adipogenesis program independently of endogenous prostanoids. AB - Lipocalin-type prostaglandin D synthase (L-PGDS) expressed preferentially in adipocytes is responsible for the synthesis of PGD(2) and its non-enzymatic dehydration products, PGJ(2) series, serving as pro-adipogenic factors. However, the role of L-PGDS in the regulation of adipogenesis is complex because of the occurrence of several derivatives from PGD(2) and their distinct receptor subtypes as well as other functions such as a transporter of lipophilic molecules. To manipulate the expression levels of L-PGDS in cultured adipocytes, cultured preadipogenic 3T3-L1 cells were transfected stably with a mammalian expression vector having cDNA encoding murine L-PGDS oriented in the sense direction. The isolated cloned stable transfectants with L-PGDS expressed higher levels of the transcript and protein levels of L-PGDS, and synthesized PGD(2) from exogenous arachidonic acid at significantly higher levels. By contrast, the synthesis of PGE(2) remained unchanged, indicating no influence on the reactions of cyclooxygenase (COX) and PGE synthase. Furthermore, the ability of those transfectants to synthesize Delta(12)-PGJ(2) increased more greatly during the maturation phase. The sustained expression of L-PGDS in cultured stable transfectants hampered the storage of fats during the maturation phase of adipocytes, which was accompanied by the reduced gene expression of adipocyte specific markers reflecting the down-regulation of the adipogenesis program. The suppressed adipogenesis was not rescued by either exogenous aspirin or peroxisome proliferator-activated receptor gamma (PPARgamma) agonists including troglitazone and Delta(12)-PGJ(2). Taken together, the results indicate the negative regulation of the adipogenesis program by the enhanced expression of L-PGDS through a cellular mechanism involving the interference of the PPARgamma signaling pathway without the contribution of endogenous pro-adipogenic prostanoids. PMID- 22100988 TI - Integrin expression during reverse remodeling in the myocardium of heart failure patients. AB - BACKGROUND: The main anchoring proteins of myocardial cells with each other and with the extracellular matrix are integrins present in the membranes of myocardial cells. These integrins are important for maintaining the architecture of the myocardial tissue and the mechanotransduction in the heart. Heart failure leads to various alterations in the myocardium, such as changes in morphology, and in expression of mRNAs, miRNAs, and proteins. Left ventricular assist device (LVAD) support in heart failure patients has been described to induce reverse remodeling of the myocardium and thus to (some degree of) reversal of the aforementioned alterations. In this study, we evaluated whether changes in expression of integrins alpha-1, -3, -5, -6, -7, -10, -11 and beta-1, -3, -5 and 6 play a role during reverse remodeling. METHODS: Three-step immunoperoxidase staining procedures were applied on frozen heart tissue sections to locate the various integrins tested. Integrin mRNA expression was established by standard Q PCR procedures. RESULTS: It was shown that mRNA expression of several integrins changes significantly during LVAD support, however without subsequent changes in immunohistochemical detectable quantities. Various integrins showed different locations within the myocardium. CONCLUSION: LVAD-induced reversed remodeling did not result in significant integrin protein expression, although changes in integrin mRNA expression suggested an adaptation to unloading. PMID- 22100989 TI - Development of a mathematical model to describe the transport of monocyte chemoattractant protein-1 through a three-dimensional collagen matrix. AB - INTRODUCTION: Monocyte chemoattractant protein-1 is a bioactive molecule that is expressed in significant amounts in all stages of atherosclerosis. The role of monocyte chemoattractant protein-1 in this disease is to recruit monocytes across the endothelium and into the arterial tissue. Eventually, the monocytes differentiate into cholesterol-engorged macrophages called "foam cells" that result in atherosclerotic plaque formation. The mechanism that monocyte chemoattractant protein-1 uses to mediate monocyte transendothelial migration is believed to be via its concentration gradient. However, the formation of the monocyte chemoattractant protein-1 concentration gradient in the extracellular matrix is still poorly understood. METHODS: A three-dimensional in vitro vascular tissue model has been developed to study the cellular mechanisms involved in the early stages of atherosclerosis. In the present study, a mathematical model is used to determine the gradient of monocyte chemoattractant protein-1 in the collagen matrix of the three-dimensional in vitro vascular tissue model. Experiments were performed to investigate the stability of monocyte chemoattractant protein-1 and the interaction between monocyte chemoattractant protein-1 and the collagen matrix. RESULTS AND CONCLUSIONS: Monocyte chemoattractant protein-1 is stable for at least 24 h under experimental conditions and monocyte chemoattractant protein-1 interacts with the collagen matrix. The diffusion coefficient for the transport of monocyte chemoattractant protein-1 in the collagen matrix and the rate constant for the binding of monocyte chemoattractant protein-1 to collagen were determined to be 0.108 mm(2) h(-1) and 0.858 h(-1), respectively. Numerical results from the model indicate that the concentration gradients of both soluble and matrix-bound (or static) monocyte chemoattractant protein-1 are formed inside the collagen matrix. PMID- 22100990 TI - Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine. AB - OBJECTIVE: Prolonged action potential and decreased outward K(+) currents are consistent findings in hypertrophic myocardium. The relation between action potential prolongation and myocyte hypertrophy has remained unclear. The present study investigated the temporal relation between action potential prolongation and myocyte hypertrophy, and the effect of enhancing repolarization on myocyte hypertrophy induced by phenylephrine. METHODS: Neonatal rabbit ventricular myocytes were cultured and treated with 10 MUmol/l phenylephrine. At 6 and 48 h after phenylephrine stimulation, myocyte hypertrophic parameters (including myocyte volume, total protein content, and membrane capacitance), action potential duration (APD), and calcineurin activity were measured; meanwhile, the effect of human-ether-a-go-go-related gene (HERG; encoding the alphasubunit of rapidly activating delayed rectifier potassium channel) transfection on the above parameters at 48 h of phenylephrine stimulation was also measured. RESULTS: At 6 h after phenylephrine treatment, APD at 90% repolarization of neonatal rabbit ventricular myocytes was prolonged by 14.3% (P<.05), but myocyte hypertrophy was not found. At 48 h after phenylephrine stimulation, APD at 90% repolarization of neonatal rabbit ventricular myocytes was furthermore prolonged by 18.8% (P<.05); at the same time, myocyte volume, total protein content, membrane capacitance, and calcineurin activity were increased by 40.0%, 41.8%, 36.4%, and 124.1%, respectively (P<.01). Neonatal rabbit ventricular myocytes transfected by pcDNA3 HERG overexpressed I(HERG,tail) current, which was about fourfold higher than I(Kr) (rapidly activating delayed rectifier K(+) current) of neonatal rabbit ventricular myocytes without transfection of HERG. HERG overexpression could accelerate repolarization and shorten APD at 90% repolarization prolonged by phenylephrine and partially inhibit myocyte hypertrophy and calcineurin activation. CONCLUSIONS: During the myocyte hypertrophy induced by phenylephrine, prolongation of APD at 90% repolarization is not secondary to but precedes myocyte hypertrophy. HERG overexpression could enhance the repolarization and inhibit the calcineurin activation and myocyte hypertrophy induced by phenylephrine. PMID- 22100991 TI - Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up. AB - BACKGROUND: Surgical clipping of intracranial aneurysms is the gold standard for the prevention of rupture. However, the biological processes that occur following clipping are poorly understood. To better understand these effects, retrieved and clipped human intracranial aneurysms were examined histologically. METHODS: At autopsy, 17 aneurysms from 10 patients were retrieved 3-21 days after clipping. The tissues were embedded in paraffin, and microtome sections were stained using hematoxylin-eosin and Movat pentachrome. Using light microscopy, clip placement relative to the internal elastic lamina of the parent artery, endothelialization of the aneurysm neck, thrombus organization inside the aneurysm sac, inflammation in the sac, wall, and parent artery, and atherosclerotic changes were determined. RESULTS: Despite complete reconstruction of the artery with the clip, diseased vessel wall was frequently observed outside the clip. By 10 days postsurgery, the beginnings of endothelialization and neointima formation were observed at the neck. However, the neck coverage was variable and incomplete at these early time points. Thrombus organization inside the aneurysm sac was rarely observed, and inflammatory cells were not present inside the aneurysm sac. Inflammatory cells were commonly observed in the aneurysm wall, and atherosclerotic change was present in each sample. CONCLUSIONS: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation. SUMMARY: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation. PMID- 22100992 TI - [Effects of exercise training on ergocycle during hemodialysis in patients with end stage renal disease: relevance of the anaerobic threshold intensity]. AB - BACKGROUND: Chronic kidney failure (CRF) in addition to cardiovascular comorbidities and aging decrease physical activity capacity. An adapted rehabilitation program might be strongly recommended in this population. The aim of the study is to evaluate a 3 months exercise training program with ergocycle at the anaerobic threshold (AT) during dialysis sessions on effort tolerance, quality of life, blood pressure and lipidic disorders. METHODS: Six patients meanly aged 72 were evaluated before (t(0)) and after (t(3)) the rehabilitation program by: maximal cardiorespiratory ergotest, a 6-Minute Walk Test (6MWT) and 2 quality of life tests: Medical Outcome Survey Short Form 36-items and the Kidney Disease Quality of Life (SF 36, KDQol). RESULTS: Physical activity during dialysis is well tolerated. There was no undesirable event during rehabilitation sessions. The dyspnea and muscular weariness threshold linked to the AT increased meanly by 39% (8.83 +/- 0.87 vs. 12.25 +/- 1.23 mL/min per kg). Distances walked during 6 MWT increased for all patients (351.83 +/- 72.17 vs. 412.80 +/- 82 meters) Moreover, physical component scale improved (+4.7), mean systolic blood pressure (-7 mmHg) and mean triglycerides concentration (-19%) decreased. CONCLUSION: An exercise training program during dialysis sessions with ergocycle and working intensity based on AT seems safe and an effective alternative to improve the effort functional capacity by hemodialysis patients. PMID- 22100993 TI - Quantitative human health risk assessment for 1,3-butadiene based upon ovarian effects in rodents. AB - A case study was prepared for noncancer risk assessment of 1,3-butadiene (BD) based upon the ovarian atrophy effects in rodents with specific consideration of the guidelines described by NAS (2009). Ovarian toxicity has been identified in the past as a sensitive endpoint for BD, and serves as the basis for noncancer risk assessment by regulatory agencies. A meta-analysis was conducted in which the available dose-response data from rats and mice were normalized using an internal dose estimate (DEB in blood) that is causally related to ovarian toxicity. A time-to-response (multistage-Weibull) model was used to simultaneously fit the pooled rodent data sets with exposure durations ranging from 13 to 105weeks. Human variation in ovarian follicle count was assumed to reflect variation in sensitivity to the adverse effects associated with follicle depletion (i.e., premature menopause). Information on follicle count in women was used in two ways: (1) the window of susceptibility (from birth to menopause) was defined as 49.6years for women born with an average follicle count, 38.7years for women born with a low follicle count, and 60.0years for women born with a high follicle count; and (2) follicle count was assumed to reflect human susceptibility due to toxicodynamic factors. The multistage-Weibull model was used to predict dose-response curves for three scenarios (average, low, and high follicle counts at birth to generate reference concentration values ranging from 0.2 to 20ppm). This case study illustrates how information on mode of action can be used to guide key decisions in the dose-response assessment with respect to identifying a dose measure, low-dose extrapolation method, background exposure, and sensitive subpopulations. PMID- 22100994 TI - The design of chronic toxicology studies of monoclonal antibodies: implications for the reduction in use of non-human primates. AB - The changing environment of monoclonal antibody (mAb) development is impacting on the cost of drug development and the use of experimental animals, particularly non-human primates (NHPs). The drive to reduce these costs is huge and involves rethinking and improving nonclinical studies to make them more efficient and more predictive of man. While NHP use might be unavoidable in many cases because of the exquisite specificity and consequent species selectivity of mAbs, our increasing knowledge base can be used to improve drug development and maximise the output of experimental data. Data on GLP regulatory toxicology studies for 58mAbs were obtained from 10 companies across a wide range of therapeutic indications. These data have been used to investigate current practice and identify study designs that minimise NHP use. Our analysis shows that there is variation in the number of animals used for similar studies. This information has been used to develop practical guidance and make recommendations on the use of science-based rationale to design studies using fewer animals taking into account the current regulatory guidance. There are eight recommendations intended to highlight areas for consideration. They include guidance on the main group size, the inclusion of recovery groups and the number of dose groups used in short and long term chronic toxicology studies. PMID- 22100996 TI - Electroporetic transfection of pepper protoplasts with plant potyviruses. AB - Potyviruses are a persistent threat to bell pepper (Capsicum annuum L.) production worldwide. Much effort has been expended to study the resistance response of pepper cultivars at whole plant levels but with only limited effort at the cellular level using protoplasts. A pepper protoplast isolation procedure is available but an inoculation procedure is needed that provides consistent and highly efficient infection. An electroporation-based procedure for inoculation of potyviruses was developed using a base procedure developed for Cucumber mosaic virus (CMV). The final parameters identified for efficient potyvirus infection of pepper protoplasts involves two 25ms pulses, 200V each pulse with a 10s interval between pulses. Depending on the method of detection, e.g., ELISA versus RT-PCR, potyvirus RNA inoculum ranged from 10 to 40MUg with infection detection occurring with samples of 50,000-100,000 protoplasts. PMID- 22100995 TI - The contribution of Plasmodium chabaudi to our understanding of malaria. AB - Malaria kills close to a million people every year, mostly children under the age of five. In the drive towards the development of an effective vaccine and new chemotherapeutic targets for malaria, field-based studies on human malaria infection and laboratory-based studies using animal models of malaria offer complementary opportunities to further our understanding of the mechanisms behind malaria infection and pathology. We outline here the parallels between the Plasmodium chabaudi mouse model of malaria and human malaria. We will highlight the contribution of P. chabaudi to our understanding of malaria in particular, how the immune response in malaria infection is initiated and regulated, its role in pathology, and how immunological memory is maintained. We will also discuss areas where new tools have opened up potential areas of exploration using this invaluable model system. PMID- 22100997 TI - Influence of the membrane dipole potential on peptide binding to lipid bilayers. AB - The implicit membrane model IMM1 is extended to include the membrane dipole potential and applied to molecular dynamics simulations of the helical peptides alamethicin, WALP23, influenza hemagglutinin fusion peptide, HIV fusion peptide, magainin, and the pre-sequence of cytochrome c oxidase subunit IV (p25). The results show that the orientation of the peptides in the membrane can be influenced by the dipole potential. The binding affinity of all peptides except for the hemagglutinin fusion peptide decreases upon increase of the dipole potential. The changes in both orientation and binding affinity are explained by the interaction of the dipole potential with the helix backbone dipole and ionic side-chains. In general, peptides that tend to insert the N-terminus in the membrane and/or have positively charged side chains will lose binding affinity upon increase of the dipole potential. PMID- 22100998 TI - Stem cell technology for drug discovery and development. AB - Stem cells have enormous potential to revolutionise the drug discovery process at all stages, from target identification through to toxicology studies. Their ability to generate physiologically relevant cells in limitless supply makes them an attractive alternative to currently used recombinant cell lines or primary cells. However, realisation of the full potential of stem cells is currently hampered by the difficulty in routinely directing stem cell differentiation to reproducibly and cost effectively generate pure populations of specific cell types. In this article we discuss how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry. PMID- 22100999 TI - Surgical treatment of locally limited tonsillar cancer. AB - BACKGROUND: This study aimed to assess the efficacy of primary surgical treatment in the management of locally limited tonsillar carcinoma and the incidence of occult cervical metastasis. METHODS: We conducted a retrospective evaluation of the records of all patients treated with primary surgery for pT1 and pT2 tonsillar carcinomas at a tertiary referral center between 1977 and 2005. All cases were assessed for disease-specific survival as well as local control rates, with respect to T and N classification, status of surgical margins, decision on neck management, and adjuvant therapy. Cases were also evaluated for incidence of major complications and incidence of tracheotomies. RESULTS: A total of 209 cases were assessed. Positive surgical margins after completion of surgical treatment and advanced neck disease were shown to be significant negative prognostic factors. The occult metastasis rate was 18.4%. CONCLUSION: Primary surgical treatment is a very effective modality against locally limited tonsillar carcinoma. Low rates of complications and permanent tracheotomies are to be expected. PMID- 22101000 TI - A new approach with less damage: intranasal delivery of tetracycline-inducible replication-defective herpes simplex virus type-1 vector to brain. AB - Gene therapy holds great potential for treating neurological disorders. However, delivering gene vectors to the brain has been either invasive or inefficacious in most studies to date. The aim of this study was to develop a safe and efficacious strategy for delivering gene vectors to the brain. A tetracycline-inducible replication-defective herpes simplex virus type-1 vector, QR9TO-LacZ, was administered to rats intranasally. QR9TO-LacZ could infect primary cortical neurons and express the reporter gene without detectable replication. QR9TO-LacZ was observed in the olfactory bulb, hippocampus, striatum, cortex, medulla, cerebellum, ventricles, and nasal septum after intranasal administration. Expression of the reporter gene could be controlled effectively by tetracycline. In vitro, introduction of QR9TO-LacZ did not change the structure of transfected neurons. In vivo, QR9TO-LacZ did not increase apoptosis in neurons and did not alter levels of interleukin 6 and tumor necrosis factor alpha in the brain after intranasal delivery. Our data suggest that intranasally applied QR9TO-LacZ has a wide distribution and expresses the reporter gene in the brain under the control of tetracycline with less cytotoxicity than intravenous or stereotactic delivery methods. PMID- 22101001 TI - 15-Hydroxyeicosatetraenoic acid (15-HETE) protects pulmonary artery smooth muscle cells from apoptosis via inducible nitric oxide synthase (iNOS) pathway. AB - 15-Hydroxyeicosatetraenoic acid (15-HETE), one of many important metabolic products of arachidonic acid (AA) catalyzed by 15-lipoxygenase, plays an important role in pulmonary vascular smooth muscle remodeling. We have previously shown its unsubstituted effects on the apoptotic responses of pulmonary artery smooth muscle cells (PASMCs), but the underlying mechanisms are still poorly manifested. Previous studies have shown that inducible nitric oxide synthase (iNOS) plays an important protective role against sepsis-induced pulmonary apoptosis. Therefore, the purpose of this study is to determine whether 15-HETE anti-apoptotic process is mediated through the iNOS pathway in rat PASMCs. To test this hypothesis, we studied the contribution of iNOS to the 15-HETE induced anti-apoptotic responses using cell viability measurement, Western blot, mitochondrial potential analysis, nuclear morphology determination and TUNEL assay. Our results showed that both exogenous and endogenous 15-HETE up-regulated iNOS protein and mRNA expression and 15-HETE enhanced the cell survival, attenuated mitochondrial depolarization, up-regulated the expression of Bcl-2 and procaspase-3 in PASMCs under serum-deprived condition. These effects were reversed by iNOS inhibitor SMT or l-canavanine. Taken together, our data indicates that iNOS is a novel signaling transduction pathway, which is necessary for the effects of 15-HETE in protection PASMCs from apoptosis and may be an important mechanism underlying the treatment of pulmonary artery hypertension and also provides a novel therapeutic insight in future. PMID- 22101002 TI - Eicosanoids and tumor necrosis factor-alpha in the kidney. AB - The thick ascending limb of Henle's loop (TAL) is capable of metabolizing arachidonic acid (AA) by cytochrome P450 (CYP450) and cyclooxygenase (COX) pathways and has been identified as a nephron segment that contributes to salt sensitive hypertension. Previous studies demonstrated a prominent role for CYP450 dependent metabolism of AA to products that inhibited ion transport pathways in the TAL. However, COX-2 is constitutively expressed along all segments of the TAL and is increased in response to diverse stimuli. The ability of Tamm-Horsfall glycoprotein, a selective marker of cortical TAL (cTAL) and medullary (mTAL), to bind TNF and localize it to this nephron segment prompted studies to determine the capacity of mTAL cells to produce TNF and determine its effects on mTAL function. The colocalization of calcium-sensing receptor (CaR) and COX-2 in the TAL supports the notion that activation of CaR induces TNF-dependent COX-2 expression and PGE2 synthesis in mTAL cells. Additional studies showed that TNF produced by mTAL cells inhibits 86Rb uptake, an in vitro correlate of natriuresis, in an autocrine- and COX-2-dependent manner. The molecular mechanism for these effects likely includes inhibition of Na+-K+-2Cl- cotransporter (NKCC2) expression and trafficking. PMID- 22101003 TI - PLA-based biodegradable and tunable soft elastomers for biomedical applications. AB - Although desirable for biomedical applications, soft degradable elastomers having balanced amphiphilic behaviour are rarely described in the literature. Indeed, mainly highly hydrophobic elastomers or very hydrophilic elastomers with hydrogel behaviours are found. In this work, we developed thermoset degradable elastomers based on the photo-cross-linking of poly(lactide)-poly(ethylene glycol) poly(lactide) (PLA-PEG-PLA) triblock prepolymers. The originality of the proposed elastomers comes from the careful choice of the prepolymer amphiphilicity and from the possible modulation of their mechanical properties and degradation rates provided by cross-linkers of different nature. This is illustrated with the hydrophobic and rigid 2,4,6-triallyloxy-1,3,5-triazine compared to the hydrophilic and soft pentaerythritol triallyl ether. Thermal properties, mechanical properties, swelling behaviours, degradation rates and cytocompatibility have been evaluated. Results show that it is possible to generate a family of degradable elastomers covering a broad range of properties from a single biocompatible and biodegradable prepolymer. PMID- 22101004 TI - Phenotypic analysis of astrocytes derived from glial restricted precursors and their impact on axon regeneration. AB - Although astrocytes are involved in the production of an inhibitory glial scar following injury, they are also capable of providing neuroprotection and supporting axonal growth. There is growing appreciation for a diverse and dynamic population of astrocytes, specified by a variety of glial precursors, whose function is regulated regionally and temporally. Consequently, the therapeutic application of glial precursors and astrocytes by effective transplantation protocols requires a better understanding of their phenotypic and functional properties and effective protocols for their preparation. We present a systematic analysis of astrocyte differentiation using multiple preparations of glial restricted precursors (GRP), evaluating their morphological and phenotypic properties following treatment with fetal bovine serum (FBS), bone morphogenetic protein 4 (BMP-4), or ciliary neurotrophic factor (CNTF) in comparison to controls treated with basic fibroblast growth factor (bFGF), which maintains undifferentiated GRP. We found that treatments with FBS or BMP-4 generated similar profiles of highly differentiated astrocytes that were A2B5-/GFAP+. Treatment with FBS generated the most mature astrocytes, with a distinct and near homogeneous morphology of fibroblast-like flat cells, whereas BMP-4 derived astrocytes had a stellate, but heterogeneous morphology. Treatment with CNTF induced differentiation of GRP to an intermediate state of GFAP+cells that maintained immature markers and had relatively long processes. Furthermore, astrocytes generated by BMP-4 or CNTF showed considerable experimental plasticity, and their morphology and phenotypes could be reversed with complementary treatments along a wide range of mature-immature states. Importantly, when GRP or GRP treated with BMP-4 or CNTF were transplanted acutely into a dorsal column lesion of the spinal cord, cells from all 3 groups survived and generated permissive astrocytes that supported axon growth and regeneration of host sensory axons into, but not out of the lesion. Our study underscores the dynamic nature of astrocytes prepared from GRP and their permissive properties, and suggest that future therapeutic applications in restoring connectivity following CNS injury are likely to require a combination of treatments. PMID- 22101005 TI - The effect of amyloid associated proteins on the expression of genes involved in amyloid-beta clearance by adult human astrocytes. AB - Astrocytes appear to be important mediators in the clearance of amyloid beta1-42 (Abeta), the key component of senile plaques characteristic of Alzheimer's disease (AD). Recently, we found the amyloid associated proteins (AAPs) alpha1 antichymotrypsin (ACT), apolipoprotein J and E (ApoJ and ApoE) and a mixture of serum amyloid P (SAP) and C1q (SAP-C1q) to modify Abeta-uptake by human astrocytes. Here we investigated the effect of oligomeric (Abetaoligo) and fibrillar Abeta (Abetafib), alone and in combination with a panel of AAPs on the astrocytic expression of genes proposed to be involved in Abeta-uptake and degradation. Primary human astrocytes (isolated from non-demented control (n=4) and AD patient (n=4) brain specimens) were exposed to either Abetaoligo or Abetafib preparations with or without the above mentioned AAPs. Quantitative gene expression analysis of Abeta-receptors Scavenger receptor B1 (SCARB1), macrophage receptor with collagenous structure (MARCO) and low density lipoprotein receptor related protein-2 (LRP2 or megalin) as well as of Abeta-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE) and metalloproteinase-9 (MMP-9) was performed by real-time PCR. Basal expression of NEP, IDE and SCARB1 was easily detected whereas expression of MARCO, LRP2 and MMP-9 could only be detected upon pre-amplification. Basal expression of NEP, IDE and SCARB1 did not change upon exposure to Abetaoligo or Abetafib alone in any of the investigated astrocyte cultures. Interestingly NEP expression was increased upon exposure to ApoE in combination with both Abeta-preparations, and also SCARB1 expression was induced upon treatment with ApoE in combination with Abetafib in astrocytes from non-demented controls. Further, SAP-C1q increased SCARB1 expression in control astrocytes when combined with Abetaoligo. These alterations were not found in astrocytes from AD patients. Thus, we conclude that Abeta alone apparently does not affect the astrocytic expression of IDE, NEP or SCARB1. However, NEP and SCARB1 expression is increased in astrocytes from non-demented subjects when exposed to Abeta combined with AAPs like ApoE. These astrocytic gene expression regulatory mechanisms appear to be defective in AD and thus might contribute to the development and progression of AD pathology. PMID- 22101006 TI - Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. AB - Early life stress, such as childhood abuse, neglect and loss, is a well established major risk factor for developing depressive disorders later in life. We here summarize and discuss current developments in human research regarding the link between early life stress and depression. Specifically, we review the evidence for the existence of sensitive periods for the adverse effects of early life stress in humans. We further review the current state of knowledge regarding gene*environment (G*E) interactions in the effects of early life stress. While multiple genes operate in multiple environments to induce risk for depression after early life stress, these same genes also seem to enhance the beneficial effects of a positive early environment. Also, we discuss the epigenetic mechanisms that might underlie these G*E interactions. Finally, we discuss the potential importance of identifying sensitive time periods of opportunity, as well as G*E interactions and epigenetic mechanisms, for early interventions that might prevent or reverse the detrimental outcomes of early life stress and its transmission across generations. PMID- 22101007 TI - Modification by the genes ALAD and VDR of lead-induced cognitive effects in children. AB - Lead has negative effect on cognitive functions in children. However, individuals differ in susceptibility. One possible explanation is a genetic predisposition. Polymorphisms in the delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) genes may modify lead metabolism and neurotoxicity, but information regarding the central nervous system is very limited. The aim of the study was to determine whether ALAD and VDR polymorphisms modify blood lead (B Pb), and the association between B-Pb and cognitive function (IQ) in children. In 2007-2010 a cohort of 175 children (age 6-10years, mean 7.8) was recruited in Southern Poland, tested for IQ (Wechsler intelligence scale) and analyzed for B Pb (range 9.0-221; mean 46.6MUg/L), ALAD (RsaI, MspI) and VDR (FokI, BsmI, TaqI) polymorphisms. ALAD or VDR genotypes were not associated with B-Pb. B-Pb was non significantly negatively associated with full scale IQ (r(S)=-0.11; P=0.14), and significantly with performance subscale results (r(S)=-0.19; P=0.01). The ALAD RsaI polymorphism modified the relationship between full scale IQ and B-Pb: RsaI T carriers had a steeper slope compared to CC homozygote carriers (beta coefficient -0.06 vs 0.32, respectively, P for interaction <0.001, adjusted for the child's age, mother's education and family income). This means that with increasing B-Pb with 1MUg/L, T carriers demonstrate 0.06 score lower IQ. For the VDR BsmI, B carriers had a steeper slope than the bb homozygotes carriers (beta coefficient -0.08 vs 0.16, respectively, P for interaction=0.001), and similar effect was found for TaqI t carriers vs TT homozygotes (P for interaction=0.02). For ALAD MspI and VDR FokI there was no significant modification. The ALAD RsaI, VDR BsmI and TaqI polymorphisms modified the relationship between IQ and B-Pb. Hence, there is a fraction of the population, which is particularly sensitive to lead neurotoxicity. PMID- 22101008 TI - Neonatal Bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus. AB - Developmental exposure to Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been purported to adversely impact reproductive function in female rodents. Because neonatal life is a critical window for the sexual dimorphic organization of the hypothalamic-pituitary-gonadal (HPG) axis, interference with this process could underlie compromised adult reproductive physiology. The goal of the present study was to determine if neonatal BPA exposure interferes with sex specific gene expression of estrogen receptor alpha (ERalpha), ER beta (ERbeta) and kisspeptin (Kiss1) in the anterior and mediobasal hypothalamus. Long Evans (LE) neonatal rats were exposed to vehicle, 10MUg estradiol benzoate (EB), 50mg/kg BPA or 50MUg/kg BPA by subcutaneous injection daily from postnatal day 0 (PND 0) to PND 2. Gene expression was assessed by in situ hybridization on PNDs 4 and 10. Within the anterior hypothalamus ERalpha expression was augmented by BPA in PND 4 females, then fell to male-typical levels by PND 10. ERbeta expression was not altered by BPA on PND 4, but significantly decreased or eliminated in both sexes by PND 10. Kiss1 expression was diminished by BPA in the anterior hypothalamus, especially in females. There were no significant impacts of BPA in the mediobasal hypothalamus. Collectively, BPA effects did not mirror those of EB. The results show that neonatal hypothalamic ER and Kiss1 expression is sensitive to BPA exposure. This disruption may alter sexually dimorphic hypothalamic organization and underlie adult reproductive deficiencies. Additionally, the discordant effects of EB and BPA indicate that BPA likely disrupts hypothalamic organization by a mechanism other than simply acting as an estrogen mimic. PMID- 22101009 TI - Nitrogen dioxide oxidizes mitochondrial cytochrome c. AB - We previously reported that high micromolar concentrations of nitric oxide were able to oxidize mitochondrial cytochrome c at physiological pH, producing nitroxyl anion (Sharpe and Cooper, 1998 Biochem. J. 332, 9-19). However, the subsequent re-evaluation of the redox potential of the NO/NO(-) couple suggests that this reaction is thermodynamically unfavored. We now show that the oxidation is oxygen-concentration dependent and non stoichiometric. We conclude that the effect is due to an oxidant species produced during the aerobic decay of nitric oxide to nitrite and nitrate. The species is most probably nitrogen dioxide, NO(2)(*) a well-known biologically active oxidant. A simple kinetic model of NO autoxidation is able to explain the extent of cytochrome c oxidation assuming a rate constant of 3*10(6)M(-1)s(-1) for the reaction of NO(2)(*) with ferrocytochrome c. The importance of NO(2)(*) was confirmed by the addition of scavengers such as urate and ferrocyanide. These convert NO(2)(*) into products (urate radical and ferricyanide) that rapidly oxidize cytochrome c and hence greatly enhance the extent of oxidation observed. The present study does not support the previous hypothesis that NO and cytochrome c can generate appreciable amounts of nitroxyl ions (NO(-) or HNO) or of peroxynitrite. PMID- 22101010 TI - Phosphorylation on the Ser 824 residue of TRPV4 prefers to bind with F-actin than with microtubules to expand the cell surface area. AB - Previously, we demonstrated that the transient receptor potential vanilloid 4 (TRPV4) cation channel, a member of the TRP vanilloid subfamily, is one of the serum glucocorticoid-induced protein kinase1 (SGK1) authentic substrate proteins, and that the Ser 824 residue of TRPV4 is phosphorylated by SGK1. In this study, we demonstrated that phosphorylation on the Ser 824 residue of TRPV4 is required for its interaction with F-actin, using TRPV4 mutants (S824D; a phospho-mimicking TRPV4 mutant and S824A; a non-phosphorylatable TRPV4 mutant) and its proper subcellular localization. Additionally, we noted that the phosphorylation of the Ser824 residue promotes its single channel activity, Ca(2+) influx, protein stability, and cell surface area (expansion of plasma membrane). PMID- 22101012 TI - Cell surface ceramide controls translocation of transferrin receptor to clathrin coated pits. AB - Transferrin receptor mediates internalization of transferrin with bound ferric ions through the clathrin-dependent pathway. We found that binding of transferrin to the receptor induced rapid generation of cell surface ceramide which correlated with activation of acid, but not neutral, sphingomyelinase. At the onset of transferrin internalization both ceramide level and acid sphingomyelinase activity returned to their basic levels. Down-regulation of acid sphingomyelinase in cells with imipramine or silencing of the enzyme expression with siRNA stimulated transferrin internalization and inhibited its recycling. In these conditions colocalization of transferrin with clathrin was markedly reduced. Simultaneously, K(+) depletion of cells which interfered with the assembly of clathrin-coated pits inhibited the uptake of transferrin much less efficiently than it did in control conditions. The down-regulation of acid sphingomyelinase activity led to the translocation of transferrin receptor to the raft fraction of the plasma membrane upon transferrin binding. The data suggest that lack of cell surface ceramide, generated in physiological conditions by acid sphingomyelinase during transferrin binding, enables internalization of transferrin/transferrin receptor complex by clathrin-independent pathway. PMID- 22101011 TI - betaarrestin1-biased agonism at human delta-opioid receptor by peptidic and alkaloid ligands. AB - We have previously reported on the differential regulation of the human delta opioid receptor (hDOR) by alkaloid (etorphine) and peptidic (DPDPE and deltorphin I) ligands, in terms of both receptor desensitization and post-endocytic sorting. Since betaarrestins are well known to regulate G protein-coupled receptors (GPCRs) signaling and trafficking, we therefore investigated the role of betaarrestin1 (the only isoform expressed in our cellular model) in the context of the hDOR. We established clonal cell lines of SK-N-BE cells over-expressing betaarrestin1, its dominant negative mutant (betaarrestin1(319-418)), and shRNA directed against endogenous betaarrestin1. Interestingly, both binding and confocal microscopy approaches demonstrated that betaarrestin1 is required for hDOR endocytosis only when activated by etorphine. Conversely, functional experiments revealed that betaarrestin1 is exclusively involved in hDOR desensitization promoted by the peptides. Taken together, these results provide substantial evidence for a betaarrestin1-biased agonism at hDOR, where betaarrestin1 is differentially involved during receptor desensitization and endocytosis depending on the ligand. PMID- 22101013 TI - Preconditioning the hyperlipidemic myocardium: fact or fantasy? AB - Ischemic heart disease is a leading cause of death worldwide. Myocardial ischemia results in reduced coronary flow, followed by diminished oxygen and nutrient supply to the heart. Reperfusion to an ischemic myocardium often augments the ischemic damage, known as ischemia-reperfusion (I/R) injury. Number of studies demonstrated that the hyperlipidemic myocardium is rather sensitive and more vulnerable to I/R-induced myocardial injury. Repeated brief ischemia and reperfusion cycles, termed as ischemic preconditioning, given before a sustained ischemia is known to reduce myocardial damage occur as a result of I/R. A plethora of evidence supports the fact that preconditioning is one of the promising interventional strategies having an ability to limit I/R-induced myocardial injury. Despite this fact, the preconditioning-mediated cardioprotection is blunted in chronic hyperlipidemic condition. This suggests that preconditioning is moderately a 'healthy heart protective phenomenon'. The mechanisms by which chronic hyperlipidemia abrogates cardioprotective effects of preconditioning are uncertain and are not completely understood. The impaired opening of mitochondrial-K(ATP) channels, eNOS uncoupling and excessive generation of superoxides in the hyperlipidemic myocardium could play a role in attenuating preconditioning-mediated myocardial protection against I/R injury. Moreover, hyperlipidemia-induced loss of cardioprotective effect of preconditioning is associated with redistribution of both sarcolemmal and mitochondrial Connexin 43. We addressed, in this review, the potential mechanisms involved in hyperlipidemia-induced impairment of myocardial preconditioning. Additionally, novel pharmacologic interventions to attenuate hyperlipidemia associated exaggerated I/R-induced myocardial injury have been discussed. PMID- 22101014 TI - A microRNA, mir133b, suppresses melanopsin expression mediated by failure dopaminergic amacrine cells in RCS rats. AB - The photopigment melanopsin and melanopsin-containing RGCs (mRGCs or ipRGCs) represent a brand-new and exciting direction in the field of visual field. Although the melanopsin is much less sensitive to light and has far less spatial resolution, mRGCs have the unique ability to project to brain areas by the retinohypothalamic tract (RHT) and communicate directly with the brain. Unfortunately, melanopsin presents lower expression levels in many acute and chronic retinal diseases. The molecular mechanisms underlying melanopsin expression are not yet really understood. MicroRNAs play important roles in the control of development. Most importantly, the link of microRNA biology to a diverse set of cellular processes, ranging from proliferation, apoptosis and malignant transformation to neuronal development and fate specification is emerging. We employed Royal College of Surgeon (RCS) rats as animal model to investigate the underlying molecular mechanism regulating melanopsin expression using a panel of miRNA by quantitative real-time reverse transcription polymerase chain reaction. We identified a microRNA, mir133b, that is specifically expressed in retinal dopaminergic amacrine cells as well as markedly increased expression at early stage during retinal degeneration in RCS rats. The overexpression of mir133b downregulates the important transcription factor Pitx3 expression in dopaminergic amacrine cells in RCS rats retinas and makes amacrine cells stratification deficit in IPL. Furthermore, deficient dopaminergic amacrine cells presented decreased TH expression and dopamine production, which lead to a failure to direct mRGCs dendrite to stratify and enter INL and lead to the reduced correct connections between amacrine cells and mRGCs. Our study suggested that overexpression of mir133b and downregulated Pitx3 suppress maturation and function of dopaminergic amacrine cells, and overexpression of mir133b decreased TH and D2 receptor expression as well as dopamine production, which finally resulted in reduced melanopsin expression. PMID- 22101015 TI - A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity. AB - Recombinant immunotoxins (RITs) are anti-cancer agents that combine the Fv of an antibody against cancer cells with a protein toxin from bacteria or plants. Since RITs contain a non-human protein, immunogenicity can be an obstacle in their development. In this study, we have explored the hypothesis that increasing stability can reduce the immunogenicity of a RIT using HA22-LR, which is composed of an anti-CD22 Fv fused to domain III of Pseudomonas exotoxin A. We introduced a disulfide bond into domain III by identifying and mutating two structurally adjacent residues to cysteines at sites suggested by computer modeling. This RIT, HA22-LR-DB, displays a remarkable increase in thermal stability and an enhanced resistance to trypsin degradation. In addition, HA22-LR-DB retains cytotoxic and anti-tumor activity, while exhibiting significantly lower immunogenicity in mice. This study demonstrates that it is possible to design mutations in a protein molecule that will increase the stability of the protein and thereby reduce its immunogenicity. PMID- 22101016 TI - Review: second-generation antipsychotics improve response in paediatric bipolar disorder, but are associated with adverse events. PMID- 22101017 TI - Multiple levels of orientation anisotropy in crowding with Gabor flankers. AB - Using oriented Gabor patches, we found that for nearly cardinal target orientations, oblique flankers' orientations induced more interference than did cardinal flankers' orientations. This pattern was observed both at the local and global levels of flankers' orientation. With respect to the global orientation (flankers' global arrangement around the target), there was no difference between the effects of the two cardinal orientations, and both induced the same amount of interference. With respect to the local orientation (Gabors' orientation), in accordance with previous reports, a difference was found between the effects of the two cardinal orientations--a considerable amount of interference with flankers equal in orientation to the target (although less than with the oblique flankers) and almost no interference from flankers orthogonal to the target. Crowding was also affected by an anisotropy based on the target-fixation axis (radial, tangential, and diagonal) and by the flankers' relations. The magnitude of these latter factors was small relative to that of the former ones. The multiple factors that affected crowding, as well as the similarities and the differences between the effects at the two orientation levels, suggest that crowding is determined by multiple sources of interference operating at several levels of representation. PMID- 22101018 TI - Beliefs alter holistic face processing ... if response bias is not taken into account. AB - The composite paradigm is widely used to quantify holistic processing (HP) of faces, but there is debate regarding the appropriate design (partial vs. complete) and measures in this task. Here, we argue that some operational definitions of HP are problematic because they are sensitive to top-down influences, even though the underlying concept is assumed to be cognitively impenetrable. In Experiment 1, we told one group of participants that the target face half would remain the same on 75% of trials and another group that it would change on 75% of trials. The true proportion of same/different trials was 50% groups only differed in their beliefs about the target halves. In Experiment 2, we manipulated the actual proportion of same/different trials in the experiment (75% of trials were the same for one group; 75% of trials were different for another group) but did not give explicit instructions about proportions. In both experiments, these manipulations influenced response biases that altered partial design measures of HP while the complete design measure was unaffected. We argue that the partial design should be abandoned because it has poor construct validity. PMID- 22101019 TI - Endogenous patient responses and the consistency principle in cost-effectiveness analysis. AB - In addition to incurring direct treatment costs and generating direct health benefits that improve longevity and/or health-related quality of life, medical interventions often have further or "unrelated" financial and health impacts, raising the issue of what costs and effects should be included in calculating the cost-effectiveness ratio of an intervention. The "consistency principle" in medical cost-effectiveness analysis (CEA) requires that one include both the cost and the utility benefit of a change (in medical expenditures, consumption, or leisure) caused by an intervention or neither of them. By distinguishing between exogenous changes directly brought about by an intervention and endogenous patient responses to the exogenous changes, and within a lifetime utility maximization framework, this article addresses 2 questions related to the consistency principle: 1) how to choose among alternative internally consistent exclusion/inclusion rules, and 2) what to do with survival consumption costs and earnings. It finds that, for an endogenous change, excluding or including both the cost and the utility benefit of the change does not alter cost-effectiveness results. Further, in agreement with the consistency principle, welfare maximization implies that consumption costs and earnings during the extended life directly caused by an intervention should be included in CEA. PMID- 22101020 TI - Hic sunt dracones: the future of health technology assessment--one economist's perspective. AB - The dragons mentioned in the title are (a) the failure of HTA methodologists to develop--and hence practitioners to use--tools for the consideration of equity in economic appraisals of health care technologies; (b) a similar and reinforcing failure to devise and implement processes of decision making that would facilitate the incorporation of equity in HTA. The draconian consequence is that equity is hardly considered at all and certainly does not get the same consideration as efficiency. Some initial suggestions are made as to how these dragons may be slain. PMID- 22101021 TI - Molecular and pharmacological characteristics of the gerbil alpha(1a)-adrenergic receptor. AB - The spiral modiolar artery supplies blood and essential nutrients to the cochlea. Our previous functional study indicates the alpha(1A)-adrenergic receptor subtype mediates vasoconstriction of the gerbil spiral modiolar artery. Although the gerbil cochlea is often used as a model in hearing research, the molecular and pharmacological characteristics of the cloned gerbil alpha(1a)-adrenergic receptor have not been determined. Thus we cloned, expressed and characterized the gerbil alpha(1a)-adrenergic receptor and then compared its molecular and pharmacological properties to those of other mammalian alpha(1a)-adrenergic receptors. The cDNA clone contained 1404 nucleotides, which encoded a 467 amino acid peptide with a deduced sequence having 96.8, 96.4 and 91.6% identity to rat, mouse and human alpha(1a)-receptors, respectively. We transiently transfected the alpha(1a)-adrenergic receptor into COS-1 cells and determined its pharmacological characteristics by [(3)H]prazosin binding. Unlabeled prazosin had a K(i) of 0.89+/-0.1nM. The alpha(1A)-adrenergic receptor-selective antagonists, 5 methylurapidil and WB-4101, bound with high affinity and had K(i) values of 4.9+/ 1 and 1.0+/-0.1nM, respectively. BMY-7378, an alpha(1D)-adrenergic receptor selective antagonist, bound with low affinity (260+/-60nM). The 91.6% amino acid sequence identity and K(i)s of the cloned gerbil alpha(1a)-adrenergic receptor are similar to those of the human alpha(1a)-adrenergic receptor clone. These results show that the gerbil alpha(1a)-adrenergic receptor is representative of the human alpha(1a)-adrenergic receptor, lending validity to the use of the gerbil spiral modiolar artery as a model in studies of vascular disorders of the cochlea. PMID- 22101022 TI - Adding irrelevant information to the content prime reduces the prime-induced unmasking effect on speech recognition. AB - Presenting the early part of a nonsense sentence in quiet improves recognition of the last keyword of the sentence in a masker, especially a speech masker. This priming effect depends on higher-order processing of the prime information during target-masker segregation. This study investigated whether introducing irrelevant content information into the prime reduces the priming effect. The results showed that presenting the first four syllables (not including the second and third keywords) of the three-keyword target sentence in quiet significantly improved recognition of the second and third keywords in a two-talker-speech masker but not a noise masker, relative to the no-priming condition. Increasing the prime content from four to eight syllables (including the first and second keywords of the target sentence) further improved recognition of the third keyword in either the noise or speech masker. However, if the last four syllables of the eight syllable prime were replaced by four irrelevant syllables (which did not occur in the target sentence), all the prime-induced speech-recognition improvements disappeared. Thus, knowing the early part of the target sentence mainly reduces informational masking of target speech, possibly by helping listeners attend to the target speech. Increasing the informative content of the prime further improves target-speech recognition probably by reducing the processing load. The reduction of the priming effect by adding irrelevant information to the prime is not due to introducing additional masking of the target speech. PMID- 22101023 TI - Effects of age and background noise on processing a mistuned harmonic in an otherwise periodic complex sound. AB - Older adults presented with short (i.e., 40 ms) harmonic complex tones show a reduced likelihood of hearing the mistuned harmonic as a separate sound. Here, we examined whether this age difference for the mistuned harmonic would generalize to a longer signal duration (i.e., 200 ms). We measured auditory evoked fields (AEFs) using magnetoencephalography while young and older adults were presented with harmonic complex tones that either had all partials of the tones in tune (single sound object) or contained a 4 or 16% mistuned harmonic (dual sound objects). The auditory stimuli were presented in isolation or embedded in low or moderate levels of continuous white noise. For each participant, we modeled the AEFs with a pair of dipoles in the superior temporal plane and examined the effects of age and noise on the amplitude and latency of the resulting source waveforms. The present study reveals similar noise-induced increases in N1m and object-related negativity in young and older adults which may be mediated via efferent feedback connections and/or changes in the temporal window of integration. We observed less age-related differences in concurrent sound segregation for stimuli that matched the duration of the temporal integration window of auditory perception (i.e., ~200 ms) than for short duration sounds (i.e., 40 ms). Possible explanations for this duration-dependent age-related decline in concurrent sound perception are a general slowing in auditory processing and/or lengthening of the temporal integration window. PMID- 22101024 TI - Plasticity of serotonergic innervation of the inferior colliculus in mice following acoustic trauma. AB - Acoustic trauma often results in permanent damage to the cochlea, triggering changes in processing within central auditory structures such as the inferior colliculus (IC). The serotonergic neuromodulatory system, present in the IC, is responsive to chronic changes in the activity of sensory systems. The current study investigated whether the density of serotonergic innervation in the IC is changed following acoustic trauma. The trauma stimulus consisted of an 8 kHz pure tone presented at a level of 113 dB SPL for six consecutive hours to anesthetized CBA/J mice. Following a minimum recovery period of three weeks, serotonergic fibers were visualized via histochemical techniques targeting the serotonin reuptake transporter (SERT) and quantified using stereologic probes. SERT positive fiber densities were then compared between the traumatized and protected hemispheres of unilaterally traumatized subjects and those of controls. A significant effect of acoustic trauma was found between the hemispheres of unilaterally traumatized subjects such that the IC contralateral to the ear of exposure contained a lower density of SERT-positive fibers than the IC ipsilateral to acoustic trauma. No significant difference in density was found between the hemispheres of control subjects. Additional dimensions of variability in serotonergic fibers were seen among subdivisions of the IC and with age. The central IC had a slightly but significantly lowered density of serotonergic fibers than other subdivisions of the IC, and serotonergic fibers also declined with age. Overall, the results indicate that acoustic trauma is capable of producing modest but significant decreases in the density of serotonergic fibers innervating the IC. PMID- 22101025 TI - Assessing infertility stress: re-examining the factor structure of the Fertility Problem Inventory. AB - BACKGROUND: Research has documented that fertility problems can negatively affect the life of infertile patients, by imposing an obstacle to one important life goal: the achievement of parenthood. The Fertility Problem Inventory (FPI) proposes a comprehensive approach in assessing infertility stress, by measuring the impact on social, marital and sexual life dimensions and the importance of parenthood in infertile patients' life. This study examined the factor structure of the FPI, testing two alternative models using confirmatory factor analysis. METHODS: A sample of 209 infertile patients was recruited in two public hospital departments of assisted reproduction technology. Measures included the FPI, the Brief Symptom Inventory and the ENRICH Marital Inventory. RESULTS: Results confirmed the original measurement model of the instrument but suggested that the inclusion of an intermediate conceptual level resulted in a better fit to the model (chi284= 147.89, P< 0.001) i.e. the instrument assesses infertility stress by assessing two main conceptual domains: the impact of infertility in infertile patients' life and representations about the importance of parenthood. The instrument revealed measurement and structure invariance and construct validity by correlating with other measures assessing similar constructs. CONCLUSIONS: This approach to the FPI has important contributions for research and clinical practice by distinguishing between the impact of infertility on different dimensions of a couple's' life and representations about the importance of parenthood, therefore extending the utility of the FPI in research and clinical practice. PMID- 22101026 TI - Does quitting smoking during pregnancy have a long-term impact on smoking status? AB - BACKGROUND: Although pregnancy is often viewed as a unique opportunity to engage women in positive health changes, including smoking cessation, it is not clear whether, or to what extent, smoking cessation initiated during pregnancy persists long term after pregnancy. The purpose of the present study was to investigate the relation between smoking cessation during pregnancy and smoking status three years later. METHOD: Data were drawn from the National Epidemiologic Survey of Alcohol and Relation Conditions (NESARC), a nationally representative sample of over 40,000 adults in the United States. Multiple logistic regression analyses were conducted to examine the relation between smoking cessation during pregnancy and odds of smoking three years later. Smoking status at follow-up of women who continued smoking during pregnancy and women who never smoked was also examined. Analyses controlled for demographic differences. RESULTS: Smoking cessation during pregnancy was not significantly related to smoking status three years later. However, continued smoking during pregnancy was associated with significantly increased odds of smoking three years later, compared to smokers who were not pregnant at baseline. Among non-smokers, pregnancy at baseline was associated with a significantly decreased likelihood of smoking three years later, compared to women who were not pregnant at baseline. CONCLUSIONS: The present study uniquely extends previous research on smoking cessation during and following pregnancy. The results call for increased efforts to develop interventions that help new mothers develop and maintain abstinence from smoking. PMID- 22101027 TI - The prevalence of cannabis-involved driving in California. AB - BACKGROUND: Various national surveys suggest that cannabis use is rising nationally and many States have passed legislation that has potential to increase usage even further. This presents a problem for public roadways, as research suggests that cannabis impairs driving ability. METHODS: Anonymous oral fluid samples and breath tests were obtained from more than 900 weekend nighttime drivers randomly sampled from six jurisdictions in California. Oral fluid samples were assayed for the presence of Schedule I drugs. Drivers also completed information on self-reported drug use and possession of a medical cannabis permit. Data from the 2007 National Roadside Survey (collected using comparable methods) were used as a comparison. RESULTS: Using the 2010 data, a total of 14.4% of weekend nighttime drivers tested positive for illegal drugs, with 8.5% testing positive for delta-9-tetrahydrocannabinol (THC). THC-positive rates varied considerably among jurisdictions, from a low of 4.3% in Fresno to a high of 18.3% in Eureka. A comparison with the 2007 NRS data found an increase in THC positive drivers in 2010, but no increase in illegal drugs other than cannabis. Drivers who reported having a medical cannabis permit were significantly more likely to test positive for THC. CONCLUSIONS: Cannabis-involved driving has increased in California since 2007. Nearly 1-in-10 weekend, nighttime drivers tested positive for THC, and in some jurisdictions, the rate was nearly 1-in-5. The possible contribution of cannabis legislation, such as decriminalization and medical cannabis usage, is discussed. PMID- 22101028 TI - The NETTAB 2009 workshop. PMID- 22101029 TI - Bioinformatics tools for the structural elucidation of multi-subunit protein complexes by mass spectrometric analysis of protein-protein cross-links. AB - Multi-subunit protein complexes are involved in many essential biochemical processes including signal transduction, protein synthesis, RNA synthesis, DNA replication and protein degradation. An accurate description of the relative structural arrangement of the constituent subunits in such complexes is crucial for an understanding of the molecular mechanism of the complex as a whole. Many complexes, however, lie in the mega-Dalton range, and are not amenable to X-ray crystallographic or nuclear magnetic resonance analysis. Techniques that are suited to structural studies of such large complexes, such as cryo-electron microscopy, do not provide the resolution required for a mechanistic insight. Mass spectrometry (MS) has increasingly been applied to identify the residues that are involved in chemical cross-links in compound protein assemblies, and have provided valuable insight into the molecular arrangement, orientation and contact surfaces of subunits within such large complexes. This approach is known as MS3D, and involves the MS analysis of cross-linked di-peptides following the enzymatic cleavage of a chemically cross-linked complex. A major challenge of this approach is the identification of the cross-linked di-peptides in a composite mixture of peptides, as well as the identification of the residues involved in the cross-link. These analyses require bioinformatics tools with capabilities beyond that of general, MS-based proteomic analysis software. Many MS3D software tools have appeared, often designed for very specific experimental methods. Here, we provide a review of all major MS3D bioinformatics programmes, reviewing their applicability to different workflows, specific experimental requirements and the computational approach taken by each. PMID- 22101031 TI - Decidualized pseudopregnant rat uterus shows marked reduction in Ang II and Ang (1-7) levels. AB - Previous studies showed that angiotensin (Ang) II and Ang-(1-7) concentrations were reduced in the implantation site at day 7 of pregnancy in Sprague-Dawley rats as compared to the site immediately adjacent to it, which does not have the embryo attached, clearly showing the importance of the blastocyst in the regulation of renin-angiotensin system (RAS). OBJECTIVE: The objective of this study was to evaluate the regulation of the RAS in the decidualized uterus in the pseudopregnant rat, a model without the presence of a conceptus. METHODS: Ovariectomized, adult female rats were sensitized for the decidual cell reaction with steroid treatments; decidualization was induced by oil-injection of the right horn; the left horn served as a control. The uterine content of Ang I, Ang II, and Ang-(1-7) was examined in the decidualized and non-decidualized uteri. RESULTS: Both Ang-(1-7) and Ang II and ACE and ACE2 mRNA were significantly reduced in the decidualized horn as compared to the non-decidualized horn. Immunocytochemical characterization of Ang II, Ang-(1-7), ACE and ACE2 demonstrated that Ang-(1-7), Ang II, and ACE2 polarize to the anti-mesometrial pole with decidualization. CONCLUSION: The decidualization process elicits marked reduction in uterine Ang II and Ang-(1-7) content as compared to the non decidualized horn. The differential immunocytochemical expression of Ang II and Ang-(1-7) with ACE2, but not ACE in the anti-mesometrial pole of the decidualized horn may favor the formation and action of Ang-(1-7) in the anti-mesometrial pole, an area which plays a role in triggering the decidualization process. PMID- 22101032 TI - Epigallocatechin gallate suppresses peritoneal fibrosis in mice. AB - Long-term peritoneal dialysis (PD) leads to histological changes in the peritoneal membrane. Angiogenesis and inflammation caused by glucose degradation products (GDPs) play crucial roles in peritoneal fibrosis. One such GDP is methylglyoxal (MGO), which enhances the formation of advanced glycation end products (AGEs). AGEs bind to their receptor (RAGE) and activate nuclear factor kappaB (NF-kappaB), which is a key regulator of angiogenesis and inflammation. Recent studies have indicated that (-)-epigallocatechin gallate (EGCG), a tea polyphenol, inhibits angiogenesis and inflammation. Here, we examined whether EGCG suppresses peritoneal fibrosis in mice. Based on preliminary examination, 2mL of 40mM MGO or PD fluid was injected intraperitoneally and EGCG (50mg/kg) or saline was injected subcutaneously for 3weeks. In comparison to PD fluid+saline treated mice, the peritoneal tissues of MGO+saline-treated mice showed marked thickening of the submesothelial compact zone. In the submesothelial compact zone of the MGO+saline-treated mice, CD31-positive vessels and vascular endothelial growth factor-positive cells were significantly increased, as were inflammation, F4/80-positive macrophages, and monocyte chemotactic protein-1. Moreover, 8 hydroxydeoxyguanosine, a marker of reactive oxygen species, and NF-kappaB, determined by Southwestern histochemistry, in the submesothelial compact zone were also increased in MGO+saline-treated mice. These changes were attenuated in MGO+EGCG-treated mice. We demonstrated that EGCG treatment suppresses peritoneal fibrosis via inhibition of NF-kappaB. Furthermore, EGCG inhibits reactive oxygen species production. The results of this study indicate that EGCG is a potentially novel candidate for the treatment of peritoneal fibrosis. PMID- 22101033 TI - Intracellular Copper Zinc Superoxide dismutase (icCuZnSOD) from Asian seabass (Lates calcarifer): molecular cloning, characterization and gene expression with reference to Vibrio anguillarum infection. AB - Copper Zinc Superoxide dismutase (CuZnSOD) is the family of most important antioxidant metalloenzymes that protects tissues from damage by reactive oxygen species (ROS). In the present study, the intracellular copper zinc SOD from the Asian seabass Lates calcarifer (Lc-icCuZnSOD) was identified by RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE) technique. The full-length cDNA of Lc-icCuZnSOD consisted of 809 nucleotides with an open-reading frame of 465 bp encoding 154 amino acids and N-Glycosylation site (NVTA) within. The predicted molecular mass of the protein is 15.84 kDa with an estimated pI of 5.52. The deduced amino acid sequence of Lc-icCuZnSOD shared high degree of homology with known CuZnSODs from other species. CuZn binding sites (H47, H49, H64, and H121 for Cu(2+) and H72, H81, and ASP84 for Zn(2+)), two cysteine residues (aa 58 and 147) that form a disulfide bond, and CuZnSOD family signature sequences (GFHVHAFGDNT, aa 45-55 and GNAGGRLACGVI, aa 139-150) were highly conserved among fish species. Temporal and tissue specific expression of Lc icCuZnSOD was significantly differentially altered in Asian seabass challenged with Vibrio anguillarum indicating possible role in antioxidant activities involved in the innate immune defense mechanisms. PMID- 22101034 TI - Salivaricin D, a novel intrinsically trypsin-resistant lantibiotic from Streptococcus salivarius 5M6c isolated from a healthy infant. AB - In this work, we purified and characterized a newly identified lantibiotic (salivaricin D) from Streptococcus salivarius 5M6c. Salivaricin D is a 34-amino acid-residue peptide (3,467.55 Da); the locus of the gene encoding this peptide is a 16.5-kb DNA segment which contains genes encoding the precursor of two lantibiotics, two modification enzymes (dehydratase and cyclase), an ABC transporter, a serine-like protease, immunity proteins (lipoprotein and ABC transporters), a response regulator, and a sensor histidine kinase. The immunity gene (salI) was heterologously expressed in a sensitive indicator and provided significant protection against salivaricin D, confirming its immunity function. Salivaricin D is a naturally trypsin-resistant lantibiotic that is similar to nisin-like lantibiotics. It is a relatively broad-spectrum bacteriocin that inhibits members of many genera of Gram-positive bacteria, including the important human pathogens Streptococcus pyogenes and Streptococcus pneumoniae. Thus, Streptococcus salivarius 5M6c may be a potential biological agent for the control of oronasopharynx-colonizing streptococcal pathogens or may be used as a probiotic bacterium. PMID- 22101035 TI - Natural niche for organohalide-respiring Chloroflexi. AB - The phylum Chloroflexi contains several isolated bacteria that have been found to respire a diverse array of halogenated anthropogenic chemicals. The distribution and role of these Chloroflexi in uncontaminated terrestrial environments, where abundant natural organohalogens could function as potential electron acceptors, have not been studied. Soil samples (116 total, including 6 sectioned cores) from a range of uncontaminated sites were analyzed for the number of Dehalococcoides like Chloroflexi 16S rRNA genes present. Dehalococcoides-like Chloroflexi populations were detected in all but 13 samples. The concentrations of organochlorine ([organochlorine]), inorganic chloride, and total organic carbon (TOC) were obtained for 67 soil core sections. The number of Dehalococcoides-like Chloroflexi 16S rRNA genes positively correlated with [organochlorine]/TOC while the number of Bacteria 16S rRNA genes did not. Dehalococcoides-like Chloroflexi were also observed to increase in number with a concomitant accumulation of chloride when cultured with an enzymatically produced mixture of organochlorines. This research provides evidence that organohalide-respiring Chloroflexi are widely distributed as part of uncontaminated terrestrial ecosystems, they are correlated with the fraction of TOC present as organochlorines, and they increase in abundance while dechlorinating organochlorines. These findings suggest that organohalide-respiring Chloroflexi may play an integral role in the biogeochemical chlorine cycle. PMID- 22101036 TI - Electron donors supporting growth and electroactivity of Geobacter sulfurreducens anode biofilms. AB - Geobacter bacteria efficiently oxidize acetate into electricity in bioelectrochemical systems, yet the range of fermentation products that support the growth of anode biofilms and electricity production has not been thoroughly investigated. Here, we show that Geobacter sulfurreducens oxidized formate and lactate with electrodes and Fe(III) as terminal electron acceptors, though with reduced efficiency compared to acetate. The structure of the formate and lactate biofilms increased in roughness, and the substratum coverage decreased, to alleviate the metabolic constraints derived from the assimilation of carbon from the substrates. Low levels of acetate promoted formate carbon assimilation and biofilm growth and increased the system's performance to levels comparable to those with acetate only. Lactate carbon assimilation also limited biofilm growth and led to the partial oxidization of lactate to acetate. However, lactate was fully oxidized in the presence of fumarate, which redirected carbon fluxes into the tricarboxylic acid (TCA) cycle, and by acetate-grown biofilms. These results expand the known ranges of electron donors for Geobacter-driven fuel cells and identify microbial constraints that can be targeted to develop better-performing strains and increase the performance of bioelectrochemical systems. PMID- 22101037 TI - Development of a new strategy for production of medium-chain-length polyhydroxyalkanoates by recombinant Escherichia coli via inexpensive non-fatty acid feedstocks. AB - Pseudomonas putida KT2440 is capable of producing medium-chain-length polyhydroxyalkanoates (MCL-PHAs) when grown on unrelated carbon sources during nutrient limitation. Transcription levels of genes putatively involved in PHA biosynthesis were assessed by quantitative real-time PCR (qRT-PCR) in P. putida grown on glycerol as a sole carbon source. The results showed that two genes, phaG and the PP0763 gene, were highly upregulated among genes potentially involved in the biosynthesis of MCL-PHAs from unrelated carbon sources. Previous studies have described phaG as a 3-hydroxyacyl-acyl carrier protein (ACP) coenzyme A (CoA) transferase, and based on homology, the PP0763 gene was predicted to encode a medium-chain-fatty-acid CoA ligase. High expression levels of these genes during PHA production in P. putida led to the hypothesis that these two genes are involved in PHA biosynthesis from non-fatty acid carbon sources, such as glucose and glycerol. The phaG(pp) and PP0763 genes from P. putida were cloned and coexpressed with the engineered Pseudomonas sp. 61-3 PHA synthase gene phaCl (STQK)(ps) in recombinant Escherichia coli. Up to 400 mg liter(-1) MCL-PHAs was successfully produced from glucose. This study has produced the largest amount of MCL-PHAs reported from non-fatty acid carbon sources in recombinant E. coli to date and opens up the possibility of using inexpensive feedstocks to produce MCL-PHA polymers. PMID- 22101038 TI - Production, secretion, and cell surface display of recombinant Sporosarcina ureae S-layer fusion proteins in Bacillus megaterium. AB - Monomolecular crystalline bacterial cell surface layers (S-layers) have broad application potential in nanobiotechnology due to their ability to generate functional supramolecular structures. Here, we report that Bacillus megaterium is an excellent host organism for the heterologous expression and efficient secretion of hemagglutinin (HA) epitope-tagged versions of the S-layer protein SslA from Sporosarcina ureae ATCC 13881. Three chimeric proteins were constructed, comprising the precursor, C-terminally truncated, and N- and C terminally truncated forms of the S-layer SslA protein tagged with the human influenza hemagglutinin epitope. For secretion of fusion proteins, the open reading frames were cloned into the Escherichia coli-Bacillus megaterium shuttle vector pHIS1525. After transformation of the respective plasmids into Bacillus megaterium protoplasts, the recombinant genes were successfully expressed and the proteins were secreted into the growth medium. The isolated S-layer proteins are able to assemble in vitro into highly ordered, crystalline, sheetlike structures with the fused HA tag accessible to antibody. We further show by fluorescent labeling that the secreted S-layer fusion proteins are also clustered on the cell envelope of Bacillus megaterium, indicating that the cell surface can serve in vivo as a nucleation point for crystallization. Thus, this system can be used as a display system that allows the dense and periodic presentation of S-layer proteins or the fused tags. PMID- 22101039 TI - Enterococcus faecium of the vanA genotype in rural drinking water, effluent, and the aqueous environment. AB - Total enterococci and vancomycin-resistant enterococci (VRE) were enumerated in samples of effluent (n = 50) and water (n = 167) from a number of sources. VRE were detected in the outflow of a wastewater treatment plant and in a single rural drinking water supply, suggesting potential for transmission to humans through environmental contamination. PMID- 22101040 TI - Streptomycin-induced expression in Bacillus subtilis of YtnP, a lactonase homologous protein that inhibits development and streptomycin production in Streptomyces griseus. AB - Bacillus subtilis induces expression of the gene ytnP in the presence of the antimicrobial streptomycin, produced by the Gram-positive bacterium Streptomyces griseus. ytnP encodes a lactonase-homologous protein that is able to inhibit the signaling pathway required for the streptomycin production and development of aerial mycelium in S. griseus. PMID- 22101041 TI - Identification and characterization of a xyloglucan-specific family 74 glycosyl hydrolase from Streptomyces coelicolor A3(2). AB - The sco6545 gene of Streptomyces coelicolor A3(2) was nominated as a putative cellulase with 863 mature-form amino acids (90.58 kDa). We overexpressed and purified Sco6545 and demonstrated that the protein is not a cellulase but a xyloglucan-specific glycosyl hydrolase which cleaves xyloglucan at unbranched glucose residues. PMID- 22101042 TI - Type three effector gene distribution and sequence analysis provide new insights into the pathogenicity of plant-pathogenic Xanthomonas arboricola. AB - Xanthomonas arboricola is a complex bacterial species which mainly attacks fruit trees and is responsible for emerging diseases in Europe. It comprises seven pathovars (X. arboricola pv. pruni, X. arboricola pv. corylina, X. arboricola pv. juglandis, X. arboricola pv. populi, X. arboricola pv. poinsettiicola, X. arboricola pv. celebensis, and X. arboricola pv. fragariae), each exhibiting characteristic disease symptoms and distinct host specificities. To better understand the factors underlying this ecological trait, we first assessed the phylogenetic relationships among a worldwide collection of X. arboricola strains by sequencing the housekeeping gene rpoD. This analysis revealed that strains of X. arboricola pathovar populi are divergent from the main X. arboricola cluster formed by all other strains. Then, we investigated the distribution of 53 type III effector (T3E) genes in a collection of 57 X. arboricola strains that are representative of the main X. arboricola cluster. Our results showed that T3E repertoires vary greatly between X. arboricola pathovars in terms of size. Indeed, X. arboricola pathovars pruni, corylina, and juglandis, which are responsible for economically important stone fruit and nut diseases in Europe, harbored the largest T3E repertoires, whereas pathovars poinsettiicola, celebensis, and fragariae harbored the smallest. We also identified several differences in T3E gene content between X. arboricola pathovars pruni, corylina, and juglandis which may account for their differing host specificities. Further, we examined the allelic diversity of eight T3E genes from X. arboricola pathovars. This analysis revealed very limited allelic variations at the different loci. Altogether, the data presented here provide new insights into the evolution of pathogenicity and host range of X. arboricola and are discussed in terms of emergence of new diseases within this bacterial species. PMID- 22101043 TI - Responses of methanogen mcrA genes and their transcripts to an alternate dry/wet cycle of paddy field soil. AB - Intermittent drainage can substantially reduce methane emission from rice fields, but the microbial mechanisms remain poorly understood. In the present study, we determined the rates of methane production and emission, the dynamics of ferric iron and sulfate, and the abundance of methanogen mcrA genes (encoding the alpha subunit of methyl coenzyme M reductase) and their transcripts in response to alternate dry/wet cycles in paddy field soil. We found that intermittent drainage did not affect the growth of rice plants but significantly reduced the rates of both methane production and emission. The dry/wet cycles also resulted in shifts of soil redox conditions, increasing the concentrations of ferric iron and sulfate in the soil. Quantitative PCR analysis revealed that both mcrA gene copies and mcrA transcripts significantly decreased after dry/wet alternation compared to continuous flooding. Correlation and regression analyses showed that the abundance of mcrA genes and transcripts positively correlated with methane production potential and soil water content and negatively correlated with the concentrations of ferric iron and sulfate in the soil. However, the transcription of mcrA genes was reduced to a greater extent than the abundance of mcrA genes, resulting in very low mcrA transcript/gene ratios after intermittent drainage. Furthermore, terminal restriction fragment length polymorphism analysis revealed that the composition of methanogenic community remained stable under dry/wet cycles, whereas that of metabolically active methanogens strongly changed. Collectively, our study demonstrated a stronger effect of intermittent drainage on the abundance of mcrA transcripts than of mcrA genes in rice field soil. PMID- 22101044 TI - Application of a receptor-binding capture quantitative reverse transcription-PCR assay to concentrate human norovirus from sewage and to study the distribution and stability of the virus. AB - Water is an important route for human norovirus (HuNoV) transmission. Using magnetic beads conjugated with blood group-like antigens (HuNoV receptors), we developed a simple and rapid receptor-binding capture and magnetic sequestration (RBCMS) method and compared it to the existing negatively charged membrane absorption/elution (NCMAE) method for concentrating HuNoV from sewage effluent. RBCMS required 6-fold-less sample volume than the NCMAE method and also resulted in a significantly higher yield of HuNoV. The NCMAE and RBCMS concentrations of genogroup I (GI) HuNoV measured by quantitative reverse transcription-PCR (qRT PCR) resulted in average threshold cycle (C(T)) values of 34.68 (8.68 copies, 252 fold concentration) versus 34.07 (13.05 copies, 477-fold concentration), respectively; the NCMAE and RBCMS concentrations of genogroup II (GII) HuNoV were measured as average C(T) values of 33.32 (24.7 copies, 239-fold concentration) versus 32.38 (46.9 copies, 333-fold concentration), respectively. The specificity of qRT-PCR was confirmed by traditional RT-PCR and an RNase I protection assay. The qRT-PCR signal from RBCMS-concentrated HuNoV treated with RNase I indicated that it was from encapsidated RNA and, probably, viable virus. In contrast, the qRT-PCR signal from NCMAE-concentrated HuNoV was not protected from RNase I and, likely, degradation. Both GI and GII HuNoV were detected from sewage effluent samples collected between April and July with average concentrations of 7.8 * 10(3) genomic copies per liter (gc/liter) and 4.3 * 10(4) gc/liter, respectively. No GI and <2% GII HuNoV were detected in sewage samples stored at room temperature for 4 weeks. We conclude that RBCMS requires less sample volume, has better recovery and sensitivity, and is faster than NCMAE for detection of HuNoV in sewage. PMID- 22101045 TI - Indole production promotes Escherichia coli mixed-culture growth with Pseudomonas aeruginosa by inhibiting quorum signaling. AB - Indole production by Escherichia coli, discovered in the early 20th century, has been used as a diagnostic marker for distinguishing E. coli from other enteric bacteria. By using transcriptional profiling and competition studies with defined mutants, we show that cyclic AMP (cAMP)-regulated indole formation is a major factor that enables E. coli growth in mixed biofilm and planktonic populations with Pseudomonas aeruginosa. Mutants deficient in cAMP production (cyaA) or the cAMP receptor gene (crp), as well as indole production (tnaA), were not competitive in coculture with P. aeruginosa but could be restored to wild-type competitiveness by supplementation with a physiologically relevant indole concentration. E. coli sdiA mutants, which lacked the receptor for both indole and N-acyl-homoserine lactones (AHLs), showed no change in competitive fitness, suggesting that indole acted directly on P. aeruginosa. An E. coli tnaA mutant strain regained wild-type competiveness if grown with P. aeruginosa AHL synthase (rhlI and rhlI lasI) mutants. In contrast to the wild type, P. aeruginosa AHL synthase mutants were unable to degrade indole. Indole produced during mixed culture growth inhibited pyocyanin production and other AHL-regulated virulence factors in P. aeruginosa. Mixed-culture growth with P. aeruginosa stimulated indole formation in E. coli cpdA, which is unable to regulate cAMP levels, suggesting the potential for mixed-culture gene activation via cAMP. These findings illustrate how indole, an early described feature of E. coli central metabolism, can play a significant role in mixed-culture survival by inhibiting quorum-regulated competition factors in P. aeruginosa. PMID- 22101046 TI - Preliminary safety evaluation of a new Bacteroides xylanisolvens isolate. AB - Besides conferring some health benefit to the host, a bacterial strain must present an unambiguous safety status to be considered a probiotic. We here present the preliminary safety evaluation of a new Bacteroides xylanisolvens strain (DSM 23964) isolated from human feces. First results suggest that it may be able to provide probiotic health benefits. Its identity was confirmed by biochemical analysis, by sequencing of its 16S rRNA genes, and by DNA-DNA hybridization. Virulence determinants known to occur in the genus Bacteroides, such the bft enterotoxin and other enzymatic activities involved in the degradation of the extracellular matrix and the capsular polysaccharide PS A, were absent in this strain. The investigation of the antibiotic susceptibility indicated that strain DSM 23964 was sensitive to metronidazole, meropenem agents, and clindamycin. Resistance to penicillin and ampicillin was identified to be conferred by the beta-lactamase cepA gene and could therefore be restored by adding beta-lactamase inhibitors. The localization of the cepA gene in the genome of strain DSM 23964 and the absence of detectable plasmids further suggest that a transfer of beta-lactamase activity or the acquisition of other antibiotic resistances are highly improbable. Taken together, the presented data indicate that the strain B. xylanisolvens DSM 23964 has no virulence potential. Since it also resists the action of gastric enzymes and low-pH conditions, this strain is an interesting candidate for further investigation of its safety and potential health-promoting properties. PMID- 22101047 TI - Casuarina root exudates alter the physiology, surface properties, and plant infectivity of Frankia sp. strain CcI3. AB - The actinomycete genus Frankia forms nitrogen-fixing symbioses with 8 different families of actinorhizal plants, representing more than 200 different species. Very little is known about the initial molecular interactions between Frankia and host plants in the rhizosphere. Root exudates are important in Rhizobium-legume symbiosis, especially for initiating Nod factor synthesis. We measured differences in Frankia physiology after exposure to host aqueous root exudates to assess their effects on actinorhizal symbioses. Casuarina cunninghamiana root exudates were collected from plants under nitrogen-sufficient and -deficient conditions and tested on Frankia sp. strain CcI3. Root exudates increased the growth yield of Frankia in the presence of a carbon source, but Frankia was unable to use the root exudates as a sole carbon or energy source. Exposure to root exudates caused hyphal "curling" in Frankia cells, suggesting a chemotrophic response or surface property change. Exposure to root exudates altered Congo red dye binding, which indicated changes in the bacterial surface properties at the fatty acid level. Fourier transform infrared spectroscopy (FTIR) confirmed fatty acid changes and revealed further carbohydrate changes. Frankia cells preexposed to C. cunninghamiana root exudates for 6 days formed nodules on the host plant significantly earlier than control cells. These data support the hypothesis of early chemical signaling between actinorhizal host plants and Frankia in the rhizosphere. PMID- 22101048 TI - Effectiveness of a simplified method for isolation of Burkholderia pseudomallei from soil. AB - Detection of environmental Burkholderia pseudomallei indicates a risk for melioidosis and is important for the development of a global risk map. We describe a simple method for detecting B. pseudomallei using direct culture of soil in enrichment broth. This gives a rate of positivity comparable to that obtained with a standard method but is cheaper and labor saving. PMID- 22101049 TI - Cultured representatives of two major phylogroups of human colonic Faecalibacterium prausnitzii can utilize pectin, uronic acids, and host-derived substrates for growth. AB - Faecalibacterium prausnitzii is one of the most abundant commensal bacteria in the healthy human large intestine, but information on genetic diversity and substrate utilization is limited. Here, we examine the phylogeny, phenotypic characteristics, and influence of gut environmental factors on growth of F. prausnitzii strains isolated from healthy subjects. Phylogenetic analysis based on the 16S rRNA sequences indicated that the cultured strains were representative of F. prausnitzii sequences detected by direct analysis of fecal DNA and separated the available isolates into two phylogroups. Most F. prausnitzii strains tested grew well under anaerobic conditions on apple pectin. Furthermore, F. prausnitzii strains competed successfully in coculture with two other abundant pectin-utilizing species, Bacteroides thetaiotaomicron and Eubacterium eligens, with apple pectin as substrate, suggesting that this species makes a contribution to pectin fermentation in the colon. Many F. prausnitzii isolates were able to utilize uronic acids for growth, an ability previously thought to be confined to Bacteroides spp. among human colonic anaerobes. Most strains grew on N acetylglucosamine, demonstrating an ability to utilize host-derived substrates. All strains tested were bile sensitive, showing at least 80% growth inhibition in the presence of 0.5 MUg/ml bile salts, while inhibition at mildly acidic pH was strain dependent. These attributes help to explain the abundance of F. prausnitzii in the colonic community but also suggest factors in the gut environment that may limit its distribution. PMID- 22101050 TI - Role of IncP-1beta plasmids pWDL7::rfp and pNB8c in chloroaniline catabolism as determined by genomic and functional analyses. AB - Broad-host-range catabolic plasmids play an important role in bacterial degradation of man-made compounds. To gain insight into the role of these plasmids in chloroaniline degradation, we determined the first complete nucleotide sequences of an IncP-1 chloroaniline degradation plasmid, pWDL7::rfp and its close relative pNB8c, as well as the expression pattern, function, and bioaugmentation potential of the putative 3-chloroaniline (3-CA) oxidation genes. Based on phylogenetic analysis of backbone proteins, both plasmids are members of a distinct clade within the IncP-1beta subgroup. The plasmids are almost identical, but whereas pWDL7::rfp carries a duplicate inverted catabolic transposon, Tn6063, containing a putative 3-CA oxidation gene cluster, dcaQTA1A2BR, pNB8c contains only a single copy of the transposon. No genes for an aromatic ring cleavage pathway were detected on either plasmid, suggesting that only the upper 3-CA degradation pathway was present. The dcaA1A2B gene products expressed from a high-copy-number vector were shown to convert 3-CA to 4 chlorocatechol in Escherichia coli. Slight differences in the dca promoter region between the plasmids and lack of induction of transcription of the pNB8c dca genes by 3-CA may explain previous findings that pNB8C does not confer 3-CA transformation. Bioaugmentation of activated sludge with pWDL7::rfp accelerated removal of 3-CA, but only in the presence of an additional carbon source. Successful bioaugmentation requires complementation of the upper pathway genes with chlorocatechol cleavage genes in indigenous bacteria. The genome sequences of these plasmids thus help explain the molecular basis of their catabolic activities. PMID- 22101051 TI - Multiple plastids collected by the dinoflagellate Dinophysis mitra through kleptoplastidy. AB - Kleptoplastidy is the retention of plastids obtained from ingested algal prey, which may remain temporarily functional and be used for photosynthesis by the predator. We showed that the marine dinoflagellate Dinophysis mitra has great kleptoplastid diversity. We obtained 308 plastid rbcL sequences by gene cloning from 14 D. mitra cells and 102 operational taxonomic units (OTUs). Most sequences were new in the genetic database and positioned within Haptophyceae (227 sequences [73.7%], 80 OTUs [78.4%]), particularly within the genus Chrysochromulina. Others were closely related to Prasinophyceae (16 sequences [5.2%], 5 OTUs [4.9%]), Dictyochophyceae (14 sequences [4.5%], 5 OTUs [4.9%]), Pelagophyceae (14 sequences [4.5%], 1 OTU [1.0%]), Bolidophyceae (3 sequences [1.0%], 1 OTU [1.0%]), and Bacillariophyceae (1 sequence [0.3%], 1 OTU [1.0%]); however, 33 sequences (10.8%) as 9 OTUs (8.8%) were not closely clustered with any particular group. Only six sequences were identical to those of Chrysochromulina simplex, Chrysochromulina hirta, Chrysochromulina sp. TKB8936, Micromonas pusilla NEPCC29, Micromonas pusilla CCMP491, and an unidentified diatom. Thus, we detected >100 different plastid sequences from 14 D. mitra cells, strongly suggesting kleptoplastidy and the need for mixotrophic prey such as Laboea, Tontonia, and Strombidium-like ciliates, which retain numerous symbiotic plastids from different origins, for propagation and plastid sequestration. PMID- 22101052 TI - Molecular clues to understand the aerotolerance phenotype of Bifidobacterium animalis subsp. lactis. AB - Oxygen is one of the abiotic factors negatively affecting the survival of Bifidobacterium strains used as probiotics, mainly due to the induction of lethal oxidative damage. Aerobic conditions are present during the process of manufacture and storage of functional foods, and aerotolerance is a desired trait for bifidobacteria intended for use in industry. In the present study, the molecular response of Bifidobacterium animalis subsp. lactis IPLA4549 to aerobic conditions is presented. Molecular targets affected by oxygen were studied using two-dimensional electrophoresis (2DE) and quantitative reverse transcriptase (qRT) PCR. Globally, oxygen stress induced a shift in the glycolytic pathway toward the production of acetic acid with a concomitant increase in ATP formation. Several changes in the expression of genes coding for enzymes involved in redox reactions were detected, although the redox ratio remained unaltered. Interestingly, cells grown under aerobic conditions were characterized by higher activity of coproporphyrinogen III oxidase, which can directly detoxify molecular oxygen, and by higher NADH oxidase specific activity, which can oxidize NADH using hydrogen peroxide. In turn, this is in agreement with the glycolytic shift toward acetate production, in that more NADH molecules may be available due to the lower level of lactic acid formation. These findings further our ability to elucidate the mechanisms by which B. animalis copes with an oxygen-containing atmosphere. PMID- 22101053 TI - Production of 7-O-methyl aromadendrin, a medicinally valuable flavonoid, in Escherichia coli. AB - 7-O-Methyl aromadendrin (7-OMA) is an aglycone moiety of one of the important flavonoid-glycosides found in several plants, such as Populus alba and Eucalyptus maculata, with various medicinal applications. To produce such valuable natural flavonoids in large quantity, an Escherichia coli cell factory has been developed to employ various plant biosynthetic pathways. Here, we report the generation of 7-OMA from its precursor, p-coumaric acid, in E. coli for the first time. Primarily, naringenin (NRN) (flavanone) synthesis was achieved by feeding p coumaric acid and reconstructing the plant biosynthetic pathway by introducing the following structural genes: 4-coumarate-coenzyme A (CoA) ligase from Petroselinum crispum, chalcone synthase from Petunia hybrida, and chalcone isomerase from Medicago sativa. In order to increase the availability of malonyl CoA, a critical precursor of 7-OMA, genes for the acyl-CoA carboxylase alpha and beta subunits (nfa9890 and nfa9940), biotin ligase (nfa9950), and acetyl-CoA synthetase (nfa3550) from Nocardia farcinica were also introduced. Thus, produced NRN was hydroxylated at position 3 by flavanone-3-hydroxylase from Arabidopsis thaliana, which was further methylated at position 7 to produce 7-OMA in the presence of 7-O-methyltransferase from Streptomyces avermitilis. Dihydrokaempferol (DHK) (aromadendrin) and sakuranetin (SKN) were produced as intermediate products. Overexpression of the genes for flavanone biosynthesis and modification pathways, along with malonyl-CoA overproduction in E. coli, produced 2.7 mg/liter (8.9 MUM) 7-OMA upon supplementation with 500 MUM p-coumaric acid in 24 h, whereas the strain expressing only the flavanone modification enzymes yielded 30 mg/liter (99.2 MUM) 7-OMA from 500 MUM NRN in 24 h. PMID- 22101054 TI - Effect of a synbiotic yogurt on levels of fecal bifidobacteria, clostridia, and enterobacteria. AB - While ingestion of synbiotic yogurts containing Bifidobacterium animalis subsp. lactis and inulin is increasing, their effect on certain microbial groups in the human intestine is unclear. To further investigate this, a large-scale, crossover design, placebo-controlled study was utilized to evaluate the effect of a synbiotic yogurt containing B. animalis subsp. lactis Bb-12 and inulin on the human intestinal bifidobacteria, clostridia, and enterobacteria. Fecal samples were collected at 14 time points from 46 volunteers who completed the study, and changes in the intestinal bacterial levels were monitored using real-time PCR. Strain Bb-12 could not be detected in feces after 2 weeks of washout. A live/dead PCR procedure indicated that the Bb-12 strain detected in the fecal samples was alive. A significant increase (P < 0.001) in the total bifidobacterial numbers was seen in both groups of subjects during the final washout period compared to the prefeeding period. This increase in total bifidobacteria corresponded with a significant decrease (P < 0.05) in numbers of clostridia but not enterobacteria. No significant differences in numbers of bifidobacteria, clostridia, or enterobacteria were observed between the probiotic and placebo groups during any of the feeding periods. However, subgrouping subjects based on lower initial bifidobacterial numbers or higher initial clostridial numbers did show corresponding significant differences between the synbiotic yogurt and placebo groups. This was not observed for a subgroup with higher initial enterobacterial numbers. While this synbiotic yogurt can increase bifidobacterial numbers and decrease clostridial numbers (but not enterobacterial numbers) in some individuals, it cannot modulate these microbial groups in the majority of individuals. PMID- 22101055 TI - Heterologous expression and characterization of two 1-hydroxy-2-naphthoic acid dioxygenases from Arthrobacter phenanthrenivorans. AB - A protein fraction exhibiting 1-hydroxy-2-naphthoic acid (1-H2NA) dioxygenase activity was purified via ion exchange, hydrophobic interactions, and gel filtration chromatography from Arthrobacter phenanthrenivorans sp. nov. strain Sphe3 isolated from a Greek creosote-oil-polluted site. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and tandem MS (MS-MS) analysis revealed that the amino acid sequences of oligopeptides of the major 45-kDa protein species, as analyzed by SDS-PAGE and silver staining, comprising 29% of the whole sequence, exhibited strong homology with 1-H2NA dioxygenase of Nocardioides sp. strain KP7. A BLAST search of the recently sequenced Sphe3 genome revealed two putative open reading frames, named diox1 and diox2, showing 90% nucleotide identity to each other and 85% identity at the amino acid level with the Nocardia sp. homologue. diox1 was found on an indigenous Sphe3 plasmid, whereas diox2 was located on the chromosome. Both genes were induced by the presence of phenanthrene used as a sole carbon and energy source, and as expected, both were subject to carbon catabolite repression. The relative RNA transcription level of the chromosomal (diox2) gene was significantly higher than that of its plasmid (diox1) homologue. Both diox1 and diox2 putative genes were PCR amplified, cloned, and overexpressed in Escherichia coli. Recombinant E. coli cells expressed 1-H2NA dioxygenase activity. Recombinant enzymes exhibited Michaelis-Menten kinetics with an apparent K(m) of 35 MUM for Diox1 and 29 MUM for Diox2, whereas they showed similar kinetic turnover characteristics with K(cat)/K(m) values of 11 * 10(6) M(-1) s(-1) and 12 * 10(6) M(-1) s(-1), respectively. Occurrence of two diox1 and diox2 homologues in the Sphe3 genome implies that a replicative transposition event has contributed to the evolution of 1-H2NA dioxygenase in A. phenanthrenivorans. PMID- 22101056 TI - Characterization, ecological distribution, and population dynamics of Saccharomyces sensu stricto killer yeasts in the spontaneous grape must fermentations of southwestern Spain. AB - Killer yeasts secrete protein toxins that are lethal to sensitive strains of the same or related yeast species. Among the four types of Saccharomyces killer yeasts already described (K1, K2, K28, and Klus), we found K2 and Klus killer yeasts in spontaneous wine fermentations from southwestern Spain. Both phenotypes were encoded by medium-size double-stranded RNA (dsRNA) viruses, Saccharomyces cerevisiae virus (ScV)-M2 and ScV-Mlus, whose genome sizes ranged from 1.3 to 1.75 kb and from 2.1 to 2.3 kb, respectively. The K2 yeasts were found in all the wine-producing subareas for all the vintages analyzed, while the Klus yeasts were found in the warmer subareas and mostly in the warmer ripening/harvest seasons. The middle-size isotypes of the M2 dsRNA were the most frequent among K2 yeasts, probably because they encoded the most intense K2 killer phenotype. However, the smallest isotype of the Mlus dsRNA was the most frequent for Klus yeasts, although it encoded the least intense Klus killer phenotype. The killer yeasts were present in most (59.5%) spontaneous fermentations. Most were K2, with Klus being the minority. The proportion of killer yeasts increased during fermentation, while the proportion of sensitive yeasts decreased. The fermentation speed, malic acid, and wine organoleptic quality decreased in those fermentations where the killer yeasts replaced at least 15% of a dominant population of sensitive yeasts, while volatile acidity and lactic acid increased, and the amount of bacteria in the tumultuous and the end fermentation stages also increased in an unusual way. PMID- 22101057 TI - DECIPHER, a search-based approach to chimera identification for 16S rRNA sequences. AB - DECIPHER is a new method for finding 16S rRNA chimeric sequences by the use of a search-based approach. The method is based upon detecting short fragments that are uncommon in the phylogenetic group where a query sequence is classified but frequently found in another phylogenetic group. The algorithm was calibrated for full sequences (fs_DECIPHER) and short sequences (ss_DECIPHER) and benchmarked against WigeoN (Pintail), ChimeraSlayer, and Uchime using artificially generated chimeras. Overall, ss_DECIPHER and Uchime provided the highest chimera detection for sequences 100 to 600 nucleotides long (79% and 81%, respectively), but Uchime's performance deteriorated for longer sequences, while ss_DECIPHER maintained a high detection rate (89%). Both methods had low false-positive rates (1.3% and 1.6%). The more conservative fs_DECIPHER, benchmarked only for sequences longer than 600 nucleotides, had an overall detection rate lower than that of ss_DECIPHER (75%) but higher than those of the other programs. In addition, fs_DECIPHER had the lowest false-positive rate among all the benchmarked programs (<0.20%). DECIPHER was outperformed only by ChimeraSlayer and Uchime when chimeras were formed from closely related parents (less than 10% divergence). Given the differences in the programs, it was possible to detect over 89% of all chimeras with just the combination of ss_DECIPHER and Uchime. Using fs_DECIPHER, we detected between 1% and 2% additional chimeras in the RDP, SILVA, and Greengenes databases from which chimeras had already been removed with Pintail or Bellerophon. DECIPHER was implemented in the R programming language and is directly accessible through a webpage or by downloading the program as an R package (http://DECIPHER.cee.wisc.edu). PMID- 22101058 TI - Bacterial chitin hydrolysis in two lakes with contrasting trophic statuses. AB - Chitin, which is a biopolymer of the amino sugar glucosamine (GlcN), is highly abundant in aquatic ecosystems, and its degradation is assigned a key role in the recycling of carbon and nitrogen. In order to study the significance of chitin decomposition in two temperate freshwater lakes with contrasting trophic and redox conditions, we measured the turnover rate of the chitin analog methylumbelliferyl-N,N'-diacetylchitobioside (MUF-DC) and the presence of chitinase (chiA) genes in zooplankton, water, and sediment samples. In contrast to the eutrophic and partially anoxic lake, chiA gene fragments were detectable throughout the oligotrophic water column and chiA copy numbers per ml of water were up to 15 times higher than in the eutrophic waters. For both lakes, the highest chiA abundance was found in the euphotic zone--the main habitat of zooplankton, but also the site of production of easily degradable algal chitin. The bulk of chitinase activity was measured in zooplankton samples and the sediments, where recalcitrant chitin is deposited. Both, chiA abundance and chitinase activity correlated well with organic carbon, nitrogen, and concentrations of particulate GlcN. Our findings show that chitin, although its overall contribution to the total organic carbon is small (~0.01 to 0.1%), constitutes an important microbial growth substrate in these temperate freshwater lakes, particularly where other easily degradable carbon sources are scarce. PMID- 22101059 TI - Disrupting the transmission of a vector-borne plant pathogen. AB - Approaches to control vector-borne diseases rarely focus on the interface between vector and microbial pathogen, but strategies aimed at disrupting the interactions required for transmission may lead to reductions in disease spread. We tested if the vector transmission of the plant-pathogenic bacterium Xylella fastidiosa was affected by three groups of molecules: lectins, carbohydrates, and antibodies. Although not comprehensively characterized, it is known that X. fastidiosa adhesins bind to carbohydrates, and that these interactions are important for initial cell attachment to vectors, which is required for bacterial transmission from host to host. Lectins with affinity to substrates expected to occur on the cuticular surface of vectors colonized by X. fastidiosa, such as wheat germ agglutinin, resulted in statistically significant reductions in transmission rate, as did carbohydrates with N-acetylglucosamine residues. Presumably, lectins bound to receptors on the vector required for cell adhesion/colonization, while carbohydrate-saturated adhesins on X. fastidiosa's cell surface. Furthermore, antibodies against X. fastidiosa whole cells, gum, and afimbrial adhesins also resulted in transmission blockage. However, no treatment resulted in the complete abolishment of transmission, suggesting that this is a complex biological process. This work illustrates the potential to block the transmission of vector-borne pathogens without directly affecting either organism. PMID- 22101061 TI - Adolescent clients' perceptions of maternity care in KwaZulu-Natal, South Africa. AB - BACKGROUND: Adolescent pregnancy continues to pose a challenge in both the developed and developing countries across the globe. Adolescent maternity clients (AMCs) have special needs and it is imperative to ensure that maternity services are able to respond appropriately to their needs. OBJECTIVE OR QUESTION: The purpose of this study was to explore adolescent maternity clients' perceptions of maternity care and to identify important characteristics of an adolescent friendly maternity service. METHOD: A qualitative approach was used and a total of 18 adolescent maternity clients, between 15 and 19 years of age, were purposively recruited from antenatal and postnatal services. Data were collected through individual and group interviews. FINDINGS OR DISCUSSION: Findings fell into 3 categories: AMC-health care provider (HCP) interaction; health care system; and health education. Participants wanted HCPs to be caring and supportive. Additionally HCPs should use appropriate interaction and body language to make adolescent clients feel respected and comfortable within the health care setting. Participants expected clinic waiting times to be decreased and measures to make the waiting rooms comfortable be put in place. AMCs also expressed the importance of having extra support during labour and birth. Health education was perceived as essential to their preparation for childbirth and parenting, with them having a role in peer education. CONCLUSION: The relationship between the HCP and AMC is essential to ensuring an optimal outcome for mother and baby. Careful consideration needs to be given to how the health care facility and system are set up in order to ensure that the AMC is comfortable within this context. PMID- 22101060 TI - GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids. AB - Modification of GABAergic inhibition is an intensely investigated hypothesis guiding research into mechanisms underlying temporal lobe epilepsy (TLE). Seizures can be initiated by blocking gamma amino butyric acid type A (GABAA receptors, GABARs), which mediate fast synaptic inhibition in the brain, and controlled by drugs that enhance their function. Derivatives of steroid hormones called neurosteroids are natural substances that physiologically enhance GABAR function and suppress seizures. GABAR structure, function, expression, assembly, and pharmacological properties are changed in the hippocampus of epileptic animals. These alterations render GABARs less sensitive to neurosteroid modulation, which may contribute to seizure susceptibility. Plasticity of GABARs could play a role in periodic exacerbation of seizures experienced by women with epilepsy, commonly referred to as catamenial epilepsy. PMID- 22101062 TI - Identification of genes involved in the regulation of 14-deoxy-11,12 didehydroandrographolide-induced toxicity in T-47D mammary cells. AB - 14-Deoxy-11,12-didehydroandrographolide is one of the principle compounds of the medicinal plant, Andrographis paniculata Nees. This study explored the mechanisms of 14-deoxy-11,12-didehydroandrographolide-induced toxicity and non-apoptotic cell death in T-47D breast carcinoma cells. Gene expression analysis revealed that 14-deoxy-11,12-didehydroandrographolide exerted its cytotoxic effects by regulating genes that inhibit the cell cycle or promote cell cycle arrest. This compound regulated genes that are known to reduce/inhibit cell proliferation, induce growth arrest and suppress cell growth. The growth suppression activities of this compound were demonstrated by a downregulation of several genes normally found to be over-expressed in cancers. Microscopic analysis revealed positive monodansylcadaverine (MDC) staining at 8h, indicating possible autophagosomes. TEM analysis revealed that the treated cells were highly vacuolated, thereby suggesting that 14-deoxy-11,12-didehydroandrographolide may cause autophagic morphology in these cells. This morphology may be correlated with the concurrent expression of genes known to affect lysosomal activity, ion transport, protein degradation and vesicle transport. Interestingly, some apoptotic-like bodies were found, and these bodies contained multiple large vacuoles, suggesting that this compound is capable of eliciting a combination of apoptotic and autophagic-like morphological characteristics. PMID- 22101063 TI - Comparative study on the efficacy of Allium sativum (garlic) in reducing some heavy metal accumulation in liver of wistar rats. AB - SCOPE: Heavy metals are known to cause damage through indirect oxidative effects. This study was undertaken to compare the therapeutic efficacy and protective ability of garlic extracts on reducing toxicity induced by mercury, lead and cadmium in the liver. METHODS AND RESULTS: Rats were fed with rat chow mixed with raw garlic (7% w/w) while mercury (10ppm), cadmium (200ppm) and lead (100ppm) were given in drinking water. Garlic was administered either at the same time with the metals (group 2), a week after exposure to heavy metals (group 3) or a week before heavy metal exposure (group 4) for 6weeks. The heavy metal accumulations in the liver were determined using AAS. The percentage protection showed a time-dependent effect and was significantly (P<0.01) higher for cadmium compared to mercury and lead-treated groups. Analysis between the groups showed that garlic treatment after exposure had a significantly (P<0.05) higher percentage protection when compared with other modes. CONCLUSION: These results suggest that garlic offered more hepatoprotective effect to cadmium followed by mercury and least protection to lead at the selected dose of each metal in this study through the processes of uptake, assimilation and elimination of these metals. PMID- 22101064 TI - Hedgehog signaling regulates myelination in the peripheral nervous system through primary cilia. AB - Myelination is an essential prerequisite for the nervous system to transmit an impulse efficiently by a saltatory conduction. In the peripheral nervous system (PNS), Schwann cells (SCs) engage in myelination. However, a detailed molecular mechanism underlying myelination still remains unclear. In this study, we hypothesized that the primary cilia of SCs are the regulators of Hedgehog (Hh) signaling-mediated myelination. To confirm our hypothesis, we used mouse dorsal root ganglion (DRG)/SC co-cultures, wherein the behavior of SCs could be analyzed by maintaining the interaction of SCs with DRG neurons. Under these conditions, SCs had primary cilia, and Hh signaling molecules accumulated on the primary cilia. When the SCs were stimulated by the addition of desert hedgehog or smoothened agonist, formation of myelin segments on the DRG axons was facilitated. On the contrary, upon administration of cyclopamine, an inhibitor of Hh signaling, myelin segments became comparable to those of controls. Of note, the ratio of SCs harboring primary cilium reached the highest point during the early phase of myelination. Furthermore, the strongest effects of Hh on myelination were encountered during the same stage. These results collectively indicate that Hh signaling regulates myelin formation through primary cilia in the PNS. PMID- 22101065 TI - Planar polarity of ependymal cilia. AB - Ependymal cells, epithelial cells that line the cerebral ventricles of the adult brain in various animals, extend multiple motile cilia from their apical surface into the ventricles. These cilia move rapidly, beating in a direction determined by the ependymal planar cell polarity (PCP). Ciliary dysfunction interferes with cerebrospinal fluid circulation and alters neuronal migration. In this review, we summarize recent studies on the cellular and molecular mechanisms underlying two distinct types of ependymal PCP. Ciliary beating in the direction of fluid flow is established by a combination of hydrodynamic forces and intracellular planar polarity signaling. The ciliary basal bodies' anterior position on the apical surface of the cell is determined in the embryonic radial glial cells, inherited by ependymal cells, and established by non-muscle myosin II in early postnatal development. PMID- 22101066 TI - The crisis of no new antibiotics--what is the way forward? AB - Antibiotic use not only underpins modern medicine, but has brought huge changes to the world, especially in expectations of survival of children into adulthood. The theme of World Health Day, 2011, was "antimicrobial resistance: no action today and no cure tomorrow". The demise of antibacterial drug discovery brings the spectre of untreatable infections. To prevent this crisis immediate action is needed and a new initiative, Antibiotic Action, has been launched. By bringing together communities who need these drugs with academia, health-care professionals, and pharmaceutical companies, this initiative aims to strengthen and enhance academic-industrial partnerships, bring about revision of costly and laborious processes of licensing and regulation of new antibiotics, and address the economics of antimicrobial drugs (cost of use vs profit). A global alliance for antibiotic drug discovery and development would provide a platform for these initiatives. PMID- 22101067 TI - Amphetamine stereotypy, the basal ganglia, and the "selection problem". AB - Amphetamine and other stimulant drugs induce stereotyped head movements in rats, which interfere with normal goal-directed behavior. However, rats given access to food while intoxicated learn to suppress these movements in order to feed. This suggests that the suppression of stereotypy is an instrumentally learned response reinforced by the ingestion of food. Consistent with this interpretation, rats learn to suppress stereotyped head movements when intraoral infusions of milk are made contingent on maintaining a stationary head position, but not when such infusions are given noncontingently. Although learning to suppress stereotypy occurs at different rates across subjects, the temporal dynamics of learning are similar in all cases. Moreover, once learned suppression is acquired, it is generally retained over long periods of time unless the contingency between suppression and reinforcement is degraded. Conceptually, the behavioral conflict between drug-induced stereotyped movements and feeding may be viewed as a special case of the "selection problem," which arises whenever organisms are confronted with competing behavioral opportunities. Interestingly, both normal response selection and stimulant-induced stereotypy are associated with overlapping cortico-basal ganglia circuits. Preliminary findings suggest that the learned suppression of stereotypy involves the activation of particular structures within the dorsal and ventral striatal output pathways. Understanding the neural mechanisms underlying the learned suppression of stimulant-induced stereotypy may provide new insights into the process by which the nervous system solves the selection problem and lead to the development of more effective treatments for disorders characterized by insufficient response inhibition, such as Tourette's syndrome and stimulant drug addiction. PMID- 22101068 TI - Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse. AB - As part of the RIKEN large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis project, we screened mice with a dominant mutation that exhibited abnormal behavior using an open-field test and a home-cage activity test. We tested 495 male progeny of C57BL/6J males treated with ENU and untreated C3H/HeJ females using the open field test and isolated behavioral mutant M101736, which exhibited a significant increase in spontaneous locomotor activity. We identified a missense mutation in the Tuba1 gene, which encodes the TUBA1 protein, and designated the mutant gene Tuba1(Rgsc1736). This mutation results in an aspartic acid to glycine substitution in the TUBA1 protein. Detailed analyses revealed that Tuba1(Rgsc1736) heterozygotes exhibited inattention to novel objects and aberrant patterns of home-cage activity. The results of a behavioral pharmacological analysis using methylphenidate and morphological analyses of embryonic and adult brains suggested that Tuba1(Rgsc1736) is a novel animal model for neurodevelopmental disorders. PMID- 22101069 TI - Additive concentration effects on dicalcium phosphate dihydrate cements prepared using monocalcium phosphate monohydrate and hydroxyapatite. AB - In our previous study, we investigated the setting time, mechanical properties and microstructure of dicalcium phosphate dihydrate cements prepared using monocalcium phosphate monohydrate (MCPM) and hydroxyapatite (HA). Despite the use of sodium citrate as a setting regulator, setting occurs rapidly in the MCPM/HA system and further studies on other retardants are needed. In the present study, sodium pyrophosphate and sulfuric acid were tested to evaluate their effectiveness in maintaining workability of the cement paste. MCPM/HA cements at a powder to liquid ratio of 1.0 with sodium pyrophosphate and sulfuric acid at 10, 25, 50, 75 and 100 mM were manufactured and studied based on their setting time, mechanical and porosity properties, phase composition, and microstructure. These measurements were compared to our previous data using sodium citrate. The results showed that the additives have a dose-dependent effect on the setting time. Their order of efficiency is sodium pyrophosphate > sodium citrate > sulfuric acid. However, the sulfuric acid group exhibited the highest compressive strength (CS) compared to the other groups. A lack of correlation between the CS and the porosity of the cements suggested that a mechanism other than porosity reduction was responsible for the CS increase. Since x-ray diffraction analysis did not indicate an effect on composition, explanations based on calcium sulfate dihydrate formation and changes in microstructure were proposed based on scanning electron micrograph observations. PMID- 22101070 TI - Effects of the commercial extract of aronia on oxidative stress in blood platelets isolated from breast cancer patients after the surgery and various phases of the chemotherapy. AB - Since the extract from berries of Aronia melanocarpa presents antioxidative properties in plasma and in blood platelets, not only from healthy group, but also from patients with benign breast diseases and in patients with invasive breast cancer before surgery, the aim of our present study was to evaluate the oxidative stress by measuring the level of various biomarkers of this process such as the generation of superoxide anion radicals (O(2)(-.)), the amount of carbonyl groups and 3-nitrotyrosine in proteins or the amount of glutathione in blood platelets isolated from breast cancer patients after the surgery and after various phases of the chemotherapy in the presence of A. melanocarpa extract (Aronox) in vitro. We demonstrated in platelet proteins from patients with invasive breast cancer (after the surgery and after various phases of the chemotherapy) higher level of carbonyl groups than in control healthy group. The level of 3-nitrotyrosine in platelet proteins from patients with invasive breast cancer was also significantly higher than in healthy subject group. We observed an increase of other biomarkers of oxidative stress such as O(2)(-.) and a decrease of GSH in platelets from patients with breast cancer (after the surgery and after various phases of the chemotherapy) compared to the healthy group. In model system in vitro our results showed that the commercial extract from berries of A. melanocarpa due to antioxidant action, significantly reduced the oxidative/nitrative stress in platelets from patients with invasive breast cancer caused by the surgery and various phases of the chemotherapy. PMID- 22101071 TI - Fed-batch fermentation for n-butanol production from cassava bagasse hydrolysate in a fibrous bed bioreactor with continuous gas stripping. AB - Concentrated cassava bagasse hydrolysate (CBH) containing 584.4 g/L glucose was studied for acetone-butanol-ethanol (ABE) fermentation with a hyper-butanol producing Clostridium acetobutylicum strain in a fibrous bed bioreactor with gas stripping for continuous butanol recovery. With periodical nutrient supplementation, stable production of n-butanol from glucose in the CBH was maintained in the fed-batch fermentation over 263 h with an average sugar consumption rate of 1.28 g/L h and butanol productivity of 0.32+/-0.03 g/L h. A total of 108.5 g/L ABE (butanol: 76.4 g/L, acetone: 27.0 g/L, ethanol: 5.1 g/L) was produced, with an overall yield of 0.32+/-0.03 g/g glucose for ABE and 0.23+/ 0.01 g/g glucose for butanol. The gas stripping process generated a product containing 10-16% (w/v) of butanol, ~4% (w/v) of acetone, a small amount of ethanol (<0.8%) and almost no acids, resulting in a highly concentrated butanol solution of ~64% (w/v) after phase separation. PMID- 22101072 TI - Enzymatic hydrolysis of microcrystalline cellulose in concentrated seawater. AB - This communication explores the use of seawater (1X) and concentrated seawater (2X and 4X) as reaction media for the enzyme-catalyzed depolymerization of cellulose. The commercially available Accellerase-1500(r) - a "cocktail" of different glycosidases - is able to depolymerize several amorphous celluloses and microcrystalline cellulose Avicel(r) in these reaction media, at slightly lower rates (ca. 90%) than those observed when reactions are performed in pure citrate buffer (control reactions). Remarkably, at concentrated seawater effluents enzymes also display significant rates of cellulose hydrolysis. Considering the expected increasing shortages in accessibility to fresh drinkable water, the herein-reported concept may provide novel inspiring leads for a smart use of resources in an environmentally-friendly and efficient manner, and for the genetic development of cellulases highly active and stable in concentrated seawater solutions. PMID- 22101073 TI - Preparation, characterization and evaluation of adsorptive properties of orange peel based activated carbon via microwave induced K2CO3 activation. AB - This work explores the feasibility of orange peel, a citrus processing biomass as an alternative precursor for preparation of activated carbon (OPAC) via microwave assisted K(2)CO(3) activation. The operational parameters, chemical impregnation ratio, microwave power and irradiation time on the carbon yield and adsorption capability were investigated. The virgin characteristics of OPAC were examined by pore structural analysis, scanning electron microscopy, Fourier transform infrared spectroscopy, nitrogen adsorption isotherm, elemental analysis, surface acidity/basicity and zeta potential measurement. The optimum conditions resulted in OPAC with a monolayer adsorption capacity of 382.75 mg/g for methylene blue and carbon yield of 80.99%. The BET surface area, Langmuir surface area and total pore volume were identified to be 1104.45 m(2)/g, 1661.04 m(2)/g and 0.615 m(3)/g, respectively. Equilibrium data were simulated using the Langmuir, Freundlich, Dubinin-Radushkevich, Redlich-Peterson, and Toth isotherms, and kinetic data were fitted to the pseudo-first-order, pseudo-second-order and Elovich kinetic models. PMID- 22101074 TI - Ethanol production from horticultural waste treated by a modified organosolv method. AB - In this study, we investigated the use of horticultural waste (HW) collected in Singapore as a renewable raw material for bioethanol production. A modified organosolv method using ethanol cooking under mild conditions followed by H(2)O(2) post-treatment was investigated for HW pretreatment. It was found that the addition of acid catalysts in the pretreatment process was not critical and post-treatment using H(2)O(2) was essential for the enhancement of HW digestibility. Enzymatic hydrolysis of the organosolv pretreated HW with 17.5% solid content, enzyme loading of 20 FPU/g HW of filter paper cellulase, and 80 CBU/g HW of beta-glucosidase resulted in a HW hydrolysate containing 26.9 g/L reducing sugar after 72 h. Fermentation of the above hydrolysate medium produced 11.69 g/L ethanol at 8h using Saccharomyces cerevisiae. It proved that horticultural waste was a potential feedstock for fuel ethanol production and organosolv pretreatment method developed in this study was effective. PMID- 22101075 TI - Acaricidal activity of Swietenia mahogani and Swietenia macrophylla ethanolic extracts against Varroa destructor in honeybee colonies. AB - The acaricidal (miticidal) activity of 90% ethanolic extracts of leaves and stem bark of Swietenia mahogani and Swietenia macrophylla were tested against Varroa destructor mite. Four concentrations were used over two different time intervals under laboratory and field conditions. In general, it was noticed that the acaricidal effect based on mortality and LC(50) of all tested extracts against the Varroa mite was concentration and time dependant. The acaricidal action against Varroa mites was relatively the least for the S. macrophylla stem bark extract at 500 ppm concentration after 48 h while it reached 100% and 95% in case of S. mahogani bark and S. macrophylla leaves, respectively. The% infestation with Varroa in colonies treated with the different extracts at various time intervals showed that the rate of infestation decreased to 0.0% after 12 days from the beginning of treatments with 500 ppm of S. mahogani leaves extract compared to 0.79% decrease after treatment with Mitac, a reference drug (60 mg/colony). The rate of infestation in case of treatments with S. mahogani bark, S. macrophylla leaves and S. macrophylla bark was decreased to 0.11%, 2.41% and 1.08%, respectively. The highest reduction was observed with S. mahogani leaves extract followed by S. mahogani bark. All the tested extracts showed less or no effect on honey bees at the different concentrations and at different bioassay times. This study suggested that the use of natural plant extracts or their products as ecofriendly biodegradable agents could be of high value for the control of Varroa mite. PMID- 22101077 TI - Identification of specific miRNAs targeting proteins of the apical junctional complex that simulate the probiotic effect of E. coli Nissle 1917 on T84 epithelial cells. AB - In the intestine, dysregulation of miRNA is associated with inflammation, disruption of the gastrointestinal barrier, and the onset of gastrointestinal disorders. This study identifies miRNAs involved in the maintenance of intercellular junctions and barrier integrity. For the functional identification of barrier affecting miRNAs, we took advantage of the barrier-enforcing effects of the probiotic bacterium Escherichia coli Nissle 1917 (EcN) which can be monitored by enhanced transepithelial resistance (TER). miRNA-profiling of T84 monolayers prior and after co-incubation with EcN revealed for the first time differentially regulated miRNAs (miR-203, miR-483-3p, miR-595) targeting tight junction (TJ) proteins. Using real-time PCR, Western blotting and specific miRNA mimics, we showed that these miRNAs are involved in the regulation of barrier function by modulating the expression of regulatory and structural components of tight junctional complexes. Furthermore, specific inhibitors directed at these miRNA abrogated the disturbance of tight junctions induced by enteropathogenic E. coli (EPEC). The half-maximal inhibitory concentration (IC(50)) was determined to 340 nM by monitoring inhibitor kinetics. In summary, we conclude that specific miRNAs effect regulatory as well as structural proteins of the junctional complex which in turn are involved in the barrier enhancing effect of EcN. Hence, we suggest that the application of miRNAs might be refined and further developed as a novel supportive strategy for the treatment of gastrointestinal disorders. PMID- 22101076 TI - Pharmacological antioxidant strategies as therapeutic interventions for COPD. AB - Cigarette/tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress are intimately associated with the progression and exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, targeting systemic and local oxidative stress with antioxidants/redox modulating agents, or boosting the endogenous levels of antioxidants are likely to have beneficial effects in the treatment/management of COPD. Various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine), have been reported to modulate various cellular and biochemical aspects of COPD. These antioxidants have been found to scavenge and detoxify free radicals and oxidants, regulate of glutathione biosynthesis, control nuclear factor-kappaB (NF-kappaB) activation, and hence inhibiting inflammatory gene expression. Synthetic molecules, such as specific spin traps like alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, iNOS and myeloperoxidase inhibitors, lipid peroxidation inhibitors/blockers edaravone, and lazaroids/tirilazad have also been shown to have beneficial effects by inhibiting cigarette smoke-induced inflammatory responses and other carbonyl/oxidative stress-induced cellular alterations. A variety of oxidants, free radicals, and carbonyls/aldehydes are implicated in the pathogenesis of COPD, it is therefore, possible that therapeutic administration or supplementation of multiple antioxidants and/or boosting the endogenous levels of antioxidants will be beneficial in the treatment of COPD. This review discusses various novel pharmacological approaches adopted to enhance lung antioxidant levels, and various emerging beneficial and/or prophylactic effects of antioxidant therapeutics in halting or intervening the progression of COPD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID- 22101078 TI - A systematic review of bacteremias in cellulitis and erysipelas. AB - OBJECTIVES: Because of the difficulty of obtaining bacterial cultures from patients with cellulitis and erysipelas, the microbiology of these common infections remains incompletely defined. Given the emergence of community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) over the past decade the proportion of infections due to S. aureus has become particularly relevant. METHODS: OVID was used to search Medline using the focused subject headings "cellulitis", "erysipelas" and "soft tissue infections". All references that involved adult patients with cellulitis or erysipelas and reported associated bacteremias and specific pathogens were included in the review. RESULTS: For erysipelas, 4.6% of 607 patients had positive blood cultures, of which 46% were Streptococcus pyogenes, 29% were other beta-hemolytic streptococci, 14% were Staphylococcus aureus, and 11% were Gram-negative organisms. For cellulitis, 7.9% of 1578 patients had positive blood cultures of which 19% were Streptococcus pyogenes, 38% were other beta-hemolytic streptococci, 14% were Staphylococcus aureus, and 28% were Gram-negative organisms. CONCLUSIONS: Although the strength of our conclusions are somewhat limited by the heterogeneity of included cases, our results support the traditional view that cellulitis and erysipelas are primarily due to streptococcal species, with a smaller proportion due to S. aureus. Our results also argue against the current distinction between cellulitis and erysipelas in terms of the relative proportion of infections due to S. aureus. PMID- 22101079 TI - Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections in patients with cancer. AB - BACKGROUND: Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections (ROYBSIs) are rare, even in cancer patients. METHODS: We retrospectively reviewed all episodes of ROYBSIs occurring from 1998 to 2010 in our cancer center. RESULTS: Of 2984 blood cultures positive for Candida and non Candida yeasts, 94 (3.1%) were positive for non-Candida yeasts, representing 41 ROYBSIs (incidence, 2.1 cases/100,000 patient-days). Catheter-associated fungemia occurred in 21 (51%) patients. Breakthrough ROYBSIs occurred in 20 (49%) patients. The yeast species distribution was Rhodotorula in 21 (51%) patients, Trichosporon in 8 (20%) patients, Saccharomyces cerevisiae in 8 (20%) patients, Geotrichum in 2 (5%) patients, Pichia anomala, and Malassezia furfur in 1 patient each. All tested Trichosporon, Geotrichum, and Pichia isolates were azole susceptible, whereas the Rhodotorula isolates were mostly azole-resistant. We noted echinocandin nonsusceptibility (minimal inhibitory concentration >= 2 mg/L) in all but the S. cerevisiae isolates. Most of the isolates (28/33 [85%]) were susceptible to amphotericin B. The mortality rate in all patients at 30 days after ROYBSIs diagnosis was 34%. Multivariate survival analysis revealed increased risk of death in patients with S. cerevisiae infections (hazard ratio, 3.7), Geotrichum infections (hazard ratio, 111.3), or disseminated infections (hazard ratio, 33.4) and reduced risk in patients who had catheter removal (hazard ratio, 0.1). CONCLUSIONS: ROYBSIs are uncommon in patients with cancer, and catheters are common sources of them. Half of the ROYBSIs occurred as breakthrough infections, and in vitro species-specific resistance to echinocandins and azoles was common. Disseminated infections resulted in the high mortality rate. PMID- 22101080 TI - Characteristics of healthcare-associated and community-acquired Klebsiella pneumoniae bacteremia in Taiwan. AB - OBJECTIVES: Klebsiella pneumoniae is the major cause of community-onset pyogenic infections in Taiwan. We investigated the clinical features and outcomes of community-acquired (CA) and healthcare-associated (HCA) infections among community-onset K. pneumoniae bacteremia. METHODS: Adult patients with community onset monomicrobial K. pneumoniae bacteremia were analysed retrospectively at a medical centre in Taiwan over a 4-year period. We compared the clinical characteristics of patients from the CA and HCA groups and identified the risk factors for infection-related mortality. RESULTS: In a total of 372 patients, HCA infections were observed in 44%. The HCA group had higher Charlson score, the Acute Physiology and Chronic Health Evaluation, version II (APACHE II) score, frequency of malignancy, rates of respiratory tract infection and bacteremia from unknown sources, and higher mortality than the CA group. Diabetes and liver abscess were predominant in the CA group. Whereas old age, APACHE II score >15, malignancy, liver cirrhosis, chronic renal failure, respiratory tract infection, skin and soft tissue infection, and inappropriate antimicrobial therapy were predictors for mortality, HCA bacteremia was not. CONCLUSIONS: HCA bacteremia showed different characteristics and higher mortality than CA bacteremia, but HCA infection was not an independent risk factor for mortality. PMID- 22101081 TI - Therapeutic mechanisms of Tongmai Dasheng Tablet on tripterygium glycosides induced rat model for premature ovarian failure. AB - ETHNOPHARMACOLOGICAL RELEVANCE: To assess the therapeutic effect of Tongmai Dasheng Tablet (TMDST) on tripterygium glycosides (TG) induced premature ovarian failure (POF) rat model and investigate the underlying mechanisms, based on the establishing method of POF model we developed in our previous work. MATERIALS AND METHODS: Rats were intragastrically administered with TG to induce POF, then were randomized into model group, premarin group and TMDST group, and were administered intragastrically with physiological saline, premarin and TMDST respectively. The estrous cycle was examined by vaginal exfoliative cystoscopy. Serum estradiol (E(2)) and progesterone (P) were measured by gamma radioimmunoassay, serum inhibin B (INHB) was measured by enzyme linked immunosorbent assay (ELISA), and the expression of estrogen receptor (ER), progesterone receptor (PR), endostatin, vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), tumor necrosis factor-alpha (TNF-alpha), type 1 tumor necrosis factor receptor (TNF-RI) and Caspase-3 in ovaries of rats was examined by immunohistochemistry method. RESULTS: TG induced POF rats restored normal estrous cycle after being treated with TMDST and presented near or above normal ovarian index, serum E2 and INHB level in comparison with those of normal controls. Significantly higher expression of ER, VEGF and VEGFR-2, significantly lower intracellular TNF-alpha and Caspase-3, thinner vascular wall and larger vascular lumen were also found in the ovaries of these TMDST treated POF rats than those of model group. CONCLUSIONS: TMDST is effective in treating TG induced POF rats, and pro-angiogenesis and anti-apoptosis are the two possible mechanisms accounting for the therapeutic effect. PMID- 22101082 TI - Antitussive, expectorant and anti-inflammatory activities of four alkaloids isolated from Bulbus of Fritillaria wabuensis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bulbus Fritillaria Cirrhosae (BFC), known by the Chinese name "Chuan-Bei-Mu", is used as an antitussive, antiasthmatic and expectorant drug for more than 2000 years in China, and Bulbus of Fritillaria wabuensis S. Y. Tang & S. C. Yueh (BFW) was recorded in the 2010 edition of China Pharmacopoeia as one of sources for BFC. The primary objective of this study was to evaluate the antitussive, expectorant and anti-inflammatory effects of alkaloids - imperialine, imperialine-beta-N-oxide, isoverticine, and isoverticine beta-N-oxide, which were isolated from BFW, and to provide experimental evidence for its traditional use. MATERIALS AND METHODS: The alkaloids were isolated using phytochemical methods, and their structures were determined by spectroscopic analysis. Their antitussive effects were measured using murine model of ammonia induced cough, the expectorant effects were evaluated by measuring mice's tracheal phenol red output, and the anti-inflammatory effects were assessed by using the murine model of xylene induced ear edema. RESULTS: The structures of the four alkaloids - imperialine, imperialine-beta-N-oxide, isoverticine, and isoverticine-beta-N-oxide isolated from BFW were confirmed. The four alkaloids significantly inhibited cough frequency and increased latent period of cough in mice induced by ammonia. Imperialine and isoverticine showed obviously antitussive activities in a dose-dependent manner. Besides, the four alkaloids markedly enhanced mice's tracheal phenol red output in expectorant assessment and significantly inhibited the development of ear edema in anti-inflammatory evaluation assay. Moreover, significant differences were found between the structure-activity relationships of the four alkaloids. CONCLUSIONS: The four alkaloids exhibited significant antitussive, expectorant and anti-inflammatory activities. We suggest that they may be the active ingredients of BFW. The results of the present study provided evidence for BFW to be used as an antitussive and expectorant Traditional Chinese Medicine (TCM). PMID- 22101083 TI - Renoprotective potential of Macrothelypteris torresiana via ameliorating oxidative stress and proinflammatory cytokines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Macrothelypteris torresiana is traditionally used in Chinese folk medicine for the treatment of edema for patients suffering from kidney/bladder problems due to its satisfactory therapeutic effectiveness. AIM OF THE STUDY: The aim of this study was to investigate the renoprotective nature of the total polyphenols fraction from Macrothelypteris torresiana (PMT). MATERIALS AND METHODS: The biochemical criterions of plasma and kidney tissues were evaluated to study the effects of PMT on puromycin aminonucleoside-induced chronic nephrotic syndrome (NS) in hyperlipidemic mice. RESULTS: In this study, the NS and hyperlipidemia were ameliorated after 9 weeks administration of PMT. Besides, PMT was able to modulate the level of renal oxidative stress and vascular endothelial growth factor-nitric oxide (VEGF-NO) pathway. CONCLUSIONS: It represented a potential resource of PMT for the treatment of NS involved in metabolic syndrome. PMID- 22101084 TI - Total saponins from Rhizoma Anemarrhenae ameliorate diabetes-associated cognitive decline in rats: involvement of amyloid-beta decrease in brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known Chinese Materia Medica Rhizoma Anemarrhenae has multiple pharmacological activities including antipyretic, anti inflammatory, anti-diabetic actions, etc. This study was designed to investigate effects of total saponins from Rhizoma Anemarrhenae (TS) on diabetes-associated cognitive decline in rats and influence on amyloid-beta (Abeta) levels in brain and inflammation. MATERIALS AND METHODS: Diabetic rats induced by intraperitoneal administration of streptozotocin, were randomized into two groups: diabetes and TS-treated diabetes. Blood glucose and body weight were measured monthly and weekly, respectively. After seven weeks, cognitive performances were evaluated with Morris water maze. Then, brain was obtained for assay of Abeta and TNF-alpha levels, and blood was collected for TNF-alpha assay. RESULTS: Abeta(1-40), Abeta(1-42) and TNF-alpha levels were dramatically (all P<0.01) increased both in temporal cortex and hippocampus of diabetic rats, coupled with impairment of cognition, compared with those of the control. Chronic TS (200mg/kg) treatment markedly (P<0.05) improved the learning ability of diabetic rats, and significantly (all P<0.05) reduced Abeta(1-40), Abeta(1-42) and TNF-alpha levels in cortex as well as Abeta(1-40) level in hippocampus, whereas showed a decreased tendency for Abeta(1-42) and TNF-alpha levels in hippocampus. Moreover, eight week treatment with TS remarkably (P<0.05) inhibited the elevation of TNF-alpha level in serum of diabetic rats, and significantly (both P<0.01) decrease the fasting blood glucose level and increase the body weight of diabectic rats. CONCLUSION: Our findings demonstrate that diabetes-associated cognitive decline is, at least in part, due to brain Abeta accumulation in diabetic condition, and efficacy of TS to diabetes-associated cognitive decline in rats is a sum of reduction of Abeta accumulation and inflammation in brain as well as attenuation of major symptoms of diabetes. PMID- 22101085 TI - Ethnobotanical study of antimalarial plants in Shinile District, Somali Region, Ethiopia, and in vivo evaluation of selected ones against Plasmodium berghei. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The study documented medicinal plants that are traditionally used for treatment of malaria in Shinile District, eastern Ethiopia, and evaluated selected medicinal plants for their antiplasmodial activities against Plasmodium berghei. MATERIALS AND METHODS: The study was conducted in four kebeles of Shinile District, Somali Region, Ethiopia. A total of 15 traditional healers were sampled based on recommendations of local elders and administrators. Specimens of the reported antimalarial plants were collected and stored at the Mini Herbarium of the Aklilu Lemma Institute of Pathobiology, Addis Ababa University, following identification. Crude aqueous and ethanol extracts of Aloe sp., Azadirachta indica and Tamarindus indica were tested in vivo against Plasmodium berghei. The three plants were selected based on the frequency antimalarial use report by healers. RESULTS: The study revealed 27 antimalarial plants, the majority of which were harvested from the wild. Root was the most frequently sought plant part. Most of the remedies were used in decoction form. Aloe sp., Azadirachta indica and Tamarindus indica were the most commonly reported plants for their antimalarial use. For the in vivo test, all the plant extracts were given to mice orally. Ethanol and aqueous leaf extracts of Aloe sp. caused 73.94% and 58.10% parasitaemia suppression, respectively at dose of 650 mg/kg. Ethanol extract of Azadirachta indica leaves induced 54.79% parasitaemia suppression at the dose of 650 mg/kg and its water extract induced 21.47% parasite suppression at a similar dose. Water extract of the fruits of Tamarindus indica showed the highest parasitaemia suppression (81.09%) at the dose of 650 mg/kg. Most Plasmodium berghei infected mice treated with high dose of plant extracts survived relatively longer compared to their respective controls although the difference was not significant. CONCLUSIONS: The result of this study may support the traditional use of Aloe sp., Azadirachta indica and Tamarindus indica in the study area against malaria. Results of this study can be used as a basis for further phytochemical and pharmacological investigations in the effort for search of new and locally affordable antimalarial agents. PMID- 22101086 TI - Antidepressant-like effects of an alkaloid extract of the aerial parts of Annona cherimolia in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Several species of Annona (Annonaceae) are used in traditional Mexican medicine by their anti-anxiety, anticonvulsant and tranquilizing properties. It has been reported that the alkaloids isolated from some species of the Annona have affinity to serotonergic 5-HT(1A) receptors and modulate dopaminergic transmission, which is involved in depressive disorders. AIM OF THE STUDY: To investigate the antidepressant-like effect of an alkaloid extract from the aerial parts of Annona cherimola (TA) in mice. MATERIALS AND METHODS: The antidepressant-like effect was evaluated in the forced swimming test. To elucidate a possible mechanism of action, experiments of synergism with antidepressant drugs, such as imipramine (IMI), clomipramine (CLIMI), and fluoxetine (FLX), were carried out. The neurotransmitter content (DA: dopamine, 5HT: serotonin and its metabolites, HVA: homovanillic acid and 5HIAA: 5 hydroxyindoleacetic) in the whole brain of mice were also determined by HPLC method. TA chemical composition was determined using high performance liquid chromatography-electrospray mass spectrometry. RESULTS: The results showed that repeated treatment with TA produced antidepressant-like effects in mice. This effect was not related to an increase in locomotor activity. Administration of TA facilitated the antidepressant effect of IMI and CLIMI as well as increased the turnover of DA and 5-HT. The alkaloids: 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H dibenzoquinoline-3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine were the main constituents of TA. CONCLUSIONS: Results showed that TA produces an antidepressant-like action from a generalized increase in monominergic turnover, supporting the use in tradicional medicine of Annona cherimolia, and strongly suggest its therapeutic potency as an antidepressant agent. PMID- 22101087 TI - Limitations of current echocardiographic nomograms for left ventricular, valvular, and arterial dimensions in children: a critical review. AB - An echocardiographic quantitative evaluation of the cardiac and vascular structures is often of critical importance for the diagnosis and management of congenital heart diseases. The authors reviewed the accuracy and limits of published echocardiographic nomograms for cardiac chamber, valve, and main vessel dimensions in children, with special attention to the neonatal age group. A computerized literature search in the National Library of Medicine using the keywords "echocardiographic normal/references values +/- children/neonates/newborns" was performed. The research was redefined adding separately the keywords "aortic valve/annulus," "aortic arch," "atrio-ventricular valve/annulus," "left ventricle," "mitral valve/annulus," "pulmonary valve/annulus," "pulmonary artery," and "tricuspid valve/annulus." The analysis highlights the accuracy of the latest studies but also underscores that some limitations remain. In many studies, the number of healthy subjects was limited, with poor differentiation among age subgroups, and neonates were fully investigated in a very limited number of studies; moreover, data for many cardiac structures were not numerous, especially for the aortic arch and pulmonary branches. Finally, several methodologic limitations were encountered, including the lack of standardization, the different types of body size measurements used for normalization, and the various ways to express normalized data. As a result, nomograms were heterogeneous and although for some cardiac structures provided comparable confidence intervals, for others showed widely different values. The lack of solid, standardized nomograms, based on a large set of healthy children, may affect accuracy in estimating the severity of defects, especially in neonates, and possibly introduce bias in the clinical decision-making process. PMID- 22101088 TI - Altered left ventricular tissue velocities, deformation and twist in children and young adults with acute myocarditis and normal ejection fraction. AB - BACKGROUND: Acute myocarditis is a significant cause of sudden death in young adults, and accurate screening for subclinical disease is needed. The aim of this study was to test the hypothesis that newer measures of tissue deformation and twist can detect ventricular dysfunction in patients with myocarditis and preserved left ventricular ejection fractions (LVEFs). METHODS: Twenty-eight consecutive patients (median age, 26.5 years; interquartile range, 19.3-33.8 years) with normal LVEFs and cardiovascular magnetic resonance features of myocarditis were prospectively recruited. Left ventricular tissue velocities, deformation, and twist were measured and compared with values in 64 healthy controls (median age, 25.1 years; interquartile range, 13.5-31.7 years). RESULTS: Patients with myocarditis had reduced annular e' velocity and longitudinal and circumferential strain parameters (P < .01) but similar LVEFs. Reduced lateral e' velocity (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.34-2.34), longitudinal strain (OR, 1.81; 95% CI, 1.38-2.38), circumferential early diastolic strain rate (OR, 1.31; 95% CI, 1.08-1.71), increased twist rate (OR, 1.02; 95% CI, 1.01-1.04), and earlier time to peak twist (OR, 0.80; 95% CI, 0.72 0.88) were identified as independent predictors of myocarditis, with abnormalities in any two of five predictors having 93% sensitivity and 91% specificity. Longitudinal strain parameters and lateral e' velocity were improved at 1 year (P <= .03) but remained reduced compared with controls (P <= .02). CONCLUSIONS: Patients with acute myocarditis and normal LVEFs had detectable left ventricular systolic and diastolic dysfunction on echocardiography. Tissue velocity, deformation, and twist parameters have the potential to improve the detection of patients with myocarditis and preserved LVEFs. PMID- 22101089 TI - Regulatory agencies, pharmaceutical information and the Internet: a European perspective. AB - The Internet facilitates access to health information and can therefore support the effectiveness of healthcare provision and empower patients in healthcare decisions. In the field of pharmaceutical therapy the electronic provision of information can improve compliance and strengthen the general understanding of pharmaceutical risks and benefits. Current political developments in Europe encourage a stronger role of the pharmaceutical industry in this regard. In light of potential conflicts inherent to the private provision of information and given their public health mandate, regulatory bodies in the pharmaceutical sector may represent an important alternative source of information. The explorative analysis in this paper reviews the websites of European pharmaceutical regulatory agencies regarding the usability and provision of information from a Layman's perspective. It is found that while the majority of agencies do provide product related information, the usability of websites from the lay perspective is subject to variation. The reluctant position of agencies can be attributed to sectoral path dependencies, the regulatory approach and a lack of regulatory resources. PMID- 22101090 TI - Detection of bacterial DNA in bile of cats with lymphocytic cholangitis. AB - In this study, we have successfully used molecular methods based on the amplification of the 16S ribosomal RNA gene on feline bile samples to show that bile of cats with LC is not sterile. This is probably due to the fact that the inflammatory process in the biliary tree causes dilatations. As a result, bacteria can easily migrate from the intestines via the common bile duct. The diversity of species identified and the presence of Helicobacter spp. DNA in both patients and controls suggests that bacteriobilia is secondary to the disease and is not the cause of LC. PMID- 22101091 TI - Globalisation and global trade influence molecular viral population genetics of Torque Teno Sus Viruses 1 and 2 in pigs. AB - Globalisation, in terms of the rapid and free movement of people, animals and food, has created a new paradigm, increasing the range and rate of distribution of many pathogens. In the present study, Torque teno sus viruses (TTSuVs) have been used as a model to evaluate the effects of global trade on viral heterogeneity, and how the movement of live pigs can affect the distribution and composition of virus populations. Seventeen countries from different parts of the world have been screened for TTSuV1 and TTSuvV2. High levels of genetic diversity have been found as well as two new TTSuV subtypes. A small fraction of this diversity (<5%) was related with spatial structure; however the majority (>50%) was best explained by the exchange of live pigs among countries, pointing to the direct relationship between the movement of hosts and the diversity of their accompanying viruses. Taking TTSuVs as sentinels, this study revealed that the distribution and diversity of comensal microflora in live animals subjected to global trade is shaped by the commercial movements among countries. In the case of TTSuVs, it appears that commercial movements of animals are eroding the genetic composition of the virus populations that may have been present in pig herds since their domestication. PMID- 22101092 TI - Genetic diversity and phylogenetic analysis of glycoprotein GP85 of ALV-J isolates from Mainland China between 1999 and 2010: coexistence of two extremely different subgroups in layers. AB - Avian leukosis virus subgroup J (ALV-J), first isolated in 1989, preferentially infects meat-type birds. However, layer flocks in China have experienced outbreaks of this virus since 2008. To understand the genetic diversity of ALV-J in Chinese layers, we compared and analyzed the GP85 gene sequences of 106 ALV-J isolates that were isolated between 1999 and 2010 in Mainland China. The GP85 gene sequences of 41 layer isolates collected from 9 provinces of China between 2008 and 2010 belonged to two separate, highly diverse subgroups and were differentiated from meat-type chicken isolates. When compared to all meat-type isolates from China, Subgroup 1 exclusively contained current layer isolates and seemed to be dominant; all the isolates in this subgroup exhibited gene diversity, and many unique amino acid mutations were present. In contrast, the viruses in Subgroup 2 were perfectly conserved and shared high identity with the prototype meat-type chicken ALV-J strain HPRS-103. The two subgroups contained only two concurrent mutations at the same position. Moreover, most of the isolates in Subgroup 1 had two additional glycosylation sites (at positions 101 and 191) when compared with those in Subgroup 2. Our study provides evidence for the coexistence of two extremely different ALV-J subgroups in Chinese layers from 2008 to 2010, supporting the need for vaccine development and purification measures to prevent ALV-J infection in layers in China. PMID- 22101093 TI - Good quality and available urban green spaces as good quality, health and wellness for human life. PMID- 22101094 TI - How to use serum ammonia. AB - Hyperammonaemia is a potentially extremely important indicator of impairment in intermediate metabolism. However, lack of experience in sample handling and confusion about what level is significant, can lead to its devaluation as a test. The aim of this article is to help the non-metabolic specialist to decide when it is appropriate to investigate for hyperammonaemia, to discuss potential investigatory pitfalls and to help in interpretation of results. PMID- 22101095 TI - Intratympanic treatment of intractable unilateral Meniere disease: gentamicin or dexamethasone? A randomized controlled trial. AB - OBJECTIVE: To determine the efficacy and safety of low-dose intratympanic gentamicin (ITG) compared with intratympanic dexamethasone (ITD) in patients with intractable unilateral Meniere disease (MD). STUDY DESIGN: Open prospective randomized controlled study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Sixty patients affected by definite unilateral MD were enrolled between January 1, 2007, and June 30, 2008. Thirty-two patients were treated with a buffered gentamicin solution injected in the middle ear (maximum of 2 injections); 28 patients were treated with ITD (4 mg/mL, 3 injections at intervals of 1 every 3 days). Mean outcome measurements consisted of control of vertigo attacks, pure tone average (PTA), speech discrimination score, functional disability score, and statistical analysis using repeated measures analysis of variance. RESULTS: In the ITG group at 2-year follow-up, complete control of vertigo (class A) was achieved in 26 patients (81%) and substantial control of vertigo (class B) in 4 patients (12.5%). In the ITD group, class A was achieved in 12 (43%), and class B in 5 (18%) patients. In the gentamicin group, 4 patients showed a reduction in PTA of >=10 dB. In the ITD group, PTA was unchanged or slightly improved in 16 patients (belonging to class A-B) and worse in 12. CONCLUSIONS: Low-dose ITG achieved better outcome than ITD in the control of vertigo attacks in patients suffering from unilateral MD, with a very low incidence of hearing deterioration. ITD offers poorer vertigo control rate, and hearing preservation is achieved only in cases with no vertigo recurrences. PMID- 22101096 TI - Prevalence, characteristics, and management of swallowing disorders following cerebellopontine angle surgery. AB - OBJECTIVE: To describe swallowing disorders encountered after cerebellopontine angle surgery and to explore variables associated with increased incidence of postoperative dysphagia. STUDY DESIGN: Case series with chart review. SETTING: Single academic medical institution. SUBJECTS AND METHODS: Chart review of 181 consecutive patients undergoing surgical excision of cerebellopontine angle pathology from January 2008 to December 2010 at the Johns Hopkins Hospital. Presence and characteristics of dysphagia were determined by review of speech pathologist reports. Other clinical variables were extracted from the electronic medical record, and statistical analyses were applied to determine factors associated with postoperative dysphagia. RESULTS: Immediate postoperative dysphagia was identified in 57 of 181 patients (31%). Oral, oropharyngeal, and pharyngeal deficits accounted for 51%, 37%, and 12% of dysphagic symptoms, respectively. Facial nerve weakness in the immediate postoperative period was noted in 91% of dysphagic subjects compared with 43% of those without. Mean House Brackmann score for dysphagic individuals was 4 compared with 2 in the nondysphagic group. Diet alterations were required for 65% of dysphagic individuals, and an additional 9% required tube feeding. Common findings during videofluoroscopic swallowing studies were pharyngeal residue, reduced pharyngeal constriction, and anterior bolus loss. Abnormal penetration-aspiration scores (>=3) were found in 59% of those undergoing videofluoroscopic swallow studies. CONCLUSIONS: Oral and pharyngeal swallowing deficits are commonly encountered after cerebellopontine angle surgery. Consultation with the speech-language pathologist appears most critical for any individuals demonstrating postoperative cranial nerve dysfunction, particularly for those with evidence of facial nerve weakness. Early consultation may help to manage short- and long-term functional difficulties. PMID- 22101097 TI - Ototoxicity of intratympanic docusate sodium and mineral oil in the guinea pig. AB - OBJECTIVES: (1) To evaluate the ototoxic potential of docusate sodium and mineral oil and (2) to compare the cerumenolytic properties of these agents to water and a commercially available product. STUDY DESIGN: Prospective animal study. SETTING: Docusate sodium and mineral oil are being used to dissolve cerumen plugs. Their ototoxicity has never been assessed. METHODS: Nineteen guinea pigs represented 38 ears, which formed 4 groups. Each group was injected with an intratympanic solution once a week for 4 weeks. Group 1 was injected with a negative control solution of saline, group 2 with docusate sodium, group 3 with a positive control solution of gentamicin, and group 4 with mineral oil. Auditory brainstem responses (ABRs) were recorded before any procedure and 1 week after the final injections. Cochleas were analyzed under scanning electron microscopy. The cerumenolytic properties of water, docusate sodium, mineral oil, and cerumol were evaluated. RESULTS: There was no significant ABR threshold increase for saline or mineral oil. Gentamicin and docusate sodium caused a significant threshold increase that averaged 51.9 dB and 44.9 dB over all the frequencies (P < .001). Electron microscopy could not be performed on the cochleas treated by docusate sodium because of very severe osteitis. All of the agents tested seemed to be effective cerumenolytics compared with no treatment, but water was significantly more effective compared with any of the other tested products (P < .001). CONCLUSION: Docusate sodium was severely ototoxic, and its use should be discouraged. Mineral oil was not ototoxic. Water seemed to be the most effective cerumenolytic agent. PMID- 22101098 TI - Making the message meaningful: a qualitative assessment of media promoting all terrain vehicle safety. AB - BACKGROUND: Millions of all-terrain vehicles (ATV) are used around the world for recreation by both adults and youth. This increase in use has led to a substantial increase in the number of injuries and fatalities each year. Effective strategies for reducing this incidence are clearly needed; however, minimal research exists regarding effective educational interventions. OBJECTIVE: This study was designed to assess rural ATV riders' preferences for and assessment of safety messages. METHODS: 13 focus group discussions with youth and adult ATV riders were conducted. 88 formative research participants provided feedback on existing ATV safety materials, which was used to develop more useful ATV safety messages. 60 evaluative focus group participants critiqued the materials developed for this project. RESULTS: Existing ATV safety materials have limited effectiveness, in part because they may not address the content or design needs of the target population. ATV riders want educational and action-oriented safety messages that inform youth and adult riders about their responsibilities to learn, educate and implement safety behaviours (eg, appropriate-sized ATV, safety gear, solo riding, speed limits, riding locations). In addition, messages should be clear, realistic, visually appealing and easily accessible. Newly designed ATV safety materials using the acronym TRIPSS (training, ride off-road, impairment, plan ahead, safety gear, single rider) meet ATV riders' safety messaging needs. CONCLUSIONS: To reach a target population, it is crucial to include them in the development and assessment of safety messages. Germane to this particular study, ATV riders provided essential information for creating useful ATV safety materials. PMID- 22101099 TI - The New Zealand serious non-fatal self-harm indicators: how valid are they for monitoring trends? AB - BACKGROUND: To monitor accurately injury incidence trends, indicators should measure incidence independently of extraneous factors. Frequencies and rates of New Zealand's serious non-fatal self-harm indicators may be prone to fluctuations in reporting owing, for example, to changing social norms. Hence, they have been considered provisional. AIM: To validate empirically the serious non-fatal self harm indicators. Methods All serious non-fatal first admissions to hospital were identified and classified according to whether principal diagnosis (PDx) was injury or mental disorder, and conversely whether contributing diagnoses were mental disorder or injury. The proportion assigned self-harm external cause of injury code (E-code) was calculated for each year from 2001 to 2007. Subsequently, all cases with a self-harm E-code were identified, and the proportion with a PDx of injury and contributing diagnosis of mental disorder, or PDx of mental disorder and contributing diagnosis of injury over time, were determined. RESULTS: No linear changes over time were detected in the proportion of cases assigned an injury PDx, or the proportion assigned a mental disorder PDx, or the proportion with a self-harm E-code. The estimated maximum observed increase in the frequency of serious non-fatal self-harm hospitalisation explained by changes in reporting was 19- 40%. CONCLUSION: Identification of serious non-fatal self-harm events using an operational definition of PDx of injury, a self-harm first listed E-code, and an appropriate severity cut-off point, is a valid method of monitoring incidence and rates in New Zealand. PMID- 22101100 TI - Problems with a great idea: referral by prehospital emergency services to a community-based falls-prevention service. AB - BACKGROUND AND AIM: Falls are the leading cause of injury in older adults. Identifying people at risk before they experience a serious fall requiring hospitalisation allows an opportunity to intervene earlier and potentially reduce further falls and subsequent healthcare costs. The purpose of this project was to develop a referral pathway to a community falls-prevention team for older people who had experienced a fall attended by a paramedic service and who were not transported to hospital. It was also hypothesised that providing intervention to this group of clients would reduce future falls-related ambulance call-outs, emergency department presentations and hospital admissions. METHODS: An education package, referral pathway and follow-up procedures were developed. Both services had regular meetings, and work shadowing with the paramedics was also trialled to encourage more referrals. A range of demographic and other outcome measures were collected to compare people referred through the paramedic pathway and through traditional pathways. RESULTS: Internal data from the Queensland Ambulance Service indicated that there were approximately six falls per week by community dwelling older persons in the eligible service catchment area (south west Brisbane metropolitan area) who were attended to by Queensland Ambulance Service paramedics, but not transported to hospital during the 2-year study period (2008 2009). Of the potential 638 eligible patients, only 17 (2.6%) were referred for a falls assessment. CONCLUSION: Although this pilot programme had support from all levels of management as well as from the service providers, it did not translate into actual referrals. Several explanations are provided for these preliminary findings. PMID- 22101101 TI - A 'Communication and Patient Safety' training programme for all healthcare staff: can it make a difference? AB - Communication breakdown is a factor contributing to most cases of patient harm, and this harm continues to occur at unacceptable levels. Responding to this evidence, the Metro South District of Queensland Health (Australia) has developed a communication skills training programme titled 'Communication and Patient Safety'. The three modules, each lasting 3½ h, cover both staff-to-patient and staff-to-staff communication issues, and an unusual feature is that clinical and non-clinical staff attend together. Following positive evaluation data from our initial pilot programme (involving 350 staff in a single hospital), the programme was expanded to all five hospitals in the district, and has now been completed by over 3000 staff. The results show that despite the significant time commitment, participants find the courses useful and relevant (Kirkpatrick level 1), they learn and retain new material (level 2), and they report changes in behaviour at individual, team and facility levels (level 3). Although it remains a challenge to obtain quantitative data showing that training such as this directly improves patient safety (level 4), our qualitative and informal feedback indicates that participants and their managers perceive clear improvements in the 'communication culture' after a workplace team has attended the courses. Improving 'communication for safety' in healthcare is a worldwide imperative, and other healthcare jurisdictions should be able to obtain similar results to ours if they develop and support interactive, non-didactic training in communication skills. PMID- 22101102 TI - Patient safety in patients who occupy beds on clinically inappropriate wards: a qualitative interview study with NHS staff. AB - OBJECTIVE: To explore NHS staff members' perceptions and experiences of the contributory factors that may underpin patient safety issues in those who are placed on a hospital ward that would not normally treat their illness (such patients are often called 'outliers' 'sleep outs' or 'boarders'). DESIGN: Qualitative study using semi-structured interviews. Setting A single large teaching hospital in the north of England. PARTICIPANTS: 29 members of NHS staff (doctors, nurses and non-clinical or management staff). RESULTS: Five themes describing contributory factors underlying safety issues were identified: competing demands on staff time created by having patients on inappropriate wards and patients who are on the correct specialty ward to care for; poor communication between the correct specialty ward and the clinically inappropriate ward; lack of knowledge or specialist expertise on clinically inappropriate wards; an unsuitable ward environment for patients on inappropriate wards; and the characteristics of patients who are placed on clinically inappropriate wards (specifically staff perceive patients on inappropriate wards to be medically fit and therefore of lower priority and moving patients between wards may disorientate confused or impaired patients). Examples of how these contributory factors may lead to safety issues are given. CONCLUSIONS: NHS staff report that placement of patients on clinically inappropriate wards is a specific patient safety concern. The application of James Reason's Swiss cheese model of accident causation suggests that placement on an inappropriate ward constitutes a 'latent condition' which may expose patients to contributory factors that underlie adverse events. PMID- 22101103 TI - Instigating change: trainee doctors' perspective. AB - In the 21st century, the core skills of trainee doctors are evolving as clinicians, leaders and innovators. Leadership skills are an essential tool for all doctors and need to be an integral part of their training and learning as set out in the General Medical Council's Good Medical Practice. It is essential to develop these skills at an early stage and continually improve them. A group of junior doctors participated in a pilot programme for leadership with the aim of executing a quality improvement (QI) project. This article describes our experiences of both the course itself and the project undertaken by our group. As part of the process of implementing change, we faced a number of challenges which contributed to our learning. These have been explored as well as potential ways to overcome them to enable the swift and smooth development of future QI projects. Using an example of a QI project looking at handover, this article demonstrates how a trainee doctor can implement their project for both professional and institutional improvement. PMID- 22101104 TI - Rapid response teams: a diagnostic dilemma. PMID- 22101105 TI - The operating room dance. PMID- 22101106 TI - HPV infections: can they be eradicated using nanotechnology? AB - Human papillomavirus (HPV) infections are considered the most common sexually transmitted diseases, with more than 450 million people worldwide infected. HPVs can cause anogenital warts and neoplasias. One prevalent cancer type caused by HPV (mostly type 16 and 18) is cervical intraepithelial neoplasia (CIN). Nanotechnology tools employed in the development of vaccines and a noninvasive treatment may provide a significant advancement in the global combat against this disease. PMID- 22101107 TI - Paclitaxel-loaded polymeric micelles based on poly(E-caprolactone)-poly(ethylene glycol)-poly(E-caprolactone) triblock copolymers: in vitro and in vivo evaluation. AB - The purpose of this study was to develop polymeric nanoscale drug-delivery system (nano-DDS) for paclitaxel (PTX) from poly(E-caprolactone)-poly(ethylene glycol) poly(E-caprolactone) (PCL-PEG-PCL, PCEC) copolymers, intended to be intravenously administered, able to improve the therapeutic efficacy of the drug and devoid of the adverse effects of Cremophor EL. Both of the PTX-loaded polymeric micelles and polymersomes were successfully prepared from PCEC copolymers. The obtained PTX-loaded micelles exhibited core-shell morphology with satisfactory size (93 nm), and were favorable for intravenous injection. In vitro cytotoxicity demonstrated that the cytotoxic effect of PTX-loaded micelles was lower than that of Taxol (Bristol-Myers Squibb, Princeton, New Jersey). Pharmacokinetic results indicated that the PTX-loaded micelles had longer systemic circulation time and slower plasma elimination rate than those of Taxol. Furthermore, PTX-loaded micelles showed greater tumor growth-inhibition effect in vivo on EMT6 breast tumor, in comparison with Taxol. Therefore, the prepared polymeric micelles might be potential nano-DDS for PTX delivery in cancer chemotherapy. PMID- 22101108 TI - Lateral order in gel, subgel and crystalline phases of lipid membranes: wide angle X-ray scattering. AB - The chain packing in ordered phases of lipid bilayers can be classified according to wide-angle X-ray diffraction (WAXS). For triclinic (T(||)) and monoclinic (M(||)) packing in crystalline L(c) phases, the wide-angle reflections index on an oblique lattice with spacings s(10)?s(01)?s(11), and each chain has four nearest neighbours. For orthorhombic (O(?)) packing in L(c) phases, and the rotationally symmetric equivalent in metastable low-temperature L(beta) phases (mL(beta)), the wide-angle reflections index on a centred rectangular lattice with spacings s(20)s(11), and each chain has two nearest neighbours. For hexagonal packing in the L(beta), P(beta') and interdigitated L(beta)(i) gel phases, the wide-angle reflections index on a centred rectangular lattice with spacings s(20)=s(11), and each chain has six nearest neighbours. The available WAXS database for phospholipid and glycolipid bilayers is classified here according to the above scheme, by using well established examples to assign the wide-angle reflections. The nearest and next nearest neighbour chain-chain spacings, a(ch) and b(ch), and the cross-sectional area per chain, A(ch), are calculated for each phase of each lipid. These parameters determine many of the properties of the ordered lipid phases and, together with the chain tilt, specify the area occupied by the lipid head groups at the surface of the bilayer. PMID- 22101109 TI - Artificial neural network modeling of biomarkers to infer characteristics of contaminant exposure in Clarias gariepinus. AB - This study examined the potential of artificial neural network (ANN) modeling to infer timing, route and dose of contaminant exposure from biomarkers in a freshwater fish. Hepatic glutathione S-transferase (GST) activity and biliary concentrations of BaP, 1-OH BaP, 3-OH BaP and 7,8D BaP were quantified in juvenile Clarias gariepinus injected intramuscularly or intraperitoneally with 10 50 mg/kg benzo[a]pyrene (BaP) 1-3 d earlier. A feedforward multilayer perceptron (MLP) ANN resulted in more accurate prediction of timing, route and exposure dose than a linear neural network or a radial basis function (RBF) ANN. MLP sensitivity analyses revealed contribution of all five biomarkers to predicting route of exposure but no contribution of hepatic GST activity or one of the two hydroxylated BaP metabolites to predicting time of exposure and dose of exposure. We conclude that information content of biomarkers collected from fish can be extended by judicious use of ANNs. PMID- 22101110 TI - The influence of natural rubber/Au nanoparticle membranes on the physiology of Leishmania brasiliensis. AB - The development of nanotechnology has generated new means of disease diagnosis and treatment. Infectious diseases, including leishmaniasis, malaria, etc., have benefited from the advent of new nanomaterials and/or nanodevices capable of detecting specific antigens and antibodies with high specificity and low cost. In this paper, we present an investigation on a single-celled protozoan Leishmaniasis parasite, a disease considered of standard infectivity, given the high degree of immunological specificity. Natural rubber (NR) membranes incorporating gold nanoparticles (GNPs) were placed in the culture medium and the physiological behavior of Leishmania brasiliensis promastigotes was evaluated. The natural rubber membranes containing GNPs decreased the population growth rate, showing a lower index of living promastigotes (attached to the membrane surface) depending on the amount of nanoparticles deposited in the membrane surface. Such membranes may be used to develop a flexible band-aid for skin lesions from degenerative infection state, inhibiting the population growth of parasites in the lesions. In addition, natural rubber membranes would also stimulate angiogenesis in damaged tissues. PMID- 22101111 TI - Stability of central binaural sound localization mechanisms in mammals, and the Heffner hypothesis. AB - Heffner (2004) provided an overview of data on the evolutionary pressures on sound localization acuity in mammals. Her most important finding was that sound localization acuity was most strongly correlated with width of field of best vision. This correlation leaves unexplained the mechanism through which evolutionary pressures affect localization acuity in different mammals. A review of the neurophysiology of binaural sound localization cue coding, and the behavioural performance it supports, led us to two hypotheses. First, there is little or no evidence that the neural mechanisms for coding binaural sound location cues, or the dynamic range of the code, vary across mammals. Rather, the neural coding mechanism is remarkably constant both across species, and within species across frequency. Second, there is no need to postulate that evolutionary pressures are exerted on the cue coding mechanism itself. We hypothesize instead that the evolutionary pressure may be on the organism's ability to exploit a 'lower envelope principle' (after Barlow, 1972). PMID- 22101112 TI - A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders. AB - Recent years have seen a rapid increase in the investigation of autism spectrum disorders (ASD) through the use of functional magnetic resonance imaging (fMRI). We carried out a systematic review and ALE meta-analysis of fMRI studies of ASD. A disturbance to the function of social brain regions is among the most well replicated finding. Differences in social brain activation may relate to a lack of preference for social stimuli as opposed to a primary dysfunction of these regions. Increasing evidence points towards a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to changing task demands in ASD. Limitations of the literature to date include the use of small sample sizes and the restriction of investigation to primarily high functioning males with autism. PMID- 22101114 TI - Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. AB - BACKGROUND: Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle invasive bladder cancer (BCa) is largely unknown. OBJECTIVE: Report long-term outcomes of patients with muscle-invasive BCa treated by CMT. DESIGN, SETTING, AND PARTICIPANTS: We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2-4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr. INTERVENTIONS: Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC-60 for less than CR and 42 for recurrent invasive tumors. MEASUREMENTS: Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3-4=53%, 49%, and 49%), respectively. Five-, 10-, and 15 yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3-4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p<0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity. CONCLUSIONS: CMT achieves a CR and preserves the native bladder in >70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients. PMID- 22101115 TI - Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guerin. AB - BACKGROUND: Controversy exists over the most important prognostic factors in T1 high-grade non-muscle-invasive bladder cancer (NMIBC) patients treated with bacillus Calmette-Guerin (BCG). OBJECTIVE: Evaluate prognostic factors for recurrence, progression, and disease-specific mortality after adjuvant intravesical BCG immunotherapy in patients with T1G3 NMIBC and long-term follow up. DESIGN, SETTING, AND PARTICIPANTS: A single-institution retrospective analysis of 146 patients with primary stage T1G3 NMIBC. INTERVENTION: All patients were treated with complete transurethral resection (TUR) plus multiple bladder biopsies that included the prostatic urethra. No second TUR was done. Patients underwent an induction course of intravesical BCG (Connaught strain, 81mg) without maintenance therapy. MEASUREMENTS: The variables analysed for time to recurrence, progression, and death due to bladder cancer (BCa) were gender, age, tumour multiplicity, diameter, aspect, substaging, concomitant carcinoma in situ (CIS), and CIS in the prostatic urethra. Cox regression models were used to assess the univariate and multivariate prognostic importance of these factors and estimate hazard ratios (HRs). Time-to-event distributions were estimated using cumulative incidence functions. RESULTS AND LIMITATIONS: The median follow-up was 8.7 yr. Sixty-five patients (44.5%) had recurrence, 25 patients (17.1%) had progression, and 18 patients (12.3%) died because of BCa. Female gender and presence of CIS in the prostatic urethra were associated with an increased risk of recurrence (p=0.0003, HR: 2.53), progression (p=0.001, HR: 3.59), and death due to BCa (p=0.004, HR: 3.53). CONCLUSIONS: In primary T1G3 bladder tumours treated with induction BCG, female gender or having CIS in the prostatic urethra were the only prognostic factors for time to recurrence, progression, and disease related mortality. It is very important to perform a biopsy of the prostatic urethra in patients with primary high-grade NMIBC as a first step to obtain this prognostic information. PMID- 22101113 TI - Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence. AB - Alcohol use disorders are characterized by compulsive drug-seeking and drug taking, loss of control in limiting intake, and withdrawal syndrome in the absence of drug. The central amygdala (CeA) and neighboring regions (extended amygdala) mediate alcohol-related behaviors and chronic alcohol-induced plasticity. Acute alcohol suppresses excitatory (glutamatergic) transmission whereas chronic alcohol enhances glutamatergic transmission in CeA. Acute alcohol facilitates inhibitory (GABAergic) transmission in CeA, and chronic alcohol increases GABAergic transmission. Electrophysiology techniques are used to explore the effects of neuropeptides/neuromodulators (CRF, NPY, nociceptin, dynorphin, endocannabinoids, galanin) on inhibitory transmission in CeA. In general, pro-anxiety peptides increase, and anti-anxiety peptides decrease CeA GABAergic transmission. These neuropeptides facilitate or block the action of acute alcohol in CeA, and chronic alcohol produces plasticity in neuropeptide systems, possibly reflecting recruitment of negative reinforcement mechanisms during the transition to alcohol dependence. A disinhibition model of CeA output is discussed in the context of alcohol dependence- and anxiety-related behaviors. PMID- 22101116 TI - Evaluation of multiple risk-associated single nucleotide polymorphisms versus prostate-specific antigen at baseline to predict prostate cancer in unscreened men. AB - BACKGROUND: Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear. OBJECTIVE: Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men. DESIGN, SETTING, AND PARTICIPANTS: This study used a nested case-control design based on the Malmo Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005. MEASUREMENTS: We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer. RESULTS AND LIMITATIONS: Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p<0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage>=T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage>=T3, metastasis, Gleason score>=8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group. CONCLUSIONS: Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmo, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline. PMID- 22101117 TI - Application of STR markers in wildlife forensic casework involving Australian black-cockatoos (Calyptorhynchus spp.). AB - Parrots and cockatoos are highly prized aviary birds and the demands for such species has fuelled their illegal trade and harvest from the wild. Here we report on three forensic case studies involving black-cockatoos (Calyptorhynchus spp.) endemic to Australia. These cases involve suspected poaching and illegal killing of endangered red- and white-tailed black-cockatoos. Through the prior development of 20 polymorphic microsatellite loci and population databases for white- and red-tailed black-cockatoos, the tools are available to conduct high resolution paternity and individual identity testing. In one case, we matched a red-tailed black-cockatoo nestling to a tree hollow from which it was poached through the use of DNA from eggshell recovered from the nest. For the second case, we utilized our provenance population database (nest sites), and identified the kinship and geographic origin of a white-tailed black-cockatoo, which was illegally harvested from the wild. The third case determined the number individual white-tailed black-cockatoos allegedly shot at a fruit grower's orchard from body part remains. These genetic investigations highlight the significance and statistical confidence of DNA profiling and associated databases for endangered taxa, such as exotic birds. Our cockatoo population databases are the first of their kind in Australia, and demonstrate the efficacy of such approaches to identify such illegal activity. With a robust set of genetic markers and methodologies in place, we aim to broaden our population databases to include other cockatoo species of conservation concern. PMID- 22101118 TI - Calcium phosphate bone cement with 10 wt% platelet-rich plasma in vitro and in vivo. AB - OBJECTIVES: The aim of this study was to evaluate the performance of a 10 wt% platelet-rich plasma (PRP) additive composite with calcium phosphate cement (CPC) in vitro and in vivo. METHODS: The in vitro testing of modulus, the apatite conversion rate, morphology, cell and alkaline phosphatase (ALP) activities, and in vivo testing of histological examinations between two groups of 10 wt% PRP/CPC and CPC were characterised and compared. RESULTS: Although the crystallite morphologies showed a retarded effect in the PRP/CPC group in vitro, the modulus results showed that the 10 wt% PRP/CPC group had a significant reduction in strength but had no significant changes in the relative conversion ratio of the apatite phase with CPC only. The osteogenic evaluation of ALP expression was significantly increased by the PRP additives group with stem cells (D1) cultured for different periods (2-32 days). Our histological examinations showed that greater remodelling and the phenomenon of isolated/detached CPC particles were significantly observed at 9 weeks after implantation when the 10 wt% PRP/CPC composite was used. CONCLUSION: The results demonstrate that CPC may be a potential candidate as a carrier with PRP additives for bone regeneration. PMID- 22101119 TI - The role of enamel crystallography on tooth shade. AB - OBJECTIVES: Tooth shade is influenced by a combination of extrinsic-stains that are adsorbed to the enamel surface and by its intrinsic-shade resulting from the interaction of light with tooth structures. This study was designed to investigate how the variations in enamel ultrastructure may affect tooth optical properties. METHODS: One-hundred extracted teeth were collected from adult patients attending McGill-Undergraduate Dental Clinics. Shade-spectrophotometry, FTIR and XRD were used to assess tooth shade, enamel chemical composition and crystallography. The data obtained was analysed for Pearson correlation analysis and multiple linear regression analysis. The statistical significance was set at P < 0.05. RESULTS: Tooth shade parameters varied dramatically within the studied population. Pearson correlation analysis demonstrated that tooth hue was associated with enamel hydroxyapatite (HA) crystal size (R = -0.358; B = -0.866; P = 0.007), tooth chroma was associated with enamel HA carbonization (R = -0.419; B = -99.06; P = 0.005), and tooth lightness was associated with both enamel HA crystal size (R = -0.313; B = -1.052; P = 0.019) and the degree of HA carbonization (R = -0.265; B=-57.95; P = 0.033). Multiple linear regression analysis demonstrated that the size of enamel HA crystals and the relative content of mineral carbonate were the most important predictors for tooth shade lightness (P = 0.018) and chroma (P=0.008), respectively. In contrast, enamel organic content had no correlation with tooth shade. CONCLUSIONS: In the present study we have revealed that the tooth shade is regulated by the size of their HA enamel crystals. On the other hand, variation in the degree of enamel HA carbonization can also affect the tooth shade. These findings are of great relevance in dentistry since it provides better understanding of tooth aesthetics. PMID- 22101120 TI - Muted dental voices on interprofessional healthcare teams. AB - This paper addresses three main themes: (1) oral health and frailty; (2) interprofessional healthcare teams; and (3) dental professionals on healthcare teams. Oral diseases exacerbate frailty, are rampant in most long-term care (LTC) facilities, and typically are not managed effectively by the medical and nursing staff. Interprofessional healthcare has attracted a diverse group of professional personnel from a wide range of backgrounds to exchange skills, but rarely do representatives from the dental professions contribute to this exchange. Barriers to dental personnel on interprofessional teams range from their limited experience on healthcare teams to the ignorance of other team members about the significance of oral health in the management of frailty. Efforts are underway to establish links throughout the personal, organisational, educational, socio economic and cultural structures of healthcare, and there are optimistic beliefs that dental voices will be strengthened when the concept of interprofessionality is accepted by educators, practitioners, professional organisations, and the public. It is likely also that dental geriatrics will improve considerably when representatives from the dental professions are heard routinely by colleagues from the other healthcare professions. PMID- 22101121 TI - These proceedings of our conference aim to give an overview on its topic "Preventive and Minimal Intervention Dentistry", which followed the same theme as our first conference in 1999. Preface. PMID- 22101122 TI - Colour stability of laminate veneers: an in vitro study. AB - OBJECTIVES: Obtaining a perfect aesthetic, especially with the translucent porcelain laminate veneers; shade of the porcelain, type of the resin cement and their long term colour stability are important factors to achieve aesthetic success. The purpose of the study was to assess the effect of different resin cement systems and UV ageing on the colour of full ceramic laminates with different shades. METHODS: 392 discs were made with A1, A3, HO and HT shades of IPS e.max Press with 0.5mm thickness. Different shades of light cured Variolink Veneer, Ivoclar Vivadent (+3, MO, -3); Rely X Veneer, 3M ESPE (A1, A3, White Opaque, Translucent); and dual cured Maxcem Elite, Kerr (White, Yellow, White Opaque, Clear); and Variolink II, Ivoclar Vivadent (White Opaque, Translucent) resin cements were applied on the porcelain discs with a thickness of 0.1mm. Colour differences of the porcelain substructures after cementation and 300 h (150 kJ/m(2)) of UV ageing test, were examined with a colorimeter (Shade Eye Ex, Shofu, Japan). The results were analysed statistically with Wilcoxon signed-rank and Kruskal-Wallis test. The mean values of L*, a*, and b* were also compared using Paired Sample t-test. Spearman's Rank Correlation test was used to analyse the correlation between ceramics with resin-cemented ceramics after ageing. The data analyses were evaluated at a significance level of p < 0.05 for all individual tests without any adjustment. RESULTS: UV ageing caused significant colour change on ceramics and also cemented ceramics (p < 0.05). Whilst L* and a* values decreased, b* values increased after ageing. Discoloration was between 0.8 1.2 DeltaE for ceramic discs and 1.4-3.1 DeltaE for cemented ceramics. There is no significant difference on the colour change of dual or light cured resin cements, which were polymerized beneath the porcelain substructure with 0.5mm thickness. Although statistically significant differences were observed for all specimens, the magnitudes of the mean colour differences were at an acceptable perception level and were considered clinically acceptable (DeltaE<3.5). CONCLUSIONS: Resin cements and ageing process influence the colour of porcelain laminate veneers. Cementation of laminates with either dual or light-cure resin cements does not effect the long term colour stability differently. PMID- 22101123 TI - A comparison between a new visual method of colour matching by intraoral camera and conventional visual and spectrometric methods. AB - OBJECTIVES: The objective of this study was to evaluate the new colour-matching Sopro Shade concept of the Sopro 717((r)) intraoral camera (assisted visual evaluation method) by comparing it with the Vita 3DMaster((r)) shade guide under the True Shade((r)) lamp and the Vita Easyshade((r)) spectrophotometric method. METHODS: The basic colour of the maxillary right central incisor and canine of 38 participants was determined by three examiners then repeated the next day using the three evaluation methods. Two examiners were experienced clinicians and one was a Sopro intraoral camera engineer. The Vita 3D-Master shade guide was used with all three colour-matching methods. Kendall's tau-b correlation coefficients between the different series of tooth-colour evaluations were computed and two tailed t-tests for paired samples were applied. RESULTS: Regardless of the tooth examined, significant intra-examiner agreement (p < 0.05) occurred between the visual and the assisted visual methods. Inter-examiner reliability was higher for canines than for central incisors, for all three methods. When comparing the two visual assessments with the spectrophotometric one, Kendall's tau-b correlation coefficients were lower. When comparing the two visual methods, significant agreement (p < 0.05) was found for both canines and central incisors. CONCLUSIONS: Within the limitations of this study, the Sopro Shade concept of the Sopro 717 intraoral camera is a reliable assistance to visual colour assessment compared with conventional visual methods. The reproducibility and reliability of all methods and examiners' measurements for canines were generally higher than those for central incisors. The possible clinical impact of the lower level of agreement between the two visual methods (conventional and assisted) compared with spectrophotometry should be studied further. PMID- 22101124 TI - Paradigm shift: Infant oral health care--primary prevention. AB - OBJECTIVES: To demonstrate that the profession and society has been historically focused on repair of disease and not health promotion. METHODS: A search of the historical and contemporary literature and the author's academic and clinical experiences. RESULTS: Progress has been made in developing programmes to prevent dental disease, but the prevalence of the disease remains high and the co morbidities are increasing. Decay in primary teeth has increased in all populations but greater in minority, less educated and poor populations. Many preventive interventions have been shown to be effective in cohort studies, but only fluoride use has received a high recommendation grade with the highest level of evidence. CONCLUSIONS: A cure for dental disease has been elusive. Until a cure is discovered, we must select those interventions that have the highest level of success and target them to at risk populations. Educational programmes must be relevant and applicable to the community and lifestyles of the targeted populations. PMID- 22101125 TI - An in vitro model for the study of chemical exchange between glass ionomer restorations and partially demineralized dentin using a minimally invasive restorative technique. AB - OBJECTIVES: This study was designed to validate an in vitro model of the Atraumatic Restorative Technique (ART). This model allowed in depth analyses of the migration of apatite forming Sr and F, from a glass-ionomer, Fuji IXGP (GC Corporation, Tokyo, Japan), into partly demineralized dentine. The second objective was to study the effects of the levels of mineral loss on such ionic exchange. METHODS: Artificial lesions were created in thirty third molars, which were divided into three groups based on time of exposure to the demineralizing solution (7, 14 and 21 days). These were restored with Fuji IXGP and left for 21 days. The method of analysis was electron probe microanalysis (EPMA) with wavelength dispersive spectrometry (WDS). This combination can yield both qualitative identification of elements as well as quantitative compositional information, with a minimum detection limit of 0.01%. RESULTS: The results indicated that there was no significant difference in the levels of Ca and P from the control and test sides for all three groups of demineralized dentine. The differences in the depth of penetration and the amount of Sr and F between control and test were significant. CONCLUSIONS: The validity of the in vitro model was confirmed. There was migration of both strontium and fluorine to the artificially demineralized dentine in a pattern consistent with remineralization and similar to what was observed in a previous in vivo study. PMID- 22101126 TI - Using statistical text mining to supplement the development of an ontology. AB - Statistical text mining was used to supplement efforts to develop a clinical vocabulary for post-traumatic stress disorder (PTSD) in the VA. A set of outpatient progress notes was collected for a cohort of 405 unique veterans with PTSD and a comparison group of 392 with other psychological conditions at one VA hospital. Two methods were employed: (1) "multi-model term scoring" used stepwise logistic regression to develop 21 separate models by varying three frequency weight and seven term weight options and (2) "iterative term refinement" which used a standard stop list followed by clinical review to eliminate non-clinical terms and terms not related to PTSD. Combined results of the two methods were reviewed by two clinicians resulting in 226 unique PTSD related terms. Results of the statistical text mining methods were compared with ongoing efforts to identify terms based on literature review, focus groups with clinicians treating PTSD and review of an existing vocabulary, lending support to the contributions of the STM analyses. PMID- 22101127 TI - Multiple valued logic approach for matching patient records in multiple databases. AB - Many problems arise when linking medical records from multiple databases. Matching these data to other data is problematic since even small errors, such as data entry errors, different text format, and missing data, can prevent the exact match algorithms. Evidence from previous studies suggested that approximate field matching represent a solution to resolve the problem by identifying equivalent string values in different representations. The purpose of this article is to explore the effectiveness of a medical record matching method using a fuzzy logic framework. This article considers quantitative measures of the typical elements in medical records, and fuzzy logic is applied to link to the linguistic concepts. Moreover, this article discusses the medical record matching from the developed framework, which is tested on a public data set. The results from the test on a public data set indicate that the medical record matching method using fuzzy logic framework provides an effective solution for dealing with linkage problems, and illustrate that the multiple valued logic method outlined can potentially be applied to address similar problems in other databases. PMID- 22101128 TI - A framework and its empirical study of automatic diagnosis of traditional Chinese medicine utilizing raw free-text clinical records. AB - Automatic diagnosis is one of the most important parts in the expert system of traditional Chinese medicine (TCM), and in recent years, it has been studied widely. Most of the previous researches are based on well-structured datasets which are manually collected, structured and normalized by TCM experts. However, the obtained results of the former work could not be directly and effectively applied to clinical practice, because the raw free-text clinical records differ a lot from the well-structured datasets. They are unstructured and are denoted by TCM doctors without the support of authoritative editorial board in their routine diagnostic work. Therefore, in this paper, a novel framework of automatic diagnosis of TCM utilizing raw free-text clinical records for clinical practice is proposed and investigated for the first time. A series of appropriate methods are attempted to tackle several challenges in the framework, and the Naive Bayes classifier and the Support Vector Machine classifier are employed for TCM automatic diagnosis. The framework is analyzed carefully. Its feasibility is validated through evaluating the performance of each module of the framework and its effectiveness is demonstrated based on the precision, recall and F-Measure of automatic diagnosis results. PMID- 22101129 TI - Exploring older adults' health information seeking behaviors. AB - OBJECTIVE: To explore older adults' (55-70 years) health information-seeking behaviors. METHODS: Using a qualitative methodology, based on grounded theory, data were collected using in-depth interviews. Participants were community living, older adults in Toronto, Canada who independently seek nutrition and health information. Interview transcripts were analyzed using a qualitative thematic coding framework. RESULTS: Twenty participants were interviewed, at which point theoretical saturation of data was achieved. Three themes describing older adults' health information-seeking behaviors emerged. This article will focus on one theme: the enabling and disabling experience of seeking nutrition and health information to support an understanding of successful aging in this population. CONCLUSIONS AND IMPLICATIONS: These findings are framed within the context of supporting older adults' information-seeking behaviors to contribute to their health and well-being. This is a relevant issue to public health professionals given the global emphasis on successful aging strategies. PMID- 22101130 TI - Sensory basis of vigilance behavior in birds: synthesis and future prospects. AB - Birds gather visual information through scanning behavior to make decisions relevant for survival (e.g., detecting predators and finding food). The goal of this study was (a) to review some visual properties involved in scanning behavior (retinal specialization for visual resolution and motion detection, visual acuity, and size of the blind area), and (b) hypothesize how the inter-specific variability in these properties may lead to different scanning strategies. The avian visual system has a high degree of heterogeneity in visual performance across the visual field, with some sectors providing higher levels of visual resolution and motion detection (e.g., retinal specializations) than others (e.g., peripheral retina and blind area). Thus, information quality will vary in different parts of the visual field, which contradicts some theoretical assumptions on information gathering. Birds need to move their eyes and heads to align the retinal specializations to different sectors of visual space. The rates of eye and head movements can then be used as proxies for scanning strategies. I propose specific predictions as to how each of the visual properties studied can affect scanning strategies in the context of predator detection in different habitat types and with different levels of predation risk. Establishing the degree of association between sensory specializations and scanning strategies can enhance our understanding of the evolution of anti-predator behavior. PMID- 22101131 TI - 4'-bromo-5,6,7-trimethoxyflavone represses lipopolysaccharide-induced iNOS and COX-2 expressions by suppressing the NF-kappaB signaling pathway in RAW 264.7 macrophages. AB - The regulations of the NO and PGE(2) productions are research topics of interest in the field of anti-inflammatory drug development. In the present study, 5,6,7 trimethoxy- and 5,6,7-trihydroxyflavones 3a-3g were synthesized from cinnamic acid derivatives. In particular, 4'-bromo-5,6,7-trimethoxyflavone (3b) most potently inhibited the productions of NO and PGE(2) in LPS-treated RAW 264.7 cells (IC(50)=14.22 +/- 1.25 and 10.98 +/- 6.25 MUM, respectively), and these inhibitory effects were more potent than those of oroxylin A or baicalein. Consistent with these findings, 3b concentration-dependently reduced the LPS induced expressions of iNOS and COX-2 at the protein and mRNA levels. In addition, the release of TNF-alpha, IL-6, and IL-1beta and the mRNA expressions of these cytokines were reduced by 3b in a concentration-dependent manner. Furthermore, 3b attenuated the LPS-induced transcriptional activities of NF kappaB and this was accompanied by parallel reductions in the degradation and phosphorylation of IkappaB-alpha, and consequently by a decrease in the nuclear translocation of the p65 subunit of NF-kappaB. Taken together, these results suggest that suppressions of the expressions of iNOS, COX-2, TNF-alpha, IL-6, and IL-1beta via NF-kappaB inactivation are responsible for the anti-inflammatory effects of 3b. PMID- 22101132 TI - Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases. AB - 5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model. PMID- 22101133 TI - Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series. AB - Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model. PMID- 22101134 TI - LDV peptidomimetics equipped with biotinylated spacer-arms: synthesis and biological evaluation on CCRF-CEM cell line. AB - The tripeptide Leu-Asp-Val (LDV) is known to bind alpha(4)beta(1) integrin in leukemia cells. Here we have synthesized a LDV peptidomimetic equipped with a biotin-conjugated spacer-arm. Compound 9 acts as an inhibitor of the alpha(4)beta(1) integrin in an adhesion assay using fluorescently labeled, alpha(4)beta(1) integrin-expressing leukemia CCRF-CEM cells. Furthermore, when bound to neutravidin-coated plates, compound 9 could capture CCRF-CEM cells. Such biotin-conjugated LDV peptidomimetic may thus represent a novel tool for biotechnological applications using avidin interaction for leukapheresis or leukemia cell targeting. PMID- 22101135 TI - An iminosugar N-pentafluorobenzyl-1-deoxynojirimycin as a novel potential immunosuppressant for the treatment of Th2-related diseases. AB - Increased levels of Th2 cytokine interleukin-4 (IL-4) have been reported to be involved in the pathogenesis of the parasite Schistosoma japonicum (S. japonicum) infection or detected in the serum of the causative agent of acquired immunodeficiency syndrome (AIDS) patients. This correlates with a worsened outcome of AIDS. The inhibition of a Th2 type response might aid in the treatment of these Th2-related diseases. Previously, we found that N-pentafluorobenzyl-1 deoxynojirimycin (5F-DNM), a new derivative of 1-deoxynojirimycin (DNM) (an inhibitor of the glycoprotein processing enzymes, glucosidase I and II), had specific inhibition effects on human CD4(+) T cells. In this study, we further found that 5F-DNM not only markedly inhibited in vitro IL-4 production from human PBMCs, CD4(+) T cells and mouse splenocytes but also strongly inhibited the production of IL-4 in splenocytes from a mouse model of S. japonicum infection. The numbers of S. japonicum worms were significantly decreased in vivo upon the treatment of mice with 5F-DNM. We demonstrated the mechanism of 5F-DNM effects on CD4(+) T cells acts via the inhibition of the IL-4/JAK1/STAT6 signaling pathway. Moreover, 5F-DNM was found to induce CD4 internalization (transfer from the cellular surface to the cytoplasm) in CD4(+) T cells and had no significant effects on the overall expression levels of CD4. These findings indicate that 5F DNM might be used as a potential candidate for the treatment of S. japonicum parasitic infection, AIDS and other Th2-related diseases. PMID- 22101136 TI - The application of discriminant analysis and Machine Learning methods as tools to identify and classify compounds with potential as transdermal enhancers. AB - Discriminant analysis (DA) has previously been shown to allow the proposal of simple guidelines for the classification of 73 chemical enhancers of percutaneous absorption. Pugh et al. employed DA to classify such enhancers into simple categories, based on the physicochemical properties of the enhancer molecules (Pugh et al., 2005). While this approach provided a reasonable accuracy of classification it was unable to provide a consistently reliable estimate of enhancement ratio (ER, defined as the amount of hydrocortisone transferred after 24h, relative to control). Machine Learning methods, including Gaussian process (GP) regression, have recently been employed in the prediction of percutaneous absorption of exogenous chemicals (Moss et al., 2009; Lam et al., 2010; Sun et al., 2011). They have shown that they provide more accurate predictions of these phenomena. In this study several Machine Learning methods, including the K nearest-neighbour (KNN) regression, single layer networks, radial basis function networks and the SVM classifier were applied to an enhancer dataset reported previously. The SMOTE sampling method was used to oversample chemical compounds with ER>10 in each training set in order to improve estimation of GP and KNN. Results show that models using five physicochemical descriptors exhibit better performance than those with three features. The best classification result was obtained by using the SVM method without dealing with imbalanced data. Following over-sampling, GP gives the best result. It correctly assigned 8 of the 12 "good" (ER>10) enhancers and 56 of the 59 "poor" enhancers (ER<10). Overall success rates were similar. However, the pharmaceutical advantages of the Machine Learning methods are that they can provide more accurate classification of enhancer type with fewer false-positive results and that, unlike discriminant analysis, they are able to make predictions of enhancer ability. PMID- 22101137 TI - Impact on electroencephalography of Adolf Beck, a prominent Polish scientist and founder of the Lviv School of Physiology. AB - Adolf Beck (1863-1942) can be regarded as the co-founder of electroencephalography. His studies on the cerebral cortex of animals have facilitated the introduction of the electroencephalogram (EEG) as a main tool for studying the brain. The localization of senses on the cortex with evoked potentials and the description of the desynchronization of the electrical brain activity upon stimulation, are hallmarks of the research of Beck. He performed his groundbreaking studies under supervision of the famous Napoleon Cybulski at the Jagiellonian University in Cracow (Poland) between 1888 and 1895. In that last year Beck was appointed professor at the University of Lemberg (Lviv), where he founded the Department of Physiology and recruited scientists to the Lviv School of Physiology. Beck was the leading authority of the University of Lemberg in the most turbulent period of the town's history. Together with Cybulski he wrote the influential textbook 'Human physiology' in 1915. PMID- 22101138 TI - Tough-skinned kids: identifying psychosocial effects of psoriasis and helping pediatric patients and families cope. AB - Outward appearance is exquisitely and undeniably tied to self-perception. Pediatric patients with psoriasis face the challenge of coping with psychosocial issues because of the visibility of their skin lesions. The burden of psoriasis also affects the quality of life of family members. This article discusses pediatric psoriasis, current literature on psychosocial impact, role of the nurse to help patients and families cope, and recommendations for further research. Through clinical intervention, patient education, and referral to resources, the nurse can hope to relieve some stress and help the child, adolescent, and family maintain their improved quality of life. PMID- 22101139 TI - Bio-inspired strategy for on-surface synthesis of silver nanoparticles for metal/organic hybrid nanomaterials and LDI-MS substrates. AB - A strategy for the on-surface synthesis of silver nanoparticles (AgNPs) on a variety of two- to three-dimensional material surfaces, utilizing polydopamine, an emerging surface modifying agent, is reported in this paper. This material independent platform for AgNP synthesis is useful for fabricating organic/inorganic hybrid nanomaterials and for preparing substrates for laser desorption-ionization time-of-flight mass spectrometry (LDI-ToF MS). PMID- 22101140 TI - Post-acquisition repetitive thought in fear conditioning: an experimental investigation of the effect of CS-US-rehearsal. AB - BACKGROUND AND OBJECTIVES: Although repetitive thought (e.g., worry) is generally assumed to be a risk factor for psychopathological disorders such as anxiety disorders, the repetitive thought processes occurring after a conditioning event have not yet received much theoretical attention. However, as repetitive thought can be mimicked by (mental) rehearsal, which is well-known to enhance memory performance, it seems worthwhile to explore the role of rehearsal in conditioning. Therefore, the current study investigates the impact of rehearsing an acquired CS-US-contingency on subsequent conditioned fear responding. METHODS: After acquiring two CS-US-contingencies with either a human scream or a white noise as US, participants were instructed to rehearse one of these CS-US-pairings during an experimental session as well as during the following week. RESULTS: Fear responding to the CS which was previously paired with the scream persisted in the participants who rehearsed the CS-US(scream)-contingency, but decreased in those participants who rehearsed the CS-US(noise)-contingency. The same pattern emerged in the US-expectancy ratings, but the effect failed to reach significance. For the CS which was paired with the noise-US, no rehearsal effect emerged. LIMITATIONS: As acquisition to the noise-US was less pronounced and less robust as compared to the scream-US, claims regarding the rehearsal effect might be hampered for the CS-US(noise)-contingency. CONCLUSIONS: Repetitive post acquisition activation of a CS-US-contingency impacts CR retention. As the USs were not rated as more intense, aversive or startling after rehearsal compared to post-acquisition, US-inflation is discarded as a possible explanation of this effect. PMID- 22101141 TI - NeuroQuest: a comprehensive analysis tool for extracellular neural ensemble recordings. AB - Analyzing the massive amounts of neural data collected using microelectrodes to extract biologically relevant information is a major challenge. Many scientific findings rest on the ability to overcome these challenges and to standardize experimental analysis across labs. This can be facilitated in part through comprehensive, efficient and practical software tools disseminated to the community at large. We have developed a comprehensive, MATLAB-based software package - entitled NeuroQuest - that bundles together a number of advanced neural signal processing algorithms in a user-friendly environment. Results demonstrate the efficiency and reliability of the software compared to other software packages, and versatility over a wide range of experimental conditions. PMID- 22101142 TI - A comparison of MR imaging of a mouse model of glioma at 0.2 T and 9.4 T. AB - Both 0.2 T and 9.4 T MRI systems were used to image a mouse model of glioma. RF coils were designed for both fields. A spin-echo, multi-echo pulse sequence was used to determine T(2) relaxation times of both brain and tumor tissues. Contrast to-noise ratio was calculated based on the selected echo time. The results showed that 0.2 T is suitable for mouse model imaging, however total scan time must be long to achieve high enough SNR. T(2) relaxation times of the tumor and brain tissues can be measured at 0.2 T and are 2.1 and 1.8 times respectively longer at 0.2 T than at 9.4 T. Contrast to noise ratio for tumor and brain was better at high field than at the low field. We concluded that 0.2 T may be used to study mouse model of glioma using spin echo pulse sequence, yet the total scan time is long (about 40 min), resolution is lower (~250 MUm * 250 MUm) and slice thickness (3mm) must be large enough to obtain sufficient SNR. PMID- 22101143 TI - BSMac: a MATLAB toolbox implementing a Bayesian spatial model for brain activation and connectivity. AB - We present a statistical and graphical visualization MATLAB toolbox for the analysis of functional magnetic resonance imaging (fMRI) data, called the Bayesian Spatial Model for activation and connectivity (BSMac). BSMac simultaneously performs whole-brain activation analyses at the voxel and region of interest (ROI) levels as well as task-related functional connectivity (FC) analyses using a flexible Bayesian modeling framework (Bowman et al., 2008). BSMac allows for inputting data in either Analyze or Nifti file formats. The user provides information pertaining to subgroup memberships, scanning sessions, and experimental tasks (stimuli), from which the design matrix is constructed. BSMac then performs parameter estimation based on Markov Chain Monte Carlo (MCMC) methods and generates plots for activation and FC, such as interactive 2D maps of voxel and region-level task-related changes in neural activity and animated 3D graphics of the FC results. The toolbox can be downloaded from http://www.sph.emory.edu/bios/CBIS/. We illustrate the BSMac toolbox through an application to an fMRI study of working memory in patients with schizophrenia. PMID- 22101144 TI - Three-dimensional alteration of microvasculature in a rat model of traumatic spinal cord injury. AB - Acute spinal cord injury (SCI) always leads to severe destruction of the microvascular networks. To investigate the three-dimensional (3D) alterations of microvasculature following SCI, we utilized an established rat SCI model. Based on the hypothesis that the spinal cord would undergo reorganization and postinjury modification of the vascular networks after SCI, we reconstructed the normal and injured angioarchitecture using micro-CT images of silicone rubber microsphere-perfused specimens. Several morphometric parameters were used to study the 3D vascular alterations in the SCI rat model, including the casting based vessel volume fraction, connectivity density, separation, thickness and thickness distribution. Our results indicated that the microvascular spatial conformations were significantly different between the normal and injured spinal cord segments. The morphometric changes showed an increase of the vessel volume fraction and separation and a decrease of vessel connectivity density during the vascular healing process after SCI. Our results may contribute to elucidation of the mechanisms of compensatory vascular reconstitution in traumatized spinal cord. The method used here has the potential to improve our understanding of changes in the spatial architecture of vascular networks after SCI compared to the conventional histomorphology techniques. In summary, we developed a new methodology to analyze neurovascular pathology based on 3D vascular network patterns and features in an experimental rat SCI model. This technique could be used as a complementary tool to investigate the efficacy and side effects of therapeutic drugs or rehabilitation regimens. PMID- 22101145 TI - Optimal band separation of extracellular field potentials. AB - Local Field Potentials (LFPs) exhibit a broadband spectral structure that is traditionally partitioned into distinct frequency bands which are thought to originate from different types of neural events triggered by different processing pathways. However, the exact frequency boundaries of these processes are not known and, as a result, the frequency bands are often selected based on intuition, previous literature or visual inspection of the data. Here, we address these problems by developing a rigorous method for defining LFP frequency bands and their boundaries. The criterion introduced for determining the boundaries delimiting the bands is to maximize the information about an external correlate carried jointly by all bands in the partition. The method first partitions the LFP frequency range into two bands and then successively increases the number of bands in the partition. We applied the partitioning method to LFPs recorded from primary visual cortex of anaesthetized macaques, and we determined the optimal band partitioning that describes the encoding of naturalistic visual stimuli. The first optimal boundary partitioned the LFP response at 60 Hz into low and high frequencies, which had been previously found to convey independent information about the natural movie correlate. The second optimal boundary divided the high frequency range at approximately 100 Hz into gamma and high-gamma frequencies, consistent with recent reports that these two bands reflect partly distinct neural processes. A third important boundary was at 25 Hz and it split the LFP range below 50 Hz into a stimulus-informative and a stimulus-independent band. PMID- 22101146 TI - Bioengineering nanotechnology: towards the clinic. PMID- 22101147 TI - Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature. AB - INTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. METHODS: Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. RESULTS: Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. CONCLUSION: Erlotinib associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity. PMID- 22101148 TI - Preferential base pairing modes of T.T mismatches. AB - It has long been recognized that T.T mismatches can adopt two different modes of exchangeable wobble base pairs in which no preferential pairing mode has been observed. In this study, we have performed a systematic nuclear magnetic resonance (NMR) investigation to study the sequence context effect on the pairing modes of T.T mismatches. Our results reveal for the first time that preferential pairing mode does exist in T.T mismatches with specific type of flanking base pairs. PMID- 22101149 TI - On the potential contribution of aspirin to healthy ageing programmes. PMID- 22101150 TI - Determinants of regurgitant volume in mitral regurgitation: contrasting effect of similar effective regurgitant orifice area in functional and organic mitral regurgitation. AB - BACKGROUND: Quantitative assessment of the severity of mitral regurgitation (MR) is based on the calculation of the effective regurgitant orifice (ERO), a measure of lesion severity, and of the regurgitant volume (RVol), a measure of left ventricular volume overload. We aimed at evaluating the determinants of RVol in both organic (OMR) and functional mitral regurgitation (FMR). METHODS AND RESULTS: MR severity was quantitatively assessed using the proximal isovelocity surface area (PISA) method in 240 patients, 142 with OMR and 98 patients with FMR. By definition, ERO and RVol were strongly correlated both in patients with OMR and FMR (both R = 0.90, P < 0.0001) but the slopes of the regression lines were significantly different (P < 0.0001). This difference remained significant in patients with elevated systolic pulmonary artery pressure (SPAP > 40 mmHg, P < 0.0001) but not in patients with normal SPAP (<=40 mmHg, P = 0.09). In multivariate analysis, independent determinants of RVol were ERO (P < 0.0001), MR mechanism (FMR/OMR) (P = 0.0003) and SPAP (P = 0.03). In patients with elevated SPAP, ERO (P < 0.0001), left ventricular ejection fraction (LVEF) (P = 0.03), and MR mechanism (P = 0.03) were independently associated with RVol, whereas in patients with normal SPAP, ERO (P < 0.0001) was the only independent determinant of RVol. CONCLUSION: In the present study, we evaluated the contrasting effect of similar lesion severity in OMR and FMR and showed that similar ERO were associated with lower RVol in FMR compared with OMR. The regurgitant volume is the result of complex interactions of anatomic lesions, LVEF, and SPAP and our results highlight the importance of taking into account these parameters when interpreting RVol values in clinical practice, especially in FMR. PMID- 22101151 TI - Residual compromised myocardial contractile reserve after valve replacement for aortic stenosis. AB - OBJECTIVE: Despite recovery of left ventricular (LV) function and morphology after aortic valve replacement (AVR) for aortic stenosis (AS), its relationship with exercise capacity remains unknown. Twenty-one AVR patients (age 61 +/- 12 years, 14 male) with normal ejection fraction (EF, 64 +/- 7%) and 21 age- and sex matched controls (57 +/- 9 years, 10 male, EF 68 +/- 8%) were studied. METHODS AND RESULTS: All subjects performed semi-supine bicycle exercise and speckle tracking echocardiography (STE) study. Peak oxygen consumption (pVO(2)) was collected during semi-supine bicycle exercise. Systolic (GLSRs) and early diastolic (GLSRe) longitudinal strain rate using STE and Doppler echocardiographic parameters were measured at rest, submaximal, peak exercise, and 4 min after exercise. The two groups had comparable resting echocardiographic measurements. At peak exercise, pVO(2) was lower in patients than controls (18.5 +/- 4.5 vs. 22.1 +/- 4.3 L/min/kg, P < 0.05). GLSRs (0.98 +/- 0.28 vs. 1.55 +/- 0.30 1/s, P < 0.001), septal Sm (7.9 +/- 1.4 vs. 11.1 +/- 2.3 cm/s, P < 0.001) and their changes between rest and peak exercise (DeltaGLSRs: 0.16 +/- 0.33 vs. 0.68 +/- 0.27 1/s, P < 0.001; DeltaSm 2.29 +/- 2.23 vs. 4.63 +/- 2.29 cm/s, P < 0.01) were significantly lower in patients than controls. There was no correlation between pVO(2) and any echocardiographic measurements in controls. In patients, pVO(2) correlated with peak exercise GLSRs (r = 0.60, P = 0.0007), septal Sm (r = 0.65, P = 0.002), and Em (r = 0.57, P = 0.009). In a multivariate model, peak exercise GLSRs (beta = 7.18, P = 0.03) was the only independent predictor of pVO(2) in the patients group. CONCLUSION: Exercise capacity is subnormal after AVR for AS, irrespective of normal LVEF suggesting residual compromised myocardial functional reserve. PMID- 22101152 TI - The rise and fall of supervised machine learning techniques. PMID- 22101153 TI - PSICOV: precise structural contact prediction using sparse inverse covariance estimation on large multiple sequence alignments. AB - MOTIVATION: The accurate prediction of residue-residue contacts, critical for maintaining the native fold of a protein, remains an open problem in the field of structural bioinformatics. Interest in this long-standing problem has increased recently with algorithmic improvements and the rapid growth in the sizes of sequence families. Progress could have major impacts in both structure and function prediction to name but two benefits. Sequence-based contact predictions are usually made by identifying correlated mutations within multiple sequence alignments (MSAs), most commonly through the information-theoretic approach of calculating mutual information between pairs of sites in proteins. These predictions are often inaccurate because the true covariation signal in the MSA is often masked by biases from many ancillary indirect-coupling or phylogenetic effects. Here we present a novel method, PSICOV, which introduces the use of sparse inverse covariance estimation to the problem of protein contact prediction. Our method builds on work which had previously demonstrated corrections for phylogenetic and entropic correlation noise and allows accurate discrimination of direct from indirectly coupled mutation correlations in the MSA. RESULTS: PSICOV displays a mean precision substantially better than the best performing normalized mutual information approach and Bayesian networks. For 118 out of 150 targets, the L/5 (i.e. top-L/5 predictions for a protein of length L) precision for long-range contacts (sequence separation >23) was >= 0.5, which represents an improvement sufficient to be of significant benefit in protein structure prediction or model quality assessment. AVAILABILITY: The PSICOV source code can be downloaded from http://bioinf.cs.ucl.ac.uk/downloads/PSICOV. PMID- 22101154 TI - Lymphatic ascites following pelvic and paraaortic lymphadenectomy procedures for gynecologic malignancies. AB - OBJECTIVE: Lymphatic ascites is an unusual complication in patients with cancer. In the gynecologic oncology patient population, the most common etiology is operative lymph node dissection. The purpose of this study was to explore the incidence, presenting symptoms, methods of diagnosis and treatment modalities utilized for lymphatic ascites in patients undergoing lymph node dissection for gynecologic cancers. METHODS: This observational study retrospectively reviewed the charts of patients who underwent lymphadenectomy as part of the surgical management for a gynecologic cancer. Patients that developed postoperative lymphatic ascites between January 2000 and December 2010 were included for analysis. Data extracted from the medical records included tumor pathology, number of harvested lymph nodes, postoperative course, method of diagnosis and treatment. RESULTS: From a total of 300 surgical staging procedures, 12 patients with lymphatic ascites were identified (4%). The most common reported symptom was leakage of clear fluid per vagina (7, 58%), followed by abdominal distension (4, 33%). The median interval from surgery to development of symptoms was 12.5 days (range 0-22 days). 5 patients had complete resolution of symptoms with dietary modifications alone while 7 patients required paracentesis. The median time from surgery to resolution of symptoms was 44 days (range 9-99). CONCLUSION: Lymphatic ascites is an under recognized and infrequently reported postoperative complication. Although it usually resolves spontaneously or with conservative management without sequelae, this condition can significantly prolong postoperative recovery and cause patient discomfort. To our knowledge this is the largest group of patients undergoing gynecologic surgical staging procedures to be reviewed for the occurrence of lymphatic ascites. PMID- 22101155 TI - Morbidly obese women with and without endometrial cancer: are there differences in measured physical fitness, body composition, or hormones? AB - OBJECTIVE: Exercise is potentially protective against cancer for obese women. The objectives were to examine differences in activity, body composition, and hormones in overweight/obese women with and without endometrial cancer. METHODS: Women >= 50 years old with a body mass index (BMI) >= 25 kg/m(2) scheduled for abdominal hysterectomy were enrolled. Demographics, physical activity, and quality of life (QOL) data were collected. Body composition/fitness was evaluated using Air Displacement Plethysmography (BodPod) and a standardized treadmill. Adiponectin, androstenedione, leptin, estradiol, estrone, progesterone, sex hormone binding globulin, insulin and glucose were measured. RESULTS: Thirty eight women enrolled in this pilot study; 22 had endometrial cancer. Mean age was 58.3 years, mean BMI, fat weight and percent body fat were 41.3 kg/m(2), 55 kg and 51% respectively. Fitness levels were poor; 90% of women had peak oxygen uptakes below the 10th percentile of population normals yet 80% still rated their fitness level as equivalent to other women. Women with and without cancer did not differ in age, BMI, co-morbidities, energy expenditures, body composition, hormones or QOL although glucose levels were higher in women with cancer (119.5 vs. 90.7 mg/dl; p=0.049). Cancer subjects scored worse on every fitness measurement, reaching statistical significance for VO(2 peak) (15.0 vs. 17.9 ml/kg/min; p=0.033). Current exercisers had a lower BMI (p=0.039), decreased fat weight (p=0.024), decreased waist circumference (p=0.05) and improved vitality compared to non-exercisers. CONCLUSION: Physical fitness levels were abysmal in these morbidly obese subjects and worse for cancer patients. Exercise correlated with improved body composition and vitality. PMID- 22101156 TI - Diagnosis of HIV-1 infection by near-infrared spectroscopy: analysis using molecular clones of various HIV-1 subtypes. AB - BACKGROUND: Previously, we investigated the possibility of using near-infrared (NIR) spectroscopy for the diagnosis of human immunodeficiency virus type-1 (HIV 1) infection. Here, we further analyze NIR spectra using molecular clones of various HIV-1 subtypes. METHODS: Culture supernatants of pNL4-3- (HIV-1 molecular clone) or pUC18- (empty vector) transfected 293 T cells were used. In addition, culture supernatants obtained using pBal (HIV-1 subtype B molecular clone) or pIndieC (HIV-1 subtype C molecular clone) were used. Near-infrared radiation (NIR) spectra, obtained using the culture supernatants, were subjected to principal component analysis (PCA) to extract and analyze their properties. RESULTS: The PCA demonstrated that HIV-1 in medium altered wavelength absorption at around 950 and 1030 nm, suggesting that the HIV-1 altered OH vibration in water. In addition, absorption varied among subtypes at around 950, 1030 and 1060 nm, suggesting that the interaction between HIV-1 and water varies among subtypes. CONCLUSIONS: These differences in the NIR spectra may make it possible to delineate HIV-1 subtypes spectroscopically. PMID- 22101157 TI - T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. AB - T cell receptor (TCR) engagement of peptide-major histocompatibility complex (pMHC) is essential to adaptive immunity, but it is unknown whether TCR signaling responses are influenced by the binding topology of the TCR-peptide-MHC complex. We developed yeast-displayed pMHC libraries that enabled us to identify new peptide sequences reactive with a single TCR. Structural analysis showed that four peptides bound to the TCR with distinct 3D and 2D affinities using entirely different binding chemistries. Three of the peptides that shared a common docking mode, where key TCR-MHC germline interactions are preserved, induced TCR signaling. The fourth peptide failed to induce signaling and was recognized in a substantially different TCR-MHC binding mode that apparently exceeded geometric tolerances compatible with signaling. We suggest that the stereotypical TCR-MHC docking paradigm evolved from productive signaling geometries and that TCR signaling can be modulated by peptides that are recognized in alternative TCR pMHC binding orientations. PMID- 22101159 TI - Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. AB - Immunological functions of mast cells remain poorly understood. Studies in Kit mutant mice suggest key roles for mast cells in certain antibody- and T cell mediated autoimmune diseases. However, Kit mutations affect multiple cell types of both immune and nonimmune origin. Here, we show that targeted insertion of Cre recombinase into the mast cell carboxypeptidase A3 locus deleted mast cells in connective and mucosal tissues by a genotoxic Trp53-dependent mechanism. Cre mediated mast cell eradication (Cre-Master) mice had, with the exception of a lack of mast cells and reduced basophils, a normal immune system. Cre-Master mice were refractory to IgE-mediated anaphylaxis, and this defect was rescued by mast cell reconstitution. This mast cell-deficient strain was fully susceptible to antibody-induced autoimmune arthritis and to experimental autoimmune encephalomyelitis. Differences comparing Kit mutant mast cell deficiency models to selectively mast cell-deficient mice call for a systematic re-evaluation of immunological functions of mast cells beyond allergy. PMID- 22101158 TI - A role for differential variable gene pairing in creating T cell receptors specific for unique major histocompatibility ligands. AB - A limited set of T cell receptor (TCR) variable (V) gene segments are used to create a repertoire of TCRs that recognize all major histocompatibility complex (MHC) ligands within a species. How individual alphabetaTCRs are constructed to specifically recognize a limited set of MHC ligands is unclear. Here we have identified a role for the differential pairing of particular V gene segments in creating TCRs that recognized MHC class II ligands exclusively, or cross-reacted with classical and nonclassical MHC class I ligands. Biophysical and structural experiments indicated that TCR specificity for MHC ligands is not driven by germline-encoded pairwise interactions.Rather, identical TCRbeta chains can have altered peptide-MHC (pMHC) binding modes when paired with different TCRalpha chains. The ability of TCR chain pairing to modify how V region residues interact with pMHC helps to explain how the same V genes are used to create TCRs specific for unique MHC ligands. PMID- 22101160 TI - Progression to insulin for patients with diabetes mellitus using the Texas Medicaid database. AB - BACKGROUND: Patients newly diagnosed with type 2 diabetes mellitus generally initiate therapy with either metformin [Met] or a sulfonylurea [SU] drug, followed by the addition of a second agent (Met, an SU drug, or a thiazolidinedione [TZD] drug) if the diabetes is not well controlled. If necessary, the usual third line of treatment is the addition of insulin. OBJECTIVE: The purpose of our study was to compare the progression to insulin among 3 cohorts receiving the oral antidiabetic (OAD) drug combinations Met/SU, Met/TZD, or SU/TZD. METHODS: This study used data from the Texas Medicaid database. The date of addition of a second OAD was considered a patient's index date and patients were followed for up to 5 years. Cox proportional hazards regression compared the progression to first insulin use among cohorts, using the Met/SU cohort as the reference group, while adjusting for demographics, comorbidities, and propensity scores. RESULTS: A total of 4083 patients were included in the study (Met/SU = 2872, Met/TZD = 438, and SU/TZD = 773). Insulin was added to the medication regimen of patients by the end of follow-up in 19.7% of the Met/SU cohort, 17.6% of the Met/TZD cohort, and 26.3% of the SU/TZD cohort. The adjusted Cox proportional model estimated that patients in the SU/TZD cohort had a 40% higher probability of progression to insulin than patients in the Met/SU cohort (odds ratio [OR] = 1.40; 95% CI, 1.19-1.64), whereas there was no significant difference between the Met/TZD and Met/SU cohorts (OR = 0.85; 95% CI, 0.67-1.08). CONCLUSIONS: It appears that mechanism of action may play a role in progression to insulin for concomitant OAD agents. A slower progression to insulin was seen for patients receiving a paired sensitizer regimen (ie, Met/TZD) compared with those receiving a secretagogue sensitizer regimen (ie, SU/TZD). PMID- 22101161 TI - Double-blind, placebo-controlled, randomized pilot study of cerebral blood flow patterns employing SPECT imaging in dental postsurgical pain patients with and without pain relief. AB - BACKGROUND: Single-photon emission computed tomography (SPECT) has been employed in the study of altered regional cerebral blood flow (CBF) in experimental and chronic pain. CBF patterns have not been evaluated in patients with acute postoperative pain. OBJECTIVE: The purpose of this pilot study was to employ SPECT to measure CBF distribution associated with postoperative dental pain and to compare these CBF patterns to subsequent images in the same patients who were experiencing pain relief versus continued or worsening pain who had received active or placebo analgesic interventions. The primary outcome measure was the percentage change in blood flow in various regions of interest. METHODS: Twenty two healthy individuals (10 males and 12 females, age range 20-29 years) who underwent the removal of >=1 partial or full bony impacted mandibular third molars were evaluated for pain intensity as the local anesthesia dissipated, employing a 0 to10 numeric rating scale (0 = no pain; 10 = worst imaginable). When the subjects' pain level reached >=4/10, they were injected intravenously with 260 MBq of technetium Tc 99m bicisate (ethyl cysteinate dimer). Under double blind conditions and 10 minutes before being placed in the SPECT scanner, the first 10 subjects were randomized to receive intravenous ketorolac 15 mg or saline while the remaining 12 subjects were randomized to receive by mouth either ibuprofen 400 mg, ibuprofen 200 mg, acetaminophen 1000 mg, or placebo. One hour after drug administration, subjects were reevaluated for pain, injected with 925 MBq of technetium Tc 99m bicisate, given rescue medication if required, and then rescanned. CBF ratios were obtained for regions of interest and by normalizing to average whole brain activity. RESULTS: Subjects generally had a moderate degree (mean [SD], 7.3% [4.0%]) of thalamic asymmetry on initial scans with pain; after treatment, subjects reporting worsening pain regardless of the intervention had higher thalamic asymmetry (8.1% vs 2.8%) than those reporting relief of pain. Subjects who reported reduced pain after the intervention had significantly different (P < 0.05) mean CBF changes compared with those reporting worsening pain in the left prefrontal cortex, left sensorimotor area, right anterior cingulate, and right caudate. CONCLUSIONS: Acute postoperative dental pain was associated with moderate thalamic asymmetry that improved following successful pain management. Sustained or worsening pain was associated with increased CBF in brain regions associated with pain pathways, whereas pain relief was associated with decreased activity in the same areas. PMID- 22101162 TI - Decreased salivary sulphotransferase activity correlated with inflammation and autoimmunity parameters in Sjogren's syndrome patients. AB - OBJECTIVES: To determine the expression and enzymatic activities of sulphotransferases involved in mucin hyposulphation in labial salivary glands (LSGs) from SS patients and to correlate sulphotransferase activity with clinical parameters such as secretion, inflammation and serology. METHODS: LSG from 31 SS patients and 31 control subjects were studied. Relative mRNA and protein levels of Gal3-O-sulphotransferases (Gal3STs) and beta1,3-galactosyltransferase-5 (beta3GalT5) were determined by quantitative RT-PCR and western blotting, respectively. Enzymatic activities were quantified using radioactively labelled donor substrates and specific acceptor substrates. Products were purified by chromatography. Spearman's correlation analysis was used to compare data. RESULTS: The levels of Gal3ST activity were significantly decreased in SS patients, without changes in mRNA and protein levels, while the enzymatic activities of glycosyltransferases involved in mucin glycosylation were similar in both groups. An inverse correlation was observed between Gal3ST activity and glandular function measured by scintigraphy, but not with unstimulated salivary flow. Gal3ST activity was inversely correlated with focus score, TNF-alpha levels and presence of the autoantibodies Ro/SS-A and La/SS-B. CONCLUSION: The decrease in sulphotransferase activity provides an explanation for mucin hyposulphation observed in the LSGs from SS patients. The decrease in Gal3STs activity was not a consequence of reduced gene expression, but probably due to alterations in the enzyme activity regulation. Interestingly, the levels of sulphotransferase activity detected correlated well with secretory function, inflammation and serology. Finally, we postulate that pro-inflammatory cytokines induced by autoantibodies, such as Ro/SS-A and La/SS-B in SS patients, may modulate Gal3ST activity, thereby altering mucin quality and leading to mouth dryness. PMID- 22101163 TI - Isolation of Bisgaardia hudsonensis from a seal bite. PMID- 22101164 TI - Infective endocarditis caused by group B Streptococcus: the role of aminoglycoside-combination. PMID- 22101165 TI - Risk factors for Mycobacterium chelonae-abscessus pulmonary disease persistence and deterioration. PMID- 22101166 TI - Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction. AB - BACKGROUND: Human epidemiological studies suggest that small size at birth and food deprivation during gestation confer an excess risk of coronary heart diseases (CHD) in adulthood, frequently in a sex-specific manner. Prior epigenetic studies indicate that such prenatal conditions are marked by persistent and sometimes sex-specific changes in DNA methylation. Here, we have investigated the association between DNA methylation and myocardial infarction (MI) at six loci sensitive to prenatal nutrition, anticipating potential sex specificity. Method Within the placebo group of the PROSPER trial on pravastatin and the risk of CHD, we compared all individuals who were event free at baseline and developed MI during 3 years' follow-up (n = 122) with a similar-sized control group. Methylation at IL10, LEP, ABCA1, IGF2, INS and GNASAS was measured in DNA extracted from leucocytes using mass spectrometry. RESULTS: DNA methylation at GNASAS was modestly higher in MI cases compared with controls (P = 0.030). A significant sex interaction was observed for INS (P = 0.014) and GNASAS (P = 0.031). Higher DNA methylation at these loci was associated with MI among women (INS: +2.5%, P = 0.002; GNASAS: +4.2%, P = 0.001). Hypermethylation at one locus and at both loci was associated with odds ratios (ORs) of 2.8 and 8.6, respectively (P(trend) = 3.0 * 10(-4)). No association was observed among men. CONCLUSIONS: The risk of MI in women is associated with DNA methylation marks at specific loci previously shown to be sensitive to prenatal conditions. This observation may reflect a developmental component of MI. PMID- 22101167 TI - Electric current focusing efficiency in a graphene electric lens. AB - In the present work, we study theoretically the electron wave's focusing phenomenon in a single-layered graphene pn junction (PNJ) and obtain the electric current density distribution of graphene PNJ, which is in good agreement with the qualitative result in previous numerical calculations (Cheianov et al 2007 Science, 315, 1252). In addition, we find that, for a symmetric PNJ, 1/4 of total electric current radiated from the source electrode can be collected by the drain electrode. Furthermore, this ratio reduces to 3/16 in a symmetric graphene npn junction. Our results obtained by the present analytical method provide a general design rule for an electric lens based on negative refractory index systems. PMID- 22101168 TI - Glucagon-like peptide 1 receptor plays a critical role in geniposide-regulated insulin secretion in INS-1 cells. AB - AIM: To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells. METHODS: Rat INS-1 insulinoma cells were cultured. The content of insulin in the culture medium was measured with ELISA assay. GLP-1R gene in INS-1 cells was knocked down with shRNA interference. The level of GLP-1R protein in INS-1 cells was measured with Western blotting. RESULTS: Geniposide (0.01-100 MUmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner. Geniposide (10 MUmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose. Blockade of GLP-1R with the GLP-1R antagonist exendin (9-39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 MUmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L). CONCLUSION: Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells. PMID- 22101169 TI - Salvianolic acid A inhibits angiotensin II-induced proliferation of human umbilical vein endothelial cells by attenuating the production of ROS. AB - AIM: To investigate the action of salvianolic acid A (SalA) on angiotensin II (Ang II)-induced proliferation of human umbilical vein endothelial cells (HUVECs) and the possible signaling pathways mediating this action. METHODS: Cell proliferation was examined with MTT assay. The expression levels of Src phosphorylation (phospho-Src), Akt phosphorylation (phospho-Akt), and NADPH oxidase 4 (Nox4) in HUVECs were determined by Western blot. The production of reactive oxygen species (ROS) was estimated using fluorescence-activated cell sorting (FACS). RESULTS: SalA (6.25-50 MUmol/L) did not affect the viability of HUVECs. Treatment of HUVECs with Ang II (1 MUmol/L) markedly increased the cell viability; pretreatment of HUVECs with SalA (12.5, 25 and 50 MUmol/L) prevented Ang II-induced increase of the cell viability in a concentration-dependent manner. Treatment of HUVECs with Ang II (1 MUmol/L) markedly up-regulated the protein expression levels of phospho-Src, phospho-Akt (473) and Nox4; pretreatment of HUVECs with SalA (12.5, 25 and 50 MUmol/L) blocked all the effects in a concentration-dependent manner. Treatment of HUVECs with Ang II (1 MUmol/L) dramatically increased ROS production in HUVECs; pretreatment of HUVECs with SalA (12.5, 25 and 50 MUmol/L) blocked the ROS production in a concentration dependent manner. CONCLUSION: SalA inhibits Ang II-induced proliferation of HUVECs via reducing the expression levels of phospho-Src and phospho-Akt (473), thereby attenuating the production of ROS. PMID- 22101170 TI - Epigallocatechin-3-gallate inhibits proliferation and migration of human colon cancer SW620 cells in vitro. AB - AIM: Epigallocatechin-3-gallate (EGCG) is the major polyphenolic constituent in green tea. The aim of this study is to investigate the effects of EGCG on proliferation and migration of the human colon cancer SW620 cells. METHODS: Proliferation and migration of SW620 cells were induced by the protease-activated receptor 2-agonist peptide (PAR2-AP, 100 MUmol/L) or factor VIIa (10 nmol/L), and analyzed using MTT and Transwell assays, respectively. The cellular cytoskeleton was stained with rhodamine-conjugated phalloidin and examined with a laser scanning confocal fluorescence microscope. The expression of caspase-7, tissue factor (TF) and matrix metalloproteinase (MMP)-9 in the cells was examined using QT-PCR, ELISA and Western blot assays. The activation of extracellular signal regulated kinase 1 and 2 (ERK1/2) and nuclear factor-kappa B (NF-kappaB) signaling pathways was analyzed with Western blot. RESULTS: Both PAR2-AP and factor VIIa promoted SW620 cell proliferation and migration, and caused cytoskeleton reorganization (increased filopodia and pseudopodia). Pretreatment with EGCG (25, 50, 75, and 100 MUg/mL) dose-dependently blocked the cell proliferation and migration induced by PAR2-AP or factor VIIa. EGCG (100 MUg/mL) prevented the cytoskeleton changes induced by PAR2-AP or factor VIIa. EGCG (100 MUg/mL) counteracted the down-regulation of caspase-7 expression and up regulation of TF and MMP-9 expression in the cells treated with PAR2-AP or factor VIIa. Furthermore, it blocked the activation of ERK1/2 and NF-kappaB (p65/RelA) induced by PAR2-AP or factor VIIa. CONCLUSION: EGCG blocks the proliferation and migration of SW620 cells induced by PAR2-AP and factor VIIa via inhibition of the ERK1/2 and NF-kappaB pathways. The compound may serve as a preventive and therapeutic agent for colon cancers. PMID- 22101171 TI - Propofol increases the Ca2+ sensitivity of BKCa in the cerebral arterial smooth muscle cells of mice. AB - AIM: Propofol has the side effect of hypotension especially in the elderly and patients with hypertension. Previous studies suggest propofol-caused hypotension results from activation of large conductance Ca(2+)-sensitive K channels (BKCa). In this study, the effects of propofol on the Ca(2+) sensitivity of BKCa were investigated in mice cerebral arterial smooth muscle cells. METHODS: Single smooth muscle cells were prepared from the cerebral arteries of mice. Perforated whole-cell recoding was conducted to investigate the whole-cell BKCa current and spontaneous transient outward K(+) current (STOC). Inside-out patch configuration was used to record the single channel current and to study the Ca(2+)- and voltage-dependence of BKCa. RESULTS: Propofol (56 and 112 MUmol/L) increased the macroscopic BKCa and STOC currents in a concentration-dependent manner. It markedly increased the total open probability (NPo) of single BKCa channel with an EC(50) value of 76 MUmol/L. Furthermore, propofol significantly decreased the equilibrium dissociation constant (K(d)) of Ca(2+) for BKCa channel. The K(d) value of Ca(2+) was 0.881 MUmol/L in control, and decreased to 0.694, 0.599 and 0.177 MUmol/L, respectively, in the presence of propofol 28, 56 and 112 MUmol/L. An analysis of the channel kinetics revealed that propofol (112 MUmol/L) significantly increased the open dwell time and decreased the closed dwell time, which stabilized BKCa channel in the open state. CONCLUSION: Propofol increases the Ca(2+) sensitivity of BKCa channels, thus lowering the Ca(2+) threshold of the channel activation in arterial smooth muscle cells, which causes greater vasodilating effects. PMID- 22101172 TI - Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation. AB - We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centronuclear myopathy. There were also many fibers with deep invaginations of the plasma membrane. The presence of necklace fibers provided clue to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the myotubularin gene, MTM1 (c.867+1G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable exon skipping. The expression of normal transcripts was markedly reduced and there was reduced expression of myotubularin protein. Although the expression of the allele without the mutation was reduced we did not obtain evidence of skewed X-chromosome inactivation. Other factors than skewed X inactivation may cause allele inactivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations. PMID- 22101173 TI - The chemotherapy agent oxaliplatin impairs the renewal of fear to an extinguished conditioned stimulus in rats. AB - Recent evidence has shown that diverse chemotherapy agents can induce cognitive impairments and neurotoxic damage to the central nervous system. Oxaliplatin (OXP), a platinum compound, has been linked with acute and chronic peripheral neuropathies. This study explored the cognitive impacts of OXP in the rat with a fear conditioning procedure. 10 days prior to conditioning and testing, rats received an intraperitoneal injection of OXP (12 mg/kg). On the first day of conditioning, the rats were conditioned to two CSs (CS-ren and CS-ext) in one set of chambers (context A). They then received three tests on separate days. First, the rats were assessed for contextual fear conditioning in context A. Next, the CSs were presented 20 times in a new context (B) until fear conditioning had extinguished. Finally, one of the CSs (CS-ext) was tested again in the extinction context (B), and the other (CS-ren) presented in a new context (C). Results showed that OXP had no effect on the ability of rats to express fear to the conditioning context (A), or on the expression and extinction of conditioned fear to either CS when presented in a second context (B). However, the administration of OXP did impair the ability of rats to renew levels of conditioned fear to CS ren when this CS was presented in a novel context (C) following extinction. This profile of impairment is consistent with hippocampal damage, and may also involve frontal cortical, amygdalar and thalamic regions important for context discrimination and the contextual modulation of behaviour. PMID- 22101174 TI - The D2 dopamine receptor and locomotor hyperactivity following bilateral vestibular deafferentation in the rat. AB - Rats and mice with bilateral vestibular loss exhibit dramatic locomotor hyperactivity and circling behaviours, which to date cannot be explained. Dysfunction of the striatal dopaminergic system is responsible for a number of known movement disorders and the D(2) dopamine receptor is known to be implicated. Therefore, it is possible that changes in striatal function are responsible for locomotor hyperactivity and circling following bilateral vestibular lesions. The aim of this study was to investigate the effects of the D(2) receptor antagonist, eticlopride (0.02, 0.04 and 0.06mg/kg; s.c.), on locomotor behaviour in rats at 5 months following bilateral vestibular deafferentation (BVD), using an open field maze. The levels of the D(2) receptor protein in the striatum were measured at 1 and 6 months post-BVD using western blotting. BVD rats exhibited locomotor hyperactivity and circling, which eticlopride did not eliminate. However, BVD rats did exhibit a decreased response to the inhibitory effect of eticlopride compared to sham controls at the 0.02 mg/kg dose. There were no changes in the amount of the D(2) receptor in the striatum at 1 or 6 months post-BVD; however, D(2) receptor levels were significantly higher on the right side than the left in both sham and BVD animals. These results suggest that locomotor hyperactivity and circling behaviours following BVD are not due simply to changes in D(2) receptor protein expression in the striatum and that other neurophysiological changes in the brain account for these behaviours following BVD. PMID- 22101175 TI - Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice: a strong model of autism. AB - BTBR T+tf/J (BTBR) mice show abnormal social, communicatory, and repetitive/stereotyped behaviors paralleling many of the symptoms of autism spectrum disorders. BTBR also show agenesis of the corpus callosum (CC) suggesting major perturbations of growth or guidance factors in the dorsal forebrain [1]. Heparan sulfate (HS) is a polysaccaride found in the brain and other animal tissues. It binds to a wide variety of ligands and through these ligands modulates a number of biological processes, including cell proliferation and differentiation, migration and guidance. It is aggregated on fractal-like structures (fractones) in the subventricular zone (SVZ), that may be visualized by laminin immunoreactivity (LAM-ir), as well as by HS immunoreactivity (HS-ir). We report that the lateral ventricles of BTBR mice were drastically reduced in area compared to C57BL/6J (B6) mice while the BTBR SVZ was significantly shorter than that of B6. In addition to much smaller fractones for BTBR, both HS and LAM ir associated with fractones were significantly reduced in BTBR, and their anterior-posterior distributions were also altered. Finally, the ratio of HS to LAM in individual fractones was significantly higher in BTBR than in B6 mice. These data, in agreement with other findings linking HS to callosal development, suggest that variations in the quantity and distribution of HS in the SVZ of the lateral ventricles may be important modulators of the brain structural abnormalities of BTBR mice, and, potentially, contribute to the behavioral pathologies of these animals. PMID- 22101176 TI - Inherited bleeding disorders in pregnancy. AB - Women with inherited bleeding disorders may face several haemostatic challenges during pregnancy and childbirth. Pregnancy in these women requires specialised and individualised care. Prenatal diagnosis is primarily considered in families affected by severe bleeding disorder such as haemophilia. Non-invasive fetal sex determination by analysis of free fetal DNA in maternal blood offers carriers of haemophilia a means of avoiding invasive testing and its associated risks in female pregnancies. With the exception of fibrinogen and factor XIII deficiencies, it is currently unclear whether women with inherited bleeding disorders are at increased risk of miscarriage or antepartum haemorrhage. However, they are at increased risk of primary and secondary postpartum haemorrhage. The fetus, if severely affected, is at risk of cranial bleeding during labour and delivery. Appropriate haemostatic cover during labour and delivery, avoidance of prolonged labour and traumatic delivery, and active management of third stage of labour can minimise the risk of bleeding complications for the mother and her fetus. PMID- 22101177 TI - Massive obstetric haemorrhage with disseminated intravascular coagulopathy. AB - Massive obstetric haemorrhage is a major contributor towards maternal morbidity and mortality. The main causes are abruptio placentae, placenta praevia and postpartum haemorrhage. Clinicians managing pregnant women should be equipped with the knowledge and skills for managing massive obstetric haemorrhage to institute timely and appropriate life-saving treatment. Prompt resuscitation and reversal of coagulopathy are critical while definitive measures are carried out to arrest the bleeding. Massive antepartum haemorrhage necessitates deliveries whereas interventions for postpartum haemorrhage range from medical to surgical measures. Algorithms such as haemostasis are useful aids to the systematic and stepwise management of postpartum haemorrhage. Surgical measures used to avoid peripartum haemorrhage include uterine compression sutures, uterine balloon tamponade, uterine artery, and internal iliac artery ligation. Tranexamic acid and recombinant factor VII are more recent medical interventions in massive postpartum haemorrhage. Education, regular drills and adherence to guidelines and protocols are important to reduce haemorrhage-related maternal deaths. PMID- 22101178 TI - Progesterone at encoding predicts subsequent emotional memory. AB - Significant sex differences in the well-documented relationship between stress hormones and memory have emerged in recent studies. The potentiating effects of glucocorticoids on memory vary across the menstrual cycle, suggesting a potential interaction between these stress hormones and endogenously cycling sex hormones. Here, we show that memory for emotional materials changes significantly in accordance with hormonal changes across the menstrual cycle, suggesting that ovarian sex hormones influence the modulation of emotional memories. Sixty healthy, naturally cycling women rated 120 images on arousal and valence. One week later they completed free recall and recognition memory tests. Their menstrual cycle phases were estimated by self-report and confirmed by salivary assay of 17beta-estradiol and progesterone. Memory for emotional items only was significantly better in the high hormone (luteal) phase compared with the low hormone (follicular) phase on the free recall test; on both tests memory correlated positively with progesterone collected at the time of encoding. These findings suggest that emotional memory performance changes across the menstrual cycle, and that this change is in part mediated by endogenous progesterone cycling. PMID- 22101179 TI - Bidirectional plasticity in striatonigral synapses: a switch to balance direct and indirect basal ganglia pathways. AB - There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1) receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence detector switching ports: When inactive, NMDA receptors lead to a dopamine dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support. PMID- 22101180 TI - Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine. AB - The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 uM NMDA for 3 min and 50 uM DHPG for 5 min, respectively. We found that Ts65Dn mice display exaggerated NMDA-induced, but not mGluR-induced, LTD in the CA1 region of the hippocampus compared with euploid control animals. In addition, this abnormal level of LTD can be pharmacologically rescued by the NMDA receptor antagonist memantine. PMID- 22101181 TI - Synthesis and in vitro anti-tumor activity of novel HPMA copolymer-drug conjugates with potential cell surface targeting property for carcinoma cells. AB - In several groups of malignant tumors including head and neck tumors, a protein named Hsp47/CBP2 leaked from the cell was expressed on the tumor cell surface. Several synthetic peptides have been identified as effective ligands for binding to Hsp47/CBP2. This study has focused on the synthesis and in vitro characterization of a targeting delivery system of 5-fluorouracil (5-FU) to human head and neck squamous cell carcinoma (HNSCC) in order to improve anti-cancer efficacy and reduce dose-limiting toxicity of 5-FU. An N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, with Hsp47/CBP2 binding peptide sequence (namely WHYPWFQNWAMA) as a targeting ligand, was synthesized by a novel and simplified synthetic route. Under the controlled synthetic conditions, 1,3-dimethylol-5-FU, derived from 5-FU, was attached to the HPMA copolymer backbone via the lysosomally degradable GFLG linker, while the WHYPWFQNWAMA was conjugated via a non-degradable Gly-Gly (GG) linker. A control polymer without targeting moiety was also synthesized (P-FU). The in vitro cytotoxicity, internalization and apoptosis assays of the polymeric conjugates were evaluated. The characteristic apoptotic morphological changes were also assessed. Compared to 5-FU and P-FU, the HPMA copolymer containing the Hsp47/CBP2 binding peptide (P-FU-peptide) exhibited the highest cytotoxic efficacy to cell line of human head and neck squamous cell carcinoma (p<0.05) and was internalized much faster than P-FU, especially after being incubated for 30 min. Both of the morphology and apoptosis analyses demonstrated that the treatment of P-FU-peptide resulted in more apoptotic and necrotic induction of tumor cells than P-FU. Meanwhile, the rate of apoptosis induced by P-FU-peptide was higher than that of necrosis. In summary, the HPMA copolymer-Hsp47/CBP2 binding peptide conjugates showed a promising future for the treatment of HNSCC with improved efficacy. PMID- 22101183 TI - Non-chemotactic influence of CXCL7 on human phagocytes. Modulation of antimicrobial activity against L. pneumophila. AB - We have investigated the role of CXCL7 in the immune response of human phagocytes against the intracellular bacteria Mycobacterium tuberculosis and Legionella pneumophila. We have observed that polymorphonuclear neutrophil (PMN) chemotaxis induced by the supernatants of infected monocyte derived macrophages (MDM) may be attributed to CXCL8 rather than CXCL7, although both chemokines are present in large quantities. We have also found that CXCL7 is present not only in the supernatants of MDM, but also in the supernatants of PMN of some, but not all, individuals. Western blot analysis revealed that, in both MDM and PMN supernatants appeared two bands with molecular weights consistent with the platelet basic protein (PBP) and the neutrophil activating protein-2 (NAP-2) sizes. Regarding the influence on infected cells, recombinant NAP-2 enhanced the antimicrobial activity of IFNgamma activated MDM against L. pneumophila, but not against M. tuberculosis. In addition, U937 cells transfected with a NAP-2 construct inhibited the intracellular multiplication of L. pneumophila, supporting its role in the modulation of the antimicrobial activity. Finally, U937 cells transfected with the NAP-2 construct showed an adherence that was dramatically enhanced when the substrate was fibronectin. We conclude that human phagocytes produce CXCL7 variants that may have a significant influence on the immune response against bacterial pathogens. PMID- 22101184 TI - Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients. AB - Toll-like receptor 2 (TLR2) is a type I pattern recognition receptor that has been shown to participate in intestinal homeostasis. Its increased expression in the lamina propria has been associated with the pathogenesis in inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). Recently, soluble TLR2 (sTLR2) variants have been shown to counteract inflammatory responses driven by the cognate receptor. Despite the evident roles of TLR2 in intestinal immunity, no study has elucidated the production and cellular source of sTLR2 in IBD. Furthermore, an increase in the population of activated macrophages expressing TLR2 that infiltrates the intestine in IBD has been reported. We aimed first to assess the production of the sTLR2 by UC and CD organ culture biopsies and lamina propria mononuclear cells (LPMCs) as well as the levels of sTLR2 in serum, and then characterize the cell population from lamina propria producing the soluble protein. Mucosa explants, LPMCs and serum were obtained from UC, CD patients and control subjects. The level of sTLR2 was higher in conditioned media from organ culture biopsies and LPMCs from UC patients in comparison to CD and controls. Moreover, an inverse correlation between the content of intestinal and serum sTLR2 levels was observed in UC patients. Additionally, when characterizing the cellular source of the increased sTLR2 by LPMCs from UC patients, an increase in TLR2(+)/CD33(+) cell population was found. Also, these cells expressed CX3CR1, which was related to the increased levels of intestinal FKN in UC patients, suggesting that a higher proportion of TLR2(+) mononuclear cells infiltrate the lamina propria. The increased production of sTLR2 suggests that a differential regulating factor of the innate immune system is present in the intestinal mucosa of UC patients. PMID- 22101185 TI - Multifractal feature descriptor for histopathology. AB - BACKGROUND: Histologic image analysis plays an important role in cancer diagnosis. It describes the structure of the body tissues and abnormal structure gives the suspicion of the cancer or some other diseases. Observing the structural changes of these chaotic textures from the human eye is challenging process. However, the challenge can be defeat by forming mathematical descriptor to represent the histologic texture and classify the structural changes via a sophisticated computational method. OBJECTIVE: In this paper, we propose a texture descriptor to observe the histologic texture into highly discriminative feature space. METHOD: Fractal dimension describes the self-similar structures in different and more accurate manner than topological dimension. Further, the fractal phenomenon has been extended to natural structures (images) as multifractal dimension. We exploited the multifractal analysis to represent the histologic texture, which derive more discriminative feature space for classification. RESULTS: We utilized a set of histologic images (belongs to liver and prostate specimens) to assess the discriminative power of the multifractal features. The experiment was organized to classify the given histologic texture as cancer and non-cancer. The results show the discrimination capability of multifractal features by achieving approximately 95% of correct classification rate. CONCLUSION: Multifractal features are more effective to describe the histologic texture. The proposed feature descriptor showed high classification rate for both liver and prostate data sample datasets. PMID- 22101186 TI - The ABCs of clinical biochemistry. PMID- 22101187 TI - The distribution of GC nucleotides and regulatory sequence motifs in genes and their adjacent sequences. AB - The genomes of warm-blooded vertebrates are a mosaic of alternating fragments, isochores, with low and high GC contents and embedded genes. The evolutionary mechanisms leading to such structures are not fully understood. We have compared the distributions of GC base pairs in coding sequences and sequences spanning 5 kb upstream and downstream of genes in human and other species annotated in the RefSeq database and in different isochores of the human genome. Using our computer application NucleoSeq (available at www.bioinformatics.aei.polsl.pl), we also compared the average distributions of AT-rich regulatory motifs and transcription factor binding sites (TFBS) for single transcription factors with those in randomized sequences of the human genome, and revealed that some TFBS have a lower average frequency in a gene's promoter than in the randomized sequence, whereas for other transcription factors the opposite is observed. TFBS for some transcription factors show a higher frequency in the coding sequence than in the regulatory and in randomized sequences, suggesting their accumulation during evolution and possible functional roles. On the basis of the GC content in genes and their adjacent sequences which was similar in all species studied here, and the distribution of regulatory motifs, we hypothesize that the first step in evolution of many genes existing today was the joining of a GC-rich coding sequence to a region with a lower GC content and the potential to create regulatory motifs. PMID- 22101188 TI - Over-expression of PKGIalpha inhibits hypoxia-induced proliferation, Akt activation, and phenotype modulation of human PASMCs: the role of phenotype modulation of PASMCs in pulmonary vascular remodeling. AB - The proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a role in pulmonary vascular remodeling (PVR). Recently, it was shown that vascular smooth muscular cell phenotype modulation is important for their proliferation in other diseases. However, little is known about the role of human PASMC phenotype modulation in the proliferation induced by hypoxia and its molecular mechanism during PVR. In this study, we found using primary cultured human PASMCs that hypoxia suppressed the expression of endogenous PKGIalpha, which was reversed by transfection with a recombinant adenovirus containing the full-length cDNA of PKGIalpha (Ad-PKGIalpha). Ad-PKGIalpha transfection significantly attenuated the hypoxia-induced downregulation of the expression of smooth muscle alpha-actin (SM alpha-actin), myosin heavy chain (MHC) and calponin in PASMCs, indicating that hypoxia-induced phenotype modulation was blocked. Furthermore, flow cytometry and (3)H-TdR incorporation demonstrated that hypoxia-induced PASMC proliferation was suppressed by upregulation of PKGIalpha. These results suggest that enhanced PKGIalpha expression inhibited hypoxia-induced PASMC phenotype modulation and that it could reverse the proliferation of PASMCs significantly. Moreover, our previous work has demonstrated that Akt protein is activated in the process of hypoxia-induced proliferation of human PASMCs. Interestingly, we found that Akt was not activated by hypoxia when PASMC phenotype modulation was blocked by Ad PKGIalpha. This result suggests that blocking phenotype modulation might be a key up-stream regulatory target. PMID- 22101189 TI - The cathelicidin-like peptide derived from panda genome is a potential antimicrobial peptide. AB - A novel cathelicidin-like antimicrobial peptide was identified by mining genome of panda. This peptide (cathelicidin-AM) was synthesized. It showed potential antimicrobial activities against wide spectrum of microorganisms including Gram negative and -positive bacteria, and fungi. It had similar antimicrobial abilities against both standard and clinically isolated drug-resistant strains. Cathelicidin-AM could rapidly exert its antibacterial activities. It just took less than 1h to kill all Staphylococcus sciuri at the concentration of 2, 4 or 10 times of minimal inhibitory concentration (MIC) while clindamycin took 6h. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analysis indicated that cathelicidin-AM killed bacteria by directly affecting bacterial cell wall and membrane. Phylogenetic analysis revealed that the panda cathelicidin had the nearest evolution relationship with dog cathelicidin. The current work provides a novel cathelicidin-like peptide with strong antimicrobial abilities. PMID- 22101190 TI - A molecular [Mn14] coordination cluster featuring two slowly relaxing nanomagnets. AB - An extended polypyrazolyl ligand has been used to assemble Mn ions into high spin entities, in the form of one stable molecule composed of two well defined clusters. The slow relaxation of the magnetisation observed is demonstrated to arise from each "half-SMM" composing this molecular cluster pair. PMID- 22101192 TI - Using control genes to correct for unwanted variation in microarray data. AB - Microarray expression studies suffer from the problem of batch effects and other unwanted variation. Many methods have been proposed to adjust microarray data to mitigate the problems of unwanted variation. Several of these methods rely on factor analysis to infer the unwanted variation from the data. A central problem with this approach is the difficulty in discerning the unwanted variation from the biological variation that is of interest to the researcher. We present a new method, intended for use in differential expression studies, that attempts to overcome this problem by restricting the factor analysis to negative control genes. Negative control genes are genes known a priori not to be differentially expressed with respect to the biological factor of interest. Variation in the expression levels of these genes can therefore be assumed to be unwanted variation. We name this method "Remove Unwanted Variation, 2-step" (RUV-2). We discuss various techniques for assessing the performance of an adjustment method and compare the performance of RUV-2 with that of other commonly used adjustment methods such as Combat and Surrogate Variable Analysis (SVA). We present several example studies, each concerning genes differentially expressed with respect to gender in the brain and find that RUV-2 performs as well or better than other methods. Finally, we discuss the possibility of adapting RUV-2 for use in studies not concerned with differential expression and conclude that there may be promise but substantial challenges remain. PMID- 22101191 TI - Nanoparticle-based monitoring of cell therapy. AB - Exogenous cell therapy aims to replace/repair diseased or dysfunctional cells and promises to revolutionize medicine by restoring tissue and organ function. To develop effective cell therapy, the location, distribution and long-term persistence of transplanted cells must be evaluated. Nanoparticle (NP) based imaging technologies have the potential to track transplanted cells non invasively. Here we summarize the most recent advances in NP-based cell tracking with emphasis on (1) the design criteria for cell tracking NPs, (2) protocols for cell labeling, (3) a comparison of available imaging modalities and their corresponding contrast agents, (4) a summary of preclinical studies on NP-based cell tracking and finally (5) perspectives and future directions. PMID- 22101193 TI - In situ prolyl oligopeptidase activity assay in neural cell cultures. AB - Prolyl oligopeptidase (PREP, E.C.3.4.21.26) is a cytosolic serine protease that hydrolyzes small (<3 kDa), proline-containing peptides on the carboxyl terminal side of proline residues, and is widely distributed in the brain. High PREP activity, due to aging or neurodegenerative disease, has been hypothesised to lead to an increased breakdown of neuropeptides, resulting in a decline of cognitive functions and an acceleration of neurodegeneration. Recent data have suggested that PREP involvement in neurodegeneration cannot be explained by its extracellular space proteolytic activity alone, but may involve intracellular PREP activities as well. In order to test this, appropriate methods for measuring PREP intracellular activity must first be developed. In the present study, we developed and validated an in situ PREP intracellular activity assay in primary rat cortical neurons, using nitroblue tetrazolium chloride salt (NBT) and a PREP specific substrate (S)-benzyl 2-(2-(4-hydroxynaphthalen-l-ylcarbanoyl)pyrrolidin l-yl)-2-oxoethylcarbamate (UAMC-00682). This novel in situ PREP activity assay was further validated in neuroblastoma SH-SY5Y cells, under conditions of PREP overexpression and inhibited PREP expression. Using this assay, we demonstrated that PREP inhibitors, Z-Pro-Pro-aldehyde-dimethylacetal, Boc-Asn-Phe-Pro aldehyde, and (S)-1-((S)-1-(4-phenylbutanoyl)-pyrrolidine-2-carbonyl)pyrrolidine 2-carbonitrile (KYP-2047), were able to inhibit intracellular PREP activity in primary rat cortical neurons. KYP-2047 was the most potent PREP inhibitor in all assay systems tested. The validated assay enables localization and quantification of in situ PREP activity in primary rat cortical neurons and neuroblastoma SH SY5Y cells, as well allows testing cell permeability and efficiency of novel PREP inhibitors. PMID- 22101194 TI - A method for generating high-yield enriched neuronal cultures from P19 embryonal carcinoma cells. AB - P19 embryonal carcinoma (EC) cells are an invaluable tool for approximating the mechanisms that govern neuronal differentiation but with an enormous degree of simplification and have primarily been used to model the early stages of neurogenesis. However, they are often cultured under conditions that promote unrestricted non-neuronal growth that compromises neuronal viability. In this study we report an improved method to differentiate P19 EC cells that gives rise to high yields of functionally and morphologically mature neurons while significantly reducing the over-growth of non-neuronal cells in the cultures. In this protocol, P19 EC cells are induced in Minimum Essential Medium alpha supplemented with all-trans retinoic acid (RA) and 2.5% serum, and cultured as a monolayer. After RA-induction, cells are cultured on Matrigel coated-plates using defined media comprised of Neurobasal-A medium temporally supplemented with N2 and then B-27 for the remaining culture period. By treating the culture with Cytosine beta-d-arabinofuranoside and 2'-Deoxycytidine for five days, the cultures are reliably promoted toward the neuronal differentiation vs non neuronal differentiation, this accounting for a progressive neuronal enrichment of the cultures reaching 56% after 20 days of culture. P19-derived neural progenitor cells progressively expressed neuronal markers such as NeuN, Calretinin, Calbindin and Synapsin I in close resemblance to that occurring in vivo in the central nervous system (CNS). Furthermore, RA-induced P19 EC cells progressively acquired functional neuronal traits and after approximately 3 weeks in culture revealed mature neurophysiological properties, characteristics of CNS neurons. This protocol allows for a more specific assessment of the neuronal differentiation processes in vitro. PMID- 22101195 TI - Pitfalls using tyramide signal amplification (TSA) in the mouse gastrointestinal tract: endogenous streptavidin-binding sites lead to false positive staining. AB - Highly sensitive immunohistochemical detection systems such as tyramide signal amplification (TSA) are widely used, since they allow using two primary antibodies raised in the same species. Most of them are based on the streptavidin biotin-peroxidase system and include streptavidin-coupled secondary antibodies. Using TSA in cryostat-sectioned tissues of mouse esophagus, we were puzzled by negative controls with unexpected staining mostly in the ganglionic areas. This prompted us to search for the causing agent and to include also other parts of the mouse gastrointestinal tract for comparison. Streptavidin-coupled antibodies bound to endogenous binding sites yet to be characterized, which are present throughout the mouse intestines. Staining was mainly localized around neuronal cell bodies of enteric ganglia. Thus, caution is warranted when applying streptavidin-coupled antibodies in the mouse gastrointestinal tract. The use of endogenous biotin-blocking kits combined with a prolonged post-fixation time could significantly reduce unintentional staining. PMID- 22101196 TI - Two weeks in the Spring of 1912: Captain Scott at the crossroads of tradition and modernity. PMID- 22101197 TI - Structural, elastic, vibrational and electronic properties of amorphous Al2O3 from ab initio calculations. AB - First-principles molecular dynamics calculations of the structural, elastic, vibrational and electronic properties of amorphous Al(2)O(3), in a system consisting of a supercell of 80 atoms, are reported. A detailed analysis of the interatomic correlations allows us to conclude that the short-range order is mainly composed of AlO(4) tetrahedra, but, in contrast with previous results, also an important number of AlO(6) octahedra and AlO(5) units are present. The vibrational density of states presents two frequency bands, related to bond bending and bond-stretching modes. It also shows other recognizable features present in similar amorphous oxides. We also present the calculation of elastic properties (bulk modulus and shear modulus). The calculated electronic structure of the material, including total and partial electronic density of states, charge distribution, electron localization function and the ionicity for each species, gives evidence of correlation between the ionicity and the coordination for each Al atom. PMID- 22101198 TI - Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis. AB - Several studies have shown that chronic GVHD (cGVHD) is more frequent in patients receiving transplants from PBSC than in those receiving BM. In the setting of PBSC-unrelated transplants, the addition of anti-T-cell globulin (ATG) has shown a significant decrease in incidence/severity of cGVHD, without an increase in relapses or infections. However, no prospective data are yet available in the sibling setting. We retrospectively analyzed the effects of intensification of standard GVHD prophylaxis (CsA+MTX) by the addition of low-dose ATG in 245 patients receiving a transplant from HLA-identical sibling. From 1996 to 2001, patients received PBSC as the preferred source (group 2), and then ATG was added before transplant (group 3) because of a high cGVHD rate. Patients receiving BM in the same time period were analyzed as a control group (group 1). The incidence of grade III-IV acute GVHD and cGVHD was not significantly different in the three groups, but extensive cGVHD was highest in group 2 (38%) compared with group 3 (21%) or group 1 (28%; P=0.03). OS, TRM and time to relapse/progression were similar in the three groups. Our analysis shows that adding ATG to PBSC sibling allogeneic transplants can lower cGVHD, without an increase of relapse. Further prospective studies are needed to confirm these findings. PMID- 22101199 TI - Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians. AB - The Pretransplantation Assessment of Mortality (PAM) score is a risk score for mortality after allogeneic hematopoietic SCT (HSCT). Ethnicity is a genetically determined factor that correlated with immune-mediated outcomes of allogeneic HSCT. We evaluated the predictive value of the PAM score for transplant outcome in 276 Japanese populations in which transplant-related complications occur less frequently than Caucasians. The PAM score effectively risk-stratified these patients for survival; overall survival (OS) at 2 years was 100%, 80.2%, 49.4%, and 13.9% in the categories 1, 2, 3, and 4, respectively, showing a clear distinction of OS by categories (P<0.001). In addition, the PAM score is useful for the prediction of transplant outcomes both in patients with standard-risk underlying diseases and those with high-risk diseases. The PAM score developed in Caucasian populations is thus useful in non-Caucasian populations. PMID- 22101200 TI - A different rescuer changing strategy between 30:2 cardiopulmonary resuscitation and hands-only cardiopulmonary resuscitation that considers rescuer factors: a randomised cross-over simulation study with a time-dependent analysis. AB - AIM: To compare the time-dependent changes in the quality of chest compressions in 30:2 cardiopulmonary resuscitation (CPR) and hands-only cardiopulmonary resuscitation (HO-CPR) and to evaluate how individual rescuer factors affect the quality of chest compressions over time for both CPR techniques. METHODS: Total 1028 adult hospital and university workers participated in CPR training programs including sessions of 30:2 CPR and HO-CPR. Tests of both CPR methods were performed in a random order using a manikin with Skill-ReporterTM. Data were collected from 863 subjects. The time-dependent changes in chest compressions quality and the effects of individual rescuer factors (age, gender, body mass index (BMI), prior CPR training and experience) were analysed using the general linear model for a repeated-measures procedure. RESULTS: In HO-CPR, the mean proportion of correct compressions depth (MPCD) decreased significantly throughout the time sectors following 20-40s (74.4-50.4% in 100-120 s) compared to 30:2 CPR (83.4-76.3% in 100-120 s) (p<0.0001). A significant decline of MPCD (MPCD<70%) was initially observed at 40-60s in HO-CPR, however, this pattern was not observed in 30:2 CPR. Individual rescuer factors minimally affected the time dependent change in MPCD during 30:2 CPR. For HO-CPR, all rescuer factors except for male or obese/overweight (BMI>=25) were associated with a significant declines of MPCD, and these decline were usually observed from 40 to 60s. CONCLUSION: Switching rescuers at an interval of 2-min is reasonable for 30:2 CPR. However, for HO-CPR switching rescuers every 1-min may be preferable except when rescuers are male or obese/overweight (BMI>=25). PMID- 22101201 TI - Protective effects of therapeutic hypothermia in post-resuscitation myocardium. AB - AIM OF THE STUDY: Post-resuscitation therapeutic hypothermia has been recommended because of its neuroprotective effects. However, a few studies have reported the effects of therapeutic hypothermia on the heart, especially in ventricular fibrillation cardiac arrest. The aim of this study was to determine whether therapeutic hypothermia attenuates post-resuscitation myocardial injury in a swine cardiac arrest model. METHODS: A prospective animal study was performed in the university hospital animal research laboratory. Ventricular fibrillation cardiac arrest was induced in domestic pigs weighing 35-40 kg. After 6 min of no flow time, cardiopulmonary resuscitation was provided to pigs, and the restoration of spontaneous circulation (ROSC) was achieved. The subjects were randomly allocated to a normothermic (NT group, n=5) or hypothermic (HT group, n=5) group. In the HT group, therapeutic hypothermia (core temperature 32-34 degrees C) was maintained for 24h, and rewarming was performed over a period of 8 h. In the NT group, core temperature was maintained at 37 degrees C throughout the experiments. Sixty hours after ROSC, blood and myocardial tissues were harvested. RESULTS: Serum troponin I was not significantly different between the groups. However, myocardial histological damage was attenuated in the HT group. Myocardial ATP contents were higher in the HT group than in the NT group. Immunohistochemistry for apoptosis-related protein showed that survivin expression was higher in the HT group, and XAF1 and cleaved caspase-3 expressions were lower in the HT group than in the NT group. CONCLUSIONS: Therapeutic hypothermia attenuated histological myocardial injury in ventricular fibrillation cardiac arrest model of pigs while preserving more ATP and decreased apoptosis. PMID- 22101202 TI - Out-of-hospital airway management and cardiac arrest outcomes: a propensity score matched analysis. AB - OBJECTIVE: It is unclear whether advanced airway management during ambulance transport is associated with improved out-of-hospital cardiac arrest (OHCA) outcomes compared with bag-valve mask ventilation (BVM). This study aimed to determine whether EMT-intermediate ETI or LMA is associated with improved OHCA outcomes in Korea. METHODS: We used a Korean national OHCA cohort database composed of hospital and ambulance data. We included all EMS-treated by level 1 EMTs (EMT-intermediate level) and OHCA with presumed cardiac etiology for the period January 2006-December 2008. We excluded cases not receiving continued resuscitation in the emergency department (ED), treated by level 2 EMT, as well as those without available hospital outcome data. The primary exposure was airway management technique during ambulance transport (endotracheal tube (ETI), laryngeal mask airway (LMA) or bag-valve-mask ventilation with an oropharyngeal airway). The primary outcomes were survival to admission and survival to hospital discharge. We compared outcomes between each airway management group using multivariable logistic regression, adjusting for sex, age, witnessed, prehospital defibrillation, bystander cardiopulmonary resuscitation (CPR), call to ambulance arrival time to the scene, call to ambulance arrival time to ED, initial ECG, metropolitan (defined as population>1 million), and level of ED (higher versus lower level). We repeated the analysis using propensity-score matched subsets. RESULTS: Of 54,496 patients with OHCA, we included 5278 (9.7%). Overall survival to admission and to discharge was 20.2% and 6.9%, respectively. ETI and LMA were performed in 250 (4.7%) and 391 (7.4%), respectively. In the full multivariable models using total patients, adjusted survival to admission and discharge were similar for ETI and BVM: OR 0.91 (0.66-1.27) and 1.00 (0.60-1.66), respectively. Adjusted survival to admission and discharge were significantly lower in LMA than BVM: OR 0.72 (0.54-0.95) and 0.52 (0.32-0.85), respectively. In the full multivariable models using propensity matched samples, adjusted survival to admission and discharge were similar for ETI and BVM; OR 1.32 (0.81-2.16) and 1.44 (0.66-3.15), respectively. Adjusted survival to admission was similar for LMA and BVM: OR 0.72 (0.50-1.02). However, survival to discharge was significantly lower for LMA than BVM: OR 0.45 (0.25-0.82). CONCLUSIONS: In Korea, EMT-I placed LMA during ambulance transport was associated with worsened OHCA survival to discharge than BVM. Outcomes were similar between EMT-I endotracheal intubation and bag-valve-mask ventilation. PMID- 22101203 TI - Airway manoeuvres to achieve upper airway patency during mask ventilation in newborn infants - An historical perspective. AB - Maintenance of upper airway patency remains a cornerstone of adequate airway management. Although various opening manoeuvres are recommended by neonatal resuscitation guidelines, none of these have been well evaluated in newly born infants. The aim of this article was to review the available literature about airway opening manoeuvres in newborn infants. We reviewed books, resuscitation manuals and articles from 1860 to the present with the search terms "Infant, Newborn", "airway management", "airway manoeuvres", "chin lift", "jaw thrust", "neutral position", "shoulder roll", "neonatal resuscitation", "positive pressure respiration" and "continuous positive airway pressure". Only human studies were included. During mask PPV, jaw thrust appears to be more effective in achieving a patent upper airway and might help to reduce airway obstruction. The additional application of chin lift might reduce leak during mask ventilation. However given the lack of available data these conclusions remains speculative and further research in this area is required. PMID- 22101204 TI - Evidence for filamentous actin in ookinetes of a malarial parasite. AB - Extracellular stages of apicomplexan parasites utilize their own actin myosin motor machinery for gliding locomotion, penetration of cell barriers, and host cell invasion. Thus far, filamentous actin could not be visualized by standard microscopic techniques in vivo. Here, we describe the generation of a novel peptide antibody against the divergent amino-terminal portion of the major Plasmodium isoform, actin I. We show that our antiserum, termed Ab-actinI-I, is conformation-specific. In motile ookinetes it recognizes actin in rod-like structures, which are sensitive to inhibitors interfering with actin polymerization. The average size of the rods is 600 nm, which is considerably longer than what has been detected in in vitro studies of actin filaments. PMID- 22101205 TI - Cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment resistant depression in primary care: the CoBalT randomised controlled trial protocol. AB - BACKGROUND: Antidepressants are often the first-line treatment for depression but only one third of patients respond fully to pharmacotherapy. This paper describes the protocol for a randomised controlled trial (RCT) designed to evaluate the clinical and cost effectiveness of cognitive behavioural therapy (CBT) as an adjunct to pharmacotherapy for patients with treatment resistant depression in primary care. METHODS/DESIGN: CoBalT is a two parallel group multi-centre pragmatic RCT. Eligible participants were those who: (i) were aged 18-75years; (ii) were currently taking antidepressant medication (for at least 6weeks at an adequate dose); (iii) scored >=14 on the Beck Depression Inventory (BDI-II); (iv) had adhered to their medication; and (v) met ICD-10 criteria for depression (assessed using the Clinical Interview Schedule - revised version). Those who gave written informed consent were randomised to one of two treatment groups: usual care or usual care plus CBT. The primary outcome is depressive symptoms assessed using the BDI-II at 6months post-randomisation. Secondary outcomes measured at 6 and 12months include quality of life, antidepressant use and health care utilisation. Outcomes will be analysed on an intention-to-treat basis. DISCUSSION: The CoBalT trial will provide evidence on the clinical and cost effectiveness of CBT as an adjunct to antidepressant medication in the treatment of depression that has not responded to pharmacotherapy. Given the move to widen access to 'talking therapies', the results of this study will be timely. PMID- 22101206 TI - An exercise trial for wheelchair users: project workout on wheels. AB - There is growing interest in promoting health for people with disabilities, yet evidence regarding community-based interventions is sparse. This paper describes the design details of a randomized controlled trial (RCT) that will test the effectiveness of a multi-component behaviorally based, intervention to promote exercise adoption (over 6 months) and maintenance (up to one year) among wheelchair users and includes descriptive data on participant characteristics at baseline. Participants were randomly assigned to either a staff-supported intervention group or a self-guided comparison group. The primary study aim is to assess the effectiveness of the multi-component behaviorally based intervention for promoting physical activity adoption and maintenance. The RCT will also assess the physical and psychosocial effects of the intervention and the complex interplay of factors that influence the effectiveness of the intervention. Therefore, the primary outcome derives from participant reports of weekly exercise (type, frequency, duration) over 52 weeks. Secondary outcomes collected on four occasions (baseline, 3 months, 6 months, 12 months) included physiological outcomes (VO(2) peak, strength), disability-related outcomes (pain, fatigue, participation), and psychosocial outcomes (exercise self-efficacy, exercise barriers, quality of life, depression, mood). This study will provide evidence regarding the effectiveness of a multi-component behaviorally based intervention for promoting exercise adoption among people with mobility impairments that necessitate wheelchair use. PMID- 22101207 TI - Recruiting adolescent girls into a follow-up study: benefits of using a social networking website. AB - BACKGROUND: Recruitment and retention of adolescent research participants presents unique challenges and considerations when conducting epidemiological studies. PURPOSE: To describe the use of the social networking website in the re recruitment and tracking of adolescent girls into a follow-up study of the Trial of Activity for Adolescent Girls (TAAG) at the University of Maryland field site. METHODS: 730 girls were recruited as 8th graders into TAAG. Re-recruitment efforts were conducted when they were 11th graders (TAAG 2). Traditional methods, including mailings and school visits, were conducted. A TAAG 2 Facebook site was created to search for girls not found through traditional recruitment methods. Chi-square and t-tests were conducted to identify differences in characteristics between those found and "friended" through Facebook and through traditional recruitment methods. RESULTS: There were 175 girls we were unable to locate using traditional recruitment methods. Of these, 78 were found on Facebook, 68 responded to our friend request, and 43 girls (6% of the girls previously recruited) participated in the study. Demographic data were similar for those who friended us on Facebook and traditional methods. 8th grade body mass index and percent body fat were lower for those recruited from Facebook (p=0.03 and 0.04, respectively). Number of daily minutes of moderate-to-vigorous physical activity tended to be lower among the TAAG 2 Facebook friends (19 +/- 11 vs 21 +/- 11, p=0.06). CONCLUSIONS: Loss to follow-up was minimized by contacting potential participants through Facebook. Social networking websites are a promising method to recruit adolescents. PMID- 22101208 TI - Using the reactive scope model to understand why stress physiology predicts survival during starvation in Galapagos marine iguanas. AB - Even though the term "stress" is widely used, a precise definition is notoriously difficult. Notwithstanding this difficulty, stress continues to be an important concept in biology because it attempts to describe how animals cope with environmental change under emergency conditions. Without a precise definition, however, it becomes nearly impossible to make testable a priori predictions about how physiological and hormonal systems will respond to emergency conditions and what the ultimate impact on the animal will be. The reactive scope model is a recent attempt to formulate testable predictions. This model provides a physiological basis to explain why corticosterone negative feedback, but not baseline corticosterone concentrations, corticosterone responses to acute stress, or the interrenal capacity to secrete corticosterone, is correlated with survival during famine conditions in Galapagos marine iguanas. Reactive scope thus provides a foundation for interpreting and predicting physiological stress responses. PMID- 22101209 TI - Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection. AB - Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury. Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking. What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity. One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors. This article is part of a Special Issue entitled 'Neurosteroids'. PMID- 22101210 TI - The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells. AB - The steroid hormone output of the adrenal gland is crucial in the maintenance of hormonal homeostasis, with hormonal imbalances being associated with numerous clinical conditions which include, amongst others, hypertension, metabolic syndrome, cardiovascular disease, insulin resistance and type 2 diabetes. Aspalathus linearis (Rooibos), which has been reported to aid stress-related symptoms linked to metabolic diseases, contains a wide spectrum of bioactive phenolic compounds of which aspalathin is unique. In this study the inhibitory effects of Rooibos and the dihydrochalcones, aspalathin and nothofagin, were investigated on adrenal steroidogenesis. The activities of both cytochrome P450 17alpha-hydroxylase/17,20 lyase and cytochrome P450 21-hydroxylase were significantly inhibited in COS-1 cells. In order to study the effect of these compounds in H295R cells, a human adrenal carcinoma cell line, a novel UPLC-MS/MS method was developed for the detection and quantification of twenty-one steroid metabolites using a single chromatographic separation. Under both basal and forskolin-stimulated conditions, the total amount of steroids produced in H295R cells significantly decreased in the presence of Rooibos, aspalathin and nothofagin. Under stimulated conditions, Rooibos decreased the total steroid output 4-fold and resulted in a significant reduction of aldosterone and cortisol precursors. Dehydroepiandrosterone-sulfate levels were unchanged, while the levels of androstenedione (A4) and 11beta-hydroxyandrostenedione (11betaOH-A4) were inhibited 5.5 and 2.3-fold, respectively. Quantification of 11betaOH-A4 showed this metabolite to be a major product of steroidogenesis in H295R cells and we confirm, for the first time, that this steroid metabolite is the product of the hydroxylation of A4 by human cytochrome P450 11beta-hydroxylase. Taken together our results demonstrate that Rooibos, aspalathin and nothofagin influence steroid hormone biosynthesis and the flux through the mineralocorticoid, glucocorticoid and androgen pathways, thus possibly contributing to the alleviation of negative effects arising from elevated glucocorticoid levels. PMID- 22101211 TI - Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase. AB - Phenobarbital treatment has long been known to influence serum and hepatic cholesterol levels in rodents and humans. Constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, mediates various biological actions of phenobarbital. We have thus investigated whether CAR transactivates cholesterogenic genes in livers. Activation of CAR in mouse livers and cultured human hepatocytes increased mRNA levels of mouse Dhcr24 and human DHCR24, both of which encode 24-dehydrocholesterol reductase (DHCR24) catalyzing the last step of cholesterol biosynthesis. CAR transactivated the expression of these genes in reporter assays with cultured hepatoma cells. Furthermore, we have identified a DR4 (direct repeat separated by 4 nucleotides) motif in the human DHCR24 distal promoter as a binding site of CAR/retinoid X receptor alpha (RXRalpha) heterodimer. We have also demonstrated that the heterodimer of pregnane X receptor (PXR)/ RXRalpha binds to the DR4 motif and that human DHCR24 reporter gene is transactivated by the ligand-activated PXR. These results suggest a role of xenobiotic-responsive nuclear receptor CAR, and also possibly PXR, in cholesterol biosynthesis in the liver of mice and humans. PMID- 22101212 TI - Curcumin inhibits hERG potassium channels in vitro. AB - Curcumin is reported to exert antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anti-tumor activities. The human ether-a-go-go related gene (hERG) encodes the rapid component of the delayed rectifier K+ currents. Inhibition of hERG K+ channels leads to cardiac repolarization prolongation, which contributes to either the anti-arrhythmic effects of anti arrhythmic drugs, or the pro-arrhythmic effects (induction of long QT syndrome) of some drugs not used for anti-arrhythmias. Since curcumin shows multiple beneficial effects and clinical significance, the aim of the present study is to investigate the effect of curcumin on hERG K+ channels, elucidating its potential cardiac therapeutic or toxic effects. In whole-cell patch-clamp experiments, we found that curcumin inhibited hERG K+ currents in HEK293 cells stably expressing hERG channels in a dose-dependent manner, with IC50 value of 5.55 MUM. The deactivation, inactivation and the recovery time from inactivation of hERG channels were significantly changed by acute treatment of 10 MUM curcumin. Incubation of 20 MUM curcumin for 24h reduced the HEK293 cell viability. Intravenous injection of maximal amount of curcumin in rabbits (20 mg/animal) did not affect the cardiac repolarization manifested with QTc value. We conclude that curcumin inhibits hERG K+ channels in vitro. PMID- 22101213 TI - Evaluation of cytotoxic, genotoxic and inflammatory responses of micro- and nano particles of granite on human lung fibroblast cell IMR-90. AB - Occupational exposure of granite workers is well known to cause lung impairment and silicosis. Toxicological profiles of different size particles of granite dust, however, are not yet understood. Present evaluation of micro- and nano particles of granite dust as on human lung fibroblast cells IMR-90, revealed that their toxic effects were dose-dependent, and nanoparticles in general were more toxic. In this study we first demonstrated that nanoparticles caused oxidative stress, inflammatory response and genotoxicity, as seen by nearly 2 fold induction of ROS and LPO, mRNA levels of TNF-alpha and IL-1beta, and induction in micronuclei formation. All these were significantly higher when compared with the effect of micro particles. Thus, the study suggests that separate health safety standards would be required for granite particles of different sizes. PMID- 22101214 TI - Toxicity of silver nanoparticles - nanoparticle or silver ion? AB - The toxicity of silver nanoparticles (AgNPs) has been shown in many publications. Here we investigated to which degree the silver ion fraction of AgNP suspensions, contribute to the toxicity of AgNPs in A549 lung cells. Cell viability assays revealed that AgNP suspensions were more toxic when the initial silver ion fraction was higher. At 1.5MUg/ml total silver, A549 cells exposed to an AgNP suspension containing 39% silver ion fraction showed a cell viability of 92%, whereas cells exposed to an AgNP suspension containing 69% silver ion fraction had a cell viability of 54% as measured by the MTT assay. In addition, at initial silver ion fractions of 5.5% and above, AgNP-free supernatant had the same toxicity as AgNP suspensions. Flow-cytometric analyses of cell cycle and apoptosis confirmed that there is no significant difference between the treatment with AgNP suspension and AgNP supernatant. Only AgNP suspensions with silver ion fraction of 2.6% or less were significantly more toxic than their supernatant as measured by MTT assays. From our data we conclude that at high silver ion fractions (>=5.5%) the AgNPs did not add measurable additional toxicity to the AgNP suspension, whereas at low silver ion fractions (<=2.6%) AgNP suspensions are more toxic than their supernatant. PMID- 22101215 TI - Single-blind, randomized controlled trial evaluating the treatment of facial seborrheic dermatitis with hydrocortisone 1% ointment compared with tacrolimus 0.1% ointment in adults. AB - BACKGROUND: Tacrolimus is a topical calcineurin inhibitor with immunomodulatory, anti-inflammatory, and fungicidal properties that may be beneficial in the treatment of facial seborrheic dermatitis. OBJECTIVES: We sought to compare the efficacy and safety of tacrolimus with standard corticosteroid treatment in adults with facial seborrheic dermatitis in a phase II, single-blind, randomized controlled trial. METHODS: Adult patients were enrolled in a 12-week study. Subjects were randomized to tacrolimus 0.1% ointment (n = 16) or hydrocortisone 1% ointment (n = 14) applied twice daily to symptomatic regions of the face. The primary efficacy measure was the severity of facial seborrhea at the end of treatment (day 84) as measured by the Seborrhea Area and Severity Index-Face. Secondary efficacy measures included physician and patient assessment of seborrhea, the frequency of medication application, and adverse events. RESULTS: The severity of facial seborrhea was similarly improved in both treatment groups (P = .86). Tacrolimus 0.1% ointment was used on significantly fewer days than 1% hydrocortisone ointment (mean missed doses per patient at first visit: 15.6 vs 7.6, P < .05; at last visit: 13.5 vs 7.7, P = .08). The majority of doses were missed because of lack of symptoms. The adverse event profile for both agents was similar; however, there was a numerically higher incidence of adverse events in the hydrocortisone group. LIMITATIONS: This was a small, open-label study. CONCLUSION: Tacrolimus 0.1% ointment required significantly fewer applications compared with hydrocortisone 1% ointment to achieve a comparable clinical response in adults with facial seborrheic dermatitis. Tacrolimus was generally well tolerated. PMID- 22101216 TI - Erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis associated with lupus erythematosus. AB - BACKGROUND: The occurrence of erythema multiforme (EM)-like lesions in association with lupus erythematosus (LE) is often referred to as "Rowell syndrome" (RS). However, the existence of RS, or at least its nosographic independence from LE, is questioned. The association of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with LE is also controversial. OBJECTIVE: We sought to define the features of EM and SJS/TEN in the setting of LE. METHODS: The worldwide literature on the topic was systematically collected and reviewed. RESULTS: A total of 132 citations were found, from which 95 cases of EM-like lesions and 47 of SJS/TEN associated with LE were retrieved. Our analysis identified a subgroup defined as "subacute cutaneous LE (CLE)/acute CLE with EM like lesions" and highlighted that this and subacute CLE/acute CLE with TEN-like lesions are variants of already known CLE subpatterns. On the other hand, RS can be considered an independent chronic CLE subtype characterized by the distinctive co-occurrence of chronic CLE and EM-like lesions and frequent, albeit mild, systemic involvement. LIMITATIONS: The study was based on retrospective data and the number of reported cases identified was relatively small. CONCLUSION: RS might be included as a chronic CLE subtype within the spectrum of LE-specific skin disease. PMID- 22101217 TI - Rapid measurement of antituberculosis drug activity in vitro and in macrophages using bioluminescence. AB - OBJECTIVES: Tuberculosis drug development is hampered by the slow growth of Mycobacterium tuberculosis. Bioluminescence, light produced by an enzymatic reaction, constitutes a rapid and highly sensitive measurement of cell metabolic function that can be used as an indirect marker of cell viability in drug screening assays. The aim of this work was to validate and standardize the use of luminescent M. tuberculosis strains to test the activity of antibacterial drugs in vitro and inside macrophages in a 96-well format. METHODS: We have used strains that express the bacterial lux operon and therefore do not require exogenous substrate to produce light, as well as strains expressing the firefly luciferase that need luciferin substrate. Results were compared with those obtained using the resazurin reduction assay and cfu plating. RESULTS: Using bioluminescence we were able to reduce the time required to measure the MIC and bactericidal concentrations of antimicrobials to just 3 and 6 days, respectively. Furthermore, antibacterial activity against intracellular mycobacteria was detected within 2 days post-infection. Results were comparable to those obtained by conventional methods. CONCLUSIONS: We have developed a simple and rapid method for screening antimycobacterial drugs in culture and in macrophages. The use of autoluminescent bacteria also facilitates the determination of growth and inhibition kinetics. The method is cost-effective, can easily be adapted to a larger scale and is amenable to automation. Current efforts are directed towards applying this technology to drug screening in vivo. PMID- 22101218 TI - Rationale, study design and sample characteristics of a randomized controlled trial of directly administered antiretroviral therapy for HIV-infected prisoners transitioning to the community - a potential conduit to improved HIV treatment outcomes. AB - BACKGROUND: HIV-infected prisoners experience poor HIV treatment outcomes post release. Directly administered antiretroviral therapy (DAART) is a CDC designated, evidence-based adherence intervention for drug users, yet untested among released prisoners. METHODS: Sentenced HIV-infected prisoners on antiretroviral therapy (ART) and returning to New Haven or Hartford, Connecticut were recruited and randomized 2:1 to a prospective controlled trial (RCT) of 6 months of DAART versus self-administered therapy (SAT); all subjects received case management services. Subjects meeting DSM-IV criteria for opioid dependence were offered immediate medication-assisted treatment. Trained outreach workers provided DAART once-daily, seven days per week, including behavioral skills training during the last intervention month. Both study groups were assessed for 6 months after the intervention period. Assessments occurred within 90 days pre release (baseline), day of release, and then monthly for 12 months. Viral load (VL) and CD4 testing was conducted baseline and quarterly; genotypic resistance testing was conducted at baseline, 6 and 12 months. The primary outcome was pre defined as viral suppression (VL<400 copies/mL) at 6 months. RESULTS: Between 2004 and 2009, 279 participants were screened, of which 202 met eligibility criteria and 154 were ultimately enrolled in the study; 103 subjects were randomized to DAART and 51 to SAT. Subjects were mostly male (81.2%), people of color (87.0%), had an alcohol use disorder (39.7%), had underlying depression (54.2%), were virally suppressed (78.8%) and had a mean CD4=390.7 cells/mL. CONCLUSIONS: Outcomes from this RCT will contribute greatly to HIV treatment outcomes after release from prison, a period associated with adverse HIV and other medical consequences. PMID- 22101219 TI - Challenges and potential solutions to meeting accrual goals in a Phase II chemoprevention trial for prostate cancer. AB - OBJECTIVE: The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. METHODS: We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure related barriers impacting accrual and revisions to protocol implemented. RESULTS: Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety-four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. CONCLUSION: A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials. PMID- 22101220 TI - Healthy Beginnings Trial Phase 2 study: follow-up and cost-effectiveness analysis. AB - BACKGROUND: In 2007, we commenced the Healthy Beginnings Trial (HBT) Phase 1 study, which is the first randomised controlled trial (RCT) to test the effectiveness of an early childhood obesity intervention in children aged up to 2 years. The results were promising with significant improvements in infant feeding practices and a lower mean body mass index (BMI). The aims of this proposed Phase 2 study are to determine if the early intervention will lead to a lower mean BMI, lower screen time, improved dietary behaviours and demonstrated cost effectiveness of the intervention, in children aged 31/2 and 5 years. METHODS/DESIGN: In Phase 1 of HBT 667 families participated in the RCT. No further intervention will be carried out in HBT Phase 2. In this study the intervention and control groups will be compared for children's outcomes at ages 31/2 and 5 years. Primary outcome measures will be 1) BMI, 2) selected dietary measures using a validated survey tool, and 3) physical activity and screen time using a new generation of tri-axial accelerometers. Intention to treat principles will be used in the analysis. Multiple imputation will be used to impute outcomes for subjects lost to follow-up. A cost-effectiveness analysis (CEA) and cost utility analysis for both HBT Phase 1 and 2 will also be conducted. DISCUSSION: This is the first time that a home-based early intervention strategy has been implemented to prevent the development of childhood obesity and obesity-conducive behaviours. The results of this trial will ascertain whether early intervention during the first 2 years of life is effective and cost-effective in preventing childhood overweight and obesity at 31/2 and 5 years old. PMID- 22101221 TI - A phase I trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour in adults. Standard treatment comprises surgery, radiotherapy and chemotherapy; however this condition remains incurable as these tumours are highly invasive and involve critical areas of the brain making it impossible to remove them surgically or cure them with radiotherapy. In the majority of cases the tumour recurs within 2 to 3 cm of the original site of tumour resection. Furthermore, the blood-brain barrier profoundly limits the access of many systemically administered chemotherapeutics to the tumour. Convection-enhanced delivery (CED) is a promising technique of direct intracranial drug delivery involving the implantation of microcatheters into the brain. Carboplatin represents an ideal chemotherapy to administer using this technique as glioblastoma cells are highly sensitive to carboplatin in vitro at concentrations that are not toxic to normal brain in vivo. This protocol describes a single-centre phase I dose-escalation study of carboplatin administered by CED to patients with recurrent or progressive GBM despite full standard treatment. This trial will incorporate 6 cohorts of 3 patients each. Cohorts will be treated in a sequential manner with increasing doses of carboplatin, subject to dose-limiting toxicity not being observed. This protocol should facilitate the identification of the maximum tolerated infused concentration of carboplatin by CED into the supratentorial brain. This should facilitate the safe application of this technique in a phase II trial, treating patients with GBM, as well as for the treatment of other forms of malignant brain tumours, including metastases. PMID- 22101222 TI - Group recruitment sessions enhance patient understanding in a small multi-centre phase III clinical trial. AB - INTRODUCTION: There is continuing concern that patient information leaflets, tailored to current regulatory requirements, fail to meet patients' needs. Provision of comprehensible information is vital if patients are to provide valid informed consent. The design of the ARIX (acupuncture for radiation induced xerostomia) trial provided an opportunity to deliver researcher led, enhanced patient information to groups of potential participants. METHODS: Between November 2009 and September 2010, 149 patients attended a trial introduction meeting at their local site. All meetings followed the same format. The study coordinator delivered a PowerPoint presentation containing standard trial information together with customised local details. This was followed by group questions and answers. Patients could sign a consent form immediately afterwards or with local staff at a later date. Participants who completed the study were invited to feedback their views on these meetings. RESULTS: One hundred and forty nine patients attended a meeting of whom 116 ultimately participated in ARIX and provided feedback. Eighty four (72%) reported that the meeting helped their understanding of the trial 'very much'. Fourteen attendees reported feeling uncomfortable at having the information presented in a group setting but of these, only one felt under pressure to join the trial. Eighty three patients (71%) felt 'not at all' uncomfortable and 111 (95%) 'not at all' under pressure to participate. CONCLUSION: Trial introduction meetings involving researcher led presentation of information, followed by group discussion, can help enhance the information provided in the patient information leaflet in a useful and non coercive manner. PMID- 22101223 TI - A varying-coefficient method for analyzing longitudinal clinical trials data with nonignorable dropout. AB - Dropout is common in longitudinal clinical trials and when the probability of dropout depends on unobserved outcomes even after conditioning on available data, it is considered missing not at random and therefore nonignorable. To address this problem, mixture models can be used to account for the relationship between a longitudinal outcome and dropout. We propose a Natural Spline Varying coefficient mixture model (NSV), which is a straightforward extension of the parametric Conditional Linear Model (CLM). We assume that the outcome follows a varying-coefficient model conditional on a continuous dropout distribution. Natural cubic B-splines are used to allow the regression coefficients to semiparametrically depend on dropout and inference is therefore more robust. Additionally, this method is computationally stable and relatively simple to implement. We conduct simulation studies to evaluate performance and compare methodologies in settings where the longitudinal trajectories are linear and dropout time is observed for all individuals. Performance is assessed under conditions where model assumptions are both met and violated. In addition, we compare the NSV to the CLM and a standard random-effects model using an HIV/AIDS clinical trial with probable nonignorable dropout. The simulation studies suggest that the NSV is an improvement over the CLM when dropout has a nonlinear dependence on the outcome. PMID- 22101225 TI - Home-based telehealth to deliver evidence-based psychotherapy in veterans with PTSD. AB - Although medical service delivery via home-based telehealth technology (HBT) is gaining wider acceptance in managing chronic illnesses such as diabetes or chronic obstructive pulmonary disease, few studies have tested HBT applications of psychotherapy. Clinicians, administrators, and researchers question whether delivering psychotherapeutic services to patients in their homes via video conferencing technology compromises patient safety, potency of treatment, or data security. Despite these concerns, HBT service delivery may increase access to evidence-based psychotherapies for veterans with posttraumatic stress disorder (PTSD), who may be less willing or less able to receive weekly treatment at a VA medical center or outpatient clinic due to symptom severity or other similar barriers to care. Indeed, although combat-exposed service members endorse high rates of psychiatric disorders, few appear to initiate mental health services or receive an adequate dose of treatment. Thus, using HBT technologies to administer evidence-based therapies remains uncharted territory in both the clinical and research arenas. This manuscript describes an ongoing four year randomized controlled trial comparing in-person Prolonged Exposure (PE) - a specialized evidence-based psychotherapy for PTSD - and PE delivered via HBT, with a particular focus on the selection, application, and strengths/weaknesses of HBT procedures. PMID- 22101224 TI - The Exercising Together project: design and recruitment for a randomized, controlled trial to determine the benefits of partnered strength training for couples coping with prostate cancer. AB - Prostate cancer can threaten quality of life for the patient and his spouse and the quality of his marital relationship. The purpose of our study is to evaluate the effects of "Exercising Together" - a partnered strength training program for married couples coping with prostate cancer - on the physical and emotional health of prostate cancer survivors (PCS) and their spouses and on marital quality. We are conducting a 6-month randomized controlled trial with two groups: 1) Exercising Together - a progressive, supervised strength training program and 2) a usual care control condition. The primary aims of this exploratory study are to: 1) Determine the effect of partnered strength training on physical and emotional health (muscle strength, physical function, body composition and self report physical and mental health) in PCS, 2) Determine the effect of partnered strength training on physical and emotional health in spouses and 3) Explore the effect of partnered strength training on marital quality (incongruence, communication, relationship quality, intimacy) of the PCS and spouse. Target accrual has been met in this study with 64 couples enrolled and randomized to exercise (n=32) or usual care (n=32) groups. This study is the first to examine the feasibility of this exercise format in both the chronically ill patient and spouse and explore benefits at the individual and couple level. PMID- 22101227 TI - Methylene blue MMX tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers. AB - Methylene blue-MMX tablets are proposed as colonic diagnostic staining. Methylene blue taken prior to colonoscopy is expected to provide an effective staining of colonic and rectal mucosa leaving unstained the dysplastic or polypoid areas. The present single dose, open-label study investigated the safety of methylene blue after single oral doses of 200 and 400mg in healthy volunteers. The absolute bioavailability was also investigated after the intake of 2L of bowel cleansing preparation in 2h and by comparing the dose of 200mg with a single iv dose of 100mg in the same subjects. Only non-serious adverse events occurred. Related events occurred to 8/22 subjects. Most of the events were mild and transient. Abnormal transaminases, gastrointestinal disorders and dysuria frequency were 13.6%. After intake of the laxative and the oral dose of 200mg, systemic exposure to methylene blue was shown in all subjects with concentrations increasing for 12h. The peak was reached in a median of 16 h. Peak blood concentration did not increase proportionally with the dose. AUC(0-t) was 32.94 MUg/mL * h after 200mg and 38.08 MUg/mL * h after 400mg. Half life ranged between 14 and 27 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative excretion was about 40% of the injected dose, 39.67% after 200mg and 23.48% after 400mg. Absolute bioavailability of methylene blue calculated as ratio between AUC(0-t) oral/iv corrected for the dose was on average F(abs)=139.19 +/- 52.00%. PMID- 22101228 TI - The Family Health Promotion Project (FHPP): design and baseline data from a randomized trial to increase colonoscopy screening in high risk families. AB - Colorectal cancer (CRC) is a significant cause of mortality and morbidity in the United States, much of which could be prevented through adequate screening. Consensus guidelines recommend that high-risk groups initiate screening earlier with colonoscopy and more frequently than average risk persons. However, a large proportion of high risk individuals do not receive regular colonoscopic screening. The Family Health Promotion Project (FHPP) is a randomized-controlled trial to test the effectiveness of a telephone-based counseling intervention to increase adherence to risk-appropriate colonoscopy screening in high risk individuals. Unaffected members of CRC families from two national cancer family registries were enrolled (n=632) and randomized to receive either a single session telephone counseling intervention using Motivational Interviewing techniques or a minimal mail-out intervention. The primary endpoint, rate of colonoscopy screening, was assessed at 6, 12 and 24 months post-enrollment. In this paper, we describe the research design and telephone counseling intervention of the FHPP trial, and report baseline data obtained from the two high risk cohorts recruited into this trial. Results obtained at baseline confirm the need for interventions to promote colonoscopy screening among these high risk individuals, as well as highlighting several key opportunities for intervention, including increasing knowledge about risk-appropriate screening guidelines, and providing both tailored risk information and barriers counseling. PMID- 22101229 TI - Effectiveness of an informational video method to improve enrollment and retention of a pediatric cohort. AB - OBJECTIVE: The Environmental Determinants of Diabetes in the Young (TEDDY), a multinational epidemiological study, is designed to identify environmental exposures triggering autoimmunity and type 1 diabetes (T1D) in children at increased genetic risk. The objective of this analysis was to evaluate the use of an informational video in the enrollment and retention of eligible participants at the Colorado TEDDY clinical center. STUDY DESIGN AND SETTING: Eligible participants were divided into two groups based on the inclusion of the video in the enrollment materials: the No-Video Group (n=449) did not receive the video and were contacted between 7/1/07 and 6/30/08. The Video Group (n=494) received the video and were contacted between 7/1/08 and 6/30/09. Multiple logistic regression compared the enrollment rates (percent of eligible subjects deciding to enroll) of those who received the video compared to those who did not. Kaplan Meier survival analysis and a multivariate Cox proportional hazards model compared the differences in study retention, as defined by active participation fifteen months after the baseline visit at three months of age. RESULTS: Both groups were demographically similar. The enrollment rate was significantly higher for the Video Group (56.9%) compared to the No-Video Group (49.9%). Differences remained significant with adjustment for other known factors. A difference in retention between the two groups was not observed. CONCLUSION: Methods and materials increasing understanding and more accurately informing participants of what is involved in participation may increase enrollment in a prospective observational study. PMID- 22101230 TI - An omics perspective of protein disorder. AB - Disordered regions within proteins have increasingly been associated with various cellular functions. Identifying the specific roles played by disorder in these functions has proved difficult. However, the development of reliable prediction algorithms has expanded the study of disorder from a few anecdotal examples to a proteome-wide scale. Moreover, the recent omics revolution has provided the sequences of numerous organisms as well as thousands of genome-wide data sets including several types of interactomes. Here, we review the literature regarding genome-wide studies of disorder and examine how these studies give rise to new characterizations and categories of this elusive phenomenon. PMID- 22101231 TI - Cocaine self-administration in Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. AB - Individuals prone to drug self-administration may be vulnerable not only to a single drug reinforcer but to a variety of drug reinforcers. It has been shown that two thirds of alcoholics regularly use drugs other than ethanol (alcohol). Up to 30% of alcohol-dependent patients report concurrent misuse of cocaine. The aim of the present study was to investigate intravenous cocaine self administration in selectively bred, alcohol-preferring WHP (Warsaw high preferring) and non-preferring WLP (Warsaw low-preferring) rats. It was hypothesized that WHPs could be more prone to cocaine self-administration in comparison to WLPs. Rats from both lines were allowed to nose-poke for cocaine infusions (0.33 mg/kg/infusion) under the FR-1, FR-2, and FR-3 schedule of reinforcement. Dose-response curves were assessed with increasing doses of cocaine (0.03, 0.1, 0.33, 1.0mg/kg/infusion). The WHP and WLP rats did not differ in cocaine self-administration. Both groups quickly acquired nose-poke responding for cocaine, presented a similar response profile when the schedule of reinforcement was increased from FR-1 to FR-3, and similar sensitivity to cocaine in the dose-response test. The present results may indicate that the selective breeding of alcohol-preferring WHP and alcohol non-preferring WLP rats did not lead to differences in cocaine's rewarding effects as assessed in the self administration procedure. PMID- 22101232 TI - Nanoparticles for intracellular-targeted drug delivery. AB - Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects. PMID- 22101233 TI - Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: implication in Alzheimer's disease pathogenesis. AB - Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2alpha) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2alpha, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. PMID- 22101234 TI - Enantioselective total synthesis of (-)-neovibsanin G and (-)-14-epi-neovibsanin G. AB - The first total synthesis of vibsane-type diterpenoids neovibsanin G and 14-epi neovibsanin G has been achieved. Key to this endeavour was a late stage EtAlCl(2) mediated skeletal rich cascade leading to the bicyclo[3.3.1]nonane core in one step. PMID- 22101235 TI - Multisite phosphorylation of human liver cytochrome P450 3A4 enhances Its gp78- and CHIP-mediated ubiquitination: a pivotal role of its Ser-478 residue in the gp78-catalyzed reaction. AB - CYP3A4, an integral endoplasmic reticulum (ER)-anchored protein, is the major human liver cytochrome P450 enzyme responsible for the disposition of over 50% of clinically relevant drugs. Alterations of its protein turnover can influence drug metabolism, drug-drug interactions, and the bioavailability of chemotherapeutic drugs. Such CYP3A4 turnover occurs via a classical ER-associated degradation (ERAD) process involving ubiquitination by both UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes for 26 S proteasomal targeting. These E3 ligases act sequentially and cooperatively in CYP3A4 ERAD because RNA interference knockdown of each in cultured hepatocytes results in the stabilization of a functionally active enzyme. We have documented that UBC7/gp78-mediated CYP3A4 ubiquitination requires protein phosphorylation by protein kinase (PK) A and PKC and identified three residues (Ser-478, Thr-264, and Ser-420) whose phosphorylation is required for intracellular CYP3A4 ERAD. We document herein that of these, Ser-478 plays a pivotal role in UBC7/gp78-mediated CYP3A4 ubiquitination, which is accelerated and enhanced on its mutation to the phosphomimetic Asp residue but attenuated on its Ala mutation. Intriguingly, CYP3A5, a polymorphically expressed human liver CYP3A4 isoform (containing Asp-478) is ubiquitinated but not degraded to a greater extent than CYP3A4 in HepG2 cells. This suggests that although Ser-478 phosphorylation is essential for UBC7/gp78-mediated CYP3A4 ubiquitination, it is not sufficient for its ERAD. Additionally, we now report that CYP3A4 protein phosphorylation by PKA and/or PKC at sites other than Ser-478, Thr-264, and Ser 420 also enhances UbcH5a/CHIP-mediated ubiquitination. Through proteomic analyses, we identify (i) 12 additional phosphorylation sites that may be involved in CHIP-CYP3A4 interactions and (ii) 8 previously unidentified CYP3A4 ubiquitination sites within spatially associated clusters of Asp/Glu and phosphorylatable Ser/Thr residues that may serve to engage each E2-E3 complex. Collectively, our findings underscore the interplay between protein phosphorylation and ubiquitination in ERAD and, to our knowledge, provide the very first example of gp78 substrate recognition via protein phosphorylation. PMID- 22101236 TI - Bisphenol A induces oxidative stress and decreases levels of insulin receptor substrate 2 and glucose transporter 8 in rat testis. AB - Bisphenol A (BPA), a monomer present in plastics, is known to impair male reproductive functions. Testis executes high-energy-demanding processes such as spermatogenesis and steroidogenesis, the successful accomplishment of which requires several factors including glucose. In this context, we sought to investigate the effects of low doses of BPA on glucose metabolism in the testis of rats and to delineate whether oxidative stress has any role to play in mediating the effects. Bisphenol A was orally administered to rats at dose levels of 0.005, 0.5, 50, and 500 ug/kg body weight for 45 days. A positive control was maintained by orally administering 17beta-estradiol at a dose of 50 ug/kg body weight. The levels of plasma glucose and insulin were significantly increased, whereas the testicular glucose level significantly decreased following exposure to BPA and estradiol. A dose-dependent increase in the level of hydrogen peroxide (H2O2) and a significant decline in the activities of hexokinase and phosphofructokinase was observed in the testis of rats treated with BPA. Western blot analyses of insulin receptor substrate 2 (IRS-2) and glucose transporter 8 (GLUT-8) in the testis showed a decline in the levels of these proteins following BPA administration. Immunolocalization of GLUT-8 protein in the testis revealed decreased expression of this protein in spermatocytes and developing spermatids of rats exposed to BPA. The results suggest that persistent exposure to low doses of BPA could disturb glucose homeostasis in the testis and thereby impair testicular functions. PMID- 22101237 TI - Identification of proteomic biomarkers in maternal plasma in the early second trimester that predict the subsequent development of gestational diabetes. AB - INTRODUCTION: This study is designed to identify proteomic biomarkers that predict the subsequent development of gestational diabetes mellitus (GDM). METHODS: Maternal blood was obtained prospectively from healthy pregnant women in the early second trimester (16-20 weeks). Twelve women subsequently diagnosed with GDM at 24 to 28 weeks were selected as cases; an equal number of normoglycemic women as controls. Proteomic analysis of the previously stored plasma was performed by surface-enhanced laser desorption/ionization time-of flight (SELDI-TOF) mass spectrometry. RESULTS: Three peaks (9122 Da, 9412 Da, and 9701 Da) that were increased in cases were characterized as isoforms of apolipoprotein CIII. Another discriminatory peak (17 105 Da) that was decreased in cases was matched to apolipoprotein AII. Enzyme-linked immunosorbent assay (ELISA) confirmed that women who subsequently developed GDM had significantly higher levels of apolipoprotein CIII than controls did. Levels of apolipoprotein AII failed to reach statistical significance. CONCLUSION: Our data suggest that there already exist biomarkers in the maternal circulation at 16 to 20 weeks in women who subsequently develop GDM. PMID- 22101238 TI - Endocrine disruptors, polychlorinated biphenyls-induced gC1qR-dependent apoptosis in human trophoblast cell line HTR-8/SVneo. AB - Although an association exists between exposure to polychlorinated biphenyls (PCBs) and spontaneous miscarriage, the mechanisms underlying this phenomenon remain unclear. In this study, PCBs content in plasma was detected by gas chromatography-mass spectrometry (GC-MS) and decidua tissues were examined for the expression of globular heads of C1q receptor (gC1qR) using Western blot in patients who underwent induced abortion and spontaneous abortion. Results showed increased PCBs content and gC1qR expression in patients who experienced spontaneous abortion. In vitro, Western blot analysis demonstrated significantly higher caspase 3 expression and apoptotic cell counts in green fluorescent protein (GFP)-gC1qR vector group. Additionally, gC1qR and caspase 3 showed decreased expression following PCBs plus gC1qR small interfering RNA (siRNA) treatment. The percentage of apoptotic cells increased in cells treated with PCBs alone or PCB plus negative siRNA. These data suggest that maternal exposure to PCBs is associated with adverse pregnancy outcomes and that upregulation of gC1qR is important for PCBs-mediated trophoblast cell apoptosis. PMID- 22101239 TI - The effects of dexamethasone treatment in early gestation on hypothalamic pituitary-adrenal responses and gene expression at 7 months of postnatal age in sheep. AB - We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3beta hydroxysteroid dehydrogenase, and 11beta hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary adrenal axis at 7 months of age. PMID- 22101240 TI - Estradiol promotes luteal regression through a direct effect on the ovary and an indirect effect from the celiac ganglion via the superior ovarian nerve. AB - There is evidence suggesting that estradiol (E(2)) regulates the physiology of the ovary and the sympathetic neurons associated with the reproductive function. The objective of this study was to investigate the effect of E(2) on the function of late pregnant rat ovaries, acting either directly on the ovarian tissue or indirectly via the superior ovarian nerve (SON) from the celiac ganglion (CG). We used in vitro ovary (OV) or ex vivo CG-SON-OV incubation systems from day 21 pregnant rats. Various concentrations of E(2 )were added to the incubation media of either the OV alone or the ganglion compartment of the CG-SON-OV system. In both experimental schemes, we measured the concentration of progesterone in the OV incubation media by radioimmunoassay at different times. Luteal messenger RNA (mRNA) expression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 20alpha hydroxysteroid dehydrogenase (20alpha-HSD) enzymes, respectively, involved in progesterone synthesis and catabolism, and of antiapoptotic B-cell lymphoma 2 (Bcl-2) and proapoptotic Bcl-2-associated X protein (Bax), were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) at the end of the incubation period. Estradiol added directly to the OV incubation or to the CG of the CG-SON-OV system caused a decline in the concentration of progesterone accumulated in the incubation media. In addition, E(2), when added to the OV incubation, decreased the expression of 3beta-HSD and the ratio of Bcl-2/Bax. We conclude that through a direct effect on the OV, E(2) favors luteal regression at the end of pregnancy in rats, in association with neural modulation from the CG via the SON. PMID- 22101241 TI - A quick and simple FISH protocol with hybridization-sensitive fluorescent linear oligodeoxynucleotide probes. AB - Fluorescence in situ hybridization (FISH) is a powerful tool used in karyotyping, cytogenotyping, cancer diagnosis, species specification, and gene-expression analysis. Although widely used, conventional FISH protocols are cumbersome and time consuming. We have now developed a FISH method using exciton-controlled hybridization-sensitive fluorescent oligodeoxynucleotide (ECHO) probes. ECHO-FISH uses a 25-min protocol from fixation to mounting that includes no stringency washing steps. We use ECHO-FISH to detect both specific DNA and RNA sequences with multicolor probes. ECHO-FISH is highly reproducible, stringent, and compatible with other fluorescent cellular labeling techniques. The resolution allows detection of intranuclear speckles of poly(A) RNA in HeLa cells and dissociated hippocampal primary cultures, and mRNAs in the distal dendrites of hippocampal neurons. We also demonstrate detection of telomeric and centromeric DNA on metaphase mouse chromosomes. The simplicity of the ECHO-FISH method will likely accelerate cytogenetic and gene-expression analysis with high resolution. PMID- 22101242 TI - Determinants of the cytotoxicity of PrrC anticodon nuclease and its amelioration by tRNA repair. AB - Breakage of tRNA(Lys(UUU)) by the Escherichia coli anticodon nuclease PrrC (EcoPrrC) underlies a host antiviral response to phage T4 infection that is ultimately thwarted by a virus-encoded RNA repair system. PrrC homologs are prevalent in other bacteria, but their activities and substrates are not defined. We find that induced expression of EcoPrrC is toxic in Saccharomyces cerevisiae and E. coli, whereas the Neisseria meningitidis PrrC (NmePrrC) is not. PrrCs consist of an N-terminal NTPase module and a C-terminal nuclease module. Domain swaps identified the EcoPrrC nuclease domain as decisive for toxicity when linked to either the Eco or Nme NTPase. Indeed, a single arginine-to-tryptophan change in the NmePrrC nuclease domain (R316W) educed a gain-of-function and rendered NmePrrC toxic to yeast, with genetic evidence for tRNA(Lys(UUU)) being the relevant target. The reciprocal Trp-to-Arg change in EcoPrrC (W335R) abolished its toxicity. Further mutagenesis of the EcoPrrC nuclease domain highlighted an ensemble of 15 essential residues and distinguished between hypomorphic alleles and potential nuclease-nulls. We report that the RNA repair phase of the bacterial virus-host dynamic is also portable to yeast, where coexpression of the T4 enzymes Pnkp and Rnl1 ameliorated the toxicity of NmePrrC-R316W. Plant tRNA ligase AtRNL also countered NmePrrC-R316W toxicity, in a manner that depended on AtRNL's 5'-kinase and ligase functions. PMID- 22101243 TI - Widespread generation of alternative UTRs contributes to sex-specific RNA binding by UNR. AB - Upstream of N-ras (UNR) is a conserved RNA-binding protein that regulates mRNA translation and stability by binding to sites generally located in untranslated regions (UTRs). In Drosophila, sex-specific binding of UNR to msl2 mRNA and the noncoding RNA roX is believed to play key roles in the control of X-chromosome dosage compensation in both sexes. To investigate broader sex-specific functions of UNR, we have identified its RNA targets in adult male and female flies by high throughput RNA binding and transcriptome analysis. Here we show that UNR binds to a large set of protein-coding transcripts and to a smaller set of noncoding RNAs in a sex-specific fashion. The analyses also reveal a strong correlation between sex-specific binding of UNR and sex-specific differential expression of UTRs in target genes. Validation experiments indicate that UNR indeed recognizes sex specifically processed transcripts. These results suggest that UNR exploits the transcript diversity generated by alternative processing and alternative promoter usage to bind and regulate target genes in a sex-specific manner. PMID- 22101245 TI - Targeting and utilizing primary tumors as live vaccines: changing strategies. AB - Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. PMID- 22101246 TI - Potent anti-respiratory syncytial virus activity of a cholestanol-sulfated tetrasaccharide conjugate. AB - A number of different viruses including respiratory syncytial virus (RSV) initiate infection of cells by binding to cell surface glycosaminoglycans and sulfated oligo- and polysaccharide mimetics of these receptors exhibit potent antiviral activity in cultured cells. We investigated whether the introduction of different lipophilic groups to the reducing end of sulfated oligosaccharides would modulate their anti-RSV activity. Our results demonstrate that the cholestanol-conjugated tetrasaccharide (PG545) exhibited ~5- to 16-fold enhanced anti-RSV activity in cultured cells compared with unmodified sulfated oligosaccharides. Furthermore, PG545 displayed virus-inactivating (virucidal) activity, a feature absent in sulfated oligosaccharides. To inhibit RSV infectivity PG545 had to be present during the initial steps of viral infection of cells. The anti-RSV activity of PG545 was due to both partial inhibition of the virus attachment to cells and a more profound interference with some post attachment steps as PG545 efficiently neutralized infectivity of the cell adsorbed virus. The anti-RSV activity of PG545 was reduced when tested in the presence of human nasal secretions. Serial passages of RSV in the presence of increasing concentrations of PG545 selected for weakly resistant viral variants that comprised the F168S and the P180S amino acid substitutions in the viral G protein. Altogether we identified a novel and potent inhibitor of RSV, which unlike sulfated oligo- and polysaccharide compounds, could irreversibly inactivate RSV infectivity. PMID- 22101247 TI - MEK1-ERKs signal cascade is required for the replication of Enterovirus 71 (EV71). AB - The role of the MEK1-ERK signaling cascade in the replication cycle of Enterovirus 71 (EV71), the primary cause of hand, foot and mouth disease (HFMD), has been analyzed. In vitro infection with EV71 induced a biphasic activation of ERK. The two phases of activation appeared to be triggered by different mechanisms, with the first phase being activated by the binding of viral particles to the membrane receptor of host cells and the second probably being in response to the production of new virus particles. Inhibition of ERK activation by U0126 was found to severely impair virus production. A similar reduction in EV71 replication was also observed when MEK1 expression was subject to knockdown using specific siRNAs. By contrast knockdown of MEK2 expression showed that it was dispensable for virus replication cycle, despite both MEK isoforms being activated and translocated to the nucleus equally well in response to virus infection. Overall, this study suggests distinct functions of the two isoforms of MEK in EV71 replication cycle, with an essential role for MEK1 in stimulating the ERK signaling cascade to promote virus replication. Taken together with our previous work on herpes simplex virus type 2 (HSV2) this study highlights MEK1 as a potential broad antiviral molecular target. PMID- 22101248 TI - Proteasome inhibitor bortezomib (PS-341) enhances RANKL-induced MDA-MB-231 breast cancer cell migration. AB - The receptor activator of nuclear factor kappaB ligand/receptor activator of nuclear factor kappaB (RANKL/RANK) pathway is crucial for the migration of RANK expressing cancer cells. The ubiquitin-proteasome protein degradation pathway plays a significant role in tumor metastasis. However, the relationship between these two pathways in tumor cell migration is unclear. In the present study, we explored the effect of the proteasome inhibitor bortezomib (PS-341) on RANKL induced MDA-MB-231 breast cancer cell migration. Transwell migration assay showed that RANKL-induced MDA-MB-231 cell migration was significantly blocked by the decoy receptor osteoprotegerin (OPG), and was also inhibited by the PI3-K inhibitor LY294002. Western blotting results showed that Akt was rapidly activated by soluble RANKL treatment. PS-341 significantly enhanced RANKL-induced MDA-MB-231 cell migration. Further study showed that the enhancement of migration by PS-341 involved upregulation of activated Akt and RANK. Our results for the first time support the theory that PS-341 treatment may be unsuitable for RANK positive breast cancer patients. PMID- 22101249 TI - Phytocomponent p-Hydroxycinnamic acid inhibits T-cell activation by modulation of protein kinase C-theta-dependent pathway. AB - The phytocomponent p-hydoxycinnamic acid (HCA) has been shown to have many beneficial effects in terms of antioxidant activity, inhibition of melanogenesis, bone resorption, and platelet activity, and stimulation of mineralization. However, effects of HCA in immune functions have not been investigated. Here, we show that HCA has a profound effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. HCA, at a concentration that optimally inhibits IL-2 production, had little effect on apoptotic or necrotic cell death of Jurkat T cells, suggesting that apoptosis is not a mechanism for HCA-induced T cell suppression. On the contrary, HCA dramatically inhibited PKC-theta accumulation and further phosphorylation at the immunological synapse which formed at the contact site between T cells and superantigen SEE-loaded antigen presenting cells. In addition, HCA significantly inhibited ERK and p38 kinase phosphorylation in both anti-CD3/28- and PMA/A23187-stimulated T cells. Consequently, HCA inhibited both AP-1 and NF-kappaB promoter activities in Jurkat T cells. Collectively, our results provide evidence for the immunosuppressive effect of HCA on activated T cells, through modulation of PKC-theta pathway. PMID- 22101250 TI - Effects of Mg(2+) on in vivo transcriptional dynamics of the lar promoter. AB - In vitro studies show that the transcriptional dynamics in Escherichia coli is sensitive to Mg(2+) concentration in the cell. We study in vivo how Mg(2+) affects the production of RNA molecules under the control of the lar promoter, P(lar), a lac promoter variant. The target RNA codes for RFP followed by 96 MS2d GFP binding sites, allowing in vivo detection of individual RNA molecules following transcription. As Mg(2+) concentration is increased, transcripts' production first increases, but then decreases. Results were confirmed by qPCR and gel assay. Analysis of cell to cell diversity in RNA production shows that the variance of RNA numbers changes with Mg(2+). Gel assay confirms changes in the structure of the target RNA. These results suggest that changes in the dynamics of elongation may also affect RNA production, along with changes in the dynamics of the promoter open complex. The findings suggest that changes in metabolite concentration can have multiple, complex effects on the in vivo dynamics of transcription. Comparative analysis of the effects on the dynamics of transcription of other metabolites confirms the significance of the effects of Mg(2+) ions. Namely, we show that Ca(2+) and Fe(2+) have almost negligible effects in comparison to Mg(2+). PMID- 22101251 TI - Ipsdienol dehydrogenase (IDOLDH): a novel oxidoreductase important for Ips pini pheromone production. AB - Ipsdienone (2-methyl-6-methylene-2,7-octadien-4-one) is an important intermediate in the biosynthesis of pheromonal ipsdienol (2-methyl-6-methylene-2,7-octadien-4 ol) and ipsenol (2-methyl-6-methylene-7-octen-4-ol) in male pine engraver beetles, Ips pini (Say). A novel ipsdienol dehydrogenase (IDOLDH) with a pheromone-biosynthetic gene expression pattern was cloned, expressed, functionally characterized, and its cellular localization analyzed. The cDNA has a 762nt ORF encoding a 253 amino acid predicted translation product of 28kDa and pI 5.8. The protein has conserved motifs of the Cp2 subfamily of "classical" short-chain dehydrogenases. Transcript levels were highest in pheromone producing tissue: the anterior midgut of fed males. The protein was detected only in male midguts and localized in the cytosolic fraction of midgut cells. Recombinant IDOLDH was produced in Sf9 cells using a baculovirus expression system. Enzyme assays of protein preparations showed IDOLDH used both NAD+ and NADP+ as coenzymes with specific activities in the nanomole range. Enzyme assays and GC/MS analysis showed that IDOLDH catalyzed the oxidation of racemic ipsdienol and (4R) (-)-ipsdienol to form ipsdienone, while (4S)-(+)-ipsdienol was not a substrate. These data strongly implicate IDOLDH as an enzyme involved in terminal pheromone biosynthetic steps, likely functioning to "tune" ipsdienol enantiomeric ratios. PMID- 22101252 TI - The oxidation state of europium in halide glasses. AB - The luminescent properties of divalent europium ions can be exploited to produce storage phosphors for x-ray imaging applications. The relatively high cost and limited availability of divalent europium halides makes it desirable to synthesize them from the readily available trivalent salts. In this work, samples of pure EuCl(3) and fluoride glass melts doped with EuCl(3) were processed at 700 800 degrees C in an inert atmosphere furnace. The Eu oxidation state in the resulting materials was determined using fluorescence and Mossbauer spectroscopy. Heat treatment of pure EuCl(3) for 10 min at 710 degrees C resulted in a material comprising approximately equal amounts of Eu(2+) and Eu(3+). Glasses made using mixtures of EuCl(2) and EuCl(3) in the starting material contained both oxidation states. This paper describes the sample preparation and analysis and discusses the results in the context of chemical equilibria in the melts. PMID- 22101253 TI - Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron sulfur cluster biogenesis. AB - Ferredoxins are iron-sulfur proteins that have been studied for decades because of their role in facilitating the monooxygenase reactions catalyzed by p450 enzymes. More recently, studies in bacteria and yeast have demonstrated important roles for ferredoxin and ferredoxin reductase in iron-sulfur cluster assembly. The human genome contains two homologous ferredoxins, ferredoxin 1 (FDX1) and ferredoxin 2 (FDX2--formerly known as ferredoxin 1L). More recently, the roles of these two human ferredoxins in iron-sulfur cluster assembly were assessed, and it was concluded that FDX1 was important solely for its interaction with p450 enzymes to synthesize mitochondrial steroid precursors, whereas FDX2 was used for synthesis of iron-sulfur clusters, but not steroidogenesis. To further assess the role of the FDX-FDXR system in mammalian iron-sulfur cluster biogenesis, we performed siRNA studies on FDX1 and FDX2, on several human cell lines, using oligonucleotides identical to those previously used, along with new oligonucleotides that specifically targeted each gene. We concluded that both FDX1 and FDX2 were important in iron-sulfur cluster biogenesis. Loss of FDX1 activity disrupted activity of iron-sulfur cluster enzymes and cellular iron homeostasis, causing mitochondrial iron overload and cytosolic iron depletion. Moreover, knockdown of the sole human ferredoxin reductase, FDXR, diminished iron sulfur cluster assembly and caused mitochondrial iron overload in conjunction with cytosolic depletion. Our studies suggest that interference with any of the three related genes, FDX1, FDX2 or FDXR, disrupts iron-sulfur cluster assembly and maintenance of normal cytosolic and mitochondrial iron homeostasis. PMID- 22101254 TI - Recovery and rebound of platelet counts in mice after thrombocytopenia induced by combination bortezomib + romidepsin. PMID- 22101255 TI - Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL. AB - Hematopoietic stem cells (HSCs) are maintained at a very low frequency in adult bone marrow under steady-state conditions. However, it is not fully understood how homeostasis of bone marrow HSCs is maintained. We attempted to identify a key molecule involved in the regulation of HSC numbers, a factor that, in the absence of Lnk, leads to HSC expansion. Here, we demonstrate that upon stimulation with thrombopoietin, expression of Bcl-xL, an antiapoptotic protein, was highly enhanced in Lnk-deficient HSCs compared to normal HSCs. As a result, Lnk deficient HSCs underwent reduced apoptosis following exposure to lethal radiation. Downregulation of Bcl-xL expression in Lnk-deficient HSCs by short hairpin RNA resulted in a great reduction of their capacity for reconstitution. These findings suggest that Lnk/Sh2b3 constrains the expression of Bcl-xL and that the loss of Lnk/Sh2b3 function enhances survival of HSCs by inhibiting apoptosis. Furthermore, our observations indicate that HSCs in patients with an Lnk/Sh2b3 mutation might become resistant to apoptosis due to thrombopoietin mediated enhanced expression of Bcl-xL. Consequently, reduced apoptosis could facilitate accumulation of HSCs with oncogenic mutations leading to development of myeloproliferative disorders. PMID- 22101256 TI - The expression pattern of aldehyde dehydrogenase 1 (ALDH1) is an independent prognostic marker for low survival in colorectal tumors. AB - BACKGROUND: Aldehyde dehydrogenase-1 (ALDH1) is involved in the regulation of cell proliferation and differentiation. Moreover, it is a marker for cancer stem cells (CSC). As CSCs were shown to be the driving force of tumor progression and metastases we suspected that the expression of ALDH1 correlated with the prognostic 5 year survival of colorectal cancer. METHODS: ALDH1 expression was analyzed in a highly stratified collective of 186 T3 N0 M0 G2 primary colorectal cancer specimens applying immunohistochemistry. For the analysis a scoring system for the expression of ALDH1 was developed that was aided by the pattern of the subcellular expression of beta-catenin which is a well known indicator for colorectal CSCs. RESULTS: First, ALDH1 expression could be assigned to two groups which correlated with the absence or presence of nuclear beta-catenin expression. Second, ALDH1 group 2 expression patterning correlated highly significantly with low long term survival (p=0.010) of patients with T3 N0 M0 G2 colorectal cancer. This correlation was found univariately and when applying the multivariate Cox model. CONCLUSION: ALDH1 expression pattern is an independent prognostic marker for survival of T3 N0 M0 G2 colorectal cancer patients. PMID- 22101257 TI - Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship. AB - Human cytomegalovirus (hCMV) infection is common. Although still controversial, there is growing evidence that active hCMV infection is associated with a variety of malignancies, including brain, breast, lung, colon, and prostate. Given that hCMV is frequently resident in salivary gland (SG) ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG mucoepidermoid carcinoma (MEC). This was initially supported by our finding that purified CMV induces malignant transformation in SG cells in an in vitro mouse model, and utilizes a pathogenic pathway previously reported for human MEC. Here we present the histologic and molecular characterizations of 39 human SG MECs selected randomly from a repository of cases spanning 2004-2011. Serial sections were obtained from formalin-fixed, paraffin embedded, tissue blocks from previous incisional or excisional biopsies. Immunohistochemical assays were performed for active hCMV proteins (IE1 and pp65) and the activated COX/AREG/EGFR/ERK signaling pathway. All four prospective causal criteria for viruses and cancer are fully satisfied: (1) protein markers for active hCMV are present in 97% of MECs; (2) markers of active hCMV are absent in non-neoplastic SG tissues; (3) hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; (4) hCMV correlates and colocalizes with an upregulation and activation of an established oncogenic signaling pathway (COX/AREG/EGFR/ERK). Thus, the evidential support reported here and previously in a mouse model is strongly confirmatory of a causal relationship between hCMV and SG mucoepidermoid carcinoma. To our knowledge, this is the first demonstration of hCMV's role in human oncogenesis that fully responds to all of Koch's Postulates as revised for viruses and cancer. In the absence of any contrary evidence, hCMV can reasonably be designated an "oncovirus." PMID- 22101258 TI - The expression level of lysophosphatidylcholine acyltransferase 1 (LPCAT1) correlates to the progression of prostate cancer. AB - BACKGROUND: Lysophosphatidylcholine acyltransferase 1 (LPCAT1), the enzyme catalyzing the reaction in remodeling of phosphatidylcholine (PC) has been reported to express in prostate. However, its diagnostic and prognostic values remain unclear. METHODS: Immunohistochemistry (IHC) for LPCAT1 was performed on the tissue microarray (TMA) slides containing 251 samples from 148 patients with various prostatic disorders. The association of expression level of LPCAT1 with the progression of prostate cancer was analyzed. RESULTS: LPCAT1 IHC mean score was the highest in metastatic prostate cancer (8.00+/-1.28), which was significantly higher than that in primary prostate cancer (4.63+/-3.00, p=9.73E 07), in high grade prostatic intraepithelial neoplasia (HGPIN, 2.72+/-2.47, p=1.02E-12), and in benign prostate (2.68, p=6.17E-12). The mean score in primary prostate cancer was significantly higher than that in HGPIN (p=4.09E-04) and in benign prostate (p=2.74E-04). There was no significant difference in the mean score between HGPIN and benign prostate (p=0.951). LPCAT1 IHC score also correlated to the tumor grade and stage of prostate cancer. Patients who underwent prostatectomy for prostate cancer and developed biochemical recurrence or clinical metastasis had higher LPCAT1 IHC score than those who underwent prostatectomy for prostate cancer and did not develop biochemical recurrence and clinical metastasis. The association of LPCAT1 with the progression of prostate cancer was independent of patient race and age, PSA level and positivity of surgical resection margins. CONCLUSIONS: LPCAT1 correlates with the progression of prostate cancer and could be a new biomarker in diagnosis, prognosis and studying the pathogenesis of prostate cancer. PMID- 22101259 TI - Attenuation of endoplasmic reticulum stress using the chemical chaperone 4 phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. AB - Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In the human heart, ischemia/reperfusion has been correlated to ER stress, and several markers of the unfolded protein response (UPR) participate during cardiac remodeling and fibrosis. Here, we used isoproterenol (ISO) injection as a model for in vivo cardiac fibrosis. ISO induced significant cardiomyocyte loss and collagen deposition in the damaged areas of the endocardium. These responses were accompanied by an increase in the protein levels of the luminal ER chaperones BIP and PDI, as well as an increase in the UPR effector CHOP. The use of the chemical chaperone 4-phenylbutyric acid (4-PBA) prevented the activation of the UPR, the increase in luminal chaperones and also, leads to decreased collagen deposition, cardiomyocyte loss into the damaged zones. Our results suggest that cardiac damage and fibrosis induced in vivo by the beta-adrenergic agonist ISO are tightly related to ER stress signaling pathways, and that increasing the ER luminal folding capacity with exogenously administrated 4-PBA is a powerful strategy for preventing the development of cardiac fibrosis. Additionally, 4-PBA might prevent the loss of cardiomyocytes. Our data suggests that the attenuation of ER stress pathways with pharmacological compounds such as the chemical chaperone 4-PBA can prevent the development of cardiac fibrosis and adverse remodeling. PMID- 22101260 TI - Compatibility drives female preference and reproductive success in the monogamous California mouse (Peromyscus californicus) more strongly than male testosterone measures. AB - Female assessment of male attractiveness and how preferred qualities impact reproductive success is central to the study of mate choice. Male attractiveness may depend on traits beneficial to the reproductive success (RS) of any female, termed 'universal quality', and/or on behavioral and biological interactions between potential mates that reflect 'compatibility'. The steroid hormone testosterone (T) often underlies male attractiveness in rodents and is associated with enhanced paternal care in the monogamous and biparental California mouse (Peromyscus californicus). We hypothesized that (1) T-characteristics are universally attractive to female California mice and that (2) if reproductive success is higher for females mated with preferred males, then females mated with males preferred by other females will also have higher reproductive success. Alternatively, we speculated that pair compatibility, based on emergent pair qualities, is important for a species with coordinated offspring care. We assessed individual T-characteristics in three ways: (1) T-response to GnRH challenges (2) baseline T-level and (3) T-response to a female. Testosterone response did not predict female preference, but females spent more time investigating males with higher baseline T (accounting for only 9.6% of the variation in investigation time). None of the T-measures was associated with RS. Females paired with males they preferred produced litters more quickly and had higher RS than females paired with their non-preferred males. Naive females who did not undergo preference tests had equivalent RS regardless of whether their mate was preferred or non-preferred by another female. These data suggest that higher male T elicits investigation, but female preference in the California mouse is more strongly linked with compatibility because individual preference was a better predictor of RS than any T measure. PMID- 22101261 TI - Micro- and nanotechnology in cardiovascular tissue engineering. AB - While in nature the formation of complex tissues is gradually shaped by the long journey of development, in tissue engineering constructing complex tissues relies heavily on our ability to directly manipulate and control the micro-cellular environment in vitro. Not surprisingly, advancements in both microfabrication and nanofabrication have powered the field of tissue engineering in many aspects. Focusing on cardiac tissue engineering, this paper highlights the applications of fabrication techniques in various aspects of tissue engineering research: (1) cell responses to micro- and nanopatterned topographical cues, (2) cell responses to patterned biochemical cues, (3) controlled 3D scaffolds, (4) patterned tissue vascularization and (5) electromechanical regulation of tissue assembly and function. PMID- 22101262 TI - Old and new functions of proneural factors revealed by the genome-wide characterization of their transcriptional targets. AB - In the developing vertebrate nervous system, bHLH proneural factors such as Ascl1 are known to play important regulatory roles at different stages of the neurogenic differentiation process. In spite of the wealth of information gathered on the cellular functions of proneural factors, little was known of the molecular basis for their activities, and in particular of the identity of their target genes. The development of genomic approaches is making possible the characterization of transcriptional programs at an unprecedented scale. Recently, we have used a combination of genomic location analysis by ChIP-on-chip and expression profiling in order to characterize the proneural transcription program regulated by Ascl1 in the ventral telencephalon of the mouse embryonic brain. Our results demonstrate that Ascl1 directly controls successive steps of neurogenesis and provide a molecular frame for previously described Ascl1 functions. In addition, we uncovered an important but previously unrecognized role for Ascl1 in promoting the proliferation of neural progenitors. Here we discuss our recent findings and review them in light of efforts from other laboratories to characterize the transcriptional programs downstream various proneural factors. PMID- 22101263 TI - HIF-1alpha localization with mitochondria: a new role for an old favorite? PMID- 22101264 TI - Understanding the molecular basis of common fragile sites instability: role of the proteins involved in the recovery of stalled replication forks. AB - Common fragile sites (CFS) are difficult-to-replicate genomic regions that show a high propensity to breakage following certain forms of DNA replication stress. Long considered a fascinating component of human chromosome structure, their relevance for biology is proven by the fact that they are frequently rearranged in cancer cells. Furthermore, CFS were found to be the preferential targets for genome instability in the early stages of human tumorigenesis. In recent years, much progress has been made in understanding the structural features of CFS and the mechanisms that monitor and regulate their integrity. From these studies it has emerged that the reason for their fragility may depend on the abnormal high frequency of fork stalling events occurring at CFS during DNA replication. Consistently, the ATR-dependent checkpoint together with several proteins involved in response to replication fork stalling have been implicated in maintaining CFS stability. Furthermore, more recent findings propose that the scarcity of replication initiation events within CFS may contribute to their expression upon replication perturbation. This review will focus on the molecular determinants responsible for genomic instability at CFS and the systems used by cells to address this eventuality. PMID- 22101265 TI - Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle. AB - Tight regulation of the cell cycle and DNA repair machinery is essential for maintaining genome stability. The APC/CCdh1 ubiquitin ligase complex is a key regulator of protein stability during the G 1 phase of the cell cycle. APC/CCdh1 regulates and promotes the degradation of proteins involved in both cell cycle regulation and DNA repair. In a recent study, we identified a novel APC/CCdh1 substrate, the ubiquitin protease USP1. USP1 is a critical regulator of both the Fanconi anemia (FA) and translesion synthesis (TLS) DNA repair pathways. Here, we provide additional mechanistic insights into the regulation of USP1 during the cell cycle. Specifically, we demonstrate that USP1 is phosphorylated in mitosis by cyclin-dependent kinases (Cdks), and that this phosphorylation event may prevent premature degradation of USP1 during normal cell cycle progression. Finally, we provide a unifying hypothesis integrating the role of G 1-specific proteolysis of USP1 with the regulation of the transcriptional repressors, Inhibitor of DNA-binding (ID) proteins. PMID- 22101266 TI - Keeping chromatin quiet: how nucleosome remodeling restores heterochromatin after replication. AB - Disruption of chromatin organization during replication poses a major challenge to the maintenance and integrity of genome organization. It creates the need to accurately reconstruct the chromatin landscape following DNA duplication but there is little mechanistic understanding of how chromatin based modifications are restored on newly synthesized DNA. ATP-dependent chromatin remodeling activities serve multiple roles during replication and recent work underscores their requirement in the maintenance of proper chromatin organization. A new component of chromatin replication, the SWI/SNF-like chromatin remodeler SMARCAD1, acts at replication sites to facilitate deacetylation of newly assembled histones. Deacetylation is a pre-requisite for the restoration of epigenetic signatures in heterochromatin regions following replication. In this way, SMARCAD1, in concert with histone modifying activities and transcriptional repressors, reinforces epigenetic instructions to ensure that silenced loci are correctly perpetuated in each replication cycle. The emerging concept is that remodeling of nucleosomes is an early event imperative to promote the re establishment of histone modifications following DNA replication. PMID- 22101267 TI - Mechanisms of mitochondria and autophagy crosstalk. AB - Autophagy is a cellular survival pathway that recycles intracellular components to compensate for nutrient depletion and ensures the appropriate degradation of organelles. Mitochondrial number and health are regulated by mitophagy, a process by which excessive or damaged mitochondria are subjected to autophagic degradation. Autophagy is thus a key determinant for mitochondrial health and proper cell function. Mitophagic malfunction has been recently proposed to contribute to progressive neuronal loss in Parkinson's disease. In addition to autophagy's significance in mitochondrial integrity, several lines of evidence suggest that mitochondria can also substantially influence the autophagic process. The mitochondria's ability to influence and be influenced by autophagy places both elements (mitochondria and autophagy) in a unique position where defects in one or the other system could increase the risk to various metabolic and autophagic related diseases. PMID- 22101268 TI - Circadian clock protein BMAL1 regulates cellular senescence in vivo. AB - Deficiency of the circadian clock transcriptional factor BMAL1 results in the development of premature aging in mice. In agreement with the accelerated aging phenotype, we observed an increase in the number of senescent cells in different tissues (lungs, liver and spleen) of Bmal1(-/-) mice, which suggests the important role of BMAL1 in the control of senescence in vivo. However, no difference in the rate of proliferation and senescence between primary fibroblasts isolated from wild-type and Bmal1(-/-) mice has been detected, suggesting that BMAL1 does not play a significant role in replicative senescence in vitro. BMAL1 deficient fibroblasts had an increased sensitivity to hydrogen peroxide treatment, and reduced sensitivity to DNA damaging anticancer drugs etoposide and daunorubicin. Increased sensitivity of Bmal1(-/-) cells to oxidative stress was p53 independent and correlated with the disrupted regulation of reactive oxygen species (ROS) homeostasis in BMAL1 deficient cells: indeed, circadian oscillations of ROS level can be induced in wild-type but not in Bmal1( /-) cells. We propose that BMAL1 is important for the regulation of oxidative stress and DNA damage responses, while deregulation of these processes upon BMAL1 deficiency leads to development of stress induced senescence in vivo. PMID- 22101269 TI - TGFbeta-induced c-Myb affects the expression of EMT-associated genes and promotes invasion of ER+ breast cancer cells. AB - Advanced breast cancer cells acquire metastatic properties in response to TGFbeta. We show here that the expression of c-Myb increases in TGFbeta-treated ER (+) breast cancer cells by protein stabilization, transcription activation and release from miR200-dependent down-regulation. In particular, we mapped 2 sites for miR200b, miR200c and miR429 binding in the 3' UTR of the human c-myb gene. These microRNAs decreased the expression of c-Myb when transfected in MCF-7 cells. In addition, luciferase activity from a vector containing the 3' UTR of the c-myb gene was inhibited by miR200s through a binding-dependent mechanism. siRNA- and shRNA-mediated down-regulation was used to investigate the role of c Myb for the effects induced by TGFbeta in ER(+) breast cancer MCF-7 and ZR-75.1 cells. Transfection with c-Myb siRNAs blocked the increase of Slug (SNAI2) and Bcl-2 expression and reversed the decrease in E-cadherin expression induced by TGF-beta treatment. Conversely, c-Myb down-regulation decreased invasion and anchorage-independent growth of breast cancer cells expressing a constitutively active TGFbeta receptor I. Finally, apoptosis induced by etoposide increased in c Myb-silenced TGFbeta-treated ER(+) cell lines. In summary, exposure of ER(+) breast cancer cells to TGFbeta induces an increase of c-Myb expression which is required for expression of EMT-associated markers, in vitro invasion and anchorage-independent growth. Furthermore, our findings suggest a potentially detrimental effect of TGFbeta and c-Myb co-expression in breast cancer. PMID- 22101270 TI - Mechanism of action of the multikinase inhibitor Foretinib. AB - Mitotic catastrophe (MC) is induced when stressed cells enter prematurely or inappropriately into mitosis and can be caused by ionizing radiation and anticancer drugs. Foretinib is a multikinase inhibitor whose mechanism of action is incompletely understood. We investigated here the effect of Foretinib on chronic myelogenous leukemia (CML) cell lines either sensitive (IM-S) or resistant (IM-R) to the tyrosine kinase inhibitor Imatinib. Foretinib decreased viability and clonogenic potential of IM-S and IM-R CML cells as well. Foretinib treated cells exhibited increased size, spindle assembly checkpoint anomalies and enhanced ploidy that collectively evoked mitotic catastrophe (MC). Accordingly, Foretinib-stimulated CML cells displayed decreased expression of Cdk1, Cyclin B1 and Plk1. In addition, Foretinib triggered caspase-2 activation that precedes mitochondrial membrane permeabilization. Accordingly, z-VAD-fmk and a caspase-2 siRNA abolished Foretinib-mediated cell death but failed to affect MC, indicating that Foretinib-mediated apoptosis and MC are two independent events. Anisomycin, a JNK activator, impaired Foretinib-induced MC and inhibition or knockdown of JNK phenotyped its effect on MC. Moreover, we found that Foretinib acted as a potent inhibitor of JNK. Importantly, Foretinib exhibited no or very little effect on normal peripheral blood mononuclear cells, monocytes or melanocytes cells but efficiently inhibited the clonogenic potential of CD34+ cell from CML patients. Collectively, our data show that the multikinase inhibitor Foretinib induces MC in CML cells and other cell lines via JNK-dependent inhibition of Plk1 expression and triggered apoptosis by a caspase 2-mediated mechanism. This unusual mechanism of action may have important implications for the treatment of cancer. PMID- 22101271 TI - The "X factor" in cellular reprogramming and proliferation. PMID- 22101272 TI - TFEB, a novel mTORC1 effector implicated in lysosome biogenesis, endocytosis and autophagy. PMID- 22101273 TI - Spindle centricity. PMID- 22101274 TI - Coloring skin with pluripotent stem cells. PMID- 22101275 TI - Drosophila endocytic neoplastic tumor suppressor genes regulate Sav/Wts/Hpo signaling and the c-Jun N-terminal kinase pathway. AB - Genetic screens in the fruit fly Drosophila melanogaster have identified a class of neoplastic tumor suppressor genes (endocytic nTSGs), which encode proteins that localize to endosomes and facilitate the trafficking of membrane-bound receptors and adhesion molecules into the degradative lysosome. Loss of endocytic nTSGs transforms imaginal disc epithelia into highly proliferative, invasive tissues that fail to differentiate and display defects in cellular apicobasal polarity, adhesion and tissue architecture. As vertebrate homologs of some Drosophila nTSGs are linked to tumor formation, identifying molecular changes in signaling associated with nTSG loss could inform understanding of neoplastic transformation in vertebrates. Here we show that mutations in genes that act at multiple steps of the endolysosomal pathway lead to autonomous activation of the Sav/Wts/Hpo (SWH) transcriptional effector Yki (YAP/TAZ in vertebrates) and the Jun N-terminal kinase (JNK), which is known to promote Yki activity in cells with disrupted polarity. Yki and JNK activity are elevated by mutations at multiple steps in the endolysosomal pathway including mutations in the AP-2sigma gene, which encodes a component of the AP-2 adaptor complex that recruits cargoes into clathrin-coated pits for subsequent internalization. Moreover, reduction of JNK activity can decrease elevated Yki-signaling caused by altered endocytosis. These studies reveal a broad requirement for components of the endocytic pathway in regulating SWH and JNK outputs, and place Drosophila endocytic nTSGs into a network that involving two major signaling pathways implicated in oncogenesis. PMID- 22101276 TI - Identification and functional annotation of GWAS risk SNPs. PMID- 22101277 TI - The mitochondrial protein C1qbp promotes cell proliferation, migration and resistance to cell death. AB - Complement 1q-Binding Protein (C1qbp) is a mitochondrial protein reported to be upregulated in cancer. However, whether C1qbp plays a tumor suppressive or tumorigenic role in the progression of cancer is controversial. Moreover, the exact effects of C1qbp on cell proliferation, migration, and death/survival have not been definitely proven. To this end, we comprehensively examined the effects of C1qbp on mitochondrial-dependent cell death, proliferation, and migration in both normal and breast cancer cells using genetic gain- and loss-of-function approaches. In normal fibroblasts, overexpression of C1qbp protected the cells against staurosporine-induce apoptosis, increased proliferation, decreased cellular ATP, and increased cell migration in a wound-healing assay. In contrast, the opposite effects were observed in fibroblasts depleted of C1qbp by RNA interference. C1qbp expression was found to be markedly elevated in 4 different human breast cancer cell lines as well as in ductal and adenocarcinoma tumors from breast cancer patients. Stable knockdown of C1qbp by shRNA in the aggressive MDA-MB-231 breast cancer cell line greatly reduced cell proliferation, increased ATP levels, and decreased cell migration compared to control shRNA-transfected cells. Moreover, C1qbp knockdown elicited a significant increase in doxorubicin induced apoptosis in the MDA-MB-231 cells. Finally, C1qbp upregulation was not restricted to breast cancer cells and tumors, as levels of C1qbp were also found to be significantly elevated in both human lung and colon cancer cell lines and carcinomas. Together, these results establish a pro-tumor, rather than anti tumor, role for C1qbp, and indicate that C1qbp could serve as a molecular target for cancer therapeutics. PMID- 22101278 TI - Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects. AB - Lactoferrin (Lf), a multifunctional protein of the innate immune response, seems to act as a permeabilizing agent of Gram negative bacteria, apparently due to its interaction with enterobacterial lipopolysaccharide (LPS) on the bacterial surface. In both human and bovine Lf, a six residue sequence lying in an 18-loop region of the lactoferricin domain is key to Lf-LPS binding. There is much evidence that, by its action on LPS, Lf destabilizes the bacterial membrane and therefore increases bacterial permeability. By itself, Lf is not an effective antibacterial agent, but it permits the penetration of the bacterial membrane by some antibacterial substances whose hydrophobicity otherwise limits their efficacy. Additionally, Lf neutralizes free LPS by keeping the latter from forming complexes that activate TLR-4 signaling pathways. Such pathways, when over-activated, lead to the abundant production of pro-inflammatory mediators such as tumor necrosis factor (TNF) with fatal consequences to the host. The effect of Lf in reducing inflammation and destabilizing Gram negative bacteria has clinical implications in the control of sepsis, multiple organ dysfunction and bacterial invasion. PMID- 22101279 TI - Spatio-temporal expression pattern of the NatB complex, Nat5/Mdm20 in the developing mouse brain: implications for co-operative versus non-co-operative actions of Mdm20 and Nat5. AB - The NatB complex, Nat5/Mdm20 acetyltransferase mediates N-acetylation to control cell cycle progression and actin dynamics in yeast. As yet, little is known about the expression pattern of Mdm20 and Nat5 in multi-cellular organisms. Here we show that Mdm20 is highly expressed in mouse embryonic brain. At E11.5, Mdm20 was widely expressed in both neural progenitors and early differentiating neurons, whereas Nat5 was expressed in Sox1/3+/Mdm20+ neural progenitors. By E14.5, both Mdm20 and Nat5 were downregulated in most ventricular zone neural progenitors, whereas both proteins were found in differentiating neurons and co-expression was maintained at E18.5 in derivatives of these cells, such as midbrain dopaminergic (DA) neurons and septal neurons. These data suggest that Nat5/Mdm20 complex mediated acetylation may play a role in the proliferation and differentiation of neural progenitors. Intriguingly, our data also showed that Mdm20 is not always co-expressed with Nat5 in all differentiated neurons, for example deep cerebellar neurons. Moreover, detailed examination of the subcellular localization of Mdm20 and Nat5 in cultured Nat5+/Mdm20+ midbrain DA neurons revealed that Mdm20 is also not necessarily co-localized with Nat5 within neurons. Given that Nat5 is only a known member of Nat family protein that interacts with Mdm20, our data imply that Mdm20 may function either with an unidentified Nat protein partner(s) or possibly in a Nat-independent manner. PMID- 22101280 TI - Dynamics of Srf, p300 and histone modifications during cardiac maturation in mouse. AB - The adaptation of the cellular network to functional changes, timing and patterning of gene expression is regulated by binding of transcription factors to gene regulatory elements, which in turn depends on co-occurring histone modifications. These two layers influence each other, enabling a further level of regulatory fine-tuning. We analyzed the interdependencies between histone 3 acetylation, histone 3 lysine 4 dimethylation, the transcription factor Srf and the histone acetyltransferase p300 in an in vivo model using chromatin immunoprecipitation in a time-series during cardiac maturation in mouse. We found a strong correlation between the presence of the two histone modifications and binding of Srf and p300. Using linear modeling techniques we could show that each factor contributes individually as well as conjointly to histone 3 acetylation and gene expression, probably aided by accompanying histone 3 lysine 4 dimethylation. We further demonstrate that changes in gene expression during cardiac maturation are attended by changes of the analyzed regulators while revealing a high variability of combinatorial regulation. Finally, we propose a model of Srf-driven gene expression in cardiomyocytes. PMID- 22101281 TI - Extrusion printed polymer structures: a facile and versatile approach to tailored drug delivery platforms. AB - A novel extrusion printing system was used to create drug delivery structures wherein dexamethasone-21-phosphate disodium salt (Dex21P) was encapsulated within a biodegradable polymer (PLGA) and water soluble poly(vinyl alcohol) (PVA) configurations. The ability to control the drug release profile through the spatial distribution of drug within the printed 3-dimensional structures is demonstrated. The fabricated configurations were characterised by optical microscopy and SEM to evaluate surface morphology. The results clearly demonstrate the successful encapsulation of dexamethasone within a laminated PLGA:PVA structure. The resulting drug release profiles from the structures show a two stage release profile with distinctly different release rates and minimal initial burst release observed. Dexamethasone release was monitored over a 4 month period. This approach clearly demonstrates that the extrusion printing technique provides a facile and versatile approach to fabrication of novel drug delivery platforms. PMID- 22101282 TI - Targeted diazeniumdiolates: localized nitric oxide release from glioma-specific peptides and proteins. AB - Nitric oxide (NO) is a small yet important biological messenger, which at sufficient concentrations has been shown to induce apoptosis as well as increase radiosensitization in tumor cells. However, the short half-life of NO gas itself has limited its utility as a therapeutic agent. The objective of this study was the development of targeted NO donors and we illustrate their utility as a potential therapeutic for treatment of glioblastoma multiforme, the most common and aggressive malignant primary brain tumor in adults. We have synthesized two diazeniumdiolate NO donors by reacting NO gas with glioma-specific targeting sequences, VTWTPQAWFQWVGGGSKKKKK (VTW) and chlorotoxin (CTX), and achieved repeatable NO release from both donors. FITC-labeled biomolecules, when incubated with glioma and control cells preferentially bound to the glioma cells and showed only minimal binding to the control cells. Additionally, tumor cell viability was significantly decreased when cells were incubated with the NO donors whereas control cell viability was not affected. PMID- 22101283 TI - Effect of disintegrants on the properties of multiparticulate tablets comprising starch pellets and excipient granules. AB - A design of experiments (DOE) approach (2-level full factorial design) was used to investigate the effect of several formulation and process variables on the properties of fast disintegrating tablets comprising starch-based pellets and excipient granules and to optimize and validate the design space. The percentage of starch pellets (30-50%, w/w), type of disintegrants (Ac-di-sol, Explotab, Polyplasdone), percentage of external disintegrant (4-8%, w/w) and compression force (5-15 kN) were the evaluated factors (24 runs+9 centre points=33 experiments), while tablet hardness, friability and disintegration time were the studied tablet properties (responses). Starch pellets were prepared by extrusion spheronisation. Excipient granules containing microcrystalline cellulose, lactose, internal disintegrant (8%) and polyvinylpyrrolidone K-30 (4%) were prepared by wet granulation. Pellets, granules (700-1000 MUm) and external disintegrant were mixed and compressed into oblong tablets (17.1mm long, 8.2mm wide). Evaluation of the effects calculated from the DOE results showed that a lower concentration of starch pellets and higher compression force were required to yield tablets with a high hardness, a low friability (<1%) and short disintegration time (<3 min). Polyplasdone granules had the lowest porosity and friability which was reflected in the DOE study, where the Polyplasdone containing tablets were harder, less friable and disintegrated faster compared to Ac-di-sol and Explotab-containing tablets. Monte carlo simulations at the optimal factor settings (30% starch pellets, 4% Polyplasdone and 10 kN compression force) indicated that a robust system was formed as the probability to exceed the limits was low for all responses. Validation of the design space (at optimal settings) showed that the results predicted via the DOE models correlated well with the observed experimental data. PMID- 22101284 TI - Caco-2 cell line as a model to evaluate mucoprotective proprieties. AB - Physical protection of mucosa surface and reduction of inflammatory processes are currently considered the main strategies in the treatment and prevention of mucosal diseases. However, the majority of models used to verify the activity of new mucoprotective agents are based on limiting instrumental assessment or the sacrifice of experimental animals. In this study, for the first time, some in vitro experimental methods using Caco-2 cell line are proposed as predicting in vivo behaviour and action of mucoprotective agents. To this purpose, hyaluronic acid and natural polysaccharides for their bioadhesive activity, hydrocortisone and natural polyphenols as anti-inflammatory agents have been chosen. The obtained results demonstrated that the techniques (Con A/o-pd assay and Franz cell system) of mucoadhesive evaluation on Caco-2 cells are useful to compare the activity of each experimental sample and to assess the adhesion time to the mucosal cell surface. Moreover, the reduction of intercellular adhesion molecule 1 (ICAM-1) expression in Caco-2 cells can be considered directly correlated to the mucosal anti-inflammatory effect induced by the hydrocortisone and natural polyphenols. In conclusion, the study supported the use of Caco-2 cell as a model to compare and investigate the effect of different active substances on the mucosa and its diseases. PMID- 22101285 TI - Investigating the effect of humidity on the alpha-relaxations of low-density polyethylene using dielectric spectroscopy. AB - A previous work from our lab reported the higher sorption of lipophilic preservatives in LDPE form-fill-seal packs that were stored at 75% relative humidity (RH) as against 25% RH. The aim of the present work was to investigate structural changes taking place in LDPE on exposure to higher humidity. The crystallinity of LDPE, determined by differential scanning calorimetry, was found to be similar for the packs charged at both humidity conditions. Dielectric spectroscopy (1.0E-02 Hz to 1.0E02 Hz in the temperature range of 75-87 degrees C), however, showed faster alpha relaxation of LDPE films exposed to higher humidity. The activation energy of alpha relaxations was lower at 75% RH (99.735 kJ/mol) than at 25% RH (113.112 kJ/mol) after two weeks of storage. This work presents previously unreported evidence of the plasticization effect of water on LDPE, using dielectric spectroscopy. Furthermore, changes in alpha relaxation on exposure to humidity support the latest theory of its origin to be from the constrained amorphous regions. The authors suggest the employment of extreme humidity conditions (low and high), during accelerated stability studies of aqueous products in plastic packs to track the sorption loss of formulation components. PMID- 22101286 TI - Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery. AB - siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6 14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth. PMID- 22101287 TI - Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids. AB - Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ~25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings. PMID- 22101288 TI - Synthesis and biological evaluation of radiolabeled photosensitizer linked bovine serum albumin nanoparticles as a tumor imaging agent. AB - In this study, we reported on the synthesis and biological evaluation of radiolabeled fluorescent dye conjugated bovine serum albumin nanoparticles within the size range 190-210 nm. The bovine serum albumin nanoparticles (BSANPs) were prepared using a desolvation method, and chemical cross-linking was performed using gluteraldehyde. Furthermore, pheophorbide-a (PH-A) was loaded on the BSANPs. The results obtained from dynamic light scattering and electron microscopy have proved that nanoparticles are highly monodisperse and near spherical shaped. The photo-physical properties of the PH-A-BSANPs were obtained using the spectrophotometric techniques. According to the results, PH-A and BSANPs show high non-covalent interaction. PH-A loaded nanoparticles were labeled with (99m)Tc and the radio-labeling efficiency was determined as 90 +/- 1.2%. Biodistribution studies of (99m)Tc labeled PH-A-BSANPs and PH-A were carried out using female Albino Wistar rats, and (99m)Tc-PH-A-BSANPs showed a significantly higher uptake in the breast and uterus than (99m)Tc-PH-A. Cell culture study was carried out in MCF-7 cell line (human breast adenocarcinoma cell line). According to the cell culture studies, (99m)Tc-PH-A-BSANPs showed a higher uptake than (99m)Tc-PH-A. Moreover, PH-A-BSANPs demonstrated good photo-physical properties and BSANPs increased the uptake of PH-A on to the MCF-7 cell line. These results confirm that (99m)Tc labeled PH-A-BSANPs could be utilized for radioimaging. PMID- 22101289 TI - Optimization of a spray drying process to prepare dry powder microparticles containing plasmid nanocomplex. AB - Successful gene delivery to the lung depends not only on precise and effective design of a nanosized nucleic acid delivery system but also on well engineered liquid or solid microparticles. In present work, we tried to statistically optimize spray dried formulations of low molecular weight chitosan-plasmid nanocomplexes via a D-optimal design with respect to five critical responses: yield of the process, microparticle sizes, nanocomplex sizes, DNA stability and relative transfection efficiency. Nonocomplex formulations prepared by different amounts of solid contents and leucine ratio, and spray dried immediately with varying inlet temperature, feed rate and spray air flow rate. Mean results fitted to 2FI models except for relative transfection efficiency, which fitted in a quadratic model. According to the fitted models, the most important pure factors influencing each response determined to be feed rate for yield and DNA stability, feed fluid concentration for microparticle size, inlet temperature for nanoparticle size and leucine concentration for relative transfection efficiency. However, two-factor interactions have more important roles in microparticle size, nanocomplex size and DNA stability. It was concluded that the optimized formulation could be obtained when all the independent variables were at their maximum tested values, except for feed fluid concentration, which should be in its middle point. PMID- 22101290 TI - Ibuprofen-phospholipid solid dispersions: improved dissolution and gastric tolerance. AB - Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen-DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen-DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 +/- 6.2, 3.9 +/- 5.3, 5.3 +/- 4.9 and 9.1 +/- 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p<0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen. PMID- 22101291 TI - Quantifying crystallisation rates of amorphous pharmaceuticals with dynamic mechanical analysis (DMA). AB - One of the stability concerns for amorphous pharmaceuticals is phase transformation to a crystalline form. Since conversion from an amorphous matrix to a crystalline lattice should result in a change in mechanical modulus of the material dynamic mechanical analysis (DMA) offers potential as a stability indicating assay for what are often complex formulations. Amorphous indomethacin glasses were used as model samples. Pockets made of a metal weave allowed the glass to be mounted in the instrument while ensuring exposure to RH. Crystallisation was manifest as an increase in the storage modulus signal with time. Conversion of the data to fraction crystallisation allowed quantitative determination of the rate and mechanism of crystallisation by application of the Urbanovici-Segal model. Rates of crystallisation were seen to increase with temperature and humidity while temperature and humidity affected the mechanism of crystallisation. High temperature and humidity resulted in three dimensional crystal growth. Reducing the humidity caused a switch in mechanism to growth from edges. Reducing temperature resulted in a mixed mechanism of growth from surfaces and edges. The DMA was also sensitive to crystallisation of phenobarbital sodium formulated in an oral film, but quantitative analysis was not possible as the onset of crystallisation was not recorded. PMID- 22101292 TI - MDSC parameter optimization for the determination of glass transitions using a design of experiments approach. AB - Optimum experimental parameters for modulated differential scanning calorimetry were determined using a design of experiments approach. Two different strategies were tested, an isothermal method only varying modulation period and amplitude and a non-isothermal method including an underlying linear heating ramp. Three different test compounds were investigated including a blank of NaCl, a small pharmaceutically active molecule (Valsartan) and a polymer (PVP-VA 64). Obtained optimum values were found to be identical for each compound tested and shown to be statistically robust for repeated daily experimentation. Optimized signals showed lower glass transition values T(g) paired with higher changes in isobaric heat capacity Deltac(p). Measured glass transition signals exhibited minimal variation during repeat analysis, and showed significantly better signal-to-noise ratios in comparison to literature data. PMID- 22101293 TI - Erythropoietin-loaded oligochitosan nanoparticles for treatment of periventricular leukomalacia. AB - In this study, a single intraperitoneal injection of erythropoietin (EPO) loaded oligochitosan nanoparticles (epo-NPs) (average diameter 266 nm) was investigated as a treatment for periventricular leukomalacia (PVL). Nanoparticles were fabricated using a gelation technology process. PVL rats models were prepared to examine the therapeutic efficacy of epo-NPs and analyze the mechanism by which epo-NPs protect white matter. The metabolization of epo-NPs in the liver was also investigated. The pathology and behavioral data show that this single injection of a low quantity of epo-NPs had an excellent therapeutic effect on the rat model of PVL. The EPO release curve in phosphate buffered saline solution was a good fit with the zero-order kinetics distribution and was maintained at around 25% in 48 h. In vivo experiments demonstrated that 50 IU/kg epo-NPs had the same effect as a 5000 IU/kg direct injection of free EPO. Nanoparticles prolonged the time course of EPO metabolization in the liver and the stable release of EPO from the nanoparticles kept the plasma concentration of EPO at around 100 IU/ml during the 8-12h post-injection. Therefore, we suggest that oligochitosan based nanoparticles are an effective vehicle for drug delivery. PMID- 22101294 TI - Mathematical modelling of the transport of hydroxypropyl-beta-cyclodextrin inclusion complexes of ranitidine hydrochloride and furosemide loaded chitosan nanoparticles across a Caco-2 cell monolayer. AB - Chitosan nanoparticles (CS-NPs) have been used to enhance the permeability of furosemide and ranitidine hydrochloride (ranitidine HCl) which were selected as candidates for two different biopharmaceutical drug classes having low permeability across Caco-2 cell monolayers. Drugs loaded CS-NPs were prepared by ionic gelation of CS and pentasodium tripolyphosphate (TPP) which added to the drugs inclusion complexes with hydroxypropyl-beta-cyclodextrin (HP-betaCD). The stability constants for furosemide/HP-betaCD and ranitidine HCl/HP-betaCD were calculated as 335 M(-1) and 410 M(-1), whereas the association efficiencies (AE%) of the drugs/HP-betaCD inclusion complexes with CS-NPs were determined to be 23.0 and 19.5%, respectively. Zetasizer and scanning electron microscopy (SEM) were used to characterise drugs/HP-betaCD-NPs size and morphology. Transport of both nano and non-nano formulations of drugs/HP-betaCD complexes across a Caco-2 cell monolayer was assessed and fitted to mathematical models. Furosemide/HP-betaCD NPs demonstrated transport kinetics best suited for the Higuchi model, whereas other drug formulations demonstrated power law transportation behaviour. Permeability experiments revealed that furosemide/HP-betaCD and ranitidine HCl/HP betaCD nano formulations greatly induce the opening of tight junctions and enhance drug transition through Caco-2 monolayers. PMID- 22101295 TI - International guidelines for education in vestibular rehabilitation therapy. AB - The Barany Society Ad Hoc Committee on Vestibular Rehabilitation Therapy has developed guidelines for developing educational programs for continuing education. These guidelines may be useful to individual therapists who seek to learn about vestibular rehabilitation or who seek to improve their knowledge bases. These guidelines may also be useful to professional organizations or therapists who provide continuing education in vestibular rehabilitation. We recommend a thorough background in basic vestibular science as well as an understating of current objective diagnostic testing and diagnoses, understanding of common tests used by therapists to assess postural control, vertigo and ability to perform activities of daily living. We recommend that therapists be familiar with the evidence supporting efficacy of available treatments as well as with limitations in the current research. PMID- 22101296 TI - Experimental parameter estimation of a visuo-vestibular interaction model in humans. AB - Visuo-vestibular interactions in monkeys can be accurately modelled using the classical Raphan and Cohen's model. This model is composed of direct vestibular and visual contributions to the vestibulo-ocular reflex (VOR) and of a velocity storage. We applied this model to humans and estimated its parameters in a series of experiments: yaw rotations at moderate (60 degrees /s) and high velocities (240 degrees /s), suppression of the VOR by a head-fixed wide-field visual stimulus, and optokinetic stimulation with measurements of optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN). We found the velocity storage time constant to be 13 s, which decreased to 8 s during visual suppression. OKAN initial velocity was 12% of the OKN stimulus velocity. The gain of the direct visual pathway was 0.75 during both visual suppression and OKN; however, the visual input to the velocity storage was higher during visual suppression than during OKN. We could not estimate the time constant of the semicircular canals accurately. Finally, we inferred from high-velocity rotations that the velocity storage saturates around 20-30 degrees /s. Our results indicate that the dynamics of visuo-vestibular interactions in humans is similar as in monkeys. The central integration of visual cues, however, is weaker in humans. PMID- 22101297 TI - Use of the Dynamic Visual Acuity Test as a screener for community-dwelling older adults who fall. AB - Adequate function of the peripheral vestibular system, specifically the vestibulo ocular reflex (VOR; a network of neural connections between the peripheral vestibular system and the extraocular muscles) is essential for maintaining stable vision during head movements. Decreased visual acuity resulting from an impaired peripheral vestibular system may impede balance and postural control and place an individual at risk of falling. Therefore, sensitive measures of the vestibular system are warranted to screen for the tendency to fall, alerting clinicians to recommend further risk of falling assessment and referral to a falling risk reduction program. Dynamic Visual Acuity (DVA) testing is a computerized VOR assessment method to evaluate the peripheral vestibular system during head movements; reduced visual acuity as documented with DVA testing may be sensitive to screen for falling risk. This study examined the sensitivity and specificity of the computerized DVA test with yaw plane head movements for identifying community-dwelling adults (58-78 years) who are prone to falling. A total of 16 older adults with a history of two or more unexplained falls in the previous twelve months and 16 age and gender matched controls without a history of falls in the previous twelve months participated. Computerized DVA with horizontal head movements at a fixed velocity of 120 deg/sec was measured and compared with the Dynamic Gait Index (DGI) a gold standard gait assessment measurement for identifying falling risk. Receiver operating characteristics (ROC) curve analysis and area under the ROC curve (AUC) were used to assess the sensitivity and specificity of the computerized DVA as a screening measure for falling risk as determined by the DGI. Results suggested a link between computerized DVA and the propensity to fall; DVA in the yaw plane was found to be a sensitive (92%) and accurate screening measure when using a cutoff logMAR value of >0.25. PMID- 22101298 TI - The reliability and response stability of dynamic testing of the vestibulo-ocular reflex in patients with vestibular disease. AB - The purpose of the study was to investigate the test-retest reliability and response stability of the Dynamic Visual Acuity (DVA) and Gaze Stabilization Test (GST) in patients with vestibular disorders. Twenty-nine patients with vestibular disease (16-78 years) participated. Subjects performed the GST and DVA in pitch and yaw planes, twice in one session and once after 7-10 days. The GST output is the maximum head velocity at which the patient was able to identify orientation of the letter E. The DVA output is the change in visual acuity when moving the head compared to static acuity. Subjects indicated their level of dizziness and visual blurring using a visual analog scale. Within- and between-sessions intraclass correlation coefficients ranged between 0-0.5 for the DVA and GST measures, with better correlations for within-session assessments. Response stability (standard error of measurement / mean) of the GST ranged between 21-32% and the DVA ranged between 25-69% with vertical DVA being most influenced by measurement error. Subjects' symptoms did not correlate with performance on either test. The current test protocol needs refinement to enhance reliability and stability in persons with vestibular disorders. PMID- 22101299 TI - Vestibular dysfunction and compensation after removal of acoustic neuroma. AB - OBJECTIVE: To evaluate vestibular function after unilateral acoustic neuroma surgery via a retrosigmoid approach. METHODS: Thirty-eight patients were tested using caloric irrigation, static posturography, and the Dizziness Handicap Inventory (DHI) before, and one week to nine months after surgery. RESULTS: Twenty-six patients were categorized as a response group and 12 as a no-response group on the basis of preoperative caloric irrigation findings. The posturographic parameters and DHI scores at one week after surgery showed significant deterioration in the response group, but not in the no-response group. However, they recovered to the preoperative baseline at 3 months after surgery. The posturographic parameters and DHI scores for older patients tended to be worse than those for younger patients at 6 and 9 months after surgery. CONCLUSION: Patients in whom caloric responses are retained preoperatively show a temporary disturbance of balance after removal of acoustic neuroma. Disequilibrium after surgery ameliorates to the preoperative baseline within three months due to vestibular compensation, regardless of preoperative vestibular function. It is possible that poorer vestibular compensation may facilitate incomplete recovery in older patients after surgery. PMID- 22101300 TI - Excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) attenuate the effects of repeated stress on weight gain: evidence for the recruitment of BNST activity by repeated, but not acute, stress. AB - Exposure to repeated stress can lead to diverse and widespread behavioral consequences, including reduction in food and water intake and subsequent diminution in weight gain. Many reports have suggested that repeated stress substantially alters the neurochemistry, morphology and physiology of neurons within the bed nucleus of the stria terminalis (BNST). Here we investigate the role of the BNST in mediating the reduced weight gain observed during repeated stress. Rats exposed to a one-week variate stress paradigm exhibited a reduction in weight gain over the course of the 7-day paradigm. Excitotoxic lesions to a subregion of the anterolateral BNST containing the oval nucleus had no effects early in the 7-day paradigm, but significantly attenuated the effects of repeated stress on weight gain by the last day of stress. These data suggest that at least two mechanisms mediate the effects of stress on body weight gain, and that when stressor exposure becomes repeated, the BNST is recruited, worsening the symptoms of stressor exposure. PMID- 22101301 TI - Lack of cyclin D2 impairing adult brain neurogenesis alters hippocampal-dependent behavioral tasks without reducing learning ability. AB - The exact function of the adult brain neurogenesis remains elusive, although it has been suggested to play a role in learning and memory processes. In our studies, we employed cyclin D2 gene knockout (cD2 KO) mice showing impaired neurogenesis as well as decreased hippocampal size. However, irrespectively of the genetic background of cD2 KO mice, this phenotype resulted in neither deficits in the hippocampal-dependent learning ability nor the memory formation. In the present study, cD2 KO mice and control littermates were subjected to hippocampal-dependent behavioral tests with little or no learning component. The knockout mice showed significant impairment in such species-typical behaviors as nest construction, digging, and marble burying. They were building none or poorer nests, digging less robustly, and burying fewer marbles than control mice. Such impairments were previously described, e.g., in animals with hippocampal lesions. Moreover, cD2 KO animals were also more active in the open field and automated motility chamber as well as showed increased explorative behavior in IntelliCage. Both increased motility and explorative behaviors were previously observed in hippocampally lesioned animals. Finally, cD2 KO mice showed normal sucrose preference, however starting from the second exposure to the sweetened solution, while control animals displayed a strong preference immediately. Presented results suggest that either morphological abnormalities of the hippocampal formation or adult brain neurogenesis impairment (or both) alter hippocampal dependent behaviors of mutant mice without influencing learning abilities. These results may also suggest that adult brain neurogenesis is involved in species typical behaviors. PMID- 22101302 TI - Contextual learning increases dendrite complexity and EphrinB2 levels in hippocampal mouse neurons. AB - Although the role of hippocampus in memory processing is well assessed, an association of experience-dependent behavioural modifications with hippocampal neuron morphological and biochemical changes deserves further characterisation. Here, we present evidence of dendritic alterations together with rapid accumulation of EphrinB2, a factor known to influence cell plasticity, in pyramidal neurons of the CA1 area of mouse hippocampus, during the formation of recent contextual fear memory. Male C57BL/6N mice exhibited a robust fear response 24h after contextual and cued fear conditioning. At this time and in the absence of the memory test, conditioned mice showed morphological alterations in hippocampal and lateral amygdala neurons. Western blot analysis of extracts from conditioned but not pseudoconditioned or naive mice showed a specific increase in the amount of EphrinB2 in the hippocampus but not the cortex. However, levels of EphA4 receptor, known to interact trans-synaptically with EphrinB2, did not change upon conditioning in extracts from the same structures. Finally, immunohistochemical analysis of the hippocampus and amygdala of conditioned mice showed increased levels of EphrinB2 in pyramidal neurons of the CA1 area, when compared to pseudoconditioned and control mice. Such increase was not observed in other hippocampal areas or the amygdala. These results suggest that rapid accumulation of EphrinB2 in hippocampal CA1 neurons is involved in the behavioural and cellular modifications induced by contextual fear conditioning. A similar mechanism does not appear to occur in lateral amygdala neurons, in spite of the robust behavioural and cellular modifications induced in such structure by cued fear conditioning. PMID- 22101303 TI - Memory deficits in the transgenic rat model of Huntington's disease. AB - Memory deficits are common in patients with Huntington's disease (HD) and have a substantial impact on the quality of life of patients and their relatives. A good model resembling the human memory deficits is needed for research purposes. In this study we investigated the memory function of the transgenic rat model of Huntington's disease (tgHD) in the object location (OLT) and the object recognition task (ORT). Several studies have shown that the recent developed tgHD rat model resembles the human phenotype of HD. Impairments of spatial and object recognition memory in the OLT and ORT, however, have to our knowledge not yet been reported in this transgenic model. Our findings show that in both early and late stages of the disease the tgHD rats have clear deficits for both visuospatial and visual object memory. Since HD patients are known to be impaired in both types of memory, these results confirm the validity of this tgHD rat as a model for the human HD phenotype. PMID- 22101304 TI - 1,3,5-Triphenylbenzene fluorophore as a selective Cu2+ sensor in aqueous media. AB - Three water-soluble fluorophores are synthesized from 1,3,5-tris-(4' iodophenyl)benzene. The compound with salicylate groups exhibits a selective fluorescent quenching by Cu(2+)via a static quenching mechanism. The addition of Triton X-100 improves the quantum efficiency of the fluorophore as well as the detection limit for Cu(2+) from 6.49 to 0.19 ppb. PMID- 22101306 TI - IFNgamma production by NK cells from HLA-sensitized patients after in vitro exposure to allo-antigens. AB - Using a novel cytokine flow cytometry test (allo-CFC), we have previously shown that incubation of allogeneic cells with peripheral blood from highly-HLA sensitized (HS) patients results in reproducible gamma-interferon (IFNgamma production in CD3(-) cells, and high (+) allo-CFC levels correlated with risk for antibody-mediated rejection (AMR). Here we report on identification of the cells and mechanisms responsible. The allo-CFC with/without modification was performed using blood from HS or normal individuals. IFNgamma producing cells were CD3( )/CD19(-), but CD3(-)/CD56(+). In vitro and in vivo B cell-depletion did not affect IFNgamma production, demonstrating NK cells as the cells responsible for IFNgamma production. NK cells from allo-CFC(+) or (-) individuals released significant amounts of IFNgamma against target cells treated with serum from allo CFC(+) individuals, but not allo-CFC(-) individuals. IFNgamma release was abrogated by protein A/G treatment of the pretreated target cells, suggesting mediation by antibodies via FcgammaRIIIa (CD16). In conclusion, NK cell IFNgamma release after allo-antigen exposure is mediated primarily through antibody dependent cellular cytotoxicity (ADCC)-like mechanisms, suggesting that NK cells may be partially responsible for graft injury during AMR including C4d(-) AMR via ADCC, and could be a potential target for modification of this process. PMID- 22101307 TI - Arterial supply to the tibial tuberosity: involvement in patellar ligament transfer in children. AB - PURPOSE: The aims were to study arterial blood supply of the tibial tuberosity, and to evaluate its remaining blood supply after patellar ligament transposition in children. METHODS: The anatomic study was carried out on 15 lower limbs after latex injection, and on two fetuses after diaphanization. RESULTS: Tibial tuberosity was vascularized by an arterial network mainly supplied by anterior tibial recurrent artery. Other arteries from the popliteal artery or its branches were also involved in the tibial tuberosity blood supply. CONCLUSIONS: Our findings confirm the safety of transposition of patellar ligament in children due to dense arterial network supplying tibial tuberosity. PMID- 22101308 TI - Order and excitation in partially Gutzwiller projected t-t'-t"-J-U models. AB - Extended t-t'-t"-J-U models in which the second-nearest-neighbor hopping (t') and third-nearest-neighbor hopping (t") are included are studied using renormalized mean field theory. The models are meant to be low-energy effective models for the Hubbard models, and hence the Heisenberg exchange integral J and Hubbard repulsion U are related by J = 4t(2)/U. The trial wavefunctions for the ground states are partially Gutzwiller projected Hartree-Fock states. The Gutzwiller projection is implemented by means of a Gutzwiller approximation, and the site double occupancy d is taken as a variational parameter. It is found that a large |t'/t| narrows the band filling range that sustains antiferromagnetism (AFM) in the ground state, enhances the d-wave singlet superconductivity (dSC) in hole overdoped systems, but suppresses the dSC in electron overdoped systems. For a system that has large |t'/t| and |t"/t'|, the superconductivity (SC) at the onset of AFM in hole doped band filling is strongly suppressed. On the excitation occurring, when an electron doped system simultaneously contains SC and AFM, the system is found to have a nodeless gap at the Fermi level. Finally, the result of this study is related to experiments on the superconducting cuprates. PMID- 22101309 TI - Multiplex PCR and a chromogenic DNA macroarray for the detection of Listeria monocytogens, Staphylococcus aureus, Streptococcus agalactiae, Enterobacter sakazakii, Escherichia coli O157:H7, Vibrio parahaemolyticus, Salmonella spp. and Pseudomonas fluorescens in milk and meat samples. AB - Food products, such as milk and meat products including cheese, milk powder, fermented milk, sausage, etc. are susceptible to the contamination by pathogenic and deteriorative bacteria. These bacteria include Listeria monocytogens, Staphylococcus aureus, Enterobacter sakazakii, Escherichia coli O157:H7, Salmonella spp., Vibrio parahaemolyticus, Streptococcus agalactiae and Pseudomonas fluorescens, etc. Traditional methods for the detection of these microorganisms are laborious and time consuming. Therefore, rapid and accurate diagnostic methods are needed. In this study, we designed the DNA probes and PCR primers for the detection of aforementioned microorganisms. By using two sets of multiplex PCR, followed by a chromogenic macroarray system, these organisms in milk or other food products could be simultaneously detected. When the system was used for the inspection of milk or meat homogenate containing 10(0) target cells per milliliter or gram of the sample, all these bacterial species could be identified after an 8h pre-enrichment step. The system consisting of a multiplex PCR step followed by macroarray allowed us to detect multiple target bacterial species simultaneously without the use of agarose gel electrophoresis. Compared to the commonly used multiplex PCR method, this approach has the additional advantage of detecting more bacterial strains because some bacterial strains generate PCR products with the same molecular sizes which can be differentiated by macroarray but not by electrophoresis. PMID- 22101310 TI - High-throughput analysis of growth differences among phage strains. AB - Although methods such as spectrophotometry are useful for identifying growth differences among bacterial strains, it is currently difficult to similarly determine whether bacteriophage strains differ in growth using high throughput methods. Here we use automated spectrophotometry to develop an in vitro method for indirectly distinguishing fitness (growth) differences among virus strains, based on direct measures of their infected bacterial hosts. We used computer simulations of a mathematical model for phage growth to predict which features of bacterial growth curves were best associated with differences in growth among phage strains. We then tested these predictions using the in vitro method to confirm which of the inferred viral growth traits best reflected known fitness differences among genotypes of the RNA phage phi-6, when infecting a Pseudomonas syringae host. Results showed that the inferred phage trait of time-to-extinction (time required to drive bacterial density below detectable optical density) reliably correlated with genotype rankings based on absolute fitness (phage titer per ml). These data suggested that the high-throughput analysis was valuable for identifying growth differences among virus strains, and that the method may be especially useful for high throughput analyses of fitness differences among phage strains cultured and/or evolved in liquid (unstructured) environments. PMID- 22101311 TI - A critical assessment of the occurrence and extend of oxygen contamination during anaerobic incubations utilizing commercially available vials. AB - For rate determinations of anaerobic metabolism it is essential to maintain strictly anoxic conditions throughout the experiment. However, even if oxygen contamination can be avoided while preparing the incubation containers, it is still possible that the incubation containers themselves contaminate the samples by oxygen diffusing from or through their plastic or rubber components. In this study, we investigated the sources and extent of oxygen contamination during anoxic incubations, and present solutions to minimize oxygen contamination. In particular, we investigated oxygen contamination in Labco(r) Exetainers, glass vials with a butyl rubber septum in the screw cap, which are frequently used in microbiological experiments. Our results show that significant oxygen contamination occurred at different stages during the incubation. Contamination occurred when Exetainers were either filled or incubated for more than 16h under oxic atmosphere, but also under an oxygen-free atmosphere due to diffusion of oxygen out of the butyl rubber septum. Therefore, to avoid oxygen contamination during incubations, we suggest (1) filling and incubating the incubation containers under anoxic atmosphere (glove bag) and (2) deoxygenating all elastomers in sample processing and incubation equipment. If initial oxygen contamination cannot be avoided, introduction of an anoxic headspace might help extract oxygen from the incubated sample and present a buffer against oxygen diffusing out of the septum. We modeled the amount of oxygen diffusing out of butyl rubber septa under different conditions, and results fitted well with the observed oxygen contamination. Thus, the model can be used to predict oxygen contamination under varying conditions and for differently sized septa. PMID- 22101316 TI - Emerging technologies for enabling proangiogenic therapy. AB - Ischemic disease causes a large number of deaths and significant clinical problems worldwide. Therapeutic angiogenesis, strengthened by advances in growth factor-based therapies, is a promising solution to ischemic pathologies. Major challenges in therapeutic angiogenesis are the lack of stability of native angiogenic proteins and also providing sustained delivery of biologically active proteins at the ischemic sites. This paper will discuss various protein engineering strategies to develop stabilized proangiogenic proteins and several biomaterial technologies used to amplify the angiogenic outcome by delivering biologically active growth factors in a sustained manner. PMID- 22101317 TI - The role of the ENaC-regulatory complex in aldosterone-mediated sodium transport. AB - The mineralocorticoid aldosterone is indispensable for the control of blood pressure and fluid volume in mammals. It acts in large part to increase the abundance and activity of the epithelial Na(+) channel (ENaC), which mediates apical Na(+) entry in the distal parts of the kidney tubules. Aldosterone acts through the mineralocorticoid receptor to alter the transcription of specific genes, including SGK1 and GILZ1. Recent evidence suggests that these key aldosterone-regulated factors function within a unique multi-protein ENaC regulatory-complex that governs the net cell surface expression and activity of the channel. Another aldosterone-induced protein, CNK3 (connector enhancer of kinase suppressor of Ras 3), also stimulates ENaC and has all of the features of a scaffolding protein. With these observations in mind, we discuss the possibility that CNK3 coordinates the dynamic assembly of the ENaC-regulatory complex, and promotes context-appropriate aldosterone signal transduction in the regulation of epithelial Na(+) transport. PMID- 22101318 TI - Novel signaling mechanisms in the ovary during oocyte maturation and ovulation. AB - During the peri-ovulatory period, the gonadotropin LH triggers major changes in both the somatic and germ cell compartments of the ovarian follicle. The oocyte completes the meiotic cell cycle to become a fertilizable egg, and dramatic changes in gene expression and secretion take place in the somatic compartment of the follicle in preparation for follicular rupture and oocyte release. The concerted changes are regulated by activation of intracellular signaling pathways as well as paracrine and autocrine regulatory loops. This review will provide a summary of the current knowledge of the molecular events triggered by LH focusing mostly on the signaling pathways required for oocyte maturation. PMID- 22101319 TI - Hyperglycosylated hCG, hCGbeta and Hyperglycosylated hCGbeta: interchangeable cancer promoters. AB - INTRODUCTION: Several groups are researching cancers, and showing that hCGbeta is a promoter of cancer growth and malignancy. Recent research shows that some hCGbeta is present as Hyperglycosylated hCGbeta. Other groups studied Hyperglycosylated hCG as a promoter of choriocarcinoma and germ cell malignancies. The question therefore arises, are Hyperglycosylated hCG, hCGbeta and Hyperglycosylated hCGbeta interrelated or interchangable promoters of cancer? METHODS: The actions of Hyperglycosylated hCGbeta, hCGbeta and Hyperglycosylated hCG are investigated in 7 cell lines, Jar and JEG-3 choriocarcinoma cell lines, NTERA germ cell cancer line, SCaBER and T24 bladder epithelial carcinoma lines, KLE and Hec-1-a endometrial adenocarcinoma and epithelial carcinoma cell lines. Actions of promoters on cell growth are investigated. RESULTS: The actions of Hyperglycosylated hCG, hCGbeta and Hyperglycosylated hCGbeta appear to be interchangeable in all cell lines investigated. DISCUSSION: All hCG-related cancer promoters seem interrelated, working through a similar mechanism, antagonism of apoptosis through know receptors such as TGFbeta receptors in all cancers studied. PMID- 22101320 TI - Peroxisome proliferator-activated receptor-alpha agonists modulate CXCL9 and CXCL11 chemokines in Graves' ophthalmopathy fibroblasts and preadipocytes. AB - Peroxisome proliferator-activated receptors (PPAR)alpha have been shown to exert immunomodulatory effects in autoimmune disorders; no study evaluated the effect of PPARalpha activation in Graves' ophthalmopathy (GO). We show the presence of PPARalpha, delta and gamma in GO fibroblasts and preadipocytes. PPARalpha activators have a potent inhibitory action on the secretion of CXCL9 and CXCL11 chemokines (induced by IFNgamma and TNFalpha) in fibroblasts and preadipocytes. The potency of the used PPARalpha agonists was maximum on the secretion of CXCL11 (67% inhibition by fenofibrate) in fibroblasts. The relative potency of the compounds in GO fibroblasts was different with each chemokine. PPARalpha agonists were stronger inhibitors of CXCL9 and CXCL11 (in GO fibroblasts and preadipocytes) than PPARgamma activators. This study first shows that PPARalpha activators inhibit CXCL9 and CXCL11 chemokines in normal and GO fibroblasts and preadipocytes, suggesting that PPARalpha may be involved in the modulation of the immune response in GO. PMID- 22101321 TI - Mild cognitive impairment: pathology and mechanisms. AB - Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follow a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases who died with a clinical diagnosis of MCI. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular, biochemical and molecular deficits, many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI suggests that there is no single event which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drives cognitive decline as a final common pathway at this stage of the dementing disease process. PMID- 22101322 TI - Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. AB - The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer's disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP 43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1-47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI. PMID- 22101323 TI - p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. AB - Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP 43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration. PMID- 22101324 TI - C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology. PMID- 22101325 TI - Targeting cathepsin S induces tumor cell autophagy via the EGFR-ERK signaling pathway. AB - Cathepsin S is a cellular cysteine protease, which is frequently over-expressed in human cancer cells and plays important role in tumor metastasis. However, the role of cathepsin S in regulating cancer cell survival and death remains undefined. The aim of this study was to determine whether targeting cathepsin S could induce autophagy/apoptosis in cancer cells. In this study, we demonstrated that targeting cathepsin S by either specific small molecular inhibitors or cathepsin S siRNA induced autophagy and subsequent apoptosis in human cancer cells, and the induction of autophagy was dependent on the phosphorylation of EGFR and activation of the EGFR-related ERK/MAPK-signaling pathway. In conclusion, the current study reveals that cathepsin S plays an important role in the regulation of cell autophagy through interference with the EGFR-ERK/MAPK signaling pathway. PMID- 22101326 TI - "Turning to one's own world": escape mechanisms employed by immigrant caregivers in Spain for relieving the burden of care. AB - PURPOSE: Although past research has focused on the coping strategies of family caregivers, how immigrant caregivers cope with the demands of caregiving remains unknown. This study examines the strategies immigrant caregivers use to relieve the burden of care. METHOD: A qualitative study based on 17 immigrant women caregivers using purposive and snowball sampling was done. Semistructured interviews and testimonies were obtained and analyzed using grounded theory procedures. FINDINGS: Turning to one's world describes how caregivers seek relief from the burden of care. They escape virtually, go to a private place, make those they care for their own, and decide to go home. These mechanisms enable them to escape from the world of caregiving in which they find themselves. DISCUSSION: Findings reveal the significance of family connections and networks for immigrants to achieve burden relief. IMPLICATIONS: The importance of promoting positive working environments and raising awareness about immigrant caregivers' need for rest. PMID- 22101327 TI - Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin. AB - Sister chromatid cohesion, mediated by cohesin and regulated by Sororin, is essential for chromosome segregation. In mammalian cells, cohesion establishment and Sororin recruitment to chromatin-bound cohesin depends on the acetyltransferases Esco1 and Esco2. Mutations in Esco2 cause Roberts syndrome, a developmental disease in which mitotic chromosomes have a 'railroad' track morphology. Here, we show that Esco2 deficiency leads to termination of mouse development at pre- and post-implantation stages, indicating that Esco2 functions non-redundantly with Esco1. Esco2 is transiently expressed during S-phase when it localizes to pericentric heterochromatin (PCH). In interphase, Esco2 depletion leads to a reduction in cohesin acetylation and Sororin recruitment to chromatin. In early mitosis, Esco2 deficiency causes changes in the chromosomal localization of cohesin and its protector Sgo1. Our results suggest that Esco2 is needed for cohesin acetylation in PCH and that this modification is required for the proper distribution of cohesin on mitotic chromosomes and for centromeric cohesion. PMID- 22101328 TI - Directionality of individual kinesin-5 Cin8 motors is modulated by loop 8, ionic strength and microtubule geometry. AB - Kinesin-5 motors fulfil essential roles in mitotic spindle morphogenesis and dynamics as slow, processive microtubule (MT) plus-end directed motors. The Saccharomyces cerevisiae kinesin-5 Cin8 was found, surprisingly, to switch directionality. Here, we have examined directionality using single-molecule fluorescence motility assays and live-cell microscopy. On spindles, Cin8 motors mostly moved slowly (~25 nm/s) towards the midzone, but occasionally also faster (~55 nm/s) towards the spindle poles. In vitro, individual Cin8 motors could be switched by ionic conditions from rapid (380 nm/s) and processive minus-end to slow plus-end motion on single MTs. At high ionic strength, Cin8 motors rapidly alternated directionalities between antiparallel MTs, while driving steady plus end relative sliding. Between parallel MTs, plus-end motion was only occasionally observed. Deletion of the uniquely large insert in loop 8 of Cin8 induced bias towards minus-end motility and affected the ionic strength-dependent directional switching of Cin8 in vitro. The deletion mutant cells exhibited reduced midzone directed motility and efficiency to support spindle elongation, indicating the importance of directionality control for the anaphase function of Cin8. PMID- 22101329 TI - Opposing effects of positive and negative stress on hippocampal plasticity over the lifespan. AB - Early developmental experience shapes neuronal circuits and influences the trajectory of cognitive aging. Just as adversity early in life can accelerate age related synaptic impairments, enhancement of neuronal metabolism and function in the developing brain could potentially protect neurons against the synaptic consequences of aging. In this regard, metabolic enhancements following exercise directly oppose the deleterious consequences of adverse stress. In this review, we examine the relationship between exercise and other forms of stress over the lifespan. Exercise is a specialized form of stress in that it is predictable and voluntary, while other forms of psychological and physiological stress are unpredictable and uncontrollable, with distinct consequences for behavior and synaptic plasticity. Themes emerging from the literature surrounding the opposing effects of adversity and exercise include epigenetic mechanisms that converge on the regulation of neurotrophic factor expression and neurogenesis. These data suggest that exercise-induced neuroprotection and neuronal endangerment following adversity may both be transferable across generations, in a manner that has the potential to impact neuroplasticity over the lifespan. PMID- 22101330 TI - Effects of physical exercise therapy on mobility, physical functioning, physical activity and quality of life in community-dwelling older adults with impaired mobility, physical disability and/or multi-morbidity: a meta-analysis. AB - This is the first meta-analysis focusing on elderly patients with mobility problems, physical disability and/or multi-morbidity. The aim of this study is to assess the effect of physical exercise therapy on mobility, physical functioning, physical activity and quality of life. A broad systematic literature search was performed in the databases PubMed, CINAHL, Embase, PEDro and The Cochrane Library. Relevant study characteristics were reviewed and meta-analyses using standardized mean differences (SMDs) were performed. The results show that physical exercise therapy has a positive effect on mobility (SMD final value: 0.18; 95% CI: 0.05, 0.30; SMD change value: 0.82; 95% CI: 0.54, 1.10) and physical functioning (SMD final value: 0.27; 95% CI: 0.08, 0.46; SMD change value: 2.93; 95% CI: 2.50, 3.36). High-intensity exercise interventions seem to be somewhat more effective in improving physical functioning than low-intensity exercise interventions (SMD final value: 0.22; 95% CI: -0.17, 0.62; SMD change value: 0.38; 95% CI: -0.48, 1.25). These positive effects are of great value for older adults who are already physically impaired. The effect on physical activity and quality of life was not evident and no definite conclusions on the most effective type of physical exercise therapy intervention can be drawn. PMID- 22101331 TI - Detection of BrdU-label retaining cells in the lacrimal gland: implications for tissue repair. AB - The purpose of the present study was to determine if the lacrimal gland contains 5-bromo-2'-deoxyuridine (BrdU)-label retaining cells and if they are involved in tissue repair. Animals were pulsed daily with BrdU injections for 7 consecutive days. After a chase period of 2, 4, or 12 weeks, the animals were sacrificed and the lacrimal glands were removed and processed for BrdU immunostaining. In another series of experiments, the lacrimal glands of 12-week chased animals were either left untreated or were injected with interleukin 1 (IL-1) to induce injury. Two and half days post-injection, the lacrimal glands were removed and processed for BrdU immunostaining. After 2 and 4 weeks of chase period, a substantial number of lacrimal gland cells were BrdU(+) (11.98 +/- 1.84 and 7.95 +/- 1.83 BrdU(+) cells/mm(2), respectively). After 12 weeks of chase, there was a 97% decline in the number of BrdU(+) cells (0.38 +/- 0.06 BrdU(+) cells/mm(2)), suggesting that these BrdU-label retaining cells may represent slow-cycling adult stem/progenitor cells. In support of this hypothesis, the number of BrdU labeled cells increased over 7-fold during repair of the lacrimal gland (control: 0.41 +/ 0.09 BrdU(+) cells/mm(2); injured: 2.91 +/- 0.62 BrdU(+) cells/mm(2)). Furthermore, during repair, among BrdU(+) cells 58.2 +/- 3.6 % were acinar cells, 26.4 +/- 4.1% were myoepithelial cells, 0.4 +/- 0.4% were ductal cells and 15.0 +/- 3.0% were stromal cells. We conclude that the murine lacrimal gland contains BrdU-label retaining cells that are mobilized following injury to generate acinar, myoepithelial and ductal cells. PMID- 22101332 TI - The role of TGF-beta in the pathogenesis of primary open-angle glaucoma. AB - Transforming growth factor-beta2 (TGF-beta2) is found in increasing amounts in aqueous humor and reactive optic nerve astrocytes of patients with primary open angle glaucoma (POAG), a major cause of blindness worldwide. The available data strongly indicate that TGF-beta2 is a key player contributing to the structural changes in the extracellular matrix (ECM) of the trabecular meshwork and optic nerve head as characteristically seen in POAG. The changes involve an induction in the expression of various ECM molecules and are remarkably similar in trabecular meshwork cells and optic nerve head astrocytes. The ECM changes in the trabecular meshwork most probably play a role in the increase of aqueous humor outflow resistance causing higher intraocular pressure (IOP). In the optic nerve head, TGF-beta2-induced changes might contribute to deformation of the optic nerve axons causing impairment of axonal transport and neurotrophic supply and leading to their continuous degeneration. The increase in IOP further adds mechanical stress and strain to optic nerve axons and accelerates degenerative changes. In addition, high IOP might induce the expression of activated TGF-beta1 in trabecular meshwork cells and optic nerve head astrocytes; this again might significantly lead to the progress of axonal degeneration. The action of TGF beta2 in POAG is largely mediated through the connective tissue growth factor, whereas the activities of TGF-beta1 and -beta2 are modulated by the blocking effects of bone morphogenetic protein-4 (BMP-4) and BMP-7, by gremlin that inhibits BMP signaling and by several species of microRNAs. PMID- 22101333 TI - Dynamics of Mycobacterium leprae transmission in environmental context: deciphering the role of environment as a potential reservoir. AB - Leprosy is a disease caused by Mycobacterium leprae. Various modes of transmission have been suggested for this disease. Transmission and risk of the infection is perhaps related to presence of the infectious cases and is controlled by environmental factors. Evidence suggests that humidity may favor survival of M. leprae in the environment. Several reports show that non-human sources like 'naturally' infected armadillos or monkeys could act as reservoir for M. leprae. Inanimate objects or fomites like articles used by infectious patients may theoretically spread infection. However, it is only through detailed knowledge of the biodiversity and ecology that the importance of this mode of transmission can be fully assessed. Our study focuses here to decipher the role of environment in the transmission of the disease. Two hundred and seven soil samples were collected from a village in endemic area where active cases also resided at the time of sample collection. Slit skin smears were collected from 13 multibacillary (MB) leprosy patients and 12 household contacts of the patients suspected to be hidden cases. DNA and RNA of M. leprae were extracted and amplified using M. leprae specific primers. Seventy-one soil samples showed presence of M. leprae DNA whereas 16S rRNA could be detected in twenty-eight of these samples. Samples, both from the environment and the patients, exhibited the same genotype when tested by single nucleotide polymorphism (SNP) typing. Genotype of M. leprae found in the soil and the patients residing in the same area could help in understanding the transmission link in leprosy. PMID- 22101334 TI - Estimation of absolute protein quantities of unlabeled samples by selected reaction monitoring mass spectrometry. AB - For many research questions in modern molecular and systems biology, information about absolute protein quantities is imperative. This information includes, for example, kinetic modeling of processes, protein turnover determinations, stoichiometric investigations of protein complexes, or quantitative comparisons of different proteins within one sample or across samples. To date, the vast majority of proteomic studies are limited to providing relative quantitative comparisons of protein levels between limited numbers of samples. Here we describe and demonstrate the utility of a targeting MS technique for the estimation of absolute protein abundance in unlabeled and nonfractionated cell lysates. The method is based on selected reaction monitoring (SRM) mass spectrometry and the "best flyer" hypothesis, which assumes that the specific MS signal intensity of the most intense tryptic peptides per protein is approximately constant throughout a whole proteome. SRM-targeted best flyer peptides were selected for each protein from the peptide precursor ion signal intensities from directed MS data. The most intense transitions per peptide were selected from full MS/MS scans of crude synthetic analogs. We used Monte Carlo cross-validation to systematically investigate the accuracy of the technique as a function of the number of measured best flyer peptides and the number of SRM transitions per peptide. We found that a linear model based on the two most intense transitions of the three best flying peptides per proteins (TopPep3/TopTra2) generated optimal results with a cross-correlated mean fold error of 1.8 and a squared Pearson coefficient R(2) of 0.88. Applying the optimized model to lysates of the microbe Leptospira interrogans, we detected significant protein abundance changes of 39 target proteins upon antibiotic treatment, which correlate well with literature values. The described method is generally applicable and exploits the inherent performance advantages of SRM, such as high sensitivity, selectivity, reproducibility, and dynamic range, and estimates absolute protein concentrations of selected proteins at minimized costs. PMID- 22101335 TI - Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. AB - Previous studies have demonstrated that curcumin induces mitochondria-mediated apoptosis. However, understanding of the molecular mechanisms underlying curcumin induced cell death remains limited. In this study, we demonstrate that curcumin treatment of cancer cells caused dose- and time-dependent caspase-3 activation, which is required for apoptosis as confirmed using the pan caspase inhibitor, z VAD. Knockdown experiments and knockout cells excluded a role of caspase-8 in curcumin-induced caspase-3 activation. In contrast, Apaf-1 deficiency or silencing inhibited the activity of caspase-3, pointing to a requisite role of Apaf-1 in curcumin-induced apoptotic cell death. Curcumin treatment led to Apaf-1 upregulation both at the protein and mRNA levels. Cytochrome c release from mitochondria to the cytosol in curcumin-treated cells was associated with upregulation of proapoptotic proteins such as Bax, Bak, Bid, and Bim. Crosslinking experiments demonstrated Bax oligomerization during curcumin-induced apoptosis, suggesting that induced expression of Bax, Bid, and Bim causes Bax channel formation on the mitochondrial membrane. The release of cytochrome c was unaltered in p53-deficient cells, whereas absence of p21 blocked cytochrome c release, caspase activation, and apoptosis. Importantly, p21-deficiency resulted in reduced expression of Apaf-1 during curcumin treatment, indicating a requirement of p21 in Apaf-1 dependent caspase activation and apoptosis. Together, our findings demonstrate that Apaf-1, Bax, and p21 as novel potential targets for curcumin or curcumin-based anticancer agents. PMID- 22101336 TI - Uncertainty analysis in protein disorder prediction. AB - A grand challenge in the proteomics and structural genomics era is the prediction of protein structure, including identification of those proteins that are partially or wholly unstructured. A number of predictors for identification of intrinsically disordered proteins (IDPs) have been developed over the last decade, but none can be taken as a fully reliable on its own. Using a single model for prediction is typically inadequate because prediction based on only the most accurate model ignores model uncertainty. In this paper, we present an empirical method to specify and measure uncertainty associated with disorder predictions. In particular, we analyze the uncertainty in the reference model itself and the uncertainty in data. This is achieved by training a set of models and developing several meta predictors on top of them. The best meta predictor achieved comparable or better results than any other single model, suggesting that incorporating different aspects of protein disorder prediction is important for the disorder prediction task. In addition, the best meta-predictor had more balanced sensitivity and specificity than any individual model. We also assessed the effects of changes in disorder prediction as a function of changes in the protein sequence. For collections of homologous sequences, we found that mutations caused many of the predicted disordered residues to be flipped to be predicted as ordered residues, while the reverse was observed much less frequently. These results suggest that disorder tendencies are more sensitive to allowed mutations than structure tendencies and the conservation of disorder is indeed less stable than conservation of structure. AVAILABILITY: five meta predictors and four single models developed for this study will be publicly freely accessible for non-commercial use. PMID- 22101337 TI - Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent. AB - Targeting DNA repair with poly(ADP-ribose) polymerase (PARP) inhibitors has shown a broad range of anti-tumor activity in patients with advanced malignancies with and without BRCA deficiency. It remains unclear what role p53 plays in response to PARP inhibition in BRCA-proficient cancer cells treated with DNA damaging agents. Using gene expression microarray analysis, we find that DNA damage response (DDR) pathways elicited by veliparib (ABT-888), a PARP inhibitor, plus topotecan comprise the G1/S checkpoint, ATM, and p53 signaling pathways in p53 wildtype cancer cell lines and BRCA1, BRCA2 and ATR pathway in p53-mutant lines. In contrast, topotecan alone induces the G1/S checkpoint pathway in p53-wildtype lines and not in p53-mutant cells. These responses are coupled with G2/G1 checkpoint effectors p21(CDKN1A) upregulation, and Chk1 and Chk2 activation. The drug combination enhances G2 cell cycle arrest, apoptosis and a marked increase in cell death relative to topotecan alone in p53-wildtype and p53-mutant or -null cells. We also show that the checkpoint kinase inhibitor UCN-01 abolishes the G2 arrest induced by the veliparib and topotecan combination and further increases cell death in both p53-wildtype and -mutant cells. Collectively, PARP inhibition by veliparib enhances DDR and cell death in BRCA-proficient cancer cells in a p53 dependent and -independent fashion. Abrogating the cell-cycle arrest induced by PARP inhibition plus chemotherapeutics may be a strategy in the treatment of BRCA proficient cancer. PMID- 22101338 TI - Phosphorylation of NuSAP by Cdk1 regulates its interaction with microtubules in mitosis. AB - Cell division in eukaryotes depends on a fine control of the dynamic changes of microtubules. Nucleolar and spindle-associated protein (NuSAP) is a microtubule binding and -bundling protein essential for the integrity of the anaphase spindle and cell division. NuSAP contains two consensus cdk phosphorylation sites in its microtubule-binding domain. Here we show NuSAP is phosphorylated by cdk1 in early mitosis. This phosphorylation inhibits the binding of NuSAP to microtubules. During metaphase-to anaphase transition, NuSAP is dephosphorylated to promote spindle midzone formation and cell cycle progression. Expression of cdk1 phosphorylation-null mutant causes extensive bundling of microtubules in the prometaphase spindle. Our results suggest that phosphorylation and dephosphorylation of NuSAP during progression of mitosis regulate spindle organization through modulation of the dynamics of microtubules. PMID- 22101339 TI - Sensitivity of acute myeloid leukemia Kasumi-1 cells to binase toxic action depends on the expression of KIT and AML1-ETO oncogenes. AB - Some RNases selectively attack malignant cells, triggering an apoptotic response, and therefore are considered as alternative chemotherapeutic drugs. Here we studied the effects of Bacillus intermedius RNase (binase) on murine myeloid progenitor cells FDC-P1; transduced FDC-P1 cells ectopically expressing mutated human KIT N822K oncogene and/or human AML1-ETO oncogene; and human leukemia Kasumi-1 cells expressing both of these oncogenes. Expression of both KIT and AML1-ETO oncogenes makes FDC-P1 cells sensitive to the toxic effects of binase. Kasumi-1 cells were the most responsive to the toxic actions of binase among the cell lines used in this work with an IC50 value of 0.56 uM. Either blocking the functional activity of the KIT protein with imatinib or knocking-down oncogene expression using lentiviral vectors producing shRNA against AML1-ETO or KIT eliminated the sensitivity of Kasumi-1 cells to binase toxic action and promoted their survival, even in the absence of KIT-dependent proliferation and antiapoptotic pathways. Here we provide evidence that the cooperative effect of the expression of mutated KIT and AML1-ETO oncogenes is crucial for selective toxic action of binase on malignant cells. These findings can facilitate clinical applications of binase providing a useful screen based on the presence of the corresponding target oncogenes in malignant cells. PMID- 22101341 TI - Coordinate inactivation of zinc finger transcription factors at mitosis. PMID- 22101340 TI - Orchestrating the nucleases involved in DNA interstrand cross-link (ICL) repair. AB - DNA interstrand cross-links (ICLs) pose a significant threat to genomic and cellular integrity by blocking essential cellular processes, including replication and transcription. In mammalian cells, much ICL repair occurs in association with DNA replication during S phase, following the stalling of a replication fork at the block caused by an ICL lesion. Here, we review recent work showing that the XPF-ERCC1 endonuclease and the hSNM1A exonuclease act in the same pathway, together with SLX4, to initiate ICL repair, with the MUS81-EME1 fork incision activity becoming important in the absence of the XPF-SNM1A-SLX4 dependent pathway. Another nuclease, the Fanconi anemia-associated nuclease (FAN1), has recently been implicated in the repair of ICLs, and we discuss the possible ways in which the activities of different nucleases at the ICL-stalled replication fork may be coordinated. In relation to this, we briefly speculate on the possible role of SLX4, which contains XPF and MUS81- interacting domains, in the coordination of ICL repair nucleases. PMID- 22101342 TI - Thromboxane A2 receptor +795T>C and chemoattractant receptor-homologous molecule expressed on Th2 cells -466T>C gene polymorphisms in patients with aspirin exacerbated respiratory disease. AB - It is well known that aspirin-exacerbated respiratory disease (AERD) is more common in women than in men, however, whether gene polymorphisms of the thromboxane A2 receptor (TBXA2R) and chemoattractant receptor-homologous molecules expressed on Th2 cells (CRTH2) are associated with the susceptibility of AERD remains unknown. In this study, we examined the gene polymorphisms in a Japanese population. DNA specimens were obtained from the following three groups: 96 patients with AERD, 500 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. The target DNA sequence of each gene was amplified, and an allelic discrimination assay for single nucleotide polymorphisms relating to expression of each gene was carried out. The frequencies of the CC/CT genotype of TBXA2R +795T>C were higher than those of the TT genotype in AERD patients compared to ATA patients (P=0.015). In female AERD patients, but not in males, frequencies of the CC/CT genotype were higher than those of the TT genotype of TBXA2R +795T>C compared to female ATA patients (P=0.013). Also, frequencies of the TT genotype of CRTH2 -466T>C were higher than those of the CC/CT genotype in AERD patients compared to ATA patients (P=0.034). In female AERD patients, but not in male, frequencies of the TT genotype were higher than those of the CC/CT genotype of CRTH2 -466T>C in AERD patients compared to female ATA patients (P=0.046). Based on our investigations, no significant relationship was found between the genotype and the clinical characteristics according to these gene polymorphisms in AERD patients. Our results suggest that an association between the TBXA2R and CRTH2 gene polymorphisms with AERD may exist in the Japanese population. PMID- 22101343 TI - Reprogramming efficiency and quality of induced Pluripotent Stem Cells (iPSCs) generated from muscle-derived fibroblasts of mdx mice at different ages. AB - Induced pluripotent stem cells (iPSCs) hold promise as a potential treatment for Duchenne muscular dystrophy (DMD). To determine the impact of the donor's age on reprogramming, we generated iPSCs from muscle-derived fibroblasts (MuFs) of mdx mice aged 6 weeks, 6 months, and 14 months. MuFs from 14-month-old mdx mice showed lower proliferative activity and lower reprogramming efficiency, compared with those from younger mdx mice. Furthermore, iPSCs derived from 14-month-old mdx mice (14m-MuF-iPSCs) gradually lost Nanog expression, and regressed in conventional ES medium during passages. Interestingly, inhibition of TGF-beta signaling and BMP signaling stabilized Nanog expression and promoted self-renewal of 14m-MuF-iPSCs. Finally, rescued mdx-derived iPSCs efficiently differentiated into the skeletal muscle lineage. PMID- 22101344 TI - A second generation integrated map of the rainbow trout (Oncorhynchus mykiss) genome: analysis of conserved synteny with model fish genomes. AB - DNA fingerprints and end sequences from bacterial artificial chromosomes (BACs) from two new libraries were generated to improve the first generation integrated physical and genetic map of the rainbow trout (Oncorhynchus mykiss) genome. The current version of the physical map is composed of 167,989 clones of which 158,670 are assembled into contigs and 9,319 are singletons. The number of contigs was reduced from 4,173 to 3,220. End sequencing of clones from the new libraries generated a total of 11,958 high quality sequence reads. The end sequences were used to develop 238 new microsatellites of which 42 were added to the genetic map. Conserved synteny between the rainbow trout genome and model fish genomes was analyzed using 188,443 BAC end sequence (BES) reads. The fractions of BES reads with significant BLASTN hits against the zebrafish, medaka, and stickleback genomes were 8.8%, 9.7%, and 10.5%, respectively, while the fractions of significant BLASTX hits against the zebrafish, medaka, and stickleback protein databases were 6.2%, 5.8%, and 5.5%, respectively. The overall number of unique regions of conserved synteny identified through grouping of the rainbow trout BES into fingerprinting contigs was 2,259, 2,229, and 2,203 for stickleback, medaka, and zebrafish, respectively. These numbers are approximately three to five times greater than those we have previously identified using BAC paired ends. Clustering of the conserved synteny analysis results by linkage groups as derived from the integrated physical and genetic map revealed that despite the low sequence homology, large blocks of macrosynteny are conserved between chromosome arms of rainbow trout and the model fish species. PMID- 22101345 TI - A study of phytohormone biosynthetic gene expression using a circadian clock related mutant in rice. AB - We have recently isolated a rice circadian clock-related mutant carrying a null mutation in Os-GIGANTEA(GI) gene, the solo ortholog of Arabidopsis GI. Time course global transcriptome analyses of leaves from wild-type and osgi mutant grown in the field have revealed that Os-GI affects gene expression of more than half of genes on rice 44k microarray. To better understand the biological significance of circadian clock function in growth and development of rice, we here investigated the gene expression involved in phytohormone biosynthesis. Here we found that mRNA levels of a few major genes encoding GA2-oxidase which can inactivate bioactive gibberellins (GAs) were remarkably increased in osgi-1 plants. This suggests that Os-GI functions to maintain bioactive GA level through the regulation of the GA-deactivating enzyme genes in rice. Consistently, osgi-1 plants showed semi-dwarf phenotype with reduced internode and leaf sheath elongation. PMID- 22101346 TI - Mitochondrial dysfunction affects chloroplast functions. AB - The transcriptomic response of A9:u-ATP9 and apetala3:u-ATP9 lines carrying a mitochondrial dysfunction in flower tissues has been characterized. Both lines showed an alteration in the transcription of several genes involved in carbon and nitrogen metabolism, stress responses, transcription factors and DNA binding proteins. Interestingly, several transcripts of photosynthetic-related genes were also affected in their expression such as the mRNAs encoding for chlorophyllase, chlorophyll binding proteins and a PSII. Moreover, chlorophyll levels were reduced and the Mg-dechelatase activity was increased, indicating an alteration in chlorophyll metabolism. Our results suggest that the mitochondrial dysfunction may also affect chloroplastic functions, and that our model could be useful to uncover retrograde signaling mechanisms operating between the three different plant genomes. PMID- 22101347 TI - Auxin-induced leaf blade expansion in Arabidopsis requires both wounding and detachment. AB - Elevation of leaf auxin (indole-3-acetic acid; IAA) levels in intact plants has been consistently found to inhibit leaf expansion whereas excised leaf strips grow faster when treated with IAA. Here we test two hypothetical explanations for this difference in growth sensitivity to IAA by expanding leaf tissues in vivo versus in vitro. We asked if, in Arabidopsis, IAA-induced growth of excised leaf strips results from the wounding required to excise tissue and/or results from detachment from the plant and thus loss of some shoot or root derived growth controlling factors. We tested the effect of a range of exogenous IAA concentrations on the growth of intact attached, wounded attached, detached intact, detached wounded as well as excised leaf strips. After 24 h, the growth of intact attached, wounded attached, and detached intact leaves was inhibited by IAA concentrations as little as 1 uM in some experiments. Growth of detached wounded leaves and leaf strips was induced by IAA concentrations as low as 10 uM. Stress, in the form of high light, increased the growth response to IAA by leaf strips and reduced growth inhibition response by intact detached leaves. Endogenous free IAA content of intact attached leaves and excised leaf strips was found not to change over the course of 24 h. Together these results indicate growth induction of Arabidopsis leaf blade tissue by IAA requires both substantial wounding as well as detachment from the plant and suggests in vivo that IAA induces parallel pathways leading to growth inhibition. PMID- 22101350 TI - Screening of protein crystallization trials by second order nonlinear optical imaging of chiral crystals (SONICC). AB - Second order nonlinear optical imaging of chiral crystals (SONICC) is a promising new method for the sensitive and selective detection of protein crystals. Relevant general principles of second harmonic generation, which underpins SONICC, are reviewed. Instrumentation and methods for SONICC measurements are described and critically assessed in terms of performance trade-offs. Potential origins of false-positives and false-negatives are also discussed. PMID- 22101351 TI - Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia. AB - Increased numbers of T regulatory (T(reg)) cells are found in B-chronic lymphocytic leukemia, but the nature and function of these T(regs) remains unclear. Detailed characterization of the T(regs) in chronic lymphocytic leukemia has not been performed and the degree of heterogeneity of among these cells has not been studied to date. Using 15-color flow cytometry we show that T(reg) cells, defined using CD4, CD25, and forkhead box P3 (FOXP3), can be divided into multiple complex subsets based on markers used for naive, memory, and effector delineation as well as markers of T(reg) activation. Furthermore FOXP3(+) cells can be identified among CD4(+)CD25(-) as well as CD8(+)CD4(-) populations in increased proportions in patients with chronic lymphocytic leukemia compared with healthy donors. Significantly different frequencies of naive and effector T(regs) populations are found in healthy donor controls compared with donors with chronic lymphocytic leukemia. A population of CCR7(+)CD39(+) T(regs) was significantly associated with chronic lymphocytic leukemia. This population demonstrated slightly reduced suppressive activity compared with total T(regs) or T(regs) of healthy donors. These data suggest that FOXP3-expressing cells, particularly in patients with chronic lymphocytic leukemia are much more complex for T(reg) sub populations and transitions than previously reported. These findings demonstrate the complexity of regulation of T-cell responses in chronic lymphocytic leukemia and illustrate the use of high-dimensional analysis of cellular phenotypes in facilitating understanding of the intricacies of cellular immune responses and their dysregulation in cancer. PMID- 22101352 TI - Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. AB - Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki 67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (P<0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P=0.03) predictor of reduced progression-free survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P=0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma. PMID- 22101353 TI - A newly-designed PE-supported arsine for efficient and practical catalytic Wittig olefination. AB - A newly designed PE-supported arsine has been developed as an excellent catalyst for catalytic Wittig-type olefination. Simple ketones, in particular inactive ketones prove to be suitable substrates for the first time. This reaction provides an easy access to di-, tri-, and tetra-substituted olefins in high yield. PMID- 22101354 TI - Nanoengineering a single-molecule mechanical switch using DNA self-assembly. AB - The ability to manipulate and observe single biological molecules has led to both fundamental scientific discoveries and new methods in nanoscale engineering. A common challenge in many single-molecule experiments is reliably linking molecules to surfaces, and identifying their interactions. We have met this challenge by nanoengineering a novel DNA-based linker that behaves as a force activated switch, providing a molecular signature that can eliminate errant data arising from non-specific and multiple interactions. By integrating a receptor and ligand into a single piece of DNA using DNA self-assembly, a single tether can be positively identified by force-extension behavior, and receptor-ligand unbinding easily identified by a sudden increase in tether length. Additionally, under proper conditions the exact same pair of molecules can be repeatedly bound and unbound. Our approach is simple, versatile and modular, and can be easily implemented using standard commercial reagents and laboratory equipment. In addition to improving the reliability and accuracy of force measurements, this single-molecule mechanical switch paves the way for high-throughput serial measurements, single-molecule on-rate studies, and investigations of population heterogeneity. PMID- 22101355 TI - Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex. AB - RATIONALE: Previous work has demonstrated a profound effect of N-methyl-D: aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear. OBJECTIVES: This series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output. METHODS: Drugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL. RESULTS: Systemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-L: phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor DL: -threo-beta-benzyloxyaspartate as well as local alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABA(A) receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABA(A) receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL. CONCLUSIONS: These findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism. PMID- 22101356 TI - Impact of the COMT Val(108/158)Met polymorphism on the mu-opioid receptor system in the human brain: mu-opioid receptor, met-enkephalin and beta-endorphin expression. AB - The Val(108/158)Met polymorphism of the catechol-O-methyltransferase gene (COMT) is known to interact with the function of various neuroreceptor systems in the brain. We have recently shown by post-mortem receptor autoradiography that the number of mu-opioid (MOP) receptor binding sites depends on the number of COMT Met(108/158) alleles in distinct human brain regions. We now investigated COMT Val(108/158)Met related levels of the MOP receptor protein and its endogenous ligands met-enkephalin and beta-endorphin in the human frontal cortex, thalamus and basal ganglia. Semiquantitative immunostaining and in situ hybridization were applied in a cohort of 17 human brain tissues from healthy donors. MOP receptor protein levels paralleled previous ligand binding results with a significantly higher MOP receptor expression in the mediodorsal nucleus of the thalamus of COMT Met(108/158) allele carriers. Also met-enkephalin peptide levels correlated with the genotype in this structure, with the lowest expression in COMT Met(108/158) homozygous individuals. Beta-endorphin was not detectable in the cortex, basal ganglia or thalamus, and therefore is unlikely to contribute to changes of the MOP receptor system. These results confirm the impact of the COMT Val(108/158)Met polymorphism on the MOP receptor system and may support the hypothesis of an enkephalin related turnover of MOP receptors at least in some brain structures. PMID- 22101357 TI - Distinctive activation patterns under intrinsically versus extrinsically driven cognitive loads in prefrontal cortex: a near-infrared spectroscopy study using a driving video game. AB - To investigate the neural bases of intrinsically and extrinsically driven cognitive loads in daily life, we measured repetitively prefrontal activation in three (one control and two experimental) groups during a driving video game using near-infrared spectroscopy. The control group drove to goal four times with distinct route-maps illustrating default turning points. In contrast, the memory group drove the memorized default route without a route-map, and the emergency group drove with a route-map, but was instructed to change the default route by an extrinsically given verbal command (turn left or right) as an envisioned emergency. The predictability of a turning point in the route in each group was relatively different: due to extrinsic dictate of others in the emergency group, intrinsic memory in the memory group, and route-map aid in the control group. We analyzed concentration changes of oxygenated hemoglobin (CoxyHb) in the three critical periods (pre-turning, actual-turning, and post-turning). The emergency group showed a significantly increasing pattern of CoxyHb throughout the three periods, and a significant reduction in CoxyHb throughout the repetitive trials, but the memory group did not, even though both experimental groups showed higher activation than the control group in the pre-turning period. These results suggest that the prefrontal cortex differentiates the intrinsically (memory) and the extrinsically (dictate of others) driven cognitive loads according to the predictability of turning behavior, although the two types of cognitive loads commonly show increasing activation in the pre-turning period as the preparation effect. PMID- 22101358 TI - An ethnobotanical study of medicinal plants used by the Yaegl Aboriginal community in northern New South Wales, Australia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Documentation of Australian bush medicines is of utmost importance to the preservation of this disappearing and invaluable knowledge. This collaboration between the Yaegl Aboriginal community in northern New South Wales (NSW), Australia and an academic institution, demonstrates an effective means of preserving and adding value to this information. MATERIALS AND METHODS: Questionnaire-guided interviews were performed with community Elders under a framework of participatory action research. Medicinal plant knowledge was collated in a handbook to aid interviews and to be used as an ongoing resource by the community. Specimens for all non-cultivar plants that were discussed were collected and deposited in herbaria with unique voucher numbers. This medicinal knowledge was checked against the literature for reports of related use and studies of biological activity. RESULTS: Nineteen Elders were interviewed, leading to discussions on fifty four plant preparations used for medicinal purposes. These plant preparations involved thirty two plants coming from twenty one families, reflecting the botanical diversity of the area. The plants retained in the Yaegl pharmacopoeia correspond to their accessibility and ease of preparation, reflected in their ongoing utilisation. Several plant uses did not appear elsewhere in the literature. CONCLUSIONS: This study is the first comprehensive documentation of the medicinal knowledge of the Yaegl Aboriginal community. It has been conducted using participatory action research methods and adds to the recorded customary knowledge of the region. The customary medicinal knowledge retained by the Yaegl Aboriginal community is related to the evolving needs of the community and accessibility of plants. PMID- 22101359 TI - Toxicity potentials of the nutraceutical Moringa oleifera at supra supplementation levels. AB - Moringa oleifera Lam. (order -Moringales, family -Moringaceae and genus -Moringa) is a well known nutraceutical used in the treatment of hypercholesterolemia and hyperglycemia, and also, as a nutritional supplementation. Its popularity use raises the question of possible toxicity at supra-supplementation levels. The objective of the study was to ascertain possible acute toxicity with supra supplementation using Sprague-Dawley (S-D) rats. In experiment 1, human peripheral blood mononuclear cells were given graded doses of Moringa oleifera aqueous leaf extract to induce cytotoxicity. In experiment 2, two groups of rats received low and high dose (LD and HD, respectively) levels (1,000 and 3,000 mg/kgb.wt, respectively) per o.s. alongside negative and positive control rats (0.9% saline and 10mg/mL N-ethyl-N-nitrosourea - administered i.m., respectively). Each group consisted of five rats. Rats were killed after 48 h and the femur bone marrow aspirate examined for polychromatic micronucleated erythrocytes (PCEMN)/normochromatic micronucleated erythrocytes (NCEMN) ratios after Giemsa/Leishman staining. In experiment 3, control, LD and HD groups were established. The LD and HD extracts were administered per o.s. to the respective groups and observed for 14 days. Each group consisted of five rats. Blood was sampled after 48 h and 14 days and examined biochemically and haematologically for acute toxicity. Experiment 1 showed that Moringa oleifera was cytotoxic at 20mg/mL. In experiment 2, PCEMN/NCEMN ratios were: negative control=2.087; LD=1.849; HD=1.397; positive control=1.257. Statistically, LD and HD ratios were significant (p=0.020). Experiment 3 showed that hepatonephro-toxicity was nil with no abnormal haematology results. Genotoxicity results have hitherto not been shown. Moringa oleifera is genotoxic at supra-supplementation levels of 3,000 mg/kg b.wt. However, intake is safe at levels <= 1,000 mg/kg b.wt. PMID- 22101360 TI - A phenomenological description of an incoherent Fermi liquid near optimal doping in high Tc cuprates. AB - Marginal Fermi-liquid physics near optimal doping in high T(c) cuprates has been explained within two competing scenarios such as the spin-fluctuation theory based on an itinerant picture and the slave-particle approach based on a localized picture. In this study we propose an alternative scenario for the anomalous transport within the context of the slave-particle approach. Although the marginal Fermi-liquid phenomenology was interpreted previously within deconfinement of the compact gauge theory, referred to as the strange metal phase, we start from confinement, introducing the Polyakov loop parameter into an SU(2) gauge theory formulation of the t-J model. The Polyakov loop parameter gives rise to incoherent electrons through the confinement of spinons and holons, which result from huge imaginary parts of self-energy corrections for spinons and holons. This confinement scenario serves a novel mechanism for the marginal Fermi liquid transport in the respect that the scattering source has nothing to do with symmetry breaking. Furthermore, the incoherent Fermi-liquid state evolves into the Fermi-liquid phase through crossover instead of an artificial second-order transition as temperature is lowered, where the crossover phenomenon does not result from the Anderson-Higgs mechanism but originates from an energy scale in the holon sector. We fit experimental data for the electrical resistivity around the optimal doping and find a reasonable match between our theory and the experiment. PMID- 22101361 TI - Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. AB - PURPOSE: Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. METHODS: iNOS-knockout (iNOS(-/-)) and C57BL/6 (WT, wild type) animals (n = 5-6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. RESULTS: Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS(-/-) mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS(-/-) mice when compared with wild-type animals that were given irinotecan. CONCLUSIONS: This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction. PMID- 22101362 TI - MM/GBSA and LIE estimates of host-guest affinities: dependence on charges and solvation model. AB - The affinities of two sets of guest-host systems were estimated using the popular end-point methods MM/GBSA (molecular-mechanics with generalised Born and surface area solvation) and LIE (linear interaction energy). A set of six primary alcohols that bind to alpha-cyclodextrin (alpha-CD) and a set of eight guest molecules to cucurbit[8]uril (CB8) were considered. Three different charge schemes were used to obtain charges for the host and guest molecules, viz., AM1 BCC, RESP, and the recently suggested xAvESP (which average ESP charges over a number of molecular dynamics snapshots). Furthermore, both the generalised Born and Poisson-Boltzmann solvation models were used in the MM/GBSA calculations. The two solvation models perform equally well in predicting relative affinities, and hence there is no point in using the more expensive Poisson-Boltzmann model for these systems. Both the LIE and MM/GBSA estimates are shown to be robust with respect to the charge model, and therefore it is recommended to use the cheapest AM1-BCC charges. Using AM1-BCC charges, the MM/GBSA method gave a MADtr (mean absolute deviation after removal of systematic error) of 17 kJ/mol and a correlation coefficient (r (2)) of 0.67 for the CB8 complexes, and a MADtr of 10 kJ/mol and an r (2) of 0.96 for the alpha-CD complexes. The LIE method gave a MADtr of 20 kJ/mol and an r (2) of 0.10 for the CB8 complexes, after optimisation of the non-polar scaling parameter. For the alpha-CD complexes, no optimisation was necessary and the method gave a MADtr of 2 kJ/mol and a r (2) of 0.96. These results indicate that both MM/GBSA and LIE are able to estimate host-guest affinities accurately. PMID- 22101363 TI - A computational analysis of the binding mode of closantel as inhibitor of the Onchocerca volvulus chitinase: insights on macrofilaricidal drug design. AB - Onchocerciasis is a leading cause of blindness with at least 37 million people infected and more than 120 million people at risk of contracting the disease; most (99%) of this population, threatened by infection, live in Africa. The drug of choice for mass treatment is the microfilaricidal Mectizan((r)) (ivermectin); it does not kill the adult stages of the parasite at the standard dose which is a single annual dose aimed at disease control. However, multiple treatments a year with ivermectin have effects on adult worms. The discovery of new therapeutic targets and drugs directed towards the killing of the adult parasites are thus urgently needed. The chitinase of filarial nematodes is a new drug target due to its essential function in the metabolism and molting of the parasite. Closantel is a potent and specific inhibitor of chitinase of Onchocerca volvulus (OvCHT1) and other filarial chitinases. However, the binding mode and specificity of closantel towards OvCHT1 remain unknown. In the absence of a crystallographic structure of OvCHT1, we developed a homology model of OvCHT1 using the currently available X-ray structures of human chitinases as templates. Energy minimization and molecular dynamics (MD) simulation of the model led to a high quality of 3D structure of OvCHIT1. A flexible docking study using closantel as the ligand on the binding site of OvCHIT1 and human chitinases was performed and demonstrated the differences in the closantel binding mode between OvCHIT1 and human chitinase. Furthermore, molecular dynamics simulations and free-energy calculation were employed to determine and compare the detailed binding mode of closantel with OvCHT1 and the structure of human chitinase. This comparative study allowed identification of structural features and properties responsible for differences in the computationally predicted closantel binding modes. The homology model and the closantel binding mode reported herein might help guide the rational development of novel drugs against the adult parasite of O. volvulus and such findings could be extrapolated to other filarial neglected diseases. PMID- 22101364 TI - Is there a future for computational chemistry in drug research? AB - Improvements in computational chemistry methods have had a growing impact on drug research. But will incremental improvements be sufficient to ensure this continues? Almost all existing efforts to discover new drugs depend on the classic one target, one drug paradigm, although the situation is changing slowly. A new paradigm that focuses on a more systems biology approach and takes account of the reality that most drugs exhibit some level of polypharmacology is beginning to emerge. This will bring about dramatic changes that can significantly influence the role that computational methods play in future drug research. But these changes require that current methods be augmented with those from bioinformatics and engineering if the field is to have a significant impact on future drug research. PMID- 22101366 TI - The presence of Abeta seeds, and not age per se, is critical to the initiation of Abeta deposition in the brain. AB - The deposition of the beta-amyloid (Abeta) peptide in senile plaques and cerebral Abeta-amyloid angiopathy can be seeded in beta-amyloid precursor protein (APP) transgenic mice by the intracerebral infusion of brain extracts containing aggregated Abeta. Previous studies of seeded beta-amyloid induction have used relatively short incubation periods to dissociate seeded beta-amyloid induction from endogenous beta-amyloid deposition of the host, thus precluding the analysis of the impact of age and extended incubation periods on the instigation and spread of Abeta lesions in brain. In the present study using R1.40 APP-transgenic mice (which do not develop endogenous Abeta deposition up to 15 months of age) we show that: (1) seeding at 9 months of age does not induce more Abeta deposition than seeding at 3 months of age, provided that the incubation period (6 months) is the same; and (2) very long-term (12 months) incubation after a focal application of the seed results in the emergence of Abeta deposits throughout the forebrain. These findings indicate that the presence of Abeta seeds, and not the age of the host per se, is critical to the initiation of Abeta aggregation in the brain, and that Abeta deposition, actuated in one brain area, eventually spreads throughout the brain. PMID- 22101365 TI - National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. AB - We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid beta deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico pathologic correlations. PMID- 22101367 TI - Optineurin is colocalized with ubiquitin in Marinesco bodies. PMID- 22101368 TI - An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene. AB - We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin. PMID- 22101369 TI - Preparation of acute living hippocampal slice from common marmoset (Callithrix jacchus) for synaptic function analysis. AB - We described the preparation of acute living slices from the hippocampus of the neonatal common marmoset (Callithrix jacchus). Slices from a temporal lobe section were prepared quickly using a rotary slicer. By this method, we successfully recorded field potentials, namely, pre-synaptic fiber volley and field excitatory post-synaptic potentials, from the hippocampal CA1 region with conventional electrophysiological techniques, and analyzed the indicators of synaptic function such as input-output curve. This study thus presents an efficient preparation method for acute living hippocampal slice from which synaptic function of the hippocampus in non-human primate can be analyzed. PMID- 22101370 TI - Brain-spinal cord neural circuits controlling male sexual function and behavior. AB - Men and women exhibit differences in sexual behavior. This indicates that neural circuits within the central nervous system (CNS) that control sexual behavior differ between the sexes, although differences in behavior are also influenced by sociocultural and hormonal factors. Sexual differentiation of the body and brain occurs during the embryonic and neonatal periods in humans and persists into adulthood with relatively low plasticity. Male sexual behavior is complex and depends on intrinsic and extrinsic factors, including olfactory, somatosensory and visceral cues. Many advances in our understanding of sexually dimorphic neural circuits have been achieved in animal models, but major issues are yet to be resolved. This review summarizes the sexually dimorphic nuclei controlling male sexual function in the rodent CNS and focuses on the interactions of the brain-spinal cord neural networks controlling male sexual behavior. Possible factors that relate findings from animal studies to human behavior are also discussed. PMID- 22101373 TI - Implications of integrase inhibitors for HIV-infected transplantation recipients: raltegravir and dolutegravir (S/GSK 1349572). AB - In the modern era of highly active antiretroviral therapy (HAART), reluctance to perform transplantation (Tx) in HIV-infected individuals is no longer justified. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs), the current first line regimens of HAART, are metabolized by the cytochrome P450 family (CYP3A4). Most NNRTIs induce CYP3A4, whereas PIs inhibit it. Calcinuerin inhibitors (CNIs), which are mandatory for Tx, need the same enzyme complex for their clearance. Therefore, a significant drug-drug interaction (DDI) is encountered between current HAART and CNIs. This results in extreme difficulty in adjusting the optimal dose of CNIs, for which the therapeutic range is narrow. Of interest, integrase inhibitors (INIs) - novel, potent anti-HIV drugs - are mainly metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and do not induce or inhibit CYP3A4. DDI is presumably absent when NNTRIs or PIs are replaced by INIs. Raltegravir (RAL), a first generation INI, has been introduced into kidney and liver Tx. There is increasing evidence that rejection is well controlled without renal impairment due to CNI over-exposure while persistent, robust suppression of HIV is achieved. Global phase III clinical trials of dolutegravir (DTG), a second generation INI, are currently in progress. In vitro data has suggested that DTG may be less prone to resistance than RAL (referred to as having a higher genetic barrier). The time has come to extensively discuss the implications of INIs in Tx for HIV positive patients. PMID- 22101374 TI - Overcoming of P-glycoprotein-mediated multidrug resistance in K562/A02 cells using riccardin F and pakyonol, bisbibenzyl derivatives from liverworts. AB - Riccardin F and pakyonol, macrocyclic bisbibenzyls from Plagiochasm intermedium, have been confirmed to possess antifungic activities against Candida albicans. Herein, we evaluated their anti-tumor activity in vitro by employing K562 and K562/A02 cells, the well-known adriamycin (ADR)-induced multidrug resistance (MDR) tumor cell lines over-expressing P-glycoprotein (P-gp). 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays showed that riccardin F and pakyonol ranging from 0 to 6 MUg/mL exhibited no inhibitory effects on the growth of the two cell lines. However, in the presence of 3 MUg/mL riccardin F or pakyonol (non-cytotoxic concentration), the IC50 of ADR against K562/A02 cells decreased by 2.51- and 4.78-fold, respectively. Flow cytometry showed that riccardin F and pakyonol significantly enhanced the accumulation of ADR in K562/A02 cells. Furthermore, fluorescence intensity detection revealed that the two natural products remarkably increased the retention of rhodamine-123 in K562/A02 cells rather than in K562 cells, indicating that the major cause for riccardin F and pakyonol to reverse P-gp-mediated MDR in K562/A02 cells is probably due to the constrained transport activity of P-gp. This study explores the potential application of bisbibenzyl type compounds as modulators of P-gp mediated MDR in tumor cells. PMID- 22101375 TI - Effects of lipoprotein lipase gene variations, a high-carbohydrate low-fat diet, and gender on serum lipid profiles in healthy Chinese Han youth. AB - A high-carbohydrate low-fat (HC/LF) diet and lipoprotein lipase gene (LPL) Ser447Stop and Hind III polymorphisms have separately been found to be associated with triacylglycerol (TG) and high density lipoprotein cholesterol (HDL-C). This study sought to test the effects of LPL polymorphisms and an HC/LF diet on the serum lipid profile of Chinese with a lower incidence of coronary artery disease (CAD) consuming a diet with less fat and more carbohydrates. Fifty-six healthy subjects (22.89 +/- 1.80 years) were given a control diet of 30.1% fat and 54.1% carbohydrates for 7 days, followed by an HC/LF diet of 13.8% fat and 70.1% carbohydrate for 6 days; there were no changes in the fatty acid composition or restrictions on total energy. Serum lipid profiles at baseline, before and after the HC/LF diet, and LPL polymorphisms were analyzed. After 6 days of the HC/LF diet, TG and the homeostasis model assessment of insulin resistance (HOMAIR) index were found to increase only in females with S447S. No decrease in HDL-C was noted. In subjects with Hind III polymorphism, increased TG was found in all females but not in males. Increased HDL-C, together with apolipoprotein (apo) AI, was found in male H- carriers but not in males with H+/H+ and females. In conclusion, LPL Ser447Stop and Hind III polymorphisms modified the effects of an HC/LF diet on the serum lipid profiles of a young Chinese population in different ways. Effective strategies for dietary interventions targeted at younger populations should take into account the interplay between genetic polymorphisms, diet, and gender. PMID- 22101376 TI - Association of p53 codon 248 (exon7) with urinary bladder cancer risk in the North Indian population. AB - p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population. PMID- 22101377 TI - Evaluation of usefulness of 3D views for clinical photography. AB - This is the first report investigating the usefulness of a 3D viewing technique (parallel viewing and cross-eyed viewing) for presenting clinical photography. Using the technique, we can grasp 3D structure of various lesions (e.g. tumors, wounds) or surgical procedures (e.g. lymph node dissection, flap) much more easily even without any cost and optical aids compared to 2D photos. Most recently 3D cameras started to be commercially available, but they may not be useful for presentation in scientific papers or poster sessions. To create a stereogram, two different pictures were taken from the right and left eye views using a digital camera. Then, the two pictures were placed next to one another. Using 9 stereograms, we performed a questionnaire-based survey. Our survey revealed 57.7% of the doctors/students had acquired the 3D viewing technique and an additional 15.4% could learn parallel viewing with 10 minutes training. Among the subjects capable of 3D views, 73.7% used the parallel view technique whereas only 26.3% chose the cross-eyed view. There was no significant difference in the results of the questionnaire about the efficiency and usefulness of 3D views between parallel view users and cross-eyed users. Almost all subjects (94.7%) answered that the technique is useful. Lesions with multiple undulations are a good application. 3D views, especially parallel viewing, are likely to be common and easy enough to consider for practical use in doctors/students. The wide use of the technique may revolutionize presentation of clinical pictures in meetings, educational lectures, or manuscripts. PMID- 22101378 TI - Oral valganciclovir versus intravenous ganciclovir as preemptive treatment for cytomegalovirus infection after living donor liver transplantation: a randomized trial. AB - It is unclear whether valganciclovir (VGCV) is effective compared with intravenous ganciclovir (GCV) for preemptive therapy of cytomegalovirus (CMV) infection in living donor liver transplantation (LDLT). A randomized trial was conducted to compare the efficacy of oral VGCV with intravenous GCV for preemptive treatment of CMV infection after LDLT. Patients who developed CMV infection within 6 months after LDLT at Tokyo University Hospital were randomly assigned to the VGCV or GCV group and received either oral VGCV 900 mg/day or intravenous GCV 5 mg/kg twice daily, respectively. The primary endpoint was the treatment success rate. Secondary endpoints were recurrence of CMV infection within 1 year after finishing the treatment, and safety and tolerability of the treatment. Twenty-two patients with CMV infection after LDLT fulfilled the inclusion criteria and were randomly assigned to the oral VGCV group (n = 11) or the intravenous GCV group (n = 11). Treatment success rates were 82% (9 of 11) and 91% (10 of 11) in the VGCV and GCV groups, respectively. One patient in the VGCV group developed recurrence, whereas no patients in the GCV group developed recurrence. All the patients completed the treatment protocol, and no patients in either group dropped out of the study. In conclusion, oral VGCV and intravenous GCV are safe, feasible options for preemptive treatment of CMV infection after LDLT. PMID- 22101379 TI - A case of Fournier's gangrene after liver transplantation: treated by hyperbaric oxygen therapy. AB - Fournier's gangrene (FG) is known as a rapidly progressing necrotizing fasciitis arising from genitourinary and colorectal infections. Misdiagnoses have occurred often because the initial presentation varies and is unclear. We report a case of FG in a 59-year-old man who had undergone a living donor liver transplant. He was in the maintenance phase of immunosuppressant treatment. FG occurred rapidly without symptoms and required prompt and aggressive debridement. Computed tomography demonstrated a small air density in his left testis. Treatment with hyperbaric oxygen therapy followed by intra- operative Gram's staining navigated debridement was additionally performed with general systematic anti-biological therapy and successfully cured the patient. Extra caution should be paid to patients who are maintained on immunosuppressants. Earlier detection and intervention will reduce the rate of mortality to a minimum. PMID- 22101380 TI - Neural signatures of economic parameters during decision-making: a functional MRI (FMRI), electroencephalography (EEG) and autonomic monitoring study. AB - Adaptive behaviour requires an ability to obtain rewards by choosing between different risky options. Financial gambles can be used to study effective decision-making experimentally, and to distinguish processes involved in choice option evaluation from outcome feedback and other contextual factors. Here, we used a paradigm where participants evaluated 'mixed' gambles, each presenting a potential gain and a potential loss and an associated variable outcome probability. We recorded neural responses using autonomic monitoring, electroencephalography (EEG) and functional neuroimaging (fMRI), and used a univariate, parametric design to test for correlations with the eleven economic parameters that varied across gambles, including expected value (EV) and amount magnitude. Consistent with behavioural economic theory, participants were risk averse. Gamble evaluation generated detectable autonomic responses, but only weak correlations with outcome uncertainty were found, suggesting that peripheral autonomic feedback does not play a major role in this task. Long-latency stimulus evoked EEG potentials were sensitive to expected gain and expected value, while alpha-band power reflected expected loss and amount magnitude, suggesting parallel representations of distinct economic qualities in cortical activation and central arousal. Neural correlates of expected value representation were localized using fMRI to ventromedial prefrontal cortex, while the processing of other economic parameters was associated with distinct patterns across lateral prefrontal, cingulate, insula and occipital cortices including default-mode network and early visual areas. These multimodal data provide complementary evidence for distributed substrates of choice evaluation across multiple, predominantly cortical, brain systems wherein distinct regions are preferentially attuned to specific economic features. Our findings extend biologically-plausible models of risky decision-making while providing potential biomarkers of economic representations that can be applied to the study of deficits in motivational behaviour in neurological and psychiatric patients. PMID- 22101382 TI - Competitive context alters plant-soil feedback in an experimental woodland community. AB - Recent findings on feedback between plants and soil microbial communities have improved our understanding of mechanisms underlying the success and consequences of invasions. However, additional studies to test for feedback in the presence and absence of interspecific competition, which may alter the strength or direction of feedbacks, are needed. We tested for soil microbial feedback in communities of the invasive grass Microstegium vimineum and commonly co-occurring native plant species. To incorporate competitive context, we used a factorial design with three plant treatments (M. vimineum alone, M. vimineum with the native plant community, and the native community without M. vimineum) and two soil inoculum treatments (experimentally invaded and uninvaded soil). When competing with M. vimineum, native communities were 27% more productive in invaded than uninvaded soil. In contrast, soil type did not significantly affect M. vimineum biomass or fecundity. At the community level, these results indicate a net negative soil microbial feedback when native plants and M. vimineum are grown in competitive mixture, but not when they are grown separately. Since positive, not negative, feedback is associated with dominance and invasion, our findings do not support plant-soil feedback as a driver of invasion in this species. Our results do show that the importance of soil feedback can change with competitive context. Such context-dependency implies that soil feedback may change when competitive interactions between natives and invading species shift as invasions progress. PMID- 22101383 TI - Methylation pattern of the putative tumor-suppressor gene LRRC3B promoter in clear cell renal cell carcinomas. AB - The leucine rich repeat containing 3B (LRRC3B) gene is a putative tumor suppressor located on human chromosome 3 in the 3p24 region. LRRC3B is frequently altered in colon and gastric cancers and also in leukaemias. In this study we investigated the promoter region methylation as a possible mechanism of LRRC3B gene inactivation in clear cell renal cell carcinomas. We found that the LRRC3B gene promoter was methylated in 43% of clear cell renal carcinoma samples. However, no correlation between DNA methylation and LRRC3B expression was found. PMID- 22101384 TI - Synthesis, X-ray crystal structure, DNA binding, antioxidant and cytotoxicity studies of Ni(ii) and Pd(ii) thiosemicarbazone complexes. AB - New complexes, [Ni(HL)(PPh(3))]Cl (1), [Pd(L)(PPh(3))](2), and [Pd(L)(AsPh(3))](3), were synthesized from the reactions of 4-chloro-5-methyl salicylaldehyde thiosemicarbazone [H(2)L] with [NiCl(2)(PPh(3))(2)], [PdCl(2)(PPh(3))(2)] and [PdCl(2)(AsPh(3))(2)]. They were characterized by IR, electronic, (1)H-NMR spectral data. Further, the structures of the complexes have been determined by single crystal X-ray diffraction. While the thiosemicarbazone coordinated as binegative tridentate (ONS) in complexes 2 and 3, it is coordinated as mono negative tridentate (ONS) in 1. The interactions of the new complexes with calf thymus DNA was examined by absorption and emission spectra, and viscosity measurements. Moreover, the antioxidant properties of the new complexes have also been tested against DPPH radical in which complex 1 exhibited better activity than that of the other two complexes 2 and 3. The in vitro cytotoxicity of complexes 1-3 against A549 and HepG2 cell lines was assayed, and the new complexes exhibited higher cytotoxic activity with lower IC(50) values indicating their efficiency in killing the cancer cells even at very low concentrations. PMID- 22101385 TI - White matter in autism spectrum disorders - evidence of impaired fiber formation. AB - BACKGROUND: Diffusion tensor imaging (DTI) enables measurements and visualization of the microstructure of neural fiber tracts. The existing literature on autism spectrum disorders (ASDs) and DTI is heterogenous both regarding methodology and results. PURPOSE: To compare brain white matter of high-functioning individuals with ASDs and controls. MATERIAL AND METHODS: Tract-based spatial statistics (TBSS), a voxel-based approach to DTI, was used to compare 27 subjects with ASDs (mean age 14.7 years, range 11.4-17.6 years, 20 boys, 7 girls) and 26 control subjects (mean age 14.5 years, range 11.7-17.3 years, 17 boys, 9 girls). Mean fractional anisotropy (FA) image (skeleton) was created and each subject's aligned FA data were then projected onto this skeleton. Voxelwise cross-subject statistics on the skeletonized FA data, mean diffusivity (MD), and measures of diffusion direction were calculated. Importantly, the data were corrected across the whole image instead of using ROI-based methods. RESULTS: The ASD group showed significantly greater FA (P < 0.05, corrected) in the area containing clusters of optic radiation and the right inferior fronto-occipital fasciculus (iFOF). In the same area, lambda(3) (representing transverse diffusion) was significantly reduced in the ASD group. No age-related changes were found. CONCLUSION: The results suggest that the reduced transverse diffusion within the iFOF is related to abnormal information flow between the insular salience processing areas and occipital visual areas. PMID- 22101386 TI - Phase 2 study of capecitabine and irinotecan combination chemotherapy (modified XELIRI regimen) in patients with advanced gastric cancer. AB - OBJECTIVE: The prognosis of patients with advanced gastric cancer (AGC) remains poor, and no single chemotherapy regimen is recognized as a global standard. A phase 2 trial was conducted to determine the efficacy and tolerability of the modified combination regimen of capecitabine and irinotecan (mXELIRI) in patients with AGC. METHODS: Patients with earlier untreated AGC received intravenous irinotecan (125 mg/m) over 90 minutes on days 1 and 8, and oral capecitabine (850 mg/m) twice daily on days 2 to 15, every 3 weeks. Treatment was continued for at most 8 cycles or until disease progression or intolerable toxicity. RESULTS: Thirty-two patients were enrolled. In total, 141 cycles of mXELIRI were administered. The overall response rate was 43.7%, with 1 complete response and 13 partial responses. At a median follow-up of 16.2 months, median time to progression and overall survival were 5.6 months (95% confidence interval, 4.27 6.93 mo) and 11.0 months (95% confidence interval, 8.71-13.29 mo), respectively. The most common hematological adverse event was neutropenia (n=18, 56.3%); grade 3 neutropenia was observed in 5 patients, with neutropenic fever in only 2 patients. The most common grade 3/4 nonhematological toxicities were anorexia (n=3, 9.4%), nausea (n=3, 9.4%), vomiting (n=2, 6.3%), and diarrhea (n=2, 6.3%). There was no treatment-related death. CONCLUSIONS: mXELIRI is a safe and effective first-line treatment for unresectable and metastatic gastric cancer with a manageable tolerability profile. It can be used as one of the first-line treatment options for patients with AGC. PMID- 22101387 TI - Retrospective review of patients with locally advanced esophageal cancer treated at the University of Pittsburgh. AB - OBJECTIVES: The management of locally advanced esophageal cancer is controversial. Treatment options include neoadjuvant chemotherapy or chemoradiation therapy (CRT) followed by definitive surgery or definitive chemoradiation. A single center experience was reviewed to determine the oncologic outcomes of these 3 approaches. METHODS: We retrospectively reviewed records of 100 patients with adenocarcinoma and squamous cell carcinoma of the esophagus of which 22 patients received neoadjuvant chemotherapy, 49 patients received neoadjuvant CRT, and 18 patients received definitive CRT. The majority of patients underwent minimally invasive esophagectomy (74%). The mean follow-up was 34 months (median, 22 mo; range, 1 to 180 mo). RESULTS: Median survival of the entire group was 22.9 months [95% confidence interval (CI) 19.3-30.4]. The 2 year and 5-year overall survival rates were 47.9% and 23.2%, respectively. Median survival of patients who received neoadjuvant chemotherapy, neoadjuvant CRT, and definitive CRT was 31.9 (95% CI 21.2-51.5), 28.7 (95% CI 20.2-40.7), and 8.9 (95% CI 5.7-14.4) months, respectively. Patients who received neoadjuvant CRT were more likely to have pathologic complete response (pCR) (20%) compared with patients who received neoadjuvant chemotherapy alone (0%; P=0.04). The 2-year and 5-year overall survival rates of patients with pCR were 75% and 50%, respectively. CONCLUSIONS: There was no survival benefit or differences in failure pattern seen among the 3 treatment approaches in this series. However, patients who received neoadjuvant CRT were more likely to have pCR and these patients showed a trend toward improved survival. PMID- 22101388 TI - How circulating tumor cells escape from multidrug resistance: translating molecular mechanisms in metastatic breast cancer treatment. AB - Resistance to anthracyclines is responsible for treatment failure in most patients with metastatic breast cancer. According to recent studies, the expression of specific drug transporters (MRPs) on circulating tumor cells is predictive of prognosis in different cancer types. We observed that patients whose circulating tumor cells expressed MRP1 and MRP2, two drug-export pumps responsible for anthracyclines efflux, who received conventional anthracyclines had a significantly shorter time to progression compared with patients sharing same characteristics who received non pegylated liposomal doxorubicin (P < 0.005). These results may highlight a new appealing role of the liposomal doxorubicin formulation, not only because of its reduced cardiac toxicity but especially referring to its theoretical efficacy in anthracycline-resistant breast cancer patients. PMID- 22101389 TI - ACR Appropriateness Criteria(r) definitive external beam irradiation in stage T1 and T2 prostate cancer. AB - PURPOSE: : External beam radiation therapy is a standard of care treatment for men who present with clinically localized (T1-T2) prostate cancer. The purpose of this review was to provide clarification on the appropriateness criteria and management considerations for the treatment of prostate cancer with external beam radiation therapy. METHODS: : A panel consisting of physicians with expertise on prostate cancer was assembled and provided with a number of clinical scenarios for consensus treatment and management guidelines. Prostate cancer patient vignettes were presented along with specific management recommendations based on an extensive review of the modern external beam radiotherapy literature. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances, where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: : Modern external beam radiation therapy series demonstrate favorable biochemical control rates for patients with localized prostate cancer. Morbidity profiles are also favorable and it is clear that this is enhanced by modern techniques like 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy. An active area of investigation is evaluating the use of hypofractionated dosing. CONCLUSIONS: : Continued investigation to refine patient selection, external beam radiation technology application, and alternative dosing schedules should result in further improvements in biochemical outcome and decreased morbidity with external beam radiation treatment for localized prostate cancer. PMID- 22101390 TI - Three-field electron/minitangent photon technique offer dosimetric advantages to a multifield, photon-only technique for accelerated partial breast irradiation if well implemented. PMID- 22101391 TI - Influence of selection bias on the test decision. A simulation study. AB - BACKGROUND: Selection bias arises in clinical trials by reason of selective assignment of patients to treatment groups. Even in randomized clinical trials with allocation concealment this phenomenon can occur if future assignments can be predicted due to knowledge of former allocations. OBJECTIVES: Considering unmasked randomized clinical trials with allocation concealment the impact of selection bias on type I error rate under permuted block randomization is investigated. We aimed to extend the existing research into this topic by including practical assumptions concerning misclassification of patient characteristics to get an estimate of type I error close to clinical routine. To establish an upper bound for the type I error rate different biasing strategies of the investigator are compared first. In addition, the aspect of patient availability is considered. METHODS: To evaluate the influence of selection bias on type I error rate under several practical situations, different block sizes, selection effects, biasing strategies and success rates of patient classification were simulated using SAS. RESULTS: Type I error rate exceeds 5 percent significance level; it reaches values up to 21 percent. More cautious biasing strategies and misclassification of patient characteristics may diminish but cannot eliminate selection bias. The number of screened patients is about three times larger than the needed number for the trial. CONCLUSIONS: Even in unmasked randomized clinical trials using permuted block randomization with allocation concealment the influence of selection bias must not be disregarded evaluating the test decision. It should be incorporated when designing and reporting a clinical trial. PMID- 22101392 TI - Practical and analytic issues in the electronic assessment of adherence. AB - Although medication adherence can be measured many ways, researchers often view electronic dose monitoring devices like the Medication Event Monitoring Systems (MEMS) as more valid than patient self-reports. MEMS are popular but have potential problems. Based on the literature and MEMS data analyses, the authors suggest the following approaches: (a) a 1- to 2-month run-in should be used to reduce MEMS reactivity, (b) MEMS should be used with other measures of adherence, (c) adherence should be measured continuously, or a cutoff should be defined based on pharmacological properties of the medication and the consequences of nonadherence, (d) MEMS data usually should be aggregated weekly or monthly and evaluated using multilevel modeling, (e) MEMS-based screening for nonadherence may miss some patients in need of intervention, and (f) researchers should use strategies like training patients to use MEMS and purchasing extra MEMS caps to improve the completeness and accuracy of MEMS data. PMID- 22101393 TI - Tricyclodecan-9-yl-xanthogenate (D609) mechanism of actions: a mini-review of literature. AB - Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine (PC)-specific phospholipase C (PC-PLC). D609 also inhibits sphingomyelin synthase (SMS). PC-PLC and/or SMS inhibition will affect lipid second messengers 1,2 diacylglycerol (DAG) and/or ceramide. Evidence indicates either PC-PLC and/or SMS inhibition affected the cell cycle and arrested proliferation, and stimulated differentiation in various in vitro and in vivo studies. Xanthogenate compounds are also potent antioxidants and D609 reduced Abeta-induced toxicity, attributed to its antioxidant properties. Zn2+ is necessary for PC-PLC enzymatic activity; inhibition by D609 might be attributed to its Zn2+ chelation. D609 has also been proposed to inhibit acidic sphingomyelinase or down-regulate hypoxia inducible factor-1alpha; however these are down-stream events related to PC-PLC inhibition. Characterization of the mammalian PC-PLC is limited to inhibition of enzymatic activity (frequently measured using Amplex red assay with bacterial PC-PLC as a standard). The mammalian PC-PLC has not been cloned; sequenced and structural information is unavailable. D609 showed promise in cancer studies, reduced atherosclerotic plaques (inhibition of PC-PLC) and cerebral infarction after stroke (PC-PLC or SMS). D609 actions as an antagonist to pro-inflammatory cytokines have been attributed to PC-PLC. The purpose of this review is to comprehensively evaluate the literature and summarize the findings and relevance to cell cycle and CNS pathologies. PMID- 22101394 TI - Cue exposure and response prevention with heavy smokers: a laboratory-based randomised placebo-controlled trial examining the effects of D-cycloserine on cue reactivity and attentional bias. AB - RATIONALE: Treatments based on exposure/response prevention (Exp/RP) produce only modest benefits in substance dependence disorders. However, a new strategy, which has shown promise in animal models of addiction involves combining Exp/RP with extinction-enhancing pharmacological treatments. A prototype of the latter is D cycloserine (DCS), a partial agonist at the glycine site of the NMDA receptor. METHODS: In a laboratory-based randomised, double-blind, placebo-controlled trial with non-treatment-seeking heavy smokers (n = 32), we examined the efficacy of Exp/RP combined with DCS (125 mg). Two sessions of Exp/RP were carried out during which cue reactivity was monitored. Effects on attentional bias and/or subjective craving and smoking behaviour were also evaluated after at least 48 h and 2 weeks following session 2 of Exp/RP. RESULTS: Within- and between-session reductions in cue reactivity were observed in both treatment groups, although the DCS group did not show an enhanced reduction by the end of session 2. However, a subtle effect of DCS on the emotionality subscale of the Tobacco Craving Questionnaire was observed, with a trend towards a sustained reduction in this aspect of craving at 2-week follow-up. CONCLUSION: Our findings suggest that two sessions of Exp/RP combined with DCS does not enhance the reduction in episodic cue reactivity in non-treatment seeking smokers. A trend towards a greater sustained reduction in the emotionality scale of the TCQ in the DCS group suggests that further detailed study of the effects of combined Exp/RP-DCS on different aspects of craving is warranted, especially in smokers with a current intention to quit. PMID- 22101397 TI - Electrostatic current switching and negative differential resistance behavior in a molecular device based on carbon nanotubes. AB - The electronic transport properties of an all-carbon mechanically controlled molecular device based on carbon nanotubes are studied using non-equilibrium Green's function in combination with density functional theory. A segment of (10,0) single-walled carbon nanutube (SWCNT) is placed concentrically outside a (5,0) SWCNT, namely, a (5,0)@(10,0) double-walled carbon nanotube (DWCNT). It is found that the position, orientation and length scaling of the (10,0) SWCNT have crucial effects on the electronic transport properties of the system. When the (10,0) SWCNT is mechanically pushed forward along the axial direction, alternation of on/off switching behavior under low bias and negative differential resistance behavior under high bias are observed. Significant changes in the electronic transport properties arise when rotating the (10,0) SWCNT around the common axis or adding carbon atom layers in the transport direction. Theoretical explanations are proposed for these phenomena. PMID- 22101398 TI - Principles of conjugating quantum dots to proteins via carbodiimide chemistry. AB - The covalent coupling of nanomaterials to bio-recognition molecules is a critical intermediate step in using nanomaterials for biology and medicine. Here we investigate the carbodiimide-mediated conjugation of fluorescent quantum dots to different proteins (e.g., immunoglobulin G, bovine serum albumin, and horseradish peroxidase). To enable these studies, we developed a simple method to isolate quantum dot bioconjugates from unconjugated quantum dots. The results show that the reactant concentrations and protein type will impact the overall number of proteins conjugated onto the surfaces of the quantum dots, homogeneity of the protein-quantum dot conjugate population, quantum efficiency, binding avidity, and enzymatic kinetics. We propose general principles that should be followed for the successful coupling of proteins to quantum dots. PMID- 22101399 TI - Chemical and pharmacological studies of Oplopanax horridus, a North American botanical. AB - Oplopanax horridus (OH), or Devil's club, is an ethnobotanical used by the indigenous people native to the Pacific Northwest of North America. There are three species in the genus Oplopanax, and OH is the only species that is distributed in North America. Compared with the extensive research on OH's "cousin," American ginseng, there is comparatively little reported about the chemical makeup and pharmacological effects of OH. Nevertheless, there has been some research over the past few years that shows promise for the future usage perspectives of OH. To date, 17 compounds were isolated and elucidated, including polyynes, glycosides, lignans, and polyenes, with most of the attention being paid to the polyynes. Gas chromatography (GC) and high-performance liquid chromatography (HPLC) were used to determine the contents of volatile compounds and polyynes in the essential oil and extracts of OH. For the pharmacological studies, antibacterial and antidiabetes effects of polyynes were reported. Our recent study has focused more on the anticancer effects of OH and the involved mechanisms of action. In this review, we will summarize the research status in the botany, phytochemistry, and pharmacology of OH. PMID- 22101400 TI - Pharmacokinetics and organ distribution of diarylheptanoid phytoestrogens from Curcuma comosa in rats. AB - Curcuma comosa is widely used as a traditional herbal medicine for gynecological diseases in South East Asia. Previous studies reported that it has phytoestrogenic activity, and several diarylheptanoids were found to be the active constituents. In this study, the pharmacokinetics profile and organ distribution of three active compounds of C. comosa hexane extract were investigated. Rats were separately administered C. comosa hexane extract intravenously at the dose of 125 mg/kg and orally at the doses of 125 and 250 mg/kg body weight, after which blood and target organs were collected at specified time intervals from 0 to 24 h. HPLC was used to measure the concentration of three major compounds, (6E)-1,7-diphenylhept-6-en-3-one (DPH1), (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (DPH2), and (6E)-1,7-diphenylhept-6-en-3 ol (DPH3), which were found to be present in the blood and tissues and were subsequently used as markers. In the intravenous study, the volumes of distribution (V(d)) were 1.06, 8.57, and 6.56 L/kg and clearance values (CL(s)) were 0.28, 5.56, and 3.39 L/kg/h for DPH1, DPH2, and DPH3, respectively. After oral administration, the three major compounds of both doses reached a maximum systemic concentration at 2 h with maximum concentration (C(max)) of 0.85, 0.17, and 0.53 mg/L for the lower dose and 1.46, 0.17, and 0.61 mg/L for the higher dose. The bioavailabilities were 31.2, 24.01, and 31.56% for lower dose and 22.61, 17.66, and 17.73% for higher dose with a terminal half-life (t(1/2)) of 10.86, 6.3, and 4.62 h for lower dose and 3.85, 2.77, and 2.10 h for higher dose for DPH1, DPH2, and DPH3, respectively. These three major compounds are all found distributed in the brain, liver, kidneys, ovaries, and uterus after oral and intravenous administration and their related pharmacokinetic parameters are described. This study provides the essential pharmacokinetic data for diarylheptanoid phytoestrogenic compounds of C. comosa extract which are required for clinical dose and dosage design. PMID- 22101401 TI - Understanding the central role of citrate in the metabolism of cancer cells. AB - Cancers cells strongly stimulate glycolysis and glutaminolysis for their biosynthesis. Pyruvate derived from glucose is preferentially diverted towards the production of lactic acid (Warburg effect). Citrate censors ATP production and controls strategic enzymes of anabolic and catabolic pathways through feedback reactions. Mitochondrial citrate diffuses in the cytosol to restore oxaloacetate and acetyl-CoA. Whereas acetyl-CoA serves de novo lipid synthesis and histone acetylation, OAA is derived towards lactate production via pyruvate and / or a vicious cycle reforming mitochondrial citrate. This cycle allows cancer cells to burn their host's lipid and protein reserves in order to sustain their own biosynthesis pathways. In vitro, citrate has demonstrated anti-cancer properties when administered in excess, sensitizing cancer cells to chemotherapy. Understanding its central role is of particular relevance for the development of new strategies for counteracting cancer cell proliferation and overcoming chemoresistance. PMID- 22101402 TI - DemQSAR: predicting human volume of distribution and clearance of drugs. AB - In silico methods characterizing molecular compounds with respect to pharmacologically relevant properties can accelerate the identification of new drugs and reduce their development costs. Quantitative structure-activity/ property relationship (QSAR/QSPR) correlate structure and physico-chemical properties of molecular compounds with a specific functional activity/property under study. Typically a large number of molecular features are generated for the compounds. In many cases the number of generated features exceeds the number of molecular compounds with known property values that are available for learning. Machine learning methods tend to overfit the training data in such situations, i.e. the method adjusts to very specific features of the training data, which are not characteristic for the considered property. This problem can be alleviated by diminishing the influence of unimportant, redundant or even misleading features. A better strategy is to eliminate such features completely. Ideally, a molecular property can be described by a small number of features that are chemically interpretable. The purpose of the present contribution is to provide a predictive modeling approach, which combines feature generation, feature selection, model building and control of overtraining into a single application called DemQSAR. DemQSAR is used to predict human volume of distribution (VD(ss)) and human clearance (CL). To control overtraining, quadratic and linear regularization terms were employed. A recursive feature selection approach is used to reduce the number of descriptors. The prediction performance is as good as the best predictions reported in the recent literature. The example presented here demonstrates that DemQSAR can generate a model that uses very few features while maintaining high predictive power. A standalone DemQSAR Java application for model building of any user defined property as well as a web interface for the prediction of human VD(ss) and CL is available on the webpage of DemPRED: http://agknapp.chemie.fu-berlin.de/dempred/ . PMID- 22101403 TI - Varus femoral osteotomy improves sphericity of the femoral head in older children with severe form of Legg-Calve-Perthes disease. AB - BACKGROUND: In the Norwegian prospective study on Legg-Calve-Perthes disease (LCPD), we found varus femoral osteotomy gave better femoral head sphericity at a mean of 5 years postoperative than physiotherapy in children older than 6.0 years at diagnosis with femoral head necrosis of more than 50%. That study did not include separate analyses for hips with 100% necrosis and those with a percentage of necrosis between 50% and 100%. QUESTIONS/PURPOSES: We asked whether (1) femoral osteotomy improves femoral head sphericity at followup in all patients with more than 50% femoral head necrosis or in selected groups only and (2) there is a critical age between 6.0 and 10.0 years over which femoral osteotomy does not improve the prognosis. METHODS: We treated 70 patients with unilateral LCPD, age at diagnosis of more than 6.0 years, and femoral head necrosis of more than 50% with varus femoral osteotomy between 1996 and 2000. We classified necrosis using the Catterall classification. We established a control group of 51 similar children who received physiotherapy. At the 5-year followup visit, the hips were graded according to femoral head shape: spherical, ovoid, or flat. RESULTS: At 5 year followup, there was no difference between the treatment groups in radiographic outcome in Catterall Group 3 hips. In Catterall Group 4 hips, femoral head sphericity was better in the osteotomy group, with flat femoral heads in 14% compared to 75% after physiotherapy. The same trend toward better head sphericity occurred when the lateral pillar classification was used. CONCLUSIONS: In children aged 6.0 to 10.0 years, in whom the whole femoral head is affected, femoral head sphericity 5 years after femoral osteotomy was better than that after physiotherapy. PMID- 22101404 TI - Surgical technique: Medial column arthrodesis in rigid spastic planovalgus feet. AB - BACKGROUND: Treatment of spastic planovalgus feet is challenging, especially in patients with severe and rigid deformities. The available techniques do provide some correction but not at the site of the deformity and sometimes the correction is lost over time. We describe a new surgical approach at the site of the deformity. TECHNIQUE: Indications for the surgery included adolescents or young adults with severe and rigid planovalgus deformities of the feet resulting from cerebral palsy. Through a medial approach, arthrodesis of the talonavicular, navicular-medial cuneiform, and medial cuneiform first metatarsal joints was internally fixed using a single-molded plate over the plantar surface of the foot, recreating the longitudinal arch. METHODS: We retrospectively reviewed 21 patients (35 feet) with spastic cerebral palsy in whom the new technique was indicated for severe and rigid deformity, gait dysfunction, and pain (mean age, 190 months; range, 96-345 months). The mean age of the patients was 16 years (range, 8-29 years). We analyzed the patients clinically and radiographically. The minimum followup was 2.5 years (mean, 58 months; range, 2.5-7.5 years). RESULTS: At last followup, 34 of the 35 feet (97%) had radiographic improvement of the deformity with no difficulties wearing shoes; one patient had persistent pain despite bone union. Union was achieved initially in eight patients (17 feet) and in another eight (10 feet) after revision surgery, of 27 of the 35 feet. The radiographic calcaneal inclination angle improved an average of 13 degrees . The lateral talocalcaneal angle decreased from a mean of 43 degrees to 26 degrees after surgery. Four patients (five feet) had revision surgery for pseudoarthrosis, and another four patients (five feet) had revision surgery for other problems. CONCLUSIONS: Based on our preliminary observations, we believe stabilization of the medial column is a reasonable option for treating selected patients with severe and rigid planovalgus feet by providing a stable and pain free foot, recreating the anatomy, and allowing the use of braces or regular shoes. Further studies with longer followup periods will be required to confirm these initial results and to verify if these findings persist over time. LEVEL OF EVIDENCE: Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22101405 TI - Editorial: Complications. PMID- 22101406 TI - 50 years ago in CORR: Biomechanics of hip prostheses. Duncan C. McKeever, MD CORR 1961;19:187-199. PMID- 22101407 TI - An in vitro investigation of metabolically sensitive biomarkers in breast cancer progression. AB - Epigenetic biomarkers are emerging as determinants of breast cancer prognosis. Breast cancer cells display unique alterations in major cellular metabolic pathways and it is becoming widely recognized that enzymes that regulate epigenetic alterations are metabolically sensitive. In this study, we used microarray data from the GEO database to compare gene expression for regulators of metabolism and epigenetic alterations among non-invasive epithelial (MCF-7, MDA-MB-361, and T-47D) and invasive mesenchymal (MDA-MB-231, Hs-578T, and BT-549) breast cancer cell lines. The expression of genes, including GLS1, GFPT2, LDHA, HDAC9, MYST2, and SUV420H2, was assessed using RT-PCR. There was differential expression between epithelial and mesenchymal cell lines. MYST2 and SUV420H2 regulate the levels of the epigenetic biomarkers histone H4 lysine 16 acetylation (H4K16ac) and histone H4 lysine 20 trimethylation (H4K20me3), respectively. Reduced amounts of H4K16ac and H4K20me3 correlated with lower levels of MYST2 and SUV420H2 in mesenchymal cells and, along with reduced amounts of histone H3 lysine 9 acetylation (H3K9ac), were found to distinguish epithelial from mesenchymal cells. In addition, both GLS1 and GFPT2 play roles in glutamine metabolism and were observed to be more highly expressed in mesenchymal cell lines, and when glutamine and glutamate levels reported in the NCI-60 metabolomics dataset were compared, the ratio of glutamate/glutamine was found to be higher in mesenchymal cells. Blocking the conversion of glutamine to glutamate using an allosteric inhibitor, Compound 968, against GLS1, increased H4K16ac in T 47D and MDA-MB-231 cells, linking glutamine metabolism to a particular histone modification in breast cancer. These findings support the concept that metabolically sensitive histone modifications and corresponding histone modifying enzymes can be used as diagnostic and prognostic biomarkers for breast cancer. It also further emphasizes the importance of glutamine metabolism in tumor progression and that inhibitors of cellular metabolic pathways may join histone deacetylase inhibitors as a form of epigenetic therapy. PMID- 22101408 TI - Prediction of menopausal status from estrogen-related gene expression in benign breast tissue. AB - The utility of archived paraffin-embedded breast tissue for risk-related research is often limited by missing menopausal status data. We tested the hypothesis that breast tissue gene expression patterns can improve menopausal stratification. Healthy high-risk participants in a clinical trial underwent breast random fine needle aspiration (rFNA); 100 ng of RNA extracted from rFNA samples was reverse transcribed; the expression of 28 estrogen-responsive genes was evaluated by real time PCR. True menopausal status (TMS) was determined by measurement of plasma hormones and age. Differentially expressed genes and age were analyzed by logistic regression. The accuracy of the menopause prediction was assessed using receiver-operator characteristic (ROC) analysis, and validated in a second independent set of 44 women. In the test set, postmenopausal women demonstrated significantly lower expression of five estrogen-responsive genes: GREB1, PGR, TFF1, PRLR, and CCND1 (adjusted P < 0.03 for all). In the validation set, three of these genes were expressed at lower levels in postmenopausal women (GREB1, PGR, TFF1) (adjusted P < 0.06 for all). In the test set, the modeled area under the curve (AUC) for age and three genes was higher than for age >50 alone (AUC 96.1% vs. 87.2%, P = 0.002), and remained better than for age alone in the validation set (99.0% vs. 95.5%, P = 0.16). Estrogen-related gene expression in breast specimens can be used to improve menopausal classification, reducing the biological noise related to menopause in studies that seek to identify RNA or protein risk biomarkers in archived breast samples. PMID- 22101409 TI - All-arthroscopic intramedullary nailing of 2- and 3-part proximal humeral fractures: a new arthroscopic technique and preliminary results. AB - PURPOSE: The most criticism of antegrade humeral nailing is the potentially deleterious effect on the shoulder function, which is caused by the trauma to the M. supraspinatus (SSP) at the nail insertion site. We describe a new technique of all-arthroscopical intramedullary nailing, which preserves the rotator cuff, and compare it with the conventional open procedure. METHODS: From 11/2009 to 12/2010 82 patients with unstable, displaced proximal humeral fractures were treated surgically. Twenty-one of these patients received an intramedullary nailing. Sixteen of 21 met the inclusion criteria. Based on the surgeon's arthroscopic experience, patients were assigned to the arthroscopic (group I, n = 8) or open group (group II, n = 8). Both groups were compared due to the replacement results, complications, time of surgery and fluoroscopy. Concomitant intraarticular pathologies were assessed (group I). First clinical results after a median follow-up of 13 months (group I) and 14 months (group II) were reported. RESULTS: Between group I and II, no significant differences were seen in patients age [77 years (range 45-90 years) vs. 76 years (range 65-92 years)], gender (6 female/2 male vs. 5 female/3 male) and fracture pattern (six 2-/two 3-part fractures vs. five 2-/three 3-part fractures). The reduction was evaluated by the caput-diaphysis-angle, which was median 137 degrees (range 120-147 degrees ) in group I and 132 degrees (range 120-158 degrees ) in group II (p = 0.959). Postoperatively, group I showed one varus-, group II two varus- and valgus deformities. Median time of surgery was 75 min (range 45-182 min) versus 70 min (range 40-146 min) (p = 0.442), fluoroscopy time 1.5 min (range, 0.6-3.7 min) versus 1.2 min (range 0.3-2.2 min) in group I and II (p = 0.336). Concomitant pathologies like one traumatic bicipital tendon-lesion and three partial lesions of the SSP were observed and treated in group I. Constant Scores and Visual Analogue Scale did not differ significantly between both groups at the time of follow-up. CONCLUSIONS: All-arthroscopical humeral nailing is possible, preserves the rotator cuff and provides equal replacement and functional results like the open technique. An arthroscopically visualized optimal nail insertion point provides less frequent head deformities. Level of evidence Level III. PMID- 22101410 TI - Effect of pomegranate juice on the pharmacokinetics of nitrendipine in rabbits. AB - Pomegranate juice (PJ) is known to be a potent inhibitor of human cytochrome enzymes. The purpose of this study was to investigate the effect of acute and chronic PJ on the pharmacokinetics of oral nitrendipine (10 mg/kg) in rabbits. Male New Zealand rabbits were pretreated with PJ for 1 week and on the last day, a single dose of nitrendipine was given orally. In another group, both PJ and nitrendipine were co-administered to evaluate the acute effect of PJ on nitrendipine pharmacokinetics. The control group received oral distilled water for 1 week and administered with nitrendipine on the last day. Blood samples were collected at different time points and nitrendipine concentration was estimated by high-performance liquid chromatography. Relative to control, the area under the concentration-time curve and peak plasma concentration of nitrendipine were 2.03- and 2-fold, respectively, greater in the PJ-pretreated group. However, co administration of PJ had no significant effect on these parameters. Further, there was no significant change in the elimination rate constant and elimination half-life of nitrendipine in both PJ co-administered and pretreated groups in comparison with control. These results suggest that PJ inhibits the intestinal metabolism of nitrendipine without affecting hepatic metabolism in rabbits. Although this potential interaction needs to be explored further, the concomitant use of PJ and nitrendipine should be avoided. PMID- 22101411 TI - Characteristics of the Shiga-toxin-producing enteroaggregative Escherichia coli O104:H4 German outbreak strain and of STEC strains isolated in Spain. AB - A Shiga-toxin-producing Escherichia coli (STEC) strain belonging to serotype O104:H4, phylogenetic group B1 and sequence type ST678, with virulence features common to the enteroaggregative E. coli (EAEC) pathotype, was reported as the cause of the recent 2011 outbreak in Germany. The outbreak strain was determined to carry several virulence factors of extraintestinal pathogenic E. coli (ExPEC) and to be resistant to a wide range of antibiotics. There are only a few reports of serotype O104:H4, which is very rare in humans and has never been detected in animals or food. Several research groups obtained the complete genome sequence of isolates of the German outbreak strain as well as the genome sequences of EAEC of serotype O104:H4 strains from Africa. Those findings suggested that horizontal genetic transfer allowed the emergence of the highly virulent Shiga-toxin producing enteroaggregative E. coli (STEAEC) O104:H4 strain responsible for the outbreak in Germany. Epidemiologic investigations supported a linkage between the outbreaks in Germany and France and traced their origin to fenugreek seeds imported from Africa. However, there has been no isolation of the causative strain O104:H4 from any of the samples of fenugreek seeds analyzed. Following the German outbreak, we conducted a large sampling to analyze the presence of STEC, EAEC, and other types of diarrheagenic E. coli strains in Spanish vegetables. During June and July 2011, 200 vegetable samples from different origins were analyzed. All were negative for the virulent serotype O104:H4 and only one lettuce sample (0.6%) was positive for a STEC strain of serotype O146:H21 (stx1, stx2), considered of low virulence. Despite the single positive case, the hygienic and sanitary quality of Spanish vegetables proved to be quite good. In 195 of the 200 samples (98%), <10 colony-forming units (cfu) of E. coli per gram were detected, and the microbiological levels of all samples were satisfactory (<100 cfu/g). The samples were also negative for other pathotypes of diarrheagenic E. coli (EAEC, ETEC, tEPEC, and EIEC). Consistent with data from other countries, STEC belonging to serotype O157:H7 and other serotypes have been isolated from beef, milk, cheese, and domestic (cattle, sheep, goats) and wild (deer, boar, fox) animals in Spain. Nevertheless, STEC outbreaks in Spain are rare. PMID- 22101412 TI - Microbial community composition of anoxic marine sediments in the Bay of Cadiz (Spain). AB - The composition of the microbial community inhabiting the anoxic coastal sediments of the Bay of Cadiz (southern Spain) was investigated using a molecular approach consisting of PCR cloning and denaturing gradient gel electrophoresis (DGGE), based on 16S rRNA sequences. The total cell count was 1-5 * 108 cells/g sediment and, as determined by catalyzed reporter deposition-fluorescent in situ hybridization (CARD-FISH), the proportion of Bacteria to Archaea was about 70:30. The analysis of 16S-rRNA gene sequences revealed a wide spectrum of microorganisms, which could be grouped into 111 operational taxonomic units (OTUs). Many of the OTUs showed high phylogenetic similarity to microorganisms living in marine sediments of diverse geographic origin. The phylogenetic groups that were predominantly detected were Firmicutes, Deltaproteobacteria, and Gammaproteobacteria, accounting for 23, 15, and 14% of the clones, respectively. Diversity in the domain Archaea was significantly lower than in the domain Bacteria. The majority of the archaeal OTUs belonged to the Crenarchaeota phylum. Since most of the sequences could not be identified precisely at the genus/species level, the functional roles of the microorganisms in the ecosystem could not be inferred. However, seven OTUs affiliated with the Delta- and Epsilonproteobacteria were identified down to the genus level, with all of the identified genera known to occur in sulfate-rich marine environments. PMID- 22101413 TI - Genomic diversity of Oenococcus oeni from different winemaking regions of Portugal. AB - Oenococcus oeni is an alcohol-tolerant, acidophilic lactic acid bacterium that plays an important role in the elaboration of wine. It is often added as a starter culture to carry out malolactic conversion. Given the economic importance of this reaction, the taxonomic structure of this species has been studied in detail. In the present work, phenotypic and molecular approaches were used to identify 121 lactic acid bacteria strains isolated from the wines of three winemaking regions of Portugal. The strains were differentiated at the genomic level by M13-PCR fingerprinting. Twenty-seven genomic clusters represented by two or more isolates and 21 single-member clusters, based on an 85% similarity level, were recognized by hierarchic numerical analysis. M13-PCR fingerprinting patterns revealed a high level of intraspecific genomic diversity in O. oeni. Moreover, this diversity could be partitioned according to the geographical origin of the isolates. Thus, M13-PCR fingerprint analysis may be an appropriate methodology to study the O. oeni ecology of wine during malolactic fermentation as well as to trace new malolactic starter cultures and evaluate their dominance over the native microbiota. PMID- 22101414 TI - A flow cell simulating a subsurface rock fracture for investigations of groundwater-derived biofilms. AB - Laboratory scale continuous-flow-through chambers (flow cells) facilitate the observation of microbes in a controlled, fully hydrated environment, although these systems often do not simulate the environmental conditions under which microorganisms are found. We developed a flow cell that mimics a subsurface groundwater-saturated rock fracture and is amenable to confocal laser scanning microscopy while allowing for the simple removal of the attached biomass. This flow cell was used to investigate the effect of toluene, a representative contaminant for non-aqueous phase liquids, on groundwater-derived biofilms. Reduced average biofilm biomass and thickness, and diminished diversity of amplifiable 16S rRNA sequences were observed for biofilms that developed in the presence of toluene, compared to the biofilms grown in the absence of toluene. The flow cell also allowed the detection of fluorescent protein-labelled cells. PMID- 22101415 TI - Genetic characterization of the mechanisms of resistance to amoxicillin/clavulanate and third-generation cephalosporins in Salmonella enterica from three Spanish hospitals. AB - The mechanisms of antimicrobial resistance were characterized in 90 Salmonella enterica isolates either resistant or with intermediate resistance to amoxicillin/clavulanate (AMC(R/I)) or resistant to third-generation cephalosporins (C3G(R)). These isolates were recovered in three Spanish hospitals during 2007-2009. The C3G(R) phenotype was expressed by three isolates that carried the following extended-spectrum beta-lactamase genes: phage-associated bla(CTX M-10) in S. Virchow, bla(CTX-M-14a) surrounded by ISEcp1 and IS903 in S. Enteritidis, and bla(CTX-M-15) linked to ISEcp1 and orf477 in S. Gnesta (first description in this serotype). The AMC(R/I) phenotype was found in 87 isolates (79 S. Typhimurim, 7 S. Enteritidis, and one S. Thompson). The bla(PSE-1) gene, followed by bla(OXA-1) was mostly found among S. Typhimurim, and the bla(TEM-1) gene among S. Enteritidis. Three different gene combinations [bla(PSE-1) +floR+aadA2+sul+tet(G); bla(OXA-1) +catA+aadA1/strA-strB+sul+tet(B) and bla(TEM 1) + cmlA1+aadA/strA-strB+sul+tet(A)/tet(B) genes] were associated with the ampicillin-chloramphenicol-streptomycin-sulfonamides-tetracycline phenotype in 68 AMC(R/I) S. enterica isolates. Class 1 integrons were observed in 79% of the isolates and in most of them (45 isolates) two integrons including the aadA2 and bla(PSE-1) gene cassettes, respectively, were detected. The bla(OXA-1) +aadA1 arrangement was detected in 23 isolates, and the aac(6')-Ib-cr+bla(OXA-1) +catB3+arr3 in another one. Non-classic class 1 integrons were found in three isolates: dfrA12+orfF+aadA2+cmlA1+aadA1 (1 isolate), dfrA12+orfF+aadA2+ cmlA1+aadA1+qacH+IS440+sul3 (1 isolate) and dfrA12+orfF+aadA2+cmlA1+aadA1+qacH+IS440+ sul3+orf1+mef(B)Delta-IS26 (1 isolate). Taken together, these results underline the need for clinical concern regarding beta-lactam resistance in Salmonella and thus for continuous monitoring. PMID- 22101416 TI - Selective sweep of a cis-regulatory sequence in a non-African population of Drosophila melanogaster. AB - Although it is thought that changes in gene expression play an important role in adaptation, the identification of gene-regulatory sequences that have been targets of positive selection has proved difficult. Here, we identify a cis regulatory element of the Drosophila melanogaster CG9509 gene that is associated with a selective sweep in a derived non-African population of the species. Expression analyses indicate that CG9509 consistently shows greater expression in non-African than in African strains of D. melanogaster. We find that a 1.8 kb region located just upstream of the CG9509 coding region is devoid of DNA sequence polymorphism in a European population sample and that this is best explained by the recent action of positive selection (within the past 4,000 10,000 years). Using a reporter gene construct and phiC31-mediated site-specific integration, we show that the European version of the CG9509 upstream region drives 2-3 times greater expression than the African version in an otherwise identical genetic background. This expression difference corresponds well to that of the native gene and indicates that sequence variation within the CG9509 upstream region can completely account for its high expression in the European population. Selection appears to have favored a quantitative increase in gene expression in the Malphigian tubule, the tissue where CG9509 is predominantly expressed. PMID- 22101417 TI - Evolution and diversification of the CYC/TB1 gene family in Asteraceae--a comparative study in Gerbera (Mutisieae) and sunflower (Heliantheae). AB - Plant-specific TCP domain transcription factors have been shown to regulate morphological novelties during plant evolution, including the complex architecture of the Asteraceae inflorescence that involves different types of flowers. We conducted comparative analysis of the CYCLOIDEA/TEOSINTE BRANCHED1 (CYC/TB1) gene family in Gerbera hybrida (gerbera) and Helianthus annuus (sunflower), two species that represent distant tribes within Asteraceae. Our data confirm that the CYC/TB1 gene family has expanded in Asteraceae, a condition that appears to be connected with the increased developmental complexity and evolutionary success of this large plant family. Phylogenetic analysis of the CYC/TB1 gene family revealed both shared and lineage-specific duplications in gerbera and sunflower, corresponding to the three gene lineages previously identified as specific to core eudicots: CYC1, CYC2, and CYC3. Expression analyses of early stages of flower primordia development indicated that especially within the CYC2 clade, with the greatest number of secondary gene duplications, gene expression patterns are conserved between the species and associated with flower and inflorescence development. All sunflower and gerbera CYC2 clade genes showed differential expression between developing flower types, being upregulated in marginal ray (and trans) flowers. One gene in gerbera (GhCYC3) and two in sunflower (HaCYC2d and HaCYC2c) were indicated to be strong candidates as regulators of ray flower identity, a function that is specific for Asteraceae. Our data further showed that other CYC2 clade genes are likely to have more specialized functions at the level of single flowers, including the late functions in floral reproductive organs that may be more conserved across plant families. The expression patterns of CYC1 and CYC3 clade genes showed more differences between the two species but still pointed to possible conserved functions during vegetative plant development. Pairwise protein-protein interaction assays gave the first molecular evidence that CYC/TB1-like proteins function in complexes. Compared with sunflower, the gerbera proteins showed higher capacity for dimerization, between as well as within CYC clades. Our data from two distant species within the Asteraceae suggest that the expansion and the apparent conservation of especially the CYC2 clade CYC/TB1-like genes are associated with the evolution of the increased complexity of the Asteraceae inflorescence architecture. PMID- 22101418 TI - Aspirations and compromises: changes in homestead space relations of the extreme poor after disaster. AB - BACKGROUND: Construction of houses in homesteads and their settings occur in the context of traditional perceptions and practices in the rural culture of Bangladesh. Functional spaces inside and around the house are produced according to need over time. Inhabitants construct their houses with locally available resources and knowledge. After devastating disasters houses are delivered as products by the development agencies to quickly cater to the needs of the sufferers. The extreme poor are the receivers and inhabitants of these new houses, which can cause significant changes in the physical and environmental characteristics of the neighborhood. In this regard the building and dwelling values of the inhabitants in relation with these houses may be changed or lost. But these values are otherwise inherent characters of the rural houses in the habitations that are shaped by the aspirations of the dwellers. METHODS AND FINDINGS: This paper investigates how relief houses serve the needs of the extreme poor after disasters and how these houses gradually blend with the surrounding environment matching with the aspirations of the inhabitants. The methodology followed was observation of the backgrounds of the pre and post disaster situations, focus group discussions, drawings sessions and interviews with the inhabitants, craftsmen and locals, use of secondary sources, and visits to the houses during and after construction to understand the techniques and space value. CONCLUSIONS: The present practice of distribution of relief houses without involvement of the owners either in the information sharing or building processes and without understanding owners' perceptions about dwellings, may compromise the compatibility and hence the sustainability of relief houses. Hence, houses may only be used as temporary or transitional shelters to sustain life in the disaster phase, and will not be used as "houses" long term. PMID- 22101419 TI - Performance curve of basic skills in single-incision laparoscopy versus conventional laparoscopy: is it really more difficult for the novice? AB - BACKGROUND: Single-incision laparoscopy is a step forward toward nearly scarless surgery. Concern has been raised that single-incision laparoscopy is technically more challenging than conventional laparoscopy. This study researched the performance curves of novice trainees for single-incision laparoscopy (SILS) versus conventional laparoscopy for performing two basic tasks on a box trainer. METHODS: In this study, 20 novice participants performed two tasks (peg transfer and a dissection task) on a standard box trainer. All the participants practiced each task 11 times and were randomized in two groups. The first group performed the tasks on a box trainer through three incisions. The second group used a single-incision access with the same box trainer. The assessment scores for errors and time were recorded. The 2nd, 8th, and 11th runs of both tasks in both settings were assessed to objectify the gain in basic laparoscopic skills. RESULTS: The performance curves for both groups improved significantly in terms of both time and errors in performing the two tasks [P < 0.01, analysis of variance (ANOVA)]. For the first task, no significant difference in time between the two groups was observed at the top of the performance curve (mean, 212 +/- 64 vs. 182 +/- 48 s), but the SILS group performed with fewer errors (1.3 +/- 1.5 vs. 2.7 +/- 2.11). However, the difference was not significant (P = 0.10). The dissection task was performed faster in the SILS group (mean, 205 +/- 78 vs. 243 +/- 40 s; P = 0, 18) with fewer errors (0.7 +/- 1.05 vs. 1.9 +/- 2.1; P = 0. 12), but the difference was not significant. CONCLUSION: This study showed a significant improvement in basic skills for both the SILS and conventional laparoscopy settings after 11 repetitions. These data suggest that box training shows no significant difference between conventional laparoscopic and single incision laparoscopic settings in terms of error or time in performing basic tasks at a low complexity level for the novice. These data also show significant improvement in basic skills over a relatively short period. PMID- 22101420 TI - Single-incision laparoscopic surgery using colon-lifting technique for colorectal cancer: a matched case-control comparison with standard multiport laparoscopic surgery in terms of short-term results and access instrument cost. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) has been used for colorectal cancer as a minimally invasive procedure. However, there are still difficulties concerning effective triangulation and countertraction. The study's purpose was to clarify the usefulness of the colon-lifting technique (CLT) in SILS for colorectal cancer. METHODS: SILS was performed for cancer (cT2N0 or less) of the right-sided colon (near the ileocecum), sigmoid, or rectosigmoid. The SILSTM Port was used for transumbilical access. A suture string was inserted through the abdominal wall and passed through the mesocolon. The colon was retracted anteriorly and fixed to the abdominal wall. The main mesenteric vessels were placed under tension. Lymph node dissection was performed by medial approach. Short-term surgical outcomes and access port costs were compared between SILS (using CLT) and the standard multiport technique (MPT). The two groups were case-matched by propensity scoring. Analyzed variables included preoperative Dukes stage and tumor location. RESULTS: From June 2009 to April 2011, 27 patients underwent SILS, and from April 2005 to April 2011, 85 patients underwent MPT. Propensity scoring generated 23 matched patients per group for SILS versus MPT comparisons. There were no significant differences in operating time, blood loss, early complications, postoperative analgesic frequency, or length of hospital stay. One MPT patient was converted to open surgery (4.5%); no SILS patients were converted. There were no significant differences in the length of distal cut margin and the number of harvested lymph nodes, except incision length (SILS vs. MPT: 33 vs. 55 mm, P < 0.001). Significant differences favored SILS in access instrument cost (SILS vs. MPT: 62,761 vs. 77,130 Japanese yen, P < 0.001). CONCLUSIONS: SILS performed using CLT was safe and effective in providing radical treatment of cT2N0 cancer in the right-sided colon, sigmoid, or rectosigmoid. SILS was advantageous with respect to cosmesis and lower cost of access instruments. PMID- 22101421 TI - The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells. AB - Lung cancer is a malignant disease with poor outcome, which has led to a search for new therapeutics. The PI3K/Akt/mTOR and Ras/raf/Erk pathways are key regulators of tumor growth and survival. In the present study, their roles were evaluated by MTT assay, flow cytometry and Western blotting in lung cancer cells. We found that a high efficacy of antitumor activity was shown with GDC-0941 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In addition, H460 cells with activating mutations of PIK3CA were relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA. Furthermore, GDC-0941 was highly efficacious in combination with U0126 in inducing cell growth inhibition, G0-G1 arrest and cell apoptosis. These antitumor activities of combined treatment may be attributed to the alterations of G0-G1 phase regulators, apoptosis-related proteins and eukaryotic translation initiation factor 4B (eIF4B), induced by concomitant blockade of the PI3K/Akt/mTOR and Ras/raf/Erk pathways. In conclusion, this study suggests that multi-targeted intervention is the most effective treatment for tumors. Additionally, the blockade of PI3K, mTOR and Erk with GDC-0941 and MEK inhibitors shows promise for treating gefitinib-resistant NSCLC. PMID- 22101422 TI - Vanadium nitrogenase: a two-hit wonder? AB - Nitrogenase catalyzes the biological conversion of atmospheric dinitrogen to bioavailable ammonia. The molybdenum (Mo)- and vanadium (V)-dependent nitrogenases are two homologous members of this metalloenzyme family. However, despite their similarities in structure and function, the characterization of V nitrogenase has taken a much longer and more winding path than that of its Mo counterpart. From the initial discovery of this nitrogen-fixing system, to the recent finding of its CO-reducing capacity, V-nitrogenase has proven to be a two hit wonder in the over-a-century-long research of nitrogen fixation. This perspective provides a brief account of the catalytic function and structural basis of V-nitrogenase, as well as a short discussion of the theoretical and practical potentials of this unique metalloenzyme. PMID- 22101423 TI - Cord blood metabolomic profiling in intrauterine growth restriction. AB - A number of metabolic abnormalities have been observed in pregnancies complicated by intrauterine growth restriction (IUGR). Metabolic fingerprinting and clinical metabolomics have recently been proposed as tools to investigate individual phenotypes beyond genomes and proteomes and to advance hypotheses on the genesis of diseases. Non-targeted metabolomic profiling was employed to study fetal and/or placental metabolism alterations in IUGR fetuses by liquid chromatography high-resolution mass spectrometry (LC-HRMS) analysis of cord blood collected soon after birth. Samples were collected from 22 IUGR and 21 appropriate for gestational age (AGA) fetuses. Birth weight differed significantly between IUGR and AGA fetuses (p < 0.001). Serum samples were immediately obtained and deproteinized by mixing with methanol at room temperature and centrifugation; supernatants were lyophilized and reconstituted in water for analysis. LC-HRMS analyses were performed on an Orbitrap mass spectrometer linked to a Surveyor Plus LC. Samples were injected into a 1.0 * 150-mm Luna C18 column. Spectra were collected in full-scan mode at a resolution of approximately 30,000. Data were acquired over the m/z range of 50-1,000, with measurements performed in duplicate. To observe metabolic variations between the two sets of samples, LC HRMS data were analyzed by a principal component analysis model. Many features (e.g., ionic species with specific retention times) differed between the two classes of samples: among these, the essential amino acids phenylalanine, tryptophan, and methionine were identified by comparison with available databases. Logistic regression coupled to a receiver-operating characteristic curve identified a cut-off value for phenylalanine and tryptophan, which gave excellent discrimination between IUGR and AGA fetuses. Non-targeted LC-HRMS analysis of cord blood collected at birth allowed the identification of significant differences in relative abundances of essential amino acids between IUGR and AGA fetuses, emerging as a promising tool for studying metabolic alterations. PMID- 22101424 TI - Determination of glyphosate in groundwater samples using an ultrasensitive immunoassay and confirmation by on-line solid-phase extraction followed by liquid chromatography coupled to tandem mass spectrometry. AB - Despite having been the focus of much attention from the scientific community during recent years, glyphosate is still a challenging compound from an analytical point of view because of its physicochemical properties: relatively low molecular weight, high polarity, high water solubility, low organic solvent solubility, amphoteric behaviour and ease to form metal complexes. Large efforts have been directed towards developing suitable, sensitive and robust methods for the routine analysis of this widely used herbicide. In the present work, a magnetic particle immunoassay (IA) has been evaluated for fast, reliable and accurate part-per-trillion monitoring of glyphosate in water matrixes, in combination with a new analytical method based on solid-phase extraction (SPE), followed by liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS), for the confirmatory analysis of positive samples. The magnetic particle IA has been applied to the analysis of about 140 samples of groundwater from Catalonia (NE Spain) collected during four sampling campaigns. Glyphosate was present above limit of quantification levels in 41% of the samples with concentrations as high as 2.5 MUg/L and a mean concentration of 200 ng/L. Good agreement was obtained when comparing the results from IA and on-line SPE-LC MS/MS analyses. In addition, no false negatives were obtained by the use of the rapid IA. This is one of the few works related to the analysis of glyphosate in real groundwater samples and the presented data confirm that, although it has low mobility in soils, glyphosate is capable of reaching groundwater. PMID- 22101425 TI - DOCUMENT: a system for classifying drug-related problems in community pharmacy. AB - BACKGROUND: Drug-related problems (DRPs) are a major burden on the Australian healthcare system. Community pharmacists are in an ideal position to detect, prevent, and resolve these DRPs. Objective To develop and validate an easy-to-use documentation system for pharmacists to classify and record DRPs, and to investigate the nature and frequency of clinical interventions undertaken by Australian community pharmacists to prevent or resolve them. Setting Australian community pharmacies. METHOD: The DOCUMENT classification system was developed, validated and refined during two pilot studies. The system was then incorporated into software installed in 185 Australian pharmacies to record DRPs and clinical interventions undertaken by pharmacists during a 12-week trial. MAIN OUTCOME MEASURE: The number and nature of DRPs detected within Australian community pharmacies. RESULTS: A total of 5,948 DRPs and clinical interventions were documented from 2,013,923 prescriptions dispensed during the trial (intervention frequency 0.3%). Interventions were commonly related to Drug selection problems (30.7%) or Educational issues (23.7%). Pharmacists made an average of 1.6 recommendations per intervention, commonly relating to A change in therapy (40.1%) and Provision of information (34.7%). Almost half of interventions (42.6%) were classified by recording pharmacists as being at a higher level of clinical significance. CONCLUSION: The DOCUMENT system provided pharmacists with a useful and easy-to-use tool for recording DRPs and clinical interventions. Results from the trial have provided a better understanding of the frequency and nature of clinical interventions performed in Australian community pharmacies, and lead to a national implementation of the system. PMID- 22101426 TI - Impact of pharmaceutical care on health outcomes in patients with COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) treatment goals are often not achieved despite the availability of many effective treatments. Furthermore, clinical pharmacist interventions to improve clinical and humanistic outcomes in COPD patients have not yet been explored and few randomized controlled trials have been reported to evaluate the impact of pharmaceutical care on health outcomes in patients with COPD. OBJECTIVE: The aim of the present study was to evaluate the impact of pharmaceutical care intervention, with a strong focus on self-management, on a range of clinical and humanistic outcomes in patients with COPD. SETTING: Outpatient COPD Clinic at the Royal Medical Services Hospital. METHOD: In a randomised, controlled, prospective clinical trial, a total of 133 COPD patients were randomly assigned to intervention or control group. A structured education about COPD and management of its symptoms was delivered by the clinical pharmacist for patients in the intervention group. Patients were followed up at 6 months during a scheduled visit. Effectiveness of the intervention was assessed in terms of improvement in health-related quality of life, medication adherence, disease knowledge and healthcare utilization. Data collected at baseline and at the 6 month assessment was coded and entered into SPSS((r)) software version 17 for statistical analysis. A P value of <0.05 was considered statistically significant. MAIN OUTCOME MEASURE: The primary outcome measure was health-related quality of life improvement. All other data collected including healthcare utilization, COPD knowledge and medication adherence formed secondary outcome measures. RESULTS: A total of 66 patients were randomized to the intervention group and 67 patients were randomized to the control group. Although the current study failed to illustrate significant improvement in health related quality of life parameters, the results indicated significant improvements in COPD knowledge (P < 0.001), medication adherence (P < 0.05), medication beliefs (P < 0.01) and significant reduction in hospital admission rates (P < 0.05) in intervention patients when compared with control group patients at the end of the study. CONCLUSION: The enhanced patient outcomes as a result of the pharmaceutical care programme in the present study demonstrate the value of an enhanced clinical pharmacy service in achieving the desired health outcomes for patients with COPD. PMID- 22101427 TI - Public reporting in Germany: the content of physician rating websites. AB - BACKGROUND: Physician rating websites (PRWs) are gaining in popularity among patients seeking quality information about physicians. However, little knowledge is available about the quantity and type of information provided on the websites. OBJECTIVE: To determine and structure the quantity and type of information about physicians in the outpatient sector provided on German-language physician rating websites. METHODS: In a first step, we identified PRWs through a systematic internet search using German keywords from a patient's perspective in the two search engines Google and Yahoo. Afterwards, information about physicians available on the websites was collected and categorised according to Donabedian's structure/process/outcome model. Furthermore, we investigated whether the information was related to the physician himself/ herself or to the practice as a whole. RESULTS: In total, eight PRWs were detected. Our analysis turned up 139 different information items on eight websites; 67 are related to the structural quality, 4 to process quality, 5 to outcomes, and 63 to patient satisfaction/experience. In total, 37% of all items focus specifically on the physician and 63% on the physician's practice. In terms of the total amount of information provided on the PRWs, results range from 61 down to 13.5 items. CONCLUSIONS: A broad range of information is available on German PRWs. While structural information can give a detailed overview of the financial, technical and human resources of a practice, other outcome measures have to be interpreted with caution. Specifically, patient satisfaction results are not risk-adjusted, and thus, are not appropriate to represent a provider's quality of care. Consequently, neither patients nor physicians should yet use the information provided to make their final decision for or against an individual physician. PMID- 22101428 TI - Fast and low sample consuming quantification of manganese in cell nutrient solutions by flow injection ICP-QMS. AB - Inductively coupled plasma mass spectrometry with quadrupole mass analyzers (ICP QMS) is one of the most powerful analytical techniques due to its superb limits of detection and the fast, quasi simultaneous quantification of different elements in one single run. However, sample consumption is typically too large for use in biological studies and spectral as well as non-spectral interferences are often hard to compensate for. Hence, a flow injection (FIA) approach for quantification of manganese (Mn) in biologically relevant cell nutrient solutions was developed, extending the sample throughput and versatility of a common system. The investigated cell nutrient solutions are, for example, used in in vitro models of the blood-brain and the blood-liquor barrier and represent a complex matrix, while Mn is of interest due to its potential neurotoxic effects, but shows several challenges in ICP-QMS analysis. Therefore, the aim of the study was not only to devise a system as simple as possible, but also to have a tool allowing the measurement of several hundreds of samples within a short period of time. Furthermore, statistical data treatment was used to evaluate the need for matrix matching and internal standardization for the four different solutions. The calculated lowest detection limits (LODs) were in the low MUg L(-1) range due to successful use of a collision/reaction cell, while only 11 MUL of sample volume was needed per injection by means of a segment sample loop filling. The analysis of a certified reference material further confirmed the suitability of this approach in biological studies. PMID- 22101429 TI - Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. AB - All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue. Acting via the beta(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, whereas it stimulates the expression of thermogenic genes, such as PPAR-gamma coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin 4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. PMID- 22101430 TI - Natural killer cells act as rheostats modulating antiviral T cells. AB - Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus infected cells may contribute to antiviral defence during some virus infections- especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans--NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV infected antigen-presenting cells. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence. PMID- 22101431 TI - Reductive carboxylation supports growth in tumour cells with defective mitochondria. AB - Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism. PMID- 22101432 TI - Physiology: Immune cells fuel the fire. PMID- 22101433 TI - Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. AB - Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of alpha ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived alpha-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells. PMID- 22101435 TI - Numerous cortical tubers and rhabdomyomas in a case of sudden unexpected infant death. AB - Sudden infant death syndrome is the leading cause of death in infants between the ages of 1 month to 1 year. Sudden infant death syndrome, a diagnosis of exclusion, can only be made after other explanations for unexpected death have been ruled out. Tuberous sclerosis complex is occasionally the findings in these patients with unexpected infant death. Here, we present a case of an unexpected infant death during sleep with multiple factors that confound the cause of death. We discuss these factors and attempt to delineate their contributions to arrive at a cause and mechanism of death. PMID- 22101434 TI - Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. AB - Tissue wounding induces the rapid recruitment of leukocytes. Wounds and tumours- a type of 'unhealed wound'--generate hydrogen peroxide (H(2)O(2)) through an NADPH oxidase (NOX). This extracellular H(2)O(2) mediates recruitment of leukocytes, particularly the first responders of innate immunity, neutrophils, to injured tissue. However, the sensor that neutrophils use to detect the redox state at wounds is unknown. Here we identify the Src family kinase (SFK) Lyn as a redox sensor that mediates initial neutrophil recruitment to wounds in zebrafish larvae. Lyn activation in neutrophils is dependent on wound-derived H(2)O(2) after tissue injury, and inhibition of Lyn attenuates neutrophil wound recruitment. Inhibition of SFKs also disrupted H(2)O(2)-mediated chemotaxis of primary human neutrophils. In vitro analysis identified a single cysteine residue, C466, as being responsible for direct oxidation-mediated activation of Lyn. Furthermore, transgenic-tissue-specific reconstitution with wild-type Lyn and a cysteine mutant revealed that Lyn C466 is important for the neutrophil wound response and downstream signalling in vivo. This is the first identification, to our knowledge, of a physiological redox sensor that mediates leukocyte wound attraction in multicellular organisms. PMID- 22101436 TI - Sudden death after exercise in an adolescent with hemoglobin SE. AB - Hemoglobin (Hb) S and Hb E are the most common variant hemoglobins, but because of the geographical separation of the areas where they are prevalent, the combination of the 2 is uncommon. Approximately 46 cases of hemoglobin SE compound heterozygosity have been reported. No deaths from the condition have been reported previously, whereas death after vigorous physical activity in individuals with sickle cell trait (hemoglobin AS) has been described in a few case reports. Here we report previously undiagnosed hemoglobinopathy SE in a 12 year-old American boy who collapsed during football practice and had a cardiac arrest on the field after a brief lucid interval. The autopsy was significant only for postmortem intravascular sickling. A postmortem hemoglobin electrophoresis test revealed 57% S, 34% E, and 1% F hemoglobins. The death is attributed to cardiac ischemia from functional vaso-occlusion by sickled erythrocytes. PMID- 22101437 TI - Penile strangulation: report of a fatal case. AB - Penile strangulation or entrapment is an unusual entity that requires urgent treatment due to its potential complications. Several cases have been reported in the medical literature, some of them describing serious injuries such as necrosis, gangrene, and amputation of the penis. However, as far as we know, no fatal cases have been described before. We present the death of an adult male secondary to the complications due to penile strangulation with a plastic bottle neck. The time of incarceration was unknown, but according to a witness it could be about 10 to 14 days. The findings of autopsy were penile strangulation, necrosis of the penis, acute pyelonephritis, and bronchopneumonia. The subject's refusal to ask for medical help was the cause of this atypical evolution. PMID- 22101438 TI - Petechiae in hanging: a retrospective study of contributing variables. AB - Petechiae, one of the classic signs of asphyxia, are thought to be more frequently observed in cases of hanging where part of the body is supporting the victim's weight, ie, cases of incomplete hanging. However, there is very little evidence-based medicine to support this claim. The present study is intended to evaluate the relationship between petechiae and the type of hanging (complete vs. incomplete). Furthermore, several other variables were analyzed to determine if they contribute significantly to the presence of petechiae. An 8.5-year retrospective study of 206 cases of death by hanging reviewed autopsy reports for the presence of petechiae. For each case, the following information was also compiled: gender and age, height and weight, body mass index, the type of hanging (complete or incomplete suspension), the type of ligature used (narrow or wide), and whether or not the victim had received cardiopulmonary resuscitation maneuvers. Statistical analysis revealed that the incidence was higher among incomplete hanging victims compared with cases of complete suspension and that the incidence of petechiae varied inversely with the height of the victims. The other factors were not shown to contribute significantly to the presence of petechiae. PMID- 22101439 TI - Control of bacterial biofilm growth on surfaces by nanostructural mechanics and geometry. AB - Surface-associated communities of bacteria, called biofilms, pervade natural and anthropogenic environments. Mature biofilms are resistant to a wide range of antimicrobial treatments and therefore pose persistent pathogenic threats. The use of surface chemistry to inhibit biofilm growth has been found to only transiently affect initial attachment. In this work, we investigate the tunable effects of physical surface properties, including high-aspect-ratio (HAR) surface nanostructure arrays recently reported to induce long-range spontaneous spatial patterning of bacteria on the surface. The functional parameters and length scale regimes that control such artificial patterning for the rod-shaped pathogenic species Pseudomonas aeruginosa are elucidated through a combinatorial approach. We further report a crossover regime of biofilm growth on a HAR nanostructured surface versus the nanostructure effective stiffness. When the 'softness' of the hair-like nanoarray is increased beyond a threshold value, biofilm growth is inhibited as compared to a flat control surface. This result is consistent with the mechanoselective adhesion of bacteria to surfaces. Therefore by combining nanoarray-induced bacterial patterning and modulating the effective stiffness of the nanoarray--thus mimicking an extremely compliant flat surface--bacterial mechanoselective adhesion can be exploited to control and inhibit biofilm growth. PMID- 22101440 TI - Red ginseng and 20(S)-Rg3 control testosterone-induced prostate hyperplasia by deregulating androgen receptor signaling. AB - Since prostate growth is governed by the androgen signaling pathway, blockade of the pathway is regarded as an appropriate strategy for the treatment of benign prostatic hyperplasia (BPH). Panax ginseng is known to have various pharmacological activities. Of several products of its root, red ginseng, having many bioactive ginsenosides, is most popularly used in Korea, and recently has been reported to control the proliferation of cancer cells. We here tested the effect of a water extract of Korean red ginseng (WKRG) on testosterone-induced prostate hyperplasia. WKRG (daily intraperitoneal injection) prevented prostate overgrowth and epithelial thickening induced by testosterone in rats, and suppressed a rat prostate kallikrein-S3. In human prostate cells, WKRG inhibited testosterone-induced cell proliferation, arrested cell cycle by inducing p21 and p27, and induced apoptosis. Testosterone-induced expression of human kallikrein-3 mRNA and activation of androgen receptor (AR) were effectively inhibited by WKRG. Of the major ginsenosides included in WKRG, 20(S)-Rg3 was identified to repress AR activity and to attenuate prostate cell growth during testosterone stimulation. Moreover, 20(S)-Rg3 downregulated AR by facilitating the degradation of AR protein. WKRG and 20(S)-Rg3 were found to have new pharmacological activities against testosterone-induced prostate overgrowth. Given that red ginseng has been used safely in Asia for 1000 years, red ginseng and 20(S)-Rg3 could be potential therapeutic regimens for treating BPH. PMID- 22101441 TI - New flav-3-en-3-ol glycosides, kaempferiaosides C and D, and acetophenone glycosides, kaempferiaosides E and F, from the rhizomes of Kaempferia parviflora. AB - Two new flav-3-en-3-ol glycosides, kaempferiaosides C (3) and D(4), and two new acetophenone glycosides, kaempferiaosides E (5) and F (6), were isolated from the Thai natural medicine Krachai Dum, the rhizomes of Kaempferia parviflora Wall. ex Baker. Their structures were established mainly on the basis of 1D and 2D NMR spectral data. PMID- 22101442 TI - An ideal microvascular decompression technique should be simple and safe. PMID- 22101443 TI - Case-controlled study of critical care or surgical ward care after elective open colorectal surgery. AB - BACKGROUND: Evidence for the benefit of critical care after surgery is limited. This study assessed the value of immediate admission to the critical care unit (CCU) after open colorectal surgery. METHODS: Patients aged over 45 years were screened with a cardiopulmonary exercise test to determine their anaerobic threshold. Less fit patients defined by an anaerobic threshold below 11 ml oxygen per kg per min were assigned to either critical care or surgical ward care. Those with an anaerobic threshold of 11 ml oxygen per kg per min or above were assigned to ward care. The outcome measure was the number of cardiac events. RESULTS: Of 153 patients who underwent exercise testing, 55 had an anaerobic threshold of at least 11 ml oxygen per kg per min (ward care) and 98 had a threshold of less than 11 ml oxygen per kg per min, of whom 39 were allocated to ward care and 51 to critical care. Median length of CCU stay was 31 (range 5-46) h. More cardiac events occurred in patients allocated to ward care (7 of 39) than in those allocated to critical care (0 of 51): absolute difference 18 (95 per cent confidence interval 10 to 26) per cent (P = 0.002). There were no cardiac events in patients with an anaerobic threshold of 11 ml oxygen per kg per min or higher. CONCLUSION: Patients with an anaerobic threshold of at least 11 ml oxygen per kg per min and those with a threshold below 11 ml oxygen per kg per min managed in the CCU had fewer cardiac events. PMID- 22101444 TI - Additional paper waste in pulping sludge for biohydrogen production by heat shocked sludge. AB - Dark anaerobic fermentation is an interesting alternative method for producing biohydrogen (H(2)) as a renewable fuel because of its low cost and various usable organic substrates. Pulping sludge from wastewater treatment containing plentiful cellulosic substrate could be feasibly utilized for H(2) production by dark fermentation. The objective of this study was to investigate the optimal proportion of pulping sludge to paper waste, the optimal initial pH, and the optimal ratio of carbon and nitrogen (C/N) for H(2) production by anaerobic seed sludge pretreated with heat. The pulping sludge was pretreated with NaOH solution at high temperature and further hydrolyzed with crude cellulase. Pretreatment of the pulping sludge with 3% NaOH solution under autoclave at 121 degrees C for 2 h, hydrolysis with 5 FPU crude cellulase at 50 degrees C, and pH 4.8 for 24 h provided the highest reducing sugar production yield (229.68 +/- 2.09 mg/g(TVS)). An initial pH of 6 and a C/N ratio of 40 were optimal conditions for H(2) production. Moreover, the supplement of paper waste in the pulping sludge enhanced the cumulative H(2) production yield. The continuous hydrogen production was further conducted in a glass reactor with nylon pieces as supporting media and the maximum hydrogen production yield was 151.70 ml/g(TVS). PMID- 22101445 TI - Improving phytase enzyme activity in a recombinant phyA mutant phytase from Aspergillus niger N25 by error-prone PCR. AB - The mutant acid phytase (phyA ( m )) gene was modified by random mutagenesis to improve enzymatic activity by using an error-prone PCR (ep-PCR) strategy. The mutated gene was linearized and inserted into plasmid vector pPIC9K and transformed by electroporation into Pichia pastoris GS115. A single transformant, PP-NP(ep)-6A, showing the strongest phytase activity from among the 5,500 transformants, was selected for detailed analyses. Southern blot analysis of the mutant yeast transformant showed that phyA ( ep ) gene was integrated into the chromosome genome through single crossover with one copy of phyA. The kinetic parameters indicated that the mutant one showed 61% higher specific activity and 53% lower k (m) value than that of PP-NP(m)-8 (P < 0.05). In addition, the overall catalytic efficiency (k (cat)/k (m)) of the mutant one was 84% higher (P < 0.05) than that of PP-NP(m)-8. Nine bases were altered in the mutant sequences, which resulted in three amino acid changes, namely, Glu156Gly, Thr236Ala, and Gln396Arg. The structural predictions indicated that the mutations generated by ep-PCR somehow reorganized or remodeled the active site, which could lead to increasing catalytic efficiency. PMID- 22101446 TI - Tandem multimer expression and preparation of hypoglycemic peptide MC6 from Momordica charantia in Escherichia coli. AB - Tandem repeat multimers of Momordica charantia (MC) peptide MC6 were designed and the recombinant plasmid containing 10 copies of MC6 gene was constructed to improve the expression level of MC6 in Escherichia coli. Under the selected conditions of cultivation and induction, the expression level of recombinant TrxA MC6(10) protein was above 25% of total bacteria protein. This fusion protein was purified and cleaved with HCl (13%, w/v). Either the un-cleaved or cleaved recombinant proteins was analyzed pharmacological activity by alloxan-induced diabetic mice and only the cleaved products of the recombinant protein showed significant hypoglycemic effects. The study provides a convenient and economical method for the large-scale production of anti-diabetic medicines for pharmaceutical applications. PMID- 22101447 TI - Cloning of thermostable cellulase genes of Clostridium thermocellum and their secretive expression in Bacillus subtilis. AB - Screening for the powerful cellulase genes with improved activities remains a challenge for the biorefinery research. In this study, five cellobiohydrolase genes and one endoglucanase gene sourced from Clostridium thermocellum DSM 1237, cbhA, celK, celO, cel48Y, cel48S, and celA were cloned into a newly established tool vector pP43JM2 and expressed in two Bacillus subtilis strains, B. subtilis WB600 and B. subtilis WB800, respectively. Most of the cellulases produced in the B. subtilis recombinants were efficiently secreted into the culture medium. These secreted soluble proteins showed distinct cellulase activities using phosphoric acid swollen cellulose (PASC) as the substrate and they also demonstrated strong synergistic effects for PASC, Avicel cellulose, and the dilute acid pretreated corn stover. The current work provided a quick secretive cloning method for screening cellulase genes and may provide a host strain for constructing a consolidated bioprocessing platform with the capacity of secretive expression of multiple cellulases. PMID- 22101448 TI - Interspecies interaction of signal peptide PapR secreted by Bacillus cereus and its effect on production of antimicrobial peptide. AB - This study was carried out to investigate the interspecies interaction of PapR peptide secreted by Bacillus cereus on production of BSAP-254, an antimicrobial peptide produced by Bacillus subtilis SC-8 isolated from the Korean fermented soybean paste and exhibited narrow antagonistic activity against the B. cereus group, but not against other foodborne pathogens. PapR is a signal peptide that activates PlcR, which is a pleiotropic regulator controlling the expression of various virulence factors in B. cereus. When B. subtilis SC-8 was co-cultured with B. cereus, it completely inhibited the growth of B. cereus within 12 h, and the rate of BSAP-254 production was increased 34.2% at 12 h. Furthermore, 5 MUM of synthetic PapR peptide added to the culture of B. subtilis SC-8 increased the rate of BSAP-254 production up to 59.7%. The growth of B. subtilis SC-8, however, was not significantly different with or without the addition of PapR. When B. cereus papR mutant was co-cultured with B. subtilis SC-8, the growth of the mutant was not inhibited and the rate of BSAP-254 production was decreased by 45%. PMID- 22101449 TI - Canine and feline obesity: frequently asked questions and their answers. AB - The diagnosis of obesity is simple and warrants intervention because of the association between obesity and increased morbidity. Pet owner commitment, a proper feeding plan, and regular monitoring are the keys to a successful weight loss program. Treatment of obesity involves caloric restriction and/or diet change. Therapeutic weight loss diets differ in fiber, moisture, and digestible carbohydrate contents, and the diet choice should be tailored to the individual patient. Appropriate feeding management is equally important. To protect against the recurrence of obesity, owners should be educated on how to monitor body condition score and adjust the feeding program to maintain proper body condition. PMID- 22101450 TI - Pimobendan and its use in treating canine congestive heart failure. AB - Pimobendan, a calcium sensitizer and phosphodiesterase III inhibitor, has positive inotropic and vasodilatory properties. Its use in patients with naturally occurring congestive heart failure (CHF) has been studied in a number of blinded, randomized, multicenter clinical trials. It has been shown to improve quality of life, reduce heart insufficiency scores, and increase median survival times for patients with CHF due to dilated cardiomyopathy and myxomatous valvular disease. Although most studies have reported positive findings, some potential adverse effects have also been described. Studies are under way to further evaluate the effects of this novel positive inotrope and vasodilator in canine cardiac disease. PMID- 22101451 TI - Purchase examinations and importation requirements for European performance horses and their semen entering the United States. AB - A comprehensive purchase examination is expected by American clients intent on importing a horse from a foreign country. American veterinarians may be involved in performing purchase examinations in foreign countries or, more often, interpreting findings from foreign veterinarians for their American clients. Exportation and importation requirements for horses and semen vary from country to country. Detailed knowledge of the requirements by all involved veterinarians is essential for efficient and successful international equine travel. PMID- 22101452 TI - Case-control study of smoking and non-melanoma skin cancer. AB - OBJECTIVE: To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case-control study was conducted in Tampa, FL. METHODS: Patients with histologically confirmed BCC/SCC were recruited from a university dermatology clinic (n = 215 BCC, 165 SCC). Controls were comprised of individuals with no history of skin cancer who screened negative for skin cancer upon physical examination at the affiliated cancer screening or primary care clinics (n = 315). Information on smoking and other risk factors was obtained from self-administered questionnaires. RESULTS: After adjustment for age, sex, and other skin cancer-risk factors, ever smoking was not associated with BCC (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 0.83-1.92), but was statistically significantly associated with SCC (OR = 1.97, 95% CI = 1.19-3.26), with significant trends observed for SCC associated with increasing cigarettes per day (p = 0.01) and pack-years smoked (p = 0.01). Among men, smoking >=20 pack-years was associated with non-significant increased risks of BCC (OR = 1.90, 95% CI = 0.88-4.12) and SCC (OR = 1.97, 95% CI = 0.84-4.66), whereas among women, no association was observed with BCC (OR = 0.98, 95% CI = 0.39-2.46) while a statistically significant three-fold risk was observed with SCC (OR = 3.00, 95% CI = 1.02-8.80). CONCLUSION: Cigarette smoking is more strongly associated with SCC than BCC, particularly among women. PMID- 22101453 TI - Increased incidence of penile cancer and high-grade penile intraepithelial neoplasia in Denmark 1978-2008: a nationwide population-based study. AB - OBJECTIVE: To assess the trends in incidence of penile cancer during 1978-2008 and high-grade penile intraepithelial neoplasia (PIN2/3) during 1998-2008 in Denmark. METHODS: Using two nationwide registries, we estimated age- and period specific incidence rates. Log-linear Poisson regression analysis was used to estimate average annual percentage change (AAPC) and 95% confidence intervals (CI). RESULTS: We identified 1,488 men with penile cancer and 285 men with PIN2/3. The incidence of penile cancer increased from 1.0 to 1.3 per 100,000 men years in 1978-1979 to 2006-2008; this represented an AAPC of 0.8% (95% CI: 0.17 1.37). Squamous cell carcinoma (SCC) was the most common histological type (91.7%). The median age at diagnosis was 67 years, and the age-specific incidence rate of penile SCC increased with increasing age. The incidence rate of PIN2/3 increased significantly (0.5 to 0.9 per 100,000 men-years) in 1998-1999 to 2006 2008, and this represented an AAPC of 7.1% (95% CI: 3.30-11.05). CONCLUSIONS: The incidence of penile cancer increased in 1978-2008 in Denmark, and the same applied to PIN2/3 in 1998-2008. A high prevalence of human papillomavirus (HPV) and a low circumcision rate in Denmark may partly explain our results. PMID- 22101454 TI - Site-directed mutagenesis studies on the L-arginine-binding sites of feedback inhibition in N-acetyl-L-glutamate kinase (NAGK) from Corynebacterium glutamicum. AB - Arginine biosynthesis in Corynebacterium glutamicum proceeds via a pathway that is controlled by arginine through feedback inhibition of NAGK, the enzyme that converts N-acetyl-L-glutamate (NAG) to N-acety-L-glutamy-L-phosphate. In this study, the gene argB encoding NAGK from C. glutamicum ATCC 13032 was site directed, and the L-arginine-binding sites of feedback inhibition in Cglu_NAGK are described. The N-helix and C-terminal residues were first deleted, and the results indicated that they are both necessary for Cglu_NAGK, whereas, the complete N-helix deletion (the front 28 residues) abolished the L-arginine inhibition. Further, we study here the impact on these functions of 12 site directed mutations affecting seven residues of Cglu_NAGK, chosen on the basis of homology structural alignment. The E19R, H26E, and H268N variants could increase the I0.5 (R) 50-60 fold, and the G287D and R209A mutants could increase the I0.5 (R) 30-40 fold. The E281A mutagenesis resulted in the substrate kinetics being greatly influenced. The W23A variant had a lower specific enzyme activity. These results explained that the five amino acid residues (E19, H26, R209, H268, and G287) located in or near N-helix are all essential for the formation of arginine inhibition. PMID- 22101455 TI - Coexisting Curtobacterium bacterium promotes growth of white-rot fungus Stereum sp. AB - White-rot basidiomycetes are the main decomposers of woody biomass in forest ecosystems. Little is known, however, about the interactions between white-rot fungi and other microorganisms in decayed wood. A wood-rotting fungus, Stereum sp. strain TN4F, was isolated from a fruit body, and its coexisting cultivable bacteria were isolated from its substrate; natural white-rot decayed wood. The effects of bacteria on fungal growth were examined by confrontational assay in vitro. A growth-promoting bacterium for this Stereum strain was identified as Curtobacterium sp. TN4W-19, using 16SrRNA sequencing. A confrontational assay revealed that Curtobacterium sp. TN4W-19 significantly promoted the mycelial growth of Stereum sp. TN4F in the direction of the bacterial colony, without direct contact between the mycelium and bacterial cells. This is the first report of a positive interaction between a white-rot fungus and a coexisting bacterial strain in vitro. PMID- 22101456 TI - Metagenome cloning and functional analysis of Na+/H+ antiporter genes from Keke Salt Lake in China. AB - Na+/H+ antiporters are ubiquitous membrane proteins and play a central role in cell homeostasis including pH regulation, osmoregulation, and Na+/Li+ tolerance in bacteria. The microbial communities in extremely hypersaline soil are an important resource for isolating Na+/H+ antiporter genes. A metagenomic library containing 35,700 clones was constructed by using genomic DNA obtained from the hypersaline soil samples of Keke Salt Lake in Northwest of China. Two Na+/H+ antiporters, K1-NhaD, and K2-NhaD belonging to NhaD family, were screened and cloned from this metagenome by complementing the triple mutant Escherichia coli strain KNabc (nhaA-, nhaB-, chaA-) in medium containing 0.2 M NaCl. K1-NhaD and K2-NhaD have 75.5% identity at the predicted amino acid sequence. K1-NhaD has 78% identity with Na+/H+ antiporter NhaD from Halomonas elongate at the predicted amino acid sequence. The predicted K1-NhaD is a 53.5 kDa protein (487 amino acids) with 13 transmembrane helices. K2-NhaD has 73% identity with Alkalimonas amylolytica NhaD. The predicted K2-NhaD is a 55 kDa protein (495 amino acids) with 12 transmembrane helices. Both K1-NhaD and K2-NhaD could make the triple mutant E. coli KNabc (nhaA-, nhaB-, chaA-) grow in the LBK medium containing 0.2 0.6 M Na+ or with 0.05-0.4 M Li+. Everted membrane vesicles prepared from E. coli KNabc cells carrying K1-NhaD or K2-NhaD exhibited Na+/H+ and Li+/H+ antiporter activities which were pH-dependent with the highest activity at pH 9.5. Little K+/H+ antiporter activity was also detected in vesicles form E. coli KNabc carrying K1-NhaD or K2-NhaD. PMID- 22101457 TI - Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. AB - Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) -1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR -2.1 (-2.8 to -1.4). Treatment duration was similar [G1 8.5 (4.0-15.2) vs G2 11.9 (6.2-14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [-0.7 (-1.5 to 0.3)] vs G2 [-2.0 (-2.3 to -1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised. PMID- 22101458 TI - Paramagnetic metal complexes of diamido donor ligands. AB - Recently, considerable attention has been given to the use of multi-dentate amido ligands in the coordination chemistry of a range of transition metals as a means of accessing novel structural motifs and unusual reactivity. Presented herein is a perspective on transition and f-block metal complexes containing diamido donor ligands of the general form [NDN](2-) (D = NR, O, PR). Particular focus is given to paramagnetic metals, which have in general been studied much less than their diamagnetic counterparts despite their potential to exhibit unique structures and diverse reactivity patterns, in addition to their magnetic properties. PMID- 22101459 TI - An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis. AB - Wnt5a is a representative ligand that activates the beta-catenin-independent pathway in Wnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown of Wnt5a reduces the ability of gastric cancer cells to metastasize in nude mice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this study was to examine whether an anti-Wnt5a antibody affects metastasis of gastric cancer cells. One anti-Wnt5a polyclonal antibody (pAb5a-5) inhibited migration and invasion activities in vitro of gastric cancer cells with a high expression level of Wnt5a. Previously, it was shown that Wnt5a induces the internalization of receptors, which is required for Wnt5a-dependent activation of Rac1. pAb5a-5 inhibited Wnt5a dependent internalization of receptors, thereby suppressed Wnt5a-dependent activation of Rac1. Laminin gamma2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5a-dependent expression of laminin gamma2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nude mice. Laminin gamma2 was required for liver metastatic ability of gastric cancer cells in vivo. Furthermore, intraperitoneal injection of pAb5a-5 inhibited the metastatic ability of gastric cancer cells. These results suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of receptors, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin gamma2. PMID- 22101460 TI - Characterization of sodium hyaluronate blends using frit inlet asymmetrical flow field-flow fractionation and multiangle light scattering. AB - We characterized ultrahigh molecular weight sodium hyaluronate (NaHA) and blended pharmaceutical products containing NaHA using flow field-flow fractionation and multiangle light scattering-differential refractive index (FlFFF-MALS-DRI). NaHA is a water-soluble polysaccharide with a range of molecular weights (MW; 10(5)~10(8) Da) that is found in body fluids and tissues. NaHA is also used commercially in pharmaceutical and cosmetic applications. We used a frit inlet asymmetrical FlFFF channel to separate aqueous polymers according to their hydrodynamic size, and we used on-line measurements of light scattering to obtain the MW distribution (MWD) as well as structural information about NaHA in aqueous solution. In this study, we investigated NaHA and anti-adhesive blend mixtures of NaHA (a commercial NaHA blend mixture containing sodium carboxymethyl cellulose and a new blend with hydroxyethyl starch (HES)) to determine the molecular weight distribution MWD of NaHA and the blend mixtures and to obtain structural information about these compounds in aqueous solution. We also examined the characteristics of NaHA-HES-polylactic-co-glycolic acid film products exposed to gamma radiation for sterilization purposes. PMID- 22101461 TI - Study of the naphthalene-2,3-dicarboxaldehyde pre-column derivatization of biogenic mono- and diamines in mixture and fluorescence-HPLC determination. AB - A new fluorescence-HPLC method was developed for the simultaneous determination of eight biogenic monoamines (histamine, methylamine, tyramine, ethylamine, propylamine, tryptamine, 2-phenylethylamine, isoamylamine) and two biogenic diamines (putrescine, cadaverine) in the presence of heptylamine as the internal standard. The amines were pre-column derivatized with naphthalene-2,3 dicarboxaldehyde in the presence of cyanide ion as the nucleophile. The effect of the derivatization reaction conditions on the reaction yield was investigated. The derivatives were separated on an Inertsil ODS-3 column (250 * 4mm i.d., 5 MUm) using gradient elution and detected fluorimetrically at excitation and emission wavelengths of 424 and 494 nm, respectively. Limits of detection between 0.002 and 0.4 ng, injected on-column (10-MUL loop), were achieved. The within- and between-day relative standard deviations ranged between 0.2-3.4% and 0.3 4.8%, respectively. The utility of the method in assaying biogenic mono- and diamine mixtures in Greek cheeses is demonstrated. Ultrasound-assisted liquid liquid extraction was applied prior to derivatization. PMID- 22101462 TI - Liquid chromatography tandem mass spectrometry determination of total budesonide levels in dog plasma after inhalation exposure. AB - A sensitive and selective method to quantify budesonide in dog plasma samples was developed and fully validated. Liquid-liquid extraction was followed by solid phase extraction and liquid chromatography-tandem mass spectrometry with electrospray ionization. After reconstitution of the analytes in the mobile phase, samples were analysed by reversed-phase liquid chromatography with isocratic elution. d8-Budesonide was used as an internal standard, and characteristic transitions of d8-budesonide and budesonide were used for quantification. The method was validated with respect to selectivity, specificity, linearity, recovery, repeatability, reproducibility and limits of detection and quantification. The validated method was successfully applied to monitor the plasma levels of budesonide in dogs exposed to clinical doses of inhaled and intravenous drug. PMID- 22101463 TI - Determination of selected pesticides by GC with simultaneous detection by MS (NCI) and MU-ECD in fruit and vegetable matrices. AB - A gas chromatography-mass spectrometry method in negative chemical ionization mode has been developed incorporating simultaneous detection using a micro electron capture detector (MU-ECD) for the determination of pesticides in fruits and vegetables. This instrument configuration uses a three-way splitter device which divides the effluent from the analytical column between the two detectors with the split ratio 1:0.1 (MSD/MU-ECD) in each run. The MU-ECD was used for confirmation purposes. Validation of the method was performed on three matrices: tomato, apple, and orange. The ethyl acetate method was assayed; recovery studies were performed at 10 and 100 MUg/kg. Recoveries between 70% and 120% were achieved and relative standard deviations lower than 20% (n = 5) were obtained for all pesticides and matrices studied. Limits of quantification lower than 10 MUg/kg were obtained for 100% of pesticides in all of the matrices. Limits of quantification lower than 2.5 MUg/kg were achieved for 77.8% of pesticides in the tomato and apple matrices, and for 72.2% of pesticides in the orange matrix. The method showed linear response in the concentration range tested (2.5-500 MUg/kg) with correlation coefficients >0.99. Good repeatability and reproducibility results were obtained in all cases, with relative standard deviations lower than 16.7% and 20%, respectively. Finally, 20 incurred samples were analyzed using the proposed method. The simultaneous use of the two detectors was satisfactory for the analysis of these real samples. The total number of pesticides identified was 25. The number of samples which contained at least one pesticide was 15-this represented 75% of the total number of samples studied. PMID- 22101464 TI - Discrimination of primitive endoderm in embryoid bodies by Raman microspectroscopy. AB - Embryoid bodies (EBs), derived from aggregated embryonic stem (ES) cells, are capable of differentiating into all three germ layers, including the endoderm, mesoderm, and ectoderm. The initial stage of EB differentiation is the formation of a primitive endoderm (PE) layer located at the periphery of the aggregate. Raman microspectroscopy was employed to segregate PE cells from undifferentiated ES cells. The Raman spectra of the PE cells of the periphery of EBs, formed upon the withdrawal of leukemia inhibitory factor (LIF), were compared with those of the undifferentiated ES cells of the core of cell aggregates, formed in the presence of LIF. It was noticed that the PE cells have high contents of proteins and low contents of nucleic acids, lipids, and carbohydrates compared with ES cells. Also, we established the presence of another population of PE cells located in the core of the EBs. In addition, we identified some specific Raman markers to distinguish PE cells from ES cells (e.g., I(1003)/I(937)). This is the first study to investigate the PE cells of live EBs and define some Raman markers to distinguish them from undifferentiated ES cells. PMID- 22101465 TI - Pathogen detection using engineered bacteriophages. AB - Bacteriophages, or phages, are bacterial viruses that can infect a broad or narrow range of host organisms. Knowing the host range of a phage allows it to be exploited in targeting various pathogens. Applying phages for the identification of microorganisms related to food and waterborne pathogens and pathogens of clinical significance to humans and animals has a long history, and there has to some extent been a recent revival in these applications as phages have become more extensively integrated into novel detection, identification, and monitoring technologies. Biotechnological and genetic engineering strategies applied to phages are responsible for some of these new methods, but even natural unmodified phages are widely applicable when paired with appropriate innovative detector platforms. This review highlights the use of phages as pathogen detector interfaces to provide the reader with an up-to-date inventory of phage-based biodetection strategies. PMID- 22101466 TI - New identification of proanthocyanidins in cinnamon (Cinnamomum zeylanicum L.) using MALDI-TOF/TOF mass spectrometry. AB - The inner bark of Ceylon cinnamon (Cinnamomum zeylanicum L.) is commonly used as a spice and has also been widely employed in the treatment and prevention of disease. The positive health effects associated with the consumption of cinnamon could in part be due to its phenolic composition; proanthocyanidins (PA) are the major polyphenolic component in commercial cinnamon. We present a thorough study of the PA profile of cinnamon obtained using matrix-assisted laser desorption/ionization tandem time-of-flight (MALDI-TOF/TOF) mass spectrometry. In addition to the advantages of MALDI-TOF as a sensitive technique for the analysis of high-molecular-weight compounds, the tandem arrangement allows the identification of the compounds through their fragmentation patterns from MS/MS experiments. This is the first time that this technique has been used to analyze polymeric PA. The results show that cinnamon PA are more complex than was previously thought. We show here for the first time that they contain (epi)gallocatechin and (epi)catechingallate units. As gallates (galloyl moieties) and the pyrogallol group in gallocatechins have been related to the biological activity of grape and tea polyphenols, the presence of these substructures may explain some of the properties of cinnamon extracts. MALDI-TOF/TOF reveals that cinnamon bark PA include combinations of (epi)catechin, (epi)catechingallate, (epi)gallocatechin, and (epi)afzelechin, which results in a highly heterogeneous mixture of procyanidins, prodelphinidins, and propelargonidins. PMID- 22101467 TI - A comment on "Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease". PMID- 22101469 TI - The Third International Symposium on Metallomics 2011. PMID- 22101468 TI - Fragmentation of singly, doubly, and triply charged hydrogen deficient peptide radical cations in infrared multiphoton dissociation and electron induced dissociation. AB - Gas phase fragmentation of hydrogen deficient peptide radical cations continues to be an active area of research. While collision induced dissociation (CID) of singly charged species is widely examined, dissociation channels of singly and multiply charged radical cations in infrared multiphoton dissociation (IRMPD) and electron induced dissociation (EID) have not been, so far, investigated. Here, we report on the gas phase dissociation of singly, doubly and triply charged hydrogen deficient peptide radicals, [M + nH]((n+1)+.) (n=0, 1, 2), in MS(3) IRMPD and EID and compare the observed fragmentation pathways to those obtained in MS(3) CID. Backbone fragmentation in MS(3) IRMPD and EID was highly dependent on the charge state of the radical precursor ions, whereas amino acid side chain cleavages were largely independent of the charge state selected for fragmentation. Cleavages at aromatic amino acids, either through side chain loss or backbone fragmentation, were significantly enhanced over other dissociation channels. For singly charged species, the MS(3) IRMPD and EID spectra were mainly governed by radical-driven dissociation. Fragmentation of doubly and triply charged radical cations proceeded through both radical- and charge-driven processes, resulting in the formation of a wide range of backbone product ions including, a-, b-, c-, y-, x-, and z-type. While similarities existed between MS(3) CID, IRMPD, and EID of the same species, several backbone product ions and side chain losses were unique for each activation method. Furthermore, dominant dissociation pathways in each spectrum were dependent on ion activation method, amino acid composition, and charge state selected for fragmentation. PMID- 22101470 TI - Characterizing the walnut genome through analyses of BAC end sequences. AB - Persian walnut (Juglans regia L.) is an economically important tree for its nut crop and timber. To gain insight into the structure and evolution of the walnut genome, we constructed two bacterial artificial chromosome (BAC) libraries, containing a total of 129,024 clones, from in vitro-grown shoots of J. regia cv. Chandler using the HindIII and MboI cloning sites. A total of 48,218 high-quality BAC end sequences (BESs) were generated, with an accumulated sequence length of 31.2 Mb, representing approximately 5.1% of the walnut genome. Analysis of repeat DNA content in BESs revealed that approximately 15.42% of the genome consists of known repetitive DNA, while walnut-unique repetitive DNA identified in this study constitutes 13.5% of the genome. Among the walnut-unique repetitive DNA, Julia SINE and JrTRIM elements represent the first identified walnut short interspersed element (SINE) and terminal-repeat retrotransposon in miniature (TRIM) element, respectively; both types of elements are abundant in the genome. As in other species, these SINEs and TRIM elements could be exploited for developing repeat DNA-based molecular markers in walnut. Simple sequence repeats (SSR) from BESs were analyzed and found to be more abundant in BESs than in expressed sequence tags. The density of SSR in the walnut genome analyzed was also slightly higher than that in poplar and papaya. Sequence analysis of BESs indicated that approximately 11.5% of the walnut genome represents a coding sequence. This study is an initial characterization of the walnut genome and provides the largest genomic resource currently available; as such, it will be a valuable tool in studies aimed at genetically improving walnut. PMID- 22101472 TI - Reactive oxygen species formation and cell death in catalase-deficient tobacco leaf discs exposed to paraquat. AB - In the present work, the response of tobacco (Nicotiana tabaccum L.) wild-type SR1 and transgenic CAT1AS plants (with a basal reduced CAT activity) was evaluated after exposure to the herbicide paraquat (PQ). Superoxide anion (O (2) (.-) ) formation was inhibited at 3 or 21 h of exposure, but H(2)O(2) production and ion leakage increased significantly, both in SR1 or CAT1AS leaf discs. NADPH oxidase activity was constitutively 57% lower in non-treated transgenic leaves than in SR1 leaves and was greatly reduced both at 3 or 21 h of PQ treatment. Superoxide dismutase (SOD) activity was significantly reduced by PQ after 21 h, showing a decrease from 70% to 55%, whereas catalase (CAT) activity decreased an average of 50% after 3 h of treatment, and of 90% after 21 h, in SR1 and CAT1AS, respectively. Concomitantly, total CAT protein content was shown to be reduced in non-treated CAT1AS plants compared to control SR1 leaf discs at both exposure times. PQ decreased CAT expression in SR1 or CAT1AS plants at 3 and 21 h of treatment. The mechanisms underlying PQ-induced cell death were possibly not related exclusively to ROS formation and oxidative stress in tobacco wild-type or transgenic plants. PMID- 22101471 TI - Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain. AB - A rigorously controlled, cell culture paradigm was used to assess the role of HIV 1 gp120 +/- morphine in mediating opioid-HIV interactive toxicity in striatal neurons. Computerized time-lapse microscopy tracked the fate of individual neurons co-cultured with mixed-glia from mouse striata during opioid and gp120 exposure. Subpopulations of neurons and astroglia displayed MU-opioid receptor, CXCR4, and CCR5 immunoreactivity. While gp120 alone was or tended to be neurotoxic irrespective of whether X4-tropic gp120(IIIB), R5-tropic gp120(ADA), or dual-tropic gp120(MN) was administered, interactive toxicity with morphine differed depending on HIV-1 strain. For example, morphine only transiently exacerbated gp120(IIIB)-induced neuronal death; however, in combination with gp120(MN), morphine caused sustained increases in the rate of neuronal death compared to gp120(MN) alone that were prevented by naloxone. Alternatively, gp120(ADA) significantly increased the rate of neuron death, but gp120(ADA) toxicity was unaffected by morphine. The transient neurotoxic interactions between morphine and gp120(IIIB) were abrogated in the absence of glia suggesting that glia contribute significantly to the interactive pathology with chronic opiate abuse and neuroAIDS. To assess how mixed-glia might contribute to the neurotoxicity, the effects of morphine and/or gp120 on the production of reactive oxygen species (ROS) and on glutamate buffering were examined. All gp120 variants, and to a lesser extent morphine, increased ROS and/or decreased glutamate buffering, but together failed to show any interaction with morphine. Our findings indicate that HIV-1 strain-specific differences in gp120 are critical determinants in shaping both the timing and pattern of neurotoxic interactions with opioid drugs. PMID- 22101473 TI - Effects of sodium selenite and germination on the sprouting of chickpeas (Cicer arietinum L.) and its content of selenium, formononetin and biochanin A in the sprouts. AB - To improve the nutritional value of chickpea food, selenium (Se)-rich chickpea sprouts were produced by germination of chickpea seeds for 6 days at 28 centigrade in the presence of various concentrations of Na(2)SeO(3) in germination solution. High concentrations of selenite were found to inhibit the growth of chickpea sprout and the biosynthesis of isoflavones formononetin and biochanin A. However, chickpea sprouts could tolerate up to ~50 mg/L of Na(2)SeO(3), under which condition the product chickpea sprouts contained a high Se content (2.14 MUg/g dry weight) and a moderate high content of isoflavones (601.56 MUg biochanin A/g dry weight and 578.11 MUg formononetin/g dry weight). Se was incorporated in chickpea sprout in the form of selenomethionine. Thus, Se enriched chickpea sprouts may serve as a convenient dietary source of Se and of isoflavones, including formononetin and biochanin A. PMID- 22101474 TI - Postnuclear supernatant: an in vitro model for assessing cadmium-induced neurotoxicity. AB - Cadmium (Cd) is a toxic heavy metal commonly found in industrial workplaces, a food contaminant and a major constituent of cigarette smoke. Most of the organs are susceptible to Cd-induced toxicity, including brain. Postnuclear supernatant (PNS) has been accepted as an in vitro model for assessing xenobiotic induced toxicity. The goal of the present study was to validate PNS as an in vitro model for investigating the effect of Cd-induced neurotoxicity. Neurotoxic induction by Cd was established in a dose-dependent manner in PNS in vitro. Enzymatic and non enzymatic antioxidants were used as biomarkers of exposure. Antioxidant enzymatic activity was measured as a significant increase in activities of catalase, superoxide dismutase, and glutathione S-transferase. On exposure to Cd, a significant increase in acetylcholinesterase and decrease in sodium-potassium ATPase activity was also observed. Non-enzymatic effect was also demonstrated as a significant elevation in reduced glutathione and non-protein thiol activity, but there was no significant increase or decrease in the concentrations of protein thiol. In accordance with the toxicity of Cd towards the studied brain structure, Cd-induced oxidative stress has been a focus of toxicological research as a possible mechanism of neurotoxicity. Our results suggest that PNS preparations can be used as a model for future investigation of xenobiotic induced neurotoxicity under in vitro conditions. PMID- 22101475 TI - Grade 1 pressure ulcers: we only see what we know. PMID- 22101478 TI - Tips for stage I PrUs in long-term care? PMID- 22101479 TI - Consider the OIG Work Plan in your 2012 internal audit schedules. AB - Wound care professionals should conduct monthly internal audits of their business processes. In addition to auditing, the coding, payment, and coverage issues that are considered issues by the Medicare contractor that processes your claims and the Medicare contractors that audit your claims and payments, be sure to include the OIG Work Plan topics that pertain to your wound care business. Remember, if atopic is important enough to make the OIG Work Plan, it should be important enough to make your 2012 internal audit plan. Because the Medicare Trust Fund is important to all US citizens, everyone has a responsibility to assist in combating fraud, waste, abuse, and mismanagement in HHS programs. Therefore, the OIG Hotline accepts tips from all sources. To provide a tip to the OIG Hotline, see Table 1 for contact information. PMID- 22101481 TI - Scar management practice and science: a comprehensive approach to controlling scar tissue and avoiding hypertrophic scarring. AB - A meta-analysis of the literature forms the basis of a treatment regimen focused on the principles of support, controlled inflammation, hydration, and hastened collagen remodeling. The presented clinical trial avoided hypertrophic scarring in more than 80% of cases, validating the theory of targeting many areas of scar control in 1 approach. PMID- 22101482 TI - Changes in heel skin temperature under pressure in hip surgery patients. AB - OBJECTIVE: The aim of the study was to examine the effect of external pressure of the bed surface on heel skin temperature in adults in the first 3 days after hip surgery. DESIGN: A quasi-experimental study in a prospective, within-subjects, repeated-measures design. SETTING: This study was performed at 2 acute-care hospitals. PARTICIPANTS: Eighteen subjects (9 men and 9 women) with a mean age of 58.3 (+/-16.1) years were recruited after hip surgery at the 2 hospitals. METHODS: Temperature sensors were placed on the plantar surface of each foot, close to the heels. Measures were taken when the heels were (1) suspended above the bed surface for 20 minutes (preload), (2) on the bed surface for 15 minutes (loading), and (3) suspended again above the bed surface for 15 minutes (unloading). MAIN OUTCOME MEASURES: Heel skin temperature and demographic data. RESULTS: Heel temperature increased during loading and unloading in both legs on postoperative days 1 (P = .003) and 3 (P = .04) but not on postoperative day 2. Heel temperature in the nonoperative leg decreased in the first 3 minutes of unloading on postoperative days 2 (P = .02) and 3 (P = .01). CONCLUSION: Heel temperature increased with loading and unloading on postoperative days 1 and 3. Upon immediate unloading, hyperemic response was present only in the nonoperative leg. Keeping the heels off the bed surface at all times may avoid heel skin temperature changes and prevent tissue damage. Further research is needed to identify the mechanisms that explain the effect of external pressure on heel temperature. PMID- 22101483 TI - Pressure ulcer staging revisited: superficial skin changes & Deep Pressure Ulcer Framework(c). AB - Deficiencies in the current pressure ulcer classification system create the impetus for the current discourse on the clinical, legal, and economic implications of staging and considering shifting the paradigm in pressure ulcer description and assessment. PMID- 22101485 TI - Mapping documentation to support your work performed: part 2. PMID- 22101486 TI - High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. AB - The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy number alterations (SCNAs) in cancer. Using a maximum likelihood approach, we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule model. This analysis suggests that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and that purifying selection, as well as positive selection, influences SCNAs during somatic evolution of cancer cells. PMID- 22101487 TI - DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. AB - Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found in such regions, and that regions replicated early and late display distinct patterns of frequencies of SCNA boundaries, SCNA size and a preference for deletions over insertions. We show that long-range interaction and replication timing data alone can identify a significant proportion of SCNAs in an independent test data set. We propose a model for the generation of SCNAs in cancer, suggesting that data on spatial proximity of regions replicating at the same time can be used to predict the mutational landscapes of cancer genomes. PMID- 22101488 TI - Technology-induced errors. The current use of frameworks and models from the biomedical and life sciences literatures. AB - OBJECTIVE: The objective of this paper is to examine the extent, range and scope to which frameworks, models and theories dealing with technology-induced error have arisen in the biomedical and life sciences literature as indexed by Medline(r). METHODS: To better understand the state of work in the area of technology-induced error involving frameworks, models and theories, the authors conducted a search of Medline(r) using selected key words identified from seminal articles in this research area. Articles were reviewed and those pertaining to frameworks, models or theories dealing with technology-induced error were further reviewed by two researchers. RESULTS: All articles from Medline(r) from its inception to April of 2011 were searched using the above outlined strategy. 239 citations were returned. Each of the abstracts for the 239 citations were reviewed by two researchers. Eleven articles met the criteria based on abstract review. These 11 articles were downloaded for further in-depth review. The majority of the articles obtained describe frameworks and models with reference to theories developed in other literatures outside of healthcare. The papers were grouped into several areas. It was found that articles drew mainly from three literatures: 1) the human factors literature (including human-computer interaction and cognition), 2) the organizational behavior/sociotechnical literature, and 3) the software engineering literature. CONCLUSIONS: A variety of frameworks and models were found in the biomedical and life sciences literatures. These frameworks and models drew upon and extended frameworks, models and theoretical perspectives that have emerged in other literatures. These frameworks and models are informing an emerging line of research in health and biomedical informatics involving technology-induced errors in healthcare. PMID- 22101489 TI - Nanostructured substrate fabricated by sectioning tendon using a microtome for tissue engineering. AB - This paper describes an efficient and versatile method for the fabrication of nanostructured substrates from a piece of tendon which comprises aligned collagen nanofibers. We used a microtome to generate the tendon slices (10-50 um thick), which were used as a scaffold for guiding directional cell growth. Highly aligned and uniform monolayer cells sheets were obtained. The tendon slices were used as a master, and the nanostructures outlined by the bundles of collagen nanofibers were successfully transferred onto a polystyrene film using standard soft lithography. The cell growing on the nanostructured polystyrene substrate showed good adhesion and alignment. The technique developed here enables one to fabricate nanostructured substrates without using any traditional micro/nanofabrication tools. The nanostructured substrate, e.g. a slice of tendon, has excellent biocompatibility and relatively good mechanical stability, which makes this technique useful in constructing complicated 3D tissues. PMID- 22101490 TI - Annexin A1 protein attenuates cyclosporine-induced renal hemodynamics changes and macrophage infiltration in rats. AB - BACKGROUND: Cyclosporine (CsA) remains an important immunosuppressant for transplantation and for treatment of autoimmune diseases. The most troublesome side effect of CsA is renal injury. Acute CsA-induced nephrotoxicity is characterized by reduced renal blood flow (RBF) and glomerular filtration rate (GFR) due to afferent arteriole vasoconstriction. Annexin A1 (ANXA1) is a potent anti-inflammatory protein with protective effect in renal ischemia/reperfusion injury. Here we study the effects of ANXA1 treatment in an experimental model of acute CsA nephrotoxicity. METHODS: Salt-depleted rats were randomized to treatment with VH (vehicles 1 mL/kg body weight/day), ANXA1 (Ac2-26 peptide 1 mg/kg body weight/day intraperitoneally), CsA (20 mg/kg body weight/day subcutaneously) and CsA + ANXA1 (combination) for seven days. We compared renal function and hemodynamics, renal histopathology, renal tissue macrophage infiltration and renal ANXA1 expression between the four groups. RESULTS: CsA significantly impaired GFR and RBF, caused tubular dilation and macrophage infiltration and increased ANXA1 renal tissue expression. Treatment with ANXA1 attenuated CSA-induced hemodynamic changes, tubular injury and macrophage infiltration. CONCLUSION: ANXA1 treatment attenuated renal hemodynamic injury and inflammation in an acute CsA nephrotoxicity model. PMID- 22101491 TI - A novel pollen tube growth assay utilizing a transmitting tract-ablated Nicotiana tabacum style. AB - Sexual plant reproduction requires multiple pollen-pistil interactions from the stigma (pollen adhesion, hydration, and germination) to the ovary (fertilization). Understanding the factors that regulate pollen tube growth is critical to understanding the processes essential to sexual reproduction. Many pollen tube growth assays (PTGAs) have shorter and slower pollen tube growth when compared to pollen tube growth through the style. The identification and study of factors that regulate pollen tube growth have been impeded by a lack of an efficient and reproducible PTGA. The objective of this research is to develop a robust assay for Nicotiana tabacum pollen tube growth in an environment that supports sustained and normal growth yet is amenable to testing the effects of specific factors. In this paper, we introduce a novel PTGA, which uses pistils from N. tabacum that lack a mature transmitting tract (TT) due to tissue-specific ablation. The TT-ablated style supports normal pollen tube growth and the hollow structure of the style allows modification of the growth environment by direct injection of test material. This PTGA is robust and allows for rapid and accurate measurement of pollen tube length and pollen tube morphology, supporting pollen tube growth from 20 to 35 degrees C and at pH ranging from 4.8 to 7.6. Use of the ablated style for a PTGA is a novel method for the culture of pollen tubes with sustained growth in vivo while permitting the application of treatments to the growing pollen tubes. PMID- 22101492 TI - The organization of cortical activity in the anterior lobe of the cat cerebellum during hindlimb stepping. AB - We recorded from over 280 single cortical neurons throughout the medial anterior lobe of the cat cerebellum during passive movements of the hindlimbs resembling stepping on a moving treadmill. We used three stepping patterns, unilateral stepping of either the ipsilateral or contralateral leg and bipedal stepping in an alternating gait pattern. We found that over 60% of the neurons, mostly Purkinje cells, responded to stepping of one or both legs, and over 40% to more than one type of stepping pattern. Responsive cells were distributed throughout the five anterior lobules, and the highest concentration was found in traditional hindlimb areas in lobules 2 and 3. A comparison of response waveforms showed that they are similar for neighboring cells in many parts of the cerebellar cortex, and they tend to form local blob-like groupings. Response patterns, i.e., relationship among responses to each stepping type, tended to be similar within a local group. The groupings extend further in the parasagittal dimension (up to about a third of a lobule) than in the transverse dimension (about 1 mm), and they may form functional modules. A principal component analysis also showed that the responses were composed of a four basis waveforms (principal components) that explained about 80% of the response waveform variance that were nearly identical to those derived from dorsal spinocerebellar tract (DSCT) responses to similar stepping movements. We reconstructed the locations of the recorded neurons on a 2D map of the cerebellar cortex showing the spatial distribution of responsive cells according to their response characteristics. We propose, on the basis of these results, that the sensory input to the cerebellum from the hindlimbs is distributed to multiple zones that may each contribute to a different component of cerebellar function. PMID- 22101493 TI - Influence of periodontal afferent inputs for human cerebral blood oxygenation during jaw movements. AB - Using functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS), we examined the role of periodontal afferent inputs on cerebral activation pattern evoked by masticatory muscle activity in twenty-two subjects. Statistical comparisons were used to identify brain regions with significant activation after subtraction of baseline activity from sham teeth-tapping (no periodontal input) and teeth-tapping (periodontal input) activity in an fMRI (N = 14) and NIRS study (N = 8). Both sham teeth-tapping and teeth-tapping significantly activated bilateral sensorimotor cortex and supplementary motor area in the fMRI study. NIRS revealed that oxygenated hemoglobin concentrations increased in sensorimotor cortex; however, there was no significant difference in degree of oxygenated hemoglobin changes between sham teeth-tapping and teeth tapping. A control study (N = 8) characterized the jaw muscle activity and amplitude of the two motor tasks and demonstrated significantly higher electromyogram (EMG) activity in the jaw closing muscles during teeth contact in the teeth-tapping session. Since the cerebral activation during sham teeth tapping and teeth-tapping was similar, we suggest that the influence of periodontal afferent inputs and associated jaw muscle activity is relatively minor compared to the rhythmic jaw movements. Although the clinical significance of the present findings remains unknown, they may have implications for the understanding of awake or sleep-related bruxism characterized by subconscious and rhythmic teeth-grinding or teeth-clenching. PMID- 22101494 TI - The stressed prefrontal cortex and goal-directed behaviour: acute psychosocial stress impairs the flexible implementation of task goals. AB - Goals are often at the basis of human actions. As an essential mechanism of behavioural adaptation, individuals need to be able to flexibly implement new task goals so as to alter their actions (switch tasks) in response to contextual changes. The present study investigated the effect of acute psychosocial stress on cognitive control processes of flexible task-goal implementation with temporal focus on the occurrence interval of the hypothalamus-pituitary-adrenal (HPA) stress response. For this, forty-eight healthy volunteers were either challenged with a standardised stress-induction protocol (the Trier Social Stress Test) or underwent a standardised control situation. Subsequently, they were exposed to a task-switching procedure with two tasks alternating in random order. Participants of the stress group displayed increased salivary alpha-amylase activity immediately after stress exposure as well as elevations of salivary cortisol from 10 min after stress cessation, reflecting the typical stress-related activity increases in the sympathetic nervous system and the HPA axis, respectively. At the time interval of elevated cortisol levels, stressed individuals persistently showed larger performance differences between task switches and task repetitions (switch costs) than controls. This effect was reliably evident when tested 5-20 min as well as 25-40 min following treatment cessation. These results indicate that acute psychosocial stress impairs cognitive control processes of flexible task-goal implementation essential for voluntary goal-directed behaviour. PMID- 22101495 TI - Effective processing of masked eye gaze requires volitional control. AB - The purpose of the present study was to establish whether the validity effect produced by masked eye gaze cues should be attributed to strictly reflexive mechanisms or to volitional top-down mechanisms. While we find that masked eye gaze cues are effective in producing a validity effect in a central cueing paradigm, we also find that the efficacy of masked gaze cues is sharply constrained by the experimental context. Specifically, masked gaze cues only produced a validity effect when they appeared in the context of unmasked and predictive gaze cues. Unmasked gaze cues, in contrast, produced reliable validity effects across a range of experimental contexts, including Experiment 4 where 80% of the cues were invalid (counter-predictive). Taken together, these results suggest that the effective processing of masked gaze cues requires volitional control, whereas the processing of unmasked (clearly visible) gaze cues appears to benefit from both reflexive and top-down mechanisms. PMID- 22101496 TI - Contact lens-related dry eye and ocular surface changes with mapping technique in long-term soft silicone hydrogel contact lens wearers. AB - PURPOSE: To evaluate ocular surface changes in long-term silicone hydrogel contact lens wearers. METHODS: Thirty patients were included in this study. Twenty patients (40 eyes) using contact lenses constituted group 1 and 10 (20 eyes) volunteers constituted group 2. The duration of average contact lens usage was 7.74 +/- 3.3 years. Ocular surface was evaluated by surface staining, tear film break-up time (TBUT), Schirmer I test, and conjunctival impression cytology with color-coded mapping technique and by the Ocular Surface Disease Index (OSDI). RESULTS: The mean break-up time was lower and staining scores were higher in group 1 (p<0.001) but Schirmer values were not significantly different from group 2 (p>0.05). The mean OSDI score was 34.59 +/- 11.93 to 19.28 +/- 6.7 in group 1 and 2. Increased metaplastic predominant changes of grade II and III were observed in the interpalpebral and perilimbal areas in group 1. Significant correlations were observed in TBUT, cornea staining, and grade II to grade III metaplasia ratios between duration of the lens usage and contact lens wear time in a day. CONCLUSIONS: Silicone hydrogel lenses produce significant changes on tear film and impression cytology of the ocular surface in long-term use. PMID- 22101497 TI - Combined intravitreal bevacizumab and grid laser photocoagulation for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To evaluate long-term efficacy of intravitreal bevacizumab (IVB) versus combined IVB and macular grid laser photocoagulation for the treatment of macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: In this prospective study, 18 eyes were randomized into 2 groups according to treatment: Group 1 (9 eyes) underwent IVB at baseline, at month 1, and at month 2; Group 2 (9 eyes) underwent same IVB protocol combined with macular grid laser photocoagulation. Macular edema and visual acuity represented the endpoints of the study. IVB reinjections were performed in both groups if recurrent macular edema was diagnosed. Spectral domain optical coherence tomography examination as well as visual acuity examination were performed during follow-up. Statistical evaluation was performed for a matched-pair analysis. RESULTS: In Group 1, median baseline central retinal thickness (CRT) decreased from 420 um (95% confidence interval 355.6-484.4) to 323 um (261.44-384.56) at month 12 (p=0.06); median baseline BCVA improved from 0.7 logMAR (0.54-0.86) to 0.4 logMAR (0.29-0.51) at month 12 (p<0.01). In Group 2, baseline CRT decreased from 386 um (353.91-418.09) to 238 um (200.58-275.42) at month 12 (p<0.01); median BCVA improved from 0.6 logMAR (0.45-0.75) to 0.2 logMAR (0.12-0.28) at month 12 (p<0.01). A statistically significant difference (p=0.03) was found regarding the median number of injections (Group 1: 4+/-1.1; Group 2: 3+/-0.4). CONCLUSIONS: Both treatment modalities appeared effective to control BRVO-induced macular edema. In the combined-treatment Group, we observed a lower number of reinjections during follow-up, suggesting the efficacy of grid laser photocoagulation to reduce the number of intravitreal injections and maintain short- and long-term results of the therapy. PMID- 22101498 TI - Generalized spin models for coupled cortical feature maps obtained by coarse graining correlation based synaptic learning rules. AB - We derive generalized spin models for the development of feedforward cortical architecture from a Hebbian synaptic learning rule in a two layer neural network with nonlinear weight constraints. Our model takes into account the effects of lateral interactions in visual cortex combining local excitation and long range effective inhibition. Our approach allows the principled derivation of developmental rules for low-dimensional feature maps, starting from high dimensional synaptic learning rules. We incorporate the effects of smooth nonlinear constraints on net synaptic weight projected from units in the thalamic layer (the fan-out) and on the net synaptic weight received by units in the cortical layer (the fan-in). These constraints naturally couple together multiple feature maps such as orientation preference and retinotopic organization. We give a detailed illustration of the method applied to the development of the orientation preference map as a special case, in addition to deriving a model for joint pattern formation in cortical maps of orientation preference, retinotopic location, and receptive field width. We show that the combination of Hebbian learning and center-surround cortical interaction naturally leads to an orientation map development model that is closely related to the XY magnetic lattice model from statistical physics. The results presented here provide justification for phenomenological models studied in Cowan and Friedman (Advances in neural information processing systems 3, 1991), Thomas and Cowan (Phys Rev Lett 92(18):e188101, 2004) and provide a developmental model realizing the synaptic weight constraints previously assumed in Thomas and Cowan (Math Med Biol 23(2):119-138, 2006). PMID- 22101499 TI - Stimulation of the endometrium with high-grade blastocyst culture supernatant (SEHB) can improve pregnancy outcome for couples undergoing intracytoplasmic sperm injection (ICSI): a randomized clinical trial. AB - PURPOSE: To evaluate the impact of stimulating the endometrium with high-grade blastocyst culture supernatant (SEHB) perfusion before blastocyst transfer (BT) on implantation rate, pregnancy rate, and pregnancy outcome in ICSI cycles. MATERIALS AND METHODS: Ninety-four infertile couples who were referred to the Valiasr department of Imam Hospital complex between January 2010 and March 2011 enrolled in this randomized clinical trial. They were randomly divided into only BT or SEHB groups. Implantation rates, pregnancy rates, abortion, preterm and term delivery rates were compared between the two groups. RESULTS: Implantation rates and pregnancy rates did not differ significantly between the two groups. The abortion rate was significantly higher in the BT only group while term delivery was significantly higher in SEHB group. Odds ratios of term delivery and abortion were 4.5 (p = 0.001) and 0.3 (p = 0.04), respectively. CONCLUSION: The SEHB application may improve pregnancy outcome in infertile couples who are candidates for the ICSI reproductive method. PMID- 22101500 TI - Variability of total thiol compounds, oxidative and nitrosative stress in uncomplicated pregnant women and nonpregnant women. AB - PURPOSE: The objective of this study was to determine the changes in total plasma thiols (homocysteine, cysteine and cysteinylglycine), lipid peroxidation and nitric oxide concentrations during normal pregnancy. METHODS: These variables were measured in 28 uncomplicated pregnant women at first, second and third trimesters and in 19 nonpregnant women. RESULTS: The mean concentrations of homocysteine, cysteine and cysteinylglycine were significantly lower in all trimesters of pregnancy compared with nonpregnant controls. There was significant elevation in serum lipid peroxidation levels of pregnant women within first and third trimesters compared with nonpregnant women. In spite of increase in mean nitric oxide levels in pregnant women, this increase did not reach statistically significant levels. CONCLUSION: This study provides information about the changes in plasma levels of many variables having important role in pregnancy complication during all trimesters in uncomplicated pregnancy compared with nonpregnant women. PMID- 22101501 TI - Pulse oximetry saturation patterns detect repetitive reductions in airflow. AB - OBJECTIVE: Postoperative patients exhibiting signs or symptoms of obstructive sleep apnea (OSA) have been identified to be at increased risk for respiratory compromise. One of the key markers associated with OSA is repetitive reductions in airflow (RRiA). A real-time pulse oximeter saturation pattern recognition algorithm (OxiMax SPDTM intended for adult in-hospital use only) designed to detect specific signatures in the SpO(2) trend associated with RRiA may provide caregivers early indication of its presence so they can treat the patient appropriately. The purpose of our study was to test the performance of saturation pattern detection (SPD) in a clinical study targeting subjects with a high prevalence of RRiA. METHODS: Overnight polysomnograph (PSG) recordings were collected on 104 sleep lab patients. RRiA was defined in terms of specific criteria from four PSG signals, evaluated in consecutive 10 min epochs. PSG scoring was conducted blind to calculation of SPD. Statistical measures of sensitivity, specificity and area under the receiver operating characteristic (ROC) curve were calculated for the detection of RRiA by SPD. RESULTS: Data were analyzed for 92 valid sets of patient recordings, encompassing 3,917 epochs. At the highest available SPD alert setting, the sensitivity was 80.2% (95% C.I. = 76.8-83.3%), the specificity was 88.3% (87.2-89.3). Area under the ROC curve was 0.87 (0.84-0.89). CONCLUSIONS: The real-time SPD algorithm was able to detect episodes of RRiA in sleep lab patients with a high degree of sensitivity and specificity. PMID- 22101502 TI - Partitioning standard base excess: a new approach. AB - 'Standard' or 'extracellular' base excess (SBE) is a modified calculation using one-third the normal hemoglobin concentration. It is a 'CO(2)-invariant' expression of meta- bolic acid-base status integrated across interstitial, plasma and erythrocytic compartments (IPE). SBE also integrates conflicting physical chemical influences on metabolic acid-base status. Until recently attempts to quantify individual contributions to SBE, for example the plasma strong ion gap, failed to span the 'CO(2-)stable' IPE dimension. The first breakthrough was from Anstey, who determined the con- centration of unmeasured charged species referenced to the IPE domain using Wooten's physical chemical version of the Van Slyke equation. In this issue Drs Wolf and DeLand present a diagnostic tool based on an IPE model which dissects a version of SBE (BEnet) into nine independent (BEind) components, all referenced to the IPE domain. The reported components are excess/deficits of free water, chlo- ride, albumin, unmeasured ions, sodium, potassium, lactate, 'Ca-Mg' (a composite divalent cation entity), and phosphate. The model also reports individualised volumes of plasma, erythrocytes and interstitial fluid. The tool is an original contribution, but there are concerns. The impact of assum- ing fixed relationships between arterial and venous acid base and saturation values in sepsis, anaemia and in differing shock states is unclear. Clinicians are also unlikely to accept that unique, accurate IPE volume determinations can be derived from a single set of blood gas and biochemistry results. Nevertheless, volume determinations aside, the tool is likely to become a valuable addition to the diagnostic armamentarium. PMID- 22101503 TI - Facile in situ synthesis of nanofluids based on ionic liquids and copper oxide clusters and nanoparticles. AB - Two stable nanofluids comprising of mixed valent copper(I,II) oxide clusters (<1 nm) suspended in 1-butyl-3-methylimidazolium acetate, [C(4)mim][OAc], and copper(II) oxide nanoparticles (<50 nm) suspended in trioctyl(dodecyl)phosphonium acetate, [P(8 8 8 12)][OAc], were synthesised in a facile one-pot reaction from solutions of copper(II) acetate hydrate in the corresponding ionic liquids. Formation of the nanostructures was studied using (13)C NMR spectroscopy and differential scanning calorimetry (DSC). From a solution of Cu(OAc)(2) in 1-ethyl 3-methylimidazolium acetate, [C(2)mim][OAc], crystals were obtained that revealed the structure of [C(2)mim][Cu(3)(OAc)(5)(OH)(2)(H(2)O)].H(2)O, indicating the formation of copper hydroxo-clusters in the course of the reaction. Synthesised nanostructures were studied using transmission electron microscopy (TEM) and X ray photoelectron spectroscopy (XPS). Physical properties of the prepared IL nanofluids were examined using IR and UV-VIS spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and densitometry. PMID- 22101504 TI - Improved survival among patients with base of tongue and tonsil cancer in the United States. AB - OBJECTIVE: To examine if survival has changed over the last 20 years in patients with base of tongue and tonsil cancers in the United States. METHODS: Using SEER data, we employed Kaplan-Meier method to draw survival curves and calculate survival rates, and estimated adjusted hazard ratios (HR). RESULTS: From the 1980s to the 2000s, the 5-year overall survival rates statistically significantly improved by 100% from 25 to 51% among patients with one primary base of tongue cancer and 28-60% among those with one primary tonsil cancer (p values for trend <0.001). In addition, the 5-year cancer-specific survival improved by 222.4 and 276%, respectively, among two types of patients. Survival improvement was more pronounced among male patients than among female patients regardless of young or old age, while the improvement was generally consistent among patients with different tumor stages and treatment methods. In contrast, however, those patients with subsequent multiple cancers showed no improvement in overall survival over time. CONCLUSIONS: The survival of patients with base of tongue and tonsil cancer has significantly improved over the last decades in the United States. Whether the improvement is associated with HPV infection, screening, or early detection is worthy to study in future. PMID- 22101505 TI - Impact of comorbidity and healthcare utilization on colorectal cancer stage at diagnosis: literature review. AB - PURPOSE: Individuals diagnosed with cancer close to death have low access to enrollment in palliative care programs. The purpose of this literature review was to assess the usefulness of pre-diagnostic comorbidity and healthcare utilization as indicators of late-stage colorectal cancer (CRC) diagnosis, to help with early identification of individuals who may benefit from palliative care. METHODS: A literature search was conducted in relevant databases using title/abstract terms which included "cancer," "stage," "diagnosis," "determinants," "predictors," and "associated." Included studies examined whether comorbidity and/or healthcare utilization had an impact on the stage at which CRC was diagnosed. A standardized data abstraction form was used to assess the eligibility of each study. Thirteen articles were included in the literature review. These studies were assessed and synthesized using qualitative methodology. RESULTS: We found much heterogeneity among study variables. The findings of this literature review point to the presence of comorbidity and non-emergent healthcare utilization as having no association with late-stage diagnosis. Conversely, emergency room presentation (ERP) was associated with late-stage diagnosis. CONCLUSIONS: The results of this literature review did not find strong evidence to suggest that comorbidity and healthcare utilization are potential indicators of late-stage diagnosis. However, ERP may be useful as a flag for consideration of prompt referral to palliative care. Additional research is required to identify potential indicators of late stage diagnosis that may be available in administrative databases, particularly in the area of healthcare utilization. PMID- 22101506 TI - Age-specific administration of chemotherapy and long-term quality of life in stage II and III colorectal cancer patients: a population-based prospective cohort. AB - PURPOSE: To investigate the age-specific pattern of administration of chemotherapy and its association with long-term survival and quality of life (QoL) in stage II and III colorectal cancer patients. METHODS: Chemotherapy allocation according to disease and patient characteristics was investigated in a population-based cohort of 562 stage II and III colorectal cancer patients. Five years after diagnosis, survival was determined and QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items and a tumor specific module. The association among chemotherapy, survival, and QoL was examined while controlling for potential confounders. RESULTS: Chemotherapy was administered in 71% of patients aged <60 years and in only 20% of patients aged >=80 years. A significant association between chemotherapy and longer survival time was found for stage III cancer only. Chemotherapy was associated with higher symptom levels for trouble with taste, anxiety, and hair loss. In age-specific analyses, younger survivors (<70 years at time of follow-up) with a history of chemotherapy reported significantly lower physical, role, and cognitive functioning and higher pain, appetite loss, hair loss, and trouble with taste symptom levels. In contrast, for older survivors (>=70 years), only two (hair loss and dry mouth) out of 38 QoL scores were significantly associated with chemotherapy. DISCUSSION: Chemotherapy is associated with lower long-term QoL, especially in younger survivors. In cases of uncertain survival benefits of chemotherapy, consideration of its long-term effects on QoL should be incorporated into final decisions on treatment. PMID- 22101507 TI - Motion and mixing for multiple ferromagnetic microswimmers. AB - This paper concerns the interaction of several ferromagnetic microswimmers, their motion and the resulting fluid mixing. Each swimmer consists of two ferromagnetic beads joined by an elastic link, and is driven by an external, time-dependent magnetic field. The external field provides a torque on a swimmer and, together with the varying attraction between the magnetic beads, generates a time irreversible motion leading to persistent swimming in a low Reynolds number environment. The aim of the present paper is to consider the interactions between several swimmers. A regime is considered in which identical swimmers move in the same overall direction, and their motion is synchronised because of driving by the external field. It is found that two swimmers tend to encircle one another while three undergo more complicated motion that may involve the braiding of swimmer trajectories. By means of approximations it is established that the interaction between pairs of swimmers gives circulatory motion which falls off with an inverse square law and is linked to their overall speed of motion through the fluid. As groups of two or more swimmers move through the fluid they process fluid, leaving behind a trail of fluid that has undergone mixing: this is investigated by following streak lines numerically. PMID- 22101508 TI - Exponentially convergent state estimation for delayed switched recurrent neural networks. AB - This paper deals with the delay-dependent exponentially convergent state estimation problem for delayed switched neural networks. A set of delay-dependent criteria is derived under which the resulting estimation error system is exponentially stable. It is shown that the gain matrix of the proposed state estimator is characterised in terms of the solution to a set of linear matrix inequalities (LMIs), which can be checked readily by using some standard numerical packages. An illustrative example is given to demonstrate the effectiveness of the proposed state estimator. PMID- 22101509 TI - Systematic review of the application of quality improvement methodologies from the manufacturing industry to surgical healthcare. AB - BACKGROUND: The demand for the highest-quality patient care coupled with pressure on funding has led to the increasing use of quality improvement (QI) methodologies from the manufacturing industry. The aim of this systematic review was to identify and evaluate the application and effectiveness of these QI methodologies to the field of surgery. METHODS: MEDLINE, the Cochrane Database, Allied and Complementary Medicine Database, British Nursing Index, Cumulative Index to Nursing and Allied Health Literature, Embase, Health Business(TM) Elite, the Health Management Information Consortium and PsycINFO((r)) were searched according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. Empirical studies were included that implemented a described QI methodology to surgical care and analysed a named outcome statistically. RESULTS: Some 34 of 1595 articles identified met the inclusion criteria after consensus from two independent investigators. Nine studies described continuous quality improvement (CQI), five Six Sigma, five total quality management (TQM), five plan-do-study-act (PDSA) or plan-do-check-act (PDCA) cycles, five statistical process control (SPC) or statistical quality control (SQC), four Lean and one Lean Six Sigma; 20 of the studies were undertaken in the USA. The most common aims were to reduce complications or improve outcomes (11), to reduce infection (7), and to reduce theatre delays (7). There was one randomized controlled trial. CONCLUSION: QI methodologies from industry can have significant effects on improving surgical care, from reducing infection rates to increasing operating room efficiency. The evidence is generally of suboptimal quality, and rigorous randomized multicentre studies are needed to bring evidence-based management into the same league as evidence-based medicine. PMID- 22101510 TI - Insulin receptors and downstream substrates associate with membrane microdomains after treatment with insulin or chromium(III) picolinate. AB - We have examined the association of insulin receptors (IR) and downstream signaling molecules with membrane microdomains in rat basophilic leukemia (RBL 2H3) cells following treatment with insulin or tris(2 pyridinecarbxylato)chromium(III) (Cr(pic)(3)). Single-particle tracking demonstrated that individual IR on these cells exhibited reduced lateral diffusion and increased confinement within 100 nm-scale membrane compartments after treatment with either 200 nM insulin or 10 MUM Cr(pic)(3). These treatments also increased the association of native IR, phosphorylated insulin receptor substrate 1 and phosphorylated AKT with detergent-resistant membrane microdomains of characteristically high buoyancy. Confocal fluorescence microscopic imaging of Di-4-ANEPPDHQ labeled RBL-2H3 cells also showed that plasma membrane lipid order decreased following treatment with Cr(pic)(3) but was not altered by insulin treatment. Fluorescence correlation spectroscopy demonstrated that Cr(pic)(3) did not affect IR cell-surface density or compete with insulin for available binding sites. Finally, Fourier transform infrared spectroscopy indicated that Cr(pic)(3) likely associates with the lipid interface in reverse-micelle model membranes. Taken together, these results suggest that activation of IR signaling in a cellular model system by both insulin and Cr(pic)(3) involves retention of IR in specialized nanometer-scale membrane microdomains but that the insulin-like effects of Cr(pic)(3) are due to changes in membrane lipid order rather than to direct interactions with IR. PMID- 22101511 TI - Escherichia coli membrane-associated energy-dependent processes and sensitivity toward antibiotics changes as responses to low-intensity electromagnetic irradiation of 70.6 and 73 GHz frequencies. AB - Escherichia coli K-12(lambda) was sensitive toward low-intensity (non-thermal, flux capacity 0.06 mW cm(-2)) electromagnetic irradiation (EMI) of extremely high frequency-70.6 and 73 GHz. 1 h exposure to EMI markedly depressed growth and cell viability of bacteria. Membrane-associated processes-total H(+) efflux and H(2) evaluation by whole cells during glucose fermentation were shown to be lowered as well. At the same time, the F(0)F(1)-ATPase activity of membrane vesicles was little depressed with 70.6 GHz irradiation only. This finding was in conformity with non-changed N,N'-dicyclohexylcarbodiimide-sensitive H(+) efflux. Furthermore, for understanding the different frequencies action mechanisms, the effects of antibiotics (chloramphenicol, ceftriaxone, kanamycin, and tetracycline) on irradiated cells growth and survival were determined. EMI with the frequencies of 70.6 and 73 GHz as with 51.8 and 53.0 GHz enhanced the sensitivity of bacteria toward antibiotics, but comparison revealed that each frequency had a different portion. Probably, EMI of specific frequency triggered changes in biological processes and afterward in growth and viability of bacteria, creating conditions when the action of antibiotics became facilitated. PMID- 22101512 TI - High resolution quantitative piezoresponse force microscopy of BiFeO3 nanofibers with dramatically enhanced sensitivity. AB - Piezoresponse force microscopy (PFM) has emerged as the tool of choice for characterizing piezoelectricity and ferroelectricity of low-dimensional nanostructures, yet quantitative analysis of such low-dimensional ferroelectrics is extremely challenging. In this communication, we report a dual frequency resonance tracking technique to probe nanocrystalline BiFeO(3) nanofibers with substantially enhanced piezoresponse sensitivity, while simultaneously determining its piezoelectric coefficient quantitatively and correlating quality factor mappings with dissipative domain switching processes. This technique can be applied to probe the piezoelectricity and ferroelectricity of a wide range of low-dimensional nanostructures or materials with extremely small piezoelectric effects. PMID- 22101514 TI - The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis. AB - How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop. PMID- 22101513 TI - Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates. AB - Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases. PMID- 22101515 TI - Influence of heterogeneous and anisotropic tissue conductivity on electric field distribution in deep brain stimulation. AB - The aim was to quantify the influence of heterogeneous isotropic and heterogeneous anisotropic tissue on the spatial distribution of the electric field during deep brain stimulation (DBS). Three finite element tissue models were created of one patient treated with DBS. Tissue conductivity was modelled as (I) homogeneous isotropic, (II) heterogeneous isotropic based on MRI, and (III) heterogeneous anisotropic based on diffusion tensor MRI. Modelled DBS electrodes were positioned in the subthalamic area, the pallidum, and the internal capsule in each tissue model. Electric fields generated during DBS were simulated for each model and target-combination and visualized with isolevels at 0.20 (inner), and 0.05 V mm(-1) (outer). Statistical and vector analysis was used for evaluation of the distribution of the electric field. Heterogeneous isotropic tissue altered the spatial distribution of the electric field by up to 4% at inner, and up to 10% at outer isolevel. Heterogeneous anisotropic tissue influenced the distribution of the electric field by up to 18 and 15% at each isolevel, respectively. The influence of heterogeneous and anisotropic tissue on the electric field may be clinically relevant in anatomic regions that are functionally subdivided and surrounded by multiple fibres of passage. PMID- 22101516 TI - Nanofiber-nanorod composites exhibiting light-induced reversible lower critical solution temperature transitions. AB - Stimuli-responsive materials are promising as smart materials for a range of applications. In this work, a photo-crosslinkable, thermoresponsive macromer was electrospun into fibrous scaffolds containing gold nanorods (AuNRs). The resulting fibrous nanocomposites composed of poly(N-isopropylacrylamide-co polyethylene glycol acrylate) (PNPA) and PEGylated AuNRs were crosslinked and swollen in water. AuNRs strongly absorb in the near-infrared (NIR) region to generate heat, which triggered the fiber thermal transition upon NIR light exposure. During the thermal transition, scaffolds collapsed both macroscopically and microscopically, with individual fibers deswelling and pulling together. Exposure to a 1.1 W NIR laser decreased the diameter of swollen fibers by 34.7% from 1332 +/- 193.3 to 868.9 +/- 168.3 nm, and increased fiber density 116% from 209.5 +/- 26.34 to 451.9 +/- 23.68 fibers mm( - 1). This transition was dependent on the incorporation of the AuNRs, and was utilized to trigger the release of encapsulated proteins from the nanocomposite fiber mats. The expulsion of water from fibers upon NIR exposure caused the release rate of incorporated protein to increase greater than tenfold, from 0.038 +/- 0.052 without external stimulus to 0.462 +/- 0.227 ug protein/mg polymer/min with NIR exposure. These results suggest that light-responsive fibrous nanocomposites can be utilized in applications such as drug delivery. PMID- 22101517 TI - AC927, a sigma receptor ligand, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells. AB - Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective sigma receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration- and time-dependent manner. N Acetylcysteine, catalase, and l-N(G)-monomethyl arginine citrate inhibited the ROS/RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of sigma receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells. PMID- 22101518 TI - Role of CXCR4 internalization in the anti-HIV activity of stromal cell-derived factor-1alpha probed by a novel synthetically and modularly modified-chemokine analog. AB - The natural ligands of two major human immunodeficiency virus type 1 (HIV-1) co receptors, CXCR4 and CCR5, can profoundly inhibit the replication of HIV-1 that uses these co-receptors for entry into the target cells. It has been postulated that these natural chemokines inhibit HIV-1 infection by blocking common binding sites on CXCR4 or CCR5 that are required for HIV-1 envelope glycoprotein gp120 interaction with its co-receptor and/or by inducing receptor internalization. To investigate whether receptor internalization caused by stromal cell-derived factor (SDF)-1alpha, a natural ligand of CXCR4, plays a role in its anti-HIV activity, we applied the SMM (synthetically and modularly modified)-chemokine approach to generate a functional probe of SDF-1alpha that retains significant CXCR4 binding but does not induce CXCR4 internalization. The antiviral study of this functional probe analog versus wild-type SDF-1alpha showed that, despite the significant CXCR4 binding activity, this probe analog displayed a complete loss of effect in causing CXCR4 internalization and greatly diminished antiviral activity. Interestingly, this new analog also showed a decreased number of overlapping binding sites with HIV-1 on CXCR4 transmembrane and extracellular domains. The correlation of the decrease in the anti-HIV activity with the loss of CXCR4 internalization observed with this probe molecule suggests that receptor internalization may play an important role in the anti-HIV activity of SDF-1alpha and possibly other natural chemokines. This further implies that any modifications in SDF-1alpha that result in a reduction or loss of internalization activity may result in analogs that are not suitable as effective HIV-1 inhibitors that target CXCR4, unless such modifications also result in improved CXCR4 interaction with increased number of overlapping binding sites with HIV-1, thus leading to more effective steric hindrance against HIV-1. PMID- 22101519 TI - Inflammatory cues modulate the expression of secretory product genes, Golgi sulfotransferases and sulfomucin production in LS174T cells. AB - The signals that mediate goblet cell expression of specific mucin chemotypes are poorly defined. Animal and in vitro studies show that acidomucin chemotypes may be altered by inflammation and changes in intestinal microbiota. To examine factors that may elicit this response, human adenocarcinoma-derived LS174T cells, which have a goblet cell-like phenotype and produce both sulfo- and sialomucins, were used to examine the effects of selected microbial and host factors on expression of goblet cell secretory product genes, sulfotransferases and sulfomucin production. Expression of genes encoding mucin 2 (MUC2), resistin-like molecule beta (RETNLB), and trefoil factor 3 (TFF3) and Golgi sulfotransferases, carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 5 (CHST5) and galactose-3 O-sulfotransferase 2 (GAL3ST2), was measured by quantitative reverse transcriptase-polymerase chain reaction following treatment with bacterial flagellin, tumor necrosis factor alpha (TNF-alpha) or the mucogenic cytokine interleukin-13 (IL-13). Expression of the toll-like receptor 5 (TLR5) gene was also analysed. Sulfomucin expression was examined via high-iron diamide/alcian blue (HID/AB) histochemistry and immunofluorescent staining for the Sulfo Le(a) antigen, which is synthesized in part by GAL3ST2. Flagellin, IL-13 and TNF-alpha all significantly increased GAL3ST2, MUC2, TFF3 and TLR5 expression, while only IL-13 increased RETNLB and CHST5 expression. Based on HID/AB histochemistry, mucin sulfation was significantly increased in response to both flagellin and IL 13 but not TNF-alpha. Only treatment with flagellin increased the expression of the Sulfo Le(a) antigen. Collectively, these results indicate that bacterial flagellin, IL-13 and TNF-alpha differentially modulate the expression of goblet cell secretory product genes, sulfotransferases and sulfomucin production. PMID- 22101520 TI - Effect of Ferula hermonis root extract on rat skeletal muscle adaptation to exercise. AB - Ferula hermonis Boiss. is an aphrodisiac plant that grows in the Mediterranean region. It has been reported that treatment with acetonic extract from the root of this plant acutely increases serum testosterone in the rat. This study investigated the effects of F. hermonis extract alone or combined with exercise on rat skeletal muscle fibers. Adult male rats were divided into four groups: control-sedentary (CS) that had no treatment or exercise; ferula-sedentary (FS) that was orally treated with ferula extract at a dose of 60 mg/kg/rat every other day over a period of 20 d; control-exercised (CE) that was trained by swimming for 40 min every other day; and ferula-exercised (FE) that received ferula and performed exercise. At the end of experiments, the fiber diameter and number of muscle nuclei of tibialis anterior were measured by using immunofluorescent techniques and software analyses. The FE group showed significant increases in muscle weight, fiber size and nuclear number compared with the other groups. However, no significant changes in the aforementioned parameters were found among the CS, FS and CE groups. Ferula treatment and exercise were additive to each other. In conclusion, short-term exercise combined with administration of F. hermonis extract was more effective in enhancing the growth of skeletal muscle fibers than exercise alone. PMID- 22101521 TI - Novel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells. AB - p66Shc, a longevity adaptor protein, is demonstrated as a key regulator of reactive oxygen species (ROS) metabolism involved in aging and cardiovascular diseases. Vascular endothelial growth factor (VEGF) stimulates endothelial cell (EC) migration and proliferation primarily through the VEGF receptor-2 (VEGFR2). We have shown that ROS derived from Rac1-dependent NADPH oxidase are involved in VEGFR2 autophosphorylation and angiogenic-related responses in ECs. However, a role of p66Shc in VEGF signaling and physiological responses in ECs is unknown. Here we show that VEGF promotes p66Shc phosphorylation at Ser36 through the JNK/ERK or PKC pathway as well as Rac1 binding to a nonphosphorylated form of p66Shc in ECs. Depletion of endogenous p66Shc with short interfering RNA inhibits VEGF-induced Rac1 activity and ROS production. Fractionation of caveolin-enriched lipid raft demonstrates that p66Shc plays a critical role in VEGFR2 phosphorylation in caveolae/lipid rafts as well as downstream p38MAP kinase activation. This in turn stimulates VEGF-induced EC migration, proliferation, and capillary-like tube formation. These studies uncover a novel role of p66Shc as a positive regulator for ROS-dependent VEGFR2 signaling linked to angiogenesis in ECs and suggest p66Shc as a potential therapeutic target for various angiogenesis dependent diseases. PMID- 22101522 TI - Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+ channels. AB - Na(+) current derived from expression of the cardiac isoform SCN5A is reduced by receptor-mediated or direct activation of protein kinase C (PKC). Previous work has suggested a possible role for loss of Na(+) channels at the plasma membrane in this effect, but the results are controversial. In this study, we tested the hypothesis that PKC activation acutely modulates the intracellular distribution of SCN5A channels and that this effect can be visualized in living cells. In human embryonic kidney cells that stably expressed SCN5A with green fluorescent protein (GFP) fused to the channel COOH-terminus (SCN5A-GFP), Na(+) currents were suppressed by an exposure to PKC activation. Using confocal microscopy, colocalization of SCN5A-GFP channels with the plasma membrane under control and stimulated conditions was quantified. A separate population of SCN5A channels containing an extracellular epitope was immunolabeled to permit temporally stable labeling of the plasma membrane. Our results demonstrated that Na(+) channels were preferentially trafficked away from the plasma membrane by PKC activation, with a major contribution by Ca(2+)-sensitive or conventional PKC isoforms, whereas stimulation of protein kinase A (PKA) had the opposite effect. Removal of the conserved PKC site Ser(1503) or exposure to the NADPH oxidase inhibitor apocynin eliminated the PKC-mediated effect to alter channel trafficking, indicating that both channel phosphorylation and ROS were required. Experiments using fluorescence recovery after photobleaching demonstrated that both PKC and PKA also modified channel mobility in a manner consistent with the dynamics of channel distribution. These results demonstrate that the activation of protein kinases can acutely regulate the intracellular distribution and molecular mobility of cardiac Na(+) channels in living cells. PMID- 22101523 TI - Minimally invasive quantification of lymph flow in mice and rats by imaging depot clearance of near-infrared albumin. AB - There is a lack of available methods to noninvasively quantify lymphatic function in small experimental animals, a necessity for studies on lymphatic system pathophysiology. We present a new method to quantify lymph flow in mice and rats, based on optically monitoring the depot clearance of near-infrared fluorescently labeled albumin and subsequent calculation of removal rate constants (k). BSA was conjugated with Alexa680 NHS ester and remained stable in protein-rich solutions without free dye dissociation. To assess lymph flow, mice or rats were imaged every 30 or 60 min during a 3- to 6-h period following an intradermal injection of 0.5 or 1 MUl Alexa680-albumin. Mice were awake between measurements, whereas rats were anesthetized throughout the experiment. The k, a parameter defined as equivalent to lymph flow, was calculated from the slopes of the resultant log linear washout curves and averaged -0.40 +/- 0.03 and -0.30 +/- 0.02%/min for control C57BL/6 and C3H mice, respectively. Local administration of the vasoconstrictor endothelin-1 in mice led to a significant reduction in k, whereas overhydration in rats increased k, reflecting the coupling between capillary filtration and lymph flow. Furthermore, k was 50% of wild type in lymphedema Chy mice where dermal lymphatics are absent. We conclude that lymph flow can be determined as its rate constant k by optical imaging of depot clearance of submicroliter amounts of Alexa680-albumin. The method offers a minimally invasive, reproducible, and simple alternative to assess lymphatic function in mice and rats. PMID- 22101524 TI - Central neural control of sympathetic nerve activity in heart failure following exercise training. AB - Typical characteristics of chronic congestive heart failure (HF) are increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation. These abnormalities lead to an increased risk of mortality, particularly in the late stage of chronic HF. Recent evidence suggests that central nervous system (CNS) mechanisms may be important in these abnormalities during HF. Exercise training (ExT) has emerged as a nonpharmacological therapeutic strategy substitute with significant benefit to patients with HF. Regular ExT improves functional capacity as well as quality of life and perhaps prognosis in chronic HF patients. The mechanism(s) by which ExT improves the clinical status of HF patients is not fully known. Recent studies have provided convincing evidence that ExT significantly alleviates the increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation in HF. This review describes and highlights the studies that examine various central pathways involved in autonomic outflow that are altered in HF and are improved following ExT. The increased sympathoexcitation is due to an imbalance between inhibitory and excitatory mechanisms within specific areas in the CNS such as the paraventricular nucleus (PVN) of the hypothalamus. Studies summarized here have revealed that ExT improves the altered inhibitory pathway utilizing nitric oxide and GABA mechanisms within the PVN in HF. ExT alleviates elevated sympathetic outflow in HF through normalization of excitatory glutamatergic and angiotensinergic mechanisms within the PVN. ExT also improves volume reflex function and thus fluid balance in HF. Preliminary observations also suggest that ExT induces structural neuroplasticity in the brain of rats with HF. We conclude that improvement of the enhanced CNS-mediated increase in sympathetic outflow, specifically to the kidneys related to fluid balance, contributes to the beneficial effects of ExT in HF. PMID- 22101525 TI - Autophagy mechanism of right ventricular remodeling in murine model of pulmonary artery constriction. AB - Although right ventricular failure (RVF) is the hallmark of pulmonary arterial hypertension (PAH), the mechanism of RVF is unclear. Development of PAH-induced RVF is associated with an increased reactive oxygen species (ROS) production. Increases in oxidative stress lead to generation of nitro-tyrosine residues in tissue inhibitor of metalloproteinase (TIMPs) and liberate active matrix metalloproteinase (MMPs). To test the hypothesis that an imbalance in MMP-to-TIMP ratio leads to interstitial fibrosis and RVF and whether the treatment with folic acid (FA) alleviates ROS generation, maintains MMP/TIMP balance, and regresses interstitial fibrosis, we used a mouse model of pulmonary artery constriction (PAC). After surgery mice were given FA in their drinking water (0.03 g/l) for 4 wk. Production of ROS in the right ventricle (RV) was measured using oxidative fluorescent dye. The level of MMP-2, -9, and -13 and TIMP-4, autophagy marker (p62), mitophagy marker (LC3A/B), collagen interstitial fibrosis, and ROS in the RV wall was measured. RV function was measured by Millar catheter. Treatment with FA decreased the pressure to 35 mmHg from 50 mmHg in PAC mice. Similarly, RV volume in PAC mice was increased compared with the Sham group. A robust increase of ROS was observed in RV of PAC mice, which was decreased by treatment with FA. The protein level of MMP-2, -9, and -13 was increased in RV of PAC mice in comparison with that in the sham-operated mice, whereas supplementation with FA abolished this effect and mitigated MMPs levels. The protein level of TIMP-4 was decreased in RV of PAC mice compared with the Sham group. Treatment with FA helped PAC mice to improve the level of TIMP-4. To further support the claim of mitophagy occurrence during RVF, the levels of LC3A/B and p62 were measured by Western blot and immunohistochemistry. LC3A/B was increased in RV of PAC mice. Similarly, increased p62 protein level was observed in RV of PAC mice. Treatment with FA abolished this effect in PAC mice. These results suggest that FA treatment improves MMP/TIMP balance and ameliorates mitochondrial dysfunction that results in protection of RV failure during pulmonary hypertension. PMID- 22101526 TI - Myofibroblasts cause heterogeneous Cx43 reduction and are unlikely to be coupled to myocytes in the healing canine infarct. AB - Following myocardial infarction (MI) inflammatory responses transform cardiac fibroblasts to myofibroblasts, which in vitro studies show form heterocellular gap junctions with cardiac myocytes via Connexin43 (Cx43). The ability to form heterocellular junctions in the intact heart and the impact of these junctions on propagation is unclear. We used a canine model of MI and characterized the distribution and quantity of myofibroblasts in surviving epicardial cells [epicardial border zone (EBZ)]. We found a significant increase in myofibroblasts within the EBZ and no gap junction plaques between myofibroblasts and myocytes. Because myofibroblasts produce IL-1beta, which downregulates Cx43, we asked whether myofibroblast proliferation causes loss of Cx43 near myofibroblast clusters. In vitro studies showed that IL-1beta caused loss of Cx43 and reduced coupling. Western blot showed a significant increase of IL-1beta in the EBZ, and immunohistochemistry showed a loss of Cx43 in regions of myofibroblasts in the intact heart. Additionally, dye studies in intact heart showed no coupling between myocytes and myofibroblasts. To quantify the effect of myofibroblasts on propagation we used a two-dimensional subcellular computer model of the EBZ, which showed that heterogeneities in myofibroblast density lead to conduction abnormalities. In conclusion, an increase of myofibroblasts in the infarcted heart causes heterogeneous Cx43 levels, possibly as a result of the release of IL 1beta and decreased cell-cell communication, which leads to conduction abnormalities following MI. PMID- 22101527 TI - Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin. AB - The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg.kg(-1).day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg.kg(-1).day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening. PMID- 22101529 TI - Geometrical models for cardiac MRI in rodents: comparison of quantification of left ventricular volumes and function by various geometrical models with a full volume MRI data set in rodents. AB - MRI has been proven to be an accurate method for noninvasive assessment of cardiac function. One of the current limitations of cardiac MRI is that it is time consuming. Therefore, various geometrical models are used, which can reduce scan and postprocessing time. It is unclear how appropriate their use is in rodents. Left ventricular (LV) volumes and ejection fraction (EF) were quantified based on 7.0 Tesla cine-MRI in 12 wild-type (WT) mice, 12 adipose triglyceride lipase knockout (ATGL(-/-)) mice (model of impaired cardiac function), and 11 rats in which we induced cardiac ischemia. The LV volumes and function were either assessed with parallel short-axis slices covering the full volume of the left ventricle (FV, gold standard) or with various geometrical models [modified Simpson rule (SR), biplane ellipsoid (BP), hemisphere cylinder (HC), single-plane ellipsoid (SP), and modified Teichholz Formula (TF)]. Reproducibility of the different models was tested and results were correlated with the gold standard (FV). All models and the FV data set provided reproducible results for the LV volumes and EF, with interclass correlation coefficients >=0.87. All models significantly over- or underestimated EF, except for SR. Good correlation was found for all volumes and EF for the SR model compared with the FV data set (R(2) ranged between 0.59-0.95 for all parameters). The HC model and BP model also predicted EF well (R(2) >= 0.85), although proved to be less useful for quantitative analysis. The SP and TF models correlated poorly with the FV data set (R(2) >= 0.45 for EF and R(2) >= 0.29 for EF, respectively). For the reduction in acquisition and postprocessing time, only the SR model proved to be a valuable method for calculating LV volumes, stroke volume, and EF. PMID- 22101528 TI - Muscle oxygen transport and utilization in heart failure: implications for exercise (in)tolerance. AB - The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is inextricably linked to structural and functional aberrations in the O(2) transport pathway. CHF reduces muscle O(2) supply while simultaneously increasing O(2) demands. CHF severity varies from moderate to severe and is assessed commonly in terms of the maximum O(2) uptake, which relates closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues' (167) classifications of heart failure, speed of the O(2) uptake kinetics following exercise onset and during recovery, and the capacity to perform submaximal exercise. As the heart fails, cardiovascular regulation shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This shift is mediated by a complex array of events that include altered reflex and humoral control of the circulation, required to prevent the skeletal muscle "sleeping giant" from outstripping the pathologically limited cardiac output and secondarily impacts lung (and respiratory muscle), vascular, and locomotory muscle function. Recently, interest has also focused on the dysregulation of inflammatory mediators including tumor necrosis factor-alpha and interleukin-1beta as well as reactive oxygen species as mediators of systemic and muscle dysfunction. This brief review focuses on skeletal muscle to address the mechanistic bases for the reduced maximum O(2) uptake, slowed O(2) uptake kinetics, and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF unveils the microvascular cause(s) and consequences of the O(2) supply (decreased)/O(2) demand (increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular) and hence patient exercise tolerance and quality of life are presented within their appropriate context of the O(2) transport pathway. PMID- 22101533 TI - Dynamic orientational disorder in crystals of fluoroelpasolites, structural refinement of (NH4)3AlF6, (NH4)3TiOF5 and Rb2KTiOF5. AB - Room-temperature crystal structures of triammonium hexafluoroaluminate, (NH(4))(3)AlF(6) (I), and triammonium oxopentafluorotitanate, (NH(4))(3)TiOF(5) (II), were refined, and the crystal structures of dirubidium potassium oxopentaflourotitanate, Rb(2)KTiOF(5), at 297 K (III) and 218 K (IV) were determined using single-crystal X-ray diffraction techniques. In ammonium fluoroelpasolites [(I) and (II)], the ligand (O, F) atoms are located in the mixed 24e + 96j position of the Fm3m unit cell. The 24e position is occupied by the ligand atoms predominantly in (III) and fully in (IV). 'Ordered' N1 and Rb atoms are tetrahedrally displaced from the 8c position into the 32f site, and the H atoms of the disordered ammonium group N2 are statistically distributed in the 96k and 32f positions. The Ti atoms in (II) and (IV) are shifted from the 4a position to 24e thus allowing identification of the O and F atoms in the octahedron on a local scale. The disorder in the crystals is of a dynamic nature. Unique Raman spectra of Rb(2)KTiOF(5) under the laser beam of 1064 nm indicate fast octahedral reorientations resulting in physical equalizations of the Ti-O and Ti-F distances as well as in the appearance of totally synchronous Ti-O and Ti-F stretching vibrations at 750 cm(-1). This phenomenon is assumed to also take place under X-rays. PMID- 22101534 TI - Structure of LaTi2Al9O19 and reanalysis of the crystal structure of La3Ti5Al15O37. AB - The non-perovskite compound LaTi(2)Al(9)O(19) was synthesized and structurally characterized by conventional X-ray powder diffraction and shown to be isostructural with SrTi(3)Al(8)O(19), as confirmed by bond-valence sum calculations. The dielectric properties of LaTi(2)Al(9)O(19) at 1 MHz were measured. The crystal structure of La(3)Ti(5)Al(15)O(37), which is referred to as the most complex structure solved ab initio from X-ray powder diffraction (XRPD) to date, is shown to be incorrect. PMID- 22101535 TI - The not so simple cubic structure of PbZr(1-x)Ti(x)O3 (PZT): complex local structural effects in perovskites. AB - High-resolution neutron diffraction on the important piezoelectric lead zirconate titanate (PZT) has found that oxygen disorder exists well into the cubic phase. This unexpected result shows that within this phase there persists a remnant of the tilted oxygen octahedra present within the room-temperature ferroelectric phase. The result is that the cubic phase, far from having a simple crystal structure, exhibits a more complex local structure than had hitherto been thought. PMID- 22101536 TI - Water channel structure of bassanite at high air humidity: crystal structure of CaSO4.0.625H2O. AB - Structure analysis using single-crystal diffraction was carried out as a contribution to the dispute about the nature of the water channel structure of bassanite (CaSO(4).0.5H(2)O). A recent result of Weiss & Brau (2009) for the crystal structure of bassanite (monoclinic, space group C2) at ambient conditions of air humidity was confirmed. In the presence of high relative air humidity the crystal structure of bassanite transformed due to the incorporation of additional water of hydration. The crystal structure of CaSO(4).0.625H(2)O was solved by single-crystal diffraction at 298 K and 75% relative air humidity. The experimental results provided an insight into both crystal structures. A model explaining the phase transition from CaSO(4).0.625H(2)O to CaSO(4).0.5H(2)O was derived. The monoclinic cell setting of CaSO(4).0.5H(2)O and the trigonal cell setting of CaSO(4).0.625H(2)O were confirmed by powder diffraction. PMID- 22101537 TI - Stacking faults and superstructures in a layered brownmillerite. AB - Single crystals of Ca(4)Fe(2)Mn(0.5)Ti(0.5)O(9) have been synthesized using a flux method. The structural characterization using single-crystal X-ray diffraction revealed the space group Amma and unit-cell dimensions of a = 5.3510 (6), b = 26.669 (3), c = 5.4914 (6) A. The structure is isotypic with Sr(3)NdFe(3)O(9) [Barrier et al. (2005). Chem. Mater. 17, 6619-6623] and exhibits separated brownmillerite-type layers. One-dimensional diffuse scattering shows that the unit cell is doubled along c by alternating the intra-layer order of tetrahedral chains, causing stacking faults along the b direction. A computer simulation was performed, proving that the observed intensity variations along the diffuse scattering rods originates from two different local structures depending on the configuration of the tetrahedral chains. Selected-area electron diffraction experiments exhibit well ordered regions characterized by satellite reflections corresponding to two different superstructures. Both superstructures can be described using the superspace group A2(1)/m(0betagamma)0s, with gamma = 0.5 and beta ? 0.27 or beta = 0. PMID- 22101538 TI - [Ni(H2O)6](NO3)2.(15-crown-5).2H2O: three phase transitions and an intermediate modulated phase stable over a range of ca 40 K. AB - In the range 308-90 K single crystals of [Ni(H(2)O)(6)](NO(3))(2).(15-crown 5).2H(2)O continue to diffract well as they undergo three phase transitions. Structures have been determined at 28 different temperatures; data were collected at six more but could not be refined satisfactorily. The transitions identified structurally are in good agreement with those found by thermal analysis. Phase I (above ca 292 K; I2/m, Z = 2, Z' = 1/4) is disordered because the 15-crown-5 molecule is located on a 2/m site. Phase II (ca 292-248 K; P2(1)/m, Z = 2, Z' = 1/2) is less disordered. Phase III (ca 248-208 K; B2(1), Z = 28, Z' = 7 in a commensurate approximation) is modulated with some regions resembling phase II and the rest resembling the fully ordered phase IV (P2(1)/c, Z = 4, Z' = 1) that is stable below ca 208 K. The modulated structure could be determined well because crystals flash-cooled to 90 K usually retain the phase III structure. The unusual phase III may be a consequence of the differing thermal contraction of two types of alternating layers, one composed of neutral 15-crown-5 molecules and the other composed of the cations, anions and lattice water molecules, which form a hydrogen-bonded network. The two kinds of layers are linked by O(ether)...H(2)O(axial)-Ni hydrogen bonds. PMID- 22101539 TI - Structural study of piracetam polymorphs and cocrystals: crystallography redetermination and quantum mechanics calculations. AB - Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis. PMID- 22101540 TI - Determining the structure of a benzene7.2-silicalite-1 zeolite using a single crystal X-ray method. AB - A simple method for preparing orthorhombic single crystals of benzene-silicalite 1 was developed. A silicalite-1 crystal was pressed with a weight of 2 g along the +c and -c crystallographic axes while the temperature was increased to 473 K. The temperature was then slowly reduced to 313 K, and these heating and cooling steps were repeated three times. After the orthorhombic single crystals adsorbed benzene, the crystal structure of the resulting benzene-silicalite-1 was determined. There were two kinds of benzene molecules in the asymmetric unit. One was located at the intersection of the straight channels and the sinusoidal channels with the benzene ring parallel to the ac plane. The other benzene was located in the middle of the straight channel. PMID- 22101541 TI - Diffuse scattering resulting from macromolecular frustration. AB - Distinctive diffuse scattering in the form of diffuse rings around Bragg positions has been observed in the diffraction patterns of a crystal of the N terminal fragment of the Gag protein from Feline Foamy Virus. It is shown that these are caused by geometric frustration as molecules try to pack on the triangular b-c mesh of the space group P6(1)22. In order to explain the strong diffuse scattering it is necessary for the crystal to contain occupational disorder such that each unit cell contains one or other of two different molecular arrangements, A and B. The frustration arises because the nearest neighbour packing prefers neighbouring cells to be AB or BA, which cannot be achieved on all three sides of a triangle simultaneously. To explain the observation that reciprocal sections hk5n, where n = integer, contain only Bragg peaks it is necessary that A and B are identical molecular arrangements differing only by a translation of 0.2c. The implications of the disorder for solving the structure of the protein by conventional techniques as well as the possibility of using the diffuse scattering for this purpose are discussed. PMID- 22101542 TI - Crystal packing and melting temperatures of small oxalate esters: the role of C H...O hydrogen bonding. AB - The simple dialkyl oxalates are generally liquids at room temperature except for dimethyl and di-tert-butyl oxalate which melt at 327 and 343 K. The crystal structures of diethyl, di-iso-propyl, di-n-butyl, di-tert-butyl and methyl ethyl oxalates were determined. The liquid esters were crystallized using the cryocrystallization technique. A comparison of the intermolecular interactions and packing features in these crystal structures was carried out. The crystal structure of dimethyl oxalate was redetermined at various temperatures. The other compounds were also studied at several temperatures in order to assess the attractive nature of the hydrogen bonds therein. A number of moderate to well defined C-H...O interactions account for the higher melting points of the two solid esters. Additionally, a diminished entropic contribution DeltaS(m) in di tert-butyl oxalate possibly increases the melting point of this compound further. PMID- 22101544 TI - The whole range of hydrogen bonds in one crystal structure: neutron diffraction and charge-density studies of N,N-dimethylbiguanidinium bis(hydrogensquarate). AB - N,N-Dimethylbiguanidinium bis(hydrogensquarate) features an impressive range of hydrogen bonds within the same crystal structure: neighbouring anions aggregate to a dianionic pair through two strong O-H...O interactions; one of these can be classified among the shortest hydrogen bonds ever studied. Cations and anions in this organic salt further interact via conventional N-H...O and nonclassical C H...O contacts to an extended structure. As all these interactions occur in the same sample, the title compound is particularly suitable to monitor even subtle trends in hydrogen bonds. Neutron and high-resolution X-ray diffraction experiments have enabled us to determine the electron density precisely and to address its properties with an emphasis on the nature of the X-H...O interactions. Sensitive criteria such as the Laplacian of the electron density and energy densities in the bond-critical points reveal the incipient covalent character of the shortest O-H...O bond. These findings are in agreement with the precise geometry from neutron diffraction: the shortest hydrogen bond is also significantly more symmetric than the longer interactions. PMID- 22101543 TI - Towards crystal structure prediction of complex organic compounds--a report on the fifth blind test. AB - Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome. PMID- 22101545 TI - Molecular origins of commercial laser dye functionality in azacoumarins and 2 quinolones: LD 425, LD 489 and LD 473. AB - The molecular structures of three compounds, LD 425 (C(13)H(14)N(2)O(3)) (1), LD 489 (C(15)H(15)F(3)N(2)O(2)) (2) and LD 473 (C(17)H(19)F(3)N(2)O) (3), are determined by single-crystal X-ray diffraction (XRD) at 180 K. Azacoumarins (1) and (2) possess para-quinoidal bond-length patterns in their benzene rings due to intramolecular charge transfer (ICT) from these rings to the adjoining rings. In contrast, substitution of O with N within the coumarin heterocycle, to form a 2 quinolone, results in the suppression of this ICT effect. Instead, charge transfer within the heterocycle is shown to become more pronounced. Resonance theory is employed to discuss these bond pattern differences and characteristic spectral blue shifts in relation to their coumarin analogues. The application of this theory offers an intuitive understanding of the structure-property relationships in azacoumarins and 2-quinolones which is further supported by quantum chemical calculations. Such an understanding is important for recognizing ICT mechanisms in these compounds which can then be used to facilitate the molecular design of new laser dyes with the desired spectral shifts. PMID- 22101546 TI - Experimental and theoretical electron-density study of three isoindole derivatives: topological and Hirshfeld surface analysis of weak intermolecular interactions. AB - A combined experimental and theoretical study of three isoindole derivatives was made on the basis of a topological analysis of their electron-density distributions. Experimental electron densities were determined from high resolution X-ray diffraction data sets measured with synchrotron radiation at 100 K, whereas theoretical calculations were performed using DFT methods at the B3LYP?6-311++G(3df,3pd) level of approximation. Both experimental and theoretical models are in good agreement with each other. Since the analysed structures possess a variety of hydrogen-bonding interactions, weak intermolecular contacts of C-H...C(pi), C,N(pi)...C,N(pi) and H...H types were subject to our special interest and are discussed in detail. They were characterized quantitatively and qualitatively by topological properties using Bader's Atoms in Molecules theory and by mapping the electron-density distribution, electrostatic potential and a geometric function on the Hirshfeld surface. This way the forces and directions of intermolecular interactions as present on the molecular surfaces were depicted and described. These interactions not only guide crystal packing, but are likewise important for recognition processes involving (aza)isoindole fragments in a biological environment. PMID- 22101547 TI - Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions. AB - Androgens increase both the size and strength of skeletal muscle via diverse mechanisms. The aim of this review is to discuss the different cellular targets of androgens in skeletal muscle as well as the respective androgen actions in these cells leading to changes in proliferation, myogenic differentiation, and protein metabolism. Androgens bind and activate a specific nuclear receptor which will directly affect the transcription of target genes. These genes encode muscle specific transcription factors, enzymes, structural proteins, as well as microRNAs. In addition, anabolic action of androgens is partly established through crosstalk with other signaling molecules such as Akt, myostatin, IGF-I, and Notch. Finally, androgens may also exert non-genomic effects in muscle by increasing Ca(2+) uptake and modulating kinase activities. In conclusion, the anabolic effect of androgens on skeletal muscle is not only explained by activation of the myocyte androgen receptor but is also the combined result of many genomic and non-genomic actions. PMID- 22101549 TI - Composition of the defensive secretion in three species of European millipedes. AB - Three European julid species, Cylindroiulus boleti, Leptoiulus trilineatus, and Megaphyllum bosniense, secrete mixtures of up to 12 different quinones. The major components in these species are 2-methoxy-3-methyl-1,4-benzoquinone and 2-methyl 1,4-benzoquinone. 2-Methoxy-5-methylhydroquinone is detected for the first time in the Class Diplopoda. 2-Hydroxy-3-methyl-1,4-benzoquinone, 2,3 dimethoxyhydroquinone, 2-methyl-3,4-methylendioxyphenol, and 2,3-dimethoxy-5 methylhydroquinone are registered for the first time in representatives of the family Julidae. The similar chemical composition of defense secretions in all analyzed European julids and Pacific spirobolids supports the idea of the chemical consistency of defensive compounds in juliform millipedes. PMID- 22101548 TI - Wide-scale screening of T-DNA lines for transcription factor genes affecting male gametophyte development in Arabidopsis. AB - Male gametophyte development leading to the formation of a mature pollen grain is precisely controlled at various levels, including transcriptional, post transcriptional and post-translational, during its whole progression. Transcriptomic studies exploiting genome-wide microarray technologies revealed the uniqueness of pollen transcriptome and the dynamics of early and late successive global gene expression programs. However, the knowledge of transcription regulation is still very limited. In this study, we focused on the identification of pollen-expressed transcription factor (TF) genes involved in the regulation of male gametophyte development. To achieve this, the reverse genetic approach was used. Seventy-four T-DNA insertion lines were screened, representing 49 genes of 21 TF families active in either early or late pollen development. In the screen, ten phenotype categories were distinguished, affecting various structural or functional aspects, including pollen abortion, presence of inclusions, variable pollen grain size, disrupted cell wall structure, cell cycle defects, and male germ unit organization. Thirteen lines were not confirmed to contain the T-DNA insertion. Among 61 confirmed lines, about half (29 lines) showed strong phenotypic changes (i.e., >= 25% aberrant pollen) including four lines that produced a remarkably high proportion (70-100%) of disturbed pollen. However, the remaining 32 lines exhibited mild defects or resembled wild-type appearance. There was no significant bias toward any phenotype category among early and late TF genes, nor, interestingly, within individual TF families. Presented results have a potential to serve as a basal information resource for future research on the importance of respective TFs in male gametophyte development. PMID- 22101550 TI - [Ralp and Rocco stitch: original technique]. AB - Incontinence and impotence are the two chief drawbacks of radical prostatectomy (RP). Incontinence is the most relevant for most of the patients, even if there is high variability in terms of prevalence and definition of continence. Incontinence seems the result of several factors, the most important being the surgical injury of some structures and the biomechanical instability associated with vesicourethral anastomosis. In the posterior urethra, which guarantees the continence mechanism, two functionally independent regions can be recognized: the proximal and the distal. The proximal region can be identified with the bladder neck, while the distal region is the rhabdosphincter urethrae. Concerning the distal functional region, two kinds of strategy can be applied: the preservation of puboprostatic ligaments and urethral attachments, or the reconstruction of the urethral rhabdosphincter, which can be anterior, posterior or total. We describe our technique of choice for posterior reconstruction, first described by Rocco and then modified by Patel et al. PMID- 22101551 TI - [Combined dutasteride and tamsulosin]. PMID- 22101552 TI - [ Monotherapy with tamsulosin]. AB - G.G. e un paziente di 62 anni, in condizioni generali discrete, che giunge alla nostra osservazione per la presenza di sintomi urinari del basso tratto urinario, International Prostate Symptom Score (IPSS) pari a 16. Anamnesi familiare negativa per carcinoma prostatico. Il paziente esegue terapia con calcio antagonista per ipertensione arteriosa. Ha subito un intervento di colecistectomia. Il paziente riferiva inoltre una qualita di vita negativamente influenzata da sintomi minzionali irritativi che lo portavano ad alzarsi piu di 3 volte a notte per urinare ed una pollachiuria diurna ogni 3 ore. Viene inoltre riferita un'attivita sessuale moderatamente insoddisfacente. PMID- 22101553 TI - Anti-microtubule organizing center with microtubule by autoimmune target test is also useful serological marker in rheumatoid arthritis evaluation. AB - Seropositivity of rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibody (anti-CCP) is one domain of scoring system in new American College of Rheumatology/European League against Rheumatism classification criteria for rheumatoid arthritis (RA). We investigated usefulness of antiperinuclear factor (APF) and autoantibody to microtubule organizing center with microtubule (anti MTOC-MT), which was detected by autoimmune target (AIT) test, as serological markers for the diagnosis of early RA. The test results of 3,503 patients from the outpatient clinic of The Hospital for Rheumatic Diseases who underwent test for RF, APF, anti-CCP and anti-MTOC-MT simultaneously for the work-up of RA were analyzed. Four kinds of tests showed same results only in 53.1% (1,861/3,503) of all subjects. The kappa coefficient between each test was distributed from -0.011 to 0.622. The agreement was best between RF and anti-CCP (kappa coefficient: 0.622), but the agreement was poor between anti-MTOC-MT and other 3 tests (kappa coefficient: 0.007 to -0.025). In both of RF- and anti-CCP-negative patients, the patients who showed positive result for APF were 4.6% (160/3,503) and for anti MTOC-MT were 13.2% (464/3,503). RF and anti-CCP positivity could not include all of APF and anti-MTOC-MT positivity. Anti-MTOC-MT detected by AIT test was independent serological marker, and it might be also helpful for the diagnosis of early RA. Therefore, the combined detection of all four serologic markers can be useful for the evaluation of suspected RA patients. PMID- 22101554 TI - Septic arthritis caused by Neisseria pharyngis in an elderly patient with knee prosthesis. PMID- 22101555 TI - Safety and efficacy of rituximab in refractory pediatric systemic lupus erythematosus nephritis: a single-center experience of Northern Greece. AB - Lupus nephritis (LN) is the major determinant of outcome in pediatric systemic lupus erythematosus (pSLE), and its treatment remains a challenge. The aim of this study was to report the experience of our center in treating with rituximab (RTX) SLE patients with severe LN. Four pSLE patients with biopsy-proven LN, who are refractory to conventional immunosuppressive treatment, received four doses of 375-500 mg/m(2) RTX, 2-3 weeks apart. All patients were concurrently receiving corticosteroids (CSs) and mycophenolate mofetil. Patients' clinical and laboratory findings were recorded at RTX initiation, after each infusion and at 3.4 +/- 2.1 month intervals thereafter. pSLE activity was assessed using the European Consensus Lupus Activity Measurement (ECLAM), while LN activity using 24 hour urine protein excretion and serum cystatin C. Patients were followed up for 6-21 months (median: 16 months). Full Beta-cell depletion was noticed 2-4 weeks after RTX initiation and lasted 4-7 months. All patients achieved complete LN remission 3.5 months (range: 2-4) after RTX initiation, which was retained in 3 patients through the follow-up period. One patient relapsed 15 months after RTX initiation and received one additional RTX dose. ECLAM scores and CSs doses were markedly reduced in all patients, while complement levels were increased. No side effects or infections were observed. In conclusion, RTX is an alternative, safe and efficient treatment for refractory LN. PMID- 22101556 TI - A profile of gout patients in Sarawak. AB - We performed a prospective study of all patients diagnosed with gout and who received treatment in Sarawak General Hospital from 1 July 2010 to 31 December 2010. There was a total of 138 patients in our study of which 92 (66.7%) were from the indigenous populations. They have a mean age of 56.5 +/- 12.5 years with a mean duration of illness of 11.6 +/- 8.7 years. The mean lag time between symptom onset to the diagnosis of gout was 2.8 +/- 4.8 years and a mean lag time to appropriate treatment of gout of 8.8 +/- 8.4 years. Sixty-six (47.8%) patients have family history of gout. The common complications of gout in our patients were tophi (47.1%), joint deformities (39.1%), kidney stones (16.7%), and uric acid nephropathy (0.7%). Hospitalization occurred in 93 (67.4%) patients. Gout is a serious medical problem in our centre. Gout affects middle-aged men, especially the indigenous populations. Almost half of our patients have a family history of gout and have tophi formations. Our gout patients have a significant delay in diagnosis and appropriate treatment, thus contributing to more complications and hospitalizations in our centre. There is an urgent need to educate both patients and healthcare workers on gout and its treatment to reduce the burden of chronic gout in Sarawak. PMID- 22101557 TI - Retracted article: Ten-year survival rates of methylprednisolone plus cyclophosphamide followed by mycophenolate mophetyl of azathiopurine for progressive systemic sclerosis patients. PMID- 22101558 TI - Intestinal sterol transporters and cholesterol absorption inhibition. AB - PURPOSE OF REVIEW: Statin therapy is the mainstay of lipid-lowering therapy; however, many patients, particularly those at high risk, do not achieve sufficient LDL-cholesterol (LDL-C) lowering. Thus, there remains an unmet medical need for more effective and well tolerated lipid-lowering agents. Guidelines recommend combining additional lipid-lowering agents with a complementary mode of action for these patients. One approach to complementing statin therapy is combination with inhibitors that block the intestinal absorption of dietary and biliary cholesterol. This review summarizes what is currently known about intestinal sterol transporters and cholesterol absorption inhibitors (CAIs). RECENT FINDINGS: The only lipid-lowering agent currently available that specifically targets an intestinal sterol transporter (Niemann-Pick C1-like 1) is the CAI, ezetimibe. It is effective in lowering LDL-C, both when given alone and when combined with a statin. Clinical outcome data with ezetimibe combined with simvastatin have recently become available, and definitive evidence that the incremental LDL-C lowering attributable to the ezetimibe component reduces cardiovascular events beyond simvastatin alone is currently under study. Other novel CAIs have been evaluated based upon the structure and properties of ezetimibe, but none remain in development. SUMMARY: Additional lipid-lowering agents are needed to fulfill an unmet medical need for those patients who do not achieve optimal LDL-C goals on statin monotherapy. The inhibition of cholesterol absorption is an important therapeutic strategy to reduce cholesterol levels. Based upon the demonstrated lipid-altering efficacy and safety of ezetimibe, several CAIs have been identified; all to date have been discontinued due to limited efficacy. PMID- 22101559 TI - Current world literature. PMID- 22101560 TI - Nutrition and metabolism--sphingolipids and branched chain amino acids: indicators and effectors of adipose tissue function and diabetes risk. PMID- 22101561 TI - Lipid droplet biogenesis: when the endoplasmic reticulum starts to fatten up. PMID- 22101562 TI - Atherosclerosis: beyond cholesterol. PMID- 22101563 TI - Hyperlipidaemia and cardiovascular disease--back to basics: dietary patterns, foods and cardiovascular risk. PMID- 22101564 TI - Therapy and clinical trials. PMID- 22101565 TI - Update on therapies targeting HDL: the mystery continues. PMID- 22101567 TI - Mycosis fungoides in the setting of T-cell large granular lymphocyte proliferative disorder. PMID- 22101568 TI - Ultrafine spatial acuity of blind expert human echolocators. AB - Echolocating organisms represent their external environment using reflected auditory information from emitted vocalizations. This ability, long known in various non-human species, has also been documented in some blind humans as an aid to navigation, as well as object detection and coarse localization. Surprisingly, our understanding of the basic acuity attainable by practitioners the most fundamental underpinning of echoic spatial perception-remains crude. We found that experts were able to discriminate horizontal offsets of stimuli as small as ~1.2 degrees auditory angle in the frontomedial plane, a resolution approaching the maximum measured precision of human spatial hearing and comparable to that found in bats performing similar tasks. Furthermore, we found a strong correlation between echolocation acuity and age of blindness onset. This first measure of functional spatial resolution in a population of expert echolocators demonstrates precision comparable to that found in the visual periphery of sighted individuals. PMID- 22101569 TI - Hands behind your back: effects of arm posture on tactile attention in the space behind the body. AB - Previous research has shown that tactile-spatial information originating from the front of the body is remapped from an anatomical to an external spatial coordinate system, guided by the availability of visual information early in development. Comparably little is known about regions of space for which visual information is not typically available, such as the space behind the body. This study tests for the first time the electrophysiological correlates of the effects of proprioceptive information on tactile-attentional mechanisms in the space behind the back. Observers were blindfolded and tactually cued to detect infrequent tactile targets on either their left or right hand and to respond to them either vocally or with index finger movements. We measured event-related potentials to tactile probes on the hands in order to explore tactile-spatial attention when the hands were either held close together or far apart behind the observer's back. Results show systematic effects of arm posture on tactile spatial attention different from those previously found for front space. While attentional selection is typically more effective for hands placed far apart than close together in front space, we found that selection occurred more rapidly for close than far hands behind the back, during both covert attention and movement preparation tasks. This suggests that proprioceptive space may "wrap" around the body, following the hands as they extend horizontally from the front body midline to the center of the back. PMID- 22101570 TI - Recombinant human interferon gamma (Gamma Immunex) in treatment of atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic, inflammatory skin disease which is characterized by severe pruritus and affects patients' quality of life. In recent years gamma interferon (IFN-gamma) has been accepted as a novel treatment for severe AD, however, its mechanism of action is not clearly identified. Present study evaluated the effect of recombinant human interferon gamma (rIFN-gamma: Gamma Immunex, Exir Pharmaceutical Company, Iran) on severity of AD (SCORAD), dermatology life quality index (DLQI) as well as serum levels of IL-4, IgE and IL 6 in AD patients. Twenty AD patients were entered in to a study in Baqiyatallah outpatient clinics and received rIFN-gamma (50 MUg/m(2) body area, 3 times per week, subcutaneously) for 1 month. SCORAD and DLQI were assessed at beginning and end of the treatment period. IL-4, IL-6 and IgE were measured in blood samples before and after 1 month treatment with rIFN-gamma. DLQI mean value before treatment was 20.80 +/- 3.95, which decreased to 8.20 +/- 2.14 after treatment (P < 0.001). SCORAD-A (percentile of the body surface involved in AD), SCORAD-B (the severity of clinical features) and SCORAD-C (patients' scaling of itching and somnolence) significantly decreased after treatment (P < 0.001, P < 0.001 and P < 0.01). Total SCORAD at the end of treatment period was less than basal value (27.83 +/- 8.48 vs. 70.04 +/- 8.48; P < 0.001). Treatment with rIFN-gamma decreased serum levels of IL-4 and IL-6 (P < 0.05), but IgE remained unchanged. Results suggested the controlling effect of rIFN-gamma treatment on clinical symptoms of AD, which involves suppression of IL-4 but not IgE production. PMID- 22101571 TI - The properties of BiSb nanoribbons from first-principles calculations. AB - The structural, electronic and magnetic properties of BiSb nanoribbons (BSNRs) with different widths and edge configurations are investigated via the first principles pseudopotential method. It is found that the pristine BSNRs with armchair edges (ABSNRs) are semiconductors and the band gaps exhibit a width dependent odd-even oscillation. In contrast, the pristine BSNRs with zigzag edges (ZBSNRs) are found to be metallic. When all the edge atoms are passivated by hydrogen, both the ABSNRs and ZBSNRs become semiconducting and the corresponding band gaps decrease monotonically with the increasing width. If, however, the edge atoms are partially passivated, the ABSNRs can be either semiconducting or metallic. Moreover, local magnetism appears when all the edge Sb atoms are passivated and there are one or more unsaturated Bi atoms. Using the nonequilibrium Green's function (NEGF) approach, we find that all the investigated odd-numbered ABSNRs have almost the same peak value of the power factor around the Fermi level. This is not the case for the even-numbered ABSNRs, where the peaks are twice that of when they are n-type doped. Our calculations indicate that BSNRs can have a very high room temperature figure of merit (ZT value), which makes them very promising candidates for thermoelectric applications. PMID- 22101572 TI - Prognostic significance of peritoneal washing cytology in patients with gastric cancer. AB - BACKGROUND: Positive peritoneal washing cytology is a poor prognostic factor in patients with gastric cancer. The right therapeutic approach for this condition has not been well documented. METHODS: Patients who underwent surgery for gastric cancer with suspected serosal invasion and peritoneal washing cytology at the Korean National Cancer Centre between May 2001 and December 2009 were included in this retrospective study. Clinicopathological factors and overall survival were analysed with respect to the cytological results and presence of peritoneal metastases. Prognostic factors were analysed in patients with positive cytology but without overt peritoneal metastases. RESULTS: A total of 1072 patients were included in the analysis, of whom 900 had negative cytology (C0 group) and 172 had positive cytology (C1 group). No peritoneal metastases (P0) were found in 830 patients (92.2 per cent) in the C0 group. Peritoneal metastases (P1) were found in 76 patients (44.2 per cent) in the C1 group. Median overall survival times in the P0 C1, P1 C0 and P1 C1 subgroups were 20.0, 14.0 and 10.0 months respectively. Multivariable analysis of the P0 C1 subgroup revealed that clinical N0-2 category and gastric resection were significantly associated with better prognosis (median survival 24.0 versus 13.0 months for N0-2 versus N3, and 21.0 versus 4.0 months for resected versus non-resected). CONCLUSION: Positive washing cytology in patients with gastric cancer is a negative prognostic factor for patients with, as well as those without, overt peritoneal metastases. Resection is an option in patients with clinical stage N0-2 disease without peritoneal metastases but with a positive washing cytology finding. PMID- 22101573 TI - Congruity influences memory and judgments of learning during survival processing. AB - A recent line of research has suggested that memory systems evolved to encode fitness-relevant information more effectively than other types of information-a phenomenon known as the "survival processing effect" (Nairne, Thompson, & Pandeirada Journal of Experimental Psychology: Learning, Memory, and Cognition 33:263-273, 2007). However, the basis for the effect has been debated. In addition, it is unknown whether or not individuals will adjust their judgments of learning (JOLs) to reflect the survival processing effect. In three experiments, participants rated 16 words for their relevance to a survival scenario and another 16 words for their relevance to a bank robbery scenario. In Experiment 1A (with no JOLs), the survival processing effect emerged; in Experiment 1B (with JOLs), no survival processing effect emerged, but JOLs were higher in the survival condition. In both cases, these findings were confounded by higher relevance ratings in the survival condition. In Experiment 2, relevance was manipulated within each list, and the survival processing effect was eliminated. Instead, both recall and JOL magnitude were related to level of congruity between the words and type of processing. Together, these results provide further evidence for the role of congruity in the survival processing effect and JOLs. PMID- 22101575 TI - The value of spreader grafts in rhinoplasty: a critical review. AB - The value of spreader grafts in rhinoplasty cannot be underestimated. Various studies have demonstrated that they play a valuable role in the restoration of nasal dorsum aesthetics, provide support for the nasal valve and maintain the straightened position of the corrected deviated cartilaginous septal dorsum. However, there is still controversy on the extent of its value in nasal patency. This study reviews the literature and describes the values and limitations of spreader grafts in rhinoplasty and the alternatives to classic spreader grafts. PMID- 22101574 TI - The surgical management of renal hyperparathyroidism. AB - Secondary and tertiary hyperparathyroidism (HPT) develop in patients with renal failure due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1,25-dihydroxy vitamin D levels. Patients present with various bone disorders, cardiovascular disease, and typical laboratory abnormalities. Medical treatment consists of controlling hyperphosphatemia, vitamin D/analog and calcium administration, and calcimimetic agents. Improved medical therapies have led to a decrease in the use of parathyroidectomy (PTX). The surgical indications include parathyroid hormone (PTH) levels >800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Transplant recipients often show decreased PTH, calcium and phosphorus levels, but some will have persistent HPT. Evidence suggests that PTX may cause deterioration in renal graft function in the short-term calling into the question the indications for PTX in these patients. Pre-operative imaging is only occasionally helpful except in re-operative PTX. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages and disadvantages which are discussed. Intraoperative PTH monitoring has a high positive predictive value of cure but a poor negative predictive value and therefore is of limited utility. Hypocalcemia is the most common complication requiring aggressive calcium administration. Benefits of surgery may include improved survival, bone mineral density and alleviation of symptoms. PMID- 22101576 TI - Intracardiac migration of a Kirschner wire: case report and literature review. AB - Migration of orthopedic wires to a solid organ or body cavity is a rare complication that can cause various symptoms and may lead to death. We report a patient with Kirschner wire (K-wire) migration from the right pelvic cavity, a previous fracture site, into the right ventricle of the heart. K-wire migration was initially detected by simple chest radiography. The origin of the foreign body was initially unclear. Cardiac CT angiography with volume-rendered imaging helped to locate the migrating K-wire in the heart; a pelvic scan showed another K-wire in the right pelvic bone. PMID- 22101577 TI - Photoacclimation in Dunaliella tertiolecta reveals a unique NPQ pattern upon exposure to irradiance. AB - Highly time-resolved photoacclimation patterns of the chlorophyte microalga Dunaliella tertiolecta during exposure to an off-on-off (block) light pattern of saturating photon flux, and to a regime of consecutive increasing light intensities are presented. Non-photochemical quenching (NPQ) mechanisms unexpectedly responded with an initial decrease during dark-light transitions. NPQ values started to rise after light exposure of approximately 4 min. State transitions, measured as a change of PSII:PSI fluorescence emission at 77 K, did not contribute to early NPQ oscillations. Addition of the uncoupler CCCP, however, caused a rapid increase in fluorescence and showed the significance of qE for NPQ. Partitioning of the quantum efficiencies showed that constitutive NPQ was (a) higher than qE-driven NPQ and (b) responded to light treatment within seconds, suggesting an active role of constitutive NPQ in variable energy dissipation, although it is thought to contribute statically to NPQ. The PSII connectivity parameter p correlated well with F', F(m)' and NPQ during the early phase of the dark-light transients in sub-saturating light, suggesting a plastic energy distribution pattern within energetically connected PSII centres. In consecutive increasing photon flux experiments, correlations were weaker during the second light increment. Changes in connectivity can present an early photoresponse that are reflected in fluorescence signals and NPQ and might be responsive to the short-term acclimation state, and/or to the actinic photon flux. PMID- 22101578 TI - Acute phase proteins as a tool for differential diagnosis of wasting diseases in growing pigs. AB - The concentrations of haptoglobin (Hp), C-reactive protein (CRP) and serum amyloid A (SAA) were measured in wasted pigs, first to evaluate their usefulness in the diagnosis of infectious, wasting diseases in pigs, and second, to evaluate whether their concentrations can distinguish the lymphoid depletion score in the lymph tissues of wasted affected pigs. Fifty-three wasted pigs and seven specific pathogen free (SPF) pigs were postmortem examined. Gross lesions were evaluated and samples for histopathological, immunohistochemical, molecular biology and microbiological analysis were taken. Thirty-one pigs were diagnosed as postweaning multisystemic wasting syndrome (PMWS) and 22 as porcine respiratory disease complex (PRDC). Lymphoid depletion degree in lymph tissues of PMWS and PRDC affected pigs was determined. Serum Hp was significantly higher in pigs with PRDC in comparison with the PMWS affected pigs. Serum CRP concentration was significantly lower in pigs with PRDC than in PMWS affected pigs (P<0.001). CRP and SAA levels increased with the lymphoid depletion score, presenting statistical differences between pigs with no depletion and pigs with low, moderate or severe lymphoid depletion (P<0.05, P<0.05 and P<0.001 for CRP and P<0.01, P<0.01 and P<0.01 for SAA, respectively). Hp was higher in pigs with no or low depletion compared with the pigs suffering severe lymphoid depletion (P<0.001 and P<0.05, respectively). PMID- 22101579 TI - Review. The Agfa Mayneord lecture: MRI of short and ultrashort T2 and T2* components of tissues, fluids and materials using clinical systems. AB - A variety of techniques are now available to directly or indirectly detect signal from tissues, fluids and materials that have short, ultrashort or supershort T2 or T2* components. There are also methods of developing image contrast between tissues and fluids in the short T2 or T2* range that can provide visualisation of anatomy, which has not been previously seen with MRI. Magnetisation transfer methods can now be applied to previously invisible tissues, providing indirect access to supershort T2 components. Particular methods have been developed to target susceptibility effects and quantify them after correcting for anatomical distortion. Specific methods have also been developed to image the effects of magnetic iron oxide particles with positive contrast. Major advances have been made in techniques designed to correct for loss of signal and gross image distortion near metal. These methods are likely to substantially increase the range of application for MRI. PMID- 22101580 TI - Dosimetric and radiobiological comparison of helical tomotherapy, forward-planned intensity-modulated radiotherapy and two-phase conformal plans for radical radiotherapy treatment of head and neck squamous cell carcinomas. AB - OBJECTIVES: The usual radical radiotherapy treatment prescribed for head and neck squamous cell carcinoma (HNSCC) is 70 Gy (in 2 Gy per fraction equivalent) administered to the high-risk target volume (TV). This can be planned using either a forward-planned photon-electron junction technique (2P) or a single phase (1P) forward-planned technique developed in-house. Alternatively, intensity modulated radiotherapy (IMRT) techniques, including helical tomotherapy (HT), allow image-guided inversely planned treatments. This study was designed to compare these three planning techniques with regards to TV coverage and the dose received by organs at risk. METHODS: We compared the dose-volume histograms and conformity indices (CI) of the three planning processes in five patients with HNSCC. The tumour control probability (TCP), normal tissue complication probability (NTCP) and uncomplicated tumour control probability (UCP) were calculated for each of the 15 plans. In addition, we explored the radiobiological rationality of a dose-escalation strategy. RESULTS: The CI for the high-risk clinical TV (CTV1) in the 5 patients were 0.78, 0.76, 0.82, 0.72 and 0.81 when HT was used; 0.58, 0.56, 0.47, 0.35 and 0.60 for the single-phase forward-planned technique and 0.46, 0.36, 0.29, 0.22 and 0.49 for the two-phase technique. The TCP for CTV1 with HT were 79.2%, 85.2%, 81.1%, 83.0% and 53.0%; for single-phase forward-planned technique, 76.5%, 86.9%, 73.4%, 81.8% and 31.8% and for the two phase technique, 38.2%, 86.2%, 42.7%, 0.0% and 3.4%. Dose escalation using HT confirmed the radiobiological advantage in terms of TCP. CONCLUSION: TCP for the single-phase plans was comparable to that of HT plans, whereas that for the two phase technique was lower. Centres that cannot provide IMRT for the radical treatment of all patients could implement the single-phase technique as standard to attain comparable TCP. However, IMRT produced better UCP, thereby enabling the exploration of dose escalation. PMID- 22101581 TI - National reference doses for dental cephalometric radiography. AB - OBJECTIVES: Diagnostic reference levels (DRLs) are an important tool in the optimisation of clinical radiography. Although national DRLs are provided for many diagnostic procedures including dental intra-oral radiography, there are currently no national DRLs set for cephalometric radiography. In the absence of formal national DRLs, the Health Protection Agency (HPA) has previously published National Reference Doses (NRDs) covering a wide range of diagnostic X-ray examinations. The aim of this study was to determine provisional NRDs for cephalometric radiography. METHODS: Measurements made by the Dental X-ray Protection Service (DXPS) of the HPA, as part of the cephalometric X-ray equipment testing service provided to dentists and dental trade companies throughout the UK, were used to derive provisional NRDs. RESULTS: Dose-area product measurements were made on 42 X-ray sets. Third quartile dose-area product values for adult and child lateral cephalometric radiography were found to be 41 mGy cm2 and 25 mGy cm2, respectively, with individual measurements ranging from 3 mGy cm2 to 108 mGy cm2. CONCLUSION: This report proposes provisional NRDs of 40 mGy cm2 and 25 mGy cm2 for adult and child lateral cephalometric radiographs, respectively; these doses could be considered by employers when establishing their local DRLs. PMID- 22101582 TI - Pictorial review. Hepatic vascular shunts: embryology and imaging appearances. AB - The purpose of this pictorial review is to understand the embryological basis of the development of congenital hepatic vascular shunts and to review the multimodality imaging appearances of congenital and acquired hepatic vascular shunts. Hepatic vascular shunts are commonly seen in imaging. Familiarity with their characteristic appearances is important in order to accurately characterise these shunts and diagnose the underlying disorders. PMID- 22101583 TI - Case of the month. The uncontrollable shaking arm. PMID- 22101584 TI - Post-radiogenic density changes on CT of the salivary gland are time-dependent. PMID- 22101587 TI - Case report. Acinar cell carcinoma with fatty change arising from the pancreas. AB - Acinar cell carcinoma of the pancreas is a rare malignant tumour developing from acinar cells, accounting for approximately 1% of pancreatic exocrine tumours. We experienced a case of an acinar cell carcinoma with fatty change. To the best of our knowledge, this is the first case report of an acinar cell carcinoma with fatty change in the clinical literature. PMID- 22101588 TI - Case report. Primary mucosa-associated lymphoid tissue lymphoma as a pleural mass. AB - Primary pleural lymphoma is a rare entity that has been described in association with human immunodeficiency virus (HIV) infection or pyothorax. It occurs in only 7% of primary lymphoma cases. We report the case of a 52-year-old male with no history of HIV infection or pyothorax who was diagnosed of obstructive sleep apnoea syndrome (OSAS) and underwent a routine chest X-ray to screen for any organic cause of the symptoms. The radiograph revealed two voluminous masses with extraparenchymatous features but without pleural effusion. A contrast-enhanced CT was performed and confirmed the existence of the pleural masses that showed homogeneous attenuation. Neither mediastinal lymphadenopathy nor pleural effusion were present. A percutaneous CT-guided fine needle aspiration cytology (FNAC) with a 25-G needle was performed (two samples were obtained) and the first diagnosis was of non-Hodgkin's lymphoma. The final diagnosis of primary pleural mucosa-associated lymphoid tissue (MALT) lymphoma was confirmed by a CT-guided core biopsy with a 20-G needle. To the best of our knowledge, no cases of MALT lymphoma presenting as pleural masses without pleural effusion have been reported in immunocompetent patients. In this report, we describe the case of a patient with a primary pleural MALT lymphoma and include a short review of the literature. PMID- 22101589 TI - Case report. Unusual presentation of a pancreatic mass in an infant: pancreatic haemangioendotheliomatosis. AB - Primary pancreatic tumours are extremely rare in children. We report a case of a 5-month-old male with a diffuse invasive tumour of the head of the pancreas. The tumour demonstrated peripancreatic extension into the porta hepatis, which occluded the portal vein and invaded the superior mesenteric artery. It was found to be haemangioendotheliomatosis of the pancreas. Imaging, pathological findings and a brief relevant classification of haemangioma are discussed. PMID- 22101590 TI - Case report. Peripancreatic intranodal haemangioma mimicking pancreatic neuroendocrine tumour: imaging and pathological findings. AB - Haemangiomas are common benign tumours that are generally detected within the skin, mucosal surfaces and soft tissues. However, intranodal haemangiomas are extremely rare and are among the benign primary vascular abnormalities of the lymph nodes that include lymphangioma, haemangioendothelioma, angiomyomatous hamartoma and haemangiomas. In this case report, we present the imaging and pathological findings of an intranodal haemangioma in the pancreatic head simulating a pancreatic neuroendocrine tumour. To the best of our knowledge, this is the first report of an intranodal haemangioma in this location. PMID- 22101591 TI - Case report. A novel approach to the management of a ruptured Type II endoleak following endovascular repair of an internal iliac artery aneurysm. AB - Endovascular repair of isolated iliac artery aneurysms is an established safe and effective management option. Type II endoleak is a potential complication, but rarely results in significant morbidity or mortality. We report a case of a patient who presented with a ruptured internal iliac artery aneurysm secondary to a Type II endoleak. To our knowledge this and the following method of managing this have not been previously reported. Established methods of managing endoleaks, such as intravascular transfemoral embolisation and open or laparoscopic ligation, were not possible. Therefore, we resorted to a novel approach to this type of aneurysm and successfully performed a transcutaneous direct puncture and embolisation of the superior gluteal artery. PMID- 22101592 TI - Case report. Spontaneous cholecystocolic fistula and locoregional liver tumour ablation: a cautionary tale. AB - A liver abscess is a feared and potentially fatal complication following transarterial chemoembolisation (TACE) and radiofrequency ablation (RFA) of liver tumours. Iatrogenic bilio-enteric communications, such as bilio-enteric anastomosis, sphincterotomy and biliary stents, are considered major risk factors and are due to bacterial colonisation of the biliary tree with enteric flora. Naturally occurring spontaneous cholecysto-enteric fistula poses a similar risk as its iatrogenic counterparts but is rarely described in the literature. We present a case where abscess formation complicated a combined TACE and RFA in an unrecognised cholecystocolic fistula. PMID- 22101593 TI - Reconfiguring hospital services. PMID- 22101594 TI - Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal. AB - A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs beta-keto-N methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances. PMID- 22101595 TI - 'Biting the hand that feeds': fever and altered sensorium following a dog bite. AB - Capnocytophaga canimorsus infection is the most severe and rapidly progressive bacterial infection transmitted by dog bite and fortunately is very rare. The authors describe a 68-year-old gentleman who presented in an acute confusional state 2 days after having been bitten on the left hand by a dog. Despite immediate broad-spectrum intravenous antibiotics, he developed significant sequelae including disseminated intravascular coagulopathy, microvascular emboli leading to peripheral necrosis, widespread local tissue destruction and septic arthritis. Our case illustrates a life-threatening presentation of infection with C canimorsus, which is known as 'the dog bite organism'. Early diagnosis and aggressive treatment is key to survival. PMID- 22101597 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: prophylactic antibiotic use to prevent Weil's disease after immersion in water. AB - A short cut review was carried out to establish whether prophylactic antibiotics should be given to prevent Weil's disease after a fall into standing water. 30 papers were found using the reported searches, of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that if there is immersion in an endemic area for leptospirosis, or if there is higher risk of water contamination such as standing water, known rat infestation, drainage channels then doxycycline would have to be recommended. Other scenarios are not as clear. PMID- 22101598 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: do wrist splints need to have a thumb extension when immobilising suspected scaphoid fractures? AB - A short cut review was carried out to establish whether wrist splints require a thumb extension when immobilising suspected scaphoid fractures. 63 papers were found using the reported searches, of which 2 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that while there is no direct evidence to answer the clinical question, the research available strongly suggests that it is reasonable to continue using standard wrist splints to immobilise patients with suspected scaphoid fractures. PMID- 22101599 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: is ketamine a viable induction agent for the trauma patient with potential brain injury. AB - A short cut review was carried out to establish whether ketamine is a viable induction agent in trauma patients with potential brain injuries. 276 papers were found using the reported searches, of which 5 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that there is no evidence to suggest harm with Ketamine use as induction agent for the patient with potential traumatic brain injury. The drug has major advantages in those patients with associated haemodynamic compromise and should potentially be regarded as the agent of choice. PMID- 22101600 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Bet 4: is intranasal fentanyl better than parenteral morphine for managing acute severe pain in children? AB - A short cut review was carried out to establish whether intranasal fentanyl is better than parenteral morphine for managing acute severe pain in children. 51 papers were found using the reported searches, of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that intranasal fentanyl is an effective and safe alternative to IV or IM morphine for managing acute pain in children presenting to the Emergency Department. PMID- 22101602 TI - Small-molecule conversion of toxic oligomers to nontoxic beta-sheet-rich amyloid fibrils. AB - Several lines of evidence indicate that prefibrillar assemblies of amyloid-beta (Abeta) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Abeta fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Abeta peptides and stabilizes the self-assembly of seeding-competent, beta-sheet rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Abeta oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Abeta oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells. PMID- 22101603 TI - Mechanical modulation of catalytic power on F1-ATPase. AB - The conformational fluctuation of enzymes has a crucial role in reaction acceleration. However, the contribution to catalysis enhancement of individual substates with conformations far from the average conformation remains unclear. We studied the catalytic power of the rotary molecular motor F(1)-ATPase from thermophilic Bacillus PS3 as it was stalled in transient conformations far from a stable pausing angle. The rate constants of ATP binding and hydrolysis were determined as functions of the rotary angle. Both rates exponentially increase with rotation, revealing the molecular basis of positive cooperativity among three catalytic sites: elementary reaction steps are accelerated via the mechanical rotation driven by other reactions on neighboring catalytic sites. The rate enhancement induced by ATP binding upon rotation was greater than that brought about by hydrolysis, suggesting that the ATP binding step contributes more to torque generation than does the hydrolysis step. Additionally, 9% of the ATP-driven rotary step was supported by thermal diffusion, suggesting that acceleration of the ATP docking process occurs via thermally agitated conformational fluctuations. PMID- 22101604 TI - Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. AB - Since 1992, there has been growing evidence that the bioactive phospholipid lysophosphatidic acid (LPA), whose amounts are increased upon tissue injury, activates primary nociceptors resulting in neuropathic pain. The TRPV1 ion channel is expressed in primary afferent nociceptors and is activated by physical and chemical stimuli. Here we show that in control mice LPA produces acute pain like behaviors, which are substantially reduced in Trpv1-null animals. Our data also demonstrate that LPA activates TRPV1 through a unique mechanism that is independent of G protein-coupled receptors, contrary to what has been widely shown for other ion channels, by directly interacting with the C terminus of the channel. We conclude that TRPV1 is a direct molecular target of the pain producing molecule LPA and that this constitutes, to our knowledge, the first example of LPA binding directly to an ion channel to acutely regulate its function. PMID- 22101605 TI - FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy. AB - Focal adhesion kinase (FAK) regulates cellular processes that affect several aspects of development and disease. The FAK N-terminal FERM (4.1 protein-ezrin radixin-moesin homology) domain, a compact clover-leaf structure, binds partner proteins and mediates intramolecular regulatory interactions. Combined chemical cross-linking coupled to MS, small-angle X-ray scattering, computational docking and mutational analyses showed that the FAK FERM domain has a molecular cleft (~998 A(2)) that interacts with sarcomeric myosin, resulting in FAK inhibition. Accordingly, mutations in a unique short amino acid sequence of the FERM myosin cleft, FP-1, impaired the interaction with myosin and enhanced FAK activity in cardiomyocytes. An FP-1 decoy peptide selectively inhibited myosin interaction and increased FAK activity, promoting cardiomyocyte hypertrophy through activation of the AKT-mammalian target of rapamycin pathway. Our findings uncover an inhibitory interaction between the FAK FERM domain and sarcomeric myosin that presents potential opportunities to modulate the cardiac hypertrophic response through changes in FAK activity. PMID- 22101606 TI - Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. AB - In recent years, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anti-cancer therapy with proven efficacy in several types of carcinoma. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do have significant side effects including fatigue and hypertension. In addition, TKI induced thyroid dysfunction is now recognized as a common toxicity that is associated with some TKI inhibitors. Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and, in some cases, may require treatment. This review provides a comprehensive assessment of literature evaluating TKI-induced thyroid dysfunction, focusing on the potential mechanisms that result in this toxicity, whether the development of thyroid dysfunction is clinically meaningful, and controversies regarding treatment with thyroid hormone therapy. PMID- 22101607 TI - Fabrication of an electrochemical platform based on the self-assembly of graphene oxide-multiwall carbon nanotube nanocomposite and horseradish peroxidase: direct electrochemistry and electrocatalysis. AB - A novel hybrid nanomaterial (GO-MWNTs) was explored based on the self-assembly of multiwall carbon nanotubes (MWNTs) and graphene oxide (GO). Compared with pristine MWNTs, such a nanocomposite could be well dispersed in aqueous solution and exhibit a negative charge. Driven by the electrostatic interaction, positively charged horseradish peroxidase (HRP) could then be immobilized onto GO MWNTs at the surface of a glassy carbon (GC) electrode to form a HRP/GO-MWNT/GC electrode under mild conditions. TEM was used to characterize the morphology of the GO-MWNT nanocomposite. UV-vis and FTIR spectra suggested that HRP was immobilized onto the hybrid matrix without denaturation. Furthermore, the immobilized HRP showed enhanced direct electron transfer for the HRP Fe(III)/Fe(II) redox center. Based on the direct electron transfer of the immobilized HRP, the HRP/GO-MWNT/GC electrode exhibited excellent electrocatalytic behavior to the reduction of H(2)O(2) and NaNO(2), respectively. Therefore, GO-MWNTs could provide a novel and efficient platform for the immobilization and biosensing of redox enzymes, and thus may find wide potential applications in the fabrication of biosensors, biomedical devices, and bioelectronics. PMID- 22101608 TI - The use of web-based interventions to prevent excessive weight gain. AB - We reviewed web-based interventions for overweight and obesity prevention. A literature search was conducted using seven electronic databases. Manually searched articles were also included. Thirty studies fulfilled the inclusion criteria. Of these, 13 studied physical activity, eight studied dietary practices and nine studied a combination of physical activity and dietary practice. Twenty eight of the studies (93%) reported positive changes in moderate to vigorous physical activity level, fruit and vegetable intake and psychological factors. A meta-analysis showed there were improvements, though not significant, in fruit and vegetable consumption (standardised mean difference, SMD = 0.61; 95% CI = 0.13 to 1.35) and physical activity (SMD = 0.15; 95% CI =-0.06 to 0.35). The review suggests that web-based interventions are a useful educational tool for increasing awareness and making healthy behaviour changes in relation to an excessive weight gain problem. PMID- 22101609 TI - Systematic review of studies of the cost-effectiveness of telemedicine and telecare. Changes in the economic evidence over twenty years. AB - A systematic review of studies of the cost-effectiveness of telemedicine and telecare was undertaken from 1990 until September 2010. Twelve databases were searched, using economic evaluation terms combined with telemedicine terms. The search identified 80 studies which were classed as full economic evaluations; the majority (38) were cost-consequence analyses. There were 15 cost-effectiveness analyses (CEA) and seven cost-utility analyses (CUA). In the period January 2004 to September 2010 there were 47 studies. Eleven were CEA and seven were CUA. Economic tools are being increasingly used for telemedicine and telecare studies, although better reporting of the methodologies and findings of the economic evaluations is required. Nonetheless, the results of the review were consistent with previous findings, i.e. there is no further conclusive evidence that telemedicine and telecare interventions are cost-effective compared to conventional health care. PMID- 22101610 TI - Telemedicine interventions for substance-use disorder: a literature review. AB - A literature review was conducted to identify research into multiple-contact (i.e. extended) telemedicine interventions for substance-use disorder. The goals were: (1) to describe the methodology used to evaluate telemedicine interventions; (2) to identify the range of interventions which have been formally evaluated; and (3) to summarize the findings. Fourteen databases and Google Scholar were searched, as well as bibliographies of relevant papers and online conference abstracts. There were 50 studies which met the inclusion criteria, of which 50% were randomized controlled trials. The studies most frequently reported the effect on substance use and 61% of those findings fully supported telemedicine interventions. Although the studies reported persistent challenges in sustaining participation, 76% of the studies reporting on satisfaction indicated that participants were enthusiastic supporters of telemedicine. Only 30% of reviewed studies addressed the effect on resource utilization. The majority of studies reported evidence of clinical effectiveness, which justifies continued research in the field. PMID- 22101611 TI - Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma. AB - PURPOSE: This analysis from an observational study of clinical practice describes the impact of febrile neutropenia (FN) on chemotherapy delivery and hospitalizations. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL) scheduled to receive >= 3 cycles of 2- or 3-weekly CHOP with rituximab (R-CHOP 14/21) were eligible. Primary outcome was incidence of FN. RESULTS: FN data were available for 409 patients receiving R-CHOP-14 and 702 patients receiving R-CHOP 21. FN incidence was R-CHOP-14, 20% (81/409) and R-CHOP-21, 19% (133/702). Rates of primary prophylaxis with granulocyte-colony stimulating factor were R-CHOP-14, 84% (345/409) and R-CHOP-21, 36% (252/702). A large number of patients experienced their first FN episode in cycle 1 (R-CHOP-14, 24/81 [30%]; R-CHOP-21, 63/133 [47%]). Multiple risk factors (>= 2) for FN were more frequent in patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 60/81 [74%] versus 179/328 [55%]; R-CHOP-21, 98/133 [74%] versus 339/569 [60%]). A similar trend was observed for unplanned hospitalizations (R-CHOP-14, 63/81 [78%] versus 68/328 [21%]; R-CHOP-21, 105/133 [79%] versus 100/569 [18%]). Achievement of chemotherapy relative dose intensity >= 90% was lower among patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 30/81 [37%] versus 234/328 [71%]; R-CHOP-21, 83/133 [62%] versus 434/569 [76%]). CONCLUSIONS: In patients with DLBCL treated with R-CHOP-14 or R-CHOP-21, patients with an event of FN were more likely to experience suboptimal chemotherapy delivery and increased incidence of unplanned hospitalizations than those without FN. FN-related hospitalizations are likely to impact chemotherapy delivery and to incur substantial costs. PMID- 22101612 TI - Evaluation of the Iranian versions of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Patient Acceptable Symptom State (PASS) in patients with ankylosing spondylitis. AB - The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) are widely used instruments in assessment of patients suffering from ankylosing spondylitis (AS). The Patient Acceptable Symptom State (PASS) is regarded as a target for patients' well-being. The aim of this study was to translate and adapt BASDAI, BASFI and PASS into the Iranian official language, Farsi, and evaluate their reliability and validity. Ninety patients with AS were included in this study. The questionnaires were translated into Farsi and back translated into English, modified until the final versions were approved with minor adaptations and the VAS was changed to numerical rating scales from 0 to 10. Forty-eight-hour test-retest agreement showed good reliability: interclass correlation coefficient (ICC) for BASDAI was 0.93 (CI at 95%, 0.90-0.95), for BASFI was 0.96 (CI at 95%, 0.94-0.97) and for PASS was 0.87 (CI at 95%, 0.79-0.92). Chronbach's alpha was 0.95, 0.96 and 0.87 for BASDAI, BASFI and PASS, respectively. BASDAI showed a significant correlation with patient global disease activity index, nocturnal back pain, total back pain, number of swollen joints, number of enthesites, morning stiffness, Bath Ankylosing Spondylitis Global Score (BAS-G), BASFI and BASMI. A significant correlation was also found between BASFI and occiput-to-wall distance, mentum-to sternum distance, chest expansion, finger-to-floor distance, number of swollen joints, number of enthesites, nocturnal back pain, total back pain, BAS-G, BASDAI and BASMI. Patients who answered "no" to PASS (found their condition unsatisfactory) reported significantly increased pain scores, patient global disease activity scores, BAS-G, BASDAI and BASFI scores. The results showed that the Iranian versions of BASDAI, BASFI and PASS are adequately reliable and valid in patients with AS. PMID- 22101614 TI - Structure, electronic configuration, and Mossbauer spectral parameters of an antiferromagnetic Fe2-peroxo intermediate of methane monooxygenase. AB - Determining structures of reaction intermediates is crucial for understanding catalytic cycles of metalloenzymes. However, short life times or experimental difficulties have prevented obtaining such structures for many enzymes of interest. We report geometric and electronic structures of a peroxo intermediate in the catalytic cycle of methane monooxygenase hydroxylase (MMOH) for which there is no crystallographic characterization. The structure was predicted via spin density functional theory using (57)Fe Mossbauer spectral parameters as a reference. Computed isomer shifts (delta(Fe) = +0.68, +0.66 mm s(-1)) and quadrupole splittings (DeltaE(Q) = -1.49, -1.48 mm s(-1)) for the predicted structure are in excellent agreement with experimental values of a peroxo MMOH intermediate. Predicted peroxo to iron charge transfer bands agree with UV-Vis spectroscopy. Peroxide binds in a cis MU-1,2 fashion and plays a dominant role in the active site's electronic structure. This induces a ferromagnetic to antiferromagnetic transition of the diiron core weakening the O-O bond in preparation for cleavage in subsequent steps of the catalytic cycle. PMID- 22101613 TI - Appraising osteoporosis care gaps. AB - To evaluate physician response to dual-energy X-ray absorptiometry (DXA) report within the Geisinger Medical Center's Mobile DXA Program and treatment adherence at 1 year. Between 10/01/2004 and 3/30/2005, 1381 DXA scans were performed in our Mobile DXA Program. Within this cohort, we identified 366 high-risk, drug-naive patients and report the percentage of patients placed on prescription drug therapy within 90 days of DXA result. Additionally, we identified 191 patients with Z-score of -1.0 or worse and report whether laboratory tests were ordered within 90 days of DXA results in this group. Finally, we determined treatment adherence at 1 year. 269 patients (74%) were offered prescription therapy within 3 months of DXA results. Of those, 210 (57%) were still adherent to drug therapy at 1 year. The main reason for discontinuation of treatment was an adverse drug side effect. Additionally, in 50% cases, physicians ordered 1 or more laboratory tests to evaluate low Z-score. Within our Mobile DXA Program, 74% of high-risk, drug-naive patients were treated. Interestingly, in 50% cases, when a low Z-score was reported, our physicians ordered 1 or more laboratory tests. Treatment adherence was 57% at 1 year. PMID- 22101615 TI - New smoke-free laws and increased tobacco taxes would have nationwide impact: reports show significant lives and money saved in every state. PMID- 22101616 TI - Advocates hope new warning labels will further reduce tobacco use. PMID- 22101617 TI - Folate may help lower risk of colorectal cancer. PMID- 22101618 TI - Deep venous thrombosis after mini-posterior total hip arthroplasty in Japanese patients. AB - We conducted a retrospective study of the occurrence of deep venous thrombosis (DVT) following mini-posterior total hip arthroplasty (THA) in Japanese patients. From May 2004 to December 2009 mini-posterior THA was performed on 1659 cases, of whom 603 cases didn't receive anticoagulants (Group 1), 547 cases received 2.5 mg percutaneous injection of fondaparinux (a factor Xa inhibitor) daily for 7 days starting the day after surgery (Group 2), and 509 cases received 2000 IU percutaneous injection of enoxaparin (low-molecular-weight heparin) twice daily for 7 days starting the day after surgery (Group 3). The baseline characteristics were very similar in each group. All patients started walking the day after surgery, were advised to wear graduated compression stockings for six weeks after the operation, and used a foot pump for 3 hours a day postoperatively for several days. A week after surgery Duplex ultrasound with colour-flow Doppler imaging of the lower extremities was performed. The occurrence of DVT was significantly different between Groups 1, 2, and 3 (p<0.001): 57 cases (9.5%), 4 cases (0.7%), and 0 cases (0%), respectively. No patients of any group had clinically detected pulmonary emboli. In this study we showed that adding anticoagulants with foot pumps further reduced the incidence of DVT, which seldom occurs following less invasive mini-posterior THA combined with early mobilisation, foot pumps, and anticoagulants. PMID- 22101619 TI - Recovery after hip fractures: influence of bipolar hemiarthroplasty on physical disability and social dependency in the elderly. AB - Surgical treatment of femoral neck fractures is associated with a significant impact on quality of life. The aim of this study was to determine the long-term influence of displaced femoral neck fractures treated by bipolar hemiarthroplasty on the activities of daily living, quality of life and social dependency. We studied 487 geriatric patients treated in the years 1989 to 2003. At the beginning of follow-up in 2004, 166 patients were alive and evaluation was carried out on 145 patients (87.3%) at 91.3 (14 - 244) months postoperatively by a standardized questionnaire. All enrolled patients had been treated with cemented bipolar hemiarthroplasty for a displaced femoral neck fracture. Patients were evaluated concerning their average pre- and postoperative ability to walk, the need for assisting devices, type of residency and the SF-12(r) Score. Femoral neck fracture and hemiarthroplasty had a significant influence on all recorded aspects of quality of life. Even though almost two thirds of the patients needed assisting devices to walk after surgery, about two thirds returned to their original type of accommodation and the majority reached their original degree of mobility. Compared to a normal population no significant impact was observed on the quality of life measured by the SF-12(r) score. We consider bipolar hemiarthroplasty an effective treatment option for displaced femoral neck fractures in geriatric patients. Most patients returned to their original type of accommodation and level of mobility, even though the majority required a number of assisting devices to do so. PMID- 22101620 TI - Hammering sound frequency analysis and prevention of intraoperative periprosthetic fractures during total hip arthroplasty. AB - Adequate fixation at the time of cementless stem implantation depends on the operator's experience. An objective evaluation method to determine whether the stem has been appropriately implanted may be helpful. We studied the relationship between the hammering sound frequency during stem implantation and internal stress in a femoral model, and evaluated the possible usefulness of hammering sound frequency analysis for preventing intraoperative fracture. Three types of cementless stem (BiCONTACT(r), SL-PLUS(r), and AI-Hip(r)) were used. Surgeons performed stem insertion using a procedure similar to that employed in a routine operation. Stress was estimated by finite element analysis, the hammering force was measured, and frequency analysis of hammering sound data obtained using a microphone. Finite element analysis showed a decrease in the hammering sound frequency with an increase in the estimated maximum stress. When a decrease in frequency was observed, adequate hammering had occurred, and the continuation of hammering risked fracture. Based on the relationship between stress and frequency, the evaluation of changes in frequency may be useful for preventing the development of intraoperative fractures. Using our method, when a decrease in frequency is observed, the hammering force should be reduced. Hammering sound frequency analysis may allow the prediction of bone fractures that can be visually confirmed, and may be a useful objective evaluation method for the prevention of intraoperative periprosthetic fractures during stem insertion. PMID- 22101621 TI - A classification-system improves the intra- and interobserver reliability of radiographic diagnosis of "pistol-grip-deformity". AB - Early detection of pistol-grip-deformity may be beneficial in optimising the outcome and the cost effectiveness of surgery. It is important to identify reliable radiographic parameters in assessing femoro-acetabular impingement (FAI) to develop a treatment algorithm. Radiographs of 47 patients ranging from "pistol grip deformity" to a normal head-neck-junction were measured for alpha angle and head ratio, and then classified by two different observers. The Bland-Altman plot was used for inter- and intraobserver agreement of alpha angle and head ratio. Inter- and intraobserver agreement for classification of "pistol grip deformity" was determined using weighted Cohen's kappa coefficient. Observer I achieved a kappa coefficient of 0.97. Observer II achieved a kappa coefficient of 0.92. An interobserver kappa coefficient between 0.87 and 0.92 was achieved by using a classification system. By testing for interobserver agreement, a bias of -0.004 with an upper limit of 0.461 and a lower limit of -0.47 was seen for the ratio and a bias of -3.7 with an upper limit of 17.2 and a lower limit of -24.6 for the alpha angle. Therefore, poor results were seen for intra- and interobserver reliability by using only a single plane for classification of "pistol grip deformity". The strength of agreement could be improved by using a classification system (based on two planes). PMID- 22101622 TI - Gaucher disease: outcome following total hip replacements and effect of enzyme replacement therapy in a cohort of UK patients. AB - Only a limited number of reports of total hip replacements (THRs) in patients with Gaucher disease (GD) have been published, with the majority showing high rates of early aseptic loosening as well as an increased number of peri-operative complications. We present a series of twelve THRs in nine affected patients, with a mean age of 39 years at the time of surgery (median 37 years; range 27-60 years). We examine the medium- to long-term results and present the outcome scores, survival, and assess the effect of enzyme replacement therapy (ERT). Four hips (33.3%) required revision for aseptic loosening at a mean time of 11.5 years. There was no significant difference in survival between the group on ERT at the time of surgery and group not on ERT. Those on ERT did, however, have fewer peri-operative complications and there was a trend to better outcome scores. Five of the 12 THRs were performed when the diagnosis of GD was unknown and all of these had early complications.?Our results show better survival of THRs in patients with GD than previously thought. The use of ERT pre-operatively did not have an effect on survival, nor outcome scores, but did reduce the peri operative complication rate. Those not on ERT at the time of surgery were commenced on it at some point in their treatment (at an average of 8.6 years following THR) and we believe the use of ERT, at any time in the treatment, could have contributed to the improved survival seen in our series compared to historical results in the literature. PMID- 22101623 TI - The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation. AB - PURPOSE: The aim of this study was to evaluate the effect of different clinical covariates on tacrolimus dose requirements in adult kidney transplant patients with a specific focus on drug interactions. PATIENTS: Tacrolimus dosing requirement, normalized by drug levels and expressed as the concentration/dose (C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to identify four categories of tacrolimus dosing requirement, namely, very high, high, small, and very-small, in very fast, fast, slow, and very slow metabolizers, respectively. Steroid weight-based doses were analyzed instead of fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and multi drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed RESULTS: Multivariate analysis on 450 adult transplant patients identified six risk factors for being slow metabolizers and therefore requiring small tacrolimus doses: male sex (OR 1.615, p = 0.020); age >60 years (OR 2.456, p = 0.0005); body mass index >= 25 (OR 1.546, p = 0.046), hepatitis C virus positivity (OR 2.800, p = 0.0004); low steroid dose <0.06 mg/kg (OR 3.101, p < 0.0001). Patients with a small tacrolimus requirement were at increased risk for multiple infections (OR 1.533, p = 0.0008) and higher systolic blood pressure (OR 1.385, p = 0.022) and showed a significant association with the CYP3A5*3/*3 genotype adjusted by MDR1 polymorphisms C3435T and C1236T (OR 8.104, p = 0.0001). CONCLUSIONS: Our results demonstrate the importance of the interaction among genetic and clinical factors in conditioning tacrolimus disposition, with corticosteroid weight-based dose being the only modifiable risk factor for tacrolimus requirement. As the tacrolimus dosing requirement increases with increasing tacrolimus clearance through concomitant steroid use, undesirable changes in tacrolimus levels may occur when steroid doses are tapered, predominantly in slow metabolizers. This often neglected drug interaction has to be monitored to optimize tacrolimus exposure in kidney transplant patients. PMID- 22101624 TI - Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. AB - PURPOSE: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION: In patients with cirrhosis, a 2 to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF. PMID- 22101625 TI - Computed tomography detection of carotid calcium and subclinical carotid atherosclerosis. AB - Computed tomography (CT) detection of coronary calcium has become a popular technique for assessing coronary atherosclerosis. Whether CT detection of carotid calcium could similarly assess carotid atherosclerosis is unknown. We thus performed a study evaluating the feasibility of carotid calcium scoring by CT. We also looked for an association between carotid calcium and subclinical carotid atherosclerosis. Subjects (n = 876) underwent non-contrast CT scanning of their carotid arteries. Carotid calcium was quantified by the Agatston method. Stenoses were detected by subsequent CT angiography. Significant subclinical atherosclerosis was defined by the presence of a >=30% carotid stenosis. The frequency of a >=30% carotid stenosis was then analyzed as a function of carotid calcium scores and various cardiovascular risk factors. CT detection of carotid calcium was feasible, robust, and reliable. Significant univariate associations for a >=30% carotid stenosis included age (P < 0.001), diabetes (P = 0.02), hypertension (P = 0.01), and the carotid calcium score (P < 0.001). Those with a >=30% carotid stenosis exhibited a median (25th, 75th percentile) carotid calcium score of 153 (19, 489), while those without a >=30% carotid stenosis had a median (25th, 75th percentile) carotid calcium score of 0 (0, 89). Conversely, when no carotid calcium was detected, there was a low (1%) frequency of significant carotid atherosclerosis. The frequency of a >=30% carotid stenosis increased as the carotid calcium score increased (P < 0.001 for trend). This association remained significant after adjustment for age, hypertension, diabetes, hyperlipidemia, and tobacco use. CT detection of carotid calcium can assess the burden of carotid atherosclerosis. PMID- 22101627 TI - Is your practice research based? PMID- 22101628 TI - Nursing profession's stars are finally in alignment: Craven & Ober policy strategists, LLC. PMID- 22101629 TI - The epidemiology, treatment, and prevention of transmission of methicillin resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has been recognized as an important cause of health care-associated infections for several decades and has more recently emerged as a common cause of infection in persons without typical health care-associated risk factors. It is important for health care providers to have an understanding of the factors associated with MRSA acquisition and infection as well as the interventions that may reduce the risk of MRSA in health care and community settings. PMID- 22101630 TI - Factors affecting the unplanned peripheral reinsertion in pediatric patients from a teaching hospital in Taiwan. AB - The purpose of this study was to investigate the factors affecting the unplanned peripheral intravenous reinsertion in pediatric inpatients at a teaching hospital in Taiwan. Researchers recruited 206 pediatric inpatients and their caretakers for the study and used multivariate regression in calculating their results. The results showed the following: whether pediatric patients received drugs (P < .001), whether the appropriate height of the drops was adhered to (P = .053), and whether the adjustment of the drip rate was done by the clients or caretakers themselves (P = .046) were significant determinants of unplanned peripheral intravenous reinsertions. It may be worthwhile to incorporate the findings regarding factors affecting the unplanned peripheral intravenous reinsertion into pediatric nurses' educational programs. PMID- 22101631 TI - Chelation therapy for iron overload: nursing practice implications. AB - Many diseases of the blood are treated with blood transfusion therapy. Chronic transfusions can cause iron overload, and, if untreated, can cause end-organ damage. Chelation therapy provides a way of treating iron overload and minimizing its adverse effects. Nurses need to understand that iron overload is a consequence of chronic blood transfusion, and they need to know what effects it has on end organs and what treatment options are available. PMID- 22101632 TI - Maintenance of peripheral venous access and its impact on the development of phlebitis: a survey of 186 catheters in a general surgery department in Portugal. AB - This article reports the results of a clinical audit conducted to assess the minimum requirements for safe maintenance of peripheral intravenous catheters. The audit also determined the incidence of phlebitis and attempted to establish a causal relationship between some of the variables used to assess a catheter's maintenance status and the development of phlebitis. PMID- 22101633 TI - Predisposing factors for infiltration in children submitted to peripheral venous catheterization. AB - AIMS: The aims were to compare characteristics of children with peripheral intravenous catheters who developed infiltration and those who did not and to identify risk factors for developing this complication. METHOD: A retrospective cohort study carried out at a university hospital, with 338 children with peripheral intravenous catheters. Variables related to the children and therapies were investigated. RESULTS: Researchers identified infiltration in 54 children (16%). Characteristics statistically different in those who developed infiltration were the following: intravenous therapy for more than 5 days, presence of predisposing factors to peripheral venipuncture failure, history of previous infiltration, catheter readjustment to vein insertion, use of infusion pump, intermittent administrations, and shorter dwell time. CONCLUSION: Only intravenous therapy variables showed a significant relation with the occurrence of infiltration and represented risk factors for its occurrence. PMID- 22101634 TI - The use of postmortem computed tomography in the diagnosis of intentional medication overdose. AB - The recognition of a well defined basal layer of radio dense material on the postmortem computed tomography (CT) images, in the setting of typical scene findings of an intentional medication overdose and unremarkable external examination of the deceased's body can, in certain circumstances, permit such cases to be managed without routine full autopsy examination. Preliminary toxicological analysis can be targeted to such cases to provide further supportive evidence of intentional medication overdose. In cases where the scene findings are ambiguous or have been contaminated the postmortem CT images may alert the pathologist of the possibility of overdose in an otherwise apparently natural death. We reviewed 61 cases of documented intentional therapeutic medication overdose and 61 control cases. In the majority of the cases of confirmed intentional therapeutic medication overdose the CT images showed no diagnostic features. However, in many cases a well defined basal layer of radio opaque material was clearly seen to line the gastric mucosa. The postmortem CT pattern which we believe to be highly suggestive of intentional medication overdose must be differentiated from other causes of increased radio density in the stomach which include CT artefacts. PMID- 22101635 TI - Mobilizing for change: a case study of a campus and community coalition to reduce high-risk drinking. AB - Campus and community coalitions include a partnership between campus leaders and community stakeholders and can effectively address the environment that may promote high-risk drinking. Despite evidence suggesting that coalitions may be effective vehicles for producing sustainable changes in college drinking, few campuses work within such a structure. The purpose of this study was to examine the effectiveness of a campus and community coalition to implement environmental changes and thereby reduce high-risk drinking and associated consequences. This study utilized a case study method to tell the story of a campus and community coalition (CCC) implemented on a large university campus in the Northeast. The study employed multiple methods including archival document review, review of campus and community level data (i.e. alcohol-related arrests and sanctions) and analysis of student level data. The case study discusses the strategies employed, the environmental changes that occurred and the impact these changes have had on student drinking and consequences. Since implementing the campus and community coalition, the campus has seen an increase in enforcement by campus and local police, changes in community by-laws, and significant reductions in student drinking and consequences. The data provide evidence that a comprehensive approach to reducing high-risk drinking can have an impact on the campus and community environment, which in turn impacts student drinking and associated consequences. The CCC utilized a strategic and comprehensive approach to substance abuse prevention, allowing all participants to have a shared understanding of the challenges and best practices. Implications for research and practice are also discussed. PMID- 22101636 TI - Concepts of healthy diet among urban, low-income, African Americans. AB - We sought to explore concepts of healthy diet and to elicit recommendations to support healthier eating among urban, low-income, African Americans. We conducted semi-structured interviews with 33 self-identified African American adults (18-81 years of age, 15 male participants) from a low-income neighborhood in west Philadelphia, PA, during summer and fall 2008. Our qualitative approach was continuous, iterative and thematic considering gender, age category, and participants' "mentions" of fast-food and fruit-and-vegetable intake from the preceding day. We found that participants shared concepts about broad nutritional principles consistent with national dietary recommendations, but disagreed about the healthfulness of specific foods-e.g. meat. On average-with little variation participants reported eating >2 "mentions" more of fast foods the preceding day than fruits and vegetables (P < 0.001). Suggested strategies to help promote eating more produce included increasing exposure, advertising, affordability, and local availability (vice versa to limit fast-food consumption), and more education on the health effects of diet and how to find and prepare healthy foods. Women's ideas reflected their roles in food shopping and food preparation; otherwise, participants' ideas did not differ appreciably by gender or age. Overall, participants generally expressed sufficient understanding of nutritional principles to eat healthfully, but disagreed about the healthfulness of specific foods and described largely unhealthy dietary consumption from the preceding day. If poor dietary intake results from barriers to recognizing, purchasing, and preparing healthy foods, then participants' suggestions to increase education and modify the environment may lead to improved diets and better health in the community. PMID- 22101637 TI - Prevalence and factors associated with high body fat in adolescents from a region of Brazil. AB - The objective of this study was to identify the prevalence and factors associated with high body fat in adolescents. A cross-sectional study conducted with 601 students from both sexes aged 14-17 years who live in Midwestern state of Santa Catarina, Brazil. Body adiposity was assessed by the sum of subscapular and triceps skinfolds. Sociodemographic variables such as lifestyle, aerobic fitness and nutritional status were assessed. For data analysis, Poisson regression multivariable was used. The prevalence of high body fat was 51.2% for girls and 31.2% for boys. Higher prevalences of high body fat were observed for girls aged 16-17 years (PR: 1.15, CI 95%: 1.07-1.24) and overweight (PR: 1.36, CI 95%: 1.27 1.44) and for boys with high socioeconomic level (PR: 1.21, CI 95%: 1.09-1.34), inadequate eating habits (PR: 1.11, CI 95%: 1.02-1.21), physically inactive (PR: 1.10, CI 95%: 1.02-1.19) and overweight (PR: 1.46, CI 95%: 1.35-1.57). The prevalence of high body fat was high and factors associated with this outcome are different for each sex; thus, interventions for prevention and control of obesity should be different for girls and boys. PMID- 22101638 TI - Cancer mortality rates in Appalachia: descriptive epidemiology and an approach to explaining differences in outcomes. AB - Cancer is a leading cause of death in the Appalachian region of the United States. Existing studies compare regional mortality rates to those of the entire nation. We compare cancer mortality rates in Appalachia to those of the nation, with additional comparisons of Appalachian and non-Appalachian counties within the 13 states that contain the Appalachian region. Lung/bronchus, colorectal, female breast and cervical cancers, as well as all cancers combined, are included in analysis. Linear regression is used to identify independent associations between ecological socioeconomic and demographic variables and county-level cancer mortality outcomes. There is a pattern of high cancer mortality rates in the 13 states containing Appalachia compared to the rest of the United States. Mortality rate differences exist between Appalachian and non-Appalachian counties within the 13 states, but these are not consistent. Lung cancer is a major problem in Appalachia; most Appalachian counties within the 13 states have significantly higher mortality rates than in-state, non-Appalachian counterparts. Mortality rates from all cancers combined also appear to be worse overall within Appalachia, but part of this disparity is likely driven by lung cancer. Education and income are generally associated with cancer mortality, but differences in the strength and direction of these associations exist depending on location and cancer type. Improving high school graduation rates in Appalachia could result in a meaningful long term reduction in lung cancer mortality. The relative importance of household income level to cancer outcomes may be greater outside the Appalachian regions within these states. PMID- 22101639 TI - Plant-food and tool transfer among savanna chimpanzees at Fongoli, Senegal. AB - Transferring food is considered a defining characteristic of humans, as such behavior is relatively uncommon in other animal species save for kin-based transfer. Chimpanzees (Pan troglodytes) are one exception, as they commonly transfer meat among nonrelatives but rarely transfer other resources. New observations at Fongoli, Senegal, show habitual transfer of wild-plant foods and other non-meat resources among community members beyond transfers from mother to offspring. We explore various explanations for these behaviors with a focus on age- and sex-class patterns in transfer events. In a total of 27 of 41 cases, male chimpanzees at Fongoli transferred wild-plant foods or tools to females. Most other cases involved transfer among males or males taking food from females. In light of male-female transfer patterns at Fongoli, we examine four hypotheses that have been applied to food transfer in apes: (1) testing for male-coercive tendency (van Noordwijk and van Schaik, Behav Ecol Sociobiol 63:883-890, 2009), (2) costly signaling (Hockings et al. PLoS ONE 2:e886, 2007), (3) food-for-sex (Gomes and Boesch, PLoS ONE 4:5116, 2009), and (4) sharing-under-pressure (Gilby, Anim Behav 71:953-963, 2006). We also consider hypotheses posed to explain transfer among callitrichids, where such behavior is more common (Ruiz-Miranda et al. Am J Primatol 48:305-320, 1999). Finally, we examine variables such as patch and food size and food transport. We discuss our findings relative to general patterns of non-meat transfer in Pan and examine them in the context of chimpanzee sociality in particular. We then contrast chimpanzee species and subspecies in terms of non-meat food and tool transfer and address the possibility that a savanna environment contributes to the unusual pattern observed at Fongoli. PMID- 22101640 TI - Bidirectional plasticity of cortical pattern recognition and behavioral sensory acuity. AB - Learning to adapt to a complex and fluctuating environment requires the ability to adjust neural representations of sensory stimuli. Through pattern completion processes, cortical networks can reconstruct familiar patterns from degraded input patterns, whereas pattern separation processes allow discrimination of even highly overlapping inputs. Here we show that the balance between pattern separation and completion is experience dependent. Rats given extensive training with overlapping complex odorant mixtures showed improved behavioral discrimination ability and enhanced piriform cortical ensemble pattern separation. In contrast, behavioral training to disregard normally detectable differences between overlapping mixtures resulted in impaired piriform cortical ensemble pattern separation (enhanced pattern completion) and impaired discrimination. This bidirectional effect was not found in the olfactory bulb; it may be due to plasticity within olfactory cortex itself. Thus pattern recognition, and the balance between pattern separation and completion, is highly malleable on the basis of task demands and occurs in concert with changes in perceptual performance. PMID- 22101641 TI - KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. AB - Mutations inactivating the potassium channel KCNQ4 (K(v)7.4) lead to deafness in humans and mice. In addition to its expression in mechanosensitive hair cells of the inner ear, KCNQ4 is found in the auditory pathway and in trigeminal nuclei that convey somatosensory information. We have now detected KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle mechanoreceptors from mice and humans. Electrophysiological recordings from single afferents from Kcnq4(-/-) mice and mice carrying a KCNQ4 mutation found in DFNA2-type monogenic dominant human hearing loss showed elevated mechanosensitivity and altered frequency response of rapidly adapting, but not of slowly adapting nor of D-hair, mechanoreceptor neurons. Human subjects from independent DFNA2 pedigrees outperformed age-matched control subjects when tested for vibrotactile acuity at low frequencies. This work describes a gene mutation that modulates touch sensitivity in mice and humans and establishes KCNQ4 as a specific molecular marker for rapidly adapting Meissner and a subset of hair follicle afferents. PMID- 22101642 TI - A catalytically silent FAAH-1 variant drives anandamide transport in neurons. AB - The endocannabinoid anandamide is removed from the synaptic space by a selective transport system, expressed in neurons and astrocytes, that remains molecularly uncharacterized. Here we describe a partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH like anandamide transporter (FLAT), that lacked amidase activity but bound anandamide with low micromolar affinity and facilitated its translocation into cells. Known anandamide transport inhibitors, such as AM404 and OMDM-1, blocked these effects. We also identified a competitive antagonist of the interaction of anandamide with FLAT, the phthalazine derivative ARN272, that prevented anandamide internalization in vitro, interrupted anandamide deactivation in vivo and exerted profound analgesic effects in rodent models of nociceptive and inflammatory pain, which were mediated by CB(1) cannabinoid receptors. The results identify FLAT as a critical molecular component of anandamide transport in neural cells and a potential target for therapeutic drugs. PMID- 22101643 TI - UNC-33 (CRMP) and ankyrin organize microtubules and localize kinesin to polarize axon-dendrite sorting. AB - The polarized distribution of neuronal proteins to axons and dendrites relies on microtubule-binding proteins such as CRMP, directed motors such as the kinesin UNC-104 (Kif1A) and diffusion barriers such as ankyrin. The causative relationships among these molecules are unknown. We show here that Caenorhabditis elegans CRMP (UNC-33) acts early in neuronal development, together with ankyrin (UNC-44), to organize microtubule asymmetry and axon-dendrite sorting. In unc-33 and unc-44 mutants, axonal proteins were mislocalized to dendrites and vice versa, suggesting bidirectional failures of axon-dendrite identity. unc-44 directed UNC-33 localization to axons, where it was enriched in a region that resembled the axon initial segment. unc-33 and unc-44 were both required to establish the asymmetric dynamics of axonal and dendritic microtubules; in their absence, microtubules were disorganized, the axonal kinesin UNC-104 invaded dendrites, and inappropriate UNC-104 activity randomized axonal protein sorting. We suggest that UNC-44 and UNC-33 direct polarized sorting through their global effects on neuronal microtubule organization. PMID- 22101644 TI - Caffeine-induced synaptic potentiation in hippocampal CA2 neurons. AB - Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A(1) adenosine receptors (A(1)Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. We found that physiological doses of caffeine in vivo or A(1)R antagonists in vitro induced robust, long-lasting potentiation of synaptic transmission in rat CA2 without affecting other regions of the hippocampus. PMID- 22101645 TI - Neural correlates of reliability-based cue weighting during multisensory integration. AB - Integration of multiple sensory cues is essential for precise and accurate perception and behavioral performance, yet the reliability of sensory signals can vary across modalities and viewing conditions. Human observers typically employ the optimal strategy of weighting each cue in proportion to its reliability, but the neural basis of this computation remains poorly understood. We trained monkeys to perform a heading discrimination task from visual and vestibular cues, varying cue reliability randomly. The monkeys appropriately placed greater weight on the more reliable cue, and population decoding of neural responses in the dorsal medial superior temporal area closely predicted behavioral cue weighting, including modest deviations from optimality. We found that the mathematical combination of visual and vestibular inputs by single neurons is generally consistent with recent theories of optimal probabilistic computation in neural circuits. These results provide direct evidence for a neural mechanism mediating a simple and widespread form of statistical inference. PMID- 22101647 TI - Stimuli-responsive releasing of gold nanoparticles and liposomes from aptamer functionalized hydrogels. AB - Controlled release of therapeutic agents is important for improving drug efficacy and reducing toxicity. Recently, hydrogels have been used for controlled release applications. While the majority of the previous work focused on releasing the cargo in response to physical stimuli such as temperature, light, electric field, and pH, we aim to trigger cargo release in the presence of small metabolites. In our system a DNA aptamer that can bind to adenosine, AMP, and ATP was used as a linker to attach either DNA-functionalized gold nanoparticles or liposomes to DNA functionalized hydrogels. In the presence of the metabolite, both the nanoparticle and liposome cargos were released. The effect of salt, temperature, target concentration, and drying has been systematically studied. Interestingly, we found that the gel can be completely dried while retaining the DNA linkages and adenosine induced release was still achieved after rehydration. Our work demonstrates that aptamers can be used to control the release of drugs and other materials attached to hydrogels. PMID- 22101646 TI - Cross-species studies of orbitofrontal cortex and value-based decision-making. AB - Recent work has emphasized the role that orbitofrontal cortex (OFC) has in value based decision-making. However, it is also clear that a number of discrepancies have arisen when comparing the findings from animal models to those from humans. Here, we examine several possibilities that might explain these discrepancies, including anatomical difference between species, the behavioral tasks used to probe decision-making and the methodologies used to assess neural function. Understanding how these differences affect the interpretation of experimental results will help us to better integrate future results from animal models. This will enable us to fully realize the benefits of using multiple approaches to understand OFC function. PMID- 22101649 TI - Palladium(II)-selenated Schiff base complex catalyzed Suzuki-Miyaura coupling: dependence of efficiency on alkyl chain length of ligand. AB - The new selenated Schiff bases L1-L4 which differ in the chain lengths (longest in L4) of non-coordinating substituents and their square planar complexes [Pd(L H)Cl] (1-4) [L = L1-L4, behaving as (Se, N, O(-)) ligand] have been synthesized and characterized by multinuclei NMR. The molecular structure of 1 has been elucidated by X-ray diffraction on its single crystal [Pd-Se = 2.3965(9) A]. All the complexes 1-4 (0.5 mol%) have been found suitable to catalyze Suzuki-Miyaura coupling reactions under mild conditions. The activity of 4 which has ligand L4 has been found highest. The formation of palladium(0) nano-particles (NPs) stablilized by organoselenium species appears to be the catalytic pathway. The length of the pendent alkyl chain present in the complex molecule unprecedentedly controls the dispersion and composition of these particles and consequently the catalytic activity. PMID- 22101650 TI - Why Cancer matters. PMID- 22101651 TI - BRACking news on triple-negative/basal-like breast cancers: how BRCA1 deficiency may result in the development of a selective tumor subtype. AB - Mutations in the BRCA1 tumor suppressor predispose to the development of breast and ovarian cancers. Noticeably, the majority of BRCA1-associated breast cancers are triple-negative (ER-, PR- and HER2-) and display a basal-like phenotype, which are features relatively uncommon among sporadic breast cancers. It is well documented that BRCA1 is involved in a number of cellular functions converging to the maintenance of genomic stability. However, the control over DNA integrity does not seem to account for the peculiar phenotype of BRCA1-associated tumors since mutations in other genes involved in such a function, namely BRCA2, associate to a broader spectrum of breast carcinoma subtypes. Indeed, an increasing body of evidence indicates that BRCA1 is implicated also in the regulation of transcription by impinging upon general components of the transcriptional machinery. Thus, elucidating the complex biochemical network regulated by BRCA1 may allow a better understanding also of the biology of sporadic triple-negative/basal-like tumors and lay down the basis for novel preventive measures and more effective therapeutic strategies. This review summarizes recent findings on the role of BRCA1 in the regulation of transcription and how this might set the ground for the development of cancers with triple-negative/basal-like features. PMID- 22101652 TI - Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. AB - Several recent papers have now provided compelling experimental evidence that the progression of tumours towards a malignant phenotype does not depend exclusively on the cell-autonomous properties of cancer cells themselves but is also deeply influenced by tumour stroma reactivity, thereby undergoing a strict environmental control. Tumour microenvironmental elements include structural components such as the extracellular matrix or hypoxia as well as stromal cells, either resident cells or recruited from circulating precursors, as macrophages and other inflammatory cells, endothelial cells and cancer-associated fibroblasts (CAFs). All these elements synergistically play a specific role in cancer progression. This review summarizes our current knowledge on the role of CAFs in tumour progression, with a particular focus on the biunivocal interplay between CAFs and cancer cells leading to the activation of the epithelial-mesenchymal transition programme and the achievement of stem cell traits, as well as to the metabolic reprogramming of both stromal and cancer cells. Recent advances on the role of CAFs in the preparation of metastatic niche, as well as the controversial origin of CAFs, are discussed in light of the new emerging therapeutic implications of targeting CAFs. PMID- 22101653 TI - Evaluating the impact of post-mortem damage in ancient DNA: a theoretical approach. AB - The growth of ancient DNA research has offered exceptional opportunities and raised great expectations, but has also presented some considerable challenges. One of the ongoing issues is the impact of post-mortem damage in DNA molecules. Nucleotide alterations and DNA strand breakages lead to a significant decrease in the quantity of DNA molecules of useful length in a sample and to errors in the final DNA sequences obtained. We present a model of age-dependent DNA damage and quantify the influence of that damage on subsequent steps in the sequencing process, including the polymerase chain reaction and cloning. Calculations using our model show that deposition conditions, rather than the age of a sample, have the greatest influence on the level of DNA damage. In turn, this affects the probability of interpreting an erroneous (possessing damage-derived mutations) sequence as being authentic. We also evaluated the effect of post-mortem damage on real data sets using a Bayesian phylogenetic approach. According to our study, damage-derived sequence alterations appear to have little impact on the final DNA sequences. This indicates the effectiveness of current methods for sequence authentication and validation. PMID- 22101654 TI - AUX: a scripting language for auditory signal processing and software packages for psychoacoustic experiments and education. AB - This article introduces AUX (AUditory syntaX), a scripting syntax specifically designed to describe auditory signals and processing, to the members of the behavioral research community. The syntax is based on descriptive function names and intuitive operators suitable for researchers and students without substantial training in programming, who wish to generate and examine sound signals using a written script. In this article, the essence of AUX is discussed and practical examples of AUX scripts specifying various signals are illustrated. Additionally, two accompanying Windows-based programs and development libraries are described. AUX Viewer is a program that generates, visualizes, and plays sounds specified in AUX. AUX Viewer can also be used for class demonstrations or presentations. Another program, Psycon, allows a wide range of sound signals to be used as stimuli in common psychophysical testing paradigms, such as the adaptive procedure, the method of constant stimuli, and the method of adjustment. AUX Library is also provided, so that researchers can develop their own programs utilizing AUX. The philosophical basis of AUX is to separate signal generation from the user interface needed for experiments. AUX scripts are portable and reusable; they can be shared by other researchers, regardless of differences in actual AUX-based programs, and reused for future experiments. In short, the use of AUX can be potentially beneficial to all members of the research community both those with programming backgrounds and those without. PMID- 22101655 TI - The construction of perceptual grouping displays using GERT. AB - To study perceptual grouping processes, vision scientists often use stimuli consisting of spatially separated local elements that, together, elicit the percept of a global structure. We developed a set of methods for constructing such displays and implemented them in an open-source MATLAB toolbox, GERT (Grouping Elements Rendering Toolbox). The main purpose of GERT is to embed a contour in a field of randomly positioned elements, while avoiding the introduction of a local density cue. However, GERT's modular implementation enables the user to create a far greater variety of perceptual grouping displays, using these same methods. A generic rendering engine grants access to a variety of element-drawing functions, including Gabors, Gaussians, letters, and polygons. PMID- 22101656 TI - Estimating linear effects in ANOVA designs: the easy way. AB - Research in cognitive science has documented numerous phenomena that are approximated by linear relationships. In the domain of numerical cognition, the use of linear regression for estimating linear effects (e.g., distance and SNARC effects) became common following Fias, Brysbaert, Geypens, and d'Ydewalle's (1996) study on the SNARC effect. While their work has become the model for analyzing linear effects in the field, it requires statistical analysis of individual participants and does not provide measures of the proportions of variability accounted for (cf. Lorch & Myers, 1990). In the present methodological note, using both the distance and SNARC effects as examples, we demonstrate how linear effects can be estimated in a simple way within the framework of repeated measures analysis of variance. This method allows for estimating effect sizes in terms of both slope and proportions of variability accounted for. Finally, we show that our method can easily be extended to estimate linear interaction effects, not just linear effects calculated as main effects. PMID- 22101657 TI - Arthrofibrosis after anterior cruciate ligament reconstruction in children and adolescents. AB - INTRODUCTION: Arthrofibrosis is a known complication after anterior cruciate ligament (ACL) reconstruction. ACL reconstruction is being performed with increased frequency in the pediatric population. The purpose of this study was to determine the prevalence of arthrofibrosis in children and adolescents and to identify risk factors for arthrofibrosis. METHODS: The study design was a retrospective case series. Medical records for 1016 consecutive ACL reconstructions in patients aged 7 to 18 years old between 1995 to 2008 at a major tertiary care children's hospital were reviewed to identify cases of postoperative arthrofibrosis. Arthrofibrosis was defined as a loss of 5 degrees or more extension compared with the contralateral knee that required a follow-up procedure or a loss of 15 degrees or more flexion compared with the contralateral knee that required a follow-up procedure. Patient data were recorded and analyzed using bivariate models to identify predictors for arthrofibrosis. Further, we reviewed the clinical course of patients with treated arthrofibrosis to assess functional outcomes of this complication. RESULTS: Nine hundred two patients with 933 knees met the inclusion criteria for this study, of which 60% were female. The mean age at the time of surgery was 15 years (range, 7 to 18 y), and the average follow-up from original ACL reconstruction was 6.3 years (range, 1.6 to 14.2 y). The overall prevalence of arthrofibrosis in our cohort was 8.3%, with 77 of the 933 knees had at least 1 procedure to treat arthrofibrosis after ACL reconstruction. Risk factors for arthrofibrosis were female sex (11.1% females, P = 0.0001), patients aged 16 to 18 years [11.6%; odds ratio (OR) 3.51; P = 0 .007], patellar tendon autograft (OR, 1.7; P = 0.026), and concomitant meniscal repair (OR, 2.08; P = 0.007). Prior knee surgery and ACL reconstruction within 1 month of injury were not significantly associated with arthrofibrosis after ACL reconstruction. Fifty-three patients had a minimum of 6 months clinical follow-up after the procedure for arthrofibrosis. Of these, 46 patients (86.8%) had full range of motion at follow-up. Thirty-two patients (60.4%) were asymptomatic at final follow-up. Eleven patients (20.8%) complained of some persistent pain. CONCLUSIONS: The rate of arthrofibrosis after ACL reconstruction in children and adolescents is 8.3%. Risk factors for arthrofibrosis are female sex, older adolescents, concurrent meniscal repair, and reconstruction with patellar tendon autograft. Surgical treatment for arthrofibrosis after ACL reconstruction in pediatric patients can satisfactorily regain motion in the reconstructed knee; however functional outcome may be compromised. LEVEL OF EVIDENCE: Level 4. PMID- 22101658 TI - Surgeon learning curve for pediatric supracondylar humerus fractures. AB - BACKGROUND: There has been an increasing trend toward referral of supracondylar humerus fractures in children to pediatric orthopaedic centers. The learning curve for treating this fracture is not well described. METHODS: We retrospectively reviewed all supracondylar fractures treated by 21 pediatric orthopaedic fellows over the 2003 to 2009 academic years, with attending cases from 2005 to 2007 to serve as a control. Type IIa, IIb, and III fractures were used in the case count of for each fellows, whereas only type III fractures were used to record fluoroscopy time, operative time, and for radiographic review. Nonideal reduction was defined as a Baumann angle outside the range of 64 to 81 degrees, or an anterior humeral line that does not intersect the capitellum. RESULTS: Of the 654 total operatively treated fractures, fellows treated 479 total and 213 type III fractures. Backup attendings were present in the operating room for 39% of type III fractures in the first academic quarter before falling to a baseline of 10% to 20% during the remaining quarters. Fluoroscopy time and operative time were consistent for fellows throughout the year. Nonideal reductions increased notably at case 7, correlating with increased fellow independence in the operating room, with reversal of the trend at case 15. There were no differences in complication rates and no malunions requiring osteotomy. CONCLUSIONS: In order to balance training and patient care, we recommend the availability of an attending backup surgeon for the first 15 cases of supracondylar humerus fractures treated by pediatric orthopaedic fellows. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 22101659 TI - A comparison of locked versus nonlocked Enders rods for length unstable pediatric femoral shaft fractures. AB - BACKGROUND: Stainless steel flexible Enders rods have been used for intramedullary fixation of pediatric femur fractures with good success. Despite intraoperative anatomic alignment, length unstable femur fractures can present postoperatively with fracture shortening. The purpose of this study was to review all length unstable pediatric femoral shaft fractures in which Enders rods were used and compare those that were locked to those that were not locked. METHODS: A retrospective clinical and radiographic review of all patients at a single institution undergoing flexible intramedullary fixation for length unstable femoral shaft fractures from 2001 to 2008. A length unstable fracture was defined as either a comminuted fracture or a spiral fracture longer than twice the diameter of the femoral shaft. A total of 107 length unstable femoral shaft fractures fixed with Enders rods were identified, of which 37 cases (35%) had both Enders rods "locked" through the eyelet in the distal femur with a 2.7 mm fully threaded cortical screw. Patient demographics, clinical course, complications, fracture characteristics, and radiographic outcomes were compared for the locked and nonlocked groups. RESULTS: There were no statistical differences between the groups in demographic data, operative variables, fracture pattern, fracture location, time to union, femoral alignment, or major complications. Shortening of the femur and nail migration measured at 1 to 6 weeks postoperatively was significantly greater for the nonlocked cases. The medial and lateral locked Enders rods moved 1.3 and 1.9 mm, respectively, and the unlocked Enders each moved 12.1 mm (P < 0.05). At final follow-up there were significantly more (P < 0.05) clinical complaints in nonlocked group, including limp, clinical shortening, and painful palpable rods. CONCLUSIONS: Locking Enders rods for length unstable pediatric fractures is an excellent option to prevent shortening and resulted in no additional complications, added surgical time, or increased blood loss. LEVEL OF EVIDENCE: Level III. PMID- 22101660 TI - Does the extent of prebending affect the stability of femoral shaft fractures stabilized by titanium elastic nails? A biomechanical investigation on an adolescent femur model. AB - BACKGROUND: Elastic stable intramedullary nailing (ESIN) is a common procedure for stabilization of femoral shaft fractures in childhood. Prebending of the nail is generally recommended to achieve optimal nail tension at the fracture site. To our knowledge there are no published data on the effects of prebending on stability. The purpose of this biomechanical study was to compare the effects of different degrees of prebending on the stability of transverse femoral fractures after ESIN using a bone model. METHODS: Standardized transverse midshaft fractures were created in 20 synthetic, biomechanically validated adolescent bones (4th Generation Composite Femur--Sawbones Europe AB, Sweden) that were stabilized with 2 titanium nails (TEN) each (4 mm diameter, Synthes) and inserted in standardized retrograde technique. The 4 test series addressed nail prebending at 0 degree, 30 degrees, 45 degrees, and 60 degrees. The models were tested biomechanically in 4-point bending in the coronal and sagittal planes, relative stiffness was determined and analyzed statistically. The level of significance was set at P < 0.05. RESULTS: Comparison of the individual groups showed no significant differences in stiffness for different degrees of prebending in the coronal plane. Significantly reduced stiffness was found in the sagittal plane for the group with 60-degree prebending compared with the 0-degree, 30-degree, and 45-degree prebending groups. Intragroup comparison in the coronal and sagittal planes yielded a significantly reduced stiffness in the sagittal plane compared with the coronal plane in the group with 60-degree prebending. The 45 degree prebending group showed a similar tendency and in the 0-degree and 30 degree prebending groups there were no significant differences. CONCLUSIONS: On a synthetic bone model, prebending of TEN was found to affect the stability of transverse fractures of the femoral shaft, whereby indiscriminate prebending will reduce stability in the sagittal plane.Despite limited extrapolation of the findings to the in vivo situation, it can be stated that prebending of TEN by 0 to 30 degrees offers the greatest stability in the coronal and sagittal planes for transverse fractures of the femoral shaft. PMID- 22101661 TI - Minimally invasive treatment for severely displaced proximal humeral fractures in children using titanium elastic nails. AB - OBJECTIVE: To evaluate the preliminary results of minimally invasive treatment for severely displaced proximal humeral fractures in children using titanium elastic nails (TENs). METHODS: Twenty-five cases of TEN treatment of severely displaced proximal humerus fractures in children were evaluated clinically and radiographically. Complications were assessed. The 14 males and 11 females were between 6 and 15 years of age at the time of surgery. Of the 10 left and 15 right humeri treated, 3 were open fractures and 2 were associated with polytrauma. Two laterally inserted retrograde TENs were used in 22 cases. In the remaining 3 cases, 1 medial and 1 lateral TEN were inserted retrograde. RESULTS: Follow-up ranged from 7 to 40 months. All fractures showed both clinical and radiographic evidence of healing within 2 months. There were no major complications related to the treatment. There were 3 cases of skin irritation adjacent to prominent distal ends of the nails, of which the 2 nails in 1 child were removed prematurely at 3 weeks without sequelae. The nails in the other 2 cases were removed at the planned 6-month postoperative time with complete resolution of symptoms. Function of the fractured arm returned to normal quickly in all cases. CONCLUSIONS: TEN for the treatment of severely displaced humerus fractures in children is an effective method with a low complication rate. PMID- 22101662 TI - Isocentric reattachment of ligamentum teres: a porcine study. AB - BACKGROUND: Recent reports reveal interest in the mechanical importance of ligamentum teres (LT) in hip dislocation. In the previously established procedure of anteroinferior acetabular LT reattachment in developmental dysplasia of the hip, the LT functions as a check-rein, showing promising results. However, this position of reattachment could potentially limit motion. The purpose of this study was to evaluate the feasibility of an isocentric point for reattachment of the LT and to study its impact on hip function using a young porcine model. METHODS: Pelvic specimens with intact anatomy were obtained from 6 skeletally immature pigs (12 hips). Through a careful anteromedial capsulotomy, the LT was detached from its acetabular insertion then reattached to 1 of 2 positions: (1) anteroinferior lip of the acetabulum; (2) proposed isocentric position. Intra articular stress distribution was measured through a complete range of motion with a prescale Fuji pressure film. Tension was then applied to the LT and the stresses were recorded again. In addition, radioopaque solution was injected into the substance of the LT, then floroscopy tracked the LT location initially and after the 2 reattachment positions through a full hip range of motion. RESULTS: Reattachment of the LT at an isocentric point is feasible in a pig model. With careful physiologic tensioning of this reattachment, hip can maintain full motion with no excessive pressure areas created within the joint. On the contrary, the initial technique of anteroinferior extra-articular attachment limits external rotation and extremes of abduction. We found this LT tracking technique (with radioopaque dye injection) to be reliable and reproducible. CONCLUSIONS: The isocentric reattachment of the LT is feasible in this pig model and serves as a natural check-rein to dislocation without limiting joint motion or causing abnormal cartilage pressures. CLINICAL RELEVANCE: Isocentric LT reattachment may provide a method for improving stability of open reductions when treating children with such conditions. PMID- 22101663 TI - Drehmann sign and femoro-acetabular impingement in SCFE. AB - BACKGROUND: Drehmann sign is a characteristic clinical feature in slipped capital femoral epiphysis (SCFE). The presence of SCFE indicates an anatomic change of the proximal femur, which induces obligatory hip external rotation with hip flexion. In contrast, a cam-type femoro-acetabular impingement (FAI) is well known as sequelae of SCFE. The purpose of this study was to clarify the relationship between Drehmann sign and radiologic FAI. METHODS: We studied 92 hips of 80 SCFE patients who had been treated with in situ fixation. The occurrence rate of Drehmann sign was analyzed according to the degree of remodeling (the Jones classification) and the radiologic alpha-angle measured in each class at the final follow-up. At a mean 12.2 years after the final follow up, the patients' present condition was clinically investigated with a questionnaire using a part of the Harris Hip Rating Scale (HHRS). In addition, 3 dimensional computed tomography analysis was performed to clarify the anatomic relationship between the femoral head and the acetabulum during testing for Drehmann sign. RESULTS: Among the 92 hips in the study, 60 were well remodeled (Jones type A), 24 were type B, and 8 were type C, with 6.5 years of mean follow up. The mean of the modified alpha-angles for the 3 groups (A, B, and C) were 61.8, 84.7, and 119.4, respectively (P < 0.05); 25%, 75%, and 100% of the hips in the 3 groups, respectively, exhibited Drehmann sign. The set of hips (n = 41) with a positive Drehmann sign had a mean alpha-angle of 85.6 versus 63.0 degrees for the set of hips (n = 51) with a negative Drehmann sign (P < 0.05). Seven (13.5%) of 52 patients responding to the questionnaire reported hip pain and/or limp in the positive Drehmann sign group, but no patient in the negative sign group complained of either. Three-dimensional computed tomography delineated FAI at 2 different positions during testing for Drehmann sign. CONCLUSIONS: Drehmann sign is highly valuable for clinically evaluating the existence of FAI and for following up with observation or realignment to prevent early osteoarthritis. PMID- 22101664 TI - Surgical management of hip subluxation and dislocation in children with cerebral palsy: isolated VDRO or combined surgery? AB - BACKGROUND: Controversy exists regarding surgical treatment of hip subluxation/dislocation in children with cerebral palsy (CP). The purpose of this study was to compare isolated varus derotational osteotomy (VDRO) and VDRO combined with open hip reduction and/or pelvic osteotomy in children with CP and hip subluxation/dislocation. METHODS: Retrospective review was performed of 75 patients with CP (116 hips) and hip subluxation/dislocation treated surgically, with a minimum of 2 years follow-up. Ninety-two hips had undergone VDRO alone, and 24 had undergone VDRO and open reduction and/or pelvic osteotomy (with the decision to proceed with open hip reduction and/or pelvic osteotomy made intraoperatively based on fluoroscopy and arthrogram). Clinical variables, functional level, radiographic variables, and complications/revisions were compared between groups. RESULTS: Patients requiring combined surgery (VDRO+) had higher baseline migration percentages (MP) (84% +/- 18 VDRO+, 51% +/- 21 VDRO), higher acetabular indices (34 +/- 10 VDRO+, 28 +/- 7 VDRO), more negative center edge angles (-36 +/- 28 VDRO+, -0.3 +/- 18 VDRO), and higher neck-shaft angles (162 +/- 12 VDRO+, 157 +/- 10 VDRO) (all P < 0.02). Postoperative radiographic variables were similar between groups. The percentage of patients with MP >30% at final follow-up was similar between groups (38% VDRO+, 33% VDRO). There were no differences in complications or revision rates between groups. Of the hips with MP >50% preoperatively and treated with VDRO alone, 41% developed postoperative MP of >= 30% and 21% developed a MP of >= 40%. CONCLUSIONS: The study results confirm that combined procedures should be considered in patients with high MP. However, this study supports a sequential approach to surgical management of subluxated/dislocated hips in patients with CP as many hips with MP >50% were successfully managed with VDRO alone. We recommend performing VDRO and soft tissue release first, assessing reduction using fluoroscopy and arthrogram and proceeding with open reduction and/or pelvic osteotomy if reduction and/or femoral head coverage are inadequate. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 22101665 TI - Can excessive lateral rotation of the ischium result in increased acetabular anteversion? A 3D-CT quantitative analysis of acetabular anteversion in children with unilateral developmental dysplasia of the hip. AB - BACKGROUND: The purposes of this study were to observe whether increased acetabular anteversion was a universal finding and whether excessive lateral rotation of the ischium was correlated with increased acetabular anteversion. METHODS: We retrospectively reviewed 90 patients with unilateral developmental dysplasia of the hip (DDH), including 77 female patients and 13 male patients with an average age of 18 months (range, 6 to 60 mo). A total of 31 children were involved in the normal control group, including 14 girls and 17 boys with an average age of 21 months (range, 7 to 48 mo). The acetabular anteversion angle (AA), pubic relative length (PRL), ischiac relative distance (IRD), lateral rotational angle of the ischium (IA), and pubic rotational angle were compared between the affected hips and the unaffected hips in the unilateral DDH group and between the right hips and left hips in the normal control group. RESULTS: No retroverted acetabulum was found in any hip. No significant differences in AA, IA, pubic rotational angle, IRD, and PRL were found between the left and right hips in the normal control group. However, the PRL was shorter in the affected hips than in the unaffected hips (P < 0.05). The average IA, AA, and IRD in the affected hips were larger than that in the unaffected hips (P < 0.05). The IA was positively correlated with AA and IRD in the DDH group. CONCLUSIONS: Increased acetabular anteversion in affected hips is a universal finding in unilateral DDH. The deficiency of the anterior wall in the acetabulum is not a unique reason for increased acetabular anteversion in unilateral DDH, because it is also correlated with excessive lateral rotation of the ischium. LEVEL OF EVIDENCE: IV. PMID- 22101666 TI - Correlations of adolescent idiopathic scoliosis and pectus excavatum. AB - STUDY DESIGN: Radiologic study of scoliosis in pectus excavatum patients. OBJECTIVES: To determine the relation between pectus excavatum deformity and adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: AIS may be related to other whole body deformities, but few reports have addressed the relation between chest deformity and scoliosis. METHODS: A total of 248 patients with a diagnosis of pectus excavatum were enrolled in this study. All study patients underwent whole spine anteroposterior radiographs and chest computed tomography. Severity and type of scoliosis and chest deformity were measured using radiographs, and relations between pectus deformity and AIS were analyzed. RESULTS: Overall, 56 of the 248 study patients had scoliosis (Cobb angle > 10 degrees)--a prevalence of 22.58%. The incidence of scoliosis was significantly higher in female patients (38.46%) (P = 0.002), and Lenke type 1 predominated in pectus patients (48.2%, P < 0.0001). Mean age was greater in the scoliosis group than in the nonscoliosis group (P < 0.0001), and the asymmetry of pectus deformity was more prominent in the scoliosis group (P = 0.007). However, pectus deformity severity was similar in the 2 groups (P = 0.061). Furthermore, although the scoliosis group showed a higher proportion of female patients (P = 0.002), the severities of chest and spinal deformities were similar in the 2 groups for both sexes (P = 0.314, P = 0.227). CONCLUSIONS: Pectus excavatum and AIS were found to have a high concomitant incidence. And, the age, sex, and type of disease were significantly different in the scoliosis and pectus excavatum groups. Surgeons should consider these relationships when deciding upon treatment in patients with chest and spinal deformities. PMID- 22101667 TI - The "shadow sign": a radiographic differentiation of stainless steel versus titanium spinal instrumentation in spine surgery. AB - BACKGROUND: Stainless steel spinal instrumentation has been supplanted in recent years by titanium instrumentation. Knowing whether stainless steel or titanium was used in a previous surgery can guide clinical decision making processes, but frequently the clinician has no way to know what type of metal was used. We describe the radiographic "shadow sign," in which superimposed titanium rods and screws remain radiolucent enough that the contour of the underlying components can be seen on a lateral radiograph, whereas superimposed stainless steel rods and screws are completely radiopaque. This technique was evaluated using a retrospective, randomized, and blinded radiographic comparison of titanium and stainless steel spinal instrumentation. The objective was to determine whether the "shadow sign" can reliably differentiate titanium from stainless steel spinal instrumentation. METHODS: Lateral radiographs from 16 cases of posterior spinal instrumentation (6 titanium, 6 stainless steel, and 2 replicates of each to assess intraobserver reliability) were randomly selected from a database of cases performed for pediatric scoliosis in a university setting from 2005 to 2009. The cases were randomized then shown to 19 orthopaedic surgery residents, 1 spine fellow, and 2 spine attendings. After the "shadow sign" was described, the surgeons were asked to determine what type of metal each implant was made of. RESULTS: The kappa value for both stainless steel and titanium versus the gold standard was 0.83 [standard error (SE) = 0.053], indicating excellent agreement. The kappa value for agreement between raters was 0.71 (SE = 0.016) and the kappa value for agreement within raters was 0.70 (SE = 0.016), both of which indicated substantial agreement. CONCLUSIONS: The "shadow sign" can help a clinician differentiate titanium from stainless steel spinal instrumentation based on radiographic appearance alone. Furthermore, our study reveals that the level of experience in diagnosing spinal lateral radiographs also enhances the use of the "shadow sign" indicator. LEVEL OF EVIDENCE: The method proposed to differentiate titanium from stainless steel falls within the diagnostic studies domain. As unaltered randomization was used to enroll radiographs and the procedure was systematic, this study may be classified in the Level II category. PMID- 22101668 TI - Guided growth for ankle valgus. AB - BACKGROUND: Ankle valgus may be insidious and common in a variety of congenital conditions including clubfoot, neuromuscular disorders and others or acquired after fracture, osteotomies, or other manipulations of the lower extremity. This can cause hindfoot pronaton, resulting in lateral impingement and excessive shoe wear. Orthoses do not change the natural history. Medial hemiepiphysiodesis of the tibia is an accepted method of correcting this problem. Difficulties with transmalleolor screw removal prompted us to adopt the tension band method. Our purpose was to outline the technique of using guided growth with a medial tension band plate and discuss the efficacy of this technique. METHODS: We undertook this retrospective review of 33 patients (57 ankles) who underwent guided growth to correct ankle valgus and were followed until attaining full correction or skeletal maturity. Most of the implants were removed when the ankle was neutral to 5 degrees of varus overcorrection. We obtained weightbearing anteroposterior radiographs of the ankles preoperatively, just before plate removal, and at final follow-up, measuring the lateral distal tibial angle and noting the fibular station. We documented the rate of correction and related complications. RESULTS: The average age at surgery was 10.4 years (range, 6.1 to 14.6 y) and an average follow-up was 27 months (range, 12 to 57.5 mo). The lateral distal tibial angle improved from an average of 78.7 to 90 degrees at implant removal and measured 88.2 degrees at final follow-up. The rate of correction was calculated to be 0.6 degrees per month. The fibular station remained the same in 36 of 57 ankles and improved in 15 ankles. There were 2 cases of skin breakdown complicated by infection. There were no instances of hardware failure, excessive varus, or premature physeal closure and no patient has required an osteotomy. CONCLUSIONS: Without appropriate radiographs, ankle valgus may be mistaken for hindfoot valgus and mismanaged accordingly. Guided growth of the distal medial tibia has become our treatment of choice for ankle valgus in the growing child or adolescent. Use of plate epiphysiodesis is safe, well tolerated, may readily be combined with other treatments, and provides a rate of correction comparable to the transmalleolar screw method. LEVEL OF EVIDENCE: IV, retrospective review, no control series. PMID- 22101669 TI - Results of intercostal nerve transfer to the musculocutaneous nerve in brachial plexus birth palsy. AB - BACKGROUND: Intercostal nerve (ICN) transfer has been one of the main extraplexal nerve transfers in treating brachial plexus root avulsion. This retrospective study evaluated results of ICN transfer for reconstruction of the musculocutaneous nerve (MCN) in brachial plexus birth palsy (BPBP). METHODS: Eighteen boys and 6 girls with BPBP, who had avulsion of at least 2 spinal nerves of the plexus, underwent ICN transfer for reconstruction of MCN, from March 2003 to October 2005. The brachial plexus lesion was diagnosed by clinical assessment, surgical exploration, and intraoperative neurophysiological investigations. The age at surgery ranged from 3 to 11 months of life, with a mean of 5 months. Two intercostals were used for one, 3 intercostals for 9, and 4 intercostals for 14 patients. The intercostals were transferred to MCN in 12 and to the anterior division of the upper trunk in the other 12 cases. RESULTS: Twenty-four children were followed up for 24 to 79 months, with an average of 53 months. No complications were found in the respiratory system. Of 14 transfers with 4 intercostals, biceps gained M4 strength in 8, M3 in 4, and M2 in 2. Of 9 transfers with 3 intercostals, biceps obtained M4 strength in 8 and M3 in 1. One transfer with 2 intercostals got M4 strength of biceps. Twelve patients whose intercostals were transferred to MCN, gained M4 strength of biceps in 11 and M3 in 1, whereas the other 12 patients with intercostals transferred to anterior division of the upper trunk, obtained M4 strength of biceps in 6, M3 in 4, and M2 in 2. The rate of M3 strength or more was 92% and that of M4 was 71%. CONCLUSIONS: ICN transfer is a safe and reliable procedure for reconstruction of the MCN in BPBP. There seems to be no difference of effects between transfers with 3 and those with 4 intercostals. The transferred nerves should be coapted to MCN, rather than a more proximal portion of the plexus. LEVEL OF EVIDENCE: Level III: retrospective comparative study. PMID- 22101670 TI - Multiple compartment syndrome in a pediatric patient with CML. AB - Compartment syndrome is a limb-threatening and life-threatening emergency resulting from elevated intracompartmental pressure. Prompt surgical intervention and treatment are necessary to prevent irreparable damage to muscle and nerve tissues. Leukemic infiltration of the muscle is an unusual cause of compartment syndrome and has been documented to occur secondary to hyperleukocytic leukemias, most commonly in acute myeloid leukemia. We present a rare case of multiple compartment syndrome in the buttock and thigh of an 11-year-old male patient with chronic myelomonocytic leukemia. The diagnosis of acute compartment syndrome was delayed, causing irreversible tissue damage. Physicians are generally unfamiliar with leukemia-induced complications and may not initially suspect leukemic compartment syndrome because of its rarity. Awareness of its clinical features is critical, because early diagnosis and prompt surgical debridement can prevent significant morbidity and even death. PMID- 22101671 TI - Inter-observer and intra-observer reliability of the Risser sign in a metropolitan scoliosis screening program. AB - BACKGROUND: Risser staging is one of several criteria used in scoliosis screening programs. This study aimed to evaluate the reliability of a radiologist's Risser interpretations from a large metropolitan scoliosis-screening program when compared to interpretations of 2 pediatric orthopaedic surgeons and 2 orthopaedic residents. METHODS: During the 2008 to 2009 school year, 275 students were reviewed as part of a metropolitan scoliosis-screening program. 100 of the radiographs were randomly chosen and de-identified for inclusion. Two attending orthopaedic surgeons and 2 orthopaedic residents independently interpreted the films on 3 occasions and assigned each a Risser stage. Inter- and intra-rater analyses using Kappa statistics were performed to determine the reliability of the Risser stage interpretations between the orthopaedic surgeons and the radiologist as well as the reliability of the interpretations among the individual surgeons. RESULTS: Inter-rater kappa values for the attending surgeons and the radiologist averaged 0.526. Inter-rater kappa values for the resident surgeons and the radiologist averaged 0.490 and 0.101. There was significant agreement between the attending surgeons on all 3 occasions (kappa = 0.764, 0.809, 0.837). The intra-rater reliability among the attending surgeons (kappa = 0.988, 0.957) and the resident surgeons (kappa = 0.813, 0.495) showed statistical significance (P < 0.0001). Only half of the films had perfect agreement between the radiologist and the surgeons and 28% of the films were interpreted with a difference of 2 or more Risser stages. The radiologist did not interpret any of the films as a Risser 4 or 5 but 21% of the films were interpreted as a 4 or 5 by the orthopaedic surgeons. CONCLUSIONS: The scoliosis-screening program utilizes a referral pathway based on the radiologist's Risser stage interpretation in conjunction with the Cobb angle. The radiologist and the orthopaedic surgeons demonstrated only moderate agreement in their interpretations of Risser stages, resulting in a possible 21% over-referral rate. This study questions the efficacy of using the Risser stage as part of a large metropolitan scoliosis screening program and warrants further investigation. PMID- 22101672 TI - Isolated navicular-medial cuneiform tarsal coalition revisited: a case report. AB - Tarsal coalitions between the navicular and the cuneiforms occur infrequently when compared with the more common talocalcaneal and calcaneonavicular coalitions. Isolated cases of navicular-medial cuneiform coalitions have only rarely been reported; however, the diagnosis is likely underrecognized. Conservative management should be pursued initially for symptomatic patients, followed by surgical options for unresponsive cases. The few reports available recommend treatment with navicular-medial cuneiform fusions, but long-term follow up is not available to assess outcome and it remains unclear whether an isolated arthrodesis of the navicular-medial cuneiform joint will in turn lead to differing biomechanics of adjacent joints. We report a case of a patient with an isolated navicular-medial cuneiform coalition, treated with resection and free fat interposition rather than arthrodesis. To our knowledge, this is the first case of a navicular-medial cuneiform coalition reported in a patient of North American ancestry. At 2 years postoperatively, she is pain-free with all activities and has full range of motion of her ankle and subtalar joints, and full mobility at the navicular-medial cuneiform joint. This unique method provided a successful solution to this difficult situation. PMID- 22101673 TI - Beyond the classical: influenza virus and the elucidation of alternative MHC class II-restricted antigen processing pathways. AB - CD4+ T cells (T(CD4+)) are activated by peptides, generally 13-17 amino acids in length, presented at the cell surface in combination with highly polymorphic MHC class II molecules. According to the classical model, these peptides are generated by endosomal digestion of internalized antigen and loaded onto MHC class II molecules in the late endosome. Historically, this "exogenous" pathway has been defined through the extensive use of purified proteins. However, the relatively recent use of clinically relevant antigens, those of influenza virus in our case, has revealed several additional pathways of peptide production, including some that are truly "endogenous", entailing synthesis of the protein within the infected cell. Indeed, some peptides appear to be created only via endogenous processing. The cell biology that underlies these alternative pathways remains poorly understood as do their relative contributions to defence against infectious agents and cancer, and the triggering of autoimmune diseases. PMID- 22101674 TI - Innate and adaptive immunity to the nematode Strongyloides stercoralis in a mouse model. AB - Mice have been used to the study the mechanisms of protective innate and adaptive immunity to larval Strongyloides stercoralis. During primary infection, neutrophils and eosinophils are attracted by parasite components and kill the larvae by release of granule products. Eosinophils also function as antigen presenting cells for the induction of a Th2 response. B cells produce both IgM and IgG that collaborate with neutrophils to kill worms in the adaptive immune response. Vaccine studies have identified a recombinant diagnostic antigen that induced high levels of immunity to infection with S. stercoralis in mice. These studies demonstrate that there are redundancies in the mechanisms used by the immune response to kill the parasite and that a vaccine with a single antigen may be suitable as a prophylactic vaccine to prevent human strongyloidiasis. PMID- 22101675 TI - Epidemiology of primary nephrotic syndrome in Egyptian children. AB - BACKGROUND: Primary nephrotic syndrome is a common renal problem in pediatrics, with great variation in patients' characteristics in different regions of the world. The aim of this study was to define these characteristics in Egyptian children with primary nephrotic syndrome. METHODS: Records of 100 primary nephrotic syndrome patients were retrospectively reviewed. Demographic, clinical, histopathological data and response to therapy were analyzed. RESULTS: The mean age of onset was 4.43 +/- 2.7 years. Thirty-four percent of patients were steroid resistant, and 66% showed initial steroid response; 46 of the latter were steroid dependent. Forty patients underwent a renal biopsy with minimal change nephrotic syndrome occurring in 30%, mesangioproliferative glomerulonephritis in 37.5% and focal segmental glomerulosclerosis in 30%. Nine percent of cases developed chronic renal insufficiency. Response to cyclophosphamide and cyclosporine occurred in 37.5% and 33.3% of steroid-resistant nephrotic syndrome patients, respectively. CONCLUSIONS: A greater percentage of steroid-resistant patients were found in our patients compared with those in other studies. Response to immunosuppressives was different from other studies, probably due to differences in the priority of selection for immunosuppressive therapy. PMID- 22101676 TI - The mechanisms of acute transplant rejection revisited. AB - For many years, acute rejection has been considered as a typical response of the adaptive immunity system. However, recent investigations have revealed a critical role for innate immunity as a pivotal trigger in adaptive immune responses. Danger signals released by cells damaged or killed by injury or disease may be intercepted by Toll-like receptors (TLRs) that alarm the dendritic cells (DCs) through the activation of transcription factors. In the presence of an inflammatory milieu created by other components of the innate immunity, DCs become mature and present the antigen to naive T cells. The activation of T cells requires both a signal engendered by the presentation of the antigen to the T cell receptor and costimulatory signals generated by the contact between molecules displayed by antigen-presenting cells (APCs) and by T cells. Once activated, T cells encode and synthesize interleukin 2 (IL-2) and other cytokines that provide the signals for cell differentiation and proliferation. Until recently, little attention was paid to the role of antibodies in renal transplantation. However, there is mounting evidence that a number of kidney allografts fail as a consequence of a rejection caused by antibodies specifically directed against major histocompatibility complex antigens, class I or II, of the recipient. A critical role in antibody-mediated rejection (AMR) is played by complement. A number of therapeutic attempts have been tried to prevent or treat AMR. The still open question is whether the antibodies we detect are those responsible for tissue damage or not. PMID- 22101677 TI - Pharmaceutical care in chronic kidney disease: experience at Grenoble University Hospital from 2006 to 2010. AB - BACKGROUND: Clinical pharmacists (CPs) specifically manage lab-test follow-up, adapt drug dosage according to guidelines and evaluate cardiovascular risk factors and decline in renal function. The aim of this study was to assess the impact of clinical pharmacy services in outpatient nephrology clinics. METHOD: For each patient, medical history and current treatment were obtained. Each intervention was classified according to the Act-IP document of the French Society of Clinical Pharmacy. This tool contains identifications and guidelines for prevention and resolution of drug-related problems (DRPs). RESULTS: From January 2008 until April 2009, 42 patients seen by the CP on at least 2 visits were included in the study. We observed 350 pharmaceutical consultations and 263 interventions. The pharmaceutical interventions concerned: untreated indication (30%), underdosage (25.9%) and overdosage (18.3%). The CP interventions consisted of: adapting doses (42.2%) and adding treatments (31.9%). The main drugs involved concerned the cardiovascular (33.1%), digestive-metabolic (28.6%) and hematopoietic (21.6%) systems. CONCLUSION: The inclusion of a CP in the management of chronic kidney disease (CKD) patients is necessary for identification and prevention of DRPs. Besides the medical improvement of CKD patients, the CP participates in the development of prescription recommendations and therapeutic education programs for patients. Moreover, redefining roles and practices of members of a clinical team proved its efficiency in optimizing the medical care of CKD patients. Furthermore, patient entry into dialysis is postponed, which leads to a reduction in costs for health care insurance. PMID- 22101678 TI - Efforts to develop a cultured sponge cell line: revisiting an intractable problem. AB - Residents of the marine environment, sponges (Porifera) have the ability to produce organic compounds known as secondary metabolites, which are not directly involved in the normal growth, development, or reproduction of an organism. Because of their sessile nature, the production of these bioactive compounds has been interpreted as a functional adaptation to serve in an important survival role as a means to counter various environmental stress factors such as predation, overgrowth by fouling organisms, or competition for limited space. Regardless of the reasons for this adaptation, a variety of isolated compounds have already proven to demonstrate remarkable anticancer, fungicidal, and antibiotic properties. A major obstacle to the isolation and production of novel compounds from sponges is the lack of a large, reliable source of sponge material. Sponge collection from the sea would be environmentally detrimental to the already stressed and sparse sponge populations. Sponge production in an aquaculture setting might appear to be an ideal alternative but would also be cost-ineffective and sponge growth is extremely slow. A third approach involves the development of a sponge cell culture system capable of producing the necessary cell numbers to harvest for research purposes as well as for the eventual commercial-scale production of promising bioactive compounds. Unfortunately, little progress has been made in this direction other than the establishment of temporary cultures containing aggregates and fragments of cells. One impediment toward successful sponge cell culture might be ascribed to a lack of published knowledge of failed methodologies, and thus, time and effort is wasted on continued reinvention of the same methods and procedures. Consequently, we have undertaken here to chart some of our unsuccessful research efforts, our methodology, and results to provide the sponge research community with knowledge to assist them to better avoid taking the same failed pathways. PMID- 22101679 TI - Endothelial colony-forming cells show a mature transcriptional response to shear stress. AB - Endothelial progenitor cells (EPC) play a central role in endothelial maintenance and repair. Endothelial colony-forming cells (ECFC) form a subpopulation of EPC. ECFC are readily attainable, can be easily isolated, possess a high proliferation potential, and are therefore a promising source of endothelial cells (EC) for future cardiovascular therapeutic applications. The extent to which these cells respond to shear stress as adult vascular EC remains to be elucidated. Here, we study the transcriptional response of ECFC induced by shear stress and compare it with the response of mature arterial and venous cells. ECFC, as well as human umbilical vein EC (HUVEC) and human umbilical artery EC (HUAEC), were subjected to low (0.5 Pa) and high (2.5 Pa) shear stress. The endothelial differentiation phenotype and transcriptional responses were analyzed using immunocytochemistry and quantitative polymerase chain reaction (Q-PCR). Performing absolute quantification of copy numbers by Q-PCR allows comparing the responses of cell types relative to each other. Our data show that isolated ECFC resemble mature EC in cobblestone morphology and endothelial marker expression. Absolute Q-PCR quantification revealed that although being truly endothelial, ECFC do not fully resemble HUVEC or HUAEC in the expression of specific differentiation markers. When subjected to shear stress, ECFC show a mature response to fluid flow, comparable to that of HUVEC and HUAEC. The capacity of endothelial progenitors to respond to fluid flow in a similar manner to HUVEC and HUAEC highlights the universal response of EC to fluid shear stress, independently of their endothelial differentiation status. This property supports the use of these cells as an EC source for tissue engineering applications. PMID- 22101680 TI - Early community contexts, race/ethnicity and young adult CVD risk factors: the protective role of education. AB - Using a sample of 13,500 adolescents (53% female and 47% male) who participated in all four waves of the National Longitudinal Study of Adolescent Health, this study used multilevel regression to examine the influence of early structural community adversity (as measured by rates of community poverty, single-parent headed families, and two indicators of employment) and racial/ethnic status on cardiovascular disease (CVD) risk factors of young adults (systolic blood pressure, diastolic blood pressure, and mean arterial pressure). The moderating role of youth's socioeconomic attainment was also examined. Results indicate that early community adversity and African American racial status place young adults at risk for CVD. Youth's socioeconomic attainment does not erase the persistent influences of early community adversity and African American racial status on CVD risk. However, the level of education attained can protect African American young adults and those experiencing early community adversity from CVD risk factors. PMID- 22101681 TI - Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. AB - Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy. Using whole-exome sequencing followed by Sanger sequencing, we identified three truncating mutations within PRRT2 (NM_145239.2) in eight Han Chinese families with histories of paroxysmal kinesigenic dyskinesia: c.514_517delTCTG (p.Ser172Argfs*3) in one family, c.649dupC (p.Arg217Profs*8) in six families and c.972delA (p.Val325Serfs*12) in one family. These truncating mutations co-segregated exactly with the disease in these families and were not observed in 1,000 control subjects of matched ancestry. PRRT2 is a newly discovered gene consisting of four exons encoding the proline-rich transmembrane protein 2, which encompasses 340 amino acids and contains two predicted transmembrane domains. PRRT2 is highly expressed in the developing nervous system, and a truncating mutation alters the subcellular localization of the PRRT2 protein. The function of PRRT2 and its role in paroxysmal kinesigenic dyskinesia should be further investigated. PMID- 22101682 TI - Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). AB - Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia. PMID- 22101683 TI - Facile preparation of a cationic poly(amino acid) vesicle for potential drug and gene co-delivery. AB - A novel pH-responsive poly(amino acid) grafted with oligocation was prepared through the combination of ring-opening polymerization (ROP) and subsequent atom transfer radical polymerization (ATRP). Firstly, poly(gamma-2-chloroethyl-L glutamate) (PCELG) with a pendent 2-chloroethyl group was synthesized through ROP of gamma-2-chloroethyl-L-glutamate N-carboxyanhydride (CELG NCA) using n hexylamine as the initiator. Then, PCELG was used to initiate the ARTP of 2 aminoethyl methacrylate hydrochloride (AMA), yielding poly(L-glutamate)-graft oligo(2-aminoethyl methacrylate hydrochloride) (PLG-g-OAMA). The pK(a) of PLG-g OAMA was 7.3 established by the acid-base titration method. The amphiphilic poly(amino acid) could directly self-assemble into a vesicle in PBS. The vesicle was characterized by TEM and DLS. Hydrophilic DOX.HCl was loaded into the hollow core of the vesicle. The in vitro release behavior of DOX.HCl from the vesicle in PBS could be adjusted by the solution pH. In vitro cell experiments revealed that the vesicle could reduce the toxicity of the DOX.HCl. In addition, the preliminary gel retardation assay displayed that PLG-g-OAMA could efficiently bind DNA at a PLG-g-OAMA/DNA weight ratio of 0.3 or above, indicating its potential use as a gene carrier. More in-depth studies of the PLG-g-OAMA vesicle for drug and gene co-delivery in vitro and in vivo are in progress. PMID- 22101684 TI - Supplement: Yearbook of physical anthropology. Preface. PMID- 22101685 TI - The Red Queen and her king: cooperation at all levels of life. AB - The Red Queen in "Through the Looking Glass" is often used as a metaphor for the relentless, unremitting competitive struggle by which Darwin described life. That imagery fits comfortably in our culture, with its emphasis on competition and inequity, but less so for nature herself. Life is manifestly much more about cooperation, at all levels and through a variety of ubiquitous mechanisms, than it is about competition. Most organisms of most species are nowhere near the proverbial Malthusian edge of survival, such that selection will detect the tiniest difference in their performance and enhance its genetic basis. Cooperation through interaction of multiple entities is inherent in many fundamental aspects of life, and its importance is not widely enough appreciated. Here we discuss a set of principles by which this works. We illustrate the points with a computer simulation of a topic of interest to anthropology, the development of the head. In a sense, our culture has its metaphors reversed. The red royal family is a more accurate symbol for the true nature of life, human or otherwise. PMID- 22101686 TI - GIS and paleoanthropology: incorporating new approaches from the geospatial sciences in the analysis of primate and human evolution. AB - The incorporation of research tools and analytical approaches from the geospatial sciences is a welcome trend for the study of primate and human evolution. The use of remote sensing (RS) imagery and geographic information systems (GIS) allows vertebrate paleontologists, paleoanthropologists, and functional morphologists to study fossil localities, landscapes, and individual specimens in new and innovative ways that recognize and analyze the spatial nature of much paleoanthropological data. Whether one is interested in locating and mapping fossiliferous rock units in the field, creating a searchable and georeferenced database to catalog fossil localities and specimens, or studying the functional morphology of fossil teeth, bones, or artifacts, the new geospatial sciences provide an essential element in modern paleoanthropological inquiry. In this article we review recent successful applications of RS and GIS within paleoanthropology and related fields and argue for the importance of these methods for the study of human evolution in the twenty first century. We argue that the time has come for inclusion of geospatial specialists in all interdisciplinary field research in paleoanthropology, and suggest some promising areas of development and application of the methods of geospatial science to the science of human evolution. PMID- 22101687 TI - Dental evidence for the diets of Plio-Pleistocene hominins. AB - Diet is fundamental to the interaction between an organism and its environment, and is therefore an important key to understanding ecology and evolution. It should come as no surprise then that paleoanthropologists have put a great deal of effort into reconstructing the diets of Plio-Pleistocene hominins. Most of this effort has focused on teeth; these durable parts of the digestive system are usually the most commonly preserved elements in vertebrate fossil assemblages. In this article, I review much of this work. Tooth size, occlusal morphology, enamel thickness, and microstructure provide evidence for the physical properties of the foods to which a species was adapted. Dental microwear can offer insights into the properties of foods that an individual ate on a day-to-day basis. Taken together, these lines of evidence can offer important insights into early hominin food choices and adaptations. New methods of analysis and theoretical perspectives are improving our understanding of the diets of Australopithecus, Paranthropus, and early Homo, and promise further progress long into the future. PMID- 22101688 TI - Skeletal biology over the life span: a view from the surfaces. AB - The biocultural interpretation of skeletal remains is based upon the foundation of skeletal biology. In this review we examine the current state of skeletal biology research outside of the mainstream anthropology literature. The focus is on the structural changes of bone development and growth, and modeling and repair in the four bone surfaces: periosteal, Haversian, endosteal, and trabecular. The pattern of skeletal changes is placed within the framework of the human life span. New perspectives and direction of research on the environmental, biological, and genetic influences on modeling and remodeling processes are discussed chronologically at each bone surface. Implications for biological anthropologists are considered. This approach emphasizes variation in skeletal biology as a dynamic record of development, maturity, and aging. PMID- 22101689 TI - The origin and antiquity of syphilis revisited: an appraisal of Old World pre Columbian evidence for treponemal infection. AB - For nearly 500 years, scholars have argued about the origin and antiquity of syphilis. Did Columbus bring the disease from the New World to the Old World? Or did syphilis exist in the Old World before 1493? Here, we evaluate all 54 published reports of pre-Columbian, Old World treponemal disease using a standardized, systematic approach. The certainty of diagnosis and dating of each case is considered, and novel information pertinent to the dating of these cases, including radiocarbon dates, is presented. Among the reports, we did not find a single case of Old World treponemal disease that has both a certain diagnosis and a secure pre-Columbian date. We also demonstrate that many of the reports use nonspecific indicators to diagnose treponemal disease, do not provide adequate information about the methods used to date specimens, and do not include high quality photographs of the lesions of interest. Thus, despite an increasing number of published reports of pre-Columbian treponemal infection, it appears that solid evidence supporting an Old World origin for the disease remains absent. PMID- 22101690 TI - The roles of the immune system in women's reproduction: evolutionary constraints and life history trade-offs. AB - Life history theory posits that, as long as survival is assured, finite resources are available for reproduction, maintenance, and growth/storage. To maximize lifetime reproductive success, resources are subject to trade-offs both within individuals and between current and future investment. For women, reproducing is costly and time-consuming; the bulk of available resources must be allocated to reproduction at the expense of more flexible systems like immune function. When reproducing women contract infectious diseases, the resources required for immune activation can fundamentally shift the patterns of resource allocation. Adding to the complexity of the reproductive-immune trade-offs in women are the pleiotropic effects of many immune factors, which were modified to serve key roles in mammalian reproduction. In this review, we explore the complex intersections between immune function and female reproduction to situate proximate immunological processes within a life history framework. After a brief overview of the immune system, we discuss some important physiological roles of immune factors in women's reproduction and the conflicts that may arise when these factors must play dual roles. We then discuss the influence of reproductive immune trade-offs on the patterning of lifetime reproductive success: (1) the effect of immune activation/infectious disease on the timing of life history events; (2) the role of the immune system, immune activation, and infectious disease on resource allocation within individual reproductive events, particularly pregnancy; and (3) the role of the immune system in shaping the offspring's patterns of future life history trade-offs. We close with a discussion of future directions in reproductive immunology for anthropologists. PMID- 22101691 TI - Enhanced ovalbumin-induced airway inflammation in CD26-/- mice. AB - In this study, we investigated the potential role of CD26 in ovalbumin (OVA) induced airway inflammation using CD26 gene knockout mice. Compared with WT counterparts, CD26(-/-) mice showed an obviously enhanced tissue response and denser pulmonary infiltrates containing eosinophils around vessels and in the parenchyma after OVA sensitization and challenge. Serum IgG, including subclasses IgG1 and IgG2a, was greatly reduced in CD26(-/-) mice, but serum IgE remained unchanged. CD26(-/-) mice had increased mRNA expression of the Th2 cytokines IL 4, IL-5, and IL-13 in the lungs compared with WT mice, whereas the levels of the pro-Th1 cytokine IL-12p40 were similar in both strains. Consequently, enhanced protein secretion of IL-4, IL-5, and IL-13 was detected in bronchoalveolar lavage (BAL) fluid from CD26(-/-) mice. In agreement with overexpressed Th2 cytokines, both mRNA transcript and protein levels of chemokines eotaxin and RANTES, as well as their receptors CC chemokine receptor 3 (CCR3) and CCR5, were elevated in CD26(-/-) mice. These results suggest a protective role for CD26 in restricting OVA-induced airway inflammation. PMID- 22101692 TI - TrueFISP of the pediatric pineal gland: volumetric and microstructural analysis. AB - PURPOSE: Although high-resolution 3D-imaging has markedly improved the imaging of the pediatric pineal gland, the prevalences of typical and atypical cysts as well as in vivo volumes are unknown. The purpose of this study was to compare the frequency of typical and atypical cysts using high-resolution 3D-sequence true fast imaging with steady state precession (trueFISP) and standard sequences and to directly measure the pineal volume in a large pediatric population. METHODS: In 54 consecutively examined children (age 0-17 years, mean age 5.4 +/- 5.6 years, 44% female, 56% male) the prevalence of typical and atypical cysts (thickened rim, trabeculations, asymmetry) was determined using trueFISP (isotropic, 0.8 mm) and standard sequences, 1.5-T, T1-weighted spin echo (T1-SE), T2-weighted turbo spin echo (T2-TSE) and fluid attenuated inversion recovery (FLAIR). Indistinct findings were noted separately. Volumetry was based on the trueFISP datasets. Solid and cystic compartments were approached separately. The pineal volume was correlated to gender and age. RESULTS: The detected frequency of pineal cysts was higher in trueFISP (57.4%) than in standard sequences (T1-SE 7.4%, T2-TSE 14.8%, and FLAIR 13.0%). In trueFISP 66.3% of the detected cysts were classified as atypical (standard sequences 0%). Indistinct findings were lowest in trueFISP. The mean pineal volume was 94.3 +/- 159.1 mm3 and no gender related differences were found. Age and volume showed a moderate correlation (r = 0.382) which was remarkably higher in completely solid glands (r = 0.659). CONCLUSIONS: TrueFISP imaging improves the detection of pineal cysts in children. A typical cysts are frequently detected as an incidental finding. Volumetric analysis of the pediatric pineal gland is feasible and reveals enormous variation. Whereas gender effects are negligible, the pineal volume in children is dependant on age. PMID- 22101693 TI - Outcomes of infants undergoing superior cavopulmonary connection in the presence of ventricular dysfunction. AB - Outcomes in patients with ventricular dysfunction undergoing superior cavopulmonary connection (SCPC) are not well known. We reviewed records of patients undergoing SCPC at our center from December 2005 to October 2009 and studied those whose pre-SCPC echocardiograms demonstrated at least moderate systemic ventricular dysfunction. Of the 213 patients undergoing SCPC, 19 (9%) met inclusion criteria. Diagnoses were hypoplastic left heart syndrome (n = 18) and rightward unbalanced atrioventricular canal with pulmonary stenosis (n = 1). In those surviving >2 months after SCPC, ventricular function was assessed by echocardiography 4.9 (range 3.5 to 9.7) months after SCPC and was improved in ten of 17 (59%), unchanged in six of 17 (35%), and worsened in one of 17 (16%) patients. After SCPC, three patients died, and one underwent heart transplant 21.9 months after SCPC. Transplant-free survival was attained by 15 of 19 (79%) patients during follow-up of 33.0 months (range 10.8 to 51.4). Fontan completion was performed on six survivors on reaching an appropriate age. Ventricular dysfunction before SCPC is not uncommon and occurs primarily in patients with a morphologic right ventricle. Ventricular performance improves in the majority of patients after SCPC, and midterm outcomes are comparable with previous reports, suggesting that these patients remain candidates for staged palliation. PMID- 22101695 TI - Complementary and alternative medicine in rheumatoid arthritis. AB - There are studies that have evidence for and are against to suggest that some of the complementary and alternative medicines (CAM) are effective against rheumatoid arthritis (RA). However, there are no adequate studies that have evaluated the role that can be played by CAM in the management of RA. A focused approach in defining the role and limitation as well as the possible adverse events and safety should help in integrating both CAM and mainstream treatment of RA. This review discussed the limitations in the available literature and the direction for future research, which can accelerate the defining role of CAM in RA. PMID- 22101694 TI - Action mechanisms of complementary and alternative medicine therapies for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized as a chronic inflammatory disease in joints and concomitant destruction of cartilage and bone. Cartilage extracellular matrix components, such as type II collagen and aggrecan are enzymatically degraded by matrix metalloproteinases (MMPs) and aggrecanases in RA. Currently, treatments targeting cytokines, including anti-tumor necrosis factor (TNF) alpha antibodies, soluble TNF receptor, anti-interleukin (IL)-6 receptor antibody, and IL-1 receptor antagonist, are widely used for treating RA in addition to antiantiinflammatory agents and disease-modifying antirheumatic drugs (DMARDs), such as inflmethotrexate, but these treatments have some problems, especially in terms of cost and the increased susceptibility of patients to infection in addition to the existence of low-responders to these treatments. Therefore, therapeutics that can be safely used for an extended period of time would be preferable. Complementary and alternative medicines including traditional Chinese medicines (TCM) have been used for the arthritic diseases through the ages. Recently, there are many reports concerning the anti-arthritic action mechanisms of TCM-based herbal formulas and crude herbal extracts or isolated ingredients. These natural herbal medicines are thought to moderately improve RA, but they exert various actions for the treatment of RA. In this review, the current status of the mechanism exploration of natural compounds and TCM-based herbal formulas are summarized, focusing on the protection of cartilage destruction in arthritic diseases including RA and osteoarthritis. PMID- 22101696 TI - The potential role of Chinese medicine in ameliorating extra-articular manifestations of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease chiefly affecting synovial membranes of multiple joints. The clinical manifestations are highly variable. Besides joint affection, extra-articular manifestations always occur in RA patients, such as lung, blood vessel, heart, endocrine glands, hematological system, and nervous system affections. In addition to Western medicine therapy, Chinese medicine also plays a significant role in the treatment of RA with good efficacy and less adverse reactions. This paper summarizes the effects of xinfeng capsule, a Chinese medicine, and the mechanisms of its action in ameliorating the extra-articular manifestations based on a series of clinical and experimental researches. PMID- 22101697 TI - Effect of xinfeng capsule on the cardiac function in patients with rheumatoid arthritis. AB - OBJECTIVE: To study the changes in cardiac function of rheumatoid arthritis (RA) patients and: to observe the effect of xinfeng capsule ( XFC) on them. METHODS: Sixty-eight RA patients were: randomly assigned to two groups by a lottery: 38 patients in the treatment group treated orally with XFC, 3 capsules, thrice a day, and 30 in the control group treated with fengshi gutong capsule (FSGTC), 4 capsules, twice a day, 30 days as one course of treatment, and two courses were given for both groups. A normal control (NC) group including 20 healthy subjects was set up. The clinical efficacy was compared between the two treated groups. The changes in cardiac function, including early diastolic peak flow velocity (E), late diastolic peak flow velocity (A), left ventricular fraction shortening (FS), and E/A, as well as uric acid (UA), erythrocyte sedimentation rate (ESR), alpha-acid glycoprotein (alpha-AGP), and hypersensitive C-reaction protein (hs CRP), were observed. The regulation T cell was determined with flow cytometry. RESULTS: (1) The total effective rate in the treatment group and the control group was 92.1%: (35/38) and 70.0% (21/30), respectively. Significant difference was shown between them (P<0.05). (2) 0.05). CONCLUSIONS: The TLR4-NFkappaB-TNFalpha pathway was quickly activated: and was independent of HSP70 in the early phase of neonatal cardiomyocyte injury induced by LPS. The protective effects of Sal B may be through inhibiting the TLR4 NFkappaB-TNFalpha pathway and are dose-dependent. PMID- 22101701 TI - Clinical evaluation of Soothing Gan and invigorating Pi acupuncture treatment on diarrhea-predominant irritable bowel syndrome. AB - OBJECTIVE: To explore the effect of Soothing Gan and invigorating Pi (SGIP) acupuncture treatment on the clinical symptoms and quality of life (QOL) in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: With a single-blinded randomized control study adopted, 63 patients who met the inclusion criteria were assigned by a random number table to two groups, 31 in the treatment group and 32 in the drug control group. The treatment group received SGIP acupuncture therapy; while the control group was treated orally with pinaverium bromide. The treatment duration of both groups was 28 days. The clinical efficacy was evaluated and compared by scoring patient's symptom and QOL. RESULTS: A significant difference was found by variance analysis in efficacies between the two groups (P<0.01), shown as the quicker initiation of effect (P<0.05) and the more evident clinical improvement in symptoms along the increase in treatment duration, as well as the more significant elevation of QOL in the acupuncture treatment group (P<0.01). SGIP displayed its superiority especially in improving dysphoria, conflict behavior, dietary restrictions, and social responses. CONCLUSION: SGIP acupuncture treatment could effectively alleviate the degree and frequency of symptoms' attack in IBS-D patients, such as abdominal pain, diarrhea, abdominal distension, etc., markedly relieve the tenesmic sensation, with the efficacy better than that of pinaverium bromide, showing a preponderance in improving patient's QOL. PMID- 22101702 TI - Treatment of recurrent respiratory infection with Chinese drug therapy of Tonifying-Shen and solidifying superficiality--a clinical case report. PMID- 22101703 TI - Omitted acknowledgement of previous spine publication of single center series reporting the rate of pulmonary function recovery using multiple time points following thoracoscopic scoliosis surgery. PMID- 22101705 TI - Artificial cervical disc arthroplasty: a systematic review. AB - STUDY DESIGN: Systematic Review. OBJECTIVE: (1) To qualitatively analyze the literature on the efficacy and effectiveness of artificial cervical disc arthroplasty (ACDA). (2) To highlight methodological and reporting issues of randomized controlled trials (RCT) reports on effectiveness of ACDA compared to cervical fusion. SUMMARY OF BACKGROUND DATA: ACDA is an alternate surgical procedure that may replace cervical fusion in selected patients suffering from cervical degenerative disc disease. METHODS: We searched seven electronic databases, including MEDLINE, Cochrane Library, and EMBASE, unpublished sources, and reference lists for studies on the efficacy and effectiveness of ACDA compared to cervical fusion--the surgical standard of care for patients with cervical degenerative disc disease. RESULTS: A total of 622 studies were retrieved, of which 18 (13 case series, four RCT reports, one nonrandomized comparative study) met the inclusion criteria for this review. The four RCTs and the nonrandomized comparative study concluded that the effectiveness of ACDA is not inferior to that of cervical fusion in the short term (up to 2-yr follow-up). The safety profile of both procedures appears similar. The case series reviewed noted improved clinical outcomes at 1 or 2 years after one or multiple-level ACDA. CONCLUSION: ACDA is a surgical procedure that may replace cervical fusion in selected patients suffering from cervical degenerative disc disease. Within 2 years of follow-up, the effectiveness of ACDA appears similar to that of cervical fusion. Weak evidence exists that ACDA may be superior to fusion for treating neck and arm pain. Future studies should report change scores and change score variance in accordance with RCT guidelines, in order to strengthen credibility of conclusions and to facilitate meta-analyses of studies. PMID- 22101707 TI - Biomolecule/nanomaterial hybrid systems for nanobiotechnology. AB - The integration of biomolecules with metallic or semiconductor nanoparticles or carbon nanotubes yields new hybrid nanostructures of unique features that combine the properties of the biomolecules and of the nano-elements. These unique features of the hybrid biomolecule/nanoparticle systems provide the basis for the rapid development of the area of nanobiotechnology. Recent advances in the implementation of hybrid materials consisting of biomolecules and metallic nanoparticles or semiconductor quantum dots will be discussed. The following topics will be exemplified: (i) The electrical wiring of redox enzymes with electrodes by means of metallic nanoparticles or carbon nanotubes, and the application of the modified electrodes as amperometric biosensors or for the construction of biofuel cells. (ii) The biocatalytic growth of metallic nanoparticles as a means to construct optical or electrical sensors. (iii) The functionalization of semiconductor quantum dots with biomolecules and the application of the hybrid nanostructures for developing different optical sensors, including intracellular sensor systems. (iv) The use of biomolecule metallic nanoparticle nanostructures as templates for growing metallic nanowires, and the construction of fuel-driven nano-transporters. PMID- 22101708 TI - Superresolution optical fluctuation imaging (SOFI). AB - Superresolution microscopy has shifted the limits for fluorescence microscopy in cell -biology. The possibility to image cellular structures and dynamics of fixed and even live cells and organisms at resolutions of several nanometers holds great promise for future biological discoveries. We recently introduced a novel superresolution technique, based on the statistical evaluation of stochastic fluctuations stemming from single emitters, dubbed "superresolution optical fluctuation -imaging" (SOFI). In comparison to previously introduced superresolution methods, SOFI exhibits favorable attributes such as simplicity, affordability, high speed, and low levels of light exposure. Here we summarize the basic working principle and recent advances. PMID- 22101709 TI - Application of nanoparticles for the detection and sorting of pathogenic bacteria by flow-cytometry. AB - In this paper we will describe a new developed contribution of fluorescence nano crystal (q-dots) as a fluorescence label for detecting pathogenic bacteria by flow cytometry (FCM) and the use of nano-magnetic particles to improve bacterial sorting by Flow cytometry cell sorting (FACS).FCM or FACS systems are based upon single cell detection by light scatter and Immunofluorescence labeling signals. The common FACS systems are based upon single or dual excitation as excitation source both for light scatter parameters and for several fluorescence detectors. Hence, for multi-labeling detection, there is a need for fluorophores with broad excitation wave length and sharp emission bands. Moreover, such fluorophores should be with high fluorescence efficiency, stable, and available for bio molecules conjugation. Q-dots benefit from practical features which meet those criteria. We will describe the use of q-dots as fluorescence labels for specific conjugates against Bacillus anthracis spores and Yersinia pestis bacteria, which enable the specific detection of the different species. A specific and sensitive multiplex analysis procedure for both pathogens was achieved, with high sensitivity down to 10(3) bacteria per ml in the sample.Sorting bacteria by FACS has a tremendous advantage for sensitive and selective analysis and sorting of sub-populations. However it has always been a difficult task due to the fact that bacteria are small particles (usually 1-3 MUm). For such small particles, light scatter signal is on the threshold level, and many positive events may be lost. Here we will present the development of a procedure for sorting of the gram negative bacteria Y. pestis from environment samples. We will show that the application of nano-magnetic particles, as a tool for the immunomagnetic labeling and separation of the bacteria, enables fast sorting in high and low bacterial concentration down to 10 (5) cfu/ml. The nano-metric physical size of the immunospecific labeling particles disguises them from the FACS detectors; hence the bacterial population becomes the major population as opposed to being "rare events population" when using standard micro-magnetic beads for pre enrichment.The procedure of separation and collection of bacteria enables sensitive detection and characterization methods of bacteria from complex samples. PMID- 22101710 TI - Advancing nanostructured porous si-based optical transducers for label free bacteria detection. AB - Optical label-free porous Si-based biosensors for rapid bacteria detection are introduced. The biosensors are designed to directly capture the target bacteria cells onto their surface with no prior sample processing (such as cell lysis). Two types of nanostructured optical transducers based on oxidized porous Si (PSiO(2)) Fabry-Perot thin films are synthesized and used to construct the biosensors. In the first system, we graft specific monoclonal antibodies (immunoglobulin G's) onto a neat electrochemically-machined PSiO(2) surface, based on well-established silanization chemistry. The second biosensor class consists of a PSiO(2)/hydrogel hybrid. The hydrogel, polyacrylamide, is synthesized in situ within the nanostructured PSiO(2) host and conjugated with specific monoclonal antibodies to provide the active component of the biosensor. Exposure of these modified-surfaces to the target bacteria results in "direct cell-capture" onto the biosensor surface. These specific binding events induce predictable changes in the thin-film optical interference spectrum of the biosensor. Our studies demonstrate the applicability of these biosensors for the detection of low bacterial concentrations, in the range of 10(3)-10(5) cell/ml, within minutes. The sensing performance of the two different platforms, in terms of their stability in aqueous media and sensitivity, are compared and discussed. This preliminary study suggests that biosensors based on PSiO(2)/hydrogel hybrid outperform the neat PSiO(2) system. PMID- 22101711 TI - Gold fibers as a platform for biosensing. AB - A new form of high surface bioelectrode based on electrospun gold microfiber with -immobilized glucose oxidase was developed. The gold fibers were prepared by electroless deposition of gold nanoparticles on a poly(acrylonitrile)-HAuCl(4) electrospun fiber. The material was characterized using electron microscopy, XRD and BET, as well as cyclic voltammetry and biochemical assay of the immobilized enzyme. The surface area of the gold microfibers was 2.5 m(2)/g. Glucose oxidase was covalently crosslinked to the gold surface using cystamine monolayer and glutardialdehyde, and portrayed characteristic catalytic currents for oxidizing glucose using a ferrocene methanol mediator. Limit of detection of glucose is 0.1 mM. The K(m) of the immobilized enzyme is 10 mM, in accordance with other reports of immobilized glucose oxidase. The microfiber electrode was reproducible and showed correlation between fiber weight, cathodic current and enzymatic loading. PMID- 22101712 TI - Surface-enhanced Raman spectroscopy of organic molecules adsorbed on metallic nanoparticles. AB - The improvements in Raman instrumentation have led to the development of portable, simple to operate, Raman instruments that can be used for on-site analysis of substances relevant for homeland security purposes such as chemical and biological warfare and explosives materials.Raman spectroscopy, however, suffers from limited sensitivity which can be overcome by Surface-Enhanced Raman Spectroscopy (SERS). SERS can enhance the Raman signal of a target molecule by 6 10 orders of magnitude. The increased sensitivity, together with Raman's molecular recognition capabilities and the availability of portable Raman instruments make SERS a powerful analytical tool for on site detection.In this work we studied the effect of target molecules and SERS-active substrate properties on the obtained SERS, using a field portable Raman spectrometer. Also reported herein is the SERS detection of the chemical warfare agent sulfur mustard (HD, 2,2 dichloroethyl sulfide). This study may serve as a basis for the development of SERS platform for homeland security purposes. PMID- 22101713 TI - Quantum dots and fluorescent protein FRET-based biosensors. AB - There has been considerable recent interest in the creation of nanoparticle biomolecule hybrid materials for uses such as in vitro and in vivo biosensing, biological imaging, and drug -delivery. Nanoparticles have a high surface to volume ratio, making them capable of being decorated with -various biomolecules on their surface which retain their biological activity. Techniques to bind these biomolecules to nanoparticle surfaces are also advancing rapidly. Here we demonstrate hybrid materials assembled around CdSe/ZnS core/shell semiconductor quantum dots (QDs). These intrinsically fluorescent materials are conjugated to the fluorescent proteins YFP, mCherry and the light harvesting complex b phycoerythrin (b-PE). QDs have fluorescent properties that make them ideal as donor fluorophores for Forster resonance energy transfer (FRET) while the fluorescent proteins are able to act as FRET acceptors displaying many advantages over organic dyes. We examine FRET interactions between QDs and all three fluorescent proteins. Furthermore, we show QD-mCherry hybrid materials can be utilized for in vitro biosensing of caspase-3 enzymatic activity. We further show that QDs and fluorescent proteins can be conjugated together intracellularly with strong potential for live-cell imaging and biosensing applications. PMID- 22101714 TI - Semiconductor quantum dots as FRET acceptors for multiplexed diagnostics and molecular ruler application. AB - Applications based on Forster resonance energy transfer (FRET) play an important role for the determination of concentrations and distances within nanometer-scale systems in vitro and in vivo in many fields of biotechnology. Semiconductor nanocrystals (Quantum dots - QDs) possess ideal properties for their application as FRET acceptors when the donors have long excited state lifetimes and when direct excitation of QDs can be efficiently suppressed. Therefore, luminescent terbium complexes (LTCs) with excited state lifetimes of more than 2 ms are ideal FRET donor candidates for QD-acceptors. This chapter will give a short overview of theoretical and practical background of FRET, QDs and LTCs, and present some recent applications of LTC-QD FRET pairs for multiplexed ultra-sensitive in vitro diagnostics and nanometer-resolution molecular distance measurements. PMID- 22101715 TI - Assembly and microscopic characterization of DNA origami structures. AB - DNA origami is a revolutionary method for the assembly of molecular nanostructures from DNA with precisely defined dimensions and with an unprecedented yield. This can be utilized to arrange nanoscale components such as proteins or nanoparticles into pre-defined patterns. For applications it will now be of interest to arrange such components into functional complexes and study their geometry-dependent interactions. While commonly DNA nanostructures are characterized by atomic force microscopy or electron microscopy, these techniques often lack the time-resolution to study dynamic processes. It is therefore of considerable interest to also apply fluorescence microscopic techniques to DNA nanostructures. Of particular importance here is the utilization of novel super resolved microscopy methods that enable imaging beyond the classical diffraction limit. PMID- 22101716 TI - DNA nanotechnology. AB - The base sequence encoded in nucleic acids yields significant structural and functional properties into the biopolymer. The resulting nucleic acid nanostructures provide the basis for the rapidly developing area of DNA nanotechnology. Advances in this field will be exemplified by discussing the following topics: (i) Hemin/G-quadruplex DNA nanostructures exhibit unique electrocatalytic, chemiluminescence and photophysical properties. Their integration with electrode surfaces or semiconductor quantum dots enables the development of new electrochemical or optical bioanalytical platforms for sensing DNA. (ii) The encoding of structural information into DNA enables the activation of autonomous replication processes that enable the ultrasensitive detection of DNA. (iii) By the appropriate design of DNA nanostructures, functional DNA machines, acting as "tweezers", "walkers" and "stepper" systems, can be tailored. (iv) The self-assembly of nucleic acid nanostructures (nanowires, strips, nanotubes) allows the programmed positioning of proteins on the DNA templates and the activation of enzyme cascades. PMID- 22101717 TI - Role of carbohydrate receptors in the macrophage uptake of dextran-coated iron oxide nanoparticles. AB - Superparamagnetic iron oxide (SPIO, Ferumoxides, Feridex), an important MRI intravenous contrast reagent, is efficiently recognized and eliminated by macrophages in the liver, spleen, lymph nodes and atherosclerotic lesions. The receptors that recognize nanoparticles are poorly defined and understood. Since SPIO is coated with bacterial polysaccharide dextran, it is important to know whether carbohydrate recognition plays a role in nanoparticle uptake by macrophages. Lectin-like receptors CD206 (macrophage mannose receptor) and SIGNR1 were previously shown to mediate uptake of bacterial polysaccharides. We transiently expressed receptors MGL-1, SIGNR-1 and msDectin-1 in non-macrophage 293T cells using lipofection. The expression was confirmed by reverse transcription PCR. Following incubation with the nanoparticles, the uptake in receptor-expressing cells was not statistically different compared to control cells (GFP-transfected). At the same time, expression of scavenger receptor SR-A1 increased the uptake of nanoparticles three-fold compared to GFP-transfected and control vector-transfected cells. Blocking CD206 with anti-CD206 antibody or with the ligand mannan did not affect SPIO uptake by J774.A1 macrophages. Similarly, there was no inhibition of the uptake by anti-CD11b (Mac-1 integrin) antibody. Polyanionic scavenger receptor ligands heparin, polyinosinic acid, fucoidan and dextran sulfate decreased the uptake of SPIO by J774A.1 macrophages and Kupffer cells by 60-75%. These data unambiguously show that SPIO is taken up via interaction by scavenger receptors, but not via dextran recognition by carbohydrate receptors. Understanding of nanoparticle-receptor interaction can provide guidance for the design of long circulating, non-toxic nanomedicines. PMID- 22101718 TI - Toxicity of gold nanoparticles on somatic and reproductive cells. AB - Along with the number of potential applications for gold nanoparticles (AuNP) especially for medical and scientific purposes, the interest in possible toxic effects of such particles is rising. The general perception views nanosized gold colloids as relatively inert towards biological systems. However, a closer analysis of pertinent studies reveals a more complex picture. While the chemical compound of which the nanoparticles consists plays an important role, further biocompatibility determining aspects have been made out. The vast majority of trials concerning AuNP-toxicity were performed using somatic cell culture lines. The results show a considerable dependency of toxic effects on size, zeta potential and surface functionalisation. In vivo studies on this subject are still rare. Based on the existing data it can be assumed, that a dosage of under <400 ug Au/kg showed no untoward effects. If higher amounts were applied toxicity depended on route of administration and particle size. Since nanoparticles have been shown to cross reproduction-relevant biological barriers such as the blood testicle and the placental barrier the question of their reprotoxicity arises. Yet data concerning this subject is far from adequate. Regarding gametes, recent experiments showed a dose-dependent sensitivity of spermatozoa towards AuNP. Oocytes have not yet been tested in that respect. Interestingly, so far no effects were detected on embryos after gold nanoparticle exposure. In conclusion, the biocompatibility of gold nanoparticles depends on a range of particle specific aspects as well as the choice of target tissue. Further clarification of such matters are subject to ongoing research. PMID- 22101719 TI - Ultrasound activated nano-encapsulated targeted drug delivery and tumour cell poration. AB - INTRODUCTION: Recently, ultrasonic drug release has been a focus of many research groups for stimuli responsive drug release. It has been demonstrated that a focused ultrasound (FUS) beam rapidly increases the temperature at the focused tissue area. One potential mechanism of drug targeting is to utilize the induced heat to release or increase penetration of chemotherapy to cancer cells. The efficiency of targeted drug delivery may increase by using FUS beam in conjugation with nano--encapsulated drug carriers.The aim of this study is to investigate the effect of heat and ultrasound on the cellular uptake and therapeutic efficacy of an anticancer drug using Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS). MATERIALS AND METHODS: Human KB cells (CCL-17 cells) were seeded into 96-well plates and heat treated at 37-55 degrees C for 2 10 min. Cell viability was determined using the colorimetric MTT assay. The cells were also subjected to MRgFUS and the degree of cell viability was determined. These experiments were conducted using an ExAblate 2000 system (InSightec, Haifa, Israel) and a GE 1.5 T MRI system, software release 15. RESULTS: We have observed a significant decrease in human KB cell viability due to heat (>41 degrees C) in the presence of Doxorubicin (DOX), in comparison with DOX at normal culture temperature (37 degrees C). The synergistic effect of heat with DOX may be explained by several mechanisms. One potential mechanism may be increased penetration of DOX to the cells during heating. In addition, we have shown that ultrasound induced cavitation causes cell necrosis. DISCUSSION AND FUTURE WORK: Further investigation is required to optimize the potential of MRgFUS to enhance cellular uptake of therapeutic agents. A novel delivery nano-vehicle developed by CapsuTech will be investigated with MRgFUS for its potential as a stimuli responsive delivery system. PMID- 22101720 TI - Ultrasound mediated localized drug delivery. AB - Chemotherapy is one of the frontline treatments for cancer patients, but the toxic side effects limit its effectiveness and potential. The goal of drug delivery is to reduce these side effects by encapsulating the drugs in a carrier which prevents release and can circulate throughout the body causing minimal damage to the healthy tissue. Slow release carriers have been developed which reduce the exposure to healthy tissue but this slow release also limits the maximum levels of drug in the tumor and nonspecific accumulation in healthy tissue remains a major hurdle. The next advance is to design these carriers to produce a rapid burst release of drug, but only in response to a localized trigger. The trigger of choice is low intensity focused ultrasound. A new particle is described here which incorporates an ultrasound sensitive microbubble of perfluorocarbon gas within a protective liposome carrier along with the payload. It is shown that this design can accomplish the desired burst release when exposed to ultrasound focused to small spatial locations within tissue phantoms. The ability to trigger release could provide a second level of spatial and temporal control beyond biochemical targeting or passive accumulation, making these promising particles for further development. PMID- 22101721 TI - Sonochemical proteinaceous microspheres for wound healing. AB - In this work, we report a novel approach using proteinaceous microspheres of bovine serum albumin (BSA), human serum albumin (HSA) and silk fibroin (SF) containing different organic solvents, namely n-dodecane, mineral oil and vegetable oil, to reduce the activity of human neutrophil elastase (HNE) found in high levels on chronic wounds. The ability of these devices to inhibit HNE was evaluated using porcine pancreatic elastase (PPE) solution as a model of wound exudates. The results obtained indicated that the level of PPE activity can be tuned by changing the organic solvent present on different protein microspheres, thus showing an innovative way of controlling the elastase-antielastase imbalance found in chronic wounds. Furthermore, these proteinaceous microspheres were shown to be important carriers of elastase inhibitors causing no cytotoxicity in human skin fibroblasts in vitro, making them suitable for biomedical applications, such as chronic wounds. PMID- 22101722 TI - Alendronate liposomes for antitumor therapy: activation of gammadelta T cells and inhibition of tumor growth. AB - Circulating gammadelta T cells are cytotoxic lymphocytes that are unique to primates. Recent -studies have shown that amino-bisphosphonates (nBP) activate gammadelta T cells to kill tumor cells in an indirect mechanism, which requires antigen presenting cells (APC). We hypothesized that selective targeting of nBP to monocytes would result in a more potent gammadelta T cells activation in circulation, and in tissue associated macrophages (TAM) following monocytes-laden drug extravasation and liposomes accumulation at the tumor site. In addition, inhibition of TAM by alendronate liposomes (ALN-L) is expected. ALN was targeted exclusively to monocytes, but not to lymphocytes, by encapsulating it in negatively-charged liposomes. The proportion of human gammad-T cells in the CD3(+) population following treatment with ALN-L or the free drug was increased, from 5.6 +/- 0.4% to 50.9 ;+/- 12.2% and 49.5 +/- 12.9%, respectively. ALN solution and liposomes treatments resulted in an increased, and in a dose dependent manner, TNFalpha secretion from h-PBMC. Preliminary results showed that ALN-L inhibited tumor growth in a nude mouse breast tumor model. It is suggested that enhanced activation of gammadelta T cells could be obtained due to interaction with circulating monocytes as well as by TAM endocytosing liposomal nBP leading to a potentiated anti-tumor effect of nBP. It should be noted that this could be validated only in primates/humans since gammadelta T cells are unique in these species. PMID- 22101723 TI - Molecular characterization of peach PR genes and their induction kinetics in response to bacterial infection and signaling molecules. AB - 'Venture' and 'BabyGold 5' are two peach cultivars with a demonstrated resistance and susceptibility, respectively, to bacterial spot disease caused by Xanthomonas campestris pv. pruni (Xcp). To explore the differences between these cultivars at the molecular level, two PR1 (Pp-PR1a, Pp-PR1b) and three PR5 (Pp-TLP1, Pp-TLP2 and Pp-TLP3) genes were isolated from peach (Prunus persica L.) and investigated by in silico and in situ approaches. The analysis of gene expression by qRT-PCR indicated that all PR genes, except Pp-PR1a, were induced to a significantly higher degree in the resistant cultivar. In response to signaling molecules, Pp PR1a was induced chiefly by SA treatment, while other PR genes were induced mainly by ethephon or MeJA treatments. The induction of the same set of PR genes in response to bacterial infection, MeJA or ethephon suggests the involvement of jasmonic acid (JA)/ethylene (ET)-signaling pathways in mediating resistance against Xcp, which is consistent with the potential hemibiotrophic nature of this bacterium. The identification of binding sites for ERF and MYC2 transcription factors in the promoter of Pp-TLP1 and Pp-TLP2 genes further supported the role of JA/ET pathways in the transcription regulation of these genes. The role of stomata in defense against Xcp was also investigated by measuring stomatal apertures in both 'Venture' and 'BabyGold 5' leaves after 1 and 3 HPI. While most stomata closed in both cultivars within 1 HPI, stomata reopened again at 3 HPI with a higher percentage recorded for 'BabyGold 5', suggesting a potential role of stomata in the susceptibility of this cultivar. PMID- 22101724 TI - Potassium sparing diuretics as adjunct to mannitol therapy in neurocritical care patients with cerebral edema: effects on potassium homeostasis and cardiac arrhythmias. AB - BACKGROUND: Mannitol therapy to treat cerebral edema induces osmotic diuresis and electrolyte loss. In neurocritical care patients, potassium is the electrolyte that most often needs replacement. Objective of this study was to evaluate the effects of adding potassium sparing diuretic (canrenone) to mannitol therapy on potassium urinary excretion, potassium plasma levels, and incidence of new cardiac arrhythmias in patients receiving neurocritical care for cerebral edema. METHODS: Fifty-six patients were prospectively assigned to mannitol or mannitol plus i.v. canrenone. Potassium urinary excretion, potassium plasma levels, urinary volume, and the incidence of new cardiac arrhythmias were recorded during the first 8 days of therapy. RESULTS: In patients treated with mannitol the potassium urinary excretion was stable over the first 3 days and significantly increased, compared to baseline, on day 4th to 8th (baseline 20.3 +/- 10.6 mEq/l/die, day 8th 24.6 +/- 10.6 mEq/l/die, P < 0.05); while potassium plasma levels significantly decreased. In patients receiving mannitol plus canrenone potassium urinary excretion decreased from day 3rd to 8th (baseline 21.9 +/- 11.6 mEq/l/die, day 8th 15.9 +/- 10.9 mEq/l/die, P < 0.015) and potassium plasma levels increased but remained within normal values range. The incidence of new cardiac arrhythmias was higher in the mannitol group than the mannitol plus canrenone group (35.7 vs. 10.7%; P < 0.01). Urinary volumes, potassium balance, and sodium plasma concentration were similar in the 2 study groups. CONCLUSION: In patients receiving neurocritical care for cerebral edema, the adjunct of a potassium sparing diuretic (canrenone) to mannitol therapy reduces potassium urinary loss, prevents hypokalemia, and reduces the incidence of new cardiac arrhythmias. PMID- 22101725 TI - Food insecurity and low self-efficacy are associated with health care access barriers among Puerto-Ricans with type 2 diabetes. AB - Racial/ethnic minorities are disproportionately affected by barriers to health care access and utilization. The primary objective was to test for an independent association between household food insecurity and health care access/utilization. In this cross-sectional survey, 211 Latinos (predominantly, Puerto-Ricans) with type 2 diabetes (T2D) were interviewed at their homes. Factor analyses identified four barriers for health care access/utilization: enabling factor, doctor access, medication access and forgetfulness. Multivariate logistic regression models examined the association between each of the barrier factors and food insecurity controlling for sociodemographic, cultural, psychosocial, and diabetes self-care variables. Higher food insecurity score was a risk factor for experiencing enabling factor (OR = 1.46; 95% CI = 1.17-1.82), medication access (OR = 1.26; 95 CI% = 1.06-1.50), and forgetfulness (OR = 1.22; 95 CI% = 1.04-1.43) barriers. Higher diabetes management self-efficacy was protective against all four barriers. Other variables associated with one or more barriers were health insurance, perceived health, depression, blood glucose, age and education. Findings suggest that addressing barriers such as food insecurity, low self efficacy, lack of health insurance, and depression could potentially result in better health care access and utilization among low income Puerto-Ricans with T2D. PMID- 22101726 TI - Acculturation, dietary practices and risk for childhood obesity in an ethnically heterogeneous population of Latino school children in the San Francisco bay area. AB - Previous studies have found increased acculturation to the US lifestyle increases risk for obesity in Latinos. However, methodologies differ, and results in children are inconsistent. Moreover, previous studies have not evaluated risk factors within the heterogeneous US population. We recruited 144 self-identified Latino school children and their mother or father in grades 4-6 in San Francisco parochial schools and South San Francisco public schools using an information letter distributed to all students. Children and parents had weights, heights, demographic information, dietary patterns and lifestyle variables collected in English or Spanish through an interview format. A high percentage of our children were overweight [>=85th percentile body mass index (BMI)] (62.5%) and obese (>=95th percentile BMI) (45.2%). Correspondingly parents also had a high percentage of overweight (BMI >= 25 & <30) (40.8%) and obesity (BMI >= 30) (45.3%). Mexico was the country of origin for 62.2% of parents, and 26.6% were from Central or South America. In multivariate logistic analysis, speaking Spanish at home was an independent risk factor for obesity [odds ratio (OR) 2.97, 95% confidence interval (CI) 1.28-6.86]. Eating breakfast daily (OR 0.34, 95% CI 0.15-0.78) and consumption of tortas (a Mexican fast food sandwich) (OR 0.45, 95% CI 0.21-1.00) were associated with decreased risk. In stratified analysis, significant differences in risk factors existed between Mexican origin versus Central/South American Latino children. The processes of acculturation likely impact eating and lifestyle practices differentially among Latino groups. Interventions should focus on ensuring that all children eat a nutritious breakfast and take into consideration ethnicity when working with Latino populations. PMID- 22101727 TI - Sentinel node navigation surgery by thoracoscopic fluorescence imaging system and molecular examination in non-small cell lung cancer. AB - PURPOSE: The application of sentinel node navigation surgery in non-small cell lung cancer (NSCLC) is not popular because of the difficulty of sentinel node identification and the low incidence of complications after systemic lymph node dissection. We report the intraoperative assessment of sentinel node metastasis by thoracoscopic ICG fluorescence imaging system and real-time reverse transcription-polymerase chain reaction (RT-PCR). METHODS: Sixty-one patients who underwent surgery between January 2009 and December 2010 were investigated for sentinel node biopsy. ICG fluorescence imaging was applied by an infrared light CCD system, and sentinel nodes were identified and dissected. Intraoperative real time quantitative RT-PCR to determine the expression of cytokeratin 19 (CK-19) was performed for evaluation of metastasis and finally histologic examination of hematoxylin and eosin-stained, paraffin-embedded sections. RESULTS: Sixteen (80%) of 20 patients with segmentectomy and 33 (80.5%) of 41 with lobectomy were identified for sentinel lymph nodes. The total identification rate was 80.3% (49 of 61). The false-negative rate was 2.1% (1 of 49). The overall accuracy rate was 78.7% (48 of 61 patients). Disease of four of these patients was upstaged to stage IIA by RT-PCR for CK-19 expression, which was positive for sentinel nodes and micrometastases. CONCLUSIONS: These results demonstrated that thoracoscopic ICG fluorescence imaging-guided surgery and real-time quantitative RT-PCR were useful for sentinel node biopsy and might be a powerful tool for more focused pathologic or molecular evaluation for staging. PMID- 22101728 TI - Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. AB - The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response. PMID- 22101729 TI - Principles of dimer-specific gene regulation revealed by a comprehensive characterization of NF-kappaB family DNA binding. AB - The unique DNA-binding properties of distinct NF-kappaB dimers influence the selective regulation of NF-kappaB target genes. To more thoroughly investigate these dimer-specific differences, we combined protein-binding microarrays and surface plasmon resonance to evaluate DNA sites recognized by eight different NF kappaB dimers. We observed three distinct binding-specificity classes and clarified mechanisms by which dimers might regulate distinct sets of genes. We identified many new nontraditional NF-kappaB binding site (kappaB site) sequences and highlight the plasticity of NF-kappaB dimers in recognizing kappaB sites with a single consensus half-site. This study provides a database that can be used in efforts to identify NF-kappaB target sites and uncover gene regulatory circuitry. PMID- 22101730 TI - AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. AB - Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection. Ahr(-/-) mice also lacked postnatally 'imprinted' cryptopatches and isolated lymphoid follicles (ILFs), but not embryonically 'imprinted' Peyer's patches. AHR induced the transcription factor Notch, which was required for NKp46(+) ILCs, whereas LTi-like ILCs, cryptopatches and ILFs were partially dependent on Notch signaling. Thus, AHR was essential for ILC22 cells and postnatal intestinal lymphoid tissues. Moreover, ILC22 subsets were heterogeneous in their requirement for Notch and their effect on the generation of intestinal lymphoid tissues. PMID- 22101731 TI - The redox-sensitive cation channel TRPM2 modulates phagocyte ROS production and inflammation. AB - The NADPH oxidase activity of phagocytes and its generation of reactive oxygen species (ROS) is critical for host defense, but ROS overproduction can also lead to inflammation and tissue injury. Here we report that TRPM2, a nonselective and redox-sensitive cation channel, inhibited ROS production in phagocytic cells and prevented endotoxin-induced lung inflammation in mice. TRPM2-deficient mice challenged with endotoxin (lipopolysaccharide) had an enhanced inflammatory response and diminished survival relative to that of wild-type mice challenged with endotoxin. TRPM2 functioned by dampening NADPH oxidase-mediated ROS production through depolarization of the plasma membrane in phagocytes. As ROS also activate TRPM2, our findings establish a negative feedback mechanism for the inactivation of ROS production through inhibition of the membrane potential sensitive NADPH oxidase. PMID- 22101732 TI - A new pliopithecid genus (primates: Pliopithecoidea) from Castell de Barbera (Valles-Penedes Basin, Catalonia, Spain). AB - Barberapithecus huerzeleri gen. et sp. nov. (Primates, Pliopithecidae) is erected on the basis of material from Castell de Barbera (Middle to Late Miocene, ca. 11.2-10.5 Ma), in the Valles-Penedes Basin (Catalonia, Spain), including: 15 teeth (representing most of the permanent dentition) from a single female individual (holotype); an isolated P/3 (paratype); and a male C1/ (referred to the hypodigm). Previously, this material had been only partially figured and described, being attributed to Pliopithecus or to a new taxon with possible crouzeliine affinities. The erection of a new genus is justified by several autapomorphic features, such as markedly buccolingually compressed and mesiodistally elongated C1/, extremely buccolingually compressed, and mesiodistally oriented C/1 main cusp, P/4 with a large trigonid subequal to the talonid, very large distal foveae on the M/1 and especially the M/2, and lower molars with a quadrangular central fovea and a mesially situated entoconid. These features are associated with a set of crouzeliine synapomorphies, such as buccolingually compressed and peripheralized cusps, well-developed crests, large and well-defined occlusal foveae, upper molars with long preprotocrista, short hypoparacrista, somewhat distally situated protocone and short distal fovea, distinct P/3 metaconid, well-developed P/4 premetacristid, and relatively narrow lower molars with a reduced entoconid. Although more primitive, Barberapithecus resembles Anapithecus in some derived features. Both taxa are included into a new tribe (Anapithecini), together with other crouzeliines except Plesiopliopithecus (tribe Crouzeliini). The retention of primitive, pliopithecine-like features in Barberapithecus suggests that anapithecins might have evolved from a Pliopithecus ancestor, so that as currently conceived the Crouzeliinae might be polyphyletic. PMID- 22101733 TI - Microfluidic DNA fragmentation for on-chip genomic analysis. AB - We report a high-throughput clog-free microfluidic deoxyribonucleic acid (DNA) fragmentation chip that is based on hydrodynamic shearing. Salmon sperm DNA has been reproducibly fragmented down to ~ 5k bp fragment lengths by applying low hydraulic pressures (<=1 bar) across micromachined constrictions positioned in larger microfluidic channels that create point-sink flow with large velocity gradients near the constriction entrance. Long constrictions (100 um) produce shorter fragment lengths compared to shorter constrictions (10 um), while increasing the hydrodynamic pressure requirement. Sample recirculation (10 *) in short constrictions reduces the mean fragment length and fragment length variation, and improves yield compared to single-pass experiments without increasing the hydrodynamic pressure. PMID- 22101734 TI - Leukocyte integrin activation and deactivation: novel mechanisms of balancing inflammation. AB - Leukocyte recruitment into tissue forms the basis of immune surveillance and direct immune defense. It proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several signaling pathways leading to leukocyte adhesion to the endothelium and transmigration through the blood vessel wall into the inflamed tissue. Whereas inflammatory reactions are beneficial and necessary for host defense, they need to be balanced and controlled to prevent harmful consequences and tissue destruction. In this article, we discuss the different signaling pathways that ensure rapid and efficient integrin activation on leukocytes. In addition, we report on a recently identified novel endogenous mechanism that counteracts and balances integrin activation, thereby limiting leukocyte recruitment and the extent of inflammation. Further investigation of this new mechanism may allow providing new approaches for the development of the next generation of anti inflammatory drugs. PMID- 22101735 TI - Topical tacrolimus is useful for avoiding suction-blister epidermal grafting depigmentation in non-segmental vitiligo: a case report. PMID- 22101736 TI - A novel GATA4 loss-of-function mutation associated with congenital ventricular septal defect. AB - Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and a major cause for the significantly increased morbidity and mortality among infants. Aggregating evidence indicates that genetic defects are involved in the pathogenesis of congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the genetic determinants for VSD in the majority of patients remain to be identified. In this study, the entire coding region of GATA4, a gene encoding a zinc finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 160 unrelated patients with VSD. The available relatives of the index patient harboring the identified mutation and 200 unrelated control individuals were subsequently genotyped. The disease-causing potential of a sequence alteration was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 variation, p.R43W, was identified in a proband with VSD, that was absent in control subjects. Genetic analysis of the family members of the variation carrier showed that the substitution co-segregated with VSD. The p.R43W variant was predicted to be a pathogenic mutation, and the functional analysis demonstrated that the GATA4 R43W mutant protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. The findings expand the mutational spectrum of GATA4 linked to VSD and provide more insight into the molecular mechanism of VSD. PMID- 22101737 TI - Insight in bipolar disorder. AB - Although there has been interest in insight in bipolar disorder, research has not been as developed as in schizophrenia. The Medline, Embase, and PsychInfo data bases were searched. The key words used in the search were "bipolar", "mania", "manic", "awareness", and "insight". Books, editorials, letters, and reports on pediatric subjects were excluded. Abstracts or full texts were screened for relevance. Better insight is associated with better adherence to treatment and better outcomes. Impairments of executive functions and memory, as well as higher severity of psychotic symptoms, are associated with impairments of insight. Insight is more impaired during an illness episode than during remission, in mixed than in pure manic episodes, in bipolar II than in bipolar I patients, in pure mania than in bipolar or unipolar depression. Psychosocial treatments improve insight and outcomes. There is a need for integration of quantitative assessment methods and their introduction into research and clinical practice. PMID- 22101738 TI - Cognitive efficacy of quetiapine in early-onset first-episode psychosis: a 12 week open label trial. AB - Twenty-three adolescents with psychotic disorders, aged from 13 to 18 years, participated in a 12-week open label trial (17 adolescents completed the study) in order to examine the impact of quetiapine on clinical status and cognitive functions (encompassing processing speed, attention, short-term memory, long-term memory and executive function). An improvement in Clinical Global Impression and Positive and Negative Symptom Scale (P's <= 0.001) was observed. In addition, after controlling for amelioration of symptoms, a significant improvement was observed on one executive function (P = 0.044; Trail Making Part B). The remaining cognitive abilities showed stability. In addition, we observed an interaction between quetiapine doses (>300 mg/day or <300 mg/day) and time, where lower doses showed more improvement in verbal short-term memory (P = 0.048), inhibition abilities (P = 0.038) and positive symptoms (P = 0.020). The neuropsychological functioning of adolescents with psychotic disorders remained mainly stable after 12 weeks of treatment with quetiapine. However, lower doses seemed to have a better impact on two components of cognition (inhibition abilities and verbal short-term memory) and on positive symptoms. PMID- 22101740 TI - Effect of valproic acid through regulation of NMDA receptor-ERK signaling in sleep deprivation rats. AB - Although the effect of mood stabilizer valproic acid (VPA) through multiple signaling pathways has been shown, its therapeutic mechanism is still largely unknown. We investigated the effect of VPA (200 mg/kg, every 12 h) in sleep deprivation (SD) rats (72 h), the manic-like animal model, focusing on the N methyl-D: -aspartic acid (NMDA) receptor and signaling mediators of synaptic plasticity such as extracellular signal-regulated protein kinase (ERK), cAMP response element-binding protein (CREB), B cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and brain-derived neurotrophic factor (BDNF). SD reduced the expression of the NR2B subunit of the NMDA receptor in the frontal cortex and hippocampus but did not affect the expression of NR1 and NR2A subunits. In comparison, VPA inhibited the SD-induced reduction of NR2B expression in both brain regions. In addition, SD attenuated ERK phosphorylation in the frontal cortex and hippocampus, whereas VPA prevented the attenuation. VPA also protected the SD-induced decrease of CREB phosphorylation, BCL2 expression, and BDNF expression in the frontal cortex but not in the hippocampus. These results indicate that VPA could regulate NMDA receptor-ERK signaling in SD rats, preventing the SD-induced decrease of the expression of NR2B subunit and the activation of ERK signaling mediators such as ERK, CREB, BCL2, and BDNF. PMID- 22101739 TI - Regulation of IL-1beta-induced cyclooxygenase-2 expression by interactions of Abeta peptide, apolipoprotein E and nitric oxide in human neuroglioma. AB - Alzheimer disease (AD) is characterized by chronic neuroinflammation, which may lead to dysfunction in neuronal circuits. Although reactive microglia are found in association with accumulation of beta amyloid (Abeta) plaques in the AD brain, their contribution to neuronal cell loss remains speculative. A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele, which has been shown to contribute significantly to neurodegeneration in AD. Many studies have documented the ability of Abeta fibrils in vitro to induce microglia to undergo phenotypic activation, which results in the secretion and/or expression of a plethora of free radicals and pro-inflammatory mediators. These mediators, such as reactive nitrogen/oxygen species and IL-1beta as well as cyclooxygenase-2 (COX-2) with associated prostaglandin E2 (PGE(2)), are believed to be neurotoxic and to contribute to the underlying cause of AD. We have used the human H4 neuroglioma cells as a model astroglial system to examine the interactions between IL-1beta and nitric oxide (NO) as co-stimulators of Abeta(1 40) in enhancing the expression of COX-2 and production of PGE(2) in the presence of recombinant human apolipoprotein E4 (apoE4). Neither Abeta(1-40) nor its reverse sequence analog Abeta(40-1) alone had a significant effect on COX-2 expression and PGE(2) production in the cells. In contrast, after co-incubation with apoE4, Abeta(1-40) increased IL-1beta-induced COX-2 expression and PGE(2) production. Abeta(12-28), which binds with high affinity to apoE4, blocked apoE4 mediated effects on Abeta(1-40). Furthermore, (+/-)-S-Nitroso-N acetylpenicillamine (SNAP), an agent that releases nitric oxide (NO) in situ, alone did not affect IL-1beta-induced COX-2 expression, but increased PGE(2) production only. Addition of Abeta(1-40) preincubated with apoE4 to H4 cells in the presence of SNAP led to an additive IL-1beta-induced COX-2 expression and PGE(2) production. These observations indicate that increased PGE(2) resulted from increased nitrosative stress, which is enhanced by apoE4. Thus a molecular understanding of the interactions of apoE4 with Abeta, NO and IL-1beta on the regulation of the COX-2/prostaglandin pathway may open new avenues in understanding the mechanism of development of neurodegenerative disease such as AD. PMID- 22101741 TI - Altered methylation of the DNA repair gene MGMT is associated with neural tube defects. AB - DNA repair is critical for proper embryogenesis, and altered expression of DNA repair genes has been associated with neural tube defects (NTDs). The expression of DNA repair enzymes may be controlled, in part, by methylation of the promoter region. To assess whether disturbed promoter methylation pattern increases the incidence of NTDs, we employed methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantify the methylation levels of multiple promoter CpG sites in normal human embryos and embryos with NTDs. Of the total seven DNA repair genes, two genes (MGMT, MSH6) were examined as having disturbed methylation levels by MS-MLPA kit, while only one gene was confirmed with a significant alternated methylation pattern by MALDI-TOF MS. In our research, methylation profiling of the DNA repair gene O (6)-methylguanine DNA methyltransferase (MGMT) showed gender difference in embryogenesis. Comparison of MGMT promoter methylation revealed that hypomethylation was associated with an increased risk for cephalic malformations, especially with female embryos (Adjusted Odds Ratio = 8.250). The majority of individual CpG units within the promoter demonstrated hypomethylation. Meanwhile, the expression of MGMT was proven to increase significant in female cases. These results underscore the role of stable promoter methylation in the DNA repair enzymes MGMT for proper embryogenesis. PMID- 22101742 TI - DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development. AB - The differentiation and activation of T cells are critically modulated by MAP kinases, which are in turn feed-back regulated by dual-specificity phosphatases (DUSPs) to determine the duration and magnitude of MAP kinase activation. DUSP4 (also known as MKP2) is a MAP kinase-induced DUSP member that is dynamically expressed during thymocyte differentiation. We generated DUSP4-deficient mice to study the function of DUSP4 in T-cell development and activation. Our results show that thymocyte differentiation and activation-induced MAP kinase phosphorylation were comparable between DUSP4-deficient and WT mice. Interestingly, activated DUSP4(-/-) CD4(+) T cells were hyperproliferative while DUSP4(-/-) CD8(+) T cells proliferated normally. Further mechanistic studies suggested that the hyperproliferation of DUSP4(-/-) CD4(+) T cells resulted from enhanced CD25 expression and IL-2 signaling through increased STAT5 phosphorylation. Immunization of DUSP4(-/-) mice recapitulated the T-cell hyperproliferation phenotype in antigen recall responses, while the profile of Th1/Th2-polarized antibody production was not altered. Overall, these results suggest that other DUSPs may compensate for DUSP4 deficiency in T-cell development, MAP kinase regulation, and Th1/Th2-mediated antibody responses. More importantly, our data indicate that DUSP4 suppresses CD4(+) T-cell proliferation through novel regulations in STAT5 phosphorylation and IL-2 signaling. PMID- 22101743 TI - Dynamic contrast enhanced-MRI for the detection of pathological complete response to neoadjuvant chemotherapy for locally advanced rectal cancer. AB - OBJECTIVE: To determine the ability of dynamic contrast enhanced (DCE-MRI) to predict pathological complete response (pCR) after preoperative chemotherapy for rectal cancer. METHODS: In a prospective clinical trial, 23/34 enrolled patients underwent pre- and post-treatment DCE-MRI performed at 1.5T. Gadolinium 0.1 mmol/kg was injected at a rate of 2 mL/s. Using a two-compartmental model of vascular space and extravascular extracellular space, K(trans), k(ep), v(e), AUC90, and AUC180 were calculated. Surgical specimens were the gold standard. Baseline, post-treatment and changes in these quantities were compared with clinico-pathological outcomes. For quantitative variable comparison, Spearman's Rank correlation was used. For categorical variable comparison, the Kruskal Wallis test was used. P <= 0.05 was considered significant. RESULTS: Percentage of histological tumour response ranged from 10 to 100%. Six patients showed pCR. Post chemotherapy K(trans) (mean 0.5 min(-1) vs. 0.2 min(-1), P = 0.04) differed significantly between non-pCR and pCR outcomes, respectively and also correlated with percent tumour response and pathological size. Post-treatment residual abnormal soft tissue noted in some cases of pCR prevented an MR impression of complete response based on morphology alone. CONCLUSION: After neoadjuvant chemotherapy in rectal cancer, MR perfusional characteristics have been identified that can aid in the distinction between incomplete response and pCR. KEY POINTS: Dynamic contrast enhanced (DCE) MRI provides perfusion characteristics of tumours. These objective quantitative measures may be more helpful than subjective imaging alone Some parameters differed markedly between completely responding and incompletely responding rectal cancers. Thus DCE-MRI can potentially offer treatment-altering imaging biomarkers. PMID- 22101744 TI - Time-resolved MR angiography of the intracranial venous system: an alternative MR venography technique. AB - OBJECTIVES: To compare time-resolved imaging of contrast kinetics (TRICKS) magnetic resonance angiography (MRA) with two-dimensional time-of-flight (TOF) magnetic resonance venography (MRV), and three-dimensional contrast-enhanced (CE) MRV in the visualisation of normal cerebral veins and dural venous sinuses. METHODS: This prospective study consisted of 35 consecutive patients. All patients were examined with TOF MRV, TRICKS MRA and CE MRV; a single dose of intravenous contrast material was administered for the last two sequences. The image quality of these techniques was assessed and compared qualitatively (by a semiquantitative scoring system) and quantitatively (by calculating signal-to noise ratios [SNRs] and contrast-to-noise ratios [CNRs]). RESULTS: Left transverse sinus, left sigmoid sinus, bilateral thalamostriate veins and Trolard veins were better visualised by TRICKS MRA and CE MRV compared with TOF MRV (P < 0.05). For left thalamostriate vein visualisation, TRICKS MRA was inferior to CE MRV (P < 0.05). With quantitative analysis the SNRs and CNRs were highest at TRICKS MRA, which was followed by CE MRV and TOF MRV (P < 0.05). CONCLUSIONS: Despite its limited spatial resolution, TRICKS MRA is comparable to static CE MRV and better than TOF MRV in the visualisation of normal dural sinuses and cerebral veins. KEY POINTS: * Time resolved magnetic resonance angiography can image the intracranial venous system dynamically * It seems comparable to contrast-enhanced MRV techniques in venous visualisation * The optimal phase for venous structures can be chosen from the dynamic data set * The diagnostic performance in venous thrombosis requires further research. PMID- 22101745 TI - Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial. AB - QUESTIONS UNDER STUDY: To compare efficacy and safety of the dopamine agonist pramipexole (PPX) versus reference treatment with dual release levodopa/benserazide (L/B) in de novo patients with restless legs syndrome (RLS). METHODS: A total of 39 men and women between 25 and 85 years old, fulfilling all clinical criteria for diagnosis of idiopathic RLS, previously untreated, participated. The study was performed as a randomised, double-blind, double-dummy crossover trial with two treatment periods of four weeks and took place in six Swiss certified sleep-centres. Interventions were PPX 0.25-0.75 mg and dual release L/B 125-375 mg. The primary outcome measure was the frequency of periodic limb movements while in bed (PLM index, PLMI). Secondary endpoints included the changes in patient ratings on the International RLS Study Group Rating Scale (IRLS). RESULTS: Both pramipexole and dual-release L/B were effective in reducing PLM and RLS symptoms. Mean PLMI reduction was -11.5 for PPX and -7.7 for L/B (baseline 21.1 and 21.5), and the mean IRLS score reduction was -7.2 and -4.0 (baseline 20.8 and 21.1). In patients with an IRLS score >20 (38%), a significantly (p = 0.047) higher PLMI reduction for PPX (-8.5), as compared to L/B (-4.3), was found. A higher incidence of "augmentations" and "involuntary movements" for L/B, and "nausea or vomiting" and "hypotension with dizziness" for PPX treatment were noted as adverse effects. CONCLUSION: This study showed comparable effects of PPX versus dual-release L/B for short-term treatment of de novo patients with mild to moderate RLS. PMID- 22101746 TI - Combining a new CO2 laser wave guide with transoral robotic surgery: a feasibility study on four patients with malignant tumors. AB - We present a series of patients treated by transoral robotic surgery (TORS) using a new CO(2) laser wave guide (CO(2) LWG) (Lumenis, Santa Clara, CA). Patients older than 18 years, with malignant pharyngo-laryngeal tumors were enrolled in this prospective study after signing an informed consent. Four patients were enrolled in the study. The mean age was 56 years. One patient had a T1 base of tongue tumor, two patients had supraglottic tumors (T1, T2), and one had a T1 palatine tonsil tumor. All the procedures could be performed using a Maryland forceps, a 0 degrees endoscope and a CO(2) LWG introduced via the robotic arm introducer. The laser parameters were: superpulse or continuous mode, 7-15 W, continuous delivery. The average set-up time was 30 min. The average surgical time was 94 min. No complications were noted due to the intraoperative use of the robot or the CO(2) LWG. One laser fiber was used for each of the surgeries. The mean coagulation depth was 200 MUm (range 100-300). The mean hospital stay was 6 days. The CO(2) LWG is a reliable tool for TORS. It allowed more than 1 h of work without any trouble. PMID- 22101747 TI - Paraganglioma of the facial nerve, a rare differential diagnosis for facial nerve paralysis: case report and review of the literature. AB - This report describes a rare case of histopathologically confirmed glomus facial tumor. The role of imaging in the differential diagnosis is discussed and therapeutic options are evaluated, along with a review of the previous literature on glomus facial tumors. A 39-year-old male patient presented with total peripheral facial nerve paralysis. He underwent radical tumor resection and facial nerve grafting for a histopathologically confirmed paraganglioma of the facial nerve. He is now tumor-free after a 4-year follow-up period, and the functional outcome after primary nerve grafting is satisfactory. Facial nerve paragangliomas are a rare cause of facial nerve paralysis. Early imaging using computed tomography and magnetic resonance imaging is essential to clarify the differential diagnosis and assess the location and extent of the tumor. Precise pathological diagnosis requires additional targeted immunohistochemical examinations. The treatment of choice in patients with preoperative facial nerve paralysis is radical tumor resection with nerve reconstruction. PMID- 22101748 TI - Toward lessening the rate of transition of acute whiplash to a chronic disorder. PMID- 22101749 TI - The influence of morphology on cervical injury characteristics. AB - STUDY DESIGN: Review of peer-reviewed literature. OBJECTIVE: Outline the effects of neck and cervical spine morphology on soft tissue injury Potential during low velocity automotive rear impacts. SUMMARY OF BACKGROUND DATA: Automotive rear impacts are mechanical events and the response of the human head-neck complex can be thought of in biomechanical terms. This manuscript reviews evidence from peer reviewed studies implicating occupant-related factors in the onset and severity of cervical spine soft-tissue injury. METHODS: Effects of anatomical characteristics, head-neck and spine orientation, facet joints, and neck muscles were reviewed. RESULTS: On the basis of existing biomechanically based research, the following occupant-related characteristics can influence the response of the cervical spine during automotive rear impacts: anatomical dimensions of the cervical spine, head-neck and cervical spine orientation at the time of impact, facet joint orientation, and neck muscle size and orientation. CONCLUSION: The response of the cervical spine to rear impacts can be described using biomechanical concepts. This review has identified occupant-related factors that can influence injury susceptibility and cited biomechanically related research to outline the method by which those factors affect the overall head-neck and cervical spine response in such a way as to increase the susceptibility or severity of injury for a given rear impact event. PMID- 22101750 TI - Does early management of whiplash-associated disorders assist or impede recovery? AB - STUDY DESIGN: Narrative review of the literature and commentary. OBJECTIVE: To discuss from an epidemiological and sociological perspective whether the early clinical management of whiplash-associated disorders can lead to iatrogenic disability. SUMMARY OF BACKGROUND DATA: There is a lack of evidence supporting the effectiveness of early rehabilitation care for whiplash-associated disorders. METHODS: We describe the epidemiological evidence on the effectiveness of early rehabilitation on health outcomes for patients with whiplash-associated disorders and analyze from a sociological perspective how the medicalization of this condition may have contributed to increasing its burden on disability. RESULTS: The evidence from randomized clinical trials suggests that education, exercise, and mobilization are effective modalities to treat whiplash-associated disorders. However, the evidence from large population-based cohort studies and a pragmatic randomized trial suggests that too much health care and rehabilitation too early after the injury can be associated with delayed recovery and the development of chronic pain and disability. These findings suggest that clinicians may be inadvertently contributing to the development of iatrogenic disability. The epidemiological evidence is supported by the sociological concepts of medicalization, iatrogenesis, and moral hazard. CONCLUSION: The current evidence suggests that too much health care too early after the injury is associated with delayed recovery. Clinicians need to be educated about the risk of iatrogenic disability. PMID- 22101751 TI - The role of educational and learning approaches in rehabilitation of whiplash associated disorders in lessening the transition to chronicity. AB - STUDY DESIGN: The study design was descriptive. OBJECTIVE: The aim of this chapter was to illustrate and discuss educational and learning perspectives in the rehabilitation of patients with acute whiplash-associated disorders (WAD). SUMMARY OF BACKGROUND DATA: WAD is a major problem for the individual and the society. Several treatment options have been studied without giving convincing results for lessening the transition to chronicity. Current management of acute WAD include among other things advice of exercise and educational activities. METHODS: A literature search on the PubMed database was conducted with additional topic discussions with the research colleagues at a symposium. These resulted the present state-of-the-art review. RESULTS: There are several possible cognitive factors and behavioral learning processes such as self-efficacy, fear of movement and (re)injury, and catastrophizing that are important to focus on in decreasing acute WAD to becoming a chronic condition. Learning based on behavioral medicine approach in physiotherapy framework has gained evidence in other musculoskeletal pain conditions. CONCLUSION: Exercise, education, and learning with a behavioral medicine approach should be focused on in the future studies of acute WAD management. PMID- 22101752 TI - Potential processes involved in the initiation and maintenance of whiplash associated disorders: discussion paper 3. AB - STUDY DESIGN: Nonsystematic review and discussion of the etiological processes involved in whiplash-associated disorders (WAD). OBJECTIVE: To summarize the research and identify priorities for future research. SUMMARY OF BACKGROUND DATA: Although there is convergent evidence of a peripheral lesion in some individuals after whiplash injury, in the majority of injured people, a lesion cannot be established with current imaging technology. Therefore, it is important to consider processes that underlie the initiation and maintenance of whiplash pain as this may allow for the development and testing of interventions to target these processes and improve outcomes. METHODS: A nonsystematic review was performed to summarize current knowledge regarding potential etiological processes involved in the initiation and maintenance of WAD and to identify future research priorities. RESULTS: There are several etiological processes potentially involved in the initiation and maintenance of WAD. These include augmented nociceptive processing, stress system responses, and psychosocial and sociocultural factors. Recent findings also indicate that morphological changes in the neck muscles of injured people show some association with poor recovery, but the mechanisms underlying these changes are not clear. Preliminary evidence indicates associations between these processes. Future research priorities include the following: more sophisticated investigation and analysis of interactions between the various processes; whether the modification of these processes is achievable and if modification can improve health outcomes; and to clarify factors involved in the initiation of whiplash pain versus those involved in symptom maintenance. CONCLUSION: Research to date indicates that there are several physiological and psychological etiological processes that may underlie the initiation and maintenance of whiplash-related pain and disability. Further research is required to determine relationships and interactions between these factors and to determine whether their modification is possible and will improve outcomes after injury. PMID- 22101753 TI - Toward optimal early management after whiplash injury to lessen the rate of transition to chronicity: discussion paper 5. AB - STUDY DESIGN: Expert debate and synthesis of research to inform future management approaches for acute whiplash disorders. OBJECTIVE: To identify a research agenda toward improving outcomes for acute whiplash-injured individuals to lessen the incidence of transition to chronicity. SUMMARY OF BACKGROUND DATA: International figures are concordant, estimating that 50% of individuals recover from pain and disability within 3 to 6 months of a whiplash injury. The remainder report continuing symptoms up to 1 to 2 years or longer postinjury. As no management approach to date has improved recovery rates, new clinical/research directions are required for early management of whiplash-injured patients. METHODS: A group of multidisciplinary researchers critically debated evidence and current research concerning whiplash from biological, psychological, and social perspectives toward informing future research directions for management of acute whiplash. RESULTS: It was recognized that effective treatments for acute whiplash are constrained by a limited understanding of causes of whiplash-associated disorders. Acute whiplash presentations are heterogeneous leading to the proposal that a research priority was development of a triage system based on modifiable prognostic indicators and clinical features to better inform individualized early management decisions. Other priorities identified included researching effective early pain management for individuals presenting with moderate to high levels of pain; development of best education/information for acute whiplash; testing the efficacy of stratified and individualized rehabilitation, researching modes of delivery considering psychosocial modulators of pain and disability; and the timing, nature, and mode of delivery of cognitive-behavioral therapies. Directions were highlighted for future biomechanical research into injury prevention. CONCLUSION: The burden of whiplash injuries, the high rate of transition to chronicity, and evidence of limited effects of current management on transition rates demand new directions in evaluation and management. Several directions have been proposed for future research, which reflect the potential multifaceted dimensions of an acute whiplash disorder. PMID- 22101754 TI - 3D texture analysis on MRI images of Alzheimer's disease. AB - This study investigated three-dimensional (3D) texture as a possible diagnostic marker of Alzheimer's disease (AD). T1-weighted magnetic resonance (MR) images were obtained from 17 AD patients and 17 age and gender-matched healthy controls. 3D texture features were extracted from the circular 3D ROIs placed using a semi automated technique in the hippocampus and entorhinal cortex. We found that classification accuracies based on texture analysis of the ROIs varied from 64.3% to 96.4% due to different ROI selection, feature extraction and selection options, and that most 3D texture features selected were correlated with the mini mental state examination (MMSE) scores. The results indicated that 3D texture could detect the subtle texture differences between tissues in AD patients and normal controls, and texture features of MR images in the hippocampus and entorhinal cortex might be related to the severity of AD cognitive impairment. These results suggest that 3D texture might be a useful aid in AD diagnosis. PMID- 22101756 TI - Glycomechanics of the metastatic cascade: tumor cell-endothelial cell interactions in the circulation. AB - Hydrodynamic shear force plays an important role in the leukocyte adhesion cascade that involves the tethering and rolling of cells along the endothelial layer, their firm adhesion or arrest, and their extravasation or escape from the circulatory system by inducing passive deformation, or cell flattening, and microvilli stretching, as well as regulating the expression, distribution, and conformation of adhesion molecules on leukocytes and the endothelial layer. Similarly, the dissemination of circulating tumor cells (CTCs) from the primary tumor sites is believed to involve tethering, rolling, and firm adhesion steps before their eventual extravasation which leads to secondary tumor sites (metastasis). Of particular importance to both the leukocyte adhesion cascade and the extravasation of CTCs, glycoproteins are involved in all three steps (capture, rolling, and firm adhesion) and consist of a variety of important selectin ligands. This review article provides an overview of glycoprotein glycosylation associated with the abnormal glycan expression on cancer cell surfaces, where well-established and novel selectin ligands that are cancer related are discussed. An overview of computational approaches on the effects of fluid mechanical force on glycoprotein mediated cancer cell rolling and adhesion is presented with a highlight of recent flow-based and selectin-mediated cell capturing/enriching devices. Finally, as an important branch of the glycoprotein family, mucins, specifically MUC1, are discussed in the context of their aberrant expression on cancer cells and their role as cancer cell adhesion molecules. Since metastasis relies heavily on glycoprotein interactions in the bloodstream where the fluid shear stress highly regulates cell adhesion forces, it is important to study and understand the glycomechanics of all relevant glycoproteins (well-established and novel) as they relate to the metastatic cascade. PMID- 22101755 TI - Engineering approaches toward deconstructing and controlling the stem cell environment. AB - Stem cell-based therapeutics have become a vital component in tissue engineering and regenerative medicine. The microenvironment within which stem cells reside, i.e., the niche, plays a crucial role in regulating stem cell self-renewal and differentiation. However, current biological techniques lack the means to recapitulate the complexity of this microenvironment. Nano- and microengineered materials offer innovative methods to (1) deconstruct the stem cell niche to understand the effects of individual elements; (2) construct complex tissue-like structures resembling the niche to better predict and control cellular processes; and (3) transplant stem cells or activate endogenous stem cell populations for regeneration of aged or diseased tissues. In this article, we highlight some of the latest advances in this field and discuss future applications and directions of the use of nano- and microtechnologies for stem cell engineering. PMID- 22101757 TI - Acoustic radiation force impulse (ARFI) imaging of zebrafish embryo by high frequency coded excitation sequence. AB - Acoustic radiation force impulse (ARFI) imaging has been developed as a non invasive method for quantitative illustration of tissue stiffness or displacement. Conventional ARFI imaging (2-10 MHz) has been implemented in commercial scanners for illustrating elastic properties of several organs. The image resolution, however, is too coarse to study mechanical properties of micro sized objects such as cells. This article thus presents a high-frequency coded excitation ARFI technique, with the ultimate goal of displaying elastic characteristics of cellular structures. Tissue mimicking phantoms and zebrafish embryos are imaged with a 100-MHz lithium niobate (LiNbO3) transducer, by cross correlating tracked RF echoes with the reference. The phantom results show that the contrast of ARFI image (14 dB) with coded excitation is better than that of the conventional ARFI image (9 dB). The depths of penetration are 2.6 and 2.2 mm, respectively. The stiffness data of the zebrafish demonstrate that the envelope is harder than the embryo region. The temporal displacement change at the embryo and the chorion is as large as 36 and 3.6 MUm. Consequently, this high-frequency ARFI approach may serve as a remote palpation imaging tool that reveals viscoelastic properties of small biological samples. PMID- 22101758 TI - Continuous and noninvasive measurement of systolic and diastolic blood pressure by one mathematical model with the same model parameters and two separate pulse wave velocities. AB - There is keen interest in continuous and noninvasive blood pressure (BP) measurement. However, many technologies have a shortcoming of complex mechanical structure. In our study, two arterial pulses are acquired by photoplethysmography (PPG) at ear and toe in order to explore a new method of measuring BP by pulse wave velocity (PWV). We previously validated and reported a BP-PWV mathematical model with measurements from humans with no evidence of cardiovascular disease, but were only able to determine PWV related to diastolic blood pressure (DBP). In this paper, we propose methods of identifying pulse transmit time (PTT) in low, normal and high systolic blood pressure (SBP) conditions. By averaging the PTT's of incident wave and reflected wave for non-systematic error reduction, we obtain a PWV that is suitable for estimating SBP. SBP and DBP are estimated by two separate PWV's based on the previously calibrated models. Experimental measurements are conducted on 26 subjects (age 19 +/- 1 and 60 +/- 1) with no evidence of cardiovascular disease. The measurement errors (Mean Deviation = 2.16 mmHg (SBP) and 1.49 mmHg (DBP); Standard Deviation = 6.23 mmHg (SBP) and 6.51 mmHg (DBP)) satisfy the accuracy criteria of Association for the Advancement of Medical Instrumentation. The results verify that SBP and DBP can be estimated by one mathematical model with the same model parameters and two separate PWV's. PMID- 22101759 TI - Opacification of shape memory polymer foam designed for treatment of intracranial aneurysms. AB - Shape memory polymer (SMP) foam possesses structural and mechanical characteristics that make them very promising as an alternative treatment for intracranial aneurysms. Our SMP foams have low densities, with porosities as high as 98.8%; favorable for catheter delivery and aneurysm filling, but unfavorable for attenuating X-rays. This lack of contrast impedes the progression of this material becoming a viable medical device. This paper reports on increasing radio opacity by incorporating a high-Z element, tungsten particulate filler to attenuate X-rays, while conserving similar physical properties of the original non-opacified SMP foams. The minimal amount of tungsten for visibility was determined and subsequently incorporated into SMP foams, which were then fabricated into samples of increasing thicknesses. These samples were imaged through a pig's skull to demonstrate radio-opacity in situ. Quantification of the increase in image contrast was performed via image processing methods and standard curves were made for varying concentrations of tungsten doped solid and foam SMP. 4% by volume loading of tungsten incorporated into our SMP foams has proven to be an effective method for improving radio-opacity of this material while maintaining the mechanical, physical and chemical properties of the original formulation. PMID- 22101760 TI - Linking interleukin-6 receptor blockade with tocilizumab and its hematological effects using a modeling approach. AB - Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. The work investigated whether the observed decline in peripheral neutrophil and platelet counts after tocilizumab administration can be directly explained by tocilizumab IL-6R blockade, thus demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R concentrations, neutrophil and platelet counts from 4 phase 3 studies in rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A population approach was applied to describe the relationship between tocilizumab and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts. Following tocilizumab administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts returning to their respective baseline levels soon after tocilizumab is eliminated from the body. Tocilizumab concentrations were described by a two compartment model with parallel linear and Michaelis-Menten elimination. The quasi-steady-state target-mediated drug disposition model described tocilizumab relationships to total sIL-6R, which allowed computation of unobserved unbound sIL-6R concentrations. The neutrophil counts were described as a direct function of unbound sIL-6R concentrations. The platelet counts were described by the transit-compartment life-span model with inhibition of production that depended on the unbound sIL-6R concentrations. Thus, the observed changes in sIL-6R, neutrophil, and platelet data are consistent with the tocilizumab mechanism of action and can be fully explained by tocilizumab binding to sIL-6R and mIL-6R. PMID- 22101761 TI - Comparison of Nonmem 7.2 estimation methods and parallel processing efficiency on a target-mediated drug disposition model. AB - The paper compares performance of Nonmem estimation methods--first order conditional estimation with interaction (FOCEI), iterative two stage (ITS), Monte Carlo importance sampling (IMP), importance sampling assisted by mode a posteriori (IMPMAP), stochastic approximation expectation-maximization (SAEM), and Markov chain Monte Carlo Bayesian (BAYES), on the simulated examples of a monoclonal antibody with target-mediated drug disposition (TMDD), demonstrates how optimization of the estimation options improves performance, and compares standard errors of Nonmem parameter estimates with those predicted by PFIM 3.2 optimal design software. In the examples of the one- and two-target quasi-steady state TMDD models with rich sampling, the parameter estimates and standard errors of the new Nonmem 7.2.0 ITS, IMP, IMPMAP, SAEM and BAYES estimation methods were similar to the FOCEI method, although larger deviation from the true parameter values (those used to simulate the data) was observed using the BAYES method for poorly identifiable parameters. Standard errors of the parameter estimates were in general agreement with the PFIM 3.2 predictions. The ITS, IMP, and IMPMAP methods with the convergence tester were the fastest methods, reducing the computation time by about ten times relative to the FOCEI method. Use of lower computational precision requirements for the FOCEI method reduced the estimation time by 3-5 times without compromising the quality of the parameter estimates, and equaled or exceeded the speed of the SAEM and BAYES methods. Use of parallel computations with 4-12 processors running on the same computer improved the speed proportionally to the number of processors with the efficiency (for 12 processor run) in the range of 85-95% for all methods except BAYES, which had parallelization efficiency of about 70%. PMID- 22101762 TI - beta2-Agonists upregulate PDE4 mRNA but not protein or activity in human airway smooth muscle cells from asthmatic and nonasthmatic volunteers. AB - beta(2)-Adrenergic receptor (beta2AR) agonists induce airway relaxation via cAMP. Phosphodiesterase (PDE)s degrade and regulate cAMP, and in airway smooth muscle (ASM) cells PDE4D degrades cAMP. Long-acting beta(2)-agonists are now contraindicated as monotherapy for asthma, and increased PDE4D has been speculated to contribute to this phenomenon. In this study we investigated the expression of PDE4D in asthmatic and nonasthmatic ASM cells and its regulation by formoterol and budesonide. Primary ASM cells from people with or without asthma were stimulated with transforming growth factor (TGF)-beta(1), formoterol, and/or budesonide. PDE4D mRNA was assessed by real-time PCR, or PCR to assess splice variant production. PDE4D protein was assessed by Western blotting, and we investigated the effect of formoterol on cAMP production and PDE activity. Interleukin (IL)-6 was assessed using ELISA. PDE4D mRNA was dose dependently upregulated by formoterol, with a single splice variant, PDE4D5, present. Formoterol did not induce PDE4D protein at time points between 3 to 72 h, whereas it did induce and increase IL-6 secretion. We pretreated cells with actinomycin D and a proteasome inhibitor, MG132, and found no evidence of alterations in mRNA, protein expression, or degradation of PDE4D. Finally PDE activity was not altered by formoterol. This study shows, for the first time, that PDE4D5 is predominantly expressed in human ASM cells from people with and without asthma and that formoterol does not upregulate PDE4D protein production. This leads us to speculate that continual therapy with beta2AR agonists is unlikely to cause PDE4 mediated tachyphylaxis. PMID- 22101763 TI - Dendritic cell functional properties in a three-dimensional tissue model of human lung mucosa. AB - In lung tissue, dendritic cells (DC) are found in close association with the epithelial cell layer, and there is evidence of DC regulation by the epithelium; that epithelial dysfunction leads to overzealous immune cell activation. However, dissecting basic mechanisms of DC interactions with epithelial cells in human tissue is difficult. Here, we describe a method to generate a three-dimensional organotypic model of the human airway mucosa in which we have implanted human DC. The model recapitulates key anatomical and functional features of lung mucosal tissue, including a stratified epithelial cell layer, deposition of extracellular matrix proteins, and the production of tight junction and adherence junction proteins. Labeling of fixed tissue model sections and imaging of live tissue models also revealed that DC distribute in close association with the epithelial layer. As functional properties of DC may be affected by the local tissue microenvironment, this system provides a tool to study human DC function associated with lung mucosal tissue. As an example, we report that the lung tissue model regulates the capacity of DC to produce the chemokines CCL17, CCL18, and CCL22, leading to enhanced CCL18 expression and reduced CCL17 and CCL22 expression. This novel tissue model thus provides a tool well suited for a wide range of studies, including those on the regulation of DC functional properties within the local tissue microenvironment during homeostasis and inflammatory reactions. PMID- 22101764 TI - The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d(-1)) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d(-1) or 300 mg d(-1) as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS. PMID- 22101765 TI - miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. AB - Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38alpha and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38alpha deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38alpha and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials. PMID- 22101766 TI - Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. AB - Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions. PMID- 22101767 TI - Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. AB - Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon gamma (IFN-gamma)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor alpha (TNF-alpha) signaling in the stem cells. We also found that, through inhibition of nuclear factor kappaB (NF kappaB), TNF-alpha converts the signaling of the IFN-gamma-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-gamma and TNF-alpha concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering. PMID- 22101768 TI - Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. AB - Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans. PMID- 22101769 TI - A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design. AB - Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate specific CD4(+) T cell clones to produce interleukins 2 and 4-cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50-100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4(+) T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy. PMID- 22101770 TI - Preparation and characterization of bioactive glass nanoparticles prepared by sol gel for biomedical applications. AB - Bioactive glass nanoparticles (BG-NPs), based on both ternary (SiO(2)-CaO P(2)O(5)) and binary (SiO(2)-CaO) systems, were prepared via an optimized sol-gel method. The pH of preparation and the effect of heat treatment temperature were evaluated, as well as the effect of suppressing P in the bioactivity ability of the materials. The morphology and composition of the BG-NPs were studied using FTIR, XRD and SEM. The bioactive character of these materials was accessed in vitro by analyzing the ability for apatite formation onto the surface after being immersed in simulated body fluid (SBF). XRD, EDX and SEM were used to confirm the bioactivity of the materials. The BG-NP effect on cell metabolic activity was assessed by seeding L929 cells with their leachables, proving the non cytotoxicity of the materials. Finally the most bioactive BG-NPs developed (ternary system prepared at pH 11.5 and treated at 700 degrees C) were successfully combined with chitosan in the production of biomimetic nanocomposite osteoconductive membranes that could have the potential to be used in guided tissue regeneration. PMID- 22101771 TI - Anesthetic management of a pediatric patient with neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome (NMS) is a rare disorder which is clinically similar to malignant hyperthermia (MH). It is characterized by hyperthermia, autonomic instability, muscle rigidity, coma, rhabdomyolysis, and acidosis. Without immediate and appropriate therapy, mortality may result. NMS is associated with administration of antipsychotic medications, anti-emetic medications, and changes in the dosage of anti-parkinsonian drugs. As several similarities exist between NMS and MH, differentiating between them can be a challenge for the clinician. We report anesthetic care during magnetic resonance imaging of the brain of a 14-year-old female with bipolar and schizoaffective disorders and the recent onset of NMS. PMID- 22101772 TI - Anesthesia and cerebrospinal microcirculation: assessment using cranial- and spinal-window techniques. PMID- 22101773 TI - Functional roles of ATP-sensitive potassium channel as related to anesthesia. PMID- 22101774 TI - Brief communication: Enamel thickness and durophagy in mangabeys revisited. AB - The documentation of enamel thickness variation across primates is important because enamel thickness has both taxonomic and functional relevance. The Old World monkeys commonly referred to as mangabeys have figured prominently in investigations of feeding ecology and enamel thickness. In this article, we report enamel thickness values for four mangabey taxa (Cercocebus atys, Cercocebus torquatus, Lophocebus aterrimus, and Lophocebus albigena), offer revised interpretation of the significance of thick enamel in papionin evolution, and place our new data in a broader comparative framework. Our data indicate that all mangabeys have thick enamel and that the values obtained for Cercocebus and Lophocebus equal or exceed those published for most extant non-human primates. In addition, new field data combined with a current reading of the dietary literature indicate that hard foods make up a portion of the diet of every mangabey species sampled to date. Clarification on the relationship between diet and enamel thickness among mangabeys is important not only because of recognition that mangabeys are not a natural group but also because of recent arguments that explain thick enamel as an evolved response to the seasonal consumption of hard foods. PMID- 22101775 TI - Management of recalcitrant hidradenitis suppurativa with ustekinumab. PMID- 22101776 TI - [Adherence to compression therapy. Psychoeducation and strengthening of resources as factors promoting adherence]. AB - Pressure garment therapy shows dropout rates between 30% and 59%. It is not the patient's health-related beliefs which lead to abandonment of therapy but the amount of negative side effects accompanying pressure garment therapy. Moreover, patients report a lack of information dealing with the garments, anxiety of damaging the skin and feelings of shame in contact with other people. The disabilities and restraints cannot be dispersed but only moderated. The two basic variables of an adherence promoting model are psychoeducation and strengthening of resources within a participative relationship between therapist and patient. PMID- 22101777 TI - [Fractures of the thoracic and lumbar spine in children and adolescents]. AB - BACKGROUND: Only 1.5-2% of all fractures in children and adolescents are fractures of the thoracic and lumbar spine. Treatment is most often conservative. This study compares the own experience with the recent literature. MATERIAL AND METHODS: Over a 48 month period all patients with fractures of the thoracic and lumbar spine, younger than 16 years were included prospectively. Of the patients 67 underwent follow-up investigations after 3-36 months. RESULTS: The average age of the patients was 11.9 years. Sports (53%) and traffic (28%) accidents were most frequent. Fractures most often appeared in the mid-thoracic (47%) and thoracolumbar spine (41%). Operative treatment was performed in 9 cases (10.4%). Secondary loss of alignment was not observed neither after conservative nor operative treatment. Neurological deficits (n=2) did not completely improve. CONCLUSIONS: Most fractures of the thoracic and lumbar spine heal fast and without any sequelae. Unstable fractures of type B and C (exclusively occurring as a result of traffic accidents) need operative stabilization as in adults. PMID- 22101778 TI - [Treatment costs for anterior cruciate ligament reconstruction: procedure related cost analysis in an university hospital]. AB - BACKGROUND: Complex procedures in knee surgery, such as anterior cruciate ligament (ACL) reconstruction with the double bundle technique are not specially recognized within the German diagnosis-related groups (G-DRG) system. Hence, the goal of the present study was to perform a cost unit calculation and evaluate how ACL reconstruction in single versus double bundle techniques is remunerated. PATIENTS AND METHODS: In 30 patients ACL reconstruction was performed with the single bundle technique (group A) and in 21 an anatomic double bundle reconstruction (group B) was performed. All costs including those for human resources, implants and materials, as well as general costs for administration and facilities were calculated. RESULTS: All cases entered one DRG category, the I30Z "complex procedures at the knee joint". Thus, the revenue in 2008 was 2,996.65 euro per case and in 2009 3,120.35 euro per case. Calculating all costs, the profit contributions in 2008 and 2009 were 592,42 euro and 716,12 euro, respectively for group A. However, in group B the profit contributions were 314,68 euro and 438,38 euro, respectively. CONCLUSION: Performing the double bundle technique for ACL reconstruction in a university hospital setting, significant cost reductions are needed to achieve the revenue generated by the single bundle technique. Additional changes of the relative weighting in the DRG are also necessary. PMID- 22101779 TI - [Persistent swelling after flushing of an abscess with Octenisept(r)]. AB - We report the case of a long-lasting cutaneous side effect after inappropriate use of Octenisept(r) solution (containing octenidine and phenoxyethanol). Following lavage of an abscess in the inguinal region, a painful erythematous induration mimicking cellulitis persisted for several months. Manual lymphatic drainage considerably improved the symptoms. Octenisept(r) shows considerable tissue toxicity in vivo including - but not restricted to - blood vessel damage. Deterioration of endothelial cells followed by oedema and continued tissue damage can be seen histologically. Despite the fact that there is a circular letter issued by the manufacturer as well as a boxed warning on the bottles, the awareness to avoid this misuse of Octenisept(r) is still lacking. PMID- 22101780 TI - Effects of baking and boiling on the nutritional and antioxidant properties of sweet potato [Ipomoea batatas (L.) Lam.] cultivars. AB - The effects of baking and boiling on the nutritional and antioxidant properties of three sweet potato cultivars (Beniazuma, Koganesengan, Kotobuki) cultivated in Turkey were investigated. The samples were analyzed for proximate composition, total phenolic content, ascorbic acid, beta-carotene, antiradical activity, and free sugars. The dry matter, protein, and starch contents of the sweet potatoes were significantly changed by the treatments while the ash and crude fiber contents did not differ as significantly. The beta-carotene contents of baked and boiled sweet potatoes were lower than those of fresh sweet potatoes; however, the total phenolic and ascorbic acid contents of the baked and boiled sweet potatoes were higher than those of the fresh samples. Generally, the antiradical activity of the sweet potatoes increased with the treatments. Sucrose, glucose, and fructose were quantified as free sugars in all fresh sweet potatoes; however, maltose was determined in the treated samples. In terms of the analyzed parameters, there were no explicit differences among the sweet potato cultivars. PMID- 22101781 TI - Mental health around and after the menopause. AB - The menopause is a time in a woman's life when it is recognized that biological and social changes can impact upon mental wellbeing. Several studies have investigated the relationship between menopause and psychological symptoms, especially depression, with mixed results. In part, this is due to a considerable overlap between depressive symptoms and those due to declining estrogen levels, causing challenges in assessment. However it appears that vulnerable women are at a higher risk of succumbing to depression during menopausal transition. Antidepressants remain the mainstay of treating depressive symptoms, with little conclusive evidence for hormone replacement therapy. Memory problems during menopause are a common complaint, but there is no demonstrated link to subsequent dementia. This paper also reviews considerations of diagnosis and treatment of postmenopausal depression. PMID- 22101782 TI - 2,4-DNT removal in intimately coupled photobiocatalysis: the roles of adsorption, photolysis, photocatalysis, and biotransformation. AB - The removal of 2,4-dinitrotoluene (2,4-DNT) by simultaneous UV-photo(cata)lysis and biodegradation was explored using intimately coupled photolysis/photocatalysis and biodegradation (ICPB) with two novel porous carriers. First, a porous ceramic carrier was used to attach the photocatalyst (TiO2) on its exterior and accumulate biomass in its interior. UV irradiation alone decomposed 71% of the 2,4-DNT in 60 h, and TiO2 catalyst improved the photolysis to 77%. Second, a macroporous sponge carrier was used to strongly adsorb 2,4-DNT and protect microorganisms from 2,4-DNT inhibition and UV irradiation. The main photolytic reactions were reduction of the nitryl to amino and hydrolysis of the amino to release NH4+. The main biodegradation reactions were oxidative release of NO3- and accelerated reductive release of NH4+. ICPB more thoroughly released inorganic N, with nearly equal amounts being oxidized to nitrate and reduced to ammonium. The genera Burkholderia and Bacillus were found inside the sponge carriers, and they are associated with biodegradation of DNT and its photolysis intermediates. Therefore, using an adsorbent and macroporous biofilm carrier enabled the effective removal of 2,4-DNT by ICPB. PMID- 22101783 TI - Isolation and characterization of a Rhodococcus strain able to degrade 2 fluorophenol. AB - A pure bacterial culture able to utilize 2-fluorophenol (2-FP) as sole carbon and energy source was isolated by selective enrichment from sediments collected from a contaminated site in Northern Portugal. 16S rRNA gene analysis showed that the organism (strain FP1) belongs to the genus Rhodococcus. When grown aerobically on 2-FP, growth kinetics of strain FP1 followed the Luong model. An inhibitory effect of increasing 2-FP concentrations was observed with no growth occurring at 2-FP levels higher than ca. 4 mM. Rhodococcus strain FP1 was able to degrade a range of other organofluorine compounds, including 2-fluorobenzoate, 3 fluorobenzoate, 4-fluorobenzoate, 3-fluorophenol, 4-fluorophenol, 3 fluorocatechol, and 4-fluorocatechol, as well as chlorinated compounds such as 2 chlorophenol and 4-chlorophenol. Experiments with cell-free extracts and partially purified enzymes indicated that the first step of 2-fluorophenol metabolism was conversion to 3-fluorocatechol, suggesting an unusual pathway for fluoroaromatic metabolism. To our knowledge, this is the first time that utilization of 2-FP as a growth substrate by a pure bacterial culture is reported. PMID- 22101784 TI - Cloning and characterization of a novel amidase from Paracoccus sp. M-1, showing aryl acylamidase and acyl transferase activities. AB - A novel amidase gene, designated pamh, was cloned from Paracoccus sp. M-1. Site directed mutagenesis and bioinformatic analysis showed that the PamH protein belonged to the amidase signature enzyme family. PamH was expressed in Escherichia coli, purified, and characterized. The molecular mass of PamH was determined to be 52 kDa with an isoelectric point of 5.13. PamH displayed its highest enzymatic activity at 45 degrees C and at pH 8.0 and was stable within a pH range of 5.0-10.0. The PamH enzyme exhibited amidase activity, aryl acylamidase activity, and acyl transferase activity, allowing it to function across a very broad substrate spectrum. PamH was highly active on aromatic and short-chain aliphatic amides (benzamide and propionamide), moderately active on amino acid amides, and possessed weak urease activity. Of the anilides examined, only propanil was a good substrate for PamH. For propanil, the k (cat) and K (m) were 2.8 s(-1) and 158 MUM, respectively, and the catalytic efficiency value (k (cat)/K (m)) was 0.018 MUM(-1) s(-1). In addition, PamH was able to catalyze the acyl transfer reaction to hydroxylamine for both amide and anilide substrates, including acetamide, propanil, and 4-nitroacetanilide; the highest reaction rate was shown with isobutyramide. These characteristics make PamH an excellent candidate for environmental remediation and an important enzyme for the biosynthesis of novel amides. PMID- 22101785 TI - Cloning and expression in Pichia pastoris of an Irpex lacteus rhamnogalacturonan hydrolase tolerant to acetylated rhamnogalacturonan. AB - In order to produce a recombinant rhamnogalacturonase from the basidiomycete Irpex lacteus using a molecular approach, PCR primers were designed based on a sequence alignment of four known ascomycete rhamnogalacturonases. Using 5' and 3' rapid amplification of cDNA ends (RACE) experiments, a 1,437-bp full-length cDNA containing an open reading frame of 1,329 bp was isolated. The corresponding putative protein sequence is of 443 amino acids and contains a secretion signal sequence of 22 amino acids. The theoretical mass of this protein is 44.6 kDa with a theoretical isoelectric point of 6.2. The amino acid sequence shared not only significant identities with ascomycete and basidiomycete putative rhamnogalacturonases but also complete similarity with peptides obtained from a recently purified rhamnogalacturonase from I. lacteus. The recombinant protein was successfully expressed in active form in Pichia pastoris. SDS-PAGE assay demonstrated that the recombinant enzyme was secreted in the culture medium and had a molar mass of 56 kDa. This recombinant rhamnogalacturonan hydrolase exhibited a pH optimum between 4.5 and 5 and a temperature optimum between 40 degrees C and 50 degrees C, which correspond to that of the native rhamnogalacturonase from I. lacteus. The study of its specificity through reaction products analysis showed that it was highly tolerant to the presence of acetyl groups on its substrate, even more than the native enzyme. PMID- 22101786 TI - Biosynthesis of phloroglucinol compounds in microorganisms--review. AB - Phloroglucinol derivatives are a major class of secondary metabolites of wide occurrence in biological systems. In the bacteria kingdom, these compounds can only be synthesized by some species of Pseudomonads. Pseudomonas spp. could produce 2,4-diacetylphloroglucinol (DAPG) that plays an important role in the biological control of many plant pathogens. In this review, we summarize knowledge about synthesis of phloroglucinol compounds based on the DAPG biosynthetic pathway. Recent advances that have been made in understanding phloroglucinol compound biosynthesis and regulation are highlighted. From these studies, researchers have identified the biosynthesis pathway of DAPG. Most of the genes involved in the biosynthesis pathway have been cloned and characterized. Additionally, heterologous systems of the model microorganism Escherichia coli are constructed to produce phloroglucinol. Although further work is still required, a full understanding of phloroglucinol compound biosynthesis is almost within reach. This review also suggests new directions and attempts to gain some insights for better understanding of the biosynthesis and regulation of DAPG. The combination of traditional biochemistry and molecular biology with new systems biology and synthetic biology tools will provide a better view of phloroglucinol compound biosynthesis and a greater potential of microbial production. PMID- 22101787 TI - Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. AB - As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1beta in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1beta in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1 dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1 independent IL-1beta release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models. PMID- 22101788 TI - Upregulation of vasohibin-1 expression with angiogenesis and poor prognosis of hepatocellular carcinoma after curative surgery. AB - Vasohibin-1 has recently been found and is known as an endogenous angiogenesis inhibitor, but the role of vasohibin-1 in hepatocellular carcinoma (HCC) is unknown. This study investigated the expression pattern of vasohibin-1, its correlation with clinicopathological features, and its potential role in tumor angiogenesis and prognosis of HCC. Expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and intratumoral microvessel density (MVD, labeled by CD34) were assessed by immunohistochemistry in 117 HCC specimens and adjacent nontumor liver tissues (ANLT). Correlation between vasohibin-1 and VEGF A, MVD, and clinicopathological features was then investigated. Prognostic value of these factors was determined using Kaplan-Meier analysis and a Cox proportional hazards regression model. Cytoplasm high expression of vasohibin-1 was detected in 38.5% (45/117) of the HCC tissues, which was significantly higher than that in 16.2% (19/117) of ANLT (P<0.001). Vasohibin-1 was statistically correlated with VEGF-A, MVD, and microvascular invasion in HCC (P=0.014, 0.035, and 0.002, respectively). Patients with vasohibin-1 high expression had significantly poor disease-free survival (DFS) and overall survival (OS) at 5 years after curative hepatectomy (P<0.001 for each). Multivariate analysis confirmed that vasohibin-1 high expression was an independent prognosticator for unfavorable DFS (HR=2.554, P<0.001) and OS (HR=2.232, P=0.002), along with VEGF-A and TNM stage. Upregulation of vasohibin-1 expression is associated with angiogenesis and poor prognosis of HCC. Vasohibin-1 and VEGF-A are the most important factors influencing the dismal prognosis based on the modulation of angiogenesis in HCC, which provides a rational approach for treatment in the future. PMID- 22101789 TI - GGCn polymorphism of eRF3a/GSPT1 gene and breast cancer susceptibility. AB - The significance of translation regulatory factors in elevating the risk of cancer has been recently recognized. Eukaryotic release factor 3a (eRF3a) is a translation termination protein that is encoded by G1 to S phase transition 1 gene (GSPT1). The eRF3a/GSPT1 exon 1 contains a trinucleotide GGC repeat coding for a polyglycine expansion in the N-terminal of the protein. In the present study, we determined the allelic length of the GGC(n) repeat in the eRF3a gene in 250 women with breast cancer and 250 age-matched controls. Our results show that the presence of the longer allele, 12-GGC, is correlated with threefold increased risk of breast cancer development. Our findings also suggest that women who are homozygous for 7-GGC allele are possibly at higher risk of developing breast cancer, especially before the age of 50. No significant effect of the allelic length of eRF3a/GSPT1 polymorphism on inheritance or the grade of this disease was observed. PMID- 22101790 TI - Inhibition of silibinin on migration and adhesion capacity of human highly metastatic breast cancer cell line, MDA-MB-231, by evaluation of beta1-integrin and downstream molecules, Cdc42, Raf-1 and D4GDI. AB - Metastasis is a property of malignant cancer cells that requires integrins which with their downstream molecules participate in a number of signaling events in cells with pivotal roles in malignancy, migration and invasion of tumor cells. Silibinin, a flavonoid antioxidant from milk thistle (Silybum marianum L.), has attracted attention in the last decades for chemoprevention and chemotherapy of tumor cells. In the present study, the effect of silibinin on migration and adhesion capacity of MDA-MB-231 cells, a highly metastatic human breast cancer cell line, was investigated by evaluation of beta1-integrin and its important downstream molecules. MTT, migration and adhesion assays were performed to evaluate the silibinin effects on proliferation, migration and adhesion of MDA-MB 231 cells. In addition, the influence of the silibinin on the expression of beta1 integrin, Raf-1, Cdc42 and D4-GDI mRNAs was assessed by RT-PCR. Results showed significant dose-dependent inhibitory effect of silibinin on proliferation, migration and adhesion of MDA-MB-231 cells. It significantly inhibited the expression of Cdc42 and D4-GDI mRNAs but had no statistically significant effect on the expression of beta1-integrin and Raf-1 mRNAs although it indirectly but effectively modulated beta1-integrin signaling pathway and RAF1 function. In conclusion, the results showed the silibinin effectson reducing the rate of metastasis, migration and adhesion of MDA-MB-231 to distant organs. PMID- 22101791 TI - Down-regulation of microRNA-200c is associated with drug resistance in human breast cancer. AB - Drug resistance remains a major clinical obstacle to successful treatment in breast cancer patients, and the evidence of microRNAs involvement in cancer drug resistance has been emerging recently. However, the role of microRNA-200c (miR 200c) in modulating chemoresistance of breast cancer remains largely unexplored. Here, we investigated the miR-200c expression in tumor specimens obtained from thirty-nine breast cancer patients who received neoadjuvent chemotherapy by quantitative real-time PCR. Down-regulated miR-200c was observed in non responders as compared to responders. In addition, miR-200c expression was observed to be down-regulated over 800-fold in human breast cancer cells resistant to doxorubicin MCF-7/ADR as compared to the parental MCF-7 cells. Up regulation of miR-200c with transfection of miR-200c mimics in breast cancer cells could enhance the chemosensitivity to epirubicin and reduce expression of multidrug resistance 1 mRNA and P-glycoprotein. Moreover, our study demonstrated that restoration of miR-200c in MCF-7/ADR cells could increase intracellular doxorubicin accumulation determined by flow cytometry. Taken together, our findings suggest that miR-200c may act as a promising therapeutic target for improvement of responsiveness to chemotherapy in breast cancer. PMID- 22101792 TI - Context for practice: filling gaps in our evidence base. PMID- 22101793 TI - 2012 research and funding/call for research proposals. PMID- 22101794 TI - CAET feature section. PMID- 22101795 TI - Who is turning the patients? PMID- 22101796 TI - Statistical hypothesis testing: associating patient characteristics with an incident condition: Kaplan-Meier curves, hazard ratios, and cox proportional hazards regression. PMID- 22101797 TI - RACE toward the goal of certification. PMID- 22101798 TI - Evaluation of a cyanoacrylate dressing to manage peristomal skin alterations under ostomy skin barrier wafers. AB - BACKGROUND: Peristomal skin alterations under ostomy barrier wafers are a commonly reported problem. While a number of interventions to manage this issue have been reported, the use of a topically applied cyanoacrylate has received little attention. This case series describes the use of a topical cyanoacrylate for the management of peristomal skin alterations in persons living with an ostomy. CASE PRESENTATIONS: Using a convenience sample, the topical cyanoacrylate dressing was applied to 11 patients with peristomal skin disruption under ostomy wafers in acute care and outpatient settings. The causes of barrier function interruption were also addressed to enhance outcomes. Patients were assessed for wound discomfort using a Likert Scale, time to healing, and number of appliance changes. Patient satisfaction was also examined. CONCLUSION: Average reported discomfort levels were 9.5 out of 10 at the initial peristomal irritation assessment visit decreased to 3.5 at the first wafer change and were absent by the second wafer change. Wafers had increasing wear time between changes in both settings with acute care patients responding faster. Epidermal resurfacing occurred within 10.2 days in outpatients and within 7 days in acute care patients. Because of the skin sealant action of this dressing, immediate adherence of the wafer was reported at all pouch changes. PMID- 22101800 TI - Prediction for steatosis in type-2 diabetes: clinico-biological markers versus 1H MR spectroscopy. AB - OBJECTIVES: The SteatoTest, fatty liver index (FLI) and hepatic steatosis index (HSI) are clinico-biological scores of steatosis validated in general or selected populations. Serum adiponectin (s-adiponectin) and retinol binding protein 4 (s RBP4) are adipokines that could predict liver steatosis. We investigated whether the Steatotest, FLI, HSI, s-adiponectin and s-RBP4 could be valid predictors of liver steatosis in type-2 diabetic (T2D) patients. METHODS: We enrolled 220 consecutive T2D patients. Reference standard was 3.0 T (1)H-MR spectroscopy (corrected for T1 and T2 decays). Intraclass correlation coefficients (ICCs), Kappa statistic measures of agreement, receiver operating characteristic (ROC) curves were assessed. RESULTS: Median liver fat content was 91 mg triglyceride/g liver tissue (range: 0-392). ICCs among the Steatotest, FLI, HSI, s-adiponectin, s-RBP4 and spectroscopy were low: 0.384, 0.281, 0.087, -0.297 and 0.048. Agreement between scores and spectroscopy was poor (Kappa range: 0.042-0.281). The areas under the ROC curves were low: 0.674, 0.647, 0.637, 0.616 and 0.540. S adiponectin and s-RBP4 levels were strongly related to the presence of diabetic nephropathy (P = 0.0037 and P = 0.004; Mann-Whitney). CONCLUSION: The SteatoTest, FLI, HSI, s-adiponectin, s-RBP4 are not valid predictors of steatosis in T2D patients. Clino-biological markers cannot replace (1)H-MR spectroscopy for the assessment of liver fat in this population. KEY POINTS: (1) H-MR spectrosopy can reliably estimate the weight fraction of liver steatosis. Type-2 diabetes provides an interesting model for assessing liver steatosis. Clinico-biological markers seem to be invalid predictors for steatosis in type-2 diabetes. PMID- 22101801 TI - Preparation and investigation of bioactive transferrin-iron complexes formed with different synergistic anions. AB - Human serum transferrin has a potential for drug-delivery systems. Oxalate and aziridine-carboxylate was conjugated to serum transferrin in order to transport into the targeted cancer cells via transferrin-receptor mediated endocytosis. Capillary zone electrophoresis and capillary isoelectric focusing were used to analyze the effectiveness of complexation reactions. The electropherograms show the differences between iron-free- and iron-complexed molecular forms of human serum transferrin. The iron-complexed transferrin sample containing the different anions as synergistic complexing agents were characterized by different electrophoretic parameters. PMID- 22101802 TI - Cloning and characterization of AKR4C14, a rice aldo-keto reductase, from Thai Jasmine rice. AB - Aldo-keto reductase (AKR) is an enzyme superfamily whose members are involved in the metabolism of aldehydes/ketones. The AKR4 subfamily C (AKR4C) is a group of aldo-keto reductases that are found in plants. Some AKR4C(s) in dicot plants are capable of metabolizing reactive aldehydes whereas, such activities have not been reported for AKR4C(s) from monocot species. In this study, we have screened Indica rice genome for genes with significant homology to dicot AKR4C(s) and identified a cluster of putative AKR4C(s) located on the Indica rice chromosome I. The genes including OsI_04426, OsI_04428 and OsI_04429 were successfully cloned and sequenced by qRT-PCR from leaves of Thai Jasmine rice (KDML105). OsI_04428, later named AKR4C14, was chosen for further studies because it shares highest homology to the dicot AKR4C(s). The bacterially expressed recombinant protein of AKR4C14 was successfully produced as a MBP fusion protein and his tagged protein. The recombinant AKR4C14 were capable of metabolizing sugars and reactive aldehydes i.e. methylglyoxal, a toxic by-product of the glycolysis pathway, glutaraldehyde, and trans-2-hexenal, a natural reactive 2-alkenal. AKR4C14 was highly expressed in green tissues, i.e. leaf sheets and stems, whereas flowers and roots had a significantly lower level of expression. These findings indicated that monocot AKR4C(s) can metabolize reactive aldehydes like the dicot AKR4C(s) and possibly play a role in detoxification mechanism of reactive aldehydes. PMID- 22101803 TI - The effects of temperature and pH on secondary structure and antioxidant activity of Crocodylus siamensis hemoglobin. AB - Crocodylus siamensis hemoglobin (cHb) was purified by gel filtration chromatography and visualized by SDS-PAGE. Effects of temperature and pH on secondary structure and conformation changes of cHb were studied using circular dichroism spectropolarimeter and fourier transform infrared spectrophotometer. The secondary structure of intact cHb was mainly alpha-helices. cHb was not heat stable when heated at 65 degrees C and cooled down to original temperature, indicating the irreversible unfolding process. The stability of cHb at different pH ranging from 2.5 to 10.5 was determined. The maximum value of the alpha-helix content was found at pH 3.5 and tended to decrease at strong acid and strong base. The antioxidant activities of heat treated cHb and cHb in solution with pH range 2.5 to 10.5 were tested by DPPH radical scavenging assay. cHb at pH 4.5, having highest beta-turn structure, showed highest radical scavenging activity. In contrast to pH, heat had no effect on antioxidant activity of cHb. PMID- 22101804 TI - Catheter related blood stream infections in critically ill patients with continuous haemo(dia)filtration and temporary non-tunnelled vascular access. AB - This prospective, single centre, observational study analysed the rate of catheter related blood stream infections in critically ill patients in intensive care units treated with haemo(dia)filtration. The infection rate was 3.8 per 1000 patient days. All infections were caused by coagulase negative staphylococci. BACKGROUND: Temporary central venous catheters in patients undergoing continuous veno-venous haemo(dia)filtration contribute to serious infectious complications. The goal of this study was to assess the incidence of catheter related blood stream infections in critically ill patients treated with continuous veno-venous haemo(dia)filtration. METHODS: Prospective observational study of all intensive care unit patients treated with continuous veno-venous haemo(dia)filtration by a central venous catheter at the University Hospital Basel. All patients underwent a standardised anti-infective protocol including screening for nasal colonisation with S. aureus on the day of catheter insertion, antiseptic catheter placement technique and daily disinfection of the insertion site followed by local mupirocin application. Catheter related blood stream infection was diagnosed according to standard guidelines of the Center of Disease Control and Prevention. Primary end point was the incidence of catheter related blood stream infection in all intensive care unit patients treated with continuous veno-venous haemo(dia)filtration. RESULTS: From 2003 to 2007 a total of 194 consecutive critically ill patients treated with continuous veno-venous haemo(dia)filtration were investigated. 173 patients (63% men) were suitable for final analysis. Median age was 68.6 years (18.9-87.8). Eight patients (4.6%) had positive blood cultures, six of them had a catheter related blood stream infection (incidence 3.8/1000 catheter days). All infections were caused by coagulase negative staphylococci. The duration of catheter use (p = 0.02) and pre-existing chronic skin disease (p = 0.042) were identified as potential risk factors for catheter related blood stream infection. CONCLUSIONS: The incidence of catheter related blood stream infection in critically ill patients on intensive care units treated with continuous veno-venous haemo(dia)filtration was 3.8 per 1000 catheter days. All catheter related blood stream infections were caused by coagulase negative staphylococci. PMID- 22101805 TI - Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism. AB - Combretastatin can prevent the supply of nutrients to cancer cells by selectively interrupting tumor blood flow (TBF). Therefore, combretastatin may serve as a new anticancer drug that utilizes starvation tactics to attack solid tumors. Among combretastatin compounds, combretastatin A-4 and a combretastatin A-4 derivative (Cderiv) are now in phase III clinical trials. These two combretastatin compounds have similar chemical structures and provide marked TBF interruption. However, their mechanisms of action are reportedly quite different and remain controversial. Precise mechanisms of action of these agents must be elucidated so as to develop safe clinical treatments and wider clinical applications. By using various kinds of rodent tumors, we showed that Cderiv produced potent interruption of TBF in all primary tumors and metastatic foci, without exception, and had beneficial therapeutic effects including significantly improved survival. Cderiv caused host arterioles to constrict. However, a tumor vascular bed scarcely reacted to a direct topical application of Cderiv. In addition, the fact that Cderiv did not have cytotoxic drug-like accumulated toxicity usually caused by repeated administration means that inhibition of tubulin polymerization by Cderiv may not occur to a great degree in vivo. Therefore, at least for Cderiv, our studies demonstrated that TBF interruption was mainly caused indirectly, via enhancement of vascular resistance of host arterioles, rather than being caused by a direct effect of Cderiv on tumor vessels. In this review, I describe cancer therapy that utilizes such TBF interruption, which leads to Cderiv-induced necrosis, and discuss details of its microcirculation mechanism. PMID- 22101806 TI - Potential molecular targets for inhibiting bone invasion by oral squamous cell carcinoma: a review of mechanisms. AB - Bone invasion is a common characteristic of oral squamous cell carcinoma (OSCC), with adverse affects on patient functionality and survival. Recent studies suggest that it is osteoclasts, rather than malignant keratinocytes themselves, which play the major role in facilitating the entry of the tumour into bone, and its progression within bone. Osteoclasts respond to a variety of local signalling pathways, initiated by products of the malignant epithelial cells. In the present review, we firstly introduce the clinical patterns of bone invasion, and then summarise these signalling pathways and their diverse roles in sequential phases of bone invasion. We also review current researches regarding the incidence and mechanisms of distant metastases to bone, and explain briefly the concept of epithelial-mesenchymal transition, which may generate cancer stem cells and initiate the bone invasion. Finally, we discuss more briefly approaches to the diagnosis and management of OSCC patients with bone invasion. With all these studies and some recent discoveries in our own laboratory, an enhanced understanding of bone invasion will be achieved, which should indicate potential molecular targets for future biotherapies. PMID- 22101808 TI - CanMEDS and other outcomes. PMID- 22101807 TI - Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. AB - Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination. PMID- 22101809 TI - Language development after cochlear implantation: an epigenetic model. AB - Growing evidence supports the notion that dynamic gene expression, subject to epigenetic control, organizes multiple influences to enable a child to learn to listen and to talk. Here, we review neurobiological and genetic influences on spoken language development in the context of results of a longitudinal trial of cochlear implantation of young children with severe to profound sensorineural hearing loss in the Childhood Development after Cochlear Implantation study. We specifically examine the results of cochlear implantation in participants who were congenitally deaf (N = 116). Prior to intervention, these participants were subject to naturally imposed constraints in sensory (acoustic-phonologic) inputs during critical phases of development when spoken language skills are typically achieved rapidly. Their candidacy for a cochlear implant was prompted by delays (n = 20) or an essential absence of spoken language acquisition (n = 96). Observations thus present an opportunity to evaluate the impact of factors that influence the emergence of spoken language, particularly in the context of hearing restoration in sensitive periods for language acquisition. Outcomes demonstrate considerable variation in spoken language learning, although significant advantages exist for the congenitally deaf children implanted prior to 18 months of age. While age at implantation carries high predictive value in forecasting performance on measures of spoken language, several factors show significant association, particularly those related to parent-child interactions. Importantly, the significance of environmental variables in their predictive value for language development varies with age at implantation. These observations are considered in the context of an epigenetic model in which dynamic genomic expression can modulate aspects of auditory learning, offering insights into factors that can influence a child's acquisition of spoken language after cochlear implantation. Increased understanding of these interactions could lead to targeted interventions that interact with the epigenome to influence language outcomes with intervention, particularly in periods in which development is subject to time-sensitive experience. PMID- 22101810 TI - Tailoring material properties of a nanofibrous extracellular matrix derived hydrogel. AB - In the native tissue, the interaction between cells and the extracellular matrix (ECM) is essential for cell migration, proliferation, differentiation, mechanical stability, and signaling. It has been shown that decellularized ECMs can be processed into injectable formulations, thereby allowing for minimally invasive delivery. Upon injection and increase in temperature, these materials self assemble into porous gels forming a complex network of fibers with nanoscale structure. In this study we aimed to examine and tailor the material properties of a self-assembling ECM hydrogel derived from porcine myocardial tissue, which was developed as a tissue specific injectable scaffold for cardiac tissue engineering. The impact of gelation parameters on ECM hydrogels has not previously been explored. We examined how modulating pH, temperature, ionic strength, and concentration affected the nanoscale architecture, mechanical properties, and gelation kinetics. These material characteristics were assessed using scanning electron microscopy, rheometry, and spectrophotometry, respectively. Since the main component of the myocardial matrix is collagen, many similarities between the ECM hydrogel and collagen gels were observed in terms of the nanofibrous structure and modulation of properties by altering ionic strength. However, variation from collagen gels was noted for the gelation temperature along with varied times and rates of gelation. These discrepancies when compared to collagen are likely due to the presence of other ECM components in the decellularized ECM based hydrogel. These results demonstrate how the material properties of ECM hydrogels could be tailored for future in vitro and in vivo applications. PMID- 22101811 TI - Self-assembly of uniform polyhedral silver nanocrystals into densest packings and exotic superlattices. AB - Understanding how polyhedra pack into extended arrangements is integral to the design and discovery of crystalline materials at all length scales. Much progress has been made in enumerating and characterizing the packing of polyhedral shapes, and the self-assembly of polyhedral nanocrystals into ordered superstructures. However, directing the self-assembly of polyhedral nanocrystals into densest packings requires precise control of particle shape, polydispersity, interactions and driving forces. Here we show with experiment and computer simulation that a range of nanoscale Ag polyhedra can self-assemble into their conjectured densest packings. When passivated with adsorbing polymer, the polyhedra behave as quasi hard particles and assemble into millimetre-sized three-dimensional supercrystals by sedimentation. We also show, by inducing depletion attraction through excess polymer in solution, that octahedra form an exotic superstructure with complex helical motifs rather than the densest Minkowski lattice. Such large-scale Ag supercrystals may facilitate the design of scalable three-dimensional plasmonic metamaterials for sensing, nanophotonics and photocatalysis. PMID- 22101812 TI - Sunlight-activated long-persistent luminescence in the near-infrared from Cr(3+) doped zinc gallogermanates. AB - Visible-light persistent phosphors are being widely used as self-sustained night vision materials because of their sufficiently strong and long afterglow (>10 h) and their ability to be excited by sunlight as well as room light. In contrast, persistent phosphors for near-infrared (NIR) wavelengths are lacking. Here we report a series of Cr(3+)-doped zinc gallogermanate NIR persistent phosphors that exhibit strong emission at 650-1,000 nm, extending beyond the typical 690-750 nm, and with a super-long afterglow of more than 360 h. These new NIR persistent phosphors are all-weather materials that can be rapidly, effectively and repeatedly charged by natural sunlight in almost all kinds of outdoor environment. Seconds to minutes of sunlight activation can result in more than two weeks of persistent NIR light emission. This new series of NIR persistent materials have potential applications in night-vision surveillance, solar energy utilization and in vivo bio-imaging. PMID- 22101813 TI - Synthesis of monolithic graphene-graphite integrated electronics. AB - Encoding electronic functionality into nanoscale elements during chemical synthesis has been extensively explored over the past decade as the key to developing integrated nanosystems with functions defined by synthesis. Graphene has been recently explored as a two-dimensional nanoscale material, and has demonstrated simple device functions based on conventional top-down fabrication. However, the synthetic approach to encoding electronic functionality and thus enabling an entire integrated graphene electronics in a chemical synthesis had not previously been demonstrated. Here we report an unconventional approach for the synthesis of monolithically integrated electronic devices based on graphene and graphite. Spatial patterning of heterogeneous metal catalysts permits the selective growth of graphene and graphite, with a controlled number of graphene layers. Graphene transistor arrays with graphitic electrodes and interconnects were formed from the synthesis. These functional, all-carbon structures were transferable onto a variety of substrates. The integrated transistor arrays were used to demonstrate real-time, multiplexed chemical sensing and more significantly, multiple carbon layers of the graphene-graphite device components were vertically assembled to form a three-dimensional flexible structure which served as a top-gate transistor array. These results represent substantial progress towards encoding electronic functionality through chemical synthesis and suggest the future promise of one-step integration of graphene-graphite based electronics. PMID- 22101814 TI - Atomic-scale transport in epitaxial graphene. AB - The high carrier mobility of graphene is key to its applications, and understanding the factors that limit mobility is essential for future devices. Yet, despite significant progress, mobilities in excess of the 2*10(5) cm(2) V( 1) s(-1) demonstrated in free-standing graphene films have not been duplicated in conventional graphene devices fabricated on substrates. Understanding the origins of this degradation is perhaps the main challenge facing graphene device research. Experiments that probe carrier scattering in devices are often indirect, relying on the predictions of a specific model for scattering, such as random charged impurities in the substrate. Here, we describe model-independent, atomic-scale transport measurements that show that scattering at two key defects- surface steps and changes in layer thickness--seriously degrades transport in epitaxial graphene films on SiC. These measurements demonstrate the strong impact of atomic-scale substrate features on graphene performance. PMID- 22101815 TI - Social norm influences on evaluations of the risks associated with alcohol consumption: applying the rank-based decision by sampling model to health judgments. AB - AIMS: The research first tested whether perceptions of other people's alcohol consumption influenced drinkers' perceptions of the riskiness of their own consumption. Second, the research tested how such comparisons are made-whether, for example, people compare their drinking to the 'average' drinker's or 'rank' their consumption amongst other people's. The latter untested possibility, suggested by the recent Decision by Sampling Model of judgment, would imply different cognitive mechanisms and suggest that information should be presented differently to people in social norm interventions. METHODS: Study 1 surveyed students who provided information on (a) their own drinking, (b) their perceptions of the distribution of drinking in the UK and (c) their perceived risk of various alcohol-related disorders. Study 2 experimentally manipulated the rank of 'target' units of alcohol within the context of units viewed simultaneously. RESULTS: In both studies, the rank of an individual's drinking in a context of other drinkers predicted perceptions of developing alcohol-related disorders. There was no evidence for the alternative hypothesis that people compared with the average of other drinkers' consumptions. The position that subjects believed they occupied in the ranking of other drinkers predicted their perceived risk, and did so as strongly as how much they actually drank. CONCLUSIONS: Drinking comparisons are rank-based, which is consistent with other judgments in social, emotional and psychophysical domains. Interventions should be designed to work with people's natural ways of information processing, through providing clients with information on their drinking rank rather than how their drinking differs from the average. PMID- 22101816 TI - High-resolution structure of a retroviral protease folded as a monomer. AB - Mason-Pfizer monkey virus (M-PMV), a D-type retrovirus assembling in the cytoplasm, causes simian acquired immunodeficiency syndrome (SAIDS) in rhesus monkeys. Its pepsin-like aspartic protease (retropepsin) is an integral part of the expressed retroviral polyproteins. As in all retroviral life cycles, release and dimerization of the protease (PR) is strictly required for polyprotein processing and virion maturation. Biophysical and NMR studies have indicated that in the absence of substrates or inhibitors M-PMV PR should fold into a stable monomer, but the crystal structure of this protein could not be solved by molecular replacement despite countless attempts. Ultimately, a solution was obtained in mr-rosetta using a model constructed by players of the online protein folding game Foldit. The structure indeed shows a monomeric protein, with the N- and C-termini completely disordered. On the other hand, the flap loop, which normally gates access to the active site of homodimeric retropepsins, is clearly traceable in the electron density. The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins. The overall fold of the protein follows the retropepsin canon, but the C(alpha) deviations are large and the active-site 'DTG' loop (here NTG) deviates up to 2.7 A from the standard conformation. This structure of a monomeric retropepsin determined at high resolution (1.6 A) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS. PMID- 22101817 TI - A thermal stability assay can help to estimate the crystallization likelihood of biological samples. AB - The identification of crystallization conditions for biological molecules largely relies on a trial-and-error process in which a number of parameters are explored in large screening experiments. Currently, construct design and sample formulation are recognized as critical variables in this process and often a number of protein variants are assayed for crystallization either sequentially or in parallel, which adds complexity to the screening process. Significant effort is dedicated to sample characterization and quality-control experiments in order to identify at an early stage and prioritize those samples which would be more likely to crystallize. However, large-scale studies relating crystallization success to sample properties are generally lacking. In this study, the thermal stability of 657 samples was estimated using a simplified Thermofluor assay. These samples were also subjected to automated vapour-diffusion crystallization screening under a constant protocol. Analysis of the data shows that samples with an apparent melting temperature (T(m)) of 318 K or higher crystallized in 49% of cases, while the crystallization success rate decreased rapidly for samples with lower T(m). Only 23% of samples with a T(m) below 316 K produced crystals. Based on this analysis, a simple method for estimation of the crystallization likelihood of biological samples is proposed. This method is easy, rapid and consumes very small amounts of sample. The results of this assay can be used to determine optimal incubation temperatures for crystallization experiments or to prioritize certain constructs. More generally, this work provides an objective test that can contribute to making decisions in both focused and structural genomics crystallography projects. PMID- 22101818 TI - Crystallographic analysis of human hemoglobin elucidates the structural basis of the potent and dual antisickling activity of pyridyl derivatives of vanillin. AB - Vanillin has previously been studied clinically as an antisickling agent to treat sickle-cell disease. In vitro investigations with pyridyl derivatives of vanillin, including INN-312 and INN-298, showed as much as a 90-fold increase in antisickling activity compared with vanillin. The compounds preferentially bind to and modify sickle hemoglobin (Hb S) to increase the affinity of Hb for oxygen. INN-312 also led to a considerable increase in the solubility of deoxygenated Hb S under completely deoxygenated conditions. Crystallographic studies of normal human Hb with INN-312 and INN-298 showed that the compounds form Schiff-base adducts with the N-terminus of the alpha-subunits to constrain the liganded (or relaxed-state) Hb conformation relative to the unliganded (or tense-state) Hb conformation. Interestingly, while INN-298 binds and directs its meta-positioned pyridine-methoxy moiety (relative to the aldehyde moiety) further down the central water cavity of the protein, that of INN-312, which is ortho to the aldehyde, extends towards the surface of the protein. These studies suggest that these compounds may act to prevent sickling of SS cells by increasing the fraction of the soluble high-affinity Hb S and/or by stereospecific inhibition of deoxygenated Hb S polymerization. PMID- 22101819 TI - The active conformation of human glucokinase is not altered by allosteric activators. AB - Glucokinase (GK) catalyses the formation of glucose 6-phosphate from glucose and ATP. A specific feature of GK amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns GK into a unique key sensor of glucose metabolism, notably in the pancreas. GK is a target of antidiabetic drugs aimed at the activation of GK activity, leading to insulin secretion. Here, the first structures of a GK-glucose complex without activator, of GK-glucose-AMP-PNP and of GK-glucose-AMP-PNP with a bound activator are reported. All these structures are extremely similar, thus demonstrating that binding of GK activators does not result in conformational changes of the active protein but in stabilization of the active form of GK. PMID- 22101820 TI - PAN-modular structure of microneme protein SML-2 from the parasite Sarcocystis muris at 1.95 A resolution and its complex with 1-thio-beta-D-galactose. AB - The microneme protein SML-2 is a member of a small family of galactose-specific lectins that play a role during host-cell invasion by the apicomplexan parasite Sarcocystis muris. The structures of apo SML-2 and the 1-thio-beta-D-galactose SML-2 complex were determined at 1.95 and 2.1 A resolution, respectively, by sulfur-SAD phasing. Highly elongated dimers are formed by PAN-domain tandems in the protomer, bearing the galactose-binding cavities at the distal apple-like domains. The detailed structure of the binding site in SML-2 explains the high specificity of galactose-endgroup binding and the broader specificity of the related Toxoplasma gondii protein TgMIC4 towards galactose and glucose. A large buried surface of highly hydrophobic character and 24 intersubunit hydrogen bonds stabilize the dimers and half of the 12 disulfides per dimer are shielded from the solvent by the polypeptide chain, thereby enhancing the resistance of the parasite protein towards unfolding and proteolysis that allows it to survive within the intestinal tracts of the intermediate and final hosts. PMID- 22101821 TI - Structures of Burkholderia thailandensis nucleoside kinase: implications for the catalytic mechanism and nucleoside selectivity. AB - The nucleoside kinase (NK) from the mesophilic Gram-negative bacterium Burkholderia thailandensis (BthNK) is a member of the phosphofructokinase B (Pfk B) family and catalyzes the Mg(2+)- and ATP-dependent phosphorylation of a broad range of nucleosides such as inosine (INO), adenosine (ADO) and mizoribine (MZR). BthNK is currently used in clinical practice to measure serum MZR levels. Here, crystal structures of BthNK in a ligand-free form and in complexes with INO, INO ADP, MZR-ADP and AMP-Mg(2+)-AMP are described. The typical homodimeric architecture of Pfk-B enzymes was detected in three distinct conformational states: an asymmetric dimer with one subunit in an open conformation and the other in a closed conformation (the ligand-free form), a closed conformation (the binary complex with INO) and a fully closed conformation (the other ternary and quaternary complexes). The previously unreported fully closed structures suggest the possibility that Mg(2+) might directly interact with the beta- and gamma phosphates of ATP to maintain neutralization of the negative charge throughout the reaction. The nucleoside-complex structures also showed that the base moiety of the bound nucleoside is partly exposed to the solvent, thereby enabling the recognition of a wide range of nucleoside bases. Gly170 is responsible for the solvent accessibility of the base moiety and is assumed to be a key residue for the broad nucleoside recognition of BthNK. Remarkably, the G170Q mutation increases the specificity of BthNK for ADO. These findings provide insight into the conformational dynamics, catalytic mechanism and nucleoside selectivity of BthNK and related enzymes. PMID- 22101822 TI - Polarizable atomic multipole X-ray refinement: weighting schemes for macromolecular diffraction. AB - In the past, weighting between the sum of chemical and data-based targets in macromolecular crystallographic refinement was based on comparing the gradients or Hessian diagonal terms of the two potential functions. Here, limitations of this scheme are demonstrated, especially in the context of a maximum-likelihood target that is inherently weighted by the model and data errors. In fact, the congruence between the maximum-likelihood target and a chemical potential based on polarizable atomic multipole electrostatics evaluated with Ewald summation has opened the door to a transferable static weight. An optimal static weight is derived from first principles and is demonstrated to be transferable across a broad range of data resolutions in the context of a recent implementation of X ray crystallographic refinement using the polarizable AMOEBA force field and it is shown that the resulting models are balanced with respect to optimizing both R(free) and MolProbity scores. Conversely, the classical automatic weighting scheme is shown to lead to underfitting or overfitting of the data and poor model geometry. The benefits of this approach for low-resolution diffraction data, where the need for prior chemical information is of particular importance, are also highlighted. It is demonstrated that this method is transferable between low and high-resolution maximum-likelihood-based crystallographic refinement, which proves for the first time that resolution-dependent parameterization of either the weight or the chemical potential is unnecessary. PMID- 22101823 TI - Apparent instability of crystallographic refinement in the presence of disordered model fragments and upon insufficiently restrained model geometry. AB - It is demonstrated that the crystallographic models of macromolecules may appear to diverge upon extended refinement against experimental data. Two regimes are identified for this phenomenon. Firstly, at higher resolution the apparent instability of the resulting models is shown to originate from the relatively small fraction of disordered atoms present in the initial model. Secondly, at lower resolution additional refinement instability may arise from insufficiently strong geometry restraints. The convergence of crystallographic refinement is proposed as one of the possible criteria in selecting a specific refinement strategy and in model validation. PMID- 22101824 TI - A suite of Switch I and Switch II mutant structures from the G-protein domain of FeoB. AB - The acquisition of ferrous iron in prokaryotes is achieved by the G-protein coupled membrane protein FeoB. This protein possesses a large C-terminal membrane spanning domain preceded by two soluble cytoplasmic domains that are together termed 'NFeoB'. The first of these soluble domains is a GTPase domain (G-domain), which is then followed by an entirely alpha-helical domain. GTP hydrolysis by the G-domain is essential for iron uptake by FeoB, and various NFeoB mutant proteins from Streptococcus thermophilus have been constructed. These mutations investigate the role of conserved amino acids from the protein's critical Switch regions. Five crystal structures of these mutant proteins have been determined. The structures of E66A and E67A mutant proteins were solved in complex with nonhydrolyzable GTP analogues, the structures of T35A and E67A mutant proteins were solved in complex with GDP and finally the structure of the T35S mutant was crystallized without bound nucleotide. As an ensemble, the structures illustrate how small nucleotide-dependent rearrangements at the active site are converted into large rigid-body reorientations of the helical domain in response to GTP binding and hydrolysis. This provides the first evidence of nucleotide-dependent helical domain movement in NFeoB proteins, suggesting a mechanism by which the G protein domain could structurally communicate with the membrane domain and mediate iron uptake. PMID- 22101825 TI - Construct optimization for studying protein complexes: obtaining diffraction quality crystals of the pseudosymmetric PSPC1-NONO heterodimer. AB - The methodology of protein crystallography provides a number of potential bottlenecks. Here, an approach to successful structure solution of a difficult heterodimeric complex of two human proteins, paraspeckle component 1 (PSPC1) and non-POU domain-containing octamer-binding protein (NONO), that are involved in gene regulation and the structural integrity of nuclear bodies termed paraspeckles is described. With the aid of bioinformatic predictions and systematic screening of a panel of constructs, bottlenecks of protein solubility, crystallization, crystal quality and crystallographic pseudosymmetry were overcome in order to produce crystals that ultimately revealed the structure. PMID- 22101826 TI - Human Suv3 protein reveals unique features among SF2 helicases. AB - Suv3 is a helicase that is involved in efficient turnover and surveillance of RNA in eukaryotes. In vitro studies show that human Suv3 (hSuv3) in complex with human polynucleotide phosphorylase has RNA degradosome activity. The enzyme is mainly localized in mitochondria, but small fractions are found in cell nuclei. Here, two X-ray crystallographic structures of human Suv3 in complex with AMPPNP, a nonhydrolysable analog of ATP, and with a short five-nucleotide strand of RNA are presented at resolutions of 2.08 and 2.9 A, respectively. The structure of the enzyme is very similar in the two complexes and consists of four domains. Two RecA-like domains form the tandem typical of all helicases from the SF2 superfamily which together with the C-terminal all-helical domain makes a ring structure through which the nucleotide strand threads. The mostly helical N terminal domain is positioned externally with respect to the core of the enzyme. Most of the typical helicase motifs are present in hSuv3, but the protein shows certain unique characteristics, suggesting that Suv3 enzymes may constitute a separate subfamily of helicases. PMID- 22101827 TI - Patients' visual analogue scale: a useful method for assessing psoriasis severity. PMID- 22101828 TI - Technical note: quantitative measures of iris color using high resolution photographs. AB - Our understanding of the genetic architecture of iris color is still limited. This is partly related to difficulties associated with obtaining quantitative measurements of eye color. Here we introduce a new automated method for measuring iris color using high resolution photographs. This method extracts color measurements in the CIE 1976 L*a*b* (CIELAB) color space from a 256 by 256 pixel square sampled from the 9:00 meridian of the iris. Color is defined across three dimensions: L* (the lightness coordinate), a* (the red-green coordinate), and b* (the blue-yellow coordinate). We applied this method to a sample of individuals of diverse ancestry (East Asian, European and South Asian) that was genotyped for the HERC2 rs12913832 polymorphism, which is strongly associated with blue eye color. We identified substantial variation in the CIELAB color space, not only in the European sample, but also in the East Asian and South Asian samples. As expected, rs12913832 was significantly associated with quantitative iris color measurements in subjects of European ancestry. However, this SNP was also strongly associated with iris color in the South Asian sample, although there were no participants with blue irides in this sample. The usefulness of this method is not restricted only to the study of iris pigmentation. High-resolution pictures of the iris will also make it possible to study the genetic variation involved in iris textural patterns, which show substantial heritability in human populations. PMID- 22101829 TI - MR spectroscopy and micro-CT in evaluation of osteoporosis model in rabbits: comparison with histopathology. AB - PURPOSE: To explore the evidence of regular alteration of bone quality in osteoporosis dynamically examined by MRS and micro-CT, comparing with histopathology. METHODS: Forty rabbits were allocated into two groups. Group A were used as sham. Group B underwent bilateral ovariectomy (OVX) combined with daily intramuscular methylprednisolone, underwent MR spectroscopy, micro-CT, and histopathology of L5 at 2, 4, 8, and 10 weeks after operation. RESULTS: Fat fraction as shown by MRS in Group B was significantly increased over the time course of osteoporosis development with significant difference between two groups at 4, 8, and 10 weeks after OVX. Continuous deterioration of cancellous bone architecture in Group B, was first detected at week 4. FF value in group B correlated with micro-CT parameters. Marrow fat as measured by MR and CT was positively correlated with both the mean density and diameter of adipocytes (both of which increased over time). CONCLUSIONS: Marrow adipogenesis occurs in synchrony with deterioration of trabecular microarchitecture.MRS may be valuable to assess the pathophysiological changes of bone marrow in osteoporosis in early stage. KEY POINTS: MRS revealed gradually increasing bone marrow fat in rabbits rendered osteoporotic. Marrow adipogenesis occurs in synchrony with deterioration of trabecular microarchitecture. Pathology revealed an early increase in number of marrow adipocytes in osteoporosis. MRS may help assess early pathophysiological bone marrow changes in osteoporosis. PMID- 22101830 TI - IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination. AB - The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent. PMID- 22101831 TI - Basic vascular research conducted by Japanese anesthesiologists: opening remarks. PMID- 22101833 TI - Endocanalicular laser dacryocystorhinostomy (ECLDCR). PMID- 22101834 TI - Mechanical behavior of scleral fibroblasts in experimental myopia. AB - BACKGROUND: The study aims to determine the changes in the biomechanical properties of the anterior and extreme posterior portions of experimental near sighted eyes by examining the mechanical behavior of guinea pig scleral desmocytes, thus finding a new approach to the pathogenesis of myopia and their corresponding therapies. METHODS: Guinea pigs (2 weeks old) were numbered and assigned into three groups (A, B, and C) with ten guinea pigs each. Concave lens induced myopic (LIM) animal models were prepared via the out-of-focus method. The other eye in the same guinea pig served as the self-control (SC) group. After modeling groups A, B, and C for 6, 15, and 30 days respectively, the lenses from the guinea pigs in the experimental group were removed. The scleral fibroblasts in each group were cultured, and passaged twice in vitro. The micropipette aspiration technique coupled with a viscoelastic solid model was utilized to investigate the viscoelastic properties of the scleral fibroblasts in normal and myopic guinea pigs. The mechanical behavior of the scleral desmocytes of the LIM and SC groups were compared. RESULTS: The mechanical behavior of the scleral desmocytes was compared between the LIM and SC groups. The Young's modulus at equilibrium and the apparent cellular viscosity of the anterior portion of the sclera in the LIM group at 6 days and 15 days after myopic induction were not significantly different from that of the SC group (P < 0.05). However, the results for the anterior portions of the sclera in the LIM group at 30 days were significantly higher than those of the LIM group at 6 and 15 days, as well as those in the SC group (P < 0.05). The Young's modulus at equilibrium and the apparent cellular viscosity of the extreme posterior portions of the sclera in the LIM group at 6 days after myopic induction not significantly from those of the SC group (P < 0.05). However, the results for the extreme posterior portions of the sclera in the LIM group after 15 days and 30 days were significantly higher than those in the LIM group at 6 days and the SC group (P < 0.05). CONCLUSIONS: The Young's modulus at equilibrium or apparent cellular viscosity of all the anterior portions of the sclera in the LIM group were longer than those in the SC group at 30 days after the induction, and the results for all the extreme posterior portions of the LIM group were larger than those of the SC group on the 15th and 30th day. Therefore, the Young's modulus and apparent viscosity of the anterior and extreme posterior portions of the sclera changed on the 15th and 30th day after induction respectively. PMID- 22101835 TI - Oxygen tension and gradient measurements in the retinal microvasculature of rats. AB - BACKGROUND: Oxygen delivery from the retinal vasculature plays a crucial role in maintaining normal retinal metabolic function. Therefore, measurements of retinal vascular oxygen tension (PO(2)) and PO(2) longitudinal gradients (gPO(2)) along retinal blood vessels may help gain fundamental knowledge of retinal physiology and pathological processes. METHODS: Three-dimensional retinal vascular PO(2) maps were generated in rats by optical section phosphorescence lifetime imaging. A major retinal artery and vein pair, and a smaller blood vessel (microvessel) between them were segmented, and PO(2) along each blood vessel was measured. In each blood vessel, an average PO(2) (mPO(2)) was calculated, and gPO(2) was determined by linear regression analysis. Reproducibility of measurements was assessed by calculating intraclass correlation coefficient (ICC) of repeated measurements. The correlations of mPO(2) and gPO(2) measurements with systemic arterial oxygen tension (P(a)O(2)) and carbon dioxide tension (P(a)CO(2)) was determined. RESULTS: Measurements of mPO(2) and gPO(2) in retinal arteries, microvessels and veins were reproducible (ICC > 0.86; p < 0.01; N = 8), except for retinal arterial gPO(2). Retinal arterial, microvessel and venous mPO(2) were 41 +/- 8, 32 +/- 8 and 25 +/- 7 mmHg, respectively (mean +/- SD; N = 27). Retinal arterial mPO(2) was correlated with P(a)O(2) and P(a)CO(2) (R > 0.44; p < 0.03), while retinal microvessel and venous mPO(2) were only correlated with P(a)CO(2) (R > 0.68; p < 0.01). Retinal microvessel gPO(2) (-3.8 +/- 1.5 mmHg/100 MUm) was significantly steeper (more negative) than venous gPO(2) (0.02 +/- 0.43 mmHg/100 MUm) (p < 0.01; N = 27), and neither were significantly correlated with P(a)O(2) or P(a)CO(2). CONCLUSIONS: Quantitative measurement of mPO(2) and gPO(2) in the retinal microvasculature was demonstrated. A significant decrease in PO(2) was observed along most retinal microvessels, indicative of substantial oxygen extraction by the retinal tissue. This method has the potential to help elucidate retinal microvascular oxygen transport in health and disease. PMID- 22101836 TI - Antimicrobial evaluation of diterpenes from Copaifera langsdorffii oleoresin against periodontal anaerobic bacteria. AB - The antimicrobial activity of four labdane-type diterpenes isolated from the oleoresin of Copaifera langsdorffii as well as of two commercially available diterpenes (sclareol and manool) was investigated against a representative panel of microorganisms responsible for periodontitis. Among all the evaluated compounds, (-)-copalic acid (CA) was the most active, displaying a very promising MIC value (3.1 ug mL-1; 10.2 uM) against the key pathogen (Porphyromonas gingivalis) involved in this infectious disease. Moreover, CA did not exhibit cytotoxicity when tested in human fibroblasts. Time-kill curve assays performed with CA against P. gingivalis revealed that this compound only inhibited the growth of the inoculums in the first 12 h (bacteriostatic effect). However, its bactericidal effect was clearly noted thereafter (between 12 and 24 h). It was also possible to verify an additive effect when CA and chlorhexidine dihydrochloride (CHD, positive control) were associated at their MBC values. The time curve profile resulting from this combination showed that this association needed only six hours for the bactericidal effect to be noted. In summary, CA has shown to be an important metabolite for the control of periodontal diseases. Moreover, the use of standardized extracts based on copaiba oleoresin with high CA contents can be an important strategy in the development of novel oral care products. PMID- 22101837 TI - Prosodic awareness skills and literacy acquisition in Spanish. AB - There has been very little research in Spanish on the potential role of prosodic skills in reading and spelling acquisition, which is the subject of the present study. A total of 85 children in 5th year of Primary Education (mean age 10 years and 9 months) performed tests assessing memory, stress awareness, phonological awareness, reading and spelling. In written language tests, errors were classified as phonological (grapheme-to-phoneme conversion rules) or stress related (placement of the stress mark). Regression analyses showed that, once memory and phonological awareness were controlled, stress awareness partially explained reading and spelling performance as well as error type; however, differences were found between reading and spelling errors. These results show a relationship between prosodic skills--namely stress sensitivity--and the acquisition of reading and spelling skills that seems to be independent of phonological awareness skills. PMID- 22101838 TI - Assessing cellular toxicities in fibroblasts upon exposure to lipid-based nanoparticles: a high content analysis approach. AB - Lipid-based nanoparticles (LNPs) are widely used for the delivery of drugs and nucleic acids. Although most of them are considered safe, there is confusing evidence in the literature regarding their potential cellular toxicities. Moreover, little is known about the recovery process cells undergo after a cytotoxic insult. We have previously studied the systemic effects of common LNPs with different surface charge (cationic, anionic, neutral) and revealed that positively charged LNPs ((+)LNPs) activate pro-inflammatory cytokines and induce interferon response by acting as an agonist of Toll-like receptor 4 on immune cells. In this study, we focused on the response of human fibroblasts exposed to LNPs and their cellular recovery process. To this end, we used image-based high content analysis (HCA). Using this strategy, we were able to show simultaneously, in several intracellular parameters, that fibroblasts can recover from the cytotoxic effects of (+)LNPs. The use of HCA opens new avenues in understanding cellular response and nanotoxicity and may become a valuable tool for screening safe materials for drug delivery and tissue engineering. PMID- 22101839 TI - The role of body size versus growth on the decision to migrate: a case study with Salmo trutta. AB - In a population exhibiting partial migration (i.e. migration and residency tactics occur in the same population), the mechanisms underlying the tactical choice are still unclear. Empirical studies have highlighted a variety of factors that could influence the coexistence of resident and migratory individuals, with growth and body size considered to be key factors in the decision to migrate. Most studies suffer from at least one of the two following caveats: (1) survival and capture probabilities are not taken into account in the data analysis, and (2) body size is often used as a proxy for individual growth. We performed a capture-mark-recapture experiment to study partial migration among juvenile brown trout Salmo trutta at the end of their first year, when a portion of the population emigrate from the natal stream while others choose residency tactic. Bayesian multistate capture-recapture models accounting for survival and recaptures probabilities were used to investigate the relative role of body size and individual growth on survival and migration probabilities. Our results show that, despite an apparent effect of both size and growth on migration, growth is the better integrative parameter and acts directly on migration probability whereas body size acts more strongly on survival. Consequently, we recommend caution if size is used as a proxy for growth when studying the factors that drive partial migration in juvenile salmonid species. PMID- 22101840 TI - Aversive odorant causing appetite decrease downregulates tyrosine decarboxylase gene expression in the olfactory receptor neuron of the blowfly, Phormia regina. AB - In the blowfly Phormia regina, exposure to d-limonene for 5 days during feeding inhibits proboscis extension reflex behavior due to decreasing tyramine (TA) titer in the brain. TA is synthesized by tyrosine decarboxylase (Tdc) and catalyzed into octopamine (OA) by TA beta-hydroxylase (Tbh). To address the mechanisms of TA titer regulation in the blowfly, we cloned Tdc and Tbh cDNAs from P. regina (PregTdc and PregTbh). The deduced amino acid sequences of both proteins showed high identity to those of the corresponding proteins from Drosophila melanogaster at the amino acid level. PregTdc was expressed in the antenna, labellum, and tarsus whereas PregTbh was expressed in the head, indicating that TA is mainly synthesized in the sensory organs whereas OA is primarily synthesized in the brain. d-Limonene exposure significantly decreased PregTdc expression in the antenna but not in the labellum and the tarsus, indicating that PregTdc expressed in the antenna is responsible for decreasing TA titer. PregTdc-like immunoreactive material was localized in the thin-walled sensillum. In contrast, the OA/TA receptor (PregOAR/TAR) was localized to the thick-walled sensillum. The results indicated that d-limonene inhibits PregTdc expression in the olfactory receptor neurons in the thin-walled sensilla, likely resulting in reduced TA levels in the receptor neurons in the antenna. TA may be transferred from the receptor neuron to the specific synaptic junction in the antennal lobe of the brain through the projection neurons and play a role in conveying the aversive odorant information to the projection and local neurons. PMID- 22101841 TI - Iron storage proteins are essential for the survival and pathogenesis of Mycobacterium tuberculosis in THP-1 macrophages and the guinea pig model of infection. AB - Iron is one of the crucial elements required for the growth of Mycobacterium tuberculosis. However, excess free iron becomes toxic for the cells because it catalyzes the production of reactive oxygen radicals, leading to oxidative damage. Hence, it is essential for the pathogen to have the ability to store intracellular iron in an iron-rich environment and utilize it under iron depletion. M. tuberculosis has two iron storage proteins, namely BfrA (Rv1876; a bacterioferritin) and BfrB (Rv3841; a ferritin-like protein). However, the demonstration of biological significance requires the disruption of relevant genes and the evaluation of the resulting mutant for its ability to survive in the host and cause disease. In this study, we have disrupted bfrA and bfrB of M. tuberculosis and demonstrated that these genes are crucial for the storage and supply of iron for the growth of bacteria and to withstand oxidative stress in vitro. In addition, the bfrA bfrB double mutant (H37Rv DeltabfrA DeltabfrB) exhibited a marked reduction in its ability to survive inside human macrophages. Guinea pigs infected with H37Rv DeltabfrA DeltabfrB exhibited a marked diminution in the dissemination of the bacilli to spleen compared to that of the parental strain. Moreover, guinea pigs infected with H37Rv DeltabfrA DeltabfrB exhibited significantly reduced pathological damage in spleen and lungs compared to that of animals infected with the parental strain. Our study clearly demonstrates the importance of these iron storage proteins in the survival and pathogenesis of M. tuberculosis in the host and establishes them as attractive targets for the development of new inhibitors against mycobacterial infections. PMID- 22101842 TI - Substrate recognition mechanism and substrate-dependent conformational changes of an ROK family glucokinase from Streptomyces griseus. AB - Carbon catabolite repression (CCR) is a widespread phenomenon in many bacteria that is defined as the repression of catabolic enzyme activities for an unfavorable carbon source by the presence of a preferable carbon source. In Streptomyces, secondary metabolite production often is negatively affected by the carbon source, indicating the involvement of CCR in secondary metabolism. Although the CCR mechanism in Streptomyces still is unclear, glucokinase is presumably a central player in CCR. SgGlkA, a glucokinase from S. griseus, belongs to the ROK family glucokinases, which have two consensus sequence motifs (1 and 2). Here, we report the crystal structures of apo-SgGlkA, SgGlkA in complex with glucose, and SgGlkA in complex with glucose and adenylyl imidodiphosphate (AMPPNP), which are the first structures of an ROK family glucokinase. SgGlkA is divided into a small alpha/beta domain and a large alpha+beta domain, and it forms a dimer-of-dimer tetrameric configuration. SgGlkA binds a beta-anomer of glucose between the two domains, and His157 in consensus sequence 1 plays an important role in the glucose-binding mechanism and anomer specificity of SgGlkA. In the structures of SgGlkA, His157 forms an HC3-type zinc finger motif with three cysteine residues in consensus sequence 2 to bind a zinc ion, and it forms two hydrogen bonds with the C1 and C2 hydroxyls of glucose. When the three structures are compared, the structure of SgGlkA is found to be modified by the binding of substrates. The substrate-dependent conformational changes of SgGlkA may be related to the CCR mechanism in Streptomyces. PMID- 22101843 TI - CitA/CitB two-component system regulating citrate fermentation in Escherichia coli and its relation to the DcuS/DcuR system in vivo. AB - Citrate fermentation by Escherichia coli requires the function of the citrate/succinate antiporter CitT (citT gene) and of citrate lyase (citCDEFXG genes). Earlier experiments suggested that the two-component system CitA/CitB, consisting of the membrane-bound sensor kinase CitA and the response regulator CitB, stimulates the expression of the genes in the presence of citrate, similarly to CitA/CitB of Klebsiella pneumoniae. In this study, the expression of a chromosomal citC-lacZ gene fusion was shown to depend on CitA/CitB and citrate. CitA/CitB is related to the DcuS/DcuR two-component system which induces the expression of genes for fumarate respiration in response to C(4)-dicarboxylates and citrate. Unlike DcuS, CitA required none of the cognate transporters (CitT, DcuB, or DcuC) for function, and the deletion of the corresponding genes showed no effect on the expression of citC-lacZ. The citAB operon is preceded by a DcuR binding site. Phosphorylated DcuR bound specifically to the promoter region, and the deletion of dcuS or dcuR reduced the expression of citC. The data indicate the presence of a regulatory cascade consisting of DcuS/DcuR modulating citAB expression (and CitA/CitB levels) and CitA/CitB controlling the expression of the citCDEFXGT gene cluster in response to citrate. In vivo fluorescence resonance energy transfer (FRET) and the bacterial two-hybrid system (BACTH) showed interaction between the DcuS and CitA proteins. However, BACTH and expression studies demonstrated the lack of interaction and cross-regulation between CitA and DcuR or DcuS and CitB. Therefore, there is only linear phosphoryl transfer (DcuS->DcuR and CitA->CitB) without cross-regulation between DcuS/DcuR and CitA/CitB. PMID- 22101844 TI - Decreased transport restores growth of a Salmonella enterica apbC mutant on tricarballylate. AB - Mutants of Salmonella enterica lacking apbC have nutritional and biochemical properties indicative of defects in iron-sulfur ([Fe-S]) cluster metabolism. An apbC mutant is unable to grow on tricarballylate as a carbon source. Based on the ability of ApbC to transfer an [Fe-S] cluster to an apoprotein, this defect was attributed to poor loading of the [Fe-S] cluster-containing TcuB enzyme. Consistent with these observations, a previous study showed that overexpression of iscU, which encodes an [Fe-S] cluster molecular scaffold, suppressed the tricarballylate growth defect of an apbC mutant (J. M. Boyd, J. A. Lewis, J. C. Escalante-Semerena, and D. M. Downs, J. Bacteriol. 190:4596-4602, 2008). In this study, tcuC mutations that suppress the growth defect of an apbC mutant by decreasing the intracellular concentration of tricarballylate are described. Collectively, the suppressor analyses support a model in which reduced TcuB activity prevents growth on tricarballylate by (i) decreasing catabolism and (ii) allowing levels of tricarballylate that are toxic to the cell to accumulate. The apbC tcuC mutant strains described here reveal that the balance of the metabolic network can be altered by the accumulation of deleterious metabolites. PMID- 22101845 TI - Unveiling unusual features of formation of septal partition and constriction in mycobacteria--an ultrastructural study. AB - The ultrastructural functions of the electron-dense glycopeptidolipid-containing outermost layer (OL), the arabinogalactan-mycolic acid-containing electron transparent layer (ETL), and the electron-dense peptidoglycan layer (PGL) of the mycobacterial cell wall in septal growth and constriction are not clear. Therefore, using transmission electron microscopy, we studied the participation of the three layers in septal growth and constriction in the fast-growing saprophytic species Mycobacterium smegmatis and the slow-growing pathogenic species Mycobacterium xenopi and Mycobacterium tuberculosis in order to document the processes in a comprehensive and comparative manner and to find out whether the processes are conserved across different mycobacterial species. A complete septal partition is formed first by the fresh synthesis of the septal PGL (S-PGL) and septal ETL (S-ETL) from the envelope PGL (E-PGL) in M. smegmatis and M. xenopi. The S-ETL is not continuous with the envelope ETL (E-ETL) due to the presence of the E-PGL between them. The E-PGL disappears, and the S-ETL becomes continuous with the E-ETL, when the OL begins to grow and invaginate into the S ETL for constriction. However, in M. tuberculosis, the S-PGL and S-ETL grow from the E-PGL and E-ETL, respectively, without a separation between the E-ETL and S ETL by the E-PGL, in contrast to the process in M. smegmatis and M. xenopi. Subsequent growth and invagination of the OL into the S-ETL of the septal partition initiates and completes septal constriction in M. tuberculosis. A model for the conserved sequential process of mycobacterial septation, in which the formation of a complete septal partition is followed by constriction, is presented. The probable physiological significance of the process is discussed. The ultrastructural features of septation and constriction in mycobacteria are unusually different from those in the well-studied organisms Escherichia coli and Bacillus subtilis. PMID- 22101847 TI - Sequential closure of the cytoplasm and then the periplasm during cell division in Escherichia coli. AB - To visualize the latter stages of cell division in live Escherichia coli, we have carried out fluorescence recovery after photobleaching (FRAP) on 121 cells expressing cytoplasmic green fluorescent protein and periplasmic mCherry. Our data show conclusively that the cytoplasm is sealed prior to the periplasm during the division event. PMID- 22101846 TI - The Vibrio cholerae mannitol transporter is regulated posttranscriptionally by the MtlS small regulatory RNA. AB - Vibrio cholerae continues to pose a health threat in many developing nations and regions of the world struck by natural disasters. It is a pathogen that rapidly adapts to aquatic environments and the human small intestine. Small regulatory RNAs (sRNAs) may contribute to this adaptability. Specifically, the mannitol operon sRNA (MtlS sRNA; previously designated the IGR7 sRNA) is transcribed antisense to the 5' untranslated region of the mtl operon, encoding the mannitol specific phosphotransferase system. Mannitol is a six-carbon sugar alcohol that accumulates in the human small intestine, the primary site of V. cholerae colonization. To better understand the V. cholerae mtl operon at a molecular level, we investigated mtlA expression in the presence of various carbon sources and the role of the MtlS sRNA. We observed that MtlA protein is present only in cells grown on mannitol sugar, whereas MtlS sRNA is expressed during growth on all sugars other than mannitol. In contrast, mtlA mRNA is expressed in similar amounts regardless of the carbon source used for bacterial growth. These observations suggest that the regulation of MtlA protein expression is a posttranscriptional event. We further demonstrate that MtlS sRNA overexpression repressed MtlA synthesis without affecting the stability of the messenger and that this process is largely independent of Hfq. We propose a model in which, when carbon sources other than mannitol are present, MtlS sRNA is transcribed, base pairs with the 5' untranslated region of the mtlA mRNA, occluding the ribosome binding site, and inhibits the synthesis of the mannitol-specific phosphotransferase system. PMID- 22101848 TI - Mur regulates the gene encoding the manganese transporter MntH in Brucella abortus 2308. AB - MntH is the only high-affinity manganese transporter identified in Brucella. A previous study showed that MntH is required for the wild-type virulence of Brucella abortus 2308 in mice (Anderson ES, et al., Infect. Immun. 77:3466-3474, 2009) and indicated that the mntH gene is regulated in a manganese-responsive manner in this strain by a Mur homolog. In the study presented here, the transcriptional start site for mntH in B. abortus 2308 was determined by primer extension analysis. Specific interactions between Mur and the mntH promoter region were demonstrated in an electrophoretic mobility shift assay (EMSA), and a Mur binding site was identified in the -55 to -24 region of the mntH promoter by DNase I footprint analysis. The specificity of the interaction of Mur with the putative Mur box was further evaluated by EMSA employing oligonucleotides in which the consensus nucleotides in this region were substituted. These studies not only confirm a direct role for Mur in the Mn-responsive regulation of mntH expression in Brucella abortus 2308 but also identify the cis-acting elements upstream of mntH that are responsible for this regulation. PMID- 22101849 TI - Willingness to participate in future HIV prevention studies among gay and bisexual men in Scotland, UK: a challenge for intervention trials. AB - This article examines willingness to participate in future HIV prevention research among gay and bisexual men in Scotland, UK. Anonymous, self-complete questionnaires and OrasureTM oral fluid samples were collected in commercial gay venues. 1,320 men were eligible for inclusion. 78.2% reported willingness to participate in future HIV prevention research; 64.6% for an HIV vaccine, 57.4% for a behaviour change study, and 53.0% for a rectal microbicide. In multivariate analysis, for HIV vaccine research, greater age, minority ethnicity, and not providing an oral fluid sample were associated with lower willingness; heterosexual orientation and not providing an oral fluid sample were for microbicides; higher education and greater HIV treatment optimism were for behaviour change. STI testing remained associated with being more willing to participate in microbicide research and frequent gay scene use remained associated with being more willing to participate in behaviour change research. Having an STI in the past 12 months remained significantly associated with being willing to participate in all three study types. There were no associations between sexual risk behaviour and willingness. Although most men expressed willingness to participate in future research, recruitment of high-risk men, who have the potential to benefit most, is likely to be more challenging. PMID- 22101850 TI - Sleep quality and duration before and after bariatric surgery. AB - BACKGROUND: Shortened sleep duration causes hormonal and metabolic changes that favor fat accumulation and weight gain. Obesity, in turn, may reduce sleep quality and contribute to sleep loss. The purpose of this study was to evaluate the sleep durations of individuals with morbid obesity, compared to their nonobese counterparts, and to determine the effects of surgical weight reduction on sleep duration and sleep quality. METHODS: The study population included 45 bariatric (BA) surgical patients (mean body mass index [BMI] = 49) and 45 gender matched nonobese controls (NC; BMI = 24). Self-reported sleep durations were obtained and overall sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The data show that average sleep durations of the preoperative BA patients were significantly (p < 0.0001) less than those of the NC, i.e., 6.0 and 7.2 h, respectively. Sleep loss for the BA patients was associated with poor sleep quality, along with an increased frequency of conditions that interfere with sleep, including coughing and snoring, difficulty breathing, feeling too hot, and experiencing pain. Overall, 78% of the BA patients, compared to 36% of the NC, had PSQI scores indicative of poor sleep quality. Surgery after 3 to 12 months resulted in significant (p < 0.0001) weight loss (percentage total change in BMI = 34) and improved sleep quality, i.e., PSQI = 8.8 preoperatively vs. 4.6 postoperatively. Sleep durations increased significantly (p < 0.0001) post-surgery from 6.0 to 6.8 h. CONCLUSIONS: Individuals with extreme obesity, compared to the nonobese, obtain less sleep and experience poorer sleep quality. Bariatric surgery improves sleep duration and quality. PMID- 22101851 TI - Obituary: Dr. Alexander M.C. Macgregor, "a giant in the field.". PMID- 22101852 TI - Routine drain placement in Roux-en-Y gastric bypass: an expanded retrospective comparative study of 755 patients and review of the literature. AB - Routine drain use after laparoscopic Roux-en-y gastric bypass (LRYGB) is still practiced by many bariatric surgeons. After a patient in our program experienced intestinal obstruction secondary to a drain, we reevaluated our practice and hypothesized drains would be of no benefit and potentially harmful after LRYGB. Retrospective record review of all patients undergoing LRYGB from August 2005 to August 2009 was performed. As we changed our practice in December 2006, we have two comparable groups: one with a drain placed at surgery and one without. All operations were otherwise performed in an identical fashion by three fellowship trained university surgeons. We compared outcomes between the two groups, particularly regarding gastrojejunal (GJ) leaks. Jejunojejunal (JJ) leaks, unlikely to be captured by these drains, were not studied. A total of 755 LRYGBs were performed during the study period, the first 272 patients with routine drains and the subsequent 483 without. Demographics were statistically similar between the two groups. There were four GJ leaks in the drain group (1.47%) and three in the nondrain group (0.62%). Among the drain patients, two required operation and two were treated nonoperatively. Among the nondrain patients, two required operation and one was treated nonoperatively. The leak and reoperation rates between the groups were not statistically different (p = 0.154 and p = 0.514). Routine drains likely have no benefit after LRYGB. Clinical parameters such as tachycardia, fever, oliguria, and increasing abdominal pain should guide further investigation for and treatment of a leak. PMID- 22101853 TI - Sensitive and specific single-molecule sequencing of 5-hydroxymethylcytosine. AB - We describe strand-specific, base-resolution detection of 5-hydroxymethylcytosine (5-hmC) in genomic DNA with single-molecule sensitivity, combining a bioorthogonal, selective chemical labeling method of 5-hmC with single-molecule, real-time (SMRT) DNA sequencing. The chemical labeling not only allows affinity enrichment of 5-hmC-containing DNA fragments but also enhances the kinetic signal of 5-hmC during SMRT sequencing. We applied the approach to sequence 5-hmC in a genomic DNA sample with high confidence. PMID- 22101854 TI - Counting absolute numbers of molecules using unique molecular identifiers. AB - Counting individual RNA or DNA molecules is difficult because they are hard to copy quantitatively for detection. To overcome this limitation, we applied unique molecular identifiers (UMIs), which make each molecule in a population distinct, to genome-scale human karyotyping and mRNA sequencing in Drosophila melanogaster. Use of this method can improve accuracy of almost any next-generation sequencing method, including chromatin immunoprecipitation-sequencing, genome assembly, diagnostics and manufacturing-process control and monitoring. PMID- 22101855 TI - Giant cell arteritis - can we decrease its relapsing course with less toxic therapy? PMID- 22101856 TI - Free-floating thrombus of the carotid artery with a homozygous methylenetetrahydrofolate reductase gene mutation: a case report. AB - Free-floating thrombus (FFT) of the carotid artery is a rare condition of currently unknown etiology. We describe a symptomatic patient with an FFT in the left common carotid artery. A duplex ultrasonography scan showed the presence of a mobile floating thrombus moving in cyclical motion with the cardiac cycles in the left common carotid artery. During emergency surgery, an FFT was seen at this location and removed. No underlying wall defect was seen at the time of surgery. In a genetic screening test, TT homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms was detected. The patient recovered uneventfully, with no neurogical events. Lifelong anticoagulant therapy was recommended. An aggressive surgical approach is recommended in the patient to prevent embolic episodes. PMID- 22101857 TI - Embolic stroke after carotid artery ligation during carotid body tumor resection. AB - This report describes a case of a delayed cerebral embolic infarction, after internal carotid artery (ICA) ligation secondary to carotid body tumor resection. We describe a 34-year-old woman who underwent left ICA ligation during a large carotid body tumor surgery. Immediately after surgery, the patient was neurologically asymptomatic; however, she subsequently developed a cerebral embolic infarction nine hours postoperatively. After beginning antiplatelet therapy, all symptoms ultimately resolved, although over a gradual course. Since the ligation of the ICA can cause thromboembolic infarctions of the cerebrum, we contend that antiplatelet agents be administered to prevent and/or treat embolic strokes. PMID- 22101858 TI - Role of Hedgehog signalling at the transition from double-positive to single positive thymocyte. AB - In the thymus, developing T cells receive signals that determine lineage choice, specificity, MHC restriction and tolerance to self-antigen. One way in which thymocytes receive instruction is by secretion of Sonic hedgehog (Shh) from thymic epithelial cells. We have previously shown that Hedgehog (Hh) signalling in the thymus decreases the CD4:CD8 single-positive (SP) thymocyte ratio. Here, we present data indicating that double-positive (DP) thymocytes are Hh-responsive and that thymocyte-intrinsic Hh signalling plays a role in modulating the production of CD4(+) (SP4), CD8(+) (SP8) and unconventional T-cell subsets. Repression of physiological Hh signalling in thymocytes altered the proportions of DP and SP4 cells. Thymocyte-intrinsic Hh-dependent transcription also attenuated both the production of mature SP4 and SP8 cells, and the establishment of peripheral T-cell compartments in TCR-transgenic mice. Additionally, stimulation or withdrawal of Hh signals in the WT foetal thymus impaired or enhanced upregulation of the CD4 lineage-specific transcription factor Gata3 respectively. These data together suggest that Hh signalling may play a role in influencing the later stages of thymocyte development. PMID- 22101859 TI - Spatial and temporal ecological diversity amongst Eocene primates of France: evidence from teeth. AB - Diet is of paramount importance in the life of a primate. It is also highly variable, as potential food sources vary in spatial distribution and availability over time. The fossil record, due to its fragmentary nature, offers few possibilities to assess the dietary range of a given primate across its spatial and temporal distribution. Here we focus on three taxa, Leptadapis magnus (Adapidae, Adapiformes), Necrolemur cf. antiquus (Microchoeridae, Omomyiformes), and Pseudoloris parvulus (Microchoeridae, Omomyiformes). These taxa occur at different localities of the Late Eocene in the south of France ranging from MP16 (Robiac, Lavergne; 39 Ma), MP17a (La Bouffie, Euzet, Fons 4; 38 Ma) to MP17b (Perriere; 37 Ma). Diets of fossil taxa are assessed here by dental microwear analysis using a comparative database of 11 species of living strepsirhines. On the whole, leaves were a preferred food for the large-bodied Leptadapis (4-5 kg). However, the diet of this taxon varied from a mix of leaves and fruit at La Bouffie, a closed tropical rain forest environment, to a strictly leaf-eating one in the more open environment of Perriere. Based on body mass (200-350 g) and dental microwear patterns, Necrolemur had a mainly fruit-based diet, perhaps supplemented by insects. However, the comparison of the different localities reveals the dietary range of this small-bodied omomyiform which seems to vary between insects and a much softer diet. Pseudoloris had a diet strictly based on insects. Contrary to Leptadapis or Necrolemur, its diet seems to have been confined to insects whatever the locality considered. PMID- 22101860 TI - Quality of life and leisure participation in children with neurodevelopmental disabilities: a thematic analysis of the literature. AB - PURPOSE: The aim of this systematic review was to document evidence of the association between leisure participation and quality of life (QoL) in children with neurodevelopmental disabilities, and to identify the main factors that further clarify this relationship. METHODS: An electronic search of the literature was conducted using Medline, Embase, PsycInfo, CINAHL, ERIC, OT Seeker, and the Cochrane library using relevant MESH heading and key words. An inductive thematic analysis was used to synthesize main findings from the studies. The mixed methods appraisal tool (MMAT) was used to assess the methodological quality of the included studies. RESULTS: Nineteen studies were included in this systematic review. All 19 studies fulfilled most of the criteria outlined by the MMAT for each study design (quantitative, qualitative, and mixed methods). Mixed methods studies had the lowest MMAT scores. Seven themes were identified that further elucidate the important relationships between leisure participation and QoL: active physical leisure participation and physical well being; leisure participation and self; leisure participation and emotional well being; leisure participation and social well-being; leisure participation and cognition; leisure preferences and well-being; and negative aspects of leisure participation. CONCLUSIONS: The use of thematic analysis enabled the synthesis of findings from quantitative, qualitative, and mixed methods study designs. Participating in both naturally occurring, spontaneous forms of leisure activities and participating in more structured types of leisure and therapeutic programs that focus on leisure contribute to improving the QoL of children with neurodevelopmental disabilities. A key aspect to consider is the child's ability to participate in his/her preferred leisure activities. Environmental adaptations may be required to ensure that the leisure opportunities meet the children's capabilities and contribute positively to their QoL. PMID- 22101861 TI - Palliative care outcomes in surgical oncology patients with advanced malignancies: a mixed methods approach. AB - PURPOSE: To prospectively compare outcomes and processes of hospital-based early palliative care with standard care in surgical oncology patients (N = 152). METHODS: A randomized, mixed methods, longitudinal study evaluated the effectiveness of a hospital-based Pain and Palliative Care Service (PPCS). Interviews were conducted presurgically and at follow-up visits up to 1 year. Primary outcome measures included the Gracely Pain Intensity and Unpleasantness Scales and the Symptom Distress Scale. Qualitative interviews assessed social support, satisfaction with care, and communication with providers. Survival analysis methods explored factors related to treatment crossover and study discontinuation. Models for repeated measures within subjects over time explored treatment and covariate effects on patient-reported pain and symptom distress. RESULTS: None of the estimated differences achieved statistical significance; however, for those who remained on study for 12 months, the PPCS group performed better than their standard of care counterparts. Patients identified consistent communication, emotional support, and pain and symptom management as positive contributions delivered by the PPCS. CONCLUSIONS: It is unclear whether lower pain perceptions despite greater symptom distress were clinically meaningful; however, when coupled with the patients' perceptions of their increased resources and alternatives for pain control, one begins to see the value of an integrated PPCS. PMID- 22101862 TI - Reactive perforating collagenosis during erlotinib therapy. PMID- 22101863 TI - Polymorphisms in Ly6 genes in Msq1 encoding susceptibility to mouse adenovirus type 1. AB - Strain-specific differences in susceptibility to mouse adenovirus type 1 (MAV-1) are linked to the quantitative trait locus Msq1 on mouse chromosome 15. This region contains 14 Ly6 or Ly6-related genes, many of which are known to be expressed on the surface of immune cells, suggesting a possible role in host defense. We analyzed these genes for polymorphisms between MAV-1-susceptible and MAV-1-resistant inbred mouse strains. Sequencing of cDNAs identified 12 coding region polymorphisms in 2010109I03Rik, Ly6e, Ly6a, Ly6c1, and Ly6c2, six of which were nonsynonymous and five of which were previously unlisted in dbSNP Build 132. We also clarified sequence discrepancies in GenBank for the coding regions of I830127L07Rik and Ly6g. Additionally, Southern blotting revealed size polymorphisms within the DNA regions of Ly6e, Ly6a, and Ly6g. Collectively, these genetic variations have implications for the structure, function, and/or expression of Ly6 and Ly6-related genes that may contribute to the observed strain-specific differences in susceptibility to MAV-1. PMID- 22101864 TI - Pseudogenes of rat VDAC1: 16 gene segments in the rat genome show structural similarities with the cDNA encoding rat VDAC1, with 8 slightly expressed in certain tissues. AB - BLAST analysis of the rat genome revealed the presence of 16 pseudogenes of isoform 1 of the mitochondrial voltage-dependent anion channel (VDAC1). Based on their structural characterization, it was concluded that these pseudogenes were formed by integration of VDAC1 cDNA into the genome, and subsequent rearrangements/mutations. By RT-PCR analysis using carefully designed primers that could not amplify the cDNA of genuine VDAC1, 8 of these 16 pseudogenes showed slight expression in certain tissues, but none of them seemed to encode a functional protein. PMID- 22101865 TI - Skeletal muscle metastases: a three-part study of a not-so-rare entity. AB - OBJECTIVE: Our purposes were to explore the epidemiology of metastases to skeletal muscle and their detection on fused positron emission tomography and computed tomography. MATERIALS AND METHODS: We evaluated the epidemiology of skeletal muscle metastases in the literature and among cases from our hospital and studied the prevalence and appearance of skeletal muscle metastases among 433 patients undergoing fused positron emission tomography and computed tomography for non-small-cell lung cancer. RESULTS: We found 264 cases of skeletal muscle metastases in 151 articles. Mean age was 57.8 years with 67% men. At our hospital we studied 70 cases. Mean patient age was 55.7 years with 63% men. The most common source was lung cancer, and the most common site of involvement was the muscles of the trunk. Among our lung cancer patients undergoing fused positron emission tomography and computed tomography, we found 7 (1.6%) with skeletal muscle metastases. In only one of these seven patients was the metastasis first discovered by another imaging modality. In one patient discovery of the metastasis at fused positron emission tomography and computed tomography changed management. CONCLUSION: Skeletal muscle metastases are not rare. They may be more apparent at fused positron emission tomography and computed tomography than at other staging examinations, particularly contrast-enhanced CT scanning. Radiologists need to be alert to their presence when interpreting staging examinations in cancer patients. PMID- 22101866 TI - Role of ultrasonography and magnetic resonance imaging in the diagnosis of intramuscular cysticercosis. AB - OBJECTIVES: Nonspecific clinical presentations often lead to misdiagnosis of focal cysticercal myositis. This report emphasizes the role of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of solitary intramuscular cysticercosis. MATERIALS AND METHODS: Six patients with persistent post-traumatic isolated muscular swelling were treated with analgesic and antibiotics, but the swelling did not subside. Radiographs showed soft tissue swelling with no bony abnormalities. Laboratory markers were inconclusive. Ultrasonographic and magnetic resonance images (MRI) showed typical features of intramuscular cysticercosis. Clinical, radiological, and fundoscopic evaluation of brain and eyes could not isolate any cysticercosis focus in these organs. Patients were treated with 3 weeks albendazole therapy. RESULTS: The identifying sonographic features of intramuscular cysticercosis, as evident from this case series, included an intramuscular elliptical or oval anechoic lesion with echogenic intralesional focus likely to be scolex. Magnetic resonance images showed orientation of the cyst along the direction of muscle fibers with T2W hyperintense signal and post-contrast perilesional enhancement. All patients responded to medical treatment. CONCLUSION: Cysticercosis may manifest as isolated muscular swelling without neurological or ocular involvement. Clinicians should be aware of this clinical condition to avoid misdiagnosis. Ultrasonography and magnetic resonance imaging are good diagnostic aids to establish soft tissue cysticercosis. PMID- 22101867 TI - Physical capacity of girls with mild and moderate idiopathic scoliosis: influence of the size, length and number of curvatures. AB - INTRODUCTION: Idiopathic scoliosis affects the locomotor system; however, it can considerably impair the function of cardiovascular and respiratory systems. The aim of the study was to assess parameters indicating the physical capacity of adolescent girls with mild or moderate idiopathic scoliosis. MATERIALS AND METHODS: The study included 97 girls, aged 10-18 years: 70 girls, aged 13.84 +/- 2.2 years, with idiopathic thoracic scoliosis (Cobb angle 10 degrees -40 degrees ) formed the study group and 27 healthy girls, aged 13.2 +/- 1.9 years, formed the control group. The girls underwent the Physical Work Capacity 170 (PWC170) test on a cycle ergometer based on two 5-min submaximal physical effort events. The maximum oxygen intake was calculated and expressed in l/min and ml/kg/min. The impact of the curvature angle value, of the number of vertebrae within the curve and of the number of the curves on the physical capacity parameters was analyzed. RESULTS: The maximal oxygen intake (l/min) and PWC170 (W; W/kg) values were considerably lower in girls with scoliosis of 25 degrees -40 degrees than in the control group. No significant differences were observed between girls with mild scoliosis (10 degrees -24 degrees ) and the control group. Statistical analysis did not show any significant impact of the number of vertebrae affected by scoliosis and the number of curvatures on VO(2)max (l/min; ml/kg/min) and the PWC170 (W) indicator. In the group of girls with scoliosis involving more than nine vertebrae, the PWC170 (W/kg) indicator was significantly lower than in the control group. A similar correlation was observed between girls with double curved scoliosis and the control group (p < 0.05). CONCLUSION: The maximum oxygen intake and the output during the PWC170 test is lower in girls with moderate scoliosis than in the control group. The value of maximum oxygen intake and output obtained during the PWC170 test in girls with mild scoliosis does not differ significantly from the values obtained in the control group. The number of vertebrae involved in scoliotic deformation and the number of curvatures cause significant decrease in only the relative value of the output obtained during an exercise test. PMID- 22101868 TI - Untreated Scheuermann's disease: a 37-year follow-up study. AB - INTRODUCTION: There are only a few follow-up studies of untreated Scheuermann's disease. The aim of this study was to investigate the relationship between vertebral changes, back pain, and disability in patients with untreated Scheuermann's disease after a 37-year follow-up. MATERIALS AND METHODS: Eighty patients responded to a postal questionnaire concerning back pain and disability and 49 of them had classic Scheuermann's disease. Degree of kyphosis, lordosis, scoliosis, the number of affected vertebrae, and mean and maximum wedge angles were measured from radiographs. Back pain and disability scores were compared to a sample of the general Finnish population (n = 3,835). RESULTS: At follow-up, the patients were on average 59 (SD 8) years old (range 44-79 years), and the mean follow-up time was 37 (SD 7) years (26-54 years). The patients comprised more males than females (3.1:1). At follow-up, male patients were on average 3 cm taller than controls (p = 0.007). At age 20, female patients compared to controls were on average 6 kg heavier (p = 0.016) and had higher body mass index (BMI) (mean 23.9 kg/m(2) vs. 20.8 kg/m(2), p = 0.001). Scheuermann's patients had 2.5 fold [odds ratio (OR); 95% confidence interval (CI); 1.4-4.5, p = 0.003] increased risk for constant back pain compared to controls. The risk for disability because of back pain during the past 5 years (OR 2.6; 95% CI 1.4-4.7, p = 0.002), risk for back pain during the past 30 days (OR 3.7; 95% CI 1.9-7.0, p < 0.001) and risk for sciatic pain (OR 2.3; 95% CI 1.3-4.3, p = 0.005) were higher compared to controls. Scheuermann's patients had higher risk for difficulties in mounting stairs (OR 5.4; 95% CI 2.8-10.3, p < 0.001) and in carrying a 5 kg load for at least 100 m (OR 7.2; 95% CI 3.9-13.3, p < 0.001). CONCLUSION: Scheuermann's patients had a higher risk for back pain and disabilities during activities of daily living than controls. However, the degree of thoracic kyphosis among Scheuermann's patients was not related to back pain, quality of life, or general health. PMID- 22101869 TI - Effect of nanogroove geometry on adipogenic differentiation. AB - We present the effect of nanotopographically defined surfaces on adipocyte differentiation using various nanogroove patterns. Parallel nanogroove arrays with equal inter-groove distance (400, 550, 800 nm width) and varying distances (550 nm width with three different spacings of 550, 1100, and 2750 nm) were fabricated by UV-assisted capillary force lithography (CFL) on 18 mm diameter glass coverslips using biocompatible polyurethane (PU)-based material. After coating with fibronectin and subsequent culture of 3T3-L1 preadipocytes, the degree of adipocyte differentiation was determined by Oil Red O staining and adipogenic gene expression. We observed that adipocyte differentiation was slightly but substantially affected by culture on various nanogrooved surfaces. In particular, the cell crawling into nanogrooves contributed substantially to an enhanced level of differentiation with higher contact guidance, suggesting that cell-to-surface interactions would play a role for the adipocyte differentiation. PMID- 22101870 TI - Effects of exercise stress on the endocannabinoid system in humans under field conditions. AB - The effects of physical exercise stress on the endocannabinoid system in humans are almost unexplored. In this prospective study, we investigated in a crossover design and under field conditions at different altitudes the effects of physical exercise on the endocannabinoid system (ECS) in 12 trained healthy volunteers. For determination of alterations on the ECS three different protocols were analyzed: Protocol A (physical exercise at lower altitude) involved strenuous hiking below 2,100 m, whereas Protocol B (physical exercise by active ascent to high altitude) involved hiking up to 3,196 m, an accommodation at the cottage and a descent the next day. Protocol C (passive ascent) included a helicopter ascent to 3,196 m, an overnight stay at this altitude and a flight back to the base camp the following day. The cumulative hiked altitude in Protocol A and B was comparable (~1,650 m). The blood EC concentrations of anandamide increased significantly in Protocol A/B from baseline (T0) 0.12 +/- 0.01/0.16 +/- 0.02 (mean +/- SEM) to 0.27 +/- 0.02/0.42 +/- 0.02 after exercise (T1) (p < 0.05). Anandamide levels in Protocol C remained stable at 0.20 +/- 0.02. We conclude that the ECS is activated upon strenuous exercise whereas the combination with hypoxic stress further increases its activity. The reduced partial pressure of oxygen at high altitude alone did not affect this system. In summary, physical exercise activates the endocannabinoid system, whereas the combination with high altitude enhances this activation. This discloses new perspectives to adaptation mechanisms to physical exercise. PMID- 22101871 TI - Effects of set-repetition configuration in eccentric exercise on muscle damage and the repeated bout effect. AB - The number of eccentric contractions is a factor affecting the magnitude of muscle damage; however, it is unknown whether set-repetition configurations for the same total number of eccentric contractions affect the muscle damage. The present study investigated whether different set-repetition configurations would result in different force output during eccentric exercise and different magnitude of muscle damage following the first and second exercise bouts. Ten non resistance-trained men (26.1 +/- 4.1 years) performed two bouts of eccentric exercise of the elbow flexors of each arm (4 bouts in total). One arm performed 3 sets of 10 maximal eccentric contractions (3 * 10) and the contralateral arm performed 10 sets of 3 maximal eccentric contractions (10 * 3), and each arm performed 20 sets of 3 maximal eccentric contractions (20 * 3) 4 weeks after the first bout. The order of the exercise (3 * 10, 10 * 3) and the use of arm (dominant, non-dominant) were counterbalanced amongst subjects. The torque produced over 30 eccentric contractions was similar between 3 * 10 and 10 * 3, and the changes in torque during 20 * 3 were similar between arms. Maximal voluntary contraction strength, range of motion, biceps brachii cross-sectional area and muscle soreness changed significantly (P < 0.05) following the exercise without significant differences between 3 * 10 and 10 * 3, and changes in the measures following 20 * 3 were similar between arms, except for range of motion (ROM). No significant difference in the changes in any measures except ROM was evident when compared between the first and second bouts. These results showed that changing the set-repetition configuration had little effect on muscle damage. PMID- 22101872 TI - Backbone 1H, 13C and 15N resonance assignments of the 39 kDa staphylococcal hemoglobin receptor IsdH. AB - During infections Stahpylococcus aureus preferentially uses heme as an iron source, which it captures from human hemoglobin using the Iron regulated surface determinant (Isd) system. On the cell surface two related staphylococcal surface receptors called IsdH and IsdB bind to hemoglobin and extract its heme. Both receptors contain multiple NEAr iron Transporter (NEAT) domains that either bind to hemoglobin, or to heme. All previous structural studies have investigated individual NEAT domains and have not explored how the domains might interact with one another to synergistically extract heme from hemoglobin. Here, we report the near complete (1)H, (13)C and (15)N backbone resonance assignments of a bi-domain unit from IsdH that contains the N2 and N3 NEAT domains, which bind to hemoglobin and heme, respectively (IsdH(N2N3), residues 326-660, 39 kDa). The assigned backbone resonances lay the foundation for future NMR studies that will explore the molecular basis of IsdH function. PMID- 22101873 TI - Factors influencing fatty acid composition of common carp (Cyprinus carpio) muscle. AB - There is evidence that n-3 highly unsaturated fatty acids (n-3 HUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for human health, especially for the cardiovascular system. The sources of n-3 HUFA, including EPA and DHA, are scarce in diet consumed by the Czech population. Thus, it would be beneficial to generally increase fish consumption and also to increase the content of the beneficial fatty acids (FA) in locally produced fish and other products. Therefore the overall aim of this paper was to review factors influencing lipid content and composition in common carp, which is the major cultured fish in the Czech Republic, and to identify long term sustainable ways for increasing the beneficial fatty acids in the carp flesh. We conclude that there are several ways to improve the FA composition of common carp in the traditional pond production. High amount of natural food, good supplemental diet containing high level of alpha-linolenic acid (ALA) and suitable processing and cooking were identified as the most important ones. PMID- 22101874 TI - Extensive, devastating prosthetic aortic valve endocarditis. AB - In this report, we present a case of a 68-year-old male who developed extensive, devastating prosthetic valve endocarditis (PVE) several months following aortic valve replacement with a tissue valve St. Jude Epic Supra. He was successfully treated with a complex surgical procedure. In the discussion, we focus on the issues of prosthetic aortic valve endocarditis and various modes of treatment. PMID- 22101875 TI - Estimation of beverage consumption and associated caloric intake in adult Czech population. An observational study. AB - BACKGROUND: Food intake is a commonly monitored issue in many studies. In contrast, almost no information has been published on beverage intake in adults. MATERIAL AND METHODS: To evaluate beverage intake, we studied a population of 1, 200 adults (656 males and 544 females, aged 18-54 years). The volumes and types of beverages were obtained from self-reported questionnaires. RESULTS: The mean beverage intake was highly variable, with a minimum of 450 mL/day and a maximum of 5,330 mL/day. A mean of 1,575 mL/day was found in the entire population (2,300 mL in males and 840 mL in females). Different patterns in the consumption of beverage types were observed between the males and females. For both males and females, the most common beverage consumed was water followed by tea. The next preferable beverages were alcoholic beer, coffee, and non-alcoholic beer in males and coffee, milk, and alcoholic beer in females. The estimated caloric intake from beverages covers, in most individuals, 10-30% of the recommended daily caloric intake. CONCLUSIONS: There is substantial variation among individuals, both in beverage intake and in caloric intake through beverages. The caloric intake from beverages reaches, in some individuals, one-third of the recommended daily caloric rate. PMID- 22101876 TI - The consumption of the carp meat and plasma lipids in secondary prevention in the heart ischemic disease patients. AB - OBJECTIVES: Omega-3 fatty acids (FA) have been shown to be protective against cardiovascular diseases (CVD). The effect of the consumption of carp meat on CVD risk factors has not yet been examined in detail. We ascertained the influence of a diet enriched with carp meat with an elevated content of omega-3FA (200 g twice weekly for 4 weeks) in a group of subjects after cardiac revascularization surgery for ischemic heart disease with a follow-up spa treatment. DESIGN: After cardiac revascularization surgery, the probands consumed either a standard spa diet (56 individuals, 41 males, 15 females, age 41-80 years) or a diet enriched with two portions of carp meat (87 individuals, 64 males, 23 females, age 50-82 years). The differences in body mass index (kg/m2), blood pressure, plasma lipids and C-reactive protein (CRP) of the groups were analyzed. RESULTS: In the group with a higher consumption of carp meat, significantly greater improvements in lipid parameters in comparison to the standard spa diet were detected (total cholesterol p<0.001, triglycerides p<0.001, LDL-C p<0.001, CRP p<0.001, HDL-C p<0.001). No differences between these groups in blood pressure and body mass index were found. CONCLUSION: We conclude that the diet enriched with carp meat significantly improved plasma lipid parameters in patients after major cardiac revascularization surgery. PMID- 22101877 TI - Number of children is associated with plasma CRP levels. AB - BACKGROUND: C-reactive protein (CRP) is an acute-phase serum protein produced by the liver. High plasma levels of CRP have been associated primarily with infection, but elevated CRP levels have also been found to be associated with more than one hundred conditions and factors, including social and economic factors. MATERIALS AND METHODS: To evaluate the possible association between individuals' number of children and plasma levels of C-reactive protein, we studied a representative population of 2,426 adults. CRP was analyzed using the high sensitivity method (hsCRP). Individuals were divided into five groups of zero, one, two, three and four and more children. RESULTS: We found that individuals with more children had significantly higher levels of plasma hsCRP than individuals without children or than individuals with a low number of children (p for trend <0.001). This association could reflect the known associations between CRP and higher economic stress, exhaustion, episodic stress and chronic stress. CONCLUSIONS: We found significantly elevated levels of plasma CRP in individuals with more children than in individuals without children or with a low number of children. PMID- 22101878 TI - Effect of rosuvastatin treatment on cholesterol efflux from human macrophages. AB - OBJECTIVES: One of the positive effects of rosuvastatin is an increase in HDL cholesterol (HDL-C). An increase in HDL-C is considered as one of the positive effects of this type of statin, although it does not necessarily correspond to the actual reverse cholesterol transport (RCT) rate. We analyzed the influence of statin induced changes in HDL-C on cholesterol efflux (CHE), the key step affecting the RCT. DESIGN: Fourteen subjects (7 men, age: 50.9 +/- 8.4 years and 7 women, age: 59.7 +/- 10.6 years) with mixed dyslipidemia received 20 mg of rosuvastatin daily for 3 months. Before the initiation of statin therapy and at the end of the study period, the CHE from 14C cholesterol-labeled macrophages was determined in addition to parameters related to lipid metabolism. CHE was calculated as the percentage of radioactivity released from the macrophages into the media containing 5% of the examined plasma. RESULTS: The rosuvastatin administration resulted in significant reductions of total cholesterol, LDL cholesterol, and apolipoprotein B and a significant increase in HDL-C (from 1.43 mmol/l to 1.52 mmol/l, p=0.05), while the levels of apolipoprotein A1 remained unchanged. There was no significant increase in CHE (from 16.1% to 17.6%, p for trend = 0.053). Individual changes in HDL-C correlated significantly (p<0.05) with individual changes of CHE (r=0.76). CONCLUSION: Administration of rosuvastatin increases HDL-C, and individual changes correlate with the individual increases of CHE from macrophages. PMID- 22101879 TI - Dietary intake reports fidelity--fact or fiction? AB - OBJECTIVES: Bias is common in the assessment of self-reported dietary intake and physical activity. Little is known about the reasons for this underreporting, which is obtained even from rural individuals and lean subjects. MATERIAL AND METHODS: Healthy volunteers (16 males, aged 18-55 years) were given two different full diets (high and low in saturated fat), each for a period of 4 weeks. RESULTS: The subjects were able to provide a report of their dietary intake with relatively high accuracy (68.4%) on day one. Accuracy declined on day two (64.2%), and on day three, the reporting accuracy was only 55.0% (p<0.05). Interestingly, on day one, individuals were more precise (p<0.05) in their dietary reports if they had consumed an unhealthy diet high in saturated fat (72.5%) than a healthy diet high in unsaturated fat (64.4%). The most frequently omitted items were fruits and vegetables. The non-reporting of food items consumed is very high, even in the short term, and individuals tend to remember unhealthy items better. CONCLUSIONS: Our pilot study showed that the inaccuracy of self-reported data includes not only the underestimation of energy intake (portion size) but also inaccurate qualitative data. PMID- 22101880 TI - An AHSG gene variant modulates basal metabolic rate and body composition development after a short-time lifestyle intervention. AB - OBJECTIVES: The AHSG (alpha2 Heremans-Schmid glycoprotein) gene is suggested to be important for the regulation of body fat and insulin sensitivity. Our study aimed to investigate the relationship between the common Thr248Met (rs4917) variant and obesity characteristics after an intervention with overweight females. MATERIAL AND METHODS: We analyzed 105 unrelated overweight/obese nondiabetic Czech adult females (49.0 +/- 12.1 years, BMI over 28.6 kg/m2, mean BMI before intervention 32.8 +/- 4.1 kg/m2) before and after 10 weeks of lifestyle modification. Biochemical and anthropometrical measurements were performed. The life style modification program consisted of a reduction of energy intake to an age-adjusted optimum and an exercise program (four units per week). The mean weight loss was 3.2 +/- 3.5 kg (3.7 +/- 4.0%). RESULTS: Thr/Thr homozygotes (N=52) increased lean muscle mass (p<0.05), decreased total body fat (kg) (p<0.005) and increased basal metabolic rate (BMR) per 1 kg body weight (p<0.005) in comparison with the Met carriers (N=52), but an association between BMI decrease and AHSG variants was not found. CONCLUSION: AHSG gene variants modify the effect of physical activity on BMR. Carriers of the Thr248Thr genotype showed a higher benefit from the lifestyle intervention (expressed as changes in body fat, active muscle and basal metabolic rate). PMID- 22101881 TI - Varying quality of fish oil capsules: fatty acids and tocopherol. AB - OBJECTIVES: To assess the content and composition of fatty acids and tocopherols in commercially available oil capsules, and to assay thiobarbituric acid reactive substances (TBARS) as a marker of oxidation in these oils. METHODS: Fish and seal oil capsules were analyzed for their contents of long-chain omega-3 fatty acids (DPA, EPA, and DHA), tocopherols, and malondialdehyde. RESULTS: Large variations were found in the levels of EPA (6.5-40.9%), and DHA (8.1-26.4%), alpha tocopherol (117-10282 MUg/g), gamma-tocopherol (406-2352 MUg/g) and delta tocopherol (127-978 MUg/g). The level of malondialdehyde was very low in all capsules. CONCLUSION: The tested samples of oil capsules showed large variation in quality with respect to long-chain n-3 polyunsaturated fatty acids and tocopherols. The low levels of malondialdehyde indicated a successful oxidation protection strategy. PMID- 22101882 TI - Fatty acids and gene expression responses to bioactive compounds in Atlantic salmon (Salmo salar L.) hepatocytes. AB - OBJECTIVES: Effects of bioactive compounds on expression of genes involved in lipid metabolism and fatty acid composition were investigated in Atlantic salmon (Salmo salar L.) primary hepatocytes. METHODS: Five treatments were investigated: I) genistein 0.005 mM, II) genistein 0.025 mM, III) lipoic acid 0.2 mM, IV) sesamin/episesamin 0.05 mM, V) sesamin 0.05 mM and compared to controls. The relative expression of genes involved in lipid homeostasis was analysed after 12h and 48h. RESULTS: Incubation with lipoic acid, sesamin and episesamin/sesamin for 48h had significant effect on all analysed genes involved in lipid uptake, beta oxidation, elongation and desaturation, some effects were detected on the expression of peroxisome prolifertor-activated receptor (PPARs). Also effects on the fatty acid composition were found. CONCLUSION: The strongest effect of bioactive copounds on hepatocyte gene expression was detected after 48 hours. PMID- 22101883 TI - APOE polymorphism as a potential determinant of functional fitness in the elderly regardless of nutritional status. AB - OBJECTIVES: Life expectancy is determined by a combination of genetic predisposition (~25%) and environmental influences (~75%). Nevertheless a stronger genetic influence is anticipated in long-living individuals. Apolipoprotein E (APOE) gene belongs among the most studied candidate genes of longevity. We evaluated the relation of APOE polymorphism and fitness status in the elderly. MATERIAL AND METHODS: We examined a total number of 128 subjects, over 80 years of age. Using a battery of functional tests their fitness status was assessed and the subjects were stratified into 5 functional categories according to Spirduso's classification. Biochemistry analysis was performed by enzymatic method using automated analyzers. APOE gene polymorphism was analysed performed using PCR-RFLP. RESULTS: APOE4 allele carriers had significantly worse fitness status compared to non-carriers (p=0.025). Multiple logistic regression analysis showed the APOE4 carriers had higher risk (p=0.05) of functional unfitness compared to APOE2/E3 individuals. CONCLUSIONS: APOE gene polymorphism seems be an important genetic contributor to frailty development in the elderly. While APOE2 carriers tend to remain functionally fit till higher age, the functional status of APOE4 carriers deteriorates more rapidly. PMID- 22101884 TI - Lifestyle modification induced weight loss and changes of cardiometabolic risk factors including lowering of inflammatory response in obese children. AB - OBJECTIVES: Obesity is associated with increased inflammation which represents a link to atherosclerosis and cardiovascular disease. Lipoprotein associated phospholipase A2 (Lp-PLA2) is an independent marker of inflammation and atherosclerosis risk. To assess the impact of weight loss on metabolic markers of atherosclerosis including Lp-PLA2 we examined a group of Czech non-diabetic obese/overweight children exposed to a lifestyle intervention. PATIENTS AND METHODS: Fourty unrelated overweight/obese non-diabetic Czech children (13.7 +/- 2.1 years, average BMI at baseline 29.8 +/- 2.6 kg/m2) underwent 4 weeks of lifestyle modification (reduction of energy intake to age matched optimum and supervised physical activity). Anthropometrical and biochemical variables were determined at baseline and after the intervention. Lp-PLA2 mass concentration was assessed using the ELISA kit. Wilcocson's rank test and Spearman's correlation were used for statistical analysis. RESULTS: A significant decrease of BMI and waist circumference was associated with significant changes of plasma lipoprotein and glycaemia levels. Mass concentration of Lp-PLA2 at the baseline was 402 +/- 94 MUg/ml, after the intervention 368 +/- 105 MUg/ml (p=0.008). Change in Lp-PLA2 was associated with triglyceride level decrease (p=0.009). CONCLUSION: Intensive lifestyle modification leading to body weight decrease results in significant changes of plasma lipoprotein levels and, also, a drop of Lp-PLA2 levels in paediatric obese patients. However, even after the intervention Lp-PLA2 concentrations in this patient group remain elevated suggesting possible increased atherosclerosis risk in later life. PMID- 22101885 TI - Prevalence of risk factors of cardiovascular diseases in men with erectile dysfunction. Are they as frequent as we believe? AB - OBJECTIVES: Vascular erectile dysfunction (ED) predicts future development of cardiovascular diseases (CVD). We performed a study in men seeking consultant medical advice regarding vascular ED for the first time without a history of cardiovascular disease, diabetes mellitus or renal insufficiency. Our goal was to evaluate the prevalence of CVD risk factors in this cohort of patients. Furthermore, we assessed the prevalence of asymptomatic subclinical atherosclerosis. MATERIAL AND METHODS: All study subjects underwent a thorough physical examination including anthropometric measurements. Laboratory analyses comprising assessment of lipid spectrum, liver and kidney function tests, glycaemia and glycated haemoglobin were measured using automated analysers. Intima-media thickness of carotid arteries was measured using SONOS machine and ankle-brachial index using a mini-duplex device. CVD risk was calculated by standard SCORE charts. Chi-square test, t-test and ANOVA were used for statistical analysis. RESULTS: We examined 35 men, average age 46.5 +/- 9.9 years. Six (17.1%) had a positive family history of CVD, 19 (54.3%) had dyslipidemia, 10 (28.6%) were obese, 9 (25.7%) were active smokers, and 14 (40.0%) had arterial hypertension. Eighteen (51.4%) subjects had subclinical atherosclerosis as determined by ABI and CIMT assessment. CONCLUSION: Patients with vascular erectile dysfunction have similar prevalence of CVD risk factors to general population. PMID- 22101886 TI - Possible effect of DHA intake on body weight reduction and lipid metabolism in obese children. AB - OBJECTIVES: The aim of the study was to determine whether increased intake of DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) would affect the weight loss or the various biochemical parameters in the blood of obese children following dietary/physical intervention. There were 120 obese (BMIs>=30 kg/m(2); mean 33.5 +/- 3.9) children included in this randomized crossover study; aged 8 12 years (10.0 +/- 1.9). METHODS: The children consumed an extra 300 mg DHA and 42 mg EPA (Haliborange (r)) daily for a period of 3 weeks. Anthropometric and biochemical parameters were measured and documented for each of the subjects at the beginning of the study, after three weeks of treatment and at the end of the study. RESULTS: The daily consumption of 300 mg DHA and 42 mg of EPA was associated with decreased body weight (with DHA: 86.4 +/- 19.6 to 80.8 +/- 20.4 kg vs. without DHA: 85.6 +/- 20.8 to 80.9 +/- 19.9 kg; p<0.005) and total cholesterol concentration (with DHA: 3.72 +/- 0.78 to 3.32 +/- 0.53 mmol/l vs. without DHA: 3.74 +/- 0.78 to 3.56 +/- 0.56 mmol/l; p<0.05 and respectively with DHA). CONCLUSION: Daily consumption of 300 mg DHA and 42 mg EPA (Haliborange(r)) for 3 weeks leads to an improvement of the anthropometric and lipid parameters in obese children following dietary physical intervention. PMID- 22101887 TI - After massive weight loss: patients' expectations of body contouring surgery. AB - BACKGROUND: Massive weight loss following bariatric surgery leads to excess skin with functional and aesthetic impairments. Surplus skin can then contribute to problems with additional weight loss or gain. The aims of the current study were to evaluate the frequency of massive soft tissue development in gastric bypass patients, to determine whether males and females experience similar post-bypass body changes, and to learn about the expectations and impairments related to body contouring surgery. METHODS: A questionnaire addressing information on the satisfaction of body image, quality of life, and expectation of body contouring surgery following massive weight loss was mailed to 425 patients who had undergone gastric bypass surgery between 2003 and 2009. Of these 425 individuals, 252 (59%) patients completed the survey. RESULTS: Ninety percent of women and 88% of men surveyed rated their appearance following massive weight loss as satisfactory, good, or very good. However, 96% of all patients developed surplus skin, which caused intertriginous dermatitis and itching. In addition, patients reported problems with physical activity (playing sports) and finding clothing that fit appropriately. Moreover, 75% of female and 68% of male patients reported desiring body contouring surgery. The most important expectation of body contouring surgery was improved appearance, followed by improved self-confidence and quality of life. CONCLUSIONS: Surplus skin resulting from gastric bypass surgery is a common issue that causes functional and aesthetic impairments in patients. Consequently, this increases the desire for body contouring surgery with high expectations for the aesthetic outcome as well as improved life satisfaction. PMID- 22101888 TI - Sleeve gastrectomy reduces blood pressure in obese (fa/fa) Zucker rats. AB - BACKGROUND: Sleeve gastrectomy constitutes an effective surgical procedure for the treatment of morbid obesity in humans and rodents with diet-induced obesity. The aim of the present study was to establish the effects of sleeve gastrectomy on weight loss and cardiovascular parameters in genetically obese (fa/fa) Zucker rats. METHODS: Eleven-week-old male obese (fa/fa) (n = 20) Zucker rats were assigned to three alternative procedures (sham operation, sleeve gastrectomy, or pair-fed to the amount of food eaten by sleeve-gastrectomized animals) and compared with lean Zucker (Fa/Fa) rats (n = 9). Systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values as well as heart rate (HR) were recorded in conscious, resting animals by non-invasive tail-cuff plethysmography before and 3 weeks after the surgical interventions. RESULTS: Sleeve-gastrectomized rats experienced a reduction in body weight (P < 0.01), total adiposity amounts (P < 0.001), together with an increased excess weight loss (%EWL) (P < 0.05) compared with sham-operated and pair-fed animals 3 weeks after the surgical interventions. Rats with sleeve gastrectomy exhibited reduced (P < 0.01) blood pressure values (DeltaSBP = -11 +/- 8 mmHg; DeltaDBP = -6 +/- 4 mmHg; DeltaMBP = -8 +/- 6 mmHg) compared with the control group, but no changes were observed in HR (P = 0.560). Sham-operated and pair-fed groups did not alter their cardiovascular variables. CONCLUSIONS: Our findings provide evidence of the beneficial effects of sleeve gastrectomy on blood pressure values in addition to the weight loss in obese (fa/fa) Zucker rats independently of surgical trauma and food intake reduction. PMID- 22101889 TI - The ESFRI Instruct Core Centre Frankfurt: automated high-throughput crystallization suited for membrane proteins and more. AB - Structure determination of membrane proteins and membrane protein complexes is still a very challenging field. To facilitate the work on membrane proteins the Core Centre follows a strategy that comprises four labs of protein analytics and crystal handling, covering mass spectrometry, calorimetry, crystallization and X ray diffraction. This general workflow is presented and a capacity of 20% of the operating time of all systems is provided to the European structural biology community within the ESFRI Instruct program. A description of the crystallization service offered at the Core Centre is given with detailed information on screening strategy, screens used and changes to adapt high throughput for membrane proteins. Our aim is to constantly develop the Core Centre towards the usage of more efficient methods. This strategy might also include the ability to automate all steps from crystallization trials to crystal screening; here we look ahead how this aim might be realized at the Core Centre. PMID- 22101890 TI - HIV and STI risk behaviors, knowledge, and testing among female adult film performers as compared to other California women. AB - A cross-sectional structured online survey was self-administered to a convenience sample of current female adult film performers via the Internet; bivariate analyses compared HIV and other STI risk behaviors, knowledge, and testing in female adult performers to California Women's Health Survey respondents. 134 female adult film performers (mean age 27.8 years) were compared to the 1,773 female respondents (mean age 31.3 years) to the 2007 CWHS. Female performers initiated sex on average 3 years younger and had 6.8 more personal sexual partners in the prior year than other California women. The majority of performers reported HIV and Chlamydia testing (94 and 82%, respectively) in the prior 12 months. They more likely to use condoms consistently in their personal life than other California women (21 vs 17%), though this difference disappeared after controlling for other variables. Adult performers are routinely tested for HIV and Chlamydia, yet they have multiple sexual partners and use condoms inconsistently. PMID- 22101891 TI - Basis for a Swiss perspective on fall prevention in vulnerable older people. AB - During the 20th century Switzerland, like many other Western countries, experienced significant ageing of the population over the age of 65. As the lifespan of the Swiss population increases, so does the prevalence of falls. A multiplicity of fall prevention programmes are available, but extracting their most effective components remains a challenge. This article summarises the results of current studies on fall prevention, with a particular focus on methodological quality and successful reduction of fall incidence in vulnerable older people. Characteristics of effective fall prevention programmes in the fields of exercise, home modifications, appropriate footwear and walking aids are assessed. We then briefly discuss how these study results can be adapted to the Swiss context. This knowledge emphasises an interdisciplinary approach in the prevention of falls, the objective being to reinforce autonomy, promote health and enhance quality of life in vulnerable older people. PMID- 22101892 TI - Direct visualization of large-area graphene domains and boundaries by optical birefringency. AB - The boundaries between domains in single-layer graphene strongly influence its electronic properties. However, existing approaches for domain visualization, which are based on microscopy and spectroscopy, are only effective for domains that are less than a few micrometres in size. Here, we report a simple method for the visualization of arbitrarily large graphene domains by imaging the birefringence of a graphene surface covered with nematic liquid crystals. The method relies on a correspondence between the orientation of the liquid crystals and that of the underlying graphene, which we use to determine the boundaries of macroscopic domains. PMID- 22101893 TI - Developmental regulation of Th17-cell capacity in human neonates. AB - Human neonates are at significantly greater risk of serious infection than immunocompetent adults. In particular, very low birth weight infants in the neonatal intensive care nursery are at high risk of developing life-threatening bacterial and fungal infections. Recent studies have identified Th17 cells as critical mediators of immunity to bacterial and fungal infections at epithelial barriers. Little is known, however, about the ontogeny of Th17-cell responses in humans. The frequency of serious bacterial infections in preterm infants and the importance of Th17 cells in providing protection against such infections in animal studies prompted us to study Th17-cell development in human neonates. Naive CD4(+) T cells from extremely preterm infants, term infants, and adults were assayed for their capacity to develop into Th17 effector cells. Surprisingly, Th17-cell capacity was inversely related to developmental age. Neonates expressed higher levels of IL-23R, RORgammat, and STAT3 prior to activation and showed a significant Th17-cell bias after activation. In contrast, adult cells expressed more TBX21 with a corresponding Th1-cell bias. CD161 expression on Th17-cell precursors was also developmentally regulated. Our results suggest there is significant developmental regulation of CD4(+) effector lineages with a strong bias toward Th17-cell development early in life. PMID- 22101894 TI - Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic-derived antigen-presenting cells. AB - It is currently thought that acute GVHD cannot be elicited in the absence of Ag presentation by radiosensitive host hematopoietic-derived APCs after allogeneic BM transplantation. Because clinical data suggest that sex-mismatched H-Y Ags may be important minor histocompatibility Ags for GVH responses, we directly tested their relevance and ability to initiate GVHD when presented by either the hematopoietic- (host or donor) or the nonhematopoietic-derived APCs. H-Y minor Ag incompatibility elicited both CD4(+) and CD8(+) T-cell driven GVHD lethality. Studies with various well-established BM chimera recipients, in contrast to the current views, have reported that in the absence of functional radiosensitive host hematopoietic-derived APCs, H-Y Ag presentation by either the donor hematopoietic-derived or the host nonhematopoietic-derived APCs is sufficient for inducing GVHD. Our data further suggest that infusion of sufficient numbers of alloreactive donor T cells will induce GVHD in the absence of radiosensitive host hematopoietic-derived APCs. PMID- 22101895 TI - Desialylation accelerates platelet clearance after refrigeration and initiates GPIbalpha metalloproteinase-mediated cleavage in mice. AB - When refrigerated platelets are rewarmed, they secrete active sialidases, including the lysosomal sialidase Neu1, and express surface Neu3 that remove sialic acid from platelet von Willebrand factor receptor (VWFR), specifically the GPIbalpha subunit. The recovery and circulation of refrigerated platelets is greatly improved by storage in the presence of inhibitors of sialidases. Desialylated VWFR is also a target for metalloproteinases (MPs), because GPIbalpha and GPV are cleaved from the surface of refrigerated platelets. Receptor shedding is inhibited by the MP inhibitor GM6001 and does not occur in Adam17(DeltaZn/DeltaZn) platelets expressing inactive ADAM17. Critically, desialylation in the absence of MP-mediated receptor shedding is sufficient to cause the rapid clearance of platelets from circulation. Desialylation of platelet VWFR therefore triggers platelet clearance and primes GPIbalpha and GPV for MP-dependent cleavage. PMID- 22101896 TI - Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis. AB - Alterations of the BM microenvironment have been shown to occur after chemoradiotherapy, during aging, and after genetic manipulations of telomere length. Nevertheless, whether BM stromal cells adopt senescent features in response to these events is unknown. In the present study, we provide evidence that exposure to ionizing radiation (IR) leads murine stromal BM cells to express senescence markers, namely senescence-associated beta-galactosidase and increased p16(INK4a)/p19(ARF) expression. Long (8 weeks) after exposure of mice to IR, we observed a reduction in the number of stromal cells derived from BM aspirates, an effect that we found to be absent in irradiated Ink4a/arf-knockout mice and to be mostly independent of the CFU potential of the stroma. Such a reduction in the number of BM stromal cells was specific, because stromal cells isolated from collagenase-treated bones were not reduced after IR. Surprisingly, we found that exposure to IR leads to a cellular nonautonomous and Ink4a/arf-dependent effect on lymphopoiesis. Overall, our results reveal the distinct sensitivity of BM stromal cell populations to IR and suggest that long-term residual damage to the BM microenvironment can influence hematopoiesis in an Ink4a/arf-dependent manner. PMID- 22101897 TI - The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen. AB - Lewis Y Ag (LeY) is a cell-surface tetrasaccharide that participates in angiogenesis. Recently, we demonstrated that LeY is a specific ligand of the recombinant lectin-like domain of thrombomodulin (TM). However, the biologic function of interaction between LeY and TM in endothelial cells has never been investigated. Therefore, the role of LeY in tube formation and the role of the recombinant lectin-like domain of TM-TM domain 1 (rTMD1)-in antiangiogenesis were investigated. The recombinant TM ectodomain exhibited lower angiogenic activity than did the recombinant TM domains 2 and 3. rTMD1 interacted with soluble LeY and membrane-bound LeY and inhibited soluble LeY-mediated chemotaxis of endothelial cells. LeY was highly expressed on membrane ruffles and protrusions during tube formation on Matrigel. Blockade of LeY with rTMD1 or Ab against LeY inhibited endothelial tube formation in vitro. Epidermal growth factor (EGF) receptor in HUVECs was LeY modified. rTMD1 inhibited EGF receptor signaling, chemotaxis, and tube formation in vitro, and EGF-mediated angiogenesis and tumor angiogenesis in vivo. We concluded that LeY is involved in vascular endothelial tube formation and rTMD1 inhibits angiogenesis via interaction with LeY. Administration of rTMD1 or recombinant adeno-associated virus vector carrying TMD1 could be a promising antiangiogenesis strategy. PMID- 22101898 TI - Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. AB - BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). However, BCR-ABL expression levels of persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. Here, we have shown that the number of BCR-ABL positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony-forming units (CFUs) compared with CML CFUs from diagnosis. Critically, lower BCR-ABL levels may indeed cause IM insensitivity, because primary murine bone marrow cells engineered to express low amounts of BCR-ABL were substantially less sensitive to IM than BCR-ABL-overexpressing cells. BCR-ABL overexpression in turn catalyzed the de novo development of point mutations to a greater extent than chemical mutagenesis. Thus, MMR is characterized by the persistence of CML clones with low BCR-ABL expression that may explain their insensitivity to IM and their low propensity to develop IM resistance through kinase point mutations. These findings may have implications for future treatment strategies of residual disease in CML. PMID- 22101899 TI - Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells. AB - The characterization and targeting of Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL)-initiating cells remains unresolved. Expression of the polycomb protein Bmi1 is up-regulated in patients with advanced stages of chronic myelogenous leukemia (CML). We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B lymphoid progenitors and by long-term animal survival, suggesting that BCR-ABL is required to maintain B-ALL and that BCR-ABL and Bmi1 cooperate toward blast transformation in vivo. Our data indicate that BCR-ABL targeting itself is required to eradicate Ph(+)/Bmi1(+) B-ALL-initiating cells and confirm their addiction to BCR-ABL signaling. PMID- 22101900 TI - The principal results of the International Immune Tolerance Study: a randomized dose comparison. AB - The International Immune Tolerance Study was a multicenter, prospective, randomized comparison of high-dose (HD; 200 IU/kg/d) and low-dose (LD; 50 IU/kg 3 times/week) factor VIII regimens in 115 "good-risk," severe high-titer inhibitor hemophilia A subjects. Sixty-six of 115 subjects reached the defined study end points: success, n = 46 (69.7%); partial response, n = 3 (4.5%); and failure, n = 17 (25.8%). Successes did not differ between treatment arms (24 of 58 LD vs 22/57 HD, P = .909). The times taken to achieve a negative titer (P = .027), a normal recovery (P = .002), and tolerance (P = .116, nonsignificant) were shorter with the HD immune tolerance induction (ITI). Peak historical (P = .026) and on-ITI (P = .002) titers were correlated inversely with success, but only peak titer on ITI predicted outcome in a multivariate analysis (P = .002). LD subjects bled more often (odds ratio, 2.2; P = .0019). The early bleed rate/month was 0.62 (LD) and 0.28 (HD; P = .000 24), decreasing by 90% once negative titers were achieved. Bleeding was absent in 8 of 58 LD versus 21 of 57 HD subjects (P = .0085). One hundred twenty-four central catheter infections were reported in 41 subjects (19 LD); infection frequency did not differ between the treatment arms. Neither bleeding nor infection influenced outcome. Although it was stopped early for futility and safety considerations, this trial contributed valuable data toward evidence-based ITI practice. PMID- 22101901 TI - Using three legacy measures to develop a health-related quality of life tool for young adult survivors of childhood cancer. AB - BACKGROUND: Little attention has been paid to selecting and developing health related quality of life (HRQOL) measurement tools for young adult survivors of childhood cancer (YASCC). The primary purpose of this study was to develop a HRQOL tool for YASCC based on three legacy instruments. METHODS: Data collected from 151 YASCC were analyzed. HRQOL was measured using the Medical Outcomes Study SF-36, Quality of Life in Adult Cancer Survivors, and Quality of Life-Cancer Survivor. We used the following stages to develop our HRQOL tool: mapping items from three instruments into a common HRQOL construct, checking dimensionality using confirmatory factor analyses (CFA), and equating items using Rasch modeling. RESULTS: We assigned 123 items to a HRQOL construct comprised of six generic and eight survivor-specific domains. CFA retained 107 items that meet the assumptions of unidimensionality and local independence. Rasch analysis retained 68 items that satisfied the indices of information-weighted/outlier-sensitive fit statistic mean square. However, items in most domains possess relatively easy measurement properties, whereas YASCC's underlying HRQOL was on the middle to higher levels. CONCLUSIONS: Psychometric properties of the established tool for measuring HRQOL of YASCC were not satisfied. Future studies need to refine this tool, especially adding more challenging items. PMID- 22101902 TI - Predicting prostate cancer many years before diagnosis: how and why? AB - Evidence of reduced prostate cancer mortality from randomized trials in Europe supports early detection of prostate cancer with prostate-specific antigen (PSA). Yet PSA screening has generated considerable controversy: it is far from clear that the benefits outweigh risks, in terms of overdiagnosis and overtreatment. One way to shift the ratio of benefits to harm is to focus on men at highest risk, who have more to benefit than average. Neither family history nor any of the currently identified genomic markers offer sufficient risk stratification for practical use. However, there is considerable evidence that the levels of PSA in blood are strongly prognostic of the long-term risk of aggressive prostate cancer. Specifically, it is difficult to justify continuing to screen men aged 60 or older if they have a PSA less than 1 or 2 ng/ml; for men 45-60, intervals between PSA tests can be based on PSA levels, with 2-4-year retesting interval for men with PSA of 1 ng/ml or higher, and tests every 6-8 years for men with PSA <1 ng/ml. Men with the top 10% of PSAs at a young age (PSA ~1.5 ng/ml or higher below 50) are at particularly high risk and should be subject to intensive monitoring. PMID- 22101903 TI - Novel options for the treatment of castration-resistant prostate cancer. AB - Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials. PMID- 22101904 TI - Successful treatment of lichen planus with adalimumab. PMID- 22101905 TI - Advantages of genomic complexity: bioinformatics opportunities in microRNA cancer signatures. AB - MicroRNAs, small non-coding RNAs, may act as tumor suppressors or oncogenes, and each regulate their own transcription and that of hundreds of genes, often in a tissue-dependent manner. This creates a tightly interwoven network regulating and underlying oncogenesis and cancer biology. Although protein-coding gene signatures and single protein pathway markers have proliferated over the past decade, routine adoption of the former has been hampered by interpretability, reproducibility, and dimensionality, whereas the single molecule-phenotype reductionism of the latter is often overly simplistic to account for complex phenotypes. MicroRNA-derived biomarkers offer a powerful alternative; they have both the flexibility of gene expression signature classifiers and the desirable mechanistic transparency of single protein biomarkers. Furthermore, several advances have recently demonstrated the robust detection of microRNAs from various biofluids, thus providing an additional opportunity for obtaining bioinformatically derived biomarkers to accelerate the identification of individual patients for personalized therapy. PMID- 22101906 TI - Immediate financial impact of computerized clinical decision support for long term care residents with renal insufficiency: a case study. AB - In a randomized trial of a clinical decision support system for drug prescribing for residents with renal insufficiency in a large long-term care facility, analyses were conducted to estimate the system's immediate, direct financial impact. We determined the costs that would have been incurred if drug orders that triggered the alert system had actually been completed compared to the costs of the final submitted orders and then compared intervention units to control units. The costs incurred by additional laboratory testing that resulted from alerts were also estimated. Drug orders were conservatively assigned a duration of 30 days of use for a chronic drug and 10 days for antibiotics. It was determined that there were modest reductions in drug costs, partially offset by an increase in laboratory-related costs. Overall, there was a reduction in direct costs (US$1391.43, net 7.6% reduction). However, sensitivity analyses based on alternative estimates of duration of drug use suggested a reduction as high as US$7998.33 if orders for non-antibiotic drugs were assumed to be continued for 180 days. The authors conclude that the immediate and direct financial impact of a clinical decision support system for medication ordering for residents with renal insufficiency is modest and that the primary motivation for such efforts must be to improve the quality and safety of medication ordering. PMID- 22101907 TI - Transmitting and processing electronic prescriptions: experiences of physician practices and pharmacies. AB - OBJECTIVE: A core feature of e-prescribing is the electronic exchange of prescription data between physician practices and pharmacies, which can potentially improve the efficiency of the prescribing process and reduce medication errors. Barriers to implementing this feature exist, but they are not well understood. This study's objectives were to explore recent physician practice and pharmacy experiences with electronic transmission of new prescriptions and renewals, and identify facilitators of and barriers to effective electronic transmission and pharmacy e-prescription processing. DESIGN: Qualitative analysis of 114 telephone interviews conducted with representatives from 97 organizations between February and September 2010, including 24 physician practices, 48 community pharmacies, and three mail-order pharmacies actively transmitting or receiving e-prescriptions via Surescripts. RESULTS: Practices and pharmacies generally were satisfied with electronic transmission of new prescriptions but reported that the electronic renewal process was used inconsistently, resulting in inefficient workarounds for both parties. Practice communications with mail-order pharmacies were less likely to be electronic than with community pharmacies because of underlying transmission network and computer system limitations. While e-prescribing reduced manual prescription entry, pharmacy staff frequently had to complete or edit certain fields, particularly drug name and patient instructions. CONCLUSIONS: Electronic transmission of new prescriptions has matured. Changes in technical standards and system design and more targeted physician and pharmacy training may be needed to address barriers to e-renewals, mail-order pharmacy connectivity, and pharmacy processing of e prescriptions. PMID- 22101908 TI - Partial least squares regression, support vector machine regression, and transcriptome-based distances for prediction of maize hybrid performance with gene expression data. AB - The performance of hybrids can be predicted with gene expression data from their parental inbred lines. Implementing such prediction approaches in breeding programs promises to increase the efficiency of hybrid breeding. The objectives of our study were to compare the accuracy of prediction models employing multiple linear regression (MLR), partial least squares regression (PLS), support vector machine regression (SVM), and transcriptome-based distances (D(B)). For a factorial of 7 flint and 14 dent maize lines, the grain yield of the hybrids was assessed and the gene expression of the parental lines was profiled with a 56k microarray. The accuracy of the prediction models was measured by the correlation between predicted and observed yield employing two cross-validation schemes. The first modeled the prediction of hybrids when testcross data are available for both parental lines (type 2 hybrids), and the second modeled the prediction of hybrids when no testcross data for the parental lines were available (type 0 hybrids). MLR, SVM, and PLS resulted in a high correlation between predicted and observed yield for type 2 hybrids, whereas for type 0 hybrids D(B) had greater prediction accuracy. The regression methods were robust to the choice of the set of profiled genes and required only a few hundred genes. In contrast, for an accurate hybrid prediction with D(B), 1,000-1,500 genes were required, and the prediction accuracy depended strongly on the set of profiled genes. We conclude that for prediction within one set of genetic material MLR is a promising approach, and for transferring prediction models from one set of genetic material to a related one, the transcriptome-based distance D(B) is most promising. PMID- 22101909 TI - Mass-like extramedullary hematopoiesis: imaging features. AB - PURPOSE: To report the imaging appearances of mass-like extramedullary hematopoiesis (EMH), to identify those features that are sufficiently characteristic to allow a confident diagnosis, and to recognize the clinical conditions associated with EMH and the relative incidence of mass-like disease. MATERIALS AND METHODS: We retrospectively identified 44 patients with EMH; 12 of which (27%) had focal mass-like lesions and formed the study group. The study group consisted of 6 male and 6 female subjects with a mean age of 58 years (range 13-80 years). All 12 patients underwent CT imaging and 3 of the 12 patients had undergone additional MR imaging. The imaging characteristics of the extramedullary hematopoiesis lesions in the study group were analyzed and recorded. The patient's clinical presentation, including any condition associated with extramedullary hematopoiesis, was also recorded. RESULTS: Ten of the 12 (83%) patients had one or more masses located along the axial skeleton. Of the 10 patients with axial masses, 9 (90%) had multiple masses and 7 (70%) demonstrated internal fat. Eight patients (80%) had paraspinal masses and 4 patients (40%) had presacral masses. Seven patients (70%) had splenomegaly. Eleven of the 12 patients had a clinical history available for review. A predisposing condition for extramedullary hematopoiesis was present in 10 patients and included various anemias (5 cases; 45%), myelofibrosis/myelodysplastic syndrome (4 cases; 36%), and marrow proliferative disorder (1 case; 9%). One patient had no known predisposing condition. CONCLUSION: Mass-like extramedullary hematopoiesis most commonly presents as multiple, fat-containing lesions localized to the axial skeleton. When these imaging features are identified, extramedullary hematopoiesis should be strongly considered, particularly when occurring in the setting of a predisposing medical condition. PMID- 22101910 TI - Rosiglitazone decreases fasting plasma peptide YY3-36 in type 2 diabetic women: a possible role in weight gain? AB - Rosiglitazone often results in weight gain. We hypothesized that rosiglitazone may modulate circulating levels of ghrelin and peptide YY(3-36) and this modulation may be related to weight-gaining effect of this agent. This study was designed as an open-label, randomized, controlled trial of 3-month duration. Women with newly diagnosed type 2 diabetes were studied. Twenty-eight of the 55 eligible participants were randomly assigned to receive rosiglitazone (4 mg/d). Twenty-seven patients with diabetes matched for age and body mass index served as controls on diet alone. We evaluated the effects of 3 months of rosiglitazone treatment on fasting peptide YY(3-36) and ghrelin levels, and anthropometric measurements. The 3-month administration of rosiglitazone reduced fasting plasma peptide YY(3-36) levels by 25%, the between-group difference was statistically significant. No effect of this thiazolidinedione compound on fasting ghrelin concentrations was observed at the end of study. The ghrelin/body mass index ratio also did not change significantly after treatment. Seventy-five percent of the women with diabetes complained of increased hunger at the end of study. Nevertheless, all subjects exhibited a decrease in fasting PYY levels after 3 months of rosiglitazone therapy, irrespective of the levels of hunger. There was no significant correlation between changes in peptide YY(3-36) and those in anthropometric parameters and insulin sensitivity at the end of the study. Rosiglitazone-induced decrease in fasting peptide YY(3-36) levels may in part contribute to orexigenic and weight-gaining effect of this thiazolidinedione derivative. PMID- 22101911 TI - Nucleation and growth of elastin-like peptide fibril multilayers: an in situ atomic force microscopy study. AB - Controlling how molecules assemble into complex supramolecular architectures requires careful consideration of the subtle inter- and intra-molecular interactions that control their association. This is particularly crucial in the context of assembly at interfaces, where both surface chemistry and structure can play a role in directing structure formation. We report here the results of a study into the self-assembly of the elastin-like peptide EP I on structurally modified highly ordered pyrolytic graphite, including the role of spatial confinement on fibril nucleation and the growth of oriented fibril multilayers. In situ atomic force microscopy performed in fluid and at elevated temperature provided direct evidence of frustrated fibril nuclei and oriented growth of independent fibril domains. These results portend the application of this in situ strategy for studies of the nucleation and growth mechanisms of other fibril- and amyloid-forming proteins. PMID- 22101913 TI - Competencies of more and less successful employment specialists. AB - The competencies of individual employment specialists influence rates of competitive employment among consumers and programs. Identifying competencies can lead to the development of more effective specialists and improve employment outcomes for consumers enrolled in employment services in community mental health care settings. The purpose of this study was to examine how more successful employment specialists performed supported employment duties in comparison to less successful employment specialists. Ethnographic researchers observed more and less successful employment specialists performing job duties related to the five phases of supported employment. Using grounded theory, they identified factors that differentiated the two groups. More successful employment specialists worked efficiently, developed egalitarian relationships with consumers, and collaborated well with other partners. Less successful employment specialists understood the model but lacked these behavioral skills. Service providers should screen and train employment specialists for efficiency, flexibility, and interpersonal skills. PMID- 22101914 TI - APOE -491 T allele may reduce the risk of atherosclerotic lesions among middle aged women. AB - Genetic variability of the APOE gene confers susceptibility to coronary artery disease (CAD). Beyond variability on the coding region, polymorphisms in the regulatory region of the APOE gene have been associated with variation on plasma cholesterol levels. It has also been demonstrated a complex and multifactorial association between, APOE gene polymorphisms, gender, plasma lipids levels and risk of CAD. In the present case-control study, we examined polymorphisms -427 T/C and -491 A/T in the promoter region of APOE in relation to lipid profile and the coronary atherosclerosis, in a sample of Argentinean adults with (cases) and without (controls) atherosclerotic injuries regarding gender and age. In females below 60 years APOE -491 T allele was less prevalent in cases than in controls (OR 0.12, 95% CI 0.04-0.76). Among females cases the T allele was more frequent with increasing age (OR 0.49, 95% CI 0.27-0.90). Female up to 45 years who were carriers of the T allele showed lower levels of total (P = 0.01) and LDL cholesterol (P = 0.02) compared with non-carriers. Levels of total and LDL cholesterol increased with the age only in female carriers (P < 0.01 and P < 0.01). No differences were observed for HDL and TG levels. Allele C of polymorphism APOE -427 was associated with higher levels of triglycerides (P < 0.01). We conclude that, in middle-aged women, APOE -491 T allele contributes keeping lower levels of LDL cholesterol in the population studied, and would have a putative protective effect for the development of CAD. PMID- 22101912 TI - Sleep and metabolic function. AB - Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health. PMID- 22101915 TI - Study of air-soil exchange of polycyclic aromatic hydrocarbons (PAHs) in the north-central part of India--a semi arid region. AB - Soil is the major environmental reservoir of organic compounds and soil-air exchange is a key process in governing the environmental fate of these compounds on a regional and global scale. Samples of air and soil were collected to study the levels of PAHs in the air and soil of the Agra region. Concentrations of PAH measured at four locations in the city of Agra, covers industrial, residential, roadside and agricultural areas. Samples were extracted with hexane by ultrasonic agitation. Extracts were then fractioned on a silica-gel column and the aromatic fraction was analysed by GC-MS. The mean concentration of the total PAH (T-PAH) in the air of Agra was 24.95, 17.95 and 14.25 ng m(-3), during winter, monsoon and summer respectively. The average concentration of T-PAH in the soil of Agra was 12.50, 8.25 and 6.44 MUg g(-1) in winter, monsoon and summer seasons respectively. The aim of this study was to investigate the rate of approach to equilibrium partitioning of PAHs between air and soil compartments and to determine the direction of net flux of the studied PAH between air and soil. Calculated soil-air fugacity quotients indicate that the soil may now be a source of some lighter weight PAHs to the atmosphere, whereas it appears to be still acting as a long-term sink for the heavier weight PAHs to some extent in this region. PMID- 22101916 TI - Translocation of particles deposited in the respiratory system: a systematic review and statistical analysis. AB - Many epidemiological studies have demonstrated that ambient particulate matter poses consistent risks for respiratory and cardiovascular disorders. The translocation of inhaled particles is one hypothesis that could explain such systemic effects. The objectives of this study were to conduct a systematic review of previous reports on particle translocation from the respiratory system and to discuss factors important for translocation. A PubMed search was conducted in August 2011 for the period from 1967 with four main keyword domains (particle, translocation, detection site, and exposure route). The systematic review identified 61 original articles written in English that met the specified criteria (i.e., information on experiment and particle detection). Categorical regression analysis was performed with the site of particle detection as the objective variable, and particle size, particle material, animal species, and exposure route as the explanatory variables. All explanatory variables showed statistically significant effects. The effects for particle size and particle material were large, while the effects for animal species and exposure route were relatively small. There was a broad relationship between particle size and detection site: <=50 nm for brain and remote organs; <=1 MUm for blood; and <=10 MUm for lung tissues. However, these results should be considered within the context of several limitations, such as deficiency of information. PMID- 22101917 TI - Discovery of a sensitive Cu(II)-cyanide "off-on" sensor based on new C-glycosyl triazolyl bis-amino acid scaffold. AB - A new functional glycosyl peptidomimetic, featuring a C-glucosyl 1,4 dimethoxynaphthalene backbone in conjugation with two triazolyl phenylalanine moieties on its adjacent C3,4-positions, was readily synthesized via click chemistry. Primary optical measurements indicated that the fluorescence of the ester form of this probe (4) could be selectively quenched by Pb(2+). In contrast, the fluorescence intensity of its analog 5 with released carboxylic groups was uniquely diminished by Cu(2+) with remarkably enhanced sensitivity and selectivity. Moreover, subsequent addition of cyanide to the methanol solution of the resulting Cu(2+)-5 complex induced its fluorescence recovery with a nanomolar detection limit, which was two orders of magnitude smaller than the regulated concentration limit of CN(-) in drinking water. This suggests the promising applicability of C-glycosyl bis-triazolyl amino acid scaffold in the future design and exploration of sensitive "off-on" Cu(II)-cyanide chemosensors. PMID- 22101919 TI - [Eye pain from an interdisciplinary perspective. Gap between clinical relevance and literature confirmation]. PMID- 22101918 TI - Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. AB - Probiotic bacteria can modulate immune responses in the host gastrointestinal tract to promote health. The genomics era has provided novel opportunities for the discovery and characterization of bacterial probiotic effector molecules that elicit specific responses in the intestinal system. Furthermore, nutrigenomic analyses of the response to probiotics have unravelled the signalling and immune response pathways which are modulated by probiotic bacteria. Together, these genomic approaches and nutrigenomic analyses have identified several bacterial factors that are involved in modulation of the immune system and the mucosal barrier, and have revealed that a molecular 'bandwidth of human health' could represent a key determinant in an individual's physiological responsiveness to probiotics. These approaches may lead to improved stratification of consumers and to subpopulation-level probiotic supplementation to maintain or improve health, or to reduce the risk of disease. PMID- 22101920 TI - [Ocular pain. Differential diagnostic aspects]. AB - Clinical ophthalmologists are often confronted with ocular pain, a symptom that can cause severe difficulties in the diagnostic assessment. The most common etiology is constituted by neurological disorders. Besides possible ophthalmologic causes for such disorders, otorhinolaryngological and oral and maxillofacial origins have to be considered. The ophthalmologist plays an important role as the first examiner, who has to rule out acute life-threatening conditions and also direct further steps in the differential diagnosis. This article clarifies such a diagnostic approach and discusses how a rudimentary knowledge of the characteristics of primary headaches is crucial as even though they do not induce ophthalmologic changes they constitute the main reason for the occurrence of ocular pain. PMID- 22101921 TI - Statins in clinical medicine. AB - Statins inhibit cholesterol biosynthesis. Their main effect is a decrease in circulating levels of LDL cholesterol, which translates into a ~ 20% relative reduction of major vascular events and coronary mortality per mmol/L LDL reduction achieved. Statins are efficient in preventing first cardiovascular events, but the cost-efficiency of primary prevention remains controversial. In primary prevention particularly, the pros and cons of statin therapy should be weighted by considering patient-specific life circumstances and assessing the individual cardiovascular risk, as provided by risk calculators. Since diabetes mellitus poses a high risk even in the absence of known coronary artery disease, statin treatment is generally indicated in these patients. There is no lower LDL threshold defining the limit of treatment benefit; rather, LDL target levels should be sought according to individual cardiovascular risk. If the necessary precautions are taken, e.g., by considering age, co-morbidities and co-medication when choosing the dose, statins are well tolerated and safe, as evidenced by many randomised controlled trials and meta-analyses. If a patient will not tolerate a statin dose necessary to achieve his or her LDL target level, ezetimibe may be added. There is no indication that statins alter cancer risk. Despite recent evidence that statin treatment is associated with a small risk of incident diabetes mellitus, this disadvantage is outweighed by the vascular benefits. Statins have pleiotropic effects, such as anti-inflammatory properties. It is still debated to what extent these effects translate into cardiovascular risk reduction beyond that conferred by LDL reduction. PMID- 22101922 TI - Separation of lipid classes by HPLC on a cyanopropyl column. AB - A new method for the separation and identification of lipid classes by normal phase HPLC on a cyanopropyl column is described. The use of a simple binary gradient, with toluene as a component, provided a rapid separation of non-polar as well as phospholipid classes. The inherent small differences in performances between possible non-polar eluent components of the gradient, such as hexane, heptane, and iso-octane, had a pronounced impact on retention times for individual phospholipid classes. Separation of molecular species within a lipid class could also be observed. PMID- 22101923 TI - A case of leprosy mistaken for cutaneous sarcoidosis. PMID- 22101924 TI - Primary malignancy in crossed fused ectopic kidney. AB - Crossed fused ectopia of kidneys is a rare congenital anomaly. It is usually associated with congenital anomalies of the gut. Development of malignancy in crossed fused ectopic kidney is uncommon. We present two cases, both females aged 47 and 60 years with crossed fused renal ectopia detected due to the development of malignancy in them. This report highlights the rare occurrence of the entity and role of US, CT scan and MRI in such patients. PMID- 22101925 TI - Genome-wide profiling of novel and conserved Populus microRNAs involved in pathogen stress response by deep sequencing. AB - MicroRNAs (miRNAs) are small RNAs, generally of 20-23 nt, that down-regulate target gene expression during development, differentiation, growth, and metabolism. In Populus, extensive studies of miRNAs involved in cold, heat, dehydration, salinity, and mechanical stresses have been performed; however, there are few reports profiling the miRNA expression patterns during pathogen stress. We obtained almost 38 million raw reads through Solexa sequencing of two libraries from Populus inoculated and uninoculated with canker disease pathogen. Sequence analyses identified 74 conserved miRNA sequences belonging to 37 miRNA families from 154 loci in the Populus genome and 27 novel miRNA sequences from 35 loci, including their complementary miRNA* strands. Intriguingly, the miRNA* of three conserved miRNAs were more abundant than their corresponding miRNAs. The overall expression levels of conserved miRNAs increased when subjected to pathogen stress, and expression levels of 33 miRNA sequences markedly changed. The expression trends determined by sequencing and by qRT-PCR were similar. Finally, nine target genes for three conserved miRNAs and 63 target genes for novel miRNAs were predicted using computational analysis, and their functions were annotated. Deep sequencing provides an opportunity to identify pathogen regulated miRNAs in trees, which will help in understanding the regulatory mechanisms of plant defense responses during pathogen infection. PMID- 22101926 TI - Biomolecular modification of carbon nanotubes for studies of cell adhesion and migration. AB - We report a strategy for tailoring and patterning carbon nanotubes (CNTs) for biospecific cell studies. We synthesized a new electroactive hydroquinone terminated pyrene molecule to tailor CNTs. These modified CNTs can be oxidized and chemoselectively reacted with oxyamine tethered ligands to generate various ligand tethered CNTs. A cell adhesive Arg-Gly-Asp peptide (RGD) is immobilized to the CNTs and a new microfluidic patterning method is employed to generate multiplex patterned surfaces for biospecific cell adhesion and migration studies. This work demonstrates the integration of a new functionalization strategy to immobilize a variety of ligands to CNTs for a range of potential drug delivery, tissue imaging and cellular behavior studies and a microfluidic patterning strategy for generating complex high-throughput surfaces for biotechnological and cell based assay applications. PMID- 22101927 TI - Transgenic banana expressing Pflp gene confers enhanced resistance to Xanthomonas wilt disease. AB - Banana Xanthomonas wilt (BXW), caused by Xanthomonas campestris pv. musacearum, is one of the most important diseases of banana (Musa sp.) and currently considered as the biggest threat to banana production in Great Lakes region of East and Central Africa. The pathogen is highly contagious and its spread has endangered the livelihood of millions of farmers who rely on banana for food and income. The development of disease resistant banana cultivars remains a high priority since farmers are reluctant to employ labor-intensive disease control measures and there is no host plant resistance among banana cultivars. In this study, we demonstrate that BXW can be efficiently controlled using transgenic technology. Transgenic bananas expressing the plant ferredoxin-like protein (Pflp) gene under the regulation of the constitutive CaMV35S promoter were generated using embryogenic cell suspensions of banana. These transgenic lines were characterized by molecular analysis. After challenge with X. campestris pv. musacearum transgenic lines showed high resistance. About 67% of transgenic lines evaluated were completely resistant to BXW. These transgenic lines did not show any disease symptoms after artificial inoculation of in vitro plants under laboratory conditions as well as potted plants in the screen-house, whereas non transgenic control plants showed severe symptoms resulting in complete wilting. This study confirms that expression of the Pflp gene in banana results in enhanced resistance to BXW. This transgenic technology can provide a timely solution to the BXW pandemic. PMID- 22101928 TI - Anti IL-17A therapy inhibits bone loss in TNF-alpha-mediated murine arthritis by modulation of the T-cell balance. AB - Tumour necrosis factor alpha (TNF-alpha) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF alpha-mediated inflammation and bone resorption. Human TNF-alpha transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1(-/-) mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-alpha induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1(-/-) mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-alpha induced bone loss by closely interacting with IL-1 in blocking bone protective T cell responses. PMID- 22101929 TI - Genetic relationships and evolution in Cucurbita pepo (pumpkin, squash, gourd) as revealed by simple sequence repeat polymorphisms. AB - Genetic relationships among 104 accessions of Cucurbita pepo were assessed from polymorphisms in 134 SSR (microsatellite) and four SCAR loci, yielding a total of 418 alleles, distributed among all 20 linkage groups. Genetic distance values were calculated, a dendrogram constructed, and principal coordinate analyses conducted. The results showed 100 of the accessions as distributed among three clusters representing each of the recognized subspecies, pepo, texana, and fraterna. The remaining four accessions, all having very small, round, striped fruits, assumed central positions between the two cultivated subspecies, pepo and texana, suggesting that they are relicts of undescribed wild ancestors of the two domesticated subspecies. In both, subsp. texana and subsp. pepo, accessions belonging to the same cultivar-group (fruit shape) associated with one another. Within subsp. pepo, accessions grown for their seeds or that are generalists, used for both seed and fruit consumption, assumed central positions. Specialized accessions, grown exclusively for consumption of their young fruits, or their mature fruit flesh, or seed oil extraction, tended to assume outlying positions, and the different specializations radiated outward from the center in different directions. Accessions of the longest-fruited cultivar-group, Cocozelle, radiated bidirectionally, indicating independent selection events for long fruits in subsp. pepo probably driven by a common desire to consume the young fruits. Among the accessions tested, there was no evidence for crossing between subspecies after domestication. PMID- 22101930 TI - Pharmacodynamic modeling of sequence-dependent antitumor activity of insulin-like growth factor blockade and gemcitabine. AB - Agents that block insulin-like growth factor (IGF) signaling are under investigation in clinical trials. Antitumor effects are likely to be enhanced when combined with other agents, but administration sequence effects on activity are not well-described. Three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs 578T) were treated with Gemcitabine and small molecule receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]1-(2-phenyl-quinolin-7 yl)-imidazo [1,5-a]pyrazin-8-ylamine (PQIP) as single agents and then in combination in the forward (Gemcitabine followed by PQIP) and reverse (PQIP followed by Gemcitabine) sequences. Antitumor effects were assessed longitudinally by Bayesian analysis using WinBUGS. The pharmacodynamic model adequately predicted the observed data. The differences in the cell-kill rate constants for the forward vs. reverse sequence ranged from 0.11 to 0.64 (day( 1)), and statistical significance was generally dependent on cell line and PQIP concentration. These data indicate that treatment with Gemcitabine first, followed by PQIP is superior to the reverse sequence in vitro. PMID- 22101931 TI - Pyruvate and creatine prevent oxidative stress and behavioral alterations caused by phenylalanine administration into hippocampus of rats. AB - Phenylketonuria is characterized by a variable degree of mental retardation and other neurological features whose mechanisms are not fully understood. In the present study we investigated the effect of intrahippocampal administration of phenylalanine, isolated or associated with pyruvate or creatine, on rat behavior and on oxidative stress. Sixty-day-old male Wistar rats were randomly divided into 6 groups: saline; phenylalanine; pyruvate; creatine; phenylalanine + pyruvate; phenylalanine + creatine. Phenylalanine was administered bilaterally in the hippocampus one hour before training; pyruvate, at the same doses, was administered in the hippocampus one hour before phenylalanine; creatine was administered intraperitoneally twice a day for 5 days before training; controls received saline solution at same volumes than the other substances. Parameters of exploratory behavior and of emotionality were assessed in both training and test sessions in the open field task. Rats receiving phenylalanine did not habituate to the open field along the sessions, indicating deficit of learning/memory, but parameters of emotionality were normal, not interfering in the habituation process. Pyruvate or creatine administration prevented the lack of habituation caused by phenylalanine. Pyruvate and creatine also prevented alterations provoked by phenylalanine on lipid peroxidation, total content of sulfhydryls, total radical-trapping antioxidant potential and total antioxidant reactivity. The results suggest that the behavioral alterations provoked by intra-hippocampal administration of phenylalanine may be caused, at least in part, by oxidative stress and/or energy deficit. If this also occurs in PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric patients. PMID- 22101932 TI - Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast. AB - The evolutionarily conserved shelterin complex has been shown to play both positive and negative roles in telomerase regulation in mammals and fission yeast. Although shelterin prevents the checkpoint kinases ATM and ATR from fully activating DNA damage responses at telomeres in mammalian cells, those kinases also promote telomere maintenance. In fission yeast, cells lacking both Tel1 (ATM ortholog) and Rad3 (ATR ortholog) fail to recruit telomerase to telomeres and survive by circularizing chromosomes. However, the critical telomere substrate(s) of Tel1(ATM) and Rad3(ATR) was unknown. Here we show that phosphorylation of the shelterin subunit Ccq1 on Thr93, redundantly mediated by Tel1(ATM) and/or Rad3(ATR), is essential for telomerase association with telomeres. In addition, we show that the telomerase subunit Est1 interacts directly with the phosphorylated Thr93 of Ccq1 to ensure telomere maintenance. The shelterin subunits Taz1, Rap1 and Poz1 (previously established inhibitors of telomerase) were also found to negatively regulate Ccq1 phosphorylation. These findings establish Tel1(ATM)/Rad3(ATR)-dependent Ccq1 Thr93 phosphorylation as a critical regulator of telomere maintenance in fission yeast. PMID- 22101933 TI - A shared structural solution for neutralizing ebolaviruses. AB - Sudan virus (genus Ebolavirus) is lethal, yet no monoclonal antibody is known to neutralize it. We here describe antibody 16F6 that neutralizes Sudan virus and present its structure bound to the trimeric viral glycoprotein. Unexpectedly, the 16F6 epitope overlaps that of KZ52, the only other antibody against the GP(1,2) core to be visualized to date. Furthermore, both antibodies against this crucial epitope bridging GP1-GP2 neutralize at a post-internalization step--probably fusion. PMID- 22101934 TI - Mechanistic insights into the activation of oncogenic forms of EGF receptor. AB - Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non-small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type EGFR, it is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have mainly relied on cell-based assays or isolated kinase domain measurements. Here we show, using purified, near full length human EGFR proteins (tEGFRs), that two oncogenic mutants are fully active independently of EGF and highly resistant to the therapeutic and endogenous inhibitors cetuximab, lapatinib and MIG6. Based on the pattern of inhibition and the effects of additional asymmetric kinase dimer interface mutations, we propose that these oncogenic EGFR mutants drive and strongly depend on the formation of the asymmetric kinase dimer for activation, which has implications for drug design and cancer treatment strategies. PMID- 22101935 TI - The RNA accordion model for template positioning by telomerase RNA during telomeric DNA synthesis. AB - Telomerase is a ribonucleoprotein (RNP) enzyme that maintains the ends of linear eukaryotic chromosomes and whose activation is a hallmark of 90% of all cancers. This RNP minimally contains a reverse transcriptase protein subunit (TERT) that catalyzes telomeric DNA synthesis and an RNA subunit (TER) that has templating, architectural and protein-scaffolding roles. Telomerase is unique among polymerases in that it synthesizes multiple copies of the template on the 3' end of a primer following a single binding event, a process known as repeat addition processivity (RAP). Using biochemical assays and single-molecule Forster resonance energy transfer (smFRET) experiments on Tetrahymena thermophila telomerase, we now directly demonstrate that TER contributes to template positioning within the active site and to the template translocation required for RAP. We propose that the single-stranded RNA elements flanking the template act as a molecular accordion, undergoing reciprocal extension and compaction during telomerase translocation. PMID- 22101936 TI - The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. AB - The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and gamma-H2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection. PMID- 22101938 TI - Click-enabled heterotrifunctional template for sequential bioconjugations. AB - A heterotrifunctional template was developed that utilizes thiol-maleimide and click chemistries (both copper-free and copper-mediated) to effect sequential biomolecule conjugations in a one-pot process. The breadth of compatible substrates was illustrated through highly efficient conjugations of protein, peptide, sugar, lipid, fluoroalkane, biotin and fluorophore molecules. This template should be useful for the creation of chemically-enhanced/enabled biotherapeutics, especially through the expression of discontinuous (and heterogeneous) epitopes. PMID- 22101937 TI - Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. AB - Arginine dimethylation plays critical roles in the assembly of ribonucleoprotein complexes in pre-mRNA splicing and piRNA pathways. We report solution structures of SMN and SPF30 Tudor domains bound to symmetric and asymmetric dimethylated arginine (DMA) that is inherent in the RNP complexes. An aromatic cage in the Tudor domain mediates dimethylarginine recognition by electrostatic stabilization through cation-pi interactions. Distinct from extended Tudor domains, dimethylarginine binding by the SMN and SPF30 Tudor domains is independent of proximal residues in the ligand. Yet, enhanced micromolar affinities are obtained by external cooperativity when multiple methylation marks are presented in arginine- and glycine-rich peptide ligands. A hydrogen bond network in the SMN Tudor domain, including Glu134 and a tyrosine hydroxyl of the aromatic cage, enhances cation-pi interactions and is impaired by a mutation causing an E134K substitution associated with spinal muscular atrophy. Our structural analysis enables the design of an optimized binding pocket and the prediction of DMA binding properties of Tudor domains. PMID- 22101939 TI - Evaluation of a temporal trend heavy metals contamination in Posidonia oceanica (L.) Delile, (1813) along the western coastline of Sicily (Italy). AB - The use of biological species in the monitoring of marine environmental quality allows the evaluation of biologically available levels of contaminants in the ecosystem and the effects of contaminants on living organisms. The seagrass Posidonia oceanica is a useful bioindicator because through the lepidochronology technique it is possible to obtain a historical contamination trend of a given area. This study aims to assess the temporal trend contamination by heavy metal investigations on dead sheaths of 100 samples of P. oceanica collected in the Protected Marine Area of "Plemmirio" (Sicily) and in the Siracusa bay. Important results were obtained because data show a significant negative temporal trend for the metals analysed especially for As, Co, Cr, Hg, Pb, Se, U and V that in the past had higher concentrations, with a stronger contamination in the Plemmirio area, the site much more exposed to the pollution of the nearby petrochemical complex. This study confirms the relevance of the use of P. oceanica as a biological indicator of metal contamination in coastal ecosystems. Thus the usefulness of P. oceanica as a tracer of spatial metal contamination and as a good tool for water quality evaluation is reinforced. PMID- 22101940 TI - Brief communication: Endocranial volumes in an ontogenetic sample of chimpanzees from the Tai Forest National Park, Ivory Coast. AB - Ontogenetic samples of endocranial volumes (EVs) from great apes and humans are critical for understanding the evolution of the brain growth pattern in the hominin lineage. However, high quality ontogenetic data are scarce, especially for nonhuman primates. Here, we provide original data derived from an osteological collection of a wild population of Pan troglodytes verus from the Tai Forest National Park, Ivory Coast. This sample is unique, because age, sex, and pedigree information are available for many specimens from behavioral observations in the wild. We scanned crania of all 30 immature specimens and 13 adult individuals using high-resolution computed tomography. We then created virtual casts of the bony braincase (endocasts) to measure EVs. We also measured cranial length, width, and height and attempted to relate cranial distances to EV via regression analysis. Our data are consistent with previous studies. The only neonate in the sample has an EV of 127 cm(3) or 34% of the adult mean. EV increases rapidly during early ontogeny. The average adult EV in this sample is 378.7 +/- 30.1 cm(3) . We found sexual dimorphism in adults; males seem to be already larger than females before adult EV is attained. Regressions on cranial width and multiple regression provide better estimates for EV than regressions on cranial length or height. Increasing the sample size and compiling more high quality ontogenetic data of EV will help to reconcile ongoing discussions about the evolution of hominin brain growth. PMID- 22101941 TI - The biodurability of covering materials for metallic stents in a bile flow phantom. AB - BACKGROUND: Covered biliary metal stents have been introduced for the purpose of overcoming tumor ingrowth and treatment of benign biliary stricture. The aim of this study was to evaluate the biodurability of three commercially available biliary metal stent covering materials [e-PTFE (expanded polytetrafluoroethylene), silicone, and polyurethane] in a bile flow phantom. MATERIALS AND METHODS: By operation of a peristaltic pump, human bile was circulated continuously in an experimental perfusion system containing covered metal stents. Each stent was removed, respectively, 1, 2, 4, and 6 months after bile exposure. We performed a gross inspection of the covered stents. The covering membrane was detached from the stent and observed by scanning electron microscopy (SEM). Finally, we measured tensile and tear strength of the membranes. RESULTS: Bile-staining of the membrane showed gradual progression after bile exposure; however, progress was the fastest in e-PTFE. SEM examination showed that the polyurethane surface was smooth, and the silicone surface was relatively smooth. However, e-PTFE had a rough and uneven surface. After bile exposure, there were no significant changes in polyurethane and silicone; however, biofilms and microcracks were observed in e-PTFE. In contrast to a gradual decrease of tensile/tear strength of polyurethane and silicone, those of e-PTFE showed a rapid reduction despite of the strongest baseline tensile and tear strength. CONCLUSION: e-PTFE tended to form biofilms more frequently than polyurethane and silicone during bile exposure. e-PTFE seemed to be less durable than silicone and polyurethane, however, as clinically applicable material because of strong absolute tensile/tear strengths. PMID- 22101942 TI - The results of transperineal versus transrectal prostate biopsy: a systematic review and meta-analysis. AB - This systematic review was performed to compare the efficacy and complications of transperineal (TP) vs. transrectal (TR) prostate biopsy. A systematic research of PUBMED, EMBASE and the Cochrane Library was performed to identify all clinical controlled trials on prostate cancer (PCa) detection rate and complications achieved by TP and TR biopsies. Prostate biopsies included sextant, extensive and saturation biopsy procedures. All patients were assigned to a TR group and a TP group. Subgroup analysis was performed according to prostate-specific antigen (PSA) levels and digital rectal examination (DRE) findings. The Cochrane Collaboration's RevMan 5.1 software was used for the meta-analysis. A total of seven trials, including three randomized controlled trials (RCTs) and four case control studies (CCS), met our inclusion criteria. There was no significant difference in the cancer detection rate between the sextant TR and TP groups (risk difference (RD), -0.02; 95% confidence interval (CI), -0.08-0.03; P=0.34). Meta-analysis for RCTs combined with CCS showed that there was no difference in the cancer detection rate between the extensive TR and TP group (RD, -0.01; 95% CI, -0.05-0.04; P=0.81). There was no significant difference in PCa detection rate between the saturation TR and TP approaches (31.4% vs. 25.7%, respectively; P=0.3). There were also no significant differences in cancer detection between the TR and TP groups in each subgroup. Although the data on complications were not pooled for the meta-analysis, no significant difference was found when comparing TR and TP studies. TR and TP biopsies were equivalent in terms of efficiency and related complications. TP prostate biopsy should be an available and alternative procedure for use by urologists. PMID- 22101943 TI - Another road leads to HIF-1 activation: implications for prostate cancer progression. PMID- 22101944 TI - Apoplastic superoxide production and peroxidase activity by intact and excised axenically grown seedling roots of sunflower. AB - Excised and cold-preincubated sunflower seedling roots were compared with intact non-preincubated roots to test the effect of the injury stress and cold preincubation on the oxidative burst measured as apoplastic superoxide (O (2) (. ) ) generation and exocellular peroxidase (ECPOX) activity. Preincubated excised or intact roots released into the medium apoplastic proteins with peroxidase activity. Intact and excised roots responded to methyl jasmonate by an immediate oxidative burst that could not be induced by salicylic acid; both phytohormones also induced a slight and slow O (2)(.-) generation and ECPOX activity on excised roots, when added to the cold preincubation medium. The results with cyanide, azide, SHAM (ECPOX inhibitors) and diphenylene iodonium (inhibitor of trans plasma membrane NAD(P)H-oxidases (NOX)-respiratory burst oxidase homologue in plants (RBOH), the trans-plasmamembrane nicotinamide adenine dinucleotide phosphate oxidase) are consistent with the hypothesis that different systems may be the origin of O (2) (.-) in intact and excised roots; ECPOX was an important component of them in both, together with NOX-RBOH in intact roots, but in excised roots the last one was replaced by an oxidase sensitive to the same inhibitors as the alternative mitochondrial oxidase. According to our hypothesis, these results could be explained if the electron flux would be deviated to different interconnected plasma membrane-redox systems, with different terminal oxidases, activated by different effectors or stresses. PMID- 22101945 TI - Morphological and photosynthetic variations in the process of spermatia formation from vegetative cells in Porphyra yezoensis Ueda (Bangiales, Rhodophyta) and their responses to desiccation. AB - Porphyra yezoensis has a macroscopic foliage gametophyte phase with only a single cell layer, and is ideally suited for the study of the sexual differentiation process, from the vegetative cell to the spermatia. Firstly, we compared variations in the responses of the vegetative and male sectors to desiccation. Later, cell tracking experiments were carried out during the formation of spermatia from vegetative cells. The two sectors showed similar tolerance to desiccation, and the formation of spermatia from vegetative cells was independent of the degree of desiccation. Both light and scanning electron microscopy (SEM) observations of the differentiation process showed that the formation of spermatia could be divided into six phases: the one-cell, two-cell, four-cell, eight-cell, pre-release and spermatia phases. Photomicrographs of Fluorescent Brightener staining showed that the released spermatia had no cell walls. Photosynthetic data showed that there was a significant rise in Y(II) in the four cell phase, indicating an increase in photosynthetic efficiency of PSII during this phase. We propose that this photosynthetic rise may be substantial and provide the increased energy needed for the formation and release of spermatia in P. yezoensis. PMID- 22101946 TI - Expression of ethylene response genes during persimmon fruit astringency removal. AB - Thirteen ethylene signaling related genes were isolated and studied during ripening of non-astringent 'Yangfeng' and astringent 'Mopan' persimmon fruit. Some of these genes were characterized as ethylene responsive. Treatments, including ethylene and CO(2), had different effects on persimmon ripening, but overlapping roles in astringency removal, such as increasing the reduction in levels of soluble tannins. DkERS1, DkETR2, and DkERF8, may participate in persimmon fruit ripening and softening. The expression patterns of DkETR2, DkERF4, and DkERF5 had significant correlations with decreases in soluble tannins in 'Mopan' persimmon fruit, suggesting that these genes might be key components in persimmon fruit astringency removal and be the linkage between different treatments, while DkERF1 and DkERF6 may be specifically involved in CO(2) induced astringency removal. The possible roles of ethylene signaling genes in persimmon fruit astringency removal are discussed. PMID- 22101947 TI - Bilateral connectivity in the brainstem respiratory networks of lampreys. AB - This study examines the connectivity in the neural networks controlling respiration in the lampreys, a basal vertebrate. Previous studies have shown that the lamprey paratrigeminal respiratory group (pTRG) plays a crucial role in the generation of respiration. By using a combination of anatomical and physiological techniques, we characterized the bilateral connections between the pTRGs and descending projections to the motoneurons. Tracers were injected in the respiratory motoneuron pools to identify pre-motor respiratory interneurons. Retrogradely labeled cell bodies were found in the pTRG on both sides. Whole-cell recordings of the retrogradely labeled pTRG neurons showed rhythmical excitatory currents in tune with respiratory motoneuron activity. This confirmed that they were related to respiration. Intracellular labeling of individual pTRG neurons revealed axonal branches to the contralateral pTRG and bilateral projections to the respiratory motoneuronal columns. Stimulation of the pTRG induced excitatory postsynaptic potentials in ipsi- and contralateral respiratory motoneurons as well as in contralateral pTRG neurons. A lidocaine HCl (Xylocaine) injection on the midline at the rostrocaudal level of the pTRG diminished the contralateral motoneuronal EPSPs as well as a local injection of 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) and (2R)-amino-5-phosphonovaleric acid (AP-5) on the recorded respiratory motoneuron. Our data show that neurons in the pTRG send two sets of axonal projections: one to the contralateral pTRG and another to activate respiratory motoneurons on both sides through glutamatergic synapses. PMID- 22101948 TI - Spatial patterns of beta-amyloid (Abeta) deposits in familial and sporadic Alzheimer's disease. AB - The spatial patterns of the diffuse, primitive, and classic beta -amyloid (Abeta) deposits were compared in cortical regions in early-onset familial Alzheimer's disease (EO-FAD) linked to mutations of the amyloid precursor protein APP) or presenilin 1 (PSEN1) genes, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The objective was to determine whether genetic factors influenced the spatial patterns of the A beta deposits. A beta deposits were distributed either in clusters which were regularly distributed parallel to the pia mater or in larger, non-regularly distributed clusters. There were no significant differences in spatial pattern of the diffuse deposits between patient groups but mean cluster size of the diffuse deposits was larger in FAD compared with SAD. Primitive A beta deposits were more frequently distributed in regular clusters and less frequently distributed in large clusters in FAD compared with SAD. Classic A beta deposits were more frequently distributed in regularly spaced clusters and less frequently distributed in large clusters in LO-FAD compared with EO-FAD. There were no significant differences in the spatial patterns or cluster sizes of A beta deposits in cases classified according to apolipoprotein E (APOE) genotype. These results suggest (1) greater deposition of A beta in the form of clusters of diffuse deposits in FAD, (2) a greater proportion of diffuse deposits may be converted to primitive deposits in SAD, (3) classic deposits are more widely distributed in EO-FAD, and (4) the presence of APOE allele epsilon4 has little effect on the spatial patterns of A beta deposits. PMID- 22101949 TI - Ultrastructural pathology of cortical capillary pericytes in human traumatic brain oedema. AB - In human traumatic brain oedema pericytes exhibit remarkable oedematous changes, increased vacuolar and vesicular transport, transient transpericytal channels, and tubular structures demonstrating pericyte brain barrier dysfunction. They show nuclear invaginations, actin and myosin-like filaments, and coupled interaction with endothelial cells through the macula occludens. Some pericytes display hypertrophic and necrotic changes, and phagocytic capacity. Hypertrophic pericytes induce basement membrane splitting. Degenerated pericytes exhibit lacunar enlargement of endoplasmic reticulum, dense osmiophilic bodies, glycogen granules, vacuolization, oedematous Golgi apparatus, and pleomorphic mitochondria. Certain micropinocytotic vesicles are orientated to the Golgi complex and multivesicular bodies, suggesting that pericytes play some role in oedema resolution. PMID- 22101950 TI - Ultrastructure of granular osmiophilic material deposits (GOM) in arterioles of CADASIL patients. AB - Granular osmiophilic material (GOM) is a pathognomonic feature of CADASIL that may be a consequence of pathological processes triggered by Notch3 mutations. Since knowledge of the effects of CADASIL-associated GOM deposits is important to understand the molecular pathogenesis of this disorder, we performed a thorough ultrastructural analysis of GOM morphology in the skin and muscle arterioles in CADASIL patients. Electron microscopy revealed numerous GOM deposits with different morphology including size, shape and osmiophilic density. Osmiophilic granular material of high density was frequently observed in part of GOM deposits located near vascular smooth muscle cells (VSMC) while a part localized distally from the cell body was less dense and loose. On the basis of our observations we postulate that GOM can be formed on the surface of VSMC in the arteriolar wall and penetrate from these cells into the basement membrane and/or extracellular matrix. The dispersion of granules, which form GOM deposits, may be one of the factors triggering the thickening and changes in the basement membrane and/or extracellular matrix. PMID- 22101951 TI - Histopathological patterns of papillary tumour of the pineal region. AB - Papillary tumour of the pineal region (PTPR) is a rare neoplasm that has been formally included in the 2007 WHO classification of central nervous system tumours. The critical diagnosis of this neoplasm is often difficult because of its similarity to other primary or secondary papillary lesions of the pineal region, including parenchymal pineal tumours, papillary ependymoma, papillary meningioma, choroid plexus papilloma and metastatic papillary carcinoma. We present the variability of the histopathological pattern in three cases of PTPR. All cases showed predominant epithelial-like morphology but with various degrees of papillary formation and intensity of cellular pleomorphism. One tumour was highly cystic and exhibited cellular sheets containing vessels covered by several layers of uniform columnar to cuboidal tumour cells. The second tumour showed distinct papillae covered by layers of polymorphous cells with atypical, often hyperchromatic nuclei. Numerous cells displayed foamy, eosinophilic or clear, sometimes vacuolated cytoplasm. The third case consisted of solid cellular areas composed of pseudostratified columnar cells, most often arranged in perivascular pseudorosette formations. The cells lining papillary structures exhibited marked polymorphism with atypical, often plump nuclei. Mitotic figures were rare and areas of necrosis were observed only in one case. Immunohistochemical staining showed diffuse immunoreactivity for neuron-specific enolase, S-100 protein, cyto keratin and vimentin. Focal reaction for synaptophysin and chromogranin A and epithelial membrane antigen (EMA) were observed. The tumours lacked expression of GFAP. The Ki-67 labelling index was relatively low but its focal increase was noted in two cases. The final diagnosis of PTPR was based on both predominant papillary morphology and immunohistochemical results. PTPR should be considered in diagnosis of pineal tumours but their natural history, therapeutic strategy and prognosis remain controversial. PMID- 22101952 TI - Some markers of neuronal damage in cerebrospinal fluid of multiple sclerosis patients in relapse. AB - In this paper the performance of cerebrospinal fluid (CSF) protein biomarkers important for monitoring damage of brain astrocytes and neurons for MS is reviewed. We estimated neurofilament, tau and phospho-tau proteins, beta-APP, Abeta, S-100B and neuron-specific enolase in CSF of MS patients during relapse. We noted elevation of neurofilament, tau and phospho-tau proteins, S-100B, neuron specific enolase and c-terminal epitopes of beta-APP; concomitantly decrease of Abeta was observed. These CSF biomarkers for MS relapse should reflect the central pathogenic processes in the brain, i.e., axonal and neuronal degeneration. PMID- 22101953 TI - Neurolysis of the conducting neuroma-in-continuity in perinatal brachial plexus palsy - evaluation of the results of surgical treatment. AB - The aim of the study was to evaluate the surgical treatment results of cases of perinatal brachial plexus palsy with presence of neuroma-in-continuity. Clinical material included 21 children, aged from 3.5 to 36 months, treated surgically between 1996 and 2005. The control examination included 19 children. The shortest postoperative observation period was 4 years. After surgical treatment during clinical evaluation of function dependent on localization of neuroma-in continuity we observed the following: in upper injury in 1 child good shoulder and elbow function; in upper-middle injuries with neuroma-in-continuity in upper trunk good elbow function in 66.6%, good shoulder function in 83.3% of cases; in upper-middle injuries with neuroma-in-continuity in upper and middle trunk in 1 examined child good function of elbow, shoulder, and wrist; in total injuries with neuroma-in-continuity in upper trunk good elbow function in 75%, and good shoulder function in 50% of cases; in total injuries with neuroma-in-continuity in upper and middle trunk good elbow function in 66.6%, good shoulder function in 33.3%, good wrist function in 66.6% of cases; in total injuries with neuroma-in continuity in lower trunk grade 2 of motor hand function and return of sensibility to a level of S3+. CONCLUSIONS: The choice of microsurgical technique during surgical treatment of perinatal brachial plexus palsies with neuroma-in continuity should be based on the whole clinical and intraoperative view. The best results after neurolysis should be expected when neuroma-in-continuity is localized in the upper trunk, the injury corresponds to third degree on Sunderland's scale, and during electric stimulation a normal motor response can be obtained. PMID- 22101954 TI - Long-term consequences of surgical brain injury - characteristics of the neurovascular unit and formation and demise of the glial scar in a rat model. AB - Neurosurgical procedures often involve, as a result of the surgeon approaching the diseased region, unavoidable trauma to the adjacent, non-diseased brain structures. Because of the priority of removing the immediate threats to health or life that underlie such interventions, side effects of surgical brain injuries were not given much attention until recently. The cause-and-effect association of the eventual delayed cognitive and/or neurological deficits is often obscure due to substantial potential of the brain for compensatory changes, long life span in man, and aging-related phenomena. However, animal and human studies have demonstrated that physical insults to the brain can initiate a cascade of changes that results, in the long run, in massive neurodegeneration and brain atrophy. Here we present a review of morphological and ultrastructural findings obtained mostly in a rat model of surgical neocortex injury, with consideration of the current view of this region as a network of specific neurovascular units. The neurovascular unit is a dynamic assembly consisting of a capillary vessel, pericytes, neurons and capillary-bound astrocytes. The integrity of this building block and the interactions between its component parts are responsible, among other things, for the proper functioning of the blood-brain barrier, brain blood circulation and the brain as a whole, and its dysregulation is associated with many CNS pathologies. The studies performed in the rat model of surgical brain injury presented in this review have brought new interesting findings regarding the consequences of such damage to the (ultra)structure and hence presumably to the function of the unit. These findings may have some relevance to human clinical situations. PMID- 22101955 TI - N-nitro-L-arginine methyl ester influence on aluminium toxicity in the brain. AB - We investigated the influence of a non-specific nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on brain nitrite concentration and acetylcholine esterase activity in AlCl3-treated Wistar rats. Animals were killed 10 min, three hours, three days and 30 days after the treatment and hippocampus and basal forebrain were removed. The biochemical changes observed in neuronal tissues show the involvement of NO in the AlCl3 toxicity and cholinergic neurotransmission, and that L-NAME may have potential neuroprotective effects. Active avoidance learning was significantly impaired after AlCl3 application, while pretreatment with L-NAME prevented the behavioural deficits caused by AlCl3. We also applied immunohistochemical techniques to identify changes induced by AlCl3, L-NAME+AlCl3, as well as L-NAME injections after survival periods of three days and 30 days. Immunoreactivity of astrocytes and phagocytic microglia based on glial fibrillary acidic protein (GFAP) and a useful marker for rat macrophages (ED1), respectively, revealed a greater inflammatory response in AlCl3-injected animals compared to controls. PMID- 22101956 TI - The neuroprotective effect of topiramate on the ultrastructure of pyramidal neurons of the hippocampal CA1 and CA3 sectors in an experimental model of febrile seizures in rats. AB - The objective of the current ultrastructural study was to explore the potentiality of the neuroprotective effect of TPM against damage of pyramidal neurons in the hippocampal CA1 and CA3 sectors in an experimental model of febrile seizures (FS) in rats. The FS group exhibited variously pronounced submicroscopic lesions of the neuronal perikarya, including total cell disintegration. Advanced changes induced by hyperthermic stress were manifested by marked degenerative abnormalities, such as substantial swelling of the mitochondria, dilation, degranulation and disintegration of the granular endoplasmic reticulum, and vacuolar changes in the Golgi complex. The most substantially damaged pyramidal neurons showed features of aponecrosis (so-called "dark neurons"), resulting in a marked neuronal loss in the explored areas of the hippocampal cortex. The neurodegenerative changes were accompanied by distinct damage to the blood-brain barrier components. The administration of topiramate at a dose of 80/kg b.m. prior to the induction of hyperthermic stress (as prevention against febrile seizures) caused a substantial neuroprotective action - the drug efficiently lightened the neuronal damage, basically reduced cell aponecrosis and enhanced cell viability. However, TPM applied directly after FS induction did not exert any distinct neuroprotective effect on the perikarya of pyramidal neurons in the hippocampal cortex. PMID- 22101957 TI - Toxic epidermal necrolysis following allergic contact dermatitis caused by occupational exposure to ultraviolet-cured inks. AB - Erythema multiforme is a relatively common skin disorder; the most common cause is herpes simplex infection, but topical sensitivities reportedly also provoke this reaction. We report here a case that progressed to toxic epidermal necrolysis due to contact with ultraviolet (UV)-cured inks. The diagnosis was confirmed by patch tests to acrylates in the UV-cured inks, histopathological studies of the lesions, and positive patch test to 1,6-hexanediol diacrylate. PMID- 22101958 TI - Genetic and environmental causes of variation in trait resilience in young people. AB - The aim of this multi-informant twin study was to determine the relative role of genetic and environmental factors in explaining variation in trait resilience in adolescents. Participants were consenting families (N = 2,638 twins in 1,394 families), from seven national cohorts (age 12-18 years, both sexes) of monozygotic and dizygotic twins reared together. Questionnaire data on the adolescents' Ego-resilience (ER89) was collected from mothers, fathers and twins, and analysed by means of multivariate genetic modelling. Variance in trait resilience was best represented in an ADE common pathways model with sex limitation. Variance in the latent psychometric resilience factor was largely explained by additive genetic factors (77% in boys, 70% in girls), with the remaining variance (23 and 30%) attributable to non-shared environmental factors. Additive genetic sources explained more than 50% of the informant specific variation in mothers and fathers scores. In twins, additive and non-additive genetic factors together explained 40% and non-shared environmental factor the remaining 60% of variation. In the mothers' scores, the additive genetic effect was larger for boys than for girls. The non-additive genetic factor found in the twins' self ratings was larger in boys than in girls. The remaining sex differences in the specific factors were small. Trait resilience is largely genetically determined. Estimates based on several informants rather than single informants approaches are recommended. PMID- 22101959 TI - The FMR1 premutation and attention-deficit hyperactivity disorder (ADHD): evidence for a complex inheritance. AB - We recently reported elevated symptoms associated with attention-deficit hyperactivity disorder (ADHD) among adult female carriers of the FMR1 premutation. To gain insight into the contribution of this mutation in the context of polygenes, we examined the proportion of variation in these symptoms due to residual genetic factors after adjustment for the effect of the premutation. To accomplish this, we performed a familial aggregation analysis of ADHD symptoms among 231 females from 82 pedigrees using scores from the Connors Adult ADHD Rating Scales. Results indicate that after accounting for the effect of FMR1, there are significant residual polygenic effects on self-reported symptoms of ADHD, as measured by the ADHD Index (p = 0.0117) and problems with self-concept (p = 0.0110), one specific symptom domain associated with ADHD. For both measures, FMR1 accounts for ~5% of the variance while polygenes account for ~50% of the residual variance, suggesting that the premutation acts in concert with additional genetic loci to influence the severity of ADHD symptoms. PMID- 22101960 TI - Regionalization in the eye of the grapsid crab Neohelice granulata (=Chasmagnathus granulatus): variation of resolution and facet diameters. AB - Crabs have panoramic compound eyes, which can show marked regional specializations of visual acuity. These specializations are thought to be related to the particular features of the animal's ecological environment. Modern knowledge on the neuroanatomy and neurophysiology of the crabs' visual system mainly derives from studies performed in the grapsid crab Neohelice granulata (=Chasmagnathus granulatus). However, the organization of the visual sampling elements across the eye surface of this animal had not yet been addressed. We analyzed the sampling resolution across the eye of Neohelice by measuring the pseudopupil displacement with a goniometer. In addition, we measured the facet sizes in the different regions of the eye. We found that Neohelice possesses an acute band of high vertical resolution around the eye equator and an increase in horizontal sampling resolution and lenses diameter towards the lateral side of the eye. Therefore, the analysis of the optical apparatus indicates that this crab possesses greater visual acuity around the equator and at the lateral side of the eye. These specializations are compared with those found in different species of crabs and are discussed in connection to the particular ecological features of Neohelice's habitat. PMID- 22101961 TI - Clinical, functional, and intertask correlations of measures developed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia Consortium. AB - The goal of the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium was to develop measures of discrete cognitive processes, allowing for the interpretation of specific deficits that could be linked to specific neural systems. Here we report on the intertask, clinical, and functional correlates of the 4 tasks that were investigated in large groups of patients with schizophrenia (>100) and healthy controls (>73) at 5 sites across the United States. In both healthy and patient groups, the key dependent measures from the CNTRACS tasks were minimally intercorrelated, suggesting that they are measuring discrete abilities. Correlations were examined between CNTRACS tasks and measures of functional capacity, premorbid IQ, symptom severity, and level of community functioning. Performance on tasks measuring relational memory encoding, goal maintenance, and visual gain control were correlated with premorbid IQ and the former 2 tasks with the functional capacity. Goal maintenance task performance was negatively correlated with negative symptom severity and informant reports of community function. These correlations reflect the relationship of specific abilities with functional outcome. They are somewhat lower than functional outcome correlations observed with conventional neuropsychological tests that confound multiple cognitive and motivational deficits. The measures of visual integration and gain control were not significantly correlated with clinical symptoms or function. These results suggest that the CNTRACS tasks measure discrete cognitive abilities, some of which relate to aspects of functional capacity/outcome in schizophrenia. PMID- 22101962 TI - Identification and characterization of prodromal risk syndromes in young adolescents in the community: a population-based clinical interview study. AB - While a great deal of research has been conducted on prodromal risk syndromes in relation to help-seeking individuals who present to the clinic, there is a lack of research on prodromal risk syndromes in the general population. The current study aimed first to establish whether prodromal risk syndromes could be detected in non-help-seeking community-based adolescents and secondly to characterize this group in terms of Axis-1 psychopathology and general functioning. We conducted in depth clinical interviews with a population sample of 212 school-going adolescents in order to assess for prodromal risk syndromes, Axis-1 psychopathology, and global (social/occupational) functioning. Between 0.9% and 8% of the community sample met criteria for a risk syndrome, depending on varying disability criteria. The risk syndrome group had a higher prevalence of co occurring nonpsychotic Axis-1 psychiatric disorders (OR = 4.77, 95% CI = 1.81 12.52; P < .01) and poorer global functioning (F = 24.5, df = 1, P < .0001) compared with controls. Individuals in the community who fulfill criteria for prodromal risk syndromes demonstrate strong similarities with clinically presenting risk syndrome patients not just in terms of psychotic symptom criteria but also in terms of co-occurring psychopathology and global functioning. PMID- 22101963 TI - The clinical translation of a measure of gain control: the contrast-contrast effect task. AB - The goal of the current project was to further develop a measure of gain control- the Contrast-Contrast Effect (CCE)--for use in clinical studies of schizophrenia. The CCE is based on an illusion in which presenting a medium contrast patch surrounded by a high-contrast patch induces individuals to perceive that center patch as having lower contrast than when the patch is presented in isolation. Thus, in the CCE, impaired gain control should lead to more accurate perceptions of the center patch. We tested 132 individuals with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, schizophrenia or schizoaffective disorder and 130 demographically similar healthy controls. The results indicated that the CCE effect can be obtained with standard equipment, simplified scoring, and a short interstimulus interval (100 ms), revealing a robust suppression of perceived contrast of the center patch when surrounded by a high-contrast annulus. Furthermore, we found a significant reduction in the effect of the high contrast surround among individuals with schizophrenia, though the effect size was smaller than original reported by Dakin. However, when we eliminated subjects who performed poorly on "catch" trials that controlled for off-task performance, the reduced surround effect among patients was no longer significant in the main analyses. Importantly, this suggests that at least part of the reduced surround effect (if not all) in schizophrenia could be attributable to impaired attentional mechanisms that contribute to off-task performance. Additional analyses suggested that the length of the task could be shortened without losing power to detect surround effects in healthy individuals. PMID- 22101964 TI - Isolation and bioactivities of a non-sericin component from cocoon shell silk sericin of the silkworm Bombyx mori. AB - The cocoon shell of the silkworm Bombyx mori consists of silk fibroin fiber (70%) surrounded by a sericin layer made up of sericin (25%) and non-sericin (5%) components. The non-sericin component which consists of carbohydrate, salt, wax, flavonoids and derivatives is often overlooked in applied research into sericin and its hydrolysate. Here, sericin and non-sericin compounds were obtained from the sericin layer of five types of cocoon shell by means of degumming in water followed by extraction and separation in ethanol. These ethanol extracts were found to mainly contain flavonoids and free amino acids possessing scavenging activities of the 2,2-diphenyl -1-picrylhydrazyl (DPPH) free radical and inhibiting activities of tyrosinase, which were much greater than the corresponding activities of the purified sericin proteins. The extracts also strongly inhibited alpha-glucosidase while the sericins had no such activity. In particular, the inhibitory activities of the ethanol extract of Daizo cocoons were much greater than those of the other cocoons. The IC(50) values of the Daizo cocoons for DPPH free radicals, tyrosinase, and alpha-glucosidase were 170, 27, and 110 MUg mL(-1), respectively. The bioactivities of the non-sericin component were much higher than the activity of sericin alone. In addition, the in vivo test showed preliminarily that the administration of the non-sericin component had effectively resistant activity against streptozocin (STZ) oxidation and that of the purified sericin could also evidently decrease the induction ratio of diabetic mice induced by STZ. Therefore, ethanol extract protocols of the sericin layer of cocoon shells provide a novel stock which, together with sericin protein, has potential uses in functional food, biotechnological and medical applications. PMID- 22101965 TI - Solubility of drugs in aqueous polymeric solution: effect of ovalbumin on microencapsulation process. AB - Microencapsulation of water-soluble drugs using coacervation-phase separation method is very challenging, as these drugs partitioned into the aqueous polymeric solution, resulting in poor drug entrapment. For evaluating the effect of ovalbumin on the microencapsulation of drugs with different solubility, pseudoephedrine HCl, verapamil HCl, propranolol HCl, paracetamol, and curcuminoid were used. In addition, drug mixtures comprising of paracetamol and pseudoephedrine HCl were also studied. The morphology, encapsulation efficiency, particle size, and in vitro release profile were investigated. The results showed that the solubility of the drug determined the ratio of ovalbumin to be used for successful microencapsulation. The optimum ratios of drug, ovalbumin, and gelatin for water-soluble (pseudoephedrine HCl, verapamil HCl, and propranolol HCl), sparingly water-soluble (paracetamol), and water-insoluble (curcuminoid) drugs were found to be 1:1:2, 2:3:5, and 1:3:4. As for the drug mixture, the optimum ratio of drug, ovalbumin, and gelatin was 2:3:5. Encapsulated particles prepared at the optimum ratios showed high yield, drug loading, entrapment efficiency, and sustained release profiles. The solubility of drug affected the particle size of the encapsulated particle. Highly soluble drugs resulted in smaller particle size. In conclusion, addition of ovalbumin circumvented the partitioning effect, leading to the successful microencapsulation of water-soluble drugs. PMID- 22101966 TI - Preparation and in vitro/in vivo evaluation of microparticle formulations containing meloxicam. AB - In this study, we have formulated chitosan-coated sodium alginate microparticles containing meloxicam (MLX) and aimed to investigate the correlation between in vitro release and in vivo absorbed percentages of meloxicam. The microparticle formulations were prepared by orifice ionic gelation method with two different sodium alginate concentrations, as 1% and 2% (w/v), in order to provide different release rates. Additionally, an oral solution containing 15 mg of meloxicam was administered as the reference solution for evaluation of in vitro/in vivo correlation (ivivc). Following in vitro characterization, plasma levels of MLX and pharmacokinetic parameters [elimination half-life (t(1/2)), maximum plasma concentration (C(max)), time for C(max) (t(max))] after oral administration to New Zealand rabbits were determined. Area under plasma concentration-time curve (AUC(0-infinity)) was calculated by using trapezoidal method. A linear regression was investigated between released% (in vitro) and absorbed% (in vivo) with a model-independent deconvolution approach. As a result, increase in sodium alginate content lengthened in vitro release time and in vivo t(max) value. In addition, for ivivc, linear regression equations with r(2) values of 0.8563 and 0.9402 were obtained for microparticles containing 1% and 2% (w/v) sodium alginate, respectively. Lower prediction error for 2% sodium alginate formulations (7.419 +/- 4.068) compared to 1% sodium alginate formulations (9.458 +/- 5.106) indicated a more precise ivivc for 2% sodium alginate formulation. PMID- 22101967 TI - Investigating the use of liquisolid compacts technique to minimize the influence of pH variations on loratadine release. AB - Loratadine is a class II water-insoluble drug and its dissolution rate and, consequently, absorption are dependent on the gastrointestinal pH. The resulting very high variability in bioavailability and related inter- and intra-subject absorption variations present a major challenge that hinders the realization of an effective and uniform therapy. Among the several techniques that have been used to minimize pH dependency of dissolution rate, liquisolid compacts technique can be suggested as a promising solution. In this study, it was hypothesized that the formulation of loratadine using liquisolid compacts technique may reduce the effect of pH variation on the drug dissolution rate. Solubilities of loratadine in propylene glycol, Tween 80, and polyethylene glycol 400 were first measured and propylene glycol was selected as for producing the highest solubility among the tested solvents. Several liquisolid tablet formulations containing various ratios of drug: propylene glycol (5%, 10%, and 20% w/w) were prepared. The ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was kept constant in all formulations. The dissolution behavior of loratadine from liquisolid compacts was investigated in several buffered media with different pH values (pH 1.2, 2.5, and 5). The results showed that the drug release rates produced by liquisolid compacts were significantly higher and less affected by pH variation compared with conventionally made (direct compression) and commercial (Clarityn) tablets. In conclusion, liquisolid compacts technique may be used as a tool to minimize the effects of pH variation on the dissolution rate of drugs with poor water solubility. PMID- 22101968 TI - Planar multipolar cells in the cochlear nucleus project to medial olivocochlear neurons in mouse. AB - Medial olivocochlear (MOC) neurons originate in the superior olivary complex and project to the cochlea, where they act to reduce the effects of noise masking and protect the cochlea from damage. MOC neurons respond to sound via a reflex pathway; however, in this pathway the cochlear nucleus cell type that provides input to MOC neurons is not known. We investigated whether multipolar cells of the ventral cochlear nucleus have projections to MOC neurons by labeling them with injections into the dorsal cochlear nucleus. The projections of one type of labeled multipolar cell, planar neurons, were traced into the ventral nucleus of the trapezoid body, where they were observed terminating on MOC neurons (labeled in some cases by a second cochlear injection of FluoroGold). These terminations formed what appear to be excitatory synapses, i.e., containing small, round vesicles and prominent postsynaptic densities. These data suggest that cochlear nucleus planar multipolar neurons drive the MOC neuron's response to sound. PMID- 22101969 TI - Surveillance of medication use: early identification of poor adherence. AB - BACKGROUND: We sought to measure population-level adherence to antihyperlipidemics, antihypertensives, and oral hypoglycemics, and to develop a model for early identification of subjects at high risk of long-term poor adherence. METHODS: Prescription-filling data for 2 million subjects derived from a payor's insurance claims were used to evaluate adherence to three chronic drugs over 1 year. We relied on patterns of prescription fills, including the length of gaps in medication possession, to measure adherence among subjects and to build models for predicting poor long-term adherence. RESULTS: All prescription fills for a specific drug were sequenced chronologically into drug eras. 61.3% to 66.5% of the prescription patterns contained medication gaps >30 days during the first year of drug use. These interrupted drug eras include long-term discontinuations, where the subject never again filled a prescription for any drug in that category in the dataset, which represent 23.7% to 29.1% of all drug eras. Among the prescription-filling patterns without large medication gaps, 0.8% to 1.3% exhibited long-term poor adherence. Our models identified these subjects as early as 60 days after the first prescription fill, with an area under the curve (AUC) of 0.81. Model performance improved as the predictions were made at later time points, with AUC values increasing to 0.93 at the 120-day time-point. CONCLUSIONS: Dispensed medication histories (widely available in real time) are useful for alerting providers about poorly adherent patients and those who will be non-adherent several months later. Efforts to use these data in point of care and decision support facilitating patient are warranted. PMID- 22101970 TI - Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study. AB - OBJECTIVE: Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype-phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems. MATERIALS AND METHODS: An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions. RESULTS: The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D. DISCUSSION: By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS. CONCLUSIONS: An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions. PMID- 22101971 TI - The NIH National Center for Integrative Biomedical Informatics (NCIBI). AB - The National Center for Integrative and Biomedical Informatics (NCIBI) is one of the eight NCBCs. NCIBI supports information access and data analysis for biomedical researchers, enabling them to build computational and knowledge models of biological systems to address the Driving Biological Problems (DBPs). The NCIBI DBPs have included prostate cancer progression, organ-specific complications of type 1 and 2 diabetes, bipolar disorder, and metabolic analysis of obesity syndrome. Collaborating with these and other partners, NCIBI has developed a series of software tools for exploratory analysis, concept visualization, and literature searches, as well as core database and web services resources. Many of our training and outreach initiatives have been in collaboration with the Research Centers at Minority Institutions (RCMI), integrating NCIBI and RCMI faculty and students, culminating each year in an annual workshop. Our future directions include focusing on the TranSMART data sharing and analysis initiative. PMID- 22101972 TI - Cloning and expression of arginine kinase from a swimming crab, Portunus trituberculatus. AB - Arginine kinase (AK) is an important phosphotransferase that plays a critical role in energy metabolism in invertebrates. In this paper, the cDNA of AK (designated as PtAK) was identified from the eyestalk cDNA library of swimming crab Portunus trituberculatus. The full-length cDNA was 1,479 bp, containing an open reading frame of 1,074 bp that coded for 357 amino acids. The estimated molecular mass of mature PtAK was 40.30 kDa and theoretical isoelectric point was 6.18. Amino acid sequence alignment showed that PtAK had very high similarity with other shrimp and crab AKs ranging from 0.876 to 0.983. The genomic DNA fragments of about 1,434 bp consisted of two exons interrupted by an intron. Totally 24 SNPs, including 17 in the coding region and seven in the non-coding region, were detected by direct sequencing of 19 genomic samples. In exon 1, the coding SNPs (cSNPs) were only found in the disease-resistant specimens. The fluorescent real-time PCR analysis revealed that the expression of PtAK was detected in all the examined tissues with the highest expression in the muscle and the lowest in the eyestalk. The expression of PtAK after Vibrio alginolyticus injection was tested in haemocytes, showing that two peak values were 5.01-fold (at 3 h) and 3.60-fold (at 24 h) compared with the control values, respectively. The results suggested that AK might play an important role in the immune response in crabs. PMID- 22101973 TI - Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat. AB - AIMS/HYPOTHESIS: Little is known about the subcellular distribution of lipids in insulin-resistant skeletal muscle. However, it has recently been suggested that lipid accumulation in the subsarcolemmal region directly contributes to insulin resistance. Therefore we hypothesised that regional differences in lipid distribution in insulin-resistant muscle may be mediated by: (1) a reduction in fatty acid trafficking into mitochondria; and/or (2) a regional increase in the enzymes regulating lipid synthesis. METHODS: Transmission electron microscopy was used to quantify lipid droplet and mitochondrial abundance in the subsarcolemmal and intermyofibrillar compartments in red and white muscles from lean and obese Zucker rats. To estimate rates of lipid trafficking into mitochondria, the metabolic fate of radiolabelled palmitate was determined. Key enzymes of triacylglycerol synthesis were also determined in each subcellular region. RESULTS: Subsarcolemmal-compartmentalised lipids represented a small absolute fraction of the overall lipid content in muscle, as regardless of fibre composition (red/white) or phenotype (lean/obese), lipid droplets were more prevalent in the intermyofibrillar region, whereas insulin-resistant white muscles were devoid of subsarcolemmal-compartmentalised lipid droplets. While, in obese animals, lipid droplets accumulated in both subcellular regions, in red muscle of these animals lipids only appeared to be trafficked away from intermyofibrillar mitochondria, a process that cannot be explained by regional differences in the abundance of triacylglycerol esterification enzymes. CONCLUSIONS/INTERPRETATION: Lipid accumulation in the subsarcolemmal region is not necessary for insulin resistance. In the intermyofibrillar compartment, the diversion of lipids away from mitochondria in insulin-resistant animals probably contributes to lipid accumulation in this subcellular area. PMID- 22101974 TI - Diabetes is associated with impairment of uterine contractility and high Caesarean section rate. AB - AIMS/HYPOTHESIS: The prevalence of births worldwide complicated by diabetes mellitus is increasing. In the UK, for example, <25% of diabetic women have a non instrumental vaginal delivery. Strikingly, more than half the Caesarean sections (CS) in these patients are non-elective, but the reasons for this are not understood. We have tested the hypothesis that poor myometrial contractility as a consequence of the disease contributes to this high CS rate. METHODS: We compared spontaneous, high K depolarisation and oxytocin-induced contractions from diabetic and matched control patients having an elective CS. To investigate the mechanism of any differences we measured intracellular Ca, and performed western blotting and compared the tissues histologically. RESULTS: There was significantly decreased contraction amplitude and duration in uteri from diabetic compared with control patients, even when possible confounders such as BMI were analysed. Reduced intracellular calcium signals and expression of calcium entry channels were found in uteruses from diabetic patients, which, along with a reduction in muscle content found on histological examination, could explain the reduced force. Myometrium from diabetic patients was responsive to oxytocin, but still did not reach the levels found in non-diabetic patients. CONCLUSIONS/INTERPRETATIONS: These are the first data investigating myometrium in diabetic patients and they support the hypothesis that there is poorer contractility even in the presence of oxytocin. The underlying mechanism is related to reduced Ca channel expression and intracellular calcium signals and a decrease in muscle mass. We conclude that these factors significantly contribute to the increased emergency CS rate in diabetic patients. PMID- 22101975 TI - Enhanced reduction of C-N multiple bonds using sodium borohydride and an amorphous nickel catalyst. AB - Amorphous nickel powder (Ni(0)) was utilised as a catalyst under mild, aqueous, basic conditions for enhancing the sodium borohydride-mediated reduction of C-N multiple bonds such as oximes, imines, hydrazones and nitriles to produce the corresponding amines in good to excellent yields. PMID- 22101976 TI - Preparation and characterization of catalase-loaded solid lipid nanoparticles based on soybean phosphatidylcholine. AB - BACKGROUND: High-purity soybean phosphatidylcholine (SPC) (94%) were prepared using macroporous resin adsorption chromatography previously. Catalase is a food enzyme for promoting health and protecting against many age-related disease. Solid lipid nanoparticles (SLN) are safe immobilizing systems for efficient protein transportation to biomembranes while avoiding adverse degradation of protein. This study was aimed at developing and characterizing catalase-loaded SLN using SPC as solubilizers and stabilizing agents, to protect catalase from proteolysis. RESULTS: Catalase-loaded SLN were prepared by the double emulsification method and solvent evaporation techniques, using acetone-methylene chloride (1:1, v/v) as an organic solvent, SPC-tripalmitin as oil phase and Poloxamer 188 as a surfactant. The optimized SLN were prepared using an SPC:tripalmitin ratio of 5% (w/w), 20 s plus 30 s sonication, 20 g L-1 Poloxamer 188 and 1:2 (v/v) of oily phase:outer aqueous phase ratio. The mean particle size of SLN was 296.0 +/- 7.0 nm, polydispersity index range and zeta potential were 0.322-0.354 and -36.4 +/- 0.6, respectively, and encapsulation efficiency reached its maximum of 77.9 +/- 1.56%. Catalase, which was found to distribute between the solid lipid and inner aqueous phase, was gradually released from SLN up to 20% within 20 h. Catalase-loaded SLN had stably retained 30% of H2O2-degrading activity for at least 24 h in a proteolytic environment, while free catalase lost its activity within 1 h. CONCLUSION: Catalase can indeed be loaded in tripalmitin based SLN using SPC as solubilizers and stabilizing agents, which protected it against proteolysis, suggesting the potential application of SPC in delivery and protection of functional food enzyme. PMID- 22101977 TI - Toxic effects of pentachlorophenol, azinphos-methyl and chlorpyrifos on the development of Paracentrotus lividus embryos. AB - The application of many current-use pesticides has increased after the disuse of persistent, bioaccumulative or toxic ones as DDT or chlordane. Many of the used pesticides are considered less dangerous towards the environment for their physico-chemical properties. This study investigated the toxic effects of three current-use pesticides, pentachlorophenol (PCP), azinphos-methyl (AZM), and chlorpyrifos, on Mediterranean sea urchin Paracentrotus lividus early development and offspring quality. The experimental results showed that the most toxic pesticides were PCP and AZM at EC50 level. Nevertheless at low concentration PCP resulted the less toxic compound and showed EC1 value more protective than NOEC. PCP at high concentration seemed to modify cytoskeleton assembly, while at low concentrations, it could alter the deposition of the larval skeleton. OPs at low concentrations until 300 MUg/l showed a similar toxicological behaviour with a trend corresponding to the pesticide concentrations. At high concentration (500 MUg/l) the effect mainly observed was the embryos pre-larval arrest. This investigation highlighted the relevance to evaluate, in coastal seawaters, the levels of the used pesticides to understand the real impact on benthic populations mainly in sites characterized by intensive agriculture or floriculture activities, such as the coastal areas of the Mediterranean Sea. PMID- 22101978 TI - Effect of nutrient density on production performance, egg quality and humoral immune response of brown laying (Dahlem Red) hens in the tropics. AB - A study was conducted to evaluate the effect of various concentrations of metabolizable energy (ME) with graded incremental levels of crude protein (CP) and essential amino acids (lysine and methionine) on production performance, egg quality and humoral immune response of Dahlem Red laying hens. Four experimental diets based on maize-soybean meal-deoiled rice bran were prepared. Diet 1 was fed as a control diet containing 2,600 kcal ME/kg, 15% CP, 0.75% Lys and 0.36% Met, and in the other three diets (D2, D3 and D4), concentrations of the above nutrients were increased by 2.5%, 5.0% and 7.5%, respectively. The levels of Ca (3.5%) and available P (0.32) were constant in all the diets. Each diet was offered ad libitum from 28 to 40 weeks of age to eight replicates containing six birds in each replicate. The egg production, egg weight and egg mass (in grams of egg per hen per day) were not affected by increasing the nutrient density up to 7.5% (2,795 kcal ME/kg diet) compared to the control group (2,600 ME/kg diet). However, feed consumption and feed efficiency (in grams of egg per gram of feed) were influenced by the variation in the nutrient density of diets. As the nutrient density increased by 5% (2,730 ME/kg diet), birds consumed significantly (P < 0.001) less feed. The birds in the 7.5% higher density group produced significantly (P < 0.05) higher egg mass per unit feed consumption compared to the control diet. Increasing nutrient density up to 7.5% had no effect on relative weight of albumen, yolk or shell. The Haugh unit, yolk colour and shell thickness were also not affected due to variation in the nutrient density. The humoral immune response measured at 34 and 40 weeks was progressively improved by increasing the nutrient density up to 5%. Increasing the nutrient density beyond 5% in the diet had no further influence on the humoral immune response. Based on the results of the present study, it can be concluded that Dahlem Red laying hens required 2,795 kcal/kg ME, 16% CP, 0.8% lysine and 0.4% methionine for eliciting optimum performance and immune response during 28 to 40 weeks of age. PMID- 22101979 TI - Responses to graded replacement of urea by maize steep liquor in diets for intensively fed lambs for meat production. AB - Urea is a common ingredient of the diets of intensively fed lambs, but is increasingly required for industrial processes. Maize steep liquor (MSL) is a by product of maize grain degradation to produce starch that may be a suitable replacement. Fifty growing lambs were fed on equinitrogenous diets in which between 0% and 80% of the urea was replaced by MSL; their growth and metabolism were recorded over 70 days. Increasing replacement of urea by MSL increased feed intake and nutrient digestibilities, leading to increased growth rates, more efficient feed conversion, and increased nitrogen retention. Concentrations of triiodothyroxin, thyroxin, glucose, and methionine were increased by replacement of urea by liquor, and plasma urea was reduced. This study suggests that MSL is a suitable replacement for up to 80% of urea in the diet of rapidly growing lambs. PMID- 22101980 TI - In sickness and in health: the widespread application of creatine supplementation. AB - There is an extensive and still growing body of the literature supporting the efficacy of creatine (Cr) supplementation. In sports, creatine has been recognized as the most effective nutritional supplement in enhancing exercise tolerance, muscle strength and lean body mass. From a clinical perspective, the application of Cr supplementation is indeed exciting. Evidences of benefits from this supplement have been reported in a broad range of diseases, including myopathies, neurodegenerative disorders, cancer, rheumatic diseases, and type 2 diabetes. In addition, after hundreds of published studies and millions of exposures creatine supplementation maintains an excellent safety profile. Thus, we contend that the widespread application of this supplement may benefit athletes, elderly people and various patient populations. In this narrative review, we aimed to summarize both the ergogenic and therapeutic effects of Cr supplementation. Furthermore, we reviewed the impact of Cr supplementation on kidney function. PMID- 22101981 TI - Carnosine protects neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. AB - Carnosine is a known protector of neuronal cells against oxidative injury which prevents both apoptotic and necrotic cellular death. It was shown earlier that carnosine serves as an intracellular buffer of free radicals. Using the model of ligand-dependent oxidative stress in neurons, we have shown that homocysteine (HC) initiates long-term activation of extracellular signal regulated kinase, isoforms 1 and 2 (ERK 1/2) and Jun N-terminal kinase (JNK) which corresponds to exitotoxic effect resulting in cellular death. L-carnosine (beta-alanyl-L histidine) protects neurons from both excitotoxic effect of homocysteine and cellular death. Its analogs, beta-alanyl-D-histidine (D-carnosine) and L-histidyl beta-alanine, restricted accumulation of free radicals and delayed activation of ERK1/2 and JNK in neuronal cells, but did not promote neuronal viability. PMID- 22101982 TI - Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated pentameric ion channels that account for the effects of nicotine. Recent genetic studies have highlighted the importance of variants of the CHRNA5/A3/B4 genomic cluster in human nicotine dependence. Among these genetic variants those found in non-coding segments of the cluster may contribute to the pathophysiology of tobacco use through alterations in the expression of these genes. To discern the in vivo effects of the cluster, we generated a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster using a bacterial artificial chromosome. Transgenic mice showed increased functional alpha3beta4-nAChRs in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine along with higher activation of the medial habenula and reduced activation of dopaminergic neurons in the ventral tegmental area after acute nicotine administration. Importantly, transgenic mice showed increased acquisition of nicotine self-administration (0.015 mg/kg per infusion) and a differential response in the progressive ratio test. Our study provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 genomic cluster in nicotine addiction through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug. PMID- 22101983 TI - Proliferation potential of human amniotic fluid stem cells differently responds to mercury and lead exposure. AB - There are considerable gaps in our knowledge on cell biological effects induced by the heavy metals mercury (Hg) and lead (Pb). In the present study we aimed to explore the effects of these toxicants on proliferation and cell size of primary human amniotic fluid stem (AFS) cells. Monoclonal human AFS cells were incubated with three dosages of Hg and Pb (single and combined treatment; ranging from physiological to cytotoxic concentrations) and the intracellular Hg and Pb concentrations were analyzed, respectively. At different days of incubation the effects of Hg and Pb on proliferation, cell size, apoptosis, and expression of cyclins and the cyclin-dependent kinase inhibitor p27 were investigated. Whereas we found Hg to trigger pronounced effects on proliferation of human AFS cells already at low concentrations, anti-proliferative effects of Pb could only be detected at high concentrations. Exposure to high dose of Hg induced pronounced downregulation of cyclin A confirming the anti-proliferative effects observed for Hg. Co-exposure to Hg and Pb did not cause additive effects on proliferation and size of AFS cells, and on cyclin A expression. Our here presented data provide evidence that the different toxicological effects of Pb and Hg on primary human stem cells are due to different intracellular accumulation levels of these two toxicants. These findings allow new insights into the functional consequences of Pb and Hg for mammalian stem cells and into the cell biological behavior of AFS cells in response to toxicants. PMID- 22101984 TI - Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes. AB - The proto-oncogenes Myc and Pim1, which are deregulated in many types of cancers, are known to cooperate in B lymphoma development. Here we show that overexpression of retrovirally transduced, doxycycline-inducible Myc alone in IL 7-deprived, growth-arrested pre-B cells enhanced cell cycle entry without impairing apoptosis. Overexpression of Pim1 decreased apoptosis, but had no effect on cell cycle entry. Co-expression of Pim1 and Myc inhibited apoptosis and led to IL-7-independent proliferation of the transduced pre-B cells in vitro, while blocking their differentiation to IgM(+) immature cells. Transplantation of Pim1/Myc overexpressing pre-BI cells into B-cell-deficient mice expanded the pre-B-cell compartments up to 100-fold within 4-8 weeks. Transformation remained dependent on the expression of both oncogenes, as removal of doxycycline in vitro and in vivo terminated proliferation and induced differentiation to IgM(+) B cells. In contrast, Pim1/Myc-transduced mature B cells that developed from the oncogene-transduced pre-BI cells in the absence of oncogene overexpression in vivo were not capable of long-term proliferation after induction of Pim and Myc overexpression, neither in vivo nor in vitro, neither with nor without stimulation by polyclonal activators. PMID- 22101985 TI - Liposuction and suspension of the orbicularis oculi for the correction of persistent malar bags: description of technique and report of a case. AB - BACKGROUND: The purpose of this study was to present an alternative surgical procedure for the correction of persistent malar bags and to review the literature. METHODS: A 45-year-old female patient with persistent malar bags, secondary to previous blepharoplasty, was admitted. Liposuction of the edema and suspension of the orbicularis muscle to the temporal region was performed through a lateral canthal incision. RESULTS: A successful malar bag removal was demonstrated, exhibiting stable results at the 6-month follow-up. CONCLUSION: Persistent malar bags resulting from previous blepharoplasty may be difficult to correct with conventional treatment. The combination of liposuction and suspension of the orbicularis oculi is proposed as an efficient alternative for the correction of persistent malar bags. PMID- 22101986 TI - Improving the longevity and results of mastopexy and breast reduction procedures: reconstructing an internal breast support system with biocompatible mesh to replace the supporting function of the ligamentous suspension. AB - BACKGROUND: The reasons for recurrent ptosis in mastopexy and breast reduction procedures are twofold. First, available surgical techniques do not reconstruct the normal breast anatomy responsible for maintaining breast shape. Second, in many instances the techniques rely on atrophied tissue to provide long-term support. The discovery in 1997 of the ligamentous suspension (the supporting system of the breast) gave rise to the concept that reconstruction of this anatomical structure was needed to ensure a sustained postoperative result. Applying the latest knowledge regarding the structural and vascular anatomy of the breast in the surgical technique and utilizing material other than atrophied breast tissue enabled us to prevent the recurrence of breast ptosis. METHODS: A surgical technique was developed to replace the supportive function of a failed ligamentous suspension in 112 patients with ptotic breasts. This was done by reconstructing an internal breast-supporting system (IBSS) with biocompatible mesh. RESULTS: Satisfactory breast shape, nipple projection, and upper breast fullness was obtained with this technique in mastopexy patients with moderate sized ptotic breasts. In patients with larger breasts good results were obtained with a simultaneous breast reduction. The longest follow-up is 6 years 3 months. CONCLUSIONS: With this technique recurrent breast ptosis can be prevented in mastopexy and breast reduction procedures. The results are such that it eliminates the need for silicone prostheses to obtain satisfactory upper-breast fullness. The surgical technique is especially indicated in patients with skin of poor quality or patients with high expectations. PMID- 22101987 TI - Anteriorly pedicled retroauricular flap for repair of auricular defects. AB - The reconstruction of the auricle is aesthetically very demanding. Various techniques have been used depending on the defect size, the defect location, and tissue involved. For better wound control and result predictability, we developed an anteriorly pedicled retroauricular flap. We used this modified double-full thickness skin graft in three patients. This anteriorly pedicled flap provides a visible wound surface which makes wound dressing easy. The aesthetic outcome is good and predictable. No major complications were encountered during surgery or the healing phase. All patients were satisfied with the outcome. The described method offers a good option for reconstructing larger auricular defects with local tissue. PMID- 22101988 TI - Bodies and other visual objects: the dialectics of reaching toward objects. AB - Participants viewed video clips of a left or right-handed reach toward an object that was orientated with a handle to the left or right. They were required to classify the object by making a left or right-handed key-press and ignore the reach. These responses were, never-the-less, affected by the observed reach in ways which largely reflected the opportunities for complementary actions in the viewed scenes, given the simultaneous constraints of the object orientation combined with the direction and hand of reach. These influences are claimed to reflect the interdependency of the action possibilities that arise from a set of objects and agents in three-dimensional space that together determine behaviour. PMID- 22101989 TI - Therapeutics in food allergy: the current state of the art. AB - Food allergy is an increasing public health dilemma in Westernized countries, yet no viable treatments are currently available for those who are afflicted. The only options available for patients with food allergies are prevention of reactions by strict avoidance of the offending food(s) and symptomatic treatment of any adverse effects from accidental exposures. Approaches are being pursued to develop treatments, and allergen-specific therapies such as oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy with different foods have shown promise. Other modalities are also being investigated, potentially leading to the discovery of novel therapeutic options. PMID- 22101990 TI - Auditory thalamic reticular nucleus of the rat: anatomical nodes for modulation of auditory and cross-modal sensory processing in the loop connectivity between the cortex and thalamus. AB - The auditory sector of the thalamic reticular nucleus (TRN) plays a pivotal role in gain and/or gate control of auditory input relayed from the thalamus to cortex. The TRN is also likely involved in cross-modal sensory processing for attentional gating function. In the present study, we anatomically examined how cortical and thalamic afferents intersect in the auditory TRN with regard to these two functional pathways. Iontophoretic injections of biocytin into subregions of the auditory TRN, which were made with the guidance of electrophysiological recording of auditory response, resulted in retrograde labeling of cortical and thalamic cells, indicating the sources of afferents to the TRN. Cortical afferents from area Te1 (temporal cortex, area 1), which contains the primary and anterior auditory fields, topographically intersected thalamic afferents from the ventral division of the medial geniculate nucleus at the subregions of the auditory TRN, suggesting tonotopically organized convergence of afferents, although they innervated a given small part of the TRN from large parts. In the caudodorsal and rostroventral parts of the auditory TRN, cortical afferents from nonprimary visual and somatosensory areas intersected thalamic afferents from auditory, visual, and somatosensory nuclei. Furthermore, afferents from the caudal insular cortex and the parvicellular part of the ventral posterior thalamic nucleus, which are associated with visceral processing, converged to the rostroventral end of the auditory TRN. The results suggest that the auditory TRN consists of anatomical nodes that mediate tonotopic and/or cross-modal modulation of auditory and other sensory processing in the loop connectivity between the cortex and thalamus. PMID- 22101991 TI - Lichen planus in childhood showing various cutaneous features. PMID- 22101992 TI - Ultrasound-based markers of carotid atherosclerosis correlate well with the number of classical atherosclerotic risk factors. AB - BACKGROUND AND PURPOSE: Ultrasound-based indicators such as mean or maximal carotid intima-media thickness (CIMT) and cross-sectional plaque area (C-SPA) have been shown to be measurable indices of atherosclerosis. We investigated whether those indicators correlated with the number of atherosclerotic risk factors assessed in routine clinical practice. MATERIALS AND METHODS: The study involved a group of 150 patients (median age, 65 years). High-resolution ultrasound was used to assess CIMT and C-SPA of their common and internal carotid arteries. The number of risk factors derived from clinical examination (e.g., hypertension, diabetes, smoking), haematological test, acute phase proteins, serum lipoproteins, homocysteine, and body mass index was assessed. RESULTS: Plaques occurred in 85 patients (57% of participants). The median plaque area was 21 mm2 (10.7-46.5 mm2), and the mean CIMT was 0.88 mm (standard deviation, 0.28 mm). The study found significant associations among most of the single as well as the total number of risk factors and mean and maximal CIMT and C-SPA. The differences among the groups of patients with different numbers of risk factors were more evident in terms of the maximal and mean CIMT than in the case of C SPA. Assessment of C-SPA could be statistically underpowered because only 57% of the investigated subjects had plaques in their carotid arteries. CONCLUSIONS: We found a significant correlation between the total number of atherosclerosis risk factors and carotid atherosclerosis as measured by ultrasonography. Along with an increase of the number of risk factors, a gradual increase of CIMT and C-SPA was observed. PMID- 22101993 TI - The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly. AB - BACKGROUND AND PURPOSE: Impaired glucose tolerance and overt diabetes mellitus are frequently associated with acro-megaly. The aim of this study was to find out whether these alterations could be reversed after transsphenoidal surgery. MATERIAL AND METHODS: Two hundred and thirty-nine acromegalic patients were studied before and 6-12 months after transsphenoidal surgery. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient, glucose and insulin concentrations were assessed during the 75 gamma oral glucose tolerance test (OGTT). To estimate insulin resistance, we used homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). RESULTS: At the moment of diagnosis, diabetes mellitus was present in 25% of the acromegalic patients. After surgery, the pre-valence of diabetes mellitus normalized to the level present in the general Polish population. We found a statistically significant reduction after surgery in plasma glucose levels both fasting (89.45 +/- 13.92 mg/dL vs. 99.12 +/- 17.33 mg/dL, p < 0.001) and during OGTT. Similarly, a prominent reduction in insulin secretion was found after surgery compared to the moment of diagnosis (15.44 +/- 8.80 mIU/mL vs. 23.40 +/- 10.24 mIU/mL, p < 0.001). After transsphenoidal surgery, there was a significant reduction in HOMA-IR (3.08 vs. 6.76, p < 0.0001) and a significant increase in QUICKI (0.32 vs. 0.29, p < 0.001). There were no statistically significant differences after surgery in fasting glucose and insulin levels between patients with controlled and in-adequately controlled disease. CONCLUSIONS: We conclude that in acromegalic patients glucose homeostasis alterations and insulin sensitivity can be normalized after transsphenoidal surgery, even if strict biochemical cure criteria are not fulfilled. PMID- 22101994 TI - Syncope and autonomic cardiovascular dysfunction in Parkinson disease. AB - BACKGROUND AND PURPOSE: The aim of the study was to investigate the relationship between syncope or presyncope occurrence and dysfunction of the cardiovascular autonomic system in patients with Parkinson disease (PD). MATERIAL AND METHODS: Twenty-four PD patients were studied, including 10 subjects with syncope/presyncope and 14 con-trols without those symptoms. Ambulatory blood pressure monitoring (ABPM), Holter electrocardiographic monitoring, carotid sinus massage, tilt test, and cardiac scintigraphy with 123I metaiodobenzylguanidine (MIBG) were performed. RESULTS: Differences between the two groups were found in myocardial scintigraphy and ABPM. The stepwise regression analyses suggest that the values of late phase reduced uptake of MIBG (95% CI: 0.0-0.77; p < 0.05) and day-time minimum systolic blood pressure (95% CI: 0.78-0.98; p = 0.007) may be related to the occurrence of syncope/presyncope. CONCLUSIONS: The findings suggest an association between syncope/presyncope occurrence and dysfunction of the cardiovascular autonomic system in PD patients. Both 123I MIBG myocardial scintigraphy and ABPM may help identify a group of patients with an elevated risk for syncopic episodes which, in turn, may affect the choice of treatment. PMID- 22101995 TI - Mucocoele and mucopyocoele of the frontal sinus penetrating to the cranial cavity and the orbit. AB - BACKGROUND AND PURPOSE: Mucocoele of the paranasal sinuses falls within the scope of interest for neurosurgery when erosion of the sinus wall and the osseous structures of the skull base develops and the lesion extends towards the cranial cavity, the orbit, the cavernous sinus or the sella turcica. The pa-per aims to present the method of treatment of extensive mucocoele which is used in our clinic. MATERIAL AND METHODS: We treated 7 patients (2 women and 5 men; age range: 27-68 years). Mucopyocoele was diagnosed in two cases, and mucocoele in the other five. In 5 cases, extension of the mucocoele to the cranial cavity and the orbit or to the ethmoid sinus and the orbit was observed. In the remaining 2 cases, mucopyocoele extended to the ethmoid sinus, the sphenoid and maxillary sinuses, cranial cavity and the orbit. The purpose of surgery was to remove the mucocoele or the mucopyocoele and to prevent recurrence. RESULTS: The postoperative course in all 7 patients was uneventful. All symptoms gradually receded. No relapse was observed in any patient during a follow-up period that varied from 10 months to 8 years; nor did incidents of inflammation of collateral sinuses occur. CONCLUSIONS: The treatment of mucocoele or mucopyocoele of the frontal sinus penetrating to the cranial cavity and the orbit consists of the following stages: cranialization of the frontal sinus, complete resection of the mucosa, tight closing of the frontal-nasal duct, and separating the air space of the opened collateral nasal sinuses from the cranial cavity with a large pedicled periosteal flap. PMID- 22101996 TI - Surgical treatment of insular tumours with tractography, functional magnetic resonance imaging, transcranial electrical stimulation and direct subcortical stimulation support. AB - BACKGROUND AND PURPOSE: Surgical treatment of insular tumours carries significant risks of limb paresis or speech disturbances due to their localization. The development of intraoperative neuromonitoring techniques that involve evoked motor potentials induced via both direct and transcranial cortical electrical stimulation as well as direct subcortical white matter stimulation, intraoperative application of preoperative tractography and functional magnetic resonance imaging (fMRI) in conjunction with neuronavigation resulted in significant reduction of postoperative disabilities that enabled widening of indications for surgical treatment. The aim of this study was to present the authors' own experience with surgical treatment of insular gliomas. MATERIAL AND METHODS: Our cohort comprises 30 patients with insular gliomas treated at the Department of Neurosurgery in Sosnowiec. Clinical symptoms included sensorimotor partial seizures in 86.6%; generalized seizures in 23.3%; persistent headaches in 16.6% and hemiparesis in 6.6%. All the patients were operated on with intraoperative neuromonitoring that included transcranial cortical stimulation, direct subcortical white matter stimulation as well as tractography and fMRI concurrently with neuronavigation. The analysis in-cluded postoperative neurological evaluation along with the assessment of the radicalism of resection evaluated based on postoperative MRI. RESULTS: Postoperatively, four patients had permanent hemiparesis (13.3%); importantly, two out of those patients had preoperative deficits (6.6%). Persistent speech disturbances were present in four patients (13.3%). Partial sensorimotor seizures were noted in two patients (6.6%). Seizures in the other patients receded. Intraoperative transcranial electrical stimulation as well as direct subcortical white matter stimulation along with tractography (DTI) and fMRI facilitated gross total resection of insular gliomas in 53.5%, subtotal in 13.3% and partial resection in 33.1%. CONCLUSIONS: Implementation of TES, direct subcortical white master stimulation, DTI and fMRI into the management protocol of the surgical treatment of insular tumours resulted in total and subtotal resections in 66% of cases with permanent motor disability in 6.6% of patients. Poor prognosis for independent living after surgery mainly affects patients with WHO grade III or IV. PMID- 22101997 TI - A volumetric magnetic resonance imaging study of brain structures in children with Down syndrome. AB - BACKGROUND AND PURPOSE: Down syndrome (DS) is the most common genetic cause of mental retardation with deficits in language and memory. Mental retardation of varying degrees is the most consistent feature of DS. The objective of this study was to use high-resolution magnetic resonance imaging (MRI) techniques to investigate the volumes of the hippocampus, amygdala, and temporal and frontal lobes in children with DS compared with healthy children. MATERIAL AND METHODS: MRI of 49 patients was reviewed prospectively. The study included 23 children with DS (9 girls and 14 boys, mean age 6.7 +/- 3.7 years) and 26 healthy children (11 girls and 15 boys, mean age 8.3 +/- 2.4 years). Volumes of the right and left hippocampus, the right and left amygdala, temporal and frontal lobes and the total brain volume were measured by a radiologist who was unaware of the diagnosis. RESULTS: Total brain volume in children with DS was significantly lower compared with controls. It was associated with significantly lower volume of the frontal and temporal lobes. Children with DS had a significantly smaller right and left hippocampus volume and a significantly smaller right and left amygdala volume than did the control group. We also found a negative correlation between mental retardation and volume of the right hippocampus. CONCLUSIONS: The presence of these abnormalities from an early age contributes to the specific cognitive and developmental deficits seen in children with DS. PMID- 22101998 TI - Dietary treatment of epilepsy: rebirth of an ancient treatment. AB - Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy. PMID- 22101999 TI - Pleomorphic xanthoastrocytoma - a clinico-pathological review. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare primary brain tumour which occurs in children and young adults. PXA is designated as low-grade astrocytoma (WHO II), although an anaplastic variant and malignant potential have been described. Pathologically, cellular pleomorphism is the rule and includes spindle cells, mononucleated and multinucleated giant cells, and granular bodies in a reticulin rich background with few mitoses; necrosis is usually absent. The tumour cells stain positive for glial fibrillary acidic protein (GFAP). Surgery is the mainstay of treatment with gross surgical resection being accomplished due to its well-circumscribed nature and peripheral location. The role of adjuvant treatment remains yet to be clearly defined. To date, the majority of PXAs have been reported as single or small case series; consequently data of this rare brain tumour are fragmentary. The present paper reviews the pathogenesis, neuroradiological features, prognostic factors and treatment options for PXA. PMID- 22102000 TI - Primary solitary hydatid cyst in paraspinal cervical muscles: a case report and review of the literature. AB - Hydatid disease caused by Echinococcus granulosus and Echinococcus multilocularis commonly presents with pulmonary and hepatic cysts. Primary paraspinal muscle cysts are a rare presentation. We report a case of hydatid cyst within paraspinal muscles presenting with cervical mass and associated pain. The hydatid disease serological test was negative. Neither hepatic nor pulmonary cystic lesions were found. Radiographic findings were unspecific for hydatid cysts. Surgical resection was planned due to the provisional diagnosis of muscular cystic neoplasm. During surgery, a cyst containing a clear liquid was found. The cyst wall was excised and the surgical field was irrigated with hypertonic saline. The patient's symptoms resolved by discharge day. Postoperative pathological examinations revealed a muscular hydatid cyst. PMID- 22102001 TI - [Familial occurrence of FXTAS caused by premutation in the FMR1 gene]. AB - The FMR1 gene premutation has recently been reported to be associated with a neurodegenerative syndrome, characterized by intention tremor, gait ataxia and cognition deficits in persons older than 50 years. We present a 74-year-old man with very severe intention tremor, slight postural tremor and gait ataxia. The molecular analysis revealed that he was a carrier of 91 CGG repeats in the FMR1 gene. His sister (68 years old), with head tremor, was found to be a carrier of 81 CGG repeats, while his younger brother, also with slight head and postural tremor, was a carrier of 98 CGG repeats. Molecular analysis of the proband's asymptomatic daughter revealed an expansion over 120 CGG. Her daughter, with mild intellectual disability, was a carrier of a full mutation. Thus, in the presented family with heterogeneous clinical presentation we found 4 premutations and one full mutation in the FMR1 gene. PMID- 22102002 TI - Primary intradural extramedullary ependymoma: report of two cases and review of the literature. AB - Primary intradural extramedullary ependymomas are very rare. They are called primary in this location as they do not have any connection with the central nervous system. They usually develop from an ectopic ependymal cell nest. To the best of our knowledge, only 10 cases have been described in the literature. We report two cases of large sausage-shaped intradural extramedullary ependymoma in the lumbosacral area. PMID- 22102003 TI - Fatal outcome of tick-borne encephalitis - a case series. AB - Tick-borne encephalitis (TBE) is a disease which may present as meningitis, encephalomeningitis and myeloencephalomeningitis. The course of the disease is usually mild although it may result in the patient's death in 1-4% of cases. Patients with myeloencephalomeningitis are the most endangered group, but also encephalomeningitis may have a fatal outcome. There are many risk factors which influence the severity of TBE, including patient's age, immunosuppression and concomitant diseases. We present four cases of patients who died because of TBE. The aim of the paper was to underline that in elderly patients or patients suffering from chronic diseases and additional infections, special attention should be paid to their treatment, including mechanical ventilation and steroid use. PMID- 22102004 TI - Cellular aging and senescence characteristics of human T-lymphocytes. AB - CD28-, CD57+ and KLRG1+ are cell surface markers that have been used to describe senescent T-lymphocytes in humans. However, the relationship among these phenotypes during aging, and their relationship with the concept of in vitro cellular aging have not been well established. Using five-colour flow cytometry, we analyzed peripheral blood T-lymphocytes for their expression of CD28, CD57 and KLRG1 in 11 young (Y) and 11 old (O) apparently healthy human subjects. The proportions of CD28- and CD57+ cells were significantly higher among the T-cell populations of O compared to Y subjects; the proportion of KLRG1+ cells was significantly higher only among CD8+ cells. Populations that were more frequent in the elderly participants were characterised as CD28+ CD57+, CD28- CD57+ or CD28- CD57-. The expression of p16 and p21, considered as markers for in vitro senescence, was higher in CD28+ CD57+ cells than in other subpopulations in both age groups. The expression of p21 was age-related, which was not the case for p16. Thus, although both p16 and p21 are involved in T-cell senescence, they appear to behave differently. CMV infection and shifts in subpopulations are unlikely as explanations of the observed differences. Their higher levels of p16 and p21 expression, coupled with their higher prevalence in the elderly participants make CD28+ CD57+ cells the subpopulation of T-cells most closely corresponding to the concept of senescent cells. PMID- 22102005 TI - Heterogeneity and dynamics of lateral line afferent innervation during development in zebrafish (Danio rerio). AB - The lateral line system of larval zebrafish is emerging as a model to study a range of topics in neurobiology, from hair cell regeneration to sensory processing. However, despite numerous studies detailing the patterning and development of lateral line neuromasts, little is known about the organization of their connections to afferent neurons and targets in the hindbrain. We found that as fish grow and neuromasts proliferate over the body surface, the number of afferent neurons increases linearly. The number of afferents innervating certain neuromasts increases over time, while it decreases for other neuromasts. The ratio of afferent neurons to neuromasts differs between the anterior and posterior lateral line system, suggesting potential differences in sensitivity threshold or spatial resolution. A single afferent neuron routinely contacts a group of neuromasts, suggesting that different afferent neurons can convey information about receptive fields along the body. When afferent projections are traced into the hindbrain, where a distinct somatotopy has been previously described, we find that this general organization is absent at the Mauthner cell. We speculate that directional input from the lateral line is less important at an early age, whereas the speed of the escape response is paramount, and that directional responses arise later in development. By quantifying morphological connections in the lateral line system, this study provides a detailed foundation to understand how hydrodynamic information is processed and ultimately translated into appropriate motor behaviors. PMID- 22102006 TI - Prognostic value of raf kinase inhibitor protein in esophageal squamous cell carcinoma. AB - Raf kinase inhibitory protein (RKIP, also PEBP1) is involved in regulation of multiple cellular signaling processes and suppressing metastasis in animal models. Downregulation of RKIP expression has been shown to promote tumor progression in a variety of human cancers. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) is still scanty. The purpose of this study was to investigate the prognostic significance of RKIP expression by immunohistochemistry in a group of patients with ESCC treated with surgical resection. RKIP expression in 233 surgically resected ESCC specimens and 49 cases of adjacent normal tissues was detected by using immunohistochemical staining. The clinical and prognostic significance of RKIP expression was statistically analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. Significant downregulation was noted for RKIP protein in ESCCs, compared to adjacent normal tissues (p < 0.001). A lower disease-free survival and overall survival of ESCC was found in patients whose tissues had low RKIP expression (both P < 0.001). In addition, RKIP expression could stratify the patient survival (disease-free survival/overall survival) in stage II (P = 0.01 and 0.02, repectively). The Cox proportionate hazard regression model also established that low expression of RKIP was significantly correlated with increased risk (RR = 3.572) of recurrence compared with high RKIP expression (P < 0.001). Furthermore, the results of multivariate analysis suggested that RKIP expression (P < 0.001) was an independent factor that affected overall survival. These findings suggest that the low expression of RKIP be associated with poor survival in resectable ESCC patients. PMID- 22102007 TI - Prevalence and distribution profiles of Candida parapsilosis, Candida orthopsilosis and Candida metapsilosis responsible for superficial candidiasis in a Chinese university hospital. AB - The Candida parapsilosis complex consists of C. parapsilosis sensu stricto, C. orthopsilosis and C. metapsilosis. Recently, many studies described the prevalence of this species complex mainly in invasive candidiasis. Additionally, data showed that these three species are different in virulence and in vitro drug susceptibility. However, to our knowledge, the prevalence and distribution of the species complex in superficial candidiasis is not very clear to date. In this study, 2,128 Candida isolates from specimens of superficial candidiasis were collected over a 1-year period. Combination of routine and molecular tools, a total of 214 samples were identified to be positive for the C. parapsilosis complex (10.1%), of which 198 (92.5%) were monofungal and 16 (7.5%) were polyfungal. Among the 198 monofungal isolates, 191 (96.5%) were identified as C. parapsilosis sensu stricto, 5 (2.5%) as C. metapsilosis, and 2 (1.0%) as C. orthopsilosis species based on the molecular method. All C. parapsilosis complex isolates from the 16 polyfungal populations were found to be C. parapsilosis sensu stricto. Further analysis showed that the distribution profiles of the C. parapsilosis complex in adult patients were different from that in pediatric patients, and the prevalence rate of it varied greatly by sites of isolation. This study provides insight into the epidemiology of the species complex in superficial candidiasis. PMID- 22102008 TI - Exploitation of detergent thermodynamics in the direct solubilization of myelin membrane proteins for two-dimensional gel electrophoresis for proteomic analysis. AB - Performing 2-DE of lipid-rich multilamellar membranes like myelin is a cumbersome task. However, for understanding its molecular organization and changes during diseases, identification of proteins of myelin is essential. Although the 2-D proteomic approach of myelin has been employed to understand the myelin proteome, representation of myelin proteins in its entirety is still a challenge. 2-DE profiling of myelin proteins is very important for the detection of immuno reactivity to myelin proteins from various biological fluids following Western blotting in diseases like multiple sclerosis. Here we developed a novel approach by exploiting the thermodynamic principles behind detergent-mediated solubilization of myelin membranes without any conventional processing of myelin involving precipitation of myelin proteins. We show that the addition of myelin to ASB-14-4 resulted in significant increase in protein representation of myelin in 2-DE compared with the addition of ASB-14-4 to myelin. Moreover, the number and resolution of spots are significantly higher in myelin to ASB-14-4 strategy than other strategies of myelin sample processing such as ASB-14-4 to myelin or ethanol or acetone or methanol-ammonium acetate precipitation of myelin proteins. In addition, the step involves no precipitation that selective removal of any proteins as a result of precipitation is nil and a qualitative representation of myelin proteins in a 2-D gel is achieved. PMID- 22102009 TI - Revision ACL reconstruction: influence of a lateral tenodesis. AB - PURPOSE: The aims of this article were to report the objective results of revision ACL reconstruction and to assess the influence of an associated lateral extra-articular tenodesis on knee stability and IKDC score. METHODS: This study focused on revision ACL reconstruction and was conducted over a 10-year period, from 1994 to 2003 with ten French orthopedic centers participating. The minimum follow-up required was 2 years. To be included, patients had to be evaluated at follow-up with the objective International Knee Documenting Committee (IKDC) scoring system. In 2006, 163 patients met the inclusion criteria. RESULTS: The objective IKDC knee score improved significantly after revision ACL reconstruction, with 72% IKDC A + B (26% A). When a lateral tenodesis was performed, 80% had a negative pivot shift, versus 63% without (P = 0.03), but there was no significant difference in the IKDC score. CONCLUSION: This study shows a significant improvement in the IKDC score after revision ACL reconstruction. The association of a lateral extra-articular tenodesis with the intra-articular graft increases knee stability after revision ACL reconstruction; however, this additional procedure does not significantly alter the IKDC score at follow-up. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 22102010 TI - Minimally invasive Unicondylar Knee Arthroplasty in a patellectomized patient. AB - Patellectomized patients may have less satisfactory clinical outcomes following total knee arthroplasty due to a decreased extensor mechanism efficiency and potential instability. The literature only reports 3 case series of patients who had a previous patellectomy undergoing a Unicondylar Knee Arthroplasty (UKA) with mixed results. A Minimally Invasive fixed-bearing UKA was performed in a patellectomized patient with excellent postoperative knee stability and clinical outcomes after 5 years. MIS UKA may be a viable option for patellectomized patients with isolated medial compartment osteoarthritis and no preoperative extensor deficiency or instability. Level of evidence IV. PMID- 22102011 TI - The PlantLIBRA project: how we intend to innovate the science of botanicals. AB - The main aim of the EC-financed R&D project PlantLIBRA (PLANT food supplements: Levels of Intake, Benefit and Risk Assessment) is to foster the safe use of food supplements containing plants or botanical preparations, by enabling science based decision making by regulators and stakeholders. To make informed decisions, competent authorities and industry need more accessible and quality-assured information, as well as better tools (e.g., databases) and procedures for safety and benefit assessments, supported by broadly accepted methodologies. Consequently, PlantLIBRA is working to develop, validate and disseminate data and methodologies for risk and benefit assessment of plant food supplements, and to implement sustainable international cooperation. International cooperation will help ensure the quality of botanicals imported in the EU. Moreover, the project will provide data on intake by conducting a harmonized consumption survey. Existing composition and safety data will be collated into a meta-database. New analytical data and methods will be investigated and validated. The consortium is working closely with competent authorities and stakeholders. PMID- 22102012 TI - Impacts of salinity and fish-exuded kairomone on the survival and macromolecular profile of Daphnia pulex. AB - Global warming is already causing salinization of freshwater ecosystems located in semi-arid regions, including Turkey. Daphnids, which are important grazers on phytoplankton and a major food source for fish and invertebrates, are sensitive to not only changes in salinity levels, but also presence of predators. In this study, the interactive effect of salinity toxicity (abiotic factor) with predation pressure mimicked by the fish-exuded kairomone (biotic factor) and the effect of salt acclimation on daphnids were investigated. Impacts of these stressors on daphnid survival, life history and molecular profile were observed. The presence of the kairomone antagonistically alters the effect of salinity, as observed from the 24- and 48-h LC(50) values and survival results. Molecular findings provided solid evidence to this antagonism at even lower salt concentrations, for which antagonism was not evident with organismal data. Fish predation counterbalances the negative effect of salinity in terms of reserve energy density. Therefore, it is important to investigate multiple stressor effects in ecotoxicological bioassays complemented with molecular techniques. The single effect of increasing salinity resulted in increased mortality, decreased fecundity, and slower somatic growth in Daphnia, despite their acclimation to salinity. This insignificance of acclimation indicates that Daphnia do not have any physiological mechanisms to buffer the adverse effects of salinity, making it a very crucial factor. Salinity-induced reduction in population growth rate of freshwater keystone species Daphnia-despite acclimation-indicates that global warming-induced salinity may cascade through the food web and lead to dramatic environmental consequences in the structure of lake ecosystems. PMID- 22102013 TI - Physiological age at harvest regulates the variability in postharvest ripening, sensory and nutritional characteristics of mango (Mangifera indica L.) cv. Coghshall due to growing conditions. AB - BACKGROUND: Climacteric fruits are harvested at the green-mature stage and ripen during their marketing cycle. However, growing conditions induce variability into the maturity stage of mangoes at harvest, with an impact on their final quality. Assuming that the physiological age can be correctly evaluated by a criterion based on the variable chlorophyll fluorescence of the skin (F(v)) and that differences in physiological age depend on growing conditions, controlled stress experiments were carried out on mango fruit by manipulating either the leaf/fruit ratio or the light environment. RESULTS: Delays from 9 to 30 days were observed, depending on stress level and harvest stage, to obtain the same F(v) value. For moderate stress, fruit composition after ripening was partially compensated for, with little or no difference in sugar, dry matter, carotenoid and aroma contents. For more pronounced stress, the major metabolites were not particularly affected, but the synthesis capacity of carotenoids and aromas was lower after maturity. CONCLUSION: The ripening ability of a fruit is acquired on the tree and defines its postharvest changes. Control of the physiological age at harvest can minimise the variability observed under natural conditions and guarantee fruit batches whose postharvest changes will be relatively homogeneous. PMID- 22102014 TI - Rapid immunofiltration assay based on colloidal gold-protein G conjugate as an alternative screening test for bovine and ovine brucellosis. AB - A non-enzymatic rapid immunofiltration assay (NERIFA) was developed as an alternative field test for rapid detection of anti-Brucella antibody in bovine and ovine sera. The assay was based on Brucella abortus lipopolysaccharide as diagnostic antigen and colloidal gold particle-protein G conjugate as detection reagent. Its diagnostic performance was evaluated using undiluted well-defined positive and negative serum samples in comparison with Rose Bengal test (RBT), complement fixation test (CFT) and a commercial and an in-house indirect enzyme linked immunosorbent assay (ELISA). A perfect test agreement was found between NERIFA and ELISAs by kappa statistics. In addition, McNemar's analysis of the results showed that the RBT for bovine sera and the CFT for ovine sera were found significantly less performant than indirect ELISAs and NERIFA. The results of the present study indicated that the NERIFA could be considered as a simple, rapid, and accurate field test for screening of ovine and bovine brucellosis. Therefore, this test constitutes a high potential to be used as an alternative model particularly in brucellosis prevalent tropical and subtropical geographical areas. PMID- 22102015 TI - Seasonal prevalence of coccidiosis in industrial broiler chickens in Faisalabad, Punjab, Pakistan. AB - The present paper reports the prevalence of coccidiosis in industrial broiler chickens in Faisalabad, Punjab, Pakistan to determine the occurrence of different species of Eimeria in the area and to assess their correlation with the environmental conditions including temperature, humidity and rainfall. The study was conducted from January 2009 to December 2010. Examination of chicken guts revealed 43.89% (n = 3,283/7,480) prevalence of coccidiosis. The highest prevalence (27.04%) was recorded of Eimeria tenella followed by Eimeria maxima (22.42%), Eimeria acervulina (19.89%) and Eimeria necatrix (4.02%). The prevalence of disease was significantly higher (P < 0.05) in autumn (60.02 +/- 4.38) followed by summer (47.42 +/- 2.92), spring (36.92 +/- 2.27) and winter (29.89 +/- 3.43). Likewise, prevalence of different species of Eimeria also varied (P < 0.05) in different seasons of the year except that of E. necatrix. A strong correlation (P < 0.05) of environmental conditions with the overall and species-wise prevalence of coccidiosis was recorded except E. necatrix. PMID- 22102016 TI - Anti-babesial activity of a potent peptide fragment derived from longicin of Haemaphysalis longicornis. AB - Babesiosis is one of the most important tick-borne diseases affecting livestock that can cause major economic losses worldwide particularly in the tropics. Control relies on controlling both the protozoan parasite and the tick vector. Antiprotozoal drugs are most commonly used for treatment, but problems on emergence of resistant strains and food residues are encountered. Longicin, a defensin-like peptide identified from the hard tick, Haemapysalis longicornis, as well as one of its synthetic partial analogs (P4), were previously reported to exert antimicrobial, fungicidal, and parasiticidal activity. Both longicin and P4 showed babesiacidal activity, in vitro and in vivo. Here, peptide fragments of P4 were studied for in vitro activity against bovine Babesia parasites. One of the peptide fragments, antimicrobial peptide 1 (AMP1), reduced the parasitemia of Babesia bigemina. No peptide had significant effect on Babesia bovis. The sequence of AMP1 corresponded to the longicin sequence which is associated with antiparasitic activity. Although AMP1 caused reduction in parasitemia of B. bigemina, the difference in morphology of the parasite compared with the control group was not statistically significant. However, the percentage occurrence of piroplasms decreased, whereas the abnormal pycnotic form increased. The results demonstrated that this shorter peptide retained the anti-babesial activity of the parent peptide, exerting an antiparasitic effect against a bovine Babesia species. Therefore, this short peptide can be considered for chemical synthesis as an alternative therapeutic agent for babesiosis. PMID- 22102017 TI - Publishing structural genomics results continued: the SSGCID special issue. PMID- 22102018 TI - Structure of New Delhi metallo-beta-lactamase 1 (NDM-1). AB - Antibiotic resistance in bacterial pathogens poses a serious threat to human health and the metallo-beta-lactamase (MBL) enzymes are responsible for much of this resistance. The recently identified New Delhi MBL 1 (NDM-1) is a novel member of this family that is capable of hydrolysing a wide variety of clinically important antibiotics. Here, the crystal structure of NDM-1 from Klebsiella pneumoniae is reported and its structure and active site are discussed in the context of other recently deposited coordinates of NDM-1. PMID- 22102019 TI - Antigen recognition by antibody C836 through adjustment of V(L)/V(H) packing. AB - C836 is a neutralizing monoclonal antibody to human interleukin IL-13 generated by mouse immunization. The crystal structure of the C836 Fab was determined at 2.5 A resolution and compared with the IL-13-bound form determined previously. This comparison indicates an induced-fit mechanism of antigen recognition through rigid-body rotation of the V(L) and V(H) domains. The magnitude of this rearrangement is one of the largest observed for antibody-protein interactions. PMID- 22102020 TI - ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase. AB - Human ATP-citrate lyase (EC 2.3.3.8) is the cytoplasmic enzyme that catalyzes the production of acetyl-CoA from citrate, CoA and ATP. The amino-terminal portion of the enzyme, containing residues 1-817, was crystallized in the presence of tartrate, ATP and magnesium ions. The crystals diffracted to 2.3 A resolution. The structure shows ADP-Mg(2+) bound to the domain that possesses the ATP-grasp fold. The structure demonstrates that this crystal form could be used to investigate the structures of complexes with inhibitors of ATP-citrate lyase that bind at either the citrate- or ATP-binding site. PMID- 22102021 TI - Structures of native and Fe-substituted SOD2 from Saccharomyces cerevisiae. AB - The manganese-specific superoxide dismutase SOD2 from the yeast Saccharomyces cerevisiae is a protein that resides in the mitochondrion and protects it against attack by superoxide radicals. However, a high iron concentration in the mitochondria results in iron misincorporation at the active site, with subsequent inactivation of SOD2. Here, the crystal structures of SOD2 bound with the native metal manganese and with the 'wrong' metal iron are presented at 2.05 and 1.79 A resolution, respectively. Structural comparison of the two structures shows no significant conformational alteration in the overall structure or in the active site upon binding the non-native metal iron. Moreover, residues Asp163 and Lys80 are proposed to potentially be responsible for the metal specificity of the Mn specific SOD. Additionally, the surface-potential distribution of SOD2 revealed a conserved positively charged electrostatic zone in the proximity of the active site that probably functions in the same way as in Cu/Zn-SODs by facilitating the diffusion of the superoxide anion to the metal ion. PMID- 22102022 TI - Structures of respiratory syncytial virus nucleocapsid protein from two crystal forms: details of potential packing interactions in the native helical form. AB - Respiratory syncytial virus (RSV) is a frequent cause of respiratory illness in infants, but there is currently no vaccine nor effective drug treatment against this virus. The RSV RNA genome is encapsidated and protected by a nucleocapsid protein; this RNA-nucleocapsid complex serves as a template for viral replication. Interest in the nucleocapsid protein has increased owing to its recent identification as the target site for novel anti-RSV compounds. The crystal structure of human respiratory syncytial virus nucleocapsid (HRSVN) was determined to 3.6 A resolution from two crystal forms belonging to space groups P2(1)2(1)2(1) and P1, with one and four decameric rings per asymmetric unit, respectively. In contrast to a previous structure of HRSVN, the addition of phosphoprotein was not required to obtain diffraction-quality crystals. The HRSVN structures reported here, although similar to the recently published structure, present different molecular packing which may have some biological implications. The positions of the monomers are slightly shifted in the decamer, confirming the adaptability of the ring structure. The details of the inter-ring contacts in one crystal form revealed here suggest a basis for helical packing and that the stabilization of native HRSVN is via mainly ionic interactions. PMID- 22102023 TI - Structure of PA4019, a putative aromatic acid decarboxylase from Pseudomonas aeruginosa. AB - The ubiX gene (PA4019) of Pseudomonas aeruginosa has been annotated as encoding a putative 3-octaprenyl-4-hydroxybenzoate decarboxylase from the ubiquinone biosynthesis pathway. Based on a transposon mutagenesis screen, this gene was also implicated as being essential for the survival of this organism. The crystal structure of recombinant UbiX determined to 1.5 A resolution showed that the protein belongs to the superfamily of homo-oligomeric flavine-containing cysteine decarboxylases. The enzyme assembles into a dodecamer with 23 point symmetry. The subunit displays a typical Rossmann fold and contains one FMN molecule bound at the interface between two subunits. PMID- 22102024 TI - Substrate binding of a GH5 endoglucanase from the ruminal fungus Piromyces rhizinflata. AB - The endoglucanase EglA from Piromyces rhizinflata found in cattle stomach belongs to the GH5 family of glycoside hydrolases. The crystal structure of the catalytic domain of EglA shows the (beta/alpha)(8)-barrel fold typical of GH5 enzymes. Adjacent to the active site of EglA, a loop containing a disulfide bond not found in other similar structures may participate in substrate binding. Because the active site was blocked by the N-terminal His tag of a neighbouring protein molecule in the crystal, enzyme-substrate complexes could not be obtained by soaking but were prepared by cocrystallization. The E154A mutant structure with a cellotriose bound to the -3, -2 and -1 subsites shows an extensive hydrogen bonding network between the enzyme and the substrate, along with a stacking interaction between Trp44 and the -3 sugar. A possible dimer was observed in the crystal structure, but retention of activity in the E242A mutant suggested that the enzyme probably does not function as a dimer in solution. On the other hand, the first 100 amino acids encoded by the original cDNA fragment are very similar to those in the last third of the (beta/alpha)(8)-barrel fold, indicating that EglA comprises at least two catalytic domains acting in tandem. PMID- 22102025 TI - Crystallization and preliminary X-ray diffraction studies of sortase A from Streptococcus pneumoniae. AB - Sortases are cell-membrane-anchored cysteine transpeptidases that are essential for the assembly and anchoring of cell-surface adhesins in Gram-positive bacteria. Thus, they play critical roles in virulence, infection and colonization by pathogens. Sortases have been classified into four types based on their primary sequence and the target-protein motifs that they recognize. All Gram positive bacteria express a class A housekeeping sortase (SrtA). Sortase A from Streptococcus pneumoniae (NP_358691) has been crystallized in two crystal forms. Diamond-shaped crystals of DeltaN(59)SrtA diffracted to 4.0 A resolution and belonged to a tetragonal system with unit-cell parameters a = b = 122.8, c = 86.5 A, alpha = beta = gamma = 90 degrees , while rod-shaped crystals of DeltaN(81)SrtA diffracted to 2.91 A resolution and belonged to the monoclinic space group P2(1) with unit-cell parameters a = 66.8, b = 103.47, c = 74.79 A, alpha = gamma = 90, beta = 115.65 degrees . The Matthews coefficient (V(M) = 2.77 A(3) Da(-1)) with ~56% solvent content suggested the presence of four molecules in the asymmetric unit for DeltaN(81)SrtA. Also, a multi-copy search using a monomer as a probe in the molecular-replacement method resulted in the successful location of four sortase molecules in the asymmetric unit, with statistics R = 41.61, R(free) = 46.44, correlation coefficient (CC) = 64.31, CC(free) = 57.67. PMID- 22102026 TI - Crystallization and preliminary X-ray crystallographic analysis of the hexameric human p97/VCP ND1 fragment in complex with the UBX domain of human FAF1. AB - The UBX domain of Fas-associated factor 1 (FAF1) binds to the N domain of p97/VCP, a multi-functional hexameric ATPase, and FAF1 thus inhibits the proteasome-mediated protein-degradation process assisted by p97/VCP. Here, crystallization of the hexameric p97/VCP ND1 fragment in complex with the FAF1 UBX domain is reported. Wild-type p97/VCP ND1 in complex with FAF1 UBX crystallized into very thin sheet-shaped crystals which turned out to be of poor diffraction quality. Therefore, in order to acquire a better diffraction-quality crystal, three mutants of p97/VCP ND1 were generated based on the surface-entropy reduction method. Of these, a triple mutant was the most successful in producing diffraction-quality crystals suitable for subsequent structural analysis. X-ray data were collected to 3.60 A resolution and the crystals belonged to space group I222, with unit-cell parameters a = 166.28, b = 170.04, c = 255.99 A. The Matthews coefficient and solvent content were estimated to be 5.78 A(3) Da(-1) and 78.72%, respectively. PMID- 22102027 TI - Expression, purification, crystallization and preliminary X-ray crystallographic studies of alkyl hydroperoxide reductase (AhpC) from the cyanobacterium Anabaena sp. PCC 7120. AB - Alkyl hydroperoxide reductase (AhpC) is a key component of a large family of thiol-specific antioxidant (TSA) proteins distributed among prokaryotes and eukaryotes. AhpC is involved in the detoxification of reactive oxygen species (ROS) and reactive sulfur species (RSS). Sequence analysis of AhpC from the cyanobacterium Anabaena sp. PCC 7120 shows that this protein belongs to the 1-Cys class of peroxiredoxins (Prxs). It has recently been reported that enhanced expression of this protein in Escherichia coli offers tolerance to multiple stresses such as heat, salt, copper, cadmium, pesticides and UV-B. However, the structural features and the mechanism behind this process remain unclear. To provide insights into its biochemical function, AhpC was expressed, purified and crystallized by the hanging-drop vapour-diffusion method. Diffraction data were collected to a maximum d-spacing of 2.5 A using synchrotron radiation. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 80, b = 102, c = 109.6 A. The structure of AhpC from Anabaena sp. PCC 7120 was determined by molecular-replacement methods using the human Prx enzyme hORF6 (PDB entry 1prx) as the template. PMID- 22102028 TI - Crystallization of the fimbrial protein FimP from Actinomyces oris and of a triple Ile-to-Met mutant engineered to facilitate selenomethionine labelling. AB - Actinomyces oris is an oral bacterium important for the development of dental plaque. It expresses two forms of fimbriae: type 1 and type 2. FimP, which is the fimbrial protein that is polymerized into the stalk of the type 1 fimbriae, was cloned, overexpressed and crystallized. X-ray data were collected and processed to 2.2 A resolution. The crystals belonged to space group P2(1)2(1)2, with one molecule in the asymmetric unit. To facilitate structure determination using single anomalous dispersion, three methionines were introduced by site-directed mutagenesis. Crystals of selenomethionine-labelled protein were obtained by streak-seeding and diffracted to 2.0 A resolution. PMID- 22102029 TI - Crystallization and preliminary X-ray diffraction analysis of prion protein bound to the Fab fragment of the POM1 antibody. AB - Prion diseases are neurodegenerative diseases that are characterized by the conversion of the cellular prion protein PrP(c) to the pathogenic isoform PrP(sc). Several antibodies are known to interact with the cellular prion protein and to inhibit this transition. An antibody Fab fragment, Fab POM1, was produced that recognizes a structural motif of the C-terminal domain of mouse prion protein. To study the mechanism by which Fab POM1 recognizes and binds the prion molecule, the complex between Fab POM1 and the C-terminal domain of mouse prion (residues 120-232) was prepared and crystallized. Crystals of this binary complex belonged to the monoclinic space group C2, with unit-cell parameters a = 83.68, b = 106.9, c = 76.25 A, beta = 95.6 degrees . PMID- 22102030 TI - Crystallization and preliminary X-ray analysis of the Entamoeba histolytica alpha actinin-2 rod domain. AB - alpha-Actinins form antiparallel homodimers that are able to cross-link actin filaments. The protein contains three domains: an N-terminal actin-binding domain followed by a central rod domain and a calmodulin-like EF-hand domain at the C terminus. Here, crystallization of the rod domain of Entamoeba histolytica alpha actinin-2 is reported; it crystallized in space group P2(1)2(1)2(1), with unit cell parameters a = 47.8, b = 79.1, c = 141.8 A. A Matthews coefficient V(M) of 2.6 A(3) Da(-1) suggests that there are two molecules and 52.5% solvent content in the asymmetric unit. A complete native data set extending to a d-spacing of 2.8 A was collected on beamline I911-2 at MAX-lab, Sweden. PMID- 22102031 TI - Influence of the N-terminal peptide on the cocrystallization of a thermophilic endo-beta-1,4-glucanase with polysaccharide substrates. AB - It is well known that protein cocrystallization is affected by several parameters such as the ratio of the protein to the ligand, the reservoir solution, the pH and the temperature. Previously, spatial blocking by the N-terminus was observed in the active site in the crystal structure of the native protein of a thermostable endoglucanase from the thermophilic bacterium Fervidobacterium nodosum Rt17-B1 (FnCel5A). It was speculated that the N-terminal alpha-helix might form interactions with the substrate-binding residues and it was believed that this spatial block is special to some extent. In order to confirm the effect on cocrystallization, two N-terminally truncated variants of FnCel5A were constructed, purified and cocrystallized at 291 K. A crystal of FnCel5AND_12-343 in complex with cellobiose was obtained using PEG 8000 as a precipitant. A 2.2 A resolution data set was collected. This crystal form (space group P4(1)2(1)2, unit-cell parameters a = b = 47.3, c = 271.4 A) differed from that of the native protein. One molecule is assumed to be present per asymmetric unit, which gives a Matthews coefficient of 2.05 A(3) Da(-1). PMID- 22102032 TI - Purification, crystallization and preliminary X-ray analysis of recombinant betaine aldehyde dehydrogenase 2 (OsBADH2), a protein involved in jasmine aroma, from Thai fragrant rice (Oryza sativa L.). AB - Fragrant rice (Oryza sativa L.) betaine aldehyde dehydrogenase 2 (OsBADH2) is a key enzyme in the synthesis of fragrance aroma compounds. The extremely low activity of OsBADH2 in catalyzing the oxidation of acetaldehyde is believed to be crucial for the accumulation of the volatile compound 2-acetyl-1-pyrroline (2AP) in many scented plants, including fragrant rice. Recombinant fragrant rice OsBADH2 was expressed in Escherichia coli as an N-terminal hexahistidine fusion protein, purified using Ni Sepharose affinity chromatography and crystallized using the microbatch method. Initial crystals were obtained within 24 h using 0.1 M Tris pH 8.5 with 30%(w/v) PEG 4000 and 0.2 M magnesium chloride as the precipitating agent at 291 K. Crystal quality was improved when the enzyme was cocrystallized with NAD(+). Improved crystals were grown in 0.1 M HEPES pH 7.4, 24%(w/v) PEG 4000 and 0.2 M ammonium chloride and diffracted to beyond 2.95 A resolution after being cooled in a stream of N(2) immediately prior to X-ray diffraction experiments. The crystals belonged to space group C222(1), with unit cell parameters a = 66.03, b = 183.94, c = 172.28 A. An initial molecular replacement solution has been obtained and refinement is in progress. PMID- 22102033 TI - Cloning, purification and preliminary crystallographic studies of the 2AB protein from hepatitis A virus. AB - The Picornaviridae family contains a large number of human pathogens such as rhinovirus, poliovirus and hepatitis A virus (HAV). Hepatitis A is an infectious disease that causes liver inflammation. It is highly endemic in developing countries with poor sanitation, where infections often occur in children. As in other picornaviruses, the genome of HAV contains one open reading frame encoding a single polyprotein that is subsequently processed by viral proteinases to originate mature viral proteins during and after the translation process. In the polyprotein, the N-terminal P1 region generates the four capsid proteins, while the C-terminal P2 and P3 regions contain the enzymes, precursors and accessory proteins essential for polyprotein processing and virus replication. Here, the first crystals of protein 2AB of HAV are reported. The crystals belonged to space group P4(1) or P4(3), with unit-cell parameters a = b = 90.42, c = 73.43 A, and contained two molecules in the asymmetric unit. Native and selenomethionine derivative crystals diffracted to 2.7 and 3.2 A resolution, respectively. PMID- 22102034 TI - Crystallization and preliminary crystallographic studies of Campylobacter jejuni ChuZ, a member of a novel haem oxygenase family. AB - The haem oxygenase ChuZ from Campylobacter jejuni, a major enteric pathogen in humans, is part of the iron-acquisition mechanism that is involved in bacterial survival and persistence in hosts. The ChuZ-haemin complex has been purified and crystallized and diffraction data have been collected to 2.4 A resolution. The ChuZ-haemin complex crystals belonged to space group C222(1), with unit-cell parameters a = 106.474, b = 106.698, c = 52.464 A, alpha = beta = gamma = 90 degrees . The asymmetric unit contained one ChuZ monomer, with a Matthews coefficient of 2.58 A(3) Da(-1). PMID- 22102035 TI - Crystallization of a paraspeckle protein PSPC1-NONO heterodimer. AB - The paraspeckle component 1 (PSPC1) and non-POU-domain-containing octamer-binding protein (NONO) heterodimer is an essential structural component of paraspeckles, ribonucleoprotein bodies found in the interchromatin space of mammalian cell nuclei. PSPC1 and NONO both belong to the Drosophila behaviour and human splicing (DBHS) protein family, which has been implicated in many aspects of RNA processing. A heterodimer of the core DBHS conserved region of PSPC1 and NONO comprising two tandemly arranged RNA-recognition motifs (RRMs), a NONA/paraspeckle (NOPS) domain and part of a predicted coiled-coil domain has been crystallized in space group C2, with unit-cell parameters a = 90.90, b = 67.18, c = 94.08 A, beta = 99.96 degrees . The crystal contained one heterodimer in the asymmetric unit and diffracted to 1.9 A resolution using synchrotron radiation. PMID- 22102036 TI - Purification and crystallization of Bacillus subtilis NrnA, a novel enzyme involved in nanoRNA degradation. AB - The final step in RNA degradation is the hydrolysis of RNA fragments five nucleotides or less in length (nanoRNA) to mononucleotides. In Escherichia coli this step is carried out by oligoribonuclease (Orn), a DEDD-family exoribonuclease that is conserved throughout eukaryotes. However, many bacteria lack Orn homologs, and an unrelated DHH-family phosphoesterase, NrnA, has recently been identified as one of the enzymes responsible for nanoRNA degradation in Bacillus subtilis. To understand its mechanism of action, B. subtilis NrnA was purified and crystallized at room temperature using the hanging drop vapor-diffusion method with PEG 4000, PEG 3350 or PEG MME 2000 as precipitant. The crystals belonged to the primitive monoclinic space group P2(1), with unit-cell parameters a = 50.62, b = 121.3, c = 123.4 A, alpha = 90, beta = 91.31, gamma = 90 degrees . PMID- 22102037 TI - Crystallization and preliminary X-ray diffraction analysis of Sfh3, a member of the Sec14 protein superfamily. AB - Sec14 is the major phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer protein in the yeast Saccharomyces cerevisiae and is the founding member of the Sec14 protein superfamily. Recent functional data suggest that Sec14 functions as a nanoreactor for PtdCho-regulated presentation of PtdIns to PtdIns kinase to affect membrane trafficking. Extrapolation of this concept to other members of the Sec14 superfamily suggests a mechanism by which a comprehensive cohort of Sec14-like nanoreactors sense correspondingly diverse pools of lipid metabolites. In turn, metabolic information is translated to signaling circuits driven by phosphoinositide metabolism. Sfh3, one of five Sec14 homologs in yeast, exhibits several interesting functional features, including its unique localization to lipid particles and microsomes. This localization forecasts novel regulatory interfaces between neutral lipid metabolism and phosphoinositide signaling. To launch a detailed structural and functional characterization of Sfh3, the recombinant protein was purified to homogeneity, diffraction-quality crystals were produced and a native X-ray data set was collected to 2.2 A resolution. To aid in phasing, SAD X-ray diffraction data were collected to 1.93 A resolution from an SeMet-labeled crystal at the Southeast Regional Collaborative Access Team at the Advanced Photon Source. Here, the cloning and purification of Sfh3 and the preliminary diffraction of Sfh3 crystals are reported, enabling structural analyses that are expected to reveal novel principles governing ligand binding and functional specificity for Sec14 superfamily proteins. PMID- 22102038 TI - Crystallization and preliminary crystallographic studies of the HA3 subcomponent of the type B botulinum neurotoxin complex. AB - The haemagglutinin subcomponent HA3 of the type B botulinum neurotoxin complex, which is important in toxin absorption from the gastrointestinal tract, has been expressed, purified and subsequently crystallized in two crystal forms at different pH values. Form I belonged to space group R32, with unit-cell parameters a = b = 357.4, c = 249.5 A, alpha = beta = 90, gamma = 120 degrees . Form II belonged to space group I4(1)32, with unit-cell parameters a = b = c = 259.0 A, alpha = beta = gamma = 90 degrees . Diffraction data were collected from these crystals to a resolution of 3.0 A for both form I and form II. PMID- 22102039 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of PBP4 from Listeria monocytogenes. AB - Penicillin-binding proteins (PBPs), which catalyze peptidoglycan synthesis, have been extensively studied as a well established target of antimicrobial agents, including beta-lactam derivatives. However, remarkable resistance to beta-lactams has developed among pathogenic bacteria since the clinical use of penicillin began. Recently, the glycosyltransferase (GT) domain of class A PBPs has been proposed as an attractive target for antibiotic development as moenomycin-bound GT-domain structures have been determined. In this study, a class A PBP4 from Listeria monocytogenes was overexpressed, purified and crystallized using the hanging-drop vapour-diffusion method. Diffraction data were collected to 2.1 A resolution using synchrotron radiation. The crystal belonged to the primitive orthorhombic space group P2(1)2(1)2, with unit-cell parameters a = 84.6, b = 127.8, c = 54.9 A. The structural information will contribute to the further development of moenomycin-derived antibiotics possessing broad-spectrum activity. PMID- 22102040 TI - Overexpression, crystallization and preliminary X-ray crystallographic analysis of the C-terminal cytosolic domain of mouse anoctamin 1. AB - Transmembrane protein 16A (TMEM16A, also known as anoctamin 1; ANO1) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+)- and Ca(2+)-mobilizing stimuli and plays important roles in a variety of physiological functions. To elucidate the structural features of ANO1, structural analysis of the C-terminal cytosolic domain of mouse ANO1 (mANO1-CTD) was initiated. mANO1-CTD was overexpressed in Escherichia coli and was crystallized at 297 K using a reservoir solution consisting of 0.2 M sodium acetate trihydrate, 0.1 M Tris-HCl pH 8.5 and 30%(w/v) PEG 4000. X-ray diffraction data were collected to 2.3 A resolution. The crystals belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 73.96, b = 103.73, c = 114.71 A. If it is assumed that eight copies of a monomer molecule are present in the crystallographic asymmetric unit, the crystal volume per protein mass (V(M)) is 2.38 A(3) Da(-1) and the solvent content is 48.38%. Attempts to solve the structure of mANO1-CTD by the MAD method using selenomethionine-labelled mANO1 CTD or heavy-atom-derivatized crystals are in progress. PMID- 22102041 TI - Purification, crystallization and preliminary crystallographic studies of the TLDc domain of oxidation resistance protein 2 from zebrafish. AB - Cell metabolic processes are constantly producing reactive oxygen species (ROS), which have deleterious effects by triggering, for example, DNA damage. Numerous enzymes such as catalase, and small compounds such as vitamin C, provide protection against ROS. The TLDc domain of the human oxidation resistance protein has been shown to be able to protect DNA from oxidative stress; however, its mechanism of action is still not understood and no structural information is available on this domain. Structural information on the TLDc domain may therefore help in understanding exactly how it works. Here, the purification, crystallization and preliminary crystallographic studies of the TLDc domain from zebrafish are reported. Crystals belonging to the orthorhombic space group P2(1)2(1)2 were obtained and diffracted to 0.97 A resolution. Selenomethionine substituted protein could also be crystallized; these crystals diffracted to 1.1 A resolution and the structure could be solved by SAD/MAD methods. PMID- 22102042 TI - Mutation and crystallization of the first KH domain of human polycytosine-binding protein 1 (PCBP1) in complex with DNA. AB - Polycytosine-binding proteins (PCBPs) are triple KH-domain proteins that play an important role in the regulation of translation of eukaryotic mRNA. They are also utilized by viral RNA and have been shown to interact with ssDNA. Underlying their function is the specific recognition of C-rich nucleotides by their KH domains. However, the structural basis of this recognition is only partially understood. Here, the preparation of a His-tagged KH domain is described, representing the first domain of PCBP1 that incorporates a C54S mutation as well as the addition of a C-terminal tryptophan. This construct has facilitated the preparation of highly diffracting crystals in complex with C-rich DNA (sequence ACCCCA). Crystals of the KH1-DNA complex were grown using the hanging-drop vapour diffusion method in 0.1 M phosphate-citrate pH 4.2, 40%(v/v) PEG 300. X-ray diffraction data were collected to 1.77 A resolution and the diffraction was consistent with space group P2(1), with unit-cell parameters a = 38.59, b = 111.88, c = 43.42 A, alpha = gamma = 90.0, beta = 93.37 degrees . The structure of the KH1-DNA complex will further our insight into the basis of cytosine specificity by PCBPs. PMID- 22102043 TI - Crystallization and preliminary crystallographic analysis of the type IIL restriction enzyme MmeI in complex with DNA. AB - Type IIL restriction enzymes have rejuvenated the search for user-specified DNA binding and cutting. By aligning and contrasting the highly comparable amino-acid sequences yet diverse recognition specificities across the family of enzymes, amino acids involved in DNA binding have been identified and mutated to produce alternative binding specificities. To date, the specificity of MmeI (a type IIL restriction enzyme) has successfully been altered at positions 3, 4 and 6 of the asymmetric TCCRAC (where R is a purine) DNA-recognition sequence. To further understand the structural basis of MmeI DNA-binding specificity, the enzyme has been crystallized in complex with its DNA substrate. The crystal belonged to space group P1, with unit-cell parameters a = 61.73, b = 94.96, c = 161.24 A, alpha = 72.79, beta = 89.12, gamma = 71.68 degrees , and diffracted to 2.6 A resolution when exposed to synchrotron radiation. The structure promises to reveal the basis of MmeI DNA-binding specificity and will complement efforts to create enzymes with novel specificities. PMID- 22102044 TI - Expression, purification, crystallization and preliminary X-ray analysis of eCGP123, an extremely stable monomeric green fluorescent protein with reversible photoswitching properties. AB - Enhanced consensus green protein variant 123 (eCGP123) is an extremely thermostable green fluorescent protein (GFP) that exhibits useful negative reversible photoswitching properties. eCGP123 was derived by the application of both a consensus engineering approach and a recursive evolutionary process. Diffraction-quality crystals of recombinant eCGP123 were obtained by the hanging drop vapour-diffusion method using PEG 3350 as the precipitant. The eCGP123 crystal diffracted X-rays to 2.10 A resolution. The data were indexed in space group P1, with unit-cell parameters a = 74.63, b = 75.38, c = 84.51 A, alpha = 90.96, beta = 89.92, gamma = 104.03 degrees . The Matthews coefficient (V(M) = 2.26 A(3) Da(-1)) and a solvent content of 46% indicated that the asymmetric unit contained eight eCGP123 molecules. PMID- 22102045 TI - Cloning, overexpression, purification, crystallization and preliminary X-ray analysis of 3-ketosteroid Delta(4)-(5alpha)-dehydrogenase from Rhodococcus jostii RHA1. AB - 3-Ketosteroid dehydrogenases are flavoproteins which play key roles in steroid ring degradation. The enzymes are abundantly present in actinobacteria, including the catabolic powerhouse Rhodococcus jostii and the pathogenic species R. equi and Mycobacterium tuberculosis. The gene for 3-ketosteroid Delta(4)-(5alpha) dehydrogenase [Delta(4)-(5alpha)-KSTD] from R. jostii RHA1 was cloned and overexpressed in Escherichia coli. His-tagged Delta(4)-(5alpha)-KSTD enzyme was purified by Ni(2+)-NTA affinity chromatography, anion-exchange chromatography and size-exclusion chromatography and was crystallized using the hanging-drop vapour diffusion method. Seeding greatly improved the number of crystals obtained. The crystals belonged to space group C222(1), with unit-cell parameters a = 99.2, b = 114.3, c = 110.2 A. Data were collected to a resolution of 1.6 A. PMID- 22102046 TI - Cloning, expression, purification, crystallization and preliminary X-ray studies of the C-terminal domain of Rv3262 (FbiB) from Mycobacterium tuberculosis. AB - During cofactor F(420) biosynthesis, the enzyme F(420)-gamma-glutamyl ligase (FbiB) catalyzes the addition of gamma-linked L-glutamate residues to form polyglutamylated F(420) derivatives. In Mycobacterium tuberculosis, Rv3262 (FbiB) consists of two domains: an N-terminal domain from the F(420) ligase superfamily and a C-terminal domain with sequence similarity to nitro-FMN reductase superfamily proteins. To characterize the role of the C-terminal domain of FbiB in polyglutamyl ligation, it has been purified and crystallized in an apo form. The crystals diffracted to 2.0 A resolution using a synchrotron source and belonged to the tetragonal space group P4(1)2(1)2 (or P4(3)2(1)2), with unit-cell parameters a = b = 136.6, c = 101.7 A, alpha = beta = gamma = 90 degrees . PMID- 22102047 TI - Crystallization and preliminary X-ray diffraction studies of the transcriptional repressor PaaX, the main regulator of the phenylacetic acid degradation pathway in Escherichia coli W. AB - PaaX is the main regulator of the phenylacetic acid aerobic degradation pathway in bacteria and acts as a transcriptional repressor in the absence of its inducer phenylacetyl-coenzyme A. The natural presence and the recent accumulation of a variety of highly toxic aromatic compounds owing to human pollution has created considerable interest in the study of degradation pathways in bacteria, the most important microorganisms capable of recycling these compounds, in order to design and apply novel bioremediation strategies. PaaX from Escherichia coli W was cloned, overexpressed, purified and crystallized using the sitting-drop vapour diffusion method at 291 K. Crystals grew from a mixture of 0.9 M Li(2)SO(4) and 0.5 M sodium citrate pH 5.8. These crystals, which belonged to the monoclinic space group C2 with unit-cell parameters a = 167.88, b = 106.23, c = 85.87 A, beta = 108.33 degrees , allowed the collection of an X-ray data set to 2.3 A resolution. PMID- 22102048 TI - Overexpression, crystallization and preliminary X-ray diffraction analysis of L ribose isomerase from Acinetobacter sp. strain DL-28. AB - Acinetobacter sp. L-ribose isomerase (L-RI) catalyzes a reversible isomerization reaction between L-ribose and L-ribulose. To date, information on L-RI remains limited and its amino-acid sequence shows no similarity to those of any known enzymes. Here, recombinant His-tagged L-RI was successfully overexpressed, purified and crystallized. Crystals of His-tagged L-RI were obtained by the hanging-drop vapour-diffusion method at room temperature as two crystal forms which belonged to the monoclinic space group C2, with unit-cell parameters a = 96.60, b = 105.89, c = 71.83 A, beta = 118.16 degrees , and the orthorhombic space group F222, with unit-cell parameters a = 96.44, b = 106.26, c = 117.83 A. Diffraction data were collected to 3.1 and 2.2 A resolution, respectively. PMID- 22102049 TI - Crystallization and preliminary X-ray diffraction analysis of phosphoglycerate kinase from Streptococcus pneumoniae. AB - Phosphoglycerate kinase (PGK) is a widespread two-domain enzyme that plays a critical role in the glycolytic pathway. Several glycolytic enzymes from streptococci have been identified as surface-exposed proteins that are involved in streptococcal virulence by their ability to bind host proteins. This binding allows pneumococcal cells to disseminate through the epithelial and endothelial layers. Crystallization of PGK from Streptococcus pneumoniae yielded orthorhombic crystals (space group I222, unit-cell parameters a = 62.73, b = 75.38, c = 83.63 A). However, the unit cell of these crystals was not compatible with the presence of full-length PGK. Various analytical methods showed that only the N-terminal domain of PGK was present in the I222 crystals. The ternary complex of PGK with adenylyl imidodiphosphate (AMP-PNP) and 3-phospho-D-glycerate (3PGA) produced monoclinic crystals (space group P2(1), unit-cell parameters a = 40.35, b = 78.23, c = 59.03 A, beta = 96.34 degrees ). Molecular replacement showed that this new crystal form contained full-length PGK, thereby indicating the relevance of including substrates in order to avoid proteolysis during the crystallization process. PMID- 22102050 TI - Crystallization of a challenging antigen-antibody complex: TLR3 ECD with three noncompeting Fabs. AB - The mechanism of action of therapeutic antibodies can be elucidated from the three-dimensional crystal structures of their complexes with antigens, but crystallization remains the primary bottleneck to structure determination. Methods that resulted in the successful crystallization of TLR3 ECD in complex with Fab fragments from three noncompeting, neutralizing anti-TLR3 antibodies are presented. The crystallization of this 238 kDa complex was achieved through fine purification of the quaternary complex of TLR3 with the three Fab fragments combined with microseed matrix screening and additive screening. Fine purification entailed the application of a very shallow gradient in anion exchange chromatography, resulting in the resolution of two separate complex peaks which had different crystallizabilities. Subsequent structure determination defined the epitopes of the respective antibodies and revealed a mechanistic hypothesis that is currently under investigation. The results also showed that cocrystallization with multiple noncompeting Fab fragments can be a viable path when an antigen complex with a single Fab proves to be recalcitrant to crystallization. PMID- 22102051 TI - Expression, purification and crystallization of an atypical class C acid phosphatase from Mycoplasma bovis. AB - Class C acid phosphatases (CCAPs) are 25-30 kDa bacterial surface proteins that are thought to function as broad-specificity 5',3'-nucleotidases. Analysis of the newly published complete genome sequence of Mycoplasma bovis PG45 revealed a putative CCAP with a molecular weight of 49.9 kDa. The expression, purification and crystallization of this new family member are described here. Standard purification procedures involving immobilized metal-ion affinity chromatography and ion-exchange chromatography yielded highly pure and crystallizable protein. Crystals were grown in sitting drops at room temperature in the presence of PEG 3350 and HEPES buffer pH 7.5 and diffracted to 2.3 A resolution. Analysis of diffraction data suggested a primitive monoclinic space group, with unit-cell parameters a = 78, b = 101, c = 180 A, beta = 92 degrees . The asymmetric unit is predicted to contain six molecules, which are likely to be arranged as three dimers. PMID- 22102052 TI - Humidity control can compensate for the damage induced in protein crystals by alien solutions. AB - The use of relative humidity control of protein crystals to overcome some of the shortcomings of soaking ligands (i.e. inhibitors, substrate analogs, weak ligands) into pre-grown apoprotein crystals has been explored. Crystals of PurE (EC 4.1.1.21), an enzyme from the purine-biosynthesis pathway of Bacillus anthracis, were used as a test case. The findings can be summarized as follows: (i) using humidity control, it is possible to improve/optimize the diffraction quality of crystals soaked in solutions of organic solvent (DMSO, ethanol) containing ligands/inhibitors; (ii) optimization of the relative humidity can compensate for the deterioration of the diffraction pattern that is observed upon desalting crystals grown in high salt; (iii) combining desalting protocols with the addition of PEG it is possible to achieve very high concentrations of weak ligands (in the 5-10 mM range) in soaking solutions and (iv) fine control of the relative humidity of crystals soaked in these solutions can compensate for the deterioration of crystal diffraction and restore 'high-resolution' diffraction for structure-based and fragment-based drug design. It is suggested that these experimental protocols may be useful in other protein systems and may be applicable in academic or private research to increase the probability of obtaining structures of protein-ligand complexes at high resolution. PMID- 22102053 TI - Predicting protein submitochondria locations by combining different descriptors into the general form of Chou's pseudo amino acid composition. AB - Knowledge of the submitochondria location of protein is integral to understanding its function and a necessity in the proteomics era. In this work, a new submitochondria data set is constructed, and an approach for predicting protein submitochondria locations is proposed by combining the amino acid composition, dipeptide composition, reduced physicochemical properties, gene ontology, evolutionary information, and pseudo-average chemical shift. The overall prediction accuracy is 93.57% for the submitochondria location and 97.79% for the three membrane protein types in the mitochondria inner membrane using the algorithm of the increment of diversity combined with the support vector machine. The performance of the pseudo-average chemical shift is excellent. For contrast, the method is also used to predict submitochondria locations in the data set constructed by Du and Li; an accuracy of 94.95% is obtained by our method, which is better than that of other existing methods. PMID- 22102054 TI - Relationship between digestibility and secondary structure of raw and thermally treated legume proteins: a Fourier transform infrared (FT-IR) spectroscopic study. AB - The secondary structure of proteins in legumes, cereals, milk products and chicken meat was studied by diffuse reflectance infrared spectroscopy in the region of the amide I band. Major secondary structure components ( beta-sheets, random coil, alpha-helix, turns), together with the low- and high-frequency side contributions, were resolved and related to the in vitro digestibility behaviour of the different foods. A strong inverse correlation between the relative spectral weights of the beta-sheet structures and in vitro protein digestibility values was measured. Structural modifications in legume proteins induced by autoclaving were monitored by the changes in the amide I spectra. The results indicate that the beta-sheet structures of raw legume proteins and the intermolecular beta-sheet aggregates, arising upon heating, are primary factors in adversely affecting the digestibility. PMID- 22102055 TI - SAR study of tyrosine-chlorambucil hybrid regioisomers; synthesis and biological evaluation against breast cancer cell lines. AB - Amino acids were transformed and coupled to chlorambucil, a well-known chemotherapeutic agent, in an attempt to create new anticancer drugs with selectivity for breast cancer cells. Among the amino acids available, tyrosine was selected to act as an estrogenic ligand. It is hypothesized that tyrosine, which shows some structural similitude with estradiol, could possibly mimic the natural hormone and, subsequently, bind to the estrogen receptor. In this exploratory study, several tyrosine-drug conjugates have been designed. Thus, ortho-, meta- and para-tyrosine-chlorambucil analogs were synthesized in order to generate new anticancer drugs with structural diversity, more specifically in regards to the phenol group location. These new analogs were produced in good yield following efficient synthetic methodology. All the tyrosine-chlorambucil hybrids were more effective than the parent drug, chlorambucil. In vitro biological evaluation on estrogen receptor positive and estrogen receptor negative (ER(+) and ER(-)) breast cancer cell lines revealed an enhanced cytotoxic activity for compounds with the phenol function located at position meta. Molecular docking calculations were performed for the pure L-ortho, L-meta- and L-para-tyrosine phenolic regioisomers. The synthesis of all tyrosine chlorambucil hybrid regioisomers and their biological activity are reported herein. Possible orientations within the targeted protein [estrogen receptor alpha (ERalpha)] are discussed in relation to the biological activity. PMID- 22102056 TI - Exercise-induced oxidative stress: the effects of beta-alanine supplementation in women. AB - The purpose of this study was to evaluate the effects of beta-alanine supplementation on markers of oxidative stress. Twenty-four women (age: 21.7+/ 2.1 years; VO2max: 2.6+/-0.3 l min(-1)) were randomly assigned, in a double-blind fashion, to a beta-alanine (BA, 2*800 mg tablets, 3* daily; CarnoSyn(r); n=13) or placebo (PL, 2*800 mg maltodextrin tablets, 3* daily; n=11) group. A graded oxygen consumption test (VO2max) was performed to evaluate VO2max, time to exhaustion, ventilatory threshold and establish peak velocity (PV). A 40-min treadmill run was used to induce oxidative stress. Total antioxidant capacity, superoxide dismutase, 8-isoprostane (8ISO) and reduced glutathione were measured. Heart rate and ratings of perceived exertion were recorded during the 40 min run. Separate three- [4*2*2; acute (base vs. IP vs. 2 vs. 4 h)*chronic (pre- vs. post )*treatment (BA vs. PL)] and two- [2*2; time (pre-supplement vs. post supplement)*treatment (BA vs. PL)] way ANOVAs were used for analyses. There was a significant increase in VO2max (p=0.009), independent of treatment, with no significant changes in TTE (p=0.074) or VT (p=0.344). Ratings of perceived exertion values were significantly improved from pre- to post-supplementation for the BA group only at 40 min (p=0.02). The ANOVA model demonstrated no significant treatment effects on oxidative stress. The chronic effects of BA supplementation demonstrated little antioxidant potential, in women, and little influence on aerobic performance assessments. PMID- 22102057 TI - Type-I IFN drives the differentiation of short-lived effector CD8+ T cells in vivo. AB - Two subsets of CD8(+) T cells are generated early during an immune response; one of these subsets forms the memory pool, known as memory precursor effector cells (MPECs), identified by high expression of CD127 and low expression of KLRG1, whereas the other subset forms short-lived effector cells (SLECs) identified by low expression of CD127 and high expression of KLRG1. Here, we studied in vivo the role of type-I IFN in this fate decision. We found that under priming conditions dominated by type-I IFN, as observed in lymphocytic choriomeningitis virus (LCMV) infection, type-I IFN signaling directly impacted the regulation of T-bet and thus the early fate decision of CD8(+) T cells. In the absence of type I IFN signaling, CD8(+) T cells failed to form SLECs but could form MPECs that give rise to functional memory CD8(+) T cells. Together, these findings identify type-I IFN as an important factor driving SLEC differentiation and thus instructing the early division between the effector and memory precursor CD8(+) T-cell pool. PMID- 22102058 TI - Enantiomeric scaffolding of alpha-tetralone and related scaffolds by EKR (enzymatic kinetic resolution) and stereoselective ketoreduction with ketoreductases. AB - Stereochemically pure compounds containing an all carbon quaternary stereocenter based on 1-tetralone, 1-indanone and 4-chromanone scaffolds have been synthesized by employing Lipase PS (Burkholderia cepacia) catalyzed kinetic resolution. These scaffolds are further functionalized by microbial ketoreductase enzymes (Geotrichum candidum, Candida parapsilosis and Aspergillus niger) to access stereochemically pure diols which, on further synthetic manipulation, yield novel cyclic compounds. PMID- 22102059 TI - Increasing heterogeneity in the organization of synaptic inputs of mature olfactory bulb neurons generated in newborn rats. AB - New neurons are added into the mammalian olfactory bulb throughout life, but it remains unknown whether the properties of new neurons generated in newborn animals differ from those added during adulthood. We compared the densities of glutamatergic synapses of granule cells (GCs) generated in newborn and adult rats over extended periods of time. We observed that, whereas adult-born GCs maintained stable cell-to-cell variability of synaptic densities soon after they integrated into the circuit, cell-to-cell variability of synaptic densities of neonatal-born GCs increased months after their integration. We also investigated whether the synaptic reorganization induced by sensory deprivation occurred differently in mature neonatal- and adult-born GCs. Sensory deprivation after new GCs had differentiated induced more pronounced changes in the synaptic densities of neonatal-born GCs than in adult-born GCs. These observations suggest that the synapses of mature neonatal-born GCs retain a higher degree of malleability in response to changes in neuronal activity than adult-born GCs. PMID- 22102060 TI - Biobleaching of wheat straw pulp with recombinant laccase from the hyperthermophilic Thermus thermophilus. AB - The recombinant laccase from Thermus thermophilus was applied to the biobleaching of wheat straw pulp. The best bleaching effect was when the pulp was treated with 3 U laccase g(-1) dry pulp at 90 degrees C, pH 4.5, 8% consistency for 1.5 h. Under these conditions, the pulp brightness was increased by 3.3% ISO, and the pulp kappa number was decreased by 5.6 U. Enzymatic treatment improved the bleachability of wheat straw pulp but caused no damage to the pulp fibers. The use of enzyme-treated pulp saved 25% H(2)O(2) consumption in subsequent peroxide bleaching without decreasing the final brightness. Pulp biobleaching in the presence of 5 mM ABTS further increased the pulp brightness by 1.5% ISO. This is the first report on the application of laccase from T. thermophilus in the pulp and paper sector. PMID- 22102061 TI - Novel antiplatelet therapies. AB - Advances in antiplatelet therapy have significantly improved outcomes in patients with ischemic heart disease. Thienopyridines remain a cornerstone of therapy along with aspirin. Recently, concerns have been raised about the use of clopidogrel due to its pharmacokinetic and pharmacogenetic interpatient variability. A third-generation thienopyridine, prasugrel, overcomes some of these problems by improving inhibition of platelet aggregation, but increasing the risk of peri-procedural bleeding. Other novel antiplatelet agents, such as ticagrelor, have shown improved efficacy in recent trials and require further investigations. The field of pharmacotherapy continues to rapidly evolve as newer agents, such as thrombin receptor antagonists, along with older agents, such as cilostazol and glycoprotein IIb/IIIa inhibitors, are being explored. PMID- 22102062 TI - Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. AB - This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome. PMID- 22102063 TI - Forest fragmentation and landscape transformation in a reindeer husbandry area in Sweden. AB - Reindeer husbandry and forestry are two main land users in boreal forests in northern Sweden. Modern forestry has numerous negative effects on the ground growing and arboreal lichens that are crucial winter resources for reindeer husbandry. Using digitized historical maps, we examined changes in the forest landscape structure during the past 100 years, and estimated corresponding changes in suitability of forest landscape mosaics for the reindeer winter grazing. Cover of old coniferous forests, a key habitat type of reindeer herding system, showed a strong decrease during the study period, whereas clear-cutting and young forests increased rapidly in the latter half of the 20th century. The dominance of young forests and fragmentation of old-growth forests (decreased patch sizes and increased isolation) reflect decreased amount of arboreal lichens as well as a lowered ability of the landscape to sustain long-term persistence of lichens. The results further showed that variation in ground lichen cover among sites was mainly related to soil moisture conditions, recent disturbances, such as soil scarification and prescribed burning, and possibly also to forest history. In general, the results suggest that the composition and configuration of the forest landscape mosaic has become less suitable for sustainable reindeer husbandry. PMID- 22102064 TI - CD99 is expressed in chordoid glioma and suggests ependymal origin. PMID- 22102065 TI - Expression of Raf-1 kinase inhibitory protein in carcinoma of the ampulla of Vater. AB - Raf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human malignancies. We have recently demonstrated that reduced expression of RKIP is significantly associated with invasion and metastasis in periampullary carcinomas, including pancreatic carcinoma, gallbladder carcinoma, and extrahepatic bile duct carcinoma. In this study, we evaluated RKIP expression in ampulla of Vater (AoV) carcinoma and investigated its prognostic significance. Immunostaining for RKIP was performed for 80 and 21 cases with primary and nodal metastatic AoV carcinoma, respectively. RKIP expression was reduced in 32.5% (26/80) and 66.7% (14/21) of primary and nodal metastatic AoV carcinoma cases, respectively. This distribution of RKIP expression was statistically significant (P < 0.001). The reduction in RKIP expression was significantly associated with the presence of nodal (P = 0.008) and distant (P = 0.002) metastases, a higher TNM stage group (P = 0.010), lymphatic invasion (P < 0.001), vascular invasion (P < 0.001), and a shorter disease-free survival (DFS; P = 0.028) and distant metastasis-free survival (DMFS; P = 0.005). In addition, reduced RKIP expression was an independent prognostic predictor for worse DFS and DMFS (P = 0.032 and P = 0.036, respectively). Our data suggest that a reduction in RKIP expression contributes to invasion and metastasis in AoV carcinoma and is a significant prognostic marker in patients with AoV carcinoma. PMID- 22102066 TI - Improved sample preparation for CE-LIF analysis of plant N-glycans. AB - In view of glycomics studies in plants, it is important to have sensitive tools that allow one to analyze and characterize the N-glycans present on plant proteins in different species. Earlier methods combined plant-based sample preparations with CE-LIF N-glycan analysis but suffered from background contaminations, often resulting in non-reproducible results. This publication describes a reproducible and sensitive protocol for the preparation and analysis of plant N-glycans, based on a combination of the 'in-gel release method' and N glycan analysis on a multicapillary DNA sequencer. Our protocol makes it possible to analyze plant N-glycans starting from low amounts of plant material with highly reproducible results. The developed protocol was validated for different plant species and plant cells. PMID- 22102067 TI - Dusky red swelling of the penis in association with fever and diarrhoea: a quiz. Metastatic Crohn's disease of the penis associated with enteric Crohn's disease. PMID- 22102068 TI - Analysis of PTEN, estrogen receptor alpha and progesterone receptor expression in endometrial hyperplasia using tissue microarray. AB - We compared the immunohistochemical expression of PTEN, estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) in a series of endometrial hyperplasia (EH) and in disordered proliferative endometrium (DPE) by tissue microarray (TMA). The material consisted of 141 endometrial curretings including 98 cases (study group) diagnosed as EH [59-simple (SH), 20-complex (CH), 19 atypical (AEH)] and 43 cases (control group) with DPE due to anovulation. The mean PTEN expression index decreased in order DPE-EH-AEH groups (p < 0.05). The mean value of the ER-alpha index increased in order DPE-SH-CH and decreased in AEH group, whereas the PR expression index decreased in order DPE-EH-AEH (p > 0.05 and p > 0.05, respectively). These results show that steroid hormone receptor status influences the architectural changes of endometriumrather than cytological ones. On the other hand, decreased PTEN expression correlates more closely with the cytological atypia in endometrial cells. In our opinion ER-alpha and PR may be useful markers predicting therapy response in EH. PTEN presents as a strong prognosticator which may help in determining the risk of progression in advanced stages of EH, especially those with atypical cytological features. PMID- 22102069 TI - Mast cells in melanocytic skin lesions. An immunohistochemical and quantitative study. AB - The mast cells participate in inflammation and possibly in carcinogenesis. The aim of the study was to study mast cells in melanocytic lesions. The material consisted of 24 pigmented nevi, 18 dysplastic nevi and 19 melanomas. The sections were stained immunohistochemically for tryptase and chymase. Positive cells were counted inside the lesions and at the interface between the lesion and dermis. The mean intralesional tryptase+ count was 15.75 for nevi, 21.78 for dysplastic nevi, and 8.07 for melanomas. The chymase+ intralesional count was 14.89 for nevi, 21.88 for dysplastic nevi, and 11.34 for melanomas. The tryptase+ perilesional count was 16.89 for nevi, 15.93 for dysplastic nevi, and 15.71 for melanomas. The chymase+ perilesional count was 16.52 for nevi, 16.16 for dysplastic nevi, and 14.77 for melanomas. The tryptase/chymase intralesional ratio was 0.93 for nevi, 1.05 for dysplastic nevi, and 1.67 for melanomas. The tryptase/chymase perilesional ratio was 1.02 for nevi, 1.09 for dysplastic nevi, and 1.00 for melanomas. The differences between intralesional mast cells, both tryptase+ and chymase+, were statistically significant. The intralesional tryptase+ count showed an inverse correlation to age (R = -0.42); this correlation was the strongest in melanomas. The results obtained in our study suggest a possible correlation between mast cells and the pathogenesis of cutaneous melanoma. PMID- 22102070 TI - Morphometric distinction of signet-ring cell adenocarcinoma cells from foamy macrophages in gastric endoscopic biopsies. AB - AIMS: To distinguish signet-ring cancer cells from foamy macrophages in the small gastric endoscopic biopsies using objective morphometric measurements of nuclei. MATERIAL AND METHODS: Using computerized image analysis, the mean nuclear area, length, breadth, perimeter and roundness were analyzed in histological sections of ten gastric endoscopic biopsies with signet-ring cell adenocarcinoma and four benign lesions with numerous foamy macrophages. RESULTS: Nuclei of signet-ring cell adenocarcinoma were significantly bigger than nuclei of foamy macrophages. Mean nuclear area (34.25 MUm2 for carcinoma cells vs. 25.41 MUm2 for macrophages) and mean nuclear breadth (5.82 MUm vs. 4.99 MUm, respectively) differed significantly (P < 0.05), whereas the remaining parameters did not. CONCLUSION: Nuclear morphometry can distinguish foamy macrophages from signet-ring cell adenocarcinoma cells in endoscopic gastric biopsies. PMID- 22102071 TI - Primary esophageal malignant melanoma. AB - Primary esophageal malignant melanoma is a highly aggressive but very rare tumour. Three cases of that malignancy treated in one medical centre are presented. They were diagnosed on the basis of microscopical examination confirmed by results of immunohistochemical reactions. Metastatic melanomas of other sites were excluded clinically. The depth of esophageal wall infiltration varied from submucosa to adventitia, but lymph node metastases were observed only in one case. One postoperative death was noted. In two other patients, lung metastases were found and the patients died 20 and 16 months after surgery. PMID- 22102072 TI - Endoscopic versus histological diagnosis of Barrett's esophagus: a cross sectional survey. AB - CONTEXT: Barrett's esophagus is a common pathological condition in patients with gastro-esophageal reflux disease. OBJECTIVE: The aim of this study was to compare endoscopic diagnosis versus histological confirmation. DESIGN: Cross-sectional. SETTING: Cancer Institute of the Imam Khomeini Hospital. MATERIAL AND METHODS: A total of 50 patients with a history of gastro-esophageal reflux were recruited and underwent upper endoscopy at this cross-sectional survey. Four-quadrant biopsy was taken from all suspected areas of intestinal metaplasia. Sections of blocks were stained with Mixed Alcian Blue (PH 2.5)/PAS and haematoxylin-eosin stainings for the diagnosis of intestinal metaplasia (complete vs. incomplete types) and goblet cell / columnar cell / dysplasia, respectively. MAIN OUTCOME MEASURE: The presence of Helicobacter pylori was assessed by Giemsa staining. RESULTS: There were 44 cases of short-segment Barrett's esophagus and 6 of long segment Barretts esophagus by endoscopy. When examined by histologic examination, 12 patients with short-segment Barrett's esophagus and 4 with long-segment Barrett's esophagus had intestinal metaplasia. Haematoxylin-eosin staining diagnosed 12 cases of intestinal metaplasia, whereas mixed alcian blue/PAS was used to diagnose 16 cases (kappa = 80%, p < 0.001). The positive predictive value in the diagnosis of goblet cell metaplasia and columnar cell metaplasia was 32% and 66%, respectively. Helicobacter pylori infection was observed in 10 cases of those with columnar cell metaplasia without goblet cells, while none of the patients with intestinal metaplasia were infected. CONCLUSION: Our findings suggest that biopsy taking is necessary in all patients with gastro-esophageal reflux disease, whose results suggest columnar cell lining in distal esophagus in endoscopy. PMID- 22102073 TI - 135G>C and 172G>T polymorphism in the 5' untranslated region of RAD51 and sporadic endometrial cancer risk in Polish women. AB - BACKGROUND: Despite advanced diagnostic and therapeutic procedures, endometrial cancer (EC) is still responsible for high morbidity and mortality of women. The genetic variability in RAD51 may contribute to the appearance and progression of various cancers including EC. AIM: We investigated the association of polymorphisms in the DNA repair genes RAD51 135G>C and 172G>T with endometrial cancer risk. MATERIAL AND METHODS: The genotypes of RAD51 135G>C and 172G>T polymorphism were determined by PCR-RFLP methods in endometrial tissue of 240 cancer subjects and 240 healthy subjects who served as controls. RESULTS: In the present work we demonstrated a significant positive association between the RAD51 C/C genotype and endometrial carcinoma, with an adjusted odds ratio (OR) of 13.0 (p < 0.0001). The distribution of genotypes for 135G>C SNP in endometrial cancer patients vs. controls was: 10% vs. 27% for GG, 13% vs. 58% for GC and 77% vs. 15% for CC genotype, respectively. Variant 135C allele of RAD51 increased the cancer risk (OR = 1.81; 95% CI 0.11-2.93, p = 0.022). The higher risk of EC occurrence was associated with the combined C135C-G172T genotype (OR = 7.69; 95% CI 3.45 17.12). CONCLUSION: The results indicated that the polymorphism 135G>C of the RAD51 gene may be positively associated with endometrial carcinoma in the Polish population. Further studies, conducted on a larger group, are required to clarify this point. PMID- 22102074 TI - Originally misdiagnosed rhabdoid tumour of the kidney. A case report and differential diagnosis. AB - Rhabdoid tumour of the kidney (RTK) is considered to be one of the most aggressive neoplasms of early life. The histogenesis of RTK still remains a matter of controversy. Immunohistochemistry usually shows diffuse reactivity for vimentin, focal reactivity to the epithelial marker, variable expression of mesenchymal and neuroectodermal markers, and loss of INI1 protein staining. Expression of the Wilms' tumour protein (WT1) was described in the RTK cases. We would like to present a case of rhabdoid tumour of the kidney in Latvia, which caused diagnostic difficulties of a 27-month-old girl, and a short review of literature. PMID- 22102075 TI - Cribriform adenocarcinoma of the tongue. AB - We report a case of a 73-year-old female with a tumour of the tongue, operated with two relapses. A single metastasis to the lymph node was present. Currently, the patient is alive without evidence of disease. The histological diagnosis of cribriform adenocarcinoma of the tongue was rendered. The differential diagnosis of adenocarcinomas of the tongue is discussed. PMID- 22102076 TI - Traumatic ulcerative granuloma with stromal eosinophilia. A case report and short literature review. AB - We introduce a case of 53-year-old female with rapidly developing tongue ulceration clinically mimicking squamous cell carcinoma of the oral mucosa. After a microscopic examination traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) was diagnosed. In a short literature review, we characterize this entity, analyse its aetiology and nature. Differential diagnosis is also discussed. PMID- 22102077 TI - Could Riedel's thyroiditis be subacute thyroiditis? A case report. AB - Our purpose in this paper is to make a case for the need to question whether Riedel's thyroiditis is in fact a rare variety of subacute thyroiditis. Total thyroidectomy was performed on a patient with a huge thyroid mass. The histopathological diagnosis was Riedel's thyroiditis with classical lymphoplasmacytic infiltration destroying thyroid tissue and invading perithyroidal soft tissue. However, in addition, histopathology showed epithelioid granulomas containing multinuclear giant cells. The existence of these giant cells led us to place this case somewhere between Hashimoto's thyroiditis and subacute thyroiditis (de Quervain's). Since giant cells are seen in the histopathology of subacute thyroiditis, we propose that the possibility of Riedel's thyroiditis being a form of subacute thyroiditis be observed and studied. PMID- 22102078 TI - A case of villous adenoma of the urinary bladder with tubulovillous architecture: characterization by immunohistochemical analysis. AB - Villous adenomas of the urinary tract are rare as compared to urothelial carcinoma. We report a case of urinary bladder villous adenoma in a 90-year-old woman. Cystoscopic examination revealed a papillary tumour in the diverticulum at the posterior wall of the urinary bladder. Transurethral resection was performed and histopathological examination revealed predominantly tubulovillous architecture, and showed an identical immunohistochemical profile to villous adenoma associated with cystitis glandularis. PMID- 22102079 TI - Benign fibrous histiocytoma of the skin metastasizing to the inguinal lymph node. AB - Benign fibrous histiocytoma (FH, dermatofibroma) is a common skin lesion but its metastasizing variant is extremely rare and only a few cases have been reported to date. The usual sites of metastases include locoregional lymph nodes and lung. In the majority of cases, the clinical course is indolent. At present, there are no reliable clinical or histological features of the primary tumour that could predict the risk of locoregional or distant metastases. Authors describe a case of metastasizing FH and briefly review available data. PMID- 22102080 TI - What is your diagnosis? PMID- 22102082 TI - Serum YKL-40 following resection for cerebral glioblastoma. AB - The lack of serum biomarkers for assessing the prognosis of patients with cerebral glioblastoma multiforme (GBM) prompted the present study in order to evaluate the significance of serum YKL-40 values in patients operated on for glioblastoma. An homogeneous population of 60 patients who underwent surgical removal of GBM underwent a standard treatment (surgery, radiotherapy, chemotherapy in the same schedule) and standard radiological monitoring (same MRI sequences at pre-defined stages). Serum YKL-40 levels (Quidel Corporation, San Diego, CA) were evaluated after dividing patients into two groups on the basis of the extent of resection (total or sub-total) according to the MRI results obtained within 48 h following surgery. YKL-40 serum values, significantly higher in GBM patients than in healthy subjects, were also higher among patients who had undergone subtotal resection than in patients who underwent extensive resection. The effect of YKL-40 on overall survival was analyzed by comparing the change in marker concentration occurring in the first postoperative week with the baseline value. A significant (P = 0.04) hazards ratio of 1.97 was found at multivariate analysis. A significant association with shorter outcome (median survival time, 76 days) was found in patients whose postoperative YKL-40 concentration increases higher than, or equal to, 100%; a 50% increase can still be considered a negative prognostic index. The evaluation of the biochemical marker YKL-40 might provide earlier and additional information to that obtained using traditional factors and be a further aid in establishing the prognosis of GBM patients who have undergone surgery. PMID- 22102081 TI - Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor. AB - The search for molecular markers which predict response to chemotherapy is an important aspect of current neuro-oncology research. MGMT promoter methylation is the only proved marker of glioblastoma. The purpose of this study was to assess the effect of topoisomerase expression on glioblastoma survival and study the mechanisms involved. The transcript levels of all isoforms of the topoisomerase family in all grades of diffuse astrocytoma were assessed. A prospective study of patients with glioblastoma treated by a uniform treatment procedure was performed with the objective of correlating outcome with gene expression. The ability of TOP2A enzyme to relax the super coiled plasmid DNA in the presence of temozolomide was evaluated to assess its effect on TOP2A. The temozolomide cyctotoxicity of TOP2A-silenced U251 cells was assessed. The transcript levels of TOP2A, TOP2B, and TOP3A are upregulated significantly in GBM in comparison with lower grades of astrocytoma and normal brain samples. mRNA levels of TOP2A correlated significantly with survival of the patients. Higher TOP2A transcript levels in GBM patients predicted better prognosis (P = 0.043; HR = 0.889). Interestingly, we noted that temozolomide inhibited TOP2A activity in in-vitro enzyme assays. We also noted that siRNA knock down of TOP2A rendered a glioma cell line resistant to temozolomide chemotherapy. We demonstrated for the first time that temozolomide is also a TOP2A inhibitor and established that TOP2A transcript levels determine the chemosensitivity of glioblastoma to temozolomide therapy. Very high levels of TOP2A are a good prognostic indicator in GBM patients receiving temozolomide chemotherapy. PMID- 22102083 TI - Bacillus berkeleyi sp. nov., isolated from the sea urchin Strongylocentrotus intermedius. AB - A bacterial strain, designated KMM 6244(T), was isolated from the sea urchin Strongylocentrotus intermedius and subjected to a polyphasic taxonomic investigation. The bacterium was found to be heterotrophic, aerobic, non-motile and spore-forming. Comparative phylogenetic analysis based on 16S rRNA gene sequencing placed the marine isolate in the genus Bacillus. The nearest neighbor of strain KMM 6244(T) was Bacillus decolorationis LMG 19507(T) with a 16S rRNA gene sequence similarity of 98.0%. Sequence similarities with the other recognized Bacillus species were less than 96.0%. The results of the DNA-DNA hybridization experiments revealed a low relatedness (37%) of the novel isolate with the type strain of B. decolorationis LMG 19507(T). Strain KMM 6244(T) grew at 4-45 degrees C and with 0-12% NaCl. It produced catalase and oxidase and hydrolyzed aesculin, casein, gelatin and DNA. The predominant fatty acids were anteiso-C(15:0), iso-C(15:0), anteiso-C(17:0), C(15:0), iso-C(16:0) and iso C(14:0). The DNA G + C content was 39.4 mol%. A combination of phylogenetic, genotypic and phenotypic data clearly indicated that strain KMM 6244(T) represents a novel species in the genus Bacillus, for which the name Bacillus berkeleyi sp. nov. is proposed. The type strain is KMM 6244(T) (KCTC 12718(T) = LMG 26357(T)). PMID- 22102084 TI - NF-kappaB p65 phosphorylated at serine-536 is an independent prognostic factor in Swedish colorectal cancer patients. AB - INTRODUCTION: The NF-kappaB transcription factor protein family has diverse cellular and biological functions, and posttranslational modification is important to regulate these functions. An important site of phosphorylation of NF kappaB p65 subunit is at serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization, and protein stability. PATIENTS AND METHODS: In this study, we investigated expression of phospho-Ser536-p65 in colorectal cancers and its relationships with clinicopathological factors. The expression of phospho-Ser536 p65 was examined by immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens, and 18 metastases in the lymph nodes. RESULTS: The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumor (p < 0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumors correlated with worse survival of the patients independently of gender, age, tumor location, stage, and differentiation (p = 0.04; hazard ratio, 1.89; 95% CI 1.03-3.47). CONCLUSION: The NF-kappaB p65 subunit phosphorylated at serine-536 is an independent prognostic factor in colorectal cancer patients. PMID- 22102085 TI - The sodium-driven chloride/bicarbonate exchanger in presynaptic terminals. AB - The sodium-driven chloride/bicarbonate exchanger (NDCBE), a member of the SLC4 family of bicarbonate transporters, was recently found to modulate excitatory neurotransmission in hippocampus. By using light and electron microscopic immunohistochemistry, we demonstrate here that NDCBE is expressed throughout the adult rat brain, and selectively concentrates in presynaptic terminals, where it is closely associated with synaptic vesicles. NDCBE is in most glutamatergic axon terminals, and is also present in the terminals of parvalbumin-positive gamma aminobutyric acid (GABA)ergic cells. These findings suggest that NDCBE can regulate glutamatergic transmission throughout the brain, and point to a role for NDCBE as a possible regulator of GABAergic neurotransmission. PMID- 22102086 TI - Fibrillary glomerulonephritis in a patient with systemic lupus erythematosus: a rare association. AB - We report the case of a 28-year-old man with systemic lupus erythematosus (SLE) and rapidly progressive glomerulonephritis (RPGN) due to fibrillary glomerulonephritis (FGN). The patient had a history of SLE and had been treated with mycophenolate mofetil, prednisone, and intravenous cyclophosphamide for his renal and extra-renal manifestations. In spite of this treatment, he developed RPGN. A subsequent renal biopsy revealed diffuse proliferative glomerulonephritis with fibrillary deposits. SLE is rarely associated with FGN, however FGN should be considered in the differential diagnosis of any SLE patient with RPGN. PMID- 22102087 TI - Plasticized methylcellulose coating for reducing oil uptake in potato chips. AB - BACKGROUND: As a result of consumers' health concerns and the trend towards healthier and low-fat food products, research has been undertaken to reduce the amount of fat absorbed in fried foods. This work focused on studying the efficacy of sorbitol and glycerol as plasticizers of methylcellulose coatings used to reduce oil uptake during the frying process of potato chips RESULTS: Changes in color, mechanical properties, water activity and lipid oxidation during storage were monitored. Also, an explanation regarding the different performances between both methylcellulose coatings with and without plasticizer was attained and techniques from the field of packaging films such as dynamic mechanical analyzer (DMA) and Fourier transform infrared spectroscopy were applied to analyze the behavior of coatings submitted to the frying operation. The application of a methylcellulose coating was an adequate choice to reduce oil absorption in fried potato chips. The most effective formulation was 10 g L(-1) methylcellulose with the addition of 7.5 g L(-1) sorbitol. With the incorporation of this formulation, oil absorption was reduced by 30%. Neither the sorbitol concentration nor the presence of the MC coating affected the puncture maximum force and color parameters L and a*. The results of the sensory analysis indicated that the panelists could not distinguish between the coated and uncoated potato chips. CONCLUSION: Methylcellulose-based coating plasticized with sorbitol could be an alternative for obtaining healthier potato chips. PMID- 22102088 TI - Domino reactions of 2-methyl chromones containing an electron withdrawing group with chromone-fused dienes. AB - Domino reactions of 2-methyl substituted chromones containing an electron withdrawing group at the 3-position with chromone-fused dienes synthesized a diverse range of benzo[a]xanthones and complicated chromone derivatives. These multiple-step reactions result in either two or three new C-C bonds without a transition metal catalyst or an inert atmosphere. PMID- 22102090 TI - Enhanced Recovery After Surgery (ERAS) program attenuates stress and accelerates recovery in patients after radical resection for colorectal cancer: a prospective randomized controlled trial. AB - BACKGROUND: The aim of this trial was to compare the Enhanced Recovery After Surgery (ERAS) program with conventional perioperative management in patients who underwent radical resection for colorectal cancer. METHODS: A combination of evidence-based and consensus methodology was used to develop the ERAS protocol. Five hundred ninety-seven consecutive patients who underwent elective colorectal resection were randomized to either the ERAS (n = 299) or the control group (n = 298). Outcomes relating to nutrition and metabolism index, stress index, and recovery index were measured and recorded. RESULTS: Demographic and operative data were similar between the two groups. Patients in the ERAS group showed improved nutritional status when compared with those of the control group. On postoperative day (POD) 1, the HOMA-IR (insulin resistance index) of the ERAS group was lower than that of the control group (p < 0.001). The cortisol level of the control group was elevated on both POD 1 (p = 0.007) and POD 5 (p = 0.002) compared to the preoperative level. However, the cortisol level of the ERAS group was not increased until POD 5 (p = 0.001). Reduced levels of TNF-alpha, IL-1beta, IL-6, and IFN-gamma in the ERAS group indicated less postoperative stress responses. In addition, ERAS was associated with accelerated recovery of gastrointestinal function. The postoperative length of stay (p < 0.001) and expense (p < 0.001) for the ERAS group were reduced in comparison to the controls. Twenty-eight cases in the control group and twenty-nine in the ERAS group suffered complications, which was not significantly different. CONCLUSION: The ERAS protocol attenuates the surgical stress response and accelerates postoperative recovery without compromising patient safety. PMID- 22102091 TI - Is pretreatment endoscopic biopsy a good predictor of signet ring cell histology in gastric carcinoma? AB - BACKGROUND: Signet ring cell (SRC) carcinoma is defined as an adenocarcinoma in which >50% of the total operative specimen consists of isolated or small groups of malignant cells containing intracytoplasmic mucins (hSRCs). We previously demonstrated that hSRCs are a predictor of poor prognosis with specific tumoral characteristics suggesting the need for a dedicated therapeutic strategy before surgery. However diagnostic accuracy and prognostic value of SRCs on pretreatment biopsies (bSRCs) is unknown. The aim of the study was to determine if bSRCs can accurately predict hSRCs and survival. METHODS: A retrospective analysis was performed among 254 patients with an adenocarcinoma. We performed pretreatment endoscopic biopsies and histopathologic analysis of the surgical specimen. Pretreatment endoscopic biopsy results were compared with definitive pathologic results and were correlated with long-term survival. RESULTS: From 254 patients enrolled, 96 had bSRCs (37.8%), and 101 (39.8%) had hSRCs. Pretreatment biopsy results were correct in 89 of 101 patients with hSRC (sensitivity 88.1%) and in 146 of 153 with histologic non-SRCs (hNSRCs) (specificity 95.4%). The positive and negative predictive values for the biopsies were 92.7, and 92.4%, respectively, with an overall accuracy of 92.5%. When compared to the biopsy results, non-SRCs (bNSRCs), bSRCs were associated with poorer survival and were identified as an independent factor for poor prognosis (hazard ratio 1.89 with 95% confidence interval 1.35 to 2.64, P < 0.001). CONCLUSIONS: The presence of signet ring cells in samples obtained from routine pretreatment endoscopic biopsies accurately predicts SRC histology and poor prognosis. The specific therapeutic strategy can consequently be considered from the initial diagnosis. PMID- 22102092 TI - Analysis of trace elements (Cu, Cd, and Zn) in the muscle, gill, and liver tissues of some fish species using anodic stripping voltammetry. AB - Heavy metal (Cu, Cd, Zn) concentration of the muscle, gill, and liver of Otolithes rubber, Pampus argenteus, Parastromateus niger, Scomberomorus commerson, and Onchorynchus mykiss are determined by anodic stripping voltammetry method. The results show that the concentration of Cu, Cd, and Zn varied between 0.44 and not detected, 0.585 and 0.001, and 0.450 and 0.005 MUg/g, respectively. It is interesting that in O. mykiss, the mean value of copper concentration was more than other marine organisms of this study, while in P. niger, the mean value of copper was minimum. The results of this study indicate that in the different tissues of fish species (O. rubber, P. argenteus, P. niger, S. commerson, and O. mykiss), the concentrations of Cu, Cd, and Zn were significantly lower than the permissible FAO/WHO levels. PMID- 22102093 TI - The field of schizophrenia: strengths, weaknesses, opportunities, and threats. PMID- 22102094 TI - CNTRICS imaging biomarkers final task selection: Long-term memory and reinforcement learning. AB - Functional imaging paradigms hold great promise as biomarkers for schizophrenia research as they can detect altered neural activity associated with the cognitive and emotional processing deficits that are so disabling to this patient population. In an attempt to identify the most promising functional imaging biomarkers for research on long-term memory (LTM), the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative selected "item encoding and retrieval," "relational encoding and retrieval," and "reinforcement learning" as key LTM constructs to guide the nomination process. This manuscript reports on the outcome of the third CNTRICS biomarkers meeting in which nominated paradigms in each of these domains were discussed by a review panel to arrive at a consensus on which of the nominated paradigms could be recommended for immediate translational development. After briefly describing this decision process, information is presented from the nominating authors describing the 4 functional imaging paradigms that were selected for immediate development. In addition to describing the tasks, information is provided on cognitive and neural construct validity, sensitivity to behavioral or pharmacological manipulations, availability of animal models, psychometric characteristics, effects of schizophrenia, and avenues for future development. PMID- 22102095 TI - Visual analogue scale: evaluation of the instrument for the assessment of pruritus. AB - The aim of this study was to evaluate the visual analogue scale (VAS) as a method of pruritus assessment. A total of 310 subjects with pruritic dermatoses (148 Caucasian subjects and 162 Asian subjects) were recruited. The patients assessed pruritus intensity using the horizontal and vertical VAS, numeric rating scale (NRS) and verbal rating scale (VRS). All scales showed very good reproducibility (intraclass coefficient (ICC) > 0.8). No significant differences were found between the horizontal and vertical VAS (5.3 +/- 2.9 vs. 5.3 +/- 3.0 points, p = 0.34). Using NRS, patients rated their pruritus significantly higher than with VAS (5.7 +/- 2.6 points, p < 0.01). VRS showed the highest correlation with NRS (R = 0.82, p < 0.001), followed by horizontal (R = 0.75, p < 0.001) and vertical VAS (R=0.74, p < 0.001). Based on detailed analysis following VAS categories were proposed: 0 = no pruritus, > 0-< 4 points = mild pruritus, >= 4-< 7 points = moderate pruritus, >= 7-< 9 points = severe pruritus, and >= 9 points = very severe pruritus. In conclusion, the VAS is a valuable method of pruritus measurement. PMID- 22102096 TI - Flavin-containing monooxygenases from Phanerochaete chrysosporium responsible for fungal metabolism of phenolic compounds. AB - We investigated the cellular responses of the white-rot basidiomycete Phanerochaete chrysosporium against vanillin. Based upon a proteomic survey, it was demonstrated that two flavin-containing monooxygenases (PcFMO1 and PcFMO2) are translationally up-regulated in response to exogenous addition of vanillin. To elucidate their catalytic functions, we cloned cDNAs and heterologously expressed them in Escherichia coli. The recombinant PcFMO1 showed catalytic activities against monocyclic phenols such as phenol, hydroquinone, and 4 chlorophenol. In addition, the product from hydroquinone was identified as 1,2,4 trihydroxybenzene, an important intermediate in a metabolic pathway of aromatic compounds in which the aromatic ring of 1,2,4-trihydroxybenzene can be further cleaved by fungal dioxygenases for mineralization. Thus, the ortho-cleavage pathway of phenolic compounds would presumably be associated with PcFMO1. PMID- 22102097 TI - The placenta and gestational diabetes mellitus. AB - By its location between maternal and fetal bloodstreams the human placenta not only handles the materno-fetal transport of nutrients and gases, but may also be exposed to intrauterine conditions adversely affecting placental and fetal development. Such adverse conditions exist in pregnancies complicated by gestational diabetes mellitus (GDM), and have been associated with alterations in placental anatomy and physiology. These alterations are mainly based on changes on the micro-anatomical and/or even molecular level including aberrant villous vascularization, a disbalance of vasoactive molecules, and enhanced oxidative stress. The consequence thereof may be impaired fetal oxygenation and changes in transplacental nutrient supply. Although transplacental glucose flux is flow limited and independent of glucose transporter availability, transport of essential and nonessential amino acids and expression of genes involved in lipid transport and metabolism are significantly affected by GDM. PMID- 22102098 TI - Immunopathology and Th1/Th2 immune response of Campylobacter jejuni-induced paralysis resembling Guillain-Barre syndrome in chicken. AB - Immunopathogenesis of Campylobacter jejuni-associated Guillain-Barre syndrome (GBS) is not yet well established probably due to lack of experimental model. Therefore, we studied the Th1/Th2 immune response and pathological changes in C. jejuni-induced chicken model for GBS. C. jejuni (5 * 10(9) CFU/ml) and placebo were fed to 30 chickens each. Stools of all birds were negative for C. jejuni by culture and PCR before experiment. The birds were regularly assessed for disease symptoms up to 30 days. Sciatic nerves from all chickens were examined at 5 days intervals by histopathology and immunohistochemistry, and also for the expression of Th1/Th2 cytokines. Twenty-two chickens (73.3%) developed diarrhea after C. jejuni infection; 18 (60.0%) experimental chickens developed GBS-like paralytic neuropathy. Pathology in the sciatic nerves of these chickens included perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration, myelin swelling and presence of macrophages within the nerve fibers on 10th-20th post infection day (PID). Cytokines (IFN-gamma, IL-1beta, TNF-alpha, IL-6 and IL-2) were elevated in early phase (5th-15th PID) and TGF-beta2, IL-10 and IL-4 in the recovery phase (25th-30th PID) of the disease. The study provides evidence that C. jejuni infection in the chicken can provide an experimental animal model of GBS. PMID- 22102099 TI - Pilot study on sex hormone levels and fertility in women with malignant gliomas. AB - The standard treatment of patients with high-grade gliomas based on conformal radiation therapy (RT) with or without chemotherapy (CT) may induce endocrine deficiencies of pituitary and subsequently also of peripheral hormones. In 24 premenopausal women with high-grade gliomas treated with RT and CT, hormonal changes and their impact on quality of life were investigated. Serum concentrations of gonadal, pituitary and of thyroid hormones were measured at various time points after initial anti-neoplastic therapy. Additionally, endovaginal ultrasound was performed and patients' quality of life (QLQ) and female role functioning were assessed. Of 24 patients, 23 (96%) reported a change in their menstrual pattern. Twenty-one patients reported at least transient amenorrhoea with a mean duration of 26.1 months (3-96 months). Increased prolactin serum levels were found in 10 women, 8 of them with amenorrhoea. Thirteen women showed menopausal or perimenopausal hormone pattern, 3 a pattern compatible with hypogonadism. Changes in thyroid hormone levels were seen in 8 patients. Furthermore, patients complained about fatigue and menopausal symptoms, like flushes, weakness and gain of weight. They felt a decrease of libido combined with the loss of attractiveness as a female, and an increased need for tender care and security. The hormonal deficiencies in female patients with malignant gliomas require thorough evaluation and individualized diagnosis and sometimes intervention. PMID- 22102100 TI - Markers of oxidative stress after ablation of atrial fibrillation are associated with inflammation, delivered radiofrequency energy and early recurrence of atrial fibrillation. AB - BACKGROUND: The role of oxidative stress after radiofrequency ablation of atrial fibrillation (AF) has not yet been well characterized. We sought to evaluate the time course of biomarkers of oxidative stress and inflammation after AF ablation and their association with clinical variables. METHODS: Thirty consecutive patients (57.9 +/- 1.7 years, 63% males) with paroxysmal AF underwent pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Biomarkers were determined in blood samples before ablation and 6 h, 1, 2, 7, 30, 90 and 180 days post-ablation. RESULTS: The pro-oxidant enzyme myeloperoxidase and oxidized low-density lipoprotein reflecting oxidant damage of lipoproteins increased 2.9 +/- 0.2-fold and 1.2 +/- 0.1-fold, respectively, and were significantly up-regulated until day 2 post-ablation. The anti-oxidant enzyme copper/zinc superoxide dismutase did not change significantly. Inflammatory markers significantly increased (high-sensitivity C-reactive protein (hs-CRP): 41 +/- 8-fold; interleukin-6: 4.4 +/- 0.7-fold) for 7 and 2 days, respectively. The increase of myeloperoxidase and hs-CRP was interrelated and both predicted early recurrence of AF within the first post-ablation week (both p < 0.05). The increase of both markers was associated with the amount of delivered radiofrequency energy (p < 0.05). The up-regulation of hs-CRP correlated with troponin T (p = 0.008), while myeloperoxidase and troponin T were borderline associated (p = 0.054). However, the oxidative and inflammatory responses did not predict long-term ablation outcome (p > 0.05). CONCLUSIONS: Markers of oxidative stress showed a significant up-regulation during the first 2 days after AF ablation. Their up-regulation was linked to inflammation, delivered radiofrequency energy, and early recurrence of AF, but did not predict long-term ablation outcome. PMID- 22102101 TI - Rapid pacing facilitates grasping and MitraClip implantation in severe mitral leaflet prolapse. PMID- 22102102 TI - Profile of an American amateur rugby union sevens series. AB - BACKGROUND: Rugby union will enter the Olympic arena as Rugby Sevens in 2016. PURPOSE: To investigate the injury rate, injury type, and nature of injuries sustained in an amateur American rugby union sevens tournament series. STUDY DESIGN: Descriptive epidemiology study. METHODS: The rate, demographics, and characteristics of injury were evaluated in 1536 rugby union sevens players, from 128 sides, competing in 4 amateur 1-day tournaments in a USA Rugby local area rugby union. RESULTS: Forty-eight injuries occurred over 4 tournaments, for an injury rate of 55.4 injuries per 1000 playing hours. Head and neck injuries were most common (33.3% of injuries), followed by upper extremity (31.3%), trunk (18.8%), lower extremity (14.6%), and physiologic injuries (2.1%). The most common type of injury was ligament sprain (25.0%); followed by concussion (14.6%), hematoma/contusion (12.5%), muscle strain (10.4%), and abrasion (8.3%). Tackling was the most common mechanism of injury (74.5%). Males were injured at a significantly higher rate than females (RR, 7.5, P < .01), but no significant difference was observed based on player position (P = .08). CONCLUSION: Injuries are common among American amateur rugby athletes, with a substantial proportion involving the head and neck region. CLINICAL RELEVANCE: Understanding injury patterns in an American rugby union will be important for formulating future injury prevention, assessment, and treatment protocols. PMID- 22102103 TI - Head and face injuries during the men's field hockey Junior World Cup 2009. AB - BACKGROUND: Head and face injuries in field hockey are a concern. However, published data on injuries in field hockey are minimal, with apparently no reports on head and face injuries in elite youth hockey players during major international tournaments. PURPOSE: To provide a descriptive account of head and face injuries in elite youth male field hockey players during the Men's Junior World Cup 2009. STUDY DESIGN: Descriptive epidemiological study. METHODS: A total of 324 players were observed during 58 matches in the tournament. The injury reporting system was based on that used in team sports during international tournaments. All the head and face injury documentation was done by direct on location observation by a trained sports medicine physician followed by confirmation from the team doctors or physical therapists. RESULTS: A total of 24 head and face injuries were documented. The overall injury frequency rate was 16 per 1000 match hours and 19 per 1000 player matches. There were 92% of injuries that were of contact type, with the head being the most common site and contusion being the most common type of injury. The incidence of injuries was higher during the second half and during the medal/ranking phase of the tournament. CONCLUSION: The risk of head and face injuries is high in elite youth players with a potential of both short- and long-term player time loss in international tournaments. Rigorous enforcement of rules prohibiting body contact can significantly reduce the chances of head and face injuries in elite youth field hockey players. In addition, player education on the injury risks and safe practices at the developmental stages is desirable to prevent injuries and prolong sporting careers. PMID- 22102104 TI - Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice. AB - Ethyl tertiary butyl ether (ETBE) is used as an additive to gasoline to reduce carbon monoxide emissions in some developed countries. So far, ETBE was not found with positive results in many genotoxic assays. This study is undertaken to investigate the modifying effects of deficiency of aldehyde dehydrogenase 2 (ALDH2) on the toxicity of ETBE in the livers of mice. Eight-week-old wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice of both sexes were exposed to 0, 500, 1,750, and 5,000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Histopathology assessments and measurements of genetic effects in the livers were performed. Significantly increased accidences of centrilobular hypertrophy were observed in the livers of WT and KO mice of both sexes in 5,000 ppm group; there was a sex difference in centrilobular hypertrophy between male and female KO mice, with more severe damage in the males. In addition, DNA strand breaks, 8 hydroxyguanine DNA-glycosylase (hOGG1)-modified oxidative base modification, and 8-hydroxydeoxyguanosine as genetic damage endpoints were significantly increased in three exposure groups in KO male mice, while these genotoxic effects were only found in 5,000 ppm group of KO female mice. In WT mice, significant DNA damage was seen in 5,000 ppm group of male mice, but not in females. Thus, sex differences in DNA damage were found not only in KO mice, but also in WT mice. These results suggest that ALDH2 polymorphisms and sex should be taken into considerations in predicting human health effects of ETBE exposure. PMID- 22102105 TI - Selenium: an element with two faces. PMID- 22102106 TI - Highlight report: the bisphenol A controversy. PMID- 22102107 TI - Tonotopic organization of the superior olivary nucleus in the chicken auditory brainstem. AB - Topographic maps are salient features of neuronal organization in sensory systems. Inhibitory components of neuronal circuitry are often embedded within this organization, making them difficult to isolate experimentally. The auditory system provides opportunities to study the topographic organization of inhibitory long-range projection nuclei, such as the superior olivary nucleus (SON). We analyzed the topographic organization of response features of neurons in the SON of chickens. Quantitative methods were developed to assess and communicate this organization. These analyses led to three main conclusions: 1) sound frequency is linearly arranged from dorsal (low frequencies) to ventral (high frequencies) in SON; 2) this tonotopic organization is less precise than the organization of the excitatory nuclei in the chicken auditory brainstem; and 3) neurons with different response patterns to pure tone stimuli are interspersed throughout the SON and show similar tonotopic organizations. This work provides a predictive model to determine the optimal stimulus frequency for a neuron from its spatial location in the SON. PMID- 22102136 TI - Isolation of metallothionein from cells derived from aggressive form of high grade prostate carcinoma using paramagnetic antibody-modified microbeads off-line coupled with electrochemical and electrophoretic analysis. AB - Prostate cancer with altered zinc(II) cell metabolism is the second most frequently diagnosed cancer in developed countries. The alterations of zinc(II) metabolism can influence metabolism of other metal ions and can also be associated with the expression and translation of metal-binding proteins including metallothioneins. The aim of this article was to optimize immunoseparation protocol based on paramagnetic beads conjugated with protein G for the isolation of metallothionein. Isolated metallothionein was determined by differential pulse voltammetry Brdicka reaction and SDS-PAGE. Optimal conditions: antigen-binding time - 60 min, temperature - 70 degrees C, and buffer composition and pH - acetate buffer, pH 4.3, were determined. Under the optimized conditions, lysates from 22Rv1 prostate cancer cells treated with various concentrations of cadmium(II) and copper(II) ions were analyzed. We observed strong correlation in all experimental groups and all lysate types (r>0.83 at p<0.041) between metallothionein concentration related to viability and concentration of copper(II) ions and cadmium(II) ions in medium. Moreover, the results were compared with standard sample preparation as heat treatment and SDS-PAGE analysis. PMID- 22102137 TI - Non-compliance to the continuous ambulatory peritoneal dialysis procedure increases the risk of peritonitis. AB - BACKGROUND: Peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) is the leading cause of technique failure. Information on the impact of non-compliance in performing CAPD exchange on peritonitis is limited. We aimed to find the prevalence of non-compliance to the CAPD procedure and its influence on the incidence of peritonitis. METHODS: This observational study included 30 adult patients undergoing CAPD. The CAPD exchange procedure was observed at home and assessed as per the structured checklist and categorized into poor, average and good compliance. The compliance was correlated with the episodes of peritonitis in previous 1 year. RESULTS: The patients' mean age was 52 +/- 13 years and the mean duration of CAPD was 2.1 +/- 0.9 years. Only 16.5% of patients were good performers, while 67% were average performers, and 16.5% were poor performers. The technique skill was similar across all the steps of the procedure. The most common improperly performed steps were: not putting on a face mask in 68%, not flushing the tubing system in 60%, and not washing hands in 24%. Poor adherence to procedure was independent of age, gender, education and duration of dialysis. Ten episodes of peritonitis occurred in 5 patients over 1-year period. Peritonitis occurred in 60% of poor performers, whereas fully compliant patients had no peritonitis. Also 40% of the poorly compliant patients had multiple episodes of peritonitis. CONCLUSIONS: Poor compliance in performing the CAPD procedure is a modifiable risk factor for peritonitis. Adherence to recommended aseptic technique is the cornerstone of peritonitis prevention. PMID- 22102138 TI - Percutaneous nephrolithotomy in polycystic kidney disease: is it safe and effective? AB - PURPOSE: Nephrolithiasis is common in patients with autosomal dominant polycystic kidney disease (ADPKD). Percutaneous management of nephrolithiasis is challenging because of a large number of parenchymal cysts and distorted calyceal anatomy. These patients also have varying grades of chronic kidney disease and are at increased risk of bleeding, which further increases the challenge. The objective of the study is to study the efficacy and safety of PCNL in ADPKD. MATERIALS AND METHODS: We retrospectively analyzed twenty-two patients of ADPKD with renal calculi managed by percutaneous nephrolithtomy (PCNL) from January 2000 to January 2010. Patients were divided into two groups: group I (serum creatinine <= 1.5 mg%), group II (serum creatinine >1.5 mg%). RESULTS: PCNL was done in 25 renal units among 22 patients. Sixteen patients had chronic kidney disease, and the average stone burden was 2.4 cm +/- 0.8 cm. The overall success rate (complete stone clearance/residual fragments <4 mm) was 88% (22/25). Two patients required relook PCNL for residual stone and one required ESWL for the incomplete clearance. Mean preoperative serum creatinine in group I was 0.9 +/- 0.1 mg% and in group II 3.1 +/- 1.2 mg%. There was improvement in serum creatinine in group II (1.4 +/- 0.5 mg%) postoperatively. Three patients required blood transfusion (13%) and four patients had fever postoperatively (18%). None of the patients required angioembolization. CONCLUSION: Despite the distorted calyceal anatomy and associated chronic kidney disease, PCNL is safe and effective in managing nephrolithiasis in polycystic kidney disease. PMID- 22102139 TI - Reducing lipid peroxidation for improving colour stability of beef and lamb: on farm considerations. AB - Meat colour and lipid stability are important sensory properties. Myoglobin oxidation is correlated with lipid oxidation, and one can exacerbate the occurrence of the other. Approaches to reduce both oxidative processes could focus on minimising oxidising agents in meat. In on-farm practices, dietary supplementation of antioxidants is a useful approach for improving lipid stability and then meat colour stability, and further improvement could be a combination of using hydrophobic and hydrophilic antioxidants. Genetic variations in the endogenous antioxidant systems could be identified for the development of a breeding strategy to bring a long-term benefit to the meat industry. To have a better understanding of oxidative stress and oxidation of long chain unsaturated fatty acids in live animals, the isoprostanes could be measured as an effective marker in vivo. PMID- 22102140 TI - Beliefs about expectations moderate the influence of expectations on pain perception. AB - BACKGROUND: Expectations congruently influence, or bias, pain perception. Recent social psychological research reveals that individuals differ in the extent to which they believe in expectation biases and that individuals who believe in expectation biases may adjust for this bias in their perceptions and reactions. That is, idiosyncratic beliefs about expectations can moderate the influence of expectations on experience. PURPOSE: Prior research has not examined whether idiosyncratic beliefs about expectations can alter the degree to which one's expectations influence pain perception. Using a laboratory pain stimulus, we examined the possibility that beliefs about expectation biases alter pain responses following both pain- and placebo-analgesic expectations. METHODS: Participants' beliefs about expectation biases were measured. Next, participants were randomly assigned to receive either a pain expectation or a placebo analgesia expectation prior to a cold-pressor task. After the task, participants rated their pain. RESULTS: Beliefs about expectation biases significantly influenced pain reports. Specifically, pain reports were more influenced by provided expectations the less participants believed in expectation biases (i.e., pain expectations resulted in more pain than analgesia expectations). CONCLUSIONS: Beliefs about the expectation bias are an important and under examined predictor of pain and placebo analgesia. PMID- 22102141 TI - Lactobacillus: host-microbe relationships. AB - Lactobacilli are a subdominant component of the human intestinal microbiota that are also found in other body sites, certain foods, and nutrient-rich niches in the free environment. They represent the types of microorganisms that mammalian immune systems have learned not to react to, which is recognized as a potential driving force in the evolution of the human immune system. Co-evolution of lactobacilli and animals provides a rational basis to postulate an association with health benefits. To further complicate a description of their host interactions, lactobacilli may rarely cause opportunistic infections in compromised subjects. In this review, we focus primarily on human-Lactobacillus interactions. We overview the microbiological complexity of this extraordinarily diverse genus, we describe where lactobacilli are found in or on humans, what responses their presence elicits, and what microbial interaction and effector molecules have been identified. The rare cases of Lactobacillus septicaemia are explained in terms of the host impairment required for such an outcome. We discuss possibilities for exploitation of lactobacilli for therapeutic delivery and mucosal vaccination. PMID- 22102142 TI - Suzuki-Miyaura cross-couplings of arenediazonium tetrafluoroborate salts with arylboronic acids catalyzed by aluminium hydroxide-supported palladium nanoparticles. AB - Suzuki-Miyaura cross-couplings of arenediazonium salts with arylboronic acids catalyzed by highly active aluminium hydroxide-supported palladium nanoparticles catalyst have been investigated for the first time. The reactions are performed at 25 degrees C in MeOH without any base and ligand to afford biaryls in good to excellent yields under non-anhydrous and non-degassed conditions. PMID- 22102143 TI - Structural property of soybean protein P34 and specific IgE response to recombinant P34 in patients with soybean allergy. AB - Soybean allergy is one of the important food allergies because soybean is widely used in processed foods. P34 has been identified as the main allergen in soybeans. The main objective was to analyze the structural property of recombinant P34 and the P34 antigen-specific IgE response in soybean allergy using recombinant P34. Recombinant P34 was expressed by the BL21 (DE3) strain of Escherichia coli. Purified recombinant P34 showed oligomerization and binding to endotoxin. The binding of recombinant P34 to endotoxin was confirmed by LPS pull down assay. High-density SDS treatment dissociated oligomeric recombinant P34 and removed endotoxin. Both native P34 and purified recombinant P34 showed almost identical structural properties as determined by circular dichroism analysis. We analyzed recombinant-P34-specific IgE antibodies by the ImmunoCAP System. In ImmunoCAP using recombinant P34, all sera from healthy controls were classified as negative. A correlation was found between the specific IgE antibodies to whole soybean and recombinant P34 (r=0.526, P<0.05). The sera from 3 of 9 (33%) patients with outgrown soybean allergy and 6 of 9 (66%) patients with soybean allergy were classified as positive. SDS-treated recombinant P34 retained its structure and biological activity. Recombinant P34 is a useful tool for the analysis of antigen-specific response in soybean allergy. It may be possible to develop a modified form of recombinant P34 for the diagnosis or treatment of soybean allergy using specific immunotherapy techniques. PMID- 22102144 TI - Design of a covalently bonded glycosphingolipid microarray. AB - Glycosphingolipids (GSLs) are well known ubiquitous constituents of all eukaryotic cell membranes, yet their normal biological functions are not fully understood. As with other glycoconjugates and saccharides, solid phase display on microarrays potentially provides an effective platform for in vitro study of their functional interactions. However, with few exceptions, the most widely used microarray platforms display only the glycan moiety of GSLs, which not only ignores potential modulating effects of the lipid aglycone, but inherently limits the scope of application, excluding, for example, the major classes of plant and fungal GSLs. In this work, a prototype "universal" GSL-based covalent microarray has been designed, and preliminary evaluation of its potential utility in assaying protein-GSL binding interactions investigated. An essential step in development involved the enzymatic release of the fatty acyl moiety of the ceramide aglycone of selected mammalian GSLs with sphingolipid N-deacylase (SCDase). Derivatization of the free amino group of a typical lyso-GSL, lyso G(M1), with a prototype linker assembled from succinimidyl-[(N maleimidopropionamido)-diethyleneglycol] ester and 2-mercaptoethylamine, was also tested. Underivatized or linker-derivatized lyso-GSL were then immobilized on N hydroxysuccinimide- or epoxide-activated glass microarray slides and probed with carbohydrate binding proteins of known or partially known specificities (i.e., cholera toxin B-chain; peanut agglutinin, a monoclonal antibody to sulfatide, Sulph 1; and a polyclonal antiserum reactive to asialo-G(M2)). Preliminary evaluation of the method indicated successful immobilization of the GSLs, and selective binding of test probes. The potential utility of this methodology for designing covalent microarrays that incorporate GSLs for serodiagnosis is discussed. PMID- 22102145 TI - Rearrangement of the cone mosaic in the retina of the rat model of retinitis pigmentosa. AB - In retinitis pigmentosa (RP), the death of cones normally follows some time after the degeneration of rods. Recently, surviving cones in RP have been studied and reported in detail. These cones undergo extensive remodeling in their morphology. Here we report an extension of the remodeling study to consider possible modifications of spatial-distribution patterns. For this purpose we used S334ter line-3 transgenic rats, a transgenic model developed to express a rhodopsin mutation causing RP. In this study, retinas were collected at postnatal (P) days P5-30, 90, 180, and P600. We then immunostained the retinas to examine the morphology and distribution of cones and to quantify the total cone numbers. Our results indicate that cones undergo extensive changes in their spatial distribution to give rise to a mosaic comprising an orderly array of rings. These rings first begin to appear at P15 at random regions of the retina and become ubiquitous throughout the entire tissue by P90. Such distribution pattern loses its clarity by P180 and mostly disappears at P600, at which time the cones are almost all dead. In contrast, the numbers of cones in RP and normal conditions do not show significant differences at stages as late as P180. Therefore, rings do not form by cell death at their centers, but by cone migration. We discuss its possible mechanisms and suggest a role for hot spots of rod death and the remodeling of Muller cell process into zones of low density of photoreceptors. PMID- 22102146 TI - Urinary incontinence after treatment for prostate cancer. PMID- 22102147 TI - An unconscious patient. PMID- 22102148 TI - Don't strike and keep negotiating, urges NHS Employers. PMID- 22102149 TI - Trusts need to highlight non-salary benefits of NHS employment, conference hears. PMID- 22102150 TI - Screens to update patients in emergency departments about their progress can help to reduce aggression. PMID- 22102151 TI - Panel recommends that assisted suicide be legalised in Canada. PMID- 22102152 TI - Drive against childhood illness is jeopardised by failure to invest in sanitation, warns charity. PMID- 22102153 TI - Characteristics of pediatric patients with enterovirus meningitis and no cerebral fluid pleocytosis. AB - Human non-polio enterovirus (EV) is the most important cause of aseptic meningitis in children. Only a few studies report the lack of cerobrospinal fluid (CSF) pleocytosis in children with confirmed EV meningitis; however, the characteristics of these children have not been well defined. This paper describes the clinical and laboratory features of EV meningitis in children with no CSF pleocytosis. Clinical, laboratory, and virological data of Dutch patients <16 years diagnosed with EV meningitis, between 2003 and 2008, were analyzed retrospectively. Data of children with and without CSF pleocytosis were compared. A total of 149 children were infected with EV. Patients presented mainly with fever (n = 113), malaise (n = 43), abdominal pain (n = 47), and irritability (n = 61). Of the 60 patients with EV meningitis, 23 had no pleocytosis. Those who lacked CSF pleocytosis were younger [odds ratio (OR) 1.00; 95% confidence interval (CI) 1.000-1.002; p = 0.001], had experienced drowsiness more (OR 9.60; 95% CI 2.24-41.15; p = 0.002), had lower white blood cell counts (OR 0.73; 95% CI 0.61-0.89; p = 0.001), and had higher C-reactive protein (OR 1.13; 95% CI 1.03 1.23; p = 0.006) than those with pleocytosis. CONCLUSION: These findings show that EV meningitis occurs in the absence of CSF pleocytosis, particularly in young infants, meaning that EV meningitis in this age group cannot be solely excluded by the absence of CSF pleocytosis. They also confirm the importance of genome detection in the diagnosis of EV meningitis in young infants. PMID- 22102154 TI - Cryptotanshinione inhibits beta-amyloid aggregation and protects damage from beta amyloid in SH-SY5Y cells. AB - The deposition of amyloid beta-protein (Abeta) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Abeta42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. Drugs that inhibit Abeta42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of AD. However, the effects of CTS on the Abeta aggregation and toxicity are unclear. The current work shows the effectiveness of CTS on the inhibition of Abeta42 aggregation and toxicity to human neuroblastoma cells. In this study, we demonstrated that CTS can inhibit Abeta42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron microscopy. Furthermore, we investigated the effects of CTS on Abeta-induced oxidative cell death in cultured SH-SY5Y cells. MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Abeta42. CTS also dramatically reduced Abeta42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS may be useful in the inhibition or prevention of AD development and progression. PMID- 22102155 TI - Expression of PirB protein in intact and injured optic nerve and retina of mice. AB - The aim of this study was to investigate the expression of PirB protein in intact mice ON (optic nerve) and retina, and to evaluate its change after ON injury. The mouse ON crush model was established. The immunohistochemistry and western blot were used to detect PirB expression. We discovered PirB signals were located as beaded arrangement along the ON long axis in intact ON, disordered in injured ON, and distributed mainly in ganglion cell layer in intact and injured retina. Both PirB expression in injured ON and retina were significantly increased at 1-day post injury (1-dpi), nearly peaked at 7-dpi, but thereafter there was no significant change of them till at least 28-dpi. We concluded the expression of PirB was positive in intact ON and retina, and significantly increased after ON injury. These findings, coupled with previous studies, may imply that PirB is probably a critical molecule in inhibition of axonal regeneration by myelin inhibitors after ON injury. PMID- 22102156 TI - Chronic daily headache in children and adolescents. AB - Chronic daily headache (CDH) may be primary or secondary. Secondary causes can be suspected through "red flags" in the history and examination. With a prevalence of at least 1% and several associations, primary CDH is a common, often complex, chronic pain syndrome in children and adolescents. The intricate associations between stressors, psychiatric disorders (especially anxiety and depression), and CDH can be explained by "the limbically augmented pain syndrome" proposed by Rome and Rome. Disorders of sleep and other pain syndromes also may co-occur. For these reasons, a multiaxial classification is ideal. Many with primary CDH have features of both chronic migraine and chronic tension-type headache, contributing to confusion in subtyping. Primary CDH is often transformed from a primary episodic headache type, stressors being most responsible. Genetic factors also may facilitate chronification. Management should be biopsychosocial, family centered, and often multidisciplinary, drugs being only one component. Treatment is still based on consensus, not evidence. Girls, migraineurs, and those with psychiatric comorbidity, medication overuse, and CDH onset before the age of 13 years and lasting for 2 years or longer, are at high risk for persistence; hence, such patients should be followed up into adult life. A classification for CDH should be included in the third edition of the International Classification of Headache Disorders. PMID- 22102157 TI - Source connectivity analysis from MEG and its application to epilepsy source localization. AB - We report an approach to perform source connectivity analysis from MEG, and initially evaluate this approach to interictal MEG to localize epileptogenic foci and analyze interictal discharge propagations in patients with medically intractable epilepsy. Cortical activities were reconstructed from MEG using individual realistic geometry boundary element method head models. Directional connectivity among cortical regions of interest was then estimated using directed transfer function. The MEG source connectivity analysis method was implemented in the eConnectome software, which is open-source and freely available at http://econnectome.umn.edu . As an initial evaluation, the method was applied to study MEG interictal spikes from five epilepsy patients. Estimated primary epileptiform sources were consistent with surgically resected regions, suggesting the feasibility of using cortical source connectivity analysis from interictal MEG for potential localization of epileptiform activities. PMID- 22102158 TI - Expression of delta-protocadherins in the spinal cord of the chicken embryo. AB - Protocadherins constitute the largest subfamily of cadherin genes and are widely expressed in the nervous system. In the present study, we cloned eight members of the delta-protocadherin subfamily of cadherins (Pcdh1, Pcdh7, Pcdh8, Pcdh9, Pcdh10, Pcdh17, Pcdh18, and Pcdh19) from the chicken, and investigated their expression in the developing chicken spinal cord by in situ hybridization. Our results showed that each of the investigated delta-protocadherins exhibits a spatially restricted and temporally regulated pattern of expression. Pcdh1, Pcdh8, Pcdh18, and Pcdh19 are expressed in restricted dorsoventral domains of the neuroepithelial layer at early developmental stages (E2.5-E4). In the differentiating mantle layer, specific expression profiles are observed for all eight delta-protocadherins along the dorsoventral, mediolateral, and rostrocaudal dimensions at intermediate stages of development (E6-E10). Expression profiles are especially diverse in the motor column, where different pools of motor neurons exhibit signal for subsets of delta-protocadherins. In the dorsal root ganglion, subpopulations of cells express combinations of Pcdh1, Pcdh7, Pcdh8, Pcdh9, Pcdh10, and Pcdh17. The ventral boundary cap cells are positive for Pcdh7, Pcdh9, and Pcdh10. Signals for Pcdh8, Pcdh18, and Pcdh19 are found in the meninges. Surrounding tissues, such as the notochord, dermomyotome, and sclerotome also exhibit differential expression patterns. The highly regulated spatiotemporal expression patterns of delta-protocadherins suggest that they have multiple and diverse functions during development of the spinal cord and its surrounding tissues. PMID- 22102159 TI - Purple corn anthocyanins retard diabetes-associated glomerulosclerosis in mesangial cells and db/db mice. AB - PURPOSE: Diabetic glomerulosclerosis is the hardening of the renal glomeruli that can lead to kidney failure. In the early stage of glomerulosclerosis occur renal mesangial expansion and renal filtration dysfunction. Purple corn has been classified as a functional food and is rich in anthocyanins exerting potential disease-preventive activities. The in vitro study using human renal mesangial cells examined that anthocyanin-rich purple corn butanol fraction (PCB) can attenuate high glucose (HG)-promoted mesangial cell proliferation and matrix accumulation. METHODS: Cells were cultured for 3 days in media containing 33 mM glucose in the presence of 1-20 MUg/mL PCB. In the in vivo animal study, db/db mice were treated with 10 mg/kg anthocyanin-rich polyphenolic extracts of purple corn (PCE) for 8 weeks. RESULTS: HG enhanced mesangial production of the fibrosis biomarkers of collagen IV and connective tissue growth factor (CTGF), which was markedly attenuated by adding PCB. Such mesangial fibrosis entailed interleukin-8 activation via eliciting Tyk2-STAT signaling pathway. PCB dampened HG-promoted mesangial hyperplasia that appeared to be attributed to increased expression of platelet-derived growth factor. The 8-week administration of PCE lowered plasma glucose level of db/db mice and ameliorated severe albuminuria. Moreover, PCE lessened collagen fiber accumulation in kidney glomeruli and CTGF expression via retarding TGF-beta signaling. Protein expressions of nephrin and podocin, key proteins for filtration barrier function of the glomerular capillary wall, were repressed by treating mice with PCE. CONCLUSION: Purple corn may be a potent therapeutic agent for the treatment for diabetes-associated glomerulosclerosis accompanying proteinuria and kidney filtration dysfunction. PMID- 22102160 TI - Online enzymatic sequencing of glycans from Trastuzumab by phospholipid-assisted capillary electrophoresis. AB - CE separations of glycans taken from the cancer drug, Trastuzumab (Herceptin((r))), were accomplished using phospholipid additives. Glycans were labeled with 1-aminopyrene-3,6,8-trisulfonic acid and were separated with efficiencies as high as 510000 theoretical plates in a 60.2 cm 25 MUm id fused silica capillary. The thermally tunable phospholipid was loaded into the capillary when it possessed a viscosity similar to that of water. The temperature was increased, and the separations were performed when the material exhibited higher viscosity. Enzymes were integrated into the separation with the phospholipid additive. Neuraminidase, beta1-4 galactosidase, and beta-N acetylglucosaminidase were injected into the capillary without covalent modification and used for enzyme hydrolysis. Exoglycosidase enzymes cleaved the terminal glycan residues. The glycan sequence could be verified based on enzyme specificity. Neuraminidase was used to determine total glycan content of the low abundance glycans containing sialic acid. beta1-4 Galactosidase and beta-N acetylglucosaminidase were used sequentially in-capillary, to determine the structure of the high-abundance glycans. PMID- 22102161 TI - Antioxidant activity of food constituents: an overview. AB - Recently, there has been growing interest in research into the role of plant derived antioxidants in food and human health. The beneficial influence of many foodstuffs and beverages including fruits, vegetables, tea, coffee, and cacao on human health has been recently recognized to originate from their antioxidant activity. For this purpose, the most commonly methods used in vitro determination of antioxidant capacity of food constituents are reviewed and presented. Also, the general chemistry underlying the assays in the present paper was clarified. Hence, this overview provides a basis and rationale for developing standardized antioxidant capacity methods for the food, nutraceutical, and dietary supplement industries. In addition, the most important advantages and shortcomings of each method were detected and highlighted. The chemical principles of these methods are outlined and critically discussed. The chemical principles of methods of 2,2' azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS(.+)) scavenging, 1,1 diphenyl-2-picrylhydrazyl (DPPH(.)) radical scavenging, Fe(3+)-Fe(2+) transformation assay, ferric reducing antioxidant power (FRAP) assay, cupric ions (Cu(2+)) reducing power assay (Cuprac), Folin-Ciocalteu reducing capacity (FCR assay), peroxyl radical scavenging, superoxide anion radical (O (2) (.-)) scavenging, hydrogen peroxide (H(2)O(2)) scavenging, hydroxyl radical (OH(.)) scavenging, singlet oxygen ((1)O(2)) quenching assay and nitric oxide radical (NO(.)) scavenging assay are outlined and critically discussed. Also, the general antioxidant aspects of main food components were discussed by a number of methods which are currently used for detection of antioxidant properties food components. This review consists of two main sections. The first section is devoted to main components in the foodstuffs and beverages. The second general section is some definitions of the main antioxidant methods commonly used for determination of antioxidant activity of components in the foodstuffs and beverages. In addition, there are given some chemical and kinetic basis and technical details of the used methods. PMID- 22102162 TI - Addressing health care disparities using public reporting. AB - The literature highlights that disparities in health care performance exist. Publicly reporting data about disparities at an actionable level is needed. The Minnesota Health Care Disparities Report is designed to publicly report medical group health care performance rates for patients enrolled in state/federally funded programs. In addition, differences between patients enrolled in state funded public programs and those in private or Medicare programs at statewide and medical group levels are presented. The endeavor is a cooperative one between Minnesota Community Measurement, an independent nonprofit community organization, and the Minnesota Department of Human Services, the state Medicaid agency. Public reporting makes transparent the gaps in the delivery of health care between patients enrolled in these programs at a medical group level and can facilitate quality improvement locally, where accountability lies and actions to address disparities can occur. PMID- 22102163 TI - United States registered nurse workforce report card and shortage forecast. AB - Registered nurses (RNs) play a critical role in health care delivery. With an aging US population, health care demand is growing at an unprecedented pace. Using projected changes in population size and age, the authors developed demand and supply models to forecast the RN job shortage in each of the 50 states. Letter grades were assigned based on projected RN job shortage ratios. The number of states receiving a grade of "D" or "F" for their RN shortage ratio will increase from 5 in 2009 to 30 by 2030, for a total national deficit of 918 232 (725,619 - 1,112,112) RN jobs. There will be significant RN workforce shortages throughout the country in 2030; the western region will have the largest shortage ratio of 389 RN jobs per 100,000. Increased efforts to understand shortage dynamics are warranted. PMID- 22102164 TI - Variable open-end wave reflection in the pulmonary arteries of anesthetized sheep. AB - The aim of this study was to re-evaluate wave reflection in the healthy pulmonary arteries of sheep utilizing the time-domain-based method of wave intensity analysis. A thorough understanding of patterns of wave reflection during health and disease may provide future sensitive markers of early pulmonary vascular disease. Wave intensity was calculated from the simultaneous acquisition of proximal pulmonary arterial pressure and velocity in 12 anesthetized open-chest sheep. Normal pulmonary arterial wave speed was 2.1 +/- 0.3 m s(-1). The incident forward compression wave generated by right ventricular systole was reflected in an open-end manner as a backward expansion wave from a site 3 cm downstream, corresponding to the main pulmonary bifurcation, and in a closed-end manner as a backward compression wave from a site 21 cm downstream, corresponding to the pulmonary microcirculation. The proximal open-end reflection site was not present throughout the entire cardiac cycle. Wave reflection was minimal with only 1% of the incident forward compression wave energy reflected as a backward expansion wave and 2% as a backward compression wave. The normal pulmonary artery in open chest sheep is characterized by variable proximal open-end reflection from the main pulmonary bifurcation and fixed closed-end reflection from the microcirculation, generating backward-travelling waves of minimal intensity. PMID- 22102165 TI - Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy. AB - Multi drug resistance capacity for Mycobacterium leprae (MDR-Mle) demands the profound need for developing new anti-leprosy drugs. Since most of the drugs target a single enzyme, mutation in the active site renders the antibiotic ineffective. However, structural and mechanistic information on essential bacterial enzymes in a pathway could lead to the development of antibiotics that targets multiple enzymes. Peptidoglycan is an important component of the cell wall of M. leprae. The biosynthesis of bacterial peptidoglycan represents important targets for the development of new antibacterial drugs. Biosynthesis of peptidoglycan is a multi-step process that involves four key Mur ligase enzymes: MurC (EC:6.3.2.8), MurD (EC:6.3.2.9), MurE (EC:6.3.2.13) and MurF (EC:6.3.2.10). Hence in our work, we modeled the three-dimensional structure of the above Mur ligases using homology modeling method and analyzed its common binding features. The residues playing an important role in the catalytic activity of each of the Mur enzymes were predicted by docking these Mur ligases with their substrates and ATP. The conserved sequence motifs significant for ATP binding were predicted as the probable residues for structure based drug designing. Overall, the study was successful in listing significant and common binding residues of Mur enzymes in peptidoglycan pathway for multi targeted therapy. PMID- 22102166 TI - Alleviation of salt stress in wheat seedlings by mammalian sex hormones. AB - BACKGROUND: Salinity is one of the most serious constraints facing agriculture today. Some mechanical, chemical and biological approaches are being pursued to cope with soil salinity. Although exogenously treated mammalian sex hormones (MSHs), progesterone, beta-estradiol and androsterone, activate significant effects in various biological aspects in plants growing under normal conditions, there is no report investigating their effects on plants growing under salt stress. The present study aimed to investigate whether MSHs could alleviate the destructive effect of salt stress on wheat seedlings and thereby increase their salt tolerance. Wheat leaves were sprayed with 10(-6), 10(-8) and 10(-10) mol L( 1) concentrations of MSH on the ninth day after sowing. MSH-treated seedlings (10 day-old seedlings) were subjected to salt stress for 5 days (between days 10 and 15). RESULTS: At all the concentrations tested, MSH treatment provided a significant protection against to detrimental effects of salt stress in wheat seedlings. It improved dry weight, sugar, proline, protein, chlorophyll and glutathione contents in comparison to salinity alone. Similarly, superoxide dismutase, peroxidase, catalase, ascorbate peroxidase and nitrate reductase activities also were augmented by MSH treatment. On the other hand, increases in lipid peroxidation level, superoxide production and hydrogen peroxide content arising from salt treatment were reduced by MSH treatment. The highest salt tolerance was obtained at the concentrations of 10(-6) mol L(-1) for progesterone and 10(-8) mol L(-1) for beta-estradiol and for androsterone. CONCLUSION: MSHs could be used effectively to protect wheat seedlings from the destructive effects of salt stress by stimulating both enzymatic and non-enzymatic antioxidant mechanism and by promoting levels of osmotic protectants such as proline and sugars resulting in osmotic adjustment, carbon storage and radical scavenging in plants. PMID- 22102167 TI - Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum. AB - We investigated the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), using as model the murine small intestine. Contractile activity of a mouse ileum longitudinal muscle was examined in vitro as changes in isometric tension. Transcripts encoding for uracil-sensitive receptors was investigated by RT-PCR. UDP induced muscular contractions, sensitive to PPADS, suramin, or MRS 2578, P2Y(6) receptor antagonist, and mimicked by PSB 0474, P2Y(6)-receptor agonist. UTP induced biphasic effects characterized by an early inhibition of the spontaneous contractile activity followed by muscular contraction. UTP excitatory effects were antagonized by PPADS, suramin, but not by MRS 2578, whilst the inhibitory effects were antagonized by PPADS but not by suramin or MRS 2578. UTPgammaS, P2Y(2)/(4) receptor agonist but not 2-thio-UTP, P2Y(2) receptor agonist, mimicked UTP effects. The inhibitory effects induced by UTP was abolished by ATP desensitization and increased by extracellular acidification. UDP or UTP responses were insensitive to TTX, atropine, or L-NAME antagonized by U-73122, inhibitor of phospholipase C (PLC) and preserved in the presence of nifedipine or low Ca(2+) solution. Transcripts encoding the uracil nucleotide-preferring receptors were expressed in mouse ileum. Functional postjunctional uracil-sensitive receptors are present in the longitudinal muscle of the mouse ileum. Activation of P2Y(6) receptors induces muscular contraction, whilst activation of P2Y(4) receptors leads to inhibition of the contractile activity. Indeed, the presence of atypical UTP-sensitive receptors leading to muscular contraction is suggested. All uracil-sensitive receptors are linked to the PLC pathway. PMID- 22102168 TI - Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity. AB - Newcastle disease virus (NDV) is a negative sense RNA paramyxovirus of birds which in human tumor cells, in contrast to human non-tumor cells, has shown replication competence leading to tumor cell death (i.e., tumor selectivity and viral oncolysis). Our study demonstrates that this virus induces high levels of pro-inflammatory cytokines in the bronchial lavage fluid of mice after nasal application and also in vitro in human dendritic cells (DCs). NDV is known as a very efficient inductor of type I interferon (IFN). The presented data show the key role played by the cell surface receptor to type I IFN (IFNAR) but not by the interferon transcription factors IRF-3 and IRF-7 in the induction of the important pro-inflammatory cytokine IL-12 upon transcription of NDV genes in DCs. We show that NDV activates in infected cells the helicase RIG-I. In Tregs, the activation of RIG-I was shown in other studies to inhibit the suppressive function of these cells. We thus conclude that NDV in tumor therapy may help to stimulate T effector cells but also to block Treg cells, thereby alleviating a brake to antitumor activity. PMID- 22102169 TI - Expression of p97/VCP and ubiquitin during postnatal development of the degenerating rat retina. AB - In this study, we aimed to investigate the distribution pattern of ubiquitin and p97/VCP in the rat retina during postnatal development. Eyeballs from 1-, 4-, 10 , 36- and 72-week-old rats were examined by immunohistochemistry, and protein colocalization was determined by immunofluorescence microscopy. In the 1-week-old rat retina, p97/VCP was strongly expressed in the neuroblast layer, however no ubiquitin immunoreactivity was observed. p97/VCP immunoreactivity was present in the ganglion cell layer (GCL), inner nuclear layer (INL), outer nuclear layer (ONL), inner segment (IS) of the photoreceptor layer, and retinal pigment epithelium in the 4- and 10-week-old rat retinas. p97/VCP immunoreactivity increased significantly in the 10-week-old rat retinas. Ubiquitin was barely seen in the 4-week-old rat retinas, and ubiquitin expression was weak in the GCL and the IPL of the 10-week-old rat retinas. In the 36- and 72-week-old rats, the presence of ubiquitin was remarkable in the IS, INL, IPL and GCL, however, p97/VCP immunoreactivity was significantly decreased. Colocalization of ubiquitin and p97/VCP was also observed in the INL, IS, GCL and ONL of 36- and 72-week-old rat retinas. Our results indicate that p97/VCP immunoreactivity in the retina significantly decreases after rats reach 10 weeks of age, whereas ubiquitin immunoreactivity increases with aging. These results suggest that an altered expression pattern of p97/VCP and ubiquitin in the developing rat retina may associate with age-related retinal degeneration. PMID- 22102170 TI - Comparative analysis of type II classic cadherin mRNA distribution patterns in the developing and adult mouse somatosensory cortex and hippocampus suggests significant functional redundancy. AB - The type II classic cadherin subfamily contains a number of extensively studied genes (cdh6, cdh8, cdh11); however, the expression and function of the other members have only been partially described. Here we employed reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization to characterize cortical and hippocampal expression of all type II cadherins (with the exception of the nonneural Cdh5) in the developing and adult mouse brain. Many of these genes have ubiquitous mRNA distribution patterns throughout development, indicating high functional redundancy, which might be necessary for safe production of the strictly laminated structure of these regions. A few of the genes examined, however, exhibit a unique spatiotemporal pattern of expression, particularly during cortical development, indicating a potentially specific function. In the developing and adult hippocampus, almost all of these genes are strongly expressed in glutamatergic neurons of the CA1-CA3 pyramidal cell layer and the granular layer of the dentate gyrus. In contrast, there are significant expression differences within the GABAergic cells of the adult hippocampus. Our results indicate that selective expression of type II cadherins may generate a flexible cell-adhesion machinery for developing neurons to selectively bind to each other, but can also provide a high level of security due to the multiple overlaps in the expression domains. PMID- 22102171 TI - Age-related changes in the morphology of cerebral capillaries do not correlate with cognitive decline. AB - The effects of age on cerebral capillaries have been examined in area 46 of the prefrontal cortices of sixteen rhesus monkeys, ranging in age from 5 to 35 years. Fourteen of the monkeys had been behaviorally tested prior to their brains being prepared for electron microscopic examination. It was found that whereas the thickness of the outer basal lamina adjacent to the glial limiting membrane increased with age and showed increasing numbers of splits, the inner basal lamina between endothelial cells and pericytes did not become thicker with age, and did not show splitting. There were also no age-related changes in the extent of the coverage of endothelial cells by pericytes and no change in the frequency of mitochondria in endothelial cells. The factors that did change with age, namely, the thickness of the outer basal lamina and the increased numbers of splits in this lamina showed no correlations with the cognitive status of the monkeys, suggesting that thickening of the outer basal lamina does not contribute to cognitive decline. PMID- 22102172 TI - Brain-derived neurotrophic factor in post-partum depressive mothers. AB - Postpartum depression (PPD) is the most common psychiatric complication observed in women after they give birth. Some women are particularly sensitive to hormonal changes, starting in early menarche, thus increasing their vulnerability to psychological stressing agents that are triggered by environmental and physiological factors throughout their lives. Decreased serum brain-derived neurotrophic factor (BDNF) levels have been associated to different neuropsychiatric conditions and BDNF has been considered as a candidate marker for such dysfunctions. The goal of this study was to compare the levels of BDNF between mothers who suffer from PPD and healthy control mothers as well as to searching for associations between BDNF levels and the severity of PPD. This is a case-control study including 36 mothers with PPD and 36 healthy control mothers. PPD was defined according to the Beck Depression Inventory (BDI). Serum BDNF was assayed with the sandwich ELISA method. RESULTS: Serum levels of BDNF were significantly lower in women with PPD than in control mothers (P <= 0.03). A significant negative correlation between BDI score and serum BDNF levels was observed (P <= 0.02 and r = -0.29). Our study demonstrated that low BDNF levels are associated with PPD. This result point out to the potential usage of BDNF in the screening of PPD, which could promote early treatment and, therefore, reduce the burden to the PPD women and to the health system. PMID- 22102173 TI - A C118T polymorphism of ERCC1 and response to cisplatin chemotherapy in patients with late-stage non-small cell lung cancer. AB - PURPOSE: To investigate the association between a single-nucleotide polymorphism (SNP) of ERCC1, Asn118Asn (C -> T), and the response of patients with late-stage non-small cell lung cancer (NSCLC) (n = 142) to cisplatin-based chemotherapy. METHODS: The SNP, Asn118Asn (C -> T), in codon 118 of ERCC1 was detected using an AllGloTM Probe-based real-time PCR kit. The short-term clinical outcomes were evaluated by measuring complete and partial responses (CR and PR), whereas progression-free survival (PFS) and overall survival (OS) were determined to indicate long-term outcomes. RESULTS: The allelic frequencies of the ERCC1 codon 118 were found to be 60.6% (C/C), 33.1% (C/T), and 6.3% (T/T), respectively. Overall, the CR and PR to cisplatin-based treatment were 33.1%. Notably, the response rate of patients carrying an ERCC1 118 C/C allele was more than twofold higher than that of patients with a C/T or T/T genotype (95% confidence interval (CI), 1.065-3.910, P = 0.032). Correspondingly, the long-term median PFS and OS of patients carrying the ERCC1 118 C/C allele were significantly longer than those of patients carrying a C/T or T/T allele (P < 0.01). Besides, positive correlation was observed between the differentiation status and tumor staging as well as the C/C genotype. CONCLUSIONS: Our results suggest that this polymorphism of ERCC1 at codon 118 is associated with patient response to cisplatin-based chemotherapy in treatments of late-stage NSCLC. Moreover, by assaying this SNP in blood cells, the ERCC1 codon 118 may represent a valuable biomarker in developing individualized treatments for NSCLC patients. PMID- 22102174 TI - The SUVmax (maximum standardized uptake value for F-18 fluorodeoxyglucose) and serum squamous cell carcinoma antigen (SCC-ag) function as prognostic biomarkers in patients with primary cervical cancer. AB - OBJECTIVE: The aim of the present study was to investigate the prognostic significance of FDG uptake measured as maximum standardized uptake value (SUVmax) in primary tumor by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET/CT) and pretreatment serum squamous cell carcinoma antigen (SCC-ag) in patients with cervical cancer. METHODS: 82 consecutive patients with biopsy-proven cervical cancer who had PET/CT before any treatment were enrolled in this study. The SUVmax of the primary cervical tumor mass was obtained and compared with pretreatment SCC-ag and pathological prognostic factors after the initial treatment. RESULTS: There was significant correlation between the SUVmax of the primary tumor and tumor maximum size (p = 0.0024). The serum SCC-ag had a statistically significant association with lymph node metastasis (p = 0.0373), although there was no correlation between the SUVmax of the primary tumor and the serum SCC-ag (r (2) = -0.57). The higher SUVmax of primary tumor (>=11.2) plus pelvic lymph node (PLN) metastasis and higher SUVmax plus higher serum SCC-ag (>=6.4 ng/nl) were two most significant variables that predicted worse prognosis (p = 0.0099 and p = 0.0020, respectively). CONCLUSIONS: Higher pretreatment SUVmax of primary tumor indicated worse prognosis, and the prognosis of patients with higher pretreatment SUVmax plus PLN metastasis was even worse both in patients of squamous cell carcinoma (SCC) and non-SCC of cervix. As for patients with SCC of cervix, higher pretreatment serum SCC-ag not only predicted worse prognosis but also predicted disease recurrence in the posttreatment surveillance. PMID- 22102175 TI - Validating potential toxicity assays to assess petroleum hydrocarbon toxicity in polar soil. AB - Potential microbial activities are commonly used to assess soil toxicity of petroleum hydrocarbons (PHC) and are assumed to be a surrogate for microbial activity within the soil ecosystem. However, this assumption needs to be evaluated for frozen soil, in which microbial activity is limited by liquid water (theta(liquid)). Influence of theta(liquid) on in situ toxicity was evaluated and compared to the toxicity endpoints of potential microbial activities using soil from an aged diesel fuel spill at Casey Station, East Antarctica. To determine in situ toxicity, gross mineralization and nitrification rates were determined by the stable isotope dilution technique. Petroleum hydrocarbon-contaminated soil (0 8,000 mg kg(-1)), packed at bulk densities of 1.4, 1.7, and 2.0 g cm(-3) to manipulate liquid water content, was incubated at -5 degrees C for one, two, and three months. Although theta(liquid) did not have a significant effect on gross mineralization or nitrification, gross nitrification was sensitive to PHC contamination, with toxicity decreasing over time. In contrast, gross mineralization was not sensitive to PHC contamination. Toxic response of gross nitrification was comparable to potential nitrification activity (PNA) with similar EC25 (effective concentration causing a 25% effect in the test population) values determined by both measurement endpoints (400 mg kg(-1) for gross nitrification compared to 200 mg kg(-1) for PNA), indicating that potential microbial activity assays are good surrogates for in situ toxicity of PHC contamination in polar regions. PMID- 22102176 TI - Web interface for Brownian dynamics simulation of ion transport and its applications to beta-barrel pores. AB - Brownian dynamics (BD) based on accurate potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for carrying out grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems. GCMC/BD simulation results for three proteins, the voltage dependent anion channel (VDAC), alpha-Hemolysin (alpha-HL), and the protective antigen pore of the anthrax toxin (PA), are presented to illustrate the system setup, input preparation, and typical output (conductance, ion density profile, ion selectivity, and ion asymmetry). Two models for the input diffusion constants for potassium and chloride ions in the pore are compared: scaling of the bulk diffusion constants by 0.5, as deduced from previous all-atom molecular dynamics simulations of VDAC, and a hydrodynamics based model (HD) of diffusion through a tube. The HD model yields excellent agreement with experimental conductances for VDAC and alpha-HL, while scaling bulk diffusion constants by 0.5 leads to underestimates of 10-20%. For PA, simulated ion conduction values overestimate experimental values by a factor of 1.5-7 (depending on His protonation state and the transmembrane potential), implying that the currently available computational model of this protein requires further structural refinement. PMID- 22102177 TI - Estimated weight centile as a predictor of perinatal outcome in small-for gestational-age pregnancies with normal fetal and maternal Doppler indices. AB - OBJECTIVE: To evaluate the risk of adverse perinatal outcome according to estimated fetal weight (EFW) in a cohort of term small-for-gestational-age (SGA) pregnancies with normal umbilical, fetal middle cerebral and maternal uterine artery Doppler indices. METHODS: A cohort of 132 term SGA fetuses with normal umbilical artery pulsatility index (PI), mean uterine artery PI and cerebroplacental ratio was compared to a control group of 132 appropriate-for gestational-age babies, matched by gestational age at delivery. The capacity of the EFW percentile to predict Cesarean delivery, Cesarean delivery for non reassuring fetal status (NRFS), neonatal acidosis and days of neonatal hospitalization was analyzed. RESULTS: As a whole, SGA fetuses with normal Doppler findings did not show a statistically significant difference for intrapartum Cesarean delivery (22.0 vs. 15.9%; P = 0.21) and neonatal acidosis (3.3 vs. 1.5%; P = 0.30), but had significantly higher risk for Cesarean delivery for NRFS (15.9 vs. 5.3%; P < 0.01) and longer neonatal hospitalization (1.39 vs. 0.87 days; P < 0.05) than did controls. SGA fetuses with EFW < 3(rd) centile had a significantly higher incidence of intrapartum Cesarean delivery (30.0 vs. 15.3%; P = 0.04), Cesarean delivery for NRFS (25.0 vs. 8.3%; P < 0.01) and longer neonatal hospitalization (2.0 vs. 0.9 days; P < 0.01) than those with EFW >= 3(rd) centile. SGA cases with EFW >= 3(rd) centile had perinatal outcomes similar to those of controls with normal EFW. CONCLUSION: Among SGA fetuses with normal placental and cerebral Doppler ultrasound findings, EFW < 3(rd) centile discriminates between those with a higher risk for adverse perinatal outcome and those with outcomes similar to those of normally grown fetuses. PMID- 22102178 TI - The crosstalk between transforming growth factor-beta1 and delta like-1 mediates early chondrogenesis during embryonic endochondral ossification. AB - Delta like-1 (Dlk1)/preadipocyte factor-1 (Pref-1)/fetal antigen-1 (FA1) is a novel surface marker for embryonic chondroprogenitor cells undergoing lineage progression from proliferation to prehypertrophic stages. However, mechanisms mediating control of its expression during chondrogenesis are not known. Thus, we examined the effect of a number of signaling molecules and their inhibitors on Dlk1 expression during in vitro chondrogenic differentiation in mouse embryonic limb bud mesenchymal micromass cultures and mouse embryonic fibroblast (MEF) pellet cultures. Dlk1/Pref-1 was initially expressed during mesenchymal condensation and chondrocyte proliferation, in parallel with expression of Sox9 and Col2a1, and was downregulated upon the expression of Col10a1 by hypertrophic chondrocytes. Among a number of molecules that affected chondrogenesis, transforming growth factor-beta1 (TGF-beta1)-induced proliferation of chondroprogenitors was associated with decreased Dlk1 expression. This effect was abolished by TGF-beta signaling inhibitor SB431542, suggesting regulation of Dlk1/FA1 by TGF-beta1 signaling in chondrogenesis. TGF-beta1-induced Smad phosphorylation and chondrogenesis were significantly increased in Dlk1(-/-) MEF, while they were blocked in Dlk1 overexpressing MEF, in comparison with wild-type MEF. Furthermore, overexpression of Dlk1 or addition of its secreted form FA1 dramatically inhibited TGF-beta1-induced Smad reporter activity. In conclusion, our data identified Dlk1/FA1 as a downstream target of TGF-beta1 signaling molecule that mediates its function in embryonic chondrogenesis. The crosstalk between TGF-beta1 and Dlk1/FA1 was shown to promote early chondrogenesis during the embryonic endochondral ossification process. PMID- 22102179 TI - Genetics of systemic sclerosis: an update. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation, and fibrosis of the skin and internal organs. Over the past few years, a role for genetics in the susceptibility for SSc has been established. This review aims to provide an update on the progress made in the past year or so within the field of SSc genetics research. This year has been of particular interest due to the publication of a large genome-wide association study, further investigations into gene-gene interactions, and the tendency to validate genetic results in functional models. PMID- 22102180 TI - Neuro-intensive care of patients with acute CNS infections. AB - Infections in the central nervous system (CNS) are caused by a wide range of microorganisms resulting in distinct clinical syndromes including meningitis, encephalitis, and pyogenic infections, such as empyema and brain abscess. Bacterial and viral infections in the CNS can be rapidly fatal and can result in severe disability in survivors. Appropriate identification and acute management of these infections often occurs in a critical care setting and is vital to improving outcomes in this group of patients. This review of diagnosis and management of acute bacterial and viral infections in the CNS provides a general approach to patients with a suspected CNS infection and also provides a more detailed review of the diagnosis and management of patients with suspected bacterial meningitis, viral encephalitis, brain abscess, and subdural empyema. PMID- 22102181 TI - Late-onset, insidious course and invasive treatment of congenital central hypoventilation syndrome in a case with the Phox2B mutation: case report. PMID- 22102186 TI - Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. AB - von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). The current report overviews the diagnosis and management of VWD as reflected by differential processes applied within centers around the world. The prevalence of VWD, as well as the frequency of different VWD types, is also reported. VWD prevalence data varies according to methodology used, with epidemiological/population screening estimates approximating 1% of the population (or 10,000 cases per million population), several orders of magnitude higher than estimates from bleeding disorders registry data or regional/center analysis (which instead range from <1 to ~450 cases per million population). Frequency of different VWD types also varies according to source and analysis, with type 1 VWD identified as the clear dominant type in most developed countries (ranging from 40% to 90% of all VWD cases), whereas type 3 VWD predominates in developing countries such as India and Iran. The frequency of qualitative (i.e., type 2) VWD also varies considerably among different reports, ranging from 3% to >50% of all VWD cases, as does the frequency of specific qualitative VWD types (i.e., 2A, 2B, 2M, and 2N). Although type 2A VWD is considered the most common form of type 2 VWD, in some reports workers consider type 2M VWD to be as, or more, common. Although not considered to be a "true" VWD, given its platelet origin, platelet type VWD is only rarely identified. Finally, management of VWD also differs according to geographic region. Most developed countries use standard therapy, employing desmopressin (DDAVP) wherever possible, factor concentrate in other situations, and antifibrinolytic therapy as required. In contrast, the relative high cost and unavailability of factor concentrates in developing countries, and sometimes the unavailability of DDAVP, requires different management strategies to be applied. PMID- 22102187 TI - Assessment of von Willebrand factor propeptide improves the diagnosis of von Willebrand disease. AB - One of the more recent findings concerning Von Willebrand disease (VWD) is that a shorter Von Willebrand factor (VWF) survival either decides or modulates the VWD phenotype by downregulating circulating VWF levels. VWF survival is currently investigated with the desmopressin (DDAVP) test, a time-consuming strategy enabling the main pharmacokinetic parameters (e.g., VWF half-life elimination time and clearance) to be defined. An alternative now available involves assaying the VWF propeptide (VWFpp) in single steady-state blood samples, which reportedly increases as VWF survival decreases. This article demonstrates how measuring VWFpp and calculating the VWFpp-to-VWF:antigen ratio (VWFpp ratio) are good alternatives to DDAVP for investigating VWF survival. In type 1 VWD, the VWFpp ratio has been found normal in patients with pure quantitative VWF defects, markedly increased in cases with an isolated decline in VWF survival, and more or less increased in patients with both quantitative defects and a shorter VWF survival. The same applies to type 2B VWD, which is characterized by an increased VWFpp ratio and a shorter VWF survival, with values that appear inversely related. Exploring VWF half-life by assaying VWFpp is useful not only for the more precise characterization of VWD but also for defining its most appropriate treatment. PMID- 22102188 TI - Platelet-type von Willebrand disease: a rare, often misdiagnosed and underdiagnosed bleeding disorder. AB - Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant rare bleeding disorder characterized by hyperresponsive platelets. This inherent platelet function defect is due to a gain-of-function mutation within the GP1BA gene coding for the platelet surface glycoprotein Ib alpha protein, the receptor for the adhesive protein von Willebrand factor (VWF). The defect results in excessive and unnecessary platelet-VWF interaction with subsequent removal of the hemostatically efficient high molecular weight VWF as well as platelets from the circulation, leading to thrombocytopenia and bleeding diathesis. Patients with PT VWD present with mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy and following aspirin ingestion or drugs that have antiplatelet activity. Laboratory testing shows low VWF:ristocetin cofactor and low or normal VWF:antigen and characteristically an enhanced ristocetin-induced platelet agglutination (RIPA). These laboratory features are also indicators of the closely similar and more common bleeding disorder type 2B VWD. Simplified RIPA mixing assays, cryoprecipitate challenge, and flow cytometry can differentiate between the two disorders. However, the gold standard is to identify mutations within the VWF gene (indicating type 2B VWD) or the platelet GP1BA gene (confirming PT-VWD). Treatment is based on making a correct diagnosis of PT-VWD where platelet concentrates instead of VWF/factor VIII preparations should be administered. A recent fairly large retrospective/prospective registry based international study showed that PT-VWD is very rare, likely to be misdiagnosed as type 2B VWD or idiopathic thrombocytopenic purpura, and represents 15% of type 2B VWD diagnoses. PMID- 22102189 TI - The international society on thrombosis and haematosis von Willebrand disease database: an update. AB - The online locus-specific database for von Willebrand disease (VWFdb) acts as a repository for sequence variant data and associated resources for those with an interest in the disorder. It currently holds details of 561 mutations and 217 polymorphisms in the von Willebrand factor (VWF) gene. Lists can be queried and displayed by VWF region or disease type. A total of 42% of the mutations are located in the large exon 28, the most heavily studied VWF region, and mutations have been reported in all but 4 of the 51 protein-coding exons. Polymorphisms are reported in the 5' and 3' untranslated regions and in 33 exons and 35 introns. Additional resources include references linked to sequence variation entries, descriptors of each VWD type, genomic and cDNA sequences, nomenclature for VWF and its attributes, Human Genome Variation Society sequence variant nomenclature recommendations, multimer images, and related densitometry traces for type 2 VWD. Analysis of recessively inherited VWD indicates that whereas the majority (69%) of type 3 VWD patients are homozygous for their mutations, the majority (62%) of 2N patients are compound heterozygous. Comparison of missense substitutions reported as mutations with those reported as polymorphisms suggests that loss or gain of cysteine, tryptophan, methionine, or glutamate residues are more likely to result in a pathogenic effect than loss/gain of other VWF residues. PMID- 22102190 TI - Diagnosis and management of von Willebrand disease in The Netherlands. AB - In the Netherlands, specialized care for patients with a bleeding disorder, including hemophilia, von Willebrand disease (VWD), and allied disorders, is concentrated in 13 Hemophilia Treatment Centers. The Dutch Hemophilia Treaters Society, the Dutch Hemophilia Nurses' Society, and the Netherlands Hemophilia Patients Society collaborate to optimize management of patients with a bleeding disorder. A recently updated consensus guideline of hemophilia and allied bleeding disorders provide guidance on the current optimal diagnostic strategy and treatment of VWD. Genetic testing is not routinely performed in the Netherlands. Desmopressin (DDAVP) is the choice of treatment in VWD patients responsive to DDAVP, as determined by a test infusion. Coagulation factor concentrates are used in nonresponsive individuals, in case of a contraindication for DDAVP, or in type 2B and type 3 VWD. These concentrates are available for all patients in the Netherlands; however, these may only be administered in a Hemophilia Treatment Center or under the care of a Hemophilia Treatment Center. Recently a study on moderate and severe VWD (the Willebrand in Netherlands study) was initiated to obtain more insight on VWD diagnosis, treatment, and the burden of the disease. PMID- 22102191 TI - Diagnosis and management of von Willebrand disease in the United Kingdom. AB - The UK treatment strategy for von Willebrand disease (VWD) is based on consensus guidelines produced by the United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) relating to the diagnosis and management of VWD. Selection of therapeutic products suitable for treatment of this complex inherited bleeding disorder is based on the observed response. Desmopressin (DDAVP), an analog of vasopressin, is the recommended treatment in individuals who respond to this drug on trial infusion. DDAVP clearly has no effect in type 3 VWD but may have variable clinical effect in individuals with other subtypes or may be contraindicated in some cases. In patients where DDAVP treatment is unsuitable, replacement factor concentrate containing von Willebrand factor (VWF) is the recommended alternative. Relevant concentrates are available for all patients in the United Kingdom, and treatment is administered by a network of 67 hemophilia treatment centers that also provide specialist care for individuals diagnosed with VWD. Patients diagnosed with the condition are registered on a national inherited bleeding disorder database administered by the UKHCDO on behalf of the Department of Health to aid in service planning and commissioning. Genetic testing is employed in the United Kingdom in certain situations, which is also performed in accordance with current UKHCDO guidelines. PMID- 22102192 TI - Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease. AB - Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagnostic procedure is complicated because VWD is highly heterogeneous, and differential diagnosis from platelet disorders may be challenging. Moreover, these defects may even coexist, impacting the bleeding phenotype. Mild and moderate VWD can be difficult to distinguish from the normal population, and VWD subtyping may also be problematic. This article summarizes the guidelines of the Nordic Haemophilia Council (NHC), which are intended to serve as a practical tool and provide the standards for diagnosing and treating VWD patients. The complete Nordic Guidelines on VWD are available at the NHC Web site (http://nordhemophilia.org). PMID- 22102193 TI - Diagnosis and management of von Willebrand disease in Spain. AB - The correct diagnosis and classification of Von Willebrand disease (VWD) is important for therapy and genetic counseling but is made difficult due to the variability of its clinical expression and limitations of laboratory methods. A national registry of VWD patients has been initiated in Spain. The results of a concise survey on the diagnosis of VWD show the frequency of VWD is fivefold greater in Spain than that expected from epidemiological studies in other European countries; this may result from overdiagnosis and/or a higher prevalence of VWD. These results clearly reinforce the need for the Spanish VWD registry. A consensus guideline for optimal treatment of VWD is being elaborated in Spain. Desmopressin (DDAVP) is the choice of treatment in responsive VWD patients. Von Willebrand factor concentrates (VWF/factor VIII) are used in individuals nonresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3. PMID- 22102194 TI - Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients. AB - Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD. PMID- 22102195 TI - The diagnosis and management of von Willebrand disease in Canada. AB - In Canada, care for individuals with inherited bleeding disorders, including Von Willebrand disease, is provided by 26 tertiary care multidisciplinary Inherited Bleeding Disorders clinics geographically spread across the country. The Association of Hemophilia Clinic Directors of Canada, the Canadian Association of Nurses in Hemophilia Care, the Canadian Physiotherapists in Hemophilia Care, the Canadian Social Workers in Hemophilia Care, and the Canadian Hemophilia Society all collaborate to provide optimal management for patients with inherited bleeding disorders. The standards of care for these patients were explicitly laid out in a 2007 document published by the Canadian Hemophilia Standards Group (with representation from all of the groups just mentioned) entitled Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. Separate Canadian guidelines for the management of patients with Hemophilia and Von Willebrand disease also exist, focused on diagnosis, comprehensive care, assessment, and treatment. PMID- 22102196 TI - Von Willebrand disease in the United States: a perspective from Wisconsin. AB - Von Willebrand disease (VWD) is a common bleeding disorder with prevalence in the United States of 0.01 to 1% and a prevalence in the region around Milwaukee, Wisconsin, of at least 0.025%. Care of local patients with VWD primarily occurs through our comprehensive treatment centers, although some patients are managed solely by their primary care physician or community hematologist. Type 1 VWD is the most common subtype, with more females carrying this diagnosis than males. Diagnosis and treatment in general follows guidelines outlined by the National Institutes of Health. An ongoing study, the Zimmerman Program for the Molecular and Clinical Biology of VWD, is currently enrolling patients with all VWD subtypes across the United States to better delineate the extent of VWD and correlate bleeding symptoms with laboratory findings and VWF ( Von Willebrand factor) sequence variations. Results so far have shown that VWF gene polymorphisms are common, particularly in African Americans, and may affect laboratory assays of VWF function. PMID- 22102197 TI - Diagnosis and management of adult patients with von Willebrand disease in South Australia. AB - We have analyzed the databases for von Willebrand disease (VWD) from the hemophilia center for adult patients with bleeding disorders in South Australia. We define the prevalence of types of VWD to determine the proportion of who would be treated with factor (F) VIII/von Willebrand factor (VWF) concentrate to prevent or control hemorrhage. In severe or moderately severe patients, we use plasma-derived FVIII/VWF concentrate, and for mild to severe cases, we use desmopressin plus tranexamic acid. There are 103 patients with VWF ristocetin (RCo) <=50 IU/dL: 38 (37%) severe (VWF:RCo <10 IU/dL), 28 (27%) moderate (VWF:RCo 10 to 29 IU/dL), and 37 (36%) mild (VWF:RCo 30 to 50 IU/dL). Hence in 66 (64%), FVIII/VWF concentrate is the mainstay of treatment. The prevalence of VWD in our region according to data from our center is ~1 per 12,000. A total of 52% of patients are type 1, 44% type 2, and 5% type 3. In our experience, type 2M (45% of type 2) is much more common than types 2A and 2B (each 9% of type 2). Mutation detection is useful for identifying some subtypes of VWD. PMID- 22102198 TI - Diagnosis and management of von Willebrand disease in Australia. AB - Von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises from deficiencies and/or defects in the plasma protein Von Willebrand factor (VWF). VWD is classified into six different types, with type 1 identifying a (partial) quantitative deficiency of VWF, type 3 defining a (virtual) total deficiency of VWF, and type 2 identifying four separate types (2A, 2B, 2M, and 2N) characterized by qualitative defects. The classification is based on phenotypic assays including factor VIII coagulant, VWF antigen, and VWF activity, primarily by ristocetin cofactor and collagen binding, as supplemented by additional testing. In Australia, >30 pathology-based laboratories perform VWD testing, and tests and test panels reflect a wide variety of practice. In our own referral laboratory, diagnosis is a staged process reflecting a combination of clinical and laboratory findings with a large panel of tests. We also use data from desmopressin trials to assist in VWD type assignment. The current report presents an overview of the VWD diagnostic process as applied within Australia, includes summary data from the Australian Bleeding Disorders Registry, and provides specific details of the diagnostic and management practice undertaken in our reference laboratory, which also maintains a local bleeding disorders database. This database currently contains 4070 entries, including 1832 suspected or confirmed cases of VWD. Excluding 311 as yet unclassified cases, 1254 cases (82.4%) would define (potential) quantitative deficiencies of VWF ("low VWF" or type 1 VWD), 241 (15.8%) qualitative defects (type 2 VWD), and 23 (1.5%) type 3 VWD. Most of the quantitative defects reflect only mild loss of VWF, and <15% of total cases would be identified to have VWF levels <35 U/dL. Most cases of type 2 remain unclassified (34.9%) because available data are limited. Type 2A and 2M VWD represent the most common qualitative defects, representing 22.8% and 22.2% of defined type 2 VWD cases. Type 2B and 2N reflect 8.3% and 12.9%, respectively, of type 2 VWD cases. PMID- 22102199 TI - Diagnosis of von Willebrand disease in South Island, New Zealand. AB - New Zealand is a small country of two islands and 4 million people, of which 1 million reside in the South Island. Canterbury Health Laboratories provides laboratory services to the whole of South Island and lower parts of North Island. There are 155 Von Willebrand disease (VWD) patients in our South Island database, of which 17 have type 2 and 3 have type 3 VWD. A brief overview of diagnostic services for VWD being followed in our region is detailed in this article. We strive continually to advance the repertoire of diagnostic tests. We also present an analysis of our experience with a flow-based functional Von Willebrand factor assay. The VWD patients are managed by hemostasis team members, who also provide screening and educational input to affected families. The Haemophilia Foundation of New Zealand is an active patient support group providing education and support both directed individually and in the group setting, through residential educational camps. PMID- 22102200 TI - Von Willebrand disease in children: diagnosis and management of a pediatric cohort in one single center in Argentina. AB - Clinical and laboratory data of children with von Willebrand disease (VWD) types have been derived from retrospective studies and small case series. This article reports on the clinical and laboratory data of a large pediatric cohort in one single Argentinian center. The biological and clinical responses to desmopressin and replacement therapies are also described. Over a 15-year period, 194 of 1150 children (16.9%) were diagnosed as having type 1 VWD (80%), type 2 VWD (19%), and type 3 VWD (1%). The distribution of the different type 2 VWD subtypes was type 2A VWD, 43%; type 2B VWD, 32%; type 2M VWD, 19%; and type 2N VWD, 6%. Eighty patients with type 1 VWD and 12 patients with type 2 VWD were prospectively evaluated to desmopressin (DDAVP) response. A complete response was observed in all children with type 1 VWD, whereas 40% of the children with severe type 1 VWD and with type 2 VWD achieved a complete response. All the children who received DDAVP as prophylaxis or treatment for bleeding had good clinical evolution. Considering the restricted availability of specialized hemostasis centers, we believe our clinical and laboratory approach appropriate for the detection of patients with different types of VWD. Further studies are necessary to determine epidemiological aspects of VWD in Argentina to estimate the necessary facilities and trained personnel for the diagnosis and management of patients with VWD. PMID- 22102201 TI - Diagnosis and management of von Willebrand disease in a single institution of Argentina. AB - Von Willebrand disease (VWD) is a bleeding disorder with variable clinical expression. In this article we describe types, clinical features, genetic testing when needed, genotype/phenotype relationships, and the response to desmopressin (DDAVP) testing, according to our experience. Our findings are possible type 1, 69.6%; type 1, 13.5%; severe type 1, 0 .35%; type 3, 0.55%; type 2A, 9.5%; probable 2B, 0.6%; type 2M, 2.5%; and probable type 2N, 3.4%. The most frequent symptoms are ecchymoses-hematomas and epistaxis, and, in females >over 13 years also menorrhagia. In pregnant patients, assessment of laboratory parameters in months 7 and 8 is recommended to plan the need for prophylaxis at term. DDAVP merits to be considered as the first-choice therapy, including pregnant women and children, and no patient showed significant unwanted effects. Because this is a safe, effective, and affordable therapy, we hope to encourage clinicians, mainly pediatricians and obstetricians, to a wider use of DDAVP, especially in developing countries. We also report two patients with prophylactic treatment. PMID- 22102202 TI - Laboratory diagnosis and management of von Willebrand disease in South Africa. AB - Patients with Von Willebrand disease (VWD) in South Africa are cared for in 17 Hemophilia Treatment Centers. The exact prevalence of the disease is uncertain, but 539 patients are annotated in registries. VWD patients are mostly diagnosed in the five largest academic centers, and the classification of the subtypes is performed by one of these, the VWD testing facility. An algorithm is used for the diagnosis of VWD. The distribution of subtypes diagnosed by the VWD reference center is 38%, 58%, and 4% for type 1, 2, and 3, respectively, and ~15% of plasma samples received are rejected due to poor storage and transport conditions. A novel single nucleotide polymorphism has been found in an African patient with type 2B VWD. From the type 1 VWD patients who were diagnosed by the VWD testing facility, 45% seem to have an increased VWF clearance phenotype with a propeptide to-antigen ratio of 1.9 +/- 0.3. VWD patients are treated with desmopressin, factor (F)VIII/VWF concentrate (Haemosolvate FVIII; National Bioproducts Institute, Durban, South Africa), and tranexamic acid. Haemosolvate FVIII contains a VWF antigen concentration of 167 +/- 27 IU/mL, a ristocetin cofactor activity of 100 +/- 29 IU/mL, a collagen binding activity of 99 +/- 29 IU/mL, normal VWF multimers, and a FVIII concentration of 50 IU/mL. Not all patients with VWD are currently classified, and many VWD patients in South Africa are probably undiagnosed. PMID- 22102203 TI - Laboratory diagnosis and management of von Willebrand disease in Turkey: Izmir experience. AB - Von Willebrand disease (VWD) is caused by a deficiency or dysfunction of Von Willebrand factor (VWF). The pathophysiology, classification, diagnosis, and management of VWD are relatively complex, but their understanding is important for proper diagnosis and management of patients with VWD. There are inherent difficulties in both the identification and classification of VWD because of clinical uncertainty and the limitations in the test processes and test panels typically used by laboratories. The most common test panel employed by laboratories, particularly in the geographic regions covered by the mutational studies, would comprise factor VIII coagulant (FVIII:C), VWF protein (antigen; VWF:Ag), and ristocetin cofactor (VWF:RCo). In our center, use of a desmopressin challenge with our core four-test panel (i.e., VWF:Ag, VWF:RCo, FVIII:C, and PFA 100) is expected to further assist laboratory diagnosis of VWD in Turkey. Molecular genetics is a rather new approach for Turkey, with gene analyses related to VWD being initiated in one center and the results used for confirmation of diagnosis in limited cases. PMID- 22102204 TI - Diagnosis and management of von Willebrand disease: a developing country perspective. AB - Special challenges exist in the management of patients with von Willebrand disease (VWD) because of limitations in diagnostic facilities and therapeutic options. However, even within these limitations, it is possible to establish comprehensive services for this condition. Our data show that among 202 patients with VWD, 107 were type 3, 62 were type 1, and the others different categories of type 2. Basic tests such as bleeding time and activated partial thromboplastin time with factor (F)VIII coagulant are able to diagnose most of those with severe disease. We have been able to adapt the specific tests such as von Willebrand factor (VWF) ristocetin cofactor and VWF antigen from the tedious batched manual methods to cost-effective automated methods on advanced coagulometers. Discriminatory tests such as VWF collagen binding, VWF:FVIIIB, ristocetin-induced platelet agglutination (RIPA) are done in batches. Therapeutic options and for the treatment of bleeding include desmopressin, cryoprecipitate, and intermediate purity VWF-containing clotting factor concentrates. Tranexamic acid is also widely used as well as hormonal therapy for menorrhagia. We have also shown that modest doses of intermediate purity FVIII (Koate DVI; Talecris Biotherapeutics, Raleigh, NC, USA) at 35 IU/kg preoperatively and 10 to 20 IU/kg after that are sufficient for surgical hemostasis in these patients. PMID- 22102205 TI - Epidemiology, diagnosis, and management of von Willebrand disease in India. AB - Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical procedures are performed in a few centers with judicious use of cryoprecipitate or FVIII concentrate containing VWF along with other supplementary therapeutic products to achieve adequate hemostasis. Awareness about the disease, establishment of the comprehensive coagulation laboratory, and treatment centers will be successful in increasing diagnosis of VWD and consequently better management of affected patients. This is likely to tilt the ratios of different VWD types, and VWD is likely to emerge as the most common of all coagulation disorders in the near future. PMID- 22102206 TI - Diagnosis and management of von Willebrand disease in Iran. AB - Little information is available on von Willebrand disease (VWD) in Iran. More than 900 patients with VWD are registered, but the real number of patients with VWD is likely to be larger. Fifteen hemophilia treatment centers in addition to 31 other academic centers are the main sites for the clinical management and treatment of VWD in Iran. All centers are staffed by specialists in the medical care of VWD. Epistaxis and menorrhagia are the most frequent clinical manifestations in Iranian patients with VWD. Von Willebrand factor/factor VIII concentrates, desmopressin, cryoprecipitates, and tranexamic acid are the main medications used routinely in Iranian patients, and they are administered based on the type of disease, the severity of bleeding, and sometimes for the prevention of bleeding during surgical procedures or delivery. It is hoped that the recent creation of a national registry for coagulation disorders and improvements in laboratory techniques will improve the diagnosis, national patients' registry, and management of VWD in Iranian patients and lead to gains in their quality of life in the near future. PMID- 22102207 TI - Diagnosis and management of von Willebrand disease in China. AB - In China, the care of patients with a bleeding disorder is not organized into designated centers with a national protocol. However, currently developed organizations of hematologists and hemophilia patients are beginning to ensure better diagnosis, treatment, and care of affected patients. The diagnosis of von Willebrand disease (VWD) in China is still at an early stage. Misdiagnosis of the disease is difficult to avoid, and there is a need to improve our current diagnostic strategy. Our data show that assessment of von Willebrand factor (VWF) antigen levels is pivotal in ranking VWD clinical severity for replacement therapy. Treatment choices for VWD in China are currently limited to replacement therapy and antifibrinolytic drugs. Most VWD patients in China do not need replacement therapy. New phenotypic assays and genetic testing of VWF for research purposes have developed with results published in the Chinese medical literature in the last few years, and many are practical and feasible for diagnostic application. However, more efforts are needed for their widespread use for precise VWD diagnosis in China. PMID- 22102208 TI - Methane storage in homogeneous armchair open-ended single-walled boron nitride nanotube triangular arrays: a grand canonical Monte Carlo simulation study. AB - The physisorption of methane in homogeneous armchair open-ended SWBNNT triangular arrays was evaluated using grand canonical ensemble Monte Carlo simulation for tubes 11.08, 13.85, 16.62, and 19.41 A [(8,8), (10,10), (12,12), and (14,14), respectively] in diameter, at temperatures of 273, 298, 323, and 373 K, and at fugacities of 0.5-9.0 Mpa. The intermolecular forces were modeled using the Lennard-Jones potential model. The absolute, excess, and delivery adsorption isotherms of methane were calculated for the various boron nitride nanotube arrays. The specific surface areas and the isosteric heats of adsorption, Q(st), were also studied, different isotherm models were fitted to the simulated adsorption data, and the model parameters were correlated. According to the results, it is possible to reach 108% and 140% of the US Department of Energy's target for CH(4) storage (180 v/v at 298 K and 35 bar) using the SWBNNT array with nanotubes 16.62 and 19.41 A in diameter, respectively, as adsorbent. The results show that for a van der Waals gap of 3.4 A, there is no interstitial adsorption except for arrays containing nanotubes with diameters of >15.8 A. Multilayer adsorption starts to occur in arrays containing nanotubes with diameters of >16.62 A, and the minimum pressure required for multilayer adsorption is 1.0 MPa. A brief comparison of the methane adsorption capacities of single-walled carbon and boron nitride nanotube arrays was also performed. PMID- 22102209 TI - Structure and stability of kaolinite/TiO2 nanocomposite: DFT and MM computations. AB - The adhesion of TiO(2) (anatase structure) nanoparticles to kaolinite substrate was investigated using molecular modeling. Universal force field computation, density function theory computation, and a combination of both two approaches were used. This study enabled the adhesion energy for the TiO(2)/kaolinite nanocomposite to be estimated, and revealed the preferred orientation of the TiO(2) nanoparticles on the kaolinite substrate. The results of all three levels of computation were compared in order to show that the accuracy of universal force field computations is sufficient in this context. The role of nanoparticle size and the importance of the nanoparticle-substrate bonding contribution are presented here and discussed. A comparison of the molecular modeling results with scanning electron microscopy observations showed that the results of the modeling were consistent with the experimental data, and that this approach can be used to help characterize nanocomposites of the nanoparticle/phyllosilicate substrate type. PMID- 22102210 TI - Predicting functional residues of the Solanum lycopersicum aspartic protease inhibitor (SLAPI) by combining sequence and structural analysis with molecular docking. AB - The Solanum lycopersicum aspartic protease inhibitor (SLAPI), which belongs to the STI-Kunitz family, is an effective inhibitor of the aspartic proteases human cathepsin D and Saccharomyces proteinase A. However, in contrast with the large number of studies on the inhibition mechanism of the serine proteases by the STI Kunitz inhibitors, the structural aspects of the inhibition mechanism of aspartic proteases from this family of inhibitors are poorly understood. In the present study, we have combined sequence and structural analysis methods with protein protein docking to gain a better understanding of the SLAPI inhibition mechanism of the proteinase A. The results suggest that: i) SLAPI loop L9 may be involved in the inhibitor interaction with the proteinase A's active site, and ii) the residues I144, V148, L149, P151, F152 and R154 are implicated in the difference in the potency shown previously by SLAPI and another STI-Kunitz inhibitor isolated from Solanum tuberosum to inhibit proteinase A. These results will be useful in the design of site directed mutagenesis experiments to understand more thoroughly the aspartic protease inhibition mechanism of SLAPI and other related STI-Kunitz inhibitors. PMID- 22102211 TI - Mobilisation of inorganic phosphorus induced by rice straw in aggregates of a highly weathered upland soil. AB - BACKGROUND: Microorganisms mediate biochemical transformations of phosphorus (P) in soil. This is of particular importance in highly weathered soils, which are usually P deficient. This study aimed to extend understanding of the separate role of bacteria and fungi in P transformations in aggregates of a highly weathered soil, by adding P-stripped rice straw and microorganism inhibitors to aggregates. RESULTS: The amount of microbial biomass phosphorus (MB-P) in the treatment with rice straw alone increased by over two-fold during 16 days. At the end of 28 d, the amount of inorganic-P in Fe-, Al-, and Ca-bound fractions decreased, whilst the amount of organic-P increased substantially (P < 0.01). The effect of bacterial inhibitors (tetracycline and streptomycin sulphate) on P immobilisation was very small in the early phase (0-4 d), but became pronounced after 8 days, whilst the fungal inhibitor (actidione) initially caused a decrease in P immobilisation by about 60%, but had no effect after that. CONCLUSION: Fungi and bacteria immobilise P in soil aggregates, with fungi being responsible initially. However, bacteria become dominant subsequently and immobilise P from the inorganic fractions. PMID- 22102213 TI - New insight into visual function with aspherical intraocular lenses (IOLs): Tecnis ZCB00 and Acrysof SN60WF. AB - In this study, we investigated the visual performance of two aspherical intraocular lenses (IOLs), Tecnis ZCB00 and Acrysof SN60WF, by measuring high order aberration, visual evoked potentials (VEP), retinal sensitivity, and fixation stability by MP-1 microperimetry and contrast sensitivity values. Twenty two patients with age-related cataract were randomly allocated to either the Tecnis or the Acrysof group. All measurements were taken from patients of both groups 2 months postoperatively. Statistical analysis was performed with Student's t test, where P-values < 0.05 were considered significant. Results were not statistically significant with regard to high-order aberration, VEP, retinal sensitivity, and fixation stability. However, the contrast sensitivity values varied significantly between Tecnis ZCB00 and Acrysof SN60WF, with Tecnis ZCB00 performing better. The anterior aspherical surface design of the Tecnis IOL indicated better mesopic contrast sensitivity at mediate and high frequencies, ensuring a better quality of vision after cataract surgery. PMID- 22102212 TI - Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy. AB - TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. PMID- 22102214 TI - Changes in liquid water alter nutrient bioavailability and gas diffusion in frozen antarctic soils contaminated with petroleum hydrocarbons. AB - Bioremediation has been used to remediate petroleum hydrocarbon (PHC) contaminated sites in polar regions; however, limited knowledge exists in understanding how frozen conditions influence factors that regulate microbial activity. We hypothesized that increased liquid water (theta(liquid) ) would affect nutrient supply rates (NSR) and gas diffusion under frozen conditions. If true, management practices that increase theta(liquid) should also increase bioremediation in polar soils by reducing nutrient and oxygen limitations. Influence of theta(liquid) on NSR was determined using diesel-contaminated soil (0-8,000 mg kg(-1)) from Casey Station, Antarctica. The theta(liquid) was altered between 0.007 and 0.035 cm(3) cm(-3) by packing soil cores at different bulk densities. The nutrient supply rate of NH 4+ and NO 3-, as well as gas diffusion coefficient, D(s), were measured at two temperatures, 21 degrees C and -5 degrees C, to correct for bulk density effects. Freezing decreased NSR of both NH 4+ and NO 3-, with theta(liquid) linked to nitrate and ammonia NSR in frozen soil. Similarly for D(s), decreases due to freezing were much more pronounced in soils with low theta(liquid) compared to soils with higher theta(liquid) contents. Additional studies are needed to determine the relationship between degradation rates and theta(liquid) under frozen conditions. PMID- 22102215 TI - Comparative transcriptome analysis of AP2/EREBP gene family under normal and hormone treatments, and under two drought stresses in NILs setup by Aday Selection and IR64. AB - The AP2/EREBP genes play various roles in developmental processes and in stress related responses in plants. Genome-wide microarrays based on the gene expression profiles of the AP2/EREBP family were analyzed under conditions of normal growth and drought stress. The preferential expression of fifteen genes was observed in specific tissues, suggesting that these genes may play important roles in vegetative and reproductive stages of growth. A large number of redundant genes were differentially expressed following phytohormone treatments (NAA, GA3, KT, SA, JA, and ABA). To investigate the gene expression responses in the root, leaf, and panicle of three rice genotypes, two drought stress conditions were applied using the fraction of transpirable soil water (FTSW) under severe (0.2 FTSW), mild (0.5 FTSW), and control (1.0 FTSW) conditions. Following treatment, transcriptomic analysis using a 44-K oligoarray from Agilent was performed on all the tissue samples. We identified common and specific genes in all tissues from two near-isogenic lines, IR77298-14-1-2-B-10 (drought tolerant) and IR77298-14-1 2-B-13 (drought susceptible), under drought stress conditions. The majority of the genes that were activated in the IR77298-14-1-2-B-10 line were members of the AP2/EREBP gene family. Non-redundant genes (sixteen) were found in the drought tolerant line, and four genes were selected as candidate novel reference genes because of their higher expression levels in IR77298-14-1-2-B-10. Most of the genes in the AP2, B3, and B5 subgroups were involved in the panicle under severe stress conditions, but genes from the B1 and B2 subgroups were down-regulated in the root. Of the four subfamilies, RAV exhibited the highest number of up regulated genes (80%) in the panicle under severe stress conditions in the drought-tolerant line compared to Minghui 63 under normal conditions, and the gene structures of the RAV subfamily may be involved in the response to drought stress in the flowering stage. These results provide a useful reference for the cloning of candidate genes from the specific subgroup for further functional analysis. PMID- 22102216 TI - Undersized dendritic arborizations in retinal ganglion cells of the rd1 mutant mouse: a paradigm of early onset photoreceptor degeneration. AB - Retinitis pigmentosa (RP) is a family of inherited diseases causing progressive photoreceptor death. Retinal ganglion cells (RGCs) form the biological substrate for various therapeutic approaches designed to restore vision in RP individuals. Assessment of survival and preservation of RGCs in animal paradigms mimicking the human disease is of key importance for appropriate implementation of vision repair strategies. Here we studied the survival of RGCs in the rd1 mutant mouse, a known model of early onset, autosomic recessive RP, at various stages of photoreceptor degeneration. Furthermore, we analyzed the morphology of various types of RGCs using the newly generated transgenic mouse rd1/Thy1-GFP, in which the rd1 mutation is associated with green fluorescent protein (GFP) expression in a small population of different RGCs. We found excellent survival of cells at up to 1 year of age, a time at which the inner retina is known to have severely reorganized and partially degenerated. However, 50% of the cells analyzed within all RGC types exhibit an undersized dendritic tree, spanning about half of the normal area. Undersized cells are found both in adult and in very young (1-month old) mice. This suggests that their aberrant phenotype is due to incomplete dendritic development, possibly as a consequence of altered visual input at the time of dendritic arbor refinement. These data show the importance of the timing of photoreceptor death in RGC dendritic development. PMID- 22102217 TI - Localization of endogenous morphine-like compounds in the mouse spinal cord. AB - Morphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on endogenous morphine-like compound distribution in the adult mouse brain has been recently improved, and new hypotheses have been suggested about the potential implications in brain physiology. Endogenous morphine-like compounds have been shown to be synthesized in the spinal cord, but their localization is unknown. Here we describe the distribution of endogenous morphine like compounds (morphine and/or its glucuronides and/or codeine) in the adult mouse spinal cord using a well-validated antibody. By using different microscopy approaches, we found the presence of morphine, codeine, or morphine glucuronides in gamma-aminobutyric acid (GABA)-ergic neurons and astrocytes of the spinal cord. Whereas GABAergic neurons containing endogenous morphine-like compounds were located primarily in the ventral horn, astrocytes that were labeled for morphine-like compounds were found throughout the gray matter and the white matter. Our study demonstrates the possibility that endogenous morphine-like compounds in the central nervous system have other functions beyond their analgesic functions. PMID- 22102218 TI - Application of activity-based protein profiling to the study of microbial pathogenesis. AB - Activity-based protein profiling (ABPP) is a powerful technology for the dissection of dynamic and complex enzyme interactions. The mechanisms involved in microbial pathogenesis are an example of just such a system, with a plethora of highly regulated enzymatic interactions between the infecting organism and its host. In this review we will discuss some of the cutting-edge applications of ABPP to the study of bacterial and parasitic pathogenesis and virulence, with an emphasis on Clostridium difficile, methicillin-resistant Staphylococcus aureus, quorum sensing, and malaria. PMID- 22102219 TI - Radicals in flavoproteins. AB - Current technical and methodical advances in electron paramagnetic resonance (EPR) spectroscopy have proven to be very beneficial for studies of stationary and short-lived paramagnetic states in proteins carrying organic cofactors. In particular, the large number of proteins with flavins as prosthetic groups can be examined splendidly by EPR in all its flavors. To understand how a flavin molecule can be fine-tuned for specific catalysis of different reactions, understanding of its electronic structure mediated by subtle protein-cofactor interactions is of utmost importance. The focus of this chapter is the description of recent research progress from our laboratory on EPR of photoactive flavoproteins. These catalyze a wide variety of important photobiological processes ranging from enzymatic DNA repair to plant phototropism and animal magnetoreception. Whereas increasing structural information on the principal architecture of photoactive flavoproteins is available to date, their primary photochemistry is still largely undetermined. Interestingly, although these proteins carry the same light-active flavin chromophore, their light-driven reactions differ significantly: Formations of photoexcited triplet states and short-lived radical pairs starting out from triplet or singlet-state precursors, as well as generation of stationary radicals have been reported recently. EPR spectroscopy is the method of choice to characterize such paramagnetic intermediates, and hence, to assist in unravelling the mechanisms of these inimitable proteins. PMID- 22102220 TI - Noncontrast functional MRI of the kidneys. AB - Functional magnetic resonance imaging (fMRI) techniques enable noninvasive assessment of renal function. Diffusion-weighted imaging, diffusion tensor imaging, blood oxygen level-dependent MRI, magnetic resonance elastography, and arterial spin labeling are some of the emerging techniques that have potential to investigate renal function without the use of exogenous gadolinium contrast. This article discusses the principles of these techniques, as well as their possible applications and limitations. This will introduce the readers to these novel imaging tools, which appear to have promising futures. PMID- 22102221 TI - Direct and seamless coupling of TiO2 nanotube photonic crystal to dye-sensitized solar cell: a single-step approach. AB - A TiO(2) nanotube layer with a periodic structure is used as a photonic crystal to greatly enhance light harvesting in TiO(2) nanotube-based dye-sensitized solar cells. Such a tube-on-tube structure fabricated by a single-step approach facilitates good physical contact, easy electrolyte infiltration, and efficient charge transport. An increase of over 50% in power conversion efficiency is obtained in comparison to reference cells without a photonic crystal layer (under similar total thickness and dye loading). PMID- 22102222 TI - Review panel for Acta Crystallographica Section F. PMID- 22102223 TI - The 1.75 A resolution structure of fission protein Fis1 from Saccharomyces cerevisiae reveals elusive interactions of the autoinhibitory domain. AB - Fis1 mediates mitochondrial and peroxisomal fission. It is tail-anchored to these organelles by a transmembrane domain, exposing a soluble cytoplasmic domain. Previous studies suggested that Fis1 is autoinhibited by its N-terminal region. Here, a 1.75 A resolution crystal structure of the Fis1 cytoplasmic domain from Saccharomyces cerevisiae is reported which adopts a tetratricopeptide-repeat fold. It is observed that this fold creates a concave surface important for fission, but is sterically occluded by its N-terminal region. Thus, this structure provides a physical basis for autoinhibition and allows a detailed examination of the interactions that stabilize the inhibited state of this molecule. PMID- 22102224 TI - Novel crystallization conditions for tandem variant R67 DHFR yield a wild-type crystal structure. AB - Trimethoprim is an antibiotic that targets bacterial dihydrofolate reductase (DHFR). A plasmid-encoded DHFR known as R67 DHFR provides resistance to trimethoprim in bacteria. To better understand the mechanism of this homotetrameric enzyme, a tandem dimer construct was created that linked two monomeric R67 DHFR subunits together and mutated the sequence of residues 66-69 of the first subunit from VQIY to INSF. Using a modified crystallization protocol for this enzyme that included in situ proteolysis using chymotrypsin, the tandem dimer was crystallized and the structure was solved at 1.4 A resolution. Surprisingly, only wild-type protomers were incorporated into the crystal. Further experiments demonstrated that the variant protomer was selectively degraded by chymotrypsin, although no canonical chymotrypsin cleavage site had been introduced by these mutations. PMID- 22102225 TI - A large conformational change in the putative ATP pyrophosphatase PF0828 induced by ATP binding. AB - ATP pyrophosphatases (ATP PPases) are widely distributed in archaea and eukaryotes. They share an HUP domain at the N-terminus with a conserved PP-motif that interacts with the phosphates of ATP. The PF0828 protein from Pyrococcus furiosus is a member of the ATP PPase superfamily and it also has a 100-residue C terminal extension that contains a strictly conserved EGG(E/D)xE(T/S) motif, which has been named the EGT-motif. Here, crystal structures of PF0828 alone and in complex with ATP or AMP are reported. The HUP domain contains a central five stranded beta-sheet that is surrounded by four helices, as in other related structures. The C-terminal extension forms a separate domain, named the EGT domain, which makes tight interactions with the HUP domain, bringing the EGT motif near to the PP-motif and defining the putative active site of PF0828. Both motifs interact with the phosphate groups of ATP. A loop in the HUP domain undergoes a large conformational change to recognize the adenine base of ATP. In solution and in the crystal PF0828 is a dimer formed by the side-by-side arrangement of the HUP domains of the two monomers. The putative active site is located far from the dimer interface. PMID- 22102226 TI - X-ray structure of the SH3 domain of the phosphoinositide 3-kinase p85beta subunit. AB - Src-homology 3 (SH3) domains are involved in extensive protein-protein interactions and constitute key elements of intracellular signal transduction. Three-dimensional structures have been reported for SH3 domains of various proteins, including the 85 kDa regulatory subunit (p85) of phosphoinositide 3 kinase. However, all of the latter structures are of p85 isoform alpha and no crystal structure of the SH3 domain of the equally important isoform beta has been reported to date. In this structural communication, the recombinant production, crystallization and X-ray structure determination at 2.0 A resolution of the SH3 domain of human p85beta is described. The structure reveals a compact beta-barrel fold very similar to that of p85alpha. However, binding studies with two classes of proline-rich ligand peptides demonstrate that the ligand-binding specificity differs slightly between the SH3 domains of human p85beta and p85alpha, despite their high structural similarity. PMID- 22102227 TI - High-resolution X-ray study of the effects of deuteration on crystal growth and the crystal structure of proteinase K. AB - Deuteration of macromolecules is an important technique in neutron protein crystallography. Solvent deuteration of protein crystals is carried out by replacing water (H(2)O) with heavy water (D(2)O) prior to neutron diffraction experiments in order to diminish background noise. The effects of solvent deuteration on the crystallization of proteinase K (PK) with polyethylene glycol as a precipitant were investigated using high-resolution X-ray crystallography. In previous studies, eight NO(3)(-) anions were included in the PK crystal unit cell grown in NaNO(3) solution. In this study, however, the PK crystal structure did not contain NO(3)(-) anions; consequently, distortions of amino acids arising from the presence of NO(3)(-) anions were avoided in the present crystal structures. High-resolution (1.1 A) X-ray diffraction studies showed that the degradation of PK crystals induced by solvent deuteration was so small that this degradation would be negligible for the purpose of neutron protein crystallography experiments at medium resolution. Comparison of the nonhydrogen structures of nondeuterated and deuterated crystal structures demonstrated very small structural differences. Moreover, a positive correlation between the root mean-squared differences and B factors indicated that no systematic difference existed. PMID- 22102228 TI - Structure of the catalytic domain of Plasmodium falciparum ARF GTPase-activating protein (ARFGAP). AB - The crystal structure of the catalytic domain of the ADP ribosylation factor GTPase-activating protein (ARFGAP) from Plasmodium falciparum has been determined and refined to 2.4 A resolution. Multiwavength anomalous diffraction (MAD) data were collected utilizing the Zn(2+) ion bound at the zinc-finger domain and were used to solve the structure. The overall structure of the domain is similar to those of mammalian ARFGAPs. However, several amino-acid residues in the area where GAP interacts with ARF1 differ in P. falciparum ARFGAP. Moreover, a number of residues that form the dimer interface in the crystal structure are unique in P. falciparum ARFGAP. PMID- 22102229 TI - Structure of cellobiose phosphorylase from Clostridium thermocellum in complex with phosphate. AB - Clostridium thermocellum is a cellulosome-producing bacterium that is able to efficiently degrade and utilize cellulose as a sole carbon source. Cellobiose phosphorylase (CBP) plays a critical role in cellulose degradation by catalyzing the reversible phosphate-dependent hydrolysis of cellobiose, the major product of cellulose degradation, into alpha-D-glucose 1-phosphate and D-glucose. CBP from C. thermocellum is a modular enzyme composed of four domains [N-terminal domain, helical linker, (alpha/alpha)(6)-barrel domain and C-terminal domain] and is a member of glycoside hydrolase family 94. The 2.4 A resolution X-ray crystal structure of C. thermocellum CBP reveals the residues involved in coordinating the catalytic phosphate as well as the residues that are likely to be involved in substrate binding and discrimination. PMID- 22102230 TI - Crystallographic analysis of the C-terminal domain of the Escherichia coli lipoprotein BamC. AB - In Gram-negative bacteria, the BAM complex catalyzes the essential process of assembling outer membrane proteins. The BAM complex in Escherichia coli consists of five proteins: one beta-barrel membrane protein, BamA, and four lipoproteins, BamB, BamC, BamD and BamE. Here, the crystal structure of the C-terminal domain of E. coli BamC (BamC(C): Ala224-Ser343) refined to 1.5 A resolution in space group H3 is reported. BamC(C) consists of a six-stranded antiparallel beta-sheet, three alpha-helices and one 3(10)-helix. Sequence and surface analysis reveals that most of the conserved residues within BamC(C) are localized to form a continuous negatively charged groove that is involved in a major crystalline lattice contact in which a helix from a neighbouring BamC(C) binds against this surface. This interaction is topologically and architecturally similar to those seen in the substrate-binding grooves of other proteins with BamC-like folds. Taken together, these results suggest that an identified surface on the C terminal domain of BamC may serve as an important protein-binding surface for interaction with other BAM-complex components or substrates. PMID- 22102231 TI - Purification, crystallization and diffraction studies of the methyltransferases BT_2972 and BVU_3255 from antibiotic-resistant pathogens of the genus Bacteroides from the human intestine. AB - The methyltransferases BT_2972 and BVU_3255 from two different Bacteroides species that are antibiotic-resistant pathogens from the human intestine were cloned, overexpressed and purified, yielding approximately 120 mg of each protein from 1 l culture. Apo BT_2972 and BVU_3255 and their complexes with S adenosylmethionine or S-adenosylhomocysteine were crystallized in four different crystal forms using the hanging-drop vapour-diffusion method. These crystals diffracted to resolutions ranging from 2.8 to 2.2 A. Sequence analysis suggested that the two proteins are homologous small-molecule methyltransferases. PMID- 22102232 TI - Expression, crystallization and preliminary X-ray characterization of the human epithelial cell-adhesion molecule ectodomain. AB - The epithelial cell-adhesion molecule (EpCAM; CD326) is a transmembrane glycoprotein involved in epithelial cell-cell adhesion, cell proliferation and differentiation. Its elevated expression level in various carcinomas is exploited by several antitumour therapies that are at various stages of clinical development. The 35 kDa polypeptide chain of EpCAM is divided into a large extracellular part, a transmembrane helix and a short cytoplasmic tail. The modular extracellular part of human EpCAM was cloned and mutated to prevent N linked glycosylation. After expression in insect cells and purification using standard chromatographic techniques, the extracellular part was crystallized. The crystals belonged to space group C2, with unit-cell parameters a = 86.83, b = 50.16, c = 66.56 A, beta = 127.9 degrees . The crystal diffracted to 1.95 A resolution and contained one molecule in the asymmetric unit. PMID- 22102233 TI - Crystallization and preliminary X-ray diffraction of the first periplasmic domain of SecDF, a translocon-associated membrane protein, from Thermus thermophilus. AB - A membrane-integrated Sec component, SecDF, associates with the SecYEG protein conducting channel and facilitates protein secretion and membrane-protein integration. SecDF contains 12 transmembrane helices and two periplasmic domains. The first periplasmic domain (P1) plays an important role in protein translocation. Here, the overexpression, purification and crystallization of the P1 domain of Thermus thermophilus SecDF are reported. The crystals diffracted X rays to 2.3 A resolution and belonged to space group C2, with unit-cell parameters a = 161.1, b = 35.8, c = 181.6 A, suggesting that they contain four molecules per asymmetric unit. The initial phases were determined by the multiple wavelength anomalous dispersion method using selenomethionine-labelled crystals. PMID- 22102234 TI - Crystallization and preliminary crystallographic analysis of an Ig-domain encompassing fragment of the giant adhesion protein SiiE from Salmonella enterica. AB - Salmonella infections can be life-threatening. SiiE is a giant adhesion molecule of 5559 amino acids that is encoded in Salmonella pathogenicity island 4 (SPI4) and that promotes the initial contact between the pathogen and polarized epithelial cells in the intestine of the host. Starting from an engineered deletion version of SiiE (mini-SiiE; 97 kDa), limited proteolysis was used to reproducibly generate a 30 kDa fragment that readily crystallized. Mass spectrometry hints that this fragment spans the predicted Ig domains 50-52 of SiiE. Crystals of both native and selenomethionine-labelled protein could be obtained in space group C2 and diffraction data were recorded to a resolution of 1.85 A. PMID- 22102235 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction crystallographic study of human synaptotagmin 5 C2A domain. AB - Synaptotagmin acts as the Ca(2+) sensor for neural and endocrine exocytosis. Synaptotagmin 5 has been demonstrated to play a key role in the acquisition of cathepsin D and the vesicular proton ATPase and in Ca(2+)-dependent insulin exocytosis. The C2 domains modulate the interaction of synaptotagmin with the phospholipid bilayer of the presynaptic terminus and effector proteins such as the SNARE complex. This study reports the cloning, expression in Escherichia coli, purification, crystallization and preliminary X-ray analysis of the C2A domain of human synaptotagmin 5 with an N-terminal His(6) tag. The crystals diffracted to 1.90 A resolution and belonged to the hexagonal space group P6(5), with unit-cell parameters a = b = 93.97, c = 28.05 A. A preliminary model of the protein structure has been built and refinement of the model is ongoing. PMID- 22102236 TI - Crystallization and preliminary X-ray diffraction studies of a complex of extracellular lipase from Streptomyces rimosus with the inhibitor 3,4 dichloroisocoumarin. AB - A recombinant lipase (triacylglycerol acylhydrolase; EC 3.1.1.3) from the bacterium Streptomyces rimosus was inhibited by the serine protease inhibitor 3,4 dichloroisocoumarin and crystallized by the hanging-drop vapour-diffusion method at 291 K. The crystals belonged to the monoclinic space group P2(1), with unit cell parameters a = 38.1, b = 78.7, c = 56.6 A, beta = 104.5 degrees and probably two molecules in the asymmetric unit. Diffraction data were collected to 1.7 A resolution using synchrotron radiation on the XRD beamline of the Elettra synchrotron, Trieste, Italy. PMID- 22102237 TI - Cloning, expression, purification, crystallization and preliminary X-ray analysis of the 31 kDa Vibrio cholerae heat-shock protein VcHsp31. AB - The Gram-negative bacterium Vibrio cholerae, which is responsible for the diarrhoeal disease cholera in humans, induces the expression of numerous heat shock genes. VcHsp31 is a 31 kDa putative heat-shock protein that belongs to the DJ-1/PfpI superfamily, functioning as both a chaperone and a protease. VcHsp31 has been cloned, overexpressed and purified by Ni(2+)-NTA affinity chromatography followed by gel filtration. Crystals of VcHsp31 were grown in the presence of PEG 6000 and MPD; they belonged to space group P2(1) and diffracted to 1.9 A resolution. Assuming the presence of six molecules in the asymmetric unit, the Matthews coefficient was estimated to be 1.97 A(3) Da(-1), corresponding to a solvent content of 37.4%. PMID- 22102238 TI - Crystallization and preliminary X-ray diffraction analysis of dihydrodipicolinate synthase 2 from Arabidopsis thaliana. AB - Dihydrodipicolinate synthase (DHDPS; EC 4.2.1.52) catalyzes the first committed step of the lysine-biosynthetic pathway in plants and bacteria. Since (S)-lysine biosynthesis does not occur in animals, DHDPS is an attractive target for rational antibiotic and herbicide design. Here, the cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of DHDPS2 from Arabidopsis thaliana are reported. Diffraction-quality protein crystals belonged to space group P2(1)2(1)2. PMID- 22102239 TI - Crystallization and preliminary X-ray analysis of the RPB5 subunit of human RNA polymerase II. AB - RPB5 is an essential subunit of eukaryotic RNA polymerase II. It has been proposed to interact with DNA and several key transcription factors during transcription. These interactions are crucial for transcription and its regulation. Here, prior to obtaining complex structures of human RPB5 and its binding partners, recombinant human RPB5 was crystallized alone by vapour diffusion in hanging drops. A complete data set was collected from a single frozen crystal employing an in-house X-ray source. The crystal diffracted to 2.8 A resolution and belonged to space group P4(3)2(1)2. The likely Matthews coefficient and solvent content of 2.67 A(3) Da(-1) and 53.92%, respectively, suggested the presence of two protein subunits in the asymmetric unit. The structure was solved using molecular replacement. PMID- 22102240 TI - Crystallization, high-resolution data collection and preliminary crystallographic analysis of Aura virus capsid protease and its complex with dioxane. AB - The C-terminal protease domain of capsid protein from Aura virus expressed in a bacterial expression system has been purified to homogeneity and crystallized. Crystals suitable for X-ray diffraction analysis were obtained by the vapour diffusion method using 0.1 M bis-tris and polyethylene glycol monomethyl ether 2000. Crystals of the C-terminal protease domain of capsid protein in complex with dioxane were also produced and crystal data were obtained. Both crystals belonged to space group C2, with unit-cell parameters a = 79.6, b = 35.2, c = 49.5 A. High-resolution data sets were collected to a resolution of 1.81 A for the native protein and 1.98 A for the complex. Preliminary crystallographic studies suggested the presence of a single molecule in the crystallographic asymmetric unit, with a solvent content of 38.5%. PMID- 22102241 TI - Crystallization and preliminary X-ray diffraction analysis of the human XRCC4-XLF complex. AB - XRCC4 and XLF are key proteins in the repair of DNA double-strand breaks through nonhomologous end-joining. Together, they form a complex that stimulates the ligation of double-strand breaks. Owing to the suggested filamentous nature of this complex, structural studies via X-ray crystallography have proven difficult. Multiple truncations of the XLF and XRCC4 proteins were cocrystallized, but yielded low-resolution diffraction (~20 A). However, a combination of microseeding, dehydration and heavy metals improved the diffraction of XRCC4(Delta157)-XLF(Delta224) crystals to 3.9 A resolution. Although molecular replacement alone was unable to produce a solution, when combined with the anomalous signal from tantalum bromide clusters initial phasing was successfully obtained. PMID- 22102242 TI - Crystallization and preliminary X-ray crystallographic study of the human MST2 SARAH domain. AB - The SARAH domain at the C-terminus of human MST2 (residues 436-484) was overproduced and purified using an Escherichia coli expression system. The purified domain was crystallized using the hanging-drop vapour-diffusion technique. Two crystal forms were obtained. The crystals belonged to space group P2, with unit-cell parameters a = 62.0, b = 119.2, c = 62.0 A, alpha = 90.0, beta = 90.5, gamma = 90.0 degrees , or to space group P6(1)22, with unit-cell parameters a = 54.5, b = 54.5, c = 303.1 A. These crystals diffracted to 2.7 and 3.0 A resolution, respectively. PMID- 22102243 TI - The macromolecular complex of ICP and falcipain-2 from Plasmodium: preparation, crystallization and preliminary X-ray diffraction analysis. AB - The malaria parasite Plasmodium depends on the tight control of cysteine-protease activity throughout its life cycle. Recently, the characterization of a new class of potent inhibitors of cysteine proteases (ICPs) secreted by Plasmodium has been reported. Here, the recombinant production, purification and crystallization of the inhibitory C-terminal domain of ICP from P. berghei in complex with the P. falciparum haemoglobinase falcipain-2 is described. The 1:1 complex was crystallized in space group P4(3), with unit-cell parameters a = b = 71.15, c = 120.09 A. A complete diffraction data set was collected to a resolution of 2.6 A. PMID- 22102244 TI - Crystallization and preliminary crystallographic analysis of dUTPase from the phi11 helper phage of Staphylococcus aureus. AB - Staphylococcus aureus superantigen-carrying pathogenicity islands (SaPIs) play a determinant role in spreading virulence genes among bacterial populations that constitute a major health hazard. Repressor (Stl) proteins are responsible for the transcriptional regulation of pathogenicity island genes. Recently, a derepressing interaction between the repressor Stl SaPIbov1 and dUTPase from the phi11 helper phage has been suggested [Tormo-Mas et al. (2010), Nature (London), 465, 779-782]. Towards elucidation of the molecular mechanism of this interaction, this study reports the expression, purification and X-ray analysis of phi11 dUTPase, which contains a phage-specific polypeptide segment that is not present in other dUTPases. Crystals were obtained using the hanging-drop vapour diffusion method at room temperature. Data were collected to 2.98 A resolution from one type of crystal. The crystal of phi11 dUTPase belonged to the cubic space group I23, with unit-cell parameters a = 98.16 A, alpha = beta = gamma = 90.00 degrees . PMID- 22102245 TI - Crystallization and preliminary X-ray diffraction analysis of an archaeal tRNA modification enzyme, TiaS, complexed with tRNA(Ile2) and ATP. AB - The cytidine at the first anticodon position of archaeal tRNA(Ile2), which decodes the isoleucine AUA codon, is modified to 2-agmatinylcytidine (agm(2)C) to guarantee the fidelity of protein biosynthesis. This post-transcriptional modification is catalyzed by tRNA(Ile)-agm(2)C synthetase (TiaS) using ATP and agmatine as substrates. Archaeoglobus fulgidus TiaS was overexpressed in Escherichia coli cells and purified. tRNA(Ile2) was prepared by in vitro transcription with T7 RNA polymerase. TiaS was cocrystallized with both tRNA(Ile2) and ATP by the vapour-diffusion method. The crystals of the TiaS tRNA(Ile2)-ATP complex diffracted to 2.9 A resolution using synchrotron radiation at the Photon Factory. The crystals belonged to the primitive hexagonal space group P3(2)21, with unit-cell parameters a = b = 131.1, c = 86.6 A. The asymmetric unit is expected to contain one TiaS-tRNA(Ile2)-ATP complex, with a Matthews coefficient of 2.8 A(3) Da(-1) and a solvent content of 61%. PMID- 22102246 TI - Crystallization and preliminary X-ray analysis of the RXLR-type effector RXLR3 from the oomycete pathogen Hyaloperonospora arabidopsidis. AB - Manipulating defence responses in infected host cells is a prerequisite for filamentous plant pathogens to complete their life cycle on infected host plants. During infection of its host Arabidopsis thaliana, the oomycete pathogen Hyaloperonospora arabidopsidis secretes numerous RXLR-type effector proteins, some of which are translocated into host cells. RXLR-type effectors share conserved N-terminal translocation motifs but show high diversity in their C terminal 'effector domains' that manipulate host defence mechanisms. Therefore, obtaining structural information on the effector domains of RXLR-type effectors will contribute to elucidating their molecular-virulence functions in infected host cells. Here, the expression, purification and crystallization of the effector domain of RXLR3 from H. arabidopsidis isolate Waco9 are reported. The crystals belonged to space group P2(1)2(1)2, with unit-cell parameters a = 61.49, b = 27.99, c = 37.59 A. X-ray data were collected to a resolution of 1.8 A from a single crystal using synchrotron radiation. PMID- 22102247 TI - Crystallization and preliminary X-ray crystallographic studies of the PYD domain of human NALP3. AB - The NALP3 inflammasome is a macromolecular complex that is responsible for the innate immune response against infection by bacterial and viral pathogens. The NALP3 inflammasome is composed of three protein components: NALP3, ASC and caspase 1. Interaction between NALP3 and ASC via PYD domains is critical for the assembly of the NALP3 inflammasome. In this study, human NALP3 PYD, corresponding to amino acids 3-110, was overexpressed in Escherichia coli using engineered C terminal His tags. NALP3 PYD was then purified to homogeneity and crystallized at 293 K. Finally, X-ray diffraction data were collected to a resolution of 1.7 A from a crystal belonging to the primitive monoclinic space group P2(1), with unit cell parameters a = 42.03, b = 60.14, c = 51.61 A, beta = 107.40 degrees . PMID- 22102248 TI - Crystallization and preliminary X-ray analysis of a dye-linked D-lactate dehydrogenase from the aerobic hyperthermophilic archaeon Aeropyrum pernix. AB - A dye-linked D-lactate dehydrogenase from the aerobic hyperthermophilic archaeon Aeropyrum pernix was crystallized using the hanging-drop vapour-diffusion method with polyethylene glycol 8000 as the precipitant. The crystals belonged to the monoclinic space group P2(1), with unit-cell parameters a = 63.4, b = 119.4, c = 70.2 A, beta = 112.0 degrees , and diffracted to 2.0 A resolution on the BL26B1 beamline at SPring-8. The overall R(merge) was 4.5% and the completeness was 99.8%. PMID- 22102249 TI - Preliminary neutron crystallographic study of human transthyretin. AB - Preliminary studies of perdeuterated crystals of human transthyretin (TTR) have been carried out using the LADI-III and D19 diffractometers at the Institut Laue Langevin in Grenoble. The results demonstrate the feasibility of a full crystallographic analysis to a resolution of 2.0 A using Laue diffraction and also illustrate the potential of using monochromatic instruments such as D19 for higher resolution studies where larger crystals having smaller unit cells are available. This study will yield important information on hydrogen bonding, amino acid protonation states and hydration in the protein. Such information will be of general interest for an understanding of the factors that stabilize/destabilize TTR and for the design of ligands that may be used to counter TTR amyloid fibrillogenesis. PMID- 22102250 TI - Crystallization and preliminary X-ray crystallographic analysis of putative tRNA modification enzymes from Pyrococcus furiosus and Thermus thermophilus. AB - Methyltransferases form a major class of tRNA-modifying enzymes that are needed for the proper functioning of tRNA. Here, the expression, purification and crystallization of two related putative tRNA methyltransferases from two kingdoms of life are reported. The protein encoded by the gene pf1002 from the archaeon Pyrococcus furiosus was crystallized in the monoclinic space group P2(1). A complete data set was collected to 2.2 A resolution. The protein encoded by the gene ttc1157 from the eubacterium Thermus thermophilus was crystallized in the trigonal space group P3(2)21. A complete data set was collected to 2.05 A resolution. PMID- 22102251 TI - Preliminary X-ray analysis of twinned crystals of the Q88Y25_Lacpl esterase from Lactobacillus plantarum WCFS1. AB - Q88Y25_Lacpl is an esterase produced by the lactic acid bacterium Lactobacillus plantarum WCFS1 that shows amino-acid sequence similarity to carboxylesterases from the hormone-sensitive lipase family, in particular the AFEST esterase from the archaeon Archaeoglobus fulgidus and the hyperthermophilic esterase EstEI isolated from a metagenomic library. N-terminally His(6)-tagged Q88Y25_Lacpl has been overexpressed in Escherichia coli BL21 (DE3) cells, purified and crystallized at 291 K using the hanging-drop vapour-diffusion method. Mass spectrometry was used to determine the purity and homogeneity of the enzyme. Crystals of His(6)-tagged Q88Y25_Lacpl were prepared in a solution containing 2.8 M sodium acetate trihydrate pH 7.0. X-ray diffraction data were collected to 2.24 A resolution on beamline ID29 at the ESRF. The apparent crystal point group was 422; however, initial global analysis of the intensity statistics (data processed with high symmetry in space group I422) and subsequent tests on data processed with low symmetry (space group I4) showed that the crystals were almost perfectly merohedrally twinned. Most probably, the true space group is I4, with unit-cell parameters a = 169.05, b = 169.05, c = 183.62 A. PMID- 22102252 TI - Purification, crystallization and preliminary X-ray analysis of the DndE protein from Salmonella enterica serovar Cerro 87, which is involved in DNA phosphorothioation. AB - The phenomenon of DNA phosphorothioation (DNA sulfur modification) is widespread among prokaryotes and may serve as a mechanism to restrict gene transfer among bacteria. DndE is one of five essential proteins that are required for the DNA phosphorothioation process. However, its exact biochemical role in sulfur modification of DNA remains unclear. In this study, the DndE protein homologue from Salmonella enterica serovar Cerro 87 was overexpressed, purified and crystallized. The crystals of the DndE protein diffracted to 2.7 A resolution and belonged to space group P3(1)21. These results will facilitate detailed structural analysis of DndE and further elucidation of its biochemical function. PMID- 22102253 TI - Crystallization and preliminary X-ray data collection of the L27(PATJ) (L27N,L27C)(Pals1)-L27(MALS) tripartite complex. AB - The L27 (LIN-2/LIN-7) domain is a protein-protein interaction module capable of assembling proteins into biologically important complexes. Pals1 contains two L27 domains: the first, L27N, interacts with PATJ, and the second, L27C, interacts with MALS, forming a tripartite complex that plays a crucial role in the establishment and maintenance of cell polarity. To provide a better understanding of the mechanism of assembly of this tripartite complex, four different L27(PATJ) (L27N,L27C)(Pals1)-L27(MALS) constructs were cloned, expressed, purified and crystallized. Crystals of tripartite complex 1 of L27(PATJ)-(L27N,L27C)(Pals1) L27(MALS) diffracted to 2.05 A resolution. These crystals belonged to either space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 145.2, c = 202.5 A. Assuming the presence of four molecules in the asymmetric unit, a Matthews coefficient of 2.69 A(3) Da(-1) was calculated, corresponding to a solvent content of 54.25%. PMID- 22102254 TI - Crystallization and preliminary X-ray diffraction crystallographic study of tRNA m(1)A58 methyltransferase from Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, TRM6 and TRM61 compose a tRNA methyltransferase which catalyzes the methylation of the N1 of adenine at position 58 in tRNAs, especially initiator methionine tRNA. TRM61 is the subunit that binds S-adenosyl L-methionine and both subunits contribute to target tRNA binding. In order to elucidate the catalytic mechanism of TRM6-TRM61 and the mode of interaction between the two subunits, expression, purification, crystallization and X-ray diffraction analysis of the TRM6-TRM61 complex were performed in this study. The crystals diffracted to 2.80 A resolution and belonged to the trigonal space group P3(1)21 or P3(2)21, with unit-cell parameters a = b = 139.14, c = 101.62 A. PMID- 22102255 TI - HisB from Mycobacterium tuberculosis: cloning, overexpression in Mycobacterium smegmatis, purification, crystallization and preliminary X-ray crystallographic analysis. AB - HisB, encoded by open reading frame Rv1601, possesses enzymatic activity as an imidazoleglycerol-phosphate dehydratase in the histidine-biosynthetic pathway of Mycobacterium tuberculosis. A recombinant form of HisB was crystallized in three crystal forms: crystals grown using 20% PEG 1500 as a precipitant belonged to either the cubic space group P432 or the tetragonal space group P4, while an orthorhombic crystal form belonging to space group P2(1)2(1)2 was obtained using 15% PEG 5000 and 10 mM MnCl(2) as precipitant. The structure of HisB in the orthorhombic crystal form was solved by the molecular-replacement method using the crystal structure of its Arabidopsis thaliana counterpart, which shares 47% sequence identity with Rv1601, as the search model. PMID- 22102256 TI - Expression, crystallization and preliminary X-ray crystallographic analysis of glucose-6-phosphate dehydrogenase from the human pathogen Trypanosoma cruzi in complex with substrate. AB - An N-terminally truncated version of the enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi lacking the first 37 residues was crystallized both in its apo form and in a binary complex with glucose 6-phosphate. The crystals both belonged to space group P2(1) and diffracted to 2.85 and 3.35 A resolution, respectively. Self-rotation function maps were consistent with point group 222. The structure was solved by molecular replacement, confirming a tetrameric quaternary structure. PMID- 22102257 TI - Crystallization and preliminary X-ray crystallographic analysis of ligand-free and arginine-bound forms of Thermotoga maritima arginine-binding protein. AB - The arginine-binding protein from Thermotoga maritima (TmArgBP) is an arginine binding component of the ATP-binding cassette (ABC) transport system in this hyperthermophilic bacterium. This protein is endowed with an extraordinary stability towards thermal and chemical denaturation. Its structural characterization may provide useful insights for the clarification of structure stability relationships and for the design of new biosensors. Crystallization trials were set up for both arginine-bound and ligand-free forms of TmArgBP and crystals suitable for crystallographic investigations were obtained for both forms. Ordered crystals of the arginine adduct of TmArgBP could only be obtained by using the detergent LDAO as an additive to the crystallization medium. These crystals were hexagonal, with unit-cell parameters a = 78.2, c = 434.7 A, and diffracted to 2.7 A resolution. The crystals of the ligand-free form were orthorhombic, with unit-cell parameters a = 51.8, b = 91.9, c = 117.9 A, and diffracted to 2.25 A resolution. PMID- 22102258 TI - Advanced preservation methods and nutrient retention in fruits and vegetables. AB - Despite the recommendations of international health organizations and scientific research carried out around the world, consumers do not take in sufficient quantities of healthy fruit and vegetable products. The use of new, 'advanced' preservation methods creates a unique opportunity for food manufacturers to retain nutrient content similar to that found in fresh fruits and vegetables. This review presents a summary of the published literature regarding the potential of high-pressure and microwave preservation, the most studied of the 'advanced' processes, to retain the natural vitamin A, B, C, phenolic, mineral and fiber content in fruits and vegetables at the time of harvest. Comparisons are made with more traditional preservation methods that utilize thermal processing. Case studies on specific commodities which have received the most attention are highlighted; these include apples, carrots, oranges, tomatoes and spinach. In addition to summarizing the literature, the review includes a discussion of postharvest losses in general and factors affecting nutrient losses in fruits and vegetables. Recommendations are made for future research required to evaluate these advanced process methods. PMID- 22102259 TI - A computational chemist approach to gas sensors: modeling the response of SnO2 to CO, O2, and H2O gases. AB - A general bottom-up modeling strategy for gas sensor response to CO, O(2), H(2)O, and related mixtures exposure is demonstrated. In a first stage, we present first principles calculations that aimed at giving an unprecedented review of basic chemical mechanisms taking place at the sensor surface. Then, simulations of an operating gas sensor are performed via a mesoscopic model derived from calculated density functional theory data into a set of differential equations. Significant presence of catalytic oxidation reaction is highlighted. PMID- 22102260 TI - The influence of visual training on predicting complex action sequences. AB - Linking observed and executable actions appears to be achieved by an action observation network (AON), comprising parietal, premotor, and occipitotemporal cortical regions of the human brain. AON engagement during action observation is thought to aid in effortless, efficient prediction of ongoing movements to support action understanding. Here, we investigate how the AON responds when observing and predicting actions we cannot readily reproduce before and after visual training. During pre- and posttraining neuroimaging sessions, participants watched gymnasts and wind-up toys moving behind an occluder and pressed a button when they expected each agent to reappear. Between scanning sessions, participants visually trained to predict when a subset of stimuli would reappear. Posttraining scanning revealed activation of inferior parietal, superior temporal, and cerebellar cortices when predicting occluded actions compared to perceiving them. Greater activity emerged when predicting untrained compared to trained sequences in occipitotemporal cortices and to a lesser degree, premotor cortices. The occipitotemporal responses when predicting untrained agents showed further specialization, with greater responses within body-processing regions when predicting gymnasts' movements and in object-selective cortex when predicting toys' movements. The results suggest that (1) select portions of the AON are recruited to predict the complex movements not easily mapped onto the observer's body and (2) greater recruitment of these AON regions supports prediction of less familiar sequences. We suggest that the findings inform both the premotor model of action prediction and the predictive coding account of AON function. PMID- 22102261 TI - Solid-state NMR reveals differences in the packing arrangements of peptide aggregates derived from the aortic amyloid polypeptide medin. AB - Several polypeptides aggregate into insoluble amyloid fibrils associated with pathologies such as Alzheimer's disease, Parkinson's disease and type 2 diabetes. Understanding the structural and sequential motifs that drive fibrillisation may assist in the discovery and refinement of effective therapies. Here we investigate the effects of three predicted amyloidogenic regions on the structure of aggregates formed by medin, a poorly characterised polypeptide associated with aortic medial amyloidosis. Solid-state NMR is used to compare the dynamics and sheet packing arrangement of the C-terminal region encompassing residues F(43) GSV within full-length medin (Med(1-50) ) and two shorter peptide fragments, Med(30-50) and Med(42-49) , lacking specific sequences predicted to be amyloidogenic.(.) Results show that all three peptides have different aggregate morphologies, and Med(30-50) and Med(1-50) have different sheet packing arrangements and dynamics to Med(42-49) . These results imply that at least two of the three predicted amyloidogenic regions are required for the formation and elongation of medin fibres observed in the disease state. PMID- 22102262 TI - Measuring insulin in human vitreous humour using LC-MS/MS. AB - Besides its particular importance as a widely used therapeutic agent, insulin (and its synthetic derivatives) has been suspected, purported, and proven to be a lethal weapon in numerous cases of attempted or successful homicide and suicide. In addition to blood and urine as common matrices for clinical diagnosis and post mortem analysis, vitreous humour has gained considerable attention in autopsy and follow-up investigations due to its ability to provide valuable information on cause and time of death. However, post-mortem insulin analyses using such specimens have been rare due to the limited penetration of peptide hormones into the vitreous body, and immunoassays were exclusively employed in those studies. In the present communication, the determination of insulin(s) from vitreous humour by means of immunopurification combined with ultrahigh performance liquid chromatography--high resolution/high accuracy (tandem) mass spectrometry is reported. Exploiting the constantly increasing sensitivity and robustness of modern mass-spectrometry-based instruments, the option to identify insulin in post-mortem vitreous samples is demonstrated with a specimen collected from a non diabetic victim who died from an insulin overdose. This communication represents the first successful mass-spectrometry-based analysis of post-mortem material related to an insulin poisoning case. PMID- 22102263 TI - Thrombocytopenic platelet disorders. PMID- 22102264 TI - Thrombocytopenic platelet disorders. PMID- 22102265 TI - Current therapies in primary immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) has long been characterized as an autoimmune disease that exhibits antibody-mediated destruction of platelets. Many of the therapies have targeted reducing the antibody production and/or the platelet destruction process within the reticuloendothelial system, including steroids, immunoglobulin, anti-RhD immunoglobulin, splenectomy, and rituximab. Relatively new insights into the pathophysiology of this disorder have led to the introduction of new therapies, such as the use of thrombopoietic agents to enhance platelet production. This review outlines many of the most commonly used therapeutic agents for the treatment of severe thrombocytopenia associated with both newly diagnosed and chronic ITP. PMID- 22102267 TI - Thrombocytopenia and disorders of platelet function in pregnancy. AB - Pregnancy is associated with physiological and pathological changes in platelet numbers and function, which can be of clinical concern because of risks for maternal and fetal or neonatal bleeding. Thrombocytopenia in pregnancy is frequently encountered and may be due to increased platelet turnover and plasma dilution, immune-mediated mechanisms, or a complication of a more severe underlying pregnancy-related disorder such as preeclampsia. Inherited defects in platelet function and number may also manifest during pregnancy with the risk of bleeding dependent on the underlying problem. In some women, the diagnosis of thrombocytopenia will precede pregnancy but in others, the problem is first identified when routine pregnancy blood tests are performed. An accurate diagnosis and risk assessment in the antenatal period are essential for developing specific plans for any antenatal interventions and for management of delivery and the postpartum periods, and the neonate. Management of pregnant women with platelet disorders requires a multidisciplinary approach and close collaboration between the obstetric and hematology teams. PMID- 22102266 TI - Piecing together the humoral and cellular mechanisms of immune thrombocytopenia. AB - The precise mechanisms leading to platelet-targeted autoimmunity in immune thrombocytopenia (ITP) are not known. Cellular checkpoints normally regulate immunological self-reactivity during the development of B and T cells through cell deletion, receptor editing, induction of anergy, and extrinsic cellular suppression. When these checkpoints fail, tolerance to self-antigens may be lost. In this review, we summarize the various immune mechanisms contributing to the development of ITP and relate them back to the checkpoint model of autoimmunity. These mechanisms, including increased levels of lymphocyte growth factors, resistance to death signals, and loss of T-regulatory function, result in an environment permissive to the development of platelet-reactive B and T cells. The mechanisms that lead to thrombocytopenia once tolerance for platelet antigens is lost are examined, including complement-dependent and apoptotic pathways. An improved understanding of ITP pathogenesis will ultimately guide the development of better therapies. PMID- 22102268 TI - Heparin-induced thrombocytopenia: real-world issues. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies. HIT sera often activate platelets without needing heparin-such heparin-"independent" platelet activation can be associated with HIT beginning or worsening despite stopping heparin ("delayed-onset HIT"). We address important issues in HIT diagnosis and therapy, using a recent cohort of HIT patients to illustrate influences of heparin type; triggers for HIT investigation; serological features of heparin-independent platelet activation; and treatment. In our cohort of recent HIT cases ( N = 13), low-molecular-weight heparin (dalteparin) was a common causative agent ( N = 8, 62%); most patients were diagnosed after HIT-thrombosis had occurred; and danaparoid was the most frequently selected treatment. Heparin-independent platelet activation was common (7/13 [54%]) and predicted slower platelet count recovery (>1 week) among evaluable patients (5/5 vs 1/6; P = 0.015). In our experience with argatroban treated patients, HIT-associated consumptive coagulopathy confounds anticoagulant monitoring. Our observations provide guidance on practical aspects of HIT diagnosis and management. PMID- 22102269 TI - Congenital thrombocytopenia and cytochrome C mutation: a matter of birth and death. AB - Thrombocytopenia (TP) Cargeeg is a unique autosomal dominant disorder, affecting a seven-generation family, caused by cytochrome C (CYCS) mutation that dysregulates platelet formation. The CYCS mutation in this disorder is a glycine 41 replacement by serine, which yields a cytochrome C variant with enhanced apoptotic pathway activity in vitro. The deregulated apoptosis in this disorder affects megakaryocytes (MK) during platelet formation, leading to early and ectopic platelet release in the bone marrow (BM). Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome C activity is not a critical regulator of physiological apoptosis in most cells. The pathophysiology of this unique inherited TP, with unaltered platelet survival and normal MK content in the BM, has implications for physiological and pathological mechanisms altering MK apoptosis, with implications for other unexplained thrombocytopenic disorders. PMID- 22102270 TI - Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. AB - Congenital amegakaryocytic thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome presenting as isolated hypomegakaryocytic thrombocytopenia at birth without other characteristic physical anomalies. Most of the patients develop a severe aplastic anemia and trilineage cytopenia during the first years of life and hematopoietic stem cell transplantation is the only curative treatment. In most of the cases the disease is caused by homozygous or compound heterozygous mutations in the gene MPL encoding the receptor for the hematopoietic growth factor thrombopoietin. The present review summarizes clinical and laboratory data for 96 patients with CAMT, reported since 1990. PMID- 22102271 TI - Inherited thrombocytopenia due to GATA-1 mutations. AB - The GATA family of transcription factors, including the founding member, GATA-1, have an important role in gene regulation. GATA-1 is integral to successful hematopoiesis. A wide variety of mutations in GATA-1 affect its function, as well as its interaction with its cofactors (especially Friend of GATA) and the genes upon which GATA-1 acts. Here we review the known mutations, focusing on the specific alterations within the amino acid sequence, the resulting effect on hematopoietic development, and the clinical manifestations that result. Attention is also paid to the relationship between Trisomy 21, also known as Down syndrome, and the phenomenon of a truncated GATA-1, named GATA-1s. The evidence for specific interaction between GATA-1 and chromosome 21, which may explain the correlation between these two mutations, is briefly reviewed. PMID- 22102272 TI - Thrombocytopenias due to gray platelet syndrome or THC2 mutations. AB - Over the last two decades the genetic causes of several Mendelian platelet disorders have been elucidated, while the genetics of many other thrombocytopenic conditions are still unresolved. Among those are the gray platelet syndrome (GPS) and the thrombocytopenia linked to the THC2 locus on human chromosome 10p11-12. GPS is an alpha-granule defect associated with the development of myelofibrosis and mild to moderate thrombocytopenia. Most forms of GPS are autosomal recessive, and recently, the recessive form of the disease was mapped to chromosome 3p21. THC2-linked thrombocytopenia is an autosomal dominant disorder in which affected family members have a mild reduction in platelet counts and occasional bleeding. Platelets in THC2-linked thrombocytopenia appear to be normal in size and function although bone marrow morphology reveals a lack of mature, polyploid megakaryocytes. To date, mutations in three different genes within the THC2 locus have been associated with congenital thrombocytopenia, including a mutation in MASTL. In this article, we summarize the recent discoveries in these two forms of thrombocytopenia, including the functional data that support a role for MASTL kinase in thrombopoiesis. PMID- 22102273 TI - Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the alphaIIbbeta3 integrin. AB - Glanzmann thrombasthenia (GT) is the most widely studied inherited disorder of platelets; it is caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the alphaIIbbeta3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21-23. Although platelet count and platelet volume (and morphology) are normal in classic GT, some reports have inferred a role for alphaIIbbeta3 in megakaryocytopoiesis and some novel but rare point mutations in either of the ITGA2B and ITGB3 genes have been associated with an altered platelet production and selective deficiencies in platelet function. This was brought to light by the discovery of mutations at Arg995 in alphaIIb and Asp723 in beta3 that lead to platelet anisotropy (increased size variation) and thrombocytopenia. Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of alphaIIbbeta3 together keeping the integrin in a bent resting state. Mutations weakening this link (if not abolishing it) increase the activation state of alphaIIbbeta3 and interfere with megakaryocytopoiesis. Other mutations affecting platelet production involve extracellular but membrane proximal domains of beta3. Our purpose is to review the mutations in the ITGA2B and ITGB3 genes that lead to anisotropy and to discuss mechanisms by which this can be brought about. PMID- 22102274 TI - Thrombocytopenia-absent radius syndrome. AB - Thrombocytopenia-absent radius (TAR) syndrome is a relatively uncommon condition characterized by absent radii with the presence of thumbs and congenital or early onset thrombocytopenia that tends to resolve in childhood. The precise cause of this condition is unknown, although recently a microdeletion of chromosome 1q21.1 has been found in all investigated individuals. However, this microdeletion alone is not sufficient to cause TAR syndrome, and another, uncharacterized genetic alteration is thought to be involved in the pathogenesis. PMID- 22102275 TI - Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. AB - Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD alpha-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from alpha-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment. PMID- 22102276 TI - Antimicrobial acrylic materials with in situ generated silver nanoparticles. AB - Polymethyl methacrylate (PMMA) is widely used to treat traumatic head injuries (cranioplasty) and orthopedic injuries (bone cement), but there is a problem with implant-centered infections. With organisms such as Acinetobacter baumannii and methicillin-resistant staphylococcus aureus developing resistance to antibiotics, there is a need for novel antimicrobial delivery mechanisms without risk of developing resistant organisms. OBJECTIVES: To develop a novel antimicrobial implant material by generating silver nanoparticles (AgNP) in situ in PMMA. RESULTS: All PMMA samples with AgNP's (AgNP-PMMA) released Ag(+) ions in vitro for over 28 days. In vitro antimicrobial assays revealed that these samples (even samples with the slowest release rate) inhibited 99.9% of bacteria against four different strains of bacteria. Long-term antimicrobial assay showed a continued antibacterial effect past 28 days. Some AgNP-loaded PMMA groups had comparable Durometer-D hardness (a measure of degree of cure) and modulus to control PMMA, but all experimental groups had slightly lower ultimate transverse strengths. CONCLUSIONS: AgNP-PMMA demonstrated a tremendously broad-spectrum and long intermediate-term antimicrobial effect with comparable mechanical properties to control PMMA. Current efforts are focused on further improving mechanical properties by reducing AgNP loading and assessing fatigue properties. PMID- 22102277 TI - Engagement of alphaIIbbeta3 (GPIIb/IIIa) with alphanubeta3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis. AB - A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis. We found that platelets interfere with a distinct step of the metastasis cascade, as they promote adhesion of melanoma cells to the endothelium in vitro under shear conditions. Constitutively active platelet receptor GPIIb/IIIa (integrin alphaIIbbeta3) expressed on Chinese hamster ovary cells promoted melanoma cell adhesion in the presence of fibrinogen, whereas blocking antibodies to anubeta3 integrin on melanoma cells or to GPIIb/IIIa significantly reduced melanoma cell adhesion to platelets. Furthermore, using intravital microscopy, we observed functional platelet melanoma cell interactions, as platelet depletion resulted in significantly reduced melanoma cell adhesion to the injured vascular wall in vivo. Using a mouse model of hematogenous metastasis to the lung, we observed decreased metastasis of B16 melanoma cells to the lung by treatment with a mAb blocking the anu subunit of anubeta3 integrin. This effect was significantly reduced when platelets were depleted in vivo. Thus, the engagement of GPIIb/IIIa with anubeta3 integrin interaction mediates tumor cell-platelet interactions and highlights how this interaction is involved in hematogenous tumor metastasis. PMID- 22102278 TI - Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2 induced epithelial-mesenchymal transition in renal tubular cells. AB - The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) into myofibroblasts contributes to the establishment of fibrosis that leads to end stage renal disease. FGF-2 induces EMT in PTECs. Because the interaction between FGF-2 and its receptor is mediated by heparan sulfate (HS) and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF 2 activity. Heparanase is crucial for the correct turnover of HS/syndecans. The aim of the present study was to assess the role of heparanase on epithelial mesenchymal transition induced by FGF-2 in renal tubular cells. In human kidney 2 (HK2) PTEC cultures, although FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced EMT is through a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase, and matrix metalloproteinase 9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays a role in the tubular-interstitial compartment favoring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an interesting pharmacological target for the prevention of renal fibrosis. PMID- 22102279 TI - Efflux permease CgAcr3-1 of Corynebacterium glutamicum is an arsenite-specific antiporter. AB - Resistance to arsenite (As(III)) by cells is generally accomplished by arsenite efflux permeases from Acr3 or ArsB unrelated families. We analyzed the function of three Acr3 proteins from Corynebacterium glutamicum, CgAcr3-1, CgAcr3-2, and CgAcr3-3. CgAcr3-1 conferred the highest level of As(III) resistance and accumulation in vivo. CgAcr3-1 was also the most active when everted membranes vesicles from Escherichia coli or C. glutamicum mutants were assayed for efflux with different energy sources. As(III) and antimonite (Sb(III)) resistance and accumulation studies using E. coli or C. glutamicum arsenite permease mutants clearly show that CgAcr3-1 is specific for As(III). In everted membrane vesicles expressing CgAcr3-1, dissipation of either the membrane potential or the pH gradient of the proton motive force did not prevent As(III) uptake, whereas dissipation of both components eliminated uptake. Further, a mutagenesis study of CgAcr3-1 suggested that a conserved cysteine and glutamate are involved in active transport. Therefore, we propose that CgAcr3-1 is an antiporter that catalyzes arsenite-proton exchange with residues Cys129 and Glu305 involved in efflux. PMID- 22102280 TI - Evidence for irreversible inhibition of glycogen synthase kinase-3beta by tideglusib. AB - Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK 3beta irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3beta obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [(35)S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3beta. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential. PMID- 22102281 TI - Biosynthesis of UDP-4-keto-6-deoxyglucose and UDP-rhamnose in pathogenic fungi Magnaporthe grisea and Botryotinia fuckeliana. AB - There is increasing evidence that in several fungi, rhamnose-containing glycans are involved in processes that affect host-pathogen interactions, including adhesion, recognition, virulence, and biofilm formation. Nevertheless, little is known about the pathways for the synthesis of these glycans. We show that rhamnose is present in glycans isolated from the rice pathogen Magnaporthe grisea and from the plant pathogen Botryotinia fuckeliana. We also provide evidence that these fungi produce UDP-rhamnose. This is in contrast to bacteria where dTDP rhamnose is the activated form of this sugar. In bacteria, formation of dTDP rhamnose requires three enzymes. Here, we demonstrate that in fungi only two genes are required for UDP-Rha synthesis. The first gene encodes a UDP-glucose 4,6-dehydratase that converts UDP-glucose to UDP-4-keto-6-deoxyglucose. The product was shown by time-resolved (1)H NMR spectroscopy to exist in solution predominantly as a hydrated form along with minor amounts of a keto form. The second gene encodes a bifunctional UDP-4-keto-6-deoxyglucose-3,5-epimerase/-4 reductase that converts UDP-4-keto-6-deoxyglucose to UDP-rhamnose. Sugar composition analysis and gene expression studies at different stages of growth indicate that the synthesis of rhamnose-containing glycans is under tissue specific regulation. Together, our results provide new insight into the formation of rhamnose-containing glycans during the fungal life cycle. The role of these glycans in the interactions between fungal pathogens and their hosts is discussed. Knowledge of the metabolic pathways involved in the formation of rhamnose-containing glycans may facilitate the development of drugs to combat fungal diseases in humans, as to the best of our knowledge mammals do not make these types of glycans. PMID- 22102282 TI - Regulation of androgen receptor-dependent transcription by coactivator MED1 is mediated through a newly discovered noncanonical binding motif. AB - Nuclear receptor (NR) activation by cognate ligand generally involves allosteric realignment of C-terminal alpha-helices thus generating a binding surface for coactivators containing canonical LXXLL alpha-helical motifs. The androgen receptor (AR) is uncommon among NRs in that ligand triggers an intramolecular interaction between its N- and C-terminal domains (termed the N/C interaction) and that coactivators can alternatively bind to surfaces in the AR N-terminal or hinge regions. The evolutionary conserved Mediator complex plays a key coregulatory role in steroid hormone-dependent transcription and is chiefly targeted to NRs via the LXXLL-containing MED1 subunit. Whereas MED1 has been demonstrated to serve as a key transcriptional coactivator for AR, the mechanisms by which AR recruits MED1 have remained unclear. Here we show that MED1 binds to a distinct AR N-terminal region termed transactivation unit-1 (Tau-1) via two newly discovered noncanonical alpha-helical motifs located between MED1 residues 505 and 537. Neither of the two MED1 LXXLL motifs is required for AR binding, whereas loss of the intramolecular AR N/C interaction decreases MED1 binding. We further demonstrate that mitogen-activated protein kinase phosphorylation of MED1 enhances the AR-MED1 interaction in prostate cancer cells. In sum, our findings reveal a novel AR-coactivator binding mechanism that may have clinical implications for AR activity in prostate cancer. PMID- 22102283 TI - Endosomal accumulation of the activated epidermal growth factor receptor (EGFR) induces apoptosis. AB - Endocytosis positively and negatively regulates cell surface receptor signaling by temporally and spatially controlling interactions with downstream effectors. This process controls receptor-effector communication. However, the relationship between receptor endocytic trafficking and cell physiology is unclear. In MDA-MB 468 cells, cell surface EGF receptors (EGFRs) promote cell growth, whereas intracellular EGFRs induce apoptosis, making these cells an excellent model for studying the endocytic regulation of EGFR signaling. In addition, MDA-MB-468 cells have limited EGFR degradation following stimulation. Here, we report that in MDA-MB-468 cells the phosphorylated EGFR accumulates on the limiting membrane of the endosome with its carboxyl terminus oriented to the cytoplasm. To determine whether perturbation of EGFR trafficking is sufficient to cause apoptosis, we used pharmacological and biochemical strategies to disrupt EGFR endocytic trafficking in HeLa cells, which do not undergo EGF-dependent apoptosis. Manipulation of HeLa cells so that active EGF.EGFRs accumulate on the limiting membrane of endosomes reveals that receptor phosphorylation is sustained and leads to apoptosis. When EGF.EGFR complexes accumulated in the intraluminal vesicles of the late endosome, phosphorylation of the receptor was not sustained, nor did the cells undergo apoptosis. These data demonstrate that EGFR-mediated apoptosis is initiated by the activated EGFR from the limiting membrane of the endosome. PMID- 22102284 TI - CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. AB - The endocannabinoid system is known to regulate neural progenitor (NP) cell proliferation and neurogenesis. In particular, CB(2) cannabinoid receptors have been shown to promote NP proliferation. As CB(2) receptors are not expressed in differentiated neurons, CB(2)-selective agonists are promising candidates to manipulate NP proliferation and indirectly neurogenesis by overcoming the undesired psychoactive effects of neuronal CB(1) cannabinoid receptor activation. Here, by using NP cells, brain organotypic cultures, and in vivo animal models, we investigated the signal transduction mechanism involved in CB(2) receptor induced NP cell proliferation and neurogenesis. Exposure of hippocampal HiB5 NP cells to the CB(2) receptor-selective agonist HU-308 led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, which, by inhibiting its downstream target p27Kip1, induced NP proliferation. Experiments conducted with the CB(2) receptor-selective antagonist SR144528, inhibitors of the PI3K/Akt/mTORC1 axis, and CB(2) receptor transient transfection vector further supported that CB(2) receptors control NP cell proliferation via activation of mTORC1 signaling. Likewise, CB(2) receptor engagement induced cell proliferation in an mTORC1-dependent manner both in embryonic cortical slices and in adult hippocampal NPs. Thus, HU-308 increased ribosomal protein S6 phosphorylation and 5-bromo-2'-deoxyuridine incorporation in wild-type but not CB(2) receptor-deficient NPs of the mouse subgranular zone. Moreover, adult hippocampal NP proliferation induced by HU-308 and excitotoxicity was blocked by the mTORC1 inhibitor rapamycin. Altogether, these findings provide a mechanism of action and a rationale for the use of nonpsychotomimetic CB(2) receptor-selective ligands as a novel strategy for the control of NP cell proliferation and neurogenesis. PMID- 22102285 TI - Fructose uptake in Bifidobacterium longum NCC2705 is mediated by an ATP-binding cassette transporter. AB - Recently, a putative ATP-binding cassette (ABC) transport system was identified in Bifidobacterium longum NCC2705 that is highly up-regulated during growth on fructose as the sole carbon source. Cloning and expression of the corresponding ORFs (bl0033-0036) result in efficient fructose uptake by bacteria. Sequence analysis reveals high similarity to typical ABC transport systems and suggests that these genes are organized as an operon. Expression of FruE is induced by fructose, ribose, or xylose and is able to bind these sugars with fructose as the preferred substrate. Our data suggest that BL0033-0036 constitute a high affinity fructose-specific ABC transporter of B. longum NCC2705. We thus suggest to rename the coding genes to fruEKFG and the corresponding proteins to FruE (sugar-binding protein), FruK (ATPase subunit), FruF, and FruG (membrane permeases). Furthermore, protein-protein interactions between the components of the transporter complex were determined by GST pulldown and Western blot analysis. This revealed interactions between the membrane subunits FruF and FruG with FruE, which in vivo is located on the external side of the membrane, and with the cytoplasmatic ATPase FruK. This is in line with the proposed model for bacterial ABC sugar transporters. PMID- 22102286 TI - beta-Glucan from Lentinus edodes inhibits nitric oxide and tumor necrosis factor alpha production and phosphorylation of mitogen-activated protein kinases in lipopolysaccharide-stimulated murine RAW 264.7 macrophages. AB - Lentinan (LNT), a beta-glucan from the fruiting bodies of Lentinus edodes, is well known to have immunomodulatory activity. NO and TNF-alpha are associated with many inflammatory diseases. In this study, we investigated the effects of LNT extracted by sonication (LNT-S) on the NO and TNF-alpha production in LPS stimulated murine RAW 264.7 macrophages. The results suggested that treatment with LNT-S not only resulted in the striking inhibition of TNF-alpha and NO production in LPS-activated macrophage RAW 264.7 cells, but also the protein expression of inducible NOS (iNOS) and the gene expression of iNOS mRNA and TNF alpha mRNA. It is surprising that LNT-S enhanced LPS-induced NF-kappaB p65 nuclear translocation and NF-kappaB luciferase activity, but severely inhibited the phosphorylation of JNK1/2 and ERK1/2. The neutralizing antibodies of anti Dectin-1 and anti-TLR2 hardly affected the inhibition of NO production. All of these results suggested that the suppression of LPS-induced NO and TNF-alpha production was at least partially attributable to the inhibition of JNK1/2 and ERK1/2 activation. This work discovered a promising molecule to control the diseases associated with overproduction of NO and TNF-alpha. PMID- 22102287 TI - A single autoimmune T cell receptor recognizes more than a million different peptides. AB - The T cell receptor (TCR) orchestrates immune responses by binding to foreign peptides presented at the cell surface in the context of major histocompatibility complex (MHC) molecules. Effective immunity requires that all possible foreign peptide-MHC molecules are recognized or risks leaving holes in immune coverage that pathogens could quickly evolve to exploit. It is unclear how a limited pool of <10(8) human TCRs can successfully provide immunity to the vast array of possible different peptides that could be produced from 20 proteogenic amino acids and presented by self-MHC molecules (>10(15) distinct peptide-MHCs). One possibility is that T cell immunity incorporates an extremely high level of receptor degeneracy, enabling each TCR to recognize multiple peptides. However, the extent of such TCR degeneracy has never been fully quantified. Here, we perform a comprehensive experimental and mathematical analysis to reveal that a single patient-derived autoimmune CD8(+) T cell clone of pathogenic relevance in human type I diabetes recognizes >one million distinct decamer peptides in the context of a single MHC class I molecule. A large number of peptides that acted as substantially better agonists than the wild-type "index" preproinsulin-derived peptide (ALWGPDPAAA) were identified. The RQFGPDFPTI peptide (sampled from >10(8) peptides) was >100-fold more potent than the index peptide despite differing from this sequence at 7 of 10 positions. Quantification of this previously unappreciated high level of CD8(+) T cell cross-reactivity represents an important step toward understanding the system requirements for adaptive immunity and highlights the enormous potential of TCR degeneracy to be the causative factor in autoimmune disease. PMID- 22102288 TI - Cathepsin B overexpression due to acid sphingomyelinase ablation promotes liver fibrosis in Niemann-Pick disease. AB - Niemann-Pick disease (NPD) is a lysosomal storage disease caused by the loss of acid sphingomyelinase (ASMase) that features neurodegeneration and liver disease. Because ASMase-knock-out mice models NPD and our previous findings revealed that ASMase activates cathepsins B/D (CtsB/D), our aim was to investigate the expression and processing of CtsB/D in hepatic stellate cells (HSCs) from ASMase null mice and their role in liver fibrosis. Surprisingly, HSCs from ASMase-knock out mice exhibit increased basal level and activity of CtsB as well as its in vitro processing in culture, paralleling the enhanced expression of fibrogenic markers alpha-smooth muscle actin (alpha-SMA), TGF-beta, and pro-collagen alpha1(I) (Col1A1). Moreover, pharmacological inhibition of CtsB blunted the expression of alpha-SMA and Col1A1 and proliferation of HSCs from ASMase-knock out mice. Consistent with the enhanced activation of CtsB in HSCs from ASMase null mice, the in vivo liver fibrosis induced by chronic treatment with CCl(4) increased in ASMase-null compared with wild-type mice, an effect that was reduced upon CtsB inhibition. In addition to liver, the enhanced proteolytic processing of CtsB was also observed in brain and lung of ASMase-knock-out mice, suggesting that the overexpression of CtsB may underlie the phenotype of NPD. Thus, these findings reveal a functional relationship between ASMase and CtsB and that the ablation of ASMase leads to the enhanced processing and activation of CtsB. Therefore, targeting CtsB may be of relevance in the treatment of liver fibrosis in patients with NPD. PMID- 22102289 TI - Global proteomics and metabolomics in cancer biomarker discovery. AB - Chromatography and electrophoresis have been used for the last half-century to separate small and large molecules. Advances in MS instrumentation and techniques for sample introduction into the mass analyzer (i.e. matrix-assisted laser desorption/ionization and electrospray ionization), chromatography in all its formats and modes and two-dimensional gel electrophoresis, including two dimensional difference gel electrophoresis, enabled the separation of complex biological mixtures, such as the proteome and the metabolome, in a biological sample. These advances have made it possible to identify compounds that can be used to discriminate between two samples taken from healthy and diseased individuals. The objective is to find proteins or metabolites that can be used as a clinical test for the early diagnosis, prognosis and monitoring of the disease and the outcome of therapy. In this manuscript, we present an overview of what has been achieved in the search for biomarkers, with emphasis on cancer, using separation science and MS. PMID- 22102290 TI - Sleep quality and asthma control and quality of life in non-severe and severe asthma. AB - PURPOSE: The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non severe (NSA) and severe (SA) asthma. METHODS: Cross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded. RESULTS: Both SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p = 0.02). The majority (88-100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates. CONCLUSIONS: These results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances. PMID- 22102291 TI - Longitudinal analyses of polysomnographic variables, serum androgens, and parameters of glucose metabolism in obese adolescents with polycystic ovarian syndrome. AB - PURPOSE: The prevalence of obstructive sleep apnea syndrome (OSAS) is clearly increased in adults with polycystic ovarian syndrome (PCOS), whereas OSAS does not seem to be frequent in adolescents with PCOS, pointing towards the fact that some patients with PCOS develop OSAS in the further course of the disease. We therefore aimed to analyze the changes of polysomnographic variables in obese adolescents with PCOS in a longitudinal analysis. METHODS: Fifteen adolescents with PCOS (age 15.3 years +/- 1.2, BMI 32.9 kg/m(2) +/- 6.4, SDS-BMI 2.5 +/- 0.8) underwent overnight 12-channel polysomnography at baseline and after a mean duration of 28 +/- 6 months (age 17.8 years +/- 1.1, BMI 32.7 kg/m(2) +/- 7.0, SDS-BMI 2.1 +/- 0.9). After performing the initial polysomnography, we treated hyperandrogenemia and insulin resistance in the study group. We determined parameters of body weight/body composition, parameters of glucose metabolism, and serum androgens in all patients at baseline and follow-up. At follow-up, we compared the polysomnographic variables of the study group to those of healthy female adults. RESULTS: The polysomnographic variables, the parameters of body weight/body composition, and the parameters of glucose metabolism in the study group did not change significantly during the observation period. The serum levels of total testosterone and sex hormone binding globulin increased significantly, whereas free androgen index decreased significantly. At follow-up, the polysomnographic variables of the study group did not differ from those of healthy female adults. CONCLUSIONS: OSAS does not seem to develop in adolescents with PCOS being treated for hyperandrogenism and insulin resistance. The pathogenesis of OSAS in PCOS needs to be examined in larger controlled studies. PMID- 22102292 TI - Self-monitoring of gaze in high functioning autism. AB - Atypical visual behaviour has been recently proposed to account for much of social misunderstanding in autism. Using an eye-tracking system and a gaze contingent lens display, the present study explores self-monitoring of eye motion in two conditions: free visual exploration and guided exploration via blurring the visual field except for the focal area of vision. During these conditions, thirteen students with High Functioning Autism Spectrum Disorders (HFASD) and fourteen typical individuals were presented naturalistic and interactive social stimuli using virtual reality. Fixation data showed a weaker modulation of eye movements according to the conditions in the HFASD group, thus suggesting impairments in self-monitoring of gaze. Moreover, the gaze-contingent lens induced a visual behaviour whereby social understanding scores were correlated with the time spent gazing at faces. The device could be useful for treating gaze monitoring deficiencies in HFASD. PMID- 22102293 TI - Training community mental health therapists to deliver a package of evidence based practice strategies for school-age children with autism spectrum disorders: a pilot study. AB - Research on moving evidence-based practice (EBP) intervention strategies to community service settings for children with autism spectrum disorders (ASD) is urgently needed. The current pilot study addresses this need by examining the feasibility, acceptability and preliminary outcomes of training therapists practicing in community mental health (CMH) clinics to deliver a package of EBP strategies aimed to reduce challenging behaviors in school-age children with ASD. Results indicate that CMH therapists participated in both initial and ongoing training, were able to deliver the intervention with fidelity, and perceived the intervention strategies as useful. Parents participated in almost all sessions with their children and remained in therapy when therapists delivered the intervention. Meaningful reductions in child problem behaviors occurred over 5 months providing promising support for the intervention. PMID- 22102294 TI - The prohormone proenkephalin possesses differential conformational features of subdomains revealed by rapid H-D exchange mass spectrometry. AB - Active enkephalin and related peptide hormones or neurotransmitters are generated by proteolytic processing of inactive prohormone precursors. Little is known about the relative accessibilities of prohormone cleavage sites and conformations of subdomains that undergo proteolytic processing. Therefore, this study investigated the conformational features of the prohormone proenkephalin (PE) by rapid hydrogen-deuterium exchange mass spectrometry (DXMS). DXMS analyzes rates of hydrogen exchange of the polypeptide backbone of PE with deuterium from D(2) O (heavy water) by mass spectrometry, accomplished at sub-second and multisecond time periods. Results showed differential accessibilities of cleavage sites and adjacent subdomains of PE to the aqueous environment. Importantly, protease cleavage sites of PE with greater relative accessibilities correspond to sites most readily cleaved by processing proteases to generate active peptide neurotransmitters. For comparison, peptides derived from PE (by pepsin digestion) displayed greater accessibility to the solvent environment, illustrated by their higher rates of H-D exchange compared to that of intact PE protein. The more limited H-D exchange accessibilities of PE protein, compared to peptides derived from PE, indicate that PE possesses tertiary conformation. These results demonstrate that differential tertiary conformations of PE subdomains undergo ordered proteolytic processing to generate active enkephalin peptides for cell cell communication in the nervous and endocrine systems. PMID- 22102295 TI - Exogenous collagen cross-linking recovers tendon functional integrity in an experimental model of partial tear. AB - We investigated the hypothesis that exogenous collagen cross-linking can augment intact regions of tendon to mitigate mechanical propagation of partial tears. We first screened the low toxicity collagen cross-linkers genipin, methylglyoxal and ultra-violet (UV) light for their ability to augment tendon stiffness and failure load in rat tail tendon fascicles (RTTF). We then investigated cross-linking effects in load bearing equine superficial digital flexor tendons (SDFT). Data indicated that all three cross-linking agents augmented RTTF mechanical properties but reduced native viscoelasticity. In contrast to effects observed in fascicles, methylglyoxal treatment of SDFT detrimentally affected tendon mechanical integrity, and in the case of UV did not alter tendon mechanics. As in the RTTF experiments, genipin cross-linking of SDFT resulted in increased stiffness, higher failure loads and reduced viscoelasticity. Based on this result we assessed the efficacy of genipin in arresting tendon tear propagation in cyclic loading to failure. Genipin cross-linking secondary to a mid-substance biopsy-punch significantly reduced tissue strains, increased elastic modulus and increased resistance to fatigue failure. We conclude that genipin cross-linking of injured tendons holds potential for arresting tendon tear progression, and that implications of the treatment on matrix remodeling in living tendons should now be investigated. PMID- 22102297 TI - Onecut transcription factors are required for the second phase of development of the A13 dopaminergic nucleus in the mouse. AB - The A13 dopaminergic nucleus belongs to the incerto-hypothalamic area. It is thought to exert autonomous roles by integrating sensory input to autonomic, neuroendocrine, and motor output. Although its early development has been well characterized, the factors that contribute to later steps of its formation remain unknown. Transcription factors of the Onecut family have been detected in the A13 nucleus, raising the question of possible roles of these factors during A13 development. Using a combination of immunofluorescence analyses on sections and after whole-mount labeling followed by 3D reconstructions, we further characterized the second phase of development of the A13 nucleus in the mouse, described the distribution of the Onecut proteins throughout A13 development, and analyzed the phenotype of this nucleus in single or compound mutant embryos for the Onecut factors. Here we show that A13 development can be divided into two successive phases. First, during radial migration toward the pial surface the A13 cells differentiate into dopaminergic neurons. Second, these cells gather in the vicinity of the third ventricle. Onecut factors are dynamically and differentially expressed in the A13 nucleus during these two phases of development. In Onecut mutant embryos, the A13 neurons differentiate normally but scatter in the diencephalon and fail to properly gather close to the third ventricle. Hence, Onecut factors are markers of the A13 nucleus throughout embryonic development. They are dispensable for the first phase of A13 development but are required for the second phase of development and for maintenance of this nucleus. PMID- 22102296 TI - Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer's disease. AB - The medial temporal lobes (MTL) and frontal cortex have been shown to subserve memory processes. Neurodegenerative diseases, such as Alzheimer's disease (AD), disrupt the neuronal networks that underlie memory processing. The epsilon4 allele of the apolipoprotein E gene is a genetic risk factor for AD and is associated with decrements in memory and in olfactory function. The present study utilized EQS, a structural equation modeling software program, to examine differences in the neuronal networks between non-demented epsilon4 carriers and epsilon4 noncarriers during a cross-modal olfactory recognition memory paradigm. Prior to fMRI scanning, participants were presented with 16 odors. During two scans, participants discriminated between names of odors presented before scanning (targets) or not presented (foils). The results indicate significant connections between bilateral frontal lobes and MTL for epsilon4 carriers when they misidentified a foil as a target. When epsilon4 noncarriers correctly identified a target, there were greater associations between the amygdala, MTL, and right frontal lobe; these associations also modeled the brain's response when epsilon4 noncarriers misidentified a foil as a target. During memory retrieval, affective cues may facilitate retrieval in epsilon4 noncarriers relative to epsilon4 carriers. Last, no model was found that best represented the functional network used by epsilon4 carriers when they correctly identified a target, which may reflect variability of neuronal recruitment within this population. PMID- 22102298 TI - Carbon isotope ratio determination and investigation of seized testosterone preparations. AB - In the present study, the content of a number of black market testosterone products collected in Austria has been analyzed. Additionally, (13) C/(12) C ratios were measured for testosterone in the products after cleavage of the testosterone ester. The aim was to determine whether some of these products had similar (13) C/(12) C ratios to those normally found for endogenous testosterone, which could prevent a positive isotopic ratio mass spectrometric (IRMS) finding in doping control. Moreover, it was investigated to what extent the preparations contained the masking agent epitestosterone, in order to lower the testosterone/epitestosterone (T/E) ratio in urinary steroid profiles. Out of 30 analyzed products, the declared ingredients differed from the actual content in 10 cases. Epitestosterone, however, could not be found in any of the products. The products displayed delta(13)C(VPDB) values between -23.6 and -29.40/00. For more than half of these products, the values were within a range reported for endogenous urinary steroids. PMID- 22102299 TI - Bridging the gap between disparity and equity: new minds, new methods. PMID- 22102300 TI - Bringing new minds and new methods to bridging health disparity and equity. PMID- 22102301 TI - Hero in pharmaceutical sciences--an outstanding researcher, accessible to humanity: Dr. Karam F. A. Soliman. PMID- 22102302 TI - Partnering to harmonize IRBs for community-engaged research to reduce health disparities. AB - Emerging advances in health disparities research include controlled trials and comparative effectiveness studies that are frequently conducted at multiple community and academic sites. Review by different institutional review boards (IRBs) presents a major impediment to the timely and effective conduct of such research. When research involves minority and underserved communities as well as multiple geographic regions, institutional requirements and interpretation of ethical standards may vary substantially. Such variations can complicate the informed consent process and research protocol, and may undermine participant respect and trial quality. In addition, multiple IRB review can lead to unnecessary delays, jeopardizing funding and capacity to perform collaborative projects. In response to these issues, the Research Centers in Minority Institutions (RCMI) Translational Research Network (RTRN) is developing a community-partnered approach to streamlining IRB review across its consortium of 18 RCMI grantee institutions that will ensure compliance while enhancing the quality of health disparities research. PMID- 22102303 TI - HIV-associated anal dysplasia: experience from a multiethnic-HIV clinic in Hawaii. AB - PURPOSE: To assess the proportion as well as predictors of anal dysplasia in HIV infected Asian/Pacific Islanders. METHODS: This was a retrospective chart review evaluating the proportion of anal dysplasia among a multiethnic population from an ambulatory university-based HIV clinic in Hawaii. Demographic, clinical, and virologic parameters were examined with respect to abnormal anal Pap smear. Variables included: Pap smear results (outcome variable), cytology results, age, self-reported ethnicity, CD4/ nadir CD4 counts, HIV viral load, antiretroviral therapy use, Hepatitis B and C co-infections, history of sexually transmitted diseases, personal history of cancer, tobacco use, alcohol use, intravenous drug abuse, family history of cancer, and history of genital/anal warts. RESULTS: There were no significant differences in rates of abnormal Pap smear among the ethnic groups. Abnormal Pap smears were associated with history of genital warts (7% normal vs. 18% abnormal, p=.01) and alcohol consumption (16% vs. 27%, p=.05). Hepatitis B infection and current anti-retroviral therapy (ART) were associated with normal Pap cytology (9.7% vs. 0%, p=.03) and (96.8% vs. 86.5%, p=.05) respectively. CONCLUSIONS: No differences in the proportion of abnormal Pap smears were seen among ethnic groups followed within an ambulatory HIV clinic. PMID- 22102304 TI - Vitamin D and cardiovascular disease: potential role in health disparities. AB - Cardiovascular disease (CVD), which includes coronary artery disease and stroke, is the leading cause of mortality in the nation. Excess CVD morbidity and premature mortality in the African American community is one of the most striking examples of racial/ ethnic disparities in health outcomes. African Americans also suffer from increased rates of hypovitaminosis D, which has emerged as an independent risk factor for all-cause and cardiovascular mortality. This overview examines the potential role of hypovitaminosis D as a contributor to racial and ethnic disparities in cardiovascular disease (CVD). We review the epidemiology of vitamin D and CVD in African Americans and the emerging biological roles of vitamin D in key CVD signaling pathways that may contribute to the epidemiological findings and provide the foundation for future therapeutic strategies for reducing health disparities. PMID- 22102305 TI - Epidemiology of influenza A 2009 H1N1 virus pandemic in the U.S. AB - A novel influenza, Influenza A 2009 H1N1 virus outbreak, emerged in mid-April 2009, and by December 2009, spread across the world. This epidemiologic analysis uses the epidemiologic problem oriented approach to gather information for, and develop a quantitative risk assessment model that evaluates the likelihood of an influenza outbreak in the U.S., utilizing weekly incidence rates (WIR) and case fatality rates (CFR) stratified by age and the 10 U.S. regions. In addition ArcGIS was used to show variability regarding morbidity rate and WIR. Using data from the Centers for Disease Control and Prevention (CDC) Emerging Infections Program and applying Monte Carlo simulations with @Risk software, the analysis revealed morbidity to be highest in region 8 (1.27*10-2) and lowest in region 2 (0.13*10-2). Heat map results revealed WIR were higher in younger children, for all regions. Case fatality rates were 10 times greater in younger people than in older people and children. Using these different temporal-spatial epidemiologic methods can help decision-makers identify high-risk population clusters and help in prevention and control of pandemics. PMID- 22102306 TI - Relationships between obesity and cardiovascular diseases in four southern states and Colorado. AB - Obesity is among the leading causes of elevated cardiovascular disease (CVD) mortality and morbidity. In the present study, the associations between the increase in body mass index (BMI) and the increase rates of CVD and high blood pressure (HBP) in the states of Mississippi, Alabama, Louisiana, Tennessee, and Colorado are examined using regression analysis and by means of neural network models for obesity and HBP. Data from Behavioral Risk Factor Surveillance System were obtained and analyzed for obesity rates, percent of myocardial infarction, stroke, and HBP from 2005-2009. Results of this study showed a low association between obesity and myocardial infarction rates (R2=0.067); a moderate association with stroke rates ((R2=0.462); and a strong association with HBP rates ((R2=0.811). The highest rates of obesity, CVD, and HBP were found in Mississippi, while Colorado had the lowest rates. Maintaining healthy weight helps reduce the risks of developing CVD. PMID- 22102307 TI - CCR5 promoter haplotype transcription complex characterization. AB - CC chemokine receptor 5 (CCR5) is a major coreceptor for cell entry of human immunodeficiency virus (HIV); its expression is highly associated with virus replication and susceptibility. Single nucleotide polymorphisms (SNPs) in the CCR5 promoter play a critical role in CCR5 transcriptional regulation. HHA and HHE represent two contrasting haplotypes of CCR5 with only two base pair differences in the promoter. Identifying the transcription factors (TFs) that differentially bind to the polymorphic sites (the SNPs) in CCR5 haplotypes aids understanding HIV transmission/pathogenesis. Promoter trapping and two dimensional southwestern blot analysis, to purify transcription complex and identify the differential TFs binding profile, is combined with HPLC-ESI-MS/MS, to determine those proteins specifically bound to one haplotype. This strategy reveals clear differences in haplotype-TF binding and has great promise for investigating how the CCR5 haplotypes may affect HIV-AIDS (acquired immune deficiency syndrome) susceptibility or disease progression. PMID- 22102308 TI - Immune response due to silica exposure in Egyptian phosphate mines. AB - Silicosis is the most common occupational lung disease in Egypt where its prevalence rate ranges from 18.5 % to 45.8% among workers exposed to free crystalline silica dust. Despite its high prevalence, there is a lack of enforcement of exposure limits, availability and use of personal protective equipment, and occupational health education programs. These factors led the authors to study this unique working population; to the best of our knowledge, this is the first work that investigates the effect of exposure to crystalline silica on select immune response of exposed Egyptian phosphate miners. The main aims of this study were to investigate the effect of exposure to free crystalline silica on pulmonary function parameters and select immune response of exposed Egyptian phosphate miners. The study involved of three groups: 50 silica-exposed workers with radiological evidence of silicosis, 50 silica-exposed workers without evidence of silicosis, and 50 healthy unexposed subjects. There were significant differences between pulmonary function parameters in exposed groups with and without silicosis, and healthy unexposed control subjects (p<.001) and pulmonary function was significantly correlated with duration of silica exposure. Smoking had an additive effect on reduction of pulmonary function. Average values of C-reactive protein, rheumatoid factor, complement component C3, IgA, IgG, and IgM were significantly higher in the exposed group with silicosis than in the exposed group without silicosis and in healthy unexposed control subjects (p<.001). PMID- 22102309 TI - Induction of cyclin D1 by arsenite and UVB-irradiation in human keratinocytes. AB - Arsenic is an environmental pollutant with carcinogenic properties that is found in many regions of the world but that poses a health risk primarily in economically disadvantaged areas. In these areas, arsenic ingestion affects various tissues, especially skin in which it acts as a comutagen with the ultraviolet component of solar radiation. Both epidemiological and experimental evidence indicates that arsenic and ultraviolet radiation act on signaling pathways that effect the expression of cyclin D1. We have previously employed an in vitro model system of human epidermal keratinocytes to study the effects of submicromolar concentrations of sodium arsenite on cyclin D1 expression. Here, we employed this system to demonstrate concordant cyclin D1-related induction profiles of ultraviolet B radiation and arsenite using cDNA microarray analysis. We also show that both of these agents act epigenetically to bring about demethylation of the cyclin D1 promoter. PMID- 22102310 TI - Condom-use patterns among women who live in public housing developments in Ponce, Puerto Rico. AB - Abstract:Background. Understanding condom-use patterns and the reasons that women have for choosing not to use condoms with their sexual partners, (both steady and non-steady), is important to the development and implementation of targeted, culturally appropriate interventions that can promote condom use in low-income and impoverished women. Methods. A total of 386 women from four public housing developments in Ponce, Puerto Rico, underwent HIV/STI testing and completed a self-administered questionnaire. Data were collected from August 2008 to October 2010. Results. Reported levels of condom use were low with both steady and non-steady sexual partners. Reasons given for not using condoms with both partner types included the respondent claiming to know her partner well, a general dislike for condoms, not having condoms available, and perceiving no need for them. Conclusions. These findings provide a foundation on which to build an intervention to promote condom use among impoverished women who live in public housing in Puerto Rico in addition to other disadvantaged or impoverished women. It is imperative that health practitioners consider the reasons that these women have for not using condoms in order to inform the development and implementation of effective HIV-prevention interventions. PMID- 22102311 TI - Socio-demographic psychosocial and clinical characteristics of participants in e HealthyStrides(c): an interactive ehealth program to improve diabetes self management skills. AB - Diabetes self-management (DSM) training helps prevent diabetic complications. eHealth approaches may improve its optimal use. The aims were to determine a) acceptability of e-HealthyStrides(c) (an interactive, Internet-based, patient driven, diabetes self-management support and social networking program) among Morehouse Community Physicians' Network diabetics; b) efficacy for DSM behavior change c) success factors for use of e-HealthyStrides(c). Baseline characteristics of pilot study participants are reported. Of those approached, 13.8% agreed to participate. Among participants, 96% were Black, 77% female; age 56+/-9.2 years; education: 44% college or higher and 15% less than 12th grade; 92.5% with home computers. Over half (51%) failed the Diabetes Knowledge Test. Nearly half (47%) were at goal A1C; 24% at goal blood pressure; 3% at goal LDL cholesterol level. Median (SD) Diabetes Empowerment Scale score = 3.93 (0.72) but managing psychosocial aspects = 3.89 (0.89) scored lower than other domains. There was low overall confidence for DSM behaviors. Assistance with healthy eating was the most frequently requested service. Requestors were more obese with worse A1C than others. Chronic care delivery scored average with high scores for counseling and problem solving but low scores for care coordination and follow up. PMID- 22102312 TI - Establishing the Morehouse School of Medicine (MSM) R-CENTER clinical and translational research web-portal: the role of focus groups. AB - The Morehouse School of Medicine (MSM) Research Centers in Minority Institutions (RCMI) Center of Excellence in Clinical and Translational Research has developed a research web-portal to foster research development and collaborations. We describe the role of focus groups (FG). Research faculty and staff were organized into three groups by research interest. Each FG discussion had five steps: Brainstorming, Reporting, Card-sorting, Priority-setting, and Discussions. Integration of top priorities across each FG culminated in a final priority setting step. Each FG generated 45 to 50 unique ideas during brainstorming that were categorized into 10 to 12 unique categories. Final priority-setting captured six top items for the initial design of the portal: ability to identify researchers working on similar research; common data management tools; access to clinical trials information; participant recruitment tools; secure access to research databases; and financial support. Focus groups allowed for a discovery period that generated common themes for the design and customization of the web portal. PMID- 22102313 TI - Intracellular acidosis and pH regulation in central respiratory chemoreceptors. AB - Dysfunctions of brainstem regions responsible for central CO2 chemoreception have been proposed as an underlying pathophysiology of Sudden Infant Death Syndrome (SIDS). We recorded respiratory motor output and intracellular pH (pHi) from chemosensitive neurons in an in vitro tadpole brainstem during normocapnia and hypercapnia. Flash photolysis of the H+ donor nitrobenzaldehyde was used to induce focal decreases in pHi alone. Hypercapnia and flash photolysis significantly decreased pHi from normocapnia. In addition, chemoreceptors did not regulate pHi during hypercapnia, but demonstrated significant pHi recovery when only pHi was reduced by flash photolysis. Respiration was stimulated by decreases in pHi (hypercapnia and flash photolysis) by decreases in burst cycle. These data represent our ability to load the brainstem with nitrobenzaldehyde without disrupting the respiration, to quantify changes in chemoreceptor pHi recovery, and to provide insights regarding mechanisms of human health conditions with racial/ethnic health disparities such as SIDS and Apnea of Prematurity (AOP). PMID- 22102314 TI - Racial and geographic disparities in late-stage prostate cancer diagnosis in Florida. AB - Abstract:Disparities in prostate cancer diagnosis among racial/ethnic groups and across Florida were mapped for the period 1996-2002 and their relationship with putative factors (individual, census tract and county level) was investigated using multilevel modeling and contingency analysis. More counties had higher rates of late-stage diagnosis for Black men than for White men and the location of these racial disparities changed with time. An important finding was the substantially larger correlation between county level rates for Black and White men in 2002 relatively to 1996, which suggests a convergence in their spatial patterns. Major significant factors for late-stage diagnosis included lack of insurance, low household income, smoking, not being married and presence of farm house. These findings should help the design of intervention programs to target counties with the greatest racial disparities in health outcomes. Additional analysis is needed to disentangle the observed racial/ethnic and geographic differences. PMID- 22102315 TI - Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. AB - Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 * 10(-56) and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1 * 10(-44) and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2 * 10( 28) for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians. PMID- 22102316 TI - Abdominal vagal afferent pathways and their distributions of intraganglionic laminar endings in the rat duodenum. AB - We examined abdominal vagal afferents (n = 33) and the distributions of their intraganglionic laminar endings (IGLEs) in the duodenum. Rats (male, Sprague Dawley) received a partial subdiaphragmatic vagotomy that spared a single branch. Wheat germ agglutinin-horseradish peroxidase (0.5-1.0 MUl) was injected into the nodose ganglion ipsilateral to the vagotomized side. We observed that the hepatic branch does not project to the stomach, that the accessory celiac and celiac branches course along the celiac artery and innervate the intestines, and that the left nodose afferents innervate predominantly the duodenum. The hepatic branch innervates the duodenum via the "hepatoduodenal" subbranch and has the densest IGLE distribution in both the dorsoventral and the rostrocaudal extensions of the first 4-cm segment. Both gastric branches have two subbranches that innervate the duodenum; the "lesser curvature" subbranches follow the lesser curvature artery and may join the "hepatoduodenal" subbranch, whereas the "pyloric" subbranches run through the antrum and pylorus to reach the proximal duodenum. Moreover, the subbranches of ventral and dorsal gastric branches innervate more in the ventral and dorsal parts of the duodenum, respectively, and have more IGLEs in the rostral region than in the caudal. A posteriori comparisons indicate that, in the first-centimeter segment, the ventral gastric branch has significantly more IGLEs, whereas, in the third- and fourth-centimeter segments, the hepatic branch has more IGLEs. The finding that three different vagal branches innervate the duodenum with different densities of afferent endings might indicate a viscerotopic receptive field that coordinates digestive functions in feeding. PMID- 22102317 TI - Analysis of lipid surface area in protein-membrane systems combining Voronoi tessellation and Monte Carlo integration methods. AB - All-atom molecular dynamics (MD) simulation has become a powerful research tool to investigate structural and dynamical properties of biological membranes and membrane proteins. The lipid structures of simple membrane systems in recent MD simulations are in good agreement with those obtained by experiments. However, for protein-membrane systems, the complexity of protein-lipid interactions makes investigation of lipid structure difficult. Although the area per lipid is one of the essential structural properties in membrane systems, the area in protein membrane systems cannot be computed easily by conventional approaches like the Voronoi tessellation method. To overcome this limitation, we propose a new method combining the two-dimensional Voronoi tessellation and Monte Carlo integration methods. This approach computes individual surface areas of lipid molecules not only in bulk lipids but also in proximity to membrane proteins. We apply the method to all-atom MD trajectories of the sarcoplasmic reticulum Ca(2+)-pump and the SecY protein-conducting channel. The calculated lipid surface area is in agreement with experimental values and consistent with other structural parameters of lipid bilayers. We also observe changes in the average area per lipid induced by the conformational transition of the SecY channel. Our method is particularly useful for examining equilibration of lipids around membrane proteins and for analyzing the time course of protein-lipid interactions. PMID- 22102318 TI - Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. AB - BACKGROUND: Patients with Crohn's disease (CD) have an intestinal dysbiosis with components of the microbiota exerting differential immune effects. Smoking is associated with an increased incidence of CD, more frequent relapse, and greater burden of surgery. This study aimed to investigate the association between smoking and the intestinal microbiota in patients with active CD. METHODS: Patients with active CD (n = 103) and healthy controls (n = 66) were recruited and demographic and clinical data recorded including current smoking behavior. Fecal samples were collected and analyzed by fluorescent in situ hybridization using probes targeting 16S rRNA of bacteria previously shown to be altered in active CD (bifidobacteria, bacteroides, Clostridium coccoides-Eubacterium rectale, Escherichia coli, and Faecalibacterium prausnitzii). RESULTS: In total, 29/101 (29%) patients with CD and 8/58 (14%) controls were current smokers (P = 0.032). Following multivariate analysis, smoking was found to have a significant and independent effect on the microbiota of patients with CD, with higher Bacteroides-Prevotella in smokers (38.4%) compared with nonsmokers (28.1%) (F((1,93)) = 12.6, P = 0.001). Healthy controls who smoked also had higher Bacteroides-Prevotella (34.8%) than nonsmokers (24.1%) (F((1,55)) = 4.5, P = 0.038). In the pooled multivariate analysis, patients with CD had higher bifidobacteria (F((1,156)) = 30.5, P < 0.001), higher Bacteroides-Prevotella (F((1,156)) = 6.5, P = 0.012), and lower F. prausnitzii (F((1,156)) = 3.8, P = 0.052) compared with healthy controls. CONCLUSIONS: Smokers have luminal microbiota that consist of significantly higher bacteroides. Investigation of whether this is one mechanism through which the negative effects of smoking on CD are mediated is warranted. PMID- 22102319 TI - Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. AB - BACKGROUND: Liver fibrosis is chronic liver damage usually caused by alcohol, viruses or other toxins and is characterised by an excessive accumulation of extracellular matrix proteins such as collagen. The aim of this study was to establish an animal model of chronic liver damage and investigate molecular mechanisms of silymarin hepatoprotective effects. RESULTS: Thioacetamide (TAA; 100 mg kg(-1) intraperitoneal (i.p.) injection three times weekly) effectively induced chronic liver fibrosis in male ICR mice. Then 24 ICR mice were randomly divided into four groups: (1) saline (i.p.) + water (gavage); (2) saline (i.p.) + 150 mg kg(-1) silymarin (gavage); (3) 100 mg kg(-1) TAA (i.p.) + water (gavage); (4) 100 mg kg(-1) TAA (i.p.) + 150 mg kg(-1) silymarin (gavage). Eight weeks of TAA treatment resulted in lower body weight, serum cholesterol and triglycerides as well as increased liver size, ALT, AST and LDH values (P < 0.05). These TAA induced effects were attenuated by silymarin (P < 0.05); therefore silymarin also ameliorated TAA-induced liver lesions. Effects of silymarin on TAA-induced chronic liver damage may be attributed to down-regulation of hepatic MMP-2, MMP 13, TIMP-1, TIMP-2, AP-1, KLF6, TGF-beta1, alpha-SMA and COL-alpha1. CONCLUSION: A mouse model of chronic liver fibrosis was successfully established by injecting 100 mg kg(-1) TAA three times weekly in male ICR mice. Meanwhile, silymarin showed hepatoprotection against TAA-induced damage. PMID- 22102321 TI - Development of a solid phase extraction protocol coupled with liquid chromatography mass spectrometry to analyze central carbon metabolites in lake sediment microcosms. AB - An ion exchange solid phase extraction (SPE) strategy is developed for application with liquid chromatography-tandem quadrupole mass spectrometry (LC MS/MS) for characterization of central carbon metabolites involved in methane assimilation and adjacent pathways in natural mixtures. For this purpose, short time microcosm samples were obtained from lake sediment known to consume methane. Three SPE procedures were developed for the recovery of 51 targeted metabolites from five compound classes (amino acids, carboxylic acids, sugar phosphates, nucleotides and acyl-CoAs). The three SPE procedures employed were mixed mode (i) strong cation exchange, (ii) strong anion exchange and (iii) weak anion exchange. By spiking stable isotopic labeled standards, validation of the SPE procedures for the sediment extracts demonstrated that a 3 cm(3), 60 mg SPE sorbent bed provided effective loading capacity for targeted metabolites with an analytical variation of 16% RSD. We readily analyzed 32 of the targeted 51 metabolites using LC-MS/MS after sediment sample extraction, cleanup and pre-concentration. The remaining 19 targeted metabolites were either at, or below, the limit of detection. The current approach provides a good workflow for absolute quantification of intermediates in C(1)-carbon metabolism in natural microbial communities. PMID- 22102320 TI - Aging enhances contraction to thromboxane A2 in aorta from female senescence accelerated mice. AB - The time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A(2) (TXA(2)), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated senescence. SAMP8 and senescence-accelerated mice-resistant (SAMR1) were divided into three groups: 3-, 6- and 10-month-old. Contractile curves to U46619 (10(-9) to 10(-6) M) were performed in aortic rings in the absence or in the presence of nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) and/or cyclooxygenase (COX) inhibitor indomethacin (10(-5) M). Protein and gene expression for COX-1 and COX-2 were determined by immunofluorescence and real-time PCR, respectively. Maximal contraction to U46619 was markedly higher in SAMP8 at all ages. In SAMR1, increases were seen at 10 months, while SAMP8 displays augmented contraction at 6 months, which was further increased at 10 months. L-NAME enhanced U46619 contractions in both 6-month-old groups, although the increase was higher on vessels from SAMR1 at this age. Indomethacin equally increased U46619 contractions in both 3-month-old groups, suggesting the production of vasodilator prostaglandin in young animals. In contrast, at 6 and 10 months indomethacin decreased U46619 contractions in both groups, indicating an aging-associated swap to a release of contractile prostanoids in aorta. In conclusion, aging enhances contractile responses to TXA(2) in aorta from female mice by a mechanism involving a decrease of NO production and increased action of contractile prostanoids. This process occurs earlier in SAMP8 mice, establishing these mice as good model to study cardiovascular aging in a convenient and standard time-course. PMID- 22102322 TI - Thoughts, attitudes, and feelings of HIV-positive MSM associated with high transmission-risk sex. AB - This study presents survey data collected from a sample of HIV-positive men (N = 182) who had high transmission-risk sex, defined as unprotected anal intercourse with a man whose HIV-status was negative or unknown, in the previous 6 months. Despite the tremendous changes in HIV treatment and their impact on people living with HIV, little recent research has examined current trends in their thoughts toward unprotected anal intercourse. Here, the authors describe the self justifications reported by HIV-positive men who have sex with men (MSM) in their current study conducted between 2006 and 2009 and explore key differences between the those of the HIV-positive MSM and those collected from a previous cohort of HIV-negative men (n = 124), who previously reported engaging in high transmission risk sex. Whereas HIV-negative men focused on themes related to the impulsivity of and gratification from unprotected intercourse, HIV-positive men focused on themes regarding the deferral of responsibility/assumption the partner is positive (i.e., "If he's doing X, he must be positive . . ."), or the role of condomless sex fulfilling emotional needs. The findings highlight unique aspects of how HIV-positive men approach decision making regarding the use of condoms, as well as how they perceive issues of responsibility for initiating safer sex practices. PMID- 22102323 TI - Sustainability of the dissemination of an occupational sun protection program in a randomized trial. AB - Sustainability of an occupational sun safety program, Go Sun Smart (GSS), was explored in a randomized trial, testing dissemination strategies at 68 U.S. and Canadian ski areas in 2004-2007. All ski areas received GSS from the National Ski Areas Association through a Basic Dissemination Strategy (BDS) using conference presentations and free materials. Half of the ski areas were randomly assigned to a theory-based Enhanced Dissemination Strategy (EDS) with personal contact supporting GSS use. GSS use was assessed at immediate and long-term follow-up posttests by on-site observation. Use of GSS declined from immediate (M = 6.24) to long-term follow-up (M = 4.72), F(1, 62) = 6.95, p = .01, but EDS ski areas (M = 6.53) continued to use GSS more than BDS ski areas (M = 4.49), F(1, 62) = 5.75, p = .02, regardless of timing of posttest, strategy * observation F(1, 60) = 0.05, p = .83. Despite declines over time, a group of ski areas had sustained high program use and active dissemination methods had sustained positive effects on implementation. PMID- 22102324 TI - Nucleus pulposus cells synthesize a functional extracellular matrix and respond to inflammatory cytokine challenge following long-term agarose culture. AB - Intervertebral disc degeneration is characterized by a cascade of cellular, biochemical and structural changes that may lead to functional impairment and low back pain. Interleukin-1 beta (IL-1beta) is strongly implicated in the etiology of disc degeneration, however there is currently no direct evidence linking IL 1beta upregulation to downstream biomechanical changes. The objective of this study was to evaluate long-term agarose culture of nucleus pulposus (NP) cells as a potential in vitro model system to investigate this. Bovine NP cells were cultured in agarose for 49 days in a defined medium containing transforming growth factor-beta 3, after which both mechanical properties and composition were evaluated and compared to native NP. The mRNA levels of NP cell markers were compared to those of freshly isolated NP cells. Glycosaminoglycan (GAG) content, aggregate modulus and hydraulic permeability of mature constructs were similar to native NP, and aggrecan and SOX9 mRNA levels were not significantly different from freshly isolated cells. To investigate direct links between IL-1beta and biomechanical changes, mature agarose constructs were treated with IL-1beta, and effects on biomechanical properties, extracellular matrix composition and mRNA levels were quantified. IL-1beta treatment resulted in upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 4, matrix metalloproteinase-13 and inducible nitric oxide sythase, decreased GAG and modulus, and increased permeability. To evaluate the model as a test platform for therapeutic intervention, co-treatment with IL-1beta and IL-1 receptor antagonist (IL-1ra) was evaluated. IL-1ra significantly attenuated degradative changes induced by IL-1beta. These results suggest that this in vitro model represents a reliable and cost-effective platform for evaluating new therapies for disc degeneration. PMID- 22102325 TI - Bromoisobutyramide as an intermolecular surface binder for the preparation of free-standing biopolymer assemblies. AB - Bromoisobutyramide (BrIBAM)-modified silica templates facilitate the formation of bio-functional thin films made of a range of biopolymers (e.g., polypeptides, nucleic acids or polysaccharides). Upon template removal, non-covalent free standing biopolymeric assemblies (e.g., hollow capsules or replicated spheres and fibers) are formed without the need for covalent cross-linking. PMID- 22102326 TI - Effect of fatigue on fracture toughness and phase transformation of Y-TZP ceramics by X-ray diffraction and Raman spectroscopy. AB - The aim of this study was to evaluate the effect of fatigue on fracture toughness and phase transformation of yttria-stabilized zirconia polycrystal materials (Cercon and Lava). The specimens were tested for indentation fracture toughness either with or without being subjected to fatigue (20,000 cycles, 2 Hz, 200 N load). X-ray diffraction (XRD) analysis was used to examine the phase composition of specimens. The indentation images were analyzed using Raman spectroscopy at indentation center (p1), indentation corner (p2), points on crack 100 MUm (p3), and 200 MUm (p4) away from the corner and a point ~80 MUm away from the crack (p5). Fracture toughness results were statistically analyzed by two-way analysis of variance (ANOVA); XRD and Raman spectroscopy results were analyzed by three way ANOVA. Fracture toughness of Cercon control (CC) and fatigue (CF) groups were 6.8 and 6.9 MPa?m, respectively, with no significant difference (p > 0.01). Fracture toughness of Lava fatigue (LF; 7.3 MPa?m) was significantly higher than Lava control (LC; p < 0.01). XRD analyses showed CC and LC consisted of tetragonal zirconia, monoclinic zirconia detected after fatigue. After indentation, relative amount of monoclinic phase significantly increased in CC, CF, and LC; decreased in LF. The Raman spectroscopy results indicated that monoclinic fraction was the highest at p2, subsequently at p1 and decreased at p3, p4, and p5 for all groups. Mechanical cycling increased fracture toughness of Cercon and Lava, the second being significant. Phase transformation was also detected after fatigue, which is higher in Lava. Analysis of indentations showed that transformation was highest was at the corner, second at center. PMID- 22102327 TI - The I domain of the AAA+ HslUV protease coordinates substrate binding, ATP hydrolysis, and protein degradation. AB - In the AAA+ HslUV protease, substrates are bound and unfolded by a ring hexamer of HslU, before translocation through an axial pore and into the HslV degradation chamber. Here, we show that the N-terminal residues of an Arc substrate initially bind in the HslU axial pore, with key contacts mediated by a pore loop that is highly conserved in all AAA+ unfoldases. Disordered loops from the six intermediate domains of the HslU hexamer project into a funnel-shaped cavity above the pore and are positioned to contact protein substrates. Mutations in these I-domain loops increase K(M) and decrease V(max) for degradation, increase the mobility of bound substrates, and prevent substrate stimulation of ATP hydrolysis. HslU-DeltaI has negligible ATPase activity. Thus, the I domain plays an active role in coordinating substrate binding, ATP hydrolysis, and protein degradation by the HslUV proteolytic machine. PMID- 22102328 TI - Proliferation and differentiation of human tenocytes in response to platelet rich plasma: an in vitro and in vivo study. AB - Platelet rich plasma (PRP) is the autologous plasma fraction with a platelet-rich cellular component which is enriched with a number of growth factors. Due to its availability and low cost, PRP has become an increasingly popular clinical tool as an alternative source of growth factors for various applications, for example, tendon regeneration but with limited success in clinical trials. The main objective of the current study was to determine whether activated PRP [i.e., platelet rich plasma-clot release (PRCR)] could be used to induce the proliferation and collagen synthesis in human tenocyte in vitro. The advantage of using PRCR is that the platelet-derived bioactive factors are more concentrated and could initiate a more rapid and accelerated healing response than PRP. Our results demonstrated that 10% PRCR treatment accelerated the extent of cell proliferation and collagen production by human tenocytes in vitro. The expression of specific tenocyte markers were similar to conventional fetal bovine serum (FBS)-treated tenocytes implanted in mice within 14 days of implantation in diffusion chambers. Moreover, relatively more collagen fibrils were evident in PRCR-treated tenocytes in vivo as compared to 10% FBS-treated cells. Overall, our feasibility study has indicated that PRCR can induce human tenocyte proliferation and collagen synthesis which could be implemented for future tendon regeneration in reconstructive surgeries. PMID- 22102329 TI - Theoretical investigation of the ethylene dimer: interaction energy and dipole moment. AB - The interaction potential energy and the interaction-induced dipole moment surfaces of the van der Waals C(2)H(4)-C(2)H(4) complex has been calculated for a broad range of intermolecular separations and configurations in the approximation of rigid interacting molecules. The calculations have been carried out using high level ab initio theory with the aug-cc-pVTZ basis set and within the framework of the analytical description of long-range interactions between ethylene molecules. Binding energy for the most stable configuration of the C(2)H(4)-C(2)H(4) complex was calculated at the CCSD(T)/CBS level of theory. The harmonic fundamental vibrational frequencies for this complex were calculated at the MP2 level of theory. PMID- 22102330 TI - Role of adenylate cyclase 1 in retinofugal map development. AB - The development of topographic maps of the sensory periphery is sensitive to the disruption of adenylate cyclase 1 (AC1) signaling. AC1 catalyzes the production of cAMP in a Ca2+/calmodulin-dependent manner, and AC1 mutant mice (AC1-/-) have disordered visual and somatotopic maps. However, the broad expression of AC1 in the brain and the promiscuous nature of cAMP signaling have frustrated attempts to determine the underlying mechanism of AC1-dependent map development. In the mammalian visual system, the initial coarse targeting of retinal ganglion cell (RGC) projections to the superior colliculus (SC) and lateral geniculate nucleus (LGN) is guided by molecular cues, and the subsequent refinement of these crude projections occurs via an activity-dependent process that depends on spontaneous retinal waves. Here, we show that AC1-/- mice have normal retinal waves but disrupted map refinement. We demonstrate that AC1 is required for the emergence of dense and focused termination zones and elimination of inaccurately targeted collaterals at the level of individual retinofugal arbors. Conditional deletion of AC1 in the retina recapitulates map defects, indicating that the locus of map disruptions in the SC and dorsal LGN of AC1-/- mice is presynaptic. Finally, map defects in mice without AC1 and disrupted retinal waves (AC1-/-;beta2-/- double KO mice) are no worse than those in mice lacking only beta2-/-, but loss of AC1 occludes map recovery in beta2-/- mice during the second postnatal week. These results suggest that AC1 in RGC axons mediates the development of retinotopy and eye-specific segregation in the SC and dorsal LGN. PMID- 22102331 TI - Effect of auditory input on activations in infant diverse cortical regions during audiovisual processing. AB - A fundamental question with regard to perceptual development is how multisensory information is processed in the brain during the early stages of development. Although a growing body of evidence has shown the early emergence of modality specific functional differentiation of the cortical regions, the interplay between sensory inputs from different modalities in the developing brain is not well understood. To study the effects of auditory input during audio-visual processing in 3-month-old infants, we evaluated the spatiotemporal cortical hemodynamic responses of 50 infants while they perceived visual objects with or without accompanying sounds. The responses were measured using 94-channel near infrared spectroscopy over the occipital, temporal, and frontal cortices. The effects of sound manipulation were pervasive throughout the diverse cortical regions and were specific to each cortical region. Visual stimuli co-occurring with sound induced the early-onset activation of the early auditory region, followed by activation of the other regions. Removal of the sound stimulus resulted in focal deactivation in the auditory regions and reduced activation in the early visual region, the association region of the temporal and parietal cortices, and the anterior prefrontal regions, suggesting multisensory interplay. In contrast, equivalent activations were observed in the lateral occipital and lateral prefrontal regions, regardless of sound manipulation. Our findings indicate that auditory input did not generally enhance overall activation in relation to visual perception, but rather induced specific changes in each cortical region. The present study implies that 3-month-old infants may perceive audio-visual multisensory inputs by using the global network of functionally differentiated cortical regions. PMID- 22102332 TI - An in vitro investigation of peak insertion torque values of six commercially available mini-implants. PMID- 22102334 TI - Butterfly-shaped nuclei in cerebrospinal fluid relapse of acute promyelocytic leukemia. PMID- 22102337 TI - Long-term outcomes of a chitosan hemostatic dressing in laparoscopic partial nephrectomy. AB - This study examined the long-term safety and effectiveness of a chitosan hemostatic dressing (CHD) in a porcine laparoscopic partial nephrectomy (LPN) model. Eighteen miniswine underwent treatment of using CHD or Surgicel((r)) and Tisseel((r)) (S/T) for renal parenchymal hemostasis after LPN. The animals were followed up for 6 and 12 months. Surgical procedure related complications, hematological and blood chemical changes were monitored. Histopathological examination was performed on the treated and untreated tissue and organs. All animals had initial hemostasis and survived without any immediate or delayed complications in both CHD and S/T groups. The animals with CHD treatment left large amounts of chitosan residuals on the resected kidney that associated with greater inflammatory scores when compared to the S/T treated animals. This long term study showed that CHD residuals remained for 12 months and resulted in local inflammation in the LPN model. Despite lack of signs and symptoms of clinical significance in the animals, a further investigation should be conducted to understand the risk of slow degradation of CHD. PMID- 22102338 TI - Sonographic evaluation of peripheral nerve injuries following the Wenchuan earthquake. AB - PURPOSE: To analyze retrospectively the sonographic characteristics of the peripheral nerve injuries (PNIs) resulted from Wunchuan earthquake. METHODS: The sonographic images of 38 patients with surgically proved PNIs were reviewed and compared with the surgical findings. RESULTS: A total of 78 nerves in 38 patients were found injured in surgery, which included 16 median nerves in the forearm (20.5%), 6 ulnar nerves in the forearm or arm (7.7%), 8 radial nerves in upper limb (10.0%), 8 sciatic nerves (10.3%) in gluteal region, 17 tibial nerves in the leg (21.8%), and 23 peroneal nerves (29.5%). The most common injured nerve in the lower extremity was the peroneal nerve (29.5%) and in upper extremity was the median nerve (20.5%). Sonography correctly diagnosed 72 earthquake-related nerve injuries (92.3%), which included 5 complete disruption (6.4%), 4 partial disruption (5.1%), 63 nerve entrapment (88.5%, included 1 entrapment by bone calus, 38 entrapments by the scar tissue, 13 entrapments by the thickened muscle or tendinous arch, and 11 entrapment in the narrowed osteofibrous tunnels). CONCLUSIONS: Nerve entrapment injury was the common sonographic finding in earthquake-related PNI. PMID- 22102339 TI - High serum glucose levels are associated with a higher perceived age. AB - Estimating perceived age by facial photographs is a good estimate of health in elderly populations. Previously, we showed that familial longevity is marked by a more beneficial glucose metabolism already at middle age. As glucose is also related to skin aging, this study aimed to investigate the association between glucose metabolism and perceived age. Perceived age was assessed using facial photographs and non-fasted glucose and insulin were measured in 602 subjects from the Leiden Longevity Study. Non-diabetic subjects (n = 569) were divided in three strata according to their glucose levels, and diabetic subjects (n = 33; as a proxy of long-term hyperglycemic exposure) were included as a fourth stratum. Considered confounding factors were gender, chronological age, current smoking, body mass index, photo-damage score, and insulin levels. Perceived age was increased from 59.6 years (SE = 0.3) in the first stratum to 61.2 years (SE = 0.6) in diabetic subjects (p for trend = 0.002). In non-diabetic subjects only, perceived age was increased from 59.6 years (SE = 0.3) in the first stratum to 60.6 years (SE = 0.3) in the third stratum (p for trend = 0.009). Continuously, perceived age increased 0.40 years (SE = 0.14, p = 0.006) per 1 mmol/L increase in glucose level in non-diabetic subjects. The present study demonstrates that, also among non-diabetic subjects, higher glucose levels are associated with a higher perceived age. Future research should be focused on elucidating possible mechanisms linking glucose levels to perceived age. PMID- 22102340 TI - STAT5 in human basophils: IL-3 is required for its FcepsilonRI-mediated phosphorylation. AB - Basophils are key effector cells in allergic inflammatory reactions. However, the mechanisms of FcepsilonRI-induced degranulation are complex and remain to be disentangled. Signal transducer and activator of transcription (STAT) molecules modulate various cell functions. STAT5 appears to be essential for IgE-mediated mast cell function, but its role in human basophils after cross-linking FcepsilonRI is unknown. In this study, STAT5 phosphorylation was investigated by flow cytometry, and combined with analyses of the degranulation marker CD63 at single cell level. Kinetics of STAT5 phosphorylation were studied in basophils of birch pollen allergic patients and showed a fast phosphorylation induced by interleukin (IL)-3, but not with antigen alone. Stimulating basophils with a mixture of allergen and IL-3 resulted in a two to three fold higher phosphorylation of STAT5 than induced by IL-3 alone. In the presence of IL-3, antigen elicited a dose-dependent STAT5 response. In conclusion, this study demonstrates that STAT5 in human basophils is activated through both the IL-3 and the FcepsilonRI signaling pathway. PMID- 22102341 TI - Diisopropylammonium chloride: a ferroelectric organic salt with a high phase transition temperature and practical utilization level of spontaneous polarization. AB - A simple organic salt, diisopropylammonium chloride, shows the highest ferroelectric phase transition temperature among molecule-based ferroelectrics with a large spontaneous polarization, making it a candidate for practical technological applications. PMID- 22102342 TI - Use of ultra-performance liquid chromatography/time-of-flight mass spectrometry with nozzle-skimmer fragmentation for comprehensive quantitative analysis of secondary metabolites in Arabidopsis thaliana. AB - This study sought to develop techniques for LC/MS-based metabolomics and to verify that an MS/MS spectral tag (MS2T) could be used in practical secondary metabolite profiling. The retention time (RT), precursor ions, and fragment ions generated by nozzle-skimmer fragmentation were determined using ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOF-MS) and compared with the MS2T. A standard mix was analyzed with UPLC/TOF-MS under the same conditions as were used to construct the MS2T. The difference in RT for the standards was less than 0.15 min and the average RSD was about 2.8%, suggesting that the analysis was highly repeatable. Both precursor ions and fragment ions were observed when the cone voltage was 75 V. Experimental data and fragmentation pattern in the MS2T annotation list were highly similar. Wild-type and cas-1 mutant Arabidopsis thaliana samples treated with an elicitor were analyzed using UPLC/TOF-MS. Sixty-five peaks were successfully annotated. Fragment ions were observed with nozzle-skimmer fragmentation in 50 of 65 (77%) peaks. The reliability of annotation may have increased as a result of fragment ions. Results of multivariate analysis suggested that cas-1 was related to induction of the biosynthesis of these flavonoids. The devised method facilitated practical secondary metabolite profiling. PMID- 22102343 TI - Scotland's surveillance review recommends rationalisation. PMID- 22102344 TI - Preserving the integrity of qualifications. PMID- 22102345 TI - New approach to cattle vaccination. PMID- 22102346 TI - Update on investigations into seasonal canine illness. PMID- 22102347 TI - Views sought on equine trading scheme. PMID- 22102348 TI - Report highlights public health risks of 'new companion animals'. PMID- 22102349 TI - Remembering the real war horses. PMID- 22102351 TI - Veterinary medicines: demonstrating safety and efficacy. PMID- 22102353 TI - Vaccination to reduce Salmonella prevalence in pigs. PMID- 22102354 TI - The appliance of science. PMID- 22102355 TI - Salinomycin toxicity in dairy calves. PMID- 22102356 TI - Non-healing hoof lesions in dairy cows. PMID- 22102357 TI - Spinal aspergillosis in pheasants. PMID- 22102358 TI - Labelling and the cascade. PMID- 22102359 TI - Genetic risk load and age at symptom onset of knee osteoarthritis. AB - To test whether a higher genetic risk load for knee osteoarthritis (OA) is associated with an earlier age at symptom onset. Six polymorphisms in GDF5, PTGS2, 7q22 locus, DVWA, DIO3, and ASPN that have been associated with knee OA were analyzed in 255 patients that had undergone total knee replacement (TKR) because of primary OA and in 457 healthy controls. We looked for association between the number of risk alleles in each patient and his age at symptom onset with linear regression and t-tests between the upper and lower quartiles. There was not even a weak trend in the direction of a younger age at symptom onset in the patients carrying more risk alleles. Patients in the upper quartile of age at symptom onset (67.0 +/- 2.8 years) carried the same number of OA risk alleles (5.4 +/- 1.4 vs. 5.3 +/- 1.0) than patients in the lower quartile (44.6 +/- 5.5 years). We did not find any evidence in support of the hypothesis of an earlier knee OA symptom onset associated with higher genetic risk load as determined by the six loci. This result suggests that old age and genetic risk act as independent factors in the pathogenesis of OA. It also indicates that designing OA genetic studies with patients selected for early symptom onset will not provide any substantial power gain. PMID- 22102360 TI - Protein topology from predicted residue contacts. AB - Residue contacts predicted from correlated positions in a multiple sequence alignment are often sparse and uncertain. To some extent, these limitations in the data can be overcome by grouping the contacts by secondary structure elements and enumerating the possible packing arrangements of these elements in a combinatorial manner. Strong interactions appear frequently but inconsistent interactions are down-weighted and missing interactions up-weighted. The resulting improved consistency in the predicted interactions has allowed the method to be successfully applied to proteins up to 200 residues in length which is larger than any structure previously predicted using sequence data alone. PMID- 22102361 TI - The molecular and mathematical basis of Waddington's epigenetic landscape: a framework for post-Darwinian biology? AB - The Neo-Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo-Darwinism. It needs to incorporate the non-linear, stochastic dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric 'epigenetic landscape', which actually represents the quasi-potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re-wiring of regulatory interactions - offering a link between genetic mutation and sudden, broad evolutionary changes. PMID- 22102362 TI - Neural events leading to and associated with detection of sounds under high processing load. AB - The neural events that lead to successful or failed detection of suprathreshold sounds are not well established. In this experiment, event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) were recorded while participants performed two tasks: a primary difficult duration judgment task on a sequence of tones presented to one ear, and a secondary target detection task on an auditory oddball stream presented to the other ear. The paradigm was designed to elicit competition and variability in detection of auditory targets despite identical input. Successful detection of auditory targets was associated mainly with greater fMRI activity in superior parietal cortex and thalamus. In the ERPs, successful detection was linked with a larger fronto-central negativity at 200 400 ms, and a later centro-posterior positivity. Failure to detect targets was associated with greater fMRI signal in the default mode network, a significantly smaller electrical fronto-central negativity and no late positivity. These findings demonstrate that variability in auditory detection is related to modulation of activity in multimodal parietal and frontal networks active ~ 200 ms after target onset. Results are consistent with a limited capacity and late selection view of attention. PMID- 22102363 TI - Higher brain centers for social tasks in worker ants, Camponotus japonicus. AB - Ants, eusocial insects, have highly elaborate chemical communication systems using a wide variety of pheromones. In the carpenter ant, Camponotus japonicus, workers and queens have the female-specific basiconic sensilla on antennae. The antennal lobe, the primary processing center, in female carpenter ants contains about 480 glomeruli, which are divided into seven groups (T1-T7 glomeruli) based on sensory afferent tracts. The axons of sensory neurons in basiconic sensilla are thought to project to female-specific T6 glomeruli. Therefore, these sensilla and glomeruli are thought to relate to female-specific social tasks in the ants. By using dye filling into local neurons (LNs) and projection neurons (PNs) in the antennal lobe, we neuroanatomically revealed the existence of an isolated processing system for signals probably relating to social tasks in the worker ant. In the antennal lobe, two categories of glomeruli, T6 glomeruli and non-T6 glomeruli, are clearly segregated by LNs. Furthermore, axon terminals of uniglomerular PNs from the respective categories of glomeruli (T6 uni-PNs and non T6 uni-PNs) are also segregated in the secondary olfactory centers, the calyces of the mushroom body and the lateral horn: T6 uni-PNs terminate in the outer layers of the basal ring and lip of mushroom body calyces and in the posterior region of the lateral horn, whereas non-T6 uni-PNs terminate in the middle and inner layers of the basal ring and lip and in the anterior region of the lateral horn. These findings suggest that information probably relating to social tasks might be isolated from other olfactory information and processed in a separate subsystem. PMID- 22102364 TI - Calcifications in an endoscopic ultrasound-guided fine-needle aspirate of chronic pancreatitis. PMID- 22102365 TI - Biomimetic collagen/apatite coating formation on Ti6Al4V substrates. AB - Hydroxyapatite and type I collagen are two major components of natural bone. They have been used extensively to engineer biomaterial surfaces for enhanced implant bone integrations. In this study, a collagen/apatite composite coating was successfully deposited on treated Ti6Al4V surfaces by coprecipitation of type I collagen and apatite in a collagen-containing modified simulated body fluid (m SBF). X-ray diffraction and Fourier-transform infrared spectroscopy results indicated that the coating achieved was a composite of bone-like carbonated apatite and collagen type I, which is similar to the composition of natural bone. The coating composition and morphology could be tailored by carefully adjusting the collagen concentration in the m-SBF. In addition, both the coating thickness and bonding strength were down regulated by the collagen concentration in the m SBF. Collagen inhibited the apatite nucleation on the metallic substrate, and thereby reduced the bonding strength of the composite coating. In addition, an in vitro cell culture study was conducted on both the apatite and the collagen apatite coating surfaces. Addition of collagen promoted osteoblast activities, which may lead to early bone formation. PMID- 22102366 TI - Iatrogenic arteriovenous fistula in the arm in an infant: diagnostic and therapeutic considerations. AB - Iatrogenic arteriovenous fistulas (AVF) are well described in adults; however, this complication is rarely described and reported in infants. We report the case of a 3-month-old infant with complicated gastroschisis requiring multiple venipunctures who presented with signs and symptoms suggestive of traumatic arteriovenous fistula. Ultrasound imaging confirmed the presence of a wide-necked AVF between the brachial artery and vein. The fistula was surgically repaired. This case report describes the clinical imaging and treatment options for infants with iatrogenic AVF. PMID- 22102367 TI - Polypropylene-containing synthetic mesh devices in soft tissue repair: a meta analysis. AB - The acute and chronic host tissue response to synthetic and biologic mesh devices for abdominal hernia repair is thought to ultimately determine clinical outcomes such as adhesion formation, device shrinkage, cellular response, and neotissue formation. A meta-analysis of 38 publications was performed to assess these outcomes in six different treatment groups depending on mesh composition: polypropylene (PP), PP in combination with nonabsorbable polymers, PP in combination with absorbable polymers, non-PP polymers, non-PP in combination with absorbable polymers, and natural materials. Despite showing the least device shrinkage, meshes made entirely from PP generally showed the most adverse host tissue response. PP devices with an absorbable component elicited a more beneficial host response with respect to connective tissue adhesion and tissue inflammation than devices made from PP alone. These devices also provided a high level of mechanical stability resulting in a reduced level of adhesion formation and device shrinkage postapplication. However, the compositional heterogeneity within certain groups, that is, devices of non-PP polymers, non-PP in combination with absorbable polymers, and natural materials, did not allow for a more detailed evaluation or the identification of a single composition with superior host tissue response characteristics. PMID- 22102368 TI - PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone. AB - Giant cell tumor of bone (GCT) presents with numerous osteoclast-like multinucleated giant cells that are principally responsible for the extensive bone resorption by the tumor. Although the precise etiology of GCT remains uncertain, the accumulation of giant cells is partially due to the high expression of the receptor activator of nuclear factor-kappaB ligand (RANKL) from the neoplastic stromal cells. Here, we have investigated whether parathyroid hormone-related protein (PTHrP) plays a role in the pathogenesis of GCT. Immunohistochemistry results revealed PTHrP expression in the stromal cells of the tumor, and that its receptor, the parathyroid hormone type 1 receptor (PTH1R), is expressed by both the stromal cells and giant cells. PCR and Western blot analyses confirmed the expression of PTHrP and PTH1R by isolated stromal cells from five patients presenting with GCT. Treatment of GCT stromal cells with varying concentrations of PTHrP (1-34) significantly increased both RANKL gene expression and the number of multinucleated cells formed from RAW 264.7 cells in co-culture experiments, whereas inhibition of PTHrP with a neutralizing antibody decreased RANKL gene expression. These results suggest that PTHrP is expressed within GCT by the stromal cells and can contribute to the abundant RANKL expression and giant cell formation within the tumor. PMID- 22102369 TI - Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. AB - The calcitonin receptor-like receptor (CRLR), a class B GPCR, forms a heterodimer with receptor activity-modifying protein 2 (RAMP2), and serves as the adrenomedullin (AM) receptor to control neovascularization, while CRLR and RAMP1 form the calcitonin gene-related peptide (CGRP) receptor. Here, we report the crystal structures of the RAMP2 extracellular domain alone and in the complex with the CRLR extracellular domain. The CRLR-RAMP2 complex exhibits several intermolecular interactions that were not observed in the previously reported CRLR-RAMP1 complex, and thus the shape of the putative ligand-binding pocket of CRLR-RAMP2 is distinct from that of CRLR-RAMP1. The CRLR-RAMP2 interactions were confirmed for the full-length proteins on the cell surface by site-specific photo crosslinking. Mutagenesis revealed that AM binding requires RAMP2 residues that are not conserved in RAMP1. Therefore, the differences in both the shapes and the key residues of the binding pocket are essential for the ligand specificity. PMID- 22102370 TI - Selective removal of caffeine from tea extracts using macroporous crosslinked polyvinyl alcohol adsorbents. AB - The hydrolysis reaction of ester groups in vinyl acetate (VAc) was used to introduce hydroxyl groups into the matrix of a macroporous adsorbent, which was itself prepared by free radical suspension copolymerization of triallyl isocyanurate (TAIC) and VAc. Therefore, the copolymerization incompatibility between the hydrophilic and the hydrophobic monomer was overcome successfully and the hydrophobic matrix of the polymeric adsorbent containing a polyvinyl alcohol (PVA) segment was obtained. Introduction of the PVA segment decreased the hydrophobic adsorption affinity of the adsorbent while producing the hydrogen bonding interaction. When isolating the two active components, polyphenols (TPh) and caffeine (CAF), from green tea extracts, this polymeric adsorbent, namely poly(TAIC-co-VA), exhibited good adsorption selectivity towards TPh over CAF. The adsorption mechanism leading to this selectivity involved a hydrophobic interaction mechanism for CAF and multiple weak hydrophobic and hydrogen-bonding interactions for TPh. The adsorption thermodynamics for TPh on poly(TAIC-co-VA) were studied. The effects of adsorbent structure and gradient desorption conditions on isolation were investigated. The result showed that adsorbent, with 20% TAIC content, was able to efficiently remove CAF from different tea extracts with different ratios of TPh and CAF. Finally, almost no CAF was detected in the TPh fraction and the recovery of TPh was greater than 95%. PMID- 22102371 TI - Establishing a model organism: a report from the first annual Nematostella meeting. AB - The sea anemone Nematostella vectensis has developed into a model organism for studying genome evolution and animal development. PMID- 22102372 TI - Polypyrrole nanoparticles: a potential optical coherence tomography contrast agent for cancer imaging. AB - A near-infrared (NIR) absorbing contrast agent based on polypyrrole nanoparticles is described. Quantitative optical coherence tomography studies on tissue phantoms and Mie scattering calculations indicate their potential application for early-stage cancer diagnosis. PMID- 22102373 TI - Separation and purification of neohesperidin from the albedo of Citrus reticulata cv. Suavissima by combination of macroporous resin and high-speed counter-current chromatography. AB - In this article, a simple and efficient protocol for rapid preparation and separation of neohesperidin from the albedo of Citrus reticulata cv. Suavissima was established by the combination of macroporous resin column chromatography and high-speed counter-current chromatography (HSCCC). Six types of resin were investigated by adsorption and desorption tests, and D101 macroporous resin was selected for the first cleaning-up procedure, in which 55% aqueous ethanol was used to elute neohesperidin. After treatment with D101 resin, the neohesperidin purity increased 11.83-fold from 4.92% in the crude extract to 58.22% in the resin-refined sample, with a recovery of 68.97%. The resin-refined sample was directly subjected to HSCCC purification with a two-phase solvent system composed of ethyl acetate-n-butanol-water (4:1:5, v/v), and 23.6 mg neohesperidin with 97.47% purity was obtained from 60 mg sample in only one run. The recovery of neohesperidin in HSCCC separation procedure was 65.85%. The chemical structure of the purified neohesperidin was identified by both HPLC and LC-MS. The established purification process will be helpful for further characterization and utilization of Citrus neohesperidin. PMID- 22102374 TI - Clearance kinetics of a hylan-based viscosupplement after intra-articular and intravenous administration in animal models. AB - Clearance of hylan fluid and hylan gel, components of the hyaluronan (HA)-derived viscosupplement hylan G-F 20, following intra-articular injection into normal, healthy rabbits was evaluated. Radiolabeled hylan G-F 20 was injected at a volume of 0.3 mL into both knee joints of 12 rabbits. At sacrifice, synovial fluid, joint tissues, blood, popliteal lymph nodes, liver, spleen, kidney, and lung were analyzed for radioactivity. The half-life of the fluid component, a high molecular weight hylan, was 1.5 +/- 0.2 days while the half-life of the hylan gel component, a crosslinked hylan, was 8.8 +/- 0.9 days. There was no radioactivity detected in the blood or the major internal organs following intra-articular injection. A rat model was used to evaluate the clearance of a large intravenous bolus of solubilized hylan gel. No accumulation of hylan gel degradation products was observed in any major organs and the half-life of hylan elimination from the blood was within normal ranges for HA elimination. The dosing used in the nonclinical rabbit intra-articular study was equivalent (v/w) to a single 6 mL dose in humans. These results are consistent with the current clinical data that demonstrates safety and effectiveness of an increased volume of hylan G-F 20 injected into the osteoarthritis knee. PMID- 22102375 TI - Development of an injectable two-phase drug delivery system for sequential release of antiresorptive and osteogenic drugs. AB - Unlike controlled release systems that deliver a single drug, dual or multidrug delivery systems with distinct release profiles are more likely to promote timely and effective tissue regeneration as they provide both temporally and concentration-dependent release of different molecules to mimic natural biological events. In this study, an injectable and biodegradable delivery system was developed to sequentially release an antiresorptive drug (clodronate) followed by an osteogenic agent (simvastatin) to treat bone disease. The injectable delivery system comprised simvastatin-loaded gelatin microspheres suspended in a viscous solution of carboxymethylcellulose (CMC) containing clodronate. Several factors (CMC concentration, glutaraldehyde concentration, simvastatin loading, and gelatin microsphere processing conditions) were investigated for their effects on drug release. Clodronate release was not affected by CMC concentration, with complete delivery within 12 hr, and simvastatin release could be modulated by cross-linking of the gelatin microspheres, loading, and washing conditions. Burst release of simvastatin was reduced from 70% to 6% in conjunction with sustained release for up to 3 weeks. The combined system showed early release of the antiresorptive clodronate sequentially followed by sustained delivery of the osteogenic simvastatin. This robust and flexible two-phase delivery system may prove useful for applications in which multiple drug delivery is desired. PMID- 22102376 TI - Coupling electrodeposition with layer-by-layer assembly to address proteins within microfluidic channels. AB - Two thin-film assembly methods are coupled to address proteins. Electrodeposition confers programmability and generates a template for layer-by-layer (LbL) assembly. LbL enables precise control of film thickness and the incorporation of labile biological components. The capabilities are demonstrated using glucose oxidase (GOx) based electrochemical biosensing within a microfabricated fluidic device. PMID- 22102377 TI - How does interoceptive awareness interact with the subjective experience of emotion? An fMRI study. AB - Recent studies in cognitive neuroscience have suggested that the integration of information about the internal bodily state and the external environment is crucial for the experience of emotion. Extensive overlap between the neural mechanisms underlying the subjective emotion and those involved in interoception (perception of that which is arising from inside the body) has been identified. However, the mechanisms of interaction between the neural substrates of interoception and emotional experience remain unclear. We examined the common and distinct features of the neural activity underlying evaluation of emotional and bodily state using functional magnetic resonance imaging (fMRI). The right anterior insular cortex and ventromedial prefrontal cortex (VMPFC) were identified as commonly activated areas. As both of these areas are considered critical for interoceptive awareness, these results suggest that attending to the bodily state underlies awareness of one's emotional state. Uniquely activated areas involved in the evaluation of emotional state included the temporal pole, posterior and anterior cingulate cortex, medial frontal gyrus, and inferior frontal gyrus. Also the precuneus was functionally associated with activity of the right anterior insular cortex and VMPFC when evaluating emotional state. Our findings indicate that activation in these areas and the precuneus are functionally associated for accessing interoceptive information and underpinning subjective experience of the emotional state. Thus, awareness of one's own emotional state appears to involve the integration of interoceptive information with an interpretation of the current situation. PMID- 22102378 TI - Patterned growth of vertically aligned polypyrrole nanowire arrays. AB - A facile strategy for preparing vertically aligned polypyrrole (PPy) nanoarrays with precisely controlled density and quantity is presented. The method involves two steps: (1) the fabrication of the patterned substrate via electron beam lithography and (2) the controlled growth of PPy nanowires via electrochemical polymerization on the patterned substrate. The electrical property of a single PPy nanowire is investigated via in situ conducting probe atomic force microscopy. PMID- 22102379 TI - A validated LC-MS/MS method for the determination of vinflunine in plasma and its application to pharmacokinetic studies. AB - A rapid, simple and sensitive LC-MS/MS method for the quantification of vinflunine in plasma was developed and validated. The analysis involved a simple liquid-liquid extraction. After making alkaline with NaOH, plasma was extracted with methyl tert-butyl ether and the organic extract was then evaporated and the residue was reconstituted in mobile phase. The reconstituted solution was injected into an HPLC system and was subjected to reverse-phase HPLC on a 5 um ODS-3 column at a flow-rate of 0.2 mL/min. The mobile phase consisted of ammonium acetate (0.02 mol/L, pH = 3.0) and acetonitrile (20:80). Vinflunine was detected in the single ion monitoring mode using target ions at m/z 817.4/160.1/142.3 for vinflunine and m/z 447.2/128.3/112.1 for gefitinib (internal standard). Standard curves were linear over the concentration range of 5-1000 ng/mL. The mean predicted concentrations of the quality control samples deviated by less than 2% from the corresponding nominal values; the intra-assay and inter-assay precisions of the assay were within 7% relative standard deviation. The extraction recovery of vinflunine was more than 80%. The validated assay was applied to a pharmacokinetic study of vinflunine in plasma following the administration of a single vinflunine injection (2 mg/kg). PMID- 22102382 TI - The diagnosis and treatment of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease of autoimmune etiology. The initial presentation of PBC is various from asymptomatic, abnormal liver biochemical tests to overt cirrhosis. The diagnosis of PBC is based on cholestatic biochemical liver tests, presence of antimitochondrial antibody and histologic findings of nonsuppurative destructive cholangitis. Although the diagnosis is straightforward, it could be underdiagnosed because of its asymptomatic presentation, or underrecognition of the disease. UDCA in a dose of 13-15 mg/kg is the widely approved therapy which can improve the prognosis of patients with PBC. However, one-third of patients does not respond to UDCA therapy and may require liver transplantation. Every effort to diagnose PBC in earlier stage and to develop new therapeutic drugs and clinical trials should be made. PMID- 22102383 TI - Durability of antiviral therapy for chronic hepatitis C after achieving sustained virological response. PMID- 22102384 TI - Durability of a sustained virological response in chronic hepatitis C patients treated with pegylated interferon alfa and ribavirin. AB - BACKGROUND/AIMS: The reappearance rates of hepatitis C virus (HCV) RNA after a sustained virological response (SVR) have been reported to be 1-2%. We investigated the reappearance rate of HCV RNA after SVR in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN) and ribavirin. METHODS: In total, 292 CHC patients who achieved an SVR after PEG-IFN and ribavirin treatment were included. They were treated with subcutaneous injections of either PEG-IFN-alpha 2a or 2b plus ribavirin orally. Liver function tests and qualitative HCV RNA assays were performed every 6 months during the follow-up period after an SVR. RESULTS: Among the 292 patients, 224 (genotype 1, 92; genotype non-1, 132) were followed up for more than 6 months after SVR. These 224 patients were aged 48.1+/-11.5 years (mean+/-SD), and 129 of them were male. The median follow-up duration was 18 months (range 6-60 months). The reappearance rate of HCV RNA during follow-up was 0%. Two patients who achieved an SVR developed hepatocellular carcinoma during the follow-up period. CONCLUSIONS: An SVR was maintained in all CHC patients treated with PEG-IFN plus ribavirin during a median follow-up of 18 months. However, a screening test for hepatocellular carcinoma is needed for patients with an SVR. PMID- 22102385 TI - The retrospective cohort study for survival rate in patients with advanced hepatocellular carcinoma receiving radiotherapy or palliative care. AB - BACKGROUND/AIMS: This study was conducted to investigate the assessment of treatment efficacy of radiotherapy (RT) and other therapeutic modalities compared with palliative care only for treatment with advanced hepatocellular carcinoma (HCC). METHODS: From 2002 to 2010, based on the case of 47 patients with advanced HCC, we have investigated each patients' Child-Pugh's class, ECOG performance, serum level of alpha fetoprotein and other baseline characteristics that is considered to be predictive variables and values for prognosis of HCC. Out of overall patients, the 29 patients who had received RT were selected for one group and the 18 patients who had received only palliative care were classified for the other. The analysis in survival between the two groups was done to investigate the efficacy of RT. RESULTS: Under the analysis in survival, the mean survival time of total patients group was revealed between 30.1 months and 45.9 months in RT group, while it was 4.8 months in palliative care group, respectively. In the univariate analysis for overall patients, there were significant factors which affected survival rate like as follows: ECOG performance, Child-Pugh's class, the tumor size, the type of tumor, alpha fetoprotein, transarterial chemoembolization, and RT. The regressive analysis in multivariate Cox for total patients. No treatment under radiotherapy and high level of Child-Pugh's class grade were independent predictors of worse overall survival rate in patients. In contrast, for the subset analysis of the twenty-nine patients treated with radiotherapy, the higher serum level of alpha fetoprotein was an independent predictors of worse overall survival rate in patients. CONCLUSIONS: We found that the survival of patients with advanced HCC was better with radiotherapy than with palliative care. Therefore, radiotherapy could be a good option for in patients with advanced HCC. PMID- 22102386 TI - Clinical features and treatment efficacy of peginterferon alfa plus ribavirin in chronic hepatitis C patients coinfected with hepatitis B virus. AB - BACKGROUND/AIMS: Cross-sectional studies have documented that 2-10% of patients who are chronically infected with hepatitis C virus (HCV) are also positive for hepatitis B virus (HBV) surface antigen (HBsAg). Data related to HCV-HBV coinfection are lacking in Korea. This study evaluated the clinical characteristics, the treatment efficacy of peginterferon alfa plus ribavirin, and the changes induced by such treatment in HBV status in chronic hepatitis C (CHC) patients coinfected with HBV. METHODS: Eighteen (2.37%) HBsAg-positive CHC patients were selected from among the 758 subjects from the K(G)yeonggi-Incheon Peginterferon alfa and ribavirin in chronic hepatitis C Treatment (KIPECT) study, which evaluated the treatment efficacy and safety of peginterferon alfa plus ribavirin in CHC patients. Data on changes in the status of HBV infections were obtained. RESULTS: HCV genotype 1b was the most common (44%). The overall sustained virologic response rate was 72% in all patients, and 60% and 87.5% in genotypes 1 and 2, respectively. Two of the 18 patients were positive for HBeAg, and 15 had baseline HBV DNA level of less than 2,000 IU/mL. Two of the three whose levels exceeded this threshold showed no detectable DNA after treatment. After the completion of treatment, serum HBV DNA levels were increased in the two patients whose baseline HBV DNA levels were less than 2,000 IU/mL. CONCLUSIONS: The prevalence of HBV coinfection in CHC patients was 2.37% and most of the patients were inactive carriers. The treatment efficacy was similar to that of HCV mono-infection. Reactivation of HBV replication was observed in some patients after CHC treatment. PMID- 22102387 TI - Clinical significance of occult hepatitis B virus infection in chronic hepatitis C patients. AB - BACKGROUND/AIMS: We investigated the frequency of occult hepatitis B virus (HBV) infection in anti-hepatitis C virus (HCV)-positive individuals and the effects of occult HBV infection on the severity of liver disease. METHODS: Seventy-one hepatitis B virus surface-antigen (HBsAg)-negative patients were divided according to their HBV serological status into groups A (anti-HBc positive, anti HBs negative; n=18), B (anti-HBc positive, anti-HBs positive; n=34), and C (anti HBc negative, anti-HBs positive/negative; n=19), and by anti-HCV positivity (anti HCV positive; n=32 vs. anti-HCV negative; n=39). Liver biopsy samples were taken, and HBV DNA was quantified by real-time PCR. RESULTS: Intrahepatic HBV DNA was detected in 32.4% (23/71) of the entire cohort, and HBV DNA levels were invariably low in the different groups. Occult HBV infection was detected more frequently in the anti-HBc-positive patients. Intrahepatic HBV DNA was detected in 28.1% (9/32) of the anti-HCV-positive and 35.9% (14/39) of the anti-HCV negative subjects. The HCV genotype did not affect the detection rate of intrahepatic HBV DNA. In anti-HCV-positive cases, occult HBV infection did not affect liver disease severity. CONCLUSIONS: Low levels of intrahepatic HBV DNA were detected frequently in both HBsAg-negative and anti-HCV-positive cases. However, the frequency of occult HBV infection was not affected by the presence of hepatitis C, and occult HBV infection did not have a significant effect on the disease severity of hepatitis C. PMID- 22102388 TI - Effect of aldosterone on the amplification of oncolytic vaccinia virus in human cancer lines. AB - BACKGROUND/AIMS: JX-594 is an oncolytic virus derived from the Wyeth vaccinia strain that causes replication-dependent cytolysis and antitumor immunity. Starting with a cross-examination of clinical-trial samples from advanced hepatocellular carcinoma patients having high levels of aldosterone and virus amplification in JX-594 treatment, we investigated the association between virus amplification and aldosterone in human cancer cell lines. METHODS: Cell proliferation was determined by a cell-counting-kit-based colorimetric assay, and vaccinia virus quantitation was performed by quantitative polymerase chain reaction (qPCR) and a viral plaque assay. Also, the intracellular pH was measured using a pH-sensitive dye. RESULTS: Simultaneous treatment with JX-594 and aldosterone significantly increased viral replication in A2780, PC-3, and HepG2 cell lines, but not in U2OS cell lines. Furthermore, the aldosterone treatment time altered the JX-594 replication according to the cell line. The JX-594 replication peaked after 48 and 24 hours of treatment in PC-3 and HepG2 cells, respectively. qPCR showed that JX-594 entry across the plasma membrane was increased, however, the changes are not significant by the treatment. This was inhibited by treatment with spironolactone (an aldosterone-receptor inhibitor). JX-594 entry was significantly decreased by treatment with EIPA [5-(N-ethyl-N isopropyl)amiloride; a Na(+)/H(+)-exchange inhibitor], but aldosterone significantly restored JX-594 entry even in the presence of EIPA. Intracellular alkalization was observed after aldosterone treatment but was acidified by EIPA treatment. CONCLUSIONS: Aldosterone stimulates JX-594 amplification via increased virus entry by affecting the H(+) gradient. PMID- 22102389 TI - Peginterferon alpha and ribavirin combination therapy in patients with hepatitis C virus-related liver cirrhosis. AB - BACKGROUND/AIMS: Pegylated interferon (peginterferon) and ribavirin combination therapy is less effective and associated with a higher frequency of serious complications in chronic hepatitis C patients with cirrhosis than in noncirrhotic patients. This study evaluated the efficacy and tolerability of peginterferon and ribavirin treatment in patients with hepatitis C virus (HCV)-related cirrhosis. METHODS: Eighty-six patients with clinically diagnosed liver cirrhosis were treated with either peginterferon alpha-2a (n=51) or peginterferon alpha-2b (n=35) plus ribavirin. The sustained virologic response (SVR) and adverse effects were analyzed retrospectively. RESULTS: Of the 86 patients (55 males), 48 patients (55.8%) had HCV genotype 1 infection and 38 (44.2%) had genotype non-1 infection. The overall SVR rate was 34.9% (30/86), and the rates of SVR in the genotype 1 and non-1 patients were 20.8% (10/48) and 52.6% (20/38), respectively. The multivariate analysis revealed that having HCV genotype 1 (P=0.003) and high baseline viral load (<8.0*10(5) IU/mL, P=0.012) were the independent predictive factors for SVR failure. In 20.9% (18/86) of the patients, treatment was not completed due to adverse events (27.8%), loss to follow-up (50.0%), and other reasons (22.2%). CONCLUSIONS: Peginterferon and ribavirin combination therapy was relatively effective and feasible for clinically diagnosed HCV patients, especially in those with genotype non-1 infection and low baseline viral load. PMID- 22102390 TI - A case of leukemoid reaction in a patient with sarcomatous hepatocellular carcinoma. AB - A leukemoid reaction is defined as reactive leukocytosis exceeding 50,000/mm(3), with a significant increase in early neutrophil precursors, and can be a paraneoplastic manifestation of various malignant tumors. A 71-year-old male patient complained of decreased appetite, fatigue, and abdominal fullness. He had a palpable, firm liver, and laboratory investigations suggested leukemoid reaction. Liver dynamic computed tomography revealed a hypervascular mass, and an ultrasound-guided fine-needle aspiration of the mass confirmed hepatocellular carcinoma (HCC) with a sarcomatoid component. The leukocyte count of the patient had increased to 147,800/mm(3), and he died 10 days after admission. This is a rare case of leukemoid reaction in a patient with sarcomatous HCC. PMID- 22102391 TI - A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage. AB - Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range. PMID- 22102392 TI - Transcatheter coil embolization of the inferior epigastric artery in a huge abdominal wall hematoma caused by paracentesis in a patient with liver cirrhosis. AB - Therapeutic paracentesis is considered to be a relatively safe procedure and is performed commonly for the control of massive ascites in patients with liver cirrhosis. The commonest puncture site, approximately 4 or 5 cm medial of left anterior superior iliac spine, can be located across the route of the inferior epigastric artery, which is one of the sites of potential massive bleeding. In a 46-year-old woman with liver cirrhosis and refractory ascites, a huge abdominal wall hematoma developed after therapeutic paracentesis. The patient was not stabilized by conservative treatment, and inferior epigastric artery injury was confirmed on angiography. Angiographic coil embolization of the inferior epigastric artery was conducted, after which the bleeding ceased and the hematoma stopped growing. This case indicates that physicians performing paracentesis should be aware of the possibility of inferior epigastric artery injury and consider early angiographic coil embolization when a life-threatening abdominal wall hematoma develops. PMID- 22102393 TI - Early hepatocellular carcinoma. PMID- 22102394 TI - Sclerosing hemangioma in the liver. PMID- 22102395 TI - Apoptosis and diagnosis of nonalcoholic steatohepatitis. PMID- 22102396 TI - Stepwise sequential aneuploidy screening in clinical practice. AB - PURPOSE: To evaluate stepwise sequential screening (SSS) efficiency in clinical practice. METHODS: All singletons undergoing SSS in a single practice by NTQR (Nuchal Translucency Quality Review Program)-credentialed providers in a 2-year period were included. Prenatal diagnosis was offered to all screen-positive women and those with a nuchal translucency >=3.5 mm or cystic hygroma at the 11- to 14 week scan. Data were extracted from prospectively ascertained serum screening and genetics databases. RESULTS: A total of 2,726 patients were screened, with SSS detecting all eight cases of trisomy 21 and all seven cases of other aneuploidies at a 4.3% screen-positive rate. CONCLUSIONS: Stepwise sequential screening offers excellent aneuploidy screening efficiency when introduced into clinical practice. PMID- 22102397 TI - Selective determination of trace thiamphenicol in milk and honey by molecularly imprinted polymer monolith microextraction and high-performance liquid chromatography. AB - A novel solid-phase microextraction (SPME) method based on molecularly imprinted polymer (MIP) monolith as the sorbent for the selective extraction of thiamphenicol (TAP) in milk and honey was developed. The newly developed MIP monolith was produced using TAP as the template molecule, 4-vinylpyridine (4-VP) as the functional monomer. The TAP-MIP monolith synthesized in a micropipette tip could be connected with syringes in different sizes simply to perform SPME process without any other treatment. The derivated MIP monolith showed high selectivity and enrichment ability for TAP. A simple, rapid and sensitive method for the determination of TAP in milk and honey using polymer monolith microextraction (PMME) based on the MIP monolith combined with high-performance liquid chromatography-photodiodes array detector was developed. Several parameters affecting MIP monolith microextraction were investigated, including the flow rate, volume, pH and salt concentration of sample, the type and volume of washing solution, the type and flow rate of eluent. The recovery of this method for TAP was investigated and high recoveries of 92.9-99.3% from milk and honey were obtained with relative standard deviations less than 4.9%. PMID- 22102398 TI - Estimation of properties of a photoinitiated silorane-based composite with potential for orthopaedic applications. AB - We have synthesized a filler-reinforced silorane composite that has potential applications in orthopaedic surgery, such as for a bone stabilizer. The purpose of the present work was to develop a method for estimating four properties of this material; namely, maximum exotherm temperature, flexural strength, flexural modulus, and fracture toughness. The method involved the use of mixture design-of experiments and regression analysis of results obtained using 23 formulations of the composite. We validated the estimation method by showing that, for each of four composite formulations that were not included in the method development, the value of each of the aforementioned properties was not significantly different from that obtained experimentally. Our estimation method has the potential for use in the development of a wide range of orthopaedic materials. PMID- 22102399 TI - Colorless and high strength MgO/Al2 O3 /SiO2 glass-ceramic dental material using zirconia as nucleating agent. AB - Glasses in the system of MgO/Al2 O3 /SiO2 with different concentrations of zirconia as nucleating agent, some of them additionally doped with ZnO or P2 O5 , were annealed in a temperature range from 950 to 1150 degrees C. The use of zirconia led to colorless glass-ceramics, which were transparent to opaque. In all studied compositions, alpha-/beta-quartz-solid-solutions, zirconia as well as spinel or gahnite (ZnAl2 O4 )/spinel-solid-solution precipitated. The highest bending strength of 475 MPa was obtained after annealing at 1000 degrees C for 3 h. The increase of the annealing temperature or an increase in the zirconia concentration resulted in an increase of the microhardness up to 13.3 GPa and of the fracture toughness up to 2.7 MPa m(1/2) . The addition of ZnO results in an increase of the hardness up to 12.5 GPa. The addition of ZnO or P2 O5 led to a fracture toughness of 2 MPa m(1/2) . The described physical properties had to be highly advantageous for the preparation of colorless high strength dental glass ceramics. PMID- 22102400 TI - Broadband neurophysiological abnormalities in the medial prefrontal region of the default-mode network in adults with ADHD. AB - Previous investigations of the default-mode network (DMN) in persons with attention-deficit/hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and posterior aspects. This finding was originally demonstrated in adults with ADHD, then in youth with ADHD, and has been tentatively linked to ultra low frequency oscillations within the DMN. The current study evaluates the specificity of DMN abnormalities to neuronal oscillations in the ultra low frequency range, and examines the regional specificity of these DMN aberrations in medicated and unmedicated adults with, and those without ADHD. An individually matched sample of adults with and without ADHD completed 6-minute sessions of resting-state magnetoencephalography (MEG). Participants with ADHD were known responders to stimulant medications and completed two sessions (predrug/postdrug). MEG data were coregistered to the participant's MRI, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to extract neuronal population activity in regions of the DMN. The unmedicated adults with ADHD exhibited broadband deficits in medial prefrontal cortices (MPFC), but not other DMN regions compared to adults without ADHD. Unmedicated patients also showed abnormal cross-frequency coupling in the gamma range between the MPFC and posterior cingulate areas, and disturbed balance within the DMN as activity in posterior regions was stronger than frontal regions at beta and lower frequencies, which dissipated at higher gamma-frequencies. Administration of pharmacotherapy significantly increased prefrontal alpha activity (8-14 Hz) in adults with ADHD, and decreased the cross frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, and that they may be primarily attributable to abnormal broadband activity in the MPFC. PMID- 22102401 TI - Microspheres consisting of optically active helical substituted polyacetylenes: preparation via suspension polymerization and their chiral recognition/release properties. AB - Cross-linked microspheres consisting of optically active helical substituted polyacetylenes are reported. For preparing the microspheres, substituted polyacetylene copolymers with pendent polymerizable C?C bonds are first prepared and then used as macromonomers to copolymerize with acrylates via suspension polymerization, providing cross-linked microspheres. The helical polymer segments render the microspheres with optical activity, whereas the acrylate-based polymers afford the swelling property. CD and UV-vis spectra demonstrate the optical activity of the microspheres. The microspheres preferably adsorb (R)-(+) 1-phenylethylamine, (R)-(+)-N-benzyl-1-phenylethylamine, and Boc-D-alanine, whereas released Boc-L-alanine rather more rapidly than its enantiomer. PMID- 22102402 TI - Study on pharmacokinetics and tissue distribution of pteryxin in mice by ultra pressure liquid chromatography with tandem mass spectrometry. AB - Pteryxin is a coumarin compound naturally occurring in the roots of Radix Peucedani, a commonly used as traditional Chinese medicine for the treatment of certain respiratory diseases and hypertension. An UPLC-MS/MS method was established to quantify pteryxin in mouse plasma and tissue homogenates. Isoimperatorin was used as internal standard (IS). The method was based on protein precipitation with methanol for sample preparation. Pteryxin and IS were separated using a UPLCTM BEH C18 column and eluted with a mobile phase consisting of methanol and water (70:30, v/v) at a flow-rate of 0.2 mL/min. MS/MS detection was carried out by monitoring the fragmentation of m/z 409.3-287.2 for pteryxin and m/z 271.3-185.2 for IS on a triple-quadrupole mass spectrometer. The total run time was only 6 min. The results showed that it had good linearity over a wide concentration range (r > 0.999), and pteryxin was rapidly distributed and then eliminated from mouse plasma (t(1/2) =1.463 h). The major distribution tissues of pteryxin in mice were liver, and pteryxin was enabled to cross the blood-brain barrier owing to its low polarity. There was no long-term accumulation of pteryxin in mouse tissues. PMID- 22102403 TI - Effects of homogeneous media, binary mixtures and microheterogeneous media on the fluorescence and fluorescence probe properties of some benzo[b][1,8]naphthyridiens with HSA and BSA. AB - A rapid and efficient method for the synthesis of various poly-substituted benzo[b][1,8]naphthyridines in high yield has been developed via the Friedlander condensation of 2-aminoquinoline-3-carbaldehyde 1 with various alicyclic ketones in a base catalyst (aq. potassium hydroxide). A series of benzo[b][1,8]naphthyridines branched with various side-chains and substituents were prepared with the aim of being investigated as a fluorescent agents. Electronic absorption and fluorescence properties of some representative benzonaphthyridines (3d, 5b and 21f) in homogeneous organic solvents, dioxane water binary mixtures and in the microheterogeneous media (sodium dodecyl sulphate (SDS), cetyl trimethyl ammonium bromide (CTAB) and Triton-X100 micelles) have been examined. A linear correlation between solvent polarity and fluorescence properties was observed. Further, the interaction of these benzonaphthyridines (3d, 5b and 21f) with human serum albumin (HSA) and bovine serum albumin (BSA) in phosphate buffer have been examined by UV-vis absorption and fluorescence spectroscopy. The fluorescence intensity of 3d, 5b and 21f increases with the increasing HSA and BSA concentration. These benzonaphthyridines also quench the 345 nm fluorescence of BSA in phosphate buffer (lambda(ex) 280 nm). These compounds have potential for use as neutral and hydrophobic fluorescence probes for examining the microenvironments in proteins, polymers, micelles, etc. PMID- 22102407 TI - Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability. AB - Appreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the transcapillary escape of water and macromolecules, acting as an integral component of the multilayered barrier provided by the walls of these microvessels (ie acting in concert with clefts or fenestrae across endothelial cell layers, basement membranes and pericytes). Dysfunction of any of these capillary wall components, including the endothelial glycocalyx, can disrupt normal microvascular permeability. Because of its ubiquitous nature, damage to the endothelial glycocalyx alters the permeability of multiple capillary beds: in the glomerulus this is clinically apparent as albuminuria. Generalized damage to the endothelial glycocalyx can therefore manifest as both albuminuria and increased systemic microvascular permeability. This triad of altered endothelial glycocalyx, albuminuria and increased systemic microvascular permeability occurs in a number of important diseases, such as diabetes, with accumulating evidence for a similar phenomenon in ischaemia-reperfusion injury and infectious disease. The detection of albuminuria therefore has implications for the function of the microcirculation as a whole. The importance of the endothelial glycocalyx for other aspects of vascular function/dysfunction, such as mechanotransduction, leukocyte-endothelial interactions and the development of atherosclerosis, indicate that alterations in the endothelial glycocalyx may also be playing a role in the dysfunction of other organs observed in these disease states. PMID- 22102408 TI - Family functioning and its clinical correlates in overweight and obese patients. AB - AIM: Our aim is to evaluate the differences in family functioning and anxiety between normal, overweight, and obese subjects. METHOD: Overweight and obese patients were selected from the outpatient clinic of internal medicine department of a university hospital. Patients were classified into three groups as normal weight (N=82), overweight (N=33) and obese (N=50) patients. The normal weight group included healthy subjects. The individuals were examined by the same psychiatrist (MA). Beck Anxiety Inventory and Family Assessment Device were applied to all groups. RESULTS: When compared to normal weight patients, obese and overweight patients had significantly higher anxiety scores and higher scores in general functions, problem solving, communication, roles, affective responsiveness, and behavior control dimensions which reflect increased dysfunctions in their families. The total level of dysfunction that patients experience was predicted by alcohol dependence in the family during childhood period, any medical disorder in the current family, anxiety level and body mass index. CONCLUSION: When treating them clinicians should keep in mind that families of obese and overweight patients may have higher levels of dysfunctions. PMID- 22102409 TI - Time course of cerebral hemodynamics in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Vascular complications are important causes of neurologic sequelae among survivors of aneurysmal subarachnoid hemorrhage (SAH). However, little is known about the time course of cerebral hemodynamics and outcome in patients with and without angiographically confirmed cerebral vasospasm. METHODS: Serial transcranial color-coded sonography (TCCS), angiography, and MRI studies were performed to measure cerebrovascular hemodynamics and assess complications following aneurysmal SAH. RESULTS: Eighteen aneurysmal SAH patients were enrolled. Angiographically confirmed cerebral vasospasm occurred in 14 patients (77.8%), 5 of whom (35.7%) were asymptomatic. The mean blood flow velocity (V(mean) ) of the middle cerebral artery increased significantly as compared with healthy volunteers from day 1 to day 15, and substantially decreased thereafter. The V(mean) of middle cerebral artery was significantly higher in patients with than in patients without angiographically confirmed cerebral vasospasm from day 3 to day 12. Compared to angiography, TCCS detected cerebral vasospasm with 85.7% sensitivity, 100% specificity, 100% positive predictive value, and 66.7% negative predictive value. MRI-evidenced cerebral infarctions occurred in nine patients (50%), three of whom (33.3%) were asymptomatic. CONCLUSIONS: This study demonstrated that approximately one-third of acute phase aneurysmal SAH patients have asymptomatic delayed cerebral infarction, which was undetected by TCCS in one-third of them. This may explain why the accuracy of TCCS to predict clinical symptomatic cerebral vasospasm is suboptimal. PMID- 22102410 TI - Binding with nucleic acids or glycosaminoglycans converts soluble protein oligomers to amyloid. AB - Ample evidence suggests that almost all polypeptides can either adopt a native structure (folded or intrinsically disordered) or form misfolded amyloid fibrils. Soluble protein oligomers exist as an intermediate between these two states, and their cytotoxicity has been implicated in the pathology of multiple human diseases. However, the mechanism by which soluble protein oligomers develop into insoluble amyloid fibrils is not clear, and investigation of this important issue is hindered by the unavailability of stable protein oligomers. Here, we have obtained stabilized protein oligomers generated from common native proteins. These oligomers exert strong cytotoxicity and display a common conformational structure shared with known protein oligomers. They are soluble and remain stable in solution. Intriguingly, the stabilized protein oligomers interact preferentially with both nucleic acids and glycosaminoglycans (GAG), which facilitates their rapid conversion into insoluble amyloid. Concomitantly, binding with nucleic acids or GAG strongly diminished the cytotoxicity of the protein oligomers. EGCG, a small molecule that was previously shown to directly bind to protein oligomers, effectively inhibits the conversion to amyloid. These results indicate that stabilized oligomers of common proteins display characteristics similar to those of disease-associated protein oligomers and represent immediate precursors of less toxic amyloid fibrils. Amyloid conversion is potently expedited by certain physiological factors, such as nucleic acids and GAGs. These findings concur with reports of cofactor involvement with disease-associated amyloid and shed light on potential means to interfere with the pathogenic properties of misfolded proteins. PMID- 22102411 TI - Distal interleukin-1beta (IL-1beta) response element of human matrix metalloproteinase-13 (MMP-13) binds activator protein 1 (AP-1) transcription factors and regulates gene expression. AB - The collagenase matrix metalloproteinase-13 (MMP-13) plays an important role in the destruction of cartilage in arthritic joints. MMP-13 expression is strongly up-regulated in arthritis, largely because of stimulation by inflammatory cytokines such as IL-1beta. Treatment of chondrocytes with IL-1beta induces transcription of MMP-13 in vitro. IL-1beta signaling converges upon the activator protein-1 transcription factors, which have been shown to be required for IL 1beta-induced MMP-13 gene expression. Using chromatin immunoprecipitation (ChIP), we detected activator protein-1 binding within an evolutionarily conserved DNA sequence ~20 kb 5' relative to the MMP-13 transcription start site (TSS). Also using ChIP, we detected histone modifications and binding of RNA polymerase II within this conserved region, all of which are consistent with transcriptional activation. Chromosome conformation capture indicates that chromosome looping brings this region in close proximity with the MMP-13 TSS. Finally, a luciferase reporter construct driven by a component of the conserved region demonstrated an expression pattern similar to that of endogenous MMP-13. These data suggest that a conserved region at 20 kb upstream from the MMP-13 TSS includes a distal transcriptional response element of MMP-13, which contributes to MMP-13 gene expression. PMID- 22102412 TI - BMP2 protein regulates osteocalcin expression via Runx2-mediated Atf6 gene transcription. AB - Bone morphogenetic protein 2 (BMP2) activates unfolded protein response (UPR) transducers, such as PERK and OASIS, in osteoblast cells. ATF6, a bZIP transcription factor, is also a UPR transducer. However, the involvement of ATF6 in BMP2-induced osteoblast differentiation has not yet been elucidated. In the present study, BMP2 treatment was shown to markedly induce the expression and activation of ATF6 with an increase in alkaline phosphatase (ALP) and OC expression in MC3T3E1 cells. In contrast, ATF6 activation by BMP2 was not observed in the Runx2(-/-) primary calvarial osteoblasts, and Runx2 overexpression recovered BMP2 action. BMP2 stimulated ATF6 transcription by enhancing the direct binding of Runx2 to the osteoblast-specific cis-acting element 2 (OSE2, ACCACA, -205 to -200 bp) motif of the Atf6 promoter region. In addition, the overexpression of ATF6 increased the Oc promoter activity by enhancing the direct binding to a putative ATF6 binding motif (TGACGT, -1126 to 1121 bp). The inhibition of ATF6 function with the dominant negative form of ATF6 (DN-ATF6) blocked BMP2- or Runx2-induced OC expression. Interestingly, OASIS, which is structurally similar to ATF6, did not induce Oc expression. ALP and Alizarin red staining results confirmed that BMP2-induced matrix mineralization was also dependent on ATF6 in vitro. Overall, these results suggest that BMP2 induces osteoblast differentiation through Runx2-dependent ATF6 expression, which directly regulates Oc transcription. PMID- 22102413 TI - Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). AB - Articular cartilage enables weight bearing and near friction-free movement in the joints. Critical to its function is the production of a specialized, mechanocompetent extracellular matrix controlled by master regulator transcription factor SOX9. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder resulting in severe skeletal defects and dwarfism. Although much is understood about how SOX9 regulates cartilage matrix synthesis and hence joint function, how this master regulator is itself regulated remains largely unknown. Here we identify a specific microRNA, miR-145, as a direct regulator of SOX9 in normal healthy human articular chondrocytes. We show that miR-145 directly represses SOX9 expression in human cells through a unique binding site in its 3'-UTR not conserved in mice. Modulation of miR-145 induced profound changes in the human chondrocyte phenotype. Specifically, increased miR 145 levels cause greatly reduced expression of critical cartilage extracellular matrix genes (COL2A1 and aggrecan) and tissue-specific microRNAs (miR-675 and miR 140) and increased levels of the hypertrophic markers RUNX2 and MMP13, characteristic of changes occurring in osteoarthritis. We propose miR-145 as an important regulator of human chondrocyte function and a new target for cartilage repair. PMID- 22102414 TI - Biochemical characterization of Warsaw breakage syndrome helicase. AB - Mutations in the human ChlR1 gene are associated with a unique genetic disorder known as Warsaw breakage syndrome characterized by cellular defects in sister chromatid cohesion and hypersensitivity to agents that induce replication stress. A role of ChlR1 helicase in sister chromatid cohesion was first evidenced by studies of the yeast homolog Chl1p; however, its cellular functions in DNA metabolism are not well understood. We carefully examined the DNA substrate specificity of purified recombinant human ChlR1 protein and the biochemical effect of a patient-derived mutation, a deletion of a single lysine (K897del) in the extreme C terminus of ChlR1. The K897del clinical mutation abrogated ChlR1 helicase activity on forked duplex or D-loop DNA substrates by perturbing its DNA binding and DNA-dependent ATPase activity. Wild-type ChlR1 required a minimal 5' single-stranded DNA tail of 15 nucleotides to efficiently unwind a simple duplex DNA substrate. The additional presence of a 3' single-stranded DNA tail as short as five nucleotides dramatically increased ChlR1 helicase activity, demonstrating the preference of the enzyme for forked duplex structures. ChlR1 unwound G quadruplex (G4) DNA with a strong preference for a two-stranded antiparallel G4 (G2') substrate and was only marginally active on a four-stranded parallel G4 structure. The marked difference in ChlR1 helicase activity on the G4 substrates, reflected by increased binding to the G2' substrate, distinguishes ChlR1 from the sequence-related FANCJ helicase mutated in Fanconi anemia. The biochemical results are discussed in light of the known cellular defects associated with ChlR1 deficiency. PMID- 22102415 TI - ATP hydrolysis by RAD50 protein switches MRE11 enzyme from endonuclease to exonuclease. AB - MRE11-RAD50 is a key early response protein for processing DNA ends of broken chromosomes for repair, yet how RAD50 nucleotide dynamics regulate MRE11 nuclease activity is poorly understood. We report here that ATP binding and ATP hydrolysis cause a striking butterfly-like opening and closing of the RAD50 subunits, and each structural state has a dramatic functional effect on MRE11. RAD50-MRE11 has an extended conformation in solution when MRE11 is an active nuclease. However, ATP binding to RAD50 induces a closed conformation, and in this state MRE11 is an endonuclease. ATP hydrolysis opens the RAD50-MRE11 complex, and MRE11 maintains exonuclease activity. Thus, ATP hydrolysis is a molecular switch that converts MRE11 from an endonuclease to an exonuclease. We propose a testable model in which the open-closed transitions are used by RAD50-MRE11 to discriminate among DNA ends and drive the choice of recombination pathways. PMID- 22102416 TI - Influence of femtosecond laser treatment on shear bond strength of composite resin bonding to human dentin under simulated pulpal pressure. AB - This in vitro study evaluated the influence of femtosecond laser (fs-laser) generated patterns on shear bond strength (SBS) of composite resin bonded to human dentin under simulated pulpal pressure. Laser treatment was used to produce two different patterns on dentin surfaces. Three test groups and a control group without laser treatment under pulpal pressure were investigated. Dentin discs of 800 nm thickness were cut from 60 extracted caries-free human molars. Using a perfusion machine, the discs were exposed to Ringer solution on their basal surfaces. Clearfil SE Bond/Herculite XRV system was used. The samples were stored in distilled water and thermocycled. Bonding failures caused by a test set-up to challenge SBS were analyzed by scanning electron microscope (SEM). An 80 MUm sized cube-shaped pattern caused more cohesive failures in dentin or resin compared with the 160 MUm-sized cube-shaped pattern. Weibull statistics demonstrated a significant difference between the two laser patterns, but only the test group with small-sized laser pattern was significantly different from the control group. The Weibull moduli ranged from 4.3 to 9.6 (control group). The 160 MUm-sized pattern enhanced the bonding quality and avoided dentin weakening. It was concluded that fs-laser treatment in a 160 MUm-sized cube-shaped pattern enabled a simplified bonding procedure by dispensing the primer without affecting SBS, compared with the control group. PMID- 22102417 TI - Is degradable antibiotic coating for synthetic meshes provide protection against experimental animal infection after fascia repair? AB - The surgical repair of pelvic organ prolapse using synthetic mesh can fail because of slow or partial implant integration due to poor biocompatibility or infection. As systemic antibiotic prophylaxis has only limited success, we have developed a system that coats standard polypropylene mesh with clinically relevant antibiotics. Amoxicillin and ofloxacin are both released from the mesh in vitro at high levels over 3 days, preventing adhesion and biofilm formation by a clinical isolate of E. coli. In an in vivo incisional hernia repair model in rats, the antibiotic-coated mesh results in appropriate tissue integration with adequate vascularization and collagen formation. When implanted animals are infected with virulent E. coli, both antibiotic coatings provide full protection against infection (as assessed both clinically and microbiologically), thus demonstrating their bioavailability. This method is a specific approach for producing a therapeutic coating that could reduce postsurgical infections. PMID- 22102418 TI - Improved method for retinotopy constrained source estimation of visual-evoked responses. AB - Retinotopy constrained source estimation (RCSE) is a method for noninvasively measuring the time courses of activation in early visual areas using magnetoencephalography (MEG) or electroencephalography (EEG). Unlike conventional equivalent current dipole or distributed source models, the use of multiple, retinotopically mapped stimulus locations to simultaneously constrain the solutions allows for the estimation of independent waveforms for visual areas V1, V2, and V3, despite their close proximity to each other. We describe modifications that improve the reliability and efficiency of this method. First, we find that increasing the number and size of visual stimuli results in source estimates that are less susceptible to noise. Second, to create a more accurate forward solution, we have explicitly modeled the cortical point spread of individual visual stimuli. Dipoles are represented as extended patches on the cortical surface, which take into account the estimated receptive field size at each location in V1, V2, and V3 as well as the contributions from contralateral, ipsilateral, dorsal, and ventral portions of the visual areas. Third, we implemented a map fitting procedure to deform a template to match individual subject retinotopic maps derived from functional magnetic resonance imaging (fMRI). This improves the efficiency of the overall method by allowing automated dipole selection, and it makes the results less sensitive to physiological noise in fMRI retinotopy data. Finally, the iteratively reweighted least squares (IRLS) method was used to reduce the contribution from stimulus locations with high residual error for robust estimation of visual evoked responses. PMID- 22102419 TI - Development of Ti-Ag-Fe ternary titanium alloy for dental application. AB - A series of titanium-silver-iron ternary alloys have been prepared in this study, and their feasibility as dental materials has been evaluated by the microstructural examination, mechanical testing, corrosion resistance evaluation, surface analysis, and cytotoxicity tests. More and more beta-Ti phase appears at room temperature and retains with the increasing of Fe content in Ti-5Ag-xFe alloy systems. The compression strength, wear resistance, and microhardness increase largely (p < 0.05) by the addition of element Fe to Ti-Ag alloy. Moreover, when comparing with commercial pure titanium (CP Ti), nobler electrochemical corrosion behavior could be obtained for Ti-5Ag-1Fe and Ti-5Ag 2.5Fe alloys in the 1% lactic acid solution (pH = 2.1) and 0.1 mol/L H(2) O(2) + 0.9% NaCl solution (pH = 4.0). The released metal ions from Ti-5Ag-xFe alloys into the simulated fluid are trace, similar to the case of CP Ti. The addition of Fe slightly decreases the corrosion resistance of Ti-5Ag alloy. All experimental Ti-5Ag-xFe alloy extracts do not present any cytotoxicity to L-929 and NIH3T3 cell lines. All in all, the combination of superior corrosion resistance and enhanced mechanical properties make Ti-5Ag-1Fe alloy and Ti-5Ag-2.5Fe alloy suitable for dental applications. PMID- 22102420 TI - Determination of famoxadone, fenamidone, fenhexamid and iprodione residues in greenhouse tomatoes. AB - BACKGROUND: Greenhouse tomato production is intended exclusively for fresh consumption. Typical greenhouse conditions provide a conducive environment for the development of different fungi, principally late blight and grey mould, that can destroy plants and fruits. For this reason, different fungicides with different sites of action are used in integrated pest management strategies. Famoxadone, fenamidone, fenhexamid and iprodione (fig. 1) are fungicides of difference classes with different actions that could be used to control tomato pests. RESULTS: The QuEChERS method showed good recoveries, and the analytical method allowed good separation of the fungicides selected. Good results were obtained in terms of repeatability and intermediate precision, with a coefficient of variation of < 9.8%. The limits of determination and quantification of the method were far below the maximum residual levels (MRLs) set by the EU for these fungicides in tomatoes. The analysis of fungicide residues showed that cv. Shiren accounted for higher residue levels than cv. Caramba. The dissipation curves were similar in the two cultivars, indicating that the decrease in pesticides was not related to the tomato type. CONCLUSIONS: Care should be taken when using pesticides in greenhouse conditions, because degradation mainly affects fruit growth. The size of the tomato, in particular its surface/weight ratio, is very important for defining pesticide residues. All fungicides used showed residue levels below the MRLs at the preharvest interval. PMID- 22102421 TI - Macrophage reactivity to different polymers demonstrates particle size- and material-specific reactivity: PEEK-OPTIMA((r)) particles versus UHMWPE particles in the submicron, micron, and 10 micron size ranges. AB - Biologic reactivity to orthopedic implant debris is generally the main determinant of long-term clinical performance where released polymeric particles of Ultra-high molecular weight polyethylene (UHMWPE) remain the most prevalent debris generated from metal-on-polymer bearing total joint arthroplasties. Polymeric alternatives to UHMWPE such as polyetherether-ketone (PEEK) may have increased wear resistance but the bioreactivity of PEEK-OPTIMA particles on peri implant inflammation remains largely uncharacterized. We evaluated human monocyte/macrophage responses (THP-1s and primary human) when challenged by PEEK OPTIMA, UHMWPE, and X-UHMWPE particles of three particle sizes (0.7 um, 2 um, and 10 um) at a dose of 20 particles-per-cell at 24- and 48-h time points. Macrophage responses were measured using cytotoxicity assays, viability assays, proliferation assays and cytokine analysis (IL-1b, IL-6, IL-8, MCP-1, and TNF alpha). In general, there were no significant differences between PEEK-OPTIMA, UHMWPE, and X-UHMWPE particles on macrophage viability or proliferation. However, macrophages demonstrated greater cytotoxicity responses to UHMWPE and X-UHMWPE than to PEEK-OPTIMA at 24 and 48 h, where 0.7 MUm-UHMWPE particles produced the highest amount of cytotoxicity. Particles of X-UHMWPE more than PEEK-OPTIMA and UHMWPE induced IL-1beta, IL-6, MCP-1, and TNF-alpha at 24 h, p < 0.05 (no significant differences at 48 h). On average, cytokine production was more adversely affected by larger 10 MUm particles than by 0.7 and 2 MUm sized particles. While limitations of in vitro analysis apply to this study, PEEK OPTIMA particles were more biocompatible than UHMWPE particles, in that they induced less inflammatory cytokine responses and thus, in part, demonstrates that PEEK-OPTIMA implant debris does not represent an increased inflammatory risk over that of UHMWPE. PMID- 22102422 TI - Sensitivity of carbon nanotubes to the storage of stress in polymers. AB - Residual stress in polymers arises from the freezing of unstable molecular conformations. Residual stress is critical because its relaxation can cause shrinkage, defects, and fractures of polymer materials. The storage of stress is purposely enhanced to develop shape memory materials. Unfortunately, the storage of mechanical stress is still poorly controlled and understood. An approach to sense the storage of stress based on the spectroscopic response of carbon nanotubes is explored. The Raman response of nanotubes exhibits a variable sensitivity to strain when embedded in polymers that have experienced different thermal and mechanical treatments. This unique feature opens up new possibilities for the use of carbon nanotubes as mechanical nanosensors. PMID- 22102423 TI - Analysis of Staphylococcus enterotoxin B using differential isotopic tags and liquid chromatography quadrupole ion trap mass spectrometry. AB - Staphylococcus aureus produces enterotoxins, which are causative agents of foodborne intoxications. Enterotoxins are single-chain polypeptides and have a molecular weight of about 26-28 kDa. The consumption of food contaminated with Staphylococcus aureus enterotoxins results in the onset of acute gastroenteritis within 2-6 h. The objective of this study was the development of a new method for the quantification of Staphylococcal enterotoxin B (SEB) in food matrices. Tryptic peptide map was generated and nine proteolytic fragments were clearly identified (sequence coverage of 35%). Among these, three specific tryptic peptides were selected to be used as surrogate peptides and internal standards for quantitative analysis using an isotopic tagging strategy along with analysis by LC-MS/MS. The linearity of the measurement by LC-MS/MS was evaluated by combining mixtures of both isotopes at 0.1, 0.2, 0.5, 1.0 and 2.0 1H/2H molar ratios with a slope near to 1, values of R2 above 0.98 and %CV obtained from six repeated measurement was below 8%. The precision and accuracy of the method were assessed using SEB spiked in chicken meat homogenate samples. SEB was fortified at 0.2, 1 and 2 pmol/g. The accuracy results indicated that the method can provide accuracy within a 84.9-91.1% range. Overall, the results presented in this manuscript show that proteomics-based methods can be effectively used to detect, confirm and quantify SEB in food matrices. PMID- 22102424 TI - Early prenatal sonographic diagnosis of gastroschisis. AB - We report a case of gastroschisis that was suspected at sonography at 11 weeks + 3 days of amenorrhea. Although early detection does not alter prenatal management of this condition nor does it affect neonatal outcome, it allows early counseling of the parents. PMID- 22102425 TI - The predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability. AB - BACKGROUND AND AIMS: To compare the predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability in community-dwelling elderly persons. METHODS: Prospective cohort study. Participants were 813 aged 70 years and older, elderly Japanese residing in the community, included in the Tsurugaya Project, who were not disabled at the baseline in 2003. Physical function was assessed by the questionnaire of "Motor Fitness Scale". Physical performance measures consisted of maximum walking velocity, timed up and go test (TUG), leg extension power, and functional reach test. The area under the curve (AUC) of the receiver operating characteristic curve for disability was used to compare screening accuracy between Motor Fitness Scale and physical performance measures. Incident disability, defined as certification for long-term care insurance, was used as the endpoint. RESULTS: We observed 135 cases of incident disability during follow-up. The third or fourth quartile for each measure was associated with a significantly increased risk of disability in comparison with the highest quartile. The AUC was 0.70, 0.72, 0.70, 0.68, 0.69 and 0.74, for Motor Fitness Scale, maxi- mum walking velocity, TUG, leg extension power, functional reach test, and total performance score, respectively. CONCLUSIONS: The predictive power of physical function assessed by the Motor Fitness Scale was equivalent to that assessed by physical performance measures. Since Motor Fitness Scale can evaluate physical function safely and simply in comparison with physical performance tests, it would be a practical tool for screening persons at high risk of disability. PMID- 22102426 TI - Removing an intersubject variance component in a general linear model improves multiway factoring of event-related spectral perturbations in group EEG studies. AB - Linear statistical models are used very effectively to assess task-related differences in EEG power spectral analyses. Mixed models, in particular, accommodate more than one variance component in a multisubject study, where many trials of each condition of interest are measured on each subject. Generally, intra- and intersubject variances are both important to determine correct standard errors for inference on functions of model parameters, but it is often assumed that intersubject variance is the most important consideration in a group study. In this article, we show that, under common assumptions, estimates of some functions of model parameters, including estimates of task-related differences, are properly tested relative to the intrasubject variance component only. A substantial gain in statistical power can arise from the proper separation of variance components when there is more than one source of variability. We first develop this result analytically, then show how it benefits a multiway factoring of spectral, spatial, and temporal components from EEG data acquired in a group of healthy subjects performing a well-studied response inhibition task. PMID- 22102427 TI - Effects of the iron-chelating agent deferoxamine on triethylene glycol dimethacrylate, 2-hydroxylethyl methacrylate, hydrogen peroxide-induced cytotoxicity. AB - Triethylene glycol dimethacrylate (TEGDMA) and 2-hydroxylethyl methacrylate (HEMA) are known to deplete glutathione in mammalian cells, generate reactive oxygen species (ROS), and cause oxidative stress. In this study, we investigated whether hydroxyl radicals (.OH), the most lethal and genotoxic ROS, and the Fenton reaction are involved in the cytotoxicity of resin monomers to four different cell types, namely MC3T3-E1 preosteoblasts, human dental pulp cells (HDPCs), human gingival fibroblasts, and L929 mouse fibroblasts. Deferoxamine (DFO), an iron chelating agent, effectively protected MC3T3-E1 cells from resin monomer-induced cytotoxicity, indicating that cytotoxicity was caused primarily by hydroxyl radicals. However, DFO only had a protective effect against relatively high concentrations of TEGDMA and HEMA in HDPCs and human gingival fibroblasts, and resin monomer-induced cytotoxicity in L929 was not attenuated by DFO. A labile iron pool (LIP) was detectable only in MC3T3-E1 cells among the four cell types. This indicates that the generation of hydroxyl radicals induced by resin monomers is likely dependent on LIP levels. In contrast to resin monomers, hydrogen peroxide (H(2)O(2))-induced cytotoxicity was not prevented by DFO in any of the cell types examined, although hydroxyl radicals were detected in MC3T3-E1 cells and HDPCs on exposure to exogenous H(2)O(2). This result suggests that generation of hydroxyl radicals is not always the primary cause of cytotoxicity in H(2)O(2)-treated cells. PMID- 22102428 TI - Towards dynamic metabolic flux analysis in CHO cell cultures. AB - Chinese hamster ovary (CHO) cells are the most widely used mammalian cell line for biopharmaceutical production, with a total global market approaching $100 billion per year. In the pharmaceutical industry CHO cells are grown in fed-batch culture, where cellular metabolism is characterized by high glucose and glutamine uptake rates combined with high rates of ammonium and lactate secretion. The metabolism of CHO cells changes dramatically during a fed-batch culture as the cells adapt to a changing environment and transition from exponential growth phase to stationary phase. Thus far, it has been challenging to study metabolic flux dynamics in CHO cell cultures using conventional metabolic flux analysis techniques that were developed for systems at metabolic steady state. In this paper we review progress on flux analysis in CHO cells and techniques for dynamic metabolic flux analysis. Application of these new tools may allow identification of intracellular metabolic bottlenecks at specific stages in CHO cell cultures and eventually lead to novel strategies for improving CHO cell metabolism and optimizing biopharmaceutical process performance. PMID- 22102429 TI - Chemically triggered C-ON bond homolysis in alkoxyamines. Part 2: DFT investigation and application of the pH effect on NMP. AB - In recent work, a 15-fold increase in the C-ON bond homolysis rate constant kd of 4-pyridylethyl-SG1-based alkoxyamine was observed upon protonation of the pyridyl moiety in organic solvent. In this report, the pH dependence of kd (pKa = 4.7) is investigated in D2O/CD3OD (v/v 1:1). A 64-fold increase in kd is observed at acidic pH. Calculations show that the increase in kd upon protonation is due to both an increase in the stabilization of the protonated 4-pyridylethyl radical and an increase of the destabilization of the starting materials through an increase in the polarity of the alkyl fragment. This new alkoxyamine is applied to NMP of styrene and sodium styrene sulfonate. PMID- 22102430 TI - Subsurface drip application of alternative fumigants to methyl bromide for controlling nematodes in replanted grapevines. AB - BACKGROUND: Many California grape growers use preplant fumigation to ensure uniform and healthy grapevine establishment in replant situations. A field study was conducted to evaluate the performance of subsurface drip-applied chemical alternatives to methyl bromide on plant-parasitic nematodes, plant vigor and fruit yield during the 6 year period following replanting. RESULTS: Subsurface drip fumigation with 1,3-dichloropropene plus chloropicrin and with iodomethane plus chloropicrin had generally similar nematicide activity as methyl bromide in three grape types, while sodium azide was less effective. The combination of 1,3 dichloropropene plus chloropicrin enhanced vine vigor similarly to methyl bromide. However, all plots treated with alternative fumigants produced less fruit yield than methyl bromide over the 4 years of evaluation. CONCLUSION: Subsurface drip fumigation with alternative chemicals to methyl bromide generally provided adequate management of plant-parasitic nematodes during the vine establishment period. However, further research is required to increase the performance of alternative chemicals against other components of the replant problem, as grape yield in vines grown in the alternative treatments was lower than in methyl bromide. PMID- 22102431 TI - Carotenoids and apocarotenoids in cellular signaling related to cancer: a review. AB - The basis for the vivid color of carotenoids and their antioxidant activity is the multiple conjugated double bonds, which are characteristic for these phytonutrients. Moreover, the cleavage of these oxidation-prone double bonds leads to the formation of apocarotenoids. A large number of carbonyl-containing oxidation products are expected to be produced as a result of carotenoid oxidation and these can be further metabolized into the corresponding acids and alcohols. As discussed in this review, many, but not all, of these potential products have been detected and identified in plants as well as in human and animal plasma and tissues. Some of these compounds were found to be biologically active as anticancer agents. In addition to the inhibition of cancer cell proliferation, several carotenoid metabolites were shown to modulate the activity of various transcription systems. These include ligand-activated nuclear receptors, such as the retinoic acid receptor, retinoid X receptor, peroxisome proliferator-activated receptor and estrogen receptor, as well as other transcription systems that have an important role in cancer, such as the electrophile/antioxidant response element pathway and nuclear factor-kappaB. Therefore, apocarotenoids can be considered as natural compounds with multifunctional, rather than monofunctional, activity and, thus, can be useful in the prevention of cancer and other degenerative diseases. PMID- 22102432 TI - Alignment of liquid crystals doped with nickel nanoparticles containing different morphologies. AB - Uniform homeotropic and homogeneous alignment of liquid crystals (LCs) is facilely achieved by dispersing Ni nanoparticles (Ni NPs) into the LCs. The alignment mode depends on the morphology of the Ni NPs. The mechanism of NP induced LC alignment is elucidated clearly, indicating that the perfect orientation arises from the adsorption of Ni NPs on the substrate. PMID- 22102436 TI - Application of hollow fiber-supported liquid-phase microextraction coupled with HPLC for the determination of guaifenesin enantiomer-protein binding. AB - A hollow fiber liquid-phase microextraction technique coupled with high performance liquid chromatography with fluorescence detection was employed for determination and evaluation of the binding characteristics of drugs to bovine serum albumin (BSA). Enantiomers of guaifenesin (an expectorant drug) were investigated as a model system. After optimization of some influencing parameters on microextraction, the proposed method was used for calculation of the target drug distribution coefficient between n-octanol and the buffer solution as well as study of drug-BSA binding in physiological conditions. The developed method shows a new, improved and simple procedure for determination of free drug concentration in biological fluids and the extent of drug-protein binding. PMID- 22102435 TI - Low-grade serous carcinomas of the ovary contain very few point mutations. AB - It has been well established that ovarian low-grade and high-grade serous carcinomas are fundamentally different types of tumours. While the molecular genetic features of ovarian high-grade serous carcinomas are now well known, the pathogenesis of low-grade serous carcinomas, apart from the recognition of frequent somatic mutations involving KRAS and BRAF, is largely unknown. In order to comprehensively analyse somatic mutations in low-grade serous carcinomas, we applied exome sequencing to the DNA of eight samples of affinity-purified, low grade, serous carcinomas. A remarkably small number of mutations were identified in seven of these tumours: a total of 70 somatic mutations in 64 genes. The eighth case displayed mixed serous and endometrioid features and a mutator phenotype with 783 somatic mutations, including a nonsense mutation in the mismatch repair gene, MSH2. We validated representative mutations in an additional nine low-grade serous carcinomas and 10 serous borderline tumours, the precursors of ovarian low-grade, serous carcinomas. Overall, the genes showing the most frequent mutations were BRAF and KRAS, occurring in 10 (38%) and 5 (19%) of 27 low-grade tumours, respectively. Except for a single case with a PIK3CA mutation, other mutations identified in the discovery set were not detected in the validation set of specimens. Our mutational analysis demonstrates that point mutations are much less common in low-grade serous tumours of the ovary than in other adult tumours, a finding with interesting scientific and clinical implications. PMID- 22102437 TI - The cerebral representation of temporomandibular joint occlusion and its alternation by occlusal splints. AB - Occlusal splints are a common and effective therapy for temporomandibular joint disorder. Latest hypotheses on the impact of occlusal splints suggest an altered cerebral control on the occlusion movements after using a splint. However, the impact of using a splint during chewing on its cerebral representation is quite unknown. We used functional magnetic resonance imaging (fMRI) to investigate brain activities during occlusal function in centric occlusion on natural teeth or on occlusal splints in fifteen healthy subjects. Comparisons between conditions revealed an increased activation for the bilateral occlusion without a splint in bilateral primary and secondary sensorimotor areas, the putamen, inferior parietal and prefrontal cortex (left dorsal and bilateral orbital) and anterior insular. In contrast, using a splint increased activation in the bilateral prefrontal lobe (bilateral BA 10), bilateral temporo-parietal (BA 39), occipital and cerebellar hemispheres. An additionally applied individually based evaluation of representation sites in regions of interest demonstrated that the somatotopic representation for both conditions in the pre- and postcentral gyri did not significantly differ. Furthermore, this analysis confirmed the decreasing effect of the splint on bilateral primary and secondary motor and somatosensory cortical activation. In contrast to the decreasing effect on sensorimotor areas, an increased level of activity in the fronto-parieto-occipital and cerebellar network might be associated with the therapeutic effect of occlusal splints. PMID- 22102438 TI - Towards automated production and drug sensitivity testing using scaffold-free spherical tumor microtissues. AB - Although the relevance of three-dimensional (3-D) culture has been recognized for years and exploited at an academic level, its translation to industrial applications has been slow. The development of reliable high-throughput technologies is clearly a prerequisite for the industrial implementation of 3-D models. In this study the robustness of spherical microtissue production and drug testing in a 96-well hanging-drop multiwell plate format was assessed on a standard 96-well channel robotic platform. Microtissue models derived from six different cell lines were produced and characterized according to their growth profile and morphology displaying high-density tissue-like reformation and growth over at least 15 days. The colon cancer cell line HCT116 was chosen as a model to assess microtissue-based assay reproducibility. Within three individual production batches the size variations of the produced microtissues were below 5%. Reliability of the microtissue-based assay was tested using two reference compounds, staurosporine and chlorambucil. In four independent drug testings the calculated IC(50) values were benchmarked against 2-D multiwell testings displaying similar consistency. The technology presented here for the automated production of a variety of microtissues for efficacy testing in a standard 96 well format will aid the implementation of more organotypic models at an early time point in the drug discovery process. PMID- 22102439 TI - Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. AB - OBJECTIVE: To evaluate the association between non-alcoholic fatty liver disease and all cause and cause specific mortality in a representative sample of the US general population. DESIGN: Prospective cohort study. SETTING: US Third National Health and Nutrition Examination Survey (NHANES III: 1988-94) with follow-up of mortality to 2006. PARTICIPANTS: 11,371 adults aged 20-74 participating in the Third National Health and Nutrition Examination Survey, with assessment of hepatic steatosis. MAIN OUTCOME MEASURE: Mortality from all causes, cardiovascular disease, cancer, and liver disease (up to 18 years of follow-up). RESULTS: The prevalence of non-alcoholic fatty liver disease with and without increased levels of liver enzymes in the population was 3.1% and 16.4%, respectively. Compared with participants without steatosis, those with non alcoholic fatty liver disease but normal liver enzyme levels had multivariate adjusted hazard ratios for deaths from all causes of 0.92 (95% confidence interval 0.78 to 1.09), from cardiovascular disease of 0.86 (0.67 to 1.12), from cancer of 0.92 (0.67 to 1.27), and from liver disease of 0.64 (0.12 to 3.59). Compared with participants without steatosis, those with non-alcoholic fatty liver disease and increased liver enzyme levels had adjusted hazard ratios for deaths from all causes of 0.80 (0.52 to 1.22), from cardiovascular disease of 0.59 (0.29 to 1.20), from cancer of 0.53 (0.26 to 1.10), and from liver disease of 1.17 (0.15 to 8.93). CONCLUSIONS: Non-alcoholic fatty liver disease was not associated with an increased risk of death from all causes, cardiovascular disease, cancer, or liver disease. PMID- 22102440 TI - Prognosis and staging of non-alcoholic fatty liver disease. PMID- 22102441 TI - Spanish haematologists warn against storing umbilical cord stem cells in private banks. PMID- 22102442 TI - Future Forum tries to influence two key government documents. PMID- 22102443 TI - Huge dielectric response and molecular motions in paddle-wheel [Cu(II)2(adamantylcarboxylate)4(DMF)2]?(DMF)2. AB - The temperature-dependent dynamic properties of [Cu(II)(2)(ADCOO)(4)(DMF)(2)]?(DMF)(2) (1) and [Cu(II)(2)(ADCOO)(4)(AcOEt)(2)] (2) crystals were examined by X-ray crystallography, (1)H NMR spectroscopy, and measurements of the dielectric constants and magnetic susceptibilities (ADCOO = adamantane carboxylate, DMF = N,N-dimethylformamide, and AcOEt = ethyl acetate). In both crystals, four ADCOO groups bridged a binuclear Cu(II)-Cu(II) bond, forming a paddle-wheel [Cu(II)(2)(ADCOO)(4)] structure. The oxygen atoms of two DMF molecules in crystal 1 and two AcOEt molecules in crystal 2 were coordinated at axial positions of the [Cu(II)(2)(ADCOO)(4)] moiety, forming [Cu(II)(2)(ADCOO)(4)(DMF)(2)] and [Cu(II)(2)(ADCOO)(4)(AcOEt)(2)], respectively. Two additional DMF molecules were included in the unit cell of crystal 1, whereas AcOEt was not included in the unit cell of crystal 2. The structural analyses of crystal 1 at 300 K showed three-fold rotation of the adamantyl groups, whereas rotation of the adamantyl groups of crystal 2 at 300 K was not observed. Thermogravimetric measurements of crystal 1 indicated a gradual elimination of DMF upon increasing the temperature above 300 K. The dynamic behavior of the crystallized DMF yielded significant temperature-dependent dielectric responses in crystal 1, which showed a huge dielectric peak at 358 K in the heating process. In contrast, only small frequency-dependent dielectric responses were observed in crystal 2 because of the freezing of the molecular rotation of the adamantyl groups. The magnetic behavior was dominated by the strong antiferromagnetic coupling between the two S = 1/2 spins of the Cu(II)-Cu(II) site, with magnetic exchange energies (J) of -265 K (crystal 1) and -277 K (crystal 2). PMID- 22102444 TI - Chronic cardiac allograft rejection: critical role of ED-A(+) fibronectin and implications for targeted therapy strategies. AB - Chronic cardiac allograft rejection is characterized by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) causing severe long term complications after heart transplantation and determining allograft function and patients' prognosis. Until now, there have been no sufficient preventive or therapeutic strategies. CAV and CIF are accompanied by changes in the extracellular matrix, including re-expression of the fetal fibronectin splice variant known as ED-A(+) fibronectin. This molecule has been shown to be crucial for the development of myofibroblasts (MyoFbs) as the main cell type in CIF and for the activation of vascular smooth muscle cells (VSMCs) as the main cell type in CAV. Relevant re-expression and protein deposition of ED-A(+) fibronectin has been demonstrated in animal models of chronic rejection, with spatial association to CAV and CIF, and a quantitative correlation to the rejection grade. The paper by Booth et al published in this issue of The Journal of Pathology could prove for the first time the functional importance of ED-A(+) fibronectin for the development of CIF as a main component of chronic cardiac rejection. Thus, promising conclusions for the development of new diagnostic, preventive, and therapeutic strategies for chronic cardiac rejection focusing on ED-A(+) fibronectin can be suggested. PMID- 22102445 TI - Nanomechanics of streptavidin hubs for molecular materials. AB - A new strategy is reported for creating protein-based nanomaterials by genetically fusing large polypeptides to monomeric streptavidin and exploiting the propensity of streptavidin monomers(SM) to self-assemble into stable tetramers. We have characterized the mechanical properties of streptavidin-linked structures and measured, for the first time, the mechanical strength of streptavidin tetramers themselves. Using streptavidin tetramers as molecular hubs offers a unique opportunity to create a variety of well-defined, self-assembled protein-based (nano)materials with unusual mechanical properties. PMID- 22102446 TI - Medullary thyroid carcinoma in a patient with Hashimoto's thyroiditis diagnosed by calcitonin washout from a thyroid nodule. AB - Serum calcitonin is a tumor marker used in the diagnosis and follow-up of medullary thyroid carcinoma. Calcitonin washout evaluation is a new method used for suspicious thyroid nodules and lymph nodes. Limited clinical data are present about the efficacy of this method. A 61-year-old female patient with known Hashimoto's thyroditis and an 8-mm hypoechoic nodule was presented with one previously benign fine-needle aspiration cytology (FNAC). On referral to our department, she had a moderately high-serum calcitonin level, and we repeated the FNAC that was reported as nondiagnostic. We performed FNAC for the third time together with calcitonin washout evaluation from the thyroid nodule. The FNAC was again nondiagnostic, but the calcitonin washout level from the thyroid nodule was 152.569 pg/mL. Total thyroidectomy was performed, and the diagnosis was confirmed as medullary thyroid carcinoma. Calcitonin washout evaluation may be a useful method in the differential diagnosis of patients with thyroid nodules having moderately high-serum calcitonin levels. PMID- 22102447 TI - Organic thin-film transistors for chemical and biological sensing. AB - Organic thin-film transistors (OTFTs) show promising applications in various chemical and biological sensors. The advantages of OTFT-based sensors include high sensitivity, low cost, easy fabrication, flexibility and biocompatibility. In this paper, we review the chemical sensors and biosensors based on two types of OTFTs, including organic field-effect transistors (OFETs) and organic electrochemical transistors (OECTs), mainly focusing on the papers published in the past 10 years. Various types of OTFT-based sensors, including pH, ion, glucose, DNA, enzyme, antibody-antigen, cell-based sensors, dopamine sensor, etc., are classified and described in the paper in sequence. The sensing mechanisms and the detection limits of the devices are described in details. It is expected that OTFTs may have more important applications in chemical and biological sensing with the development of organic electronics. PMID- 22102448 TI - From molecule to materials: crystalline superlattices of nanoscopic CdS clusters. AB - Make way for a superlattice! A crystalline 3D superlattice of 2.3 nm molecular CdS nanoclusters was prepared from a convenient mononuclear cadmium thiophenolate precursor. HRTEM and STEM tomography show highly crystalline repetition of monodisperse frameworks. This combined with elemental and thermogravimetric analyses suggests an approximate formula [Cd(130)S(103)(SPh)(54)]. PMID- 22102449 TI - The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. AB - The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of beta amyloid (Abeta). Recent in vitro studies have shown that Abeta can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1alpha (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tau pathology or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from Abeta deposits. Our findings provide new pathological insight into the close association between p-tau and UPR activation in tauopathies. PMID- 22102452 TI - Ultrasound in the diagnosis of mononeuropathy: future directions. PMID- 22102453 TI - Endplate contributions to the safety factor for neuromuscular transmission. AB - The neuromuscular junction (NMJ), for most extremity and axial skeletal muscle fibers, with the exception of extraocular, middle ear, and some facial and pharyngeal muscles, is a 'slave' synapse that is designed to activate the muscle fiber every time the nerve terminal is activated. The fidelity of the NMJ hinges upon the electrical depolarization produced by activation of acetylcholine receptors (AChRs), called the endplate potential (EPP), being larger than is needed to trigger an action potential (AP) in the skeletal muscle fiber. The safety factor (SF) is a measure of how much larger the EPP is than the depolarization needed to trigger an AP (EAP). The SF depends on the amount of transmitter released, AChR density, EAP, and the effectiveness of the EPP in stimulating the Na(+) channels that trigger the AP. This study focuses on the postsynaptic factors that influence the SF and how the SF is altered in myasthenia gravis. PMID- 22102454 TI - Sonographic features in hereditary neuropathy with liability to pressure palsies. AB - INTRODUCTION: Diagnostic nerve ultrasound is becoming more commonly used by both radiologists and clinicians. The features of different neuromuscular conditions must be described to broaden our understanding and ability to interpret findings. METHODS: Our study examines the sonographic features of 7 subjects with hereditary neuropathy with liability to pressure palsies (HNPP) in comparison to 32 controls by measuring the nerve cross-sectional area (CSA) of the median, ulnar and tibial nerves. RESULTS: Significant differences (P < 0.05) in nerve size were found. The HNPP group had a larger CSA for the median nerve at the wrist and ulnar nerve at the elbow (entrapment sites), but not the forearms. The tibial nerve at the ankle was also larger in the HNPP group, suggesting possible concomitant tibial neuropathy at the ankle. CONCLUSION: These results will help shape imaging protocols to better detect conditions with non-uniform nerve enlargements. PMID- 22102455 TI - Ultrasound evaluation of peripheral neuropathy in POEMS syndrome. AB - INTRODUCTION: Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia whose main neurological feature is a demyelinating polyneuropathy. The aim of our study was to assess the pattern of ultrasound (US) nerve abnormalities in POEMS syndrome patients. METHODS: Eight POEMS syndrome patients underwent neurological examination and US evaluation of the median, ulnar, fibular, tibial, and sural nerves. Nerve cross-sectional area and echogenicity abnormalities were analyzed. RESULTS: US abnormalities were mostly localized at entrapment sites. Enlargements outside the entrapment sites were uncommon. No correlation was found between muscle weakness and focal US findings. CONCLUSIONS: No specific pattern of US abnormalities was identified in this cohort of patients with POEMS syndrome. The lack of correlation between US and clinical findings may be secondary to the chronic nerve damage that is common in POEMS syndrome, where the diagnosis is often delayed. PMID- 22102456 TI - Reproducibility of sensory nerve conduction studies of the sural nerve using ultrasound-guided needle positioning. AB - INTRODUCTION: In this study we sought to evaluate the reproducibility of sensory nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP). METHODS: Orthodromic NCS of the sural nerve using needle electrodes with USNP as well as surface electrodes were conducted twice in 20 healthy volunteers. RESULTS: The mean sensory nerve action potential (SNAP) amplitude in the initial examination was 39.5 MUV using needle electrodes with USNP, and 12.5 MUV using surface electrodes (P < 0.0001). The mean SNAP amplitude in the follow-up examination was 39.2 MUV using needle electrodes with USNP, and 12.4 MUV using surface electrodes (P < 0.0001). The mean intraindividual change in SNAP amplitude (test-retest) was 21.2% using needle electrodes with USNP, and 24.8% using surface electrodes (P = 0.6). CONCLUSIONS: Sensory NCS of the sural nerve using needle electrodes with USNP have reliable test-retest reproducibility and yield greater SNAP amplitudes than sensory NCS using surface electrodes. PMID- 22102457 TI - Prevalence and risk factors of muscle complications secondary to statins. AB - INTRODUCTION: The aim of the study was to investigate the prevalence and risk factors of muscle complications among patients using statins. METHODS: We conducted a prospective comparative study on 345 patients receiving statins and compared the findings with an age- and gender-matched control group of 85 subjects. Univariate and multivariate analyses with logistic regression models were used to study the association of different patient and disease characteristics with muscle complications. RESULTS: Adverse reactions were reported by 21% of patients and 5.9% of controls (P = 0.0013). Objective weakness was found in 15% of the patients who reported muscle symptoms (3.2% of the total cohort), but not in controls. Older age, longer duration of statin use, diabetes, stroke, and lower body mass index were associated with increased risk of developing these symptoms. CONCLUSIONS: Adverse reactions to statins may be more common than previously reported, and they may be affected by specific patient and disease characteristics. PMID- 22102458 TI - Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise. AB - INTRODUCTION: The most common side effect of statins, myopathy, is more likely in exercisers. We investigated the interaction of statin treatment with novel vs. accustomed exercise on muscle function, heat shock protein (Hsp) expression, and caspase activation. METHODS: Mice received daily cerivastatin or saline for 2 weeks, with/without wheel running (RW) (novel/sedentary). Accustomed groups completed 2 weeks of RW before statins. At 4 weeks, plantarflexor isometric force, Hsp25, alphaB-crystallin, caspase-3 and -9, and plasma creatine kinase (CK) were quantified. RESULTS: Statins reduced force in sedentary and novel groups, compared with saline, by 15% and 27%, respectively. Muscle fatigability increased 21% and 30% with statins compared with saline in sedentary and novel groups, respectively. Accustomed exercise prevented statin-associated force loss and increased fatigability. CK did not correlate with functional outcomes. RW increased Hsp protein in all groups. CONCLUSION: Our results suggest that exercise prior to statin treatment can protect against decrements in muscle function. PMID- 22102459 TI - Correction and transformation of normative neurophysiological data: is there added value in the diagnosis of distal symmetrical peripheral neuropathy? AB - INTRODUCTION: Despite theoretical advantages, the practical impact of mathematical correction of normative electrodiagnostic data is poorly quantified. METHODS: One hundred five healthy volunteers had clinical and neurophysiological assessment. The effects of age, height, gender, weight, and body mass index were explored using stepwise regression modeling. Reference values were derived from raw and adjusted data, which were transformed to allow appropriate use of parametric statistics. The diagnostic accuracy of derived limits was tested in patients at risk of distal symmetric peripheral neuropathy (DSPN) from chemotherapy. RESULTS: The variability of our normative data was reduced by up to 69% through the use of regression modeling, but the overall benefits of mathematical correction were marginal. The most accurate reference limits were established using the 2.5th and 97.5th percentiles of the raw data. CONCLUSIONS: Stepwise statistical regression and mathematical transformation improve the distribution of normative data, but their practical impact for diagnosis of distal symmetrical polyneuropathy is small. PMID- 22102460 TI - Feasibility of contact heat evoked potentials for detection of diabetic neuropathy. AB - INTRODUCTION: The involvement of small myelinated fibers in the early stages of diabetic neuropathy (DN) has been suggested, but few objective methods can identify minimal neuropathy. The purpose of this study was to determine whether there are differences in contact heat evoked potential (CHEP) parameters between healthy adults and diabetics with and without lower limb symptoms. METHODS: CHEP was recorded at the midline channels. A peak stimulating temperature of 51 degrees C was applied to the dorsum of the foot and at a point 10 cm proximal to the lateral malleolus. RESULTS: There was a significant difference in N1-P1 amplitude in the three groups after stimulation of the dorsum of the foot (P = 0.028) and the point 10 cm proximal to the lateral malleolus (P = 0.006). DISCUSSION: CHEP can help to detect early A-delta fiber damage in diabetic patients with minimal neuropathy. PMID- 22102461 TI - Cost analysis of myasthenia gravis from a large U.S. insurance database. AB - INTRODUCTION: Little is known about the costs of managing rare diseases, and comprehensive healthcare costs have not been reported for myasthenia gravis (MG). We evaluated the direct costs and healthcare resource utilization in insured MG patients. METHODS: Costs were obtained from 1288 patients diagnosed with MG who were identified from the Accordant Health Services nationwide medical and pharmacy claims database. RESULTS: Average annual medical/pharmacy claims costs per patient were: $6710/$1196 (age 0-19 years); $17,949/$19,573 (20-39 years); $15,112/$12,498 (40-64 years); and $12,597/$8,089 (65(+) years). Total annual MG related pharmacy costs were $9.4 million; IVIg accounted for 85% of all MG related pharmacy costs. Non-steroidal immunosuppressives, cholinesterase inhibitors, and corticosteroids accounted for 9.3%, 5.7%, and 0.2% of pharmacy costs, respectively. CONCLUSIONS: Costs related to the treatment of MG are higher than those of many other chronic neurological diseases. A large percentage of costs result from IVIg use, particularly among a subset of patients who receive frequent IVIg infusions. PMID- 22102462 TI - Concentric needle jitter on stimulated frontalis and extensor digitorum in 20 myasthenia gravis patients. AB - INTRODUCTION: Our objective was to study jitter parameters using a concentric needle electrode (CNE) in the extensor digitorum (ED) and frontalis (FR) muscles. METHODS: Twenty myasthenia gravis (MG) patients, mean age 44.5 years, were studied. Percutaneous (FR) and intramuscular needle (ED) stimulation approaches were used. Jitter was expressed as the mean consecutive difference (MCD). The filter settings were from 1000 HZ to 10 kHZ. RESULTS: Abnormal MCD was found in 85% for both ED and FR and in 90% when combining the two muscles. An abnormal percentage of outliers was found in 90% for ED and 85% for FR. The mean MCD did not show a difference for ED and FR, but the percentage of outliers and blocking were higher in FR. Abnormality was found in 93.7% (generalized) and in 75% (ocular) of MG cases. For ED outliers abnormality was greater than the MCD. CONCLUSION: CNE jitter is reliable for investigation of MG, although borderline findings should be judged with caution. PMID- 22102463 TI - Reinnervation by the contralateral facial nerve in patients with peripheral facial palsy. AB - INTRODUCTION: Reinnervation activity is triggered after complete unilateral peripheral facial palsy (PFP). METHODS: In 27 patients with PFP we recorded electromyographic activity with a concentric needle electrode inserted 1 cm lateral to the oral commissure of the affected side. We applied electrical stimuli to the unaffected (contralateral) facial nerve from the tragus to the mid lower lip and measured the response latency variability and segmental conduction velocity. RESULTS: Responses to electrical stimulation of the unaffected facial nerve were found in all patients. Mean conduction velocity was 49.6 +/- 6.2 m/s between tragus and oral commissure, and 6.0 +/- 1.9 m/s between oral commissure and mid-lower lip. Latency variability was 0.27 ms to facial nerve stimulation and 0.08 ms to oral commissure stimulation. CONCLUSION: Short distance sprouting of axons that innervate muscle fibers, which originate from the unaffected facial nerve, results in propagation of impulses to muscle fibers in the midline. PMID- 22102464 TI - Botulinum toxin-induced focal paresis in mice is unaffected by muscle activity. AB - INTRODUCTION: To test the hypothesis that the efficacy of botulinum toxin depends on the activity of the neuromuscular junction, we developed an in vivo paradigm to determine the degree and duration of low-dose botulinum toxin-induced focal paresis in mice. METHODS: We combined an automated wheel-running paradigm with low-dose botulinum toxin injections into the calf muscles of wild-type mice. Half of the mice were injected either before the nightly running or before the daily resting period. RESULTS: After botulinum toxin injections, running distance and maximum velocity decreased dose-dependently. The degree and duration of decrease between the respective groups with regard to the time-points of injection were identical. CONCLUSIONS: This in vivo paradigm quantifies the degree of otherwise clinically inapparent botulinum toxin-induced focal calf muscle paresis. Increased muscle activity after low-dose injections does not influence the efficacy of botulinum toxin in normal muscles. PMID- 22102465 TI - Intersession reliability of the electromyographic signal during incremental cycle ergometry: quadriceps femoris. AB - INTRODUCTION: The purposes of this investigation were to determine the: (1) reproducibility of the patterns of responses for electromyographic (EMG) amplitude and mean power frequency (MPF); and (2) intraclass correlation coefficient (ICC) of the EMG amplitude and MPF during three incremental cycle ergometer tests separated by 48 hours. METHODS: Ten men performed incremental cycle ergometry tests to exhaustion on three separate occasions. Surface EMG signals were recorded simultaneously from the three superficial quadriceps muscles at each trial. RESULTS: Polynomial regression indicated that, for >95% of the cases, the best-fit model was the same at each trial for EMG amplitude but not for EMG MPF. The ICC values were high for EMG amplitude but low for EMG MPF. CONCLUSIONS: These results indicate that EMG amplitude is a reliable measure of motor unit activation strategy during incremental cycle ergometry, whereas the EMG MPF was unreliable. PMID- 22102466 TI - PGC-1alpha protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We sought to determine whether peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) would have a beneficial effect on this disease. METHODS: PGC-1alpha transgenic mice were crossed with SOD1 mutant G93A DL mice. RESULTS: We observed a moderate but non-significant increase in average lifespan in PGC-1alpha/G93A DL mice, as compared with G93A DL mice (292 +/- 3 days vs. 274 +/- 7 days). Although the onset of ALS was not altered, progression of the disease was significantly slower (~34% increase in duration) in the PGC-1alpha/G93A DL mice. These mice also exhibited markedly improved performance on the rotarod test, and the improved motor activity was associated with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. CONCLUSION: A sustained level of excitatory amino acid transporter protein 2 (EAAT2) in astrocytes of the PGC-1alpha/G93A DL mice may contribute to neuronal protection. PMID- 22102467 TI - The octapeptide repeat PrP(C) region and cobalamin-deficient polyneuropathy of the rat. AB - INTRODUCTION: Cobalamin (Cbl) deficiency affects the peripheral nervous system (PNS) morphologically and functionally. We investigated whether the octapeptide repeat (OR) region of prion protein (PrP(C)) (which is claimed to have myelinotrophic properties) is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) polyneuropathy. METHODS: We intracerebroventricularly administered antibodies (Abs) against the OR region (OR-Abs) to Cbl-D rats to prevent myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrP(C)s to normal rats to reproduce PNS Cbl-D-like lesions. We measured nerve PrP(C) levels and MNCV. RESULTS: The OR-Abs normalized myelin ultrastructure, MNCV values, and tumor necrosis factor (TNF)-alpha levels in the sciatic and tibial nerves of Cbl D rats. PrP(C) levels increased in Cbl-D nerves. The nerves of the PrP(C)-treated rats showed typical Cbl-D lesions, significantly decreased MNCV values, and significantly increased TNF-alpha levels. CONCLUSIONS: OR-Abs prevent the myelin damage caused by increased OR regions, and excess TNF-alpha is involved in the pathogenesis of Cbl-D polyneuropathy. PMID- 22102468 TI - Evidence for cell density affecting C2C12 myogenesis: possible regulation of myogenesis by cell-cell communication. AB - INTRODUCTION: Community effect is a phenomenon caused by cell-cell communication during myogenesis. In myogenic C2C12 cells in vitro, the confluent phase is needed for myogenesis induction. METHODS: To examine the cell-density effect, growth kinetics and myogenic differentiation were investigated in cells plated at four different cell densities. RESULTS: We found that expression of a myogenic differentiation marker was high in a density-dependent manner. At high density, where cell-cell contact was obvious, contact inhibition after the proliferation stage was accompanied by microarray findings demonstrating upregulation of negative regulating cell-cycle markers, including CDKI p21 and the muscle differentiation markers MyoD and myogenin. Interestingly, developmentally regulated protein expression (drebrin) protein expression was also upregulated in a density-dependent manner. CONCLUSIONS: These results suggest that contact inhibition after the proliferation stage may induce growth arrest via cell-cell communication through the expression of CDKI p21 and may be responsible for progressing cell fusion. PMID- 22102469 TI - Age-related changes in dystrophin-glycoprotein complex and in utrophin are not correlated with intrinsic laryngeal muscles protection in mdx mice. AB - In this study we investigate whether dystrophic intrinsic laryngeal muscles (ILM) from aged mdx mice show alterations in dystrophin-glycoprotein complex (DGC) components.Immunofluorescence and immunoblotting analyses of beta-sarcoglycan, beta-dystroglycan, and utrophin showed that aged ILM had a similar pattern of changes in aged affected muscles (diaphragm and limb), suggesting that aging leads to changes in utrophin and DGC proteins in dystrophic ILM that cannot be correlated with their protection from dystrophic change. PMID- 22102470 TI - Magnetic resonance imaging signal hyperintensity of neural tissues in diffuse chronic pain syndromes: a pilot study. AB - In this pilot study we use T2-weighted magnetic resonance imaging (MRI) to identify possible peripheral nerve inflammation in 4 patients with diffuse chronic pain. In all 4 patients, there was an increase in median and ulnar nerve T2 signal intensity at the wrist (P < 0.05 vs. controls). Positive clinical signs of peripheral nerve mechanosensitivity combined with MRI findings suggest that these patients may have an underlying peripheral nerve pathology. PMID- 22102471 TI - Endogenous TWIST expression and differentiation are opposite during human muscle development. AB - TWIST is a transcription factor expressed during early embryonic development. In this study we investigate the expression of TWIST during human muscle development. Human TWIST was found to be endogenously expressed in human fetal myoblasts, and its expression decreased during late stages of development. Myoblasts showed an increasing capacity to differentiate in vitro during development. This inversely proportional relation between TWIST and differentiation capacity of myoblasts suggests that TWIST is involved in the regulation of muscle development. PMID- 22102472 TI - NMDA receptors at the endplate of rat skeletal muscles: precise postsynaptic localization. AB - In this study we demonstrate expression of the N-methyl-D-aspartate receptor NR1 subunit in the rat neuromuscular junction of skeletal muscles of different functional types (extensor digitorum longus, soleus, and diaphragm muscles) using fluorescence immunocytochemistry. Electron microscopic immunocytochemistry has shown that the NR1 subunit is localized solely on the sarcolemma in the depths of the postsynaptic folds. These findings suggest participation of the glutamatergic signaling system in functioning of the adult mammalian neuromuscular junction. PMID- 22102473 TI - Broken heart syndrome in myasthenia gravis. AB - Broken heart syndrome or stress-induced non-ischemic cardiomyopathy (SICM) has rarely been reported in the setting of myasthenic crisis. We describe a case of reversible SICM that occurred simultaneously with myasthenic crisis in a 77-year old man without prior cardiac history, and we discuss the previous findings that support an association of other cardiac disorders with myasthenia gravis. PMID- 22102474 TI - A case of acute sarcoid myositis treated with weekly low-dose methotrexate. AB - A 25-year-old man was referred to our hospital with a 2-month history of progressive proximal extremity weakness. His serum creatine kinase (CK) level was extremely elevated, and chest X-ray revealed bilateral hilar lymphadenopathy and small nodules in bilateral lung fields. Biopsy specimens obtained from muscle and lung revealed non-caseating epithelioid cell granulomas. On the basis of these findings, the patient was diagnosed with sarcoidosis and acute sarcoid myositis. Although steroid pulse therapy was administered repeatedly, the muscle symptoms did not improve, and the serum CK level remained high. We added 7.5 mg oral methotrexate once per week to oral prednisolone, and this improved both the muscle weakness and the CK level. Concurrent administration of methotrexate could be a therapeutic option for cases with acute sarcoid myositis refractory to steroid therapy. PMID- 22102475 TI - Practice parameters in myasthenia gravis. PMID- 22102479 TI - Evaluation of EGFR mutation status in cytology specimens: an institutional experience. AB - Epidermal growth factor receptor (EGFR) mutation status has been shown to predict response to anti-EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). In patients with advanced-stage NSCLC, evaluation of mutational status is increasingly requested on biopsy or fine-needle aspiration specimens, which often have limited material. There are limited data on the suitability of cytology cell blocks (CB) for EGFR mutation testing. In this study, we report our institutional experience with cytology cell block material for EGFR mutation testing. We retrospectively reviewed EGFR mutation analyses performed on 234 surgical (SP) and cytology (CB) from October 2007 to May 2010. One hundred ninety two SP specimens and 42 CB specimens were evaluated for EGFR mutation. CB specimens were evaluated for overall specimen size based on aggregate cellularity in comparison to small biopsy specimens, and percent tumor. Of the 192 SP and 42 CB specimens, 31 (16.1%) and 11 (26.2%) were positive for EGFR mutation, respectively; there does not appear to be an association between mutation detection rate and the source of the specimen (P = 0.124). Limited DNA was obtained from 70.0% (29/42), including 81.8% (9/11) of those which were mutation positive. Additionally, 45.4% (5/11) of mutation positive specimens had extremely low DNA yields. Although 16.6% (7/42) of CB specimens had <10% tumor, all 11 mutation positive CB cases had >10% tumor. These data indicate that CB specimens provide an alternative source for molecular evaluation of NSCLC, and that tumor percentage may be more important than specimen size and/or DNA yield in determining the suitability of these specimens for testing. PMID- 22102480 TI - Novel surface-modified nanostructured lipid carriers with partially deacetylated water-soluble chitosan for efficient ocular delivery. AB - The objective of this study was to propose novel surface-modified nanostructured lipid carriers with partially deacetylated water-soluble chitosan (NLC-PDSC) as an efficient ocular delivery system to improve its transcorneal penetration and precorneal retention. PDSC with a deacetylation degree of around 50% was synthesized using an improved method. NLC loaded with flurbiprofen (FB) were prepared by melt emulsification method. They presented spherical morphology under both transmission electron microscope and scanning electron microscope. After coating with 0.15% (w/v) PDSC solution, the NLC showed a core-shell structure and a reversed zeta potential. The enhanced transcorneal penetration of the coated NLC was evaluated using isolated rabbit corneas, with significantly increased apparent permeability coefficient being 1.40- and 1.75-fold of the NLC and FB phosphate solution (FB-sol; p < 0.05), respectively. Precorneal retention assessed by gamma scintigraphy in vivo showed that the area under the remaining activity-time curve of the PDSC-coated formulation was 1.3-fold of the NLC and 2.4-fold of FB-sol. Moreover, in vivo ocular tolerance study indicated that there was no difference in irritation between the coated and noncoated NLC. In conclusion, novel NLC demonstrate high potential for ocular drug delivery. PMID- 22102481 TI - 7-T MR--from research to clinical applications? AB - Over 20,000 MR systems are currently installed worldwide and, although the majority operate at magnetic fields of 1.5 T and below (i.e. about 70%), experience with 3-T (in high-field clinical diagnostic imaging and research) and 7-T (research only) human MR scanners points to a future in functional and metabolic MR diagnostics. Complementary to previous studies, this review attempts to provide an overview of ultrahigh-field MR research with special emphasis on emerging clinical applications at 7 T. We provide a short summary of the technical development and the current status of installed MR systems. The advantages and challenges of ultrahigh-field MRI and MRS are discussed with special emphasis on radiofrequency inhomogeneity, relaxation times, signal-to noise improvements, susceptibility effects, chemical shifts, specific absorption rate and other safety issues. In terms of applications, we focus on the topics most likely to gain significantly from 7-T MR, i.e. brain imaging and spectroscopy and musculoskeletal imaging, but also body imaging, which is particularly challenging. Examples are given to demonstrate the advantages of susceptibility-weighted imaging, time-of-flight MR angiography, high-resolution functional MRI, (1)H and (31)P MRSI in the human brain, sodium and functional imaging of cartilage and the first results (and artefacts) using an eight-channel body array, suggesting future areas of research that should be intensified in order to fully explore the potential of 7-T MR systems for use in clinical diagnosis. PMID- 22102482 TI - Change of coronary flow velocity during the cold pressor test is related to endothelial markers in subjects with chest pain and a normal coronary angiogram. AB - BACKGROUND: Several studies demonstrated that endothelial or atherosclerotic biomarkers, including plasma free insulin-like growth factor-I(IGF-I), soluble CD40 ligand (sCD40L), adiponectin, and leptin have an influence on coronary endothelial function. HYPOTHESIS: The aim of the present study was to investigate whether change of coronary flow velocity of the distal left anterior descending artery (LAD) during the cold pressor test (CPT) with transthoracic Doppler echocardiography (TTE) was associated with these biomarkers in subjects with chest pain and a normal coronary angiogram. METHODS: In 190 subjects (mean age, 54+/-11 years; male:female, 113:77) with chest pain and a normal coronary angiogram, peak diastolic velocity (PDV) of the distal LAD during the CPT with TTE was assessed. Acetylcholine provocation test was performed in 58 subjects (mean age, 51+/-10 years) who were clinically suspected of vasospasm. CPT%PDV was defined as the percent change in PDV during the CPT. Associations between CPT%PDV and clinical parameters were analyzed. RESULTS: According to multiple regression analysis, CPT%PDV was associated with plasma free IGF-I in the entire study population (beta=0.295, P<0.001 in all subjects; beta=0.341, P=0.001 in males; beta=0.243, P=0.037 in females; beta=0.303, P=0.002 in nonsmokers; and beta=0.256, P=0.047 in smokers), and sCD40L in males (beta=-0.269, P=0.008)and smokers (beta=-0.261, P=0.046). Subjects with vasospasm to intracoronary acetylcholine had lower plasma free IGF-I(6.9+/-3.3 vs 8.9+/-3.4, P=0.026) and CPT%PDV (8.8+/-24.9 vs 52.7+/-26.0, P<0.001) than the others. Plasma adiponectin and leptin were not associated with CPT%PDV. CONCLUSIONS: Change of coronary flow velocity assessed using the CPT with TTE may be related to endothelial markers, especially plasma free IGF-I. PMID- 22102483 TI - Comparison between eight- and sixteen-channel TEM transceive arrays for body imaging at 7 T. AB - Eight- and sixteen-channel transceive stripline/TEM body arrays were compared at 7 T (297 MHz) both in simulation and experiment. Despite previous demonstrations of similar arrays for use in body applications, a quantitative comparison of the two configurations has not been undertaken to date. Results were obtained on a male pelvis for assessing transmit, signal to noise ratio, and parallel imaging performance and to evaluate local power deposition versus transmit B(1) (B(1) (+) ). All measurements and simulations were conducted after performing local B(1) (+) phase shimming in the region of the prostate. Despite the additional challenges of decoupling immediately adjacent coils, the sixteen-channel array demonstrated improved or nearly equivalent performance to the eight-channel array based on the evaluation criteria. Experimentally, transmit performance and signal to noise ratio were 22% higher for the sixteen-channel array while significantly increased reduction factors were achievable in the left-right direction for parallel imaging. Finite difference time domain simulations demonstrated similar results with respect to transmit and parallel imaging performance, however, a higher transmit efficiency advantage of 33% was predicted. Simulations at both 3 and 7 T verified the expected parallel imaging improvements with increasing field strength and showed that, for a specific B(1) (+) shimming strategy used, the sixteen-channel array exhibited lower local and global specific absorption rate for a given B(1) (+) . PMID- 22102484 TI - Decoration of diatom biosilica with noble metal and semiconductor nanoparticles (<10 nm): assembly, characterization, and applications. AB - Diatom-templated noble metal (Ag, Pt, Au) and semiconductor (CdTe) nanoparticle arrays were synthesized by the attachment of prefabricated nanoparticles of defined size. Two different attachment techniques-layer-by-layer deposition and covalent linking-could successfully be applied. The synthesized arrays were shown to be useful for surface-enhanced Raman spectroscopy (SERS) of components, for catalysis, and for improved image quality in scanning electron microscopy (SEM). PMID- 22102485 TI - The presence of alveolar structures in invasive ductal NOS breast carcinoma is associated with lymph node metastasis. PMID- 22102486 TI - Neurodevelopmental outcome of fetuses with increased nuchal translucency and apparently normal prenatal and/or postnatal assessment: a systematic review. AB - OBJECTIVES: To systematically review and, when feasible, pool, published data regarding the prevalence of childhood neurodevelopmental delay in fetuses with increased first-trimester nuchal translucency (NT), normal karyotype and absence of structural defects or identifiable syndromes. METHODS: MEDLINE and SCOPUS searches using combinations of the terms 'nuchal translucency' AND 'outcome*' were complemented by perusal of the references of the retrieved articles and an additional automated search using the 'search for related articles' PubMed function. Only children with a normal karyotype and no structural defects or syndromic abnormalities were included in the analysis. Between-studies heterogeneity was assessed using the I(2) statistic. RESULTS: The total prevalence of developmental delay in all 17 studies was 28/2458 (1.14%; 95% CI, 0.79-1.64; I(2) = 57.6%). Eight studies (n = 1567) used NT > 99(th) centile as the cut-off; 15 children (0.96%; 95% CI, 0.58-1.58%) were reported as having developmental delay (I(2) = 72.2%). Four studies (n = 669) used the 95(th) centile as the cut-off for increased NT; seven children (1.05%; 95% CI, 0.51 4.88%) were reported as having developmental delay (I(2) = 29.2%). Five studies used 3.0 mm as the cut-off for increased NT; the pooled rate of developmental delay was six of 222 children (2.70%; 95% CI, 1.24-5.77%; I(2) = 0.0%). CONCLUSION: The rate of neurodevelopmental delay in children with increased fetal NT, a normal karyotype, normal anatomy and no identifiable genetic syndromes does not appear to be higher than that reported for the general population. More large scale, prospective case-control studies would be needed to enhance the robustness of the results. PMID- 22102487 TI - Pressure-temperature state diagram for the phase relationships between benfluorex hydrochloride forms I and II: a case of enantiotropic behavior. AB - The active pharmaceutical ingredient racemic benfluorex hydrochloride (benfluorex HCl) has an interesting phase behavior due to an elusive solid-solid phase transition. The stability hierarchy between different phases is often determined based on heat-related experiments only or slurry interconversion. It is shown that if pressure and volume are taken into account, not only the phase equilibria are correctly positioned in the pressure-temperature phase diagram, but the experimental data also improves. Thus, it has been found that the racemic benfluorex-HCl is enantiotropic under "ordinary conditions" with polymorph II and polymorph I, respectively, being the low- and the high-temperature phases. Above ~ 151 MPa, the system becomes monotropic and polymorph II is the single stable phase. PMID- 22102488 TI - Threshold level of low-density lipoprotein cholesterol for the short-term benefit of statin therapy in the acute phase of myocardial infarction. AB - BACKGROUND: Little is known about the threshold level of low-density lipoprotein cholesterol (LDL-C) for statin therapy in acute myocardial infarction (AMI). HYPOTHESIS: The aim of this study was to investigate the short-term benefit of the statin in post-MI patients with low LDL-C levels. METHODS: Between November 2005 and January 2008, 6866 statin-naive patients were selected from the Korea AMI registry. Major adverse cardiac event (MACE) was defined as a composite of death, recurrent MI, and revascularizations. RESULTS: The 6-month MACE and mortality showed a U-shaped curve, with the lowest rate at 114-122 mg/dL. Propensity scores for statin use were calculated for patients with LDL-C <= 113 mg/dL, and they were used to match the patients who received statin (statin user, n = 1031) with those who did not receive it (statin nonuser, n = 1031). The 6 month MACE was not significantly different between statin users and statin nonusers (9.4% vs 11.0%; hazard ratio [HR]: 0.847, 95% confidence interval [CI]: 0.646-1.111, P = 0.230), whereas the 6-month mortality was significantly lower in statin users (7.2% vs 9.7%; HR: 0.728, 95% CI: 0.539-0.984, P = 0.039). However, when the analyses were repeated in the patients with LDL-C <= 105 mg/dL, not only the 6-month MACE (9.5% vs 9.9%; HR: 0.945, 95% CI: 0.700-1.277, P = 0.713) but also the 6-month mortality (7.0% vs 8.7%; HR: 0.793, 95% CI: 0.566-1.111, P = 0.177) was not significantly different between statin users and statin nonusers (n = 876 in each group). CONCLUSIONS: The beneficial effects of statin therapy seem to vanish when LDL-C is below a certain level in AMI patients. PMID- 22102489 TI - Robust method for 3D arterial spin labeling in mice. AB - Arterial spin labeling is a versatile perfusion quantification methodology, which has the potential to provide accurate characterization of cerebral blood flow (CBF) in mouse models. However, a paucity of physiological data needed for accurate modeling, more stringent requirements for gradient performance, and strong artifacts introduced by magnetization transfer present special challenges for accurate CBF mapping in the mouse. This article describes robust mapping of CBF over three-dimensional brain regions using amplitude-modulated continuous arterial spin labeling. To provide physiological data for CBF modeling, the carotid artery blood velocity distribution was characterized using pulsed-wave Doppler ultrasound. These blood velocity measurements were used in simulations that optimize inversion efficiency for parameters meeting MRI gradient duty cycle constraints. A rapid slice positioning algorithm was developed and evaluated to provide accurate positioning of the labeling plane. To account for enhancement of T(1) due to magnetization transfer, a binary spin bath model of magnetization transfer was used to provide a more accurate estimate of CBF. Finally, a study of CBF was conducted on 10 mice with findings of highly reproducible inversion efficiency (mean +/- standard-error-of-the-mean, 0.67 +/- 0.03), statistically significant variation in CBF over 12 brain regions (P < 0.0001) and a mean +/- standard-error-of-the-mean whole brain CBF of 219 +/- 6 mL/100 g/min. PMID- 22102490 TI - Effect of the aromatase inhibitor anastrozole on uterine and leiomyoma Doppler blood flow in patients scheduled for hysterectomy: a pilot study. PMID- 22102491 TI - Fine-needle aspiration cytology of basaloid squamous cell carcinoma and small cell carcinoma-a comparison study. AB - The cytopathologic diagnosis of basaloid squamous cell carcinoma can be problematic as there are several components of the differential diagnosis that share common cytomorphologic features. In this study, we report the fine-needle aspiration (FNA) findings of 16 basaloid squamous cell carcinoma cases and compare those cases to 16 cases of small cell carcinoma. To our knowledge, this is the largest series of basaloid squamous cell carcinoma FNA cases ever reported. The following cytomorphologic features were compared for both tumors: cohesive tissue fragments, single cells, adenoid cystic-like features (cribriform pseudoglandular lumina with hyaline materials), necrosis, nuclear size, nuclear molding, nucleoli, cytoplasm, and the presence of single keratinized cells. Adenoid cystic-like features and the presence of single keratinized cells were specific for basaloid squamous cell carcinoma (P < 0.05). PMID- 22102492 TI - PyA-modified oligodeoxyadenylates: expanded fluorescence phenomena and structural formation. PMID- 22102494 TI - Label-free analysis in chip electrophoresis applying deep UV fluorescence lifetime detection. AB - Herein we introduce deep UV fluorescence lifetime detection in microfluidics applied for label-free detection and identification of various aromatic analytes in chip electrophoresis. For this purpose, a frequency quadrupled Nd:YAG (neodymium-doped yttrium aluminum garnet) picosecond laser at 266 nm was incorporated into an inverse fluorescence microscope setup with time-correlated single photon counting detection. This allowed recording of photon timing with sub-nanosecond precision. Thereby fluorescence decay curves are gathered on-the fly and average lifetimes can be determined for each substance in the electropherogram. The aromatic compounds serotonin, propranolol, 3-phenoxy-1,2 propanediol and tryptophan were electrophoretically separated using a fused silica microchip. Average lifetimes were independently determined for each compound via bi-exponential tail fitting. Time-correlated single photon counting also allows the discrimination of background fluorescence in the time domain. This results in improved signal-to-noise-ratios as demonstrated for the above model analytes. Microchip electrophoretic separations with fluorescence lifetime detection were also performed with a protein mixture containing lysozyme, trypsinogen and chymotrypsinogen emphasizing the potential for biopolymer analysis. PMID- 22102495 TI - Justification of rapid prototyping in the development cycle of thermoplastic based lab-on-a-chip. AB - During the developmental cycle of lab-on-a-chip devices, various microstructuring techniques are required. While in the designing and assay implementation phase direct structuring or so-called rapid-prototyping methods such as milling or laser ablation are applied, replication methods like hot embossing or injection moulding are favourable for large quantity manufacturing. This work investigated the applicability of rapid-prototyping techniques for thermoplastic chip development in general, and the reproducibility of performances in dependency of the structuring technique. A previously published chip for prenatal diagnosis that preconcentrates DNA via electrokinetic trapping and field-amplified-sample stacking and afterwards separates it in CGE was chosen as a model. The impact of structuring, sealing, and the integration of membranes on the mobility of the EOF, DNA preconcentration, and DNA separation was studied. Structuring methods were found to significantly change the location where preconcentration of DNA occurs. However, effects on the mobility of the EOF and the separation quality of DNA were not observed. Exchange of the membrane has no effect on the chip performance, whereas the sealing method impairs the separation of DNA within the chip. The overall assay performance is not significantly influenced by different structuring methods; thus, the application of rapid-prototyping methods during a chip development cycle is well justified. PMID- 22102496 TI - An integrated microfluidic culture device to regulate endothelial cell differentiation from embryonic stem cells. AB - We developed an integrated microfluidic culture device to regulate embryonic stem (ES) cell fate. The integrated microfluidic culture device consists of an air control channel and a fluidic channel with 4*4 micropillar arrays. We hypothesized that the microscale posts within the micropillar arrays would enable the control of uniform cell docking and shear stress profiles. We demonstrated that ES cells cultured for 6 days in the integrated microfluidic culture device differentiated into endothelial cells. Therefore, our integrated microfluidic culture device is a potentially powerful tool for directing ES cell fate. PMID- 22102497 TI - Contactless dielectrophoretic spectroscopy: examination of the dielectric properties of cells found in blood. AB - The use of non-invasive methods to detect and enrich circulating tumor cells (CTCs) independent of their genotype is critical for early diagnostic and treatment purposes. The key to using CTCs as predictive clinical biomarkers is their separation and enrichment. This work presents the use of a contactless dielectrophoresis (cDEP) device to investigate the frequency response of cells and calculate their area-specific membrane capacitance. This is the first demonstration of a cDEP device which is capable of operating between 10 and 100 kHz. Positive and negative dielectrophoretic responses were observed in red blood cells, macrophages, breast cancer, and leukemia cells. The area-specific membrane capacitances of MDA-MB231, THP-1 and PC1 cells were determined to be 0.01518 +/- 0.0013, 0.01719 +/- 0.0020, 0.01275 +/- 0.0018 (F/m(2)), respectively. By first establishing the dielectrophoretic responses of cancerous cells within this cDEP device, conditions to detect and enrich tumor cells from mixtures with non transformed cells can be determined providing further information to develop methods to isolate these rare cells. PMID- 22102498 TI - Rapid qualitative evaluation of DNA transcription factor NF-kappaB by microchip electrophoretic mobility shift assay in mammalian cells. AB - We have developed a separation technique for DNA-protein complex based on electrophoretic mobility shift assay (EMSA) by microchip electrophoresis, which we call microchip electrophoretic mobility shift assay (MUEMSA). To evaluate the MUEMSA, we employed recombinant human nuclear factor-kappaB (rhNF-kappaB) and its consensus double-stranded oligonucleotide (dsOligo) fluorescently labeled with Cy5. We carried out the electrophoretic separation of the consensus dsOligo-rhNF kappaB complex and the unbound dsOligo in methylcellulose solution and confirmed rapid (~200 s) and reliable identification and semi-quantitation of the specific interaction between dsOligo and rhNF-kappaB. The binding specificity of rhNF kappaB was confirmed by introducing non-fluorescently labeled consensus oligonucleotide as a competitor. The progression of the binding reaction under various incubation times was monitored, and it was found that the dsOligo and rhNF-kappaB complex formation reached equilibrium (ca. 90% of the dsOligo was bound to rhNF-kappaB) after 5 min. Furthermore, without any purification process, even crude NF-kappaB in nuclear extracts from HeLa cells was specifically detected within 120 s by the MUEMSA. PMID- 22102499 TI - Reassemblable quasi-chip free-flow electrophoresis with simple heating dispersion for rapid micropreparation of trypsin in crude porcine pancreatin. AB - An increasing number of small biosamples (e.g. proteins and enzymes) need micropreparation in lab. However, neither large-scale free-flow electrophoresis (LS-FFE) nor chip FFE (C-FFE) could fit the growing demands. Herein, a simple quasi-chip FFE (QC-FFE) was constructed. In contrast to C-FFE, the features of QC FFE are as follows: (i) its separation chamber is reassemblable and rewashable avoiding discard of C-FFE due to blockage of solute precipitation in chamber; (ii) its chamber size is 45 mm * 30 mm * (80-500) MUm (108-654 MUL volume) having function of micropreparation; (iii) there are up to 16 outlets in QC-FFE bestowing fine fraction for micropurification. The QC-FFE was used for the micropurification of model enzyme of self-digestible trypsin in crude pancreatin. Under the given conditions, the purification factor of enzyme was 11.7, the specific activity reached 6236 U/mg, the run time for 19 MUL sample purification was 45 s and the throughput of trypsin was 3.34 mg/h, and the yield of pure trypsin was 55.2%. All of the results show the feasibility of enzyme micropreparation via QC-FFE. The developed device and procedure have potential use to other micropurification of protein or peptide sample. PMID- 22102500 TI - Numerical analysis of a rapid magnetic microfluidic mixer. AB - This paper presents a detailed numerical investigation of the novel active microfluidic mixer proposed by Wen et al. (Electrophoresis 2009, 30, 4179-4186). This mixer uses an electromagnet driven by DC or AC power to induce transient interactive flows between a water-based ferrofluid and DI water. Experimental results clearly demonstrate the mixing mechanism. In the presence of the electromagnet's magnetic field, the magnetic nanoparticles create a body force vector that acts on the mixed fluid. Numerical simulations show that this magnetic body force causes the ferrofluid to expand significantly and uniformly toward miscible water. The magnetic force also produces many extremely fine finger structures along the direction of local magnetic field lines at the interface in both upstream and downstream regions of the microchannel when the external steady magnetic strength (DC power actuation) exceeds 30 Oe (critical magnetic Peclet number Pe(m),cr = 2870). This study is the first to analyze these pronounced finger patterns numerically, and the results are in good agreement with the experimental visualization of Wen et al. (Electrophoresis 2009, 30, 4179 4186). The large interfacial area that accompanies these fine finger structures and the dominant diffusion effects occurring around the circumferential regions of fingers significantly enhance the mixing performance. The mixing ratio can be as high as 95% within 2.0 s. at a distance of 3.0 mm from the mixing channel inlet when the applied peak magnetic field supplied by the DC power source exceeds 60 Oe. This study also presents a sample implementation of AC power actuation in a numerical simulation, an experimental benchmark, and a simulation of DC power actuation with the same peak magnetic strength. The simulated flow structures of the AC power actuation agree well with the experimental visualization, and are similar to those produced by DC power. The AC and DC power actuated flow fields exhibited no significant differences. This numerical study suggests approaches to maximize the performance of the proposed rapid magnetic microfluidic mixer, and confirms its exciting potential for use in lab-on-a-chip systems. PMID- 22102501 TI - Electrophoretic mobility measurements of fluorescent dyes using on-chip capillary electrophoresis. AB - We present an experimental study of the effect of pH, ionic strength, and concentrations of the electroosmotic flow (EOF)-suppressing polymer polyvinylpyrrolidone (PVP) on the electrophoretic mobilities of commonly used fluorescent dyes (fluorescein, Rhodamine 6G, and Alexa Fluor 488). We performed on-chip capillary zone electrophoresis experiments to directly quantify the effective electrophoretic mobility. We use Rhodamine B as a fluorescent neutral marker (to quantify EOF) and CCD detection. We also report relevant acid dissociation constants and analyte diffusivities based on our absolute estimate (as per Nernst-Einstein diffusion). We perform well-controlled experiments in a pH range of 3-11 and ionic strengths ranging from 30 to 90 mM. We account for the influence of ionic strength on the electrophoretic transport of sample analytes through the Onsager and Fuoss theory extended for finite radii ions to obtain the absolute mobility of the fluorophores. Lastly, we briefly explore the effect of PVP on adsorption-desorption dynamics of all three analytes, with particular attention to cationic R6G. PMID- 22102504 TI - Use of a human recombinant immunoglobulin G1 CH3 domain as a probe for detecting alternatively folded human IgG in intravenous Ig products. AB - It has been previously reported that intravenous immunoglobulin (IVIg) contains alternatively folded (aggregation-prone) monomeric immunoglobulin (Ig) G molecules. These alternatively folded IgG molecules may act as precursors for Fc Fc-mediated dimerization and/or aggregation in IVIg. To study this phenomenon, we set up a fluid-phase binding assay using an acid-shocked (pH 2.5) recombinant human IgG1 CH3 domain as a probe in combination with size-exclusion chromatography. Three IVIg products and a recombinant IgG1 antibody were analyzed. Besides CH3 probe binding to monomeric IgG derived from all IVIg products, the CH3 probe also bound to IgG4 half-molecules. This IgG4 binding could be distinguished from binding to IgG molecules on the basis of molecular weight. In contrast, no CH3 probe binding to IgG from the recombinant IgG1 antibody was observed. After acid-induced aggregation of either IVIg or a recombinant IgG1 antibody, CH3 probe binding to oligomeric complexes was observed, but no longer to monomeric IgG, demonstrating that the alternatively folded monomeric IgG molecules had oligomerized. Our results indicate that the tested IVIg products contain traces of alternatively folded IgG molecules within the "normal" monomeric IgG fraction. Furthermore, we conclude that the fluid phase binding assay is sensitive to detect these alternatively folded IgG molecules in IVIg. PMID- 22102505 TI - Homo- and methano[60]fullerenes with chiral attached moieties--1H and 13C NMR chemical shift assignments and diastereotopicity effects. AB - (1)H and (13)C NMR chemical shift predictions of homo- and methano[60]fullerenes containing chiral centers in attached fragment were made using the two dimensional NMR technique (HH COSY, (1)H-(13)C HSQC and HMBC) and the quantum chemistry GIAO calculation method in the PBE/3zeta approach. The influence of a chiral substituent on the (13)C chemical shifts of diastereotopic fullerene carbons was estimated by comparing the calculated and experimental (13)C NMR spectra. The resonances of the fullerene carbons in alpha-, beta- and delta positions relative to the position of the substituent exhibit the greatest diastereotopic splitting. PMID- 22102506 TI - Pleomorphic adenoma of lacrimal gland in a 5-year-old child: diagnosed on aspiration cytology. PMID- 22102507 TI - Biometry and fetal weight estimation by two-dimensional and three-dimensional ultrasonography: an intraobserver and interobserver reliability and agreement study. AB - OBJECTIVE: To evaluate and compare the intraobserver and interobserver reliability and agreement for the biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) obtained by two-dimensional ultrasound (2D-US) and three-dimensional ultrasound (3D-US). METHODS: Singleton pregnant women between 24 and 40 weeks were invited to participate in this study. They were examined using 2D-US in a blinded manner, twice by one observer, intercalated by a scan by a second observer, to determine BPD, AC and FL. In each of the three examinations, three 3D-US datasets (head, abdomen and thigh) were acquired for measurements of the same parameters. We determined EFW using Hadlock's formula. Systematic errors between 3D-US and 2D-US were examined using the paired t-test. Reliability and agreement were assessed by intraclass correlation coefficients (ICCs), limits of agreement (LoA), SD of differences and proportion of differences below arbitrary points. RESULTS: We evaluated 102 singleton pregnancies. No significant systematic error between 2D US and 3D-US was observed. The ICC values were higher for 3D-US in both intra- and interobserver evaluations; however, only for FL was there no overlap in the 95% CI. The LoA values were wider for 2D-US, suggesting that random errors were smaller when using 3D-US. Additionally, we observed that the SD values determined from 3D-US differences were smaller than those obtained for 2D-US. Higher proportions of differences were below the arbitrarily defined cut-off points when using 3D-US. CONCLUSION: 3D-US improved the reliability and agreement of fetal measurements and EFW compared with 2D-US. PMID- 22102508 TI - Apathy: a separate syndrome from depression in dementia? A critical review. AB - Apathy and depression are the most prevalent neuropsychiatric symptoms in Alzheimer's disease and mild cognitive impairment. Despite much research on apathy and depression in dementia, the nosological position of apathy as a separate syndrome from depression remains debated. This literature review provides a critical analysis of the areas of clinical manifestation, symptomatology, assessment, prevalence and neuropathology. Evidence does not provide a clear view of the nosological position of apathy in dementia for symptoms and neuropathology. However, the ambiguity of the evidence may be attributed in large part to a lack of clarity in definition and etiology, clinical criteria and assessment overlap. Given the evidence, it is concluded that the argument in favor of apathy as a separate syndrome from depression in dementia is persuasive. Reaching a consensus on the definition and nosological position of apathy within dementia is vital to provide patients and caregivers with the support they require, increase understanding of risk factors, and enable comparisons across research and practice. PMID- 22102509 TI - Homonuclear SQ-DQ correlations in solids: applications of the broadband BaBa scheme to reveal 31P-31P spatial correlations in two-, three-, four-, and five spin systems. AB - In this paper, we report on the use and limitations of the popular double-quantum recoupling sequence back-to-back in studies of (31)P-(31)P spatial proximities in Pd-phosphine complexes at medium field (9.38 T) under the conditions of fast MAS. The effects of internuclear distances in different spin systems and the impact of isotropic chemical shift and chemical shift anisotropy (CSA) offsets on the detectibility of SQ-DQ correlations were of particular interest to us. Selected model compounds with these requirements in mind were synthesized. By optimization of the excitation times of SQ-DQ correlations up to 4.6 A could be obtained even in four-spin systems; however, certain long-range correlations may be weak or missing. Although under fast MAS, CSA values up to 270 ppm are well tolerated, in multi-spin systems in cases of isotropic chemical shift offsets larger than 50 ppm, the DQ coherences cannot be properly excited. PMID- 22102510 TI - Modulation of transient receptor potential melastatin related 7 channel by presenilins. AB - Presenilins (PS1 and PS2) are multifunctional proteins involved in a diverse array of molecular and cellular functions, including proteolysis, development, neurogenesis, synaptic plasticity, ion channel regulation and phospholipid metabolism. Mutations in presenilin genes are responsible for the majority of Familial Alzheimer disease (FAD). Consequently, FAD-associated mutations in genes encoding PS1 or PS2 lead to several key cellular phenotypes, including alterations in proteolysis of beta-amyloid precursor protein (APP) and Ca(2+) entry. The mechanism underlying presenilin (PS)-mediated modulation of Ca(2+) entry remains to be determined. Our previous studies showed that the PS-dependent down-regulation of phosphatidylinositol-4,5-bisphosphate (PIP2) is attributable to the observed Ca(2+) deficits. In this study, we attempted to identify the ion channel that is subject to the PIP2 and PS-dependent modulation. We found that Ca(2+) or Zn(2+) entry via the transient receptor potential melastatin 7 (TRPM7) channel was attenuated by the presence of FAD-associated PS1 mutants, such as DeltaE9 and L286V. TRPM7 has been implicated in Mg(2+) homeostasis and embryonic development. The intracellular delivery of PIP2 restored TRPM7-mediated Ca(2+) influx, indicating that the observed deficits in Ca(2+) entry are due to downregulation of PIP2. Conversely, PS1 and PS2 deficiency, previously shown to upregulate PIP2 levels, potentiated TRPM7-mediated Ca(2+) influx. PS-dependent changes in Ca(2+) influx could be neutralized by a TRPM7 channel blocker. Collectively, these results indicate that TRPM7 may underlie the Ca(2+) entry deficits observed in FAD-associated PS mutants and suggest that the normal function of PS involves regulation of TRPM7 through a PIP2-dependent mechanism. PMID- 22102511 TI - PPARgamma Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet. AB - SCOPE: The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma (PPARgamma) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARgamma polymorphism in a Spanish overweight/obese population. MATERIALS AND METHODS: We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARgamma2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene-diet interaction between the PPARgamma Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARgamma Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). CONCLUSION: Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARgamma2 for BMI. Our detection of a gene diet interaction between PPARgamma Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies. PMID- 22102512 TI - Simultaneous EEG and MEG source reconstruction in sparse electromagnetic source imaging. AB - Electroencephalography (EEG) and magnetoencephalography (MEG) have different sensitivities to differently configured brain activations, making them complimentary in providing independent information for better detection and inverse reconstruction of brain sources. In the present study, we developed an integrative approach, which integrates a novel sparse electromagnetic source imaging method, i.e., variation-based cortical current density (VB-SCCD), together with the combined use of EEG and MEG data in reconstructing complex brain activity. To perform simultaneous analysis of multimodal data, we proposed to normalize EEG and MEG signals according to their individual noise levels to create unit-free measures. Our Monte Carlo simulations demonstrated that this integrative approach is capable of reconstructing complex cortical brain activations (up to 10 simultaneously activated and randomly located sources). Results from experimental data showed that complex brain activations evoked in a face recognition task were successfully reconstructed using the integrative approach, which were consistent with other research findings and validated by independent data from functional magnetic resonance imaging using the same stimulus protocol. Reconstructed cortical brain activations from both simulations and experimental data provided precise source localizations as well as accurate spatial extents of localized sources. In comparison with studies using EEG or MEG alone, the performance of cortical source reconstructions using combined EEG and MEG was significantly improved. We demonstrated that this new sparse ESI methodology with integrated analysis of EEG and MEG data could accurately probe spatiotemporal processes of complex human brain activations. This is promising for noninvasively studying large-scale brain networks of high clinical and scientific significance. PMID- 22102513 TI - Sleep quality and sleep problems in Mexican Americans aged 75 and older. AB - BACKGROUND AND AIMS: Sleep complaints and poor sleep quality are common in the elderly population. The aim of this study was to determine factors associated with sleep complaints and poor sleep quality among older Mexican Americans over a 3-year period. METHODS: One thousand eighty-five non-institutionalized Mexican American aged 75 years and older. Sociodemographic characteristics, medical conditions, depressive symptoms, disability cognitive impairment, body mass index, sleep problems (trouble falling asleep, waking up several times per night, trouble staying asleep and awaking not rested) and overall sleep quality were obtained. RESULTS: Of 1085 participants, 12.6% reported trouble falling asleep, 30% waking up several times per night, 11.4 % trouble staying asleep, 9.4% awaking not rested and 16.6% poor sleep quality. Depressive symptoms and heart attack predicted trouble falling asleep; diabetes, cancer and obesity predicted waking up several times per night; diabetes, hypertension, cancer and depressive symptoms predicted both trouble staying asleep and awaking not rested. Being female, married, heart attack and depressive symptoms were associated with poor quality sleep. CONCLUSIONS: Different risk factors were associated with different aspects of sleep complaints. Since poor sleep has been linked to poor outcomes, a good understanding of these factors may help in designing interventions to improve sleep quality in this population. PMID- 22102514 TI - Rapid determination of protein binding constant by a pressure-mediated affinity capillary electrophoresis method. AB - A new pressure-mediated affinity capillary electrophoresis method for the rapid and accurate determination of drug-protein binding constants is described. A special combination of pressure and electrophoresis is used to shorten the electrophoresis and the overall analysis time to only a few minutes. At the same time, the suitability of this method is checked against a traditional fluorescence spectroscopy method. The binding constants of bovine serum albumin and a total of eight drugs with different pK(a) have been evaluated and compared with those determined by the fluorescence spectroscopy method and other methods in literature. The results indicate that the P-ACE method is well suited for the determination of binding constants with weak interaction (K(b) <10(5) M(-1)). PMID- 22102515 TI - Spirodiclofen and spirotetramat bioassays for monitoring resistance in citrus red mite, Panonychus citri (Acari: Tetranychidae). AB - BACKGROUND: Citrus red mite, Panonychus citri (McGregor), is a key pest of San Joaquin Valley California citrus. Spirodiclofen was registered for mite control in 2007, and spirotetramat for scale control in 2008. Because of the potential for resistance to spirodiclofen to develop in spider mites, and cross-resistance to spirotetramat used for other citrus pests, bioassay methods for resistance monitoring were developed. RESULTS: The responses of four populations of adult female, egg and larval stages of P. citri to spirodiclofen were compared to determine the most robust bioassay method for this pesticide. Adult females responded with a higher LC(99) and larval stages exhibited higher control mortality and a lower slope of response compared with the egg stage. Thus, the egg stage was found to be the most suitable stage for testing. Egg production and egg shape were significantly affected by spirodiclofen treatment of adult female mites. Bioassays with the related compound spirotetramat revealed that P. citri egg hatch was less affected by this compound, requiring the assessment of mortality to be extended to 11 days after treatment when the hatched larvae succumbed to the pesticide. Discriminating concentrations of 10 ppm for spirodiclofen and 31.6 ppm for spirotetramat in an 11 day bioassay were tested against eight field populations of P. citri, and 99-100% mortality resulted. CONCLUSION: These results provide a baseline for the response of P. citri to spirodiclofen and spirotetramat that will aid resistance management in California citrus. PMID- 22102516 TI - Predictive value of sequential models of uterine artery Doppler in pregnancies at high risk for pre-eclampsia. AB - OBJECTIVE: To evaluate the performance of models described previously for the prediction of pre-eclampsia (PE), based on the sequential evaluation of uterine artery resistance at 11-13 weeks and 19-22 weeks, in a high-risk population. METHODS: This was a prospective study in 135 women with singleton pregnancies and at least one of the following high-risk conditions: PE and/or intrauterine growth restriction in a previous pregnancy, chronic hypertension, pregestational diabetes, renal disease, body mass index > 30 kg/m(2) , autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome or rheumatoid arthritis) and thrombophilia. Mean uterine artery pulsatility index (mUtA-PI) at 11-13 and at 19-22 weeks' gestation was measured and analyzed according to quantitative and semi-quantitative models, to predict late PE (resulting in delivery >= 34 weeks) and early PE (delivery < 34 weeks). RESULTS: Late PE developed in 21 (15.6%) pregnancies and early PE in six (4.4%). Using mUtA-PI, the detection rates of late and early PE for a false-positive rate of 10% were 14.3% and 33.3%, respectively, at 11-13 weeks, and 19.0% and 66.7%, respectively, at 19-22 weeks. Using a semi-quantitative approach, the group of pregnant women with mUtA-PI >= 90(th) percentile at both 11-13 and 19-22 weeks had a greater risk for early PE (odds ratio, 21.4 (95% CI, 2.5-184.7)) compared with the group with mUtA-PI < 90(th) percentile at both periods. Using a quantitative approach, there was relative worsening in the mUtA-PI (multiples of the median) from the first to the second trimester in all cases of early PE. CONCLUSION: The application of semi quantitative and especially quantitative models to evaluate sequential changes in uterine artery Doppler findings between the first and second trimesters could be of additional value in assessing high-risk women regarding their true risk of developing early PE. PMID- 22102517 TI - Parapharyngeal chordoma: a diagnostic challenge and potential mimic of pleomorphic adenoma on fine-needle aspiration cytology. AB - Chordomas are rare tumors that are usually located in the sacrococcygeal and sphenooccipital region. Their cytologic diagnosis is rather straightforward when sampled by fine-needle aspiration (FNA) from these characteristic locations, especially when physalipherous cells are present. However, chordomas may pose difficult diagnostic challenges when encountered in unusual locations, such as the parapharyngeal region. We report the cytologic findings of a recurrent chordoma sampled through transoral FNA from the parapharyngeal space of a 66-year old woman. As the prior history of chordoma was not available during the rapid onsite evaluation, the presence of bland epithelioid nonvacuolated cells and spindle cells intimately admixed with a fibrillary, intensely metachromatic material led to an initial diagnosis of pleomorphic adenoma. Review of the patient's prior pathology specimen and of the Papanicolaou-stained smears and cellblock sections showing rare multivacuolated (physalipherous) cells led to the correct diagnosis, which was supported by immunoperoxidase stains (cytokeratin AE1/AE3+, S100+, GFAP-). A review of the literature found no previous instances in which chordomas mimicked pleomorphic adenoma on FNA. However, since the two tumors show significant cytomorphologic overlap, including the presence of abundant fibrillary matrix with embedded neoplastic cells and single bland spindle and epithelioid tumor cells with occasional intranuclear pseudoinclusions, we compared their cytologic features. A review of the FNA cytologic features of this case of chordoma and of 17 consecutive cases of pleomorphic adenoma found that the presence of a more abundant, focally vacuolated cytoplasm favors chordoma over pleomorphic adenoma. PMID- 22102518 TI - Quadruple-responsive nanocomposite based on dextran-PMAA-PNIPAM, iron oxide nanoparticles, and gold nanorods. AB - A quadruple-responsive nanocomposite that responds to temperature, pH, magnetic field, and NIR is obtained by incorporating superparamagnetic iron oxide nanoparticles (SPIONs) and gold nanorods (AuNRs) into a dextran-based smart copolymer network. The dual-sensitive copolymer is prepared by sequential RAFT polymerization of methacrylic acid and N-isopropylacrylamide from trithiocarbonate groups linked to dextran in one pot. These functionalized nanocomposites with superior stability can respond to the four stimuli mentioned above well. As evidenced by UV-vis and TEM measurements, the temperature-induced unusual blue-shift in the longitudinal plasmon band is possibly due to the side to-side assembly of AuNRs. PMID- 22102519 TI - Design and assessment of a wrapped cylindrical Ca-P AZ31 Mg alloy for critical size ulna defect repair. AB - Recently, magnesium has been investigated as a promising bioresorbable orthopedic biomaterial. Its mechanical properties are very similar to natural bone, making it appropriate for load-bearing orthopedic fracture repair applications. However, significant hurdles remain regarding the design of practical implants and methods to control degradation and enhance biocompatibility. Although attempts have been made to hinder magnesium's rapid corrosion via alloying and coating, these studies have used solid monoliths. In an effort to reduce the amount of alloy used for implantation in a shape that mimics cortical bone shape, this study used a thin sheet of Mg AZ31 which was rolled into hollow cylindrical scaffolds. The scaffold was coated with different amounts of Ca-P; this implant demonstrated slowed corrosion in simulated body fluid (SBF) as well as enhanced biocompatibility for mesenchymal stem cells (MSC). In vivo implantation of magnesium alloy scaffold adjacent to the rat femur showed significant biointegration with further deposition of complex Mg-Ca phosphates/carbonates typical of natural bone. Finally, the implant was placed in a critical-size ulna defect in live rabbits, which lead to radiographic union and partial restoration of biomechanical strength in the defect. This study demonstrated that a thin sheet of coated Mg alloy that was spirally wrapped wound be a promising orthopedic biomaterial for bone repair. PMID- 22102520 TI - Simultaneous quantification of centchroman and its 7-demethylated metabolite in rat dried blood spot samples using LC-MS/MS. AB - An approach has been developed for the quantitative determination of concentrations of centchroman (I), a nonsteroidal once-a-week oral contraceptive, and its major metabolite (7-desmethyl centchroman, II) using dried blood spots (DBS) on paper, rather than conventional plasma samples. The assay employed simple solvent extraction of the DBS sample circle (6 mm) requiring small blood volumes (30 MUL) followed by reversed-phase HPLC separation, combined with multiple reaction monitoring mass spectrometric detection. The calibration plot in matrix using d-trans-hydroxy chroman as internal standard (IS) was linear (r2 = 0.998) over ranges of 1.5-240 and 4.5-720 ng/mL for I and II, respectively. The recoveries of both I and II were always >60% with quantification limits (signal to-noise ratio = 10) of 1.5 and 4.5 ng/mL for I and II, respectively. The intra day and inter-day precision (%RSD) and accuracy (%bias) variations in blood spots for both I and II were better than 13%. Moreover, both I and II were stable in DBS for at least 3 months when stored at room temperature. The developed method was successfully applied to the pharmacokinetic interaction study after oral administration of centchroman with and without co-administration of carbamazepine in female Sprague-Dawley rats using serial sampling and results were comparable with the plasma concentrations reported earlier. PMID- 22102521 TI - Dopamine transporter imaging in autopsy-confirmed Parkinson's disease and multiple system atrophy. AB - Dopamine transporter single-photon emission computerized tomography can visualize dopaminergic degeneration in Parkinson's disease and multiple system atrophy. Some studies have suggested that dopamine transporter imaging can distinguish these disorders based on a more diffuse and symmetric striatal dopamine transporter binding loss in multiple system atrophy. The present study compared patterns of striatal dopamine transporter distribution in postmortem-confirmed Parkinson's disease and multiple system atrophy. Patients with a postmortem diagnosis of multiple system atrophy (n = 6) or Parkinson's disease (n = 8) who had undergone dopamine transporter imaging were included. Imaging had been performed after a mean disease duration of 3.6 and 4.1 years in multiple system atrophy and Parkinson's disease, respectively. Visual analysis showed bilaterally reduced binding in all patients. Mean overall striatal binding was reduced by 53% in multiple system atrophy and 52% in Parkinson's disease. There was a trend for greater asymmetry of striatal binding in multiple system atrophy compared with Parkinson's disease (23% +/- 15% vs 10.5% +/- 7%, respectively; P = .071), with 3 multiple system atrophy patients showing more asymmetry of striatal binding than any Parkinson's disease patient. Putamen/caudate binding ratios did not differ between the groups. This is the first study comparing dopamine transporter imaging in autopsy-confirmed multiple system atrophy and Parkinson's disease. Unexpectedly, we found a tendency for greater asymmetry of striatal binding in multiple system atrophy than in Parkinson's disease. Our findings demonstrate that these conditions cannot be differentiated by subregional analysis of striatal dopamine transporter binding. PMID- 22102522 TI - Quantification of pralidoxime (2-PAM) in urine by ion pair chromatography-diode array detection: application to in vivo samples from minipig. AB - Pralidoxime (2-PAM) is a monopyridinium oxime used as an antidote for the treatment of poisoning with organophosphorus (OP) compounds, for example, pesticides and nerve agents, reactivating OP-inhibited acetylcholinesterase. However, appropriate dosing and efficacy remains a matter of discussion requiring experimental data. Therefore, we developed and validated an ion pair chromatography-diode array detection (IPC-DAD) method suitable for quantitative analysis of 2-PAM in human and porcine urine. Before injection of 20 ul, urine was acidified with trichloroacetic acid, mixed with internal standard (pyridine-4 aldoxime, 4-PAO), and diluted with IPC solvent yielding a total dilution of 1:49.5 and a 100% recovery. Isocratic separation was carried out at 25 degrees C on a LiChrospher 60 RP-select B column (125 x 4.0 mm I.D.) using phosphate buffer (7.5 mM Na(2) HPO(4) , 7.5 mM KH(2) PO(4) , pH 2.6) mixed with octanesulfonate (2.5 mM) as ion pair reagent and acetonitrile (6% v/v) as organic modifier (1 ml/min). 2-PAM was detected at 293 nm and 4-PAO at 275 nm. The method is rugged, selective, and characterized by good intra-day and inter-day precision (RSD, 1.3 6.0%) and accuracy (88-100%) with a limit of detection at 4.9 ug/ml, a limit of quantification at 9.8 ug/ml, and a broad calibration range from 4.9-2500 ug/ml. The procedure was applied to urine samples obtained from dimethoate poisoned minipigs receiving 2-PAM therapy (intravenous bolus injection and infusion). Results indicate that 60-80% of infused 2-PAM is rapidly (within 1-2 h) excreted in the urine. PMID- 22102523 TI - Dietary anthocyanin-rich plants: biochemical basis and recent progress in health benefits studies. AB - Anthocyanins are one type of flavonoid phytopigment. Although the role of anthocyanins as a functional food factor remains relatively less established than that of other flavonoids, progress in this area has been made at the molecular level in recent years. This review discusses the potential health benefits of plant-derived anthocyanin-rich foods, with a focus on the role of anthocyanins in obesity control, diabetes control, cardiovascular disease prevention, and improvement of visual and brain functions, areas that have attracted much attention. Such health benefits are not necessarily derived from the antioxidant effect of anthocyanins, but in fact are produced by currently unestablished chemical properties beyond the antioxidant capacity of the molecules. However, a better understanding of the physiological functionality of anthocyanins remains to be elucidated. It is desirable, therefore, to clarify the molecular type and composition of the anthocyanins that confer specific health benefits and to conduct further investigation into the underlying molecular mechanisms. The pharmacological actions of anthocyanins could not be fully established without knowledge on the effects of treatment of anthocyanins alone, the effects of non anthocyanin components, and the possible interactions between anthocyanin and non anthocyanin species. PMID- 22102524 TI - Abnormal motor cortex excitability is associated with reduced cortical thickness in X monosomy. AB - Turner syndrome (TS) is a noninherited genetic disorder caused by the absence of one or part of one X chromosome. It is characterized by physical and cognitive phenotypes that include motor deficits that may be related to neuroanatomical abnormalities of sensorimotor pathways. Here, we used transcranial magnetic stimulation (TMS) and cortical thickness analysis to assess motor cortex excitability and cortical morphology in 17 individuals with TS (45, X) and 17 healthy controls. Exploratory analysis was performed to detect the effect of parental origin of the X chromosome (X(mat), X(pat)) on both measures. Results showed that long-interval intracortical inhibition was reduced and motor threshold (MT) was increased in TS relative to controls. Areas of reduced thickness were observed in the precentral gyrus of individuals with TS that correlated with MT. A significant difference between X(mat) (n = 11) and X(pat) (n = 6) individuals was found on the measure of long-interval intracortical inhibition. These findings demonstrate the presence of converging anatomical and neurophysiological abnormalities of the motor system in X monosomy. PMID- 22102525 TI - Work ability as a determinant of old age disability severity: evidence from the 28-year Finnish Longitudinal Study on Municipal Employees. AB - BACKGROUND AND AIMS: Lower occupational class correlates with a higher disability risk later in life. However, it is not clear whether the demands made by mental and physical work relative to individual resources in midlife predict well-being in old age. This study investigated prospectively whether work ability in midlife predicts disability severity in activities of everyday living in old age. METHODS: Data come from the population-based 28-year follow-up called Finnish Longitudinal Study of Municipal Employees. A total of 2879 occupationally active persons aged 44-58 years answered a questionnaire on work ability at baseline in 1981 and activities of daily living in 2009. At baseline, perceived work ability relative to lifetime best was categorized into excellent, moderate, and poor work ability. At follow-up, disability scales were constructed based on the severity and frequency of difficulties reported in self-care activities of daily living (ADL) and instrumental activities of daily living (IADL). RESULTS: There was a graded prevalence of ADL and IADL disability severity, according to excellent, moderate and poor midlife work ability (p<0.001). Employees with moderate midlife work ability had an 11 to 20% higher mean ADL or IADL disability severity score, compared with those with excellent midlife work ability (reference), incidence rate ratios (IRR) ranging from 1.11 (95% CI 1.01-1.22) to 1.20 (95% CI 1.10 1.30). Those with poor midlife work ability had a mean ADL or IADL disability severity score 27 to 38% higher than the referent, IRRs ranging from 1.27 (95% CI 1.09-1.47) to 1.38 (95% CI 1.25-1.53). Adjusting for socio-economics, lifestyle factors and chronic diseases only slightly attenuated the associations. CONCLUSIONS: Work ability, an indicator of the de- mands made by mental and physical work relative to individuals' mental and physical resources, predicted disability severity 28 years later among middle-aged municipal employees. PMID- 22102526 TI - Contact and fumigant toxicity of Armoracia rusticana essential oil, allyl isothiocyanate and related compounds to Dermatophagoides farinae. AB - BACKGROUND: The toxicity to adult Dermatophagoides farinae of allyl isothiocyanate identified in horseradish, Armoracia rusticana, oil and another 27 organic isothiocyanates was evaluated using contact + fumigant and vapour-phase mortality bioassays. Results were compared with those of two conventional acaricides, benzyl benzoate and dibutyl phthalate. RESULTS: Horseradish oil (24 h LC(50), 1.54 ug cm(-2)) and allyl isothiocyanate (2.52 ug cm(-2)) were highly toxic. Benzyl isothiocyanate (LC(50) , 0.62 ug cm(-2)) was the most toxic compound, followed by 4-chlorophenyl, 3-bromophenyl, 3,5 bis(trifluoromethyl)phenyl, cyclohexyl, 2-chlorophenyl, 4-bromophenyl and 2 bromophenyl isothiocyanates (0.93-1.41 ug cm(-2)). All were more effective than either benzyl benzoate (LC(50) , 4.58 ug cm(-2)) or dibutyl phthalate (24.49 ug cm(-2)). The structure-activity relationship indicates that types of functional group and chemical structure appear to play a role in determining the isothiocyanate toxicities to adult D. farinae. In the vapour-phase mortality bioassay, these isothiocyanates were consistently more toxic in closed versus open containers, indicating that their mode of delivery was, in part, a result of vapour action. CONCLUSION: In the light of global efforts to reduce the level of highly toxic synthetic acaricides in indoor environments, the horseradish oil derived compounds and the isothiocyanates described herein merit further study as potential acaricides for the control of house dust mite populations as fumigants with contact action. PMID- 22102527 TI - Ultrasound safety in early pregnancy: reduced energy setting does not compromise obstetric Doppler measurements. AB - OBJECTIVES: We hypothesized that first-trimester Doppler ultrasonography can be carried out at lower output energies than the currently advocated limits without compromising clinically important information. METHODS: We recruited 42 pregnant women for an ultrasound examination at 12 weeks' gestation. Twenty-one women were examined with a transvaginal transducer, the rest with a transabdominal transducer. We used pulsed Doppler to measure pulsatility index (PI) and peak systolic velocity (PSV) in five clinically relevant fetal and maternal blood vessels. The energy indicator thermal index for bone (TIb) was set at 1.0, 0.5 and 0.1. Each measurement was repeated three times. A mixed linear regression model accounting for correlation between measurements was used to assess the effect of different TIb levels and transducers. RESULTS: We were able to visualize the vessels by color Doppler and measure PI and PSV in all vessels at all energy levels in all the participants with the exception of the ductus venosus in two participants, yielding 1872 recordings for statistical analysis. A reduction in TIb from 1.0 to 0.5 and 0.1 had no effect on the PI or PSV values, nor was there any trend towards higher parameter variance with decreasing TIb. There was no difference between measured values of PI and PSV between the transducers, but the transabdominal technique was associated with a greater parameter variance. CONCLUSION: Reliable first-trimester Doppler data can be obtained with output energy reduced to a TIb of 0.5 or 0.1. PMID- 22102528 TI - Standardized methods to quantify thrombogenicity of blood-contacting materials via thromboelastography. AB - Blood coagulation is the most significant complication of vascular biomaterials. A straightforward, sensitive, and standard measure of the compatibility of these materials with whole blood (hemocompatibility) is necessary to avoid coagulation. Current techniques used quantify only individual clotting components and are poor predictors of coagulation. The thromboelastograph (TEG) provides a measure of overall clot formation from whole blood. Although TEG is very common in clinical settings, its application to biomaterials is limited partly due to difficulty in sample preparation. In this protocol, whole blood samples are incubated with (1) biomaterials (tube with clamped ends) and (2) endothelial cells cultured on biomaterial surfaces (12-well plate) under controlled shearing conditions (10 rpm on rocker, at 37 degrees C), and then the blood is transferred to the TEG to measure clot formation. TEG clearly discriminates among the R-times (time until initial clot formation) of expanded poly(tetrafluoroethylene), poly(urethane), and Tygon tubing. Marked differences in R-time are also seen when endothelial cells are cultured on various extracellular matrix proteins and proteoglycans. Thus, R-time provides a robust metric of overall thrombogenicity of biomaterials, and these procedures provide a standardized method for TEG to facilitate direct comparison among candidate biomaterials undergoing in-vitro testing. PMID- 22102529 TI - Fine needle aspiration cytology of Sertoli-Leydig cell tumors of ovary masquerading as dysgerminoma. AB - Herein, we described a case of a 29-year-old female with a large ovarian mass. Fine needle aspiration cytology (FNAC) of the mass showed discrete round to oval cells in a fatty vacuolated background. FNAC diagnosis of dysgerminoma was suggested. The histology of the tumors showed features of poorly differentiated Sertoli-Leydig cell tumors. We discussed the diagnostic pitfalls of this case on FNAC. PMID- 22102530 TI - Cloning and mRNA expression levels of GDF9, BMP15, and BMPR1B genes in prolific and non-prolific goat breeds. PMID- 22102531 TI - Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome. AB - BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic alpha-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by alpha-N acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward alpha-synuclein aggregation. METHODS: We typed the 2 single nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-alpha-synuclein antibody, Per7. RESULTS: Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 * 10(-3) ). Intracellular alpha-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases. CONCLUSIONS: This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for alpha synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD. PMID- 22102532 TI - Ferroelectric thin films in fluidic environments: a new interface for sensing and manipulation of matter. AB - For decades ferroelectric thin films (FETFs) have been the focus of research and development for next-generation memory and semiconductor devices. FETFs are attractive because their polarization states are highly localized, stable, and switchable. These unique properties are also attractive for (bio)molecular sensing and separation applications. Polarization of both polymer and ceramic FETF results in the expression of a sustained high, non-Faradaic, surface charge density. If these surface charges are maintained in aqueous environments, then the resulting electrostatic forces should induce the formation of electrolyte gradients and aid in the localization of charged species to the surface. Recently, there has been a growing interest in the interfacial properties of FETFs, specifically how they interact with liquid or gaseous phases. Recent work has shown that the FETF polarization state affects adsorption from the gaseous phase, surface catalysis, and cell growth. Encouraged by these findings, the use of FETFs in aqueous environments is explored. After an introduction to FETFs, the growing body of literature on the FETF interface is reviewed, along with the limited number of studies demonstrating FETF function in gas and liquid environments. Finally, the exciting possibilities that FETFs could bring to interfacial engineering and lab-on-chip (LOC) device design is reviewed. PMID- 22102533 TI - The detection of the urinary metabolites of 3-[(adamantan-1-yl)carbonyl]-1 pentylindole (AB-001), a novel cannabimimetic, by gas chromatography-mass spectrometry. AB - 3-[(Adamantan-1-yl)carbonyl]-1-pentylindole (AB-001), a synthetic cannabimimetic, was identified in head shop products in Ireland in 2010. German authorities also reported it to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) in 2011. As indole-derived cannabimimetics, such as JWH-018, JWH-073, and JWH-250, undergo extensive metabolism, it was expected that AB-001 would behave similarly. To include it in our toxicological screening protocols, we have identified its urinary metabolites in humans following oral administration. The major metabolites were found to be adamantane mono-hydroxylated and adamantane mono-hydroxylated/N-dealkylated products. No parent compound was found in urine, and metabolites were detectable for up to 160 h following administration. PMID- 22102534 TI - Concise review: Inner ear stem cells--an oxymoron, but why? AB - Hearing loss, caused by irreversible loss of cochlear sensory hair cells, affects millions of patients worldwide. In this concise review, we examine the conundrum of inner ear stem cells, which obviously are present in the inner ear sensory epithelia of nonmammalian vertebrates, giving these ears the ability to functionally recover even from repetitive ototoxic insults. Despite the inability of the mammalian inner ear to regenerate lost hair cells, there is evidence for cells with regenerative capacity because stem cells can be isolated from vestibular sensory epithelia and from the neonatal cochlea. Challenges and recent progress toward identification of the intrinsic and extrinsic signaling pathways that could be used to re-establish stemness in the mammalian organ of Corti are discussed. PMID- 22102535 TI - Descriptive epidemiology of selected heritable birth defects in Texas. AB - BACKGROUND: Few population-based studies exist on descriptive epidemiologic characteristics of rare heritable birth defects. The number of birth defect cases in the Texas Birth Defects Registry (one of the largest active birth defects surveillance systems in the world) enabled us to examine six different heritable disorders (aqueductal stenosis, infantile polycystic kidney disease, achondroplasia, thanatophoric dwarfism, chondrodysplasia/dwarfism not otherwise specified (NOS), and osteogenesis imperfecta) for a variety of descriptive demographic variables. METHODS: The Texas Birth Defects Registry was used to identify infants or fetuses with heritable birth defects. Crude prevalence rates were calculated and Poisson regression was used to test the association of each demographic variable (e.g., maternal age) with each of the selected genetic birth defects. RESULTS: White non-Hispanics exhibited higher rates of achondroplasia and osteogenesis imperfecta than other race/ethnic groups. Lower maternal education level and to a lesser extent, paternal education level, was associated with higher rates of several disorders. The birth prevalence rate for achondroplasia decreased from 1999 through 2006. CONCLUSION: The use of a large birth defects registry provides a sufficient count of cases to perform some basic epidemiologic analysis on selected rare heritable birth defects. PMID- 22102536 TI - Measurement of spiral artery jets: general principles and differences observed in small-for-gestational-age pregnancies. AB - OBJECTIVE: To investigate whether the jets of blood from the mouths of the spiral arteries could be measured reliably, as well as their relationship with the uterine artery (UtA) and any differences in small-for-gestational-age (SGA) pregnancies. METHODS: Participants underwent serial ultrasound scans, from 11 weeks' gestation. Pulsatility index (PI) and resistance index (RI) of jets into the intervillous space (IVS) and UtA were recorded at every visit. Intra- and interobserver variability studies were performed. Customized birth weight centiles were calculated and SGA was defined as < 10(th) centile. Linear mixed model analysis was used to allow for the longitudinal nature of the data. RESULTS: Sixty-six women were recruited; 58 remained normotensive and delivered at term. Of these, six women delivered SGA newborns and 52 delivered appropriate for-gestational-age newborns. All had pulsatile jets until 20 weeks' gestation. The PI and RI of the jets decreased with advancing gestation, following a trend similar to that of the UtAs. There was no correlation between the jets and UtA waveforms when gestational age was controlled for. For intraobserver variability the intraclass correlation coefficient was 0.9. The interobserver study showed no significant difference between the observers. Mixed model analysis demonstrated that PI and RI of jets were different in SGA pregnancies (P < 0.06). This difference was not seen for the UtAs (P = 0.8). CONCLUSION: This technique enables examination of characteristics of the jets of blood flowing from spiral arteries into the IVS. It is both precise and reproducible, with biologically plausible results. Further work is required to assess differences in pregnancies with adverse outcomes. PMID- 22102537 TI - Structural and in vitro adhesion analysis of a novel covalently coupled bioactive composite. AB - The interfacial adhesion between a restorative composite and tooth is one of the major factors that determine the ultimate performance of composite restoration. A novel polyurethane (PU) composite material was prepared by chemically binding the nano-hydroxyapatite (nHA) to the diisocyanate component in the PU backbone by utilizing solvent polymerization. The procedure involved stepwise addition of monomeric units of the PU and optimizing the reagent concentrations. The resultant materials were characterized structurally (Raman Spectroscopy) and in vitro bioactive analysis was conducted in modified-simulated body fluid for periodical time intervals. The in vitro study evaluated the push-out bond strength of existing obturating material and novel covalently linked PU/nHA composites to dentin after long-term storage in deionized water and artificial saliva. Human extracted molar roots were filled with experimental samples and analyzed at predetermined time intervals. The shear bond strength of samples was measured and surface morphologies were evaluated. Covalent bond formation was achieved between PU and nHA without intermediate coupling agent. With the increase in concentration of nHA, the composite showed more bioactivity and adhesion toward tooth structure. Bond strength of this new composite were in accordance with obutrating material, therefore, the material can be used as an obturating material because of its direct adhesion with tooth structure. PMID- 22102538 TI - Expression of GATA1 in the ovine conceptus and endometrium during the peri attachment period. AB - The transcription factor GATA1 is known to play an essential role in hematopoiesis, but its other roles have not been well characterized. The purpose of this study was to determine relationships between GATA1 and GATA2 and/or GATA3, and to identify their possible functions in ovine development. GATA1 mRNA was found in ovine conceptuses and endometrial epithelial regions of Day 15 (Day 0=day of estrus) cyclic and Days 15, 17, and 21 pregnant ovine uteri. GATA1 mRNA was strongly expressed in conceptuses on Day 21, when trophoblast attachment to the maternal endometrium progressed. Similarly, GATA1 protein expression was relatively high on Day 21. To localize GATA1 mRNA, ovine conceptuses and pregnant uteri were subjected to in situ hybridization on Days 15, 17, and 21, confirming that GATA1 mRNA was expressed in trophoblasts and uterine endometrial epithelial cells in these gestation days. The presence of GATA1 protein was further confirmed by immunohistochemistry. Because high GATA1 expression appeared to coincide with reduced GATA2/3 expression, a potential role of GATA1 was examined through transfection of a mouse Gata1 expression plasmid into bovine trophoblast F3 cells. This over-expression resulted in the down-regulation of endogenous GATA2 transcripts. These observations indicate that GATA1 exists in the ovine conceptus and uterus during the peri-attachment period, and suggest that GATA1 is integral to conceptus and endometrial development through the regulation of GATA2 and possibly other developmentally important genes. PMID- 22102539 TI - Transbronchial fine needle aspiration biopsy and rapid on-site evaluation in the setting of superior vena cava syndrome. AB - There is a paucity of prospective data on flexible bronchoscopy with rapid on site evaluation (ROSE) in the setting of superior vena cava (SVC) syndrome. The aims of this prospective study were to assess the diagnostic yield and safety of these investigations and specifically to evaluate the role of ROSE in limiting the need for tissue biopsies. Over a 5-year period 48 patients (57.4 +/- 9.7 years) with SVC syndrome secondary to intrathoracic tumors underwent flexible bronchoscopy with TBNA and ROSE. Endobronchial Forceps biopsy was reserved for visible endobronchial tumors with no on-site confirmation of diagnostic material. ROSE confirmed diagnostic material in 41 cases (85.4%), and in only one of the remaining cases did the addition of a forceps biopsy increase the diagnostic yield (overall diagnostic yield of 87.5%). No serious complications were noted. The final diagnoses made included nonsmall lung cancer (n = 27), small cell lung cancer (n = 16), and metastatic carcinoma (n = 3). Two undiagnosed cases died of suspected advanced neoplasms (unknown primary tumors). We conclude that TBNA has a high diagnostic yield and is safe in the setting of SVC syndrome. With the addition of ROSE, tissue biopsy is required in the minority of cases. PMID- 22102540 TI - The effects of agomelatine on sexual function in depressed patients and healthy volunteers. AB - BACKGROUND: Selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor antidepressants are associated with high rates of treatment-emergent sexual dysfunction (TESD) due to stimulation of serotonin receptors. OBJECTIVE: The objective is to evaluate the effect of agomelatine on sexual function in depressed patients. METHODS: This paper reviews published and unpublished data on sexual function with agomelatine in depressed patients and healthy volunteers. RESULTS: Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and antagonist of 5-HT2 receptors, is associated with similar rates of sexual dysfunction compared with placebo and lower rates compared with other antidepressants. Twice as many sexually active depressed patients (n = 193) reported a deterioration of sexual function during 12 weeks of treatment with venlafaxine compared with agomelatine (15.2% vs. 8.2%, p < 0.0001); however, no differences were found with respect to arousal. Using the Arizona Sexual Experience Scale in depressed patients (n = 399), the incidence of treatment emergent sexual dysfunction (TESD) with agomelatine (3%) was significantly lower than placebo (8.6%) and selective serotonin reuptake inhibitors (10.1%). Among healthy male volunteers (n = 92), TESD was not increased compared with placebo in either agomelatine (25 and 50 mg/day) group over 8 weeks, and both were significantly lower than TESD with paroxetine (p < 0.0001). Moderate or severe TESD occurred in less than 5% of subjects receiving agomelatine versus 62% who received paroxetine (p < 0.001). CONCLUSION: Agomelatine demonstrates favorable sexual acceptability. PMID- 22102541 TI - Interactions of human endothelial cells with gold nanoparticles of different morphologies. AB - The interactions between noncancerous, primary endothelial cells and gold nanoparticles with different morphologies but the same ligand capping are investigated. The endothelial cells are incubated with gold nanospheres, nanorods, hollow gold spheres, and core/shell silica/gold nanocrystals, which are coated with monocarboxy (1-mercaptoundec-11-yl) hexaethylene glycol (OEG). Cell viability studies show that all types of gold particles are noncytotoxic. The number of particles taken up by the cells is estimated using inductively coupled plasma (ICP), and are found to differ depending on particle morphology. The above results are discussed with respect to heating efficiency. Using experimental data reported earlier and theoretical model calculations which take into account the physical properties and distribution of particles in the cellular microenvironment, it is found that collective heating effects of several cells loaded with nanoparticles must be included to explain the observed viability of the endothelial cells. PMID- 22102542 TI - Healthy people: a 2020 vision for the social determinants approach. AB - For the past three decades, the Healthy People initiative has represented an ambitious yet achievable health promotion and disease prevention agenda for the nation. The recently released fourth version-Healthy People 2020-builds on the foundations of prior iterations while newly embracing and elevating a comprehensive "social determinants" perspective. By clearly articulating a new overarching goal to "create social and physical environments that promote good health for all" and a new topic area dedicated to defining the social determinants of health approach, it breaks new ground. Specifically, the 2020 plan emphasizes the need to consider factors such as poverty, education, and numerous aspects of the social structure that not only influence the health of populations but also limit the ability of many to achieve health equity. Improving health is too multifaceted to be left to those working in the health sector alone. Using a social determinants approach can reframe the way the public, policy makers, and the private sector think about achieving and sustaining health. This article describes why such a social determinants approach can enhance our collective efforts to improve population health. This is achieved by defining the context for this new perspective, the process by which the Healthy People 2020 goals and objectives were developed, and the challenges and opportunities ahead. Adding this broad, social determinants perspective and vision for shared societal responsibility for change leaves Healthy People 2020 poised to promote a stronger legacy for a healthier nation and reaffirm a unity of purpose for the future. PMID- 22102543 TI - Healthy people 1980-2020: raising the ante decennially or just the name from public health education to health promotion to social determinants? PMID- 22102544 TI - Stem cell media culture of melanoma results in the induction of a nonrepresentative neural expression profile. AB - The ability of cell lines to accurately represent cancer is a major concern in preclinical research. Culture of glioma cells as neurospheres in stem cell media (SCM) has been shown to better represent the genotype and phenotype of primary glioblastoma in comparison to serum cell lines. Despite the use of neurosphere like models of many malignancies, there has been no robust analysis of whether other cancers benefit from a more representative phenotype and genotype when cultured in SCM. We analyzed the growth properties, transcriptional profile, and genotype of melanoma cells grown de novo in SCM, as while melanocytes share a common precursor with neural cells, melanoma frequently demonstrates divergent behavior in cancer stem cell assays. SCM culture of melanoma cells induced a neural lineage gene expression profile that was not representative of matched patient tissue samples and which could be induced in serum cell lines by switching them into SCM. There was no enrichment for expression of putative melanoma stem cell markers, but the SCM expression profile did overlap significantly with that of SCM cultures of glioma, suggesting that the observed phenotype is media-specific rather than melanoma-specific. Xenografts derived from either culture condition provided the best representation of melanoma in situ. Finally, SCM culture of melanoma did not prevent ongoing acquisition of DNA copy number abnormalities. In conclusion, SCM culture of melanoma does not provide a better representation of the phenotype or genotype of metastatic melanoma, and the resulting neural bias could potentially confound therapeutic target identification. PMID- 22102546 TI - Deproteinization technique stabilizes the adhesion of the fiberglass post relined with resin composite to root canal. AB - To evaluate the effects of pretreatment of root dentin by 5.25% sodium hypochlorite (NaOCl) alone, associated with 2% chlorhexidine in gel base (CHX) and/or ethanol (EtOH), and the air-drying technique (Air) on the bond strength and adhesive durability of fiberglass post relined with resin composite to root dentin. A total of 100 bovine incisor roots were divided into 10 groups: G1 (control), irrigation with physiologic solution; G2, Air; G3, NaOCl; G4, NaOCl + Air; G5, NaOCl + EtOH; G6, NaOCl + EtOH + Air; G7, NaOCl + CHX; G8, NaOCl + CHX + Air; G9, NaOCl + CHX + EtOH; G10, NaOCl + CHX + EtOH + Air. Fiberglass post relined with resin composite was cemented and each group was randomly divided into two subgroups: 24 h of water storage and 12 months of water storage. The push-out test was performed and bond strength values were analyzed by ANOVA and Tukey's test. The use of NaOCl alone or associated with CHX had the highest values of bond strength with or without Air in the immediate and stored groups, being statistically similar to the immediate control group (p > 0.05). The groups using EtOH or Air alone had lower bond strength in the immediate and stored groups (p < 0.05). A significant decrease with the time of the bond strength in the control group was observed after 12 months of storage (p > 0.05). The use of NaOCl or NaOCl associated with CHX preserved the bond strength immediate and for 12 months. The air-drying technique and the other associations decreased the immediate bond strength values. PMID- 22102545 TI - Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. AB - BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, but its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects. METHODS: Using data from the National Birth Defects Prevention Study (NBDPS)-a multi-site, population-based, case control study-we examined whether NVP or its treatment was associated with the most common noncardiac defects in the NBDPS (nonsyndromic cleft lip with or without cleft palate [CL/P], cleft palate alone [CP], neural tube defects, and hypospadias) compared with randomly selected nonmalformed live births. RESULTS: Among the 4524 cases and 5859 controls included in this study, 67.1% reported first-trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or neural tube defects, but modest risk reductions were observed for CL/P (adjusted odds ratio [aOR] = 0.87; 95% confidence interval [CI], 0.77-0.98) and hypospadias (aOR = 0.84; 95% CI, 0.72-0.98). Regarding treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR = 4.36; 95% CI, 1.21-15.81), steroids and hypospadias (aOR = 2.87; 95% CI, 1.03-7.97), and ondansetron and CP (aOR = 2.37; 95% CI, 1.18-4.76), whereas antacids were associated with a reduced risk for CL/P (aOR = 0.58; 95% CI, 0.38-0.89). CONCLUSIONS: NVP was not observed to be associated with an increased risk of birth defects; however, possible risks related to three treatments (i.e., proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation. PMID- 22102547 TI - The cytologic diagnosis of gangliocytic paraganglioma: a case report. AB - Gangliocytic paragangliomas are rare tumors primarily found in the duodenum. We report a case of a woman who presented with a retroperitoneal lymph node involved by metastatic gangliocytic paraganglioma. Subsequently, fine-needle aspiration (FNA) cytology was used to identify the primary duodenal gangliocytic paraganglioma. The smears of the aspirate material were highly cellular and contained a dominant population of epithelioid cells, a second population of ganglion cells and a third population of small, bland spindled cells. To our knowledge, the cytologic features of gangliocytic paraganglioma have not previously been documented. PMID- 22102548 TI - The nature and time-course of medial temporal lobe contributions to semantic retrieval: an fMRI study on verbal fluency. AB - Recent investigations have shown that the medial temporal lobe (MTL), a region thought to be exclusive to episodic memory, can also influence performance on tests of semantic memory. The present study examined further the nature of MTL contributions to semantic memory tasks by tracking MTL activation as participants performed category fluency, a traditional test of semantic retrieval. For categories that were inherently autobiographical (e.g. names of friends), the MTLs were activated throughout the time period in which items were generated, consistent with the MTLs role in retrieving autobiographical memories. For categories that could not benefit from autobiographical or spatial/context information (e.g. governmental offices), the MTL was not implicated at any time point. For categories for which both prototypical and episodically-related information exists (e.g. kitchen utensils), there was more robust MTL activity for the open-ended, late generation periods compared with the more well-defined, early item generation time periods. We interpret these results as suggesting that early in the generation phase, responses are based on well-rehearsed prototypical knowledge whereas later performance relies more on open-ended strategies, such as deriving exemplars from personally relevant contextual information (e.g. imagining one's own kitchen). These findings and interpretation were consistent with the results of an initial, separate behavioral study (Expt 1), that used the distinctiveness of responses as a measure of open-endedness across the generation phase: Response distinctiveness corresponded to the predicted open-endedness of the various tasks at early and late phases. Overall, this is consistent with the view that as generation of semantic information becomes open-ended, it recruits processes from other domains, such as episodic memory, to support performance. PMID- 22102549 TI - Comment on 'Hidden Markov models for zero-inflated Poisson counts with an application to substance use' by S. M. DeSantis and D. Bandyopadhyay. PMID- 22102551 TI - Identification of ten new designer drugs by GC-MS, UPLC-QTOF-MS, and NMR as part of a police investigation of a Danish internet company. AB - The ability of forensic laboratories to detect and identify unknown compounds is highly important since new, non-controlled designer drugs are appearing on the market with increasing frequency. In this study, the combined use of gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC-QTOF-MS) was used for screening of new unknowns. In one large seizure from a Danish Internet company, ten different drugs were identified. Several of the compounds were seized for the first time in Denmark. The GC-MS and UPLC-QTOF-MS analyses were supplemented by nuclear magnetic resonance (NMR) spectra for the structural elucidation of p-fluoroamphetamine, mephedrone (4-methylmethcathinone), flephedrone (4-fluoromethcathinone), PPP (alpha-pyrrolidinopropiophenone), MDPV (3,4-methylenedioxypyrovalerone), Bk-MBDB (2-methylamino-1-(3,4 methylenedioxyphenyl)butan-1-one), pFBT (3-(pfluorobenzoyl)-tropane), and JWH-073 (1-butyl-3-(1-naphthoyl)indol), whereas methylone (3,4 methylenedioxymethcathinone) and N-ethylcathinone matched electron impact-mass spectrometry (EI-MS) library spectra and therefore the screenings were considered sufficient. EI-MS spectra and the proposed main fragmentation patterns are presented as well as QTOF-MS exact masses and fragments and NMR chemical shifts. For the beta-ketophenylethylamines (mephedrone, flephedrone, PPP, MDPV, Bk-MBDB, methylone, and N-ethylcathinone) some general fragmentation patterns observed in the EI-MS and QTOF-MS spectra are further discussed and compared to other beta ketophenylethylamines. PMID- 22102552 TI - Photoinduced silver nanoparticles/nanorings on plasmid DNA scaffolds. AB - Biological scaffolds are being actively explored for the synthesis of nanomaterials with novel structures and unexpected properties. Toroidal plasmid DNA separated from the Bacillus host is applied as a sacrificial mold for the synthesis of silver nanoparticles and nanorings. The photoirradiation method is applied to reduce Ag(I) on the plasmid. The nanoparticles are obtained by varying the concentration of the Ag(I) ion solution and the exposure time of the plasmid Ag(I) complex under UV light at 254 nm and room temperature. It is found that the plasmid serves not only as a template but also as a reductant to drive the silver nucleation and deposition. The resulting nanoparticles have a face-centered cubic (fcc) crystal structure and 20-30 nm average diameter. The detailed mechanism is discussed, and other metals or alloys could also be synthesized with this method. PMID- 22102553 TI - Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Several studies have demonstrated the prognostic utility of absolute lymphocyte count (ALC) during therapy for a range of malignancies, with low ALC associated with adverse outcome. Here we investigated whether ALC retained independent prognostic significance with respect to minimal residual disease (MRD) status in children with acute lymphoblastic leukemia (ALL). PROCEDURE: We reviewed 171 cases of pediatric ALL treated on the Children's Oncology Group P9900 series of treatment trials. Variables analyzed included ALC at several time points during Induction, age at diagnosis, cytogenetics, initial white blood cell count, and MRD status at Day 29 of Induction (MRD-29). RESULTS: We found high ALC at Induction Day 29 (ALC-29) to be an independent, clinically significant predictor of improved relapse-free and overall survival (OS). Patients with ALC 29 >1,500 cells/ul had a superior 6-year relapse-free survival (80 +/- 4% vs. 62 +/- 8%, P = 0.018) and overall survival (96 +/- 2% vs. 74 +/- 8%, P = 0.001). Moreover, ALC-29 identified distinct prognostic subgroups within cases stratified by MRD-29. In subjects with >0.01% MRD, ALC-29 > or <1,500 cells/ul had a significant 51% difference in 6-year OS (92 +/- 7% vs. 41 +/- 16%, P = 0.0001). CONCLUSIONS: ALC, a readily obtainable test, constitutes a significant and independent prognostic factor in childhood ALL that may refine current MRD-based risk stratification algorithms and provide key prognostic information in settings where MRD determination is not feasible. PMID- 22102554 TI - Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo. AB - Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that are predominantly localized in the bone marrow (BM). Mesenchymal stromal cells (MSCs) give rise to most BM stromal cells that interact with MM cells. However, the direct involvement of MSCs in the pathophysiology of MM has not been well addressed. In this study, in vitro and in vivo migration assays revealed that MSCs have tropism toward MM cells, and CCL25 was identified as a major MM cell-produced chemoattractant for MSCs. By coculture experiments, we found that MSCs favor the proliferation of stroma-dependent MM cells through soluble factors and cell to cell contact, which was confirmed by intrafemoral coengraftment experiments. We also demonstrated that MSCs protected MM cells against spontaneous and Bortezomib-induced apoptosis. The tumor-promoting effect of MSCs correlated with their capacity to enhance AKT and ERK activities in MM cells, accompanied with increased expression of CyclinD2, CDK4, and Bcl-XL and decreased cleaved caspase-3 and poly(ADP-ribose) polymerase expression. In turn, MM cells upregulated interleukin-6 (IL-6), IL-10, insulin growth factor-1, vascular endothelial growth factor, and dickkopf homolog 1 expression in MSCs. Finally, infusion of in vitro-expanded murine MSCs in 5T33MM mice resulted in a significantly shorter survival. MSC infusion is a promising way to support hematopoietic recovery and to control graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation. However, our data suggest that MSC-based cytotherapy has a potential risk for MM disease progression or relapse and should be considered with caution in MM patients. PMID- 22102555 TI - Cellular proliferation, cellular viability, and biocompatibility of HA-ZnO composites. AB - One of the important issues in the development of hydroxyapatite (HA)-based biomaterials is the prosthetic infection, which limits wider use of monolithic HA despite superior cellular response. Recently, we reported that ZnO addition to HA can induce bactericidal property. It is therefore important to assess how ZnO addition influences the cytotoxicity property and cell adhesion/proliferation on HA-ZnO composite surfaces in vitro. In the above perspective, the objective of this study is to investigate the cell type and material composition dependent cellular proliferation and viability of pressureless sintered HA-ZnO composites. The combination of cell viability data as well as morphological observations of cultured human osteoblast-like SaOS2 cells and mouse fibroblast L929 cells suggests that HA-ZnO composites containing 10 Wt % or lower ZnO exhibit the ability to support cell adhesion and proliferation. Both SaOS2 and L929 cells exhibit extensive multidirectional network of actin cytoskeleton and cell flattening on the lower ZnO containing (<=10 Wt %) HA-ZnO composites. The in vitro results illustrate how variation in ZnO content can influence significantly the cell vitality, as evaluated using MTT biochemical assay. Also, the critical statistical analysis reveals that ZnO addition needs to be carefully tailored to ensure good in vitro cytocompatibility. The underlying reasons for difference in biological properties are analyzed. It is suggested that surface wettability as well as dissolution of ZnO, both contribute to the observed differences in cellular viability and proliferation. PMID- 22102556 TI - Endoscopic ultrasound guided fine-needle aspiration of a splenic hemangioma with extramedullary hematopoiesis. AB - Extramedullary hematopoiesis (EMH) is the production of mature blood elements outside of the bone marrow and can occur as a compensatory result of a marrow replacing process or from marrow space occupying lesions such as tumor or marrow fibrosis. EMH can also be induced by factors elicited by neoplasms, such as vascular endothelial growth factor (VEGF). Usually, EMH is a diffuse process most commonly observed in lymph nodes, liver, and spleen. Rarely, EMH can form a mass lesion. Although the spleen is a common site for diffuse EMH, it is a rare location for a mass forming EMH. Hemangiomas are the most common benign tumors of the spleen. A case of a discrete, 8 cm lesion was noted incidentally on CT scan in a 59-year-old man with no significant past medical history. Endoscopic ultrasound guided fine-needle aspiration (EUS FNA) biopsy was performed and cytologic examination revealed trilinear hematopoiesis, with the most distinctive elements being megakaryocytes and erythroid precursors. A diagnosis of EMH was made. On resection, the mass was a hemangioma with EMH. EUS guided FNA is a useful tool for diagnosing splenic masses. Awareness of EMH, both as a mass forming lesion and a feature associated with benign and malignant vascular lesions is important, especially in patients with hematologic malignancies or marrow replacing processes. PMID- 22102557 TI - Myocardial edema imaging in acute coronary syndromes. AB - Acute coronary syndromes (ACS) continue to be the most common morbid condition of industrialized nations. The advent of and technical improvements in revascularization and medical therapy have led to a steady decline in mortality rates. However, many patients who suffer unstable angina or myocardial infarction require further testing and risk stratification to guide therapeutic selection and prognosis assignment. Myocardial edema imaging with cardiac magnetic resonance (CMR) affords the ability to define the amount of myocardium at risk, refine estimates of prognosis and provide guidance for therapies with excellent sensitivity compared with standard clinical markers. This review will discuss the rationale for edema imaging, how it is performed using CMR, and potential clinical applications. PMID- 22102558 TI - MR spectroscopy in schizophrenia. AB - The purpose of this study is to review the MR spectroscopic literature regarding schizophrenia. However, as there are over 250 primary MRS articles and dozens of MRS review articles on the subject already, this study will take a different approach. First, the clinical features of schizophrenia will be described. The background neuroanatomy and biochemistry relevant to schizophrenia will be reviewed, as many readers of this journal are unlikely to be familiar with these fields. A current model of the abnormal neural circuitry in schizophrenia will be presented, and predictions extrapolated about relevant metabolite changes over time. Finally, the existing MRS literature will be reviewed in the context of our existing anatomical and chemical knowledge, and future MRS research directions will be elaborated. PMID- 22102561 TI - Inverse correlation between clinical response to paroxetine and plasma drug concentration in patients with major depressive disorders. AB - OBJECTIVE: There are few data concerning a clear relationship between the clinical effect of paroxetine and plasma drug concentrations, although therapeutic ranges have been established for some tricyclic antidepressants. METHODS: In this study, 120 patients with major depressive disorders were treated with 10-40 mg/day of paroxetine for 6 weeks, and a total of 89 patients completed the protocol. A clinical evaluation using the Montgomery-Asberg Depression Rating Scale (MADRS) was performed at 0, 1, 2, 4 and 6 weeks. RESULTS: Significant correlations were found between the plasma concentrations of paroxetine and the percentage improvement in the total MADRS scores (r = -0.282, p < 0.01) and the final MADRS scores at 6 weeks (r = 0.268, p < 0.05). The conventional receiver operating-characteristic curve showed the fraction of true positive results and false negative results for various cut-off levels of paroxetine concentration for response and remission. The thresholds for both response and remission that gave the maximal sensitivity and specificity for paroxetine concentrations were 64.2 ng/ml. CONCLUSIONS: These results suggest that plasma paroxetine concentrations are negatively associated with improvement and that response occurs at the upper threshold of 64.2 ng/ml of paroxetine. These findings should be replicated with a larger patient sample. PMID- 22102562 TI - Electron-induced dynamics of heptathioether beta-cyclodextrin molecules. AB - Variable-temperature scanning tunneling microscopy (STM) and spectroscopy (STS) measurements are performed on heptathioether beta-cyclodextrin (beta-CD) self assembled monolayers (SAMs) on Au. The beta-CD molecules exhibit very rich dynamical behavior, which is not apparent in ensemble-averaged studies. The dynamics are reflected in the tunneling current-time traces, which are recorded with the STM feedback loop disabled. The dynamics are temperature independent, but increase with increasing tunneling current and sample bias, thus indicating that the conformational changes of the beta-CD molecules are induced by electrons that tunnel inelastically. Even for sample biases as low as 10 mV, well-defined levels are observed in the tunneling current-time traces. These jumps are attributed to the excitations of the molecular vibration of the macrocyclic beta CD molecule. The results are of great importance for a proper understanding of transport measurements in SAMs. PMID- 22102564 TI - The syntheses and characterization 3beta-(4-fluorobenzoyloxy)tropane (fluorotropacocaine) and its 3alpha isomer. AB - 3beta-(4-Fluorobenzoyloxy)tropane (3beta-FBT, fluorotropacocaine) was first reported by Finnish authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) in 2008 and our own laboratory tentatively identified it in 2010 in several products purchased from head shops. Very little is known about this cocaine-like drug and, as no reference standards were available, we have synthesized and characterized both 3beta-FBT and its 3alpha isomer for use as reference standards. The two compounds are separable by gas chromatography (GC) but their electron-impact (EI) mass spectra were found to be almost identical. 19F NMR spectroscopy was also found to be a useful technique for distinguishing the two isomers. PMID- 22102563 TI - Testing of the Akt/PKB inhibitor MK-2206 by the Pediatric Preclinical Testing Program. AB - BACKGROUND: MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer. PROCEDURES: MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0 nM-10 uM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180 mg/kg. RESULTS: In vitro, the median relative IC(50) value for MK-2206 was 2.2 uM. Four cell lines with IC(50) values < 200 nM included two ALL cell lines (COG-LL-317 and RS4;11), an AML cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10). In vivo, MK-2206 induced significant differences in EFS distribution compared to control in 12 of 29 (41%) of the evaluable solid tumor xenografts and in 2 of 8 (25%) of the evaluable ALL xenografts. Significant differences in EFS distribution were most frequently noted in the osteosarcoma panel (6 of 6). A single solid tumor xenograft (OS-31) had a greater than twofold increase in time to event compared to control animals, with all other solid tumor xenografts showing lesser degrees of tumor growth inhibition. Objective responses were not observed for either the solid tumor or ALL xenografts. CONCLUSIONS: MK-2206 showed its most consistent activity in vitro against ALL cell lines and in vivo against osteosarcoma xenografts. However, no objective responses were observed in solid tumor or ALL xenografts. Further preclinical work evaluating MK-2206 in pediatric models in the combination therapy setting may contribute to its pediatric development. PMID- 22102565 TI - Concise review: Embryonic stem cells versus induced pluripotent stem cells: the game is on. AB - Extraordinary advances in pluripotent stem cell research have initiated an era of hope for regenerative strategies to treat human disease. Besides embryonic stem cells, the discovery of induced pluripotent stem cells widened the possibility of patient-specific cell therapy, drug discovery, and disease modeling. Although similar, it has become clear that these two pluripotent cell types display significant differences. In this review, we explore current knowledge of the molecular and functional similarities and differences between these two cell types to emphasize the necessity for thorough characterization of their properties as well as their differentiation capabilities in the pluripotent state. Such comparative studies will be crucial for determining the more suitable cell type for future stem cell-based therapies for human degenerative diseases. PMID- 22102566 TI - Topographic characterization and protein quantification of esophageal basement membrane for scaffold design reference in tissue engineering. AB - Basement membrane (BM) has been investigated widely and applied in the field of bio-synthesized scaffold design in tissue engineering. However, this respect of investigation has seen scarcely in the field of esophageal tissue engineering. This study reports BM's basic topographic characters and quantification of structural and major proteins involving collagen IV, laminin, entactin, proteoglycans of porcine esophagus. Several methods were adopted to strip epithelium from mucosa tissue. For example, ethylene diamine tetraacetic acid, sonication, dithiothreitol, cold sodium chloride (NaCl), mechanical force of glass coverslip, and cold trypsin and so forth. Assessed experimental results under different conditions, the optimal condition to isolate epithelium from BM was established. After the reaction of cold trypsin at 4 degrees C for 15 h, the BM was isolated from epithelium and exposed integratedly. Hematoxylin and eosin staining and immunohistochemical staining verified the effectiveness of epithelium removal and the integrity of BM. The topographic features of the exposed BM were observed under transmission electron microscopy and scanning electron microscopy. It displayed a rugged surface and 3-D topography consisting of pores and fibers with sub-100 nm range via ImageJ software. The major proteins existing in BM were quantitatively analyzed by enzyme-linked immune sorbent assay. All these results will provide references for the design of synthesized scaffolds and protein modification in esophageal tissue-engineering research. PMID- 22102567 TI - In Papanicolaou smears, benign appearing endometrial cells bear no significance in predicting uterine endometrial adenocarcinomas. AB - Reporting of benign appearing endometrial cells (BECs) in the Papanicolaou smears of women aging 40 years or older was mandated in the Bethesda System 2001 aiming at predicting the uterine pathology. The purpose of this study was to determine the clinical significance of the BECs in patients in our Medical Center. A two arm study was designed in >=40-years-old women with BECs and without BECs in their Pap smears from January 2002 to December 2004. Of 21,965 patients, 882 had BECs in their Pap smears and the rest did not. Among the patients with BECs, 186 (study group) and among those without BECs, 2,064 (control group) had histopathologic follow-ups. There were 4 patients in the study and 47 in the control groups who had uterine adenocarcinoma. The Chi-square P-value for adenocarcinoma between the two groups was 0.91; indicating insignificant differences between the two groups. We conclude that presence of BECs in the Pap smears of >=40-years-old women signal no significance as a harbinger of endometrial adenocarcinoma. PMID- 22102569 TI - Gene prediction with Glimmer for metagenomic sequences augmented by classification and clustering. AB - Environmental shotgun sequencing (or metagenomics) is widely used to survey the communities of microbial organisms that live in many diverse ecosystems, such as the human body. Finding the protein-coding genes within the sequences is an important step for assessing the functional capacity of a metagenome. In this work, we developed a metagenomics gene prediction system Glimmer-MG that achieves significantly greater accuracy than previous systems via novel approaches to a number of important prediction subtasks. First, we introduce the use of phylogenetic classifications of the sequences to model parameterization. We also cluster the sequences, grouping together those that likely originated from the same organism. Analogous to iterative schemes that are useful for whole genomes, we retrain our models within each cluster on the initial gene predictions before making final predictions. Finally, we model both insertion/deletion and substitution sequencing errors using a different approach than previous software, allowing Glimmer-MG to change coding frame or pass through stop codons by predicting an error. In a comparison among multiple gene finding methods, Glimmer MG makes the most sensitive and precise predictions on simulated and real metagenomes for all read lengths and error rates tested. PMID- 22102568 TI - The Gene Ontology: enhancements for 2011. AB - The Gene Ontology (GO) (http://www.geneontology.org) is a community bioinformatics resource that represents gene product function through the use of structured, controlled vocabularies. The number of GO annotations of gene products has increased due to curation efforts among GO Consortium (GOC) groups, including focused literature-based annotation and ortholog-based functional inference. The GO ontologies continue to expand and improve as a result of targeted ontology development, including the introduction of computable logical definitions and development of new tools for the streamlined addition of terms to the ontology. The GOC continues to support its user community through the use of e-mail lists, social media and web-based resources. PMID- 22102570 TI - ProPortal: a resource for integrated systems biology of Prochlorococcus and its phage. AB - ProPortal (http://proportal.mit.edu/) is a database containing genomic, metagenomic, transcriptomic and field data for the marine cyanobacterium Prochlorococcus. Our goal is to provide a source of cross-referenced data across multiple scales of biological organization--from the genome to the ecosystem- embracing the full diversity of ecotypic variation within this microbial taxon, its sister group, Synechococcus and phage that infect them. The site currently contains the genomes of 13 Prochlorococcus strains, 11 Synechococcus strains and 28 cyanophage strains that infect one or both groups. Cyanobacterial and cyanophage genes are clustered into orthologous groups that can be accessed by keyword search or through a genome browser. Users can also identify orthologous gene clusters shared by cyanobacterial and cyanophage genomes. Gene expression data for Prochlorococcus ecotypes MED4 and MIT9313 allow users to identify genes that are up or downregulated in response to environmental stressors. In addition, the transcriptome in synchronized cells grown on a 24-h light-dark cycle reveals the choreography of gene expression in cells in a 'natural' state. Metagenomic sequences from the Global Ocean Survey from Prochlorococcus, Synechococcus and phage genomes are archived so users can examine the differences between populations from diverse habitats. Finally, an example of cyanobacterial population data from the field is included. PMID- 22102571 TI - Pseudouridine synthase 1: a site-specific synthase without strict sequence recognition requirements. AB - Pseudouridine synthase 1 (Pus1p) is an unusual site-specific modification enzyme in that it can modify a number of positions in tRNAs and can recognize several other types of RNA. No consensus recognition sequence or structure has been identified for Pus1p. Human Pus1p was used to determine which structural or sequence elements of human tRNA(Ser) are necessary for pseudouridine (Psi) formation at position 28 in the anticodon stem-loop (ASL). Some point mutations in the ASL stem of tRNA(Ser) had significant effects on the levels of modification and compensatory mutation, to reform the base pair, restored a wild type level of Psi formation. Deletion analysis showed that the tRNA(Ser) TPsiC stem-loop was a determinant for modification in the ASL. A mini-substrate composed of the ASL and TPsiC stem-loop exhibited significant Psi formation at position 28 and a number of mutants were tested. Substantial base pairing in the ASL stem (3 out of 5 bp) is required, but the sequence of the TPsiC loop is not required for modification. When all nucleotides in the ASL stem other than U28 were changed in a single mutant, but base pairing was retained, a near wild-type level of modification was observed. PMID- 22102572 TI - STAP Refinement of the NMR database: a database of 2405 refined solution NMR structures. AB - According to several studies, some nuclear magnetic resonance (NMR) structures are of lower quality, less reliable and less suitable for structural analysis than high-resolution X-ray crystallographic structures. We present a public database of 2405 refined NMR solution structures [statistical torsion angle potentials (STAP) refinement of the NMR database, http://psb.kobic.re.kr/STAP/refinement] from the Protein Data Bank (PDB). A simulated annealing protocol was employed to obtain refined structures with target potentials, including the newly developed STAP. The refined database was extensively analysed using various quality indicators from several assessment programs to determine the nuclear Overhauser effect (NOE) completeness, Ramachandran appearance, chi(1)-chi(2) rotamer normality, various parameters for protein stability and other indicators. Most quality indicators are improved in our protocol mainly due to the inclusion of the newly developed knowledge-based potentials. This database can be used by the NMR structure community for further development of research and validation tools, structure-related studies and modelling in many fields of research. PMID- 22102573 TI - DBETH: a Database of Bacterial Exotoxins for Human. AB - Pathogenic bacteria produce protein toxins to survive in the hostile environments defined by the host's defense systems and immune response. Recent progresses in high-throughput genome sequencing and structure determination techniques have contributed to a better understanding of mechanisms of action of the bacterial toxins at the cellular and molecular levels leading to pathogenicity. It is fair to assume that with time more and more unknown toxins will emerge not only by the discovery of newer species but also due to the genetic rearrangement of existing bacterial genomes. Hence, it is crucial to organize a systematic compilation and subsequent analyses of the inherent features of known bacterial toxins. We developed a Database for Bacterial ExoToxins (DBETH, http://www.hpppi.iicb.res.in/btox/), which contains sequence, structure, interaction network and analytical results for 229 toxins categorized within 24 mechanistic and activity types from 26 bacterial genuses. The main objective of this database is to provide a comprehensive knowledgebase for human pathogenic bacterial toxins where various important sequence, structure and physico-chemical property based analyses are provided. Further, we have developed a prediction server attached to this database which aims to identify bacterial toxin like sequences either by establishing homology with known toxin sequences/domains or by classifying bacterial toxin specific features using a support vector based machine learning techniques. PMID- 22102574 TI - TopFIND 2.0--linking protein termini with proteolytic processing and modifications altering protein function. AB - Protein termini provide critical insights into the functional state of individual proteins. With recent advances in specific proteomics approaches to enrich for N- and C-terminomes, the global analysis of whole terminomes at a proteome-wide scale is now possible. Information on the actual N- and C-termini of proteins in vivo and any post-translational modifications, including their generation by proteolytic processing, is rapidly accumulating. To access this information we present version 2.0 of TopFIND (http://clipserve.clip.ubc.ca/topfind), a knowledgebase for protein termini, terminus modifications and underlying proteolytic processing. Built on a protein-centric framework TopFIND covers five species: Homo sapiens, Mus musculus, Arabidopsis thaliana, Saccharomyces cerevisiae and Escherichia coli and incorporates information from curated community submissions, publications, UniProtKB and MEROPS. Emphasis is placed on the detailed description and classification of evidence supporting the reported identification of each cleavage site, terminus and modification. A suite of filters can be applied to select supporting evidence. A dynamic network representation of the relationship between proteases, their substrates and inhibitors as well as visualization of protease cleavage site specificities complements the information displayed. Hence, TopFIND supports in depth investigation of protein termini information to spark new hypotheses on protein function by correlating cleavage events and termini with protein domains and mutations. PMID- 22102575 TI - YeTFaSCo: a database of evaluated yeast transcription factor sequence specificities. AB - The yeast Saccharomyces cerevisiae is a prevalent system for the analysis of transcriptional networks. As a result, multiple DNA-binding sequence specificities (motifs) have been derived for most yeast transcription factors (TFs). However, motifs from different studies are often inconsistent with each other, making subsequent analyses complicated and confusing. Here, we have created YeTFaSCo (The Yeast Transcription Factor Specificity Compendium, http://yetfasco.ccbr.utoronto.ca/), an extensive collection of S. cerevisiae TF specificities. YeTFaSCo differs from related databases by being more comprehensive (including 1709 motifs for 256 proteins or protein complexes), and by evaluating the motifs using multiple objective quality metrics. The metrics include correlation between motif matches and ChIP-chip data, gene expression patterns, and GO terms, as well as motif agreement between different studies. YeTFaSCo also features an index of 'expert-curated' motifs, each associated with a confidence assessment. In addition, the database website features tools for motif analysis, including a sequence scanning function and precomputed genome browser tracks of motif occurrences across the entire yeast genome. Users can also search the database for motifs that are similar to a query motif. PMID- 22102576 TI - The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. AB - The MetaCyc database (http://metacyc.org/) provides a comprehensive and freely accessible resource for metabolic pathways and enzymes from all domains of life. The pathways in MetaCyc are experimentally determined, small-molecule metabolic pathways and are curated from the primary scientific literature. MetaCyc contains more than 1800 pathways derived from more than 30,000 publications, and is the largest curated collection of metabolic pathways currently available. Most reactions in MetaCyc pathways are linked to one or more well-characterized enzymes, and both pathways and enzymes are annotated with reviews, evidence codes and literature citations. BioCyc (http://biocyc.org/) is a collection of more than 1700 organism-specific Pathway/Genome Databases (PGDBs). Each BioCyc PGDB contains the full genome and predicted metabolic network of one organism. The network, which is predicted by the Pathway Tools software using MetaCyc as a reference database, consists of metabolites, enzymes, reactions and metabolic pathways. BioCyc PGDBs contain additional features, including predicted operons, transport systems and pathway-hole fillers. The BioCyc website and Pathway Tools software offer many tools for querying and analysis of PGDBs, including Omics Viewers and comparative analysis. New developments include a zoomable web interface for diagrams; flux-balance analysis model generation from PGDBs; web services; and a new tool called Web Groups. PMID- 22102577 TI - Fosmid-based whole genome haplotyping of a HapMap trio child: evaluation of Single Individual Haplotyping techniques. AB - Determining the underlying haplotypes of individual human genomes is an essential, but currently difficult, step toward a complete understanding of genome function. Fosmid pool-based next-generation sequencing allows genome-wide generation of 40-kb haploid DNA segments, which can be phased into contiguous molecular haplotypes computationally by Single Individual Haplotyping (SIH). Many SIH algorithms have been proposed, but the accuracy of such methods has been difficult to assess due to the lack of real benchmark data. To address this problem, we generated whole genome fosmid sequence data from a HapMap trio child, NA12878, for which reliable haplotypes have already been produced. We assembled haplotypes using eight algorithms for SIH and carried out direct comparisons of their accuracy, completeness and efficiency. Our comparisons indicate that fosmid based haplotyping can deliver highly accurate results even at low coverage and that our SIH algorithm, ReFHap, is able to efficiently produce high-quality haplotypes. We expanded the haplotypes for NA12878 by combining the current haplotypes with our fosmid-based haplotypes, producing near-to-complete new gold standard haplotypes containing almost 98% of heterozygous SNPs. This improvement includes notable fractions of disease-related and GWA SNPs. Integrated with other molecular biological data sets, this phase information will advance the emerging field of diploid genomics. PMID- 22102578 TI - COLT-Cancer: functional genetic screening resource for essential genes in human cancer cell lines. AB - Genome-wide pooled shRNA screens enable global identification of the genes essential for cancer cell survival and proliferation and provide a 'functional genetic' map of human cancer to complement genomic studies. Using a lentiviral shRNA library targeting approximately 16,000 human genes and a newly developed scoring approach, we identified essential gene profiles in more than 70 breast, pancreatic and ovarian cancer cell lines. We developed a web-accessible database system for capturing information from each step in our standardized screening pipeline and a gene-centric search tool for exploring shRNA activities within a given cell line or across multiple cell lines. The database consists of a laboratory information and management system for tracking each step of a pooled shRNA screen as well as a web interface for querying and visualization of shRNA and gene-level performance across multiple cancer cell lines. COLT-Cancer Version 1.0 is currently accessible at http://colt.ccbr.utoronto.ca/cancer. PMID- 22102579 TI - Novel non-specific DNA adenine methyltransferases. AB - The mom gene of bacteriophage Mu encodes an enzyme that converts adenine to N(6) (1-acetamido)-adenine in the phage DNA and thereby protects the viral genome from cleavage by a wide variety of restriction endonucleases. Mu-like prophage sequences present in Haemophilus influenzae Rd (FluMu), Neisseria meningitidis type A strain Z2491 (Pnme1) and H. influenzae biotype aegyptius ATCC 11116 do not possess a Mom-encoding gene. Instead, at the position occupied by mom in Mu they carry an unrelated gene that encodes a protein with homology to DNA adenine N(6) methyltransferases (hin1523, nma1821, hia5, respectively). Products of the hin1523, hia5 and nma1821 genes modify adenine residues to N(6)-methyladenine, both in vitro and in vivo. All of these enzymes catalyzed extensive DNA methylation; most notably the Hia5 protein caused the methylation of 61% of the adenines in lambda DNA. Kinetic analysis of oligonucleotide methylation suggests that all adenine residues in DNA, with the possible exception of poly(A)-tracts, constitute substrates for the Hia5 and Hin1523 enzymes. Their potential 'sequence specificity' could be summarized as AB or BA (where B = C, G or T). Plasmid DNA isolated from Escherichia coli cells overexpressing these novel DNA methyltransferases was resistant to cleavage by many restriction enzymes sensitive to adenine methylation. PMID- 22102580 TI - Pso2 (SNM1) is a DNA structure-specific endonuclease. AB - Many types of DNA structures are generated in response to DNA damage, repair and recombination that require processing via specialized nucleases. DNA hairpins represent one such class of structures formed during V(D)J recombination, palindrome extrusion, DNA transposition and some types of double-strand breaks. Here we present biochemical and genetic evidence to suggest that Pso2 is a robust DNA hairpin opening nuclease in budding yeast. Pso2 (SNM1A in mammals) belongs to a small group of proteins thought to function predominantly during interstrand crosslink (ICL) repair. In this study, we characterized the nuclease activity of Pso2 toward a variety of DNA substrates. Unexpectedly, Pso2 was found to be an efficient, structure-specific DNA hairpin opening endonuclease. This activity was further shown to be required in vivo for repair of chromosomal breaks harboring closed hairpin ends. These findings provide the first evidence that Pso2 may function outside ICL repair and open the possibility that Pso2 may function at least in part during ICL repair by processing DNA intermediates including DNA hairpins or hairpin-like structures. PMID- 22102581 TI - ProRepeat: an integrated repository for studying amino acid tandem repeats in proteins. AB - ProRepeat (http://prorepeat.bioinformatics.nl/) is an integrated curated repository and analysis platform for in-depth research on the biological characteristics of amino acid tandem repeats. ProRepeat collects repeats from all proteins included in the UniProt knowledgebase, together with 85 completely sequenced eukaryotic proteomes contained within the RefSeq collection. It contains non-redundant perfect tandem repeats, approximate tandem repeats and simple, low-complexity sequences, covering the majority of the amino acid tandem repeat patterns found in proteins. The ProRepeat web interface allows querying the repeat database using repeat characteristics like repeat unit and length, number of repetitions of the repeat unit and position of the repeat in the protein. Users can also search for repeats by the characteristics of repeat containing proteins, such as entry ID, protein description, sequence length, gene name and taxon. ProRepeat offers powerful analysis tools for finding biological interesting properties of repeats, such as the strong position bias of leucine repeats in the N-terminus of eukaryotic protein sequences, the differences of repeat abundance among proteomes, the functional classification of repeat containing proteins and GC content constrains of repeats' corresponding codons. PMID- 22102582 TI - Bacterial ribosome requires multiple L12 dimers for efficient initiation and elongation of protein synthesis involving IF2 and EF-G. AB - The ribosomal stalk in bacteria is composed of four or six copies of L12 proteins arranged in dimers that bind to the adjacent sites on protein L10, spanning 10 amino acids each from the L10 C-terminus. To study why multiple L12 dimers are required on the ribosome, we created a chromosomally engineered Escherichia coli strain, JE105, in which the peripheral L12 dimer binding site was deleted. Thus JE105 harbors ribosomes with only a single L12 dimer. Compared to MG1655, the parental strain with two L12 dimers, JE105 showed significant growth defect suggesting suboptimal function of the ribosomes with one L12 dimer. When tested in a cell-free reconstituted transcription-translation assay the synthesis of a full-length protein, firefly luciferase, was notably slower with JE105 70S ribosomes and 50S subunits. Further, in vitro analysis by fast kinetics revealed that single L12 dimer ribosomes from JE105 are defective in two major steps of translation, namely initiation and elongation involving translational GTPases IF2 and EF-G. Varying number of L12 dimers on the ribosome can be a mechanism in bacteria for modulating the rate of translation in response to growth condition. PMID- 22102583 TI - Mouse Phenome Database (MPD). AB - The Mouse Phenome Project was launched a decade ago to complement mouse genome sequencing efforts by promoting new phenotyping initiatives under standardized conditions and collecting the data in a central public database, the Mouse Phenome Database (MPD; http://phenome.jax.org). MPD houses a wealth of strain characteristics data to facilitate the use of the laboratory mouse in translational research for human health and disease, helping alleviate problems involving experimentation in humans that cannot be done practically or ethically. Data sets are voluntarily contributed by researchers from a variety of institutions and settings, or in some cases, retrieved by MPD staff from public sources. MPD maintains a growing collection of standardized reference data that assists investigators in selecting mouse strains for research applications; houses treatment/control data for drug studies and other interventions; offers a standardized platform for discovering genotype-phenotype relationships; and provides tools for hypothesis testing. MPD improvements and updates since our last NAR report are presented, including the addition of new tools and features to facilitate navigation and data mining as well as the acquisition of new data (phenotypic, genotypic and gene expression). PMID- 22102584 TI - i-ADHoRe 3.0--fast and sensitive detection of genomic homology in extremely large data sets. AB - Comparative genomics is a powerful means to gain insight into the evolutionary processes that shape the genomes of related species. As the number of sequenced genomes increases, the development of software to perform accurate cross-species analyses becomes indispensable. However, many implementations that have the ability to compare multiple genomes exhibit unfavorable computational and memory requirements, limiting the number of genomes that can be analyzed in one run. Here, we present a software package to unveil genomic homology based on the identification of conservation of gene content and gene order (collinearity), i ADHoRe 3.0, and its application to eukaryotic genomes. The use of efficient algorithms and support for parallel computing enable the analysis of large-scale data sets. Unlike other tools, i-ADHoRe can process the Ensembl data set, containing 49 species, in 1 h. Furthermore, the profile search is more sensitive to detect degenerate genomic homology than chaining pairwise collinearity information based on transitive homology. From ultra-conserved collinear regions between mammals and birds, by integrating coexpression information and protein protein interactions, we identified more than 400 regions in the human genome showing significant functional coherence. The different algorithmical improvements ensure that i-ADHoRe 3.0 will remain a powerful tool to study genome evolution. PMID- 22102585 TI - GenomeView: a next-generation genome browser. AB - Due to ongoing advances in sequencing technologies, billions of nucleotide sequences are now produced on a daily basis. A major challenge is to visualize these data for further downstream analysis. To this end, we present GenomeView, a stand-alone genome browser specifically designed to visualize and manipulate a multitude of genomics data. GenomeView enables users to dynamically browse high volumes of aligned short-read data, with dynamic navigation and semantic zooming, from the whole genome level to the single nucleotide. At the same time, the tool enables visualization of whole genome alignments of dozens of genomes relative to a reference sequence. GenomeView is unique in its capability to interactively handle huge data sets consisting of tens of aligned genomes, thousands of annotation features and millions of mapped short reads both as viewer and editor. GenomeView is freely available as an open source software package. PMID- 22102587 TI - SABIO-RK--database for biochemical reaction kinetics. AB - SABIO-RK (http://sabio.h-its.org/) is a web-accessible database storing comprehensive information about biochemical reactions and their kinetic properties. SABIO-RK offers standardized data manually extracted from the literature and data directly submitted from lab experiments. The database content includes kinetic parameters in relation to biochemical reactions and their biological sources with no restriction on any particular set of organisms. Additionally, kinetic rate laws and corresponding equations as well as experimental conditions are represented. All the data are manually curated and annotated by biological experts, supported by automated consistency checks. SABIO RK can be accessed via web-based user interfaces or automatically via web services that allow direct data access by other tools. Both interfaces support the export of the data together with its annotations in SBML (Systems Biology Markup Language), e.g. for import in modelling tools. PMID- 22102586 TI - Enhanced analysis of real-time PCR data by using a variable efficiency model: FPK PCR. AB - Current methodology in real-time Polymerase chain reaction (PCR) analysis performs well provided PCR efficiency remains constant over reactions. Yet, small changes in efficiency can lead to large quantification errors. Particularly in biological samples, the possible presence of inhibitors forms a challenge. We present a new approach to single reaction efficiency calculation, called Full Process Kinetics-PCR (FPK-PCR). It combines a kinetically more realistic model with flexible adaptation to the full range of data. By reconstructing the entire chain of cycle efficiencies, rather than restricting the focus on a 'window of application', one extracts additional information and loses a level of arbitrariness. The maximal efficiency estimates returned by the model are comparable in accuracy and precision to both the golden standard of serial dilution and other single reaction efficiency methods. The cycle-to-cycle changes in efficiency, as described by the FPK-PCR procedure, stay considerably closer to the data than those from other S-shaped models. The assessment of individual cycle efficiencies returns more information than other single efficiency methods. It allows in-depth interpretation of real-time PCR data and reconstruction of the fluorescence data, providing quality control. Finally, by implementing a global efficiency model, reproducibility is improved as the selection of a window of application is avoided. PMID- 22102588 TI - Regulation of 6S RNA by pRNA synthesis is required for efficient recovery from stationary phase in E. coli and B. subtilis. AB - 6S RNAs function through interaction with housekeeping forms of RNA polymerase holoenzyme (Esigma(70) in Escherichia coli, Esigma(A) in Bacillus subtilis). Escherichia coli 6S RNA accumulates to high levels during stationary phase, and has been shown to be released from Esigma(70) during exit from stationary phase by a process in which 6S RNA serves as a template for Esigma(70) to generate product RNAs (pRNAs). Here, we demonstrate that not only does pRNA synthesis occur, but it is an important mechanism for regulation of 6S RNA function that is required for cells to exit stationary phase efficiently in both E. coli and B. subtilis. Bacillus subtilis has two 6S RNAs, 6S-1 and 6S-2. Intriguingly, 6S-2 RNA does not direct pRNA synthesis under physiological conditions and its non release from Esigma(A) prevents efficient outgrowth in cells lacking 6S-1 RNA. The behavioral differences in the two B. subtilis RNAs clearly demonstrate that they act independently, revealing a higher than anticipated diversity in 6S RNA function globally. Overexpression of a pRNA-synthesis-defective 6S RNA in E. coli leads to decreased cell viability, suggesting pRNA synthesis-mediated regulation of 6S RNA function is important at other times of growth as well. PMID- 22102589 TI - UniPathway: a resource for the exploration and annotation of metabolic pathways. AB - UniPathway (http://www.unipathway.org) is a fully manually curated resource for the representation and annotation of metabolic pathways. UniPathway provides explicit representations of enzyme-catalyzed and spontaneous chemical reactions, as well as a hierarchical representation of metabolic pathways. This hierarchy uses linear subpathways as the basic building block for the assembly of larger and more complex pathways, including species-specific pathway variants. All of the pathway data in UniPathway has been extensively cross-linked to existing pathway resources such as KEGG and MetaCyc, as well as sequence resources such as the UniProt KnowledgeBase (UniProtKB), for which UniPathway provides a controlled vocabulary for pathway annotation. We introduce here the basic concepts underlying the UniPathway resource, with the aim of allowing users to fully exploit the information provided by UniPathway. PMID- 22102591 TI - IBIS (Inferred Biomolecular Interaction Server) reports, predicts and integrates multiple types of conserved interactions for proteins. AB - We have recently developed the Inferred Biomolecular Interaction Server (IBIS) and database, which reports, predicts and integrates different types of interaction partners and locations of binding sites in proteins based on the analysis of homologous structural complexes. Here, we highlight several new IBIS features and options. The server's webpage is now redesigned to allow users easier access to data for different interaction types. An entry page is added to give a quick summary of available results and to now accept protein sequence accessions. To elucidate the formation of protein complexes, not just binary interactions, IBIS currently presents an expandable interaction network. Previously, IBIS provided annotations for four different types of binding partners: proteins, small molecules, nucleic acids and peptides; in the current version a new protein-ion interaction type has been added. Several options provide easy downloads of IBIS data for all Protein Data Bank (PDB) protein chains and the results for each query. In this study, we show that about one third of all RefSeq sequences can be annotated with IBIS interaction partners and binding sites. The IBIS server is available at http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.cgi and updated biweekly. PMID- 22102590 TI - Reorganizing the protein space at the Universal Protein Resource (UniProt). AB - The mission of UniProt is to support biological research by providing a freely accessible, stable, comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase, with extensive cross-references and querying interfaces. UniProt is comprised of four major components, each optimized for different uses: the UniProt Archive, the UniProt Knowledgebase, the UniProt Reference Clusters and the UniProt Metagenomic and Environmental Sequence Database. A key development at UniProt is the provision of complete, reference and representative proteomes. UniProt is updated and distributed every 4 weeks and can be accessed online for searches or download at http://www.uniprot.org. PMID- 22102592 TI - The Human OligoGenome Resource: a database of oligonucleotide capture probes for resequencing target regions across the human genome. AB - Recent exponential growth in the throughput of next-generation DNA sequencing platforms has dramatically spurred the use of accessible and scalable targeted resequencing approaches. This includes candidate region diagnostic resequencing and novel variant validation from whole genome or exome sequencing analysis. We have previously demonstrated that selective genomic circularization is a robust in-solution approach for capturing and resequencing thousands of target human genome loci such as exons and regulatory sequences. To facilitate the design and production of customized capture assays for any given region in the human genome, we developed the Human OligoGenome Resource (http://oligogenome.stanford.edu/). This online database contains over 21 million capture oligonucleotide sequences. It enables one to create customized and highly multiplexed resequencing assays of target regions across the human genome and is not restricted to coding regions. In total, this resource provides 92.1% in silico coverage of the human genome. The online server allows researchers to download a complete repository of oligonucleotide probes and design customized capture assays to target multiple regions throughout the human genome. The website has query tools for selecting and evaluating capture oligonucleotides from specified genomic regions. PMID- 22102593 TI - Cleavage mediated by the P15 domain of bacterial RNase P RNA. AB - Independently folded domains in RNAs frequently adopt identical tertiary structures regardless of whether they are in isolation or are part of larger RNA molecules. This is exemplified by the P15 domain in the RNA subunit (RPR) of the universally conserved endoribonuclease P, which is involved in the processing of tRNA precursors. One of its domains, encompassing the P15 loop, binds to the 3' end of tRNA precursors resulting in the formation of the RCCA-RNase P RNA interaction (interacting residues underlined) in the bacterial RPR-substrate complex. The function of this interaction was hypothesized to anchor the substrate, expose the cleavage site and result in re-coordination of Mg(2+) at the cleavage site. Here we show that small model-RNA molecules (~30 nt) carrying the P15-loop mediated cleavage at the canonical RNase P cleavage site with significantly reduced rates compared to cleavage with full-size RPR. These data provide further experimental evidence for our model that the P15 domain contributes to both substrate binding and catalysis. Our data raises intriguing evolutionary possibilities for 'RNA-mediated' cleavage of RNA. PMID- 22102594 TI - The development of a comprehensive needs assessment tool for cancer-caregivers in patient-caregiver dyads. AB - OBJECTIVE: The assessment of a caregiver's needs is a critical step for determining appropriate support services, providing high quality care, and achieving caregiver satisfaction. However, a systematic assessment of family caregiver's needs is rarely practiced. This study reports the development and validation of a comprehensive needs assessment tool for cancer caregivers (CNAT C). METHODS: Items of CNAT-C were generated through literature review and refined through expert consultation and caregiver interview, and pilot test. Final 41 item needs assessment tool for cancer was developed and validated in a large scale multi-center survey involving 600 cancer patients-family caregiver dyads in 10 cancer centers fairly distributed throughout Korea. RESULTS: The content validity of CNAT-C was established throughout the development process. Principal component analysis resulted in a seven-factor structure explaining 66.4% of the total variance: (1) health and psychological problems (6 items), (2) family/social support (5 items), (3) health-care staff (8 items), (4) information (8 items), (5) religious/spiritual support (2 items), (6) hospital facilities and services (6 items), and (7) practical support (6 items). The Cronbach alpha was 0.96 for the total scale, and those for the subscales ranged from 0.79 to 0.95. Caregiver needs were not highly correlated with patient needs when compared domain-by-domain. Known-group validity was also supported by the tool's ability to detect significant differences according to various patient and caregiver characteristics. CONCLUSIONS: The CNAT-C appears to be a valid and reliable measure to assess comprehensive and multidimensional needs in caregivers of cancer patients. PMID- 22102595 TI - Graphene as a nanocarrier for tamoxifen induces apoptosis in transformed cancer cell lines of different origins. AB - A cationic amphiphile, cholest-5en-3beta-oxyethyl pyridinium bromide (PY(+) Chol), is able to efficiently disperse exfoliated graphene (GR) in water by the physical adsorption of PY(+) -Chol on the surface of GR to form stable, dark aqueous suspensions at room temperature. The GR-PY(+) -Chol suspension can then be used to solubilize Tamoxifen Citrate (TmC), a breast cancer drug, in water. The resulting TmC-GR-PY(+) -Chol is stable for a long time without any precipitation. Fluorescence emission and UV absorption spectra indicate the existence of noncovalent interactions between TmC, GR, and PY(+) -Chol in these suspensions. Electron microscopy shows the existence of segregated GR sheets and TmC 'ribbons' in the composite suspensions. Atomic force microscopy indicates the presence of 'extended' structures of GR-PY(+) -Chol, which grows wider in the presence of TmC. The slow time-dependent release of TmC is noticed in a reconstituted cell culture medium, a property useful as a drug carrier. TmC-GR PY(+) -Chol selectively enhanced the cell death (apoptosis) of the transformed cancer cells compared to normal cells. This potency is found to be true for a wide range of transformed cancer cells viz. HeLa, A549, ras oncogene-transformed NIH3T3, HepG2, MDA-MB231, MCF-7, and HEK293T compared to the normal cell HEK293 in vitro. Confocal microscopy confirmed the high efficiency of TmC-GR-PY(+) -Chol in delivering the drug to the cells, compared to the suspensions devoid of GR. PMID- 22102596 TI - Plenty of smoke--why no fire? PMID- 22102597 TI - Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. AB - The rationale of this article is enhancing the therapeutic potential of stem cells in ischemic microenvironments by novel preconditioning strategies is critical for improving cellular therapy. We tested the hypothesis that inhibition of phosphodiesterase-5 (PDE-5) with sildenafil (Viagra) or knockdown with a silencing vector in adipose-derived stem cells (ASCs) would improve their survival and enhance cardiac function following myocardial implantation in vivo. ASCs were treated with sildenafil or PDE-5 silencing vector short hairpin RNA (shRNA(PDE-5)) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNA(PDE-5) significantly improved viability, decreased necrosis, apoptosis, and enhanced the release of growth factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor. Inhibition of protein kinase G reversed these effects. To show the beneficial effect of preconditioned ASCs in vivo, adult male CD-1 mice underwent myocardial infarction. Preconditioned ASCs (4 * 10(5)) were directly injected intramyocardially. Preconditioned ASC-treated hearts showed consistently superior cardiac function when compared with nonpreconditioned ASCs after 4 weeks of treatment. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis when compared with mice receiving nonpreconditioned ASCs. VEGF, b-FGF, and Angiopoietin-1 were also significantly elevated 4 weeks after cell therapy with preconditioned ASCs. We conclude that preconditioning by inhibition of PDE-5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction. PMID- 22102598 TI - End-tidal carbon dioxide monitoring in very low birth weight infants: correlation and agreement with arterial carbon dioxide. AB - OBJECTIVE: We aimed to determine the correlation and the agreement between end tidal carbon dioxide (ETCO(2)) and partial pressure of arterial carbon dioxide (PaCO(2) ) in very low birth weight infants (VLBWI); furthermore, we assessed factors that could affect the ETCO(2)-PaCO(2) relationship. METHODS: Simultaneous end-tidal and arterial CO(2) pairs were obtained from ventilated VLBWI who were monitored by mainstream capnography and had umbilical arterial catheter. Correlation and agreement between ETCO(2) and PaCO(2) were evaluated by using Spearman test and Bland-Altman method, respectively. RESULTS: A total of 143 simultaneous ETCO(2)-PaCO(2) pairs were analyzed from 45 ventilated VLBWI. There was a significant correlation (r = 0.69; P < 0.0001) between ETCO(2) and PaCO(2) values. The ETCO(2) value was lower than the corresponding PaCO(2) value in 94% pairs, with a mean bias of 13.5 +/- 8.4 mmHg (95% agreement levels, -3.0 to 29.9 mmHg). Mean PaCO(2)-ETCO(2) bias was similar between ELBWI (13.1 +/- 7.7 mmHg; 95% agreement levels, -1.9 and 28.2 mmHg) and infants with birth weight 1,001 1,500 g (14.8 +/- 9.7 mmHg; 95% agreement levels -4.3 and 33.8 mmHg). The bias between ETCO(2) and PaCO(2) was significantly increased with increasing FiO(2), mean airway pressure and oxygenation index. Within each patient, there was a positive correlation (r = 0.78, P < 0.0001) between the changes in PaCO(2) and the simultaneous changes in ETCO(2). CONCLUSIONS: In ventilated VLBWI, the correlation between mainstream ETCO(2) and PaCO(2) is good, but the agreement is poor and negatively influenced by the severity of pulmonary disease. Capnography is feasible in ELBWI. ETCO(2) should not replace PaCO(2) measurements in ventilated VLBWI, but may have a role to detect trends of PaCO(2). PMID- 22102599 TI - Synthesis and characterization of silver/silicon-cosubstituted nanohydroxyapatite. AB - Favorable cell-material interaction and the absence of undesirable reaction from the host body defence system play a critical role in determining the success and long-term survival of the implants. Substitution of various elements into hydroxyapatite (HA) has been done to alter its chemical composition, thereby mimicking that of the bone mineral. In this study, a cosubstituted nanosized apatite (Ag/Si-HA) containing Ag (0.3 wt %) and Si (0.8 wt %) was synthesized by an aqueous precipitation technique. The synthesized Ag/Si-HA displayed a rod-like morphology of dimensions ~50 nm in length and ~15 nm in width, as observed from the transmission electron microscope image. With an increase in temperature, the aspect ratio of nanosized Ag/Si-HA decreased, whilst the size increased. Autoclaving was used to achieve sufficient crystallinity while maintaining the rod-like morphology and size that were comparable to that of the bone apatite. A pure Ag/Si-HA was produced without any undesirable secondary phases, as evidenced from the X-ray diffraction and thermal gravimetric results. The Ag/Si cosubstitution affected the lattice cell parameters, in particularly the a- and c axes which further led to an expansion of the unit cell volume. In addition, the relative intensity of the hydroxyl vibrational bands was reduced. These results demonstrated that a stable phase-pure Ag/Si-HA was produced using an aqueous precipitation reaction. PMID- 22102600 TI - Differential contribution of Neurog1 and Neurog2 on the formation of cranial ganglia along the anterior-posterior axis. AB - BACKGROUND: The neural crest (NC) and placode are transient neurogenic cell populations that give rise to cranial ganglia of the vertebrate head. The formation of the anterior NC- and placode-derived ganglia has been shown to depend on the single activity of either Neurog1 or Neurog2. The requirement of the more posterior cranial ganglia on Neurog1 and Neurog2 is unknown. RESULTS: Here we show that the formation of the NC-derived parasympathetic otic ganglia and placode-derived visceral sensory petrosal and nodose ganglia are dependent on the redundant activities of Neurog1 and Neurog2. Tamoxifen-inducible Cre lineage labeling of Neurog1 and Neurog2 show a dynamic spatiotemporal expression profile in both NC and epibranchial placode that correlates with the phenotypes of the Neurog-mutant embryos. CONCLUSION: Our data, together with previous studies, suggest that the formation of cranial ganglia along the anterior-posterior axis is dependent on the dynamic spatiotemporal activities of Neurog1 and/or Neurog2 in both NC and epibranchial placode. PMID- 22102601 TI - Problem posing and cultural tailoring: developing an HIV/AIDS health literacy toolkit with the African American community. AB - The rate of HIV infection among African Americans is disproportionately higher than for other racial groups in the United States. Previous research suggests that low level of health literacy (HL) is an underlying factor to explain racial disparities in the prevalence and incidence of HIV/AIDS. The present research describes a community and university project to develop a culturally tailored HIV/AIDS HL toolkit in the African American community. Paulo Freire's pedagogical philosophy and problem-posing methodology served as the guiding framework throughout the development process. Developing the HIV/AIDS HL toolkit occurred in a two-stage process. In Stage 1, a nonprofit organization and research team established a collaborative partnership to develop a culturally tailored HIV/AIDS HL toolkit. In Stage 2, African American community members participated in focus groups conducted as Freirian cultural circles to further refine the HIV/AIDS HL toolkit. In both stages, problem posing engaged participants' knowledge, experiences, and concerns to evaluate a working draft toolkit. The discussion and implications highlight how Freire's pedagogical philosophy and methodology enhances the development of culturally tailored health information. PMID- 22102602 TI - Community perspectives on barriers and strategies for promoting locally grown produce from an urban agriculture farm. AB - Although much is understood about barriers to healthy food consumption in low income, urban communities, knowledge regarding the crucial next step of building feasible, community-supported approaches to address those barriers remains limited. This qualitative study used in-depth interviews (n = 20), focus groups (n = 2), and participant observations (n = 3) to identify strategies to promote locally grown produce from an urban food security project, Produce From the Park (PFP), an urban farm. Informants included community organization representatives and residents from low-income neighborhoods in a mid-Atlantic city. Informants identified structural and cultural barriers to purchasing healthy food, including price, location, food culture, and lack of interest. Participants proposed a number of strategies, such as distribution through mobile food carts and farm stands, marketing new foods through taste tests and cooking demonstrations, and youth mentorship. Informants also described their perceptions of the local urban farm and suggested ways to increase community buy-in. Strategies mentioned were inexpensive and incorporated cultural norms and local assets. These community perspectives can provide insights for those promoting healthy eating in urban African American communities through urban food security projects. PMID- 22102603 TI - The examination of process evaluation use in church-based health interventions: a systematic review. AB - Churches have been a popular site for the implementation of health promotion interventions. Although the efficacy of church-based health programs have been established, it is unknown which aspects of church-based health promotion drive health behavior change. Process evaluation is a way to increase our understanding of key components of church-based health promotion and to move the field forward. Thus, a systematic review of the utilization of process evaluation in church based health programs was conducted. Articles from 1990 to 2008 were screened for eligibility, resulting in the analysis of 67 articles. The majority of church based health programs assessed recruitment (88.1%) and reach (80.6%). About 28.4% assessed dose delivered, and 27.3% measured dose received. Context and fidelity was assessed by 34.3% and 20.9%, respectively, of church-based interventions. Approximately 9% of church-based programs measured fidelity. On average, only three of seven possible components of process evaluation were measured among the studies reviewed. The number of process evaluation components assessed did not differ by program feature (e.g., target population, target health condition, program objective, etc.). Consistency in the conceptualization and measurement of process evaluation may facilitate the implementation of a comprehensive process evaluation effort in church-based and other health promotion interventions. PMID- 22102604 TI - Photovoice in the Red River Basin of the north: a systematic evaluation of a community-academic partnership. AB - A community-academic partnership was formed in Minnesota's Red River Basin for a 1-year planning grant preceding a larger intervention to reduce pesticide exposure among children. Photovoice, developed by Dr. Caroline Wang, was used by mothers to document pathways to pesticide exposure for their children along with other health and safety concerns. An evaluation of the partnership was conducted for mothers, and for the research team of local stakeholders and academics. Surveys consisting of structured and open-ended questions elicited information on the perception of the process and short-term outcomes. Questions were created based on objectives of the Photovoice project, satisfaction, and principles of community-based participatory research (CBPR). A high percentage of study participants and researchers indicated that the objectives of the effort had been met, the principles of CBPR had been realized and they were satisfied with the benefits of participation. A need for more thorough planning was identified related to long-term dissemination of knowledge generated. The evaluation provides insight on the strengths and weaknesses of the project, demonstrates to team members and funders that formative and summative outcomes were met, and serves as a model for community-academic partnerships utilizing Photovoice as one CBPR method. PMID- 22102605 TI - NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells. AB - Stem cells are maintained by both stem cell-extrinsic niche signals and stem cell intrinsic factors. During murine spermatogenesis, glial cell line-derived neurotrophic factor (GDNF) signal emanated from Sertoli cells and germ cell intrinsic factor NANOS2 represent key regulators for the maintenance of spermatogonial stem cells. However, it remains unclear how these factors intersect in stem cells to control their cellular state. Here, we show that GDNF signaling is essential to maintain NANOS2 expression, and overexpression of Nanos2 can alleviate the stem cell loss phenotype caused by the depletion of Gfra1, a receptor for GDNF. By using an inducible Cre-loxP system, we show that NANOS2 expression is downregulated upon the conditional knockout (cKO) of Gfra1, while ectopic expression of Nanos2 in GFRA1-negative spermatogonia does not induce de novo GFRA1 expression. Furthermore, overexpression of Nanos2 in the Gfra1-cKO testes prevents precocious differentiation of the Gfra1-knockout stem cells and partially rescues the stem cell loss phenotypes of Gfra1-deficient mice, indicating that the stem cell differentiation can be suppressed by NANOS2 even in the absence of GDNF signaling. Taken together, we suggest that NANOS2 acts downstream of GDNF signaling to maintain undifferentiated state of spermatogonial stem cells. PMID- 22102606 TI - Reference values of nocturnal oxygenation for use in outpatient oxygen weaning protocols in premature infants. AB - OBJECTIVE: To define reference ranges for oxygen saturation (SpO(2) ) values in healthy full-term infants in the first days of life and in preterm infants off supplemental oxygen as they approach neonatal intensive care unit (NICU) discharge. METHODS: From April 2009 to March 2010, we enrolled convenience samples of full-term infants from the newborn nursery and former preterm infants who did not require supplemental oxygen at the time of discharge from the NICU. Overnight SpO(2) and signal quality recordings were obtained and analyzed for duration of artifact-free recording time (AFRT), time (s) with SpO(2) less than several different target saturations (90-95%), and number of falls in SpO(2) by >=4% and >=10%. RESULTS: We studied 102 full-term infants and 52 preterm infants. Preterm and full-term infants spent similar amounts of time less than 90%, 91%, 92%, 93%, 94%, and 95% although preterm infants had more falls in SpO(2) by >=4% per hour of AFRT. Over 67% of term and preterm infants spent less than 6% of their time below 93%. CONCLUSION: These data represent reference SpO(2) ranges for both preterm infants not requiring supplemental oxygen at NICU discharge and full-term infants in the first days of life. As we currently lack guidelines dictating the optimal target oxygen saturations for infants and the acceptable maximal time that they can safely spend below set target saturations, our data may serve as a guide to interpreting SpO(2) recordings of premature outpatient infants who are weaning from supplemental oxygen. PMID- 22102607 TI - Antifungal prophylaxis in pediatric hematology/oncology: new choices & new data. AB - A severe complication of the treatment of pediatric cancers is the development of an invasive fungal infection (IFI). The data to support antifungal prophylaxis in pediatric oncology patients derive primarily from adult patients, and thus the optimal agent to utilize is not clear. Fluconazole has been a standard option, but agents with antimold activity are now available, each with limitations. Pediatric dosing for voriconazole and posaconazole is uncertain and multiple drug interactions exist. The echinocandins are well-tolerated, but only available in intravenous form. Ultimately, studies demonstrating biologic risk factors for the development of IFI may lead to personalized prophylactic strategies. PMID- 22102608 TI - Fibrous membrane of nano-hybrid poly-L-lactic acid/silica xerogel for guided bone regeneration. AB - Nanofibrous membranes, consisting of a poly(L-lactic acid) (PLLA)-silica xerogel hybrid material, were successfully fabricated from a hybrid sol using the electrospinning technique for guided bone regeneration (GBR) application. These hybrid nanofibers exhibited a homogeneous and continuous morphology, with a nano sized dispersed silica xerogel phase in the PLLA fiber matrix. The mechanical properties, such as the tensile strength and the elastic modulus, were improved as the silica xerogel content increased up to 40%. All of the hybrid membranes exhibited highly hydrophilic surfaces and good proliferation levels. After culturing for 13 days, the cells that were cultured on the hybrid membranes exhibited a significantly higher ALP activity compared to the pure PLLA membrane. Moreover, the in vivo animal experiments that used the rat calvarial defect model revealed a remarkably improved bone regeneration ability for the hybrid membrane compared to pure PLLA. These results demonstrated the feasibility of these hybrid membranes for efficient GBR. PMID- 22102609 TI - Increased beta-catenin activity in the anterior neural plate induces ectopic mid hindbrain characteristics. AB - BACKGROUND: The early telencephalon shares molecular features with the early mid hindbrain region. In particular, these two developing brain areas each have a signaling center that secretes FGFs and an adjacent one that secretes WNTs. WNTs and FGFs each play essential roles in regulating cell fates in both the telencephalon and mid-hindbrain. Despite this similarity, telencephalic and mid hindbrain precursors express distinct genes and ultimately generate different cell types, tissue morphologies, and neural functions. RESULTS: Here we show that genetically increasing the level of beta-catenin, a mediator of canonical WNT signaling, in the anterior neural plate causes a loss of telencephalic characteristics and a gain of mid-hindbrain characteristics. CONCLUSION: These results, together with previous ones demonstrating that increased WNT signaling in the anterior neural plate increases FGF expression, suggest that the levels of WNT and FGF signaling regulate telencephalic versus mid-hindbrain fates. PMID- 22102610 TI - Stereoselective separation and determination of triadimefon and triadimenol in wheat, straw, and soil by liquid chromatography-tandem mass spectrometry. AB - A sensitive and rapid analytical method was developed for simultaneous determination of triadimefon (TF) and triadimenol (TN) stereoisomers in wheat, straw, and soil by liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS). The direct enantioseparation of TF and TN was performed on a Lux cellulose-1 column packed with cellulose-tris-(3,5 dimethylphenylcarbamate). The effects of mobile-phase composition on the separation were investigated and stereoisomeric elution orders were confirmed with a polarimeter detector. The pesticides were extracted from samples with acetonitrile and cleaned up by solid-phase extraction or activated carbon. Based on the developed stereoselective LC-MS/MS method, for TF and TN stereoisomers, good linearities were obtained over the concentration range of 0.003-4 mg/L; recoveries were 84.2-102.7% in wheat, 84.0-104.0% in straw, and 85.2-106.8% in soil at spiked concentrations of 0.007-2.0 mg/kg; intra-day and inter-day assay precisions were below 12.2%. Limits of detection (LODs) and limits of quantification (LOQs) in wheat, straw, and soil were 0.001-0.005 mg/kg and 0.007 0.02 mg/kg, respectively. Finally, the method was successfully applied to detect TF and TN stereoisomers in wheat, straw, and soil samples from residual trials in farm. PMID- 22102611 TI - Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties. AB - It has been proposed that epithelial-mesenchymal transition (EMT) in mammary epithelial cells and breast cancer cells generates stem cell features, and that the presence of EMT characteristics in claudin-low breast tumors reveals their origin in basal stem cells. It remains to be determined, however, whether EMT is an inherent property of normal basal stem cells, and if the presence of a mesenchymal-like phenotype is required for the maintenance of all their stem cell properties. We used nontumorigenic basal cell lines as models of normal stem cells/progenitors and demonstrate that these cell lines contain an epithelial subpopulation ("EpCAM+," epithelial cell adhesion molecule positive [EpCAM(pos)]/CD49f(high)) that spontaneously generates mesenchymal-like cells ("Fibros," EpCAM(neg)/CD49f(med/low)) through EMT. Importantly, stem cell/progenitor properties such as regenerative potential, high aldehyde dehydrogenase 1 activity, and formation of three-dimensional acini-like structures predominantly reside within EpCAM+ cells, while Fibros exhibit invasive behavior and mammosphere-forming ability. A gene expression profiling meta-analysis established that EpCAM+ cells show a luminal progenitor-like expression pattern, while Fibros most closely resemble stromal fibroblasts but not stem cells. Moreover, Fibros exhibit partial myoepithelial traits and strong similarities with claudin-low breast cancer cells. Finally, we demonstrate that Slug and Zeb1 EMT-inducers control the progenitor and mesenchymal-like phenotype in EpCAM+ cells and Fibros, respectively, by inhibiting luminal differentiation. In conclusion, nontumorigenic basal cell lines have intrinsic capacity for EMT, but a mesenchymal-like phenotype does not correlate with the acquisition of global stem cell/progenitor features. Based on our findings, we propose that EMT in normal basal cells and claudin-low breast cancers reflects aberrant/incomplete myoepithelial differentiation. PMID- 22102612 TI - Prevention of bacterial infection in pediatric oncology: what do we know, what can we learn? AB - Bacterial sepsis continues to be a leading cause of morbidity and toxic death in children receiving intensive therapy for cancer. Empiric therapy for suspected infections and treatment of documented infections are well-established standards of care. The routine use of prophylactic strategies is much less common in pediatric oncology. This paper will review the current literature on the use and risks of antimicrobial prophylaxis as well as non-pharmacological methods for infection prevention and will address areas in need of further research. PMID- 22102613 TI - Biological functionalization of dental implants with collagen and glycosaminoglycans-A comparative study. AB - Biological implant surface coatings are an emerging technology to increase bone formation. Such an approach is of special interest in anatomical regions like the maxilla. In the present study, we hypothesized that the coating of titanium implants with components of the organic extracellular matrix increases bone formation and implant stability compared to an uncoated reference. The implants were coated using collagen-I with either two different concentrations of chondroitin sulfate (CS) or two differentially sulfated hyaluronans. Implant coatings were characterized biochemically and with atomic force microscopy. Histomorphometry was used to assess bone-implant contact (BIC) and bone-volume density (BVD) after 4 and 8 weeks of submerged healing in the maxilla of 20 minipigs. Further, implant stability was measured by resonance frequency analysis (RFA). Implants containing the lower CS concentration had significantly more BIC, compared to the uncoated reference at both times of interest. No significant increase was measured from week 4 to 8. Differences in BVD and RFA were statistically not significant. A higher concentration of CS and the application of sulfated hyaluronans showed no comparable increase in BIC. This study demonstrates a positive effect of a specific collagen-glycosaminoglycan combination on early bone formation in vivo. PMID- 22102614 TI - A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. AB - Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS. PMID- 22102615 TI - The evolution of renal function and the incidence of end-stage renal disease in patients aged >= 50 years. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) is high, especially among older patients. METHODS: In order to identify risk factors for the evolution towards end-stage renal disease (ESRD), a cohort of patients >= 50 years of age for whom at least four serum creatinine measurements were available were selected from a primary care-based database. The slope of changes in estimated glomerular filtration rate (eGFR) (using the Modification of Diet in Renal Disease formula) was calculated, and ESRD was defined as eGFR <15 mL/min. Risk factors for ESRD were analysed using Cox regression analysis. RESULTS: The cohort included 24,682 patients (13,305 women) with a mean age at first available measurement of 64 years. During follow-up (average 7.8 years), 212 patients (0.9%) developed ESRD. The incidence of ESRD per 10,000 person-years is low and depends on baseline eGFR (Stages 0-2: 3, Stage 3A: 13, Stage 3B: 121 and Stage 4: 765). Adjusted hazard ratios (HRs) for patients with baseline eGFR in Stage 3B or 4 depended on age (HR = 0.47 or 0.41 for patients 65-79 years and HR = 0.26 or 0.32 for patients >= 80 years compared with patients aged 50-64 years). Females (HR = 1.48) and patients with diabetes (HR = 1.20), hypertension (HR = 1.25), high total cholesterol (HR = 1.28) or high low-density lipoprotein (LDL) cholesterol (HR = 1.39) were at higher risk for ESRD. CONCLUSIONS: Baseline eGFR, diabetes, high cholesterol, high LDL, hypertension and female gender are independent risk factors for developing ESRD. Older age at baseline predicts a lower risk. PMID- 22102616 TI - Fibrosis, regeneration and cancer: what is the link? AB - Tubulo-interstitial fibrosis constitutes the final common pathway for all pathological conditions that evolve towards chronic kidney disease, and transforming growth factor-beta1 plays a key role in this process. Furthermore, neutrophil gelatinase-associated lipocalin appears not only to be a simple marker of renal injury but also an active player in disease progression. We are not yet able to control and modulate this phenomenon. Therefore, a better understanding of fibrogenic molecular mechanisms is necessary to detect possible therapeutic strategies that interfere with fibrosis and then stop the progression of renal disease. The line of research called 'regenerative medicine' works toward this. According to many authors, the formation of a fibrotic extracellular matrix disrupts the cells' polarity and stimulates their proliferation, creating conditions for cancer development. However, there is another plausible hypothesis: is it possible that fibrosis provides a sort of 'protection' from the development of a cancer as a consequence of the intense proliferation that characterizes any inflammatory process? In superior organisms, and also in humans, regeneration may have been selected negatively and replaced by fibrosis in the course of evolution, to warrant species survival: in fact, unchecked pluripotent cell production and proliferation can lead to tumour development and the potential death of a single individual. Hence, tumours might be the outcome of the failure of fibrotic processes, most likely due to some mediators predominating over others. So, valid experimental models are necessary to understand the interactions that exist between fibrosis and tumours and to evaluate the real advantage of therapies that aim to inhibit the fibrotic process at the renal level or that of other organs. The ideal approach would be to limit fibrosis and then organ function loss but without exposing the patient to risks of developing a tumour, starting from as early as the drugs prescribed. PMID- 22102617 TI - Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease. AB - BACKGROUND: Fractures are common in individuals with chronic kidney disease (CKD), and tests of neuromuscular function (NMT) discriminate well among fractured and non-fractured patients with Stage 5 CKD on dialysis. The ability of NMT to discriminate fracture status in patients with Stages 3-5 CKD is unknown. METHODS: In this cross-sectional study, we sought to determine in adult patients with Stages 3-5 CKD (eGFR by the Modification of Diet in Renal Disease equation) if NMT [timed up and go (TUG), 6-min walk (6MW) and grip strength] could discriminate fracture status (self-reported low-trauma fractures since age 40 and/or vertebral fractures by morphometry). We conducted logistic regression and receiver-operating characteristic (ROC) curves for each predictor [expressed as area under the ROC curves (AUROC) with 95% confidence intervals (CI)]. RESULTS: Data was available for 125 men and 86 women. The mean age was 63.3 +/- 15.5 years, duration of CKD was 96.7 +/- 125.3 months and one-third had diabetes. Patients with fractures were older and fell more frequently (P < 0.05). After adjusting for age, weight and sex, for every standard deviation increase in TUG and 6MW, the risk of fracture increased [odds ratio (OR): 1.68; 95% CI: 1.40 2.02] and decreased (OR: 0.53; 95% CI: 0.52-0.54), respectively. Both the TUG and 6MW could discriminate among those with and without fractures (AUROC: 0.90; 95% CI:0.84-0.95, AUROC: 0.87; 95% CI: 0.80-0.94, respectively). CONCLUSIONS: The TUG and 6MW are able to discriminate fracture status in patients with Stages 3-5 CKD. These tests do not require specialized expertise/equipment and are an inexpensive method to assess for the presence of fractures. PMID- 22102618 TI - Combination of solid-phase extraction-hollow fiber for ultra-preconcentration of some triazole pesticides followed by gas chromatography-flame ionization detection. AB - In this study, an extraction and preconcentration technique using solid-phase extraction (SPE) along with hollow fiber (HF) has been developed as an ultra preconcentration technique for some triazole pesticides in aqueous samples. Triazole pesticides were employed as model compounds to assess the method and were monitored by gas chromatography-flame ionization detection (GC-FID). Initially, an aqueous solution of target analytes was passed through an RP-8 SPE cartridge and then the adsorbed analytes were eluted with MUL amounts of toluene. The collected elute was slowly introduced into an HF that had one end blocked. This allowed precipitation inside the lumen and pores of the HF. Finally, the obtained HF was mounted on a home-made solid-phase microextraction syringe and entered into the GC injection port for thermal desorption-GC analysis. The effect of various experimental parameters including injection port temperature, desorption time, state of HF, washing solvent, elution solvent and its volume, sample volume, etc. were investigated for finding the optimum conditions. The calibration graphs were linear in the ranges of 2-1000 ng/mL (penconazole and hexaconazole), 5-1000 ng/mL (tebuconazole), 15-1000 ng/mL (triticonazole) and the detection limits (LODs) ranged from 0.6 to 4.5 ng/mL. The enhancement factors were in the range of 870-950. The relative standard deviations (RSD%) for five repeated experiments (C=250 ng/mL of each pesticide) varied from 4.5 to 8.7%. The relative recoveries obtained for analytes in grape juice samples, spiked with different levels of each pesticide, were in the range of 87-119%. PMID- 22102619 TI - Epidemiology and potential preventative measures for viral infections in children with malignancy and those undergoing hematopoietic cell transplantation. AB - In pediatric patients with malignancy and those receiving hematopoietic stem cell transplants, bacterial and fungal infections have been the focus of fever and neutropenia episodes for decades. However, improved diagnostic capabilities have revealed viral pathogens as a significant cause of morbidity and mortality. Because of limited effective antiviral therapies, prevention of viral infections is paramount. Pre-exposure and post-exposure prophylaxis and antiviral suppressive therapeutic approaches are reviewed. Additionally, infection control practices specific to this patient population are discussed. A comprehensive approach utilizing each of these can be effective at reducing the negative impact of viral infections. PMID- 22102620 TI - Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD. AB - Primary ciliary dyskinesia (PCD) is an inherited disorder causing significant upper and lower respiratory tract morbidity and impaired fertility. Half of PCD patients show abnormal situs. Human disease loci have been identified but a mouse model without additional deleterious defects is elusive. The inversus viscerum mouse, mutated at the outer arm dynein heavy chain 11 locus (Dnahc11) is a known model of heterotaxy. We demonstrated immotile tracheal cilia with normal ultrastructure and reduced sperm motility in the Dnahc11(iv) mouse. This is accompanied by gross rhinitis, sinusitis, and otitis media, all indicators of human PCD. Strikingly, age-related progression of the disease is evident. The Dnahc11(iv) mouse is robust, lacks secondary defects, and requires no intervention to precipitate the phenotype. Together these findings show the Dnahc11(iv) mouse to be an excellent model of many aspects of human PCD. Mutation of the homologous human locus has previously been associated with hyperkinetic tracheal cilia in PCD. Two PCD patients with normal ciliary ultrastructure, one with immotile and one with hyperkinetic cilia were found to carry DNAH11 mutations. Three novel DNAH11 mutations were detected indicating that this gene should be investigated in patients with normal ciliary ultrastructure and static, as well as hyperkinetic cilia. PMID- 22102621 TI - Strontium-loaded mineral bone cements as sustained release systems: Compositions, release properties, and effects on human osteoprogenitor cells. AB - This study aims to evaluate in vitro the release properties and biological behavior of original compositions of strontium (Sr)-loaded bone mineral cements. Strontium was introduced into vaterite CaCO3 -dicalcium phosphate dihydrate cement via two routes: as SrCO3 in the solid phase (SrS cements), and as SrCl2 dissolved in the liquid phase (SrL cements), leading to different cement compositions after setting. Complementary analytical techniques implemented to thoroughly investigate the release/dissolution mechanism of Sr-loaded cements at pH 7.4 and 37 degrees C during 3 weeks revealed a sustained release of Sr and a centripetal dissolution of the more soluble phase (vaterite) limited by a diffusion process. In all cases, the initial burst of the Ca and Sr release (highest for the SrL cements) that occurred over 48 h did not have a significant effect on the expression of bone markers (alkaline phosphatase, osteocalcin), the levels of which remained overexpressed after 15 days of culture with human osteoprogenitor (HOP) cells. At the same time, proliferation of HOP cells was significantly higher on SrS cements. Interestingly, this study shows that we can optimize the sustained release of Sr(2+) , the cement biodegradation and biological activity by controlling the route of introduction of strontium in the cement paste. PMID- 22102622 TI - Determination of phenolic compounds in environmental water samples after solid phase extraction with beta-cyclodextrin-bonded silica particles coupled with a novel liquid-phase microextraction followed by gas chromatography-mass spectrometry. AB - A novel approach for the sample pre-treatment and determination of eight phenolic compounds in environmental water samples has been developed by hyphenating solid phase extraction (SPE) and liquid-phase microextraction (LPME) techniques based on solid organic drop combined with gas chromatography-mass spectrometry detection (GC-MS). After pre-concentration and purification of the sample through column containing 60 mg of beta-cyclodextrin-bonded silica particles as stationary phase, under the optimum conditions, LPME technique has been performed on the eluent solution. Under the selected conditions, limit of detection (LOD) of 0.002-0.04 MUg/L (S/N=3), limit of quantification (LOQ) of 0.007-0.15 MUg/L (S/N=10), pre-concentration factor of 752-3135 and linearity range of 0.01-25 MUg/L have been obtained. A reasonable repeatability (RSD<=9.5%, n=5) with satisfactory coefficient of determination has been obtained between 0.9981 and 0.9997. The relative recoveries of the waste, sea, river and well water samples were higher than 79%. PMID- 22102623 TI - A sustainable model for pediatric oncology nursing education in low-income countries. AB - Effectiveness of a nurse educator in the pediatric oncology unit in Guatemala was assessed by measuring completion of an education course, chemotherapy and central line competency, continuing education, and cost. All newly hired nurses completed the education course. Of the nurses employed, 86% participated in the chemotherapy course, and 93% achieved competency; 57% participated in the central line course, and 79% achieved competency. The nurses completed a mean of 26 hours continuing education yearly. The annual direct cost of the educator ($244/nurse) was markedly less than other models. This is an effective and sustainable means to educate nurses in low-income countries. PMID- 22102624 TI - Power and perceived expressed emotion of voices: their impact on depression and suicidal thinking in those who hear voices. AB - Considerable focus has been given to the interpersonal nature of the voice hearing relationship and how appraisals about voices may be linked with distress and depression (the 'cognitive model'). Research hitherto has focused on appraisals of voice power, but the supportive and affiliative quality of voices, which may act to mitigate distress, is not understood. We explored appraisals of voices' power and emotional support to determine their significance in predicting depression and suicidal thought. We adapted the concept of expressed emotion (EE) and applied it to measure voice hearers' perception of the relationship with their voice(s). In a sample of 74 voice hearers, 55.4% were moderately depressed. Seventy-eight who rated their voices as high in both power and EE had a large and significant elevation in depression, suggesting that co-occurrence of these appraisals impacts on depression. Analysis of the relationship between power and EE revealed that many voices perceived as low in power were, nevertheless, perceived as high in EE. Those rating their voices as emotionally supportive showed the lowest levels of depression and suicidal thinking. These findings highlight the protective role that the supportive dimension of the voice/voice hearer relationship may have. PMID- 22102625 TI - Vasopressin V1 receptor-mediated aldosterone production as a result of selective V2 receptor antagonism: a potential explanation for the failure of tolvaptan to reduce cardiovascular outcomes in the EVEREST trial. PMID- 22102626 TI - Clinical trials update from the European Society of Cardiology Meeting 2011: ARISTOTLE, SMART-AV: QLV substudy, SHIFT: echocardiography and quality of life substudies, European CRT Survey, and Basic Science Update. AB - This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the European Society of Cardiology meeting held in Paris, France in August 2011. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. Results from ARISTOTLE suggest that apixaban is more effective than warfarin for the prevention of stroke in patients with atrial fibrillation. Electrical dyssynchrony, measured by the time from onset of electrical activity on the surface ECG to activation of myocardium by intrinsic conduction at the pacing site (QLV), was a strong and independent predictor of improvement in ventricular function after cardiac resynchronization therapy (CRT) in an observational analysis of a subgroup of patients from the SMART-AV study. Subgroup analyses from SHIFT suggest that heart rate reduction with ivabradine causes favourable left ventricular remodelling and improves quality of life in patients with symptomatic systolic heart failure and an increased heart rate. The European CRT Survey reported outcome data. PMID- 22102627 TI - SU-6656, a selective Src kinase inhibitor, attenuates mecamylamine-precipitated nicotine withdrawal syndrome in mice. AB - INTRODUCTION: Src kinase is reported to regulate neuronal nicotinic acetylcholine receptor activity, which is among the principal receptor systems acted upon by nicotine. Src kinase is documented to mediate the pathogenesis of substance dependence. Therefore, the present study has been designed to investigate the effect of SU-6656, selective src kinase inhibitor, on the development of nicotine dependence in a mouse model of mecamylamine-induced nicotine withdrawal syndrome. METHODS: Our experimental protocol consisted of administration of nicotine (2.5 mg/kg, subcutaneously), 4 times daily for 7 days. In order to precipitate nicotine withdrawal, mice were given 1 injection of mecamylamine (3 mg/kg, intraperitoneally), 1 hr after the last nicotine injection on the test day (Day 8). Behavioral observations were made for a period of 30 min immediately after mecamylamine treatment. Withdrawal syndrome was quantitated in terms of a composite withdrawal severity score (WSS), and withdrawal syndrome-related anxiety was assessed by elevated plus maze test results. RESULTS: SU-6656 markedly and dose dependently (p < .01) attenuated mecamylamine-induced experimental nicotine withdrawal syndrome in mice measured in terms of WSS and anxiety score. CONCLUSIONS: Thus, it is suggested that src kinase is involved in the development of nicotine dependence-induced precipitation of its withdrawal syndrome and thus may serve as a viable pharmacological target to tackle the problem of nicotine addiction. PMID- 22102628 TI - Internet chameleons: an experimental study on imitating smoking peers through digital interaction. AB - INTRODUCTION: Existing experimental studies indicate that young adults are more likely to smoke in the company of real-life smoking peers. However, it is still unclear whether imitation can explain these findings or whether alternatively the mere smell and not the smoking behavior may have been the trigger to smoke. One way to study this issue is by analyzing the exposure to real-life smoking peers without the possibility of smelling the smoker's cigarette, for example, during digital interaction on the Internet. Although many youngsters meet and interact with each other online, research on exposure to smoking peers through the Internet has not yet been investigated. METHODS: This experiment was conducted among 36 daily smoking young people aged 16-24 years. Smoking behavior was observed during a 30-min joint music assignment. During this assignment, the confederate and participant sat in 2 separate rooms and interacted with each other online and via webcam. RESULTS: The findings show that young adults interacting with heavy-smoking peers on the Internet and via webcam smoked significantly more cigarettes than those who interacted with nonsmoking peers. CONCLUSIONS: Young adult smokers strongly imitate smoking in interaction with peers in online communication via webcam, without smelling the smoker's cigarette. Antismoking policies and smoking cessation programs should focus on (raising awareness of) avoiding smoking peers, even during digital interaction. PMID- 22102629 TI - Dissection of the phenotypic and genotypic associations with nicotinic dependence. AB - INTRODUCTION: Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968, rs6474412, rs3733829, and rs1329650 in large scale Genome-Wide Association Studies. We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures. METHODS: Four genetic variants were analyzed in 2,047 subjects of European descent (1,062 cases and 985 controls). Nicotine dependence was assessed with multiple smoking measures, including the Fagerstrom Test for Nicotine Dependence, the Diagnostic and Statistical Manual for Mental Disorders IV (DSM-IV) nicotine dependence, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives. Single-item measures of cigarettes per day (CPD) and time to first cigarette (TTF) in the morning were also examined. RESULTS: Among the variants, association effect sizes were largest for rs16969968, with measures of craving and heavy smoking, especially cigarettes smoked per day, showing the largest effects. Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650. None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did CPD. CONCLUSIONS: CPD is an important simple measure that captures in part the genetic associations of CHRNA5 and nicotine dependence, even when other more comprehensive measures of smoking behaviors are examined. The CHRNA5 gene is associated with heavy compulsive smoking and craving; this should inform the mission to improve the diagnostic validity of DSM-V. PMID- 22102630 TI - Asymmetric collimation can significantly reduce patient radiation dose during pulmonary vein isolation. AB - AIMS: Current fluoroscopic and 3D image-guided treatment of atrial fibrillation (AF) by radiofrequency ablation is characterized by a substantial amount of X-ray radiation. We investigated the potential of an asymmetric collimation technique to reduce dose. METHODS AND RESULTS: For 30 patients, referred for AF ablation, we determined the received fluoroscopy dose for various collimation scenarios: a single collimation window encompassing all veins as used in most labs (Sc 1), an optimal adjusted symmetric collimation window encompassing each two ipsilateral veins (Sc 2) or each individual vein (Sc 3) and an optimal asymmetric collimation window encompassing each two ipsilateral veins (Sc 4) or each individual vein (Sc 5). Twenty patients were studied retrospectively and 10 were studied prospectively. Total fluoroscopy effective dose for all collimation strategies amounted to 45 +/- 31 mSv for a single collimation field (Sc 1), 36 +/- 25 mSv (Sc 2), and 24 +/- 14 mSv (Sc 3) for a symmetrically adjusted collimation window and 15 +/- 10 (Sc 4) and 5 +/- 3 mSv (Sc 5) for an asymmetrically adjusted collimation approach. Validation of symmetric (Sc 2) and asymmetric (Sc 4) collimation in 10 patients confirmed the retrospective analysis. CONCLUSIONS: Implementation and effective application of an optimal asymmetric collimation approach would yield an average three- to nine-fold reduction of fluoroscopy dose during AF ablation procedures. This reduction exceeds what has been previously reported by implementing an electromagnetic catheter tracking approach. Furthermore, it can be easily integrated in the clinical workflow with limited additional one-time cost. Manufacturers of imaging systems should consider its implementation a priority, and physicians should adopt it in their workflow. PMID- 22102631 TI - Pandemic influenza H1N1 vaccination intention: psychosocial determinants and implications from a national survey, Taiwan. AB - BACKGROUND: Vaccination has been recommended as an effective way to protect people from severe illness during influenza pandemics; however, little is known about the acceptability and psychosocial determinants of intention to receive vaccination against pandemic influenza A/H1N1 (pH1N1). METHODS: A national computer-assisted telephone interview survey using random digit dialing was conducted during 28-30 October 2009 among residents of Taiwan aged >=15 years. RESULTS: Of the 1079 participants interviewed, 70.1% reported intention to receive pH1N1 vaccination. Multivariate logistic regression analysis showed that participants who perceived pH1N1 in Taiwan to be much more severe than that in other countries [adjusted odds ratio (AOR) = 1.94; 95% confidence interval (CI) = 1.05-3.60], who agreed (AOR = 2.44; 95% CI = 1.30-4.58) or strongly agreed (AOR = 2.53; 95% CI = 1.38-4.65) that contracting pH1N1 would have a great impact on their daily life, who perceived pH1N1 vaccination to be very effective in preventing pH1N1 (AOR = 2.64; 95% CI = 1.61-4.33) and who considered receiving vaccination not very difficult (AOR = 8.97; 95% CI = 6.05-13.29) or not at all difficult (AOR = 30.72; 95% CI = 19.24-49.04) were more inclined towards getting vaccinated against pH1N1. CONCLUSION: These specific and modifiable health beliefs have practical implications for prevention and policy making, and highlight the importance of minimizing perceived barriers while convincing the public of the seriousness of the disease and effectiveness of vaccination when promoting vaccination programmes. PMID- 22102633 TI - Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. AB - OBJECTIVE: Free-radical-induced reperfusion injury has been recognised as an important cause of brain tissue damage after birth asphyxia. Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia-reperfusion damage. In this study the long-term outcome of neonatal allopurinol treatment after birth asphyxia was examined. DESIGN: Follow-up of 4 to 8 years of two earlier performed randomised controlled trials. SETTING: Leiden University Medical Center, University Medical Center Groningen and University Medical Center Utrecht, The Netherlands. PATIENTS: Fifty-four term infants were included when suffering from moderate-to-severe birth asphyxia in two previously performed trials. INTERVENTION: Infants either received 40 mg/kg allopurinol (with an interval of 12 h) starting within 4 h after birth or served as controls. MAIN OUTCOME MEASURES: Children, who survived, were assessed with the Wechsler Preschool and Primary Scales of Intelligence test or Wechsler Intelligence Scale for Children and underwent a neurological examination. The effect of allopurinol on severe adverse outcome (defined as mortality or severe disability at the age of 4-8 years) was examined in the total group of asphyxiated infants and in a predefined subgroup of moderately asphyxiated infants (based on the amplitude integrated electroencephalogram). RESULTS: The mean age during follow-up (n=23) was 5 years and 5 months (SD 1 year and 2 months). There were no differences in long-term outcome between the allopurinol-treated infants and controls. However, subgroup analysis of the moderately asphyxiated group showed significantly less severe adverse outcome in the allopurinol-treated infants compared with controls (25% vs 65%; RR 0.40, 95%CI 0.17 to 0.94). CONCLUSIONS: The reported data may suggest a (neuro)protective effect of neonatal allopurinol treatment in moderately asphyxiated infants. PMID- 22102632 TI - Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. AB - Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth. PMID- 22102634 TI - Neonatal resuscitation: are your trainees performing as you think they are? A retrospective review of a structured resuscitation assessment for neonatal medical trainees over an 8-year period. AB - OBJECTIVE: To ascertain whether Newborn Life Support Course (NLS) accredited trainees could demonstrate resuscitation skills appropriate to their level of training by providing standardised assessments of both junior and senior paediatric trainees during their induction period. DESIGN: Retrospective review of medical staff resuscitation assessments over an 8-year period from 2003 to 2010. SETTING: A network-lead tertiary neonatal service with over 11 000 deliveries annually. PARTICIPANTS: Neonatal medical staff: junior (speciality trainee(ST) of years 1-3) and senior trainees (ST 4-8 with tier 2 on-call responsibilities). INTERVENTION: A standardised criterion-referenced assessment was performed by two NLS instructors. Junior trainee assessment focused on the basic airway skills learnt on an NLS course. Senior trainees demonstrated resuscitation of a baby with meconium-stained liquor, focusing on advanced life support, including intubation of the mannequin. MAIN OUTCOME MEASURES: Assessment outcomes were pass/fail; fails were categorised as algorithm failure, technical skills failure or both. For trainees who failed the first assessment, the outcome of the second assessment following appropriate feedback was recorded. RESULTS: Two hundred and sixty-two assessments were performed: 160 junior and 102 senior trainees; 98/160 (61%) of junior and 57/102 (56%) of senior trainees passed their first assessment; 69% of junior trainees who failed the first assessment had a second assessment recorded. There was a 79% pass rate at second assessment; 89% of senior trainees who failed a first assessment had a second assessment recorded. There was an 85% pass rate at second assessment. The majority of trainees who failed an assessment had problems with both the resuscitation algorithm and technical skills. CONCLUSIONS: Significant numbers of trainees who have been formally trained in neonatal resuscitation skills previously do not pass the standardised resuscitation assessment, thus require an additional input to maintain their competence in neonatal resuscitation. PMID- 22102635 TI - Effective ventilation at conventional rates with tidal volume below instrumental dead space: a bench study. AB - OBJECTIVE: The authors previously showed that 48% of infants <800 g were ventilated with tidal volume (VT) < dead space (DS) using volume guarantee (VG) ventilation. Here, The authors sought to confirm those findings under the rigorous conditions of a bench study. DESIGN AND METHODS: The authors measured the time to wash out CO2 from a 45-ml test lung using end-tidal CO(2) monitor (ETCO(2)). The test lung was filled with 100% CO(2), then ventilated using VG at VT ranging from DS+2 ml to DS-1.5 ml. With ventilation, ETCO(2) declined exponentially as CO(2) was washed out, the rate being proportional to VT - effective instrumental DS. The time from initiation of ventilation to threshold of accurate detection was determined in triplicate. RESULTS: Halving the theoretical 'alveolar ventilation' (DS+2 ml to DS+1 ml) only increased the elimination time by 26%, not the 100%, as predicted by conventional physiology. CO(2) washout was less efficient, but still occurred even at VT=DS and VT=DS-1.5 ml. Halving the theoretical 'alveolar ventilation' by decreasing respiratory rate from 80 to 40 breaths/min only increased elimination time by 35%, not 100%, as predicted by conventional physiology. Twenty minutes of continuous positive airway pressure prior to ventilation did not alter the elimination time, verifying that CO(2) did not diffuse or leak out of the test lung. Size of the endotracheal tube (ETT; 2.5, 3.0 and 3.5 mm) flow rate (4, 6 and 10 l/min) and inspiratory time (0.25 vs 0.35 s) did not affect the results. CONCLUSIONS: Contrary to conventional physiology, effective CO(2) elimination appears to be possible with VT500 ml), severe PPH (blood loss >1000 ml) and median blood loss were compared in two cohorts of LMWH users and non-users. Results The incidence of PPH was 18% in LMWH users (N=95) and 22% in non-users (N=524) (RR 0.8; 95% CI 0.5 to 1.4). The incidence of severe PPH was 6% in both groups (RR 1.2; 0.5 to 2.9). The median amount of blood loss differed only in normal vaginal deliveries. It was 200 ml in LMWH users and 300 ml in non-users (difference -100 ml; 95% CI -156 to -44). Conclusion Therapeutic doses of LMWH in pregnancy were observed not to be associated with a clinically meaningful increase in the incidence of PPH or severe PPH in women delivered in this hospital, although this observation may be confounded by the differential use of strategies to prevent bleeding. A randomised controlled trial is necessary to provide a definite answer about the optimal dose of LMWH in pregnancy. PMID- 22102642 TI - Physiotherapy rehabilitation for whiplash associated disorder II: a systematic review and meta-analysis of randomised controlled trials. AB - Objective To evaluate effectiveness of physiotherapy management in patients experiencing whiplash associated disorder II, on clinically relevant outcomes in the short and longer term. Design Systematic review and meta-analysis. Two reviewers independently searched information sources, assessed studies for inclusion, evaluated risk of bias and extracted data. A third reviewer mediated disagreement. Assessment of risk of bias was tabulated across included trials. Quantitative synthesis was conducted on comparable outcomes across trials with similar interventions. Meta-analyses compared effect sizes, with random effects as primary analyses. Data sources Predefined terms were employed to search electronic databases. Additional studies were identified from key journals, reference lists, authors and experts. Eligibility criteria for selecting studies Randomised controlled trials (RCTs) published in English before 31 December 2010 evaluating physiotherapy management of patients (>16 years), experiencing whiplash associated disorder II. Any physiotherapy intervention was included, when compared with other types of management, placebo/sham, or no intervention. Measurements reported on >=1 outcome from the domains within the international classification of function, disability and health, were included. Results 21 RCTs (2126 participants, 9 countries) were included. Interventions were categorised as active physiotherapy or a specific physiotherapy intervention. 20/21 trials were evaluated as high risk of bias and one as unclear. 1395 participants were incorporated in the meta-analyses on 12 trials. In evaluating short term outcome in the acute/sub-acute stage, there was some evidence that active physiotherapy intervention reduces pain and improves range of movement, and that a specific physiotherapy intervention may reduce pain. However, moderate/considerable heterogeneity suggested that treatments may differ in nature or effect in different trial patients. Differences between participants, interventions and trial designs limited potential meta-analyses. Conclusions Inconclusive evidence exists for the effectiveness of physiotherapy management for whiplash associated disorder II. There is potential benefit for improving range of movement and pain short term through active physiotherapy, and for improving pain through a specific physiotherapy intervention. PMID- 22102643 TI - Oral contraceptive use is associated with prostate cancer: an ecological study. AB - Background Several recent studies have suggested that oestrogen exposure may increase the risk of prostate cancer (PCa). Objectives To examine associations between PCa incidence and mortality and population-based use of oral contraceptives (OCs). It was hypothesised that OC by-products may cause environmental contamination, leading to an increased low level oestrogen exposure and therefore higher PCa incidence and mortality. Methods The hypothesis was tested in an ecological study. Data from the International Agency for Research on Cancer were used to retrieve age-standardised rates of prostate cancer in 2007, and data from the United Nations World Contraceptive Use 2007 report were used to retrieve data on contraceptive use. A Pearson correlation and multivariable linear regression were used to associate the percentage of women using OCs, intrauterine devices, condoms or vaginal barriers to the age standardised prostate cancer incidence and mortality. These analyses were performed by individual nations and by continents worldwide. Results OC use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.61 and r=0.53, respectively; p<0.05 for all). PCa incidence was also associated with OC use in Europe (r=0.545, p<0.05) and by continent (r=0.522, p<0.05). All other forms of contraceptives (ie, intra-uterine devices, condoms or vaginal barriers) were not correlated with prostate cancer incidence or mortality. On multivariable analysis the correlation with OC was independent of a nation's wealth. Conclusion A significant association between OCs and PCa has been shown. It is hypothesised that the OC effect may be mediated through environmental oestrogen levels; this novel concept is worth further investigation. PMID- 22102644 TI - Exploring differences in patient mix in a cohort of GP trainees and their trainers. AB - Background During specialty training for general practice, trainees acquire the required competencies through work-based learning. Previous small-scale and older studies suggest that the patient mix of general practitioner (GP) trainees differs from that of their trainers: trainees are exposed to more minor illnesses, and fewer chronic diseases and severe conditions, which may influence the development of their competency. Research question What are the differences in the patient mix between trainees and trainers? Methods 49 first- and 24 third year trainees and their trainers (n=114) were included in the study. International Classification of Primary Care (ICPC) contact and diagnosis codes were extracted from electronic patient records over 6 months. Results Trainers had double the number of face-to-face consultations, and treble the number of telephone consultations compared with trainees. The trainees' patient mix consisted of significantly more patients with eye diseases, ear diseases, respiratory diseases, skin diseases and minor illnesses compared with their trainers. Trainers encountered significantly more patients with circulatory diseases, psychiatric diseases, metabolic diseases, male genital conditions, social problems, and chronic and oncological diseases. Female trainers and trainees encountered almost twice the number of female conditions compared with their male counterparts, while for male conditions, the opposite was found. Discussion Considerable differences between the patient mix of trainers and trainees were found. Specialty trainers and teachers must be aware of areas of low exposure. Trainers should ensure trainees handle more chronic, complex, psychosocial and circulatory conditions. PMID- 22102645 TI - The At Home/Chez Soi trial protocol: a pragmatic, multi-site, randomised controlled trial of a Housing First intervention for homeless individuals with mental illness in five Canadian cities. AB - Introduction Housing First is a complex housing and support intervention for homeless individuals with mental health problems. It has a sufficient knowledge base and interest to warrant a test of wide-scale implementation in various settings. This protocol describes the quantitative design of a Canadian five city, $110 million demonstration project and provides the rationale for key scientific decisions. Methods A pragmatic, mixed methods, multi-site field trial of the effectiveness of Housing First in Vancouver, Winnipeg, Toronto, Montreal and Moncton, is randomising approximately 2500 participants, stratified by high and moderate need levels, into intervention and treatment as usual groups. Quantitative outcome measures are being collected over a 2-year period and a qualitative process evaluation is being completed. Primary outcomes are housing stability, social functioning and, for the economic analyses, quality of life. Hierarchical linear modelling is the primary data analytic strategy. Ethics and dissemination Research ethics board approval has been obtained from 11 institutions and a safety and adverse events committee is in place. The results of the multi-site analyses of outcomes at 12 months and 2 years will be reported in a series of core scientific journal papers. Extensive knowledge exchange activities with non-academic audiences will occur throughout the duration of the project. Trial registration number This study has been registered with the International Standard Randomised Control Trial Number Register and assigned ISRCTN42520374. PMID- 22102646 TI - Effect of intravenous GLutamine supplementation IN Trauma patients receiving enteral nutrition study protocol (GLINT Study): a prospective, blinded, randomised, placebo-controlled clinical trial. AB - Background Trauma patients are characterised by alterations in the immune system, increased exposure to infectious complications, sepsis and potentially organ failure and death. Glutamine supplementation to parenteral nutrition has been proven to be associated with improved clinical outcomes. However, glutamine supplementation in patients receiving enteral nutrition and its best route are still controversial. Previous trials have been limited by a small sample size, use of surrogate outcomes or a limited period of supplementation. The aim of this trial is to investigate if intravenous glutamine supplementation to trauma patients receiving enteral nutrition is associated with improved clinical outcomes in terms of decreased organ dysfunction, infectious complications and other secondary outcomes. Methods/design Eighty-eight critically ill patients with multiple trauma receiving enteral nutrition will be recruited in this prospective, triple-blind, block-randomised, placebo-controlled clinical trial to receive either 0.5 g/kg/day intravenous undiluted alanyl-glutamine or intravenous placebo by continuous infusion (24 h/day). Both groups will be receiving the same standard enteral nutrition protocol and the same standard intensive care unit care. Supplementation will continue until discharge from the intensive care unit, death or a maximum duration of 3 weeks. The primary outcome will be organ dysfunction evaluation assessed by the pattern of change in sequential organ failure assessment score over a 10-day period. The secondary outcomes are: the changes in total sequential organ failure assessment score on the last day of treatment, infectious complications during the ICU stay, 60-day mortality, length of stay in the intensive care unit and body-composition analysis. Discussion This study is the first trial to investigate the effect of intravenous alanyl glutamine supplementation in multiple trauma patients receiving enteral nutrition on reducing severity of organ failure and infectious complications and preservation of lean body mass. Trial registration number This trial is registered at http://www.clinicaltrials.gov. NCT01240291. PMID- 22102647 TI - Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials. AB - Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), beta-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy. PMID- 22102649 TI - The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases. AB - The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research. PMID- 22102648 TI - Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at MU opioid receptor-expressing glia. AB - Individuals infected with human immunodeficiency virus-1 who abuse opiates can have a higher incidence of virus-associated neuropathology. Human immunodeficiency virus does not infect neurons, but viral proteins such as transactivator of transcription and glycoprotein 120, originating from infected glia, are neurotoxic. Moreover, functional changes in glial cells that enhance inflammation and reduce trophic support are increasingly implicated in human immunodeficiency virus neuropathology. In previous studies, co-exposure with morphine enhanced transactivator of transcription neurotoxicity towards cultured striatal neurons. Since those cultures contained u-opioid receptor-expressing astroglia and microglia, and since glia are the principal site of infection in the central nervous system, we hypothesized that morphine synergy might be glially mediated. A 60 hour, repeated measures paradigm and multiple co-culture models were used to investigate the cellular basis for opiate-enhanced human immunodeficiency virus neurotoxicity. Morphine co-exposure significantly enhanced transactivator of transcription-induced neuron death when glia were present. Synergistic effects of morphine on transactivator of transcription neurotoxicity were greatest with neuron-glia contact, but also occurred to a lesser extent with glial conditioned medium. Importantly, synergy was lost if glia, but not neurons, lacked u-opioid receptors, indicating that opiate interactions with human immunodeficiency virus converge at the level of u-opioid receptor-expressing glia. Morphine enhanced transactivator of transcription-induced inflammatory effectors released by glia, elevating reactive oxygen species, increasing 3 nitrotyrosine production by microglia, and reducing the ability of glia to buffer glutamate. But neuron survival was reduced even more with glial contact than with exposure to conditioned medium, suggesting that noxious elements associated with cell contact augment the toxicity due to soluble factors. Similar morphine transactivator of transcription synergy was also observed in studies with the clade C sequence of HIV-1 transactivator of transcription, which did not cause neuron death unless morphine was present. Several paradoxical observations related to opiate effects were noted when u-opioid receptors were specifically ablated from either glia or neurons. This suggests that u-opioid receptor loss in isolated cell types can fundamentally distort cell-to-cell signalling, revealing opponent processes that may exist in individual cell types. Our findings show the critical role of glia in orchestrating neurotoxic interactions of morphine and transactivator of transcription, and support the emerging concept that combined exposure to opiates and human immunodeficiency virus drives enhanced pathology within the central nervous system. PMID- 22102651 TI - Aerobic oral and rectal bacteria of free-ranging Steller sea lion pups and juveniles (Eumetopias jubatus) in Alaska. AB - Bacteriologic cultures from oral, rectal, and lesion samples from free-ranging Steller sea lion (SSL, Eumetopias jubatus) pups and juveniles in Alaska (2001 2005) were examined to determine frequency of infection by a specific subset of common and pathogenic aerobic bacteria. Associations between isolated bacteria and age, sex, body condition, location, and sampling season were investigated. Salmonella spp. isolates were further evaluated to determine spatial clustering (n=48) and to identify serovars (n=13) and antimicrobial susceptibility patterns (n=11). We sampled 356 SSL pups (n=272) and juveniles (n=84), and identified 988 isolates of 13 bacterial genera of specific interest. Pasteurella spp. (43.8%), beta-hemolytic Streptococcus spp. (30.6%), and Mannheimia spp. (18.2%) were the most commonly isolated oral bacteria (n=499 isolates), whereas Escherichia coli (47.6%), beta-hemolytic E. coli (32.4%), Salmonella spp. (10.4%), and Campylobacter spp. (7.8%) were the most frequently isolated rectal bacteria (n=460 isolates). Salmonella was most commonly found in pups from western stocks and in samples collected during fall/winter seasons. A significant Salmonella cluster was detected at the Perry Island haulout. Five serovars were isolated: Enteritidis, Infantis, Newport, Reading, and Stanley. Pulsed-field gel electrophoresis provided evidence that Salmonella isolates were most likely being maintained within the SSL population in Alaska. PMID- 22102650 TI - Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. AB - Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are 'primed' by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also 'primed' the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events. PMID- 22102652 TI - Prevalence of Coxiella burnetii in western grey kangaroos (Macropus fuliginosus) in Western Australia. AB - We investigated the role of the western grey kangaroo (Macropus fuliginosus) in the maintenance and transmission of Coxiella burnetii in Western Australia. Sera from 1,017 kangaroos were tested using an indirect enzyme-linked immunosorbent assay (ELISA) for the presence of C. burnetii antibodies. The overall antibody prevalence across 12 locations throughout mid- to southwestern Western Australia was 24.1% (95% CI: 21.6-26.8). Feces from 990 of the same animals were tested using PCR to identify active shedding of C. burnetii in excreta. Coxiella burnetii DNA was detected in 4.1% (95% CI: 3.1-5.6) of samples. Our results suggest that kangaroos are reservoirs for C. burnetii in Western Australia and may contribute to transmission of the organism to domestic livestock and humans. PMID- 22102653 TI - Acute phase protein response in the capybara (Hydrochoerus hydrochaeris). AB - We evaluated the acute phase protein response in capybaras (Hydrochoerus hydrochaeris). Three animal groups were used: 1) healthy animals (n=30), 2) a group in which experimental inflammation with turpentine was induced (n=6), and 3) a group affected with sarcoptic scabies (n=14) in which 10 animals were treated with ivermectin. Haptoglobin (Hp), acid-soluble glycoprotein (ASG) and albumin were analyzed in all animals. In those treated with turpentine, Hp reached its maximum value at 2 wk with a 2.7-fold increase, whereas ASG increased 1.75-fold and albumin decreased 0.87-fold 1 wk after the induction of inflammation. Capybaras affected with sarcoptic scabies presented increases in Hp and ASG of 4.98- and 3.18-fold, respectively, and a 0.87-fold decrease in albumin, compared with healthy animals. Haptoglobin and ASG can be considered as moderate, positive acute phase proteins in capybaras because they showed less than 10-fold increases after an inflammatory process and reached their peak concentrations 1 wk after the induction of inflammation. Conversely, albumin can be considered a negative acute phase protein in capybaras because it showed a reduction in concentration after inflammatory stimulus. PMID- 22102654 TI - Health and habitat quality assessment for the eastern hellbender (Cryptobranchus alleganiensis alleganiensis) in Indiana, USA. AB - The eastern hellbender (Cryptobranchus alleganiensis alleganiensis) has experienced precipitous population declines throughout its range. Numerous factors are speculated to be involved, but no empirical evidence has been presented for any. We implemented a population-wide health assessment in Indiana, USA, examining both the physical well-being of individuals and the quality of their habitat. Physicochemical parameters were analyzed directly in the field and later in the laboratory, when appropriate. Samples were collected June 2008 October 2008 and June 2009-September 2009 for reproductive analysis, blood screening, and disease prevalence. Of 27 chemicals screened in water samples, three were found in the study site, including atrazine. Atrazine was found at levels reported to cause reproductive problems in other amphibians. Vitellogenin was detected only in females and proved a reliable indicator of sex. Sperm parameters were generally of high quality and similar to other populations. Most plasma parameters were similar between sexes, although there were significant differences in calcium and potassium concentrations. Abnormalities were common, occurring in 68% of individuals. No hemoparasites were found, but amphibian chytrid fungus (Batrachochytrium dendrobatidis) was detected on one individual. Our findings establish a baseline for hematology and water-quality parameters that can be used as a model for evaluating population health throughout the hellbender range. PMID- 22102655 TI - Low haemosporidian diversity and one key-host species in a bird malaria community on a mid-Atlantic island (Sao Miguel, Azores). AB - When host species colonize new areas, the parasite assemblage infecting the hosts might change, with some parasite species being lost and others newly acquired. These changes would likely lead to novel selective forces on both host and its parasites. We investigated the avian blood parasites in the passerine bird community on the mid-Atlantic island of Sao Miguel, Azores, a bird community originating from continental Europe. The presence of haemosporidian blood parasites belonging to the genera Haemoproteus, Plasmodium, and Leucocytozoon was assessed using polymerase chain reaction. We found two Plasmodium lineages and two Leucocytozoon lineages in 11 bird species (84% of all breeding passerine species) on the island. These lineages were unevenly distributed across bird species. The Eurasian Blackbird (Turdus merula) was the key-host species (total parasite prevalence of 57%), harboring the main proportion of parasite infections. Except for Eurasian Blackbirds, all bird species had significantly lower prevalence and parasite diversity compared to their continental populations. We propose that in evolutionary novel bird communities, single species may act as key hosts by harboring the main part of the parasite fauna from which parasites "leak" into the other species. This would create very different host-parasite associations in areas recently colonized by hosts as compared to in their source populations. PMID- 22102656 TI - Presence and seasonal prevalence of Plasmodium spp. in a rare endemic New Zealand passerine (tieke or Saddleback, Philesturnus carunculatus). AB - The conservation and management of Saddlebacks (Philesturnus carunculatus) and other New Zealand birds, currently relies on the translocation of individuals to predator-free sites. Avian malaria has been identified as one of the diseases to be tested for prior to translocations in New Zealand, with the aim of translocating disease-free individuals. We describe avian malaria lineages and their seasonal prevalence in 2007-2008 in Saddlebacks from Mokoia Island, a source of birds for translocations, and investigate their pathogenicity. Three lineages of avian malaria were found at low prevalence (<=10.6%) and parasitemia (all but one infection were below 1/10,000 erythrocytes), typical of chronic infections. Two lineages clustered with previously identified lineages of Plasmodium relictum and one with a lineage of Plasmodium (Huffia) elongatum. Prevalence of malaria infection was higher in the spring with no significant difference in prevalence between juvenile and adult birds. We found no effect of stress on infections or any indication of pathogenicity. PMID- 22102657 TI - Free-ranging wild boar: a disease threat to domestic pigs in Switzerland? AB - The risk of transmission of pathogens from free-ranging wild boars (Sus scrofa scrofa) to outdoor domestic pigs (S. scrofa domesticus) is of increasing concern in many European countries. We assess this risk, using Switzerland as an example. We estimated 1) the prevalence of important pathogens in wild boars and 2) the risk of interactions between wild boars and outdoor pigs. First, we tested 252 wild boars from selected areas between 2008 and 2010 for infection with Brucella spp. Bacterial prevalence was estimated to 28.8% (confidence interval [CI] 23.0 34.0) when using bacterial culture (B. suis Biovar 2) and real-time polymerase chain reaction. Antibody prevalence was 35.8% (CI 30.0-42.0), which was significantly higher than in previous studies in Switzerland. We also tested 233 wild boars for porcine reproductive and respiratory syndrome virus (PRRSV). Antibody prevalence was 0.43% (CI 0.01-2.4) for EU-PRRSV and real-time reverse transcription polymerase chain reaction results were negative. These findings suggest that B. suis is increasingly widespread in wild boars and PRRSV is currently not of concern. Second, we documented the spatial overlap between free ranging wild boars and outdoor piggeries by mapping data on their respective occurrence. Wild boars are most widespread in the mountain range along the western and northern Swiss borders, while most piggeries are located in central lowlands. A risk of interaction is mainly expected at the junction between these two bioregions. This risk may increase if wild boars expand eastward and southward beyond anthropogenic barriers believed to limit their range. Therefore, we evaluated the potential of expansion of the wild boar population. Population trends suggest a continuous increase of wild boars for the past 15 yr. Surveillance of selected wildlife passages using cameras on highways and main roads indicates that these barriers are permeable (average of up to 13 wild boar crossings per 100 days). Thus an increase of wild boar range should be considered. There may be a risk of B. suis spillover from wild boars in Switzerland, which could increase in the future. Data on the occurrence of interactions between pigs and wild boars are needed to assess this risk. PMID- 22102658 TI - Prevalence of Salmonella in fecal samples of western grey kangaroos (Macropus fuliginosus). AB - This is the first extensive study of the prevalence of naturally acquired Salmonella infection in wild-caught kangaroos in Australia. Given the close association between kangaroos, livestock, and humans and the growing popularity of kangaroo meat, it is important to identify epidemiologic factors associated with infection in these marsupials in order to minimize the risk of Salmonella transmission. The overall prevalence of fecal Salmonella in 645 western grey kangaroos (Macropus fuliginosus) sampled across 10 locations in Western Australia was 3.6% (95% CI: 2.3-5.3). Seven Salmonella serovars were identified including Salmonella enterica serovar Muenchen, Kiambu, Rubislaw, Lindern, Champaign, Saintpaul and II 42:g,t:-. Prevalence was significantly associated with rainfall (P<0.05) and was highest in the April-June quarter (P<0.05). There was no association between age or sex and the prevalence of Salmonella in fecal samples. Our results suggest that, while kangaroos are infected with Salmonella in their natural habitat, infection is less common than in hand-reared joeys, pet kangaroos, and macropods raised in captivity. Care should be taken to maintain hygiene during the evisceration, processing, and handling of kangaroos and to adequately cook kangaroo meat prior to consumption to reduce the risk of salmonellosis. PMID- 22102659 TI - Assessment of a recombinant F1-V fusion protein vaccine intended to protect Canada lynx (Lynx canadensis) from plague. AB - As part of an ongoing restoration program in Colorado, USA, we evaluated adverse reactions and seroconversion in captive Canada lynx (Lynx canadensis) after vaccination with a recombinant F1-V fusion protein vaccine against Yersinia pestis, the bacterium that causes plague. Ten adult female lynx received the F1-V vaccine; 10 source- and age-matched lynx remained unvaccinated as controls. All of the vaccinated and control lynx remained apparently healthy throughout the confinement period. We observed no evidence of injection site or systemic reactions to the F1-V vaccine. Among vaccinated lynx, differences in log(10) reciprocal antibody titers measured in sera collected before and after vaccination (two doses) ranged from 1.2 to 5.2 for anti-F1 antibodies and from 0.6 to 5.2 for anti-V antibodies; titers in unvaccinated lynx did not change appreciably over the course of confinement prior to release, and thus differences in anti-F1 (P=0.003) and anti-V (P=0.0005) titers were greater among vaccinated lynx than among controls. Although our findings suggest that the F1-V fusion protein vaccine evaluated here is likely to stimulate antibody responses that may help protect Canada lynx from plague, we observed no apparent differences in survival between vaccinated and unvaccinated subject animals. Retrospectively, 22 of 50 (44%; 95% confidence interval 29-59%) unvaccinated lynx captured or recaptured in Colorado during 2000-08 had passive hemagglutination antibody titers >1:16, consistent with exposure to Y. pestis; paired pre- and postrelease titers available for eight of these animals showed titer increases similar in magnitude to those seen in response to vaccination, suggesting at least some lynx may naturally acquire immunity to plague in Colorado habitats. PMID- 22102660 TI - Hair-loss epizootic in moose (Alces alces) associated with massive deer ked (Lipoptena cervi) infestation. AB - Deer keds (Lipoptena cervi) are blood-sucking flies in the family Hippoboscidae; moose (Alces alces) are their main host in Scandinavia. There are no detailed reports of the negative impacts of deer keds on moose. In 2006 and 2007, hunters in southeastern Norway and midwestern Sweden found several moose cadavers with severe alopecia; numerous moose had extensive hair loss. Between February 2006 and June 2007, materials from 23 moose were submitted for laboratory examination and large numbers of deer keds were found in the coat of most animals. The body condition of the moose varied but was poor in animals with severe alopecia. The findings of enormous numbers of deer keds in the coat of the majority of the affected animals and a consistent histologic image (acute to chronic, multifocal to coalescing, eosinophilic to lymphocytic dermatitis), concurrent with the absence of any other lesions, trace element deficiencies, or dermal infections which are known to cause alopecia, suggest that the hair-loss epizootic was linked to massive infestations with deer keds. The emergence of this hair-loss syndrome implies that the dynamics between parasite and host have been disrupted by a currently unknown environmental or ecological factor. A high moose density, combined with extraordinarily mild weather June 2006-June 2007 and a particularly long period with the absence of night-frost in autumn of 2006, may have been ideal for deer ked development, survival, and optimal host acquisition. PMID- 22102661 TI - The role of lead in a syndrome of clenched claw paralysis and leg paresis in Swamp Harriers (Circus approximans). AB - We investigated the hypothesis that lead poisoning was the cause of the clinical syndrome of clenched feet paralysis and leg paresis in wild raptors. Swamp Harriers (Circus approximans) are one of three extant native raptor species in New Zealand. Harriers with the syndrome were found to have statistically significantly higher blood lead concentrations than those without clenched feet (t-test; t=-4.06, df=5, P=0.01). However, elevated blood lead concentrations were also present in 60% of wild harriers without the clinical syndrome of clenched feet paralysis and leg paresis. There were features of the response to chelation treatment, electroneurodiagnostics, and pathology that were inconsistent with lead poisoning as reported in other birds of prey. We conclude that lead may be a factor in the expression of this clinical syndrome of clenched claw paralysis but that other factors not identified in our study play a role in the expression of the disease. PMID- 22102662 TI - Treatment of equine sarcoid in seven Cape mountain zebra (Equus zebra zebra). AB - Equine sarcoid has been diagnosed in endangered Cape mountain zebra (Equus zebra zebra) in at least two game reserves in South Africa, with prevalence as high as 53% in Bontebok National Park. Seven Cape mountain zebras with sarcoids were treated with either surgical excision, 5-fluorouracil, allogenous vaccine, or a combination of 5-fluorouracil and allogenous vaccine. One of the two sarcoids on one of the 5-fluorouracil-treated zebras was left untreated. The microscopic features of the tumors evaluated showed either all or most of the typical epidermal and dermal histologic features of equine sarcoid. The zebras were examined 2 yr posttreatment to determine outcome. All sarcoids had resolved except on the zebra on which one of the sarcoids was left untreated. The efficacy of the three treatment methods in Cape mountain zebra is encouraging. PMID- 22102663 TI - Midazolam as an adjunctive therapy for capture myopathy in Bar-tailed Godwits (Limosa lapponica baueri) with prognostic indicators. AB - Capture myopathy is a complication of capture and handling in many species of birds and mammals. Muscular necrosis leads to ataxia, paralysis, and pain, whereas metabolic disturbances can result in death. We conducted an opportunistic clinical trial on Bar-tailed Godwits (Limosa lapponica baueri) that developed capture myopathy after a cannon-net capture in New Zealand in October 2008. We assessed the beneficial effects of midazolam, a benzodiazepine with the effects of anxiolysis, muscle relaxation, and sedation, in the adjunctive treatment of capture myopathy. Physical and biochemical parameters were analyzed retrospectively for their potential as indicators for survival until release. Birds (n=16) were treated with subcutaneous fluid therapy, a nonsteroidal anti inflammatory (meloxicam), gavage feeding, and sling therapy twice daily. The treatment group (n=8) was treated twice daily with intramuscular midazolam injections, 1.5 mg/kg. Surviving godwits were released over 1-9 days, with 6 of 8 treated birds (75%) surviving to release, compared with 3 of 8 controls (38%). Inability to counteract weight loss in captivity was the most significant problem for both groups. Lack of waterproofing and predation were contributing causes of death for at least two godwits after release. Birds treated with midazolam showed subjective benefits including improved tolerance of handling and sling therapy. Clinical parameters (change in body mass, packed cell volume [PCV], plasma creatine kinase [CK], aspartate aminotransferase [AST], total protein, and uric acid [UA] over time) were not statistically different between groups, although peak average values for CK, AST, and UA were lower in the treatment group. Decline in body mass (%), PCV, final plasma UA, and peak plasma CK were the most useful prognostic indicators. Midazolam shows potential as an ancillary treatment for capture myopathy in birds and is worthy of continued study and use. PMID- 22102664 TI - The Pied Crow (Corvus albus) is insensitive to diclofenac at concentrations present in carrion. AB - Diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), kills vultures (Gyps spp.) that consume tainted carcasses. As a result, vulture populations in India, Nepal, and Pakistan have been devastated. Studies on meloxicam and ketoprofen demonstrated that the toxicity of the NSAIDs is unpredictable, thereby necessitating individual testing of all available NSAIDs. Because it is no longer practical to use vultures for toxicity testing, we evaluated the Pied Crow (Corvus albus) as a model. Pied Crows (n=6) were exposed to a dose of 0.8 and 10 mg/kg of diclofenac, with no signs of toxicity, and a rapid half-life of elimination. Using primary renal cell and hepatocyte cultures, a high tolerance was demonstrated at the cellular level. Meta-analysis of pharmacokinetic data for the Domestic Chicken (Gallus gallus) and the African White-backed (Gyps africanus), Cape Griffon (Gyps coprotheres), and Turkey Vultures (Cathartes aura) showed a trend toward toxicity when the half-life of elimination increased. We conclude that the crow is not susceptible to diclofenac and, more important, that toxicity in the Gyps species is probably related to zero-order metabolism. PMID- 22102665 TI - Rabies in the arctic fox population, Svalbard, Norway. AB - Arctic foxes, 620 that were trapped and 22 found dead on Svalbard, Norway (1996 2004), as well as 10 foxes trapped in Nenets, North-West Russia (1999), were tested for rabies virus antigen in brain tissue by standard direct fluorescent antibody test. Rabies antigen was found in two foxes from Svalbard and in three from Russia. Blood samples from 515 of the fox carcasses were screened for rabies antibodies with negative result. Our results, together with a previous screening (1980-1989, n=817) indicate that the prevalence of rabies in Svalbard has remained low or that the virus has not been enzootic in the arctic fox population since the first reported outbreak in 1980. Brain tissues from four arctic foxes (one from Svalbard, three from Russia) in which rabies virus antigen was detected were further analyzed by reverse-transcriptase polymerase chain reaction direct amplicon sequencing and phylogenetic analysis. Sequences were compared to corresponding sequences from rabies virus isolates from other arctic regions. The Svalbard isolate and two of the Russian isolates were identical (310 nucleotides), whereas the third Russian isolate differed in six nucleotide positions. However, when translated into amino acid sequences, none of these substitutions produced changes in the amino acid sequence. These findings suggest that the spread of rabies virus to Svalbard was likely due to migration of arctic foxes over sea ice from Russia to Svalbard. Furthermore, when compared to other Arctic rabies virus isolates, a high degree of homology was found, suggesting a high contact rate between arctic fox populations from different arctic regions. The high degree of homology also indicates that other, and more variable, regions of the genome than this part of the nucleoprotein gene should be used to distinguish Arctic rabies virus isolates for epidemiologic purposes. PMID- 22102666 TI - Betaherpesvirus sequences in eastern spiny mice and Wagner's dipodils. AB - Eastern spiny mice (Acomys dimidiatus; also known as Sinai spiny mice) have been extensively studied in terms of the influence of parasite load on population size and reproductive fitness. The physical isolation of these rodent populations makes them interesting models for disease interactions in a real-life population as opposed to a laboratory. We identify betaherpesvirus sequences in eastern spiny mice and Wagner's dipodils (Dipodillus dasyurus), species that inhabit dry montane wadis (dry creek valleys) of the Sinai, highlighting the need for a comprehensive analysis of the full pathogen repertoire of these rodents in long term studies. PMID- 22102667 TI - First description of nodular onchocercosis (Onchocerca jakutensis) in free ranging Italian red deer (Cervus elaphus). AB - Onchocercosis is a vector-transmitted parasitic disease involving wild and domestic ungulates, humans, and dogs. Red deer (Cervus elaphus) host numerous Onchocerca spp. which have precise anatomic sites in the host and two species, Onchocerca flexuosa Wedl, 1856 and Onchocerca jakutensis Guba-now, 1964, are found inside subcutaneous nodules. Between September and November 2007, subcutaneous nodules were observed on both thighs in shot red deer of a Tuscany population. We observed cystic structures, surrounded by a fibrous capsule, containing nematodes. Filamentous worms were male and female; microfilariae were also described. Although morphologically we could not distinguish between O. flexuosa and O. jakutensis, genetic studies implicated O. jakutensis. This is the first report of this parasite in Italy. PMID- 22102668 TI - Population differences in host immune factors may influence survival of Gunnison's prairie dogs (Cynomys gunnisoni) during plague outbreaks. AB - Over the past 40 yr, epizootics of plague (Yersinia pestis) in northern Arizona have reduced populations of the Gunnison's prairie dog (Cynomys gunnisoni), with the exception of a large population found in the Aubrey Valley (AV). To examine potential mechanisms accounting for their survival, we collected prairie dog serum samples in 2005-2006 from AV and a neighboring population near Seligman (SE), Arizona. We quantified gene expression at 58 diverse immune proteins using a multiplexed enzyme-linked immunosorbent assay panel. We found a subset of proteins important in coagulation and inflammation (tissue factor [TF], calbindin [Cal], and thrombopoietin [TPO]) and T-cell responses (CD40L and CD40) that were present in AV at levels two to eight times greater than SE. These results suggest that AV and SE animals might differ in their ability to mount an immune response. PMID- 22102669 TI - Absence of Mycobacterium bovis in feral swine (Sus scrofa) from the southern Texas border region. AB - Free-ranging wildlife, such as feral swine (Sus scrofa), harbor a variety of diseases that are transmissible to livestock and could negatively impact agricultural production. Information is needed regarding the exposure and infection rates of Mycobacterium bovis and many other diseases and parasites in feral swine occurring in the Texas border region. Our main objective was to determine exposure rates and possible infection rates of M. bovis in feral swine by opportunistically sampling animals from the Texas border region. From June to September 2010, we obtained samples from 396 feral swine and tested 98 samples for M. bovis by histopathology and mycobacteriologic culture. We found no evidence of M. bovis infection. We believe that it is important to periodically and strategically sample feral swine for M. bovis in high-risk areas of the United States because they are capable of becoming reservoirs of the disease. PMID- 22102670 TI - Congenital scoliosis of a bottlenose dolphin. AB - There are many reports of cetaceans with deformed and twisted bodies. Skeletal pathology descriptions have shown changes to axial skeletons because of injury, trauma, or disease. We present a bottlenose dolphin (Tursiops truncatus) that shows characteristic patterns of congenital skeletal deformity, including malformed vertebrae, ribs, and sternum. These malformations were consistent with segmentation and formation defects arising during early embryonic development, with a resulting cascade of deformity and compensatory pathology. In spite of severe deformities, the dolphin lived 18 yr, raised two calves, and likely would have lived longer had she not succumbed to sepsis and the piercing of the aorta caused by a stingray barb. PMID- 22102671 TI - Serologic surveillance of pathogens in a declining harbor seal (Phoca vitulina) population in Glacier Bay National Park, Alaska, USA and a reference site. AB - The harbor seal population in Glacier Bay National Park, Alaska, has declined by over 70% since 1992. The reasons for this decline are not known. We examined serum antibodies and feces for evidence of exposure to multiple pathogens in this population. We also studied harbor seals from a reference site on Kodiak Island. In 2007, we found antibodies against Leptospira spp. in 31% of specimens from harbor seals in Glacier Bay, but no detectable serum antibodies in samples from Kodiak. In 2008, no samples had detectable antibodies against Leptospira spp. No serum antibodies against Toxoplasma gondii, morbilliviruses, or presence of Cryptosporidium in fecal samples were detected. However, Giardia was found in 6% of the fecal samples from Glacier Bay. Our results indicate that the harbor seal population in Glacier Bay National Park could be immunologically naive to distemper viruses and therefore vulnerable to these pathogens. Given the relatively low prevalence of antibodies and low titers, pathogens likely are not the reason for the harbor seal decline in Glacier Bay. PMID- 22102672 TI - Avian poxvirus epizootic in a breeding population of Lesser Flamingos (Phoenicopterus minor) at Kamfers Dam, Kimberley, South Africa. AB - Avian pox has a worldwide distribution, but prior to this investigation has not been reported in free-ranging flamingo populations. During observations of the first successful breeding of Lesser Flamingos on a purpose-built island, at Kamfers Dam near Kimberley, South Africa, multiple small, raised, crusted plaques on the legs and facial area were noticed on 30% of the fledgling flamingos. A diagnosis of avipoxvirus infection was made on the basis of the macroscopic, histologic, and electron microscopic features, and was further confirmed by DNA sequence analysis. The avipoxvirus detected was very similar to that previously detected in albatross and falcons. PMID- 22102673 TI - Surveillance and isolation of HPAI H5N1 from wild Mandarin Ducks (Aix galericulata). AB - Highly pathogenic avian influenza (HPAI) H5N1 virus circulates among a variety of free-ranging wild birds and continually poses a threat to animal and human health. During the winter of 2010-2011, we surveyed Korean wild bird habitats. From 728 fresh fecal samples, 14 HPAI H5N1 viruses were identified. The isolates phylogenetically clustered with other recently isolated clade 2.3.2 HPAI H5N1 viruses isolated from wild birds in Mongolia. All HPAI-positive fecal samples were analyzed by DNA barcoding for host-species identification. Twelve of the 14 HPAI-positive samples were typed as Mandarin Duck (Aix galericulata). The high incidence of HPAI subtype H5N1 viruses in wild Mandarin Duck droppings is a novel finding and underscores the need for enhanced avian influenza virus surveillance in wild Mandarin Ducks. Further investigation of the susceptibility of Mandarin Ducks to HPAI H5N1 clade 2.3.2 virus would aid the understanding of HPAI ecology and epidemiology in wild birds. PMID- 22102674 TI - Mycobacterial infections in free-living cervids in Germany (2002-2006). AB - We examined 1,022 free-living roe deer, red deer, and fallow deer for mycobacteria in Germany, 2002-2006. Retropharyngeal lymph nodes and other tissues were processed for culture and isolates were identified with the use of polymerase chain reaction and DNA sequencing. Mycobacteria were found in 18.3% of deer, with Mycobacterium avium in 14.8%. Other atypical mycobacteria were detected in 5.3%. Members of the Mycobacterium tuberculosis complex were not detected. PMID- 22102675 TI - Prevalence and molecular characterization of Mycoplasma ovis in selected free ranging Brazilian deer populations. AB - Mycoplasma ovis is a hemoplasma that may cause anemia and mortality in small ruminants. Our aim was to determine whether M. ovis infects populations of free ranging deer in Brazil. Buffy coat samples from 64 Blastocerus dichotomus from Porto Primavera, 18 Ozotocerus bezoarticus from Pantanal, and 21 O. bezoarticus from Emas National Park were tested. Using a M. ovis PCR protocol to amplify extracted DNA, 46/64 (72%) of deer from Porto Primavera, 10/18 (56%) from Pantanal, and 4/21 (19%) from Emas National Park were positive, giving an overall positive rate of 58% for hemoplasma in these wild deer. Sequencing and phylogenetic analysis of the 16S rRNA gene revealed 3 genetically distinct hemoplasmas including M. ovis, 'Candidatus Mycoplasma erythrocervae', and a hemoplasma most closely related to M. ovis. Phylogenetic analysis of the 23S rRNA gene from selected sequences confirmed these relationships. PMID- 22102676 TI - Histologic findings in free-ranging Sarasota Bay bottlenose dolphin (Tursiops truncatus) skin: mercury, selenium, and seasonal factors. AB - Full-thickness epidermal biopsy samples were collected from free-ranging common bottlenose dolphins (Tursiops truncatus) in Sarasota Bay, Florida, USA. Season (summer or winter) of collection, mercury (Hg) concentration, and selenium (Se) concentration were compared to histologic parameters. Epidermal Hg concentration was positively related to age (P<0.001) and negatively related to height of the stratum spinosum (P<0.05). The mitotic index and heights of the stratum externum and intermedium were lower in summer than in winter (P<0.01). Transmission electron microscopic examination revealed variation in the diameters (60-138 nm) and arrangements of collagen fibers, regardless of age or concentrations of Hg and Se. The significance of the variation in height of the stratum spinosum and the perivascular collagen degeneration to dolphin health need further investigation. PMID- 22102677 TI - Balanoposthitis, dyspareunia, and treponema in the critically endangered Gilbert's potoroo (Potorous gilbertii). AB - The Gilbert's potoroo (Potorous gilbertii) is one of Australia's most critically endangered mammals with a current estimated population of 70 individuals. Both the wild and captive populations have a long history of balanoposthitis with associated crusting, ulceration, and preputial discharge. We sought to identify the microbial species found in the discharge, determine their significance in causing balanoposthitis, and correlate these findings with reproductive success and survivorship. Bacteriologic examination revealed the discharge to be a polymicrobial infection involving Treponema spp., Actinobacillus spp., and Pasteurella spp. Preputial histopathology reported a moderate, chronic, erosive inflammatory response with diffuse, moderate to marked secondary epithelial hyperplasia in conjunction with moderate numbers of spirochetes, suggesting a causative relationship. Clinical examination, preputial biopsies, and serologic screening found no evidence of associated systemic disease. The clinical investigation of Treponema is significant with respect to the overall recovery of Gilbert's potoroo, given the clinical and histopathologic similarities to Treponema paraluis-cuniculi found in rabbits, causing dyspareunia, and the severity of the associated balanoposthitis. PMID- 22102678 TI - Serum amyloid A (SAA) as a biomarker of chronic infection due to boat strike trauma in a free-ranging Florida manatee (Trichechus manatus latirostris) with incidental polycystic kidneys. AB - Watercraft-related trauma is the predominant cause of human-induced mortality in manatees (Trichechus manatus latirostris), a federal- and state-listed endangered species. Pyothorax (documented in this case report) and other secondary infections are common sequelae of inhalation of water and the open wounds caused by boat propellers. These secondary infections can lead to the demise of the animal weeks to months after the traumatic incident when external wounds have healed. Diagnosis of underlying disease on physical examination during capture and restraint can be difficult. Acute phase proteins, including serum amyloid A, fibrinogen, and albumin can be used to diagnose inflammatory disease in manatees and improve quality of medical care and husbandry. We also provide the first report of polycystic kidneys in Sirenians. PMID- 22102679 TI - Preliminary evaluation of Raboral V-RG(r) oral rabies vaccine in Arctic foxes (Vulpes lagopus). AB - We tested the Raboral V-RG(r) recombinant oral rabies vaccine for its response in Arctic foxes (Vulpes lagopus), the reservoir of rabies virus in the circumpolar North. The vaccine, which is currently the only licensed oral rabies vaccine in the United States, induced a strong antibody response and protected foxes against a challenge of 500,000 mouse intracerebral lethal dose 50% of an Arctic rabies virus variant. However, one unvaccinated control fox survived challenge with rabies virus, either indicating a high resistance of Arctic foxes to rabies infection or a previous exposure that induced immunity. This preliminary study suggested that Raboral V-RG vaccine may be efficacious in Arctic foxes. PMID- 22102680 TI - Genetic diversity of parvovirus isolates from dogs and wild animals in China. AB - We isolated three new parvovirus variants in China. The isolate from a blue fox was related to feline parvovirus, but possessed a mutation of VP2 residue A300P. Isolates from a raccoon dog and a masked civet were antigenically similar to canine parvovirus-2a but had a substitution of VP2 residue G300S. PMID- 22102681 TI - Diffuse multicentric large B-cell lymphoma invading the central nervous system in a European wild boar (Sus scrofa). AB - We describe a diffuse, multicentric, large B-cell lymphoma in a wild boar (Sus scrofa) involving the abdomen, head, and nose and invading the frontal leptomeninges. The tumor was predominantly composed of dense, basophilic, round to-polygonal cells. Immunohistochemistry for CD79 and Ki-67 was positive in all masses. PMID- 22102682 TI - Citrobacter freundii septicemia in a stranded newborn Cuvier's beaked whale (Ziphius cavirostris). AB - Citrobacter freundii, a gram-negative enterobacterium, may cause fatal septicemia in humans and animals. Its potential pathogenic role in cetaceans (bottlenose dolphins and beluga whales) has been hypothesized. Here we describe fatal C. freundii septicemia in a stranded newborn Cuvier's beaked whale (Ziphius cavirostris). PMID- 22102683 TI - Gender differences in haemogregarine infections in American alligators (Alligator mississippiensis) at Savannah River, South Carolina, USA. AB - We report a host gender bias in haemogregarine infection characteristics in the American alligator (Alligator mississippiensis) at the Savannah River Site, South Carolina, USA. Prevalence and severity in female alligators was higher than it was in males. The reason for this pattern is not clear. PMID- 22102684 TI - Condition of wings is an important criterion of bat health: a response to Francl et al. PMID- 22102688 TI - Short-term biomarker modulation prevention study of anastrozole in women at increased risk for second primary breast cancer. AB - The selective estrogen receptor modulators (SERM), Tamoxifen and raloxifen reduce risk breast cancer. Patient acceptance of SERMs for breast cancer prevention is low due to toxicities. New agents with a better toxicity profile are needed. Aromatase inhibitors (AI) reduce the risk of contralateral breast cancer and risk of new breast cancer in high risk women. However, the mechanism by which AIs reduce breast risk is not known. Surrogate biomarkers are needed to evaluate the effect of preventive agents. The objective of this prospective short-term prevention study was to evaluate the effect of anastrozole on biomarkers in breast tissue and serum of women at increased risk for developing a contralateral breast cancer. Women with a history of stage I, II breast cancer who started anastrozole for standard adjuvant treatment were eligible. Patients underwent baseline fine needle aspiration of the unaffected breast and serum collection for biomarker analysis before starting anastrozole at 1 mg per oral/day and again at 6 months. Biomarkers included changes in cytology, insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3. Thirty-seven patients were enrolled. There was a significant modulation in serum IGFBP-1 levels between pre- and postsamples (P = 0.02). No change was observed in IGF-1, IGFBP-3, and breast cytology.We showed a significant modulation of IGFBP-1 levels with six months anastrozole. Anastrozole is currently being studied as a prevention agent in a large phase III trial and our results provide support for continued evaluation of IGFBP-1 as a surrogate endpoint biomarker in prospective breast chemoprevention studies. PMID- 22102689 TI - Relationships between eccentric hip isokinetic torque and functional performance. AB - CONTEXT: Recently, attention in sports has been given to eccentric hip-muscle function, both in preventing musculoskeletal injuries and improving performance. OBJECTIVE: To determine the key isokinetic variables of eccentric hip torque that predict the functional performance of women in the single-leg triple long jump (TLJ) and the timed 6-m single-leg hop (TH). DESIGN: Within-subject correlational study. SETTING: Musculoskeletal laboratory. PARTICIPANTS: 32 healthy women age 18 25 y. INTERVENTION: The participants performed 2 sets of 5 eccentric hip abductor/adductor and lateral/medial-rotator isokinetic contractions (30 degrees /s) and 3 attempts in the TLJ and TH. MAIN OUTCOME MEASUREMENTS: The independent variables were the eccentric hip-abductor and -adductor and medial- and lateral rotator isokinetic peak torque, normalized according to body mass (Nm/kg). The dependent variables were the longest distance achieved in the TLJ normalized according to body height and the shortest time spent during the execution of the TH. RESULTS: The forward-stepwise-regression analysis showed that the combination of the eccentric hip lateral-rotator and -abductor isokinetic peak torque provided the most efficient estimate of both functional tests, explaining 65% of the TLJ variance (P < .001) and 55% of the TH variance (P < .001). CONCLUSIONS: Higher values for eccentric hip lateral-rotator and hip-abductor torques reflected better performance. Thus, the eccentric action of these muscles should be considered in the development of physical training programs that aim to increase functional performance. PMID- 22102690 TI - Practice concepts and policy studies: the new divide. PMID- 22102691 TI - Relationship of olive oil polyphenols and oxidation biomarkers. PMID- 22102692 TI - HMGB1 promotes drug resistance in osteosarcoma. AB - Osteosarcoma is the most commonly occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. In this study, we implicate the DNA-binding protein HMGB1, which also exerts immunoregulatory effects in its secreted form, in the development of drug resistance in osteosarcoma. Anticancer agents including doxorubicin, cisplatin, and methotrexate each induced HMGB1 upregulation in human osteosarcoma cells, and RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of osteosarcoma cells in vivo and in vitro. Mechanistic investigation revealed that HMGB1 increased drug resistance by inducing autophagy, an intracellular self defense mechanism known to confer drug resistance. We found that HMGB1 bound to the autophagy regulator Beclin1 and regulated the formation of the Beclin1-PI3KC3 [PI3KC3, phosphatidylinositol 3-kinase class 3] complex that facilitates autophagic progression. In addition, we found that interaction between HMGB1 and Beclin1 relied upon the autophagic complex ULK1-mAtg13-FIP200. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance, and it offers a novel target for improving osteosarcoma therapy. PMID- 22102693 TI - Stress-regulated transcription factor ATF4 promotes neoplastic transformation by suppressing expression of the INK4a/ARF cell senescence factors. AB - Many cancers overexpress ATF4, a stress-induced transcription factor that promotes cell survival under hypoxic conditions and other stresses of the tumor microenvironment, but the potential contributions of ATF4 to oncogenesis itself have been little explored. Here, we report that ATF4 promotes oncogene-induced neoplastic transformation by suppressing the expression of cellular senescence associated genes. Strikingly, primary embryo fibroblasts from ATF4-deficient mice were resistant to transformation by coexpression of H-ras(V12) and SV40 large T antigen. In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclin-dependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence. Our findings define a central function for ATF4 in promoting oncogenic transformation by suppressing a central pathway of cellular senescence. PMID- 22102694 TI - Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. AB - Malignant cells express ligands for the natural killer cell immunoreceptor NKG2D, which sensitizes to early recognition and elimination by cytotoxic lymphocytes and provides an innate barrier against tumor development. However, the mechanisms that control NKG2D ligand (NKG2DL) expression in tumor cells remain unknown. We recently identified the NKG2DL ULBP2 as strong prognostic marker in human malignant melanoma. Here, we provide evidence that the tumor-suppressive microRNAs (miRNA) miR-34a and miR-34c control ULBP2 expression. Reporter gene analyses revealed that both miRNAs directly targeted the 3'-untranslated region of ULBP2 mRNA and that levels of miR-34a inversely correlated with expression of ULBP2 surface molecules. Accordingly, treatment of cancer cells with miRNA inhibitors led to upregulation of ULBP2, whereas miR-34 mimics led to downregulation of ULBP2, diminishing tumor cell recognition by NK cells. Treatment with the small molecule inhibitor Nutlin-3a also decreased ULBP2 levels in a p53-dependent manner, which was due to a p53-mediated increase in cellular miR-34 levels. Taken together, our study shows that tumor-suppressive miR-34a and miR-34c act as ULBP2 repressors. These findings also implicate p53 in ULBP2 regulation, emphasizing the role of the specific NKG2DL in tumor immune surveillance. PMID- 22102695 TI - Dammarenediol-II production confers TMV tolerance in transgenic tobacco expressing Panax ginseng dammarenediol-II synthase. AB - Panax ginseng is one of the famous medicinal plants. Ginsenosides, a class of tetracyclic triterpene saponins, are mainly responsible for its pharmacological activity. Most ginsenosides are composed of dammarenediol-II aglycone with various sugar moieties. Dammarenediol-II synthase is the first enzyme in the biosynthesis of ginsenosides. Here, we report that transgenic tobacco expressing the P. ginseng dammarenediol-II synthase gene (PgDDS) produced dammarenediol-II, and conferred resistance to Tobacco mosaic virus (TMV). Upon infection with TMV, lesions developed more rapidly in transgenic tobacco plants, and their size was smaller than those of wild-type plants. Transgenic tobacco plants showed a low level of both the viral titer and mRNA accumulation of TMV coat protein (CP) compared with the wild type. The production of dammarenediol-II in transgenic tobacco stimulated the expression of tobacco pathogenesis-related genes (PR1 and PR2) under both virus-untreated and -treated conditions. When the leaves of wild type plants were inoculated with a mixture of TMV and dammarenediol-II, the leaves exhibited a reduced viral concentration and TMV-CP expression than those receiving TMV treatment alone. When the leaves of P. ginseng were infected with TMV, transcription of PgDDS was significantly increased. Transgenic P. ginseng plants harboring a beta-glucuronidase (GUS) gene driven by the PgDDS promoter were constructed. The GUS expression was activated when the transgenic ginseng plants were treated with TMV. These results indicate that the medicinally important dammarenediol-II can be ectopically produced in tobacco, and the production of dammarenediol-II in tobacco plants allows them to adopt a viral defense system. PMID- 22102696 TI - A deletion mutation in the spacing within the psaA core promoter enhances transcription in a cyanobacterium Synechocystis sp. PCC 6803. AB - Transcriptional regulation of PSI reaction center psaA is one of the important physiological responses to changing environments. We previously reported that the Rrf2-type transcriptional regulator Slr0846 activates transcription of psaA in Synechocystis sp. PCC 6803. In the Deltaslr0846 mutant, transcripts from two promoters, P1 and P2, were downshifted and, as a result, a lower Chl content and slower growth were observed. Here, we report spontaneous suppressors which recovered Chl accumulation and photoautotrophic growth. Sequencing of the whole promoter region revealed in some suppressors the same single nucleotide deletion in a 9 bp G stretch (-21 to -29 from the transcriptional start point of P1), which is located between the -35 and -10 elements of the P1 core promoter (hereafter the -G mutation). The transcripts from P1 were higher in abundance in this pseudorevertant than in the Deltaslr0846 mutant. When the promoter was fused to a reporter gene, the -G mutation conferred ~4 times higher expression than the wild-type promoter. It has been shown that the P1 promoter activity of psaA is regulated by a high light regulatory element 1 just upstream of -35. The -G mutated P1 promoter still retained the high light response. Thus, the -G mutation enhanced the expression level of psaA without a loss of the response to the high light conditions. This is the first study of the spontaneous mutation of a spacer length of a promoter for expression in cyanobacteria. PMID- 22102697 TI - Unique defense strategy by the endoplasmic reticulum body in plants. AB - The endoplasmic reticulum (ER) is a site for the production of secretory proteins. Plants have developed ER subdomains for protein storage. The ER body is one such structure, which is observed in Brassicaceae plants. ER bodies accumulate in seedlings and roots or in wounded leaves in Arabidopsis. ER bodies contain high amounts of the beta-glucosidases PYK10/BGLU23 in seedlings and roots or BGLU18 in wounded tissues. These results suggest that ER bodies are involved in the metabolism of glycoside molecules, presumably to produce repellents against pests and fungi. When Arabidopsis roots are homogenized, PYK10 formed large protein aggregates that include other beta-glucosidases (BGLU21 and BGLU22), GDSL lipase-like proteins (GLL22) and cytosolic jacalin-related lectins (PBP1/JAL30, JAL31, JAL33, JAL34 and JAL35). Glucosidase activity increases by the aggregate formation. NAI1, a basic helix-loop-helix transcription factor, regulates the expression of the ER body proteins PYK10 and NAI2. Reduced expression of NAI2, PYK10 and BGLU21 resulted in abnormal ER body formation, indicating that these components regulate ER body formation. PYK10, BGLU21 and BGLU22 possess hydrolytic activity for scopolin, a coumaroyl glucoside that accumulates in the roots of Arabidopsis, and nai1 and pyk10 mutants are more susceptible to the symbiotic fungus Piriformospora indica. Therefore, it appears that the ER body is a unique organelle of Brassicaceae plants that is important for defense against pests and fungi. PMID- 22102698 TI - Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk. AB - Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case-control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65-5.39; P(interact) = 3.6 * 10(-4); FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 7.2 * 10(-4); FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk. PMID- 22102699 TI - Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses. AB - Meningiomas are among the most common intracranial tumors and are mostly curable by surgical resection. However, some populations of meningiomas with benign histological profiles show malignant behavior. The reasons for this inconsistency are yet to be ascertained, and novel diagnostic criteria other than the histological one are urgently needed. The aim of the present study is to subclassify meningiomas from the viewpoint of gene methylation and to determine the subgroup with malignant characteristics. Thirty meningiomas were analyzed using microarrays for 6157 genes and were classified into three clusters on the basis of their methylation status; these were found to be independent of the histological grading. One of the clusters showed a high frequency of recurrence, with a marked accumulation of methylation in a subset of genes. We hypothesized that the aggressive meningiomas universally share characteristic methylation in certain genes; therefore, we chose the genes that strongly contributed to cluster formation. The quantified methylation values of five chosen genes (HOXA6, HOXA9, PENK, UPK3A and IGF2BP1) agreed well with microarray findings, and a scoring system consisting of the five genes significantly correlated with a high frequency of recurrence in an additional validation set of 32 patients. Of particular note is that three cases with malignant transformation already showed hypermethylation at histologically benign stage. In conclusion, a subgroup of meningiomas is characterized by aberrant hypermethylation of the subset of genes in the early stage of tumorigenesis, and our findings highlight the possibility of speculating potential malignancy of meningiomas by assessing methylation status. PMID- 22102700 TI - A role for activated endothelial cells in red blood cell clearance: implications for vasopathology. AB - BACKGROUND: Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and alpha(v) integrin. Phagocytosis via the phosphatidylserine-lactadherin-alpha(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes. DESIGN AND METHODS: Endothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity. RESULTS: Red blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects. CONCLUSIONS: Activated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease. PMID- 22102701 TI - Value of infliximab (Remicade(r)) in patients with low-risk myelodysplastic syndrome: final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group. AB - Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade((r))) is an anti-tumor necrosis factor alpha chimeric antibody that is used in the treatment of patients with rheumatoid arthritis or Crohn's disease. Forty-six patients with myelodysplastic syndromes and a relatively low risk of developing acute leukemia were included in a randomized phase II study assessing the therapeutic activity of two dosages of infliximab administration (3 mg/kg vs. 5 mg/kg). The primary end point was the response rate. Responses were observed in 3 of 22 patients (13.1%) randomized to the 3 mg/kg arm, versus 0 of 21 patients randomized in the 5 mg/kg arm. According to the statistical design of the current study, neither of the two infliximab dose schedules tested showed sufficient activity as a single agent in this cohort of unselected patients with early myelodysplastic syndrome. PMID- 22102702 TI - Erythropoiesis-stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes. AB - BACKGROUND: There are limited reports of thrombosis among myelodysplastic syndrome patients exposed to erythropoiesis stimulating agents. It is not clear whether erythropoiesis stimulating agents are associated with an increased risk of thrombosis in myelodysplastic syndromes, as they are among patients with solid tumors. DESIGN AND METHODS: The association between use of erythropoiesis stimulating agent and transient thrombosis risk in patients with myelodysplastic syndromes was assessed in a case-crossover study nested within a cohort of incident myelodysplastic syndrome patients. Using the US Surveillance, Epidemiology, and End Results Medicare-linked database, cases with an incident diagnosis of deep vein thrombosis were identified. Using conditional logistical regression, the odds of exposure to erythropoiesis stimulating agents in the 12 weeks prior to the incident deep vein thrombosis (hazard period) was compared to the exposure odds in a prior 12-week comparison period. RESULTS: Within the cohort of eligibles with myelodysplastic syndromes (n = 5,673) there were 212 incident cases of deep vein thrombosis events. Mean age was 76.2 (standard deviation = +/- 8.6) years. Use of erythropoiesis stimulating agents was not associated with deep vein thrombosis in the crude nor the adjusted models (OR = 1.21, 95% CI: 0.60, 2.43). Central venous catheter placement (OR = 6.47, 95% CI: 2.37, 17.62) and red blood cell transfusion (OR = 4.60, 95% CI: 2.29, 9.23) were associated with deep vein thrombosis. CONCLUSIONS: Despite the link between use of erythropoiesis stimulating agents and thrombosis among patients with solid tumors, this study provides evidence that their safety profile may be different among patients with myelodysplastic syndromes. PMID- 22102703 TI - BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. AB - The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-kappaB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-kappaB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-kappaB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma. PMID- 22102704 TI - Abrogation of RUNX1 gene expression in de novo myelodysplastic syndrome with t(4;21)(q21;q22). AB - The disruption of RUNX1 function is one of the main mechanisms of disease observed in hematopoietic malignancies and the description of novel genetic events that lead to a RUNX1 loss of function has been accelerated with the development of genomic technologies. Here we describe the molecular characterization of a new t(4;21)(q21;q22) in a de novo myelodysplastic syndrome that resulted in the deletion of the RUNX1 gene. We demonstrated by quantitative real-time RT-PCR an almost complete depletion of the expression of the RUNX1 gene in our t(4;21) case compared with CD34(+) cells that was independent of mutation or DNA methylation. More importantly, we explored and confirmed the possibility that this abrogation also prevented transactivation of RUNX1 target genes, perhaps confirming the genetic origin of the thrombocytopenia and the myelodysplastic features observed in our patient, and certainly mimicking what has been observed in the presence of the RUNX1/ETO fusion protein. PMID- 22102705 TI - Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults. AB - We investigated whether mutations in the KLF1 gene are associated with increased Hb F levels in ethnically diverse patients referred to our laboratory for hemoglobinopathy investigation. Functionally effective KLF1 mutations were identified in 11 out of 131 adult samples with an elevated Hb F level (1.5 25.0%). Eleven different mutations were identified, 9 of which were previously unreported. KLF1 mutations were not identified in a matched cohort of 121 samples with normal Hb F levels (<1.0%). A further novel KLF1 mutation was also found in a sickle cell disease patient with a Hb F level of 20.3% who had a particularly mild phenotype. Our results indicate KLF1 mutations could make a significant contribution to Hb F variance in malarial regions where hemogobinopathies are common. All the mutations identified were heterozygous providing further in vivo evidence that a single altered KLF1 allele is sufficient to increase Hb F levels. PMID- 22102706 TI - Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience. AB - BACKGROUND: Posaconazole is effective as primary antifungal prophylaxis of invasive fungal diseases in patients with acute myeloid leukemia. DESIGN AND METHODS: The impact of primary antifungal prophylaxis administered during front line chemotherapy for acute myeloid leukemia was evaluated by comparing 58 patients who received oral amphotericin B (control group) to 99 patients who received oral posaconazole (posaconazole group). The primary endpoint was the incidence of proven/probable invasive fungal diseases. Secondary endpoints included incidence of invasive aspergillosis, survival at 4 and 12 months after the diagnosis of acute myeloid leukemia and costs. RESULTS: Proven/probable invasive fungal diseases were documented in 51.7% of patients in the control group and in 23.2% in the posaconazole group (P=0.0002). Invasive aspergillosis was documented in 43% of patients in the control group and in 15% in the posaconazole group (P=0.002). No survival difference was observed in patients aged over 60 years. In patients aged 60 years or less, a statistically significant survival advantage was observed at 4 months, but no longer at 12 months, in the posaconazole group (P=0.03). It was calculated that in the posaconazole group there was a mean 50% cost reduction for the antifungal drugs. CONCLUSIONS: Primary antifungal prophylaxis with posaconazole during front-line chemotherapy was effective in preventing invasive fungal diseases in a "real life" scenario of patients with acute myeloid leukemia, resulted in an early but transitory survival advantage in younger patients and was economically advantageous. PMID- 22102707 TI - A novel compound heterozygous HAX1 mutation in a Chinese patient with severe congenital neutropenia and chronic myelomonocytic leukemia transformation but without neurodevelopmental abnormalities. PMID- 22102708 TI - Decrease in JAK2 V617F allele burden is not a prerequisite to clinical response in patients with polycythemia vera. AB - BACKGROUND: Although reduction in the JAK2(V617F) allele burden (%V617F) has been suggested as a criterion for defining disease response to cytoreductive therapy in polycythemia vera, its value as a response monitor is unclear. The purpose of this study is to determine whether a reduction in %V617F in polycythemia vera is a prerequisite to achieving hematologic remission in response to cytoreductive therapy. DESIGN AND METHODS: We compared the clinical and hematologic responses to change in %V617F (molecular response) in 73 patients with polycythemia vera treated with either interferon (rIFNalpha-2b: 28, Peg-rIFNalpha-2a: 18) or non interferon drugs (n=27), which included hydroxyurea (n=8), imatinib (n=12), dasatinib (n=5), busulfan (n=1), and radioactive phosphorus (n=1). Hematologic response evaluation employed Polycythemia Vera Study Group criteria, and molecular response evaluation, European Leukemia Net criteria. RESULTS: Of the 46 treated with interferon, 41 (89.1%) had a hematologic response, whereas only 7 (15.2%) had a partial molecular response. Of the 27 who received non-interferon treatments, 16 (59.3%) had a hematologic response, but only 2 (7.4%) had a molecular response. Median duration of follow up was 2.8 years. Statistical agreement between hematologic response and molecular response was poor in all treatment groups. CONCLUSIONS: Generally, hematologic response was not accompanied by molecular response. Therefore, a quantitative change in %V617F is not required for clinical response in patients with polycythemia vera. PMID- 22102709 TI - Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909. AB - BACKGROUND: In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. DESIGN AND METHODS: Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. RESULTS: Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. CONCLUSIONS: Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma. PMID- 22102710 TI - MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response. AB - BACKGROUND: MicroRNAs can play an important role in tumorigenesis through post transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma. DESIGN AND METHODS: MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets. RESULTS: The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574 3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, 30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, 9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502 3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively. CONCLUSIONS: Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival. PMID- 22102711 TI - Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma. AB - BACKGROUND: Genetic abnormalities are common in patients with multiple myeloma, and may deregulate gene products involved in tumor survival, proliferation, metabolism and drug resistance. In particular, translocations may result in a high expression of targeted genes (termed spike expression) in tumor cells. We identified spike genes in multiple myeloma cells of patients with newly-diagnosed myeloma and investigated their prognostic value. DESIGN AND METHODS: Genes with a spike expression in multiple myeloma cells were picked up using box plot probe set signal distribution and two selection filters. RESULTS: In a cohort of 206 newly diagnosed patients with multiple myeloma, 2587 genes/expressed sequence tags with a spike expression were identified. Some spike genes were associated with some transcription factors such as MAF or MMSET and with known recurrent translocations as expected. Spike genes were not associated with increased DNA copy number and for a majority of them, involved unknown mechanisms. Of spiked genes, 36.7% clustered significantly in 149 out of 862 documented chromosome (sub)bands, of which 53 had prognostic value (35 bad, 18 good). Their prognostic value was summarized with a spike band score that delineated 23.8% of patients with a poor median overall survival (27.4 months versus not reached, P<0.001) using the training cohort of 206 patients. The spike band score was independent of other gene expression profiling-based risk scores, t(4;14), or del17p in an independent validation cohort of 345 patients. CONCLUSIONS: We present a new approach to identify spike genes and their relationship to patients' survival. PMID- 22102712 TI - Iron deficiency does not compromise the diagnosis of high HbA(2) beta thalassemia trait. PMID- 22102720 TI - Is there a typical germinal center? A large-scale immunohistological study on the cellular composition of germinal centers during the hapten-carrier-driven primary immune response in mice. AB - Germinal centers (GCs) are complex, multicell-type, transient structures that form in secondary lymphatic tissues in response to T cell-dependent stimulation. This process is crucial to the adaptive immune response because it is the source of affinity maturation and long-lived B cell memory. Our previous studies showed that the growth of murine splenic GCs is nonsynchronized, involving broad-volume distributions of individual GCs at any time. This raises the question whether such a thing as a typical GC exists. To address this matter, we acquired large scale confocal data on GCs throughout the course of the 2-phenyl-5-oxazolone chicken serum albumin-driven primary immune response in BALB/c mice. Semiautomated image analysis of 3457 GC sections revealed that, although there is no typical GC in terms of size, GCs have a typical cellular composition in that the cell ratios of resident T cells, macrophages, proliferating cells, and apoptotic nuclei are maintained during the established phase of the response. Moreover, our data provide evidence that the dark zone (DZ) and light zone (LZ) compartments of GCs are about the same size and led us to estimate that the minimal cell loss rate in GCs is 3% per hour. Furthermore, we found that the population of GC macrophages is larger and more heterogeneous than previously thought, and that despite enrichment of T cells in the LZ, the DZ of murine splenic GCs is not poor in T cells. DZ and LZ differ in the T cell-to-macrophage ratio rather than in the density of T cells. PMID- 22102721 TI - A novel pathway responsible for lipopolysaccharide-induced translational regulation of TNF-alpha and IL-6 expression involves protein kinase C and fascin. AB - Fascin, as a substrate of protein kinase C (PKC), is a well-known cytoskeletal regulatory protein required for cell migration, invasion, and adhesion in normal and cancer cells. In an effort to identify the role of fascin in PKC-mediated cellular signaling, its expression was suppressed by stable transfection of specific short hairpin RNAs (shRNAs) in mouse monocytic leukemia RAW264.7 cells. Suppression of fascin expression resulted in impaired cellular migration and invasion through extracellular matrix proteins. Unexpectedly, the specific shRNA transfectants exhibited a marked reduction in LPS-induced expression of TNF-alpha and IL-6 by blocking the translation of their mRNAs. Transient transfection assay using a luciferase expression construct containing the 3' untranslated region of TNF-alpha or IL-6 mRNA revealed a significant reduction in both LPS- and PMA- (the direct activator of PKC) induced reporter activity in cells transfected with fascin-specific shRNA, indicating that fascin-mediated translational regulation targeted 3' untranslated region. Furthermore, LPS-induced translational activation of reporter expression was blocked by a pharmacological inhibitor of PKC, and the dominant-negative form of PKCalpha attenuated LPS-induced translational activation. The same type of regulation was also observed in the human monocytic leukemia cell line THP-1 and in mouse peritoneal macrophages. These data demonstrate the involvement of fascin in the PKC-mediated translational regulation of TNF-alpha and IL-6 expression during the LPS response. PMID- 22102722 TI - P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals. AB - Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL 1alpha, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1alpha, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1beta by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout. PMID- 22102723 TI - Deciphering the pathways of death of Histoplasma capsulatum-infected macrophages: implications for the immunopathogenesis of early infection. AB - Apoptosis of leukocytes is known to strongly influence the immunopathogenesis of infection. In this study, we dissected the death pathways of murine macrophages (MPhis) infected with the intracellular pathogen Histoplasma capsulatum. Yeast cells caused apoptosis of MPhis at a wide range of multiplicity of infection, but smaller inocula resulted in delayed detection of apoptosis. Upon infection, caspases 3 and 1 were activated, and both contributed to cell death; however, only the former was involved in apoptosis. The principal driving force for apoptosis involved the extrinsic pathway via engagement of TNFR1 by TNF-alpha. Infected MPhis produced IL-10 that dampened apoptosis. The chronology of TNF alpha and IL-10 release differed in vitro. The former was detected by 2 h postinfection, and the latter was not detected until 8 h postinfection. In vivo, the lungs of TNFR1(-/-) mice infected for 1 d contained fewer apoptotic MPhis than wild-type mice, whereas the lungs of IL-10(-/-) mice exhibited more. Blockade of apoptosis by a pan-caspase inhibitor or by simvastatin sharply reduced the release of TNF-alpha but enhanced IL-10. However, these treatments did not modify the fungal burden in vitro over 72 h. Thus, suppressing cell death modulated cytokine release but did not alter the fungal burden. These findings provide a framework for the early pathogenesis of histoplasmosis in which yeast cell invasion of lung MPhis engenders apoptosis, triggered in part in an autocrine TNF-alpha-dependent manner, followed by release of IL-10 that likely prevents apoptosis of newly infected neighboring phagocytes. PMID- 22102724 TI - Interaction of streptavidin-based peptide-MHC oligomers (tetramers) with cell surface TCRs. AB - The binding of oligomeric peptide-MHC (pMHC) complexes to cell surface TCR can be considered to approximate TCR-pMHC interactions at cell-cell interfaces. In this study, we analyzed the equilibrium binding of streptavidin-based pMHC oligomers (tetramers) and their dissociation kinetics from CD8(pos) T cells from 2C-TCR transgenic mice and from T cell hybridomas that expressed the 2C TCR or a high affinity mutant (m33) of this TCR. Our results show that the tetramers did not come close to saturating cell-surface TCR (binding only 10-30% of cell-surface receptors), as is generally assumed in deriving affinity values (K(D)), in part because of dissociative losses from tetramer-stained cells. Guided by a kinetic model, the oligomer dissociation rate and equilibrium constants were seen to depend not only on monovalent association and dissociation rates (k(off) and k(on)), but also on a multivalent association rate (MU) and TCR cell-surface density. Our results suggest that dissociation rates could account for the recently described surprisingly high frequency of tetramer-negative, functionally competent T cells in some T cell responses. PMID- 22102725 TI - Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation. AB - PGD(2) is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD(2) synthesis, the hematopoietic PGD synthase (H PGDS). In this study, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD(2). PGD(2) synthesis was evaluated within human blood eosinophils, in vitro differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD(2) was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within nonstimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1-5 MUM) evoked PGD(2) synthesis, which was located at the nuclear envelope and was inhibited by pretreatment with HQL-79 (10 MUM), a specific H-PGDS inhibitor. Prestimulation of human eosinophils with arachidonic acid (10 MUM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD(2) synthesis, which, by acting on membrane-expressed specific receptors (D prostanoid receptors 1 and 2), displayed an autocrine/paracrine ability to trigger leukotriene C(4) synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD(2) in response to arachidonic acid stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD(2)-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD(2), hence representing during allergic inflammation an extra cell source of PGD(2), which functions as an autocrine signal for eosinophil activation. PMID- 22102726 TI - BAFF/APRIL inhibition decreases selection of naive but not antigen-induced autoreactive B cells in murine systemic lupus erythematosus. AB - BAFF inhibition is a new B cell-directed therapeutic strategy for autoimmune disease. Our purpose was to analyze the effect of BAFF/APRIL availability on the naive and Ag-activated B cell repertoires in systemic lupus erythematosus, using the autoreactive germline D42 H chain (glD42H) site-directed transgenic NZB/W mouse. In this article, we show that the naive Vkappa repertoire in both young and diseased glD42H NZB/W mice is dominated by five L chains that confer no or low-affinity polyreactivity. In contrast, glD42H B cells expressing L chains that confer high-affinity autoreactivity are mostly deleted before the mature B cell stage, but are positively selected and expanded in the germinal centers (GCs) as the mice age. Of these, the most abundant is VkappaRF (Vkappa16-104*01), which is expressed by almost all IgG anti-DNA hybridomas derived from the glD42H mouse. Competition with nonautoreactive B cells or BAFF/APRIL inhibition significantly inhibited selection of glD42H B cells at the late transitional stage, with only subtle effects on the glD42H-associated L chain repertoire. However, glD42H/VkappaRF-encoded B cells were still vastly overrepresented in the GC, and serum IgG anti-DNA Abs arose with only a slight delay. Thus, although BAFF/APRIL inhibition increases the stringency of negative selection of the naive autoreactive B cell repertoire in NZB/W mice, it does not correct the major breach in B cell tolerance that occurs at the GC checkpoint. PMID- 22102727 TI - Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration. AB - AIMS: In atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate into the subendothelial space and proliferate, contributing to neointimal formation. The goal of this study was to define the signalling pathway by which Nox1 NAPDH oxidase mediates SMC migration. METHODS AND RESULTS: SMCs were cultured from thoracic aorta from Nox1(-/y) (Nox1 knockout, KO) and wild-type (WT) mice. In response to thrombin, WT but not Nox1 KO SMCs generated increased levels of reactive oxygen species (ROS). Deficiency of Nox1 prevented thrombin induced phosphorylation of Src and the subsequent transactivation of the epidermal growth factor receptor (EGFR) at multiple tyrosine residues. Next, activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and matrix metalloproteinase-9 (MMP-9) by thrombin was inhibited by the EGFR inhibitor AG1478 and in Nox1 KO SMCs. Thrombin-induced shedding of N-cadherin from the plasma membrane was dependent on the presence of Nox1 and was blocked by AG1478 and an inhibitor of metalloproteinases. Migration of SMCs to thrombin was impaired in the Nox1 KO SMCs and was restored by expression of Nox1. Finally, treatment of WT SMCs with AG1478 abrogated Nox1-dependent SMC migration. CONCLUSIONS: The Nox1 NADPH oxidase signals through EGFR to activate MMP-9 and promote the shedding of N-cadherin, thereby contributing to SMC migration. PMID- 22102728 TI - A remembrance of Baruj Benacerraf (AAI '57) 1920-2011. PMID- 22102729 TI - Comment on "The inhibiting Fc receptor for IgG, FcgammaRIIB, is a modifier of autoimmune susceptibility". PMID- 22102730 TI - Cytokine signaling: birth of a pathway. PMID- 22102731 TI - Pillars article: A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992. 70: 313-322. PMID- 22102732 TI - Pillars article: Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992. 257: 809-813. PMID- 22102733 TI - Synergistic adaptive mutations in the hemagglutinin and polymerase acidic protein lead to increased virulence of pandemic 2009 H1N1 influenza A virus in mice. AB - Influenza impressively reflects the paradigm of a viral disease in which continued evolution of the virus is of paramount importance for annual epidemics and occasional pandemics in humans. Because of the continuous threat of novel influenza outbreaks, it is essential to gather further knowledge about viral pathogenicity determinants. Here, we explored the adaptive potential of the influenza A virus subtype H1N1 variant isolate A/Hamburg/04/09 (HH/04) by sequential passaging in mice lungs. Three passages in mice lungs were sufficient to dramatically enhance pathogenicity of HH/04. Sequence analysis identified 4 nonsynonymous mutations in the third passage virus. Using reverse genetics, 3 synergistically acting mutations were defined as pathogenicity determinants, comprising 2 mutations in the hemagglutinin (HA[D222G] and HA[K163E]), whereby the HA(D222G) mutation was shown to determine receptor binding specificity and the polymerase acidic (PA) protein F35L mutation increasing polymerase activity. In conclusion, synergistic action of all 3 mutations results in a mice lethal pandemic H1N1 virus. PMID- 22102734 TI - Prevalence and correlates of Mycoplasma genitalium infection among female sex workers in Kampala, Uganda. AB - BACKGROUND: The importance of Mycoplasma genitalium in human immunodeficiency virus (HIV)-burdened sub-Saharan Africa is relatively unknown. We assessed the prevalence and explored determinants of this emerging sexually transmitted infection (STI) in high-risk women in Uganda. METHODS: Endocervical swabs from 1025 female sex workers in Kampala were tested for Mycoplasma genitalium using a commercial Real-TM polymerase chain reaction assay. Factors associated with prevalent Mycoplasma genitalium, including sociodemographics, reproductive history, risk behavior, and HIV and other STIs, were examined using multivariable logistic regression. RESULTS: The prevalence of Mycoplasma genitalium was 14% and higher in HIV-positive women than in HIV-negative women (adjusted odds ratio [OR], 1.64; 95% confidence interval [CI], 1.12-2.41). Mycoplasma genitalium infection was less prevalent in older women (adjusted OR, 0.61; 95% CI, .41-.90 for women ages 25-34 years vs <25 years; adjusted OR, 0.32; 95% CI, .15-.71 for women >= 35 years vs those <25 years) and in those who had been pregnant but never had a live birth (adjusted OR, 2.25; 95% CI, 1.04-4.88). Mycoplasma genitalium was associated with Neisseria gonorrhoeae (adjusted OR, 1.84; 95% CI, 1.13-2.98) and with Candida infection (adjusted OR, 0.41; 95% CI, .18-.91), and there was some evidence of association with Trichomonas vaginalis (adjusted OR, 1.56; 95% CI, 1.00-2.44). CONCLUSIONS: The relatively high prevalence of Mycoplasma genitalium and its association with prevalent HIV urgently calls for further research to explore the potential role this emerging STI plays in the acquisition and transmission of HIV infection. PMID- 22102735 TI - Formylated peptides are important virulence factors in Staphylococcus aureus arthritis in mice. AB - BACKGROUND: Staphylococcus aureus is the most common pathogen causing septic arthritis in humans. The affected joints are often rapidly and permanently damaged despite antibiotic treatment, indicating that the elicited host immune response contributes substantially to joint destruction. Bacterial formylated peptides are important chemotactic molecules mediating neutrophil recruitment into infected tissues as an important first step of host defense against invading bacteria. The role of formylated peptides in S. aureus infections has been unknown. METHODS: Mice were intravenously inoculated with wild-type S. aureus strain RN4220 or its isogenic mutant strain (Deltafmt) lacking the ability to produce formylated peptides. The development of arthritis was followed clinically and histopathologically. RESULTS: Mice inoculated with the formyl peptide producing wild-type strain showed a significantly increased frequency and severity of arthritis and subsequent joint destruction as compared with Deltafmt mutant strain-inoculated mice. The wild-type S. aureus strain also induced significantly more weight loss than the Deltafmt mutant strain. The recruitment of neutrophils into infected kidneys and synovial tissue was significantly higher in mice inoculated with the wild-type strain. CONCLUSIONS: Our data show that formylated peptides function as important virulence factors in S. aureus arthritis, partly by mediating neutrophil recruitment, which contributes substantially to the joint damage. PMID- 22102736 TI - A comparison of multimodality treatment: two and four courses of neoadjuvant chemotherapy using S-1/CDDP or S-1/CDDP/docetaxel followed by surgery and S-1 adjuvant chemotherapy for macroscopically resectable serosa-positive gastric cancer: a randomized phase II trial (COMPASS-D trial). AB - This randomized Phase II trial will compare the outcome of neoadjuvant chemotherapy using two and four courses of S-1 plus cisplatin or S-1 plus cisplatin plus docetaxel by a two-by-two factorial design for patients with macroscopically resectable serosa-positive gastric cancer. After neoadjuvant chemotherapy, patients will receive D2 gastrectomy followed by S-1 chemotherapy for 1 year postoperatively. The primary endpoint is the 3-year overall survival. The sample size is 120 for the two hypotheses: the superiority of four courses compared with two courses and the superiority of S-1 plus cisplatin plus docetaxel compared with S-1 plus cisplatin. This trial will be able to define the more suitable number of cycles and better regimen of neoadjuvant chemotherapy for gastric cancer. PMID- 22102737 TI - Number of lymph nodes retrieved is an important determinant of survival of patients with stage II and stage III colorectal cancer. AB - OBJECTIVE: The number of lymph nodes retrieved is recognized to be a prognostic factor of Stage II colorectal cancer. However, the prognostic significance of the number of lymph nodes retrieved in Stage III colorectal cancer remains controversial. METHODS: The relationship between the number of lymph nodes retrieved and clinical and pathological factors, and significance of the number of lymph nodes retrieved for prognosis of Stage II and III colorectal cancer were investigated. A total of 16 865 patients with T3/T4 colorectal cancer who had R0 resection were analysed. RESULTS: The arithmetic mean of the number of lymph nodes retrieved of all cases was 20.0. The number of lymph nodes retrieved were varied according to several clinical and pathological variables with significant difference, and the greater difference was observed in scope of nodal dissection. Survival of Stages II and III was significantly associated with the number of lymph nodes retrieved. Five-year overall survival of the patients with <= 9 of the number of lymph nodes retrieved and those with >27 differed by 6.4% for Stage II colon cancer, 8.8% for Stage III colon cancer, 12.5% for Stage II rectal cancer and 10.6% for Stage III rectal cancer. With one increase in the number of lymph nodes retrieved, the mortality risk was decreased by 2.1% for Stage II and by 0.8% for Stage III, respectively. The cut-off point of the number of lymph nodes retrieved was not obtained. CONCLUSIONS: The number of lymph nodes retrieved was shown to be an important prognostic variable not only in Stage II but also in Stage III colorectal cancer, and it was most prominently determined by the scope of nodal dissection. A cut-off value for the number of lymph nodes retrieved was not found, and it is necessary to carry out appropriate nodal dissection and examine as many lymph nodes as possible. PMID- 22102738 TI - Lessons learned from experiences in academic leadership. PMID- 22102739 TI - To record or not to record? PMID- 22102740 TI - Academic performance in a pharmacotherapeutics course sequence taught synchronously on two campuses using distance education technology. AB - OBJECTIVE: To compare the academic performance of campus-based students in a pharmacotherapeutics course with that of students at a distant campus taught via synchronous teleconferencing. METHODS: Examination scores and final course grades for campus-based and distant students completing the case-based pharmacotherapeutics course sequence over a 5-year period were collected and analyzed. RESULTS: The mean examination scores and final course grades were not significantly different between students on the 2 campuses. CONCLUSIONS: The use of synchronous distance education technology to teach students does not affect students' academic performance when used in an active-learning, case-based pharmacotherapeutics course. PMID- 22102741 TI - Perceptions of pharmacy technicians and students regarding technicians as pharmacy instructors. AB - OBJECTIVE: To understand technicians' attitudes toward teaching student pharmacists and students' attitudes toward learning from technicians. METHODS: Survey data concerning technicians' perceived importance of pharmacy skills and their confidence in teaching those skills to student pharmacists were collected, as was survey data concerning students' comfort level with learning skills from technicians. Skills included in each survey aligned with common student pharmacist competencies and the pharmacy technician certification examination. RESULTS: Fifty-eight (92.1%) responses were received from technicians and 141(97.9%) student survey instruments were returned. The skills that pharmacy technicians perceived to be most important and felt most comfortable teaching included filling a prescription and communicating effectively with patients. With the exception of communication, these skills also aligned with what the students were most comfortable learning from technicians. CONCLUSIONS: Student pharmacists have learning goals that align with the daily tasks of pharmacy technicians. The survey results highlight areas in which technicians could be used to educate student pharmacists. PMID- 22102742 TI - Impact of interprofessional activities on health professions students' knowledge of community pharmacists' role and services. AB - OBJECTIVES: To determine the impact of health professions students' participation in interprofessional activities on their knowledge of the roles of community pharmacists and community pharmacist-provided services. METHODS: Students at the Medical University of South Carolina were surveyed via a self-administered online survey tool to determine their participation in interprofessional activities as well as their knowledge of the role of community pharmacists and community pharmacist-provided services. RESULTS: Over 600 students completed the survey instrument. Nonpharmacy students who attended the university-sponsored Interprofessional Day were more knowledgeable of pharmacist-provided services. Previous interaction with a pharmacist increased nonpharmacy students' awareness of the services that pharmacists provide. CONCLUSION: Participation in interprofessional activities increased health professions students' awareness of the role of pharmacists. Continued education among healthcare professions about the role of and services provided by pharmacists is needed to ensure that pharmacists have the greatest possible impact on patient care. PMID- 22102743 TI - Job and career satisfaction among pharmacy preceptors. AB - OBJECTIVES: To examine the perceived benefit of job and career satisfaction among pharmacist preceptors and to explore other factors that might influence satisfaction. METHODS: A cross-sectional self-administered survey instrument was mailed to pharmacists in the South Central region of the United States who had active 2010 licenses to investigate whether being a pharmacist preceptor increases job and career satisfaction. RESULTS: Twenty-three percent of the 363 respondents were active preceptors and 62% of these reported that they had been preceptors at some point in the past. Being an active preceptor was significantly related to increased job satisfaction (p = 0.01) but not to career satisfaction. Having a perceived benefit of continuing education and being professionally challenged at work also were associated with increased job and career satisfaction (p < 0.001). CONCLUSIONS: Pharmacist preceptors have higher levels of self-reported job satisfaction. PMID- 22102744 TI - The role of curriculum committees in pharmacy education. AB - OBJECTIVE: To conduct a follow-up survey of curriculum committee chairs in US colleges and schools of pharmacy to describe current committee structures and functions and determine whether changes have occurred over time. METHODS: A descriptive cross-sectional study design using a 30-item survey instrument regarding the structure, function, and charges of curriculum committees was sent to 100 curriculum committee chairs. Several new variables were added to the questionnaire to explore the use of systematic reviews, oversight of experiential education, and the impact of accreditation standards on work focus. RESULTS: Eighty-five chairs responded. Curriculum committees are on average 1 person larger, less likely to have a student vote, more likely to have formal charges, and more likely to be involved in implementing an outcomes-based curriculum compared with 1994. Committees have shifted their work focus from review of curricular content to curricular revision. CONCLUSIONS: Curriculum committees continue to evolve as they respond to changes in pharmacy education and accreditation standards. PMID- 22102745 TI - Relationship between admission data and pharmacy student involvement in extracurricular activities. AB - OBJECTIVES: To assess pharmacy student involvement in leadership and service roles and to evaluate the association between admissions data and student involvement. METHODS: Doctor of pharmacy (PharmD) students were invited to complete a 56-item online survey instrument containing questions regarding leadership and service involvement, work experiences, perceived contribution of involvement to skill development, and perceived importance of involvement. Responses were linked to admissions data to identify possible associations. RESULTS: Five hundred fourteen (82.4%) pharmacy students completed the survey instrument. Students with higher admissions application and interview scores were more likely to be involved in organizations and hold leadership roles, while students with higher admissions grade point averages were less likely to be involved in organizations and leadership roles. CONCLUSIONS: Assessing students' involvement in leadership and service roles can assist in the evaluation of students' leadership skills and lead to modification of curricular and co curricular activities to provide development opportunities. Student involvement in extracurricular activities may encourage future involvement in and commitment to the pharmacy profession. PMID- 22102746 TI - Physical assessment experience in a problem-based learning course. AB - OBJECTIVE: To evaluate the impact of a physical-assessment learning experience implemented in the problem-based learning (PBL) format of the third year of a doctor of pharmacy (PharmD) program. DESIGN: Students enrolled in a PBL course completed survey instruments to measure knowledge and confidence before and after participating in the learning experience. A simulation stethoscope was used to teach students abnormal pulmonary and cardiovascular sounds in 1-hour sessions for each of 12 PBL groups. ASSESSMENT: The 92 students enrolled in the PBL course completed pre- and post-experience survey instruments. Students' scores on knowledge questions increased significantly (p < 0.0001) from 40.4% +/- 11.4% at baseline to 62.5% +/- 13.7% and 63.1 +/- 11.6%, respectively, on the 2 sets of post-experience questions. Students scored a median of 3 or 4 on a 5-point Likert scale after a learning experience on questions measuring confidence. CONCLUSION: Use of a simulation stethoscope in a physical-assessment learning experience increased pharmacy students' knowledge in performing pulmonary and cardiovascular assessment techniques. PMID- 22102747 TI - A course assessment process for curricular quality improvement. AB - OBJECTIVE: To describe a systematic assessment process that provides continuous improvement in the curriculum, supports faculty development, and enhances student learning outcomes. DESIGN: Teams of faculty members, students, and course instructors conducted course assessments, which consisted of monitoring the delivered instruction for agreement with planned content and course integration within the curriculum, and providing ongoing feedback for improving course content, course management, faculty teaching, and student learning experiences. ASSESSMENT: Areas needing improvement were identified and appropriate changes were made. Improvements were achieved in course policy standardization, course integration within the curriculum, faculty teaching behaviors, and student experiences. CONCLUSION: The curriculum assessment plan provides a structured method of monitoring and delivering continuous quality improvement. PMID- 22102748 TI - Impact of the geriatric medication game on pharmacy students' attitudes toward older adults. AB - OBJECTIVE: To examine the impact of participation in the Geriatric Medication Game on pharmacy students' perceptions of and attitudes toward older adults and familiarity with common disabilities that affect them and the process of seeking health care. DESIGN: In the game, first-year pharmacy students "became" older adults during a 3-hour pharmacy practice laboratory. They were given aging related challenges (eg, impaired vision or mobility) and participated as patients in simulated healthcare scenarios, such as a visit to a physician's office and a pharmacy. ASSESSMENT: After playing the game, students completed a 5-question reflection about their experiences and attitudes toward older adults. Content analysis was performed to identify themes from 4 years of student (n = 625) reflections. Predominant themes included: improved attitudes toward older adults, better understanding of patient experiences, and increased willingness to provide assistance. CONCLUSIONS: Incorporating the Geriatric Medication Game into the pharmacy curriculum may facilitate students' understanding of the challenges that older adults face and improve future interactions. PMID- 22102749 TI - An introductory pharmacy practice experience providing pharmaceutical care to elderly patients. AB - OBJECTIVE: To develop, integrate, and assess an introductory pharmacy practice experience (IPPE) in providing pharmaceutical care to patients at senior centers (Silver Scripts). DESIGN: First-year pharmacy students learned and practiced the pharmaceutical care process in the classroom to prepare for participation in the Silver Scripts program, in which the students, under faculty mentorship, conducted comprehensive medication reviews for senior citizens attending senior centers in Pittsburgh, Pennsylvania. ASSESSMENT: Students, preceptors, and senior center staff members indicated the experience was positive. Specifically, first year students felt they gained benefit both from an educational standpoint and in their own personal growth and development, while staff contacts indicated the patients appreciated the interaction with the students. CONCLUSION: The Silver Scripts experience is a model for linking classroom experiences and experiential learning. The cycle of experiencing, reflecting, and learning has provided not only a meaningful experience for our P1 students but also a worthwhile focused review of seniors' medication use. This experience could be used as a model for other colleges and schools of pharmacy and their communities. PMID- 22102750 TI - Historical development and emerging trends of community pharmacy residencies. AB - Clinical pharmacy services necessitate appropriately trained pharmacists. Postgraduate year one (PGY1) community pharmacy residency programs (CPRPs) provide advanced training for pharmacists to provide multiple patient care services in the community setting. These programs provide an avenue to translate innovative ideas and services into clinical practice. In this paper, we describe the history and current status of PGY1 community pharmacy residency programs, including an analysis of the typical settings and services offered. Specific information on the trends of community programs compared with other PGY1 pharmacy residencies is also discussed. The information presented in this paper is intended to encourage discussion regarding the need for increasing the capacity of PGY1 community pharmacy residency programs. PMID- 22102751 TI - Medicinal chemistry and the pharmacy curriculum. AB - The origins and advancements of pharmacy, medicinal chemistry, and drug discovery are interwoven in nature. Medicinal chemistry provides pharmacy students with a thorough understanding of drug mechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A comprehensive understanding of the chemical basis of drug action equips pharmacy students with the ability to answer rationally the "why" and "how" questions related to drug action and it sets the pharmacist apart as the chemical expert among health care professionals. By imparting an exclusive knowledge base, medicinal chemistry plays a vital role in providing critical thinking and evidence-based problem-solving skills to pharmacy students, enabling them to make optimal patient-specific therapeutic decisions. This review highlights the parallel nature of the history of pharmacy and medicinal chemistry, as well as the key elements of medicinal chemistry and drug discovery that make it an indispensable component of the pharmacy curriculum. PMID- 22102752 TI - Patient safety instruction in US health professions education. AB - OBJECTIVE: To describe patient safety instruction in health professional curricula, including medicine, nursing, pharmacy, and dentistry. METHODS: A systematic review of the literature from 1966 through 2010 was conducted using 6 databases and based on 3 search criteria: safety management, patient safety, and curriculum. RESULTS: One hundred fifty-four articles were identified and 23 met inclusion criteria. A variety of educational methods have been used in health profession curricula to promote patient safety including lectures, workshops, objective structured clinical examinations, standardized patients, simulation exercises, root cause analysis, quality assurance projects, and other interactive learning methods. The development of patient safety curricula has been primarily discipline-specific, with little interdisciplinary research found. CONCLUSIONS: Safe, patient-centered care is directly influenced by the quality of education that healthcare professions students receive. From this literature review, research is needed to guide curricular change, specifically focusing on instructional methods and interdisciplinary collaborations. PMID- 22102753 TI - Faculty perceptions of the Educating Pharmacy Students to Improve Quality (EPIQ) program. AB - OBJECTIVE: To investigate users' initial perceptions of and potential applications for the Educating Pharmacy Students and Pharmacists to Improve Quality (EPIQ) program, a 5-module education program designed to educate pharmacists and pharmacy students about quality improvement in pharmacy practice. METHODS: The 5-module EPIQ program was distributed to pharmacy faculty members, pharmacy practitioners, and other health professionals across the country upon request. A 6-item survey instrument was sent to the first 97 people who requested the program. RESULTS: Twenty-seven (56%) of the 55 respondents had reviewed the EPIQ program and 22 (82%) intended to use some or all of the content to teach about quality improvement or patient safety primarily in pharmacy management and medication safety courses. CONCLUSION: Initial perceptions of the EPIQ program were positive; however, further evaluation is needed after more extensive implementation of the program in pharmacy colleges and schools and other settings. PMID- 22102754 TI - Key performance outcomes of patient safety curricula: root cause analysis, failure mode and effects analysis, and structured communications skills. AB - As colleges and schools of pharmacy develop core courses related to patient safety, course-level outcomes will need to include both knowledge and performance measures. Three key performance outcomes for patient safety coursework, measured at the course level, are the ability to perform root cause analyses and healthcare failure mode effects analyses, and the ability to generate effective safety communications using structured formats such as the Situation-Background Assessment-Recommendation (SBAR) situational briefing model. Each of these skills is widely used in patient safety work and competence in their use is essential for a pharmacist's ability to contribute as a member of a patient safety team. PMID- 22102755 TI - Vital role of interest in improvement of pharmacy education in India and worldwide. PMID- 22102756 TI - A new paradigm in clinical pharmacy teaching in Pakistan. PMID- 22102757 TI - Standardization in the evaluation system of Pakistan's Pharmacy Institutes. PMID- 22102758 TI - Address of the president. PMID- 22102759 TI - Carotenoid response to retinal excitation and photoisomerization dynamics in xanthorhodopsin. AB - We present a comparative study of xanthorhodopsin, a proton pump with the carotenoid salinixanthin serving as an antenna, and the closely related bacteriorhodopsin. Upon excitation of retinal, xanthorhodopsin exhibits a wavy transient absorption pattern in the region between 470 and 540 nm. We interpret this signal as due to electrochromic effect of the transient electric field of excited retinal on salinixanthin. The spectral shift decreases during the retinal dynamics through the ultrafast part of the photocycle. Differences in dynamics of bacteriorhodopsin and xanthorhodopsin are discussed. PMID- 22102760 TI - A systematic examination of different parameters of presession exposure to tangible stimuli that maintain problem behavior. AB - We examined the effects of three different presession conditions on tangibly maintained problem behavior for 2 students with autism, using individual participant multielement designs. First, an analogue functional analysis demonstrated that problem behavior was maintained by access to tangible items. Next, topographies of item rejection were identified. Finally, students were exposed to (a) brief access, (b) no access, and (c) satiation to the tangible items prior to tangible sessions. The results demonstrated high levels of problem behavior following the brief-access and no-access presession conditions and low levels of problem behavior following the satiation condition. The findings are discussed in the context of how satiation might best be defined for these sorts of evaluations. PMID- 22102761 TI - Religion in families 1999 to 2009: A relational spirituality framework. AB - This review examines the role of religion, for better and worse, in marital and parent-child relationships according to peer reviewed studies from 1999-2009. A conceptual framework labeled "relational spirituality" is used to: (a) organize the breadth of findings into the three stages of the formation, maintenance, and transformation of family relationships, and (b) illustrate three in-depth sets of mechanisms to delve into unique ways religion may shape family bonds. Topics include union formation, fertility, spousal roles, marital satisfaction and conflict, divorce, domestic violence, infidelity, pregnancy, parenting children, parenting adolescents, and coping with family distress. Conclusions emphasize moving beyond markers of general religiousness and identifying specific spiritual beliefs and practices that could prevent or intensify problems in traditional and nontraditional families. PMID- 22102762 TI - Methodological Advances Permit the Stereocontrolled Construction of Diverse Fully Synthetic Tetracyclines Containing an All-Carbon Quaternary Center at Position C5a. AB - Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of compounds in this important family of therapeutic agents. In the key transformation and an important extension of the powerful Michael-Claisen cyclization (AB plus D) approach to the construction of fully synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon center can be assembled by highly stereocontrolled coupling reactions of beta-substituted AB enones and o-toluate ester anion D-ring precursors. Novel and versatile beta-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 1 (the key precursor to fully synthetic tetracyclines) into a diverse range of beta-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a beta methyl ester-substituted AB enone. A C5a-C11a-bridged cyclopropane tetracycline precursor was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged cyclopropane intermediate served as (further) diversifiable branch-points, allowing maximally expedient synthesis of C5a substituted tetracyclines by final-step diversification. PMID- 22102763 TI - Long Term-Survival after Radical Prostatectomy for men with High Gleason Sum. PMID- 22102764 TI - The Sparse Laplacian Shrinkage Estimator for High-Dimensional Regression. AB - We propose a new penalized method for variable selection and estimation that explicitly incorporates the correlation patterns among predictors. This method is based on a combination of the minimax concave penalty and Laplacian quadratic associated with a graph as the penalty function. We call it the sparse Laplacian shrinkage (SLS) method. The SLS uses the minimax concave penalty for encouraging sparsity and Laplacian quadratic penalty for promoting smoothness among coefficients associated with the correlated predictors. The SLS has a generalized grouping property with respect to the graph represented by the Laplacian quadratic. We show that the SLS possesses an oracle property in the sense that it is selection consistent and equal to the oracle Laplacian shrinkage estimator with high probability. This result holds in sparse, high-dimensional settings with p ? n under reasonable conditions. We derive a coordinate descent algorithm for computing the SLS estimates. Simulation studies are conducted to evaluate the performance of the SLS method and a real data example is used to illustrate its application. PMID- 22102765 TI - Adolescents' Sexual Initiation: The Interaction of Race/Ethnicity and Immigrant Status. AB - This paper provides an in-depth examination of the joint effects of race/ethnicity and immigrant status on adolescents' intercourse risk. We employ a sample of 4,535 females and 3,759 males from the National Education Longitudinal Study (NELS 88/94) who were followed for 6 years beginning in the eighth grade. We use discrete-time logistic regression models to estimate the associations of race/ethnicity and immigrant generational status with first intercourse hazard, and to evaluate the statistical interactions between race/ethnicity and immigrant status. Overall, Asian and Hispanic girls had lower and non-Hispanic Black girls had higher estimated risks relative to non-Hispanic White girls. Hispanic boys and White non-Hispanic boys had similar intercourse risks, but Black boys had higher and Asian boys lower relative risks. However, these patterns are contingent on immigrant status. Among girls, the protective effects of Asian or Hispanic identity are found only among second generation youth. Risk profiles for boys are more complex: being a third-plus generation Hispanic is associated with a higher risk while an Asian identity is associated with a lower risk only among first- and second-generation youth. These findings confirm the importance of accounting for the overlap between race/ethnicity and immigrant status in models of adolescent behavior. As the demographic diversity of the US population grows, researchers must include both race/ethnicity and immigrant status in their models of adolescent behavior. PMID- 22102766 TI - Neighborhood Disadvantage, Residential Stability, and Perceptions of Instrumental Support among New Mothers. AB - Using longitudinal data from the Fragile Families and Child Wellbeing study (N = 4,211), we examine neighborhood disadvantage and perceptions of instrumental support among mothers with young children. We find that: (a) living in a disadvantaged neighborhood is associated with less instrumental support, particularly financial assistance, from family and friends; (b) residential stability is associated with stronger personal safety nets irrespective of neighborhood quality; and (c) mothers who move to a more disadvantaged neighborhood experience a small but significant decline in perceived instrumental support compared to those who do not move. In interpreting these results, we suggest instrumental support may be either a cause or consequence of living in an advantaged neighborhood, but, in either case, neighborhood and social network disadvantages go hand in hand. PMID- 22102767 TI - The occupational and quality of life consequences of chronic fatigue syndrome/myalgic encephalomyelitis in young people. AB - INTRODUCTION: Chronic fatigue syndrome, termed myalgic encephalomyelitis in the United Kingdom (CFS/ME), is a debilitating condition involving severe exhaustion, cognitive difficulties, educational and vocational losses, and disruption of social activities and relationships. CFS/ME may affect volition (that is, value, interest and sense of competence). PURPOSE: To test Model of Human Occupation (MOHO) concepts by comparing young people with and without CFS/ME in terms of occupational participation, volition and health-related quality of life during infection and over time. METHOD: Three hundred and one people (12-18 years old) diagnosed with glandular fever were evaluated at the time of acute infection (baseline). Six months following diagnosis, 39 of them met the criteria for CFS/ME. A further 39 who recovered were randomly selected and matched to CFS/ME participants. Both groups were re-evaluated at 12 months and 24 months. The Occupational Self Assessment and the Child General Health Questionnaire were used to compare occupational participation. RESULTS: Those with CFS/ME reported lower levels of perceived competency, more difficulties with physical functioning and poorer general health status than those who recovered. CONCLUSION: Those with CFS/ME report lower perceived competency, and compromises in physical functioning, school performance, social activities, emotional functioning and general health. This supports the MOHO assertion that impairments affect volition and quality of life. PMID- 22102768 TI - A Simple Distribution-Free Algorithm for Generating Simulated High-Dimensional Correlated Data with an Autoregressive Structure. AB - A distribution-free method to generate high-dimensional sequences of dependent variables with an autoregressive structure is presented. The quantile or fractile correlation (i.e., the moment correlation of the quantiles) is used as measure of dependence among a set of contiguous variables. The proposed algorithm breaks the sequence in small parts and avoids having to define one large correlation matrix for the entire high-dimensional sequence of variables. Simulations based on proteomics data are presented. Results suggest that negligible or no loss of fractile correlation occurs by splitting the generation of a sequence into small parts. PMID- 22102769 TI - Skin Testing With Water Buffalo's Milk in Children With Cow's Milk Allergy. AB - BACKGROUND: Cow's milk allergy is the most common food allergy in young children. In areas outside the United States, milk from other mammals has been studied as a possible and desirable alternative for children with cow's milk allergy. OBJECTIVES: We chose to further investigate water buffalo's milk as an alternative for cow's milk allergic children in the United States. METHODS: Children with cow's milk allergy were skin prick tested with water buffalo's milk. Additionally, subjects were followed clinically for 1 year after the test to determine how many of the subjects had persistent cow's milk allergy. RESULTS: In total, 30 children, age 8 months to 8 years, were skin prick tested to water buffalo's milk with 73% (22/30) having a positive test. All children with a negative water buffalo's milk skin test also had a negative cow's milk skin test. In follow-up, most (7 of 8) of the children with a negative skin prick test (SPT) to water buffalo's milk were found to have outgrown their cow's milk allergy. In comparison, all of the subjects with a positive skin test to water buffalo's milk had persistent cow's milk allergy. After adjusting for this, we determined that 96% (22/23) of the children with persistent cow's milk allergy were positive on skin testing to water buffalo's milk. CONCLUSIONS: In this population, the vast majority of children with persistent cow's milk allergy were positive on skin prick testing to water buffalo's milk. These results indicate that water buffalo's milk is unlikely to be a successful alternative for children with cow's milk allergy. PMID- 22102770 TI - An efficient approach to the deployment of complex open source information systems. AB - Complex open source information systems are usually implemented as component based software to inherit the available functionality of existing software packages developed by third parties. Consequently, the deployment of these systems not only requires the installation of operating system, application framework and the configuration of services but also needs to resolve the dependencies among components. The problem becomes more challenging when the application must be installed and used on different platforms such as Linux and Windows. To address this, an efficient approach using the virtualization technology is suggested and discussed in this paper. The approach has been applied in our project to deploy a web-based integrated information system in molecular genetics labs. It is a low-cost solution to benefit both software developers and end-users. PMID- 22102771 TI - EuDBase: An online resource for automated EST analysis pipeline (ESTFrontier) and database for red seaweed Eucheuma denticulatum. AB - Functional genomics has proven to be an efficient tool in identifying genes involved in various biological functions. However the availability of commercially important seaweed Eucheuma denticulatum functional resources is still limited. EuDBase is the first seaweed online repository that provides integrated access to ESTs of Eucheuma denticulatum generated from samples collected from Kudat and Semporna in Sabah, Malaysia. The database stored 10,031 ESTs that are clustered and assembled into 2,275 unique transcripts (UT) and 955 singletons. Raw data were automatically processed using ESTFrontier, an in-house automated EST analysis pipeline. Data was collected in MySQL database. Web interface is implemented using PHP and it allows browsing and querying EuDBase through search engine. Data is searchable via BLAST hit, domain search, Gene Ontology or KEGG Pathway. A user-friendly interface allows the identification of sequences either using a simple text query or similarity search. The development of EuDBase is initiated to store, manage and analyze the E. denticulatum ESTs and to provide accumulative digital resources for the use of global scientific community. EuDBase is freely available from http://www.inbiosis.ukm.my/eudbase/. PMID- 22102772 TI - Identification of hub proteins from sequence. AB - Identification of hub proteins from sequence is a challenge in molecular biology. Therefore, it is of interest to predict protein hubs in networks. We describe the prediction of protein "hub" using physiochemical, thermodynamic and conformational properties of amino acid residues in sequence. We have used twenty sequence based features to identify hub behaviour. Linear discriminant analysis and normalised Bayesian approach were utilized for identifying hub proteins solely using these sequence features in E. coli/H. sapiens datasets with accuracies of 99.5/98.6, 87.8/89.6 and 90.1/92.6, respectively. PMID- 22102773 TI - An improved hybrid of SVM and SCAD for pathway analysis. AB - Pathway analysis has lead to a new era in genomic research by providing further biological process information compared to traditional single gene analysis. Beside the advantage, pathway analysis provides some challenges to the researchers, one of which is the quality of pathway data itself. The pathway data usually defined from biological context free, when it comes to a specific biological context (e.g. lung cancer disease), typically only several genes within pathways are responsible for the corresponding cellular process. It also can be that some pathways may be included with uninformative genes or perhaps informative genes were excluded. Moreover, many algorithms in pathway analysis neglect these limitations by treating all the genes within pathways as significant. In previous study, a hybrid of support vector machines and smoothly clipped absolute deviation with groups-specific tuning parameters (gSVM-SCAD) was proposed in order to identify and select the informative genes before the pathway evaluation process. However, gSVM-SCAD had showed a limitation in terms of the performance of classification accuracy. In order to deal with this limitation, we made an enhancement to the tuning parameter method for gSVM-SCAD by applying the B-Type generalized approximate cross validation (BGACV). Experimental analyses using one simulated data and two gene expression data have shown that the proposed method obtains significant results in identifying biologically significant genes and pathways, and in classification accuracy. PMID- 22102774 TI - Comparative Study of different msDNA (multicopy single-stranded DNA) structures and phylogenetic comparison of reverse transcriptases (RTs): evidence for vertical inheritance. AB - The multi-copy single-stranded DNA (msDNA) is yielded by the action of reverse transcriptase of retro-element in a wide range of pathogenic bacteria. Upon this phenomenon, it has been shown that msDNA is only produced by Eubacteria because many Eubacteria species contained reverse transcriptase in their special retro element. We have screened around 111 Archaea at KEGG (Kyoto Encyclopedia of Genes and Genomes) database available at genome net server and observed three Methanosarcina species (M.acetivorans, M.barkeri and M.mazei), which also contained reverse transcriptase in their genome sequences. This observation of reverse transcriptase in Archaea raises questions regarding the origin of this enzyme. The evolutionary relationship between these two domains of life (Eubacteria and Archaea) hinges upon the phenomenon of retrons. Interestingly, the evolutionary trees based on the reverse transcriptases (RTs) and 16S ribosomal RNAs point out that all the Eubacteria RTs were descended from Archaea RTs during their evolutionary times. In addition, we also have shown some significant structural features among the newly identified msDNA-Yf79 in Yersinia frederiksenii with other of its related msDNAs (msDNA-St85, msDNA-Vc95, msDNA Vp96, msDNA-Ec78 and msDNA-Ec83) from pathogenic bacteria. Together the degree of sequence conservation among these msDNAs, the evolutionary trees and the distribution of these ret (reverse transcriptase) genes suggest a possible evolutionary scenario. The single common ancestor of the organisms of Eubacteria and Archaea subgroups probably achieved this ret gene during their evolution through the vertical descent rather than the horizontal transformations followed by integration into this organism genome by a mechanism related to phage recognition and/or transposition. PMID- 22102775 TI - Characterization of mitogen activated protein kinases (MAPKs) in the Curcuma longa expressed sequence tag database. AB - Mitogen activated protein kinase (MAPK) cascades are universal signal transduction modules that play crucial role in plant growth and development as well as biotic and abiotic stress responses. 20 and 17 MAPKs have been characterized in Arabidopsis and rice respectively, which are used for identification of the putative MAPKs in other higher plants. However, no MAPK gene sequences have yet been characterized for asexually reproducing plants. We describe the analysis of MAPK EST sequences from Curcuma longa (an asexually reproducible plant of great medicinal and economic significance). The four Curcuma MAPKs contains all 11 MAPK conserved domains and phosphorylation activation motif, TEY. Phylogenetic analysis grouped them in the subgroup A and C as identified earlier for Arabidopsis. The Curcuma MAPKs identified showed high sequence homology to rice OsMPK3, OsMPK4 and OsMPK5 suggesting the presence of similar key element in signaling biotic and abiotic stress responses. Although further in vivo and in vitro analysis are required to establish the physiological role of Curcuma MAPKs, this study provides the base for future research on diverse signaling pathways mediated by MAPKs in Curcuma longa as well as other asexually reproducing plants. PMID- 22102776 TI - MD simulation and experimental evidence for Mg2+ binding at the B site in human AP endonuclease 1. AB - Apurinic/apyrimidinic endonuclease 1 (APE1), a central enzyme in the base excision repair pathway, cleaves damaged DNA in Mg(2+) dependent reaction. Despite characterization of nine X-ray crystallographic structures of human APE1, in some cases, bound to various metal ions and substrate/product, the position of the metal ion and its stoichiometry for the cleavage reaction are still being debated. While a mutation of the active site E96Q was proposed to eliminate Mg(2+) binding at the "A" site, we show experimentally that this mutant still requires Mg(2+) at concentration similar to that for the wild type enzyme to cleave the AP site in DNA. Molecular dynamics simulations of the wild type APE1, E96Q and a double missense mutant E96Q + D210N indicate that Mg(2+) placed at the A-site destabilizes the bound AP site-containing DNA. In these simulations, the H bond chain D238-H309-AP site oxygen is broken and the substrate DNA is shifted away from its crystal structure position (1DE9). In contrast, simulations with the Mg(2+) at site B or A+B sites leave the substrate DNA at the position shown in the crystal structure (1DE9). Taken together our MD simulations and biochemical analysis suggests that Mg(2+) binding at the B site is involved in the reaction mechanism associated with endonuclease function of APE1. PMID- 22102777 TI - Active compound from the leaves of Vitex negundo L. shows anti-inflammatory activity with evidence of inhibition for secretory Phospholipase A(2) through molecular docking. AB - Novel compounds with significant medicinal properties have gained much interest in therapeutic approaches for treating various inflammatory disorders like arthritis, odema and snake bites and the post-envenom (impregnating with venom) consequences. Inflammation is caused by the increased concentration of secretory Phospholipases A(2) (sPLA(2)s) at the site of envenom. A novel compound Tris(2,4 di-tert-butylphenyl) phosphate (TDTBPP) was isolated from the leaves of Vitex negundo and the crystal structure was reported recently. The acute anti inflammatory activity of TDTBPP was assessed by Carrageenan-induced rat paw odema method. TDTBPP reduced the raw paw odema volume significantly at the tested doses of 50 mg/kg and 70 mg/kg body weight. Molecular docking studies were carried out with the X-ray crystal structures of Daboia russelli pulchella's (Vipera russelli, Indian Russell's viper) venom sPLA(2) and Human non-pancreatic secretory PLA(2) (Hnps PLA(2)) as targets to illustrate the antiinflammatory and antidote activities of TDTBPP. Docking results showed hydrogen bond (H-bond) interaction with Lys69 residue lying in the anti-coagulant loop of D. russelli's venom PLA(2), which is essential in the catalytic activity of the enzyme and hydrophobic interactions with the residues at the binding site (His48, Asp49). Docking of TDTBPP with Hnps PLA(2) structure showed coordination with calcium ion directly as well as through the catalytically important water molecule (HOH1260) located at the binding site. PMID- 22102778 TI - Molecular modeling and identification of substrate binding site of orphan human cytochrome P450 4F22. AB - Cytochrome P450s are superfamily of heme proteins which generally monooxygenate hydrophobic compounds. The human cytochrome P450 4F22 (CYP4F22) was categorized into "orphan" CYPs because of its unknown function. CYP4F22 is a potential drug target for cancer therapy. However, three-dimensional structure, the active site topology and substrate specificity of CYP4F22 remain unclear. In this study, a three-dimensional model of human P450 4F22 was constructed by comparative modeling using Modeller 9v5. The resulting model was refined by energy minimization subjected to the quality assessment from both geometric and energetic aspects and was found to be of reasonable quality. Docking approach was employed to dock arachidonic acid into the active site of CYP4F22 in order to probe the ligand-binding modes. As a result, several key residues were identified to be responsible for the binding of arachidonic acid with CYP4F22. These findings provide useful information for understanding the biological roles of CYP4F22 and structure-based drug design. PMID- 22102779 TI - New or otherwise interesting lichenized and lichenicolous fungi from Montenegro. AB - A list of 256 taxa of lichens (252 species) and 2 species of lichenicolous fungi from Montenegro is presented, including 58 taxa (57 species) new to Montenegro. The list is based on specimens kept in the lichen collections of the herbaria GZU, H, Podgorica, and in the private herbarium of Klaus Kalb, and on recent field work in various parts of the country. The genera Biatoridium, Carbonea, Cercidospora, Heppia, Hyperphyscia, Hypocenomyce, Leprocaulon, Lethariella, Megalospora, Orphniospora, Psorinia and Vahliella are reported from Montenegro for the first time. PMID- 22102780 TI - Additional lichens and some lichenicolous fungi from the Una National Park (Bosnia and Herzegovina). AB - A list of 62 taxa (61 species) of lichens and 7 species of lichenicolous fungi from the Una National Park in the north-western part of Bosnia and Herzegovina is presented. The lichens Caloplaca crenulatella, Dimerella pineti, Lecanora expallens, Lopadium disciforme, Placynthiella icmalea, Toninia athallina and the lichenicolous fungi Abrothallus bertianus, A. parmeliarum, Cornutispora lichenicola, Endococcus rugulosus, and Sphaerellothecium parmeliae are new to Bosnia and Herzegovina. PMID- 22102781 TI - The etiology of mathematical self-evaluation and mathematics achievement: understanding the relationship using a cross-lagged twin study from age 9 to 12. AB - The genetic and environmental origins of individual differences in mathematical self-evaluation over time and its association with later mathematics achievement were investigated in a UK sample of 2138 twin pairs at ages 9 and 12. Self evaluation indexed how good children think they are at mathematical activities and how much they like those activities. Mathematics achievement was assessed by teachers based on UK National Curriculum standards. At both ages self-evaluation was approximately 40% heritable, with the rest of the variance explained by non shared environment. The results also suggested moderate reciprocal associations between self-evaluation and mathematics achievement across time, with earlier self-evaluation predicting later performance and earlier performance predicting later self-evaluation. These cross-lagged relationships were genetically rather than environmentally mediated. PMID- 22102782 TI - High School Gay-Straight Alliances (GSAs) and Young Adult Well-Being: An Examination of GSA Presence, Participation, and Perceived Effectiveness. AB - Gay-Straight Alliances (GSAs) are student-led, school-based clubs that aim to provide a safe environment in the school context for lesbian, gay, bisexual, and transgender (LGBT) students, as well as their straight allies. The present study examines the potential for GSAs to support positive youth development and to reduce associations among LGBT-specific school victimization and negative young adult well-being. The sample includes 245 LGBT young adults, ages 21-25, who retrospectively reported on the presence of a GSA in their high school, their participation in their school's GSA, and their perceptions of whether or not their GSA was effective in improving school safety. Findings revealed that the presence of a GSA, participation in a GSA, and perceived GSA effectiveness in promoting school safety were differentially associated with young adult well being and in some cases, buffered the negative association between LGBT-specific school victimization and well-being. Implications for future research and schools are discussed. PMID- 22102783 TI - Troponin elevation in conditions other than acute coronary syndromes. AB - Acute coronary syndromes comprise a large spectrum of clinical conditions ranging from unstable angina pectoris to acute ST-elevation myocardial infarction. Chest pain is usually the major symptom of atherosclerotic heart disease; however, it may be challenging to diagnose correctly, especially in the emergency department, because of the ambiguous way that pain is characterized by some patients. Cardiac troponins are sensitive and specific biomarkers used in the diagnosis of myocardial infarction that are released into the bloodstream when cardiac myocytes are damaged by acute ischemia or any other mechanism. They are the cornerstone for the diagnosis, risk assessment, prognosis, and determination of antithrombotic and revascularization strategies. However, troponin elevation indicates the presence, not the mechanism, of myocardial injury. There are many clinical conditions other than myocardial infarction that cause troponin elevation; thus, the physician should be aware of the wide spectrum of disease states that may result in troponin elevation and have a clear understanding of the related pathophysiology to effectively make a differential diagnosis. This review focuses on causes of troponin elevation other than acute coronary syndromes. PMID- 22102784 TI - Indications for and utilization of angiotensin receptor II blockers in patients at high cardiovascular risk. AB - The worldwide burden of cardiovascular disease is growing. In addition to lifestyle changes, pharmacologic agents that can modify cardiovascular disease processes have the potential to reduce cardiovascular events. Antihypertensive agents are widely used to reduce the risk of cardiovascular events partly beyond that of blood pressure-lowering. In particular, the angiotensin II receptor blockers (ARBs), which antagonize the vasoconstrictive and proinflammatory/pro proliferative effects of angiotensin II, have been shown to be cardio vascularly protective and well tolerated. Although the eight currently available ARBs are all indicated for the treatment of hypertension, they have partly different pharmacology, and their pharmacokinetic and pharmacodynamic properties differ. ARB trials for reduction of cardiovascular risk can be broadly categorized into those in patients with/without hypertension and additional risk factors, in patients with evidence of cardiovascular disease, and in patients with severe cardiovascular disease, such as heart failure. These differences have led to their indications in different populations. For hypertensive patients with left ventricular hypertrophy, losartan was approved to have an indication for stroke prevention, while for most patients at high-risk for cardiovascular events, telmisartan is an appropriate therapy because it has a cardiovascular preventive indication. Other ARBs are indicated for narrowly defined high-risk patients, such as those with hypertension or heart failure. Although in one analysis a possible link between ARBs and increased risks of cancer has surfaced, several meta-analyses, using the most comprehensive data available, have found no link between any ARB, or the class as a whole, and cancer. Most recently, the US Food and Drug Administration completed a review of the potential risk of cancer and concluded that treatment with an ARB medication does not increase the risk of developing cancer. This review discusses the clinical evidence supporting the different indications for each of the ARBs and the outstanding safety of this drug class. PMID- 22102785 TI - Retrograde rotational thrombectomy with the Rotarex catheter system: treatment option for an acute thrombotic occlusion of a subclavian artery. AB - PURPOSE: The Rotarex catheter system is an effective tool for endovascular therapy of acute occluded arteries of the lower extremities, especially for the femoral artery. The authors report the use of the Rotarex catheter system for retrograde percutaneous thrombectomy of an occluded subclavian artery. CASE PRESENTATION: A 79-year-old male patient was referred because of acute pain and paleness of his left arm. Ultrasound examination and computed tomography angiography proved an occlusion of the left subclavian artery from the origin of the vessel. A retrograde recanalization was attempted using the 6F Rotarex catheter and combined with initiation of a local low-dose lytic therapy. A normal blood flow to the left arm was restored. Follow-up examination 3 months later showed a normal perfusion situation of the left upper extremity. CONCLUSION: The Rotarex catheter system is an effective tool for endovascular therapy of acute occluded arteries and efficacy is not restricted to the lower extremities. PMID- 22102786 TI - Prevalence of significant carotid artery stenosis in Iranian patients with peripheral arterial disease. AB - BACKGROUND: Generalized screening for carotid artery stenosis with carotid duplex ultrasonography in patients with peripheral arterial disease is controversial. OBJECTIVES: The aim of the present study was to determine the prevalence of significant internal carotid artery (ICA) stenosis in a group of Iranian patients with peripheral arterial disease. METHODS: We prospectively screened 120 patients with a known diagnosis of peripheral vascular disease for carotid artery stenosis. Based on the angiographic assessment of abdominal aorta and arteries of the lower extremities, patients with stenosis greater than 70% in the lower extremity arteries were included. A group of healthy individuals aged >= 50 years was recruited as a control. Risk factors for atherosclerosis including smoking, diabetes mellitus, hyperlipidemia, ischemic heart disease, and cerebrovascular disease were recorded. Common carotid arteries (CCAs) and the origins of the internal and external arteries were scanned with B-mode ultrasonography. Significant ICA stenosis, > 70% ICA stenosis but less than near occlusion of the ICA, was diagnosed when the ICA/CCA peak systolic velocity ratio was >= 3.5. RESULTS: Ninety-five patients, with a mean age of 58.52 +/- 11.04 years, were studied. Twenty-five patients had a history of smoking, six patients had a history of coronary artery disease, six patients had hypertension, and ten patients had diabetes mellitus. Significant ICA stenosis was present in four patients (4.2%) with peripheral arterial disease in one healthy individual (1%) of the control group (P > 0.05). In terms of the risk factors for atherosclerosis, no statistically significant relationship was found between individual atherosclerotic risk factors and significant ICA stenosis (P > 0.05). CONCLUSION: The prevalence of significant ICA stenosis in Iranian patients with peripheral arterial disease is low. In addition, there is no relationship between individual atherosclerotic risk factors and significant ICA stenosis. PMID- 22102787 TI - Effects of smoking cessation on central blood pressure and arterial stiffness. AB - PURPOSE: Smoking affects arterial stiffness, thus causing an elevation in central blood pressure (CBP). The present study was designed to examine whether smoking cessation treatment improved CBP and arterial stiffness. PATIENTS AND METHODS: We conducted an observational study of 70 patients receiving smoking cessation treatment. Before and 60 weeks after the start of a 12-week varenicline treatment, we measured brachial blood pressure, CBP, brachial-ankle pulse wave velocity (baPWV), normalized radial augmentation index (rAIx@75), left ventricular weight, and left ventricular diastolic function of each patient. The data were compared between the patients who succeeded in quitting smoking (smoking cessation group; n = 37) and those who failed to quit smoking (smoking group; n = 33). RESULTS: Baseline characteristics were similar in both groups. Brachial blood pressure remained unchanged in both groups. CBP, baPWV, and rAIx@75 decreased significantly in the smoking cessation group, while these parameters showed no significant change in the smoking group. Thus, CBP, baPWV, and rAIx@75 showed greater decrease in the smoking cessation group than in the smoking group (CBP, -7.1 +/- 1.4 mmHg vs 1.2 +/- 2.7 mmHg; P < 0.01; baPWV, -204 +/- 64 cm/s vs -43 +/- 72 cm/s; P < 0.01; rAIx@75, -6.4 +/- 2.8% vs -1.0 +/- 3.9%; P < 0.01). Left ventricular weight and left ventricular diastolic function remained unchanged in both groups. CONCLUSION: Patients in the smoking cessation group showed significant improvement in CBP, baPWV, and rAIx@75. These results indicate that smoking cessation can improve arterial stiffness and CBP. PMID- 22102789 TI - Demand-Withdraw Patterns in Marital Conflict in the Home. AB - The present study extended laboratory-based findings of demand-withdraw communication into marital conflict in the home and further explored its linkages with spousal depression. U.S. couples (N = 116) provided diary reports of marital conflict and rated depressive symptoms. Hierarchical linear modeling results indicated that husband demand-wife withdraw and wife demand-husband withdraw occurred in the home at equal frequency, and both were more likely to occur when discussing topics that concerned the marital relationship. For both patterns, conflict initiator was positively linked to the demander role. Accounting for marital satisfaction, both demand-withdraw patterns predicted negative emotions and tactics during marital interactions and lower levels of conflict resolution. Spousal depression was linked to increased likelihood of husband demand-wife withdraw. PMID- 22102788 TI - Strategies for the prevention and treatment of sudden cardiac death. AB - Cardiovascular diseases account for 40% of all deaths in the West. Sudden cardiac death (SCD) is a major health problem affecting over 300,000 patients annually in the United States alone. Presence of coronary artery disease (CAD), usually in the setting of diminished left ventricular ejection fraction, is still the single major risk factor for SCD. Additionally, acute myocardial ischemia, structural cardiac defects, anomalous coronary arteries, cardiomyopathies, genetic mutations, and ventricular arrhythmias are all attributed to SCD, demonstrating the perplexity of this condition. With the recent advancements in cardiovascular medicine, the incidence of SCD is expected to increase steeply as the prevalence of CAD and heart failure is uprising in general population. Considering SCD, the major challenge confronting contemporary cardiology, multiple strategies for prevention against SCD have been developed. beta-blockers have been shown to reduce the risk of SCD, whereas implantable cardioverter-defibrillator devices are found to be effective at terminating the malignant arrhythmias. In recent years, multiple clinical trials were carried out to identify patients who may benefit from preventive intervention, including medical therapy and automatic cardioverter-defibrillator implantations. This review article provides insight into the advanced strategies for the prevention and treatment of SCD based on the data available in medical literature to date. PMID- 22102790 TI - Graph Theoretic Foundations of Multibody Dynamics Part I: Structural Properties. AB - This is the first part of two papers that use concepts from graph theory to obtain a deeper understanding of the mathematical foundations of multibody dynamics. The key contribution is the development of a unifying framework that shows that key analytical results and computational algorithms in multibody dynamics are a direct consequence of structural properties and require minimal assumptions about the specific nature of the underlying multibody system. This first part focuses on identifying the abstract graph theoretic structural properties of spatial operator techniques in multibody dynamics. The second part paper exploits these structural properties to develop a broad spectrum of analytical results and computational algorithms.Towards this, we begin with the notion of graph adjacency matrices and generalize it to define block-weighted adjacency (BWA) matrices and their 1-resolvents. Previously developed spatial operators are shown to be special cases of such BWA matrices and their 1 resolvents. These properties are shown to hold broadly for serial and tree topology multibody systems. Specializations of the BWA and 1-resolvent matrices are referred to as spatial kernel operators (SKO) and spatial propagation operators (SPO). These operators and their special properties provide the foundation for the analytical and algorithmic techniques developed in the companion paper.We also use the graph theory concepts to study the topology induced sparsity structure of these operators and the system mass matrix. Similarity transformations of these operators are also studied. While the detailed development is done for the case of rigid-link multibody systems, the extension of these techniques to a broader class of systems (e.g. deformable links) are illustrated. PMID- 22102791 TI - Graph Theoretic Foundations of Multibody Dynamics Part II: Analysis and Algorithms. AB - This second, of a two part paper, uses concepts from graph theory to obtain a deeper understanding of the mathematical foundations of multibody dynamics. The first part [7] established the block-weighted adjacency (BWA) matrix structure of spatial operators associated with serial and tree topology multibody system dynamics, and introduced the notions of spatial kernel operators (SKO) and spatial propagation operators (SPO). This paper builds upon these connections to show that key analytical results and computational algorithms are a direct consequence of these structural properties and require minimal assumptions about the specific nature of the underlying multibody system. We formalize this notion by introducing the notion of SKO models for general tree-topology multibody systems. We show that key analytical results, including mass matrix factorization, inversion, and decomposition hold for all SKO models. It is also shown that key low-order scatter/gather recursive computational algorithms follow directly from these abstract-level analytical results. Application examples to illustrate the concrete application of these general results are provided. The paper also describes a general recipe for developing SKO models. The abstract nature of SKO models allows the application of these techniques to a very broad class of multibody systems. PMID- 22102792 TI - Cyclic electrowinning/precipitation (CEP) system for the removal of heavy metal mixtures from aqueous solutions. AB - The description and operation of a novel cyclic electrowinning/precipitation (CEP) system for the simultaneous removal of mixtures of heavy metals from aqueous solutions are presented. CEP combines the advantages of electrowinning in a spouted particulate electrode (SPE) with that of chemical precipitation and redissolution, to remove heavy metals at low concentrations as solid metal deposits on particulate cathode particles without exporting toxic metal precipitate sludges from the process. The overall result is very large volume reduction of the heavy metal contaminants as a solid metal deposit on particles that can either be safely discarded as such, or further processed to recover particular metals. The performance of this system is demonstrated with data on the removal of mixtures of copper, nickel, and cadmium from aqueous solutions. PMID- 22102793 TI - GENES AS INSTRUMENTS FOR STUDYING RISK BEHAVIOR EFFECTS: AN APPLICATION TO MATERNAL SMOKING AND OROFACIAL CLEFTS. AB - This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child's risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered "weak" in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4-5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the "causal" effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes. PMID- 22102794 TI - Replacing fossil oil with fresh oil - with what and for what? AB - Industrial chemicals and materials are currently derived mainly from fossil-based raw materials, which are declining in availability, increasing in price and are a major source of undesirable greenhouse gas emissions. Plant oils have the potential to provide functionally equivalent, renewable and environmentally friendly replacements for these finite fossil-based raw materials, provided that their composition can be matched to end-use requirements, and that they can be produced on sufficient scale to meet current and growing industrial demands. Replacement of 40% of the fossil oil used in the chemical industry with renewable plant oils, whilst ensuring that growing demand for food oils is also met, will require a trebling of global plant oil production from current levels of around 139 MT to over 400 MT annually. Realisation of this potential will rely on application of plant biotechnology to (i) tailor plant oils to have high purity (preferably >90%) of single desirable fatty acids, (ii) introduce unusual fatty acids that have specialty end-use functionalities and (iii) increase plant oil production capacity by increased oil content in current oil crops, and conversion of other high biomass crops into oil accumulating crops. This review outlines recent progress and future challenges in each of these areas.Practical applications: The research reviewed in this paper aims to develop metabolic engineering technologies to radically increase the yield and alter the fatty acid composition of plant oils and enable the development of new and more productive oil crops that can serve as renewable sources of industrial feedstocks currently provided by non-renewable and polluting fossil-based resources. As a result of recent and anticipated research developments we can expect to see significant enhancements in quality and productivity of oil crops over the coming decades. This should generate the technologies needed to support increasing plant oil production into the future, hopefully of sufficient magnitude to provide a major supply of renewable plant oils for the industrial economy without encroaching on the higher priority demand for food oils. Achievement of this goal will make a significant contribution to moving to a sustainable carbon-neutral industrial society with lower emissions of carbon dioxide to the atmosphere and reduced environmental impact as a result. PMID- 22102795 TI - Molecular Self Assembly: Solvent Guests Tune the Conformation of a Series of 2,6 Bis(2-anilinoethynyl)pyridine-Based Ureas. AB - The conformations of 2,6-bis(2-anilinoethynyl)pyridine-based urea receptors were studied by single crystal X-ray diffraction methods and revealed a rich conformational flexibility influenced by solvents. Whereas receptor L(1) in DMSO prefers an "S" conformation, receptor L(1) crystallizes in an "O" conformation from DMSO/CH(3)OH binary solvent system, and a "W" conformation in the ternary solvent mixture DMSO/toluene/1,4-dioxane. In the case of L(2), the molecule adopts an "S" conformation where water molecules are sandwiched between two molecules of L(2) to form a dimer. Similar to L(2), L(3) also forms a dimer where water molecules are sandwiched between L(3) molecules, which are capped with two molecules of DMSO. Such a capping DMSO solvate is lacking in the case of L(2). Taken together, these results demonstrate that the conformation of 2,6-bis(2 anilinoethynyl) pyridine-based urea receptors can be dramatically manipulated and tuned by the choice of crystallization solvents. PMID- 22102796 TI - Enhancing Drug Treatment Program Staff's Self-Efficacy to Support Patients' HCV Needs. AB - To increase HCV-related support for patients in substance abuse treatment programs, we implemented an on-site staff training in 16 programs throughout the United States. It aimed to increase participants' self-efficacy in assisting patients with their HCV-related needs. Findings indicate that participants' self efficacy increased both 1- and 3-months post-training, resulting in providers' perceptions that they were better able to support patients regarding HCV. Implementing an engaging and interactive HCV training for social workers and other substance abuse treatment program staff has the potential to increase their HCV knowledge, self-efficacy, and the HCV-related assistance provided to patients both in the short- and longer-term. PMID- 22102797 TI - "Children" Having Children. PMID- 22102798 TI - Georgia Health - Go Local: Using Multidisciplinary Partnerships to Promote a Statewide Consumer Health Website. AB - The National Library of Medicine ended its support of the Go Local program in 2010 due to declining usage, but in many ways Georgia's project was a success. From its beginning, Georgia Health - Go Local was a model of successful collaboration among a variety of partners and institutions throughout the state. The high usage statistics for the Go Local website and the support garnered by the project exemplify the positive nature of the collaborations that made the project possible. PMID- 22102799 TI - Healthy DC - Go Local: It Takes a Village. AB - Since the acceptance of the Healthy DC - Go Local proposal in November 2007, members of the District of Columbia Area Health Sciences Libraries group supported the project by offering their time to select health care services, perform data entry, review records, and promote the database to their organizations. Although the amount of work required to sustain the database became more than the Go Local team was able to handle, the collaboration, dedication, and persistence of project managers, volunteers, and part-time staff members was what made the project a truly collaborative one and an ultimately successful resource for Washington, DC health care consumers. PMID- 22102800 TI - Identification of biochemical network modules based on shortest retroactive distances. AB - Modularity analysis offers a route to better understand the organization of cellular biochemical networks as well as to derive practically useful, simplified models of these complex systems. While there is general agreement regarding the qualitative properties of a biochemical module, there is no clear consensus on the quantitative criteria that may be used to systematically derive these modules. In this work, we investigate cyclical interactions as the defining characteristic of a biochemical module. We utilize a round trip distance metric, termed Shortest Retroactive Distance (ShReD), to characterize the retroactive connectivity between any two reactions in a biochemical network and to group together network components that mutually influence each other. We evaluate the metric on two types of networks that feature feedback interactions: (i) epidermal growth factor receptor (EGFR) signaling and (ii) liver metabolism supporting drug transformation. For both networks, the ShReD partitions found hierarchically arranged modules that confirm biological intuition. In addition, the partitions also revealed modules that are less intuitive. In particular, ShReD-based partition of the metabolic network identified a 'redox' module that couples reactions of glucose, pyruvate, lipid and drug metabolism through shared production and consumption of NADPH. Our results suggest that retroactive interactions arising from feedback loops and metabolic cycles significantly contribute to the modularity of biochemical networks. For metabolic networks, cofactors play an important role as allosteric effectors that mediate the retroactive interactions. PMID- 22102801 TI - Computational modeling and analysis of insulin induced eukaryotic translation initiation. AB - Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS 1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow. PMID- 22102802 TI - Stochastic delay accelerates signaling in gene networks. AB - The creation of protein from DNA is a dynamic process consisting of numerous reactions, such as transcription, translation and protein folding. Each of these reactions is further comprised of hundreds or thousands of sub-steps that must be completed before a protein is fully mature. Consequently, the time it takes to create a single protein depends on the number of steps in the reaction chain and the nature of each step. One way to account for these reactions in models of gene regulatory networks is to incorporate dynamical delay. However, the stochastic nature of the reactions necessary to produce protein leads to a waiting time that is randomly distributed. Here, we use queueing theory to examine the effects of such distributed delay on the propagation of information through transcriptionally regulated genetic networks. In an analytically tractable model we find that increasing the randomness in protein production delay can increase signaling speed in transcriptional networks. The effect is confirmed in stochastic simulations, and we demonstrate its impact in several common transcriptional motifs. In particular, we show that in feedforward loops signaling time and magnitude are significantly affected by distributed delay. In addition, delay has previously been shown to cause stable oscillations in circuits with negative feedback. We show that the period and the amplitude of the oscillations monotonically decrease as the variability of the delay time increases. PMID- 22102803 TI - Representational switching by dynamical reorganization of attractor structure in a network model of the prefrontal cortex. AB - The prefrontal cortex (PFC) plays a crucial role in flexible cognitive behavior by representing task relevant information with its working memory. The working memory with sustained neural activity is described as a neural dynamical system composed of multiple attractors, each attractor of which corresponds to an active state of a cell assembly, representing a fragment of information. Recent studies have revealed that the PFC not only represents multiple sets of information but also switches multiple representations and transforms a set of information to another set depending on a given task context. This representational switching between different sets of information is possibly generated endogenously by flexible network dynamics but details of underlying mechanisms are unclear. Here we propose a dynamically reorganizable attractor network model based on certain internal changes in synaptic connectivity, or short-term plasticity. We construct a network model based on a spiking neuron model with dynamical synapses, which can qualitatively reproduce experimentally demonstrated representational switching in the PFC when a monkey was performing a goal-oriented action-planning task. The model holds multiple sets of information that are required for action planning before and after representational switching by reconfiguration of functional cell assemblies. Furthermore, we analyzed population dynamics of this model with a mean field model and show that the changes in cell assemblies' configuration correspond to those in attractor structure that can be viewed as a bifurcation process of the dynamical system. This dynamical reorganization of a neural network could be a key to uncovering the mechanism of flexible information processing in the PFC. PMID- 22102804 TI - Dynamical and structural analysis of a T cell survival network identifies novel candidate therapeutic targets for large granular lymphocyte leukemia. AB - The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a bird's-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network. PMID- 22102805 TI - A density-dependent switch drives stochastic clustering and polarization of signaling molecules. AB - Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization. PMID- 22102806 TI - Reversible and noisy progression towards a commitment point enables adaptable and reliable cellular decision-making. AB - Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation. We found that sporulation proceeded through noisy and reversible steps towards an irreversible, all-or-none commitment point. Specifically, we observed cell-autonomous and spontaneous bursts of gene expression and transient protein localization events during sporulation. Based on these measurements we developed mathematical population models to investigate how the degree of reversibility affects cellular decision-making. In particular, we evaluated the effect of reversibility on the 1) reliability in the progression to sporulation, and 2) adaptability under changing extracellular stress conditions. Results show that reversible progression allows cells to remain responsive to long-term environmental fluctuations. In contrast, the irreversible commitment point supports reliable execution of cell fate choice that is robust against short-term reductions in stress. This combination of opposite dynamic behaviors (reversible and irreversible) thus maximizes both adaptable and reliable decision-making over a broad range of changes in environmental conditions. These results suggest that decision-making systems might employ a general hybrid strategy to cope with unpredictably fluctuating environmental conditions. PMID- 22102807 TI - The role of the P2X7 receptor in infectious diseases. AB - ATP is an extracellular signal for the immune system, particularly during an inflammatory response. It is sensed by the P2X7 receptor, the expression of which is upregulated by pro-inflammatory cytokines. Activation of the P2X7 receptor opens a cation-specific channel that alters the ionic environment of the cell, activating several pathways, including (i) the inflammasome, leading to production of IL-1beta and IL-18; (ii) the stress-activated protein kinase pathway, resulting in apoptosis; (iii) the mitogen-activated protein kinase pathway, leading to generation of reactive oxygen and nitrogen intermediates; and (iv) phospholipase D, stimulating phagosome-lysosome fusion. The P2X7 receptor can initiate host mechanisms to remove pathogens, most particularly those that parasitise macrophages. At the same time, the P2X7 receptor may be subverted by pathogens to modulate host responses. Moreover, recent genetic studies have demonstrated significant associations between susceptibility or resistance to parasites and bacteria, and loss-of-function or gain-of-function polymorphisms in the P2X7 receptor, underscoring its importance in infectious disease. PMID- 22102808 TI - West Nile virus experimental evolution in vivo and the trade-off hypothesis. AB - In nature, arthropod-borne viruses (arboviruses) perpetuate through alternating replication in vertebrate and invertebrate hosts. The trade-off hypothesis proposes that these viruses maintain adequate replicative fitness in two disparate hosts in exchange for superior fitness in one host. Releasing the virus from the constraints of a two-host cycle should thus facilitate adaptation to a single host. This theory has been addressed in a variety of systems, but remains poorly understood. We sought to determine the fitness implications of alternating host replication for West Nile virus (WNV) using an in vivo model system. Previously, WNV was serially or alternately passed 20 times in vivo in chicks or mosquitoes and resulting viruses were characterized genetically. In this study, these test viruses were competed in vivo in fitness assays against an unpassed marked reference virus. Fitness was assayed in chicks and in two important WNV vectors, Culex pipiens and Culex quinquefasciatus. Chick-specialized virus displayed clear fitness gains in chicks and in Cx. pipiens but not in Cx. quinquefasciatus. Cx. pipiens-specialized virus experienced reduced fitness in chicks and little change in either mosquito species. These data suggest that when fitness is measured in birds the trade-off hypothesis is supported; but in mosquitoes it is not. Overall, these results suggest that WNV evolution is driven by alternate cycles of genetic expansion in mosquitoes, where purifying selection is weak and genetic diversity generated, and restriction in birds, where purifying selection is strong. PMID- 22102809 TI - Murid herpesvirus-4 exploits dendritic cells to infect B cells. AB - Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4), infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells. PMID- 22102810 TI - Phytophthora sojae avirulence effector Avr3b is a secreted NADH and ADP-ribose pyrophosphorylase that modulates plant immunity. AB - Plants have evolved pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) to protect themselves from infection by diverse pathogens. Avirulence (Avr) effectors that trigger plant ETI as a result of recognition by plant resistance (R) gene products have been identified in many plant pathogenic oomycetes and fungi. However, the virulence functions of oomycete and fungal Avr effectors remain largely unknown. Here, we combined bioinformatics and genetics to identify Avr3b, a new Avr gene from Phytophthora sojae, an oomycete pathogen that causes soybean root rot. Avr3b encodes a secreted protein with the RXLR host-targeting motif and C-terminal W and Nudix hydrolase motifs. Some isolates of P. sojae evade perception by the soybean R gene Rps3b through sequence mutation in Avr3b and lowered transcript accumulation. Transient expression of Avr3b in Nicotiana benthamiana increased susceptibility to P. capsici and P. parasitica, with significantly reduced accumulation of reactive oxygen species (ROS) around invasion sites. Biochemical assays confirmed that Avr3b is an ADP-ribose/NADH pyrophosphorylase, as predicted from the Nudix motif. Deletion of the Nudix motif of Avr3b abolished enzyme activity. Mutation of key residues in Nudix motif significantly impaired Avr3b virulence function but not the avirulence activity. Some Nudix hydrolases act as negative regulators of plant immunity, and thus Avr3b might be delivered into host cells as a Nudix hydrolase to impair host immunity. Avr3b homologues are present in several sequenced Phytophthora genomes, suggesting that Phytophthora pathogens might share similar strategies to suppress plant immunity. PMID- 22102811 TI - Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. AB - Human beta-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of beta-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by alpha-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of beta-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria. PMID- 22102812 TI - Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR. AB - Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen. PMID- 22102813 TI - The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB. AB - Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands. PMID- 22102814 TI - CD4 T cell immunity is critical for the control of simian varicella virus infection in a nonhuman primate model of VZV infection. AB - Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses. PMID- 22102815 TI - Galactosaminogalactan, a new immunosuppressive polysaccharide of Aspergillus fumigatus. AB - A new polysaccharide secreted by the human opportunistic fungal pathogen Aspergillus fumigatus has been characterized. Carbohydrate analysis using specific chemical degradations, mass spectrometry, 1H and 13C nuclear magnetic resonance showed that this polysaccharide is a linear heterogeneous galactosaminogalactan composed of alpha1-4 linked galactose and alpha1-4 linked N acetylgalactosamine residues where both monosacharides are randomly distributed and where the percentage of galactose per chain varied from 15 to 60%. This polysaccharide is antigenic and is recognized by a majority of the human population irrespectively of the occurrence of an Aspergillus infection. GalNAc oligosaccharides are an essential epitope of the galactosaminogalactan that explains the universal antibody reaction due to cross reactivity with other antigenic molecules containing GalNAc stretches such as the N-glycans of Campylobacter jejuni. The galactosaminogalactan has no protective effect during Aspergillus infections. Most importantly, the polysaccharide promotes fungal development in immunocompetent mice due to its immunosuppressive activity associated with disminished neutrophil infiltrates. PMID- 22102816 TI - CD11b+, Ly6G+ cells produce type I interferon and exhibit tissue protective properties following peripheral virus infection. AB - The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these actions. Here we demonstrate that innate immune effector cells contain a peripheral poxvirus infection, preventing systemic spread of the virus. These innate immune effector cells are comprised primarily of CD11b+Ly6C+Ly6G- monocytes that accumulate initially at the site of infection, and are then supplemented and eventually replaced by CD11b+Ly6C+Ly6G+ cells. The phenotype of the CD11b+Ly6C+Ly6G+ cells resembles neutrophils, but the infiltration of neutrophils typically occurs prior to, rather than following, accumulation of monocytes. Indeed, it appears that the CD11b+Ly6C+Ly6G+ cells that infiltrated the site of VACV infection in the ear are phenotypically distinct from the classical description of both neutrophils and monocyte/macrophages. We found that CD11b+Ly6C+Ly6G+ cells produce Type I interferons and large quantities of reactive oxygen species. We also observed that depletion of Ly6G+ cells results in a dramatic increase in tissue damage at the site of infection. Tissue damage is also increased in the absence of reactive oxygen species, although reactive oxygen species are typically thought to be damaging to tissue rather than protective. These data indicate the existence of a specialized population of CD11b+Ly6C+Ly6G+ cells that infiltrates a site of virus infection late and protects the infected tissue from immune-mediated damage via production of reactive oxygen species. Regulation of the action of this population of cells may provide an intervention to prevent innate immune-mediated tissue destruction. PMID- 22102817 TI - EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription. AB - Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus. PMID- 22102818 TI - Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner. AB - Despite its relatively poor efficacy, Bacillus Calmette-Guerin (BCG) has been used as a tuberculosis (TB) vaccine since its development in 1921. BCG induces robust T helper 1 (Th1) immune responses but, for many individuals, this is not sufficient for host resistance against Mycobacterium tuberculosis (M. tb) infection. Here we provide evidence that early secreted antigenic target protein 6 (ESAT-6), expressed by the virulent M. tb strain H37Rv but not by BCG, promotes vaccine-enhancing Th17 cell responses. These activities of ESAT-6 were dependent on TLR-2/MyD88 signalling and involved IL-6 and TGF-beta production by dendritic cells. Thus, animals that were previously infected with H37Rv or recombinant BCG containing the RD1 region (BCG::RD1) exhibited improved protection upon re challenge with virulent H37Rv compared with mice previously infected with BCG or RD1-deficient H37Rv (H37RvDeltaRD1). However, TLR-2 knockout (TLR-2-/-) animals neither showed Th17 responses nor exhibited improved protection in response to immunization with H37Rv. Furthermore, H37Rv and BCG::RD1 infection had little effect on the expression of the anti-inflammatory microRNA-146a (miR146a) in dendritic cells (DCs), whereas BCG and H37RvDeltaRD1 profoundly induced its expression in DCs. Consistent with these findings, ESAT-6 had no effect on miR146a expression in uninfected DCs, but dramatically inhibited its upregulation in BCG-infected or LPS-treated DCs. Collectively, our findings indicate that, in addition to Th1 immunity induced by BCG, RD1/ESAT-6-induced Th17 immune responses are essential for optimal vaccine efficacy. PMID- 22102819 TI - Cross-reactive T cells are involved in rapid clearance of 2009 pandemic H1N1 influenza virus in nonhuman primates. AB - In mouse models of influenza, T cells can confer broad protection against multiple viral subtypes when antibodies raised against a single subtype fail to do so. However, the role of T cells in protecting humans against influenza remains unclear. Here we employ a translational nonhuman primate model to show that cross-reactive T cell responses play an important role in early clearance of infection with 2009 pandemic H1N1 influenza virus (H1N1pdm). To "prime" cellular immunity, we first infected 5 rhesus macaques with a seasonal human H1N1 isolate. These animals made detectable cellular and antibody responses against the seasonal H1N1 isolate but had no neutralizing antibodies against H1N1pdm. Four months later, we challenged the 5 "primed" animals and 7 naive controls with H1N1pdm. In naive animals, CD8+ T cells with an activated phenotype (Ki-67+ CD38+) appeared in blood and lung 5-7 days post inoculation (p.i.) with H1N1pdm and reached peak magnitude 7-10 days p.i. In contrast, activated T cells were recruited to the lung as early as 2 days p.i. in "primed" animals, and reached peak frequencies in blood and lung 4-7 days p.i. Interferon (IFN)-gamma Elispot and intracellular cytokine staining assays showed that the virus-specific response peaked earlier and reached a higher magnitude in "primed" animals than in naive animals. This response involved both CD4+ and CD8+ T cells. Strikingly, "primed" animals cleared H1N1pdm infection significantly earlier from the upper and lower respiratory tract than the naive animals did, and before the appearance of H1N1pdm-specific neutralizing antibodies. Together, our results suggest that cross-reactive T cell responses can mediate early clearance of an antigenically novel influenza virus in primates. Vaccines capable of inducing such cross reactive T cells may help protect humans against severe disease caused by newly emerging pandemic influenza viruses. PMID- 22102820 TI - Towards a structural comprehension of bacterial type VI secretion systems: characterization of the TssJ-TssM complex of an Escherichia coli pathovar. AB - Type VI secretion systems (T6SS) are trans-envelope machines dedicated to the secretion of virulence factors into eukaryotic or prokaryotic cells, therefore required for pathogenesis and/or for competition towards neighboring bacteria. The T6SS apparatus resembles the injection device of bacteriophage T4, and is anchored to the cell envelope through a membrane complex. This membrane complex is composed of the TssL, TssM and TagL inner membrane anchored proteins and of the TssJ outer membrane lipoprotein. Here, we report the crystal structure of the enteroaggregative Escherichia coli Sci1 TssJ lipoprotein, a two four-stranded beta-sheets protein that exhibits a transthyretin fold with an additional alpha helical domain and a protruding loop. We showed that TssJ contacts TssM through this loop since a loop depleted mutant failed to interact with TssM in vitro or in vivo. Biophysical analysis of TssM and TssJ-TssM interaction suggest a structural model of the membrane-anchored outer shell of T6SS. Collectively, our results provide an improved understanding of T6SS assembly and encourage structure-aided drug design of novel antimicrobials targeting T6SS. PMID- 22102821 TI - Relative burden of large CNVs on a range of neurodevelopmental phenotypes. AB - While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID associated phenotypes compared to autism (p = 9.58 * 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 * 10(-18), odds ratio = 14.45), or controls (p = 2.75 * 10( 17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 * 10(-6), odds ratio = 6) or ID (16%, p = 3.55 * 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33). PMID- 22102822 TI - Multiple means to the same end: the genetic basis of acquired stress resistance in yeast. AB - In nature, stressful environments often occur in combination or close succession, and thus the ability to prepare for impending stress likely provides a significant fitness advantage. Organisms exposed to a mild dose of stress can become tolerant to what would otherwise be a lethal dose of subsequent stress; however, the mechanism of this acquired stress tolerance is poorly understood. To explore this, we exposed the yeast gene-deletion libraries, which interrogate all essential and non-essential genes, to successive stress treatments and identified genes necessary for acquiring subsequent stress resistance. Cells were exposed to one of three different mild stress pretreatments (salt, DTT, or heat shock) and then challenged with a severe dose of hydrogen peroxide (H(2)O(2)). Surprisingly, there was little overlap in the genes required for acquisition of H(2)O(2) tolerance after different mild-stress pretreatments, revealing distinct mechanisms of surviving H(2)O(2) in each case. Integrative network analysis of these results with respect to protein-protein interactions, synthetic-genetic interactions, and functional annotations identified many processes not previously linked to H(2)O(2) tolerance. We tested and present several models that explain the lack of overlap in genes required for H(2)O(2) tolerance after each of the three pretreatments. Together, this work shows that acquired tolerance to the same severe stress occurs by different mechanisms depending on prior cellular experiences, underscoring the context-dependent nature of stress tolerance. PMID- 22102823 TI - Serratia symbiotica from the aphid Cinara cedri: a missing link from facultative to obligate insect endosymbiont. AB - The genome sequencing of Buchnera aphidicola BCc from the aphid Cinara cedri, which is the smallest known Buchnera genome, revealed that this bacterium had lost its symbiotic role, as it was not able to synthesize tryptophan and riboflavin. Moreover, the biosynthesis of tryptophan is shared with the endosymbiont Serratia symbiotica SCc, which coexists with B. aphidicola in this aphid. The whole-genome sequencing of S. symbiotica SCc reveals an endosymbiont in a stage of genome reduction that is closer to an obligate endosymbiont, such as B. aphidicola from Acyrthosiphon pisum, than to another S. symbiotica, which is a facultative endosymbiont in this aphid, and presents much less gene decay. The comparison between both S. symbiotica enables us to propose an evolutionary scenario of the transition from facultative to obligate endosymbiont. Metabolic inferences of B. aphidicola BCc and S. symbiotica SCc reveal that most of the functions carried out by B. aphidicola in A. pisum are now either conserved in B. aphidicola BCc or taken over by S. symbiotica. In addition, there are several cases of metabolic complementation giving functional stability to the whole consortium and evolutionary preservation of the actors involved. PMID- 22102824 TI - Caenorhabditis elegans cyclin D/CDK4 and cyclin E/CDK2 induce distinct cell cycle re-entry programs in differentiated muscle cells. AB - Cell proliferation and differentiation are regulated in a highly coordinated and inverse manner during development and tissue homeostasis. Terminal differentiation usually coincides with cell cycle exit and is thought to engage stable transcriptional repression of cell cycle genes. Here, we examine the robustness of the post-mitotic state, using Caenorhabditis elegans muscle cells as a model. We found that expression of a G1 Cyclin and CDK initiates cell cycle re-entry in muscle cells without interfering with the differentiated state. Cyclin D/CDK4 (CYD-1/CDK-4) expression was sufficient to induce DNA synthesis in muscle cells, in contrast to Cyclin E/CDK2 (CYE-1/CDK-2), which triggered mitotic events. Tissue-specific gene-expression profiling and single molecule FISH experiments revealed that Cyclin D and E kinases activate an extensive and overlapping set of cell cycle genes in muscle, yet failed to induce some key activators of G1/S progression. Surprisingly, CYD-1/CDK-4 also induced an additional set of genes primarily associated with growth and metabolism, which were not activated by CYE-1/CDK-2. Moreover, CYD-1/CDK-4 expression also down regulated a large number of genes enriched for catabolic functions. These results highlight distinct functions for the two G1 Cyclin/CDK complexes and reveal a previously unknown activity of Cyclin D/CDK-4 in regulating metabolic gene expression. Furthermore, our data demonstrate that many cell cycle genes can still be transcriptionally induced in post-mitotic muscle cells, while maintenance of the post-mitotic state might depend on stable repression of a limited number of critical cell cycle regulators. PMID- 22102825 TI - Capture of microRNA-bound mRNAs identifies the tumor suppressor miR-34a as a regulator of growth factor signaling. AB - A simple biochemical method to isolate mRNAs pulled down with a transfected, biotinylated microRNA was used to identify direct target genes of miR-34a, a tumor suppressor gene. The method reidentified most of the known miR-34a regulated genes expressed in K562 and HCT116 cancer cell lines. Transcripts for 982 genes were enriched in the pull-down with miR-34a in both cell lines. Despite this large number, validation experiments suggested that ~90% of the genes identified in both cell lines can be directly regulated by miR-34a. Thus miR-34a is capable of regulating hundreds of genes. The transcripts pulled down with miR 34a were highly enriched for their roles in growth factor signaling and cell cycle progression. These genes form a dense network of interacting gene products that regulate multiple signal transduction pathways that orchestrate the proliferative response to external growth stimuli. Multiple candidate miR-34a regulated genes participate in RAS-RAF-MAPK signaling. Ectopic miR-34a expression reduced basal ERK and AKT phosphorylation and enhanced sensitivity to serum growth factor withdrawal, while cells genetically deficient in miR-34a were less sensitive. Fourteen new direct targets of miR-34a were experimentally validated, including genes that participate in growth factor signaling (ARAF and PIK3R2) as well as genes that regulate cell cycle progression at various phases of the cell cycle (cyclins D3 and G2, MCM2 and MCM5, PLK1 and SMAD4). Thus miR-34a tempers the proliferative and pro-survival effect of growth factor stimulation by interfering with growth factor signal transduction and downstream pathways required for cell division. PMID- 22102826 TI - Consequences of eukaryotic enhancer architecture for gene expression dynamics, development, and fitness. AB - The regulatory logic of time- and tissue-specific gene expression has mostly been dissected in the context of the smallest DNA fragments that, when isolated, recapitulate native expression in reporter assays. It is not known if the genomic sequences surrounding such fragments, often evolutionarily conserved, have any biological function or not. Using an enhancer of the even-skipped gene of Drosophila as a model, we investigate the functional significance of the genomic sequences surrounding empirically identified enhancers. A 480 bp long "minimal stripe element" is able to drive even-skipped expression in the second of seven stripes but is embedded in a larger region of 800 bp containing evolutionarily conserved binding sites for required transcription factors. To assess the overall fitness contribution made by these binding sites in the native genomic context, we employed a gene-replacement strategy in which whole-locus transgenes, capable of rescuing even-skipped(-) lethality to adulthood, were substituted for the native gene. The molecular phenotypes were characterized by tagging Even-skipped with a fluorescent protein and monitoring gene expression dynamics in living embryos. We used recombineering to excise the sequences surrounding the minimal enhancer and site-specific transgenesis to create co-isogenic strains differing only in their stripe 2 sequences. Remarkably, the flanking sequences were dispensable for viability, proving the sufficiency of the minimal element for biological function under normal conditions. These sequences are required for robustness to genetic and environmental perturbation instead. The mutant enhancers had measurable sex- and dose-dependent effects on viability. At the molecular level, the mutants showed a destabilization of stripe placement and improper activation of downstream genes. Finally, we demonstrate through live measurements that the peripheral sequences are required for temperature compensation. These results imply that seemingly redundant regulatory sequences beyond the minimal enhancer are necessary for robust gene expression and that "robustness" itself must be an evolved characteristic of the wild-type enhancer. PMID- 22102827 TI - Arabidopsis homologs of retinoblastoma-associated protein 46/48 associate with a histone deacetylase to act redundantly in chromatin silencing. AB - RNA molecules such as small-interfering RNAs (siRNAs) and antisense RNAs (asRNAs) trigger chromatin silencing of target loci. In the model plant Arabidopsis, RNA triggered chromatin silencing involves repressive histone modifications such as histone deacetylation, histone H3 lysine-9 methylation, and H3 lysine-27 monomethylation. Here, we report that two Arabidopsis homologs of the human histone-binding proteins Retinoblastoma-Associated Protein 46/48 (RbAp46/48), known as MSI4 (or FVE) and MSI5, function in partial redundancy in chromatin silencing of various loci targeted by siRNAs or asRNAs. We show that MSI5 acts in partial redundancy with FVE to silence FLOWERING LOCUS C (FLC), which is a crucial floral repressor subject to asRNA-mediated silencing, FLC homologs, and other loci including transposable and repetitive elements which are targets of siRNA-directed DNA Methylation (RdDM). Both FVE and MSI5 associate with HISTONE DEACETYLASE 6 (HDA6) to form complexes and directly interact with the target loci, leading to histone deacetylation and transcriptional silencing. In addition, these two genes function in de novo CHH (H = A, T, or C) methylation and maintenance of symmetric cytosine methylation (mainly CHG methylation) at endogenous RdDM target loci, and they are also required for establishment of cytosine methylation in the previously unmethylated sequences directed by the RdDM pathway. This reveals an important functional divergence of the plant RbAp46/48 relatives from animal counterparts. PMID- 22102828 TI - The ERI-6/7 helicase acts at the first stage of an siRNA amplification pathway that targets recent gene duplications. AB - Endogenous small interfering RNAs (siRNAs) are a class of naturally occuring regulatory RNAs found in fungi, plants, and animals. Some endogenous siRNAs are required to silence transposons or function in chromosome segregation; however, the specific roles of most endogenous siRNAs are unclear. The helicase gene eri 6/7 was identified in the nematode Caenorhabditis elegans by the enhanced response to exogenous double-stranded RNAs (dsRNAs) of the null mutant. eri-6/7 encodes a helicase homologous to small RNA factors Armitage in Drosophila, SDE3 in Arabidopsis, and Mov10 in humans. Here we show that eri-6/7 mutations cause the loss of 26-nucleotide (nt) endogenous siRNAs derived from genes and pseudogenes in oocytes and embryos, as well as deficiencies in somatic 22 nucleotide secondary siRNAs corresponding to the same loci. About 80 genes are eri-6/7 targets that generate the embryonic endogenous siRNAs that silence the corresponding mRNAs. These 80 genes share extensive nucleotide sequence homology and are poorly conserved, suggesting a role for these endogenous siRNAs in silencing of and thereby directing the fate of recently acquired, duplicated genes. Unlike most endogenous siRNAs in C. elegans, eri-6/7-dependent siRNAs require Dicer. We identify that the eri-6/7-dependent siRNAs have a passenger strand that is ~19 nt and is inset by ~3-4 nts from both ends of the 26 nt guide siRNA, suggesting non-canonical Dicer processing. Mutations in the Argonaute ERGO 1, which associates with eri-6/7-dependent 26 nt siRNAs, cause passenger strand stabilization, indicating that ERGO-1 is required to separate the siRNA duplex, presumably through endonucleolytic cleavage of the passenger strand. Thus, like several other siRNA-associated Argonautes with a conserved RNaseH motif, ERGO-1 appears to be required for siRNA maturation. PMID- 22102829 TI - FOXO regulates organ-specific phenotypic plasticity in Drosophila. AB - Phenotypic plasticity, the ability for a single genotype to generate different phenotypes in response to environmental conditions, is biologically ubiquitous, and yet almost nothing is known of the developmental mechanisms that regulate the extent of a plastic response. In particular, it is unclear why some traits or individuals are highly sensitive to an environmental variable while other traits or individuals are less so. Here we elucidate the developmental mechanisms that regulate the expression of a particularly important form of phenotypic plasticity: the effect of developmental nutrition on organ size. In all animals, developmental nutrition is signaled to growing organs via the insulin-signaling pathway. Drosophila organs differ in their size response to developmental nutrition and this reflects differences in organ-specific insulin-sensitivity. We show that this variation in insulin-sensitivity is regulated at the level of the forkhead transcription factor FOXO, a negative growth regulator that is activated when nutrition and insulin signaling are low. Individual organs appear to attenuate growth suppression in response to low nutrition through an organ specific reduction in FOXO expression, thereby reducing their nutritional plasticity. We show that FOXO expression is necessary to maintain organ-specific differences in nutritional-plasticity and insulin-sensitivity, while organ autonomous changes in FOXO expression are sufficient to autonomously alter an organ's nutritional-plasticity and insulin-sensitivity. These data identify a gene (FOXO) that modulates a plastic response through variation in its expression. FOXO is recognized as a key player in the response of size, immunity, and longevity to changes in developmental nutrition, stress, and oxygen levels. FOXO may therefore act as a more general regulator of plasticity. These data indicate that the extent of phenotypic plasticity may be modified by changes in the expression of genes involved in signaling environmental information to developmental processes. PMID- 22102830 TI - Histone H3K56 acetylation, CAF1, and Rtt106 coordinate nucleosome assembly and stability of advancing replication forks. AB - Chromatin assembly mutants accumulate recombinogenic DNA damage and are sensitive to genotoxic agents. Here we have analyzed why impairment of the H3K56 acetylation-dependent CAF1 and Rtt106 chromatin assembly pathways, which have redundant roles in H3/H4 deposition during DNA replication, leads to genetic instability. We show that the absence of H3K56 acetylation or the simultaneous knock out of CAF1 and Rtt106 increases homologous recombination by affecting the integrity of advancing replication forks, while they have a minor effect on stalled replication fork stability in response to the replication inhibitor hydroxyurea. This defect in replication fork integrity is not due to defective checkpoints. In contrast, H3K56 acetylation protects against replicative DNA damaging agents by DNA repair/tolerance mechanisms that do not require CAF1/Rtt106 and are likely subsequent to the process of replication-coupled nucleosome deposition. We propose that the tight connection between DNA synthesis and histone deposition during DNA replication mediated by H3K56ac/CAF1/Rtt106 provides a mechanism for the stabilization of advancing replication forks and the maintenance of genome integrity, while H3K56 acetylation has an additional, CAF1/Rtt106-independent function in the response to replicative DNA damage. PMID- 22102831 TI - De novo origin of human protein-coding genes. AB - The de novo origin of a new protein-coding gene from non-coding DNA is considered to be a very rare occurrence in genomes. Here we identify 60 new protein-coding genes that originated de novo on the human lineage since divergence from the chimpanzee. The functionality of these genes is supported by both transcriptional and proteomic evidence. RNA-seq data indicate that these genes have their highest expression levels in the cerebral cortex and testes, which might suggest that these genes contribute to phenotypic traits that are unique to humans, such as improved cognitive ability. Our results are inconsistent with the traditional view that the de novo origin of new genes is very rare, thus there should be greater appreciation of the importance of the de novo origination of genes. PMID- 22102832 TI - De novo origins of human genes. PMID- 22102833 TI - When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. More than 90% of ALS cases are sporadic, and the majority of sporadic ALS patients do not carry mutations in genes causative of familial ALS; therefore, investigation specifically targeting sporadic ALS is needed to discover the pathogenesis. The motor neurons of sporadic ALS patients express unedited GluA2 mRNA at the Q/R site in a disease-specific and motor neuron selective manner. GluA2 is a subunit of the AMPA receptor, and it has a regulatory role in the Ca(2+)-permeability of the AMPA receptor after the genomic Q codon is replaced with the R codon in mRNA by adenosine-inosine conversion, which is mediated by adenosine deaminase acting on RNA 2 (ADAR2). Therefore, ADAR2 activity may not be sufficient to edit all GluA2 mRNA expressed in the motor neurons of ALS patients. To investigate whether deficient ADAR2 activity plays pathogenic roles in sporadic ALS, we generated genetically modified mice (AR2) in which the ADAR2 gene was conditionally knocked out in the motor neurons. AR2 mice showed an ALS-like phenotype with the death of ADAR2-lacking motor neurons. Notably, the motor neurons deficient in ADAR2 survived when they expressed only edited GluA2 in AR2/GluR-B(R/R) (AR2res) mice, in which the endogenous GluA2 alleles were replaced by the GluR-B(R) allele that encoded edited GluA2. In heterozygous AR2 mice with only one ADAR2 allele, approximately 20% of the spinal motor neurons expressed unedited GluA2 and underwent degeneration, indicating that half-normal ADAR2 activity is not sufficient to edit all GluA2 expressed in motor neurons. It is likely therefore that the expression of unedited GluA2 causes the death of motor neurons in sporadic ALS. We hypothesize that a progressive downregulation of ADAR2 activity plays a critical role in the pathogenesis of sporadic ALS and that the pathological process commences when motor neurons express unedited GluA2. PMID- 22102834 TI - Ca permeable AMPA channels in diseases of the nervous system. AB - Since the discovery and molecular characterization of Ca(2+)-permeable AMPA channels just over two decades ago, a large body of evidence has accumulated implicating contributions of these unusual glutamate activated channels to selective neurodegeneration in certain conditions, including ischemia and amyotrophic lateral sclerosis. Factors likely involved in their contributions to disease include their distinct patterns of expression in certain neuronal populations, their upregulation via various mechanisms in response to disease associated stresses, and their high permeability to Zn(2+) as well as to Ca(2+). However, full characterization of their contributions to certain diseases as well as development of therapeutics has been limited by the lack of selective and bioavailable blockers of these channels that can be employed in animals or humans. This review summarizes some of the clues that have emerged over recent years to the contributions of these channels in disease. PMID- 22102835 TI - Temporal sensitivity changes with extended training in a bisection task in a transgenic rat model. AB - The present study investigated temporal perception in a Huntington disease transgenic rat model using a temporal bisection procedure. After initial discrimination training in which animals learned to press one lever after a 2-s tone duration, and the other lever after a 8-s tone duration for food reward, the bisection procedure was implemented in which intermediate durations with no available reinforcement were interspersed with trials with the anchor durations. Bisection tests were repeated in a longitudinal design from 4 to 8 months of age. The results showed that response latencies evolved from a monotonic step-function to an inverted U-shaped function with repeated testing, a precursor of non responding on trials with intermediate durations. We inferred that temporal sensitivity and incentive motivation combined to control the transformation of the bisection task from a two-choice task at the outset of testing to a three choice task with repeated testing. Changes in the structure of the task and/or continued training were accompanied by improvement in temporal sensitivity. In sum, the present data highlight the possible joint roles of temporal and non temporal factors in the temporal bisection task, and suggested that non-temporal factors may compensate for deficits in temporal processing. PMID- 22102837 TI - Artists and the mind in the 21st century. AB - In 2008, Lesley University Professors Geoffrey Koetsch and Ellen Schon conducted an informal survey of New England artists to ascertain the degree to which recent work in neuroscience had impacted the visual arts. The two curators mounted an exhibition (MINDmatters May-June, 2008) at the Laconia Gallery in Boston in which they showcased the work of artists who had chosen mental processes as their primary subject. These artists were reacting to the new vision of the mind revealed by science; their inquiry was subjective, sensory, and existential, not empirical. They approached consciousness from several vantage points. Some of the artists had had personal experience with pathologies of the brain such as dementia or cancer and were puzzling out the phenomenon consuming the mind of a loved one. They looked to neuroscience for clarity and understanding. Some artists were personally involved with new techniques of cognitive psychotherapy. Others were inspired by the sheer physical beauty of the brain as revealed by new imaging technologies. Two of the artists explored the links between meditation, mindfulness practice and neuroscience. Issues such as the "boundary" and "binding" problems were approached, as well as the challenge of creating visual metaphors for neural processes. One artist visualized the increasing transparency of the body as researchers introduce more and more invasive technologies. PMID- 22102836 TI - Identifying a network of brain regions involved in aversion-related processing: a cross-species translational investigation. AB - The ability to detect and respond appropriately to aversive stimuli is essential for all organisms, from fruit flies to humans. This suggests the existence of a core neural network which mediates aversion-related processing. Human imaging studies on aversion have highlighted the involvement of various cortical regions, such as the prefrontal cortex, while animal studies have focused largely on subcortical regions like the periaqueductal gray and hypothalamus. However, whether and how these regions form a core neural network of aversion remains unclear. To help determine this, a translational cross-species investigation in humans (i.e., meta-analysis) and other animals (i.e., systematic review of functional neuroanatomy) was performed. Our results highlighted the recruitment of the anterior cingulate cortex, the anterior insula, and the amygdala as well as other subcortical (e.g., thalamus, midbrain) and cortical (e.g., orbitofrontal) regions in both animals and humans. Importantly, involvement of these regions remained independent of sensory modality. This study provides evidence for a core neural network mediating aversion in both animals and humans. This not only contributes to our understanding of the trans-species neural correlates of aversion but may also carry important implications for psychiatric disorders where abnormal aversive behavior can often be observed. PMID- 22102838 TI - A computational theory for the learning of equivalence relations. AB - Equivalence relations (ERs) are logical entities that emerge concurrently with the development of language capabilities. In this work we propose a computational model that learns to build ERs by learning simple conditional rules. The model includes visual areas, dopaminergic, and noradrenergic structures as well as prefrontal and motor areas, each of them modeled as a group of continuous valued units that simulate clusters of real neurons. In the model, lateral interaction between neurons of visual structures and top-down modulation of prefrontal/premotor structures over the activity of neurons in visual structures are necessary conditions for learning the paradigm. In terms of the number of neurons and their interaction, we show that a minimal structural complexity is required for learning ERs among conditioned stimuli. Paradoxically, the emergence of the ER drives a reduction in the number of neurons needed to maintain those previously specific stimulus-response learned rules, allowing an efficient use of neuronal resources. PMID- 22102839 TI - Stimulus fractionation by interocular suppression. AB - Can human observers distinguish physical removal of a visible stimulus from phenomenal suppression of that stimulus during binocular rivalry? As so often happens, simple questions produce complex answers, and that is the case in the study reported here. Using continuous flash suppression to produce binocular rivalry, we were able to identify stimulus conditions where most - but not all - people utterly fail to distinguish physical from phenomenal stimulus removal, although we can be certain that those two equivalent perceptual states are accompanied by distinct neural events. More interestingly, we find subtle variants of the task where distinguishing the two states is trivially easy, even for people who utterly fail under the original conditions. We found that stimulus features are differentially vulnerable to suppression. Observers are able to be aware of existence/removal of some stimulus attributes (flicker) but not others (orientation), implying that interocular suppression breaks down the unitary awareness of integrated features belonging to a visual object. These findings raise questions about the unitary nature of awareness and, also, place qualifications on the utility of binocular rivalry as a tool for studying the neural concomitants of conscious visual awareness. PMID- 22102840 TI - Nine criteria for a measure of scientific output. AB - Scientific research produces new knowledge, technologies, and clinical treatments that can lead to enormous returns. Often, the path from basic research to new paradigms and direct impact on society takes time. Precise quantification of scientific output in the short-term is not an easy task but is critical for evaluating scientists, laboratories, departments, and institutions. While there have been attempts to quantifying scientific output, we argue that current methods are not ideal and suffer from solvable difficulties. Here we propose criteria that a metric should have to be considered a good index of scientific output. Specifically, we argue that such an index should be quantitative, based on robust data, rapidly updated and retrospective, presented with confidence intervals, normalized by number of contributors, career stage and discipline, impractical to manipulate, and focused on quality over quantity. Such an index should be validated through empirical testing. The purpose of quantitatively evaluating scientific output is not to replace careful, rigorous review by experts but rather to complement those efforts. Because it has the potential to greatly influence the efficiency of scientific research, we have a duty to reflect upon and implement novel and rigorous ways of evaluating scientific output. The criteria proposed here provide initial steps toward the systematic development and validation of a metric to evaluate scientific output. PMID- 22102841 TI - Altered amygdala resting-state functional connectivity in post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is often characterized by aberrant amygdala activation and functional abnormalities in corticolimbic circuitry, as elucidated by functional neuroimaging. These "activation" studies have primarily relied on tasks designed to induce region-specific, and task-dependent brain responses in limbic (e.g., amygdala) and paralimbic brain areas through the use of aversive evocative probes. It remains unknown if these corticolimbic circuit abnormalities exist at baseline or "at rest," in the absence of fear/anxiety-related provocation and outside the context of task demands. Therefore the primary aim of the present experiment was to investigate aberrant amygdala functional connectivity patterns in combat-related PTSD patients during resting-state. Seventeen Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD (PTSD group) and 17 combat-exposed OEF/OIF veterans without PTSD [combat-exposed control (CEC) group] underwent an 8-min resting state functional magnetic resonance imaging scan. Using an anatomically derived amygdala "seed" region we observed stronger functional coupling between the amygdala and insula in the PTSD group compared to the CEC group, but did not find group differences in amygdala-prefrontal connectivity. These findings suggest that the aberrant amygdala and insula activation to fear-evocative probes previously characterized in PTSD may be driven by an underlying enhanced connectivity between the amygdala, a region known for perceiving threat and generating fear responses, and the insula, a region known for processing the meaning and prediction of aversive bodily states. This enhanced amygdala-insula connectivity may reflect an exaggerated, pervasive state of arousal that exists outside the presence of an overt actual threat/danger. Studying amygdala functional connectivity "at rest" extends our understanding of the pathophysiology of PTSD. PMID- 22102842 TI - Additive factors do not imply discrete processing stages: a worked example using models of the stroop task. AB - Previously, it has been shown experimentally that the psychophysical law known as Pieron's Law holds for color intensity and that the size of the effect is additive with that of Stroop condition (Stafford et al., 2011). According to the additive factors method (Donders, 1868-1869/1969; Sternberg, 1998), additivity is assumed to indicate independent and discrete processing stages. We present computational modeling work, using an existing Parallel Distributed Processing model of the Stroop task (Cohen et al., 1990) and a standard model of decision making (Ratcliff, 1978). This demonstrates that additive factors can be successfully accounted for by existing single stage models of the Stroop effect. Consequently, it is not valid to infer either discrete stages or separate loci of effects from additive factors. Further, our modeling work suggests that information binding may be a more important architectural property for producing additive factors than discrete stages. PMID- 22102843 TI - Defining the focus of attention: effects of attention on perceived exertion and fatigue. AB - This manuscript presents two experiments designed to explore the effects of attention on perceived exertion and time to failure in a fatiguing athletic task. There were two major motivating factors for these experiments. First, there are few studies evaluating attentional focus effects in endurance tasks and, second, there is a lack of integration between studies of attentional focus as external/internal (e.g., Wulf, 2007a) compared to associative/dissociative (e.g., Stevinson and Biddle, 1998). In Experiment 1, we used a fatiguing wall-sit posture (essentially a complex, isometric task) to compare two different types of external attention with an internal focus on the position of the legs. An external focus (regardless of type) increased the time taken to failure and reduced perceived exertion. In Experiment 2, we manipulated subjects' expectancy of fatigue to test the interaction of attention and expectancy (both top-down factors) in this highly fatiguing task. Previous theories of attention during endurance tasks have suggested that as fatigue/pain increase, bottom-up factors begin to dominate subjects' attention. While this may be true, Experiment 2 showed that even in a highly fatiguing task, attentional strategies, and expectancies affected the time to failure and perceived exertion. PMID- 22102844 TI - Enhanced Actin Pedestal Formation by Enterohemorrhagic Escherichia coli O157:H7 Adapted to the Mammalian Host. AB - Upon intestinal colonization, enterohemorrhagic Escherichia coli (EHEC) induces epithelial cells to generate actin "pedestals" beneath bound bacteria, lesions that promote colonization. To induce pedestals, EHEC utilizes a type III secretion system to translocate into the mammalian cell bacterial effectors such as translocated intimin receptor (Tir), which localizes in the mammalian cell membrane and functions as a receptor for the bacterial outer membrane protein intimin. Whereas EHEC triggers efficient pedestal formation during mammalian infection, EHEC cultured in vitro induces pedestals on cell monolayers with relatively low efficiency. To determine whether growth within the mammalian host enhances EHEC pedestal formation, we compared in vitro-cultivated bacteria with EHEC directly isolated from infected piglets. Mammalian adaptation by EHEC was associated with a dramatic increase in the efficiency of cell attachment and pedestal formation. The amounts of intimin and Tir were significantly higher in host-adapted than in in vitro-cultivated bacteria, but increasing intimin or Tir expression, or artificially increasing the level of bacterial attachment to mammalian cells, did not enhance pedestal formation by in vitro-cultivated EHEC. Instead, a functional assay suggested that host-adapted EHEC translocate Tir much more efficiently than does in vitro-cultivated bacteria. These data suggest that adaptation of EHEC to the mammalian intestine enhances bacterial cell attachment, expression of intimin and Tir, and translocation of effectors that promote actin signaling. PMID- 22102845 TI - Bimolecular Complementation to Visualize Filovirus VP40-Host Complexes in Live Mammalian Cells: Toward the Identification of Budding Inhibitors. AB - Virus-host interactions play key roles in promoting efficient egress of many RNA viruses, including Ebola virus (EBOV or "e") and Marburg virus (MARV or "m"). Late- (L-) domains conserved in viral matrix proteins recruit specific host proteins, such as Tsg101 and Nedd4, to facilitate the budding process. These interactions serve as attractive targets for the development of broad-spectrum budding inhibitors. A major gap still exists in our understanding of the mechanism of filovirus budding due to the difficulty in detecting virus-host complexes and mapping their trafficking patterns in the natural environment of the cell. To address this gap, we used a bimolecular complementation (BiMC) approach to detect, localize, and follow the trafficking patterns of eVP40-Tsg101 complexes in live mammalian cells. In addition, we used the BiMC approach along with a VLP budding assay to test small molecule inhibitors identified by in silico screening for their ability to block eVP40 PTAP-mediated interactions with Tsg101 and subsequent budding of eVP40 VLPs. We demonstrated the potential broad spectrum activity of a lead candidate inhibitor by demonstrating its ability to block PTAP-dependent binding of HIV-1 Gag to Tsg101 and subsequent egress of HIV 1 Gag VLPs. PMID- 22102846 TI - Magnetic particles in ultrasensitive biomarker protein measurements for cancer detection and monitoring. AB - IMPORTANCE OF THE FIELD: Devices for the reliable detection of panels of biomarker proteins facilitated by magnetic bead-based technologies have the potential to greatly improve future cancer diagnostics. The reason for this review is to highlight promising research on emerging procedures for protein capture, transport and detection featuring magnetic particles. AREAS COVERED IN THIS REVIEW: The review covers applications of magnetic particles in protein immunoassays in emerging research and commercial methods, and stresses multiplexed protein assays for reliable future cancer diagnostics. Research literature over the past dozen years has been surveyed and specific examples are presented in detail. EXPERT OPINION: Magnetic particles are important components of emerging protein detection systems. They need to be integrated into simple inexpensive systems for accurate, sensitive detection of fully validated panels of biomarker proteins to be widely useful in clinical cancer diagnostics. PMID- 22102847 TI - Preventing Chronic Pain following Acute Pain: Risk Factors, Preventive Strategies, and their Efficacy. AB - Chronic pain is the leading cause of disability in the United States. The transition from acute to persistent pain is thought to arise from maladaptive neuroplastic mechanisms involving three intertwined processes, peripheral sensitization, central sensitization, and descending modulation. Strategies aimed at preventing persistent pain may target such processes. Models for studying preventive strategies include persistent post-surgical pain (PPP), persistent post-trauma pain (PTP) and post-herpetic neuralgia (PHN). Such entities allow a more defined acute onset of tissue injury after which study of the long-term effects is more easily examined. In this review, we examine the pathophysiology, epidemiology, risk factors, and treatment strategies for the prevention of chronic pain using these models. Both pharmacological and interventional approaches are described, as well as a discussion of preventive strategies on the horizon. PMID- 22102848 TI - Elucidation of mu-Opioid Gene Structure: How Genetics Can Help Predict Responses to Opioids. AB - Opioid drugs are among the most commonly used and effective human analgesics. To date, the clinical benefits of opioid analgesics have not been fully realized due to substantial individual variations in the responses to opioids, insufficient drug dosing, and a high rate (up to 66%) of adverse events. As such, there is a substantial need to identify the genetic and molecular biological mechanisms that mediate individual responses to opioid therapy. Recent discoveries show that genetic variations in the MU-opioid receptor (OPRM1) gene locus play an essential role in inter-individual responses. The majority of genetic association studies have focused on the A118G polymorphism, which codes for a non-synonymous change in OPRM1 exon 1. In addition to the A118G polymorphism, another functional SNP (rs563649), which is located within an alternatively-spliced OPRM1 isoform (MOR 1K), has been identified. The MOR-1k isoform codes for 6TM OPRM1 isoforms that display excitatory rather than the inhibitory cellular effects, which are characteristic of the canonical 7TM isoforms. Thus, stimulation of the 6TM isoforms may engage the molecular mechanisms mediating opioid-dependent hyperalgesia, tolerance and dependence. Future clinical and basic studies that seek to identify the functional genetic variants within OPRM1 locus, and associated molecular mechanisms, will result in a better understanding of individual responses to opioid therapy and ultimately to the development new pharmacotherapeutics and diagnostic tools. PMID- 22102849 TI - Can Broad Consent be Informed Consent? AB - In biobanks, a broader model of consent is often used and justified by a range of different strategies that make reference to the potential benefits brought by the research it will facilitate combined with the low level of risk involved (provided adequate measures are in place to protect privacy and confidentiality) or a questioning of the centrality of the notion of informed consent. Against this, it has been suggested that the lack of specific information about particular uses of the samples means that such consent cannot be fully autonomous and so is unethical. My answer to the title question is a definite 'yes'. Broad consent can be informed consent and is justified by appeal to the principle of respect for autonomy. Indeed, I will suggest that the distinction between the various kinds of consent is not a distinction between kinds of consent but between the kinds of choice a person makes. When an individual makes a choice (of any kind) it is important that they do so according to the standards of informed consent and consistent with the choice that they are making. PMID- 22102850 TI - Use of the Twin Design to Examine Evocative Gene-Environment Effects within a Conversational Context. AB - The purpose of this study was to highlight the role of twin designs in understanding children's conversational interactions. Specifically, we (a) attempted to replicate the findings of genetic effects on children's conversational language use reported in DeThorne et al. (2008), and (b) examined whether the language used by examiners in their conversation with twins reflected differences in the children's genetic similarity. Behavioral genetic analyses included intraclass correlations and model fitting procedures applied to 514 same sex twins (202 MZ, 294 DZ, 10 unknown zygosity) from the Western Reserve Reading Project (Petrill, Deater-Deckard, Thompson, DeThorne, & Schatschneider, 2006). Analyses focused on child and examiner measures of talkativeness, average utterance length, vocabulary diversity, and grammatical complexity from a fifteen minute conversational exchange. Substantial genetic effects on children's conversational language measures replicated results from DeThorne et al. (2008) using an expanded sample. However, no familiality was reflected in the examiner language measures. Modest phenotypic correlations between child and examiner language measures suggested that differences in examiner language use may elicit differences in child language use, but evidence of evocative rGE in which genetic differences across children evoke differences in examiner language use, was not found. The discussion focuses on a comparison of findings to previous studies and implications for future research. PMID- 22102851 TI - H. pylori-Induced Higher C-Reactive Protein in Obese African Americans. AB - African Americans are more susceptible to develop insulin resistance, obesity, Type 2 Diabetes, and coronary heart disease (CHD), and systemic inflammation is central to the pathophysiology of these chronic diseases. African Americans are also more likely to contract H. pylori (cagA) infections during their childhood. However, the contribution of H. pylori infection to the degree of overall systemic inflammation in these chronic diseases is not known. Therefore, we studied 46 apparently healthy African Americans, over 40 years of age who were, infected with H. pylori (cagA). These volunteers were assessed at baseline and after treatment with triple regimen drug therapy to eradicate H. pylori. All but 3 subjects were found to be free of this infection by urea breath test (UBT) after the treatment period. No hyperhomocysteinemia was found in these subjects and there were no significant changes in the level of homocysteine (tHcy), folate and B(12); however, CRP levels measured by high sensitivity assay showed a significant (p=0.02) decrease 2 months after the eradication. We further stratified CRP values according to the BMI < 27 and > 27. There was more profound reduction in CRP in the more obese group (i.e., BMI>27) from 54.26 +/- 23.67 to 18.73 +/- 17.39 mg/l (p=0.01), compared with the leaner subjects in whom CRP decreases from 8.88 +/- 6.23 to 4.94 +/- 6.21 mg/L (p=0.04), after eradication of the H. pylori (cagA) infection. The level of CRP, however, remained significantly higher in the obese subjects even after the eradication of this infection, indicative of a smaller residual influence of adiposity on CRP. Thus, a major component of systemic inflammation in African Americans may be attributable to chronic H. pylori infection. PMID- 22102852 TI - The role of PKR/eIF2alpha signaling pathway in prognosis of non-small cell lung cancer. AB - BACKGROUND: In this study, we investigated whether PKR protein expression is correlated with mRNA levels and also evaluated molecular biomarkers that are associated with PKR, such as phosphorylated PKR (p-PKR) and phosphorylated eIF2alpha (p-eIF2alpha). METHODOLOGY AND FINDINGS: We determined the levels of PKR protein expression and mRNA in 36 fresh primary lung tumor tissues by using Western blot analysis and real-time reverse-transcriptase PCR (RT-PCR), respectively. We used tissue microarrays for immunohistochemical evaluation of the expression of p-PKR and p-eIF2alpha proteins. We demonstrated that PKR mRNA levels are significantly correlated with PKR protein levels (Spearman's rho = 0.55, p<0.001), suggesting that PKR protein levels in tumor samples are regulated by PKR mRNA. We also observed that the patients with high p-PKR or p-eIF2alpha expression had a significantly longer median survival than those with little or no p-PKR or p-eIF2alpha expression (p = 0.03 and p = 0.032, respectively). We further evaluated the prognostic effect of combined expression of p-PKR plus PKR and p-eIF2alpha plus PKR and found that both combinations were strong independent prognostic markers for overall patient survival on stage I and all stage patients. CONCLUSIONS: Our findings suggest that PKR protein expression may controlled by transcription level. Combined expression levels of PKR and p-PKR or p-eIF2alpha can be new markers for predicting the prognosis of patients with NSCLC. PMID- 22102853 TI - Prdm9, a major determinant of meiotic recombination hotspots, is not functional in dogs and their wild relatives, wolves and coyotes. AB - Meiotic recombination is a fundamental process needed for the correct segregation of chromosomes during meiosis in sexually reproducing organisms. In humans, 80% of crossovers are estimated to occur at specific areas of the genome called recombination hotspots. Recently, a protein called PRDM9 was identified as a major player in determining the location of genome-wide meiotic recombination hotspots in humans and mice. The origin of this protein seems to be ancient in evolutionary time, as reflected by its fairly conserved structure in lineages that diverged over 700 million years ago. Despite its important role, there are many animal groups in which Prdm9 is absent (e.g. birds, reptiles, amphibians, diptera) and it has been suggested to have disruptive mutations and thus to be a pseudogene in dogs. Because of the dog's history through domestication and artificial selection, we wanted to confirm the presence of a disrupted Prdm9 gene in dogs and determine whether this was exclusive of this species or whether it also occurred in its wild ancestor, the wolf, and in a close relative, the coyote. We sequenced the region in the dog genome that aligned to the last exon of the human Prdm9, containing the entire zinc finger domain, in 4 dogs, 17 wolves and 2 coyotes. Our results show that the three canid species possess mutations that likely make this gene non functional. Because these mutations are shared across the three species, they must have appeared prior to the split of the wolf and the coyote, millions of years ago, and are not related to domestication. In addition, our results suggest that in these three canid species recombination does not occur at hotspots or hotspot location is controlled through a mechanism yet to be determined. PMID- 22102854 TI - Bayesian multimodel inference for geostatistical regression models. AB - The problem of simultaneous covariate selection and parameter inference for spatial regression models is considered. Previous research has shown that failure to take spatial correlation into account can influence the outcome of standard model selection methods. A Markov chain Monte Carlo (MCMC) method is investigated for the calculation of parameter estimates and posterior model probabilities for spatial regression models. The method can accommodate normal and non-normal response data and a large number of covariates. Thus the method is very flexible and can be used to fit spatial linear models, spatial linear mixed models, and spatial generalized linear mixed models (GLMMs). The Bayesian MCMC method also allows a priori unequal weighting of covariates, which is not possible with many model selection methods such as Akaike's information criterion (AIC). The proposed method is demonstrated on two data sets. The first is the whiptail lizard data set which has been previously analyzed by other researchers investigating model selection methods. Our results confirmed the previous analysis suggesting that sandy soil and ant abundance were strongly associated with lizard abundance. The second data set concerned pollution tolerant fish abundance in relation to several environmental factors. Results indicate that abundance is positively related to Strahler stream order and a habitat quality index. Abundance is negatively related to percent watershed disturbance. PMID- 22102855 TI - Hypoxia imaging using PET and SPECT: the effects of anesthetic and carrier gas on [Cu]-ATSM, [Tc]-HL91 and [F]-FMISO tumor hypoxia accumulation. AB - BACKGROUND: Preclinical imaging requires anaesthesia to reduce motion-related artefacts. For direct translational relevance, anaesthesia must not significantly alter experimental outcome. This study reports on the effects of both anaesthetic and carrier gas upon the uptake of [64Cu]-CuATSM, [(99m)Tc]-HL91 and [18F]-FMISO in a preclinical model of tumor hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: The effect of carrier gas and anaesthetic was studied in 6 groups of CaNT-bearing CBA mice using [64Cu]-CuATSM, [(99m)Tc]-HL91 or [18F]-FMISO. Mice were anaesthetised with isoflurane in air, isoflurane in pure oxygen, with ketamine/xylazine or hypnorm/hypnovel whilst breathing air, or in the awake state whilst breathing air or pure oxygen. PET or SPECT imaging was performed after which the mice were killed for organ/tumor tracer quantitation. Tumor hypoxia was confirmed. Arterial blood gas analysis was performed for the different anaesthetic regimes. The results demonstrate marked influences on tumor uptake of both carrier gas and anaesthetic, and show differences between [(99m)Tc]-HL91, [18F]-FMISO and [64Cu] CuATSM. [(99m)Tc]-HL91 tumor uptake was only altered significantly by administration of 100% oxygen. The latter was not the case for [18F]-FMISO and [64Cu]-CuATSM. Tumor-to-muscle ratio (TMR) for both compounds was reduced significantly when either oxygen or anaesthetics (isoflurane in air, ketamine/xylazine or hypnorm/hypnovel) were introduced. For [18F]-FMISO no further decrease was measured when both isoflurane and oxygen were administered, [64Cu]-CuATSM did show an additional significant decrease in TMR. When using the same anaesthetic regimes, the extent of TMR reduction was less pronounced for [64Cu]-CuATSM than for [18F]-FMISO (40-60% versus 70% reduction as compared to awake animals breathing air). CONCLUSIONS/SIGNIFICANCE: The use of anaesthesia can have profound effects on the experimental outcome. More importantly, all tested anaesthetics reduced tumor-hypoxia uptake. Anaesthesia cannot be avoided in preclinical studies but great care has to be taken in preclinical models of hypoxia as anaesthesia effects cannot be generalised across applications, nor disease states. PMID- 22102856 TI - Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast. AB - BACKGROUND: The emergence of artemisinin-resistant P. falciparum malaria in South East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies. METHODS: On the Kenyan coast we studied the treatment responses in 474 children 6-59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995). RESULTS: The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005-2006 to 87% in 2007-2008 (odds ratio, 5.4, 95%CI, 2.7-11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7-9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005-2006 and 2007 2008 (OR body temperature >37.5 degrees C, 2.8, 1.9-4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof. CONCLUSIONS: The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN88705995. PMID- 22102857 TI - Kallikreins 5, 6 and 10 differentially alter pathophysiology and overall survival in an ovarian cancer xenograft model. AB - Human tissue kallikreins (KLKs) are members of a multigene family of serine proteases aberrantly expressed in many cancer types. In ovarian cancer, 12 KLKs are upregulated, and of those KLK5, 6 and 10 have been the focus of investigations into new diagnostic and prognostic biomarkers. However, little is known about the contributions of KLK5, 6 and 10 to ovarian cancer pathophysiology.In this study, a panel of 13 human ovarian cancer cell lines was screened by ELISA for secretion of KLK5, 6, 8, 10, 13, and 14. The ES-2 cell line, devoid of these kallikreins, was transfected with expression vectors of KLK5, 6 and 10 individually or in pairs. Co-expression of KLK5, 6 and 10 was correlated with lessened aggressivity of ovarian cancer cell lines as defined by reduced colony formation in soft agar and tumorigenicity in nude mice. ES-2 clones overexpressing KLK5, 10/5, 10/6, 5/6 made significantly fewer colonies in soft agar. When compared to control mice, survival of mice injected with ES-2 clones overexpressing KLK10, 10/5, 10/6, 5/6 was significantly longer, while KLK6 was shorter. All groups displaying a survival advantage also differed quantitatively and qualitatively in their presentation of ascites, with both a reduced incidence of ascites and an absence of cellular aggregates within those ascites. The survival advantage conferred by KLK10 overexpression could be recapitulated with the exogenous administration of a recombinant KLK10. In conclusion, these findings indicate that KLK5, 6 and 10 may modulate the progression of ovarian cancer, and interact together to alter tumour pathophysiology. Furthermore, results support the putative role of KLK10 as a tumour suppressor and suggest it may hold therapeutic potential in ovarian cancer. PMID- 22102858 TI - Characterization of the Na+/H+ antiporter from Yersinia pestis. AB - Yersinia pestis, the bacterium that historically accounts for the Black Death epidemics, has nowadays gained new attention as a possible biological warfare agent. In this study, its Na+/H+ antiporter is investigated for the first time, by a combination of experimental and computational methodologies. We determined the protein's substrate specificity and pH dependence by fluorescence measurements in everted membrane vesicles. Subsequently, we constructed a model of the protein's structure and validated the model using molecular dynamics simulations. Taken together, better understanding of the Yersinia pestis Na+/H+ antiporter's structure-function relationship may assist in studies on ion transport, mechanism of action and designing specific blockers of Na+/H+ antiporter to help in fighting Yersinia pestis -associated infections. We hope that our model will prove useful both from mechanistic and pharmaceutical perspectives. PMID- 22102859 TI - MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer. AB - MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and gammaH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41-0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5 year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer. PMID- 22102860 TI - Cryptosexuality and the genetic diversity paradox in coffee rust, Hemileia vastatrix. AB - BACKGROUND: Despite the fact that coffee rust was first investigated scientifically more than a century ago, and that the disease is one of the major constraints to coffee production--constantly changing the socio-economic and historical landscape of the crop--critical aspects of the life cycle of the pathogen, Hemileia vastatrix, remain unclear. The asexual urediniospores are regarded as the only functional propagule: theoretically, making H. vastatrix a clonal species. However, the well-documented emergence of new rust pathotypes and the breakdown in genetic resistance of coffee cultivars, present a paradox. METHODS AND RESULTS: Here, using computer-assisted DNA image cytometry, following a modified nuclear stoichiometric staining technique with Feulgen, we show that meiosis occurs within the urediniospores. Stages of spore development were categorised based on morphology, from the spore-mother cell through to the germinating spore, and the relative nuclear DNA content was quantified statistically at each stage. CONCLUSIONS: Hidden sexual reproduction disguised within the asexual spore (cryptosexuality) could explain why new physiological races have arisen so often and so quickly in Hemileia vastatrix. This could have considerable implications for coffee breeding strategies and may be a common event in rust fungi, especially in related genera occupying the same basal phylogenetic lineages. PMID- 22102861 TI - Dissolution of calcite in the twilight zone: bacterial control of dissolution of sinking planktonic carbonates is unlikely. AB - We investigated the ability of bacterial communities to colonize and dissolve two biogenic carbonates (Foraminifera and oyster shells). Bacterial carbonate dissolution in the upper water column is postulated to be driven by metabolic activity of bacteria directly colonising carbonate surfaces and the subsequent development of acidic microenvironments. We employed a combination of microsensor measurements, scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) and image analysis and molecular documentation of colonising bacteria to monitor microbial processes and document changes in shell surface topography. Bacterial communities rapidly colonised shell surfaces, forming dense biofilms with extracellular polymeric substance (EPS) deposits. Despite this, we found no evidence of bacterially mediated carbonate dissolution. Dissolution was not indicated by Ca2+ microprofiles, nor was changes in shell surface structure related to the presence of colonizing bacteria. Given the short time (days) settling carbonate material is actually in the twilight zone (500-1000 m), it is highly unlikely that microbial metabolic activity on directly colonised shells plays a significant role in dissolving settling carbonates in the shallow ocean. PMID- 22102862 TI - Sample size requirements for studies of treatment effects on beta-cell function in newly diagnosed type 1 diabetes. AB - Preservation of beta-cell function as measured by stimulated C-peptide has recently been accepted as a therapeutic target for subjects with newly diagnosed type 1 diabetes. In recently completed studies conducted by the Type 1 Diabetes Trial Network (TrialNet), repeated 2-hour Mixed Meal Tolerance Tests (MMTT) were obtained for up to 24 months from 156 subjects with up to 3 months duration of type 1 diabetes at the time of study enrollment. These data provide the information needed to more accurately determine the sample size needed for future studies of the effects of new agents on the 2-hour area under the curve (AUC) of the C-peptide values. The natural log(x), log(x+1) and square-root (?x) transformations of the AUC were assessed. In general, a transformation of the data is needed to better satisfy the normality assumptions for commonly used statistical tests. Statistical analysis of the raw and transformed data are provided to estimate the mean levels over time and the residual variation in untreated subjects that allow sample size calculations for future studies at either 12 or 24 months of follow-up and among children 8-12 years of age, adolescents (13-17 years) and adults (18+ years). The sample size needed to detect a given relative (percentage) difference with treatment versus control is greater at 24 months than at 12 months of follow-up, and differs among age categories. Owing to greater residual variation among those 13-17 years of age, a larger sample size is required for this age group. Methods are also described for assessment of sample size for mixtures of subjects among the age categories. Statistical expressions are presented for the presentation of analyses of log(x+1) and ?x transformed values in terms of the original units of measurement (pmol/ml). Analyses using different transformations are described for the TrialNet study of masked anti-CD20 (rituximab) versus masked placebo. These results provide the information needed to accurately evaluate the sample size for studies of new agents to preserve C-peptide levels in newly diagnosed type 1 diabetes. PMID- 22102863 TI - Generation of tactile maps for artificial skin. AB - Prior research has shown that representations of retinal surfaces can be learned from the intrinsic structure of visual sensory data in neural simulations, in robots, as well as by animals. Furthermore, representations of cochlear (frequency) surfaces can be learned from auditory data in neural simulations. Advances in hardware technology have allowed the development of artificial skin for robots, realising a new sensory modality which differs in important respects from vision and audition in its sensorimotor characteristics. This provides an opportunity to further investigate ordered sensory map formation using computational tools. We show that it is possible to learn representations of non trivial tactile surfaces, which require topologically and geometrically involved three-dimensional embeddings. Our method automatically constructs a somatotopic map corresponding to the configuration of tactile sensors on a rigid body, using only intrinsic properties of the tactile data. The additional complexities involved in processing the tactile modality require the development of a novel multi-dimensional scaling algorithm. This algorithm, ANISOMAP, extends previous methods and outperforms them, producing high-quality reconstructions of tactile surfaces in both simulation and hardware tests. In addition, the reconstruction turns out to be robust to unanticipated hardware failure. PMID- 22102864 TI - Detection of the onset of ischemia and carcinogenesis by hypoxia-inducible transcription factor-based in vivo bioluminescence imaging. AB - An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential. PMID- 22102865 TI - Long distance dispersal of zooplankton endemic to isolated mountaintops--an example of an ecological process operating on an evolutionary time scale. AB - Recent findings suggest a convergence of time scales between ecological and evolutionary processes which is usually explained in terms of rapid micro evolution resulting in evolution on ecological time scales. A similar convergence, however, can also emerge when slow ecological processes take place on evolutionary time scales. A good example of such a slow ecological process is the colonization of remote aquatic habitats by passively dispersed zooplankton. Using variation at the protein coding mitochondrial COI gene, we investigated the balance between mutation and migration as drivers of genetic diversity in two Branchipodopsis fairy shrimp species (Crustacea, Anostraca) endemic to remote temporary rock pool clusters at the summit of isolated mountaintops in central South Africa. We showed that both species colonized the region almost simultaneously c. 0.8 My ago, but exhibit contrasting patterns of regional genetic diversity and demographic history. The haplotype network of the common B. cf. wolfi showed clear evidence of 11 long distance dispersal events (up to 140 km) with five haplotypes that are shared among distant inselbergs, as well as some more spatially isolated derivates. Similar patterns were not observed for B. drakensbergensis presumably since this rarer species experienced a genetic bottleneck. We conclude that the observed genetic patterns reflect rare historic colonization events rather than frequent ongoing gene flow. Moreover, the high regional haplotype diversity combined with a high degree of haplotype endemicity indicates that evolutionary- (mutation) and ecological (migration) processes in this system operate on similar time scales. PMID- 22102866 TI - GNC and CGA1 modulate chlorophyll biosynthesis and glutamate synthase (GLU1/Fd GOGAT) expression in Arabidopsis. AB - Chloroplast development is an important determinant of plant productivity and is controlled by environmental factors including amounts of light and nitrogen as well as internal phytohormones including cytokinins and gibberellins (GA). The paralog GATA transcription factors GNC and CGA1/GNL up-regulated by light, nitrogen and cytokinin while also being repressed by GA signaling. Modifying the expression of these genes has previously been shown to influence chlorophyll content in Arabidopsis while also altering aspects of germination, elongation growth and flowering time. In this work, we also use transgenic lines to demonstrate that GNC and CGA1 exhibit a partially redundant control over chlorophyll biosynthesis. We provide novel evidence that GNC and CGA1 influence both chloroplast number and leaf starch in proportion to their transcript level. GNC and CGA1 were found to modify the expression of chloroplast localized GLUTAMATE SYNTHASE (GLU1/Fd-GOGAT), which is the primary factor controlling nitrogen assimilation in green tissue. Altering GNC and CGA1 expression was also found to modulate the expression of important chlorophyll biosynthesis genes (GUN4, HEMA1, PORB, and PORC). As previously demonstrated, the CGA1 transgenic plants demonstrated significantly altered timing to a number of developmental events including germination, leaf production, flowering time and senescence. In contrast, the GNC transgenic lines we analyzed maintain relatively normal growth phenotypes outside of differences in chloroplast development. Despite some evidence for partial divergence, results indicate that regulation of both GNC and CGA1 by light, nitrogen, cytokinin, and GA acts to modulate nitrogen assimilation, chloroplast development and starch production. Understanding the mechanisms controlling these processes is important for agricultural biotechnology. PMID- 22102867 TI - Integrating overlapping structures and background information of words significantly improves biological sequence comparison. AB - Word-based models have achieved promising results in sequence comparison. However, as the important statistical properties of words in biological sequence, how to use the overlapping structures and background information of the words to improve sequence comparison is still a problem. This paper proposed a new statistical method that integrates the overlapping structures and the background information of the words in biological sequences. To assess the effectiveness of this integration for sequence comparison, two sets of evaluation experiments were taken to test the proposed model. The first one, performed via receiver operating curve analysis, is the application of proposed method in discrimination between functionally related regulatory sequences and unrelated sequences, intron and exon. The second experiment is to evaluate the performance of the proposed method with f-measure for clustering Hepatitis E virus genotypes. It was demonstrated that the proposed method integrating the overlapping structures and the background information of words significantly improves biological sequence comparison and outperforms the existing models. PMID- 22102868 TI - Deep sequencing of MYC DNA-binding sites in Burkitt lymphoma. AB - BACKGROUND: MYC is a key transcription factor involved in central cellular processes such as regulation of the cell cycle, histone acetylation and ribosomal biogenesis. It is overexpressed in the majority of human tumors including aggressive B-cell lymphoma. Especially Burkitt lymphoma (BL) is a highlight example for MYC overexpression due to a chromosomal translocation involving the c MYC gene. However, no genome-wide analysis of MYC-binding sites by chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) has been conducted in BL so far. METHODOLOGY/PRINCIPAL FINDINGS: ChIP-Seq was performed on 5 BL cell lines with a MYC-specific antibody giving rise to 7,054 MYC-binding sites after bioinformatics analysis of a total of approx. 19 million sequence reads. In line with previous findings, binding sites accumulate in gene sets known to be involved in the cell cycle, ribosomal biogenesis, histone acetyltransferase and methyltransferase complexes demonstrating a regulatory role of MYC in these processes. Unexpectedly, MYC-binding sites also accumulate in many B-cell relevant genes. To assess the functional consequences of MYC binding, the ChIP-Seq data were supplemented with siRNA- mediated knock-downs of MYC in BL cell lines followed by gene expression profiling. Interestingly, amongst others, genes involved in the B-cell function were up-regulated in response to MYC silencing. CONCLUSION/SIGNIFICANCE: The 7,054 MYC-binding sites identified by our ChIP-Seq approach greatly extend the knowledge regarding MYC binding in BL and shed further light on the enormous complexity of the MYC regulatory network. Especially our observations that (i) many B-cell relevant genes are targeted by MYC and (ii) that MYC down-regulation leads to an up-regulation of B-cell genes highlight an interesting aspect of BL biology. PMID- 22102869 TI - Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. AB - Cardiac cachexia is a serious complication of chronic heart failure with a prevalence of 10-16% and poor prognosis. There are no current therapy options for cardiac cachexia. Ghrelin is the natural ligand for the GHS-1a-receptor and a potential target for conditions associated with cachexia. Ghrelin has been shown to increase weight in several species. The GHS-1a-receptor is not only found in the brain, but also in other tissues, including the myocardium. Human clinical trials with native ghrelin in cardiac cachexia demonstrated increases in appetite, weight and cardiac output. METHODS: Human ghrelin or one of two analogues BIM-28125 and BIM-28131 (also known as RM-131) were tested at 50 nmole/kg/d and 500 nmole/kg/d versus placebo in a rat model of heart failure (myocardial infarction). Animals (SD-rats, approx. 225 g at surgery) received diuretics from day 14 and compounds from day 28 for 4 weeks using osmotic pumps. Weight was monitored and body composition analysed (NMR-scanning). Cardiac function was assessed by echocardiography and hemodynamics. RESULTS: Animals with MI gained less weight compared to sham rats until start of the therapy (311 g vs 324 g, p = 0.0129). Animals treated with BIM-28131 at 50 nmole/kg/d or all compounds at 500 nmole/kg/d displayed stronger weight gain compared to placebo and sham (all p<0.001). Before treatment, body composition was similar in all groups (average: 36 g fat, 248 g lean). Placebo-treated rats gained no fat, but only lean mass. The active compounds induced both fat and lean mass gain, but to a different extent. The fat-to-muscle-ratio of tissue gain was 0.9+/-0.07 for BIM 28131 at 50 nmole/kg/d, whereas at 500 nmole/kg/d it was 0.76+/-0.07 for BIM 28131, 0.68+/-0.12 for BIM-28125, and 0.48+/-0.05 for ghrelin. MuRF-1 and MAFbx were differentially regulated by treatment. CONCLUSION: Ghrelin is a very promising treatment option for cardiac cachexia, with the analogue BIM-28131 (RM 131) being the most effective compound. PMID- 22102870 TI - Dicationic alkylammonium bromide gemini surfactants. Membrane perturbation and skin irritation. AB - Dicationic alkylammonium bromide gemini surfactants represent a class of amphiphiles potentially effective as skin permeation enhancers. However, only a limited number of studies has been dedicated to the evaluation of the respective cytotoxicity, and none directed to skin irritation endpoints. Supported on a cell viability study, the cytotoxicity of gemini surfactants of variable tail and spacer length was assessed. For this purpose, keratinocyte cells from human skin (NCTC 2544 cell line), frequently used as a model for skin irritation, were employed. The impact of the different gemini surfactants on the permeability and morphology of model vesicles was additionally investigated by measuring the leakage of calcein fluorescent dye and analyzing the NMR spectra of 31P, respectively. Detail on the interaction of gemini molecules with model membranes was also provided by a systematic differential scanning calorimetry (DSC) and molecular dynamics (MD) simulation. An irreversible impact on the viability of the NCTC 2544 cell line was observed for gemini concentrations higher than 25 mM, while no cytotoxicity was found for any of the surfactants in a concentration range up to 10 mM. A higher cytotoxicity was also found for gemini surfactants presenting longer spacer and shorter tails. The same trend was obtained in the calorimetric and permeability studies, with the gemini of longest spacer promoting the highest degree of membrane destabilization. Additional structural and dynamical characterization of the various systems, obtained by 31P NMR and MD, provide some insight on the relationship between the architecture of gemini surfactants and the respective perturbation mechanism. PMID- 22102871 TI - Transmission of MRSA between companion animals and infected human patients presenting to outpatient medical care facilities. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in both human and veterinary medicine. The importance of companion animals as reservoirs of human infections is currently unknown. The companion animals of 49 MRSA-infected outpatients (cases) were screened for MRSA carriage, and their bacterial isolates were compared with those of the infected patients using Pulsed Field Gel Electrophoresis (PFGE). Rates of MRSA among the companion animals of MRSA-infected patients were compared to rates of MRSA among companion animals of pet guardians attending a "veterinary wellness clinic" (controls). MRSA was isolated from at least one companion animal in 4/49 (8.2%) households of MRSA infected outpatients vs. none of the pets of the 50 uninfected human controls. Using PFGE, patient-pets MRSA isolates were identical for three pairs and discordant for one pair (suggested MRSA inter-specie transmission p-value = 0.1175). These results suggest that companion animals of MRSA-infected patients can be culture-positive for MRSA, representing a potential source of infection or re-infection for humans. Further studies are required to better understand the epidemiology of MRSA human-animal inter-specie transmission. PMID- 22102872 TI - Heterogeneous nuclear ribonucleoprotein k interacts with Abi-1 at postsynaptic sites and modulates dendritic spine morphology. AB - BACKGROUND: Abelson-interacting protein 1 (Abi-1) plays an important role for dendritic branching and synapse formation in the central nervous system. It is localized at the postsynaptic density (PSD) and rapidly translocates to the nucleus upon synaptic stimulation. At PSDs Abi-1 is in a complex with several other proteins including WASP/WAVE or cortactin thereby regulating the actin cytoskeleton via the Arp 2/3 complex. PRINCIPAL FINDINGS: We identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a 65 kDa ssDNA/RNA-binding protein that is involved in multiple intracellular signaling cascades, as a binding partner of Abi-1 at postsynaptic sites. The interaction with the Abi-1 SH3 domain is mediated by the hnRNPK-interaction (KI) domain. We further show that during brain development, hnRNPK expression becomes more and more restricted to granule cells of the cerebellum and hippocampal neurons where it localizes in the cell nucleus as well as in the spine/dendritic compartment. The downregulation of hnRNPK in cultured hippocampal neurons by RNAi results in an enlarged dendritic tree and a significant increase in filopodia formation. This is accompanied by a decrease in the number of mature synapses. Both effects therefore mimic the neuronal morphology after downregulation of Abi-1 mRNA in neurons. CONCLUSIONS: Our findings demonstrate a novel interplay between hnRNPK and Abi-1 in the nucleus and at synaptic sites and show obvious similarities regarding both protein knockdown phenotypes. This indicates that hnRNPK and Abi-1 act synergistic in a multiprotein complex that regulates the crucial balance between filopodia formation and synaptic maturation in neurons. PMID- 22102873 TI - Chemoprophylaxis in contacts of patients with cholera: systematic review and meta analysis. AB - INTRODUCTION: There is a pressing need for effective measures to prevent the spread of cholera. Our systematic review assesses the effects of chemoprophylaxis in preventing cholera among exposed contacts. METHODS AND FINDINGS: We considered published and unpublished reports of studies up to July 2011. For this we searched: PubMed (1966 to July, 2011), Embase (1980 to July 2011), Cochrane Central Register of Controlled Trials (6; 2011), LILACS (1982 to July, 2011), the International Clinical Trials Registry Platform (July 2011) and references of identified publications. We included controlled clinical trials (randomized and non-randomized) in which chemoprophylaxis was used to prevent cholera among patient contacts. The main outcome measures were hospitalization and laboratory diagnosis of cholera in contacts for cholera patients. We assessed the risk of bias. We identified 2638 references and these included 2 randomized trials and 5 controlled trials that added up to a total of 4,154 participants. The risk of bias scored high for most trials. The combined results from two trials found that chemoprophylaxis reduced hospitalization of contacts during the follow-up period by 8-12 days (2826 participants; RR 0.54 95% CI 0.40-0.74;I2 0%). A meta-analysis of five trials found a significant reduction in disease among contacts with at least one positive sample who received chemoprophylaxis during the overall follow up (range 4-15 days) (1,414 participants; RR 0.35 95% CI 0.18-0.66;I2 74%). A significant reduction in the number of positive samples was also found with chemoprophylaxis (3 CCT; 6,918 samples; RR 0.39 95% CI 0.29-0.51;I2 0%). CONCLUSION: Our findings suggest that chemoprophylaxis has a protective effect among household contacts of people with cholera but the results are based on studies with a high risk of bias. Hence, there is a need for adequate reliable research that allows balancing benefits and harms by evaluating the effects of chemoprophylaxis. PMID- 22102874 TI - Expansion of intestinal epithelial stem cells during murine development. AB - Murine small intestinal crypt development is initiated during the first postnatal week. Soon after formation, overall increases in the number of crypts occurs through a bifurcating process called crypt fission, which is believed to be driven by developmental increases in the number of intestinal stem cells (ISCs). Recent evidence suggests that a heterogeneous population of ISCs exists within the adult intestine. Actively cycling ISCs are labeled by Lgr5, Ascl2 and Olfm4; whereas slowly cycling or quiescent ISC are marked by Bmi1 and mTert. The goal of this study was to correlate the expression of these markers with indirect measures of ISC expansion during development, including quantification of crypt fission and side population (SP) sorting. Significant changes were observed in the percent of crypt fission and SP cells consistent with ISC expansion between postnatal day 14 and 21. Quantitative real-time polymerase chain reaction (RT PCR) for the various ISC marker mRNAs demonstrated divergent patterns of expression. mTert surged earliest, during the first week of life as crypts are initially being formed, whereas Lgr5 and Bmi1 peaked on day 14. Olfm4 and Ascl2 had variable expression patterns. To assess the number and location of Lgr5 expressing cells during this period, histologic sections from intestines of Lgr5 EGFP mice were subjected to quantitative analysis. There was attenuated Lgr5-EGFP expression at birth and through the first week of life. Once crypts were formed, the overall number and percent of Lgr5-EGFP positive cells per crypt remain stable throughout development and into adulthood. These data were supported by Lgr5 in situ hybridization in wild-type mice. We conclude that heterogeneous populations of ISCs are expanding as measured by SP sorting and mRNA expression at distinct developmental time points. PMID- 22102875 TI - Decreased MCM2-6 in Drosophila S2 cells does not generate significant DNA damage or cause a marked increase in sensitivity to replication interference. AB - A reduction in the level of some MCM proteins in human cancer cells (MCM5 in U20S cells or MCM3 in Hela cells) causes a rapid increase in the level of DNA damage under normal conditions of cell proliferation and a loss of viability when the cells are subjected to replication interference. Here we show that Drosophila S2 cells do not appear to show the same degree of sensitivity to MCM2-6 reduction. Under normal cell growth conditions a reduction of >95% in the levels of MCM3, 5, and 6 causes no significant short term alteration in the parameters of DNA replication or increase in DNA damage. MCM depleted cells challenged with HU do show a decrease in the density of replication forks compared to cells with normal levels of MCM proteins, but this produces no consistent change in the levels of DNA damage observed. In contrast a comparable reduction of MCM7 levels has marked effects on viability, replication parameters and DNA damage in the absence of HU treatment. PMID- 22102876 TI - Calcium-release channels in paramecium. Genomic expansion, differential positioning and partial transcriptional elimination. AB - The release of Ca2+ from internal stores is a major source of signal Ca2+ in almost all cell types. The internal Ca2+ pools are activated via two main families of intracellular Ca2+-release channels, the ryanodine and the inositol 1,4,5-trisphosphate (InsP3) receptors. Among multicellular organisms these channel types are ubiquitous, whereas in most unicellular eukaryotes the identification of orthologs is impaired probably due to evolutionary sequence divergence. However, the ciliated protozoan Paramecium allowed us to prognosticate six groups, with a total of 34 genes, encoding proteins with characteristics typical of InsP3 and ryanodine receptors by BLAST search of the Paramecium database. We here report that these Ca2+-release channels may display all or only some of the characteristics of canonical InsP3 and ryanodine receptors. In all cases, prediction methods indicate the presence of six trans membrane regions in the C-terminal domains, thus corresponding to canonical InsP3 receptors, while a sequence homologous to the InsP3-binding domain is present only in some types. Only two types have been analyzed in detail previously. We now show, by using antibodies and eventually by green fluorescent protein labeling, that the members of all six groups localize to distinct organelles known to participate in vesicle trafficking and, thus, may provide Ca2+ for local membrane-membrane interactions. Whole genome duplication can explain radiation within the six groups. Comparative and evolutionary evaluation suggests derivation from a common ancestor of canonical InsP3 and ryanodine receptors. With one group we could ascertain, to our knowledge for the first time, aberrant splicing in one thoroughly analyzed Paramecium gene. This yields truncated forms and, thus, may indicate a way to pseudogene formation. No comparable analysis is available for any other, free-living or parasitic/pathogenic protozoan. PMID- 22102877 TI - Disordering of human telomeric G-quadruplex with novel antiproliferative anthrathiophenedione. AB - Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)~106 M-1) for human telomeric antiparallel quadruplex d(TTAGGG)4 and duplex d(TTAGGG)4?d(CCCTAA)4. Importantly, a ~100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs. PMID- 22102878 TI - Seroprevalence of pandemic H1N1 antibody among health care workers in Hong Kong following receipt of monovalent 2009 H1N1 influenza vaccine. AB - BACKGROUND: Healthcare workers in many countries are recommended to receive influenza vaccine to protect themselves as well as patients. A monovalent H1N1 vaccine became available in Hong Kong in December 2009 and around 10% of local healthcare workers had received the vaccine by February 2010. METHODS: We conducted a cross-sectional study of the prevalence of antibody to pandemic (H1N1) 2009 among HCWs in Hong Kong in February-March 2010 following the first pandemic wave and the pH1N1 vaccination campaign. In this study we focus on the subset of healthcare workers who reported receipt of non-adjuvanted monovalent 2009 H1N1 vaccine (Panenza, Sanofi Pasteur). Sera collected from HCWs were tested for antibody against the pH1N1 virus by hemagglutination inhibition (HI) and viral neutralization (VN) assays. RESULTS: We enrolled 703 HCWs. Among 104 HCWs who reported receipt of pH1N1 vaccine, 54% (95% confidence interval (CI): 44% 63%) had antibody titer >=1?40 by HI and 42% (95% CI: 33%-52%) had antibody titer >=1?40 by VN. The proportion of HCWs with antibody titer >=1?40 by HI and VN significantly decreased with age, and the proportion with antibody titer >=1?40 by VN was marginally significantly lower among HCWs who reported prior receipt of 2007-08 seasonal influenza vaccine (odds ratio: 0.43; 95% CI: 0.19-1.00). After adjustment for age, the effect of prior seasonal vaccine receipt was not statistically significant. CONCLUSIONS: Our findings suggest that monovalent H1N1 vaccine may have had suboptimal immunogenicity in HCWs in Hong Kong. Larger studies are required to confirm whether influenza vaccine maintains high efficacy and effectiveness in HCWs. PMID- 22102879 TI - Differential expression of NK receptors CD94 and NKG2A by T cells in rheumatoid arthritis patients in remission compared to active disease. AB - OBJECTIVE: TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal. METHODS: Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = -15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56-), NK-(CD3-CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry. RESULTS: Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56- cell expression of NKG2A was inversely related to DAS28 (r = -0.612, p<0.005). CONCLUSION: High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy. PMID- 22102880 TI - Chimeric anti-staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB. AB - Staphylococcal enterotoxin B (SEB) is one of a family of toxins secreted by Staphylococcus aureus that act as superantigens, activating a large fraction of the T-cell population and inducing production of high levels of inflammatory cytokines that can cause toxic shock syndrome (TSS) and death. Extracellular engagement of the TCR of T-cells and class II MHC of antigen presenting cells by SEB triggers the activation of many intracellular signaling processes. We engineered chimeric antibodies to block the extracellular engagement of cellular receptors by SEB and used a statin to inhibit intracellular signaling. Chimeric human-mouse antibodies directed against different neutralizing epitopes of SEB synergistically inhibited its activation of human T-cells in vitro. In the in vivo model of lethal toxic shock syndrome (TSS) in HLA-DR3 transgenic mice, two of these antibodies conferred significant partial protection when administered individually, but offered complete protection in a synergistic manner when given together. Similarly, in vivo, lovastatin alone conferred only partial protection from TSS similar to single anti-SEB antibodies. However, used in combination with one chimeric neutralizing anti-SEB antibody, lovastatin provided complete protection against lethal TSS in HLA-DR3 transgenic mice. These experiments demonstrate that in vivo protection against lethal doses of SEB can be achieved by a statin of proven clinical safety and chimeric human-mouse antibodies, agents now widely used and known to be of low immunogenicity in human hosts. PMID- 22102881 TI - A new piece of the Shigella Pathogenicity puzzle: spermidine accumulation by silencing of the speG gene [corrected]. AB - The genome of Shigella, a gram negative bacterium which is the causative agent of bacillary dysentery, shares strong homologies with that of its commensal ancestor, Escherichia coli. The acquisition, by lateral gene transfer, of a large plasmid carrying virulence determinants has been a crucial event in the evolution towards the pathogenic lifestyle and has been paralleled by the occurrence of mutations affecting genes, which negatively interfere with the expression of virulence factors. In this context, we have analysed to what extent the presence of the plasmid-encoded virF gene, the major activator of the Shigella regulon for invasive phenotype, has modified the transcriptional profile of E. coli. Combining results from transcriptome assays and comparative genome analyses we show that in E. coli VirF, besides being able to up-regulate several chromosomal genes, which potentially influence bacterial fitness within the host, also activates genes which have been lost by Shigella. We have focused our attention on the speG gene, which encodes spermidine acetyltransferase, an enzyme catalysing the conversion of spermidine into the physiologically inert acetylspermidine, since recent evidence stresses the involvement of polyamines in microbial pathogenesis. Through identification of diverse mutations, which prevent expression of a functional SpeG protein, we show that the speG gene has been silenced by convergent evolution and that its inactivation causes the marked increase of intracellular spermidine in all Shigella spp. This enhances the survival of Shigella under oxidative stress and allows it to better face the adverse conditions it encounters inside macrophage. This is supported by the outcome of infection assays performed in mouse peritoneal macrophages and of a competitive-infection assay on J774 macrophage cell culture. Our observations fully support the pathoadaptive nature of speG inactivation in Shigella and reveal that the accumulation of spermidine is a key determinant in the pathogenicity strategy adopted by this microrganism. PMID- 22102882 TI - Working memory in attention deficit/hyperactivity disorder is characterized by a lack of specialization of brain function. AB - Working memory impairments are frequent in Attention Deficit/Hyperactivity Disorder (ADHD) and create problems along numerous functional dimensions. The present study utilized the Visual Serial Addition Task (VSAT) and functional magnetic resonance imaging (fMRI) to explore working memory processes in thirteen typically developing (TD) control and thirteen children with ADHD, Combined type. Analysis of Variance (ANOVA) was used to examine both main effects and interactions. Working memory-specific activity was found in TD children in the bilateral prefrontal cortex. In contrast the within-group map in ADHD did not reveal any working-memory specific regions. Main effects of condition suggested that the right middle frontal gyrus (BA6) and the right precuneus were engaged by both groups during working memory processing. Group differences were driven by significantly greater, non-working memory-specific, activation in the ADHD relative to TD group in the bilateral insula extending into basal ganglia and the medial prefrontal cortex. A region of interest analysis revealed a region in left middle frontal gyrus that was more active during working memory in TD controls. Thus, only the TD group appeared to display working memory-modulated brain activation. In conclusion, children with ADHD demonstrated reduced working memory task specific brain activation in comparison to their peers. These data suggest inefficiency in functional recruitment by individuals with ADHD represented by a poor match between task demands and appropriate levels of brain activity. PMID- 22102883 TI - BMI not WHR modulates BOLD fMRI responses in a sub-cortical reward network when participants judge the attractiveness of human female bodies. AB - In perceptual terms, the human body is a complex 3d shape which has to be interpreted by the observer to judge its attractiveness. Both body mass and shape have been suggested as strong predictors of female attractiveness. Normally body mass and shape co-vary, and it is difficult to differentiate their separate effects. A recent study suggested that altering body mass does not modulate activity in the reward mechanisms of the brain, but shape does. However, using computer generated female body-shaped greyscale images, based on a Principal Component Analysis of female bodies, we were able to construct images which covary with real female body mass (indexed with BMI) and not with body shape (indexed with WHR), and vice versa. Twelve observers (6 male and 6 female) rated these images for attractiveness during an fMRI study. The attractiveness ratings were correlated with changes in BMI and not WHR. Our primary fMRI results demonstrated that in addition to activation in higher visual areas (such as the extrastriate body area), changing BMI also modulated activity in the caudate nucleus, and other parts of the brain reward system. This shows that BMI, not WHR, modulates reward mechanisms in the brain and we infer that this may have important implications for judgements of ideal body size in eating disordered individuals. PMID- 22102884 TI - Epstein-Barr virus BART9 miRNA modulates LMP1 levels and affects growth rate of nasal NK T cell lymphomas. AB - Nasal NK/T cell lymphomas (NKTCL) are a subset of aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin's lymphomas. The role of EBV in pathogenesis of NKTCL is not clear. Intriguingly, EBV encodes more than 40 microRNAs (miRNA) that are differentially expressed and largely conserved in lymphocryptoviruses. While miRNAs play a critical role in the pathogenesis of cancer, especially lymphomas, the expression and function of EBV transcribed miRNAs in NKTCL are not known. To examine the role of EBV miRNAs in NKTCL, we used microarray profiling and qRT-PCR to identify and validate expression of viral miRNAs in SNK6 and SNT16 cells, which are two independently derived NKTCL cell lines that maintain the type II EBV latency program. All EBV BART miRNAs except BHRF-derived miRNAs were expressed and some of these miRNAs are expressed at higher levels than in nasopharyngeal carcinomas. Modulating the expression of BART9 with antisense RNAs consistently reduced SNK6 and SNT16 proliferation, while antisense RNAs to BARTs 7 and -17-5p affected proliferation only in SNK6 cells. Furthermore, the EBV LMP 1 oncoprotein and transcript levels were repressed when an inhibitor of BART9 miRNA was transfected into SNK6 cells, and overexpression of BART9 miRNA increased LMP-1 protein and mRNA expression. Our data indicate that BART9 is involved in NKTCL proliferation, and one of its mechanisms of action appears to be regulating LMP-1 levels. Our findings may have direct application for improving NKTCL diagnosis and for developing possible novel treatment approaches for this tumor, for which current chemotherapeutic drugs have limited effectiveness. PMID- 22102885 TI - Novel SSR markers from BAC-end sequences, DArT arrays and a comprehensive genetic map with 1,291 marker loci for chickpea (Cicer arietinum L.). AB - Chickpea (Cicer arietinum L.) is the third most important cool season food legume, cultivated in arid and semi-arid regions of the world. The goal of this study was to develop novel molecular markers such as microsatellite or simple sequence repeat (SSR) markers from bacterial artificial chromosome (BAC)-end sequences (BESs) and diversity arrays technology (DArT) markers, and to construct a high-density genetic map based on recombinant inbred line (RIL) population ICC 4958 (C. arietinum)*PI 489777 (C. reticulatum). A BAC-library comprising 55,680 clones was constructed and 46,270 BESs were generated. Mining of these BESs provided 6,845 SSRs, and primer pairs were designed for 1,344 SSRs. In parallel, DArT arrays with ca. 15,000 clones were developed, and 5,397 clones were found polymorphic among 94 genotypes tested. Screening of newly developed BES-SSR markers and DArT arrays on the parental genotypes of the RIL mapping population showed polymorphism with 253 BES-SSR markers and 675 DArT markers. Segregation data obtained for these polymorphic markers and 494 markers data compiled from published reports or collaborators were used for constructing the genetic map. As a result, a comprehensive genetic map comprising 1,291 markers on eight linkage groups (LGs) spanning a total of 845.56 cM distance was developed (http://cmap.icrisat.ac.in/cmap/sm/cp/thudi/). The number of markers per linkage group ranged from 68 (LG 8) to 218 (LG 3) with an average inter-marker distance of 0.65 cM. While the developed resource of molecular markers will be useful for genetic diversity, genetic mapping and molecular breeding applications, the comprehensive genetic map with integrated BES-SSR markers will facilitate its anchoring to the physical map (under construction) to accelerate map-based cloning of genes in chickpea and comparative genome evolution studies in legumes. PMID- 22102886 TI - An RNA-Seq strategy to detect the complete coding and non-coding transcriptome including full-length imprinted macro ncRNAs. AB - Imprinted macro non-protein-coding (nc) RNAs are cis-repressor transcripts that silence multiple genes in at least three imprinted gene clusters in the mouse genome. Similar macro or long ncRNAs are abundant in the mammalian genome. Here we present the full coding and non-coding transcriptome of two mouse tissues: differentiated ES cells and fetal head using an optimized RNA-Seq strategy. The data produced is highly reproducible in different sequencing locations and is able to detect the full length of imprinted macro ncRNAs such as Airn and Kcnq1ot1, whose length ranges between 80-118 kb. Transcripts show a more uniform read coverage when RNA is fragmented with RNA hydrolysis compared with cDNA fragmentation by shearing. Irrespective of the fragmentation method, all coding and non-coding transcripts longer than 8 kb show a gradual loss of sequencing tags towards the 3' end. Comparisons to published RNA-Seq datasets show that the strategy presented here is more efficient in detecting known functional imprinted macro ncRNAs and also indicate that standardization of RNA preparation protocols would increase the comparability of the transcriptome between different RNA-Seq datasets. PMID- 22102887 TI - MicroRNA expression in abdominal and gluteal adipose tissue is associated with mRNA expression levels and partly genetically driven. AB - To understand how miRNAs contribute to the molecular phenotype of adipose tissues and related traits, we performed global miRNA expression profiling in subcutaneous abdominal and gluteal adipose tissue of 70 human subjects and characterised which miRNAs were differentially expressed between these tissues. We found that 12% of the miRNAs were significantly differentially expressed between abdominal and gluteal adipose tissue (FDR adjusted p<0.05) in the primary study, of which 59 replicated in a follow-up study of 40 additional subjects. Further, 14 miRNAs were found to be associated with metabolic syndrome case control status in abdominal tissue and three of these replicated (primary study: FDR adjusted p<0.05, replication: p<0.05 and directionally consistent effect). Genome-wide genotyping was performed in the 70 subjects to enable miRNA expression quantitative trait loci (eQTL) analysis. Candidate miRNA eQTLs were followed-up in the additional 40 subjects and six significant, independent cis located miRNA eQTLs (primary study: p<0.001; replication: p<0.05 and directionally consistent effect) were identified. Finally, global mRNA expression profiling was performed in both tissues to enable association analysis between miRNA and target mRNA expression levels. We find 22% miRNAs in abdominal and 9% miRNAs in gluteal adipose tissue with expression levels significantly associated with the expression of corresponding target mRNAs (FDR adjusted p<0.05). Taken together, our results indicate a clear difference in the miRNA molecular phenotypic profile of abdominal and gluteal adipose tissue, that the expressions of some miRNAs are influenced by cis-located genetic variants and that miRNAs are associated with expression levels of their predicted mRNA targets. PMID- 22102888 TI - Serum fatty acid-binding protein 4 is a predictor of cardiovascular events in end stage renal disease. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown that FABP4 is secreted from adipocytes and that FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the impact of FABP4 concentrations on prognosis. We tested the hypothesis that FABP4 level predicts prognosis of patients with end-stage renal disease (ESRD), a group at high risk for atherosclerosis-associated morbidity and mortality. METHODS AND RESULTS: Biochemical markers including FABP4 were determined in 61 ESRD patients on chronic hemodialysis (HD). Serum FABP4 level in females (404.2+/ 30.5 ng/ml) was significantly higher than that in males (315.8+/-30.0 ng/ml), and the levels in ESRD patients were about 20-times higher than those in age-, gender and body mass index (BMI)-matched control subjects with normal renal function. FABP4 level was decreased by 57.2% after HD and was positively correlated with blood pressure, BMI, and levels of lipids and insulin. Multiple regression analysis indicated that HD duration, BMI, and triglycerides level were independent determinants for FABP4 level. ESRD patients with high FABP4 levels had higher cardiovascular mortality during the 7-year follow-up period. Cox proportional hazard regression analysis showed that logarithmically transformed FABP4 level was an independent predictor of cardiovascular death adjusted for age, gender, HD duration, BMI, and triglycerides level (hazard ratio, 7.75; 95% CI, 1.05-25.31). CONCLUSION: These findings suggest that FABP4 level, being related to adiposity and metabolic disorders, is a novel predictor of cardiovascular mortality in ESRD. PMID- 22102889 TI - Qilin is essential for cilia assembly and normal kidney development in zebrafish. AB - Defects in the cilium, a once thought vestigial organelle, have recently been implicated in many human diseases, including a number of cystic kidney diseases such as polycystic kidney disease (PKD), Bardet Bieldl Syndrome, and Meckel Gruber Syndrome. In a forward genetic screen, qilin was identified as a novel gene important in the pathogenesis of kidney cysts in zebrafish. In this paper we characterized qilin(hi3959A) mutant's phenotypes in detail, investigated cilia formation in this mutant and performed structural and functional analysis of the Qilin protein. Results reveal Qilin's essential role in cilia assembly and maintenance in multiple organs, including the kidney, the lateral line organ, and the outer segment of the photoreceptor cell. In addition, rescue experiments suggest that defective pronephric cilia correlate with the formation of kidney cysts in qilin(hi3959A) mutants. Further, genetic analysis suggests that qilin interacts with multiple intraflagellar transport (IFT) complex B genes, which is supported by the striking phenotypic similarities between qilin(hi3959A) and IFT complex B mutants. Finally, through deletion analysis we provide evidence that the well-conserved N-terminus and the coiled-coil domain of Qilin are both essential and sufficient for its function. Taken all the observations together, we propose that Qilin acts in a similar role as IFT complex B proteins in cilia assembly, maintenance and kidney development in zebrafish. PMID- 22102890 TI - Sequence-based classification using discriminatory motif feature selection. AB - Most existing methods for sequence-based classification use exhaustive feature generation, employing, for example, all k-mer patterns. The motivation behind such (enumerative) approaches is to minimize the potential for overlooking important features. However, there are shortcomings to this strategy. First, practical constraints limit the scope of exhaustive feature generation to patterns of length <= k, such that potentially important, longer (> k) predictors are not considered. Second, features so generated exhibit strong dependencies, which can complicate understanding of derived classification rules. Third, and most importantly, numerous irrelevant features are created. These concerns can compromise prediction and interpretation. While remedies have been proposed, they tend to be problem-specific and not broadly applicable. Here, we develop a generally applicable methodology, and an attendant software pipeline, that is predicated on discriminatory motif finding. In addition to the traditional training and validation partitions, our framework entails a third level of data partitioning, a discovery partition. A discriminatory motif finder is used on sequences and associated class labels in the discovery partition to yield a (small) set of features. These features are then used as inputs to a classifier in the training partition. Finally, performance assessment occurs on the validation partition. Important attributes of our approach are its modularity (any discriminatory motif finder and any classifier can be deployed) and its universality (all data, including sequences that are unaligned and/or of unequal length, can be accommodated). We illustrate our approach on two nucleosome occupancy datasets and a protein solubility dataset, previously analyzed using enumerative feature generation. Our method achieves excellent performance results, with and without optimization of classifier tuning parameters. A Python pipeline implementing the approach is available at http://www.epibiostat.ucsf.edu/biostat/sen/dmfs/. PMID- 22102891 TI - Enhanced anticancer activity of gemcitabine in combination with noscapine via antiangiogenic and apoptotic pathway against non-small cell lung cancer. AB - BACKGROUND: The aim of this investigation was to evaluate the anticancer activity of Noscapine (Nos) and Gemcitabine (Gem) combination (NGC) against non-small cell lung cancer (NSCLC) and to elucidate the underlying mechanism of action. METHODS: Isobolographic method was used to calculate combination index values from cytotoxicity data. In vitro antiangiogenic and apoptotic activity of Nos, Gem and NGC was evaluated. For in vivo studies, female athymic Nu/nu mice were xenografted with H460 tumors and the efficacy of Nos, Gem, or NGC was determined. Protein expressions by immunohistochemical staining were evaluated in harvested tumor tissues. RESULTS: The CI values (<0.59) were suggestive of synergistic behavior between Nos and Gem. NGC treatment showed significantly inhibited tube formation and increased percentage of apoptotic cells. NGC, Gem and Nos treatment reduced tumor volume by 82.9+/-4.5 percent, 39.4+/-5.8 percent and 34.2+/-5.7 percent respectively. Specifically, NGC treatment decreased expression cell survival proteins; VEGF, CD31 staining and microvessel density and enhanced DNA fragmentation and cleaved caspase 3 levels compared to single agent treated and control groups. CONCLUSION: Nos potentiated the anticancer activity of Gem in an additive to synergistic manner against lung cancer via antiangiogenic and apoptotic pathways. These findings suggest potential benefit for use of NGC chemotherapy for treatment of lung cancer. PMID- 22102892 TI - Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes. AB - BACKGROUND: Oxidative stress induced by the accumulation of reactive oxygen species (ROS) has a causal role in the development of insulin resistance, whereas ROS themselves function as intracellular second messengers that promote insulin signal transduction. ROS can act both positively and negatively on insulin signaling, but the molecular mechanisms controlling these dual actions of ROS are not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: Here, we directly treated H4IIEC hepatocytes with hydrogen peroxide (H2O2), a representative membrane permeable oxidant and the most abundant ROS in cells, to identify the key factors determining whether ROS impair or enhance intracellular insulin signaling. Treatment with high concentrations of H2O2 (25-50 uM) for 3 h reduced insulin stimulated Akt phosphorylation, and increased the phosphorylation of both JNK and its substrate c-Jun. In contrast, lower concentrations of H2O2 (5-10 uM) enhanced insulin-stimulated phosphorylation of Akt. Moreover, lower concentrations suppressed PTP1B activity, suggesting that JNK and phosphatases such as PTP1B may play roles in determining the thresholds for the diametrical effects of H2O2 on cellular insulin signaling. Pretreatment with antioxidant N-acetyl-L-cysteine (10 mM) canceled the signal-promoting action of low H2O2 (5 uM), and it canceled out further impairment of insulin of insulin signaling induced by high H2O2 (25 uM). CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that depending on its concentration, H2O2 can have the positive or negative effect on insulin signal transduction in H4IIEC hepatocytes, suggesting that the concentration of intracellular ROS may be a major factor in determining whether ROS impair or enhance insulin signaling. PMID- 22102893 TI - An intermediate level of BMP signaling directly specifies cranial neural crest progenitor cells in zebrafish. AB - The specification of the neural crest progenitor cell (NCPC) population in the early vertebrate embryo requires an elaborate network of signaling pathways, one of which is the Bone Morphogenetic Protein (BMP) pathway. Based on alterations in neural crest gene expression in zebrafish BMP pathway component mutants, we previously proposed a model in which the gastrula BMP morphogen gradient establishes an intermediate level of BMP activity establishing the future NCPC domain. Here, we tested this model and show that an intermediate level of BMP signaling acts directly to specify the NCPC. We quantified the effects of reducing BMP signaling on the number of neural crest cells and show that neural crest cells are significantly increased when BMP signaling is reduced and that this increase is not due to an increase in cell proliferation. In contrast, when BMP signaling is eliminated, NCPC fail to be specified. We modulated BMP signaling levels in BMP pathway mutants with expanded or no NCPCs to demonstrate that an intermediate level of BMP signaling specifies the NCPC. We further investigated the ability of Smad5 to act in a graded fashion by injecting smad5 antisense morpholinos and show that increasing doses first expand the NCPCs and then cause a loss of NCPCs, consistent with Smad5 acting directly in neural crest progenitor specification. Using Western blot analysis, we show that P-Smad5 levels are dose-dependently reduced in smad5 morphants, consistent with an intermediate level of BMP signaling acting through Smad5 to specify the neural crest progenitors. Finally, we performed chimeric analysis to demonstrate for the first time that BMP signal reception is required directly by NCPCs for their specification. Together these results add substantial evidence to a model in which graded BMP signaling acts as a morphogen to pattern the ectoderm, with an intermediate level acting in neural crest specification. PMID- 22102894 TI - Extending transfer entropy improves identification of effective connectivity in a spiking cortical network model. AB - Transfer entropy (TE) is an information-theoretic measure which has received recent attention in neuroscience for its potential to identify effective connectivity between neurons. Calculating TE for large ensembles of spiking neurons is computationally intensive, and has caused most investigators to probe neural interactions at only a single time delay and at a message length of only a single time bin. This is problematic, as synaptic delays between cortical neurons, for example, range from one to tens of milliseconds. In addition, neurons produce bursts of spikes spanning multiple time bins. To address these issues, here we introduce a free software package that allows TE to be measured at multiple delays and message lengths. To assess performance, we applied these extensions of TE to a spiking cortical network model (Izhikevich, 2006) with known connectivity and a range of synaptic delays. For comparison, we also investigated single-delay TE, at a message length of one bin (D1TE), and cross correlation (CC) methods. We found that D1TE could identify 36% of true connections when evaluated at a false positive rate of 1%. For extended versions of TE, this dramatically improved to 73% of true connections. In addition, the connections correctly identified by extended versions of TE accounted for 85% of the total synaptic weight in the network. Cross correlation methods generally performed more poorly than extended TE, but were useful when data length was short. A computational performance analysis demonstrated that the algorithm for extended TE, when used on currently available desktop computers, could extract effective connectivity from 1 hr recordings containing 200 neurons in ~5 min. We conclude that extending TE to multiple delays and message lengths improves its ability to assess effective connectivity between spiking neurons. These extensions to TE soon could become practical tools for experimentalists who record hundreds of spiking neurons. PMID- 22102895 TI - Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes. AB - Human islets exhibit distinct islet architecture with intermingled alpha- and beta-cells particularly in large islets. In this study, we quantitatively examined pathological changes of the pancreas in patients with type 2 diabetes (T2D). Specifically, we tested a hypothesis that changes in endocrine cell mass and composition are islet-size dependent. A large-scale analysis of cadaveric pancreatic sections from T2D patients (n = 12) and non-diabetic subjects (n = 14) was carried out combined with semi-automated analysis to quantify changes in islet architecture. The method provided the representative islet distribution in the whole pancreas section that allowed us to examine details of endocrine cell composition in individual islets. We observed a preferential loss of large islets (>60 um in diameter) in T2D patients compared to non-diabetic subjects. Analysis of islet cell composition revealed that the beta-cell fraction in large islets was decreased in T2D patients. This change was accompanied by a reciprocal increase in alpha-cell fraction, however total alpha-cell area was decreased along with beta-cells in T2D. Delta-cell fraction and area remained unchanged. The computer-assisted quantification of morphological changes in islet structure minimizes sampling bias. Significant beta-cell loss was observed in large islets in T2D, in which alpha-cell ratio reciprocally increased. However, there was no alpha-cell expansion and the total alpha-cell area was also decreased. Changes in islet architecture were marked in large islets. Our method is widely applicable to various specimens using standard immunohistochemical analysis that may be particularly useful to study large animals including humans where large organ size precludes manual quantitation of organ morphology. PMID- 22102896 TI - Use of respondent driven sampling (RDS) generates a very diverse sample of men who have sex with men (MSM) in Buenos Aires, Argentina. AB - BACKGROUND: Prior research focusing on men who have sex with men (MSM) conducted in Buenos Aires, Argentina, used convenience samples that included mainly gay identified men. To increase MSM sample representativeness, we used Respondent Driven Sampling (RDS) for the first time in Argentina. Using RDS, under certain specified conditions, the observed estimates for the percentage of the population with a specific trait are asymptotically unbiased. We describe, the diversity of the recruited sample, from the point of view of sexual orientation, and contrast the different subgroups in terms of their HIV sexual risk behavior. METHODOLOGY: 500 MSM were recruited using RDS. Behavioral data were collected through face-to face interviews and Web-based CASI. CONCLUSION: In contrast with prior studies, RDS generated a very diverse sample of MSM from a sexual identity perspective. Only 24.5% of participants identified as gay; 36.2% identified as bisexual, 21.9% as heterosexual, and 17.4% were grouped as "other." Gay and non-gay identified MSM differed significantly in their sexual behavior, the former having higher numbers of partners, more frequent sexual contacts and less frequency of condom use. One third of the men (gay, 3%; bisexual, 34%, heterosexual, 51%; other, 49%) reported having had sex with men, women and transvestites in the two months prior to the interview. This population requires further study and, potentially, HIV prevention strategies tailored to such diversity of partnerships. Our results highlight the potential effectiveness of using RDS to reach non-gay identified MSM. They also present lessons learned in the implementation of RDS to recruit MSM concerning both the importance and limitations of formative work, the need to tailor incentives to circumstances of the less affluent potential participants, the need to prevent masking, and the challenge of assessing network size. PMID- 22102897 TI - Trend in obesity prevalence in European adult cohort populations during follow-up since 1996 and their predictions to 2015. AB - OBJECTIVE: To investigate trends in obesity prevalence in recent years and to predict the obesity prevalence in 2015 in European populations. METHODS: Data of 97,942 participants from seven cohorts involved in the European Prospective Investigation into Cancer and Nutrition (EPIC) study participating in the Diogenes project (named as "Diogenes cohort" in the following) with weight measurements at baseline and follow-up were used to predict future obesity prevalence with logistic linear and non-linear (leveling off) regression models. In addition, linear and leveling off models were fitted to the EPIC-Potsdam dataset with five weight measures during the observation period to find out which of these two models might provide the more realistic prediction. RESULTS: During a mean follow-up period of 6 years, the obesity prevalence in the Diogenes cohort increased from 13% to 17%. The linear prediction model predicted an overall obesity prevalence of about 30% in 2015, whereas the leveling off model predicted a prevalence of about 20%. In the EPIC-Potsdam cohort, the shape of obesity trend favors a leveling off model among men (R2 = 0.98), and a linear model among women (R2 = 0.99). CONCLUSION: Our data show an increase in obesity prevalence since the 1990ies, and predictions by 2015 suggests a sizeable further increase in European populations. However, the estimates from the leveling off model were considerably lower. PMID- 22102898 TI - Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption. AB - BACKGROUND: Long-term benefits of combination antiretroviral therapy (cART) initiation during primary HIV-1 infection are debated. METHODS: The evolution of plasma HIV-RNA (432 measurements) and cell-associated HIV-DNA (325 measurements) after cessation of cART (median exposure 18 months) was described for 33 participants from the Zurich Primary HIV Infection Study using linear regression and compared with 545 measurements from 79 untreated controls with clinically diagnosed primary HIV infection, respectively a known date for seroconversion. RESULTS: On average, early treated individuals were followed for 37 months (median) after cART cessation; controls had 34 months of pre-cART follow-up. HIV RNA levels one year after cART interruption were -0.8 log10 copies/mL [95% confidence interval -1.2;-0.4] lower in early treated patients compared with controls, but this difference was no longer statistically significant by year three of follow-up (-0.3 [-0.9; 0.3]). Mean HIV-DNA levels rebounded from 2 log10 copies [1.8; 2.3] on cART to a stable plateau of 2.7 log10 copies [2.5; 3.0] attained 1 year after therapy stop, which was not significantly different from cross-sectional measurements of 9 untreated members of the control group (2.8 log10 copies [2.5; 3.1]). CONCLUSIONS: The rebound dynamics of viral markers after therapy cessation suggest that early cART may indeed limit reservoir size of latently infected cells, but that much of the initial benefits are only transient. Owing to the non-randomized study design the observed treatment effects must be interpreted with caution. PMID- 22102899 TI - Geographic variation in cardiovascular inflammation among healthy women in the Women's Health Study. AB - BACKGROUND: Geographic variation in traditional cardiovascular disease (CVD) risk factors has been observed among women in the US. It is not known whether state level variation in cardiovascular inflammation exists or could be explained by traditional clinical risk factors and behavioral lifestyle factors. METHODS AND RESULTS: We used multilevel linear regression to estimate state-level variation in inflammatory biomarker patterns adjusted for clinical and lifestyle characteristics among 26,029 women free of CVD. Participants derived from the Women's Health Study, a national cohort of healthy middle-aged and older women. Inflammatory biomarker patterns (plasma levels of high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1), and fibrinogen) were compared to state-level patterns of traditional CVD risk factors and global risk scores. We found that all three inflammatory biomarkers exhibited significant state-level variation including hsCRP (lowest vs. highest state median 1.3 mg/L vs. 2.7 mg/L, unadjusted random effect estimate 1(st) to 99(th) percentile range for log hsCRP 0.52, p<.001), sICAM-1 (325 ng/ml vs. 366ng/ml, unadjusted random effect estimate 1(st) to 99(th) percentile range 0.44, p<.001), and fibrinogen (322 mg/dL vs. 367 mg/dL, unadjusted random effect estimate 1(st) to 99(th) percentile range 0.41, p = .001). Neither demographic, clinical or lifestyle characteristics explained away state-level effects in biomarker patterns. Southern and Appalachian states (Arkansas, West Virginia) had the highest inflammatory biomarker values. Regional geographic patterns of traditional CVD risk factors and risk scores did not completely overlap with biomarkers of inflammation. CONCLUSIONS: There is state-level geographic variation in inflammatory biomarkers among otherwise healthy women that cannot be completely attributed to traditional clinical risk factors or lifestyle characteristics. Future research should aim to identify additional factors that may explain geographic variation in biomarkers of inflammation among healthy women. PMID- 22102900 TI - A non-motor microtubule binding site is essential for the high processivity and mitotic function of kinesin-8 Kif18A. AB - BACKGROUND: Members of the kinesin-8 subfamily are plus end-directed molecular motors that accumulate at the plus-ends of kinetochore-microtubules (kt-MTs) where they regulate MT dynamics. Loss of vertebrate kinesin-8 function induces hyperstable MTs and elongated mitotic spindles accompanied by severe chromosome congression defects. It has been reported that the motility of human kinesin-8, Kif18A, is required for its accumulation at the plus tips of kt-MTs. METHODOLOGY/FINDINGS: Here, we investigate how Kif18A localizes to the plus-ends of kt-MTs. We find that Kif18A lacking its C-terminus does not accumulate on the tips of kt-MTs and fails to fulfill its mitotic function. In vitro studies reveal that Kif18A possesses a non-motor MT binding site located within its C-proximal 121 residues. Using single molecule measurements we find that Kif18A is a highly processive motor and, furthermore, that the C-terminal tail is essential for the high processivity of Kif18A. CONCLUSION/SIGNIFICANCE: These results show that Kif18A like its yeast orthologue is a highly processive motor. The ability of Kif18A to walk on MTs for a long distance without dissociating depends on a non motor MT binding site located at the C-terminus of Kif18A. This C-proximal tail of Kif18A is essential for its plus-end accumulation and mitotic function. These findings advance our understanding of how Kif18A accumulates at the tips of kt MTs to fulfill its function in mitosis. PMID- 22102901 TI - Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. AB - BACKGROUND: Galectin-3 (Gal-3) and active (GTP-bound) K-Ras contribute to the malignant phenotype of many human tumors by increasing the rate of cell proliferation, survival, and migration. These Gal-3-mediated effects result from a selective binding to K-Ras.GTP, causing increased nanoclustering in the cell membrane and leading to robust Ras signaling. Regulation of the interactions between Gal-3 and active K-Ras is not fully understood. METHODS AND FINDINGS: To gain a better understanding of what regulates the critical interactions between these two proteins, we examined the role of Gal-3 in the regulation of K-Ras by using Gal-3-knockout mouse embryonic-fibroblasts (Gal-3-/- MEFs) and/or Gal-3/Gal 1 double-knockout MEFs. We found that knockout of Gal-3 induced strong downregulation (~60%) of K-Ras and K-Ras.GTP. The downregulation was somewhat more marked in the double-knockout MEFs, in which we also detected robust inhibition(~50%) of ERK and Akt activation. These additional effects are probably attributable to inhibition of the weak interactions of K-Ras.GTP with Gal-1. Re expression of Gal-3 reversed the phenotype of the Gal-3-/- MEFs and dramatically reduced the disappearance of K-Ras in the presence of cycloheximide to the levels seen in wild-type MEFs. Furthermore, phosphorylation of Gal-3 by casein kinase-1 (CK-1) induced translocation of Gal-3 from the nucleus to the cytoplasm and the plasma membrane, leading to K-Ras stabilization accompanied by downregulation of the tumor suppressor miRNA let-7c, known to negatively control K-Ras transcription. CONCLUSIONS: Our results suggest a novel cross-talk between Gal-3 mediated downregulation of let 7c microRNA (which in turn negatively regulates K Ras transcription) and elucidates the association among Gal-3 let-7c and K-Ras transcription/translation, cellular compartmentalization and activity. PMID- 22102902 TI - Data partitions, Bayesian analysis and phylogeny of the zygomycetous fungal family Mortierellaceae, inferred from nuclear ribosomal DNA sequences. AB - Although the fungal order Mortierellales constitutes one of the largest classical groups of Zygomycota, its phylogeny is poorly understood and no modern taxonomic revision is currently available. In the present study, 90 type and reference strains were used to infer a comprehensive phylogeny of Mortierellales from the sequence data of the complete ITS region and the LSU and SSU genes with a special attention to the monophyly of the genus Mortierella. Out of 15 alternative partitioning strategies compared on the basis of Bayes factors, the one with the highest number of partitions was found optimal (with mixture models yielding the best likelihood and tree length values), implying a higher complexity of evolutionary patterns in the ribosomal genes than generally recognized. Modeling the ITS1, 5.8S, and ITS2, loci separately improved model fit significantly as compared to treating all as one and the same partition. Further, within-partition mixture models suggests that not only the SSU, LSU and ITS regions evolve under qualitatively and/or quantitatively different constraints, but that significant heterogeneity can be found within these loci also. The phylogenetic analysis indicated that the genus Mortierella is paraphyletic with respect to the genera Dissophora, Gamsiella and Lobosporangium and the resulting phylogeny contradict previous, morphology-based sectional classification of Mortierella. Based on tree structure and phenotypic traits, we recognize 12 major clades, for which we attempt to summarize phenotypic similarities. M. longicollis is closely related to the outgroup taxon Rhizopus oryzae, suggesting that it belongs to the Mucorales. Our results demonstrate that traits used in previous classifications of the Mortierellales are highly homoplastic and that the Mortierellales is in a need of a reclassification, where new, phylogenetically informative phenotypic traits should be identified, with molecular phylogenies playing a decisive role. PMID- 22102903 TI - Systemic autoimmunity and lymphoproliferation are associated with excess IL-7 and inhibited by IL-7Ralpha blockade. AB - Lupus is characterized by disturbances in lymphocyte homeostasis, as demonstrated by the marked accumulation of activated/memory T cells. Here, we provide evidence that proliferation of the CD8+ precursors for the accumulating CD4-CD8- T cells in MRL-Fas(lpr) lupus-predisposed mice is, in part, driven by commensal antigens. The ensuing lymphadenopathy is associated with increased production of IL-7 due to expansion of fibroblastic reticular cells, the primary source of this cytokine. The excess IL-7 is not, however, consumed by CD4-CD8- T cells due to permanent down-regulation of IL-7Ralpha (CD127), but instead supports proliferation of autoreactive T cells and progression of autoimmunity. Accordingly, IL-7R blockade reduced T cell activation and autoimmune manifestations even when applied at advanced disease stage. These findings indicate that an imbalance favoring production over consumption of IL-7 may contribute to systemic autoimmunity, and correction of this imbalance may be a novel therapeutic approach in lymphoproliferative and autoimmune syndromes. PMID- 22102904 TI - M5 muscarinic receptors mediate striatal dopamine activation by ventral tegmental morphine and pedunculopontine stimulation in mice. AB - Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M5 muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M5 muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M5 knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M5 knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M5-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M5 receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine. PMID- 22102905 TI - Higher frequency of T-cell response to M. tuberculosis latency antigen Rv2628 at the site of active tuberculosis disease than in peripheral blood. AB - RATIONALE: Due to the invasive nature of the procedures involved, most studies of Mycobacterium tuberculosis (Mtb)-specific immunity in humans have focused on the periphery rather than the site of active infection, the lung. Recently, antigens associated with Mtb-latency and -dormancy have been described using peripheral blood (PB) cells; however their response in the lung is unknown. The objective of this report was to evaluate, in patients prospectively enrolled with suspected active tuberculosis (TB), whether the latency antigen Rv2628 induces local specific immune response in bronchoalveolar lavage (BAL) cells compared to PB cells. MATERIAL/METHODS: Among the 41 subjects enrolled, 20 resulted with active TB. Among the 21 without active disease, 9 were defined as subjects with latent TB-infection (LTBI) [Quantiferon TB Gold In-tube positive]. Cytokine responses to Rv2628 were evaluated by enzyme linked immunospot (ELISPOT) assay and flow cytometric (FACS) analysis. RD1-secreted antigen stimulation was used as control. RESULTS: There was a significantly higher frequency of Rv2628- and RD1-specific CD4+ T-cells in the BAL of active TB patients than in PB. However the trend of the response to Rv2628 in subjects with LTBI was higher than in active TB in both PB and BAL, although this difference was not significant. In active TB, Rv2628 and RD1 induced a cytokine-response profile mainly consisting of interferon (IFN) gamma-single-positive over double-IFN-gamma/interleukin (IL)-2 T-cells in both PB and BAL. Finally, BAL-specific CD4+ T-cells were mostly effector memory (EM), while peripheral T-cell phenotypes were distributed among naive, central memory and terminally differentiated effector memory T-cells. CONCLUSIONS: In this observational study, we show that there is a high frequency of specific T-cells for Mtb-latency and RD1-secreted antigens (mostly IFN-gamma-single-positive specific T-cells with an EM phenotype) in the BAL of active TB patients. These data may be important for better understanding the pathogenesis of TB in the lung. PMID- 22102906 TI - PLD$ is involved in phagocytosis of microglia: expression and localization changes of PLD4 are correlated with activation state of microglia. AB - Phospholipase D4 (PLD4) is a recently identified protein that is mainly expressed in the ionized calcium binding adapter molecule 1 (Iba1)-positive microglia in the early postnatal mouse cerebellar white matter. Unlike PLD1 and PLD2, PLD4 exhibits no enzymatic activity for conversion of phosphatidylcholine into choline and phosphatidic acid, and its function is completely unknown. In the present study, we examined the distribution of PLD4 in mouse cerebellar white matter during development and under pathological conditions. Immunohistochemical analysis revealed that PLD4 expression was associated with microglial activation under such two different circumstances. A primary cultured microglia and microglial cell line (MG6) showed that PLD4 was mainly present in the nucleus, except the nucleolus, and expression of PLD4 was upregulated by lipopolysaccharide (LPS) stimulation. In the analysis of phagocytosis of LPS stimulated microglia, PLD4 was co-localized with phagosomes that contained BioParticles. Inhibition of PLD4 expression using PLD4 specific small interfering RNA (siRNA) in MG6 cells significantly reduced the ratio of phagocytotic cell numbers. These results suggest that the increased PLD4 in the activation process is involved in phagocytosis of activated microglia in the developmental stages and pathological conditions of white matter. PMID- 22102907 TI - Functional recruitment of human complement inhibitor C4B-binding protein to outer membrane protein Rck of Salmonella. AB - Resistance to complement mediated killing, or serum resistance, is a common trait of pathogenic bacteria. Rck is a 17 kDa outer membrane protein encoded on the virulence plasmid of Salmonella enterica serovars Typhimurium and Enteritidis. When expressed in either E. coli or S. enterica Typhimurium, Rck confers LPS independent serum resistance as well as the ability to bind to and invade mammalian cells. Having recently shown that Rck binds the inhibitor of the alternative pathway of complement, factor H (fH), we hypothesized that Rck can also bind the inhibitor of the classical and lectin pathways, C4b-binding protein (C4BP). Using flow cytometry and direct binding assays, we demonstrate that E. coli expressing Rck binds C4BP from heat-inactivated serum and by using the purified protein. No binding was detected in the absence of Rck expression. C4BP bound to Rck is functional, as we observed factor I-mediated cleavage of C4b in cofactor assays. In competition assays, binding of radiolabeled C4BP to Rck was reduced by increasing concentrations of unlabeled protein. No effect was observed by increasing heparin or salt concentrations, suggesting mainly non-ionic interactions. Reduced binding of C4BP mutants lacking complement control protein domains (CCPs) 7 or 8 was observed compared to wt C4BP, suggesting that these CCPs are involved in Rck binding. While these findings are restricted to Rck expression in E. coli, these data suggest that C4BP binding may be an additional mechanism of Rck-mediated complement resistance. PMID- 22102908 TI - Ago-2-mediated slicer activity is essential for anti-flaviviral efficacy of RNAi. AB - RNA interference can be mediated by fully complementary siRNA or partially complementary miRNA. siRNAs are widely used to suppress viral replication and the fully complementary siRNA bound Ago-2 in the RISC is known to degrade the target RNA. Although other argonaute proteins lacking slicer activity can also bind oligonucleotides with both si and miRNA structures, whether they can also contribute to antiviral effects is not entirely clear. We tested si and miRNA structured oligos for target repression in dual luciferase assays as well as for inhibition of Dengue and West Nile virus replication in ES cells expressing individual Ago proteins. In luciferase assays, both fully complementary and partially complementary oligos effectively repressed their targets in all individual Ago expressing cell lines, although the efficacy with fully complementary oligos was higher in Ago-2+ cells. However, partially complementary oligos had no effect on virus replication in any cell line, while fully complementary siRNAs were highly effective in Ago-2 expressing, but not in cells expressing other Ago proteins. This occurred irrespective of whether the target sequences were located in the coding region or 3'UTR of the virus. We conclude that Ago-2 slicer activity is essential for anti-viral efficacy of siRNAs and miRNA-mediated translational repression/transcript destabilization is too weak to suppress the abundantly expressed flaviviral proteins. PMID- 22102909 TI - Clinical outcome of high-risk patients with severe aortic stenosis and reduced left ventricular ejection fraction undergoing medical treatment or TAVI. AB - INTRODUCTION: Reduced left ventricular function in patients with severe symptomatic valvular aortic stenosis is associated with impaired clinical outcome in patients undergoing surgical aortic valve replacement (SAVR). Transcatheter Aortic Valve Implantation (TAVI) has been shown non-inferior to SAVR in high-risk patients with respect to mortality and may result in faster left ventricular recovery. METHODS: We investigated clinical outcomes of high-risk patients with severe aortic stenosis undergoing medical treatment (n = 71) or TAVI (n = 256) stratified by left ventricular ejection fraction (LVEF) in a prospective single center registry. RESULTS: Twenty-five patients (35%) among the medical cohort were found to have an LVEF<=30% (mean 26.7+/-4.1%) and 37 patients (14%) among the TAVI patients (mean 25.2+/-4.4%). Estimated peri-interventional risk as assessed by logistic EuroSCORE was significantly higher in patients with severely impaired LVEF as compared to patients with LVEF>30% (medical/TAVI 38.5+/ 13.8%/40.6+/-16.4% versus medical/TAVI 22.5+/-10.8%/22.1+/-12.8%, p <0.001). In patients undergoing TAVI, there was no significant difference in the combined endpoint of death, myocardial infarction, major stroke, life-threatening bleeding, major access-site complications, valvular re-intervention, or renal failure at 30 days between the two groups (21.0% versus 27.0%, p = 0.40). After TAVI, patients with LVEF<=30% experienced a rapid improvement in LVEF (from 25+/ 4% to 34+/-10% at discharge, p = 0.002) associated with improved NYHA functional class at 30 days (decrease >=1 NYHA class in 95%). During long-term follow-up no difference in survival was observed in patients undergoing TAVI irrespective of baseline LVEF (p = 0.29), whereas there was a significantly higher mortality in medically treated patients with severely reduced LVEF (log rank p = 0.001). CONCLUSION: TAVI in patients with severely reduced left ventricular function may be performed safely and is associated with rapid recovery of systolic left ventricular function and heart failure symptoms. PMID- 22102910 TI - Locomotion-related oscillatory body movements at 6-12 Hz modulate the hippocampal theta rhythm. AB - The hippocampal theta rhythm is required for accurate navigation and spatial memory but its relation to the dynamics of locomotion is poorly understood. We used miniature accelerometers to quantify with high temporal and spatial resolution the oscillatory movements associated with running in rats. Simultaneously, we recorded local field potentials in the CA1 area of the hippocampus. We report that when rats run their heads display prominent vertical oscillations with frequencies in the same range as the hippocampal theta rhythm (i.e., 6-12 Hz). In our behavioral set-up, rats run mainly with speeds between 50 and 100 cm/s. In this range of speeds, both the amplitude and frequency of the "theta" head oscillations were increasing functions of running speed, demonstrating that the head oscillations are part of the locomotion dynamics. We found evidence that these rhythmical locomotor dynamics interact with the neuronal activity in the hippocampus. The amplitude of the hippocampal theta rhythm depended on the relative phase shift with the head oscillations, being maximal when the two signals were in phase. Despite similarity in frequency, the head movements and LFP oscillations only displayed weak phase and frequency locking. Our results are consistent with that neurons in the CA1 region receive inputs that are phase locked to the head acceleration signal and that these inputs are integrated with the ongoing theta rhythm. PMID- 22102911 TI - Characterization of five fungal endophytes producing Cajaninstilbene acid isolated from pigeon pea [Cajanus cajan (L.) Millsp]. AB - Five fungal endophytes (K4, K5, K6, K9, K14) producing Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) were isolated from the roots of pigeon pea [Cajanus cajan (L.) Millsp.]. CSA is responsible for the prominent pharmacological activities in pigeon pea. The amount of CSA in culture solution varied among the five fungal endophytes. K4 produced the highest levels of CSA (1037.13 ug/L) among the endophytes tested after incubation for five days. Both morphological characteristics and molecular methods were used for species identification of fungal endophytes. The five endophytic isolates were characterized by analyzing the internal transcribed spacer (ITS) rRNA and beta tubulin genes. The K4, K5, K9 and K14 strains isolated from pigeon pea roots were found to be closely related to the species Fusarium oxysporum. K6 was identified as Neonectria macrodidym. The present study is the first report on the isolation and identification of fungal endophytes producing CSA in pigeon pea. The study also provides a scientific base for large scale production of CSA. PMID- 22102912 TI - Selection of stable reference genes for quantitative rt-PCR comparisons of mouse embryonic and extra-embryonic stem cells. AB - Isolation and culture of both embryonic and tissue specific stem cells provide an enormous opportunity to study the molecular processes driving development. To gain insight into the initial events underpinning mammalian embryogenesis, pluripotent stem cells from each of the three distinct lineages present within the preimplantation blastocyst have been derived. Embryonic (ES), trophectoderm (TS) and extraembryonic endoderm (XEN) stem cells possess the developmental potential of their founding lineages and seemingly utilize distinct epigenetic modalities to program gene expression. However, the basis for these differing cellular identities and epigenetic properties remain poorly defined.Quantitative reverse transcription-polymerase chain reaction (qPCR) is a powerful and efficient means of rapidly comparing patterns of gene expression between different developmental stages and experimental conditions. However, careful, empirical selection of appropriate reference genes is essential to accurately measuring transcriptional differences. Here we report the quantitation and evaluation of fourteen commonly used references genes between ES, TS and XEN stem cells. These included: Actb, B2m, Hsp70, Gapdh, Gusb, H2afz, Hk2, Hprt, Pgk1, Ppia, Rn7sk, Sdha, Tbp and Ywhaz. Utilizing three independent statistical analysis, we identify Pgk1, Sdha and Tbp as the most stable reference genes between each of these stem cell types. Furthermore, we identify Sdha, Tbp and Ywhaz as well as Ywhaz, Pgk1 and Hk2 as the three most stable reference genes through the in vitro differentiation of embryonic and trophectoderm stem cells respectively.Understanding the transcriptional and epigenetic regulatory mechanisms controlling cellular identity within these distinct stem cell types provides essential insight into cellular processes controlling both embryogenesis and stem cell biology. Normalizing quantitative RT-PCR measurements using the geometric mean CT values obtained for the identified mRNAs, offers a reliable method to assess differing patterns of gene expression between the three founding stem cell lineages present within the mammalian preimplantation embryo. PMID- 22102913 TI - siPRED: predicting siRNA efficacy using various characteristic methods. AB - Small interfering RNA (siRNA) has been used widely to induce gene silencing in cells. To predict the efficacy of an siRNA with respect to inhibition of its target mRNA, we developed a two layer system, siPRED, which is based on various characteristic methods in the first layer and fusion mechanisms in the second layer. Characteristic methods were constructed by support vector regression from three categories of characteristics, namely sequence, features, and rules. Fusion mechanisms considered combinations of characteristic methods in different categories and were implemented by support vector regression and neural networks to yield integrated methods. In siPRED, the prediction of siRNA efficacy through integrated methods was better than through any method that utilized only a single method. Moreover, the weighting of each characteristic method in the context of integrated methods was established by genetic algorithms so that the effect of each characteristic method could be revealed. Using a validation dataset, siPRED performed better than other predictive systems that used the scoring method, neural networks, or linear regression. Finally, siPRED can be improved to achieve a correlation coefficient of 0.777 when the threshold of the whole stacking energy is >=-34.6 kcal/mol. siPRED is freely available on the web at http://predictor.nchu.edu.tw/siPRED. PMID- 22102914 TI - Pain following stroke: a population-based follow-up study. AB - BACKGROUND AND PURPOSE: Chronic pain is increasingly recognized as a consequence of stroke. This study aimed to describe the prevalence and pain types of new onset chronic pain ("novel pain") in patients with stroke compared with a randomly selected reference group from the general population and to identify factors associated with pain development in stroke patients. METHODS: In a population-based follow-up design, development of chronic pain after stroke was assessed by a questionnaire sent to consecutive stroke patients, registered in a Danish national stroke database, two years after their stroke. A randomly selected sex- and age-matched reference group from the same catchment area received a similar questionnaire about development of new types of chronic pain in the same time period. A total of 608 stroke patients and 519 reference subjects were included in the study. RESULTS: Development of novel pain was reported by 39.0% of stroke patients and 28.9% of reference subjects (OR 1.57, CI 1.21-2.04), and was associated with low age and depression in a multivariate model. Daily intake of pain medication for novel pain was reported by 15.3% and 9.4% of the stroke and reference population, respectively. Novel headache, shoulder pain, pain from increased muscle stiffness, and other types of novel pain were more common in stroke patients, whereas joint pain was equally common in the two groups. CONCLUSIONS: Development of chronic pain is more common in stroke patients compared with sex- and age-matched reference subjects. Evaluation of post-stroke pain should be part of stroke follow-up. PMID- 22102915 TI - ErbB2 and NFkappaB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer. AB - Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFkappaB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFkappaB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFkappaB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFkappaB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFkappaB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC. PMID- 22102916 TI - Substrate-favored lysosomal and proteasomal pathways participate in the normal balance control of insulin precursor maturation and disposal in beta-cells. AB - Our recent studies have uncovered that aggregation-prone proinsulin preserves a low relative folding rate and maintains a homeostatic balance of natively and non natively folded states (i.e., proinsulin homeostasis, PIHO) in beta-cells as a result of the integration of maturation and disposal processes. Control of precursor maturation and disposal is thus an early regulative mechanism in the insulin production of beta-cells. Herein, we show pathways involved in the disposal of endogenous proinsulin at the early secretory pathway. We conducted metabolic-labeling, immunoblotting, and immunohistochemistry studies to examine the effects of selective proteasome and lysosome or autophagy inhibitors on the kinetics of proinsulin and control proteins in various post-translational courses. Our metabolic-labeling studies found that the main lysosomal and ancillary proteasomal pathways participate in the heavy clearance of insulin precursor in mouse islets/beta-cells cultured at the mimic physiological glucose concentrations. Further immunoblotting and immunohistochemistry studies in cloned beta-cells validated that among secretory proteins, insulin precursor is heavily and preferentially removed. The rapid disposal of a large amount of insulin precursor after translation is achieved mainly through lysosomal autophagy and the subsequent basal disposals are carried out by both lysosomal and proteasomal pathways within a 30 to 60-minute post-translational process. The findings provide the first clear demonstration that lysosomal and proteasomal pathways both play roles in the normal maintenance of PIHO for insulin production, and defined the physiological participation of lysosomal autophagy in the protein quality control at the early secretory pathway of pancreatic beta-cells. PMID- 22102917 TI - A peptide that binds specifically to the beta-amyloid of Alzheimer's disease: selection and assessment of anti-beta-amyloid neurotoxic effects. AB - The accumulation of the amyloid-beta peptide (Abeta) into amyloid plaques, an essential event in Alzheimer's disease (AD) pathogenesis, has caused researchers to seek compounds that physiologically bind Abeta and modulate its aggregation and neurotoxicity. In order to develop new Abeta-specific peptides for AD, a randomized 12-mer peptide library with Abeta1-10 as the target was used to identify peptides in the present study. After three rounds of selection, specific phages were screened, and their binding affinities to Abeta1-10 were found to be highly specific. Finally, a special peptide was synthesized according to the sequences of the selected phages. In addition, the effects of the special peptide on Abeta aggregation and Abeta-mediated neurotoxicity in vitro and in vivo were assessed. The results show that the special peptide not only inhibited the aggregation of Abeta into plaques, but it also alleviated Abeta-induced PC12 cell viability and apoptosis at appropriate concentrations as assessed by the cell counting kit-8 assay and propidium iodide staining. Moreover, the special peptide exhibited a protective effect against Abeta-induced learning and memory deficits in rats, as determined by the Morris water maze task. In conclusion, we selected a peptide that specifically binds Abeta1-10 and can modulate Abeta aggregation and Abeta-induced neuronal damage. This opens up possibilities for the development of a novel therapeutic approach for the treatment of AD. PMID- 22102918 TI - Rapid colorimetric testing for pyrazinamide susceptibility of M. tuberculosis by a PCR-based in-vitro synthesized pyrazinamidase method. AB - Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug. But PZA susceptibility test is challenging because PZA activity is optimal only in an acid environment that inhibits the growth of M. tuberculosis. For current phenotypic methods, inconsistent results between different labs have been reported. Direct sequencing of pncA gene is being considered as an accurate predictor for PZA susceptibility, but this approach needs expensive sequencers and a mutation database to report the results. An in-vitro synthesized Pyrazinamidase (PZase) assay was developed based on PCR amplification of pncA gene and an in vitro wheat germ system to express the pncA gene into PZase. The activity of the synthesized PZase was used as an indicator for PZA susceptibility. Fifty-one clinical isolates were tested along with pncA sequencing and the BACTEC MGIT 960 methods. The in-vitro synthesized PZase assay was able to detect PZA susceptibility of M. tuberculosis within 24 h through observing the color difference either by a spectrometer or naked eyes. This method showed agreements of 100% (33/33) and 88% (14/16) with the pncA sequencing method, and agreements of 96% (27/28) and 65% (15/23) with the BACTEC MGIT 960 method, for susceptible and resistant strains, respectively. The novel in-vitro synthesized PZase assay has significant advantages over current methods, such as its fast speed, simplicity, no need for expensive equipment, and the potentials of being a direct test, predicting resistance level and easy reading results by naked eyes. After confirmation by more clinical tests, this method may provide a radical change to the current PZA susceptibility assays. PMID- 22102919 TI - A simultaneous test of synchrony causal factors in muskrat and mink fur returns at different scales across Canada. AB - BACKGROUND: Synchrony among populations has been attributed to three major hypotheses: dispersal, the Moran effect, and trophic-level interactions. Unfortunately, simultaneous testing of these hypotheses demands complete and detailed data, which are scarce for ecological systems. METHODOLOGY/PRINCIPAL FINDINGS: Hudson's Bay Company data on mink and muskrat fur returns in Canada represent an excellent opportunity to test these hypotheses because of the detailed spatial and temporal data from this predator-prey system. Using structural equation modelling, support for each hypothesis was evaluated at two spatial scales: across Canada and dividing the country into three regions longitudinally. Our results showed that at both scales mink synchrony is a major factor determining muskrat synchrony, supporting the hypothesis of trophic-level interactions, but the influence of winter precipitation synchrony is also important in eastern Canada. Moreover, mink synchrony is influenced principally by winter precipitation synchrony at the level of all Canada (Moran effect), but by distance at regional level, which might suggest some influence of dispersal at this level. DISCUSSION/SIGNIFICANCE: Our result is one of the few reports of synchrony mediated by trophic-level interactions, highlighting the importance of evaluation of scale effects in population synchrony studies. PMID- 22102920 TI - Effects of Alloyed Metal on the Catalysis Activity of Pt for Ethanol Partial Oxidation: Adsorption and Dehydrogenation on Pt(3)M (M=Pt, Ru, Sn, Re, Rh, and Pd). AB - The adsorption and dehydrogenation reactions of ethanol over bimetallic clusters, Pt(3)M (M = Pt, Ru, Sn, Re, Rh, and Pd), have been extensively investigated with density functional theory. Both the alpha-hydrogen and hydroxyl adsorptions on Pt as well as on the alloyed transition metal M sites of PtM were considered as initial reaction steps. The adsorptions of ethanol on Pt and M sites of some PtM via the alpha-hydrogen were well established. Although the alpha-hydrogen adsorption on Pt site is weaker than the hydroxyl, the potential energy profiles show that the dehydrogenation via the alpha-hydrogen path has much lower energy barrier than that via the hydroxyl path. Generally for the alpha-hydrogen path the adsorption is a rate-determining-step because of rather low dehydrogenation barrier for the alpha-hydrogen adsorption complex (thermodynamic control), while the hydroxyl path is determined by its dehydrogenation step (kinetic control). The effects of alloyed metal on the catalysis activity of Pt for ethanol partial oxidation, including adsorption energy, energy barrier, electronic structure, and eventually rate constant were discussed. Among all of the alloyed metals only Sn enhances the rate constant of the dehydrogenation via the alpha-hydrogen path on the Pt site of Pt(3)Sn as compared with Pt alone, which interprets why the PtSn is the most active to the oxidation of ethanol. PMID- 22102921 TI - The field-testing of a novel integrated mapping protocol for neglected tropical diseases. AB - BACKGROUND: Vertical control and elimination programs focused on specific neglected tropical diseases (NTDs) can achieve notable success by reducing the prevalence and intensity of infection. However, many NTD-endemic countries have not been able to launch or scale-up programs because they lack the necessary baseline data for planning and advocacy. Each NTD program has its own mapping guidelines to collect missing data. Where geographic overlap among NTDs exists, an integrated mapping approach could result in significant resource savings. We developed and field-tested an innovative integrated NTD mapping protocol (Integrated Threshold Mapping (ITM) Methodology) for lymphatic filariasis (LF), trachoma, schistosomiasis and soil-transmitted helminths (STH). METHODOLOGY/PRINCIPAL FINDINGS: The protocol is designed to be resource efficient, and its specific purpose is to determine whether a threshold to trigger public health interventions in an implementation unit has been attained. The protocol relies on World Health Organization (WHO) recommended indicators in the disease-specific age groups. For each disease, the sampling frame was the district, but for schistosomiasis, the sub-district rather than the ecological zone was used. We tested the protocol by comparing it to current WHO mapping methodologies for each of the targeted diseases in one district each in Mali and Senegal. Results were compared in terms of public health intervention, and feasibility, including cost. In this study, the ITM methodology reached the same conclusions as the WHO methodologies regarding the initiation of public health interventions for trachoma, LF and STH, but resulted in more targeted intervention recommendations for schistosomiasis. ITM was practical, feasible and demonstrated an overall cost saving compared with the standard, non-integrated, WHO methodologies. CONCLUSIONS/SIGNIFICANCE: This integrated mapping tool could facilitate the implementation of much-needed programs in endemic countries. PMID- 22102922 TI - Global cross-talk of genes of the mosquito Aedes aegypti in response to dengue virus infection. AB - BACKGROUND: The mosquito Aedes aegypti is the primary vector of dengue virus (DENV) infection in humans, and DENV is the most important arbovirus across most of the subtropics and tropics worldwide. The early time periods after infection with DENV define critical cellular processes that determine ultimate success or failure of the virus to establish infection in the mosquito. METHODS AND RESULTS: To identify genes involved in these processes, we performed genome-wide transcriptome profiling between susceptible and refractory A. aegypti strains at two critical early periods after challenging them with DENV. Genes that responded coordinately to DENV infection in the susceptible strain were largely clustered in one specific expression module, whereas in the refractory strain they were distributed in four distinct modules. The susceptible response module in the global transcriptional network showed significant biased representation with genes related to energy metabolism and DNA replication, whereas the refractory response modules showed biased representation across different metabolism pathway genes including cytochrome P450 and DDT [1,1,1-Trichloro-2,2-bis(4-chlorophenyl) ethane] degradation genes, and genes associated with cell growth and death. A common core set of coordinately expressed genes was observed in both the susceptible and refractory mosquitoes and included genes related to the Wnt (Wnt: wingless [wg] and integration 1 [int1] pathway), MAPK (Mitogen-activated protein kinase), mTOR (mammalian target of rapamycin) and JAK-STAT (Janus Kinase - Signal Transducer and Activator of Transcription) pathways. CONCLUSIONS: Our data revealed extensive transcriptional networks of mosquito genes that are expressed in modular manners in response to DENV infection, and indicated that successfully defending against viral infection requires more elaborate gene networks than hosting the virus. These likely play important roles in the global-cross talk among the mosquito host factors during the critical early DENV infection periods that trigger the appropriate host action in susceptible vs. refractory mosquitoes. PMID- 22102923 TI - Ebola virus glycoprotein needs an additional trigger, beyond proteolytic priming for membrane fusion. AB - BACKGROUND: Ebolavirus belongs to the family filoviridae and causes severe hemorrhagic fever in humans with 50-90% lethality. Detailed understanding of how the viruses attach to and enter new host cells is critical to development of medical interventions. The virus displays a trimeric glycoprotein (GP(1,2)) on its surface that is solely responsible for membrane attachment, virus internalization and fusion. GP(1,2) is expressed as a single peptide and is cleaved by furin in the host cells to yield two disulphide-linked fragments termed GP1 and GP2 that remain associated in a GP(1,2) trimeric, viral surface spike. After entry into host endosomes, GP(1,2) is enzymatically cleaved by endosomal cathepsins B and L, a necessary step in infection. However, the functional effects of the cleavage on the glycoprotein are unknown. PRINCIPAL FINDINGS: We demonstrate by antibody binding and Hydrogen-Deuterium Exchange Mass Spectrometry (DXMS) of glycoproteins from two different ebolaviruses that although enzymatic priming of GP(1,2) is required for fusion, the priming itself does not initiate the required conformational changes in the ectodomain of GP(1,2). Further, ELISA binding data of primed GP(1,2) to conformational antibody KZ52 suggests that the low pH inside the endosomes also does not trigger dissociation of GP1 from GP2 to effect membrane fusion. SIGNIFICANCE: The results reveal that the ebolavirus GP(1,2) ectodomain remains in the prefusion conformation upon enzymatic cleavage in low pH and removal of the glycan cap. The results also suggest that an additional endosomal trigger is necessary to induce the conformational changes in GP(1,2) and effect fusion. Identification of this trigger will provide further mechanistic insights into ebolavirus infection. PMID- 22102925 TI - FDA approval for use of medications in pregnancy: an uphill battle. PMID- 22102926 TI - Comment on "management of first trimester pregnancy loss can be safely moved into the office". PMID- 22102924 TI - Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice. AB - BACKGROUND: The current knowledge of immunological responses to schistosomiasis, a major tropical helminthic disease, is insufficient, and a better understanding of these responses would support vaccine development or therapies to control granuloma-associated immunopathology. CD4(+) T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis. The induction of T helper (Th)1, Th2 and T regulatory (Treg) cells and their roles in schistosome infections are well-illustrated. However, little in vivo data are available on the dynamics of Th17 cells, another important CD4(+) T cell subset, after Schistosoma japonicum infection or whether these cells and their defining IL-17 cytokine mediate host protective responses early in infection. METHODOLOGY: Levels of Th17 and the other three CD4(+) T cell subpopulations and the cytokines related to induction or repression of Th17 cell generation in different stages of S. japonicum infection were observed. Contrary to reported in vitro studies, our results showed that the Th17 cells were induced along with the Th1, Th2, Treg cells and the IFN-gamma and IL-4 cytokines in S. japonicum infected mice. The results also suggested that S. japonicum egg antigens but not adult worm antigens preferentially induced Th17 cell generation. Furthermore, decreasing IL-17 with a neutralizing anti-IL-17 monoclonal antibody (mAb) increased schistosome-specific antibody levels and partial protection against S. japonicum infection in mice. CONCLUSIONS: Our study is the first to report the dynamics of Th17 cells during S. japonicum infection and indicate that Th17 cell differentiation results from the integrated impact of inducing and suppressive factors promoted by the parasite. Importantly, our findings suggest that lower IL-17 levels may result in favorable host protective responses. This study significantly contributes to the understanding of immunity to schistosomiasis and may aid in developing interventions to protect hosts from infection or restrain immunopathology. PMID- 22102927 TI - The diagnosis of polycystic ovary syndrome in adolescents. AB - Polycystic ovary syndrome (PCOS) is recognized as the most common endocrinopathy in reproductive-aged women. The symptoms of PCOS vary with age, race, weight, and medications, adding to the challenges of accurate diagnosis. Adolescent patients pose particular diagnostic problems because characteristics of normal puberty often overlap with signs and symptoms of PCOS. This article reviews the diagnosis of PCOS in adolescents. PMID- 22102928 TI - Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. AB - Folate (vitamin B(9)) is an essential nutrient that is required for DNA replication and as a substrate for a range of enzymatic reactions involved in amino acid synthesis and vitamin metabolism. Demands for folate increase during pregnancy because it is also required for growth and development of the fetus. Folate deficiency has been associated with abnormalities in both mothers (anemia, peripheral neuropathy) and fetuses (congenital abnormalities). This article reviews the metabolism of folic acid, the appropriate use of folic acid supplementation in pregnancy, and the potential benefits of folic acid, as well as the possible supplementation of l-methylfolate for the prevention of pregnancy related complications other than neural tube defects. PMID- 22102929 TI - Progesterone supplementation and the prevention of preterm birth. AB - Preterm birth is currently the most important problem in maternal-child health in the United States and possibly throughout the world. It complicates one in eight US deliveries, and accounts for over 85% of all perinatal morbidity and mortality. Although survival of preterm infants has increased steadily over the past four decades-due in large part to the use of antenatal corticosteroids, improvements in neonatal resuscitation, and the introduction of neonatal intensive care units-efforts to prevent preterm birth have been largely unsuccessful. On February 3, 2011, the US Food and Drug Administration (FDA) approved the use of progesterone supplementation (hydroxyprogesterone caproate) during pregnancy to reduce the risk of recurrent preterm birth in women with a history of at least one prior spontaneous preterm delivery. This is the first time that the FDA has approved a medication for the prevention of preterm birth, and represents the first approval of a drug specifically for use in pregnancy in almost 15 years. This article reviews the evidence behind the use of progesterone for the prevention of preterm birth, and provides guidelines for the use of progesterone supplementation in clinical practice. A number of areas of ongoing controversy are addressed, including the optimal formulation and route of administration, the safety of progesterone supplementation in pregnancy, and its proposed mode of action. PMID- 22102930 TI - Hysteroscopic morcellation for treating intrauterine pathology. AB - Changes in hysteroscopic capabilities have been preceded by technological advances that have enabled them. Modern operative hysteroscopes rely on a variety of different-sized optical, inflow, outflow, and working channels to enable clear visualization of the endometrial cavity as well as the surgical removal of intracavitary lesions such as polyps and myomas. This review examines the relative merits of various hysteroscopic treatment options with a focus on the most recent operative hysteroscopic technique, hysteroscopic morcellation, and how this new technology fits into the armamentarium of the gynecologist. PMID- 22102931 TI - Prevention of vulvovaginal sequelae in stevens-johnson syndrome and toxic epidermal necrolysis. AB - Vulvovaginal sequelae of Stevens-Johnson syndrome and toxic epidermal necrolysis are well documented in the literature, although little consensus exists about effective prevention strategies. This review summarizes the available literature and offers expert opinion about how to minimize long-term vaginal impairment from these rare but often devastating illnesses. PMID- 22102932 TI - The use of blood in obstetrics and gynecology in the developing world. AB - Access to safe blood is critical in comprehensive emergency obstetric care and for reducing maternal mortality. Many countries have inadequate blood supplies, and this disproportionately affects women and children in need of life-saving blood transfusions. Although preventative measures aimed at reducing postpartum hemorrhage by treating underlying anemia and infectious diseases are critical, they are insufficient for obstetric hemorrhage. In the developing world, efforts should focus on alternative means of providing safe blood in cases of hemorrhage, with particular focus on rapid testing, donation of warm whole blood, and autologous blood transfusion. PMID- 22102933 TI - Modern medical microbiology. PMID- 22102934 TI - Cesarean technique. PMID- 22102935 TI - Early external cephalic version. PMID- 22102936 TI - Delivering twins. PMID- 22102937 TI - Second trimester termination of pregnancy. PMID- 22102938 TI - Snippets. PMID- 22102939 TI - Correction. AB - In Reviews in Obstetrics & Gynecology, Volume 4, Number 1 on page 34 [Rev Obstet Gynecol. 2011;4(1):34 doi 10.3909/riog0145d], a typographical error resulted in an incorrect value. Simon and colleagues reported on the safety of 10 MUg of 17beta-estradiol, not 10 mg.The editorial staff of Reviews in Obstetrics & Gynecology carefully reviews each issue, attempting to ensure that all of the information presented is correct and complete. Occasionally, however, something gets past us and makes it into print. We apologize for any inconvenience this error may have caused you.[This corrects the article on p. 34 in vol. 4.]. PMID- 22102940 TI - Separation of Betti Reaction Product Enantiomers: Absolute Configuration and Inhibition of Botulinum Neurotoxin A. AB - The racemic product of the Betti reaction of 5-chloro-8-hydroxyquinoline, benzaldehyde and 2-aminopyridine was separated by chiral HPLC to determine which enantiomer inhibited botulinum neurotoxin serotype A. When the enantiomers unexpectedly proved to have comparable activity, the absolute structures of (+) (R)-1 and (-)-(S)-1 were determined by comparison of calculated and observed circular dichroism spectra. Molecular modeling studies were undertaken in an effort to understand the observed bioactivity and revealed different ensembles of binding modes, with roughly equal binding energies, for the two enantiomers. PMID- 22102941 TI - A Novel High-Throughput Screening Assay to Identify Inhibitors of HIV-1 gp120 Protein Interaction with DC-SIGN. AB - The 2010 UNAIDS report states that approximately 34 million people are living with human immunodeficiency virus type 1 (HIV-1), despite highly active antiretroviral therapy (HAART). Despite being effective, ARV therapy has many disadvantages including a cost trajectory unsustainable for economically challenged countries, serious side effects, and the development of drug-resistant strains. Several measures are under way to develop alternatives for ARV therapy, particularly for the control of early HIV-1 infection, but lack of efficient drug targets and assays hinders the search of potential ARV molecules. The dendritic cells present in the mucosal tissue, together with CD4(+) T lymphocytes and macrophages, are among the first cells to encounter HIV-1. The dendritic cell specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) molecule plays a crucial role in binding HIV-1 through high affinity interaction with viral envelope glycoprotein gp120. DC-SIGN, a mannose-binding C-type lectin expressed on cells in the mucosal tissue of the rectum, uterus and cervix, facilitates early HIV-1 infection after sexual transmission. In this study we report a novel target-specific high-throughput screening (HTS) assay capable of quantifying the binding as well as the inhibition of DC-SIGN and gp120. The specificity of the assay was determined through competitive inhibition while optimization occurred for DMSO tolerance (0.5%), Z' factor (0.51), signal-to noise ratio (3.26), and coefficient of variation (5.1%). For assay validation previously recognized antagonists of DC-SIGN/gp120 binding were tested to detect inhibition demonstrating the suitability of the assay for future HTS screen of potential inhibitors that block the binding between DC-SIGN and gp120 which may prevent early HIV-1 infection. PMID- 22102943 TI - A computed tomography-based anatomic comparison of three different types of c7 posterior fixation techniques : pedicle, intralaminar, and lateral mass screws. AB - OBJECTIVE: The intralaminar screw (ILS) fixation technique offers an alternative to pedicle screw (PS) and lateral mass screw (LMS) fixation in the C7 spine. Although cadaveric studies have described the anatomy of the pedicles, laminae, and lateral masses at C7, 3-dimensional computed tomography (CT) imaging is the modality of choice for pre-surgical planning. In this study, the goal was to determine the anatomical parameter and optimal screw trajectory for ILS placement at C7, and to compare this information to PS and LMS placement in the C7 spine as determined by CT evaluation. METHODS: A total of 120 patients (60 men and 60 women) with an average age of 51.7+/-13.6 years were selected by retrospective review of a trauma registry database over a 2-year period. Patients were included in the study if they were older than 15 years of age, had standardized axial bone window CT imaging at C7, and had no evidence of spinal trauma. For each lamina and pedicle, width (outer cortical and inner cancellous), maximal screw length, and optimal screw trajectory were measured, and the maximal screw length of the lateral mass were measured using m-view 5.4 software. Statistical analysis was performed using Student's t-test. RESULTS: At C7, the maximal PS length was significantly greater than the ILS and LMS length (PS, 33.9+/-3.1 mm; ILS, 30.8+/ 3.1 mm; LMS, 10.6+/-1.3; p<0.01). When the outer cortical and inner cancellous width was compared between the pedicle and lamina, the mean pedicle outer cortical width at C7 was wider than the lamina by an average of 0.6 mm (pedicle, 6.8+/-1.2 mm; lamina, 6.2+/-1.2 mm; p<0.01). At C7, 95.8% of the laminae measured accepted a 4.0-mm screw with a 1.0 mm of clearance, compared with 99.2% of pedicle. Of the laminae measured, 99.2% accepted a 3.5-mm screw with a 1.0 mm clearance, compared with 100% of the pedicle. When the outer cortical and inner cancellous height was compared between pedicle and lamina, the mean lamina outer cortical height at C7 was wider than the pedicle by an average of 9.9 mm (lamina, 18.6+/-2.0 mm; pedicle, 8.7+/-1.3 mm; p<0.01). The ideal screw trajectory at C7 was also measured (47.8+/-4.8 degrees for ILS and 35.1+/-8.1 degrees for PS). CONCLUSION: Although pedicle screw fixation is the most ideal instrumentation method for C7 fixation with respect to length and cortical diameter, anatomical aspect of C7 lamina is affordable to place screw. Therefore, the C7 intralaminar screw could be an alternative fixation technique with few anatomic limitations in the cases when C7 pedicle screw fixation is not favorable. However, anatomical variations in the length and width must be considered when placing an intralaminar or pedicle screw at C7. PMID- 22102942 TI - Characterization of invading glioma cells using molecular analysis of leading edge tissue. AB - OBJECTIVE: We have introduced a method of characterization of invading glioma cells by using molecular analysis of marginal invading tumor cells and molecular profiles of glioma tumor margin. METHODS: Each of tumor core and marginal tissues was obtained in 22 glioma patients. Tumor core cells and marginal cells from each glial tumor were collected by laser capture microdissection or intraoperative microdissection under the operating microscope. Expression of MMP-2, MMP-9, CD44 and RHAMM mRNA by invading glioma cells compared with tumor core was confirmed by realtime-PCR of twenty-four glioma specimens. Clinical data also were reviewed for invasion and recurrence pattern of the gliomas radiologically and invasive rim pattern microscopically. RESULTS: Overall results of the molecular analysis showed that relative overexpression of MMP-2, MMP-9 and RHAMM were noted at the invasive edge of human glioma specimens comparing to the tumor core but CD44 was highly expressed in the tumor core comparing to the margin. High marginal expression of MMP-2 and MMP-9 were noted in poorly ill-defined margin on the pathological finding. High marginal expression of CD44 and MMP-2 were demonstrated in the midline cross group on the radiological review, and that of RHAMM and MMP-2 were showed in the aggressive recurrence group. High expression of MMP-2 seems to be involved in the various invasion-related phenomenons. CONCLUSION: Up-regulation of MMP-2, MMP-9, CD44 and RHAMM was noted in invasive edge of gliomas according to the various clinical situations. PMID- 22102944 TI - Changes in gene expression in the rat hippocampus after focal cerebral ischemia. AB - OBJECTIVE: The rat middle cerebral artery thread-occlusion model has been widely used to investigate the pathophysiological mechanisms of stroke and to develop therapeutic treatment. This study was conducted to analyze energy metabolism, apoptotic signal pathways, and genetic changes in the hippocampus of the ischemic rat brain. METHODS: Focal transient cerebral ischemia was induced by obstructing the middle cerebral artery for two hours. After 24 hours, the induction of ischemia was confirmed by the measurement of infarct size using 2,3,5 triphenyltetrazolium chloride staining. A cDNA microarray assay was performed after isolating the hippocampus, and was used to examine changes in genetic expression patterns. RESULTS: According to the cDNA microarray analysis, a total of 1,882 and 2,237 genes showed more than a 2-fold increase and more than a 2 fold decrease, respectively. When the genes were classified according to signal pathways, genes related with oxidative phosphorylation were found most frequently. There are several apoptotic genes that are known to be expressed during ischemic brain damage, including Akt2 and Tnfrsf1a. In this study, the expression of these genes was observed to increase by more than 2-fold. As energy metabolism related genes grew, ischemic brain damage was affected, and the expression of important genes related to apoptosis was increased/decreased. CONCLUSION: Our analysis revealed a significant change in the expression of energy metabolism related genes (Atp6v0d1, Atp5g2, etc.) in the hippocampus of the ischemic rat brain. Based on this data, we feel these genes have the potential to be target genes used for the development of therapeutic agents for ischemic stroke. PMID- 22102945 TI - Therapeutic effect of gamma knife radiosurgery for multiple brain metastases. AB - OBJECTIVE: The aim of this study is to evaluate the therapeutic effects of gamma knife radiosurgery (GKRS) in patients with multiple brain metastases and to investigate prognostic factors related to treatment outcome. METHODS: We retrospectively reviewed clinico-radiological and dosimetric data of 36 patients with 4-14 brain metastases who underwent GKRS for 264 lesions between August 2008 and April 2011. The most common primary tumor site was the lung (n=22), followed by breast (n=7). At GKRS, the median Karnofsky performance scale score was 90 and the mean tumor volume was 1.2 cc (0.002-12.6). The mean prescription dose of 17.8 Gy was delivered to the mean 61.1% isodose line. Among 264 metastases, 175 lesions were assessed for treatment response by at least one imaging follow-up. RESULTS: The overall median survival after GKRS was 9.1+/-1.7 months. Among various factors, primary tumor control was a significant prognostic factor (11.1+/-1.3 months vs. 3.3+/-2.4 months, p=0.031). The calculated local tumor control rate at 6 and 9 months after GKRS were 87.9% and 84.2%, respectively. Paddick's conformity index (>0.75) was significantly related to local tumor control. The actuarial peritumoral edema reduction rate was 22.4% at 6 months. CONCLUSION: According to our results, GKRS can provide beneficial effect for the patients with multiple (4 or more) brain metastases, when systemic cancer is controlled. And, careful dosimetry is essential for local tumor control. Therefore, GKRS can be considered as one of the treatment modalities for multiple brain metastase. PMID- 22102946 TI - Extracranial-intracranial bypass surgery using a radial artery interposition graft for cerebrovascular diseases. AB - OBJECTIVE: To investigate the efficacy of extracranial-intracranial (EC-IC) bypass surgery using a radial artery interposition graft (RAIG) for surgical management of cerebrovascular diseases. METHODS: The study involved a retrospective analysis of 13 patients who underwent EC-IC bypass surgery using RAIG at a single neurosurgical institute between 2003 and 2009. The diseases comprised intracranial aneurysm (n=10), carotid artery occlusive disease (n=2), and delayed stenosis in the donor superficial temporal artery (STA) following previous STA-middle cerebral artery bypass surgery (n=1). Patients were followed clinically and radiographically. RESULTS: Bypass surgery was successful in all patients. At a mean follow-up of 53.4 months, the short-term patency rate was 100%, and the long-term rate was 92.3%. Twelve patients had an excellent clinical outcome of Glasgow Outcome Scale (GOS) 5, and one case had GOS 3. Procedure related complications were a temporary dysthesia on the graft harvest hand (n=1) and a hematoma at the graft harvest site (n=1), and these were treated successfully with no permanent sequelae. In one case, spasm occurred which was relieved with the introduction of mechanical dilators. CONCLUSION: EC-IC bypass using a RAIG appears to be an effective treatment for a variety of cerebrovascular diseases requiring proximal occlusion or trapping of the parent artery. PMID- 22102947 TI - Vein of galen aneurysmal malformation : endovascular management of 6 cases in a single institute. AB - OBJECTIVE: The aim of this study was to analyze the treatment outcome of patients with vein of Galen aneurysmal malformations (VGM). METHODS: Clinical and angiographic data of six consecutive patients with VGM were retrospectively reviewed. VGMs were angiographically classified by Yasargil's method. Treatment outcomes were evaluated. RESULTS: Mean age at initial treatment was 4.4+/-5.7 months. Angiographic types of VGMs were type II in two patients and type III in four. Three patients had cardiac symptoms and the others were asymptomatic. Two patients were treated with transvenous embolization, three with transarterial embolization, and one was managed conservatively. Two patients died due to venous hypertension few days after transvenous approach. Of three patients who were transarterially embolized, one was completely occluded with Onyx and two were incompletely occluded. During the follow-up period (range, one to six years) two of three patients treated with transarterial approach were asymptomatic and the other showed mild symptoms. One patient who was managed conservatively showed normal performance. CONCLUSION: Transarterial embolization of VGMs may be better than transvenous approach in terms of the treatment outcome and complication. Further studies are needed because of the rarity of the disease and rapid advancement of endovascular techniques. PMID- 22102948 TI - Profiles of Spinal Cord Tumors Removed through a Unilateral Hemilaminectomy. AB - OBJECTIVE: To present the profiles of spinal cord tumors that can be removed through a unilateral hemilaminectomy and to demonstrate its usefulness for benign spinal cord tumors that significantly occupy the spinal canal. METHODS: From June 2004 to October 2010, 25 spinal cord tumors were approached with unilateral hemilaminectomy. We calculated the cross-sectional occupying ratio (CSOR) of tumor to spinal canal before and after the operations. RESULTS: The locations of the tumors were intradural extramedullary in 20 cases, extradural in 2, and intramedullary in 3. The levels of the tumors were lumbar in 12, thoracic 9, and cervical 4. In all cases, the tumor was removed grossly and totally without damaging spinal cord or roots. The mean height and width of the lesions we195re 17.64 mm (3-47.5) and 12.62 mm (4-32.7), respectively. The mean CSOR was 69.40% (range, 27.8-96.9%). Postoperative neurological status showed improvement in all patients except one whose neurologic deficit remained unchanged. Postoperative spinal stability was preserved during the follow-up period (mean, 21.5 months) in all cases. Tumor recurrence did not develop during the follow-up period. CONCLUSION: Unilateral hemilaminectomy combined with microsurgical technique provides sufficient space for the removal of diverse spinal cord tumors. The basic profiles of the spinal cord tumors which can be removed through the unilateral hemilaminectomy demonstrate its role for the surgery of the benign spinal cord tumors in various sizes. PMID- 22102949 TI - Changes in the cross-sectional area of multifidus and psoas in unilateral sciatica caused by lumbar disc herniation. AB - OBJECTIVE: To quantitatively evaluate the asymmetry of the multifidus and psoas muscles in unilateral sciatica caused by lumbar disc herniation using magnetic resonance imaging (MRI). METHODS: Seventy-six patients who underwent open microdiscectomy for unilateral L5 radiculopathy caused by disc herniation at the L4-5 level were enrolled, of which 39 patients (51.3%) had a symptom duration of 1 month or less (group A), and 37 (48.7%) had a symptom duration of 3 months or more (group B). The cross-sectional areas (CSAs) of the multifidus and psoas muscles were measured at the mid-portion of the L4-5 disc level on axial MRI, and compared between the diseased and normal sides in each group. RESULTS: The mean symptom duration was 0.6+/-0.4 months and 5.4+/-2.7 months for groups A and B, respectively (p<0.001). There were no differences in the demographics between the 2 groups. There was a significant difference in the CSA of the multifidus muscle between the diseased and normal sides (p<0.01) in group B. In contrast, no significant multifidus muscle asymmetry was found in group A. The CSA of the psoas muscle was not affected by disc herniation in either group. CONCLUSION: The CSA of the multifidus muscle was reduced by lumbar disc herniation when symptom duration was 3 months or more. PMID- 22102950 TI - A comparison of the effect of epidural patient-controlled analgesia with intravenous patient-controlled analgesia on pain control after posterior lumbar instrumented fusion. AB - OBJECTIVE: Retrospective analysis to compare the effect and complication of epidural patient-controlled analgesia (epidural PCA) with intravenous patient controlled analgesia (IV PCA) for the treatment of the post-operative pain after posterior lumbar instrumented fusion. METHODS: Sixty patients who underwent posterior lumbar instrumented fusion for degenerative lumbar disease at our institution from September 2007 to January 2008 were enrolled in this study. Out of sixty patients, thirty patients received IV PCA group and thirty patients received epidural PCA group. The pain scale was measured by the visual analogue scale (VAS) score. RESULTS: There were no significant difference between IV PCA group and epidural PCA group on the PCA related complications (p=0.7168). Ten patients in IV PCA group and six patients in epidural PCA group showed PCA related complications. Also, there were no significant differences in reduction of VAS score between two groups on postoperative 2 hours (p=0.9618) and 6 hours (p=0.0744). However, postoperative 12 hours, 24 hours and 48 hours showed the significant differences as mean of reduction of VAS score (p=0.0069, 0.0165, 0.0058 respectively). CONCLUSION: The epidural PCA is more effective method to control the post-operative pain than IV PCA after 12 hours of spinal fusion operation. However, during the first twelve hours after operation, there were no differences between IV PCA and epidural PCA. PMID- 22102951 TI - Outcome evaluation with signal activation of functional MRI in spinal cord injury. AB - OBJECTIVE: The authors investigated the changes of cortical sensorimotor activity in functional MRI (fMRI) and functional recovery in spinal cord injury (SCI) patients who had been treated by bone marrow cell transplantation. METHODS: Nineteen patients with SCI were included in this study; ten patients with clinical improvement and nine without. The cortical sensorimotor activations were studied using the proprioceptive stimulation during the fMRI. RESULTS: Diagnostic accuracy of fMRI with neurological improvement was 70.0% and 44.4% for sensitivity and specificity, respectively. Signal activation in the ipsilateral motor cortex in fMRI was commonly observed in the clinically neurological improved group (p-value=0.002). Signal activation in the contralateral temporal lobe and basal ganglia was more commonly found in the neurological unimproved group (p-value<0.001). Signal activation in other locations was not statistically different. CONCLUSION: In patients with SCI, activation patterns of fMRI between patients with neurologic recovery and those without varied. Such plasticity should be considered in evaluating SCI interventions based on behavioral and neurological measurements. PMID- 22102952 TI - Postoperative survival and ambulatory outcome in metastatic spinal tumors : prognostic factor analysis. AB - OBJECTIVE: The purposes of this study are to estimate postoperative survival and ambulatory outcome and to identify prognostic factors thereafter of metastatic spinal tumors in a single institute. METHODS: We reviewed the medical records of 182 patients who underwent surgery for a metastatic spinal tumor from January 1987 to January 2009 retrospectively. Twelve potential prognostic factors (age, gender, primary tumor, extent and location of spinal metastases, interval between primary tumor diagnosis and metastatic spinal cord compression, preoperative treatment, surgical approach and extent, preoperative Eastern Cooperative Oncology Group (ECOG) performance status, Nurick score, Tokuhashi and Tomita score) were investigated. RESULTS: The median survival of the entire patients was 8 months. Of the 182 patients, 80 (44%) died within 6 months after surgery, 113 (62%) died within 1 year after surgery, 138 (76%) died within 2 years after surgery. Postoperatively 47 (26%) patients had improvement in ambulatory function, 126 (69%) had no change, and 9 (5%) had deterioration. On multivariate analysis, better ambulatory outcome was associated with being ambulatory before surgery (p=0.026) and lower preoperative ECOG score (p=0.016). Survival rate was affected by preoperative ECOG performance status (p<0.001) and Tomita score (p<0.001). CONCLUSION: Survival after metastatic spinal tumor surgery was dependent on preoperative ECOG performance status and Tomita score. The ambulatory functional outcomes after surgery were dependent on preoperative ambulatory status and preoperative ECOG performance status. Thus, prompt decompressive surgery may be warranted to improve patient's survival and gait, before general condition and ambulatory function of patient become worse. PMID- 22102953 TI - Radiological and clinical results of laminectomy and posterior stabilization for severe thoracolumbar burst fracture : surgical technique for one-stage operation. AB - OBJECTIVE: This study aimed to show the possibility of neural canal enlargement and restoration of bony fragments through laminectomy and minimal facetectomy without pediculectomy or an anterior approach, and also to prove the adequacy of posterior stabilization of vertebral deformities after thoracolumbar bursting fracture. METHODS: From January 2003 to June 2009, we experienced 45 patients with thoracolumbar burst fractures. All patients enrolled were presented with either a neural canal compromise of more than 40% with a Benzel-Larson Grade of VI, or more than 30% compromise with less than a Benzel-Larson Grade of V. Most important characteristic of our surgical procedure was repositioning retropulsed bone fragments using custom-designed instruments via laminectomy and minimal facetectomy without removing the fractured bone fragments. Beneath the dural sac, these custom-designed instruments could push the retropulsed bone fragments within the neural canal after the decompression and bone fragment repositioning. RESULTS: The mean kyphotic deformities measured preoperatively and at follow-up within 12 months were 17.7 degrees (+/-6.4 degrees) and 9.6 degrees (+/-5.2 degrees), respectively. The mean midsagittal diameter improved from 8.8 mm (+/ 2.8 mm) before surgery to 14.2 mm (+/-1.6 mm) at follow-up. The mean traumatic vertebral body height before surgery was 41.3% (+/-12.6%). At follow-up assessment within 12 months, this score showed a statistically significant increase to 68.3% (+/-12.8%). Neurological improvement occurred in all patients. CONCLUSION: Though controversy exists in the treatment of severe thoracolumbar burst fracture, we achieved effective radiological and clinical results in the cases of burst fractures causing severe canal compromise and spinal deformity by using this novel custom-designed instruments, via posterior approach alone. PMID- 22102954 TI - Epidural fluid collection after cranioplasty : fate and predictive factors. AB - OBJECTIVE: Infection and bone resorption are major complications of cranioplasty and have been well recognized. However, there are few clinical series describing the epidural fluid collection (EFC) as complication of cranioplasty. This study was planned to identify the predictive factors and fate of EFC after cranioplasty. METHODS: We reviewed retrospectively the demographic, clinical, and radiographic data in 59 patients who underwent a first cranioplsty following decompressive craniectomy during a period of 6 years, from January 2004 to December 2009. We compared demographic, clinical, and radiographic factors between EFC group and no EFC group. The predictive factors associated with the development of EFC were assessed by logistic regression analysis. RESULTS: Overall, 22 of 59 patients (37.3%) suffered from EFC following cranioplasty. EFC had disappeared (n=6, 31.8%) or regressed (n=6, 31.8%) over time on follow up brain computed tomographic (CT) scans. However, 5 patients (22.7%) required reoperation due to symptomatic and persistent EFC. Predictive factors for EFC were male [odds ratio (OR), 5.48; 95% CI, 1.26-23.79], air bubbles in the epidural space (OR, 12.52; 95% CI, 2.26-69.28), and dural calcification on postoperative brain CT scan (OR, 4.21; 95% CI, 1.12-15.84). CONCLUSION: The most of EFCs could be treated by conservative therapy. Air bubble in the epidural space and dural calcification are proposed to be the predictive factors in the formation of EFC after cranioplasty. PMID- 22102955 TI - Radiation-induced glioblastoma multiforme in a remitted acute lymphocytic leukemia patient. AB - Radiation therapy has been widely applied for cancer treatment. Childhood acute lymphocytic leukemia (ALL), characterized by frequent central nervous system involvement, is a well documented disease for the effect of prophylactic cranio spinal irradiation. Irradiation, however, acts as an oncogenic factor as a delayed effect and it is rare that glioblastoma multiforme develops during the remission period of ALL. We experienced a pediatric radiation-induced GBM patient which developed during the remission period of ALL, who were primarily treated with chemotherapeutic agents and brain radiation therapy for the prevention of central nervous system (CNS) relapse. Additionally, we reviewed the related literature regarding on the effects of brain irradiation in childhood and on the prognosis of radiation induced GBM. PMID- 22102956 TI - Supratentorial clear cell ependymoma mimicking oligodendroglioma : case report and review of the literature. AB - Clear cell ependymomas (CCEs) are rare variants of ependymomas. Tumors show anaplastic histological features and behave as an aggressive manner. CCEs have a predilection for extraneural metastases and early recurrence, and they demonstrate characteristic radiographic features. These tumors should be radiologically and pathologically differentiated from oligodendrogliomas. On microscopic examination, CCEs are composed of sheets of cells and resemble oligodendroglioma. However, upon closer examination, the nature of CCEs can be detected earlier, resulting in prompt treatment of the tumor. Although we report only one case, we emphasize the importance of early diagnosis and treatment. Future description of more cases of these rare cancers is necessary to aid in their diagnosis and treatment. PMID- 22102957 TI - Supratentorial cortical ependymoma in a 21-month-old boy. AB - Two-thirds of ependymomas arise in the infratentorial or intraventricles, whereas one-third are located supratentorially. But supratentorial "cortical" ependymomas are very rare. We report a case of a cortical ependymoma in a 21-month-old boy. The patient presented with simple partial seizures. This tumor was located in the postcentral gyrus and he had gross total excision. Microscopy and immunohistochemistry showed grade II differentiation ependymoma. PMID- 22102958 TI - A case of pial arteriovenous fistula with giant venous aneurysm and multiple varices treated with coil embolization. AB - Intracranial pial arteriovenous fistulas (AVFs) are rare vascular lesions of the brain. These lesions consist of one or more arterial connection to a single venous channel without true intervening nidus. A 24-year-old woman visited to our hospital because of headache, vomiting, dizziness and memory disturbance that persisted for three days. She complained several times of drop attack because of sudden weakness on both leg. Cerebral angiograms demonstrated a giant venous aneurysm on right frontal lobe beyond the genu of corpus callosum, multiple varices on both frontal lobes fed by azygos anterior cerebral artery, and markedly dilated draining vein into superior sagittal sinus, suggesting single channel pial AVF with multiple varices. Transarterial coil embolization of giant aneurysm and fistulous portion resulted in complete disappearance of pial AVF without complication. PMID- 22102959 TI - Painless dissecting aneurysm of the aorta presenting as simultaneous cerebral and spinal cord infarctions. AB - Authors report a case of a painless acute dissecting aneurysm of the descending aorta in a patient who presented with unexplained hypotension followed by simultaneous paraplegia and right arm monoparesis. To our knowledge, case like this has not been reported previously. Magnetic resonance imaging of the brain and spine revealed hemodynamic cerebral infarction and extensive cord ischemia, respectively. Computerized tomography angiography confirmed a dissecting aneurysm of the descending aorta. The cause of the brain infarction may not have been embolic, but hemodynamic one. Dissection-induced hypotension may have elicited cerebral perfusion insufficiency. The cause of cord ischemia may be embolic or hemodynamic. The dissected aorta was successfully replaced into an artificial patch graft. The arm monoparesis was improved, but the paraplegia was not improved. In rare cases of brain and/or spinal cord infarction caused by painless acute dissecting aneurysm of the aorta, accurate diagnosis is critical because careless thrombolytic therapy can result in life-threatening bleeding. PMID- 22102960 TI - Unpredictable postoperative global cerebral infarction in the patient of williams syndrome accompanying moyamoya disease. AB - We report a rare case of Williams syndrome accompanying moyamoya disease in whom postoperative global cerebral infarction occurred unpredictably. Williams syndrome is an uncommon hereditary disorder associated with the connective tissue abnormalities and cardiovascular disease. To our knowledge, our case report is the second case of Williams syndrome accompanying moyamoya disease. A 9-year-old boy was presented with right hemiparesis after second operation for coarctation of aorta. He was diagnosed as having Williams syndrome at the age of 1 year. Brain MRI showed left cerebral cortical infarction, and angiography showed severe stenosis of bilateral internal carotid arteries and moyamoya vessels. To reduce the risk of furthermore cerebral infarction, we performed indirect anastomosis successfully. Postoperatively, the patient recovered well, but at postoperative third day, without any unusual predictive abnormal findings the patient's pupils were suddenly dilated. Brain CT showed the global cerebral infarction. Despite of vigorous treatment, the patient was not recovered and fell in brain death one week later. We suggest that in this kind of labile patient with Williams syndrome accompanying moyamoya disease, postoperative sedation should be done with more thorough strict patient monitoring than usual moyamoya patients. Also, we should decide the revascularization surgery more cautiously than usual moyamoya disease. The possibility of unpredictable postoperative ischemic complication should be kept in mind. PMID- 22102961 TI - A case of intraosseous dural arteriovenous fistulas involving diploic vein treated with transarterial onyx embolization. AB - Intracranial dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous connections that lie within the dura. Intraosseous DAVFs involving diploic venous system are extremely rare. A 46-year-old woman presented with headache and right pulsatile tinnitus for three weeks. The tinnitus started after yelling. Digital subtraction angiography revealed DAVF within the basal portion of right parietal bone along the middle meningeal artery (MMA) groove. The fistula was fed by frontal branch of right MMA and drained into right transverse sigmoid sinus junction through dilated middle meningeal vein. The intraosseous DAVF involving diploic vein was successfully obliterated with Onyx embolization via transarterial route. PMID- 22102962 TI - A dumbbell-shaped meningioma mimicking a schwannoma in the thoracic spine. AB - A 50-year-old man presented bilateral hypesthesia on and below the T6 dermatome and paresthesia. Magnetic resonance imaging (MRI) showed an intraspinal extradural tumor, which located from the 6th thoracic vertebral body to the upper margin of the 7th vertebral body, continuing dumbbell-like through the intervertebral foramen into the right middle thorax suggesting a neurogenic tumor (neurofibroma or neurilemmoma). With the patient in a prone position, we exposed and excised the tumor via a one stage posterior approach through a hemi laminictomy of T6. Histologic examination showed a grade 1 meningothelial meningioma, according to the World Health Organization classification. Initially, we assumed the mass was a schwannoma because of its location and dumbbell shape. However, the tumor was actually a meningioma. Postoperatively, hypesthesia resolved completely and motor power of the leg gradually full recovered. A postoperative MRI revealed no evidence of residual tumor. PMID- 22102963 TI - Spontaneous resolution of nontraumatic acute spinal subdural hematoma. AB - Spinal subdural hematoma (SSDH) is an extremely uncommon condition. Causative factors include trauma, anticoagulant drug administration, hemostatic disorders, and vascular disorders such as arteriovenous malformations and lumbar punctures. Of SSDH cases, those that do not have any traumatic event can be considered cases of nontraumatic acute spinal subdural hematoma, which is known to have diverse clinical progress. Treatment typically consists of surgical decompression and cases in which the condition is relieved with conservative treatment are rarely reported. We report two nontraumatic acute spinal subdural hematoma patients who were successfully treated without surgery. PMID- 22102964 TI - Rapid-growing juvenile xanthogranuloma on the scalp in 18-month-old girl. AB - Juvenile xanthogranuloma (JXG) is an uncommon histiocytic cutaneous lesion. An 18 month-old girl visited our clinic due to rapid growing orange-yellowish lesion on scalp. Enlarging time from 1 mm to 12 mm was just 8 weeks. We excised the tumor and adjacent normal tissue. Histopathological study showed numerous eosinophils and Touton giant cells within the lesion. Immunohistochemical study revealed positive immunoreactivity for CD68 in most areas. No recurrence was seen during 12 months after resection. We report a case with rapidly growing JXG on scalp with peculiar histopathologic findings. PMID- 22102965 TI - Chronic subdural hematoma after spontaneous intracranial hypotension : a case treated with epidural blood patch on c1-2. AB - Spontaneous cerebrospinal fluid (CSF) leak is a recognized cause of spontaneous intracranial hypotension (SIH). Subdural hematoma (SDH) is a serious but rare complication of SIH. An autologous epidural blood patch at the CSF-leak site can effectively relieve SIH. We report a case of bilateral SDH with SIH caused by a CSF leak originating at the C1-2 level. A 55-year-old male complained of orthostatic headache without neurological signs. His symptoms did not respond to conservative treatments including bed rest, hydration and analgesics. Magnetic resonance imaging showed a subdural hematoma in the bilateral fronto-parietal region, and computed tomography (CT) myelography showed a CSF leak originating at the C1-2 level. The patient underwent successful treatment with a CT-guided epidural blood patch at the CSF-leak site after trephination for bilateral SDH. PMID- 22102966 TI - The Appalachian Tri-State Node Experiences with the National Institute on Drug Abuse Clinical Trials Network. AB - The National Institute on Drug Abuse (NIDA)-sponsored Clinical Trial Network (CTN) recently celebrated 10 years of conducting "real world" research into the treatment of addiction. This article reviews the history and results of the most recent CTN studies and describes the experiences of one of the 13 participating research affiliates, the Appalachian Tri-State (ATS) Node. We discuss our "bidirectional" collaboration with multiple community treatment programs (CTPs) on research and dissemination activities and include their experiences as a member of our ATS Node.Results of CTN clinical trials have found unexpectedly that treatment as usual (TAU) is often almost as good as evidence-based interventions such as Motivational Interviewing (MI), possibly due to the difficulty in implementing evidence-based practices most effectively among divergent treatment sites and heterogeneous clinical populations. Some expected findings from the reviewed research are that severity of addiction and comorbidity moderate treatment outcomes and must be accounted for in future CTN sponsored studies. Notwithstanding these results, much has been learned and recommendations are suggested for changes in CTN research designs that will address methodological limitations and increase treatment effectiveness in future CTN studies. PMID- 22102967 TI - Bioactive polymeric composites for tooth mineral regeneration: physicochemical and cellular aspects. AB - Our studies of amorphous calcium phosphate (ACP)-based dental materials are focused on the design of bioactive, non-degradable, biocompatible, polymeric composites derived from acrylic monomer systems and ACP by photochemical or chemically activated polymerization. Their intended uses include remineralizing bases/liners, orthodontic adhesives and/or endodontic sealers. The bioactivity of these materials originates from the propensity of ACP, once exposed to oral fluids, to release Ca and PO(4) ions (building blocks of tooth and bone mineral) in a sustained manner while spontaneously converting to thermodynamically stable apatite. As a result of ACP's bioactivity, local Ca- and PO(4)-enriched environments are created with supersaturation conditions favorable for the regeneration of tooth mineral lost to decay or wear. Besides its applicative purpose, our research also seeks to expand the fundamental knowledge base of structure-composition-property relationships existing in these complex systems and identify the mechanisms that govern filler/polymer and composite/tooth interfacial phenomena. In addition to an extensive physicochemical evaluation, we also assess the leachability of the unreacted monomers and in vitro cellular responses to these types of dental materials. The systematic physicochemical and cellular assessments presented in this study typically provide model materials suitable for further animal and/or clinical testing. In addition to their potential dental clinical value, these studies suggest the future development of calcium phosphate-based biomaterials based on composite materials derived from biodegradable polymers and ACP, and designed primarily for general bone tissue regeneration. PMID- 22102968 TI - Is There Any Relationship between the Chronicity of Chronic Anal Fissure and Endothelin-1? PMID- 22102969 TI - The synchronous prevalence of colorectal neoplasms in patients with stomach cancer. PMID- 22102970 TI - Lymph node ratio for nodal staging in colorectal cancer - a promising, but premature tool. PMID- 22102971 TI - Colorectal cancer with multiple metastases: is palliative surgery needed? AB - In patients with symptomatic incurable metastatic colorectal cancer (mCRC), the goal of resection of the primary lesion is to palliate cancer-related morbidity, including obstruction, bleeding, or perforation. In patients with asymptomatic primary tumors and incurable metastatic disease, however, the necessity of primary tumor resection is less clear. Although several retrospective analyses suggest survival benefit in patients who undergo resection of the primary tumor, applying this older evidence to modern patients is out of date for several reasons. Modern chemotherapy regimens incorporating the novel cytotoxic agents oxaliplatin and irinotecan, as well as the target agents bevacizumab and cetuximab, have improved median survival from less than 1 year with the only available single-agent 5-fluorouracil until the mid-1990s to over 2 years. In addition to significant prolongation of overall survival, combinations of novel chemotherapeutic and target agents have allowed improved local and distant tumor control, decreasing the likelihood of local tumor-related complications requiring surgical resection. Resection of an asymptomatic primary tumor risks surgical complications and may postpone the administration of chemotherapy that may offer both systemic and local control. In conclusion, the morbidity and the mortality of unnecessary surgery or surgery that does not improve quality of life or survival in patients with mCRC of a limited life expectancy should be carefully evaluated. With the availability of effective combinations of chemotherapy and target agents, systemic therapy for the treatment of life-threatening metastases would be a preferable treatment strategy for unresectable asymptomatic patients with mCRC. PMID- 22102972 TI - Correlation between Liver Metastases and the Level of PRL-3 mRNA Expression in Patients with Primary Colorectal Cancer. AB - PURPOSE: Phosphatase of regenerating liver-3 (PRL-3) has been associated with metastasis promotion. However, clinical applications of this association have not yet been clearly demonstrated. In this study, we evaluated the relation of PRL-3 mRNA level in primary colorectal cancer to the corresponding stage and to other clinicopathologic factors. METHODS: Two hundred forty-five patients with histologically-proven colorectal cancer underwent surgery between January 2004 and December 2006. RNA was extracted and cDNA was prepared by using reverse transcription. Quantification of PRL-3 was done using a real-time polymerase chain reaction. RESULTS: Eighty-six cases with well-preserved specimens were enrolled: 53 males and 33 females. The mean age was 63.4 years. According to tumour node metastasis (TNM) stage of the American Joint Committee on Cancer (AJCC), stage I was 11 cases, stage II was 38 cases, stage III was 23 cases, and stage IV was 14 cases. Among stage IV cases, one case was combined with liver and lung metastases, and one case was combined with liver metastases and peritoneal dissemination. The remaining stage IV patients were combined with only liver metastases. There was a significant correlation in PRL-3 mRNA expression between primary colorectal cancer and corresponding tumor stage. PRL-3 mRNA expression was increased in the liver metastases cases. Lymphatic and vascular invasion were significantly related with PRL-3 mRNA levels. CONCLUSION: Advanced stage prediction may be obtained by measuring the level of PRL-3 mRNA expression in primary colorectal cancer. Especially, the risk of liver metastases may be predicted by measuring the level of PRL-3 mRNA expression in primary colorectal cancer. Further study is required to confirm these preliminary results. PMID- 22102973 TI - Is There Any Relationship between the Chronicity of Chronic Anal Fissure and Endothelin-1? AB - PURPOSE: Many kinds of substances are produced on vascular endothelial activation. The aim of this study is to confirm an increase in Endothelin-1 (ET 1), the most potent vasoconstrictor, which is produced by endothelial activation, in patients with chronic anal fissure and to infer the relationship between ET-1 and anal fissure chronicity. METHODS: The study groups are divided into three different groups with 30 subjects each. Group 1 is comprised of healthy volunteers, group 2 of chronic anal fissure patients, and Group 3 of patients with higher than 3rd degree hemorrhoids. Blood samples were taken to measure the ET-1 levels in subject's serum and to compare the results with those for the control groups. RESULTS: Among the 90 subjects, 38 were male, and 52 were female. The average age was 36.8. The average ET-1 level marked 1.47 +/- 0.78 pg/mL for male subjects and 1.16 +/- 0.47 pg/mL for female subjects (P = 0.02). The average ET-1 level in the patient groups is as follow: 1.21 +/- 0.44 pg/mL in group 1, 1.46 +/- 0.83 pg/mL in group 2, and 1.20 +/- 0.56 pg/mL in group 3 (P = 0.14). CONCLUSION: Group 2, the chronic anal fissure patient group, showed a higher ET-1 level than groups 1 and 3, the control group and the hemorrhoid patient group, but this difference had no statistical significance. PMID- 22102974 TI - Laparoscopic versus open appendectomy for appendicitis in elderly patients. AB - PURPOSE: The appendectomy is the most common emergent surgical procedure in elderly patients. The increasing number of elderly persons has been accompanied by an increase in the number of cases of acute appendicitis in the elderly. In order to understand the clinical significance of a laparoscopic appendectomy for elderly patients with appendicitis, we investigated the results of a laparoscopic appendectomy for treating patients over 60 years of age with appendicitis and compared them with the results for an open technique. METHODS: We studied retrospectively patients over 60 years of age who underwent an appendectomy with either a laparoscopic (LA) or open (OA) technique for appendicitis between July 2007 and December 2009. There were 30 patients in the LA group and 47 patients in the OA group. The demographic data, operative time, length of the hospital stay, bowel movement, pain control, cost, complications and pre-existing disease were assessed. RESULTS: There were no significant differences between the LA and the OA groups with respect to pre-existing diseases, gender, age, American Society of Anesthesiologists (ASA) score and the number of cases of complicated appendicitis, operative time, length of hospital stay, and times of analgesics use. However, the proportion of early gas out (within POD #2) was significantly greater in the LA group (80% vs. 57%, P < 0.05), and postoperative complications were significantly lower in the LA group (7% vs. 32%, P < 0.01). The costs for the two groups were not significantly different. CONCLUSION: A laparoscopic appendectomy is a safe and effective procedure in elderly patients and is not associated with any increase in morbidity. It can be recommended for routine use in treating elderly patients with appendicitis. PMID- 22102975 TI - The synchronous prevalence of colorectal neoplasms in patients with stomach cancer. AB - PURPOSE: The association between stomach cancer and colorectal cancer is controversial. The purpose of this study was to determine the synchronous prevalence of colorectal neoplasms in patients with stomach cancer. METHODS: A total of 123 patients with stomach cancer (86 male) and 246 consecutive, age- and sex-matched persons without stomach cancer were analyzed from July 2005 to June 2010. All of them underwent colonoscopy within 6 months after undergoing gastroscopy. RESULTS: The prevalence of colorectal neoplasms was significantly higher in the stomach cancer group (35.8%) than in the control group (17.9%) (P < 0.001). Colorectal neoplasms were more prevalent in the patients with stomach cancer (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.71 to 5.63). In particular, the difference in the prevalence of colorectal neoplasms was more prominent in the patients above 50 years old (OR, 3.54; 95% CI, 1.80 to 6.98). CONCLUSION: The results showed that the synchronous prevalence of colorectal neoplasms was higher in patients with stomach cancer than in those without stomach cancer. Therefore, patients with stomach cancer should be regarded as a high-risk group for colorectal neoplasms, and colonoscopy should be recommended for screening. PMID- 22102976 TI - Prognostic Significance of Lymph Node Ratio in Stage III Rectal Cancer. AB - PURPOSE: Although nodal metastasis is the most powerful prognostic factor in rectal cancer, marked heterogeneity exists within stage III rectal cancer. Recent studies of rectal cancer have shown a prognostic superiority of the lymph node ratio (LNR) compared with N stage. The purpose of this study was to investigate the prognostic value of the LNR in the era of the 7th edition of the TNM classification. METHODS: We included 190 patients who underwent a curative resection for rectal cancer with nodal metastasis. The patients were divided into four groups on the basis of statistically calculated cut-off values as 0.21, 0.32, and 0.61. RESULTS: The LNR was an independent risk factor for overall survival (OS; P = 0.008) and for systemic recurrence-free survival (SRFS; P = 0.002). However, the LNR was not a predictive factor for local recurrence. When the N stage of the sixth TNM staging system was separately analyzed as a covariate, the LNR was also found to be a predictive factor for both OS and SRFS (P = 0.012 and P = 0.004, respectively). A LNR value of 0.21 offered the best cut off to separate patients into two prognostic groups. CONCLUSION: The defined cut off values of the LNR were an independent risk factor for OS and distant metastasis-free survival in patients with rectal cancer, irrespective of the sixth or the seventh version of the TNM classification, and the LNR should be considered as a prognostic variable in any future staging system. PMID- 22102977 TI - Clinical Significance of Lymph Node Ratio in Stage III Colorectal Cancer. AB - PURPOSE: Recent literature has shown that lymph node ratio is superior to the absolute number of metastatic lymph nodes in predicting the prognosis in several malignances other than colorectal cancer. The aim of this study was to evaluate the prognostic significance of the lymph node ratio (LNR) in patients with stage III colorectal cancer. METHODS: We included 186 stage III colorectal cancer patients who underwent a curative resection over a 10-year period in one hospital. The cutoff point of LNR was chosen as 0.07 because there was significant survival difference at that LNR. The Kaplan-Meier and the Cox proportional hazard models were used to evaluate the prognostic effect according to LNR. RESULTS: There was statistically significant longer overall survival in the group of LNR > 0.07 than in the group of LNR <= 7 (P = 0.008). Especially, there was a survival difference for the N1 patients group (LN < 4) according to LNR (5-year survival of N1 patients was lower in the group of LNR > 0.07, P = 0.025), but there was no survival difference for the N2 group (4 >= LN) according to LNR. The multivariate analysis showed that the LNR is an independent prognostic factor. CONCLUSIONS: LNR can be considered as a more accurate and potent modality for prognostic stratifications in patients with stage III colorectal cancer. PMID- 22102978 TI - Oxaliplatin-induced Pulmonary Fibrosis: Two Case Reports. AB - Oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX regimen) is the one of the standard chemotherapy regimens for treating a colorectal carcinoma. The most common side effects include neutropenia, diarrhea, vomiting and peripheral neuropathy, and these are moderate and manageable. However, pulmonary toxicity is rarely reported to be associated with the FOLFOX regimen. Moreover, there is no established guideline for the management of this side effect. Here, along with a literature review, we report two cases of rapidly developing pulmonary fibrosis related to the use of the FOLFOX regimen in patients with colorectal carcinomas. PMID- 22102979 TI - Recurrent renal leiomyosarcoma mimicking a colonic submucosal tumor: a case report. AB - A primary leiomyosarcoma of the kidney is a rare, but highly aggressive, neoplasm, accounting for only 0.1% of all invasive renal tumors. Local or systemic recurrence is common, but a leiomyosarcoma is difficult to diagnose preoperatively. We recently encountered an interesting case of an unusual recurrence of a renal leiomyosarcoma. A 57-year-old woman visited our hospital complaining of lower abdominal pain. Four years previously, she had undergone a left nephrectomy. She had a primary leiomyosarcoma of the kidney that had been misdiagnosed as a renal cell carcinoma. Colonoscopy revealed the presence of a lesion similar to a submucosal tumor in the descending colon. Postoperative pathologic examination confirmed that the mass was a recurrent leiomyosarcoma. We report this unusual case and present a review of the literature. PMID- 22102980 TI - Vascular Protection Following Cerebral Ischemia and Reperfusion. AB - Despite considerable research that has contributed to a better understanding of the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed. The only effective treatment for ischemic stroke is rapid recanalization of an occluded vessel by dissolving the clot with tissue plasminogen activator (tPA). However, stroke adversely affects vascular function as well that can cause secondary brain injury and limit treatment that depends on a patent vasculature. In middle cerebral arteries (MCA), ischemia/reperfusion (I/R) cause loss of myogenic tone, vascular paralysis, and endothelial dysfunction that can lead to loss of autoregulation. In contrast, brain parenchymal arterioles retain considerable tone during I/R that likely contributes to expansion of the infarct into the penumbra. Microvascular dysregulation also occurs during ischemic stroke that causes edema and hemorrhage, exacerbating the primary insult. Ischemic injury of vasculature is progressive with longer duration of I/R. Early postischemic reperfusion has beneficial effects on stroke outcome but can impair vascular function and exacerbate ischemic injury after longer durations of I/R. This review focuses on current knowledge on the effects of I/R on the structure and function of different vascular segments in the brain and highlight some of the more promising targets for vascular protection. PMID- 22102981 TI - Identification and Quantification of Abundant Species from Pyrosequences of 16S rRNA by Consensus Alignment. AB - 16S rRNA gene profiling has recently been boosted by the development of pyrosequencing methods. A common analysis is to group pyrosequences into Operational Taxonomic Units (OTUs), such that reads in an OTU are likely sampled from the same species. However, species diversity estimated from error-prone 16S rRNA pyrosequences may be inflated because the reads sampled from the same 16S rRNA gene may appear different, and current OTU inference approaches typically involve time-consuming pairwise/multiple distance calculation and clustering. I propose a novel approach AbundantOTU based on a Consensus Alignment (CA) algorithm, which infers consensus sequences, each representing an OTU, taking advantage of the sequence redundancy for abundant species. Pyrosequencing reads can then be recruited to the consensus sequences to give quantitative information for the corresponding species. As tested on 16S rRNA pyrosequence datasets from mock communities with known species, AbundantOTU rapidly reported identified sequences of the source 16S rRNAs and the abundances of the corresponding species. AbundantOTU was also applied to 16S rRNA pyrosequence datasets derived from real microbial communities and the results are in general agreement with previous studies. PMID- 22102983 TI - Implicit methods for efficient musculoskeletal simulation and optimal control. AB - The ordinary differential equations for musculoskeletal dynamics are often numerically stiff and highly nonlinear. Consequently, simulations require small time steps, and optimal control problems are slow to solve and have poor convergence. In this paper, we present an implicit formulation of musculoskeletal dynamics, which leads to new numerical methods for simulation and optimal control, with the expectation that we can mitigate some of these problems. A first order Rosenbrock method was developed for solving forward dynamic problems using the implicit formulation. It was used to perform real-time dynamic simulation of a complex shoulder arm system with extreme dynamic stiffness. Simulations had an RMS error of only 0.11 degrees in joint angles when running at real-time speed. For optimal control of musculoskeletal systems, a direct collocation method was developed for implicitly formulated models. The method was applied to predict gait with a prosthetic foot and ankle. Solutions were obtained in well under one hour of computation time and demonstrated how patients may adapt their gait to compensate for limitations of a specific prosthetic limb design. The optimal control method was also applied to a state estimation problem in sports biomechanics, where forces during skiing were estimated from noisy and incomplete kinematic data. Using a full musculoskeletal dynamics model for state estimation had the additional advantage that forward dynamic simulations, could be done with the same implicitly formulated model to simulate injuries and perturbation responses. While these methods are powerful and allow solution of previously intractable problems, there are still considerable numerical challenges, especially related to the convergence of gradient-based solvers. PMID- 22102982 TI - Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review. AB - Homeostasis of metal ions such as Zn(2+) is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn(2+)-levels is long and steadily growing, including Parkinson's and Alzheimer's disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson's disease and Pick's disease. Furthermore, alterations in Zn(2+)-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn(2+) levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn(2+) in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn(2+) concentrations within the brain are still in their infancy. Since the use of dietary Zn(2+) supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn(2+) chelators or nanoparticle technologies to elevate or decrease intracellular Zn(2+) levels. Therefore, this review briefly summarizes the role of Zn(2+) in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn(2+)-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn(2+)-levels in order to treat brain disorders are evaluated. PMID- 22102984 TI - Resolution of phenolic antioxidant mixtures employing a voltammetric bio electronic tongue. AB - This work reports the application of a Bio-Electronic Tongue (BioET) system made from an array of enzymatic biosensors in the analysis of polyphenols, focusing on major polyphenols found in wine. For this, the biosensor array was formed by a set of epoxy-graphite biosensors, bulk-modified with different redox enzymes (tyrosinase and laccase) and copper nanoparticles, aimed at the simultaneous determination of the different polyphenols. Departure information was the set of voltammograms generated with the biosensor array, selecting some characteristic features in order to reduce the data for the Artificial Neural Network (ANN). Finally, after the ANN model optimization, it was used for the resolution and quantification of each compound. Catechol, caffeic acid and catechin formed the three-analyte case study resolved in this work. Good prediction ability was attained, therefore allowing the separate quantification of the three phenols with predicted vs. expected slope better than 0.970 for the external test set (n = 10). Finally, BioET has been also tested with spiked wine samples with good recovery yields (values of 104%, 117% and 122% for catechol, caffeic acid and catechin, respectively). PMID- 22102985 TI - Modern analytical techniques in metabolomics analysis. AB - Metabolomics is the comprehensive assessment of endogenous metabolites and attempts to systematically identify and quantify metabolites from a biological sample. Small-molecule metabolites have an important role in biological systems and represent attractive candidates to understand disease phenotypes. Metabolites represent a diverse group of low-molecular-weight structures including lipids, amino acids, peptides, nucleic acids, organic acids, vitamins, thiols and carbohydrates, which makes global analysis a difficult challenge. The recent rapid development of a range of analytical platforms, including GC, HPLC, UPLC, CE coupled to MS and NMR spectroscopy, could enable separation, detection, characterization and quantification of such metabolites and related metabolic pathways. Owing to the complexity of the metabolome and the diverse properties of metabolites, no single analytical platform can be applied to detect all metabolites in a biological sample. The combined use of modern instrumental analytical approaches has unravelled the ideal outcomes in metabolomics, and is beneficial to increase the coverage of detected metabolites that can not be achieved by single-analysis techniques. Integrated platforms have been frequently used to provide sensitive and reliable detection of thousands of metabolites in a biofluid sample. Continued development of these analytical platforms will accelerate widespread use and integration of metabolomics into systems biology. Here, the application of each hyphenated technique is discussed and its strengths and limitations are discussed with selected illustrative examples; furthermore, this review comprehensively highlights the role of integrated tools in metabolomic research. PMID- 22102986 TI - Rapid analysis of pyrethroid insecticides in aquaculture seawater samples via membrane-assisted solvent extraction coupled with gas chromatography-electron capture detection. AB - A simple, efficient, and environmentally friendly membrane-assisted solvent extraction (MASE) method for the extraction and preconcentration of six pyrethroid insecticides from aquaculture seawater samples followed by gas chromatography-electron capture detection (GC-ECD) was successfully proposed. The operating conditions for MASE, such as the extraction solvent, solvent volume, NaCl concentration, stirring rate, extraction time, and temperature, were optimized. Compared to conventional Florisil-solid phase extraction (SPE), higher extraction recoveries (85.9% to 105.9%) of three spiked levels of the six pyrethroid pesticides in aquaculture seawater were obtained using MASE, and the RSD values were lower than 7.9%. The limits of detection (LOD, signal-to-noise ratio (S/N)=3) and quantification (LOQ, S/N = 10) were in the range of 0.037 0.166 and 0.12-0.55 MUg L(-1), respectively. The results demonstrate the excellent applicability of the MASE method in analyzing the six pyrethroid pesticides in aqueous samples. The proposed method exhibited a high potential for routine monitoring analysis of pyrethroid insecticides in seawater samples. PMID- 22102988 TI - Baker's yeast raises hope for a vaccine against aspergillosis: study shows that inactivated baker's yeast is protective against Aspergillus in mice. PMID- 22102987 TI - Columnar self-assembly of rhomboid macrocyclic molecules via step-like intermolecular interaction. Crystal formation and gelation. AB - Two macrocyclic compounds with a rhomboid molecular shape, composed of a pi conjugated framework and an imine or amine functionality, were synthesized. The amine-containing macrocycle crystallizes with step-like interaction of each molecule, forming a columnar arrangement, although dispersion of the imine gelates upon ultrasonification. PMID- 22102989 TI - Study sheds further light on the immune response to chronic infections: new findings could help in the design of vaccines and therapeutics against chronic infection. PMID- 22102990 TI - Study provides insight into HIV-neutralizing antibody evolution via deep sequencing and structural analysis. PMID- 22102991 TI - Nanopatterning of ferritin molecules and the controlled size reduction of their magnetic cores. AB - A nanopatterning method to deposit ferritin proteins with nanoscale accuracy over large areas is reported. Selective deposition is driven by the electrostatic interactions existing between the proteins and nanoscale features. Upon deposition, the protein shell can be removed by heating the patterns in an oxygen atmosphere. This leaves exposed the iron oxide core, which can be further reduced in size by plasma-etching methods. In this way, the initial ferritin molecules, which have a nominal size of 12 nm, are reduced to 2 nm nanoparticles. Magnetic force measurements confirm the magnetic activity of the as-deposited and etched nanoparticles. PMID- 22102992 TI - Membrane development for vanadium redox flow batteries. AB - Large-scale energy storage has become the main bottleneck for increasing the percentage of renewable energy in our electricity grids. Redox flow batteries are considered to be among the best options for electricity storage in the megawatt range and large demonstration systems have already been installed. Although the full technological potential of these systems has not been reached yet, currently the main problem hindering more widespread commercialization is the high cost of redox flow batteries. Nafion, as the preferred membrane material, is responsible for about 11% of the overall cost of a 1 MW/8 MWh system. Therefore, in recent years two main membrane related research threads have emerged: 1) chemical and physical modification of Nafion membranes to optimize their properties with regard to vanadium redox flow battery (VRFB) application; and 2) replacement of the Nafion membranes with different, less expensive materials. This review summarizes the underlying basic scientific issues associated with membrane use in VRFBs and presents an overview of membrane-related research approaches aimed at improving the efficiency of VRFBs and making the technology cost-competitive. Promising research strategies and materials are identified and suggestions are provided on how materials issues could be overcome. PMID- 22102993 TI - Hybrid materials that integrate living cells: improved eco-adaptation and environmental applications. PMID- 22102994 TI - Multimodal zeolite-beta-based catalysts with a hierarchical, three-level pore structure. PMID- 22102995 TI - The effects of distal limb segment shortening on locomotor efficiency in sloped terrain: implications for Neandertal locomotor behavior. AB - Past studies of human locomotor efficiency focused on movement over flat surfaces and concluded that Neandertals were less efficient than modern humans due to a truncated limb morphology, which may have developed to aid thermoregulation in cold climates. However, it is not clear whether this potential locomotor disadvantage would also exist in nonflat terrain. This issue takes on added importance since Neandertals likely spent a significant proportion of their locomotor schedule on sloped, mountainous terrains in the Eurasian landscape. Here a model is developed that determines the relationship between lower limb segment lengths, terrain slope, excursion angle at the hip, and step length. The model is applied to Neandertal and modern human lower limb reconstructions. In addition, for a further independent test that also allows more climateterrain cross comparisons, the same model is applied to bovids living in different terrains and climates. Results indicate that: (1) Neandertals, despite exhibiting shorter lower limbs, would have been able to use similar stride frequencies per speed as longer-limbed modern humans on sloped terrain, due to their lower crural indices; and (2) shortened distal limb segments are characteristic of bovids that inhabit more rugged terrains, regardless of climate. These results suggest that the shortened distal lower limb segments of Neandertals were not a locomotor disadvantage within more rugged environments. PMID- 22102996 TI - Profile of HIV infected children from Delhi and their response to antiretroviral treatment. AB - OBJECTIVES: (i) To study the clinical and immunological profile of HIV infected children attending the ART centre; (ii) To correlate CD4 count with clinical staging at diagnosis; and, iii) To study the clinical and immunological response to antiretroviral treatment. SETTING: Antiretroviral therapy (ART) centres of two tertiary care hospitals of Delhi. PATIENTS: 100 children attending the centres between December 2008 to June 2009. METHODS: The clinical features, immunological profile (CD4 count) and response to ART were recorded in a structured proforma. DESIGN: Prospective follow-up. RESULTS: Average age of enrolled children was 6.24 y (range 1-14 years) and mode of transmission was parent to child in 92%. Most common clinical presentation was fever (83%), cough (50.8%) and diarrhea (38.9%). Tuberculosis was the most common opportunistic infection seen in 11% of children. 59% of enrolled children were malnourished. Antiretroviral treatment (ART) was initiated in 33 children. Children who were initiated on ART had a significant improvement in both clinical and immunological staging at the 6 months follow up. Immunological response (rise in CD4 count) to ART was better in children with lesser degree of immunosuppression. The measure of agreement between the clinical and immunological stage at presentation was poor. CONCLUSIONS: Baseline CD4 counts rather than clinical staging can be a primary determinant for initiation of antiretroviral treatment in HIV infected children. PMID- 22102997 TI - Wilhelm Gottlieb Tilesius--a forgotten dermatologist. PMID- 22102998 TI - Principles of neural coding. PMID- 22102999 TI - Addendum: Kremer et al., Late emergence of the vibrissa direction selectivity map in the rat barrel cortex. PMID- 22103000 TI - Graphene: Piecing it together. AB - Graphene has a multitude of striking properties that make it an exceedingly attractive material for various applications, many of which will emerge over the next decade. However, one of the most promising applications lie in exploiting its peculiar electronic properties which are governed by its electrons obeying a linear dispersion relation. This leads to the observation of half integer quantum hall effect and the absence of localization. The latter is attractive for graphene-based field effect transistors. However, if graphene is to be the material for future electronics, then significant hurdles need to be surmounted, namely, it needs to be mass produced in an economically viable manner and be of high crystalline quality with no or virtually no defects or grains boundaries. Moreover, it will need to be processable with atomic precision. Hence, the future of graphene as a material for electronic based devices will depend heavily on our ability to piece graphene together as a single crystal and define its edges with atomic precision. In this progress report, the properties of graphene that make it so attractive as a material for electronics is introduced to the reader. The focus then centers on current synthesis strategies for graphene and their weaknesses in terms of electronics applications are highlighted. PMID- 22103001 TI - Towards ultrastrong glasses. AB - The development of new glassy materials is key for addressing major global challenges in energy, medicine, and advanced communications systems. For example, thin, flexible, and large-area glass substrates will play an enabling role in the development of flexible displays, roll-to-roll processing of solar cells, next generation touch-screen devices, and encapsulation of organic semiconductors. The main drawback of glass and its limitation for these applications is its brittle fracture behavior, especially in the presence of surface flaws, which can significantly reduce the practical strength of a glass product. Hence, the design of new ultrastrong glassy materials and strengthening techniques is of crucial importance. The main issues regarding glass strength are discussed, with an emphasis on the underlying microscopic mechanisms that are responsible for mechanical properties. The relationship among elastic properties and fracture behavior is also addressed, focusing on both oxide and metallic glasses. From a theoretical perspective, atomistic modeling of mechanical properties of glassy materials is considered. The topological origin of these properties is also discussed, including its relation to structural and chemical heterogeneities. Finally, comments are given on several toughening strategies for increasing the damage resistance of glass products. PMID- 22103002 TI - Genetics and imaging of hepatocellular adenomas: 2011 update. Invited commentary. PMID- 22103003 TI - Life sciences: Biomarkers on the brain. PMID- 22103004 TI - Marc Lipsitch, Winner of the Kenneth Rothman Epidemiology Prize, 2011. PMID- 22103006 TI - A greener past? An assessment of South African environmental historiography. PMID- 22103005 TI - A large-scale complex haploinsufficiency-based genetic interaction screen in Candida albicans: analysis of the RAM network during morphogenesis. AB - The morphogenetic transition between yeast and filamentous forms of the human fungal pathogen Candida albicans is regulated by a variety of signaling pathways. How these pathways interact to orchestrate morphogenesis, however, has not been as well characterized. To address this question and to identify genes that interact with the Regulation of Ace2 and Morphogenesis (RAM) pathway during filamentation, we report the first large-scale genetic interaction screen in C. albicans.Our strategy for this screen was based on the concept of complex haploinsufficiency (CHI). A heterozygous mutant of CBK1(cbk1Delta/CBK1), a key RAM pathway protein kinase, was subjected to transposon-mediated, insertional mutagenesis. The resulting double heterozygous mutants (6,528 independent strains) were screened for decreased filamentation on SpiderMedium (SM). From the 441 mutants showing altered filamentation, 139 transposon insertion sites were sequenced,yielding 41 unique CBK1-interacting genes. This gene set was enriched in transcriptional targets of Ace2 and, strikingly, the cAMP-dependent protein kinase A (PKA) pathway, suggesting an interaction between these two pathways. Further analysis indicates that the RAM and PKA pathways co-regulate a common set of genes during morphogenesis and that hyperactivation of the PKA pathway may compensate for loss of RAM pathway function. Our data also indicate that the PKA regulated transcription factor Efg1 primarily localizes to yeast phase cells while the RAM-pathway regulated transcription factor Ace2 localizes to daughter nuclei of filamentous cells, suggesting that Efg1 and Ace2 regulate a common set of genes at separate stages of morphogenesis. Taken together, our observations indicate that CHI-based screening is a useful approach to genetic interaction analysis in C. albicans and support a model in which these two pathways regulate a common set of genes at different stages of filamentation. PMID- 22103007 TI - HIV/AIDS in south Africa: a case of failed responses because of stigmatization, discrimination and morality, 1983-1994. PMID- 22103008 TI - A history of masculinities in South Africa: context and parameters. PMID- 22103009 TI - Another side to warfare: caring for white destitutes during the Anglo-Boer War (October 1899 - May 1900). PMID- 22103010 TI - From apartheid to development: science policy and the politics of race in South Africa. PMID- 22103011 TI - "Stinkafrikaners" and social stereotypes: the Anglo Boer War reminiscences of L. J. Groenewald. PMID- 22103012 TI - The beginnings of middle class suburbanization in a small town: a case study of Aberystwyth, c. 1870-1930. PMID- 22103013 TI - [An investigation of the agrarian population and land in North China during the Qing era]. PMID- 22103014 TI - Microbial Carbohydrates. PMID- 22103015 TI - [The development of the Jiayi region in Taiwan and environmental change during the Qing]. PMID- 22103016 TI - Sanitation and public works in late nineteenth century, Mexico City. PMID- 22103017 TI - [Changing concepts of marriage and the family in the late Qing]. PMID- 22103018 TI - [Yongzheng and alchemy]. PMID- 22103019 TI - [An analysis of the impact of natural disasters on primitive accumulation during the early stages of industrialization in China: research on famines and the Self-Strengthening Movement. Part 2]. PMID- 22103020 TI - Medicare program; end-stage renal disease prospective payment system and quality incentive program; ambulance fee schedule; durable medical equipment; and competitive acquisition of certain durable medical equipment prosthetics, orthotics and supplies. Final rule. AB - This final rule updates and makes certain revisions to the End-Stage Renal Disease (ESRD) prospective payment system (PPS) for calendar year (CY) 2012. We are also finalizing the interim final rule with comment period published on April 6, 2011, regarding the transition budget-neutrality adjustment under the ESRD PPS,. This final rule also sets forth requirements for the ESRD quality incentive program (QIP) for payment years (PYs) 2013 and 2014. In addition, this final rule revises the ambulance fee schedule regulations to conform to statutory changes. This final rule also revises the definition of durable medical equipment (DME) by adding a 3-year minimum lifetime requirement (MLR) that must be met by an item or device in order to be considered durable for the purpose of classifying the item under the Medicare benefit category for DME. Finally, this final rule implements certain provisions of section 154 of the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) related to the durable medical equipment, prosthetics, orthotics and supplies (DMEPOS) Competitive Acquisition Program and responds to comments received on an interim final rule published January 16, 2009, that implemented these provisions of MIPPA effective April 18, 2009. (See the Table of Contents for a listing of the specific issues addressed in this final rule.) PMID- 22103021 TI - Updating fire safety standards. Final rule; affirmation. AB - This document affirms as final, without changes, a provision included in a final rule with request for comments that amended the Department of Veterans Affairs (VA) regulations concerning community residential care facilities, contract facilities for certain outpatient and residential services, and State home facilities. That provision established a five-year period within which all covered buildings with nursing home facilities existing as of June 25, 2001, must conform to the automatic sprinkler requirement of the 2009 edition of the National Fire Protection Association (NFPA) 101. This rule helps ensure the safety of veterans in the affected facilities. PMID- 22103022 TI - African identity and slavery in the Americas. PMID- 22103023 TI - Beyond midwives: teaching gender, science, and medicine from antiquity to the present. PMID- 22103024 TI - Citizens or consumers?: Environmentalism and the public sphere in postsocialist Hungary. PMID- 22103025 TI - Cuba, 1898: rethinking race, nation, and empire. PMID- 22103026 TI - Histories of disturbance. PMID- 22103027 TI - [Marriage, interest, family: a conflict between the first-born and last-born in the Cadorna family in the late 18th century]. PMID- 22103028 TI - [The rice shortage in central Burma and Shan province during the Japanese occupation]. PMID- 22103029 TI - [Recent studies on the history of philanthropic associations in China: private philanthropic associations in early modern China]. PMID- 22103030 TI - The culture of medicine and the culture of the academy. PMID- 22103031 TI - Species differences in the interaction of thrombin and fibrinogen. PMID- 22103032 TI - "The Great Patients": heroes and anti-heroes in a medical history course. PMID- 22103033 TI - [More raw material! Distinct perspectives on the indigenous population of central Mexico]. PMID- 22103034 TI - Blood coagulation in fish. AB - Blood coagulation systems in cyclostome, elasmobranch, and teleost fish were studied and compared. The plasma of all these fish contained a fibrinogen molecule, capable of being clotted by human thrombin, and a prothrombin molecule, capable of being converted into thrombin which could hydrolyze p-tosyl l-arginine methyl ester. The prothrombin activity could be adsorbed on barium sulfate. Accurate assessment of prothrombin conversion factors is confounded by the "species specificity" of protein-protein interactions, but preliminary observations were made on both the extrinsic and intrinsic clotting schemes. Fish thrombocytes play a central role in the intrinsic conversion of prothrombin to thrombin, and are responsible for clot retraction. The plasma of the smooth dogfish exemplifies a clotting diathesis which can be overcome in vitro by the addition of large amounts of calcium. Under such conditions, other parts of the coagulation scheme become greatly exaggerated, and a very large thrombin generation ensues, subsequently followed by an intense fibrinolysis. A powerful serum inhibition occurs which was shown to be caused by the breakdown products of the fibrinolysis. PMID- 22103035 TI - [Water in Mexico City during the Porfiriato: a surmounted reality?]. PMID- 22103036 TI - Civic self-fashioning in Renaissance Bologna: historical and scholarly contexts. PMID- 22103037 TI - Heralds of a well-instructed mind': Nicolosa Sanuti's defence of women and their clothes. PMID- 22103038 TI - How to (and how not to) get married in sixteenth-century Venice. PMID- 22103039 TI - [Montezuma's banquet: conjectures of a field anthropologist on systems of classification and social structure in 16th-century Mexico]. PMID- 22103040 TI - Irritable bowel syndrome: the role of the intestinal microbiota, pathogenesis and therapeutic targets. AB - Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that predominantly affects women and accounts for up to 40% of the gastroenterology unit outpatient visits. The pathophysiology is complex and multifactorial. In the present review we will focus on the role of intestinal dysbiosis in its pathogenesis and treatment. Post-infectious IBS (PI-IBS) can put light on the mechanisms underlying IBS. Modified commensal gut flora may lead to mucosal inflammation. Several changes such as an increase in mucosal cellularity (enterochromaffin cells, lamina propria T lymphocytes and mast cells), modified pro-inflammatory/anti-inflammatory cytokine balance and disordered neurotransmission have been observed. The normal microbiota is an essential factor in health. A modification of the flora, such as small intestinal bacterial overgrowth (SIBO) is thought to play a pathogenic role in IBS. Changes in the composition of the luminal and mucosal colonic flora have been linked to IBS. It is not clear however, whether these changes are a cause or a consequence of the syndrome. The comprehension of the interaction between the dysbiotic microbiota and the host will probably lead to the development of focused therapies. Based on these assumptions, treatments modulating the microbiota have been investigated. On the one hand several probiotics have shown a reduction in IBS symptoms by an immunomodulatory and analgesic effects. On the other hand antibiotic treatment has proven efficacy in treating IBS with or without associated SIBO. Due to its complex pathophysiology, treating IBS nowadays implies multiple approaches, one of which may be modulation of the intestinal flora. PMID- 22103041 TI - Acute upper gastrointestinal bleeding in cirrhosis: changes and advances over the past two decades. AB - BACKGROUND AND AIMS: Few studies have compared two or more cohorts of cirrhotic patients admitted for upper gastrointestinal bleeding (UGIB) several decades apart. Our aim was to compare epidemiological, clinical, therapeutic and prognostic characteristics of UGIB (whatever the source) in two cohorts of cirrhotic patients admitted to the emergency room of the same general hospital 2 decades apart. METHODS: One-hundred cases of UGIB in cirrhotic patients consecutively admitted between 1984 and 1990 (cohort A) were compared with 100 similar cases admitted between 2004 and 2009 (cohort B). RESULTS: The sex ratio (M/F: 2/1), mean age (approximately 55Y) and the proportion of patients with alcoholic cirrhosis (approximately 80%) did not change. Mean Child-Pugh score and the proportion of patients in Child-Pugh stage C increased from 7.6 and 19% in cohort A to 8.8 and 35% in cohort B (p < 0.001). Therapeutic intervention was performed during initial endoscopy in 13 cases from cohort A and 50 from cohort B (p < 0.001), respectively. The number of transfused patients (85 in cohort A, 58 in cohort B) and the number of red blood cell units administered on the first day (median: 4 in cohort A, 2 in cohort B) were significantly decreased in cohort B (p < 0.001). The rate of rebleeding (45 in cohort A, 11 in cohort B), the need for rescue surgery (8 in cohort A, 0 in cohort B) and the in-hospital mortality (24 in cohort A, 9 in cohort B) significantly decreased in the more recent cohort (p < 0.005). CONCLUSION: This study demonstrated that several characteristics of cirrhotic patients admitted with UGIB have changed over the past 2 decades. Above all, outcome has improved despite an increase in the severity of cirrhosis. PMID- 22103042 TI - Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. AB - AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated to obesity and type 2 diabetes, but may occur in the absence of these factors. Based on a large series of liver biopsies, we have evaluated the clinical, biochemical, metabolic and pathological characteristics of a new entity, which we refer to as "lean-NAFLD". METHODS: Among 1,777 patients, who underwent liver biopsy for chronic liver disease, Lean-NAFLD, defined as patients with NAFLD without obesity (BMI < 30 kg/m2) and without diabetes was found in 50 of them (2.8%), being the most frequent cause (38%) of cryptogenic liver disease. Thirty-one patients from the Lean-NAFLD group were compared to 48 Obese-NAFLD patients diagnosed during the same period and 8 healthy control patients. Insulin resistance was determined using the homeostasis model assessment method. RESULTS: In the Lean-NAFLD group as compared to the obese-NAFLD group, patients were younger : median 40 vs. 49 years, p = 0.047, with male predominance: 71 vs. 46%, p = 0.037. Fasting glucose and HbA1c were lower, as was insulin sensitivity: 1.7 vs. 3.0, p = 0.049. Blood pressure was significantly lower (p = 0.001) while triglycerides and HDL cholesterol were similar. Although there was less inflammation (p = 0.038) and fibrosis (p = 0.029), non-alcoholic steatohepatitis and fibrosis were present in 61% and 55% of the Lean-NAFLD group, respectively. Compared to healthy controls, Lean-NAFLD were less insulin sensitive, with a insulin sensitivity index of 59 vs. 110 (p = 0.015), and more hypertriglyceridemic (p = 0.003). CONCLUSIONS: Lean NAFLD is a new unrecognized clinicopathological entity, a frequent cause of cryptogenic liver disease. PMID- 22103043 TI - The importance of upper gastrointestinal lesions detected with capsule endoscopy in patients with obscure digestive bleeding. AB - STUDY AIMS: Small bowel capsule endoscopy (SBCE) is the first line procedure for detecting small bowel lesions in patients with an obscure gastrointestinal bleeding (OGIB). Missed upper gastrointestinal (UGI) lesions at the initial endoscopy may account for the so-called OGIB. This retrospective study was designed to assess the role of SBCE in detecting missed UGI lesions. METHODS: All consecutive SBCE that were performed in the last year for patients with OGIB were included in our study. We evaluated the visibility of the gastric mucosa, the anatomic landmarks, the presence of UGI lesions as well as their clinical importance. The SBCE findings were compared with the reports of previous UGI endoscopies. RESULTS: 118 patients (45 males, 73 females, mean age 61 +/- 19 years) were included in the analysis. The indication for SBCE was obscure overt and occult OGIB in 60 and in 58 patients, respectively. SBCE identified lesions in the small bowel in 42% of the patients. An excellent visibility of gastric mucosa was observed in 83/118 cases (703%). SBCE identified gastric lesions with potential clinical significance (high bleed potential) in 25/118 (21.2%) patients. In 12/118 (10.2%) patients the UGI lesions detected by SBCE were considered as the only potential source of bleeding. CONCLUSIONS: In patients with OGIB, SBCE detected not only small bowel lesions but also significant UGI lesions that were missed or underestimated at the initial endoscopy in 21% of cases. It is therefore necessary to carefully read the gastric images when performing an SBCE. PMID- 22103044 TI - Single-centre experience on use of videocapsule endoscopy for obscure gastrointestinal bleeding in 120 consecutive patients. AB - BACKGROUND AND STUDY AIMS: Capsule endoscopy (CE) has become first choice for evaluation of the small bowel in case of obscure gastrointestinal bleeding (OGIB). The influence of clinical factors on CE diagnostic yield remains controversial and little is known about the exact impact of CE on management and outcome. We aimed to identify the ideal candidates for CE examination in daily practice by reviewing our own data and the available literature. PATIENTS AND METHODS: We retrospectively analyzed data of 120 consecutive patients with OGIB (33 overt - 87 occult) that underwent CE in a single centre. RESULTS: Complete evaluation of the small bowel was achieved in 82.5%, with only one case of capsule retention. The overall diagnostic yield was 47.5% and no difference was noted in the overt versus the occult group. Only the presence of cardiovascular comorbidity was associated with a statistically significant increase in diagnostic yield (p = 0,041). Arterio-venous malformation (AVM) was diagnosed most frequently in 68.4% of positive studies. Specific management alterations were made in 22 patients (18.3%) following CE, mostly guided by a positive result (91%) (p = 0,0001). CONCLUSION: In daily practice it remains very difficult to predict pathology detection rate on CE as well as to estimate the impact on further management and outcome in the individual patient. Diagnostic yield is significantly higher in patients with cardiovascular comorbidity than in those without. PMID- 22103045 TI - "7, 10 and 14-days rabeprazole-based standard triple therapies for H. pylori eradication: are they still effective? A randomized trial". AB - BACKGROUND & STUDY AIMS: Increasing data suggests that the efficiency of standard triple therapies of 7-10-14 days duration has fallen below the threshold for acceptability (80% cure rates in intention to treat analysis). Use of rabeprazole, a PPI less influenced by CYP2C19 gene polymorphisms is reported to lead to improved eradication rates. This study aims to re-examine the effectiveness of 7-10-14 days triple therapies based on rabeprazole in Greek patients. PATIENTS AND METHODS: 307 patients, from 2 endoscopic centers in Greece, were randomized to receive Rabeprazole 20 mg bid, Clarithromycin 500 mg bid, and Amoxycillin 1gr bid for 7-days, for 10-days or for 14-days. Cure rates were assessed by CLO-test and histology. Clarithromycin sensitivity tests were carried out in the cultured pre-treatment H.pylori strains. The success rates were calculated by both intention-to-treat (ITT) and per protocol (PP) analyses. RESULTS: The eradication rates according to ITT analyses were 74.5% (95% CI: 66.5 82.9%) for 7-days, 80.6% (95% CI: 73.2-88.2%) for 10-days and 90.2% (95% CI: 84.5 95.9%) for 14-days treatment. PP cure rates were 76% (95% CI: 68.4-85.0%) for 7 days, 83% (95% CI: 76.6-91.0%) for 10-days and 93.9% (95% CI: 86.7-973%) for 14 days treatment. Side effects were generally minor and comparable in all treatment groups. CONCLUSIONS: Both 10- and 14-days rabeprazole-based triple regimens reached eradication rates above the threshold of 80% on an intention to treat basis. In our setting, the current regimen using rabeprazole, amoxicillin and clarithromycin was well tolerated, is still effective and should continue to be recommended as first-line therapy for H. pylori eradication. PMID- 22103046 TI - FAPA--familial adenomatous polyposis association the Belgian Polyposis Registry. PMID- 22103047 TI - Familial adenomatous polyposis: clinical presentation, detection and surveillance. AB - Colorectal cancer (CRC) is a leading cause of cancer related death in the western countries. It remains an important health problem, often under-diagnosed. The symptoms can appear very late and about 25% of the patients are diagnosed at metastatic stage. Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome, characterized by the early onset of hundred to thousands of adenomatous polyps in the colon and rectum. Left untreated, there is a nearly 100% cumulative risk of progression to CRC by the age of 35-40 years, as well as an increased risk of various other malignancies. CRC can be prevented by the identification of the high risk population and by the timely implementation of rigid screening programs which will lead to special medico-surgical interventions. PMID- 22103048 TI - The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP). AB - FAP is characterized by 100-1000s of adenomatous polyps in colon and rectum, and is in 70% of the patients associated with extracolonic manifestations. Attenuated FAP (AFAP) is a less severe form of FAP, marked by the presence of < 100 polyps and a later onset of colorectal cancer (CRC). (A)FAP is caused by autosomal dominantly inherited mutations in the APC (Adenomatous polyposis coli) gene, a tumour suppressor gene that controls beta-catenin turnover in the Wnt pathway. De novo occurrence is reported in 30-40% of the patients. Mutations are detected in 85% of classical FAP families, while only 20%-30% of AFAP cases will exhibit a germline APC mutation. MUTYH is the second (A)FAP-related gene and is involved with base-excision repair of DNA damaged by oxidative stress. MUTYH mutations are inherited in an autosomal recessive way and account for 10%-20% of classical FAP cases without an APC mutation and for 30% of AFAP cases. Genotype-phenotype correlations exist for mutations in the APC gene, however, contradictions in the literature caution against the sole use of the genotype for decisions regarding clinical management. Once the family's specific APC mutation is identified in the proband, predictive testing for first degree relatives is possible from the age of 10 to 12 years on. For AFAP, relatives are tested at age 18 and older. Opinions about the appropriate ages at which to initiate genetic testing may vary. Physicians must have a discussion about prenatal testing with patients in childbearing age. They may either opt for conventional prenatal diagnosis (amniocentesis or chorionic villous sampling) or for preimplantation genetic diagnosis (PGD). PMID- 22103049 TI - Different surgical strategies in the treatment of familial adenomatous polyposis: what's the role of the ileal pouch-anal anastomosis? AB - BACKGROUND AND STUDY AIMS: Restorative coloproctectomy (RCP) with ileal pouch anal anastomosis (IPAA), is one of the surgical responses to the crucial question of prophylactic treatment in familial adenomatous polyposis (FAP). No consensus has been reached, until now, to choose between IPAA and ileo-rectal anastomosis (IRA), the rectal sparing prophylactic colectomy. This paper aims to review the latest issues related to IPAA and highlights its specificities compared to IRA. METHODS: PubMed database was searched using the following search items: familial adenomatous polyposis, surgery, ileal pouch-anal anastomosis, ileo-rectal anastomosis. Papers published between 1978 and 2010 were selected. RESULTS: Absence of mortality, acceptable morbidity and good functional results combined to high quality of life have promoted the IPAA technique. New technical issues such as the double stapled technique, mesenteric lengthening, omission of temporary protective stoma can be addressed almost systematically for these patients. A laparoscopic approach, lessening the body image impact, has proven to be as effective and safe as the open approach to perform IPAA. Further advantages of laparoscopic IPAA rely on the lower adhesion formation resulting in less small bowel occlusion. Sexuality, fertility and childbirth are important functional issues often cited as threatened by the pelvic manoeuvres of the IPAA technique which can be prevented by close rectal wall dissection and a laparoscopic approach. CONCLUSION: IPAA offers the best available prophylaxis in FAP patients. Technical enhancements in IPAA will most probably decrease the functional risks. Thus IPAA remains the alternative to IRA for the prophylactic treatment of FAP.Nevertheless, based on the latest evidence, the choice between both procedures is still matter of debate. PMID- 22103050 TI - Different surgical strategies in the treatment of familial adenomatous polyposis: what's the role of the ileorectal anastomosis? AB - Prophylactic (procto-) colectomy is the treatment of choice to reduce the risk of colorectal cancer in FAP patients with multiple adenomas. Because patients present at young age, rectum-sparing surgery is sometimes advocated, so that there is no pelvic dissection with impact on quality of life, preserved pelvic innervation and sexual function and fertility. The main disadvantage of a total colectomy with an ileorectal anastomosis (IRA) is a rectal cancer risk of 50% at the age of 50 years and a cumulative risk of 25.8% after 25 years of follow-up. Therefore, this procedure should be reserved for patients with an unaffected rectum. There should be no discussion to perform a primary IPAA in patients with multiple rectal adenomas (> 20) or those with a severe dysplastic or large (> 3 cm) rectal adenoma or a cancer elsewhere in the colon. A patient with an IRA should undergo yearly follow-up by rectoscopy. PMID- 22103051 TI - Psychological implications of living with familial adenomatous polyposis. AB - BACKGROUND AND STUDY AIMS: Psychosocial implications of living with FAP remain largely unexplored. This article reviews available literature on three topics: 1) Implications of living with FAP 2) genetic testing and reproductive decision making and 3) family communication. PATIENTS AND METHODS: Papers published until 2009 about psychosocial and behavioral issues in FAP were identified. RESULTS: Psychometric data indicate that FAP patients and at-risk relatives as a group do not exhibit clinical symptoms of mental health problems after clinical or genetic diagnosis. However, some subgroups revealed to be more vulnerable to distress. Also, concerns related to the disease and its consequences were reported. While interest in prenatal diagnosis or preimplantation genetic diagnosis seems to be high it is important to study actual uptake because this may reveal to be much lower. Family members are an important source of information and the few available data suggest that family communication is problematic. The findings described have several shortcomings. They were obtained from only a few studies often conducted using specific or mixed study groups, originating from the 90ties and mostly cross-sectional in nature. CONCLUSIONS: For clinical practice, it is important to have more research data on how FAP patients at different ages cope with the disease, on the impact of genetic testing on reproductive decision making and on family communication. Results reported here need to be confirmed by additional research and new themes need to be explored. PMID- 22103052 TI - Quality of care indicators in rectal cancer. AB - Quality of health care is a hot topic, especially with regard to cancer. Although rectal cancer is, in many aspects, a model oncologic entity, there seem to be substantial differences in quality of care between countries, hospitals and physicians. PROCARE, a Belgian multidisciplinary national project to improve outcome in all patients with rectum cancer, identified a set of quality of care indicators covering all aspects of the management of rectal cancer. This set should permit national and international benchmarking, i.e. comparing results from individual hospitals or teams with national and international performances with feedback to participating teams. Such comparison could indicate whether further improvement is possible and/or warranted. PMID- 22103053 TI - Acute adult intussusception caused by primary cecal non Hodgkin lymphoma. AB - Intussusception of the bowel is rather rare in adults and in about 80-90% of the cases is secondary to an underlying intraluminal pathology that serves as a lead point. In cases of colonic intussusception malignancy occurs in 63-66% of patients and it is usually adenocarcinoma and rarely lymphoma. The presenting symptoms are non specific and are in most cases of long duration, consistent with a chronic intussusception causing partial intestinal obstruction. We present a rare case of primary colorectal lymphoma in a 29 years old female that was complicated by acute ileocecal intussusception, treated with en bloc resection without reduction. PMID- 22103054 TI - Macroscopic endoscopic lesions in microscopic collagenous colitis: double case report and review of the literature. AB - Collagenous colitis is a cause of chronic diarrhea of incompletely elucidated origin, defined by normal laboratory tests, a normal endoscopic appearance of colonic mucosa and specific microscopic inflammatory features on colonic biopsies. We report two cases of macroscopic endoscopic lesions observed in patients suffering from chronic diarrhea, whose biopsies confirmed a diagnosis of collagenous colitis and who were successfully treated in that setting, achieving clinical and endoscopic remissions. By means of a literature review, we summarize what is known about collagenous colitis. We particularly discuss macroscopic findings in that context, drawing attention on the so called "microscopic colitis" in the differential diagnosis of that type of lesions. PMID- 22103055 TI - Anaphylactic shock as a single presentation of Echinococcus cyst. AB - We describe the case of a 14-year-old boy of Turkish origin, presenting with anaphylactic shock after a minor abdominal trauma. Further investigations revealed a hepatic Echinococcal cyst without evidence of rupture. Anti-helminthic therapy was administered. Because of aggravating symptoms and recurrent anaphylaxis, surgical excision was performed. Intra-operative, a rupture into the biliary tree was seen. After surgery, the anaphylactic symptoms disappeared and the patient recovered. This case-report supports the fact that anaphylactic shock can be the only presentation of a hydatid cyst. Microscopic spillage can possibly be sufficient to cause major anaphylaxis. PMID- 22103056 TI - Splenic arteriovenous fistula--late complications of splenectomy. AB - This is a case report of a 30-year-old female patient with a splenic arteriovenous fistula of rare, atypical clinical course. The patient was admitted to the hospital due to strong abdominal pains and fever. 13 years earlier, the patient underwent splenectomy due to post-traumatic rupture of the spleen. On imaging examinations prior to surgery (ultrasonography, CT), a splenic arteriovenous fistula was diagnosed. The patient was operated on due to increasing abdominal pain. The fistula was closed by splenic artery and splenic vein banding during the course of laparotomy. This case report will be discussed based on literature review. PMID- 22103057 TI - Collagenous colitis and collagenous gastritis in a 9 year old girl: a case report and review of the literature. AB - Collagenous gastritis is a rare disease in the general population and collagenous colitis has seldom been reported in children. We report a girl with both diseases and review the literature on this association afetr a systematic search of Pubmed, Medline and Embase databases.. The girl, diagnosed of collagenous colitis at the age of 2 years, started with abdominal pain and anaemia at the age of 9 years and was diagnosed of collagenous gastritis in the gastric biopsies. After review of the literature, we found 66 reported cases (33 children, 33 adults, 68% females), 56 patients with collagenous gastritis and 16 children with collagenous colitis. Both disorders coexisted in 20 patients. The main presenting symptoms are abdominal pain and anaemia in patients with collagenous gastritis and diarrhoea and weight loss in patients with both disorders. Hypoalbuminemia was found in 9 patients with both diseases and protein losing enteropathy was demonstrated in 3 cases. Deposits of collagen in the duodenum were observed in 13 of 19 patients with both diseases. Seventeen of 66 patients had associated autoimmune disorders, particularly in patients with both diseases (35%). These conditions have a chronic course but gastric or colonic malignancies have not been communicated to date. In conclusion, collagenous gastritis and collagenous colitis mainly affects women and can occur at any age. Their association is exceptional. These disorders, although rare, should be considered in patients with anaemia and epigastric pain, watery diarrhoea or protein losing enteropathy. PMID- 22103058 TI - Immediate post-operative hypersensitivity reaction to Cetuximab in patients preoperatively treated by the monoclonal antibody: what's wrong? PMID- 22103059 TI - Advanced adenocarcinoma in a laterally spreading adenoma within a colonic diverticulum, followed-up for 4 years. PMID- 22103060 TI - Gallbladder involvement of diffuse large B-cell lymphoma mimicking gallbladder carcinoma. PMID- 22103061 TI - A tight esophageal stricture secondary to a misplaced band and its management. PMID- 22103062 TI - Ectopic pancreas mimicking submucosal gastric tumor. PMID- 22103063 TI - Graphene synthesis and band gap opening. AB - Graphene-the wonder material has attracted a great deal of attention from varied fields of condensed matter physics, materials science and chemistry in recent times. Its 2D atomic layer structure and unique electronic band structure makes it attractive for many applications. Its high carrier mobility, high electrical and thermal conductivity make it an exciting material. However, its applicability cannot be effectively realised unless facile techniques to synthesize high quality, large area graphene are developed in a cost effective way. Besides that a great deal of effort is required to develop techniques for modifying and opening its band structure so as to make it a potential replacement for silicon in future electronics. Considerable research has been carried out for synthesizing graphene and related materials by a variety of processes and at the same time a great deal of work has also taken place for manipulating and opening its electronic band structure. This review summarizes recent developments in the synthesis methods for graphene. It also summarizes the developments in graphene nanoribbon synthesis and methods to open band gap in graphene, in addition to pointing out a direction for future research and developments. PMID- 22103064 TI - Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti cancer drug paclitaxel according to preclinical assessment. AB - Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel. PMID- 22103065 TI - Intracellular delivery of etoposide loaded biodegradable nanoparticles: cytotoxicity and cellular uptake studies. AB - The preferred delivery systems for anticancer drugs would be the one which would have selective and effective destruction of cancer cells. In the present study etoposide (ETO) loaded nanoparticles (NP) were prepared using PLGA (ETO-PLGA NP), PLGA-MPEG block copolymer (ETO-PLGA-MPEG NP) and PLGA-Pluronic copolymer (ETO PLGA-PLU NP) and they were evaluated for cytotoxicity and cellular uptake studies using two cancer cell lines, L1210 and DU145. The IC50 values for L1210 cells were 18.0, 6.2, 4.8 and 5.4 microM and for DU145 cells the IC50 values were 98.4, 75.1, 60.1 and 71.3 microM for ETO, ETO-PLGA NP, ETO-PLGA-MPEG NP and ETO-PLGA PLU NP respectively. The increased cytotoxicities were attributed to increased uptake of the NPs by the cells. Moreover the ETO loaded PLGA-MPEG NP and PLGA Pluronic NP showed a sustained cytotoxic effect till 5 days on both the cell lines. Results of the long term cytotoxicity study concluded that the drug loaded PLGA nanoparticulate formulations were efficient in decreasing the viability of the L1210 cells over a period of three days, whereas the pure drug exerted its maximum efficiency on the day one itself. Z-stack confocal images of NPs showed fluorescence activity in each section of DU 145 and L1210 cells indicating that the nanoparticles were internalized by the cells. The study concluded that ETO loaded PLGA NPs had higher cytotoxicity compared with that of the free drug and ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP had higher cell uptake efficiency compared with that of ETO-PLGA NP. The developed PLGA based NPs shows promise to be used for cancer therapy. PMID- 22103066 TI - Carbon-Pt nanoparticles modified TiO2 nanotubes for simultaneous detection of dopamine and uric acid. AB - The present work describes sensing application of modified TiO2 nanotubes having carbon-Pt nanoparticles for simultaneous detection of dopamine and uric acid. The TiO2 nanotubes electrode was prepared using anodizing method, followed by electrodeposition of Pt nanoparticles onto the tubes. Carbon was deposited by decomposition of polyethylene glycol in a tube furnace to improve the conductivity. The C-Pt-TiO2 nanotubes modified electrode was characterized by cyclic voltammetry and differential pulse voltammetry methods. The modified electrode displayed high sensitivity towards the oxidation of dopamine and uric acid in a phosphate buffer solution (pH 7.00). The electro-oxidation currents of dopamine and uric acid were linearly related to the concentration over a wide range of 3.5 x 10(-8) M to 1 x 10(-5) M and 1 x 10(-7) M to 3 x 10(-5) M respectively. The limit of detection was determined as 2 x 10(-10) M for dopamine at signal-to-noise ratio of 3. The interference of uric acid was also investigated. Electro-oxidation currents of dopamine in the presence of fix amount of uric acid represented a linear behaviour towards successive addition of dopamine in range of 1 x 10(-7) M to 1 x 10(-5) M. Furthermore, in a solution containing dopamine, uric acid and ascorbic acid the overlapped oxidation peaks of dopamine and ascorbic acid could be easily separated by using C-Pt-TiO2 nanotubes modified electrode. PMID- 22103067 TI - Development and evaluation of nanostructured lipid carriers of cytarabine for treatment of meningeal leukemia. AB - Lipid matrix based carriers are able to provide sustained release, increase the drug transport into cancer cells and overcome the drug resistance. Therefore, nanostructured lipid carriers (NLC) were prepared and coated with polysorbate 80 to overcome the blood brain barrier for achieving effective treatment of meningeal leukemia. NLC were prepared by melt emulsification followed by ultrasonication, producing particles of 90.7 +/- 4.28 nm size with appreciable amount of drug entrapment (49.5 +/- 2.24%), considering the hydrophilic nature of the drug. The polysorbate 80 coated cytarabine loaded NLC (Cyt-NLC) thus produced were non-aggregated and had almost spherical, smooth and uniform shape. Results of DSC and XRD studies indicated that Cyt was entrapped inside the lipid as molecular dispersion. In-vitro release pattern showed initial fast release (15.87 +/- 1.524% in 1 h) followed by sustained release upto 72 h (89.90 +/- 1.11%). In vitro cell line studies demonstrated that blank NLC showed no significant cytotoxic effects on leukemic EL-4 cells whereas Cyt-NLC exhibited concentration dependent cytotoxicity. At 48 and 72 h, cytotoxicity of Cyt-NLC was found to be significantly more than that of Cyt solution and the percentage cell viability decreased with increasing concentration of Cyt-NLC. The lyophilized Cyt-NLC formulation was found to be stable with respect to size and total drug content at refrigerated condition (2-8 degrees C) for 3 months. These results suggest that polysorbate 80 coated Cyt-NLC can be explored for treatment of meningeal leukemia owing to their ability of sustained drug release and improved cytotoxic effect in leukemic EL-4 cell line. PMID- 22103068 TI - Zinc oxide nanorods modified indium tin oxide surface for amperometric urea biosensor. AB - ZnO nanorods (ZnONR) grown onto indium-tin-oxide (ITO) coated glass surface using zinc nitrate hexahydrate/hexamethylenetetramine (HMT) in aqueous phase has been utilized for urea biosensor. Urease (Urs) was immobilized onto ZnONR/ITO at physiological pH via electrostatic interactions between Urs and ZnO to fabricate Urs/ZnONR/ITO bioelectrode. ZnONR/ITO electrode has been characterized using XRD, FE-SEM techniques and Urs/ZnONR/ITO bioelectrode using electrochemistry. The XRD and FE-SEM measurements confirm the formation of ZnO nanorods in wurtzite structure. Cyclic voltammetric and amperometric measurements on the Urs/ZnONR/ITO biolectrode for urea concentrations in the range of 1-20 mM reveal 0.4 microA mM( 1) sensitivity, with a response time of 3 seconds, and a detection limit of 0.13 mM. The Michaelis-Menten constant (Km) was calculated to be 9.09 mM. Results indicate that ZnO nanorods provide suitable microenvironment for urease immobilization and can be utilized in biosensor design and other biological applications. PMID- 22103069 TI - Bimodal mesoporous silicas functionalized with different level and species of the amino groups for adsorption and controlled release of aspirin. AB - The synthesis of modified bimodal mesoporous materials (BMMs) with a small pore size of around 2.9 nm and a large pore size of about 20 nm has been performed via post-grafting methods. To study the application of functionalized BMMs in drug delivery, loading and releasing profiles using aspirin as model drug were carried out. XRD, SEM, TEM, N2 adsorption, FT-IR, 29Si-NMR, TG and UV-Vis spectroscopy were used to characterize the related samples. The post-grafting modification was performed through the weak chemical interaction or hydrogen bonding in between OH groups of the mesopore surface and 3-aminopropyltriethoxysilane (N-TES) or 3-(2 aminoethylamino) propyItrimethoxysilane (NN-TES). The results showed that N-TES groups with different amount and NN-TES groups were successfully incorporated onto the mesopore surface. Subsequently, the controlled aspirin delivery properties from the resulting modified BMMs were investigated in detail. The aspirin adsorption experiments indicated that the adsorption capacities of modified BMMs were improved with the increasing amount of N-TES groups, while the NN-TES functionalized samples showed higher adsorption capacity than N-TES modified samples with the same ratio of modification. The most reason is that the interaction between the NN-TES groups and aspirin molecules is stronger than that between the N-TES groups and aspirin molecules. The in vitro tests exhibited that aspirin release behaviors mainly depended on the variation of the amount and species of the functional groups in mesoporous carries. According to the Korsmeyer-Peppas model, it is found that the kinetic release constant k reduced with the increase amount of the amino groups on the mesopore surface of modified BMMs, suggesting that the aspirin release rate from the pores of BMMs was influenced directly by organic groups on the surface. The release exponent n of all the situations were above 0.5, indicating the drug release mechanism followed a non-Fickian model that was diffusion based. Therefore, this type of materials described in this paper is of strong potential for the controlled drug release applications. PMID- 22103070 TI - Role of alumina nanoporosity in acute cell response. AB - This work studied the effect of nanoporous alumina in acute cellular response in an in vivo model. Nanoporous alumina membranes, with pore size diameters of 20 and 200 nm, were fabricated by anodic oxidation of aluminium. The membranes were thereafter characterized in terms of pore size distribution and chemical composition. To evaluate acute inflammatory response, the membranes were implanted in the peritoneal cavity of mice. Cell recruitment to the implant site was determined by fluorescence activated cell sorting (FACS) analysis. Cell adhesion to material surfaces was studied in terms of cell number, type, and morphology using scanning electron microscopy (SEM) and immunocytochemical staining followed by fluorescence microscopy. The fabricated nanoporous alumina membranes were found to have narrow pore size distribution. The in vivo study showed that 200 nm alumina membranes induced stronger inflammatory response than 20 nm membranes. This was reflected by the number of implant-associated phagocytes and the number of cells recruited to the implantation site. Since both pore-size membranes possess similar chemical composition, we believe that the observed difference in cell recruitment and adhesion is an effect of the material nanotopography. Our results suggest that nanotopography can be used to subtly control the recruitment and adherence of phagocytic cells during the acute inflammatory response to alumina membranes. PMID- 22103071 TI - Toward preserving the structure of the antigenic peptide p17-1 from the HIV-1 p17 protein in nanostructured films. AB - Antigenic peptides may be immobilized in nanostructured films in order to build highly specific immunosensors and other devices that require molecular recognition, with no need to use complex molecules. A major challenge for such endeavors, however, is to preserve the secondary structure of the peptides after immobilization. In this study, we show that the peptide p17-1 (LSGGELDRWEKIRLRPGG), derived from the HIV-1 p17 protein, may be immobilized in Layer-by-Layer (LbL) films made with polyelectrolytes. Its structure was preserved only if incorporated into phospholipid liposomes, according to fluorescence and circular dichroism (CD) spectroscopy. The lack of secondary structure for the peptide in the LbL film may be associated with the film-forming procedure in which p17-1 was adsorbed from an aqueous solution, where it does not form alpha helices. The importance of structure preservation was clear in the attempts to produce electrochemical immunosensors with the p17-1 peptide without being protected in liposomes in an LbL film. There was no detectable influence of the presence of anti-p17 antibodies, though some molecular interaction could be inferred from the voltammograms. In contrast, for p17-1 incorporated in liposomes electrochemical immunosensors could be obtained with the voltamogramms showing strong molecular recognition with the antibodies. These results indicated that phospholipids serve as a suitable matrix for immobilization of peptides, and confirmed the importance of structure preservation in electrochemical immunosensors. PMID- 22103072 TI - Cathodic stripping synthesis and cytotoxity studies of glutathione-capped CdTe quantum dots. AB - A cathodic stripping of Te precursor in the presence of Cd2+ and biocompatible glutathione (GSH) was reported for facile synthesis of lowly cytotoxic and highly luminescent CdTe quantum dots (QDs) in aqueous solution. The photoluminescence, electrogenerated chemiluminescence (ECL), toxicity, and cyto-osmosis of the QDs were evaluated to reveal their potential bio-applications. The morphology and composition of as-prepared QDs were investigated by HRTEM and powder XRD spectroscopy, which indicated that the QDs consisted of a CdTe core coated with a CdS shell. The obtained CdTe/CdS core/shell QDs possessed good crystallinity, narrow monodispersity and long-term stability. These QDs showed high fluorescence quantum yields of 49% to 63% over a broad spectral range of 540-650 nm. Efficient and stable ECL of QDs was observed on the anodic potential region upon the electrode potential cycled between 1.5 and -2.0 V versus Ag/AgCl. Furthermore, human liver cancer HepG2 cells were chosen as model cells for toxicity assay of QDs. Effects of the concentration, size, and incubation time of CdTe QDs capped with GSH or mercaptoacetic acid (MAA) on the cell metabolic viability and cyto osmosis were evaluated. GSH-capped CdTe QDs could infiltrate cytomembrane and karyothecas, and were less cytotoxic than MAA-capped ones under the same experimental conditions. The reported CdTe QDs could be good candidates of fluorescent and ECL probes for biosensing and cell imaging. PMID- 22103073 TI - The synergistic effect of aligned nanofibers and hyaluronic acid modification on endothelial cell behavior for vascular tissue engineering. AB - The endothelialization of tissue-engineered vascular grafts (TEVGs) is considered to be an effective strategy to prevent the coagulation and restenosis of small diameter vascular grafts. In this study, we fabricated well aligned nanofibrous scaffolds with PCL using a high speed rotating collector, modified those surfaces with hyaluronic acid (HA) and studied the synergistic effect of the scaffolds on the endothelial cells behavior in vitro. The well-aligned oriented architecture was observed by SEM images in the nanofibrous scaffolds. The contact angle measurements and FTIR-ATR evidenced that HA was successfully modified on the PCL nanofibrous scaffolds and hydrophilicity of the scaffolds was increased after HA coating. The results of adhesion and morphology of human umbilical vein endothelial cells (HUVECs) showed that the HA-coating aligned PCL (HA-aPCL) nanofibrous scaffolds could highly promote attachment and guide HUVECs bipolar spread with the parallel aligned nanofibers. Furthermore, HUVECs on the HA-aPCL formed a confluent monoendothelial cell layer and exhibited superior protein expression levels of von Willebrand factor (vWF). This study suggested that the combination of aligned nanostructure and HA modification was more capable of promoting the regeneration of functional endothelium for vascular tissue engineering than individual use. PMID- 22103074 TI - Converted growth mechanism and photoluminescence of Tb3+ doped YBO3 micropancakes and NaYF4 nanorods synthesized from the identical precursor. AB - YBO3 micropancakes and NaYF4 nanorods were synthesized through a two-step hydrothermal chemical conversion route. The uniform sheetlike yttrium precursor was first hydrothermally prepared. Well-crystallized YBO3 and NaYF4 were then obtained at the expense of the precursor. The two steps were both carried out in aqueous conditions without any template, surfactant, or catalyst. The formation mechanisms of our samples are both governed by the dissolution-recrystallization. During the recrystallization, oriented attachment attributes most to the final morphology of our products. We have investigated the relation between their growth habits and inherent crystal structures in detail for the first time and the results afford some guidance for the green synthesis of other inorganic nano /micro-materials with specific morphology. We have also investigated the luminescence properties of Tb3+ doped YBO3 and NaYF4, which preserved the same morphology as the undoped samples. PMID- 22103075 TI - One-step preparation of FeCo nanoparticles in a SBA-16 matrix as catalysts for carbon nanotubes growth. AB - Nanocomposites containing FeCo alloy nanoparticles dispersed in a highly ordered 3D cubic Im3m mesoporous silica (SBA-16) matrix were prepared by a novel, single step templated-assisted sol-gel technique. Two different approaches were used in the synthesis of nanocomposites; a pure SBA-16 sample was also prepared for comparison. Low-angle X-ray diffraction, transmission electron microscopy and N2 physisorption at 77 K show that after metal loading, calcination at 500 degrees C and reduction in H2 flux at 800 degrees C the nanocomposites retain the cubic mesoporous structure with pore size not very different from the pure matrix. X ray absorption fine structure (EXAFS) analysis at Fe and Co K-edges demonstrates that the FeCo nanoparticles have the typical bcc structure. The final nanocomposites were tested as catalysts for the production of carbon nanotubes by catalytic chemical vapour deposition and high-resolution TEM shows that good quality multi-walled carbon nanotubes are obtained. PMID- 22103076 TI - Salts responsive nanovesicles through pi-stacking induced self-assembly of backbone modified tripeptides. AB - A set of backbone modified peptides of general formula Boc-Xx-m-ABA-Yy-OMe where m-ABA is meta-aminobenzoic acid and Xx and Yy are natural amino acids such as Phe, Gly, Pro, Leu, Ile, Tyr and Trp etc., are found to self-assemble into soft nanovesicular structures in methanol-water solution (9:1 by v/v). At higher concentration the peptides generate larger vesicles which are formed through fusion of smaller vesicles. The formation of vesicles has been facilitated through the participation of various noncovalent interactions such as aromatic pi stacking, hydrogen bonding and hydrophobic interactions. Model study indicates that the pi-stacking induced self-assembly, mediated by m-ABA is essential for well structured vesicles formation. The presence of conformationally rigid m-ABA in the backbone of the peptides also helps to form vesicular structures by restricting the conformational entropy. The vesicular structures get disrupted in presence of various salts such as KCI, CaCl2, N(n-Bu)4Br and (NH4)2SO4 in methanol-water solution. Fluorescence microscopy and UV studies reveal that the soft nanovesicles encapsulate organic dye molecules such as Rhodamine B and Acridine Orange which could be released through salts induced disruption of vesicles. PMID- 22103077 TI - Enhancement in insulation and mechanical properties of PMMA nanocomposite foams infused with multi-walled carbon nanotubes. AB - In this study, PMMA/CNTs composite materials with carboxyl-multi walled carbon nanotubes (c-MWNTs) or untreated MWNTs were prepared via in-situ bulk polymerization. The as-prepared PMMA/CNTs composite materials were then characterized by Fourier-Transformation infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). The molecular weights of PMMA extracted from PMMA/CNTs composite materials and bulk PMMA were determined by gel permeation chromatography (GPC) with THF used as the eluant. The PMMA/CNTs composite materials were used to produce foams by a batch process in an autoclave using nitrogen as foaming agent. The cellular microstructure, insulation and compressive mechanical properties of PMMA/CNTs composite foams were also investigated in detail. Compared to neat PMMA foam, the presence of CNTs increases in cell density and reduces cell size. The insulation and compressive mechanical properties of PMMA/CNTs composite foams were found to improve substantially those of neat PMMA foam. In particular, 22.6% decrease in thermal conductivity, 19.7% decrease in dielectric constant and 160% increase in compressive modulus were observed with the addition of 0.3 wt% carboxyl-multi walled carbon nanotubes (c-MWNTs). PMID- 22103078 TI - Morphologies and luminescence properties of SrZnO2 microstructure. AB - The SrZnO2 of beardlike and sheetlike nanobundles, rod and treelike nanostructures have been synthesized by a citrate-gel combusting synthesis approach. As-prepared SrZnO2 shows orthorhombic structure with Pnma space group and unit cell with the lattice parameters: a = 5.830 A, b = 3.340 A and c = 11.348 A. By increasing the sintering temperature, the beardlike nanobundle gradually dissolved to form microrods and treelike microstructure. Citrate acid exerts a major influence in directing the formation of these unique SrZnO2 microstructures. These materials were analyzed for their use to luminescence materials. The as-made samples exhibit an efficient absorption and excitation band in the UV spectral region (centered at 380 nm). In the same time, the samples of with different morphologies showed a broad yellow emission peak centered at approximately 545 nm which should been associated with the composition and morphologies of sample or from the oxygen vacancies of semiconductor SrZnO2. The material may be used as novel conversion phosphors or host material of phosphor for white-light LEDs. PMID- 22103079 TI - Preparation and tunable luminescent characteristics of SiO2 coated ZnO:LiAc nanoparticles. AB - ZnO:LiAc nanopaticles were successfully synthesized though a colloidal-sol technique in nonaqueous solution under ultrasonic irradiation. The luminescent characteristics from blue to red can be tunable by varying [Li]/[Zn] ratios. The possible reason of tunable luminescent characteristics can be attributed to the increase of density of oxygen vacancies caused by Li+ adsorbed in the surface of magic-sized ZnO nanocrystals based on XRD, zeta potential and XPS results. What's more, it is found that SiO2 shell coated on ZnO:LiAc nanoparticles can improve the surface property of ZnO nanoparticles and enhance the PL emission intensity and optical stability. Due to its excellent luminescent characteristic and optical stability, as-prepared SiO2 coated ZnO:LiAc nanoparticles may be a promising candidate for some applications in high-efficiency low-voltage phosphor, solar cells and biological luminescent labels. PMID- 22103080 TI - Synthesis and characterization of waterborne polyurethane/Cu(II)-loaded hydroxyapatite nanocomposites with antibacterial activity. AB - A novel kind of environmentally friendly nanocomposites, waterborne polyurethane (WBPU)/Cu(II)-loaded hydroxyapatite (CuHAp), with improved physical properties and antibacterial activity have been prepared via in-situ polymerization from functionalized CuHAp nanoparticles (CuHAp NPs). The interaction of the CuHAp NPs with isophorone diisocyanate to form the functionalized CuHAp NPs containing isocyanate groups (CuHAp-g-NCO) has been studied. The microstructure and particle distribution of the nanocomposites were observed using scanning electron microscopy. The improvements of mechanical properties, thermal stability and water resistance of the nanocomposites have also been evaluated. Finally, the antibacterial activity was tested against G(-) Escherichia coli and G(+) Staphylococcus aureus by the zone of inhibition test and the direct contact test. The long-lasting antibacterial activity was studied by measuring antibacterial ability of the nanocomposites after being immersed in water. The results indicate that WBPU incorporation with CuHAp NPs shows strong antibacterial activity upon contact, and long-lasting antibacterial property. PMID- 22103081 TI - Electrical conductivity measurements of nanofluids and development of new correlations. AB - In this study the electrical conductivity of aluminum oxide (Al2O3), silicon dioxide (SiO2) and zinc oxide (ZnO) nanoparticles dispersed in propylene glycol and water mixture were measured in the temperature range of 0 degrees C to 90 degrees C. The volumetric concentration of nanoparticles in these fluids ranged from 0 to 10% for different nanofluids. The particle sizes considered were from 20 nm to 70 nm. The electrical conductivity measuring apparatus and the measurement procedure were validated by measuring the electrical conductivity of a calibration fluid, whose properties are known accurately. The measured electrical conductivity values agreed within +/- 1% with the published data reported by the manufacturer. Following the validation, the electrical conductivities of different nanofluids were measured. The measurements showed that electrical conductivity of nanofluids increased with an increase in temperature and also with an increase in particle volumetric concentration. For the same nanofluid at a fixed volumetric concentration, the electrical conductivity was found to be higher for smaller particle sizes. From the experimental data, empirical models were developed for three nanofluids to express the electrical conductivity as functions of temperature, volumetric concentration and the size of the nanoparticles. PMID- 22103082 TI - Study on adsorption of Co(II) and Ni(II) onto mesoporous Ti-containing MCM-48. AB - Ti-containing MCM-48 (Ti-MCM-48) material with mesoporous structure was synthesized and characterized, and the absorption processes of Co(II) and Ni(II) on the material were investigated in detail in the present study. The Ti- MCM-48 was synthesized by hydrothermal reaction and characterized by XRD, FT-IR and nitrogen sorption methods. Optimum pH value for maximum adsorption rate is 8.0, and the saturated adsorption capacities of Ti-MCM-48 for Co(II) and Ni(II) are 9.870 and 22.94 mg g(-1) respectively, which are greater than those of the reported materials Adsorption isotherms of Co(II) and Ni(II) on Ti-MCM-48 accord well with the Langmuir adsorption models. Kinetic data of adsorption reactions and the adsorption equilibrium parameters were also determined, and the obtained data correlated linearly with the pseudo-second order equation. PMID- 22103083 TI - Self-assembled InAs/GaAs quantum dots covered by different strain reducing layers exhibiting strong photo- and electroluminescence in 1.3 and 1.55 microm bands. AB - The effect of different InGaAs and GaAsSb strain reducing layers on photoluminescence and electroluminescence from self-assembled InAs/GaAs quantum dots grown by metal-organic vapour phase epitaxy was investigated. The aim was to shift their luminescence maximum towards optical communication wavelengths at 1.3 or 1.55 microm. Results show that covering by InGaAs strain reducing layer provides stronger shift of photoluminescence maximum (up to 1.55 microm) as compared to GaAsSb one with similar strain in the structure. This is caused by the increase of quantum dot size during InGaAs capping and reduction of quantum confinement of the electron wave function which spreads into the cap. Unfortunately, the weaker electron confinement in quantum dots is a reason of a considerable blue shift of electroluminescence from these InGaAs structures since optical transitions move to InGaAs quantum well. Although strong electroluminescence at 1300 nm was achieved from quantum dots covered by both types of strain reducing layers, the GaAsSb strain reducing layer is more suitable for long wavelength electroluminescence due to higher electron confinement potential allowing suppression of thermal carrier escape from quantum dots. PMID- 22103084 TI - Synthesis of blue fluorescence CdS quantum dots stabilized by L-cysteine in aqueous phase. AB - In this paper we report a novel synthesis method of blue fluorescence CdS quantum dots stabilized by L-cysteine in aqueous phase. When pH value of the core/shell CdTe/CdS colloid solution changed from 11.6 to 1.5, blue fluorescence CdS QDs was obtained. The fluorescence emission wavelength yielded a hypsochromic shift from 540 nm to 438 nm corresponding to the absorption peak position gave a hypsochromic shift from 518 nm to 352 nm. The CdS QDs were characterized by XPS and TEM. And the photostability of CdS QDs solution irradiated with UV lamp under open air condition at room temperature was very stable. PMID- 22103085 TI - Humidity sensing performance of in-situ fabricated Cu/Cu2O/Cu2S-polymer nanocomposite via polyphenylene sulphide cyclisation route. AB - We herein report the feasibility of novel polymer-inorganic solid state reaction route for simultaneous in situ generation of Cu2S and Cu nanostructures in polymer network. Polyphenylene Sulphide (PPS) which is engineering thermoplastic acts as chalcogen source as well as stabilizing matrix for the resultant nano products. Typical solid state reaction was accomplished by simply heating the physical admixtures of the two reactants i.e., copper acetate and PPS by varying molar ratios mainly 1:1, 1:5, 1:10, 1:15, 1:20 at the crystalline melting temperature (285 degrees C) of PPS. The synthesized products were characterized using various physicochemical characterization techniques like X-ray Diffractometry, Field emission Scanning Electron Microscopy, Transmission Electron Microscopy, UV-Visible spectroscopy and X-ray photoelectron spectroscopy. The prima facie observations suggest occurrence of nanocrystalline Cu2S in case of product obtained with equimolar ratio, whereas remaining samples show mixture of Cu and Cu2O. The TEM analysis reveals nanoscale polydispersity (5 60 nm) and prevalence of mainly spherical morphological features in all the cases with occasional indications of plate like and cubical morphological features depending upon the molar ratio of the reactants. The humidity sensing characterization of these nanocomposites was also performed. The resistivity response with the level of humidity (20 to 70% RH) was compared for these nanocomposites. The linear response is obtained for all the samples. The sensitivity of 1:1 molar ratio sample was found to be maximum among all the samples. PMID- 22103086 TI - Morphological control of porous SiC templated by As-synthesized form of mesoporous silica. AB - Porous silicon carbide with fiber like morphology was successfully prepared via a hard templating approach using as-synthesized form of mesoporous silica SBA-15 as template and sucrose as carbon precursor. The obtained materials have been characterized by various sophisticated techniques such as XRD, nitrogen adsorption, HRTEM, HRSEM, FT-IR and TGA. The XRD and the nitrogen adsorption results revealed that the materials are highly crystalline and exhibit porous structure with excellent textural characteristics. It has been demonstrated that the morphology of the materials can be finely controlled from rod shaped morphology to fiber like nanostructures by the simple adjustment of the reaction time from 5 to 12 h at the reaction temperature of 1300 degrees C. The reaction time of 12 h at 1300 degrees C was found to be the best condition to obtain highly crystalline nanofiber like morphology. The obtained materials display beautiful nanofiber morphology which has the diameter of 20 to 60 nm and a length of 7 to 10 microm which is much longer than the previously reported SiC nanofibers. PMID- 22103087 TI - Deep level transient spectroscopy of hole traps related to CdTe self-assembled quantum dots embedded in ZnTe matrix. AB - The capacitance-voltage (C-V) and deep level transient spectroscopy (DLTS) measurements have been made on a Schottky Ti-ZnTe (p-type) diode containing CdTe self-assembled quantum dots (QD) and control diode without dots. The C-V curve of the QD diode exhibits a characteristic step associated with the QD states whereas the reference diode shows ordinary bulk behavior. A quasistatic model based on the self-consistent solution of the Poisson's equation is used to simulate the capacitance. By comparison of the calculated C-V curve with the experimental one, hole binding energy at the QD states is found to be equal about 0.12 eV. The results of DLTS measurements for the sample containing QDs reveal the presence of a low-temperature peak which is not observed for the control diode. Analysis of its behavior at different bias conditions leads to the conclusion that this peak may be related to the hole emission from the QD states to the ZnTe valence band. Its thermal activation energy obtained from related Arrhenius plot equals to 0.12 eV in accordance with the energy obtained from the Poisson's equation. Thus based on the C-V and DLTS studies it may be concluded that the thermal activation energy of holes from the QD states to the ZnTe valence band in the CdTe/ZnTe QD system is equal about 0.12 eV. PMID- 22103088 TI - Charge storage characteristics of silicon nanoclusters in silicon nitride matrix grown by laser assisted chemical vapor deposition method. AB - The capacitance-voltage (C-V) and charge retention characteristics of the metal insulator-semiconductor (MIS) structure, in which the insulator layer was composed of silicon nanocluster-embedded silicon nitride, were studied. The memory effect of this MIS structure was dominantly attributed to the charge storage in the silicon nanoclusters. The relation between the flatband voltage shift and the amount of charges stored in the nanocluster-embedded insulator layer was discussed. The capacitance-time (C-t) relation of MIS structures, conventionally used to follow the discharge process, was further analyzed, indicating that care should be taken in the C-t measurement for obtaining correct discharging behavior. Then the charge retention characteristics of the fabricated MIS structures under various charging conditions were derived by the capacitance time (C-t) measurement. The results showed that the devices, charged for a longer time or under a lower charging voltage, discharge slower. The observed charge retention behaviors can be reasonably attributed to the spatial distribution of silicon nanoclusters in the silicon nitride layer and the dispersion of the nanocluster sizes PMID- 22103089 TI - Controlled nanostructuring of Ag films by ion beam sputter deposition for surface plasmon resonance applications. AB - The growth of Ag nanostrucutres on borosilicate glass substrates by ion beam sputter deposition in the Ar ion energy range from 150 to 600 eV is demonstrated. Rates of deposition as low as 0.01 nm/s are achieved at an Ar ion energy of 150 eV. This leads to the formation of a random array of nearly spherical Ag particles with a mean size of approximately 100 nm, separated by distances of similar order of magnitude. The particles organize themselves into arrays over lengths of at least 10 microm. As the thickness is increased from 3 to 18 nm there is a transition in morphology from an array to linear chains and finally a dense continuous film. There is a similar microstructural evolution as a function of increasing ion energy. The plasmon resonances can be tuned depending on shape, size and interparticle distances. As the thickness of the films increase, the main plasmon peaks can be tuned from 380 to 680 nm. The spheroidal shape of the particles induces additional peaks (localized surface plasmons) centered around 430 +/- 10 nm. Detailed simulations have been carried out based on Maxwell Garnett theory to distinguish the effects of shape and size on plasmon resonances. It is demonstrated that shape rather than the size of the particles has a stronger influence on the shift in plasmon resonances. PMID- 22103090 TI - Electrorheological analysis of colloidal dispersions of aluminum oxide and silicone oil. AB - The electrorheological properties of colloidal dispersions of aluminum oxide nanotubes and nanoparticles in silicone oil were investigated. The shear storage modulus of colloidal dispersions containing 5 wt% of aluminum oxide nanotubes increased by four orders of magnitude upon the application of an external electric field of as low as 400 V/mm. The storage modulus of the nanotube systems increased further by increasing the concentration of nanotubes. The electrorheological response of aluminum oxide nanoparticles dispersions was significantly lower than that of the dispersions containing the same weight fraction of aluminum oxide nanotubes at the same external electric field. This result reflects the effect of shape anisotropy on the electrorheological features of colloidal dispersions. PMID- 22103091 TI - Environmentally stable flexible metal-insulator-metal capacitors using zirconium silicate and hafnium-silicate thin film composite materials as gate dielectrics. AB - Fully flexible metal-insulator-metal (MIM) capacitors fabricated on 25 microm thin polyimide (PI) substrates via the surface sol-gel process using 10-nm-thick zirconium-silicate (ZrSixOy) and hafnium-silicate (HfSimOn) films as gate dielectrics. The surface morphology of the ZrSixOy and HfSimOn films were investigated using atomic force microscopy and scanning electron microscopy, which confirmed that continuous and crack-free surface growth had occurred on the PI. Both the films treated with oxygen (O2) plasma and annealing (ca. 250 degrees C) consisted of amorphous phase; confirmed by X-ray diffraction. We employed X ray photoelectron spectroscopy (XPS) at high resolution to examine the chemical composition of the films subjected to various treatment conditions. The shift of the XPS peaks towards higher binding energy revealed the O2 plasma-pretreatment followed by annealing was the most effective process to the surface oxidation at relatively low-temperature, for further passivate the grease traps and making dielectric films thermally stable. The ZrSixOy and HfSimOn films in sandwich-like MIM configuration on the PI substrates exhibited the low leakage current densities of 7.1 x 10(-9) and 8.4 x 10(-9) A/cm2 at applied electric field of 10 MV/cm and maximum capacitance densities of 7.5 and 5.3 fF/microm2 at 1 MHz, respectively. In addition, the ZrSixOy and HfSimOn films in MIM capacitors showed the estimated dielectric constants of 8.2 and 6.0, respectively. Prior to use of flexible MIM capacitors in advanced flexible electronic devices; the reliability test was studied by applying day-dependent leakage current density measurements up to 30 days. These films of silicate-surfactant mesostructured materials have special interest to be used as gate dielectrics in future for flexible metal oxide-semiconductor devices. PMID- 22103092 TI - Calcium carbonate nanoparticles: synthesis, characterization and biocompatibility. AB - The synthesis of nanoparticles and their functionalization to effectively utilize them in biological applications including drug delivery is currently a challenge. Calcium carbonate among many other inorganic nanosized particles offers promising results for such applications. We have synthesized calcium carbonate nanoparticles using polymer mediated growth technique, where one of the ions bound within polymer matrix and the other diffuses and reacts to form desired compound. The synthesized nanoparticles are characterized using X-ray diffraction, Scanning Electron Microscopy and spectroscopic techniques such as Fourier-Transform Infra-red spectroscopy and UV-Vis spectroscopy. The diameter of the calcium carbonate nanoparticles is estimated to be 39.8 nm and their biocompatibility studies showed no significant induction of oxidative stress or cell death even at higher concentrations (50 microg) upon exposure to HeLa and LE cells. Here, we report that the synthesized calcium carbonate nanosized particles using polymer mediated growth technique are biocompatible and can be safely used for biomedical applications. PMID- 22103093 TI - General synthesis route to fabricate uniform upconversion luminescent gadolinium oxide hollow spheres. AB - Uniform upconversion luminescent gadolinium oxide hollow spheres were successfully synthesized via a homogeneous precipitation method with carbon spheres as template followed by a calcination process. During the annealing process, the carbon spheres template can be effectively removed and the amorphous precursor has converted to crystalline Gd2O3, which can be confirmed by the XRD and TG-DSC analysis. SEM and TEM images indicate that the Gd2O3 hollow spheres with diameters of 300-400 nm are uniform in size and distribution. The rare earth activator ions Ln3+-doped Gd2O3 hollow spheres exhibit intense upconversion luminescence with different colors under 980 nm light excitation, which may find potential applications in the fields such as drug delivery or biological labeling. Moreover, the upconversion luminescent mechanisms of the hollow spherical phosphors were investigated in detail. PMID- 22103094 TI - Growth of high-aspect ratio horizontally-aligned ZnO nanowire arrays. AB - A method of fabricating horizontally-aligned zinc-oxide (ZnO) nanowire (NW) arrays with full control over the width and length is demonstrated. SEM images reveal the hexagonal structure typical of zinc oxide NWs. Arrays of high-aspect ratio horizontal ZnO NWs are fabricated by making use of the lateral overgrowth from dot patterns created by electron beam lithography (EBL). An array of patterned wires are lifted off and transferred to a flexible PDMS substrate with possible applications in several key nanotechnology areas. PMID- 22103095 TI - Photocatalytic properties of silver nanoparticles decorated nanobranched TiO2 nanofibers. AB - In this study, nanobranched TiO2 nanofibers and silver loaded nanobranched TiO2 nanofibers were prepared by electrospinning technique followed by TiCl4 aqueous solution treatment and silver photodeposition method. Field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) were employed to investigate the morphology of the products. X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) were conducted on the samples to study their chemical composition as well as crystallographic structure. The photocatalytic activities of these produced nanofibers were examined with two organic dyes, methylene blue and methyl orange, under ultraviolet (UV) light irradiation. The effect of nanobranches and silver modification on TiO2 nanofibers was revealed in the photocatalysis process. The photocatalytic degradation rates of silver loaded on nanobranched TiO2 nanofibers were 1.6 and 1.7 times as that of pure TiO2 nanofibers in the presence of methylene blue and methyl orange, respectively, which indicated silver nanoparticles combined nanobranches modified on the surface of TiO2 nanofibers could enhance the photocatalytic ability. PMID- 22103096 TI - Design parameters for carbon nanobottles to absorb and store methane. AB - We investigate the internal mechanics for methane storage in a nanobottle, which is assumed to comprise a metallofullerene located inside a carbon nanobottle, which is constructed from a half-fullerene as the base, and two nanotubes which are joined by a nanocone. The interaction potential energy for the metallofullerene is obtained from the 6-12 Lennard-Jones potential and the continuum approximation, which assumes that a discrete atomic structure can be replaced by an average atomic surface density. This potential energy shows that the metallofullerene has two minimum energy positions, which are located close to the neck of the bottle and at the base of the nanobottle, and therefore it may be used as a bottle-stopper to open or to close the nanobottle. At the neck of the bottle, the encapsulated metallofullerene closes the nanobottle, and by applying an external electrical force, the metallofullerene can overcome the energy barrier of the nanotube, and pass from the neck of the nanobottle to the base so that the nanobottle is open. For methane storage, the metallofullerene serves the dual purposes of opening and closing the nanobottle, as well as an attractor for the methane gas. The analytical formulation gives rise to a rapid computational capacity, and enables the direct determination of the optimal dimensions necessary to ensure the correct working function of the nanobottle, and specific ranges for the critical parameters are formulated. PMID- 22103097 TI - Rigid polyurethane foam/cellulose whisker nanocomposites: preparation, characterization, and properties. AB - Novel rigid polyurethane nanocomposite foams have been prepared by the polymerization of a sucrose-based polyol, a glycerol-based polyol and polymeric diphenylmethane diisocyanate in the presence of cellulose whiskers. Varying amounts of sulfuric acid hydrolyzed cellulose whiskers (0.25, 0.50, 0.75 and 1.00 wt%) prepared from a commercial fully bleached softwood kraft pulp were incorporated to investigate the effect of its dosage on the mechanical and thermal properties of polyurethane nanocomposites. Fourier transform infrared spectra of the nanocomposite foams suggested that additional hydrogen bonds were developed and crosslinking occurred between the hydroxyl groups of cellulose whiskers and isocyanate groups which increased the phase separation of soft and hard segments in the polyurethane. The closed cells of control foam and nanocomposite foams were homogeneously dispersed and the cell sizes were approximately 350 microm in diameter as observed by scanning electron microscope. A substantial improvement of mechanical properties at low whisker content (< or = 1.00 wt%) was obtained, especially the compressive strength and modulus at 1.00 wt% whiskers content which were increased by 269.7% and 210.0%, respectively. Thermal stability of the nanocomposites was also enhanced as determined by differential scanning calorimetry and thermogravimetric analysis. PMID- 22103098 TI - Broadband optical absorption enhancement in Au-coated ZnO nanotips. AB - The enhancement of broadband optical absorption in zinc oxide (ZnO) nanotip (NT) arrays coated with evaporated gold (Au) on fluorine-doped SnO2 (FTO)/glass by a simple hydrothermal growth and subsequent Au evaporation is reported. As the core of ZnO NT arrays is gradually coated with evaporated Au, the reflectance is slightly increased at lambda > approximately 800 nm while the transmittance is decreased at lambda approximately 400-1800 nm. For both FTO/glass and ZnO NT arrays on FTO/glass, the coating of Au improves the light absorption due to the antireflective geometry compared to the flat Au films and the absorptance is also enhanced by increasing the nominal thickness of Au with evaporation time. For the ZnO NT arrays with an Au evaporated for 600 s at 0.5 A/s, a high absorptance of >72% is achieved over the wavelength range of 250-2000 nm, indicating a significant increase due to the enhanced antireflection property as well as the increased surface area compared to the Au-coated FTO/glass without ZnO NT arrays. PMID- 22103099 TI - Fabrication of micro-nano structure nanofibers by solvent etching. AB - Micro-Nano structure nanofibrous affinity membranes of poly(ether sulfones) (PES) blended with a functional polymer poly(ethyleneimine) (PEI) were fabricated by electrospinning technique followed by solvent etching in crosslinking solution. The surface SEM image of the water washed PES/PEI nanofibrous membrane confirmed that PEI was concentrated on the fiber surface. The nanofibrous PES/PEI membranes were crosslinked in a mixture of acetone and water with glutaraldehyde (crosslinking agent, GA), and the micro-nano structural surface of the nanofibrous membranes was created by solvent etching due to the solvation between PEI and the solvent water in the crosslinking solution during the crosslinking process. The influence of the component of the crosslinking bath on the mophology of the resulting PES/PEI nanofibers was investigated. It was found that the relatively uniform micro-nano spherules grew on the surface of the nanofibers when the content of water in crosslinking solution was more than 20 wt%, and the diameters of the spherules were in the range of 50-250 nm. The advantage of the micro-nano structrue for the heavy metal ions removal in wastwater has been demonstrated by taking a series of static adsorption experiments. It was found that the micro-nano structrue of PES/PEI nanofibrous membranes could bring high performance of adsorption capacity for heavy metal ions, indicating that the unique morphology could bring much more large surface area per unit mass and high effectivity for heavy metal ions removal from aqueous solutions. PMID- 22103100 TI - Synthesis of continuous mesoporous Ga-doped titania films with anatase crystallized framework. AB - Here we report synthesis of ordered mesoporous titania films with various amounts of Ga content. The influence of Ga contents on mesostructural ordering, surface morphology, thermal stability, and anatase crystallinity is carefully investigated, by using grazing incidence small angle X-ray scattering (GISAXS), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), and Raman spectroscopy. The presence of highly dispersed Ga contents in the titania frameworks can promote the thermal stability of mesoporous titania structures, resulting that the anatase crystallization successfully proceeds without collapse of mesostructures. PMID- 22103101 TI - Fabrication and photoluminescence properties of graphite fiber/ZnO nanorod core shell structures. AB - Graphite fiber/ZnO nanorod core-shell structures were synthesized by thermal evaporation process. The core-shell hybrid architectures were comprised of ZnO nanorods grown on the surface of graphite fiber. In addition, Hollow ZnO hierarchical structure can be obtained by oxidizing the graphite fiber. Room temperature photoluminescence (PL) of the as-made graphite fiber/ZnO nanorod structures shows two UV peaks at around 3.274 eV and 3.181 eV. The temperature dependent photoluminescence spectra demonstrate the two UV emissions are attributed to the intrinsic optical transitions and extrinsic defect-related emissions in ZnO. These hybrid structures may be used as the building block for fabrication of nanodevices. PMID- 22103102 TI - Morphological variations and structural properties of ZnO nanostructures grown by rapid thermal CVD. AB - Various nanostructures of ZnO such as nanowires, sea urchin like and nano needles were grown using rapid thermal chemical vapor deposition technique (RTCVD), in oxygen ambient. For the growth of such structures, oxygen pressure was kept as 0.1 Torr whereas the chamber base pressure was 10(-5) Torr. The growth temperature was varied from 600 degrees C to 850 degrees C, which resulted in morphological variations. X-ray diffraction measurement revealed the hexagonal wurtzite structure of ZnO preferably oriented in [001] direction, which was further confirmed by high-resolution transmission electron microscopic (HRTEM) observations. X-ray photoelectron spectroscopy (XPS) analysis suggests the presence of Zn 2p and O 1s. Raman E2 high peaks at approximately 434 cm(-1) has the highest intensity compared to other modes supports XRD results. Presence of low E2 peaks at approximately 330 cm(-1) indicates defects and oxygen vacancies. PMID- 22103103 TI - Growth time-dependent density and surface evolution of silicon nanowires in a vapor-liquid-solid process. AB - Single crystalline silicon nanowires (SiNWs) were grown on Si(100) substrate using a gold (Au)-catalyzed vapor-liquid-solid (VLS) approach. The dependence of the growth time (i.e., the time of exposure to the Si source) on the density and surface evolution of the grown SiNWs is considered. It was observed that the density of grown SiNWs on Si substrate increased with increasing growth time. The highest density (approximately 1.1 x 10(6) mm(-2)) was reached at 4 hr. Upon further exposure to the Si source, we observed that the density was maintained for up to 9 hr. We suggest that the increased Si chemical potential in Au-Si droplets with increased growth time enhanced the SiNW growth rate at the interfaces between Au-Si droplets and SiNWs, and enhanced the transition of the NWs from the existing Au-Si droplets onto Si substrate. This allows the SiNW density to increase with increased growth time of up to 4 hr. Moreover, we examined the influence of the growth time on surface evolution including Au diffusion, facet and taper formation, and vapor-solid (VS) growth of the SiNWs. To explain the behavior of the grown SiNWs in the VLS process, we propose a combined model using the VLS and VS growth mechanisms. PMID- 22103104 TI - Beta-MnO2/SiO2 core-shell nanorods: synthesis and dielectric properties. AB - Large-scale beta-MnO2/SiO2 core-shell nanorods were synthesized by hydrolysis process. The product was characterized by XRD, EDS, SEM and TEM. The thickness of the SiO2 shell layer is about 3 nm approximately 5 nm, which can be tuned by changing the amount of tetraethyl orthosilicate (TEOS) and the reaction time. The dielectric properties of the synthesized core-shell nanorods at the temperature range from 373 K to 773 K in X-band were investigated in detail and the mechanism of the dielectric response was discussed. The dielectric loss of the SiO2-coated MnO2 nanorods at 773 K was about twice than that at 373 K. The high dielectric loss is mainly attributed to the interfacial polarization and the electromagnetic impedance match between the SiO2 shell layer and MnO2 core layer. The quantitative formula between the permittivity of beta-MnO2/SiO2 core-shell nanorods and the thickness of the SiO2 shell is established, which can be used to tune the dielectric properties of the core-shell nanorods through controlling the thickness of the SiO2 shell layer. PMID- 22103105 TI - Nanocrystalline zinc indium vanadate: a novel photocatalyst for hydrogen generation. AB - Hydrogen is a future fuel and hence production of cheap hydrogen is an important area of research. Recently, the photocatalysts were used to generate hydrogen from water and hydrogen sulfide splitting under solar light. Hence, we designed Zinc Indium Vanadate, a novel visible light active photocatalyst and used for the generation of hydrogen by using solar light. We have demonstrated the synthesis of ZnIn2V2O9 (ZIV) catalyst by sonochemical route using NH4VO3, In (NO3)3 and Zn(CH3COO)2 as a precursors and PVP as a capping agent. The obtained product was further characterized by XRD, UV-DRS and FESEM. The XRD pattern reveals the existence of monoclinic crystal structure and broader peaks indicating the nanocrystalline nature of the material. The particle size was observed in the range of 50-70 nm. The optical study showed the absorption edge cut off at 520 nm with estimated band gap about 2.3 eV. Considering the band gap in visible range, ZnIn2V2O9 was used as a photocatalyst for photodecomposition of H2S under visible light irradiation to produce hydrogen. We observed excellent photocatalytic activity for the hydrogen generation by using this photocatalyst. PMID- 22103106 TI - Fabrication of SiO2@ZrO2@Y2O3:Eu3+ core-multi-shell structured phosphor. AB - ZrO2 interface was designed to block the reaction between SiO2 and Y2O3 in SiO2@Y2O3:Eu coreshell structure phosphor. SiO2@ZrO2@Y2O3:Eu core-multi-shell phosphors were successfully synthesized by combing an LBL method with a Sol-gel process. Based on electron microscopy, X-ray diffraction, and spectroscopy experiments, compelling evidence for the formation of the Y2O3:Eu outer shell on ZrO2 were presented. The presence of ZrO2 layer on SiO2 core can block the reaction of SiO2 core and Y2O3 shell effectively. By this kind of structure, the reaction temperature of the SiO2 core and Y2O3 shell in the SiO2@Y2O3:Eu core shell structure phosphor can be increased about 200-300 degrees C and the luminescent intensity of this structure phosphor can be improved obviously. Under the excitation of ultraviolet (254 nm), the Eu3+ ion mainly shows its characteristic red (611 nm, 5D0-7F2) emissions in the core-multi-shell particles from Y2O3:Eu3+ shells. The emission intensity of Eu3+ ions can be tuned by the annealing temperatures, the number of coating times, and the thickness of ZrO2 interface, respectively. PMID- 22103107 TI - Bonding temperature optimization and property evolution of SU-8 material in metal/adhesive hybrid wafer bonding. AB - Bonding temperature optimization of SU-8 material for metal/adhesive hybrid bonding was investigated. The good bond quality of SU-8 adhesive can be achieved with the bonding temperature between 150 degrees C and 250 degrees C, while bond failures of SU-8 wafers are observed starting from 275 degrees C. IR transmittance spectra measurements indicate the crosslinks inside SU-8 break and further bond failure is observed due to the large decomposition of epoxy rings and phenyl in plane bending above 275 degrees C. This research provides guidelines of material selection and bonding parameters for heterogeneous integration, 3DIC and MEMS applications using metal/adhesive hybrid bonding. PMID- 22103108 TI - Uniformly gold nanoparticles derived from P2VP-b-PCHMA block copolymer templates with different reduction methods. AB - The micellization of poly(2-vinylpyridine)-block-poly(cyclohexyl methacrylate) (P2VP-b-PCHMA) in THF can be induced by the complexation between the P2VP blocks and HAuCl4, forming composite polymeric micelles with PCHMA being the shell and P2VP/HAuCl4 complex being the core. In order to obtain regular arrays of gold nanoparticles (Au NPs), monolayer of HAuCl4-loaded surface micelles have been produced by spin-coating the micellar solution, and Au NPs in different size have been obtained by oxygen plasma with different reduction processes. In addition, pyrole (PY) has been used as an efficient reducing agent to fabricate dispersed Au NPs within micellar structure in a short reducing time, resulting in a raspberry-like morphology of the Au-polymer composites. With the addition of annealing processes or longer reducing time (one month), different shapes of Au NPs have been observed in the cast films. Furthermore, core-shell nanostructures of gold-polypyrole (Au-PPY) have also been observed by employing vapor phase polymerization of PY onto HAuCl4-loaded polymeric solution-cast films. PMID- 22103109 TI - One-dimensional SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrite nanofibers and enhancement magnetic property. AB - SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrite nanofibers of diameters about 100 nm with mass ratio 1:1 have been prepared by the electrospinning and calcination process. The SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrites are formed after calcined at 700 degrees C for 2 hours. The composite ferrite nanofibers are fabricated from nanosized Ni(0.5)Zn(0.5)Fe2O4 and SrFe12O19 ferrite grains with a uniform phase distribution. The ferrite grain size increases from about 11 to 36 nm for Ni(0.5)Zn(0.5)Fe12O4 and 24 to 56 nm for SrFe12O19 with the calcination temperature increasing from 700 to 1100 degrees C. With the ferrite grain size increasing, the coercivity (Hc) and remanence (Mr) for the SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrite nanofibers initially increase, reaching a maximum value of 118.4 kA/m and 31.5 Am2/kg at the grain size about 40 nm (SrFe12O19) and 24 nm (Ni(0.5)Zn(0.5)Fe2O4) respectively, and then show a reduction tendency with a further increase of the ferrite grain size. The specific saturation magnetization (Msh) of 63.2 Am2/kg for the SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrite nanofibers obtained at 900 degrees C for 2 hours locates between that for the single SrFe12O19 ferrite (48.5 Am2/kg) and the single Ni(0.5)Zn(0.5)Fe2O4 ferrite (69.3 Am2/kg). In particular, the Mr value 31.5 Am2/kg for the SrFe12O19/Ni(0.5)Zn(0.5)Fe2O4 composite ferrite nanofibers is much higher than that for the individual SrFe12O19 (25.9 Am2/kg) and Ni(0.5)Zn(0.5)Fe2O4 ferrite (11.2 Am2/kg). These enhanced magnetic properties for the composite ferrite nanofibers can be attributed to the exchange-coupling interaction in the composite. PMID- 22103110 TI - Structure of diglycerol monomyristate reverse micelles in styrene: a small-angle X-ray scattering (SAXS) study. AB - Structure of diglycerol monomyristate (designated as C14G2) nonionic surfactant reverse micelles in aromatic solvent styrene has been investigated as a function of surfactant concentration, temperature, and water addition by using small-angle X-ray scattering (SAXS) technique. Structure of micelles in real-space so called pair-distance distribution function, p(r), was obtained by the generalized indirect fourier transformation (GIFT) evaluation of SAXS data. It was found that C14G2 spontaneously self-assembles into spheroid reverse micelles with maximum diameter approximately 3.0 nm when added into styrene under ambient condition. The micellar shape and size remained essentially the same despite a wide variation in surfactant concentration (5 to 30%) but an opposite trend was observed with the rise of temperature; size decreased by approximately 25% with increase in temperature from 25 to 75 degrees C. Addition of traces water favored micellar growth and eventually ellipsoid prolate type micelles were formed, whose scenario is understood in terms of decrease in the critical packing parameter (cpp); water hydrates the surfactant's headgroup and decreases cpp. At a particular concentration of water, increasing temperature decreased the micellar size due to dehydration of headgroup. It is interesting to note that size of 1.57% water incorporated micelle is approximately 2.5 times bigger than the empty micelles. PMID- 22103111 TI - Honey derivatized Au and Ag nanoparticles and evaluation of its antimicrobial activity. AB - Biomolecules hosting the synthesis of nanoparticles has achieved considerable attention in recent decades due to their abundant availability, excellent biocompatibility and low toxicity. The present study demonstrates a rapid, cost effective and eco-friendly fabrication of gold and silver nanoparticles at room temperature using natural honey as a source of stabilizing and reducing agent. The nanoparticles obtained were unambiguously characterized by using various characterization techniques such as transmission electron microscopy (TEM), UV Visible absorption spectroscopy, X-ray diffraction and energy dispersive (EDX) X ray analysis. The average size of Au and Ag nanoparticles are 10 and 12 nm respectively. Ag nanoparticles capped by honey exhibited superior antimicrobial activity while Au nanoparticles revealed passable activity against pathogenic bacteria and Candida albicans, including multi-resistant strains for the first time. PMID- 22103112 TI - Nickel-cobalt nanoparticles supported on single-walled carbon nanotubes and their catalytic hydrogenation activity. AB - Single-walled carbon nanotubes were synthesized from graphite using the arc discharge technique. A nickel/yttrium/graphite mixture was used as the catalyst. After purification by sonication in a Triton X-100 solution, nickel-cobalt metal nanoparticles were deposited on the surface of the single-walled carbon nanotubes. The resulting material and/or the nanotubes themselves were characterized by physisorption, Raman spectroscopy, high-resolution transition electron microscopy and X-ray diffraction. Raman spectroscopy indicates that the nanotubes, prepared by the arc discharge technique, are semi-conducting with a diameter centering at 1.4 nm. The average nickel-cobalt particle size is estimated to be in the region of 8 nm. The catalytic activity of the material was examined for the hydrogenation of unsaturated fatty acid methyl esters obtained from avocado oil. The carbon nanotube supported nickel-cobalt particles effectively hydrogenate polyunsaturated methyl linoleate to monounsaturated methyl oleate. In contrast to a conventional nickel on kieselghur catalyst, further hydrogenation of methyl oleate to undesired methyl stearate was not observed. PMID- 22103113 TI - Nickel electroplating for nanostructure mold fabrication. AB - We demonstrated a practical process of fabricating nickel molds for nanoimprinting. Dual-side polished glass is chosen as the substrate on which nickel nanostructures are successfully electroplated. Photonic crystal structures with 242 nm diameters and other nanoscale pillars down to 9 nm diameters are achieved over a large area. The electroplating parameters are investigated and optimized. This process extends the feasibility of electroplating process to nanoscale and shows great potential in nanoimprint mold fabrication with its low cost, straightforward process and controllable pattern structures. PMID- 22103114 TI - Enhancement of field emission characteristics of carbon nanotubes on oxidation. AB - Vertically aligned multi-walled carbon nanotubes (CNTs) were grown on p-type silicon wafer using thermal chemical vapor deposition process and subsequently treated with oxygen plasma for oxidation. It was observed that the electron field emission (EFE) characteristics are enhanced. It showed that the turn-on electric field (E(TOE)) of CNTs decreased from 0.67 (untreated) to 0.26 V/microm (oxygen treated). Raman spectra showed that the numbers of defects are increased, which are generated by oxygen-treatment, and absorbed molecules on the CNTs are responsible for the enhancement of EFE. Scanning electron microscopy and Transmission electron microscopy images were used to identify the quality and physical changes of the nanotube morphology and surfaces; revealing the evidence of enhancement in the field emission properties after oxygen-plasma treatment. PMID- 22103115 TI - Photocatalytic titanium dioxide composite. AB - In recent years, Titanium Dioxide (TiO2) has gained much more interest for its semiconducting properties for use as photocatalytic material because it rapidly and completely mineralizes organic without harmful byproducts. Based on inspiration from biology, which uses organic structures to guide nucleation and growth of minerals, we demonstrate controlled synthesis of TiO2 using a hydrophilic synthetic polymer. In the absence of the polymer, TiO2 completely transforms to rutile by 72 hours, however with the addition of the polymer larger anatase crystallites are observed due to the reduced number of nuclei formed. Under these conditions, complete transformation to rutile was not observed due to diffusion-limited growth of TiO2 as well as the presence of an organic coating on the crystallites. However nanoparticles are difficult to recover from effluent streams. We use the polymer to develop bulk composite TiO2-organic structures which can be fabricated and tailored as a stand alone photocatalysts, eliminating the need for nanoparticle recovery systems, thereby reducing processing costs. PMID- 22103116 TI - Controlled growth of related defects on oxide nanowires. AB - This study analyzed correlations between semiconducting properties and defects in oxide nanowires by changing the growth temperature and adding a reducing agent. Oxide nanowires each showed different emission spectra and semiconducting properties depending on growth factors caused by structural/intrinsic defects on the surface of the oxide nanowires. In particular, the substrate temperature played a key role in controlling defects during nanowire growth, and defects were reduced more effectively by adding a reducing agent to the source material. Oxide nanowires with reduced defects showed transistor characteristics with an on current 2.5 times higher and a mobility 3 times higher than as-grown nanowires. PMID- 22103117 TI - A facile synthesis of lipid stabilized gold nanoparticles: a step towards biodegradable biosensors. AB - A new class of polylactone was successfully synthesized and utilized for the encapsulation and stabilization of gold nanoparticles. Core/shell nanoparticle architecture, in which a layer of this polymer surrounds the nanoparticle core have been investigated both as a means to improve the stability and surface chemistry and as a way of accessing unique physical properties that are not possible from one nano-material alone. Given the fact that only few systems has so far been developed for the encapsulation of nanoparticles, our success in using a new biodegradable biopolymer with inbuilt functionality reveals the robustness of this work. The biodegradability of this polylactone was evaluated using scanning electron microscopy (SEM). The morphology and stability of these gold-polymer hybrids were evaluated by using the transmission electron microscopy (TEM) and UV-VIS spectroscopy. PMID- 22103118 TI - Single-walled carbon nanotube incorporated novel three phase carbon/epoxy composite with enhanced properties. AB - In the present work, single-walled carbon nanotubes were dispersed within the matrix of carbon fabric reinforced epoxy composites in order to develop novel three phase carbon/epoxy/single-walled carbon nanotube composites. A combination of ultrasonication and high speed mechanical stirring at 2000 rpm was used to uniformly disperse carbon nanotubes in the epoxy resin. The state of carbon nanotube dispersion in the epoxy resin and within the nanocomposites was characterized with the help of optical microscopy and atomic force microscopy. Pure carbon/epoxy and three phase composites were characterized for mechanical properties (tensile and compressive) as well as for thermal and electrical conductivity. Fracture surfaces of composites after tensile test were also studied in order to investigate the effect of dispersed carbon nanotubes on the failure behavior of composites. Dispersion of only 0.1 wt% nanotubes in the matrix led to improvements of 95% in Young's modulus, 31% in tensile strength, 76% in compressive modulus and 41% in compressive strength of carbon/epoxy composites. In addition to that, electrical and thermal conductivity also improved significantly with addition of carbon nanotubes. PMID- 22103119 TI - Self-assembled zinc/copper hydroxide carbonates with tunable hierarchical nanostructure. AB - Here, we report a synthetic, polymer-mediated method for the self-assembly of zinc/copper hydroxide carbonate superstructures including 3D hierarchical sunflower-like, urchin-like, alga-like, and rotiform-like zinc hydroxide carbonate (ZHC) microstructures, and hierarchical copper hydroxide carbonate (CHC) microspheres with radiating nanoplates and nanorods. As a capping agent, poly(vinylpyrrolidone) (PVP) was found to play an important role in directing the growth and self-assembly of such unique structures. The crystal structure of the products and the resulting hierarchical superstructure morphology, as controlled by the molecular weight and concentration of PVP, were systematically investigated. A possible growth mechanism for the formation of hierarchical superstructures with different morphologies is also proposed. PMID- 22103120 TI - Visualizing topological insulating Bi2Te3 quintuple layers on SiO2-capped Si substrates and its contrast optimization. AB - Thin Bi2Te3 flakes, with as few as 3 quintuple layers, are optically visualized on the SiO2-capped Si substrates. Their optical contrasts vary with the illumination wavelength, flake thickness and capping layers. The maximum contrast appears at the optimized light with the 570 nm wavelength. The contrast turns reversed when the flake is reduced to less than 20 quintuple layers. A calculation based on the Fresnel law describes the above observation with the constructions of the layer number-wave length-contrast three-dimensional (3D) diagram and the cap thickness-wavelength-contrast 3D diagram, applicative in the current studies of topological insulating flakes. PMID- 22103121 TI - Interpenetrating polymer networks of poly(N-vinylacetamide) and stimuli responsive polymers applied to novel amphiphilic gel. AB - The swelling behaviors of IPN with poly(N-vinylacetamide) (PNVA), which possibly converts from nonionic gel to cationic gel, and the stimuli responsive polymers, such as poly(acrylic acid) (PAAc) and poly(N-isopropylacrylamide) (PNIPAm) were investigated in order to prepare the stimuli responsive amphiphilic gel. When the monomer concentrations were uniformed at the IPN preparation, the obtained PNVA/PAAc IPN showed the pH responsivity with around 100 of swelling ratio at pH 4 to around 1 of swelling ratio at pH 2, although it lost the amphiphilicity due to the lack of swelling in ethanol. On the other hand, the gelation of N vinylacetamide at 2 M in PNIPAM gel resulted in thermosensitive and amphiphilic hydrogel, that the swelling ratio in EtOH/water (3/7, v/v) also decreased, compared to the value in water at 25 degrees C. PMID- 22103122 TI - Epidermal growth factor receptor imaging of A431 cancer cells using gold nanorods. AB - In this study, we report the synthetic processing of gold nanorods and a method for the molecular imaging of epidermal growth factor receptors (EGFRs) on A431 cancer cells using synthesized gold nanorods and confocal laser scanning microscopy. Through this study, we confirm the potential of this imaging method instead of using fluorophores and quantum dots. PMID- 22103123 TI - Superparamagnetic iron oxide nanoparticles-loaded polymersome-mediated gene delivery guided by enhanced magnetic resonance signal. AB - Positively charged superparamagnetic iron oxide nanoparticle (SPION)-loaded polymersome was prepared in order to deliver genes to the target sites, which was monitored by magnetic resonance imaging (MRI), concomitantly. The transfection efficiency in vitro was tested by treating CT-26 colon cancer cell line with luciferase-expressing plasmids/SPION complex. MRI was also used to check the detectability of SPION in vitro and in vivo. SPION-loaded polymersome, carrying genetic materials, was delivered and then accumulated at the tumor site of the murine colon cancer xenograft model after intravenous injection, possibly through a passive targeting mechanism. Clinical MRI monitored this accumulation. This result indicates that the SPION-loaded polymersomecan be applied to MR image guided gene therapy. PMID- 22103124 TI - Multi-spot porous silicon chip prepared from asymmetric electrochemical etching for human immunoglobin G sensor. AB - Multi-spot porous silicon (MSPS)-based optical biosensor was developed to specify the biomolecules. MSPS chip was generated by an electrochemical etching of silicon wafer using an asymmetric electrode configuration in aqueous ethanolic HF solution and constituted with nine arrayed porous silicon. MSPS prepared from anisotropic etching conditions displayed the Fabry-Perot fringe patterns which varied spatially across the porous silicon (PS). Each spot displayed different reflection resonances and different pore characteristics as a function of the lateral distance from the Pt counter electrode. The sensor system consists of the 3 x 3 spot array of porous silicon modified with Protein A. The system was probed with various fragments of an aqueous Human Immunoglobin G (Ig G) analyte. The sensor operated by measurement of the reflection patterns in the white light reflection spectrum of MSPS. Molecular binding and specificity was detected as a shift in wavelength of these Fabry-Perot fringe patterns. PMID- 22103125 TI - Effects of immobilization of hyaluronic acid and carboxymethyl chitosan onto a NH2 functionalized titanium surfaces on MG 63 cell proliferations. AB - The purpose of this study is the development of bioactive functionalized titanium surface by immobilizing hyaluronic acid (HA) and carboxymethyl chitosan (CMCH) onto -NH2 functionalized titanium surfaces to improve biological and chemical properties of titanium. The in vitro biological evaluation showed that introducing the CMCH and HA to the Ti/NH2 enhanced initial cell proliferation compared to untreated Ti surface. PMID- 22103126 TI - Fabrication of biofilm in nanoscale consisting of cytochrome f/2-MAA bilayer on Au surface for bioelectronic devices by self-assembly technique. AB - We developed the nanoscale biofilm consisting of cytochrome f self-assembled on 2 MAA layer to apply bioelectronic devices. As cytochrome f has redox property, it can be possible to apply bioelectronic devices. The fabricated biofilm was confirmed by SPR and STM experiment. And the electrochemical property was checked by CV, CA, and STS. PMID- 22103127 TI - Biodegradable particulate delivery of vascular endothelial growth factor plasmid from polycaprolactone/polyethylenimine electrospun nanofibers for the treatment of myocardial infarction. AB - In this study, we present nanofiber-mediated gene delivery for myocardial infarction (MI). Branched polyethylenimine cross-linked via disulfide bonds (ssPEI) complexed with vascular endothelial growth factor (VEGF) were immobilized on electrospun polycaprolactone (PCL)/polyethylenimine (PEI) nanofibers for the local expression of VEGF angiogenic factor. We studied whether the production of VEGF from myoblast cells adhering on the nanofibers has therapeutic potential for MI. In this method, the non-specific adsorption of VEGF nanoparticles to the nanofibers occurred uniformly over all of the surface area of the nanofibers, resulting in increased transgene uptake and expression in a great number of cells. The amount of DNA required for transfection was also minimal compared to bolus delivery, because the adhered DNA was directly available in the cell microenvironment, which also helps in localized delivery. Reporter genes luciferase (Luc), red fluorescence protein (RFP), and therapeutic gene VEGF were tested to evaluate the transfection efficiency of ssPEI nanoparticles immobilized on the nanofiber surface. Our results demonstrated that the delivery of therapeutic genes from biodegradable nanoparticles immobilized on the nanofiber represented minimal cytotoxicity of H9C2 myoblasts than branched PEI 25 kDa did. According to Luc assay, fluorescence microscope analysis, and reverse transcription polymerase chain reaction (RT-PCR), this vector showed high transgene expression efficiency to the reporter gene and VEGF gene. The surface mediated delivery of the DNA nanoparticles did not adversely affect cell growth, and facilitated the transgene expression inside the cells. PMID- 22103128 TI - Evaluation of PEG-transferrin-PEI nanocomplex as a gene delivery agent. AB - Polyethylenimine (PEI) has been shown to be an efficient nonviral delivery vector. To improve its specificity and reduce its cytotoxicity, PEI should be modified. Transferrin (Tf) is a cell-binding ligand and Tf-receptors are expressed in malignant cells. Modification of cationic polymer by polyethylene glycol (PEG) can reduce the protein interaction and cell cytotoxicity of delivery vectors. We have synthesized PEG-Tf-PEI conjugate as an efficient and safe carrier of plasmid DNA (pDNA). Nanocomplexes of conjugates with pDNA were characterized by measuring the particle size and the surface charge. Transfection efficiency of nanocomplexes in Jurkat cells was improved and cytotoxicity was decreased compared with those of PEI complex. This was due to a reduction in the membrane damaging effect via shielding of the positive charge on the nanocomplex surface by PEG. PMID- 22103129 TI - The specific hybridization of p53 gene on bead-quantum dot complex in microfluidic chip. AB - Recently, nanobiosensors using nanoparticles, such as gold, silver, and quantum dots, have been studied extensively. Among them, fluorescence resonance energy transfer (FRET)-based DNA sensor is prominent device, especially for the medical diagnosis and biomolecular investigations. FRET is a phenomenon of the emitted energy transfer from one fluorescent dye to another dye through a convoluted wavelength for the excitation. PDMS-based microfluidic chips with pillar structure were prepared for the detection of exon 7 of p53 gene by using QD-DNA probe attached to polystyrene micro beads. The specific hybridization was investigated with 4 different target oligonucleotides. Fluorescence quenching was observed only from the target oligonucleotide for exon 7 with proper sequence for the hybridization. The fluorescence intensity from QDs decreased rapidly due to hybridization and FRET between QDs and intercalating dyes. PMID- 22103130 TI - Cell chip with nano-scale peptide layer to detect dopamine secretion from neuronal cells. AB - A cell chip with a nano-scaled thin film of cysteine modified synthetic oligopeptide C(RGD)4 was fabricated to detect dopamine secretion from neuronal cells. Thin C(RGD)4 peptide layer was fabricated on chip surface for increasing the binding affinity of cells to gold electrode surface, which is essential for the electrochemical detection of dopamine released from PC12 cells. The structural formation of the peptide thin film was confirmed by both atomic force microscopy (AFM) and scanning electron microscopy (SEM). Redox characteristics of chemical dopamine were firstly characterized by voltammetric tool to compare the dopamine released from PC12 cells. Cells grown on the chip were then subjected to cyclic voltammetric (CV) analysis after 48 hours of incubation. The intensities of reduction peaks were found to be increased with increasing the concentrations of PC12 cells. In addition, the electrochemical redox signal increased more in the cells treated with glucose and potassium compared to the control group. Hence, the developed cell chip can be used to determine the effects of drugs on living cells electrochemically. PMID- 22103131 TI - Mucoadhesive alginate/poly (L-lysine)/thiolated alginate microcapsules for oral delivery of Lactobacillus salivarius 29. AB - In this study, thiolated alginate was synthesized by introduction of cysteine to alginate to prepare mucoadhesive alginate/poly (L-lysine)/thiolated alginate (APTA) microcapsules for efficient oral delivery of Lactobacillus salivarius 29 (LS29), a novel therapeutic Lactobacillus strain, in vitro and in vivo. About 759 +/- 32.4 microM of cysteine per gram of alginate was introduced by estimation of Ellman's reagent reaction. LS29-loaded APTA microcapsules provided suitable morphology, size, and a high loading content and efficiency. LS29 in LS29-loaded APTA microcapsules were effectively protected from simulated gastric condition (pH 2.0) than that of unprotected LS29. LS29 were released from APTA microcapsules in simulated intestinal condition (pH 7.2) with a time-dependent manner. The in vitro and in vivo mucoadhesion study suggested that APTA microcapsules had remarkably stronger mucoadhesive property and provided a promising delivery system for oral administration of LS29. PMID- 22103132 TI - Expression of dynamin II in odontoblast during mouse tooth development. AB - Odontoblasts secrete a collagen-based matrix and release numerous membrane-bound matrix vesicles, which are involved in dentin formation during tooth development. Dynamin II is a GTPase protein that contributes a variety of vesicular budding events, such as endocytotic membrane fission, caveolae internalization and protein trafficking in the Golgi apparatus. However, the expression and function of dynamin II in odontoblasts has not been reported. Therefore, this study examined the expression and possible role of dynamin II in odontoblasts during tooth development and mineralization. The levels of mRNA and protein expression in MDPC23 cells were significantly high at the early stages of differentiation and then decreased gradually thereafter. Immunohistochemistry showed that dynamin II was not expressed near the region of the odontoblasts at embryonic day 17 (E17) and E21. However, dynamin II was expressed strongly in the odontoblast layer at postnatal day 1 (PN1) and decreased gradually at PN3 and PN5. In addition, at PN15 in the functional stage, the dynamin II protein was also expressed in the odontoblast process as well as adjacent to the nuclear region. In conclusion, dynamin II may be involved in the transport of vesicles containing collageneous and non-collageneous proteins for dentin formation in odontoblast, suggesting that it is a good nanomolecule as a candidate to regulate the secretion of collagen on the bone and other nano material. PMID- 22103133 TI - Improved cell viability of biocompatible nutrient-contained polymeric nanofibers. AB - Nanofibers containing cell nutrients (PGDs) were fabricated by mixing 5 wt% poly(epsilon-caprolactone) (P), 4 wt% gelatin (G), and 0-2.4 wt% Dulbecco's Modified Eagle's Medium (D). The contact angles showed a considerable decrease from 118.4 degrees on the P scaffold to 17.6 degrees on PGD1.6 (containing 1.6 wt% D). The weight loss ratios between PGD1.6 and the P nanofiber, and between PGD1.6 and the PG nanofiber by degradation after 28 days were approximately 3.1 and 1.4, respectively. The rate of cell proliferation on PGD1.6 was greater than that on the PG nanofiber by 14% and 38% for the exchanged and unexchanged culture media, respectively. The physicochemical measurement results showed that the PGDs exhibited enhanced hydrophilic properties and rapid biodegradation. The PGD nanofibers with increasing D content showed better conditions for long-term cell viability. The growth mechanism of the cells on the PGDs was explained by an attachment and growth process. PMID- 22103134 TI - Phenanthroline-based magnetic nanoparticles as a general agent to bind histidine tagged proteins. AB - We herein report the preparation of PSMN (phenanthroline-based silica coated magnetic nanoparticles), and their applications for protein purification as selective magnetic probes of histidine-tagged proteins in cell lysates. This simple system serves as a useful alternative to existing protocols for his-tagged protein separation and as a versatile agent for transporting and anchoring proteins. PMID- 22103135 TI - Histomorphometric evaluation of an implant with a nanotubular surface treatment in a beagle femur. AB - This study examined the effects of a nanotubular surface treatment on an implant by anodic oxidation. Forty two screw-shaped implants were classified into 3 groups; machined surface (control group), nanotube formation on the machined surface (group N) and nanotube formation on the RBM surface (group RN). A total of 36 implants were inserted into a beagle femur. Two implants from each group were observed by scanning electron microscopy. Histomorphometric analyses were performed after 4 and 12 weeks. After 4 weeks, the average bone to implant contact (BIC) ratio of groups N and RN was significantly higher than that of the control group (P < .05). After 12 weeks, a nanotubular surface treatment showed a significantly higher BIC ratio only in the marrow space adjacent to the implant apex (P < .05). This in vivo study revealed the enhanced osseointegration of nanotubes. PMID- 22103136 TI - Antibacterial effect of visible light reactive TiO2/Ag nanocomposite thin film on the orthodontic appliances. AB - This study evaluated the antibacterial effect of a visible light reactive TiO2/Ag nanocomposite thin film on dental orthodontic wire (STS 304 wire). The growth of S. mutans and A. actinomycetemcomitans was suppressed on the specimens coated with TiO2/Ag compared to the uncoated specimens. The antibacterial effect of the TiO2/Ag nanocomposite thin film was improved under visible light irradiation. PMID- 22103137 TI - Impact of drift gap, N-layer, and deep N+ sinker on breakdown voltage and saturation current of lateral double-diffused metal oxide semiconductor transistor. AB - In this paper, we discuss on the optimal design of a High-Side n-channel Lateral Double-diffused Metal Oxide Semiconductor Field Effect Transistor (LDMOSFET) whose breakdown voltage is over 100 V with 0.35 microm Bipolar-CMOS-DMOS (BCD) process. The proposed nLDMOSFET has been fabricated and tested in order to confirm the features of a deep N+ sinker and a gap of between the drift region (DEEP N-WELL) and the center of the source. The surface is implanted by the N layer for high breakdown voltage and simultaneously the low specific on resistance. The computer simulation of the proposed High-Side LDMOS exhibits BVdss of 115 V and Ron,sp of as low as 2.20 m ohms cm2, which is consistent with the experimental results. PMID- 22103138 TI - Improvement of anti-oxidation properties of carbon fibers by SiC/SiO2 ceramic coating. AB - To improve the anti-oxidation properties of carbon fibers (CFs), the sol-gel method followed by pyrolysis was used to coat CFs with SiC/SiO2 ceramic coatings. The SiO2 sol-gel coating was performed by dip coating a PAN(polyacrylonitrile) based stabilized fiber (PSF) in a silica sol prepared by the polycondensation of tetraethylorthosilicate (TEOS) in the presence of an acidic catalyst. The PSF coated with SiO2 sol then underwent heat treatments at high temperatures in an inert atmosphere to deposit the SiC/SiO2 and carbonize the deposited fibers. The surface morphology of the CFs deposited with SiC/SiO2 was characterized using a scanning electron microscope (SEM). The relative oxidation resistance of the SiC/SiO2 layer deposited on the CFs was determined by the weight loss due to the use of a thermogravimetric analyzer (TGA) under flowing air, and the data were used to calculate the activation energies through an Arrhenius plot. PMID- 22103139 TI - Dimensional changes and phase transformation of TiO2 nanotubes heat-treated under oxygen-containing atmosphere. AB - The purpose of this study was to investigate the dimensional changes and phase transition of nanotubular titanium oxide arrays after heat treatment under an oxygen-containing atmosphere. The thermodynamic background for the oxidation of titanium to titanium oxide was theoretically investigated as a function of the oxygen partial pressure. The anodized titanium nanotubes had lengths between 400 and 500 nm, thicknesses of 11 nm and an amorphous structure. The specimens heat treated at higher oxygen partial pressures preferentially had rutile phase rather than anatase phase. The thickness of the TiO2 nanotubes was increased at a lower oxygen partial pressure. PMID- 22103140 TI - Studies on the dehydration of glycerol over niobium catalysts. AB - The dehydration of glycerol over nanosize niobium catalysts was conducted in a stainless steel autoclave reactor. The catalysts were prepared by the calcination of niobium oxalate between 200 and 700 degrees C. Catalysts were characterized by N2 Physisorption, XRD and TPD of ammonia to investigate the effect of the calcination temperature and water on catalytic performance, catalysts' structures and acidity. Acrolein was mainly produced about 51-71% with useful by-products such as acetaldehyde and methanol. Amorphous Nb2O5 catalysts calcined at 200-400 degrees C significantly showed higher conversion of glycerol than the crystallized Nb2O5 catalyst calcined at 500-700 degrees C. Also the conversion of glycerol and selectivity of acrolein was increased with increasing the acidity of catalyst, which can be controlled by calcination temperature. PMID- 22103141 TI - Reversibility of electrowetting on hydrophobic surfaces and dielectrics under continuous applied DC voltage. AB - Various properties of electrowetting such as reversibility, reproducibility and mobility have been investigated experimentally. A conductive water drop on a thin hydrophobic film of amorphous fluropolymers coated on the counter electrode showed unexpectedly the poor reversibility under the discontinuous voltage, so called the contact angle hysteresis. The hysteresis could not been completely suppressed by inserting additionally a thick parylene-C film which has the high dielectric constant and no pinholes. However, both the reversibility and the reproducibility have been enhanced under the continuous voltage starting from the highest absolute electric potential. PMID- 22103142 TI - Metal-induced crystallization of amorphous Si thin films assisted by atomic layer deposition of nickel oxide layers. AB - Atomic layer deposition (ALD) of nickel oxide was applied to the nickel-induced crystallization of amorphous Si thin films. The nickel-induced crystallization was monitored as a function of annealing temperature and time using Raman spectroscopy. Since Raman spectroscopy allows for the numerical quantification of structural components, the incubation time and the crystallization rates were estimated as functions of the annealing temperature. The spatial locations of a nickel-based species, probably NiSi2, were investigated using X-ray photoelectron spectrometry. The formed NiSi2 seeds appeared to accelerate the crystallization kinetics in amorphous Si thin films deposited onto glass substrates. The ramifications of the atomic layer deposition are discussed with regard to large panel displays, with special emphasis on the sophisticated control of the catalytic elements, especially nickel. PMID- 22103143 TI - Fabrication of a nanosize-Pt-embedded membrane electrode assembly to enhance the utilization of Pt in proton exchange membrane fuel cells. AB - A procedure to locate the Pt nanostructure inside the hydrophilic channel of a Nafion membrane was developed in order to enhance Pt utilization in PEMFCs. Nanosize Pt-embedded MEA was constructed by Cu electroless plating and subsequent Pt electrodeposition inside the hydrophilic channels of the Nafion membrane. The metallic Pt nanostructure fabricated inside the membrane was employed as an oxygen reduction catalyst for a PEMFC and facilitated effective use of the hydrophilic channels inside the membrane. Compared to the conventional MEA, a Pt embedded MEA with only 68% Pt loading showed better PEMFC performance. PMID- 22103144 TI - Fabrication of ordered Cr nanostructures by self agglomeration on porous anodic alumina membranes. AB - In this paper, we propose an efficient and effective method to fabricate highly ordered Cr nanoarrays with sub-gaps less than 15 nm and particle size less than 50 nm on the top surface of a modified porous anodic alumina membrane (PAA). In addition, the factors that influence the structural parameters of the fabricated nanostructures were studied. With the aid of SEM and AFM images, the amount of sputter-coated Cr was tailored to the given PAA surface morphology. The mechanism of formation of the Cr nanostructures was also discussed. PMID- 22103145 TI - Highly efficient and stable white organic light emitting diode base on double recombination zones of phosphorescent blue/orange emitters. AB - We demonstrated efficient and stable white phosphorescent organic light-emitting diodes (OLEDs) with double-emitting layers (D-EMLs), which were comprised of two emissive layers with a hole transport-type host of N,N'-dicarbazolyl-3,5-benzene (mCP) and a electron transport-type host of 2,2',2"-(1,3,5-benzenetryl)tris(1 phenyl)-1H-benzimidazol (TPBi) with blue/orange emitters, respectively. We fabricated two type white devices with single emitting layer (S-EML) and D-EML of orange emitter, maintaining double recombination zone of blue emitter. In addition, the device architecture was developed to confine excitons inside the D EMLs and to manage triplet excitons by controlling the charge injection. As a result, light-emitting performances of white OLED with D-EMLs were improved and showed the steady CIE coordinates compared to that with S-EML of orange emitter, which demonstrated the maximum luminous efficiency and external quantum efficiency were 21.38 cd/A and 11.09%. It also showed the stable white emission with CIE(x,y) coordinates from (x = 0.36, y = 0.37) at 6 V to (x = 0.33, y = 0.38) at 12 V. PMID- 22103146 TI - Effects of TiO2 nanorod length and post-annealing on the electrical properties of TiO2 nanobarbed fiber structures. AB - TiO2 nanobarbed fiber (NBF) structures consisting of TiO2 nanorods (NRs) on TiO2 nanofibers (NFs) were fabricated. The mean length and diameter of the TiO2 NRs grown for 6 h was 1.38 microm and 71 nm, respectively. One NR was connected to other NRs and the junction points between the TiO2 NRs increased with increasing TiO2 NR length. The crystal structure of the TiO2 NFs and NRs was rutile and anatase, respectively. After post-annealing, only the intensity of the TiO2 NBF peaks increased without any significant structural changes. Raman spectroscopy showed that the TiO2 NBF structure consisted of anatase (TiO2 NFs) and rutile (TiO2 NRs). The bandgap of the TiO2 NBF structure prepared during a TiO2 NR growth time from 0 to 6 h decreased from 3.23 eV to 3.10 eV. The conductivity of the TiO2 NBFs with longer NRs was enhanced by post-annealing. PMID- 22103147 TI - Controlling of the electrical resistivity of GaN layer using AIN nucleation layer. AB - The sheet resistance (Rs) of undoped GaN films on AIN/c-plane sapphire substrate was investigated. The Rs was strongly dependent on the AIN layer thickness and semi-insulating behavior was observed. To clarify the effect of crystalline property on Rs, the crystal structure of the GaN films has been studied using X ray scattering and transmission electron microscopy. A compressive strain was introduced by the presence of AIN nucleation layer (NL) and was gradually relaxed as increasing AIN NL thickness. This relaxation produced more threading dislocations (TD) of edge-type. Moreover, the surface morphology of the GaN film was changed at thicker AIN layer condition, which was originated by the crossover from planar to island grains of AIN. Thus, rough surface might produce more dislocations. The edge and mixed dislocations propagating from the interface between the GaN film and the AIN buffer layer affected the electric resistance of GaN film. PMID- 22103148 TI - Fabrication of gradient optical filter containing anisotropic Bragg nanostructure. AB - New gradient optical filters containing asymmetric Bragg structure were prepared from the distributed Bragg reflector (DBR) porous silicon (PSi). Anisotropic DBR PSi displaying a rainbow-colored reflection was generated by using an asymmetric etching configuration. Flexible anisotropic DBR PSi composite films were obtained by casting of polymer solution onto anisotropic DBR PSi thin films. The surface and cross-sectional images images of anisotropic DBR PSi composite films obtained with cold field emission scanning electron microscope indicated that the average pore size and the thickness of porous layer decreased as the lateral distance increased. As lateral distance increased, the reflection resonance shifted to shorter wavelength. PMID- 22103149 TI - Electrodeposition of hydroxyapatite nanoparticles onto ultra-fine TiO2 nanotube layer by electrochemical reaction in mixed electrolyte. AB - Electrochemical depositions of HAp nanoparticles onto Ultra-fine TiO2 nanotube layer were carried out by the electrochemical reaction in mixed electrolyte of 1.6 M (NH4)H2PO4 + 0.8 M NH4F containing 0.15 and 0.25 wt% HAp. The Ca/P ratios of the HAp nanoparticles were evaluated by EDS analysis and their values were 1.53 and 1.66 respectively. The distribution quantity of Ca and P were remained at the middle region of TiO2 nanotube, but the Ti element was mainly stayed at the bottom of barrier layer from the result of line scanning diagram. Especially, adsorbed phosphate ions facilitated nucleation of nanophase calcium phosphate material inside the TiO2 nanotubu layer that resulted in vertical growth of HAp nanoparticles. These surfaces and structures were all effective for biocompatibility from the SBF tests. PMID- 22103150 TI - Remediation of TCE-contaminated groundwater using nanocatalyst and bacteria. AB - The objective of this study was to develop and evaluate the remediation of trichloroethene (TCE)-contaminated groundwater using both a nanocatalyst (bio-Zn magnetite) and bacterium (similar to Clostridium quinii) in anoxic environments. Of the 7 nanocatalysts tested, bio-Zn-magnetite showed the highest TCE dechlorination efficiency, with an average of ca. 90% within 8 days in a batch experiment. The column tests confirmed that the application of bio-Zn-magnetite in combination with the bacterium achieved high degradation efficiency (ca. 90%) of TCE within 5 days compared to the nanocatalyst only, which degraded only 30% of the TCE. These results suggest that the application of a nanocatalyst and the bacterium have potential for the remediation of TCE-contaminated groundwater in subsurface environments. PMID- 22103151 TI - Thermoelectric properties of Ca(1-x-y)Dy(x)CeyMnO3 for power generation. AB - The sintered Ca(1-x-y)Dy(x)CeyMnO3 bodies were a single phase with a perovskite structure without any impurity phases. The calculated crystallite sizes of the Ca(1-x-y)Dy(x)CeyMnO3 were in the range of 43.3 to 63.3 nm. The composition significantly affected their microstructural and thermoelectric characteristics. The doped Dy led to both an increase in the electrical conductivity as well as the absolute value of the Seebeck coefficient, resulting in an enhanced power factor. The highest power factor (5.1 x 10(-4) Wm(-1) K(-2)) was obtained for Ca(0.8)Dy(0.2)MnO3 at 800 degrees C. In this study, we systematically discussed the thermoelectric properties of the Ca(1-x-y)Dy(x)CeyMnO3, with respect to the substitution of Dy and/or Ce for Ca. PMID- 22103152 TI - Ultralong ZnO nanowire arrays synthesized by hydrothermal method using repetitive refresh. AB - Long ZnO nanowire arrays (> or = 10 microm) were fabricated using the hydrothermal method and the refresh process of the reactant solution. The diameter of the synthesized nanowires was controlled by varying the solution concentration of the seed layers, without reducing their length. The maximum temperature in this process was 95 degrees C and the repeated refresh process at 95 degrees C provided the driving force for the growth of ultralong nanowires by exchanging the reactants. Interestingly, the diameter of the refreshed ZnO nanowires strongly depended on the solution temperature during refresh. The exchange of the reactant solution at the same temperature as the synthesis temperature induced the synthesis of ultralong nanowires and the length of the resultant nanowires can be controlled by varying the repetition number. The illumination of the ultraviolet light induced considerably enhanced current flow in the ultralong nanowires from mid 10(-10) to 10(-7) A at 5 V. PMID- 22103153 TI - Carrier dynamics and activation energy of CdxZn(1-x)Te/ZnTe quantum dots on GaAs and Si substrates. AB - We have investigated the carrier dynamics and activation energy of CdxZn(1 x)Te/ZnTe quantum dots (QDs) on GaAs and Si substrates. The carrier dynamics of QDs on GaAs and Si substrates is studied using time-resolved photoluminescence (PL) measurements, revealing shorter exciton lifetimes of QDs on Si substrate. In particular, the activation energy of electrons confined in QDs on the GaAs substrate, as obtained from temperature-dependent PL spectra, is higher than that of electrons confined in QDs on the Si substrate. Both results confirm that defects and dislocations in QDs on the Si substrate provide nonradiative channels. PMID- 22103154 TI - A quartz crystal microbalance-based sensor system coated with functional polymers for SO2 and NO2 detection. AB - In this work, a quartz crystal microbalance (QCM)-based adsorption sensor system with high sensitivity, selectivity, and reproducibility is designed and fabricated. The functional polymers such as polypyrrole, poly(3,4 ethylenedioxythiophene) (PEDOT), and polystyrene are coated on 8 MHz AT-cut quartz crystal surfaces as sensing materials for SO2 and NO2. All sensing materials on the QCM surface are characterized experimentally by SEM and AFM. The frequency shifts of the QCM by adsorption and desorption of gases are measured and analyzed to assess the practical applicability of the sensor system. The overall results show that the QCM coated with polypyrrole is highly selective for SO2 gas and that coated with PEDOT is for NO2. It is proven that the QCM-based adsorption sensor system is possible for monitoring SO2 and NO2 gases in the mixture of ppm level. PMID- 22103155 TI - Preparation and electrochemical properties of carbon nanofiber composite dispersed with silver nanoparticles using polyacrylonitrile and beta cyclodextrin. AB - A simple one-step method was used for preparing the beta cyclodextrin/polyacrylonitrile (PAN) nanofibers deposited with silver nanoparticles by electrospinning and followed by the reduction of the Ag+ ions. The nano-composite fibers were stabilized at 280 degrees C in air and activated at 800 degrees C for 1 h in steam/N2. The structures of nano-composite fibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), fourier-transform infrared (FTIR) spectroscopy, and X-ray diffraction analysis (XRD). The electrochemical behaviors of the composite of carbon nano-fibers were investigated by cyclic voltammetry and charge/discharge tests. PMID- 22103156 TI - Efficient phosphorescent white organic light-emitting diodes using Ir(4-Me-2,3 dpq)2(przl-C6H4F) as a red emitter. AB - We demonstrated white organic light-emitting diodes (WOLED) using the iridium bis(4-methyl-2,3-phenylquinolinato-N,C2) fluorophenylpyrazolonate complex (Ir(4 Me-2,3-dpq)2(przl-C6H4F)) as a phosphorescent red dopant and iridium bis[(4,6 difluorophenyl)-pyridinato-N,C2] picolinate (Flrpic) as a phosphorescent blue dopant. The WOLED with Ir(4-Me-2,3-dpq)2(przl-C6H4F) had better exciton confinement in emitting layer and indicated smaller movement of exciton than the WOLED with iridium bis(2-phenylquinoline) acetylacetonate (Ir(2-pq)2(acac)) as phosphorescent red dopant. The optimized WOLED had a peak external quantum efficiency of 7.16%, current efficiency of 11.84 cd/A, and Commission Internationale de l'Eclairage (CIE(x,y)) coordinates of (0.35, 0.32). The WOLED also exhibited the minimal change with delta CIE(x,y) coordinates of +/- (0.01, 0.00) from 100 to 4000 cd/m2. PMID- 22103157 TI - Preparation and characterization of the transparent hybrids of silicone epoxy resin and titanium dioxide nanoparticles via sol-gel reactions. AB - In order to prepare transparent hybrid films of high refractive index, nanoparticles of TiO2 were prepared and dispersed in a silicone epoxy (SE) resin synthesized from diphenyl silane diol and [2-(3,4-epoxycyclohexyl)ethyl] trimethoxysilane by sol-gel reactions. It was found that amorphous TiO2 nanoparticles of about 5 nm modified with hexahydro-4-methyl phthalic anhydride [HMPA] were dispersed in the SE resin without agglomerations. The refractive index of the hybrids increased linearly with increasing the TiO2 contents. The hybrid containing 30 wt% of the TiO2 particles showed light transmittance of 94% at 450 nm and refractive index of 1.63. The fine dispersion of the TiO2 nanoparticles was attributable to the sol-gel reactions between the SE resin and TiO2 nanoparticles and the modification of the TiO2 particles with HMPA. PMID- 22103158 TI - Preparation of molecularly imprinted polymers for the detection of aromatic hydrocarbons. AB - In this study, the molecularly imprinted polymers (MIPs) are designed to improve their sensitivity and selectivity for specific aromatic hydrocarbons such as benzene, toluene, and xylene isomers. The MIPs based on methyl acrylate (MA) monomer are prepared using toluene and ethylene glycol dimetacrylate (EGDMA) as a template and a cross linking agent, respectively. The binding sites on the MIPs are characterized by using Fourier transform infrared spectrometry (FT-IR), nitrogen adsorption isotherms, and transmission electron microscopy (TEM). The selective behaviors of the MIPs are evaluated by their adsorption properties on a gravimetric apparatus. It is found that the performance is strongly influenced by the composition ratios of cross-linker, functional monomer, and template molecule. The molecular recognition ability can be assessed on the basis of an imprinting effect. The results indicate that the prepared MIPs can be used for the aromatic hydrocarbon sensor materials with high sensitivity and selectivity. PMID- 22103159 TI - Preparation of hydrogen titanate nanotube/FTO glass thin film obtained by the layer-by-layer-self assembling method for water splitting. AB - Hydrogen titanate nanotube (H-TiNT) particles were coated porously on a fluorine doped tin oxide glass using the layer-by-layer self assembling method and then heat-treated at temperatures below 600 degrees C for 10 min in air. The microstructure, crystallinity, and optical absorbance of the heat-treated H-TiNT thin film were investigated using scanning electron microscopy, X-ray diffraction, Raman spectroscopy, and UV-vis spectroscopy, respectively. Also, I-V characteristics of the fibrous H-TiNT particles in the thin film using linear cycle voltammetry under ultraviolet-A irradiation were analyzed to have a maximum current value at applied voltages with the increase in heating temperature for economic water splitting. PMID- 22103160 TI - Seed-mediated synthesis of iron oxide and gold/iron oxide nanoparticles. AB - In this study, we prepared magnetic iron oxide and gold/iron oxide nanoparticles (NPs) and characterized their morphologies and properties by XRD, TEM, EDX, VSM and UV-vis measurements. The magnetite iron oxide NPs of 10 nm were synthesized by coprecipitation of Fe2+ and Fe+3 in the solution of NH4OH and then they were used as seed particles for the subsequent growth to prepare the magnetite NPs of different particle sizes and also to prepare gold/iron oxide composite NPs. All those magnetite NPs are superparamagnetic and the gold/iron oxide composite NPs combine the optical and magnetic properties, which are contributed by gold and iron oxide components, respectively. PMID- 22103161 TI - Characterization of luminescence properties of V2O5-capped ZnSe nanowires. AB - ZnSe-core/V2O5-shell nanowires were synthesized by the thermal evaporation of ZnSe powders on gold-coated Si (100) substrates followed by the sputter depositon of V2O5. Scanning electron microscopic images showed that the core-shell nanowires were a few tens to a few hundreds of nanometers in diameter and a few hundreds of micrometers in length. Transmission electron microscopy and X-ray diffraction analyses revealed that the core and shell of the core-shell nanowires were single crystal wurtzite-structured ZnSe and amorphous V2O5, respectively. Photoluminescence measurement showed that the core-shell nanowires as-synthesized or annealed in an oxidative atmosphere had a green emission band centered at around 520 nm whereas the as-synthesized ZnSe nanowires and the ZnSe-core/V2O5 shell nanowires annealed in a reducing atmosphere had a yellow emission band centered at around 590 nm. Our results also showed that V2O5 capping with an optimal thickness and subsequent annealing in a reducing atmosphere could significantly enhance the emission intensity of the ZnSe nanowires. In addition, the origins of the enhancement in intensity and the blue shift of the major emission by V2O5 capping are discussed. PMID- 22103162 TI - Fabrication and radio frequency characterization of carbon nanotube field effect transistor: evidence of quantum capacitance. AB - We fabricated an radio frequency (RF) carbon nanotube field effect transistor (CNTFET) whose electrode shapes were standard RF designed ground-signal-ground (GSG)-type pads. The S-parameters measured from our RF CNTFET in the frequency range up to 6 GHz were fitted with an RF equivalent circuit, and the extracted gate capacitance was shown to be the capacitance value of the series combination of the electrostatic capacitance and the quantum capacitance. The effect of the channel resistance and the kinetic inductance was also discussed. PMID- 22103163 TI - Development of a backscattering type ultraviolet apertureless near-field scanning optical microscope. AB - A backscattering type ultraviolet apertureless near-field scanning optical microscope (ANSOM) for the correlated measurement of topographical and optical characteristics of photonic materials with high optical resolution was developed. The near-field Rayleigh scattering image of GaN covered with periodic submicron Cr dots showed that optical resolution around 40 nm was achievable. By measuring the tip scattered photoluminescence of InGaN/GaN multi quantum wells, the applicability of the developed microscope for high resolution fluorescence measurement was also demonstrated. PMID- 22103164 TI - Charge trapping and luminance mechanisms of organic light-emitting devices with a 5,6,11,12-tetraphenylnaphthacene emission layer. AB - The electrical and the optical properties of the organic light-emitting devices fabricated utilizing a 5,6,11,12-tetraphenylnaphthacene (rubrene) emission layer (EML) were investigated to clarify their charge trapping and luminance mechanisms. The increase in the thickness of the rubrene EML extended the width of the recombination zone, resulting in the enhancement of the efficiency and in the variation of the shoulder peak intensity of the electroluminescence spectra. The charge trapping and luminance mechanisms were affected by the total thickness of the rubrene layer, regardless of the existence of the barrier layers. The charge trapping and luminance mechanisms are described on the basis of the experimental results. PMID- 22103165 TI - Structural and electrical characteristics of gallium tin oxide thin films prepared by electron cyclotron resonance-metal organic chemical vapor deposition. AB - Gallium tin oxide composite (GTO) thin films were prepared by electron cyclotron resonance-metal organic chemical vapor deposition (ECR-MOCVD). The organometallics of tetramethlytin and trimethylgallium were used for precursors of gallium and tin, respectively. X-ray diffraction (XRD) characterization indicated that the gallium tin oxide composite thin films show the nanopolycrystalline of tetragonal rutile structure. Hall measurement indicated that the Ga/[O+Sn] mole ratio play an important role to determine the electrical properties of gallium tin composite oxide thin films. n-type conducting film obtained Ga/[O+Sn] mole ratio of 0.05 exhibited the lowest electrical resistivity of 1.21 x 10(-3) ohms cm. In our experimental range, the optimized carrier concentration of 3.71 x 10(18) cm(-3) was prepared at the Ga/[O+Sn] mole ratio of 0.35. PMID- 22103166 TI - Influence of ZnO nanorod morphology on optical confinement--finite-difference time-domain numerical simulation study. AB - We studied the influence of nanorod (NR) morphology on the optical confinement. In order to understand the optical field confinement by the ZnO NR, we obtained the spatial intensity distribution inside/outside the NR by solving Maxwell equations using the finite-difference time-domain numerical simulation. The hexagonal cylinder-shaped NR exhibits a strong confinement and the circular cylinder-shaped NR shows also similar confinement effect. Meanwhile, the rectangular cylinder-shaped NR, the tapered NR, and the NR with sharp cone show a weak confinement of optical field as compared to that of the hexagonal cylinder shaped NR. Next, as the rod length and/or the rod diameter increase, the high intensity region increases. This suggests that longer nanorod will exhibit more efficient lasing action. PMID- 22103167 TI - Characterization of magnetite-organic complex nanoparticles by metal-reducing bacteria. AB - Magnetite nanoparticles exhibit clear technological potential for biomedical applications. The objectives of this study were to synthesize magnetite-organic complex nanoparticles through the use of metal-reducing bacteria and characterize the mineralogical and surface chemical properties of these nanoparticles as well as to test their potential applications in biomedical technology with regards to their protein immobilization capacity. The microbially formed magnetite nanoparticles had a size of around 10 nm with a spherical shape and were coated with organics containing an abundance of reactive carboxyl groups without any chemical process for functionalizing them. These microbial processes may lead to a simple preparation of functional magnetite-organic complex nanoparticles which have benefits for biomedical applications. PMID- 22103168 TI - Effect of resin infiltration on the thermal and mechanical properties of nano sized silica-based thermal insulation. AB - Several kinds of nano-sized silica-based thermal insulation were prepared by dry processing of mixtures consisting of fumed silica, ceramic fiber, and a SiC opacifier. Infiltration of phenolic resin solution into the insulation, followed by hot-pressing, was attempted to improve the mechanical strength of the insulation. More than 22% resin content was necessary to increase the strength of the insulation by a factor of two or more. The structural integrity of the resin infiltrated samples could be maintained, even after resin burn-out, presumably due to reinforcement from ceramic fibers. For all temperature ranges and similar sample bulk density values, the thermal conductivities of the samples after resin burn-out were consistently higher than those of the samples obtained from the dry process. Mercury intrusion curves indicated that the median size of the nanopores formed by primary silica aggregates in the samples after resin burn-out is consistently larger than that of the sample without resin infiltration. PMID- 22103169 TI - Highly efficient blue light-emitting materials based on arylamine substituted DPVBi derivatives. AB - A series of arylamine substituted DPVBi derivatives (1-4) were synthesized via the Horner-Wadsworth-Emmons reaction. Their electroluminescent properties were examined by fabricating a multilayer OLED device with the following structure: ITO/DNTPD (40 nm)/NPB (20 nm)/2% DPVBi derivatives (1-4) doped in MADN (20 nm)/Alq3 (40 nm)/Liq (1.0 nm)/Al. All devices showed efficient blue emission. In particular, a high efficiency blue OLED was fabricated using compound 1 as a dopant in the emitting layer. The maximum luminance, luminous efficiency, power efficiency and CIE coordinates of the blue OLED using compound 1 as a dopant were 16110 cd/m2 at 10 V, 10.1 cd/A at 20 mA/cm2, 4.37 Im/W at 20 mA/cm2, and (x = 0.197, y = 0.358) at 8 V, respectively. Moreover, a device using compound 4 as the dopant exhibited efficient deep blue emission with a luminance, luminous efficiency, power efficiency and CIE coordinates of 7005 cd/m2 at 10 V, 6.25 cd/A at 20 mA/cm2, 2.50 Im/W at 20 mA/cm2 and (x = 0.151, y = 0.143) at 8 V, respectively. PMID- 22103170 TI - Permeation of solvents through disk type rice husk silica membrane modified with alkyl silylation reagents. AB - Rice husk silica (RHS) which was obtained with thermal treatment of rice husk has the size of approximately 10 micrometer with 4-5 nm pore. RHS can be mold to a disk type membrane. The membrane may have submicron pore originated from the space among the particles, and the nano pores of the rice husk silica (RHS pore). Even it is difficult to adjust the size of the pores, we can suggest that the membrane shows different permeability for the organic/inorganic solvents if the affinity between the surface of the pores and the permeating molecule is changed. In this study, we investigated the permeation of the typical solvents such as water, ethanol and toluene to the RHS membranes sintered at 1100 degrees C, 1150 degrees C and 1200 degrees C and modified with triethoxymethyl silane (CH3)Si(C2H5O)3, diethoxydiemethyl silane (CH3)2Si(C2H5O)2 and ethoxytriemethyl silane (CH3)3Si (C2H5O). The result showed that permeability of original membranes for water (e.g., 1100 degrees C, 2.87 x 10(-3) mol/m2 s Pa) was larger than ethanol (1100 degrees C, 5.51 x 10(-4) mol/m2 s Pa) and toluene (1100 degrees C, 3.09 x 10(-4) mol/m2 s Pa) at the sintering temperatures. For the silane modified membranes, the permeability for water decreased drastically while those for ethanol and toluene increased. PMID- 22103171 TI - Rapid consolidation of nanostuctured TiCu compounds. AB - TiCu nanopowder was produced using an electrical wire explosion method and subsequently consolidated into dense nanostuctured TiCu by a high frequency induction heated sintering method. The consolidation was accomplished by the combination of an induced current and a high mechanical pressure within two minutes. This process results in very quick densification to near the theoretical density and prohibits grain growth in nano-structured materials. The grain sizes and mechanical properties of the sintered TiCu were investigated. PMID- 22103172 TI - Synthesis of air stable iron nanopowders with various methods. AB - Magnetic properties and microstructures of iron-based nanopowders fabricated by several methods, such as sol-gel, thermal decomposition, and self-propagating combustion methods, were investigated. During a subsequent reduction annealing, added aluminum atoms formed coherent oxide shells with a hercynite structure around iron cores in all the nanopowders. In particular, the nanopowders synthesized by the self-propagating combustion method showed the highest saturation magnetization of 175.68 emu/g and oxidation stability to 200 degrees C in air. PMID- 22103173 TI - Processing of SiO2 protective layer using HMDS precursor by combustion CVD. AB - Hexamethyldisilazane (HMDS, [(CH3)3Si]2NH) was used as a precursor to form SiO2 protective coatings on IN738LC alloys by combustion chemical vapor deposition (CCVD). SEM and XPS showed that the processed coatings were composed mainly of SiO2. The amount of HMDS had the largest effect on the size of the SiO2 agglomerates and the thickness of the deposited coatings. The specimens coated with SiO2 using the 0.05 mol/l HMDS solution showed a significantly higher temperature oxidation resistance than those deposited under other conditions. PMID- 22103174 TI - Crystalline characterization and photodecomposition properties of rod-shaped Na2Ti6O13 powder prepared by molten salt process. AB - To prepare one-dimensional nanostructured Na2Ti6O13 powder, the starting materials of TiO2, NaCl and Na2CO3 were mixed and then heat-treated at 1000 degrees C for 2 hrs in air under molten state of NaCl. Changes in shape and phase, photo absorbance and photocatalytic ability of TiO2 particle were observed controlling added amount of Na2CO3 under constant weight ratio of TiO2 to NaCl using SEM, X-ray diffractometer, Raman spectroscopy, and UV-Vis spectroscopy. The TiO2 particle was changed into rod-shape Na2Ti6O13 with the addition of Na2CO3, showing increase in optical energy band-gap of the powder as well as gradual decrease of the photo-decomposition ability. PMID- 22103175 TI - Sol-gel synthesis and characterization of nanostructured TiO2/gamma-Al2O3 composite membranes. AB - Nanostructured TiO2/gamma-Al2O3 composite membranes with various compositions were prepared by sol-gel method. The structural and textural properties of the composite membranes could be modified by the mixing ratio of boehmite sol and titania sol, and calcination temperature. The existence of alumina in the composite membranes retarded anatase-to-rutile phase transformation, resulting in stabilization of textural properties. Defect-free composite membranes were confirmed by gas permeation test. PMID- 22103176 TI - Effect of zinc content on the refractive index of Co-sputtered Zn-doped ITO films. AB - In this study, we investigated the possibility of using Zn-doped ITO film as an alternative material for conventional SiO2 waveguides used in optical communication. The Zn-doped ITO films were deposited on quartz substrates using a combinatorial sputtering system, which yielded composition spread Zn-In-Sn-O (ZITO) films by co-sputtering two targets of ITO and ZnO. The Zn-doped ITO films deposited at room temperature exhibited an amorphous phase in the Zn content [Zn/(Zn+In+Sn)] range of 39-54 at%. The Zn-doped ITO films deposited at low oxygen partial pressure showed resistivity below 10(-3) ohms cm and optical transmittance of approximately 85% at 550 nm. The refractive index calculated by the Swanepoel method was found to be dependent on the Zn content in the Zn-doped ITO films. The calculated bending loss from the refractive index indicated that Zn-doped ITO could be utilized as a new waveguide material for various optical devices, such as optical splitters, wavelength division multiplexers (WDMs), optical modulators, and optical switches. PMID- 22103177 TI - Experimental analysis of nanomechanics of spherical titanium oxide nanooils in reducing friction. AB - This work explores the nanomechanics of sphere titanium oxide nanooils in reducing friction between two pieces of cast iron. A friction test is performed using an ATE-77 Reciprocal Tribological Tester made by Cameron-Plint Tribology Limited, England. The friction between two pieces of cast iron was determined 25 135 degrees C using home-made titanium oxide nanooils. In elastohydrodynamic lubrication (EHL), the lubricant is subjected to enormous pressures, there is considerable local heating, and the assumption of constant viscosity no longer holds up. The derivation of the governing equations for elastohydrodynamic lubrication, the pressure and temperature dependence of viscosity is recognized after the lubrication thin film approximation has been made. The viscosity of the nanooils consistently exceeded that of the paraffin oil enlarging the partial EHL area with a complete lubricating film between two move iron surfaces. The spherical geometry of TiO2 nanoparticles caused them to act as a rolling medium when the machine parts move which is in the solid friction area. Because they provide a rolling function, spherical titanium oxide nanoparticles have feasible tribological and lubrication applications in the mechanical industry to reduce noise, vibration and friction wear. PMID- 22103178 TI - Grain size and film thickness effect on the thermal expansion coefficient of FCC metallic thin films. AB - Thin films are used in wide range of applications in industry, such as solar cells and LEDs. When thin films are deposited on substrates, various stresses are generated due to the mechanical difference between the film and substrate. These stresses can cause defects, such as cracking and buckling. Therefore, knowledge of the mechanical properties is important for improving their reliability and stability. In this study, the thermal expansion coefficient of FCC metallic thin films, such as Ag and Cu, which have different grain sizes and thicknesses, were calculated using the thermal cycling method. As a result, thermal expansion coefficient increased with increasing grain size. However, the film thickness had no remarkable effect. PMID- 22103179 TI - Enhanced photoelectrochemical cell property from alpha-Fe2O3 nanoparticle decoration on vertically grown TiO2 nanotubes arrays. AB - TiO2 nanotube arrays decorated with alpha-Fe2O3 were prepared by forming a nanotube-like TiO2 film on a Ti sheet using an anodization process, followed by electrochemical deposition to decorate hematite (alpha-Fe2O3) nanoparticles on the TiO2 nanotube arrays. The SEM and XRD results revealed that the alpha-Fe2O3 nanoparticles were homogeneously embedded on the surface of the TiO2 nanotube arrays. The photoelectrochemical properties of the alpha-Fe2O3/TiO2 nanotube arrays as photoanode were studied by photocurrent-potential behavior in 1 M NaOH electrolyte under 100 mW/cm2 UV-Visible light irradiation. Also, the length dependence of TiO2 nanotubes and the amount dependence of alpha-Fe2O3 nanoparticles on the photocatalytic ability were studied and thus the optimum conditions were determined. PMID- 22103180 TI - Optimized Li4Ti5O12 nanoparticles by solvothermal route for Li-ion batteries. AB - Li4Ti5O12 (LTO) nanoparticles were successfully synthesized by solvothermal technique using cost-effective precursors in polyol medium and post-annealed at temperatures of 400, 500, and 600 degrees C. The XRD patterns of the samples were clearly indexed to the spinel shaped Li4Ti5O12 (space group, Fd-3 m). The particle size and morphology of samples were identified using field-emission SEM. The electrochemical performance of solvothermal samples revealed fairly high initial discharge/charge specific capacities in the range 230-235 and 170-190 mAh/g, at 1 C-rate, while that registered for the solid-state sample has been 160 and 150 mAh/g, respectively. Furthermore, among these samples, LTO annealed at 500 degrees C exhibited highly improved rate performances at C-rates as high as 30 and 60 C. This was attributed to the achievement of small particle sizes with high crystallinity in nano-scale dimensions and hence shorter diffusion paths combined with larger contact area at the electrode/electrolyte interface. PMID- 22103181 TI - Large scale synthesis and enhanced field emission properties from hybrid CuO/ZnO nanorod. AB - Upper-directionally grown nanorods were synthesized on a large scale by a simple method of direct heating of Cu foil in air. Hybrid CuO/ZnO nanorods were fabricated by ZnO thin film coating using magnetron sputtering. Field emission (FE) measurements of CuO and hybrid CuO/ZnO nanorod films show that they have turn-on field of 3.81 and 3.24 V/microm and a current density of 0.39 and 1.1 microA/cm2 under an applied field of about 6.6 V/microm, respectively. By comparing X-ray photoelectron spectroscopy analysis and the FE properties of two types of samples, we concluded that the narrowing of band gap due to the change of electron binding energy of hybrid CuO/ZnO nanorods effectively improved FE. PMID- 22103182 TI - Effect of Mn precursors on benzene oxidation with ozone over MnOx/MCM-41 at low temperature. AB - Low temperature benzene oxidation in the presence of ozone on MnOx/MCM-41 catalysts has been studied. MnOx/MCM-41 catalysts were prepared from two different precursors, Mn(NO3)2 and Mn(CH3COO)2, and these samples were characterized by N2 sorption, X-ray diffraction, X-ray photoelectron spectroscopy and temperature programmed reduction. The characterization results showed that the MnOx/MCM-41 prepared from Mn(CH3COO)2 had higher oxygen mobility and dispersion than the MnOx/MCM-41 from Mn(NO3)2. As a result, the MnOx/MCM-41 obtained from Mn(CH3COO)2 showed higher catalytic activity for the oxidation of benzene using ozone; however, without ozone, the catalytic activity was negligible. PMID- 22103183 TI - Efficient organic photovoltaic devices by using PEDOT:PSSs with excellent hole extraction ability. AB - We have demonstrated the poly(3-hexyl-thiophene-1,5-diyl) (P3HT):[6,6]-phenyl C61 butyric acid methyl ester (PCBM) bulk heterojunction (BHJ) organic photovoltaic (OPV) devices on various poly(3,4-ethylene-dioxythiophene):poly(styrenesulfonate) (PEDOT:PSSs). The device with PEDOT:PSS of PH 500 adding 1% dimethyl sulfoxide (DMSO) showed the best performances in term of the fill factor and power conversion efficiency (PCE) than others. The hole extraction ability of PEDOT:PSS is very important to balance between holes and electrons mobility because the carrier mobility of PCBM (approximately 10(-4) cm2/Vs) is higher than that of P3HT (approximately 10(-6) cm2/Vs) in P3HT:PCBM BHJ structure. The optimized BHJ OPV with PEDOT:PSS of PH 500 adding 1% DMSO showed a short-circuit current density of 8.92 mA/cm2 and a PCE of 2.97%, which was nearly increased to 2.5 times than that of control device with PEDOT:PSS of P VP Al 4083. PMID- 22103184 TI - Aqueous phase reforming of glycerol over Ni-based catalysts for hydrogen production. AB - Aqueous phase reforming of glycerol over Ni-based catalysts for hydrogen production was carried out at 225 degrees C, 23 bar and LHSV = 4 h(-1). The Ni based catalyst was prepared by an incipient wetness impregnation method. The catalysts before and after the reaction were characterized by N2 physisorption, CO chemisorption, XRD, TPR, SEM and TEM techniques. It was found that Ni(20 wt%) Co(3 wt%)/gamma-Al2O3 catalyst showed higher glycerol conversion and hydrogen selectivity than Ni(20 wt%)/gamma-Al2O3 catalyst. There are no major changes in Ni particles after the reaction over Ni-Co/gamma-Al2O3 catalyst. The results suggest that the Ni-Co/gamma-Al2O3 catalyst can be applied to the hydrogen production system using APR of glycerol. PMID- 22103185 TI - Growth of TiO2 anti-reflection layer on textured Si (100) wafer substrate by metal-organic chemical vapor deposition method. AB - Recently anti-reflective films (AR) have been intensely studied. Particularly for textured silicon solar cells, the AR films can further reduce the reflection of the incident light through trapping the incident light into the cells. In this work, TiO2 anti-reflection films have been grown on the textured Si (100) substrate which is processed in two steps, and the films are deposited using metal-organic chemical vapor deposition (MOCVD) with a precursor of titanium tetra-isopropoxide (TTIP). The effect of the substrate texture and the growth conditions of TiO2 films on the reflectance has been investigated. Pyramid size of textured silicon had approximately 2-9 microm. A well-textured silicon surface can lower the reflectance to 10%. For more reduced reflection, TiO2 anti reflection films on the textured silicon were deposited at 600 degrees C using titanium tetra-isopropoxide (TTIP) as a precursor by metal-organic chemical vapor deposition (MOCVD), and the deposited TiO2 layers were then treated by annealing for 2 h in air at 600 and 1000 degrees C, respectively. In this process, the treated samples by annealing showed anatase and rutile phases, respectively. The thickness of TiO2 films was about 75 +/- 5 nm. The reflectance at specific wavelength can be reduced to 3% in optimum layer. PMID- 22103186 TI - Effects of seed layer patterns on the structural characteristics of hydrothermally grown ZnO nanorods. AB - We investigated the effects of surface pattern size and shape on the characteristics of hydrothermally grown ZnO nanorods. For this purpose, the structural characteristics of ZnO nanorods were examined using X-ray diffraction and scanning electron microscopy. The sputtered ZnO seed layer was patterned using photolithography techniques on a Si substrate. ZnO nanorods with a [0001] texturing structure were successfully grown on selective areas by hydrothermal processes. In our experiments, however, it was observed that the diameter and the texture of the ZnO nanorods were strongly influenced by the size of the surface pattern. PMID- 22103187 TI - Surface modification of carbon post arrays by atomic layer deposition of ZnO film. AB - The applicability of atomic layer deposition (ALD) process to the carbon microelectromechanical system technology was studied for a surface modification method of the carbon post electrodes. A conformal coating of the ALD-ZnO film was successfully demonstrated on the carbon post arrays which were fabricated by the traditional photolithography and subsequent two-step pyrolysis. A significant Zn diffusion into the underlying carbon posts was observed during the ALD process. The addition of a sputter-deposited ZnO interfacial layer efficiently blocked the Zn diffusion without altering the microstructure and surface morphology of the ALD-ZnO film. PMID- 22103188 TI - A facile method for morphological control of MgZnO nanostructures on GaAs substrates and their optical properties. AB - This research reports on morphological changes depending on the growth temperature in MgZnO nanostructures grown on GaAs substrates by metalorganic chemical vapor deposition as well as the investigation of their optical properties. As the growth temperature increased, the morphology of the MgZnO nanostructure changed from one-dimensional nanowires (480 degrees C) to pseudo two-dimensional nanowalls (500 degrees C) to pyramid-shaped structures (520 degrees C). Among these structures, the nanowalls exhibited the best optical properties due to the large active surface area and high crystalline quality. PMID- 22103189 TI - Synthesis and characterization of platinum(II) complexes with 2,2'-bipyridine derivative supporting ligands. AB - The reaction of the [Pt(bpy-R)Cl2](bpy-R: R=H (2,2'-bipyridine); R=CH3 (4,4' dimethyl-2,2'-biypridine (DM-bpy), 3,3'-5,5'-tertamethyl-2,2'-bipyridiyl (TM bpy)) with 1,4-Bis(5'-2',2"-bipyridine)benzene (bpy-Ph-bpy) affords the following mono- and di-platinum complexes of [(bpy)Pt(bpy-Ph-bpy)][PF6]2 (1), [(bpy)Pt(bpy Ph-bpy)Pt(bpy)])[PF6]4 (2), [(DM-bpy)Pt(bpy-Ph-bpy)])][PF6]2 (3), and [(TM bpy)Pt(bpy-ph-bpy)[PF6]2 (4), respectively. These complexes were characterized by NMR, IR, UV/VIS, PL and cyclic voltammetry. The internal quantum yields of these platinum(II) complexes are very high (0.83-0.99) and these complexes emit light at deep blue regions (373-417 nm). The redox behavior of complexes 1 and 2 shows quasi-reversible process. PMID- 22103190 TI - Fabrication of dye-sensitized solar cells using Nb2O5 blocking layer made by sol gel method. AB - In this study, nanocrystalline Nb2O5 thin film has been prepared via sol-gel process using niobium ethoxide as a precursor. Sol-gel films using various ratios of H2O/Nb have been prepared on fluorinated tin oxide (FTO) glass substrate, and used as electron-blocking layer of dye-sensitized solar cell (DSSC). The Nb2O5 film as deposited was amorphous, but became crystalline with hexagonal phase after heat treatment at 600 degrees C. With higher H2O/Nb molar ratio, denser and more uniform Nb2O5 film surface was obtained. DSSCs with the structure of FTO/Nb2O5/TiO2/Dye/EL/Pt/FTO have been prepared, and their solar-cell performance was evaluated. By introduction of Nb2O5 sol-gel film between FTO and TiO2 layer in DSSCs, energy conversion efficiency could be improved. PMID- 22103191 TI - Electrical characterization of n/p-type nickel silicide/silicon junctions by Sb segregation. AB - In this paper, n/p-type nickel-silicided Schottky diodes were fabricated by incorporating antimony atoms near the nickel silicide/Si junction interface and the electrical characteristics were studied through measurements and simulations. The effective Schottky barrier height (SBH) for electron, extracted from the thermionic emission model, drastically decreased from 0.68 to less than 0.1 eV while that for hole slightly increased from 0.43 to 0.53 eV. In order to identify the current conduction mechanisms, the experimental current-temperature-voltage characteristics for the n-type diode were fitted based on various models for transport of charge carrier in Schottky diodes. As the result, the large change in effective SBH for electron is ascribed to trap-assisted tunneling rather than barrier height inhomogeneity. PMID- 22103193 TI - Preparation of platinum nanoparticle and its catalytic activity for toluene oxidation. AB - Colloidal Pt nanoparticles are prepared using H2PtCl6 as a precursor, polyvinylpyrrolidone (PVP: molecular weight = 10,000 and 40,000) and hydrogen as a stabilizing agent and a reducing agent, respectively. The amounts of the precursor and the stabilizing agent and the molecular weight of PVP have an effect on the formation of Pt nanoparticles. Supported Pt catalyst (CSPt) is prepared from colloidal Pt nanoparticles and y-Al2O3. Another supported Pt catalyst (ISPt) is prepared by using the conventional incipient wetness impregnation method with an aqueous H2PtCl6 solution and gamma-Al2O3. The catalytic activities of CSPt and ISPt catalysts are compared for VOC (toluene) oxidation. Transmission Electron Microscopy (TEM), UV-vis, X-ray diffraction (XRD) and temperature programmed reduction (TPR) are used to characterize CSPt and ISPt catalysts. The experimental results reveal that the catalytic activity of CSPt is superior to that of ISPT. PMID- 22103192 TI - Hyaluronic acid immobilization on the poly-allylamine coated nano-network TiO2 surface. AB - Recently, biocompatibility report revealed that the TiO2 nano-network (TiO2 NT) structure has much higher cells colonization than the native TiO2 on Ti surface. In this study, we prepared the hyaluronic acid (HA) immobilized TiO2 NT layer by plasma surface modification and then evaluated biological behavior of MC3T3-E1 on the Ti, TiO2 NT and TiO2 NT/NH2/HA surface. The cell viability tests revealed slightly enhanced viability on the TiO2 NT/NH2/HA surfaces than on the untreated Ti surfaces. PMID- 22103194 TI - Structure of BaO on hierarchical macro-meso-microporous alumina and its effect of interaction with Pt nanoparticle on NO2 desorption. AB - Recently, the lean NOx trap technology using supported Pt catalyst on alumina was devised to store NOx under lean condition and to reduce into N2 and water under rich condition in lean burn engine. In this work, the effect of the Pt nanoparticle supported on hierarchical macro-meso-microporous BaO-Al2O3 on NO2 desorption has been investigated with NO2 temperature programmed desorption, TEM, SEM, TGA and hydrogen chemisorption. Crystalline BaO phase of 20-30 nm thickness were obtained on the hierarchical macro-meso-microporous Al2O3 with a simple impregnation of Ba(NO3)2 and Ba(ClO4)2. The interaction of Pt and BaO was resulted in the formation of atomically dispersed Pt nanoparticles and also decreased the desorption temperature of NO2 adsorbed on BaO at much lower temperature than that from the BaO-Al2O3 support only. This synergistic lowering of NO2 desorption temperature may be originated from the interaction between Pt and BaO. PMID- 22103195 TI - Photocatalytic properties of titanate nanotube powders prepared by alkaline hydrothermal method. AB - This paper reports the photocatalytic activities of titanate nanotubes (TNTs) synthesized using different methods and compares them with that of P25. Rhodamine B was selected as the organic compound to be decomposed by the microwave/UV/photocatalyst hybrid process. The as-prepared TNT had titanate crystalline structure, whereas the TNT calcined at 723 K was phase-transformed into anatase structure. When the as-prepared TNT was ion-exchanged using HCl, Na+ content was reduced from 8.36 wt% to 0.03 wt%. The ion-exchanged TNT showed the highest photocatalytic activity among the TNTs tested in this study, but it was lower than that of P25. PMID- 22103196 TI - Synthesis and photoluminescence of nano-sized (Gd,Y)PO4:Eu3+ by solution combustion method. AB - We synthesized (Gd(1-x)Yx)(0.94)PO4:Eu(0.06) (0 < or = x < or = 1.0) phosphor powders of an ultra-fine size (approximately 23 nm), smooth surface, and spherical and regular morphologies by the solution combustion method. The crystallite sizes of the annealed (Gd(1-x)Yx)(0.94)PO4:Eu(0.06) phosphors with x = 0, 0.25, 0.5, 0.75, and 1.0 were 63.3, 62.3, 49.9, 45.1, and 43.3 nm, respectively. The photoluminescent characteristics of the phosphors were studied under vacuum ultraviolet excitation, depending on the Y3+ concentration. The intensity of the peaks corresponding to the red emission increased with increases in the Y3+ concentration. The Y(0.94)PO4:Eu(0.06) phosphor emitted the strongest intensity and the purest red color. PMID- 22103197 TI - Preparation of in-situ Pt nanoparticles into frameworks of mesoporous silica for improving thermal stability. AB - The Pt/sulfur-containing mesoporous silica (SMS) was obtained through in-situ co condensation of TESPTS and TEOS in the presence of a triblock copolymer template. Strong interaction between the Pt NPs and S moieties of TESPTS in the SMS frameworks played an important role in the stabilization of Pt NPs against the sintering or coalescence problems. The Pt/SMS significantly improved the thermal stability at high temperature. PMID- 22103198 TI - Carbon nanotube modification using gum arabic and its effect on the dispersion and tensile properties of carbon nanotubes/epoxy nanocomposites. AB - In this study, the effects of a MWCNT treatment on the dispersion of MWCNTs in aqueous solution and the tensile properties of MWCNT/epoxy nanocomposites were investigated. MWCNTs were treated using acid and gum arabic, and MWCNT/epoxy nanocomposites were fabricated with 0.3 wt.% unmodified, oxidized and gum-treated MWCNTs. The dispersion states of the unmodified, oxidized, and Gum-treated MWCNTs were characterized in distilled water. The tensile strengths and elastic modulus of the three nanocomposites were determined and compared. The results indicated that the gum treatment produced better dispersion of the MWCNTs in distilled water and that gum-treated MWCNT/epoxy nanocomposites had a better tensile strength and elastic modulus than did the unmodified and acid-treated MWCNT/epoxy nanocomposites. Scanning electron microscope examination of the fracture surface showed that the improved tensile properties of the gum-treated MWCNT/epoxy nanocomposites were attributed to the improved dispersion of MWCNTs in the epoxy and to interfacial bonding between nanotubes and the epoxy matrix. PMID- 22103199 TI - Rapid synthesis and characterization of silver nanoparticle/bis(o phenolpropyl)silicone composites by platinum. AB - The formation of silver nanoparticle/bis(o-phenolpropyl)silicone composites have been promoted by the addition of chloroplatinic acid (<2 wt%) to the reaction of silver nitrate with bis(o-phenolpropyl)silicone BPPS [(o-phenolpropyl)2(SiMe2O)n, = 2, 3, 8, 236]. TEM and FE-SEM data exhibit that the silver nanoparticles having the size of <20 nm are well dispersed throughout the BPPS matrix in the composites. XRD patterns are consistent with those for polycrystalline silver. The addition of small amount of platinum to the silver accelerated the rate of composite formation by forming a Ag-Pt bimetallic alloy. The size of silver nanoparticles increased with increasing the relative molar concentration of silver salts added with respect to BPPS. However, the addition of platinum (1-5 wt%) to the AgNO3-BPPS mixture did not affect the size distribution of silver nanoparticles appreciably. It was found that in the absence of BPPS, most of the silver nanoparticles undergo macroscopic precipitation by agglomeration, indicating that BPPS is essential to stabilize the silver nanoparticles by coordination. PMID- 22103200 TI - Superhard nanocrystalline titanium nitride films formed by inductively coupled plasma-assisted sputtering. AB - Nano fabrication technology of superhard TiN films with sub-nanometered crystallites was developed using an Inductively coupled plasma (ICP) during deposition. Nanocrystalline TiN coatings were fabricated by ICP assisted sputtering and the properies of the coatings were investigated. The ICP assisted TiN coatings showed a much higher nano-hardness (>43 GPa) compared to coatings produced by the conventional DC sputtering process. The ICP assisited TiN coatings also showed superior properties in dense microstructure and surface roughness compared to the DC sputtered TiN coatings. The superior mechanical properties of ICP assistted TiN coatings were attributed to the fine and dense microstructure and high compressive residual stress. PMID- 22103201 TI - Decomposition of MEK and toluene over nanolayered TiO2 photocatalyts prepared from metallic titanium chip. AB - The Nanolayered TiO2 photocatalysts were prepared by thermal treatment of metallic titanium chips. Photocatalytic activity for methyl ethyl ketone (MEK) and toluene was investigated using a closed circulating system. The photocatalysts were characterized by SEM and XRD. Surface of the Ti chips changed to be rough with increase of treatment temperature, and severe oxidation over 900 degrees C resulted in TiO2 powder. Uniform TiO2 nanolayer was formed as a rutile type on the metallic chip. Photocatalytic decomposition of MEK over the TiO2 photocatalysts occurred efficiently by UV-C irradiation. The maximum activity for MEK was obtained over Ti Chip treated at 700 degrees C. It was known that the prepared photocatalyts could be applied to remove various VOCs. PMID- 22103202 TI - Synthesis and characterization of a polyacetylene derivative with phenylazobenzene moieties. AB - A new polyacetylene derivative was prepared by the activated polymerization of 2 ethynylpyridine by using 4-(phenylazo)benzoyl chloride without any additional initiator or catalyst in high yield. The chemical structure of poly[2-ethynyl-N (4-(phenylazo)benzoyl) pyridinium chloride [PEPABPC] was characterized by such instrumental methods as NMR, IR, and UV-visible spectroscopies to have a conjugated polymer backbone system with the designed azobenzene moieties. The electrooptical and electrochemical properties of PEPABPC were studied. The photoluminescence spectrum showed that the PL peak is at 597 nm corresponding to the photon energy of 2.07 eV. The cyclovoltammograms of PEPABPC exhibited the irreversible electrochemical behaviors between the oxidation and reduction peaks. The oxidation current density of PEPABPC versus the scan rates is approximately linear relationship in the range of 30 mV/sec-150 mV/sec. It was found that the the kinetics of the redox process of this polymer is controlled by the reactant diffusion process from the oxidation current density of PEPABPC versus the scan rates. PMID- 22103203 TI - Patterning of polymer nanocomposite resists containing metal nanoparticles by electron beam lithography. AB - Poly(vinyl pyrrolidone) (PVP)-stabilized silver nanoparticles (NPs) were used as a new nanocomposite resist for electron beam lithography. A nanocomposite resist prepared by reducing silver nitrate in an alcoholic PVP solution was patterned by using a scanning electron microscope equipped with a nanometer pattern generation system. Well-defined negative tone patterns with a good sensitivity of 200 microC/cm2 and a contrast of 2.83 were obtained using the prepared nanocomposite resist. In addition, the changes in the morphology and structure of the resist patterns with a thermal treatment temperature were investigated by a FE-SEM with an EDX. The results revealed that the patterns of Ag NPs were formed through sintering the formed resist patterns at above 300 degrees C. PMID- 22103204 TI - Steam reforming of glycerol into hydrogen over nano-size Ni-based hydrotalcite like catalysts. AB - Steam reforming (SR) of glycerol for the production of hydrogen was investigated over the nano-sized Ni-based catalysts. The Ni-based catalysts were prepared by solid phase crystallization and impregnation methods, and characterized by N2 physisorption, CO chemisorption, XRD, SEM, and TEM techniques. The Ni/gamma-Al2O3 catalyst showed higher conversion and H2 selectivity. However, it was slowly deactivated due to the carbon formation on the surface of catalyst and the sintering. It was found that the Ni based hydrotalcite-like catalyst (spc Ni/MgAl) showed higher catalytic activity to prevent carbon formation than Ni/gamma-Al2O3 catalyst in the SR of glycerol. PMID- 22103205 TI - Nano-Ag-Nafion modified Pt electrode for oxidation of volatile organic compounds: an electrochemical study. AB - In this work, we describe Nano-Ag-Nafion coated pt electrode for oxidation of volatile organic compound (VOC), here acetaldehyde. Electrochemically synthesized Nano-Ag-Nafion film on Pt was analyzed by electrochemically in various electrolyte solutions like nitric acid, sulfuric acid, potassium nitrate, and potassium hydroxide for its stability. High stability of Nano-Ag-Nafion film appeared in potassium hydroxide medium among electrolyte solutions studied. Electrocatalysis of acetaldehyde was occurred only in acid and neutral medium. A catalytic oxidative peak during cathodic voltammetric reduction scan was observed at 1.75 V, which, unusual redox behavior, follows EC' reaction path way between electrogenerated Ag(II) and acetaldehyde. For Nano-Ag potential applicability, a calibration plot was drawn from various concentration range of acetaldehyde to check the maximum concentration level of acetaldehyde degradation in air. PMID- 22103206 TI - Photoluminescence study of encapsulated dye inside single-walled carbon nanotubes dispersed in solvents. AB - Photo-luminescent dye, 1-(2-amino-phenyl) naphthalene-2-ylamine (APNA) molecules were synthesized and encapsulated inside single-walled carbon nanotubes (APNA@SWNTs) in vacuum. Here we measured X-ray diffraction (XRD) pattern and attenuated total reflectance (ATR) spectrum to confirm the encapsulation of APNA molecules inside SWNTs. Strong photoluminescence (PL) spectrum was observed around 400 nm at an excitation of 326 nm. We employed the PL intensity of the dye to reveal suspension stability of SWNTs in solvents. The intensity of PL spectrum increased as a function of SWNTs suspension stability, i.e., the PL intensity was proportional to suspension stability of SWNTs in various solvents. PMID- 22103207 TI - A high-coverage nanoparticle monolayer for the fabrication of a subwavelength structure on InP substrates. AB - Subwavelength structures (SWSs) were fabricated on the Indium Phosphide (InP) substrate by utilizing the confined convective self-assembly (CCSA) method followed by reactive ion etching (RIE). The surface condition of the InP substrate was changed by depositing a 30-nm-thick SiO2 layer and subsequently treating the surface with O2 plasma to achieve better surface coverage. The surface coverage of nanoparticle monolayer reached 90% by using O2 plasma-treated SiO2/InP substrate among three kinds of starting substrates such as the bare InP, SiO2/InP and O2 plasma-treated SiO2/InP substrate. A nanoparticle monolayer consisting of polystyrene spheres with diameter of 300 nm was used as an etch mask for transferring a two-dimensional periodic pattern onto the InP substrate. The fabricated conical SWS with an aspect ratio of 1.25 on the O2 plasma-treated SiO2/InP substrate exhibited the lowest reflectance. The average reflectance of the conical SWS was 5.84% in a spectral range between 200 and 900 nm under the normal incident angle. PMID- 22103208 TI - Particle size control of Pd/C for improved electrocatalytic activity in a formic acid oxidation. AB - Carbon-supported Pd electrocatalyst is prepared by an improved aqueous impregnation method applying a reducing agent of HCHO and an acidic sedimentation promoter of HCl. We investigate the effect of a solution pH on the zeta potential of both Pd particles and carbon support. The opposite sign of zeta potential results in uniform dispersion of Pd on carbon surface without aggregation problem. TEM analysis shows that optimal solution pH of 4.27 adjusted by NaOH provides a mean particle diameter of 3.2 nm with narrow size distribution. Cyclic voltammograms indicate that home-made Pd/C catalyst exhibits significantly higher electrochemical active surface area and better stability compared with commercial 40 wt.% Pd/C in a formic acid oxidation. PMID- 22103209 TI - Growth behavior of iridium on Si substrates prepared by plasma enhanced atomic layer deposition. AB - Growth behavior of iridium (Ir) thin film on Si substrates prepared by plasma enhanced atomic layer deposition (PEALD) was systematically studied. Ir(EtCp)(COD) and oxygen was employed as a precursor and reactant, respectively. To obtain optimal conditions for depositing nanometer scale Ir thin film, deposition temperature, cycle dependence and precursor feeding time dependence were studied. Uniform 12 nm thick Ir layer with sharp interface was grown at the temperature range of 330-360 degrees C at the fixed deposition cycles of 300. The grown Ir film showed linear properties as a function of deposition cycles which is a typical self-limiting characteristic of ALD. The XRD patterns revealed that IrOx was not formed due to relatively low partial pressure of oxygen. The optimal conditions obtained for 12 nm thick Ir thin film were 330 degrees C of deposition temperature, 300 deposition cycles, and 10 sec of precursor feeding time. PMID- 22103210 TI - Structural, optical and electrical properties of nitrogen ion implanted ZnO nanorods. AB - This study examined the micro-structural and electrical properties of N+-ion implanted ZnO nanorods. Nitrogen ions with energies of 10-90 keV and beam fluxes of 10(13)-10(16) ions/cm2 were implanted on vertically-aligned ZnO nanorods. Energy dispersive X-ray spectroscopy measurements showed that N+ ions were spread uniformly over the nanorods. Extended X-ray absorption fine structure measurements revealed that the implanted N+s had partially substituted for the oxygen sites. Photoluminescence measurements showed a neutral-donor bound exciton peak at 3.36 eV and a two-electron-satellite peak at 3.33 eV independent of the ion energy and flux. The I-V characteristic curves showed that the current density was not changed by the N+ ion energy and flux much. These results strongly suggested that the N ions substituted for the oxygen sites were neutral. PMID- 22103211 TI - Preparation of properties of SWNT/graphene oxide type flexible transparent conductive films. AB - Single walled carbon nanotube (SWNT)/graphene oxide (GO) hybrid films were prepared by a facile bar coating method on a polyethylene terephthalate substrate using a mixed solution of SWCNTs and GO. An acryl type polymer was employed as a dispersion agent to obtain SWCNT and GO suspension in ethyl alcohol. The SWCNT/GO hybrid films were highly transparent and electrically conductive, showing 80% transmittance and 1.8 x 10(3) ohm/sq surface resistance. The surface resistance of the SWCNT/GO film could be further improved to 750 ohm/sq by hydrazine vapor reduction. PMID- 22103212 TI - Electrochemical oxide nanotube formation on the Ti-35Ta-xHf alloys for dental materials. AB - In this study, we investigated the electrochemical oxide nanotube formation on the Ti-35Ta-xHf alloys for dental materials. The Ti-35Ta-xHf alloys contained from 3 wt.% to 15 wt.% Hf were manufactured by arc melting furnace. The nanotube oxide layers were formed on Ti-35Ta-xHf alloy by anodic oxidation method in 1 M H3PO4 electrolytes containing 0.5 wt.% NaF and 0.8 wt.% NaF at room temperature. The surface characteristics of Ti-35Ta-xHf alloy and nanotube morphology were determined by FE-SEM, STEM, and XRD. The nano-porous surface of Ti-35Ta-xHf alloys showed in 0.5 wt% NaF solution and nanotubular surface showed in 0.8 wt% NaF solution, respectively. The highly ordered nanotube layer without regular knots was formed on the Ti-35Ta-15Hf alloy in the 0.5 wt% NaF solution compared to on Ti-35Ta-3Hf and Ti-35Ta-7Hf alloys in 0.8 wt% NaF solution. Also, the nanotube length of Ti-35Ta-xHf alloys increased as Hf content increased. PMID- 22103213 TI - Nanotubular oxide surface and layer formed on the Ti-35Ta-xZr alloys for biomaterials. AB - Titanium and its alloys are widely used as a dental implant material in clinical dentistry and as an orthopedic implant materials due to their good mechanical properties, corrosion resistance, and biocompatibility. In this study, nanotubular oxide surface and layer formed on the Ti-35Ta-xZr alloys for biomaterials have been investigated by using electrochemical methods. Ti-35Ta-xZr alloys were prepared by arc melting and heat treated for 24 hr at 1000 degrees C in argon atmosphere, and then water quenching. Ti oxide nanotubes were formed on the Ti-35Ta-xZr alloys by anodizing in H3PO4 containing 0.8 wt% NaF solution at 25 degrees C. Anodization was carried out using a scanning potentiostat. Microstructures of the alloys and nanotube surface were examined by FE-SEM, EDX, and XRD. Crystallization treatment of nanotube surface was carried out for 3 hr at 450 degrees C. Microstructures of the Ti-35Ta-xZr alloys were changed from beta phase to alpha'' phase, and changed from an equiaxed to a needle-like structure with increasing Zr content. Nanotubular oxide surface and layers consisting of highly ordered nanotubes with a wide range of diameters (approximately 150-200 nm) and lengths (approximately 4-10 microm) can be formed on alloys in the Ti-35Ta-xZr alloys with Zr content. As the Zr content increased from 3% to 15%, length of step between the bamboo knob-like had increasing values of approximately 50 nm, 80 nm, and 140 nm, respectively. The nanotubes formed on the Ti-35Ta-xZr alloy surface were amorphous structure before heat treatment, but oxide surface had mainly an anatase structure by heat treatment. PMID- 22103214 TI - Morphologies of nano-sized apatite formed on titanium substrate by biomimetic process. AB - The apatite was formed on the titanium plates with NaOH and heat treatments by biomimetic process. The influence of titanium surface microstructure on the apatite formation onto titanium substrate in SBF solution was investigated. After biomimetic process, nano-sized apatite layers were found on the Ti plates with NaOH and heat treatments. However, the morphologies of formed apatite on substrate had different shapes such as coated, load-like, and linked. The morphology of apatite formed by biomimetic process would be affected by alkaline treatment, and substrate morphology and phase. PMID- 22103215 TI - Analysis of the inorganic component of autogenous tooth bone graft material. AB - This study was performed to identify the calcium phosphate minerals, chemical element and Ca/P ratio and to examine the surface structure of autogenous tooth bone grafting material (AutoBT) which recently developed and applied clinically as a bone graft materials. The analytical results showed that AutoBT is composed of low-crystalline hydroxyapatite (HA) and possibly other calcium phosphate minerals, which is similar to the minerals of human bone tissues. And the dental crown portion was composed of high-crystalline calcium phosphate minerals (mainly HA) with higher Ca/P ratio while the root portion was mainly composed of low crystalline calcium phosphates with relatively low Ca/P ratio. PMID- 22103216 TI - Synthesis of TiO2 supported on SBA-15 using different method and their photocatalytic activity. AB - SBA-15 mesoporous materials were successfully prepared by the conventional hydrothermal method and TiO2 nanoparticles were supported on them using different loading methods. The synthesized materials were characterized and their activity as photocatalysts for the decomposition of methylene blue was evaluated. The loading of titanium dioxide on the framework of SBA-15 makes the pore diameter and pore volume decrease compared to that of SBA-15. The chelating method causes the support to have a much better dispersion capacity for TiO2 particles as compared to the other two methods. The TiO2 supported by chelating method showed the highest photocatalytic activity among the photocatalysts prepared by different method. PMID- 22103217 TI - Fabrication and evaluation of nanostructure Al-SiCp composite by accumulative roll-bonding. AB - A nanostructured Al/SiCp composite was fabricated by accumulative roll bonding (ARB) process. The amount of SiC particles introduced into aluminum sheet by one cycle ARB was 0.22 mg/cm2. Increment of the number of ARB cycles increased the amount of SiC particles and enhanced the homogeneity of the distribution of SiC particles. Microstructural change in aluminum matrix with proceeding of the ARB was very similar to that of the ARB-processed unreinforced aluminum; showing a dislocation cell and/or sub-grain structure in samples of lower ARB cycles and ultrafine grained structure in samples of higher ARB cycles. The variation of tensile strength with the ARB was also very similar to that of unreinforced aluminum. However, the effect of strengthening by the ARB was higher in the Al/SiCp composite than in unreinforced aluminum due to an existence of the SiC particles and the formation of finer grains. PMID- 22103218 TI - Effect of phosphorous on the properties of titania produced from Ti-salt flocculated sludge in water treatment. AB - In this study, the removal of phosphorous (P) using Ti-salt flocculation of biologically treated sewage effluent (BTSE) was investigated for a year. The pH, alkalinity and concentration of P, before and after Ti-salt flocculation, were measured and compared. The sludge of Ti-salt flocculation was incinerated at 600 degrees C to produce titania nanoparticles which found to be doped with P Titania nanoparticles were characterised and their photocatalytic activity under UV light irradiation were also tested. Results indicated that the removal of P, which exceeded 97% in average, was not affected by the pH and the alkalinity of BTSE. The concentration of P in titania had no effect on the characteristics of titania nanoparticles in different seasons. Titania nanoparticles exhibited superior properties in terms of BET surface area and photocatalytic activity. PMID- 22103219 TI - Fabrication and characterization of photoelectrode thin films with different morphologies of TiO2 nanoparticles for dye-sensitized solar cells. AB - This study deals with the fabrication of three different morphologies of TiO2 nanoparticles to fabricate two-layer photoelectrode thin film for dye-sensitized solar cells (DSSC). The four different TiO2 morphologies are titania nanotubes (Tnt), TiO2 nanoparticles (H220), TiO2 nanoparticle (SP) and commercial DP-25 nanoparticles (P-25). To prepare the thin films of the photoelectrodes, the first layer is coated by H220 TiO2 nanoparticles, and the second is coated by 3 kinds of materials optimally proportionally mixed - P25, SP and Tnt. The photoelectric conversion efficiency of DSSCs with photoelectrodes fabricated using H220 reached 6.31%. Finally, the TiO2 nanaomaterials with four different morphologies were used to prepare a two layer photoelectrode with the structure of H220/P25-Tnt-SP which was combined with a Pt counter electrode to assemble DSSCs. These DSSCs had photoelectric conversion efficiencies of as high as 7.47%. PMID- 22103220 TI - Synthesis and characterization of Nafion/TiO2 nanocomposite membrane for proton exchange membrane fuel cell. AB - In this study, the syntheses and characterizations of Nafion/TiO2 membranes for a proton exchange membrane fuel cell (PEMFC) were investigated. Porous TiO2 powders were synthesized using the sol-gel method; with Nafion/TiO2 nanocomposite membranes prepared using the casting method. An X-ray diffraction analysis demonstrated that the synthesized TiO2 had an anatase structure. The specific surface areas of the TiO2 and Nafion/TiO2 nanocomposite membrane were found to be 115.97 and 33.91 m2/g using a nitrogen adsorption analyzer. The energy dispersive spectra analysis indicated that the TiO2 particles were uniformly distributed in the nanocomposite membrane. The membrane electrode assembly prepared from the Nafion/TiO2 nanocomposite membrane gave the best PEMFC performance compared to the Nafion/P-25 and Nafion membranes. PMID- 22103221 TI - Relative impacts of sintering and condensational obliteration on nanoparticle structure. AB - During the nanoparticle growth, primary particles merge with one another due to sintering and condensational obliteration destructing the aggregate structure of nanoparticles. Because the property and behavior of the nanoparticles depend on the aggregate size and structure, it is crucial to understand the roles of sintering and condensational obliteration quantitatively. In this study, the relative impacts of sintering and condensational obliteration on nanoparticle structure were investigated using numerical simulations on generation of TiO2 nanoparticles at a wide range of temperature. The effect of condensational obliteration was shown to be significant at low temperature, whereas sintering was more important at high temperature. The simulation results demonstrated that both sintering and condensational obliteration must be taken into account in the model to predict the nanoparticle structure accurately. PMID- 22103222 TI - Effect of water addition on catalytic activity of nanosized gold catalysts for CO oxidation. AB - The effect of water in the reactant gas on the catalytic activity for CO oxidation over Au/Co3O4 catalysts has been investigated. Water in the reactant gas had a negative effect on the catalytic activity for CO oxidation in Au/Co3O4 catalyst. Furthermore, it was observed that the average particle size of gold on Au/Co3O4 catalysts increased after stability testing both in dry and wet conditions. PMID- 22103223 TI - Characterization of La(0.8)Sr(0.2)MnO(3 +/-delta) nanopowders synthesized by aerosol flame synthesis for SOFC cathode. AB - Lanthanum strontium manganite (La(0.8)Sr(0.2)MnO(3 +/- delta), LSM) powders with a high specific surface area (55.26 m2/g) were successfully synthesized by aerosol flame synthesis (AFS) technique. The crystallinity and morphology of the synthesized powders sintered at various temperatures were studied by XRD, TEM and BET. The synthesized powders exhibited spherical shape mostly in a few nanometer ranges with a relatively high crystallinity due to thermal plasma reactions in a high temperature of oxy-hydrogen flame. To analyze electrochemical performances of synthesized LSM powders, impedance spectroscopy (IS) was carried out with the symmetric cells prepared by slurry based electrostatic spray deposition (ESD) onto the YSZ electrolyte pellet. The interfacial polarization resistances were 3.04 ohms cm2 at 750 degrees C which is relatively lower than that of micro porous film (7.24 ohms cm2) applying micro-sized powders deposited on same condition. PMID- 22103224 TI - Effects of precursor concentrations and thermal annealing on ZnO nanorods grown by hydrothermal method. AB - ZnO nanorods were grown on spin-coated ZnO seed layers by hydrothermal method. The ZnO nanorods were grown with various precursor concentrations ranging from 0.01 to 0.3 M. Field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and photoluminescence (PL) were carried out to investigate the structural and optical properties of the ZnO nanorods. The average diameter and length of the ZnO nanorods is increased as the precursor concentration increased from 0.01 to 0.3 M. From XRD, the intensity of ZnO (002) peak is increased and full width at half maximum (FWHM) of ZnO (002) decreased as the precursor concentration increased. The FWHM of near-band-edge emission (NBE) decreased and intensity ratio of the NBE to the deep-level emission (DLE) increased as the precursor concentration increased which indicated the optical property is improved. The DLE is red-shifted from yellow- to red-emission and its intensity is increased as the annealing temperature increased due to thermal diffusion process. PMID- 22103225 TI - High density polyethylene membrane filled with alumina prepared by a gamma ray irradiation. AB - High density polyethylene (HDPE) membrane filled with alumina particles was prepared by a wet process for a Li-ion secondary battery. Soybean oil and dibutyl phthalate (DBP) were premixed as the co-diluents. Gamma ray irradiation was used for crosslinking of HDPE. The HDPE membrane filled with alumina particles had excellent mechanical property and thermal stability due to the alumina particles and irradiation crosslinking. The tensile strength of the membrane increased with an increased amount of alumina up to 15 wt%. The thermal shrinkage of the membrane decreased with an increased amount of alumina up to 15 wt%. The electrochemical stability of the irradiated membrane after extraction was improved with irradiation dose up to 50 kGy. PMID- 22103226 TI - Dispersion stabilization of yttria-stabilized zirconia slurry for spray coating by PVB polymeric adsorption. AB - In this study, the dispersion stabilization characteristics of the poly(vinyl butyral) (PVB) adsorbed yttria-stabilized zirconia (YSZ) was investigated. The addition of PVB showed remarkable dispersion effect to the YSZ slurry prepared with isopropyl alcohol (IPA) and toluene as a bi-solvent system, PVB as a dispersant medium and YSZ powders. The agglomerated YSZ particle size decreased with PVB addition until 3 wt% and PVB added more than 3 wt% acted as a binder. The smallest particle size was obtained at 3 wt% PVB and the more PVB addition causes reflocculation of YSZ particles. The relative amount of adsorbed PVB onto the YSZ surface increased with increasing PVB contents. It turns out that the YSZ slurry dispersion stabilization was improved by the interaction between the hydroxyl group of YSZ surface and O-H group in PVB which is newly formed Zr-O-C bonding. PMID- 22103227 TI - Thermoelectric properties of Sb2Te3 thin films by electron beam evaporation. AB - This study applies the thermoelectric grains of Sb2Te3 on conductive glass to evaporate Sb2Te3 thin films by the electron beam evaporation method. Through experimental tests with different evaporation process parameters and film annealing conditions, thin films with better Seebeck coefficient, resistivity (p) and power fact (PF) can be obtained. Experimental results show that when thin films are annealed, their defects can be decreased accordingly, and carrier mobility can be enhanced to further elevate the conductivity of thin films. When the substrate temperature is set at 200 degrees C to fabricate Sb2Te3 thin films by the evaporation process and by annealing at 220 degrees C for 60 minutes, the Seebeck coefficient of Sb2Te3 thin films increase from 87.6 microV/K to 177.7 microV/K; resistivity falls from 6.21 m ohms-cm to 2.53 m ohms-cm and PF can achieve the maximum value of 1.24 10(-3) W/K2 m. Finally, this study attempts to add indium (In) to Sb2Te3 thin films. Indium has been successfully fabricated In3SbTe, thin films. This study also analyzes the effects of In on the thermoelectric properties of In3SbTe2 thin films. PMID- 22103228 TI - Fabrication of 380 nm ultra violet light emitting diodes on nano-patterned n-type GaN substrate. AB - 380 nm ultraviolet (UV) light emitting diodes (LEDs) were grown on patterned n type GaN substrate (PNS) with silicon dioxide (SiO2) nano pattern to improve the light output efficiency. Wet etched self assembled indium tin oxide (ITO) nano clusters serves as dry etching mask for converting the SiO2 layer grown on n-GaN template into SiO2 nano patterns by inductively coupled plasma etching. Three different diameter of ITO such as 200, 250 and 300 nm were used for SiO2 nano pattern fabrication. PNS is obtained by n-GaN regrowth on SiO2 nano patterns and UV LEDs were grown on PNS template by MOCVD. Enhanced light output intensity was observed by employing SiO2 nano patterns on n-GaN. Among different PNS UV LEDs, LED grown on PNS with 300 nm ITO diameter showed enhancement in light output intensity by 2.1 times compared to the reference LED without PNS. PMID- 22103229 TI - Synthesis and characterization of natural dye and counter electrode thin films with different carbon materials for dye-sensitized solar cells. AB - This study aims to deal with the film of the counter electrode of dye-sensitized solar cells (DSSCs) and the preparation, structure and characteristics of the extract of natural dye. This study adopts different commercial carbon materials such as black lead, carbon black and self-made TiO2-MWCNT compound nanoparticle as the film of the counter electrodes. Moreover, for the preparation of natural dyes, anthocyanins and chlorophyll dyes are extracted from mulberry and pomegranate respectively. Furthermore, the extracted anthocyanins and chlorophyll are blended into cocktail dye to complete the preparation of natural dye. Results show that the photoelectric conversion efficiency of the single-layer TiO2-MWCNT counter electrode film and the cocktail dye of the DSSCs is 0.462%. PMID- 22103230 TI - Mechanical properties of porous Al2O3 composite with surface modified multi walled carbon nanotubes (MWCNTs). AB - Multi-walled carbon nanotubes (MWCNTs) have been reinforced in alumina (Al2O3) matrix to overcome the inherent brittleness of the Al2O3 matrix. In this work, MWCNTs were treated by acid to provide hydrophilicity to hydrophobic MWCNTs, inducing the homogeneous dispersion of MWCNTs in an aqueous solution. Aluminum hydroxide (Al(OH)3) as a Al2O3 precursor was added in the solution with the modified MWCNTs, and then this mixture solution was filtered at room temperature. The prepared powders were calcinated at 800-1000 degrees C to reduce the gas pocket in the matrix by decomposition of Al(OH)3. Then the calcinated powders were formed, and heat-treated. The porous MWCNTs-Al2O3 composites show higher mechanical properties in flexure strength and hardness than the porous Al2O3 without the reinforcement phase, which is attributed to the high mechanical properties of MWCNTs. However, higher MWCNTs contents in the composites decrease the mechanical properties due to the aggregation of MWCNTs in the composites. Therefore, control of the MWCNTs content and its dispersibility in the matrix are key factors to be considered for the fabrication of the porous MWCNT-Al2O3 composites. PMID- 22103231 TI - A study on single-layered white organic light-emitting diodes based on Co-host system using solution process. AB - Two color white organic light-emitting diode (WOLED) that used a co-host system in a solution process method was prepared. A device configuration is ITO/PEDOT:PSS (40 nm)/emitting layer (50 nm)/TPBi (20 nm)/LiF (1 nm)/Al. The emitting layer consists of TATa+ alpha-NPB or beta-NPB + DPAVBi (blue dopant) + Rubrene (yellow dopant). The device using alpha-NPB or beta-NPB showed white color of CIE (0.30, 0.40) and (0.29, 0.39), respectively. Device efficiency of alpha-NPB was 3.85 cd/A at 100 mA/cm2, which is about 15% higher than beta-NPB's. PMID- 22103232 TI - Electrical characteristics of nanoscale NAND silicon-oxide-nitride-oxide-silicon flash memory devices fabricated on SOI substrates. AB - NAND silicon-oxide-nitride-oxide-silicon (SONOS) flash memory devices with double gates fabricated on silicon-on-insulator (SOI) substrates were proposed. The current-voltage characteristics related to the programming operation of the designed nanoscale NAND SONOS flash memory devices on a SOI substrate and on the conventional bulk-Si substrate were simulated and compared in order to investigate device characteristics of the scaled-down memory devices. The simulation results showed that the short channel effect and the subthreshod leakage current for the memory device with a large spacer length were lower than that of the memory device with a small spacer length due to increase of the effective channel length. The device performance of the memory device utilizing the SOI substrate exhibited a smaller subthreshold swing and a larger drain current level in comparison with those on the bulk-Si substrate. These improved electrical characteristices for the SOI devices could be explained by comparing the electric field distribution in a channel region for both devices. PMID- 22103233 TI - Detection of dopamine using a silicon nanowire patterned by nanoimprint lithography. AB - Dopamine is one of the most important catecholamine neurotransmitter in the nucleus accumbens of wide variety of animals, including humans. In this study, silicon nanowire FET device was fabricated by UV-assisted NIL method and dopamine was successfully measured by conductance versus time characteristics within 10 pM to 100 nM. PMID- 22103234 TI - Social categorization of social robots: anthropomorphism as a function of robot group membership. AB - Previous work on social categorization has shown that people often use cues such as a person's gender, age, or ethnicity to categorize and form impressions of others. The present research investigated effects of social category membership on the evaluation of humanoid robots. More specifically, participants rated a humanoid robot that either belonged to their in-group or to a national out-group with regard to anthropomorphism (e.g., mind attribution, warmth), psychological closeness, contact intentions, and design. We predicted that participants would show an in-group bias towards the robot that ostensibly belonged to their in group--as indicated by its name and location of production. In line with our hypotheses, participants not only rated the in-group robot more favourably- importantly, they also anthropomorphized it more strongly than the out-group robot. Our findings thus document that people even apply social categorization processes and subsequent differential social evaluations to robots. PMID- 22103235 TI - Even simple forms of social learning rely on intention attribution in marmoset monkeys (Callithrix jacchus). AB - Intention attribution guides the cognitively most demanding forms of social learning, such as imitation, thereby scaffolding cumulative cultural evolution. However, it is not thought to be necessary for more basic forms of social learning. Here we present evidence that in marmoset monkeys (Callithrix jacchus) even most basic forms of social learning such as enhancement depend on intention attribution. Marmosets perceived the behavior of a conspecific and a conspecific like robot, but not that of a moving black box, as goal directed. Their subsequent choice behavior was shaped by social facilitation and stimulus enhancement, that is, by very simple forms of social learning, but only when exposed to the conspecific and robot, which they previously had perceived as intentional agents. We discuss the implications of this finding for contemporary debates about social learning, including emulation learning and ghost control studies, the necessity of goal-directed copying for cumulative cultural evolution, and the limits of current classification systems of social learning for the evolution of social and asocial learning. PMID- 22103236 TI - Femtosecond ligand/core dynamics of microwave-assisted synthesized silicon quantum dots in aqueous solution. AB - A microwave-assisted reaction has been developed to produce hydrogen-terminated silicon quantum dots (QDs). The Si QDs were passivated for water solubility via two different methods: hydrosilylation produced 3-aminopropenyl-terminated Si QDs, and a modified Stober process produced silica-encapsulated Si QDs. Both methods produce water-soluble QDs with maximum emission at 414 nm, and after purification, the QDs exhibit intrinsic fluorescence quantum yield efficiencies of 15 and 23%, respectively. Even though the QDs have different surfaces, they exhibit nearly identical absorption and fluorescence spectra. Femtosecond transient absorption spectroscopy was used for temporal resolution of the photoexcited carrier dynamics between the QDs and ligand. The transient dynamics of the 3-aminopropenyl-terminated Si QDs is interpreted as a formation and decay of a charge-transfer (CT) excited state between the delocalized pi electrons of the carbon linker and the Si core excitons. This CT state is stable for ~4 ns before reverting back to a more stable, long-living species. The silica encapsulated Si QDs show a simpler spectrum without CT dynamics. PMID- 22103237 TI - Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B. AB - AIM: The factors associated with hepatitis recurrence after discontinuation of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B were analyzed to predict the risk of relapse more accurately. METHODS: A total of 126 patients who discontinued NA therapy were recruited retrospectively. The clinical conditions of a successful discontinuation were set as alanine aminotransferase (ALT) below 30 IU/L and serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL. RESULTS: Relapse of hepatitis B were judged to occur when maximal serum ALT became higher than 79 IU/L or when maximal serum HBV DNA surpassed 5.7 log copies/mL following NA discontinuation since these values corresponded with mean values of ALT (30 IU/L) and HBV DNA (4.0 log copies/mL), respectively. At least 90% of patients with either detectable hepatitis B e antigen or serum HBV DNA higher than 3.0 log copies/mL at the time of NA discontinuation relapsed within one year. In the remaining patients, higher levels of both hepatitis B surface and core-related antigens at the time of discontinuation, as well as a shorter course of NA treatment, were significantly associated with relapse by multivariate analysis. CONCLUSIONS: It appears that negative results for hepatitis B e antigen and serum HBV DNA lower than 3.0 log copies/mL are essential for successful NA discontinuation, which may be attained by a longer treatment period. Levels of hepatitis B surface and core-related antigens are also significant factors independently associated with relapse of hepatitis. PMID- 22103239 TI - FGF23 contributes to insulin sensitivity in obese adolescents - preliminary results. AB - Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels. Recent investigations revealed that besides a key role in the pathogenesis of calcium-phosphorus disorders, in some patients FGF23 may be an indicator of cardiovascular complications. As a 'hormone-like' factor, it may also be involved in some metabolic processes, especially in the metabolism of glucose and fat. Its potential contribution to metabolic syndrome (MS) development has not been confirmed yet. OBJECTIVE: The study was to examine the possible correlations between FGF23 serum levels and body composition, blood pressure and selected parameters of glucose, insulin and fat metabolism in adolescents with simple obesity. PATIENTS AND DESIGN: In 68 (35 female) adolescents (mean age 13.9 years) with simple obesity [mean BMI SDS 4.9 (95% CI 4.4-5.4)], the levels of FGF23, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides were measured. Standard oral glucose tolerance tests were performed with the assessment of fasting and after 120' postload glucose and insulin levels; the insulin resistance index HOMA-IR was calculated. RESULTS: Regardless of gender, there was a significant inverse correlation between FGF23 and fasting insulin level (r = -0.3), as well as HOMA-IR (r = -0.29). Multiple regression model showed the independent association between FGF23 and HOMA-IR. CONCLUSION: FGF23 seems to be a novel factor contributing to insulin sensitivity. Further investigations are needed to define its role in the development of MS. PMID- 22103241 TI - Tuning the photophysical properties of pyrene-based systems: a theoretical study. AB - Recently new molecular systems based on the pyrene moiety were developed for photovoltaic applications. Here we present the results of a quantum chemical study focused on the effects induced by some different substituents on the electronic properties of pyrene, to obtain general hints for the molecular design of new pyrene-based systems. In particular, a series of electron-donating (hydroxy, amino, acetylamino) and electron-withdrawing (cyano, carbamoyl, formyl, ethynyl, ethenyl) groups were considered. Furthermore, in addition to the single pyrene molecule, two pyrene units linked by ethenylene, ethynylene, 2,5 thienylene, and ethynylene-p-phenylene containing chains of different lengths were taken into account. For all of the model structures presented, the ground state geometries have been optimized using the density functional approach, while the vertical transition energies were calculated using the time-dependent density functional theory. We will show that the tuning of the lowest electronic excitation energy (i.e., the HOMO-LUMO energy gap) as well as the localization of the spatial distributions of the frontier molecular orbitals (i.e., the nature of the electron-hole pair, generated by photon absorption) can be obtained through the analysis of the pyrene frontier molecular orbitals. This approach allows to evaluate the most suitable position of the substituents on the pyrene moiety giving rise to enhanced electronic effects also in function of their electronic nature. In this way, pyrene-structures with tailored electronic properties could be modeled. Our screening shows that promising candidates for photovoltaic applications could be molecular structures formed by two pyrene units joined/linked by a short conjugated bridge containing double or triple bonds (henceforth pyrene-linked dimers). As far as the single pyrene units are considered, the most significant reduction of the transition energy of the lowest optical electronic excitation is obtained with disubstituted pyrenes with push pull character. PMID- 22103240 TI - Selective cytotoxicity of rhodium metalloinsertors in mismatch repair-deficient cells. AB - Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents. PMID- 22103242 TI - Dronedarone prevents microcirculatory abnormalities in the left ventricle during atrial tachypacing in pigs. AB - BACKGROUND AND PURPOSE: Atrial fibrillation induces ischaemic microcirculatory flow abnormalities in the ventricle, contributing to the risk for acute coronary syndromes. We evaluated the effect of dronedarone on ventricular perfusion during rapid atrial pacing (RAP). EXPERIMENTAL APPROACH: Coronary and fractional flow reserve (CFR/FFR) were measured in the left anterior descending artery in 29 pigs. Six received RAP, six received RAP with dronedarone (RAP/D), seven received dronedarone alone, four received RAP with amiodarone (RAP/A), and six received neither (sham). In ventricular tissue, oxidative stress/ischaemia-related gene and protein expression was evaluated by RT-PCR and Western blotting; Isoprostanes were measured by GC-MS procedures. KEY RESULTS: CFR was decreased in the RAP group, compared with other groups. FFR was not different between groups. Effective refractory period was reduced in RAP compared with RAP/D. RAP-activated PKC phosphorylation tended to be decreased by dronedarone (P= 0.055) RAP induced NOX-1 and NOX-2 protein and the mRNA for hypoxia-inducible factor-1alpha (HIF 1alpha). Dronedarone reduced the pacing-dependent increase in the expression of NOX-2 protein and of HIF-1alpha mRNA. The oxidative stress marker, F(2) isoprostane, was increased by RAP and this increase was attenuated by dronedarone. Other oxidative stress/ischaemia-related genes were induced by RAP compared with sham and were decreased by dronedarone treatment. In HL1 cells, dronedarone significantly inhibited the increased phosphorylation of PKCalpha after oxidative stress, with an almost significant effect (P= 0.059) on that after RAP. CONCLUSIONS AND IMPLICATIONS: Dronedarone abolished RAP-induced ventricular microcirculatory abnormalities by decreasing oxidative stress/ischaemia-related gene and protein expression in the ventricle. PMID- 22103243 TI - Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon like peptide-1 receptor. AB - A novel cyclobutane class of nonpeptidic glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by 3, was identified using receptor binding and multiple response element/cAMP response element (MRE/CRE)-driven reporter gene assays. The structures of 3 and its three isomers were elucidated by NMR, HRESIMS, and X-ray crystallography. A series of structural modifications were also made based on the core structure of 3 with different substitution groups at the west and east ends. Among these analogues, compound 16 was found to be 4- to 5-fold more potent than 3 both in vitro and in vivo. PMID- 22103244 TI - Landscape urbanization and economic growth in China: positive feedbacks and sustainability dilemmas. AB - Accelerating urbanization has been viewed as an important instrument for economic development and reducing regional income disparity in some developing countries, including China. Recent studies (Bloom et al. 2008) indicate that demographic urbanization level has no causal effect on economic growth. However, due to the varying and changing definition of urban population, the use of demographic indicators as a sole representing indicator for urbanization might be misleading. Here, we re-examine the causal relationship between urbanization and economic growth in Chinese cities and provinces in recent decades, using built-up areas as a landscape urbanization indicator. Our analysis shows that (1) larger cities, both in terms of population size and built-up area, and richer cities tend to gain more income, have larger built-up area expansion, and attract more population, than poorer cities or smaller cities; and (2) that there is a long term bidirectional causality between urban built-up area expansion and GDP per capita at both city and provincial level, and a short-term bidirectional causality at provincial level, revealing a positive feedback between landscape urbanization and urban and regional economic growth in China. Our results suggest that urbanization, if measured by a landscape indicator, does have causal effect on economic growth in China, both within the city and with spillover effect to the region, and that urban land expansion is not only the consequences of economic growth in cities, but also drivers of such growth. The results also suggest that under its current economic growth model, it might be difficult for China to control urban expansion without sacrificing economic growth, and China's policy to stop the loss of agricultural land, for food security, might be challenged by its policy to promote economic growth through urbanization. PMID- 22103245 TI - Investigation of nonmechanical findings during spinal movement screening for identifying and/or ruling out metastatic cancer. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the diagnostic accuracy of lumbar movement restrictions and pain in patients with metastatic bone cancer. BACKGROUND: When evaluating patients with low back pain, physical therapists have used the presence of nonmechanical findings during a spinal movement screen as 1 factor in determining whether physician referral is necessary. There are no studies that have investigated the accuracy of this strategy in a situation of diagnostic uncertainty. METHODS: This study included 1,109 patients (655 women) with low back pain (mean age=54.8+/-16.3 years) seen at a spine surgery center who received a clinical movement screen and an imaging supported diagnosis by an orthopedic surgeon. No report of pain during movement and no limitation of movement were considered the 2 targeted findings as these are associated with nonmechanical findings. RESULTS: Sixty-six patients were diagnosed with metastatic cancer, 61 with metastatic bone cancer and concomitant diagnoses. Pain-free lumbar movements in all directions for patients with metastatic bone cancer without concomitant diagnoses were associated with a posttest probability of 0.00 (+likelihood ratio=2.4; -likelihood ratio=0.0), which may be useful in ruling out spinal cancer. In situations where a concomitant diagnosis was present with cancer, the value of a movement screen was poor. CONCLUSION: Nonmechanical findings during a traditional movement screen are not specific to sinister conditions such as metastatic spinal cancer. Clinicians should expect concomitant conditions to exhibit painful or limited findings in patients with and without cancer. PMID- 22103246 TI - A simplified technique for solving the transfer problem of implant-supported fixed partial dentures for patients with microstomia. AB - Techniques for treating a fully or partially edentulous patient with microstomia have been developed to overcome the challenge of accessing the oral cavity. Management of the problems associated with providing implant-supported fixed partial dentures for patients with microstomia has not been well reported. This article describes a solution for the transfer problem that occurs when making an impression of an implant-supported fixed partial dentures for patients with microstomia. PMID- 22103247 TI - Adaptive evolution of the matrix extracellular phosphoglycoprotein in mammals. AB - BACKGROUND: Matrix extracellular phosphoglycoprotein (MEPE) belongs to a family of small integrin-binding ligand N-linked glycoproteins (SIBLINGs) that play a key role in skeleton development, particularly in mineralization, phosphate regulation and osteogenesis. MEPE associated disorders cause various physiological effects, such as loss of bone mass, tumors and disruption of renal function (hypophosphatemia). The study of this developmental gene from an evolutionary perspective could provide valuable insights on the adaptive diversification of morphological phenotypes in vertebrates. RESULTS: Here we studied the adaptive evolution of the MEPE gene in 26 Eutherian mammals and three birds. The comparative genomic analyses revealed a high degree of evolutionary conservation of some coding and non-coding regions of the MEPE gene across mammals indicating a possible regulatory or functional role likely related with mineralization and/or phosphate regulation. However, the majority of the coding region had a fast evolutionary rate, particularly within the largest exon (1467 bp). Rodentia and Scandentia had distinct substitution rates with an increased accumulation of both synonymous and non-synonymous mutations compared with other mammalian lineages. Characteristics of the gene (e.g. biochemical, evolutionary rate, and intronic conservation) differed greatly among lineages of the eight mammalian orders. We identified 20 sites with significant positive selection signatures (codon and protein level) outside the main regulatory motifs (dentonin and ASARM) suggestive of an adaptive role. Conversely, we find three sites under selection in the signal peptide and one in the ASARM motif that were supported by at least one selection model. The MEPE protein tends to accumulate amino acids promoting disorder and potential phosphorylation targets. CONCLUSION: MEPE shows a high number of selection signatures, revealing the crucial role of positive selection in the evolution of this SIBLING member. The selection signatures were found mainly outside the functional motifs, reinforcing the idea that other regions outside the dentonin and the ASARM might be crucial for the function of the protein and future studies should be undertaken to understand its importance. PMID- 22103248 TI - Robust multilayer thin films containing cationic thiol-functionalized gold nanorods for tunable plasmonic properties. AB - Gold nanorods have great potential in a variety of applications because of their unique physical properties. In this article, we present the layer-by-layer (LbL) assembly of thin films containing positively charged gold nanorods that are covalently functionalized by cationic thiol molecules. The cationic gold nanorods are uniformly distributed in ultrathin nanocomposite LbL thin films. We studied the collective surface plasmon resonance coupling in the LbL films via UV-visible spectroscopy and evaluated their application in the surface-enhanced Raman scattering detection of rhodamine 6G probe molecules. Furthermore, we successfully manufactured freestanding nanoscale thin films containing multilayers of gold nanorods with a total thickness of less than 50 nm. The surface morphology and their optical and mechanical properties were systematically investigated, and the polycationic gold nanorods were found to play an important role in manipulating the properties of the nanocomposite thin films. Our findings reveal that such nanorods are excellent building blocks for constructing functional LbL films with tunable plasmonic behavior and robust mechanical properties. PMID- 22103249 TI - The diagnosis of pertussis: which method to choose? AB - Despite the introduction of routine vaccination against pertussis for more than a half century, leading to a drastic decline in the number of reported cases, pertussis continues to be an important respiratory disease afflicting unvaccinated infants and previously vaccinated children as well as adults in whom immunity has waned. The diagnosis of pertussis is challenging and accurate laboratory identification of Bordetella infections remains problematic. Common laboratory diagnostic methods used for pertussis diagnosis include culture, direct-fluorescent-antibody testing (DFA), serology and polymerase chain reaction (PCR). Culture of Bordetella pertussis is highly specific but fastidious and has limited sensitivity. DFA provides a much more rapid result, but has the disadvantage of poor sensitivity and specificity. Serology is not useful in infants. In older persons, it is hampered by the limitations of paired sera and it provides mainly a retrospective diagnosis. Such limitations of conventional diagnosis testing have led to the development of PCR assays. Notwithstanding its lack of standardization, PCR has been found to be more sensitive and more specific than other methods. In this report, we aimed to review current knowledge about the available diagnostic methods and tests that accurately diagnose pertussis. PMID- 22103256 TI - Shaping phases by phasing shapes. AB - Incorporation of shape-shifting building blocks into self-assembled systems has emerged as a promising concept for dynamic structural control. The computational work by Nguyen et al. reported in this issue of ACS Nano examines the phase reconfigurations and kinetic pathways for systems built from shape-shifting building blocks. The studies illustrate several unique properties of such systems, including more efficient packings, novel structures that are distinctive from those obtained through conventional self-assembly, and reversible multistep shape-shifting pathways. The proposed assembly strategy is potentially applicable to a diverse range of systems because it relies on a change of geometrical constraints, which are common across all length scales. Recent developments in the areas of responsive materials and self-assembly methods provide feasible platforms for experimental realizations of shape-shifting reconfigurations; such systems might enable the next generation of dynamically switchable materials and reconfigurable devices. PMID- 22103257 TI - Meditations on the ubiquity and mutability of nano-sized materials in the environment. AB - A wide variety of nanomaterials can be found naturally occurring in the environment, although finding and characterizing these materials remains a challenge due to their size. Recent studies in the field have shown that natural nanomaterials are common in many geochemical systems. In this issue of ACS Nano, Hutchison and co-workers make us realize that manmade nanomaterials can often be practically identical to those that spontaneously form in the environment. This Perspective discusses the prevalence of nanomaterials in nature, including anthropogenic and naturally occurring nanomaterials, and the dynamic behavior of these materials in the environment. PMID- 22103258 TI - Study of DNA-deltamethrin binding by voltammetry, competitive fluorescence, thermal denaturation, circular dichroism, and atomic force microscopy techniques. AB - The interaction of deltamethrin (DM), a synthetic insecticide, with calf thymus DNA was studied. The cyclic voltammetric (CV) results revealed that DM has two irreversible cathodic peaks. The first peak (a) was devoted to reduction of -CN by 4 electrons and the second peak (b) was devoted to reduction of the -C = C- moiety by two electrons. By using non-linear regression analysis of CV data of peak (a), the binding constant, binding site size, and diffusion coefficient for free DM (D(f)) and DNA-DM (D(b)) were calculated as: 2.6 * 10(4), 1.6, 3.2 * 10( 4)Cm(2) S(-1), and 8.5 * 10(-6)Cm(2) S(-1), respectively. The thermal denaturation, competitive fluorescence, and AFM results revealed that the mode of interaction may be non-intercalative. Also the circular dichroism spectra showed that the conformation of CT DNA was converted from right-handed B-DNA to A-DNA due to the destacking of the adjacent guanine bases in pH 7.3 solution. PMID- 22103259 TI - Objective definition and detection of transient lower esophageal sphincter relaxation revisited: is there room for improvement? AB - BACKGROUND: The advent of drugs that inhibit transient lower esophageal sphincter relaxation (TLESR) necessitates accurate identification and scoring. We assessed the intra- and inter-assessor variability of the existing objective criteria for TLESR, improving them where necessary. METHODS: Two 3-h postprandial esophageal manometric and pH recordings were performed in 20 healthy volunteers. Each recording was duplicated. The recordings were analyzed by five experienced observers for TLESRs based on their expert opinion. TLESRs were also analyzed for the presence of the original four criteria as well as inhibition of the crural diaphragm (ID), a prominent after-contraction (AC), acid reflux and an esophageal common cavity. KEY RESULTS: The overall inter- and intra-observer agreements for TLESRs scored, according to observer's expert opinion, were 59% (range 56-67%) and 74% (60-89%), respectively. When TLESRs were restricted to those fulfilling the original criteria, these agreements fell to 46% (40-53%) and 60% (44-67%), respectively. Cleaning the recordings by removal of technically flawed sections improved agreements by 5%. Inclusion of additional criteria (ID and AC) resulted in inter- and intra-observer agreements of 62% (52-70%) and 69% (53-79%), respectively. A consensus analysis performed collectively by three observers and based on the new criteria (original +/- ID and AC) resulted in 84% agreement between the paired recordings. CONCLUSIONS & INFERENCES: The original criteria for the definition of TLESRs allows for substantial inter- and intra-observer variability, which can be reduced by incorporation of additional objective criteria. However, the highest level of intra-observer agreement can be achieved by consensus analysis. PMID- 22103260 TI - Absence of fetal transmission of H1N1 despite severe maternal infection. PMID- 22103261 TI - Homeopathy and heart rate variability: concerns and issues. PMID- 22103262 TI - Proteomic consequences of a single gene mutation in a colorectal cancer model. AB - The proteomic effects of specific cancer-related mutations have not been well characterized. In colorectal cancer (CRC), a relatively small number of mutations in key signaling pathways appear to drive tumorigenesis. Mutations in adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, occur in up to 60% of CRC tumors. Here we examine the proteomic consequences of a single gene mutation by using an isogenic CRC cell culture model in which wildtype APC expression has been ectopically restored. Using LC-MS/MS label free shotgun proteomics, over 5000 proteins were identified in SW480Null (mutant APC) and SW480APC (APC restored). We observed 155 significantly differentially expressed proteins between the two cell lines, with 26 proteins showing opposite expression trends relative to gene expression measurements. Protein changes corresponded to previously characterized features of the APCNull phenotype: loss of cell adhesion proteins, increase in cell cycle regulators, alteration in Wnt signaling related proteins, and redistribution of beta-catenin. Increased expression of RNA processing and isoprenoid biosynthetic proteins occurred in SW480Null cells. Therefore, shotgun proteomics reveals proteomic differences associated with a single gene change, including many novel differences that fall outside known target pathways. PMID- 22103263 TI - Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress. AB - OBJECTIVES: HIV and antiretroviral (ART) exposure in utero may have deleterious effects on the infant, but uncertainty still exists. The objective of this study was to evaluate aspects of mitochondrial DNA (mtDNA) content, mitochondrial function and oxidative stress simultaneously in placenta, umbilical cord blood and infant blood in HIV/ART-exposed infants compared with uninfected controls. METHODS: HIV-1-infected pregnant women and HIV-1-uninfected healthy pregnant controls were enrolled in the study prospectively. Placenta and umbilical cord blood were obtained at delivery and infant blood was obtained within 48 h of delivery. mtDNA content was determined for each specimen. Nuclear [subunit IV of cytochrome c-oxidase (COX IV)]- and mitochondrial (COX II)-encoded polypeptides of the oxidative phosphorylation enzyme cytochrome c-oxidase were quantified in cord and infant blood. Placental mitochondria malondialdehyde (MDA) concentrations were measured as a marker of oxidative stress. RESULTS: Twenty HIV positive/HIV-exposed and 26 control mother-infant pairs were enrolled in the study. All HIV-infected women and their infants received ART. Placental MDA concentration and mtDNA content in placenta and cord blood were similar between groups. The cord blood COX II:IV ratio was lower in the HIV-positive group than in the controls, whereas the infant peripheral blood mtDNA content was higher in the HIV-exposed infants, but the infant peripheral blood COX II:IV ratio was similar. No infant had clinical evidence of mitochondrial disease or acquired HIV infection. In multivariable regression analyses, the significant findings in cord and infant blood were both most associated with HIV/ART exposure. CONCLUSIONS: HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART associated mitochondrial toxicity. PMID- 22103264 TI - Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease. AB - The EC (entorhinal cortex) is fundamental for cognitive and mnesic functions. Thus damage to this area appears as a key element in the progression of AD (Alzheimer's disease), resulting in memory deficits arising from neuronal and synaptic alterations as well as glial malfunction. In this paper, we have performed an in-depth analysis of astroglial morphology in the EC by measuring the surface and volume of the GFAP (glial fibrillary acidic protein) profiles in a triple transgenic mouse model of AD [3xTg-AD (triple transgenic mice of AD)]. We found significant reduction in both the surface and volume of GFAP-labelled profiles in 3xTg-AD animals from very early ages (1 month) when compared with non Tg (non-transgenic) controls (48 and 54%, reduction respectively), which was sustained for up to 12 months (33 and 45% reduction respectively). The appearance of Abeta (amyloid beta-peptide) depositions at 12 months of age did not trigger astroglial hypertrophy; nor did it result in the close association of astrocytes with senile plaques. Our results suggest that the AD progressive cognitive deterioration can be associated with an early reduction of astrocytic arborization and shrinkage of the astroglial domain, which may affect synaptic connectivity within the EC and between the EC and other brain regions. In addition, the EC seems to be particularly vulnerable to AD pathology because of the absence of evident astrogliosis in response to Abeta accumulation. Thus we can consider that targeting astroglial atrophy may represent a therapeutic strategy which might slow down the progression of AD. PMID- 22103265 TI - Vapor-phase staining of cyanoacrylate-fumed latent fingerprints using p dimethylaminobenzaldehyde. AB - Contrasting or enhancing of cyanoacrylate ester-fumed latent fingerprints deposited on solvent-sensitive materials such as oil marker writings and rough surface materials such as unglazed earthenware is not easy by conventional dye solutions dipping or dye powder dusting. In this study, a new vapor-phase staining method using p-dimethylaminobenzaldehyde (DMAB) is proposed for staining such materials. DMAB has high volatility and selective absorbability to cyanoacrylate-fumed fingerprints, so that cyanoacrylate-treated samples can be easily stained by leaving them simply in a closed container along with DMAB crystals for 48-96 h at room temperature or in conjunction with the use of mild heating. The stained fingerprint could be excited by UV irradiation (365 nm), and the fluorescent fingerprint was photographed through a UV cut-off filter (420 nm). The new method achieved minimally destructive fluorescent staining for the solvent-sensitive samples and the rough surfaced samples. PMID- 22103266 TI - The IgE repertoire in children and adolescents resolved at component level: a cross-sectional study. AB - BACKGROUND: It is well known that allergy evolves at clinical level from the birth to adulthood, and this has been clearly demonstrated also at a level of sensitization. However, little information is available on the evolution of the IgE repertoire directed to single allergenic components. In this cross-sectional, observational study, the evolution of the IgE repertoire was analysed at component level. METHODS: Serum samples from 901 allergic patients, stratified in 6 groups according to age, were analysed by ImmunoCAP ISAC, a microarray chip that allows to identify the presence of specific IgE towards 103 different allergen components. Total IgE were also evaluated. RESULTS: The behaviour of total IgE according to age strictly paralleled that of the sum of specific IgE directed to molecular components. As expected, food-related components (in particular those of milk and egg) were the most frequently recognized in the earliest ages, whereas specific IgE to plant allergens appeared invariably later. Nonetheless, IgE specific to mite components was the most represented in all age classes. Of note, specific IgE against cross-reacting allergens was virtually absent in the first years and tended to appear only after the age of 6. CONCLUSION: Despite this was not a study performed on a cohort of patients followed up from birth to adolescence, the molecular patterns of allergen recognition resulted modified according to age. These findings may support, at molecular level, the clinical features of the allergic march. PMID- 22103267 TI - The Concerns about Counseling Racial Minority Clients scale. AB - The purpose of this study was to develop and validate the Concerns about Counseling Racial Minority Clients (CCRMC) scale among counselor trainees. Sample 1 was used for an exploratory factor analysis and confirmatory factor analysis. Four factors were identified, Managing Cultural Differences (alpha = .82), Offending or Hurting Clients (alpha = .87), Biased Thoughts and Behaviors (alpha = .81), and Client Perceptions (alpha = .77). The coefficient alpha for the CCRMC was .90. The results support the validity of the scale. The scores on the CCRMC and its subscales have positive associations with fear of negative evaluation from others (r = .19 to .40) and negative associations with general counseling self-efficacy (r = -.30 to -.46) and multicultural intervention self-efficacy (r = -.30 to -.64). The CCRMC significantly predicted fear of negative evaluation, session management self-efficacy, and multicultural intervention self-efficacy over and above multicultural social desirability. The validity evidence was not different between White and minority graduate trainees. In Sample 2, the estimated 1-week test-retest reliabilities ranged from .75 to .96 for the CCRMC and its four subscales. PMID- 22103268 TI - Counseling psychology trainees' perceptions of training and commitments to social justice. AB - This mixed methods study examined social justice commitments of counseling psychology graduate trainees. In the quantitative portion of the study, a national sample of trainees (n = 260) completed a web-based survey assessing their commitments to social justice and related personal and training variables. Results suggested that students desired greater social justice training than what they experienced in their programs. In the qualitative portion, we used a phenomenological approach to expand and elaborate upon quantitative results. A subsample (n = 7) of trainees who identified as strong social justice activists were interviewed regarding their personal, professional, and training experiences. Eleven themes related to participants' meanings of and experiences with social justice emerged within 4 broad categories: nature of social justice, motivation for activism, role of training, and personal and professional integration. Thematic findings as well as descriptive statistics informed the selection and ordering of variables in a hierarchical regression analysis that examined predictors of social justice commitment. Results indicated that trainees' perceptions of training environment significantly predicted their social justice commitment over and above their general activist orientation and spirituality. Findings are discussed collectively, and implications for training and future research are provided. PMID- 22103269 TI - A review of opioid prescribing practices and associations with repeat opioid prescriptions in a contemporary outpatient HIV clinic. AB - OBJECTIVES: Among persons in current HIV outpatient care, data on opioid prescribing are lacking. This study aims to evaluate predictors of repeat opioid prescribing and to characterize outpatient opioid prescribing practices. METHODS: Retrospective cross-sectional study of persons >=18 years in HIV outpatient care who completed an annual behavioral assessment between June 2008 and June 2009. Persons were grouped by <=1 and >=2 opioid prescriptions (no-repeat-opioid and repeat-opioids, respectively). Independent predictors for repeat-opioids were evaluated. Opioid prescribing practices were characterized in a sub-study of persons prescribed any opioid. RESULTS: Overall, 659 persons were included, median age 43 years, 70% men, and 68% African American. Independent predictors of repeat-opioids (88 [13%] persons) included opportunistic illnesses (both current and previous), depression, peripheral neuropathy, and hepatitis C coinfection (P<0.05). In the subgroup, 140 persons received any opioid prescription (96% short-acting, 33% tramadol). Indications for opioid prescribing were obtained in 101 (72%) persons, with 97% for noncancer-related pain symptoms. Therapeutic response was documented on follow-up in 67 (48%) persons, with no subjective relief of symptoms in 63%. Urine drug screens were requested in 6 (4%) persons, and all performed were positive for illicit drugs. CONCLUSIONS: Advanced HIV disease and greater medical and neuropsychiatric comorbidity predict repeat opioid prescribing, and these findings reflect the underlying complexities in managing pain symptoms in this population. We also highlight multiple deficiencies in opioid prescribing practices and nonadherence to guidelines, which are of concern as effective and safe pain management for our HIV-infected population is an optimal goal. PMID- 22103270 TI - Implications of caries diagnostic strategies for clinical management decisions. AB - OBJECTIVES: In clinical practice, a visual-tactile caries examination is frequently supplemented by bitewing radiography. This study evaluated strategies for combining visual-tactile and radiographic caries detection methods and determined their implications for clinical management decisions in a low-caries population. METHODS: Each of four examiners independently examined preselected contacting interproximal surfaces in 53 dental students aged 20-37 years using a visual-tactile examination and bitewing radiography. The visual-tactile examination distinguished between noncavitated and cavitated lesions while the radiographic examination determined lesion depth. Direct inspection of the surfaces following tooth separation for the presence of cavitated or noncavitated lesions was the validation method. The true-positive rate (i.e. the sensitivity) and the false-positive rate (i.e. 1-specificity) were calculated for each diagnostic strategy. RESULTS: Visual-tactile examination provided a true-positive rate of 34.2% and a false-positive rate of 1.5% for the detection of a cavity. The combination of a visual-tactile and a radiographic examination using the lesion in dentin threshold for assuming cavitation had a true-positive rate of 76.3% and a false-positive rate of 8.2%. When diagnostic observations were translated into clinical management decisions using the rule that a noncavitated lesion should be treated nonoperatively and a cavitated lesion operatively, our results showed that the visual-tactile method alone was the superior strategy, resulting in most correct clinical management decisions and most correct decisions regarding the choice of treatment. PMID- 22103271 TI - Modeling the influence of histone proteins on the sensitivity of DNA to ionizing radiation. AB - The DNA-binding proteins that are present in chromatin significantly affect the sensitivity of cells to ionizing radiation and to the radiation chemistry of DNA damage. The interaction between protein and DNA modifies the radiation chemistry of the latter. To model these processes, we have examined the effects of ionizing radiation on the minichromosome form of SV40 (which contains histone proteins arranged in nucleosomes) and also on plasmid DNA in the presence of lysozyme. Although high concentrations of lysozyme can bring about an extensive radioprotection by condensation of the plasmid, at lower levels it still produces significant radioprotective effects under conditions where this associative phase separation does not take place. The presence of histones or of lysozyme decreases the yield of modified guanines produced by ionizing radiation. Comparison with previous observations made with oligopeptides suggests that the mechanism responsible is electron donation to guanyl radicals in the DNA by tryptophan and tyrosine residues in the proteins. However, there was no evidence for DNA-protein crosslink formation. PMID- 22103272 TI - Commentary on the combined disaster in Japan. PMID- 22103273 TI - Reduction of spontaneous somatic mutation frequency by a low-dose X irradiation of Drosophila larvae and possible involvement of DNA single-strand damage repair. AB - The third instar larvae of Drosophila were irradiated with X rays, and the somatic mutation frequency in their wings was measured after their eclosion. In the flies with normal DNA repair and apoptosis functions, 0.2 Gy irradiation at 0.05 Gy/min reduced the frequency of the so-called small spot (mutant cell clone with reduced reproductive activity) compared with that in the sham-irradiated flies. When apoptosis was suppressed using the baculovirus p35 gene, the small spot frequency increased four times in the sham-irradiated control group, but the reduction by the 0.2-Gy irradiation was still evident. In a non-homologous end joining-deficient mutant, the small spot frequency was also reduced by 0.2 Gy radiation. In a mutant deficient in single-strand break repair, no reduction in the small spot frequency by 0.2 Gy radiation was observed, and the small spot frequency increased with the radiation dose. Large spot (mutant cell clone with normal reproductive activity) frequency was not affected by suppression of apoptosis and increased monotonically with radiation dose in wild-type larvae and in mutants for single- or double-strand break repair. It is hypothesized that some of the small spots resulted from single-strand damage and, in wild-type larvae, 0.2 Gy radiation activated the normal single-strand break repair gene, which reduced the background somatic mutation frequency. PMID- 22103274 TI - beta-Adrenergic receptors stimulate interleukin-6 production through Epac dependent activation of PKCdelta/p38 MAPK signalling in neonatal mouse cardiac fibroblasts. AB - BACKGROUND AND PURPOSE IL-6 plays crucial roles in cardiac hypertrophy, cardiac fibrosis and heart failure. Activation of beta-adrenoceptors induced IL-6 production in neonatal mouse cardiac fibroblasts (NMCFs) through a G(s) /adenylate cyclase/cAMP/p38 MAPK pathway but independent of PKA. However, how cAMP activates p38 MAPK is still not defined. In this study, we have assessed the role of the exchange protein directly activated by cAMP (Epac) and PKCdelta in p38 MAPK activation and IL-6 production by stimulated by the beta-adrenoceptor agonist isoprenaline in NMCFs. EXPERIMENTAL APPROACH The IL-6 concentration in cell culture supernatants was measured by ELISA. The levels of phosphorylated and total p38 MAPK and PKCdelta were determined by Western blot analysis. The translocation of PKCdelta was determined by immunoblotting the soluble and particulate fractions. Expression of Epac1 or PKCdelta was knocked down by the corresponding, adenovirus-mediated, small hairpin RNA (shRNA). RESULTS In NMCFs, activation of beta-adrenoceptors enhanced PKCdelta phosphorylation and translocation. Furthermore, knock-down of the PKCdelta isoform using an adenovirus-mediated shRNA markedly down-regulated IL-6 induction by NMCFs stimulated with isoprenaline. Moreover, knock-down of Epac1 confirmed that Epac1 was upstream of PKCdelta in IL-6 production. Additionally, both Epac1 and PKCdelta mediated the p38 MAPK activation induced by isoprenaline. CONCLUSIONS AND IMPLICATIONS beta-Adrenoceptor agonists activate a cAMP/Epac/PKCdelta/p38 MAPK pathway to produce IL-6 in NMCFs. This study identifies Epac as the link between cAMP and p38 MAPK signalling pathways and demonstrates that PKCdelta can function as a novel downstream effector of this beta-adrenoceptor/cAMP/Epac pathway. PMID- 22103275 TI - The role of the antebrachiocarpal ligaments in the prevention of hyperextension of the antebrachiocarpal joint. AB - OBJECTIVE: To evaluate the role of the medial collateral ligament, lateral collateral ligament, and the palmar carpal ligaments in the prevention of hyperextension of the antebrachiocarpal (AC) joint. STUDY DESIGN: In vitro experiment. ANIMALS: Cadaveric canine thoracic limbs (n = 12 pair). METHODS: Thoracic limbs from 12 healthy mixed breed dogs, free of carpal joint pathology, were assigned to 1 of 6 groups, defined by the order in which the ligaments stabilizing the AC joint were cut. The antebrachium, carpus, and proximal metacarpal (MC) bones were stripped of all muscle tissue, preserving the carpal joint capsule. After specimens were prepared for biomechanical testing, the manus was loaded using a system of weights and pulleys to extend the carpus. Extension was measured using a single motion tracking sensor fixed to the MC bones. All specimens were tested with all ligaments intact and after cutting each of the ligaments. RESULTS: Cutting each of the ligaments resulted in a significant change in the angle of extension of the carpus when compared with carpal extension with the ligaments intact. Cutting the palmar AC ligaments resulted in a significantly larger change in extension angle than occurred after cutting the medial and lateral collateral ligaments. CONCLUSION: Each of the ligaments tested contribute to the prevention of hyperextension of the AC joint. PMID- 22103276 TI - Monitoring oxidative stress in acute-on-chronic liver failure by advanced oxidation protein products. AB - AIM: Increased oxidative stress is important in the pathogenesis of acute-on chronic liver failure (ACLF). This study aimed to investigate whether advanced oxidation protein products (AOPP) levels can monitor oxidative stress of ACLF patients. Furthermore, we aimed to study plasma exchange (PE) treatment and determine whether it can eliminate AOPP. METHODS: We measured AOPP levels in 50 ACLF patients, 30 patients with compensated liver cirrhosis (CR), 30 patients with chronic hepatitis B (CHB) and 50 healthy controls by spectrophotometric assay. AOPP concentrations were also measured before and after PE treatment in ACLF patients. As an apoptosis marker, serum cytokeratin 18 (CK18 M 30) levels were detected to investigate the relationship between AOPP and apoptosis in ACLF patients. RESULTS: Significantly higher AOPP levels at admission were found in patients with ACLF compared with CR, CHB and healthy controls (69.45 +/- 29.04 umol/L vs. 19.67 +/- 7.02 umol/L, 26.75 +/- 5.21 umol/L and 21.35 +/- 6.15 umol/L, respectively; P < 0.001). There was a positive relationship with total bilirubin, Child-Pugh, model for end-stage liver disease scores and CK18 M 30. In ACLF patients, AOPP levels were higher in non-survivors than survivors. An AOPP cut-off of 74.21 umol/L was used for predicting poor prognosis. Multivariate Cox regression analysis demonstrated that AOPP were independent risk factors for prognosis. Dynamic change of AOPP levels associated with prognosis appeared earlier than total bilirubin. Following PE treatment, AOPP levels reduced to 34.65 +/- 18.14 umol/L (P < 0.001). CONCLUSIONS: Advanced oxidation protein products were suitable for monitoring the levels of oxidative stress in ACLF patients. Increased AOPP may serve as an important biological marker of worse outcome. In addition, PE therapy was effective in reducing AOPP. PMID- 22103277 TI - Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats. AB - BACKGROUND AND PURPOSE: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model. METHODS: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma. RESULTS: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force. INTERPRETATION: Scl-Ab increases bone formation and screw fixation to a similar degree in loaded and unloaded bone. PMID- 22103278 TI - Correlation between disability and MRI findings in lumbar spinal stenosis. PMID- 22103279 TI - The long-term in vivo behavior of polymethyl methacrylate bone cement in total hip arthroplasty. AB - BACKGROUND AND PURPOSE: The long-term success of cemented total hip arthroplasty (THA) has been well established. Improved outcomes, both radiographically and clinically, have resulted mainly from advances in stem design and improvements in operating techniques. However, there is concern about the durability of bone cement in vivo. We evaluated the physical and chemical properties of CMW1 bone cements retrieved from patients undergoing revision THA. METHODS: CMW1 cements were retrieved from 14 patients who underwent acetabular revision because of aseptic loosening. The time in vivo before revision was 7-30 years. The bending properties of the retrieved bone cement were assessed using the three-point bending method. The molecular weight and chemical structure were analyzed by gel permeation chromatography and Fourier-transform infrared spectroscopy. The porosity of the bone cements was evaluated by 3-D microcomputer tomography. RESULTS: The bending strength decreased with increasing time in vivo and depended on the density of the bone cement, which we assume to be determined by the porosity. There was no correlation between molecular weight and time in vivo. The infrared spectra were similar in the retrieved cements and in the control CMW1 cements. INTERPRETATION: Our results indicate that polymer chain scission and significant hydrolysis do not occur in CMW1 cement after implantation in vivo, even in the long term. CMW1 cement was stable through long-term implantation and functional loading. PMID- 22103280 TI - Metal ion levels and functional results after either resurfacing hip arthroplasty or conventional metal-on-metal hip arthroplasty. AB - BACKGROUND: Modern metal-on-metal hip resurfacing was introduced as a bone preserving method of joint reconstruction for young and active patients; however, the large diameter of the bearing surfaces is of concern for potentially increased metal ion release. PATIENTS AND METHODS: 71 patients (< 65 years old) were randomly assigned to receive either a resurfacing (R) hip arthroplasty (n = 38) or a conventional metal-on-metal (C) hip arthroplasty (n = 33). Functional outcomes were assessed preoperatively and at 6, 12, and 24 months. Cobalt and chromium blood levels were analyzed preoperatively and at 3, 6, 12, and 24 months. RESULTS: All functional outcome scores improved for both groups. At 12 and 24 months, the median UCLA activity score was 8 in the R patients and 7 in the C patients (p < 0.05). At 24 months, OHS was median 16 in C patients and 13 in R patients (p < 0.05). However, in spite of randomization, UCLA scores also appeared to be higher in R patients at baseline. Satisfaction was similar in both groups at 24 months. Cobalt concentrations were statistically significantly higher for R patients only at 3 and 6 months. Chromium levels remained significantly higher for R patients until 24 months. No pseudotumors were encountered in either group. One R patient was revised for early aseptic loosening and in 2 C patients a cup insert was exchanged for recurrent dislocation. INTERPRETATION: R patients scored higher on UCLA, OHS, and satisfaction at some time points; however, as for the UCLA, preoperative levels were already in favor of R. The differences, although statistically significant, were of minor clinical importance. Chromium blood levels were statistically significantly higher for R patients at all follow-up measurements, whereas for cobalt this was only observed up to 6 months. The true value of resurfacing hip arthroplasty over conventional metal-on-metal hip arthroplasty will be determined by longer follow-up and a possible shift of balance between their respective (dis)advantages. PMID- 22103281 TI - Outcome of the cementless Taperloc stem. PMID- 22103282 TI - Total hip replacement in young adults with hip dysplasia. PMID- 22103287 TI - Phytochemical screening of Nepeta cataria extracts and their in vitro inhibitory effects on free radicals and carbohydrate-metabolising enzymes. AB - This research was performed to investigate in vitro the biological activities of successive as well as 70% ethanol extracts of Nepeta cataria on some biochemical parameters including oxidative markers and carbohydrate-hydrolysing enzyme activities (alpha-amylase, beta-galactosidase and alpha-glucosidase). Powdered N. cataria and its successive extracts were screened for their phytochemical constituents. Tests for tannins, carbohydrates, glycosides and flavonoids were positive in ethanolic extract, but those for steroids and terpenoids were positive in petroleum ether and chloroform extracts. Also, different extracts were chromatographically investigated. The results obtained demonstrated that different successive extracts of N. cataria exhibited an inhibitory effect on oxidative stress indices and carbohydrate-hydrolysing enzymes. It is observed that 70% ethanol, petroleum ether and chloroform extracts showed, respectively, the most potent inhibitory activities, while ethyl acetate and ethanol successive extracts appeared with moderate or low reducing activities. PMID- 22103288 TI - The antimicrobial activity of thyme essential oil against multidrug resistant clinical bacterial strains. AB - AIM: The aim of this work was to investigate the antimicrobial activity of thyme essential oil against clinical multidrug resistant strains of Staphylococcus, Enterococcus, Escherichia, and Pseudomonas genus. MATERIALS: The antibacterial activity of oil was tested against standard strains of bacteria and 120 clinical strains isolated from patients with infections of the oral cavity, abdominal cavity, respiratory and genitourinary tracts, skin, and from the hospital environment. METHODS: Agar diffusion was used to determine the microbial growth inhibition of bacterial growth at various concentrations of oil from Thymus vulgaris. Susceptibility testing to antibiotics was carried out using disk diffusion. RESULTS: Thyme essential oil strongly inhibited the growth of the clinical strains of bacteria tested. CONCLUSIONS: The use of phytopharmaceuticals based on an investigated essential oil from thyme in the prevention and treatment of various human infections may be reasonable. PMID- 22103289 TI - Influence of sampler configuration on the uptake kinetics of a passive air sampler. AB - Passive air samplers (PAS) are simple and cost-effective tools to monitor semivolatile organic compounds in air. Chemical uptake occurs by molecular diffusion from ambient air to a passive sampling medium (PSM). Previous calibration studies indicate that even for the same type of PAS, passive air sampling rates (R, m(3)(air)/d) can be highly variable due to the influence of a number of factors. Earlier studies mainly focused on factors (e.g., wind speed and temperature) influencing R via the kinetic resistance posed by the air boundary layer surrounding the PSM because that layer was deemed to be the main factor determining the uptake kinetics. Whereas recent calibration studies suggest that the PAS configuration can influence R, so far few studies have specifically focused on this factor. In this study, with the objective to understand the effect of PAS configurations on R, we applied a gravimetrical approach to study the kinetics of water vapor uptake from indoor air by silica gel placed inside cylindrical PAS of various configurations. We also conducted an indoor calibration for polychlorinated biphenyls on the same type of PAS using XAD-resin as the PSM. R was found to be proportional to the interfacial transfer area of the PSM but not the amount of the PSM because chemicals mainly accumulated in the outer layer of the PSM during the deployment time of the PAS. The sampler housing and the PSM can introduce kinetic resistance to chemical uptake as indicated by changes in R caused by positioning the PSM at different distances from the opening of the sampler housing and by using PSM of different diameters. Information gained from this study is useful for optimizing the PAS design with the objective to reduce the material and shipping costs without sacrificing sampling efficiency. PMID- 22103290 TI - Bond energies and structures of ammonia-sulfuric acid positive cluster ions. AB - New particle formation in the atmosphere is initiated by nucleation of gas-phase species. The small molecular clusters that act as seeds for new particles are stabilized by the incorporation of an ion. Ion-induced nucleation of molecular cluster ions containing sulfuric acid generates new particles in the background troposphere. The addition of a proton-accepting species to sulfuric acid cluster ions can further stabilize them and may promote nucleation under a wider range of conditions. To understand and accurately predict atmospheric nucleation, the stabilities of each molecular cluster within a chemical family must be known. We present the first comprehensive measurements of the ammonia-sulfuric acid positive ion cluster system NH(4)(+)(NH(3))(n)(H(2)SO(4))(s). Enthalpies and entropies of individual growth steps within this system were measured using either an ion flow reactor-mass spectrometer system under equilibrium conditions or by thermal decomposition of clusters in an ion trap mass spectrometer. Low level ab initio structural calculations provided inputs to a master equation model to determine bond energies from thermal decomposition measurements. Optimized ab initio structures for clusters up through n = 3, s = 3 are reported. Upon addition of ammonia and sulfuric acid pairs, internal proton transfer generates multiple NH(4)(+) and HSO(4)(-) ions within the clusters. These multiple-ion structures are up to 50 kcal mol(-1) more stable than corresponding isomers that retain neutral NH(3) and H(2)SO(4) species. The lowest energy n = s clusters are composed entirely of ions. The addition of acid-base pairs to the core NH(4)(+) ion generates nanocrystals that begin to resemble the ammonium bisulfate bulk crystal starting with the smallest n = s cluster, NH(4)(+)(NH(3))(1)(H(2)SO(4))(1). In the absence of water, this cluster ion system nucleates spontaneously for conditions that encompass most of the free troposphere. PMID- 22103291 TI - Carbon dioxide capture from the air using a polyamine based regenerable solid adsorbent. AB - Easy to prepare solid materials based on fumed silica impregnated with polyethylenimine (PEI) were found to be superior adsorbents for the capture of carbon dioxide directly from air. During the initial hours of the experiments, these adsorbents effectively scrubbed all the CO(2) from the air despite its very low concentration. The effect of moisture on the adsorption characteristics and capacity was studied at room temperature. Regenerative ability was also determined in a short series of adsorption/desorption cycles. PMID- 22103292 TI - Chemical inhibitors suggest endophytic fungal paclitaxel is derived from both mevalonate and non-mevalonate-like pathways. AB - Taxus trees possess fungal endophytes reported to produce paclitaxel. Inhibitors that block early steps in plant paclitaxel biosynthesis were applied to a paclitaxel-producing fungus to determine whether these steps are shared. The plant paclitaxel backbone is reportedly derived from the non-mevalonate terpenoid pathway, while the side chain is phenylalanine-derived. Evidence that the shikimate pathway contributes to fungal paclitaxel was shown by decreased paclitaxel accumulation following inhibition of phenylalanine ammonia lyase. Expression of another shikimate pathway enzyme, 3-dehydroquinate synthase, coincided with paclitaxel production. The importance of the mevalonate pathway in fungal paclitaxel biosynthesis was shown by inhibition of fungal paclitaxel accumulation using compactin, a specific inhibitor of 3-hydroxy-3-methyl-glutaryl CoA reductase. Expression of another mevalonate pathway enzyme, 3-hydroxy-3 methyl-glutaryl-CoA synthase, coincided with fungal paclitaxel accumulation. Unexpectedly, results from using fosmidomycin suggested that fungal paclitaxel requires 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an enzyme in the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway normally found in bacteria/plants. Additional lines of evidence support this finding; first, a plant DXR antibody recognized a fungal peptide of the correct size; second, expression of an apparent fungal DXR ortholog correlated to changes in paclitaxel production; finally, BLAST searching identified a gene putatively encoding 1 deoxy-D-xylulose-5-phosphate synthase, the first enzyme in the MEP pathway in Aspergillus. PMID- 22103293 TI - Assessment of gastric motor function in childhood functional dyspepsia and obesity. AB - BACKGROUND: The aim was to compare gastric emptying rate and nutrient tolerance during a satiety drinking test in children with functional dyspepsia (FD) and obesity and to study the relationship between daily caloric intake and the satiety drinking test. METHODS: A total of 28 dyspeptic children (22 girls, mean age 12.5 +/- 3.1 years) and 15 obese children (five girls, 13.3 +/- 1.8 years) were studied. The patients underwent an octanoic acid gastric emptying breath test and a satiety drinking test. Prior to both tests, a dyspepsia questionnaire was filled out to calculate the mean calorie intake. KEY RESULTS: The most prevalent dyspeptic symptoms were early satiety (96.4%), postprandial fullness (89.2%), and epigastric pain (78.6%), followed by nausea (50%). All dyspeptic and obese children (n = 43) started the satiety drinking test and 41 children completed the test until a score of 5 was reached. The maximum ingested volume in FD was significantly lower than in obesity or in age-matched healthy controls (252 +/- 85 vs 479 +/- 199 and 359 +/- 29 mL respectively, both P < 0.05). As a group, dyspeptic children had significantly slower gastric emptying than obese children (89.7 +/- 54.8 min vs 72.5 +/- 26.0 min, P = 0.05). Daily calorie intake was significantly higher in obese children than that in dyspeptic children (2325 +/- 469 vs 1503 +/- 272 cal, P < 0.0001). The endpoint of the satiety drinking test was significantly correlated with body weight or BMI (both R = 0.41, P = 0.04), but not with daily calorie intake, gastric emptying rate or age. CONCLUSIONS & INFERENCES: The satiety drinking test is a potentially useful non invasive tool in the investigation of children with FD and obesity. PMID- 22103295 TI - Authors' reply to response to "Mindfulness and psychological well-being: are they related to type of meditation technique practiced?". PMID- 22103294 TI - Microbial symbionts: a resource for the management of insect-related problems. AB - Microorganisms establish with their animal hosts close interactions. They are involved in many aspects of the host life, physiology and evolution, including nutrition, reproduction, immune homeostasis, defence and speciation. Thus, the manipulation and the exploitation the microbiota could result in important practical applications for the development of strategies for the management of insect-related problems. This approach, defined as 'Microbial Resource Management' (MRM), has been applied successfully in various environments and ecosystems, as wastewater treatments, prebiotics in humans, anaerobic digestion and so on. MRM foresees the proper management of the microbial resource present in a given ecosystem in order to solve practical problems through the use of microorganisms. In this review we present an interesting field for application for MRM concept, i.e. the microbial communities associated with arthropods and nematodes. Several examples related to this field of applications are presented. Insect microbiota can be manipulated: (i) to control insect pests for agriculture; (ii) to control pathogens transmitted by insects to humans, animals and plants; (iii) to protect beneficial insects from diseases and stresses. Besides, we prospect further studies aimed to verify, improve and apply MRM by using the insect-symbiont ecosystem as a model. PMID- 22103296 TI - Complex trait subtypes identification using transcriptome profiling reveals an interaction between two QTL affecting adiposity in chicken. AB - BACKGROUND: Integrative genomics approaches that combine genotyping and transcriptome profiling in segregating populations have been developed to dissect complex traits. The most common approach is to identify genes whose eQTL colocalize with QTL of interest, providing new functional hypothesis about the causative mutation. Another approach includes defining subtypes for a complex trait using transcriptome profiles and then performing QTL mapping using some of these subtypes. This approach can refine some QTL and reveal new ones.In this paper we introduce Factor Analysis for Multiple Testing (FAMT) to define subtypes more accurately and reveal interaction between QTL affecting the same trait. The data used concern hepatic transcriptome profiles for 45 half sib male chicken of a sire known to be heterozygous for a QTL affecting abdominal fatness (AF) on chromosome 5 distal region around 168 cM. RESULTS: Using this methodology which accounts for hidden dependence structure among phenotypes, we identified 688 genes that are significantly correlated to the AF trait and we distinguished 5 subtypes for AF trait, which are not observed with gene lists obtained by classical approaches. After exclusion of one of the two lean bird subtypes, linkage analysis revealed a previously undetected QTL on chromosome 5 around 100 cM. Interestingly, the animals of this subtype presented the same q paternal haplotype at the 168 cM QTL. This result strongly suggests that the two QTL are in interaction. In other words, the "q configuration" at the 168 cM QTL could hide the QTL existence in the proximal region at 100 cM. We further show that the proximal QTL interacts with the previous one detected on the chromosome 5 distal region. CONCLUSION: Our results demonstrate that stratifying genetic population by molecular phenotypes followed by QTL analysis on various subtypes can lead to identification of novel and interacting QTL. PMID- 22103297 TI - High prevalence of unintended pregnancies in HIV-positive women of reproductive age in Ontario, Canada: a retrospective study. AB - OBJECTIVES: There is speculation, but there are few data, on the high rates of unintended pregnancies in HIV-positive women. We investigated rates and correlates of unintended pregnancies among HIV-positive women of reproductive age. METHODS: A cross-sectional study was conducted with recruitment stratified to match the geographical distribution of HIV-positive women of reproductive age (18-52 years) living in Ontario, Canada. Women, recruited from 38 sites between October 2007 and April 2009, were invited to complete a 189-item self administered survey. This analysis focused on questions relating to pregnancy and whether the last pregnancy was intended. Logistic regression models were fitted to calculate unadjusted and adjusted odds ratios of correlates of unintended pregnancies occurring after HIV diagnosis. Happiness with unintended pregnancies was also assessed. RESULTS: The median age at the time of the survey of the 416 participating HIV-positive women who were previously pregnant (53% before and 47% after HIV diagnosis) was 38 years [interquartile range (IQR) 33-44 years] and their last pregnancy was a median of 8 years (IQR 3-14 years) prior to the survey (n=283). Fifty-nine per cent were born outside Canada and 47% were of African ethnicity. Of the 416, 56% [95% confidence interval (CI) 51-61%] identified that their last pregnancy was unintended (57% before and 54% after HIV diagnosis). In the multivariable model, significant correlates of unintended pregnancy after HIV diagnosis were: marital status (P=0.01) and never having given birth (P=0.01). Women were less happy if their pregnancy was unintended (P<0.01). CONCLUSIONS: The prevalence of unintended pregnancy was high in this cohort. Pregnancy planning programmes are needed for this population to decrease fetal and maternal complications and reduce vertical and horizontal transmission. PMID- 22103298 TI - Protein composition of immunoprecipitated synaptic ribbons. AB - The synaptic ribbon is an electron-dense structure found in hair cells and photoreceptors. The ribbon is surrounded by neurotransmitter-filled vesicles and considered to play a role in vesicle release. We generated an objective, quantitative analysis of the protein composition of the ribbon complex using a mass spectrometry-based proteomics analysis. Our use of affinity-purified ribbons and control IgG immunoprecipitations ensure that the identified proteins are indeed associated with the ribbon complex. The use of mouse tissue, where the proteome is complete, generated a comprehensive analysis of the candidates. We identified 30 proteins (comprising 56 isoforms and subunits) associated with the ribbon complex. The ribbon complex primarily comprises proteins found in conventional synapses, which we categorized into 6 functional groups: vesicle handling (38.5%), scaffold (7.3%), cytoskeletal molecules (20.6%), phosphorylation enzymes (10.6%), molecular chaperones (8.2%), and transmembrane proteins from the presynaptic membrane firmly attached to the ribbon (11.3%). The 3 CtBP isoforms represent the major protein in the ribbon whether calculated by molar amount (30%) or by mass (20%). The relatively high quantity of phosphorylation enzymes suggests a very active and regulated structure. The ribbon appears to comprise a concentrated cluster of proteins dealing with vesicle creation, retention and distribution, and consequent exocytosis. PMID- 22103300 TI - Current practices by forensic anthropologists in adult skeletal age estimation. AB - When determining an age estimate from adult skeletal remains, forensic anthropologists face a series of methodological choices. These decisions, such as which skeletal region to evaluate, which methods to apply, what statistical information to use, and how to combine information from multiple methods, ultimately impacts the final reported age estimate. In this study, a questionnaire was administered to 145 forensic anthropologists, documenting current trends in adult age at death estimation procedures used throughout the field. Results indicate that the Suchey-Brooks pubic symphysis method (1990) remains the most highly favored aging technique, with cranial sutures and dental wear being the least preferred, regardless of experience. The majority of respondents stated that they vary their skeletal age estimate process case-by case and ultimately present to officials both a narrow and broad possible age range. Overall, respondents displayed a very high degree of variation in how they generate their age estimates, and indicated that experience and expertise play a large role in skeletal age estimates. PMID- 22103299 TI - Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease. AB - HD (Huntington's disease) is caused by an expanded polyQ (polyglutamine) repeat in the htt (huntingtin protein). GABAergic medium spiny neurons in the striatum are mostly affected in HD. However, mhtt (mutant huntingtin)-induced molecular changes in these neurons remain largely unknown. The present study focuses on the effect of mhtt on the subcellular localization of GAD (glutamic acid decarboxylase), the enzyme responsible for synthesizing GABA (gamma-aminobutyric acid). We report that the subcellular distribution of GAD is significantly altered in two neuronal cell lines that express either the N-terminus of mhtt or full-length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal htt; however, it diffuses in the cytosol of cells expressing mhtt. As a result, vesicle-associated GAD65 trafficking is impaired. Since palmitoylation of GAD65 is required for GAD65 trafficking, we then demonstrate that palmitoylation of GAD65 is reduced in the HD model. Furthermore, overexpression of HIP14 (huntingtin-interacting protein 14), the enzyme responsible for palmitoylating GAD65 in vivo, could rescue GAD65 palmitoylation and vesicle-associated GAD65 trafficking. Taken together, our data support the idea that GAD65 palmitoylation is important for the delivery of GAD65 to inhibitory synapses and suggest that impairment of GAD65 palmitoylation by mhtt may lead to altered inhibitory neurotransmission in HD. PMID- 22103301 TI - Timing matters: length of leave and working mothers' daily reentry regrets. AB - Dealing with developmental tasks in work and family domains is an important challenge for young and middle-aged adults. We investigated a transition that has evolved into a normative task for women, namely, the retransition back to paid work following maternity leave. In a diary study with 149 mothers who had just returned to work, we examined the daily experienced regrets concerning this return. In addition to personal resources (i.e., emotional stability, feeling prepared for the transition) and financial requirements needed to return to work, daily experienced family stress predicted decisional regrets. Moreover, our results suggest that leave length is related to psychological resilience in the face of day-to-day stress experiences: Late returners reported fewer regrets in general and were unaffected by daily family stress. Return-to-work regrets, in turn, were predictive of withdrawal intentions. This underlines the relevancy of the timing of the transition back to work in terms of successful development during this life phase. PMID- 22103302 TI - Peer relationships and depressive symptomatology in boys at puberty. AB - The physical changes of puberty coincide with an increase in the salience of peer relationships and a growing risk for depression and other forms of psychopathology. Previously, we reported that pubertal tempo, defined as a child's rate of intraindividual change in pubertal status (measured using parent reported Tanner stages; Marshall & Tanner, 1970), was associated with changes in boys'--but not girls'--depressive symptoms over and above effects explained by pubertal timing (Mendle, Harden, Brooks-Gunn, & Graber, 2010). The present study extends this previous research by examining changes in the quality of peer relationships in the association between individual differences in pubertal development and change in boys' depressive symptoms. Boys (N = 128, M = 9.61 years, SD = 0.70, at Time 1) were recruited from public schools and assessed annually for 4 years. Results from latent growth curve models indicated that earlier pubertal timing and more rapid pubertal tempo were associated with greater decrements in the quality of boys' peer relationships. After accounting for the association between change in peer relationships and depressive symptoms, the direct effects of pubertal timing and tempo on depressive symptoms were no longer significant. These results highlight a multifaceted approach to studying puberty and emphasize how social mechanisms may intersect with biological risk to produce psychological distress. PMID- 22103303 TI - Generalizing norms and preferences within social categories and individuals. AB - Under what conditions will people generalize and remember observed social information? Preschool- (n = 44) and young school-age (n = 46) children and adults (n = 40) heard short vignettes describing characters' actions and motives on a single occasion. Characters were introduced using either proper names or category labels. Test questions asked for prediction and memory of motives for the same (individual) or a different (category member) person in a future event. Critical items contrasted behaviors motivated by psychological states with those motivated by normative obligations. The hypothesis was that norms would generalize across members of social categories. In contrast, psychological states would be generalized to the same individual across time. Results supported both these hypotheses and revealed some developmental differences. Preschool-age children seemed most attentive to normative properties of social categories. Young school-age children were most attentive to psychological properties of individuals. Such differences may reflect a shift from early focus on within category similarities to a later focus on within-category differences. PMID- 22103304 TI - Dopamine, working memory, and training induced plasticity: implications for developmental research. AB - Cognitive deficits and particularly deficits in working memory (WM) capacity are common features in neuropsychiatric disorders. Understanding the underlying mechanisms through which WM capacity can be improved is therefore of great importance. Several lines of research indicate that dopamine plays an important role not only in WM function but also for improving WM capacity. For example, pharmacological interventions acting on the dopaminergic system, such as methylphenidate, improve WM performance. In addition, behavioral interventions for improving WM performance in the form of intensive computerized training have recently been associated with changes in dopamine receptor density. These two different means of improving WM performance--pharmacological and behavioral--are thus associated with similar biological mechanisms in the brain involving dopaminergic systems. This article reviews some of the evidence for the role of dopamine in WM functioning, in particular concerning the link to WM development and cognitive plasticity. Novel data are presented showing that variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity. PMID- 22103305 TI - The implications of adult identity for educational and work attainment in young adulthood. AB - This study investigates the relation of young adult identities (ages 18-22 years), reflecting subjective age and psychosocial maturity, to educational and career attainment in young adulthood (ages 25-29 years). Add Health data show that having an older subjective age alone does not curtail attainment; the critical issue is the level of psychosocial maturity that accompanies subjective age. Those with older subjective ages and low psychosocial maturation have the lowest attainment at ages 25-29 years, while those with older subjective ages and high psychosocial maturation show considerable progress toward work-related attainment. For those with younger subjective ages, a lower level of psychosocial maturity is not as detrimental to attainment. PMID- 22103306 TI - Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: insights from molecular genetic research and implications for adult cognitive development. AB - Attention and working memory are fundamental for selecting and maintaining behaviorally relevant information. Not only do both processes closely intertwine at the cognitive level, but they implicate similar functional brain circuitries, namely the frontoparietal and the frontostriatal networks, which are innervated by cholinergic and dopaminergic pathways. Here we review the literature on cholinergic and dopaminergic modulations of visual-spatial attention and visual working memory processes to gain insights on aging-related changes in these processes. Some extant findings have suggested that the cholinergic system plays a role in the orienting of attention to enable the detection and discrimination of visual information, whereas the dopaminergic system has mainly been associated with working memory processes such as updating and stabilizing representations. However, since visual-spatial attention and working memory processes are not fully dissociable, there is also evidence of interacting cholinergic and dopaminergic modulations of both processes. We further review gene-cognition association studies that have shown that individual differences in visual-spatial attention and visual working memory are associated with acetylcholine- and dopamine-relevant genes. The efficiency of these 2 transmitter systems declines substantially during healthy aging. These declines, in part, contribute to age related deficits in attention and working memory functions. We report novel data showing an effect of dopamine COMT gene on spatial updating processes in older but not in younger adults, indicating potential magnification of genetic effects in old age. PMID- 22103307 TI - Breastfeeding modulates neonatal innate immune responses: a prospective birth cohort study. AB - BACKGROUND: Neonatal Toll-like receptor (TLR) responses are biased toward Th2 polarizing responses at birth and rapidly mature toward more balanced responses during the first month of life. Postnatal TLR maturation may be guided by environmental exposure. AIMS: To determine the environmental determinants of neonatal TLR function. MATERIALS AND METHODS: A prospective birth cohort study was performed in 291 healthy term neonates. Mode of delivery, breastfeeding, birth month, siblings, pets and parental smoking were analyzed in relation to neonatal innate immune parameters at the age of 1 month. Whole blood concentrations of innate immune cells were measured by flow cytometry. In vitro TLR-mediated cytokine production was determined by ELISA. RESULTS: Breastfeeding was the major determinant of neonatal innate immunity, associated with 5 (31%) of neonatal innate immune parameters, of which the association with TLR7-mediated IL 10 production was most significant (76 pg/ml in breastfed neonates vs. 293 pg/ml in formula-fed neonates, p = 0.001). Of innate immune variables, TLR3-mediated IL 12p70 production was highly associated with environmental exposures (pets, breastfeeding and mode of delivery), whereas TLR9-mediated cytokine responses were not associated with any environmental factor. CONCLUSION: Neonatal innate immune responses are differentially modulated by environmental exposure in the first month of life. The protective effect of breastfeeding against subsequent infections and atopy might be explained by its innate immune modulatory effects in the first month of life. PMID- 22103308 TI - Pharmacological challenge and synaptic response - assessing dopaminergic function in the rat striatum with small animal single-photon emission computed tomography (SPECT) and positron emission tomography (PET). AB - Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4 iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2 pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3 (4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention deficit/hyperactivity disorder, schizophrenia or drug abuse. PMID- 22103309 TI - A role for adhesion and degranulation-promoting adapter protein in collagen induced platelet activation mediated via integrin alpha(2) beta(1). AB - BACKGROUND: Collagen-induced platelet activation is a key step in the development of arterial thrombosis via its interaction with the receptors glycoprotein (GP)VI and integrin alpha(2) beta(1) . Adhesion and degranulation-promoting adapter protein (ADAP) regulates alpha(IIb) beta(3) in platelets and alpha(L) beta(2) in T cells, and is phosphorylated in GPVI-deficient platelets activated by collagen. OBJECTIVES: To determine whether ADAP plays a role in collagen-induced platelet activation and in the regulation and function of alpha(2) beta(1). METHODS: Using ADAP(-/-) mice and synthetic collagen peptides, we investigated the role of ADAP in platelet aggregation, adhesion, spreading, thromboxane synthesis, and tyrosine phosphorylation. RESULTS AND CONCLUSIONS: Platelet aggregation and phosphorylation of phospholipase Cgamma2 induced by collagen were attenuated in ADAP(-/-) platelets. However, aggregation and signaling induced by collagen related peptide (CRP), a GPVI-selective agonist, were largely unaffected. Platelet adhesion to CRP was also unaffected by ADAP deficiency. Adhesion to the alpha(2) beta(1) -selective ligand GFOGER and to a peptide (III-04), which supports adhesion that is dependent on both GPVI and alpha(2) beta(1), was reduced in ADAP(-/-) platelets. An impedance-based label-free detection technique, which measures adhesion and spreading of platelets, indicated that, in the absence of ADAP, spreading on GFOGER was also reduced. This was confirmed with non-fluorescent differential-interference contrast microscopy, which revealed reduced filpodia formation in ADAP(-/-) platelets adherent to GFOGER. This indicates that ADAP plays a role in mediating platelet activation via the collagen-binding integrin alpha(2) beta(1). In addition, we found that ADAP(-/-) mice, which are mildly thrombocytopenic, have enlarged spleens as compared with wild-type animals. This may reflect increased removal of platelets from the circulation. PMID- 22103310 TI - Patterns of school readiness forecast achievement and socioemotional development at the end of elementary school. AB - A person-oriented approach examined patterns of functioning in social and executive function domains at 54 months and in turn forecasted 5th-grade socioemotional and achievement outcomes for 944 children. Six distinct profiles of 54-month school readiness patterns predicted outcomes in 5th grade with indications of cross-domain association between 54-month performance and later functioning. A group of children at 54 months characterized by low working memory exhibited elevated levels of socioemotional problems and low achievement in 5th grade. Patterns in which high social competence or high working memory were prominent predicted high 5th-grade achievement. Unexpectedly, a group distinguished by attention problems performed well on later achievement outcomes. After controlling for children's early demographics, readiness profiles accounted for math achievement in 5th grade. PMID- 22103311 TI - Benign paroxysmal positional vertigo: is vestibular evoked myogenic potential testing useful? AB - CONCLUSIONS: In benign paroxysmal positional vertigo (BPPV), vestibular evoked myogenic potentials (VEMPs) help to better define the extent of saccular damage and the patient's prognosis. OBJECTIVES: To report the results of VEMPs in patients affected by BPPV of the posterior semicircular canal (PSC) in order to evaluate the presence of signs of saccular dysfunction compared to the normal population and to correlate them with the clinical picture. METHODS: This was a prospective study in a tertiary referral center; 23 patients affected by BPPV of the PSC and 24 controls were evaluated. All patients underwent complete clinical history and otoneurologic and audiovestibular evaluation consisting of pure-tone audiometry, caloric testing, and registration of VEMPs. RESULTS: VEMP thresholds and latencies were not different between patients and controls. As a group BPPV patients presented significantly higher abnormal VEMPs compared with controls (p < 0.001). Age positively correlated with VEMP threshold in the affected ear of patients and in controls; the number of BPPV attacks positively correlated with threshold and negatively with amplitude of VEMPs in the affected ear; duration of the last attack was negatively correlated with the effect of the maneuver performed. PMID- 22103312 TI - Standing laparoscopic peritoneal flap hernioplasty technique for preventing recurrence of acquired strangulating inguinal herniation in stallions. AB - OBJECTIVE: To describe a standing laparoscopic peritoneal flap hernioplasty (PFH) technique for closure of the vaginal ring, and to evaluate its effect on prevention of recurrent herniation in stallions, previously treated for acquired strangulating inguinal hernia (SIH). STUDY DESIGN: Case series. ANIMALS: Stallions (n = 30) aged 3-15 that had previous acquired SIH. METHODS: Bilateral standing laparoscopic PFH was performed on 30 stallions that had previous acquired SIH treated without castration. The vaginal rings were approached from 3 portals, 2 in the paralumbar fossa and a 3rd between the 17th and 18th ribs on the ipsilateral side. A large inverted U-shaped peritoneal flap was dissected from the abdominal wall proximal and cranial to the vaginal ring, reflected caudally over the vaginal ring, and secured to the abdominal wall with laparoscopic staples. In the first 11 stallions, only the cranial and mid third of the vaginal ring was covered. For the next 19 stallions, complete closure of the vaginal ring including the entire caudal aspect of the vaginal ring was achieved. RESULTS: SIH recurrence occurred in 4 of 11 stallions with incomplete ring closure whereas no SIH recurrence occurred when the entire vaginal ring was closed. No major complications occurred and cosmetic outcome was excellent. All breeding stallions were successfully used for breeding. CONCLUSION: Standing laparoscopic closure of the vaginal ring using a PFH is an effective way to prevent recurrence of SIH provided the entire vaginal ring, including the caudal aspect is covered by the flap. There seems to be no effect on subsequent fertility. PMID- 22103313 TI - Multifunctional membrane vesicles in Pseudomonas aeruginosa. AB - Gram-negative bacteria secrete small particles called membrane vesicles (MVs) into the extracellular milieu. While MVs have important roles in delivering toxins from pathogenic bacteria to eukaryotic cells, these vesicles also play ecological roles necessary for survival in various environmental conditions. Pseudomonas aeruginosa, which lives in soil, ocean, plant, animal and human environments, has become a model organism for studying these small extracellular particles. Such studies have increased our understanding of the function and biogenesis of bacterial MVs. Pseudomonas aeruginosa MVs possess versatile components and chemical substances with unique structures. These characteristics allow MVs to play their multifunctional biological roles, including microbial interaction, maintenance of biofilm structure and host infection. This review summarizes the comprehensive biochemical and physiochemical properties of MVs derived from P. aeruginosa. These studies will help us understand their biological roles of MVs not only in pathogenicity but also in microbial ecology. Also, the mechanisms of MV production, as currently understood, are discussed. PMID- 22103318 TI - A lupane triterpenoid and other constituents of Salvia eremophila. AB - Phytochemical investigation of the aerial parts of Salvia eremophila led to the isolation of a lupane triterpenoid, 3beta, 20-dihydroxylupane-28-oic acid (1), together with eight other compounds, comprising three diterpene, two triterpene, two flavonoids and a steroidal glucoside. Their structures were elucidated by interpretation of their one-dimensional and two-dimensional NMR spectra and completed by the analysis of the HRESIMS data. Compounds 1, 2-4 and 8 were evaluated for their cytotoxicities against five human tumour cell lines. Compounds 1 and 3 hold a good potential for use in future studies due to their anti-cancer properties. PMID- 22103319 TI - The insulin-like growth factor system, metabolic syndrome, and cardiovascular disease risk. AB - The metabolic syndrome is a combination of metabolic and clinical features that aggregate in individuals and increase cardiovascular disease (CVD) risk considerably. It is believed, although sometimes controversially, that the underlying basis for this syndrome is insulin resistance (IR) and accompanying compensatory hyperinsulinemia. Insulin and insulin-like growth factors (IGFs) have significant homology and interact with differing affinity with the same receptors. Therefore, their actions can be complementary, and this becomes particularly significant clinico-pathologically when their circulating levels are altered. This review of currently available information attempts to answer the following questions: (1) Is there any evidence for changes in the components of the IGF system in individuals with established CVD or with increased CVD risk as with the metabolic syndrome? (2) What are the underlying mechanisms for interactions, if any, between insulin and the IGF system, in the genesis of CVD? (3) Can knowledge of the pathophysiological changes in the IGF system observed in macrosomic newborn infants and growth hormone (GH)-treated children and adults explain some of the observations in relation to the IGF system and the metabolic syndrome? (4) Can the experimental and clinical evidence adduced from the foregoing be useful in designing novel therapies for the prevention, treatment, and assignment of prognosis in metabolic syndrome-associated disease, particularly ischemic heart disease? To answer these questions, we have performed a literature review using bibliographies from PubMed, Medline, and Google Scholar published within the last 10 years. We suggest that IGF-1 levels are reduced consistently in individuals with the metabolic syndrome and its components and in those with ischemic CVD. Such changes are also seen with GH deficiency in which these changes are partially reversible with GH treatment. Furthermore, changes are seen in levels and interactions of IGF-binding proteins in these disorders, and some of these changes appear to be independent of IGF-binding capability and could potentially impact on risk for the metabolic syndrome and CVD. The promising therapeutic implications of these observations are also discussed. PMID- 22103320 TI - Effects of Cd, Cu, Ni, and Zn on brown tide alga Aureococcus anophagefferens growth and metal accumulation. AB - Trace metals play important roles in regulating phytoplankton growth and could influence algal bloom development. Laboratory studies were conducted to evaluate the influence of environmentally relevant concentrations of Cd, Cu, Ni, and Zn on Aureococcus anophagefferens bloom (brown tide) development. Results show that the elevated Ni(2+) concentrations, e.g. those of brown tide waters in the northeastern US, greatly stimulated A. anophagefferens growth (as compared to the control without Ni addition), yet, only low amounts of dissolved Ni were sequestered, thus leaving excessive Ni directly promoting A. anophagefferens blooms. The medium effective concentration EC(50) (Me(2+)) suggests A. anophagefferens has similar Cd sensitivity but much greater Cu tolerance as compared to cyanobacteria, as such, excessive Cu could indirectly promote A. anophagefferens blooms by inhibiting competitors such as Synechococcus sp. The effects of Ni and Cu promoting growth are consistent with the recent genomic study of this alga. In addition, Zn(2+) concentrations lower than those in brown tide waters enhance A. anophagefferens growth, but Zn sequestration in A. anophagefferens would not substantially reduce total dissolved Zn in these waters. Overall, this study, showing that excessive Cu and Ni likely promote brown tides, provides evidence for trace metal linkages in algal bloom development. PMID- 22103321 TI - Dithizone and its oxidation products: a DFT, spectroscopic, and X-ray structural study. AB - Air oxidation of ortho-fluorodithizone resulted in the first X-ray resolved structure of a disulfide of dithizone, validating the last outstanding X-ray structure in the oxidation of dithizone, H(2)Dz, which proceeds via the disulfide, (HDz)(2), to the deprotonated dehydrodithizone tetrazolium salt, Dz. Density functional theory calculations established the energetically favored tautomers along the entire pathway; in gas phase and in polar as well as nonpolar solvent environments. DFT calculations using the classic pure OLYP and PW91, or the newer B3LYP hybrid functional, as well as MP2 calculations, yielded the lowest energy structures in agreement with corresponding experimental X-ray crystallographic results. Atomic charge distribution patterns confirmed the cyclization reaction pathway and crystal packing of Dz. Time dependent DFT for the first time gave satisfactory explanation for the solvatochromic properties of dithizone, pointing to different tautomers that give rise to the observed orange color in methanol and green in dichloromethane. Concentratochromism of H(2)Dz was observed in methanol. Computed orbitals and oscillators are in close agreement with UV-visible spectroscopic experimental results. PMID- 22103322 TI - Metal-mesh lithography. AB - Metal-mesh lithography (MML) is a practical hybrid of microcontact printing and capillary force lithography that can be applied over millimeter-sized areas with a high level of uniformity. MML can be achieved by blotting various inks onto substrates through thin copper grids, relying on preferential wetting and capillary interactions between template and substrate for pattern replication. The resulting mesh patterns, which are inverted relative to those produced by stenciling or serigraphy, can be reproduced with low micrometer resolution. MML can be combined with other surface chemistry and lift-off methods to create functional microarrays for diverse applications, such as periodic islands of gold nanorods and patterned corrals for fibroblast cell cultures. PMID- 22103323 TI - Lipoprotein biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination and full virulence of Bacillus anthracis. AB - Bacterial lipoproteins play a crucial role in virulence in some gram-positive bacteria. However, the role of lipoprotein biosynthesis in Bacillus anthracis is unknown. We created a B. anthracis mutant strain altered in lipoproteins by deleting the lgt gene encoding the enzyme prolipoprotein diacylglyceryl transferase, which attaches the lipid anchor to prolipoproteins. (14)C-palmitate labelling confirmed that the mutant strain lacked lipoproteins, and hydrocarbon partitioning showed it to have decreased surface hydrophobicity. The anthrax toxin proteins were secreted from the mutant strain at nearly the same levels as from the wild-type strain. The TLR2-dependent TNF-alpha response of macrophages to heat-killed lgt mutant bacteria was reduced. Spores of the lgt mutant germinated inefficiently in vitro and in mouse skin. As a result, in a murine subcutaneous infection model, lgt mutant spores had markedly attenuated virulence. In contrast, vegetative cells of the lgt mutant were as virulent as those of the wild-type strain. Thus, lipoprotein biosynthesis in B. anthracis is required for full virulence in a murine infection model. PMID- 22103324 TI - Explorative probes and biomarkers, chronic Salmonella infections and future vaccines. PMID- 22103325 TI - A genotype-phenotype analysis of the 8q22.1 variant in migraine with aura. AB - BACKGROUND AND PURPOSE: Although the genetics of familial hemiplegic migraine are being unraveled, this is not the case for the prevalent types of migraine. However, a recent genome wide association study (GWAS) reported an association of the single nucleotide polymorphism (SNP) rs1835740 and migraine. The aim of this study is to evaluate the association of clinical characteristics in migraine with aura (MA) with the newly discovered minor allele A of rs1835740 at 8q22.1. METHODS: Participants were recruited from the Danish Headache Center and from specialist practices during the periods 1999-2002 and 2005-2006, and diagnosed according to the International Classification of Headache Disorders (ICHD-II) using a validated physician-conducted semi-structured interview. A large number of clinical characteristics were systematically determined. Caucasians of Danish ancestry diagnosed with MA and successfully genotyped for the SNP rs1835740 were included. Patients with hemiplegic migraine were excluded. Blood samples were collected for extraction of genomic DNA and genotyped for the common susceptibility variant rs1835740. RESULTS: Six hundred and ninety one successfully genotyped MA patients with substantial description of their clinical characteristics were included. Two hundred and fifty one were heterozygous and 40 were homozygote for the variant marker. Carriers of the rs1835740 variant showed a non-significant tendency towards having a higher frequency of aura symptoms and a non-significant tendency towards milder migraine headache characteristics and fewer accompanying symptoms. These tendencies were not increased in homozygote carriers. CONCLUSION: None of the clinical characteristics of MA were significantly influenced by the common susceptibility variant on 8q22.1. PMID- 22103326 TI - Incentivized recruitment of a population sample to a mobile HIV testing service increases the yield of newly diagnosed cases, including those in need of antiretroviral therapy. AB - OBJECTIVE: The aim of the study was to compare the yields of newly diagnosed cases of HIV infection and advanced immunodeficiency between individuals attending a mobile HIV counselling and testing (HCT) service as participants in a population-based HIV seroprevalence survey and those accessing the same service as volunteers for routine testing. METHODS: The study was conducted in a peri urban township within the Cape Metropolitan Region, South Africa. Survey participants (recruited testers) were randomly selected, visited at home and invited to attend the mobile HCT service. They received 70 South African Rand food vouchers for participating in the survey, but could choose to test anonymously. The yield of HIV diagnoses was compared with that detected in members of the community who voluntarily attended the same HIV testing facility prior to the survey and did not receive incentives (voluntary testers). RESULTS: A total of 1813 individuals were included in the analysis (936 recruited and 877 voluntary testers). The prevalence of newly diagnosed HIV infection was 10.9% [95% confidence interval (CI) 9.0-13.1%] among recruited testers and 5.0% (3.7 6.7%) among voluntary testers. The prevalence of severe immune deficiency (CD4 count <= 200 cells/ MUL) among recruited and voluntary testers was 17.8% (10.9 26.7%) and 4.6% (0.0-15.4%), respectively. Linkage to HIV care in recruited testers with CD4 counts <= 350 cells/ MUL was 78.8%. CONCLUSION: Compared with routine voluntary HCT, selection and invitation in combination with incentives doubled the yield of newly diagnosed HIV infections and increased the yield almost fourfold of individuals needing antiretroviral therapy. This may be an important strategy to increase community-based HIV diagnosis and access to care. PMID- 22103327 TI - A gene-based SNP resource and linkage map for the copepod Tigriopus californicus. AB - BACKGROUND: As yet, few genomic resources have been developed in crustaceans. This lack is particularly evident in Copepoda, given the extraordinary numerical abundance, and taxonomic and ecological diversity of this group. Tigriopus californicus is ideally suited to serve as a genetic model copepod and has been the subject of extensive work in environmental stress and reproductive isolation. Accordingly, we set out to develop a broadly-useful panel of genetic markers and to construct a linkage map dense enough for quantitative trait locus detection in an interval mapping framework for T. californicus--a first for copepods. RESULTS: One hundred and ninety Single Nucleotide Polymorphisms (SNPs) were used to genotype our mapping population of 250 F2 larvae. We were able to construct a linkage map with an average intermarker distance of 1.8 cM, and a maximum intermarker distance of 10.3 cM. All markers were assembled into linkage groups, and the 12 linkage groups corresponded to the 12 known chromosomes of T. californicus. We estimate a total genome size of 401.0 cM, and a total coverage of 73.7%. Seventy five percent of the mapped markers were detected in 9 additional populations of T. californicus. Of available model arthropod genomes, we were able to show more colocalized pairs of homologues between T. californicus and the honeybee Apis mellifera, than expected by chance, suggesting preserved macrosynteny between Hymenoptera and Copepoda. CONCLUSIONS: Our study provides an abundance of linked markers spanning all chromosomes. Many of these markers are also found in multiple populations of T. californicus, and in two other species in the genus. The genomic resource we have developed will enable mapping throughout the geographical range of this species and in closely related species. This linkage map will facilitate genome sequencing, mapping and assembly in an ecologically and taxonomically interesting group for which genomic resources are currently under development. PMID- 22103328 TI - Differential protein pathways in 1,25-dihydroxyvitamin d(3) and dexamethasone modulated tolerogenic human dendritic cells. AB - Tolerogenic dendritic cells (DC) that are maturation-resistant and locked in a semimature state are promising tools in clinical applications for tolerance induction. Different immunomodulatory agents have been shown to induce a tolerogenic DC phenotype, such as the biologically active form of vitamin D (1,25(OH)(2)D(3)), glucocorticoids, and a synergistic combination of both. In this study, we aimed to characterize the protein profile, function and phenotype of DCs obtained in vitro in the presence of 1,25(OH)(2)D(3), dexamethasone (DEX), and a combination of both compounds (combi). Human CD14(+) monocytes were differentiated toward mature DCs, in the presence or absence of 1,25(OH)(2)D(3) and/or DEX. Cells were prefractionated into cytoplasmic and microsomal fractions and protein samples were separated in two different pH ranges (pH 3-7NL and 6-9), analyzed by 2D-DIGE and differentially expressed spots (p < 0.05) were identified after MALDI-TOF/TOF analysis. In parallel, morphological and phenotypical analyses were performed, revealing that 1,25(OH)(2)D(3)- and combi-mDCs are closer related to each other than DEX-mDCs. This was translated in their protein profile, indicating that 1,25(OH)(2)D(3) is more potent than DEX in inducing a tolerogenic profile on human DCs. Moreover, we demonstrate that combining 1,25(OH)(2)D(3) with DEX induces a unique protein expression pattern with major imprinting of the 1,25(OH)(2)D(3) effect. Finally, protein interaction networks and pathway analysis suggest that 1,25(OH)(2)D(3), rather than DEX treatment, has a severe impact on metabolic pathways involving lipids, glucose, and oxidative phosphorylation, which may affect the production of or the response to ROS generation. These findings provide new insights on the molecular basis of DC tolerogenicity induced by 1,25(OH)(2)D(3) and/or DEX, which may lead to the discovery of new pathways involved in DC immunomodulation. PMID- 22103329 TI - Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects. AB - Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy. PMID- 22103330 TI - CaMKII-gamma mediates phosphorylation of BAD at Ser170 to regulate cytokine dependent survival and proliferation. AB - Phosphorylation of the BH3 (Bcl-2 homology domain 3)-only protein BAD (Bcl-2/Bcl X(L)-antagonist, causing cell death) can either directly disrupt its association with the pro-survival proteins Bcl-X(L) and/or Bcl-2, or cause association of BAD with 14-3-3 proteins. In the present study, we further characterize phosphorylation of BAD at Ser170, a unique site with unclear function. We provide further evidence that mutation of Ser170 to a phospho-mimetic aspartic acid residue (S170D) can have a profound inhibitory effect on the pro-apoptosis function of BAD. Furthermore, mutated BAD with an alanine substitution inhibited cell proliferation, slowing progression specifically through S-phase. We identify the kinase responsible for phosphorylation at this site as CaMKII-gamma (gamma isoform of Ca2+/calmodulin-dependent kinase II), but not the other three isoforms of CaMKII, revealing an extraordinary specificity among these closely related kinases. Furthermore, cytokine treatment increased BAD-Ser170-directed CaMKII gamma activity and phosphorylation of CaMKII-gamma at an activating site, and CaMKII activity directed to the BAD-Ser170 site was elevated during S-phase. Treating cells with a selective inhibitor of CaMKII caused apoptosis in cells expressing BAD, but not in cells expressing the BAD-S170D mutant. The present study provides support for BAD-Ser170 phosphorylation playing a key role not only in regulating BAD's pro-apoptotic activity, but also in cell proliferation. PMID- 22103331 TI - Virtual morality: emotion and action in a simulated three-dimensional "trolley problem". AB - Experimentally investigating the relationship between moral judgment and action is difficult when the action of interest entails harming others. We adopt a new approach to this problem by placing subjects in an immersive, virtual reality environment that simulates the classic "trolley problem." In this moral dilemma, the majority of research participants behaved as "moral utilitarians," either (a) acting to cause the death of one individual in order to save the lives of five others, or (b) abstaining from action, when that action would have caused five deaths versus one. Confirming the emotional distinction between moral actions and omissions, autonomic arousal was greater when the utilitarian outcome required action, and increased arousal was associated with a decreased likelihood of utilitarian-biased behavior. This pattern of results held across individuals of different gender, age, and race. PMID- 22103332 TI - Dermoscopic, histological and immunohistochemical evaluation of cancerous features in acquired melanocytic nevi that have been repeatedly exposed to UVA or UVB. AB - Previous studies have reported that repeated solar and artificial UVB (280-320 nm) and UVA (320-400 nm) exposures can modify acquired melanocytic nevi (AMN). We therefore investigated the clinical, dermoscopic, histological and immunohistochemical changes in AMN exposed to UVB and UVA radiation. Twenty healthy volunteers with at least three AMN on the trunk were enrolled in the present study and randomized into two groups to receive equally effective doses of narrow-band (NB)-UVB or UVA1. Three exposures per week were delivered for a total of 4 weeks. During exposures, one AMN was left unprotected, a second one was shielded with an opaque adhesive tape and the third nevus was covered with a commercial sunscreen. After the irradiation cycle, the AMN were surgically removed and underwent histological and immunohistochemical assessment of melanocyte/melanogenesis-related proteins (MART-1, tyrosinase, HMB-45), cell cycle activation markers (Ki-67, topoisomerase IIalpha, p53, Cdk2) and transcription factors (microphthalmia-associated transcription factor, STAT3). Nevi that were exposed to NB-UVB or UVA1 also showed statistically significant increase in size and changes in their dermoscopic features, including overall darkening, increased pigment network expression, formation of branched streaks, and increased number and size of brown globules and dots. AMN that had been covered with opaque tape or sunscreen did not show changes in size or dermoscopic features following UVA1 or NB-UVB exposure. Histological and immunohistochemical analysis did not show any significant change in exposed AMN in comparison with AMN shielded with an opaque adhesive tape or covered with the sunscreen. PMID- 22103333 TI - Time trends in surgery for non-traumatic shoulder disorders and postoperative risk of permanent work disability: a nationwide cohort study. AB - OBJECTIVES: Three previous randomized controlled trials found no overall difference in the effect of surgery compared with non-surgical treatment including exercise for patients with non-traumatic shoulder disorders. We assessed Danish temporal trends in the incidence of surgery for rotator cuff related shoulder disorders, frozen shoulder, and osteoarthritis (OA) of the acromioclavicular (AC) joint, and the subsequent risk of permanent work disability. METHODS: Based on registers, we calculated annual incidence rates for the Danish population aged 18-63 years between 1996 and 2008. For a cohort of 19 264 first-time shoulder-operated patients who were in the labour market on admission, we used Cox proportional hazards models to assess risk of permanent work disability within 2 years after surgery. RESULTS: The annual incidence increased from 3.5 to 14.8 per 10 000, and 9.8% of the patients became permanently work disabled. No time trend was observed in this percentage. Formal education level was an important prognostic factor. Using 'higher or medium-level education' as a reference, the hazard ratio (HR) was 1.5 [95% confidence interval (CI) 1.3-1.8] for 'vocational education and training' and 2.0 (95% CI 1.8-2.3) for 'low education level'. For 'missing information on education', the HR was 0.7 (95% CI 0.6-0.9). CONCLUSIONS: We found a fourfold increase in surgery rates and a substantial risk of postoperative permanent work disability that remained constant over time. The risk was related to education level. These findings suggest that indications for surgery may need to be revisited and that attention should be given to supporting return to work, especially for blue-collar workers. PMID- 22103334 TI - Region-specific deletions of RIM1 reproduce a subset of global RIM1alpha(-/-) phenotypes. AB - The presynaptic protein RIM1alpha mediates multiple forms of presynaptic plasticity at both excitatory and inhibitory synapses. Previous studies of mice lacking RIM1alpha (RIM1alpha(-/-) throughout the brain showed that deletion of RIM1alpha results in multiple behavioral abnormalities. In an effort to begin to delineate the brain regions in which RIM1 deletion mediates these abnormal behaviors, we used conditional (floxed) RIM1 knockout mice (fRIM1). By crossing these fRIM1 mice to previously characterized transgenic cre lines, we aimed to delete RIM1 selectively in the dentate gyrus (DG), using a specific preproopiomelanocortin promoter driving cre recombinase (POMC-cre) line , and in pyramidal neurons of the CA3 region of hippocampus, using the kainate receptor subunit 1 promoter driving cre recombinase (KA-cre). Neither of these cre driver lines was uniquely selective to the targeted regions. In spite of this, we were able to reproduce a subset of the global RIM1alpha(-/-) behavioral abnormalities, thereby narrowing the brain regions in which loss of RIM1 is sufficient to produce these behavioral differences. Most interestingly, hypersensitivity to the pyschotomimetic MK-801 was shown in mice lacking RIM1 selectively in the DG, arcuate nucleus of the hypothalamus and select cerebellar neurons, implicating novel brain regions and neuronal subtypes in this behavior. PMID- 22103335 TI - Associations of periodontal microorganisms with salivary proteins and MMP-8 in gingival crevicular fluid. AB - OBJECTIVE: We investigated in subjects with and without periodontitis, the levels of certain salivary proteins and matrix metalloproteinase-8 (MMP-8) in gingival crevicular fluid (GCF), in relation to the presence of specific periodontal pathogens. METHODS: Clinical parameters were recorded at baseline, in 1985 and in 2009 from 99 subjects; 56 with and 43 without periodontitis (mean age 59.2 +/- SD 2.9). Saliva samples collected in 2009 were analysed for salivary albumin, total protein and immunoglobulins A, G and M. GCF was collected for analysis of MMP-8 levels and for the PCR-analysis of the microorganisms Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola and Tannerella forsythia. RESULTS: Periodontitis patients were more often infected by P. gingivalis (p < 0.05), P. intermedia and T. denticola (p = 0.01) than controls. Salivary albumin and protein concentrations were significantly higher in subjects with T. denticola (p < 0.05). MMP-8 levels were significantly higher in subjects with T. denticola (p < 0.001) and T. forsythia (p < 0.01). No corresponding results were found in salivary immunoglobulin concentrations. CONCLUSION: The presence of T. denticola seemed to increase salivary albumin and total protein concentrations, and GCF levels of MMP-8. Both T. denticola and T. forsythia seemed to induce a cascade of host response with increased MMP-8 in GCF. PMID- 22103336 TI - Sources of continuity and change in activity level in early childhood. AB - Actigraphs and parent and observer ratings were used to explore genetic influences on continuity and change in activity level (AL) in early childhood. Over 300 pairs of twins wore actigraphs for a 48-hr period in the home and laboratory at ages 2 and 3. AL was genetically influenced at both ages with little evidence of differential heritability across age. For all measures, genetic influences contributed to phenotypic continuity. With the exception of the actigraph measure of AL in the home, new genetic effects emerged at age 3 indicating that genetic factors influence both continuity and change in AL in early childhood. Nonshared environmental influences were also a source of change in AL across the transition from infancy to early childhood. PMID- 22103337 TI - Characteristics of cochlear microphonics in infants and young children with auditory neuropathy. AB - CONCLUSIONS: Cochlear microphonics (CMs) play an important role in the diagnosis of auditory neuropathy (AN). It is necessary and helpful to diagnose the sites-of lesion in infants and children with AN by analyzing the patterns of CM amplitudes and I/O functions together. OBJECTIVES: To investigate the characteristics and clinical significance of CMs in the diagnosis of AN among infants and children. METHODS: A total of 36 infants and children (16 males and 20 females) were divided into two groups. Group A included 15 children (30 ears) with auditory brainstem response (ABR) absent and distortion product otoacoustic emissions (DPOAEs) present and group B included 21 children (30 ears) with ABR absent and DPOAEs absent. Fifteen normal-hearing infants (30 ears) made up the control group. Click eliciting CMs were recorded at stimulus levels of 100, 90, 80, and 70 dB nHL for each ear using a button electrode placed at the top of the forehead. A tube-clamping method was used to distinguish CMs from artifacts, and an averaging algorithm was used to obtain a clear CM waveform. The time delay and amplitude of CMs were measured in both children with AN and normal-hearing infants on (C-R)/2 waveforms, and an I/O function curve for each group was plotted with the stimulating level as input and the CM amplitude as output. RESULTS: The largest identifiable CMs were generally found between 0.5 and 0.8 ms after stimulation with mean delay of 0.63 +/- 0.04 ms in both group A and the control group, and 0.63 +/- 0.07 ms in group B. There was no significant difference between the AN group and the control group in CM time delay. There was no significant difference (p > 0.05) between group A (AN with OAEs present, 0.47 +/- 0.15 MUV) and the control group (0.45 +/- 0.13 MUV) in CM amplitude, while CM amplitudes in children with AN with DPOAEs absent (0.24 +/- 0.08 MUV) were significantly lower than those in either the control group or group A (p < 0.01). The amplitude of CMs reduced with stimulus intensity in all the subjects. There was obvious nonlinearity in group A and the control group, while there was a more linear tendency in amplitude increasing on the I/O function curve in group B. PMID- 22103338 TI - Attempted medical management of suspected ascending colon displacement in horses. AB - OBJECTIVE: To determine the success of medical management of suspected displacement of the ascending (large) colon in horses. STUDY DESIGN: Retrospective case series. ANIMALS: Horses (n = 127) with suspected large colon displacement. METHODS: Medical records (January 1998-September 2008) of horses admitted for colic were reviewed. Suspected large colon displacement was diagnosed from clinical examination and in some cases, subsequent surgical examination. Medically managed horses were exercised and administered intravenous fluids and analgesia. Horses with suspected left dorsal displacement (LDD) of the large colon were also administered phenylephrine. RESULTS: Medical management had a high success rate for treatment of suspected right dorsal displacement (RDD) (64%) and LDD (76%) of the large colon; 4 horses died (1) or were euthanatized (3) and 36 horses had surgery. Of 127 horses treated medically or surgically for a colon displacement, 94% survived to hospital discharge. CONCLUSIONS: Horses with suspected RDD or LDD of the large colon may respond to medical management including exercise. PMID- 22103339 TI - A giant cell surface protein in Synechococcus WH8102 inhibits feeding by a dinoflagellate predator. AB - Diverse strains of the marine planktonic cyanobacterium Synechococcus sp. show consistent differences in their susceptibility to predation. We used mutants of Sargasso Sea strain WH8102 (clade III) to test the hypothesis that cell surface proteins play a role in defence against predation by protists. Predation rates by the heterotrophic dinoflagellate Oxyrrhis marina on mutants lacking the giant SwmB protein were always higher (by 1.6 to 3.9*) than those on wild-type WH8102 cells, and equalled predation rates on a clade I strain (CC9311). In contrast, absence of the SwmA protein, which comprises the S-layer (surface layer of the cell envelope that is external to the outer membrane), had no effect on predation by O. marina. Reductions in predation rate were not due to dissolved substances in Synechococcus cultures, and could not be accounted for by variations in cell hydrophobicity. We hypothesize that SwmB defends Synechococcus WH8102 by interfering with attachment of dinoflagellate prey capture organelles or cell surface receptors. Giant proteins are predicted in the genomes of multiple Synechococcus isolates, suggesting that this defence strategy may be more general. Strategies for resisting predation will contribute to the differential competitive success of different Synechococcus groups, and to the diversity of natural picophytoplankton assemblages. PMID- 22103340 TI - A new triterpenoid saponin from the roots of Silene viscidula. AB - A new triterpenoid saponin, silenoviscoside F (1), was isolated from the roots of Silene viscidula, together with three known saponins, dianchinenoside D (2), sinocrassuloside I (3) and sinocrassuloside II (4). The structure of compound 1 was elucidated by spectroscopic data, GC-MS and chemical methods. The structures of compounds 2-4 were determined on the basis of spectroscopic data comparison with the literature values, which were isolated from the genus Silene for the first time. PMID- 22103341 TI - Carbohydrate profiling of fungal cell wall surface glycoconjugates of Aspergillus species in brain and lung tissues using lectin histochemistry. AB - The aim of this study was to evaluate, through lectin histochemistry, the expression of N-acetyl-D-glucosamine, L-fucose, D-galactose and glucose/mannose on the cell wall surfaces of Aspergillus species in histopathological specimens of brain (n = 1) and lung (n = 6) tissues obtained during autopsy of patients diagnosed postmortem as having had invasive aspergillosis. Concanavalin A (Con A), wheat germ agglutinin (WGA), Ulex europeus agglutinin I (UEA-I) and peanut agglutinin (PNA), all conjugated with horseradish peroxidase, were employed. Lectin-binding was visualized using 3,3-diaminobendizine (DAB) and hydrogen peroxide in phosphate buffer solution (PBS). We observed expression of N-acetyl-D glucosamine and methyl-alpha-D-mannoside on the cell wall surfaces of all evaluated Aspergillus species, while the expression of L-fucose and D-galactose demonstrated inter and intra-specific variations. The results obtained from this study indicate that the use of WGA and Con A lectins permits visualization of Aspergillus structures such as hyphae, conidial heads and conidia in histopathological specimens of brain and lung tissues. PMID- 22103342 TI - Fatal septic shock due to a disseminated chronic form of paracoccidioidomycosis in an aged woman. AB - Once rare, septic shock (SS) due to disseminated fungal infections has been increasingly reported due to a growing number of immunocompromised patients, but remains rare in non-immune-compromised individuals. In paracoccidioidomycosis, it has been described in only three patients with the severe, acute form of the disease. We describe the development of a refractory, fatal septic shock due to a severe disseminated chronic form of paracoccidioidomycosis in an older woman without any other microbial insults. A striking event in the evolution of her case was the severe depletion of lymphocytes from the peripheral blood and lymphoid organs. Lymphocyte depletion due to apoptosis is described in the late phase of sepsis and can contribute both to immunosuppression and the progression of SS. The possible mechanisms involved in the induction of SS in the chronic form of paracoccidioidomycosis are discussed. PMID- 22103343 TI - Favorable outcome of chronic disseminated candidiasis in four pediatric patients with hematological malignancies. AB - Four children were diagnosed with chronic disseminated candidiasis (CDC) during treatment for hematological malignancies. All presented with persistent fever, not responsive to broad-spectrum antibiotics, abdominal distension and hepatosplenomegaly. Two children needed artificial ventilation because of respiratory insufficiency. The time between onset of neutropenic fever and diagnosis of CDC ranged from 20-49 days. Ultrasound and computed tomography failed to demonstrate CDC during the neutropenic phase. All children needed a liver or spleen biopsy to establish the diagnosis of CDC. Three of four patients continued chemotherapy during treatment for the fungal infection. All patients had a favorable outcome, both in terms of the invasive Candida infections, as well as their underlying malignancies. PMID- 22103344 TI - Internal transcribed spacer region sequence analysis using SmartGene IDNS software for the identification of unusual clinical yeast isolates. AB - Rapid and accurate identification of clinically important yeasts is essential given their inherent differences in antifungal susceptibility. We implemented nucleic acid sequencing for those species that could not be identified by phenotypic methods. Internal Transcribed Spacer region 1 and 2 (ITS1 and ITS2) sequences were investigated using SmartGene IDNS software, an rDNA sequence database and analysis program for microbial identification (ID). Over a 2.5-year period, 2,938 specimens were evaluated. Most (94%) isolates were fully identified by conventional methods, with Candida species accounting for the majority of them. Of the 169 organisms that required molecular analysis, 79% were identified to species level, 19% to genus and 2% remained unresolved. Sequenced isolates encompassed 33 unique species of which approximately half (52%) were common pathogens with atypical biochemical profiles and the remainder were rarer yeast species. A significant proportion (33%) of sequenced organisms displayed elevated MICs to fluconazole. Our experience supports the use of molecular techniques as an adjunct to conventional methods for the identification of medically important yeasts. Susceptibility testing alone may provide valuable treatment information in situations where phenotypic assessments are inconclusive and molecular or proteomic testing is not readily available. PMID- 22103345 TI - Cunninghamella bertholletiae pneumonia showing a reversed halo sign on chest computed tomography scan following cord blood transplantation. AB - This is the first reported case of a patient who developed fungal pneumonia caused by Cunninghamella bertholletiae (= C. elegans) following cord blood transplantation and who showed a reversed halo sign on a chest computed tomography scan (CT). In addition, the pathological findings related to the reversed halo sign are described in detail for the first time. The patient died due to respiratory failure and at autopsy, a consolidation corresponding to the reversed halo sign noted on CT was found histologically to be composed of a central infarct with some retained air spaces surrounded by a peripheral ring like hemorrhagic band. Pulmonary vasculatures were occluded by thrombi containing numerous Zygomycetes hyphae within the central infarct and less frequently along the surrounding hemorrhagic band. A reversed halo sign may be an early marker to initiate preemptive therapy against Zygomycetes including C. bertholletiae. PMID- 22103346 TI - Association between indoor fungi in Delhi homes and sensitization in children with respiratory allergy. AB - Indoor fungi are potential sensitizing agents in children and their detection and quantification in indoor air are important in the diagnosis and environmental management of fungal allergies. The objective of this investigation was to assess the prevalence of fungal allergies in children in Delhi and to study the association between mold counts in the homes of children and their sensitization to respective fungal extracts. Fungal concentrations and seasonality were studied at two-week intervals for one year using Andersen Volumetric and Burkard Slide samplers. Sensitization to fungi frequently encountered in patients' homes was assessed by Skin Prick Tests (SPTs). Total fungal specific IgE was measured by ELISA in the sera of patients positive to fungal extracts. Skin Prick Tests revealed that 39.3% (33/84) of patients were markedly positive (2 + and above) to one or the other fungal allergens. Raised serum IgE to predominant indoor fungal species was observed in patients with marked SPT results. Highest marked skin reactivity (2 + and above) was obtained with Alternaria alternata allergens in 17.9% of the children, which was followed by the response to fungal antigens of Aspergillus fumigatus and Penicillium citrinum (15.5%). Exposure to high fungal counts of some dominant fungi (Penicillium, A. nidulans and A. fumigatus) was found associated with increased fungal sensitization in the patients. Total serum IgE level was revealed to be significantly linked with the intensity of skin reactions, as well as with skin index (r(2) = 0.052; P < 0.05). We concluded that children in Delhi are exposed to high concentrations of fungi in the indoor environment and that respiratory allergies were connected with higher prevalence of skin sensitization. PMID- 22103347 TI - Weekly liposomal amphotericin B as secondary prophylaxis for invasive fungal infections in patients with hematological malignancies. AB - There have been no published studies evaluating the efficacy and safety of weekly liposomal amphotericin B as secondary prophylaxis in leukemic patients with invasive fungal infections (IFIs). We found in a retrospective review of our experience with 14 such patients admitted from 2003-2009 that the use of this approach was associated with frequent relapse of IFIs (36%) and kidney injury (36%). PMID- 22103348 TI - Isoprene epoxydiols as precursors to secondary organic aerosol formation: acid catalyzed reactive uptake studies with authentic compounds. AB - Isoprene epoxydiols (IEPOX), formed from the photooxidation of isoprene under low NO(x) conditions, have recently been proposed as precursors of secondary organic aerosol (SOA) on the basis of mass spectrometric evidence. In the present study, IEPOX isomers were synthesized in high purity (>99%) to investigate their potential to form SOA via reactive uptake in a series of controlled dark chamber studies followed by reaction product analyses. IEPOX-derived SOA was substantially observed only in the presence of acidic aerosols, with conservative lower-bound yields of 4.7-6.4% for beta-IEPOX and 3.4-5.5% for delta-IEPOX, providing direct evidence for IEPOX isomers as precursors to isoprene SOA. These chamber studies demonstrate that IEPOX uptake explains the formation of known isoprene SOA tracers found in ambient aerosols, including 2-methyltetrols, C(5) alkene triols, dimers, and IEPOX-derived organosulfates. Additionally, we show reactive uptake on the acidified sulfate aerosols supports a previously unreported acid-catalyzed intramolecular rearrangement of IEPOX to cis- and trans 3-methyltetrahydrofuran-3,4-diols (3-MeTHF-3,4-diols) in the particle phase. Analysis of these novel tracer compounds by aerosol mass spectrometry (AMS) suggests that they contribute to a unique factor resolved from positive matrix factorization (PMF) of AMS organic aerosol spectra collected from low-NO(x), isoprene-dominated regions influenced by the presence of acidic aerosols. PMID- 22103350 TI - Self-diffusion of lithium in LiAlSi2O6 glasses studied using mass spectrometry. AB - In order to improve our understanding of the transport mechanisms of lithium in glasses, we have performed diffusion and ionic conductivity studies on spodumene composition (LiAlSi(2)O(6)) glasses. In diffusion couple experiments pairs of chemically identical glasses with different lithium isotopy (natural Li vs pure (7)Li) were processed at temperatures between 482 and 732 K. Profiles of lithium isotopes were measured after the diffusion runs innovatively applying femtosecond UV laser ablation combined with inductively coupled plasma mass spectrometry (LA ICP-MS). Self-diffusion coefficients of lithium in the glasses were determined by fitting the isotope profiles. During some of the diffusion experiments the electrical conductivity of the samples was intermittently measured by impedance spectrometry. Combining ionic conductivity and self-diffusivity yields a temperature-independent correlation factor of ~0.50, indicating that motions of Li ions are strongly correlated in this type of glasses. Lithium self-diffusivity in LiAlSi(2)O(6) glass was found to be very similar to that in lithium silicate glasses although Raman spectroscopy demonstrates structural differences between these glasses; that is, the aluminosilicate is completely polymerized while the lithium silicate glasses contain large fractions of nonbridging oxygen. PMID- 22103349 TI - Nondegradative ubiquitination of apoptosis inducing factor (AIF) by X-linked inhibitor of apoptosis at a residue critical for AIF-mediated chromatin degradation. AB - Apoptosis inducing factor (AIF) is a mediator of caspase-independent cell death that is also necessary for mitochondrial energy production. How these seemingly opposite cellular functions of AIF are controlled is poorly understood. X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of caspases that also regulates several caspase-independent signaling pathways. The RING domain of XIAP possesses E3 ubiquitin ligase activity, though the importance of this function to signal regulation remains incompletely defined. XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination. Unlike canonical ubiquitination, XIAP-dependent AIF ubiquitination did not lead to proteasomal degradation of AIF. Experiments using ubiquitin mutants demonstrated that the XIAP-dependent ubiquitin linkage was not formed through the commonly used lysine 48, suggesting a noncanonical ubiquitin linkage is employed. Further studies demonstrated that only lysine 255 of AIF was a target of XIAP-dependent ubiquitination. Using recombinant AIF, we determined that mutating lysine 255 of AIF interferes with the ability of AIF not only to bind DNA but also to degrade chromatin in vitro. These data indicate that XIAP regulates the death-inducing activity of AIF through nondegradative ubiquitination, further defining the role of XIAP in controlling AIF and caspase independent cell death pathways. PMID- 22103351 TI - Controlled release of levofloxacin sandwiched between two plasma polymerized layers on a solid carrier. AB - Targeted delivery and controlled local release of drugs has a number of advantages over conventional systemic drug delivery approaches. Novel platforms for local delivery from solid drug carriers are needed to satisfy the requirements of various medical applications, in particular for the incorporation and release of hydrophilic drugs from a solid carrier material. We have utilized the plasma polymerization of n-heptylamine for the generation of two thin coated layers that serve two distinct purposes. First, an n-heptylamine plasma polymer layer is applied onto the surface of the solid carrier material in order to facilitate spreading of the drug, which is applied by solvent casting; levofloxacin in ethanol was used for this study. A second n-heptylamine plasma polymer coating then serves as a thin barrier coating to control the release. We show that the rate of release can be adjusted via the thickness of the plasma polymer overlayer. We also show that this modality of controlled release of levofloxacin completely inhibits Methicillin-resistant Staphylococcus aureus (MRSA) colonization and biofilm formation on and near the coated biomaterial surface. PMID- 22103352 TI - Dynamic-covalent macromolecular stars with boronic ester linkages. AB - Macromolecular stars containing reversible boronic ester linkages were prepared by an arm-first approach by reacting well-defined boronic acid-containing block copolymers with multifunctional 1,2/1,3-diols. Homopolymers of 3 acrylamidophenylboronic acid (APBA) formed macroscopic dynamic-covalent networks when cross-linked with multifunctional diols. On the other hand, adding the diol cross-linkers to block copolymers of poly(N,N-dimethylacrylamide (PDMA))-b poly(APBA) led to nanosized multiarm stars with boronic ester cores and PDMA coronas. The assembly of the stars under a variety of conditions was considered. The dynamic-covalent nature of the boronic ester cross-links allowed the stars to reconfigure their covalent structure in the presence of monofunctional diols that competed for bonding with the boronic acid component. Therefore, the stars could be induced to dissociate via competitive exchange reactions. The star formation dissociation process was shown to be repeatable over multiple cycles. PMID- 22103353 TI - Rectal single dose immunization of mice with Escherichia coli O157:H7 bacterial ghosts induces efficient humoral and cellular immune responses and protects against the lethal heterologous challenge. AB - Bacterial ghosts (BGs) have been applied through oral, aerogenic, intraocular or intranasal routes for mucosal immunization using a wide range of experimental animals. All these applications required a booster after primary immunization to achieve protective immunity against the lethal challenge. Here we report for the first time that a single rectal dose of BGs produced from enterohaemorrhagic Escherichia coli (EHEC) O157:H7 fully protects mice against a 50% lethal challenge with a heterologous EHEC strain given at day 55. BGs from EHEC O157:H7 were prepared by a combination of protein E-mediated cell lysis and expression of staphylococcal nuclease A guaranteeing the complete degradation of pathogen residual DNA. The lack of genetic material in the EHEC BGs vaccine abolished any potential hazard for horizontal gene transfer of plasmid encoded antibiotic resistance genes or pathogenic islands to the recipient's gut flora. Single rectal immunization using EHEC O157:H7 BGs without any addition of adjuvant significantly stimulated efficient humoral and cellular immune responses, and was equally protective as two immunizations, which indicates the possibility to develop a novel efficacious single dose mucosal EHEC O157:H7 BGs vaccine using a simplified immunization regimen. PMID- 22103354 TI - Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the mutation status of PANK2 among Korean patients with pantothenate kinase-associated neurodegeneration (PKAN) and to document the outcome of pallidal deep brain stimulation (DBS). METHODS: Direct sequencing and deletion/duplication analysis of PANK2 were conducted in 12 patients (11 unrelated) with PKAN, diagnosed on the basis of extrapyramidal dysfunction and the 'eye-of-the-tiger sign' on brain magnetic resonance imaging (MRI). Pallidal DBS was conducted in four patients, and the outcomes were measured using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: A PANK2 mutation was identified in both alleles in all patients. The most prevalent mutation was c.1319G>C (p.R440P) in 8/22 mutated alleles (36%). An intragenic deletion ranging from exons 2 to 4 was found in one allele (1/22, 4.5%) using deletion/duplication analysis. The outcome of pallidal DBS was favorable in two patients with atypical PKAN and moderate severity of dystonia. However, two patients with typical PKAN and relatively severe symptoms showed variable responses. CONCLUSIONS: The c.1319G>C (p.R440P) mutation appears to be a founder genotype among Korean patients with PKAN. Furthermore, this study provides additional data for the recent international effort to evaluate the efficacy of pallidal DBS in the treatment of patients with PKAN. PMID- 22103355 TI - Development of a xylazine constant rate infusion with or without butorphanol for standing sedation of horses. AB - OBJECTIVE: To elaborate constant rate infusion (CRI) protocols for xylazine (X) and xylazine/butorphanol (XB) which will result in constant sedation and steady xylazine plasma concentrations. STUDY DESIGN: Blinded randomized experimental study. ANIMALS: Ten adult research horses. METHODS: Part I: After normal height of head above ground (HHAG = 100%) was determined, a loading dose of xylazine (1 mg kg(-1) ) with butorphanol (XB: 18 MUg kg(-1) ) or saline (X: equal volume) was given slowly intravenously (IV). Immediately afterwards, a CRI of butorphanol (XB: 25 MUg kg(-1) hour(-1)) or saline (X) was administered for 2 hours. The HHAG was used as a marker of depth of sedation. Sedation was maintained for 2 hours by additional boluses of xylazine (0.3 mg kg(-1)) whenever HHAG >50%. The dose of xylazine (mg kg(-1) hour(-1)) required to maintain sedation was calculated for both groups. Part II: After the initial loading dose, the calculated xylazine infusion rates were administered in parallel to butorphanol (XB) or saline (X) and sedation evaluated. Xylazine plasma concentrations were measured by HPLC-MS MS at time points 0, 5, 30, 45, 60, 90, and 120 minutes. Data were analyzed using paired t-test, Wilcoxon signed rank test and a 2-way anova for repeated measures (p < 0.05). RESULTS: There was no significant difference in xylazine requirements (X: 0.69, XB: 0.65 mg kg(-1) hour(-1)) between groups. With treatment X, a CRI leading to prolonged sedation was developed. With XB, five horses (part I: two, part II: three) fell down and during part II four horses appeared insufficiently sedated. Xylazine plasma concentrations were constant after 45 minutes in both groups. CONCLUSION: Xylazine bolus, followed by CRI, provided constant sedation. Additional butorphanol was ineffective in reducing xylazine requirements and increased ataxia and apparent early recovery from sedation in unstimulated horses. CLINICAL RELEVANCE: Data were obtained on unstimulated healthy horses and extrapolation to clinical conditions requires caution. PMID- 22103356 TI - Involvement of interleukin-1beta mediated nuclear factor kappaB signalling pathways to down-regulate prostate-specific antigen and cell proliferation in LNCaP prostate cancer cells. AB - Involvement of NF-kappaB (nuclear factor kappaB) mediated by IL-1beta (interleukin-1beta) on cell proliferation and PSA (prostate-specific antigen) production of LNCaP prostate cell lines and the possible cross-talk with Akt (also known as protein kinase B) signalling pathway has been investigated. NF kappaB and Akt were analysed by Western blotting from LNCaP cells treated by IL 1beta before proliferation and PSA production were measured. IL-1beta inhibited proliferation and decreased PSA production. The Akt pathway was not sensitive, whereas NF-kappaB phosphorylation occurred as a result of treatment. PSA production and proliferation of LNCaP cells were down-regulated by NF-kappaB mediated by IL-1beta promoting anti-apoptotic signalling and co-suppressor factors of PSA expression. IL-1beta through NF-kappaB activation provides a rationale for therapeutic approaches in the anticancer treatment of prostate. PMID- 22103388 TI - Field melanin mapping of the hairless scalp. AB - BACKGROUND: Mottled subclinical melanoderma (MSM) is frequently seen on facial skin using the ultraviolet light enhanced visualization (ULEV) method. The corresponding aspect on the hairless scalp remains unknown. OBJECTIVE: To explore the field distribution of melanin on the scalp of fair-skinned Caucasian subjects. METHOD: The scalp was examined in 43 men with androgenic alopecia. The Visioscan((r)) camera provided the ULEV pictures. Another optical (Visioface((r)) Quick) device was used under white light illumination followed by colour contrast enhancement. This was reached after specific computer filtration of the cyan hue wavelengths. RESULTS: Under white light illumination, the scalp looked normal. MSM patterns were disclosed by both optical procedures as evenly scattered discrete patchy fields of hypermelanosis. The smaller rounded spots were restricted to the lips of the hair infundibula. Larger irregularly shaped spots predominated in the interfollicular areas. A few hypomelanotic spots were scattered over the scalp. CONCLUSION: The present observations based on dual optical methods possibly provide information about a patterned pathobiology of melanocytes on the scalp. The spotty MSM pattern looked similar to the reported aspects on the face. It somewhat resembled the widespread PUVA-induced lentiginosis. PMID- 22103389 TI - Photophysical characterization of 1,8 naphthalimide in micelle-diblock copolymer nano-composite: a case of morphological transformation and vesicle formation. AB - This paper reports a morphological transition of the spherical colloidal structures of the sodium dodecyl sulfate-polyethylene-b-polyethylene glycol (SDS PE-b-PEG) complex and anionic micelle (SDS) to "rod-shaped" colloidal structures induced by a charge transfer dye, 1,8-naphthalimide (NAPMD) (forms anions in aqueous solution by intermolecular charge transfer). The distinct steady-state results of NAPMD in the above two media point toward the formation of a new microenvironment. SDS and SDS-PE-b-PEG form unilamellar (ULV) and multilamellar vesicles (MLV), respectively, along with the rod-shaped colloidal structures as observed from transmission electron microscopy (TEM) images. This dye causes a variation in the hydrophilic/hydrophobic ratio and forms a hydrogen bond with the copolymer in the SDS-PE-b-PEG complex and subjected to electrostatic interaction with the SDS micelle in aqueous solution, which causes this morphological transformation. These vesicles show complete encapsulation of a hydrophobic dye in its interior as evident from the TEM images. ULV get ruptured at low pH, pointing toward their lower stability over MLV at low pH value. The formation of these vesicles with complete idea of its mechanism, encapsulation of bioactive molecules and its rupture at lower pH raise hope as a potential nanoscale vehicle for biologically relevant compounds and their release at low pH medium. PMID- 22103390 TI - Does ultrasound guidance improve the outcomes of arthrocentesis and corticosteroid injection of the knee? AB - OBJECTIVE: The present randomized controlled trial compared arthrocentesis of the effusive knee followed by corticosteroid injection performed by the conventional anatomic landmark palpation-guided technique to the same procedure performed with ultrasound (US) needle guidance. METHODS: Sixty-four palpably effusive knees were randomized to (i) palpation-guided arthrocentesis with a conventional 20-mL syringe (22 knees), (ii) US-guided arthrocentesis with a 25-mL reciprocating procedure device (RPD) mechanical aspirating syringe (22 knees), or (iii) US guided arthrocentesis with a 60-mL automatic aspirating syringe (20 knees). The one-needle two-syringe technique was used. Outcome measures included patient pain by the Visual Analogue Scale (VAS) for pain (0-10 cm), the proportion of diagnostic samples, synovial fluid volume yield, complications, and therapeutic outcome at 2 weeks. RESULTS: Sonographic guidance resulted in 48% less procedural pan (VAS; palpation-guided: 5.8 +/- 3.0 cm, US-guided: 3.0 +/- 2.8 cm, p < 0.001), 183% increased aspirated synovial fluid volumes (palpation-guided: 12 +/- 10 mL, US-guided: 34 +/- 25 mL, p < 0.0001), and improved outcomes at 2 weeks (VAS; palpation-guided: 2.8 +/- 2.4 cm, US-guided: 1.5 +/- 1.9 cm, p = 0.034). Outcomes of sonographic guidance with the mechanical syringe and automatic syringe were comparable in all outcome measures. CONCLUSIONS: US-guided arthrocentesis and injection of the knee are superior to anatomic landmark palpation-guided arthrocentesis, resulting in significantly less procedural pain, improved arthrocentesis success, greater synovial fluid yield, more complete joint decompression, and improved clinical outcomes. PMID- 22103391 TI - Vasoactive Intestinal Peptide Knockout (VIP KO) mouse model of sulfite-sensitive asthma: up-regulation of novel lung carbonyl reductase. AB - BACKGROUND: We earlier reported spontaneous features of asthma in Vasoactive Intestinal Peptide knockout mice (VIP KO): 1) peribronchiolar airway inflammation, with accumulation of lymphocytes and eosinophils, 2) pro inflammatory cytokine production of IL-5, IL-6, with IFN-gamma, and 3) airway hyper-responsiveness to inhaled methacholine. In human asthma, a phenotype with sulfite sensitivity leads to airway inflammation and hyper-responsiveness to inhaled sulfites, and is associated with upregulation of anti-oxidant protein lung carbonyl reductase. For the present experiments, we examined the role of VIP in modulating anti-oxidant genes and their proteins, including lung carbonyl reductase. RESULTS: Four male VIP KO mice and four wild-type age- and gender matched mice had lungs examined for whole genome microarray and a proteomics approach using mass spectrometry. The proteomics analysis revealed that a novel variant of anti-oxidant protein lung carbonyl reductase (car3) was uniquely and markedly elevated in the VIP KO mice. RT-PCR indicated that carbonic anhydrase 3, which is an anti-oxidant protein, was elevated in the VIP KO mice. CONCLUSIONS: These data support the concept that VIP influences the endogenous oxidant/antioxidant balance. One potential implication is that VIP and its analogues may be used to treat inflammatory diseases, including asthma. PMID- 22103392 TI - Indocyanine green fluorescence-guided sentinel lymph node biopsy in dermato oncology. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc-99m). The SLNE is controversially discussed internationally. This is especially given to the high false-negative rate up to 44 %. An alternative could be the fluorescent dye indocyanine green (ICG). MATERIAL AND METHODS: We investigated the advantage of intraoperative fluorescence detection of lymphatic vessels and SLN with a Near-Infrared (NIR) camera in comparison to conventional methods using preoperative lymphoscintigraphy and SPECT/CT in 22 patients with malignant melanoma. RESULTS: A total of 61 SLNs were removed in 22 operative procedures. In 7 SLN (10.3 %; 7/68) the histopathological assessment could demonstrate a metasta-tic involvement. 11 additional SLN (19.1 %) in 8 patients were only identified using the fluorescent labeling. Two of these additional SLN (9.1 %; 2/22) showed metastatic involvement. CONCLUSION: The ICG fluorescence-guided SLNB is an innovative imaging technique for dermato-oncology, reliable and providing additional information in the detection of SLN. Therefore SLNB with fluorescence dye is an attractive option with intraoperative real-time lymphoscintigraphy to improve the detection of SLN in cutaneous malignancies and potential reduction of the false negative rate in SLN. PMID- 22103393 TI - Consideration of immediate and future consequences, smoking status, and body mass index. AB - OBJECTIVE: Health-related behaviors often involve immediate costs to achieve long term benefits. How one considers the future outcomes of present day behaviors (e.g., temporal orientation) may play a role in engagement in healthy behaviors. The Consideration of Future Consequences Scale (CFCS) measures temporal orientation on a unidimensional continuum. Recently, 2 subscales of the CFCS have been reported: immediate (CFC-I) and future (CFC-F) consequences. These support a multidimensional conceptualization of temporal orientation. Confirmatory factor analysis was performed on CFCS data. The associations between 2 health-related variables [smoking and body mass index (BMI)] and each subscale were then explored, controlling for sociodemographic variables. METHOD: A random sample of 2,000 individuals aged 18 years or over was selected from the edited electoral role for one English city and sent a postal questionnaire, including the CFCS and questions on age, gender, socioeconomic position, and self-reported current smoking status and BMI. RESULTS: Complete data was provided by 800 participants (response rate = 40.0%). The 2-factor model fitted CFCS data better than the 1 factor model. In multiple linear regression, CFC-I was positively associated with BMI, B (95% confidence interval [CI]) = 0.47 (0.06 to 0.88), p = .025; and odds of being a current smoker, odds ratio (95% CI) = 1.28 (1.02 to 1.60), p = .035; CFC-F was not associated with health-related variables. CONCLUSIONS: These data support the multidimensional conceptualization of temporal orientation. Consideration of immediate consequences may be a more important determinant of health-related behaviors than consideration of future consequences. PMID- 22103394 TI - Proteomic and biochemical evidence support a role for transport vesicles and endosomes in stress response and secondary metabolism in Aspergillus parasiticus. AB - Aflatoxin is among the most potent naturally occurring carcinogens known. Previous studies demonstrated that endosomes in the filamentous fungus Aspergillus parasiticus carry enzymes that catalyze the final two steps in aflatoxin synthesis, and these structures also play a role in aflatoxin storage and export. We hypothesized that endosomes house a complete and functional aflatoxin biosynthetic pathway. To address this hypothesis, we purified a cellular fraction containing endosomes, transport vesicles, and vacuoles (V fraction) from A. parasiticus grown under aflatoxin inducing and noninducing conditions. We also added (fed) aflatoxin pathway intermediates to V fraction to test the functional status of aflatoxin pathway enzymes. High throughput LC-MS/MS analysis of proteins in V fraction detected 8 aflatoxin enzymes with high reliability and 8 additional enzymes at lower reliability, suggesting that most aflatoxin pathway enzymes are present. Purified V fraction synthesized aflatoxin and addition of the pathway intermediate versicolorin A increased aflatoxin synthesis, confirming that middle and late aflatoxin enzymes in V fraction are functional. Of particular significance, proteomic and biochemical analysis strongly suggested that additional secondary metabolic pathways as well as proteins involved in response to heat, osmotic, and oxidative stress are housed in V fraction. PMID- 22103395 TI - Managing a basal cell carcinoma overlying a pacemaker. PMID- 22103396 TI - A psychobiological perspective on working memory performance at 8 months of age. AB - Fifty 8-month-old infants participated in a study of the interrelations among cognition, temperament, and electrophysiology. Better performance on a working memory task (assessed using a looking version of the A-not-B task) was associated with increases in frontal-parietal EEG coherence from baseline to task, as well as elevated levels of frontal-occipital coherence during both baseline and task. Enhanced performance was also associated with decreased heart period (increased heart rate) from baseline to task. Infants with better working memory performance had parents who rated them high on activity level and distress to limitations. When considered collectively, EEG coherence and heart period contributed unique variance in the prediction of high and low performance groups. Implications for the study of infant cognition are discussed. PMID- 22103397 TI - Nerve-muscle pedicle implantation in the denervated thyroarytenoid muscle of aged rats. AB - CONCLUSION: Nerve-muscle pedicle (NMP) implantation was effective in the recovery of atrophic changes in the denervated thyroarytenoid (TA) muscle in aged rats. OBJECTIVES: To evaluate the effects of NMP implantation on the denervated TA muscle in aged rats. METHODS: Wistar rats aged 20 months and 8 weeks were respectively divided into two groups in which the left recurrent laryngeal nerve (RLN) was transected without (aged/young DNV group) or with (aged/young NMP group) NMP implantation. The aged DNV and NMP groups were further divided into two subgroups, based on the period after RLN transection (10 or 20 weeks). In the DNV groups, we assessed the area of muscle and the number of neuromuscular junctions (NMJs) histologically. In the NMP groups, we performed electromyography and histological assessments. For electromyography, we stimulated the transferred nerve and evaluated the muscle action potentials (MAPs) of the TA muscle. RESULTS: The muscle areas in the aged NMP groups were significantly larger than those in the aged DNV groups. More NMJs were found in aged NMP groups compared with aged DNV groups. MAPs were seen in all NMP animals. No significant differences were observed between the aged and young NMP groups in histological and physiological assessments. PMID- 22103398 TI - Chemical composition and antioxidant activity of essential oil from berries of Schisandra chinensis (Turcz.) Baill. AB - Essential oils of Schisandra chinensis seeds and berries without seeds were separately extracted. A total of 55 compounds were identified in the essential oil of berries without seeds (EOB), representing 85.75% of the total content. A total of 52 compounds were identified in the essential oil of seeds (EOS), representing 89.74% of the total content. For EOB, the top three content compounds were alpha-cis-bergamotene (10.79%), 4,11-selinadiene (5.28%) and alpha cadinol (5.19%), while the top three content compounds of EOS were ylangene (10.16%), beta-himachalene (9.46%) and di-epi-alpha-cedrene (8.92%). The antioxidant activity of the essential oil was tested using the DPPH radical scavenging method. The antioxidant activity of EOB was higher than EOS. The IC(50) values of EOB and EOS were 8.4 and 15.8 mg/mL, respectively. This study concluded that EOB and EOS were not only different in extraction yield but also in chemical composition and antioxidant activity. PMID- 22103399 TI - Arytenoid lateralization for management of combined laryngeal paralysis and laryngeal collapse in small dogs. AB - OBJECTIVE: To identify combined laryngeal paralysis and collapse in small dogs and describe postoperative outcome after arytenoid lateralization. STUDY DESIGN: Case series. ANIMALS: Small nonbrachycephalic breed dogs with laryngeal paralysis and collapse (n = 6). METHODS: Medical records of small breed dogs with airway problems and undergoing laryngeal surgery (January-December 2008) were reviewed. Dogs with combined laryngeal paralysis and laryngeal collapse (LPLC) had arytenoid lateralization. The immediate, 4 week and 6 month postoperative outcomes were described. RESULTS: Direct visual laryngeal exam under a light plane of anesthesia revealed bilateral failure of arytenoid and vocal fold movement and concurrent bilateral medial folding with contact of the cuneiform processes in all dogs. None of the dogs had intra- or immediate postoperative complications after arytenoid lateralization. Two dogs required a 2nd contralateral procedure. Follow-up after 6 months revealed marked improvement in clinical signs related to upper airway obstruction, but all dogs continued to have mild respiratory noise. CONCLUSION: Concurrent laryngeal paralysis and collapse should be considered as part of the differential diagnosis for small, nonbrachycephalic dogs with upper airway disease. Arytenoid lateralization resulted in improvement of clinical signs related to obstructive airway disease. PMID- 22103400 TI - GJB2 and GJB6 genes and the A1555G mitochondrial mutation are only minor causes of nonsyndromic hearing loss in the Qatari population. AB - OBJECTIVE: This study reports results from the first survey of the genetic causes of nonsyndromic sensorineural hearing loss (NSHHL) in the Qatari population. DESIGN AND STUDY SAMPLES: Data were collected from 126 Qatari patients (58 males and 68 females) belonging to inbred families (56%), showing an autosomal recessive pattern of inheritance (96%). Fifty-three patients were less than 10 years old, 55 in the age range of 10 to 20 years, while 18 were aged between 20 and 30 years. All subjects had moderate to severe sensorineural hearing loss and were screened for GJB2 mutations, GJB6 deletion, and for A1555G mitochondrial mutation. RESULTS: Four patients were homozygous and one was heterozygous for c.35delG; five were homozygous for the IVS1 + 1G < A, and two were heterozygous for c.229 T > C. Only 8.3% of the pathogenic alleles were detected. No patients were positive for GJB6 deletion or for A1555G . CONCLUSIONS: These findings: (1) demonstrate that GJB2, GJB6 deletion and A1555G mutation account for a minor proportion of NSHHL in the Qatari population, (2) further strengthen the need to search for causative genes, (3) clearly contribute to establishing preventive strategies for NSHHL in Qatar and in the Gulf area. PMID- 22103401 TI - A conversation analytic view of continuous discourse tracking as a rehabilitative tool. AB - OBJECTIVE: With increasing focus on the consequences of aural rehabilitation for the everyday conversational difficulties arising from adult acquired hearing impairment, this study aimed to compare patterns of repair behaviour arising in conversation and a widely used aural rehabilitation tool, continuous discourse tracking (de Filippo & Scott, 1978), in order to better understand the procedure's role in the assessment and training of repair behaviour. DESIGN: A parallel case study design was adopted. Communication dyads undertook a 20-minute conversation followed by a 20-minute session of tracking. The interactions were audio-recorded, transcribed, and analysed for patterns of repair according to current conversation analytic conventions (Schegloff et al, 1977). The research questions were addressed via both qualitative and quantitative methods. STUDY SAMPLE: Three communication pairs (dyads), each comprising an adult with acquired hearing impairment and their chosen familiar communication partner, participated in this study. RESULTS: Analysis revealed that patterns of repair were constrained by the task requirement in tracking for the receiver/hearing-impaired adult to repeat text segments spoken by the sender/familiar communication partner with 100% accuracy. CONCLUSIONS: Whilst tracking has a number of useful conversational qualities, it may have only limited ecological validity when applied to the evaluation and training of repair behaviour. PMID- 22103402 TI - Functional analysis of Plasmodium vivax VIR proteins reveals different subcellular localizations and cytoadherence to the ICAM-1 endothelial receptor. AB - The subcellular localization and function of variant subtelomeric multigene families in Plasmodium vivax remain vastly unknown. Among them, the vir superfamily is putatively involved in antigenic variation and in mediating adherence to endothelial receptors. In the absence of a continuous in vitro culture system for P. vivax, we have generated P. falciparum transgenic lines expressing VIR proteins to infer location and function. We chose three proteins pertaining to subfamilies A (VIR17), C (VIR14) and D (VIR10), with domains and secondary structures that predictably traffic these proteins to different subcellular compartments. Here, we showed that VIR17 remained inside the parasite and around merozoites, whereas VIR14 and VIR10 were exported to the membrane of infected red blood cells (iRBCs) in an apparent independent pathway of Maurer's clefts. Remarkably, VIR14 was exposed at the surface of iRBCs and mediated adherence to different endothelial receptors expressed in CHO cells under static conditions. Under physiological flow conditions, however, cytoadherence was only observed to ICAM-1, which was the only receptor whose adherence was specifically and significantly inhibited by antibodies against conserved motifs of VIR proteins. Immunofluorescence studies using these antibodies also showed different subcellular localizations of VIR proteins in P. vivax-infected reticulocytes from natural infections. These data suggest that VIR proteins are trafficked to different cellular compartments and functionally demonstrates that VIR proteins can specifically mediate cytoadherence to the ICAM-1 endothelial receptor. PMID- 22103403 TI - Effects of plasminogen activator inhibitor-1-specific RNA aptamers on cell adhesion, motility, and tube formation. AB - The serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is associated with the pathophysiology of several diseases, including cancer and cardiovascular disease. The extracellular matrix protein vitronectin increases at sites of vessel injury and is also present in fibrin clots. Integrins present on the cell surface bind to vitronectin and anchor the cell to the extracellular matrix. However, the binding of PAI-1 to vitronectin prevents this interaction, thereby decreasing both cell adhesion and migration. We previously developed PAI 1-specific RNA aptamers that bind to (or in the vicinity of) the vitronectin binding site of PAI-1. These aptamers prevented cancer cells from detaching from vitronectin in the presence of PAI-1, resulting in an increase in cell adhesion. In the current study, we used in vitro assays to investigate the effects that these aptamers have on human aortic smooth muscle cell (HASMC) and human umbilical vein endothelial cell (HUVEC) migration, adhesion, and proliferation. The PAI-1-specific aptamers (SM20 and WT15) increased attachment of HASMCs and HUVECs to vitronectin in the presence of PAI-1 in a dose-dependent manner. Whereas PAI-1 significantly inhibited cell migration through its interaction with vitronectin, both SM20 and WT15 restored cell migration. The PAI-1 vitronectin binding mutant (PAI-1AK) did not facilitate cell detachment or have an effect on cell migration. The effect on cell proliferation was minimal. Additionally, both SM20 and WT15 promoted tube formation on matrigel that was supplemented with vitronectin, thereby reversing the PAI-1's inhibition of tube formation. Collectively, results from this study show that SM20 and WT15 bind to the PAI-1's vitronectin binding site and interfere with its effect on cell migration, adhesion, and tube formation. By promoting smooth muscle and endothelial cell migration, these aptamers can potentially eliminate the adverse effects of elevated PAI-1 levels in the pathogenesis of vascular disease. PMID- 22103404 TI - Enzymatic hydrolysis of organic phosphates adsorbed on mineral surfaces. AB - Esters of phosphoric acid constitute a sizable fraction of the total phosphorus supply in the environment and thus play an important role in the global phosphorus cycle. Enzymatic hydrolysis of these esters to produce orthophosphate is often a required reaction preceding phosphorus uptake by plants and microorganisms. Generally, adsorption to environmental particles is assumed to limit this process. Here we show, however, that the rate of enzymatic hydrolysis of glucose-1-phosphate (G1P) adsorbed on goethite by acid phosphatase (AcPase) can be of the same order of magnitude as in aqueous solution. The surface process releases carbon to the solution whereas orthophosphate remains adsorbed on goethite. This hydrolysis reaction is strictly an interfacial process governed by the properties of the interface. A high surface concentration of substrate mediates the formation of a catalytically active layer of AcPase, and although adsorption likely reduces the catalytic efficiency of the enzyme, this reduction is almost balanced by the fact that enzyme and substrate are concentrated at the mineral surfaces. Our results suggest that mineral surfaces with appropriate surface properties can be very effective in concentrating substrates and enzymes thereby creating microchemical environments of high enzymatic activity. Hence, also strongly adsorbed molecules in soils and aquatic environments may be subjected to biodegradation by extracellular enzymes. PMID- 22103405 TI - Initial- and processive-cut products reveal cellobiohydrolase rate limitations and the role of companion enzymes. AB - Efforts to improve the activity of cellulases, which catalyze the hydrolysis of insoluble cellulose, have been hindered by uncertainty surrounding the mechanistic origins of rate-limiting phenomena and by an incomplete understanding of complementary enzyme function. In particular, direct kinetic measurements of individual steps occurring after enzymes adsorb to the cellulose surface have proven to be experimentally elusive. This work describes an experimental and analytical approach, derived from a detailed mechanistic model of cellobiohydrolase action, for determining rates of initial- and processive-cut product generation by Trichoderma longibrachiatum cellobiohydrolase I (TlCel7A) as it catalyzes the hydrolysis of bacterial microcrystalline cellulose (BMCC) alone and in the presence of Talaromyces emersonii endoglucanase II (TemGH5). This analysis revealed that the rate of TlCel7A-catalyzed hydrolysis of crystalline cellulose is limited by the rate of enzyme complexation with glycan chains, which is shown to be equivalent to the rate of initial-cut product generation. This rate is enhanced in the presence of endoglucanase enzymes. The results confirm recent reports about the role of morphological obstacles in enzyme processivity and also provide the first direct evidence that processive length may be increased by the presence of companion enzymes, including small amounts of TemGH5. The findings of this work indicate that efforts to improve cellobiohydrolase activity should focus on enhancing the enzyme's ability to complex with cellulose chains, and the analysis employed provides a new technique for investigating the mechanism by which companion enzymes influence cellobiohydrolase activity. PMID- 22103406 TI - Electronic states of the benzene dimer: a simple case of complexity. AB - Electronic structure calculations of the excited states of the benzene dimer using equation-of-motion coupled-cluster method are reported. The calculations reveal large density of electronic states, including multiple valence, Rydberg, and mixed Rydberg-valence states. The calculations of the oscillator strengths for the transitions between the excimer state (i.e., the lowest excited state of the dimer, 1(1)B(1g)) and other excited states allowed us to identify the target state responsible for the excimer absorption as the E(1u) state of a mixed Rydberg-valence character at 3.04 eV above the excimer (1(1)B(1g)). Although at D(6h) the 1(1)B(1g) -> E(1u) transition is symmetry-forbidden, small geometric displacements (to D(2h)) that have a negligible effect on the excitation energy split this degenerate state into the dark (4B(3u)) and bright (4B(2u)) components (oscillator strength of 0.3 au). The excitation energy for this transition depends strongly on the dimer structure, which explains the broad character of the experimentally observed excimer absorption spectrum. PMID- 22103407 TI - Molecular structure, physicochemical characterization, and in vitro degradation of barley protein films. AB - Barley protein films were prepared by thermopressing using glycerol as a plasticizer. The combined effects of heating temperature and amount of plasticizer interacted to determine protein conformation and, subsequently, the properties of the film matrix. The film barrier and mechanical properties were systematically investigated using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), SDS-PAGE, and protein solubility tests. These experiments demonstrated that heat treatment induced barley protein unfolding and then protein aggregation and the formation of covalent disulfide bonds to enhance film strength. Increasing the amount of plasticizer reduced protein denaturation and limited protein interactions, resulting in significantly improved film flexibility at the cost of reduced film moisture barrier property and tensile strength. In vitro degradation experiments demonstrated that barley films were resistant in gastric conditions, yet can still be completely degraded by intestinal enzymes, and they possess low cytotoxicity to Caco-2 cells. The prepared barley films have potential for development as delivery systems for gastric-sensitive bioactive compounds to the intestine for release. PMID- 22103408 TI - (211)-Orientation preference of transparent conducting In2O3:Sn films and its formation mechanism. AB - Dominantly (211)-oriented In(2)O(3):Sn (ITO) transparent conducting oxide (TCO) films were first fabricated at high sputtering power in the weak reducing ambient with superior electrical and optical properties. The dependence of ITO film orientation on growth condition was systematically investigated, and the formation mechanism was studied by surface energy calculation and band structure simulation. The unique properties of the (211)-oriented films should be ascribed to the richest In-terminated surface of the (211) plane, which is tightly correlated with the comparably highest surface energy and highest conduction band surface comparing with the other two typical planes of (222) and (400). The as prepared (211)-oriented ITO films with the In-rich ending atoms on the surface are of great significance for the transparent electrode applications. PMID- 22103409 TI - Molecular mechanisms of neuronal specification. PMID- 22103410 TI - Specification and regionalisation of the neural plate border. AB - During early vertebrate development, the embryonic ectoderm becomes subdivided into neural, neural plate border (border) and epidermal regions. The nervous system is derived from the neural and border domains which, respectively, give rise to the central and peripheral nervous systems. To better understand the functional nervous system we need to know how individual neurons are specified and connected. Our understanding of the early development of the peripheral nervous system has been lagging compared to knowledge regarding central nervous system and epidermal cell lineage decision. Recent advances have shown when and how the specification of border cells is initiated. One important insight is that border specification is already initiated at blastula stages, and can be molecularly and temporally distinguished from rostrocaudal regionalisation of the border. From findings in several species, it is clear that Wnt, Bone Morphogenetic Protein and Fibroblast Growth Factor signals play important roles during the specification and regionalisation of the border. In this review, we highlight the individual roles of these signals and compare models of border specification, including a new model that describes how temporal coordination and epistatic interactions of extracellular signals result in the specification and regionalisation of border cells. PMID- 22103411 TI - Dependence on the transcription factor Shox2 for specification of sensory neurons conveying discriminative touch. AB - Touch sensation is mediated by specific subtypes of sensory neurons which develop in a hierarchical process from common early progenitor neurons, but the molecular mechanism that underlies diversification of touch-sensitive mechanoreceptive neurons is not fully known. Here, we use genetically manipulated mice to examine whether the transcription factor short stature homeobox 2 (Shox2) participates in the acquisition of neuronal subtypes conveying touch sensation. We show that Shox2 encodes the development of category I low-threshold mechanoreceptive neurons in glabrous skin, i.e. discriminative touch-sensitive neurons which form innervations of epidermal Merkel cell and Meissner corpuscles. In contrast, other sensory fiber endings, including those innervating Pacinian corpuscles, are not dependent on Shox2. Shox2 is expressed in neurons of most or all classes of sensory neurons at early embryonic stages and is later confined to touch sensitive neurons expressing Ret and/or TrkB. Conditional deletion of Shox2 and analysis of Runx3(-/-);Bax(-/-) mutant mice reveals that Runx3 is suppressing Shox2 while Shox2 is necessary for TrkB expression, and that these interactions are necessary for diversification of TrkB(+) and TrkC(+) mechanoreceptive neurons. In particular, development of TrkB(+)/Ret(+) and TrkB(+)/Ret(-) touch sensitive neurons is critically dependent on Shox2. Consistently, Shox2 conditional mutant mice demonstrate a dramatic impairment of light touch responses. These results show that Shox2 is required for specification of a subclass of TrkB(+) sensory neurons which convey the sensation of discriminative touch arising from stimuli of the skin. PMID- 22103412 TI - Decoding the transcriptional basis for GABAergic interneuron diversity in the mouse neocortex. AB - The locally projecting GABAergic interneurons of the mammalian cerebral cortex are a highly heterogeneous population, whose malfunction or deficit has been implicated in a wide range of neurological disorders. However, the low incidence of the various distinct interneuron populations within the neocortex, combined with the lack of molecular or physiological markers specific to these subtypes, have hampered investigations into their function in the normal and dysfunctional brain. A number of research groups have begun to elucidate the developmental genetic mechanism that underpins this diversity in the mouse neocortex, spurred on by the knowledge that the temporal and spatial origin of an interneuron in the embryonic brain is predictive of its eventual intrinsic properties in the mature cortex. In this review we highlight a number of recent findings that strengthen our understanding of the transcription factor code that is at the heart of generating this diversity. Further understanding of this code will enable selective observation, targeting and manipulation of interneuron subtypes across both in vitro and in vivo systems. PMID- 22103413 TI - Development of raphe serotonin neurons from specification to guidance. AB - The main features of the development of the serotonin (5-HT) raphe neurons have been known for many years but more recent molecular studies, using mouse genetics, have since unveiled several intriguing aspects of the specification of the raphe serotonergic system. These studies indicated that, although all 5-HT neurons in the raphe follow the same general program for their specification, there are also clear regional differences in the way that these neurons are specified and are guided towards different brain targets. Here we overview recent progress made in the understanding of the developmental programming of serotonergic neurons in the mouse raphe, emphasizing data showing how heterogeneous subsets of 5-HT neurons may be generated. Serotonergic progenitors are produced in the brainstem in different rhombomeres under the influence of a set of secreted factors, sonic hedgehog and fibroblast growth factors, which determine their position in the neural tube. Two main transcriptional gene networks are involved in the specification of 5-HT identity, with Lmx1b and Pet1 transcription factors as main players. A differential requirement for Pet1 was, however, revealed, which underlies an anatomical and functional diversity. Transcriptional programs controlling 5-HT identity could also impact axon guidance mechanisms directing 5-HT neurons to their targets. Although no direct links have yet been established, a large set of molecular determinants have already been shown to be involved in the growth, axon guidance and targeting of 5 HT raphe neurons, particularly within the forebrain. Alterations in the molecular mechanisms involved in 5-HT development are likely to have significant roles in mood disease predisposition. PMID- 22103414 TI - Transcriptional control of differentiation and neurogenesis in autonomic ganglia. AB - Autonomic neuron development is controlled by a network of transcription factors, which is induced by bone morphogenetic protein signalling in neural crest progenitor cells. This network intersects with a transcriptional program in migratory neural crest cells that pre-specifies autonomic neuron precursor cells. Recent findings demonstrate that the transcription factors acting in the initial specification and differentiation of sympathetic neurons are also important for the proliferation of progenitors and immature neurons during neurogenesis. Elimination of Phox2b, Hand2 and Gata3 in differentiated neurons affects the expression of subtype-specific and/or generic neuronal properties or neuron survival. Taken together, transcription factors previously shown to act in initial neuron specification and differentiation display a much broader spectrum of functions, including control of neurogenesis and the maintenance of subtype characteristics and survival of mature neurons. PMID- 22103415 TI - Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. AB - Prenatal development is highly sensitive to maternal drug use due to the vulnerability for disruption of the fetal brain with its ongoing neurodevelopment, resulting in lifelong consequences that can enhance risk for psychiatric disorders. Cannabis and cigarettes are the most commonly used illicit and licit substances, respectively, among pregnant women. Although the behavioral consequences of prenatal cannabis and cigarette exposure have been well documented in epidemiological and clinical studies, only recently have investigations into the molecular mechanisms associated with the developmental impact of early drug exposure been addressed. This article reviews the literature relevant to long-term gene expression disturbances in the human fetal brain in relation to maternal cannabis and cigarette use. To provide translational insights, we discuss animal models in which protracted molecular consequences of prenatal cannabis and cigarette exposure can be better explored and which enable future evaluation of epigenetic pathways, such as DNA methylation and histone modification, that could potentially maintain abnormal gene regulation and related behavioral disturbances. Altogether, this information may help to address the current gaps of knowledge regarding the impact of early drug exposure that set in motion lifelong molecular disturbances that underlie vulnerability to psychiatric disorders. PMID- 22103416 TI - Differential gene expression in migratory streams of cortical interneurons. AB - Cortical interneurons originate in the ganglionic eminences of the subpallium and migrate into the cortex in well-defined tangential streams. At the start of corticogenesis, two streams of migrating neurons are evident: a superficial one at the level of the preplate (PPL), and a deeper one at the level of the intermediate zone (IZ). Currently, little is known about the signalling mechanisms that regulate interneuron migration, and almost nothing is known about the molecules that may be involved in their choice of migratory stream. Here, we performed a microarray analysis, comparing the changes in gene expression between cells migrating in the PPL and those migrating in the IZ at embryonic day 13.5. This analysis identified genes, many of them novel, that were upregulated in one of the two streams. Moreover, polymerase chain reaction, in situ hybridization experiments and immunohistochemistry showed the expression of these genes in interneurons migrating within the PPL or IZ, suggesting that they play a role in their migration and choice of stream. PMID- 22103417 TI - Cell-autonomous and cell-to-cell signalling events in normal and altered neuronal migration. AB - The cerebral cortex is a complex six-layered structure that contains an important diversity of neurons, and has rich local and extrinsic connectivity. Among the mechanisms governing the cerebral cortex construction, neuronal migration is perhaps the most crucial as it ensures the timely formation of specific and selective neuronal circuits. Here, we review the main extrinsic and extrinsic factors involved in regulating neuronal migration in the cortex and describe some environmental factors interfering with their actions. PMID- 22103419 TI - Forward signaling by EphB1/EphB2 interacting with ephrin-B ligands at the optic chiasm is required to form the ipsilateral projection. AB - EphB receptor tyrosine kinases direct axonal pathfinding through interactions with ephrin-B proteins following axon-cell contact. As EphB:ephrin-B binding leads to bidirectional signals, the contributions of signaling into the Eph expressing cell (forward signaling) or the ephrin-expressing cell (reverse signaling) cannot be assigned using traditional protein null alleles. To determine if EphB1 is functioning solely as a receptor during axon pathfinding, a new knock-in mutant mouse was created, EphB1(T-lacZ), which expresses an intracellular-truncated EphB1-beta-gal fusion protein from the endogenous locus. As in the EphB1(-/-) protein null animals, the EphB1(T-lacZ/T-lacZ) homozygotes fail to form the ipsilateral projecting subpopulation of retinal ganglion cell axons. This indicates that reverse signaling through the extracellular domain of EphB1 is not required for proper axon pathfinding of retinal axons at the optic chiasm. Further analysis of other EphB and ephrin-B mutant mice shows that EphB1 is the preferred receptor of ephrin-B2 and, to a lesser degree, ephrin-B1 in mediating axon guidance at the optic chiasm despite the coexpression of EphB2 in the same ipsilaterally projecting retinal axons. PMID- 22103418 TI - The axon initial segment in nervous system disease and injury. AB - The axon initial segment (AIS), with its dense clusters of voltage-gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine-tuning of neuronal excitability. Therefore, it is not surprising that mutations in AIS related genes, disruption of the molecular organization of the AIS and altered AIS ion channel expression, function, location and/or density are emerging as key players in neurological disorders. Here, we consider the role of the AIS in nervous system disease and injury. PMID- 22103420 TI - DAGL-dependent endocannabinoid signalling: roles in axonal pathfinding, synaptic plasticity and adult neurogenesis. AB - Until recently, endocannabinoid (eCB) signalling was largely studied in the context of synaptic plasticity in the postnatal brain in the absence of detailed knowledge of the nature of the enzyme(s) responsible for the synthesis of the eCBs. However, the identification of two diacylglycerol lipases (DAGLalpha and DAGLbeta) responsible for the synthesis of 2-arachidonoylglycerol (2-AG) has increased the understanding of where this eCB is synthesised in relationship to the expression of cannabinoid receptor (CB)1 and CB2. Furthermore, the generation of knockout animals for each enzyme has allowed for the direct testing of their importance for established and emerging eCB functions. Based on this, we now know that DAGLalpha is enriched in dendritic spines that appose CB1-positive synaptic terminals, and that 2-AG functions as a retrograde signal controlling synaptic strength throughout the nervous system. Consequently, we have built on the principle that expression of eCB components dictates function to identify additional physiological functions of this signalling cassette. A number of studies have now provided support for DAGL-dependent eCB signalling playing important roles in brain development and in cellular plasticity in the adult nervous system. In this article, we will review evidence based on the localisation of the enzymes, as well as from genetic and pharmacological studies, that show DAGL-dependent eCB signalling to play an important role in axonal growth and guidance during development, in retrograde synaptic signalling at mature synapses, and in the control of adult neurogenesis in the hippocampus and subventricular zone. PMID- 22103421 TI - Axon-axon interactions in neuronal circuit assembly: lessons from olfactory map formation. AB - During the development of the nervous system, neurons often connect axons and dendrites over long distances, which are navigated by chemical cues. During the past few decades, studies on axon guidance have focused on chemical cues provided by the axonal target or intermediate target. However, recent studies have shed light on the roles and mechanisms underlying axon-axon interactions during neuronal circuit assembly. The roles of axon-axon interactions are best exemplified in recent studies on olfactory map formation in vertebrates. Pioneer follower interaction is essential for the axonal pathfinding process. Pre-target axon sorting establishes the anterior-posterior map order. The temporal order of axonal projection is converted to dorsal-ventral topography with the aid of secreted molecules provided by early-arriving axons. An activity-dependent process to form a discrete map also depends on axon sorting. Thus, an emerging principle of olfactory map formation is the 'self-organisation' of axons rather than the 'lock and key' matching between axons and targets. In this review, we discuss how axon-axon interactions contribute to neuronal circuit assembly. PMID- 22103422 TI - From filopodia to synapses: the role of actin-capping and anti-capping proteins. AB - Actin-capping and anti-capping proteins are crucial regulators of actin dynamics. Recent studies have indicated that these proteins may be heavily involved in all stages of synaptogenesis, from the emergence of filopodia, through neuritogenesis and synaptic contact stabilization, to the structural changes occurring at the synapse during potentiation phenomena. In this review, we focus on recent evidence pointing to an active role of actin-capping and anti-capping proteins in orchestrating the processes controlling neuronal connectivity and plasticity. PMID- 22103424 TI - Electrical activity patterns and the functional maturation of the neocortex. AB - At the earliest developmental stages, sensory neocortical areas in various species reveal distinct patterns of spontaneous neuronal network activity. These activity patterns either propagate over large neocortical areas or synchronize local neuronal ensembles. In vitro and in vivo experiments indicate that these spontaneous activity patterns are generated from neuronal networks in the cerebral cortex, in subcortical structures or in the sensory periphery (retina, cochlea, whiskers). At early stages spontaneous periphery-driven and also sensory evoked activity is relayed to the developing cerebral cortex via the thalamus and the neocortical subplate, which amplifies the afferent sensory input. These early local and large-scale neuronal activity patterns influence a variety of developmental processes during corticogenesis, such as neurogenesis, apoptosis, neuronal migration, differentiation and network formation. The experimental data also indicate that disturbances in early neuronal patterns may have an impact on the development of cortical layers, columns and networks. In this article we review our current knowledge on the origin of early electrical activity patterns in neocortical sensory areas and their functional implications on shaping developing cortical networks. PMID- 22103425 TI - Postnatal differentiation of cortical interneuron signalling. AB - Most GABAergic interneurons in the cortex are born at embryonic stages in the ganglionic eminences and migrate tangentially to their final destination. They continue, however, to differentiate and functionally integrate in the circuitry until later postnatal stages of the rodent brain. Recent investigations show that interneurons undergo marked changes in their morphological, intrinsic and synaptic properties as they mature. Action potential shape and its propagation, the period of transmitter release and the time course of the postsynaptic GABA(A) receptor-mediated conductance become faster during the first three to four postnatal weeks, resulting in a developmental switch of interneurons from slow to fast signalling units. At the same time, the nature of GABAergic signalling is classically considered to shift from depolarizing to hyperpolarizing. However, recent studies oppose this view as interneuron synapses can be shunting, excitatory or hyperpolarizing in the mature cortex, demonstrating the coexistence of diverse developmental rules for the emerging effects of GABAergic synapses. Thus, mature interneuron signalling comes in many forms and is apparently optimized to the network in which the neurons are embedded. PMID- 22103423 TI - What can we get from 'barrels': the rodent barrel cortex as a model for studying the establishment of neural circuits. AB - Sensory inputs triggered by external stimuli are projected into discrete arrays of neuronal modules in the primary sensory cortex. This whisker-to-barrel pathway has gained in popularity as a model system for studying the development of cortical circuits and sensory processing because its clear patterns facilitate the identification of genetically modified mice with whisker map deficits and make possible coordinated in vitro and in vivo electrophysiological studies. Numerous whisker map determinants have been identified in the past two decades. In this review, we summarize what have we learned from the detailed studies conducted in various mutant mice with cortical whisker map deficits. We will specifically focus on the anatomical and functional establishment of the somatosensory thalamocortical circuits. PMID- 22103426 TI - Climbing fiber synapse elimination in cerebellar Purkinje cells. AB - Innervation of Purkinje cells (PCs) by multiple climbing fibers (CFs) is refined into mono-innervation during the first three postnatal weeks of rodents' lives. In this review article, we will integrate the current knowledge on developmental process and mechanisms of CF synapse elimination. In the 'creeper' stage of CF innervation (postnatal day 0 (P0)~), CFs creep among PC somata to form transient synapses on immature dendrites. In the 'pericellular nest' stage (P5~), CFs densely surround and innervate PC somata. CF innervation is then displaced to the apical portion of PC somata in the 'capuchon' stage (P9~), and translocate to dendrites in the 'dendritic' (P12~) stage. Along with the developmental changes in CF wiring, functional and morphological distinctions become larger among CF inputs. PCs are initially innervated by more than five CFs with similar strengths (~P3). During P3-7 only a single CF is selectively strengthened (functional differentiation), and it undergoes dendritic translocation from P9 on (dendritic translocation). Following the functional differentiation, perisomatic CF synapses are eliminated nonselectively; this proceeds in two distinct phases. The early phase (P7-11) is conducted independently of parallel fiber (PF)-PC synapse formation, while the late phase (P12-17) critically depends on it. The P/Q-type voltage-dependent Ca(2+) channel in PCs triggers selective strengthening of single CF inputs, promotes dendritic translocation of the strengthened CFs, and drives the early phase of CF synapse elimination. In contrast, the late phase is mediated by the mGluR1-Galphaq-PLCbeta4-PKCgamma signaling cascade in PCs driven at PF-PC synapses, whose structural connectivity is stabilized and maintained by the GluRdelta2-Cbln1-neurexin system. PMID- 22103427 TI - Transcriptional profiling of vaccine-induced immune responses in humans and non human primates. AB - There is an urgent need for pre-clinical and clinical biomarkers predictive of vaccine immunogenicity, efficacy and safety to reduce the risks and costs associated with vaccine development. Results emerging from immunoprofiling studies in non-human primates and humans demonstrate clearly that (i) type and duration of immune memory are largely determined by the magnitude and complexity of the innate immune signals and (ii) genetic signatures highly predictive of B cell and T-cell responses can be identified for specific vaccines. For vaccines with similar composition, e.g. live attenuated viral vaccines, these signatures share common patterns. Signatures predictive of vaccine efficacy have been identified in a few experimental challenge studies. This review aims to give an overview of the current literature on immunoprofiling studies in humans and also presents some of our own data on profiling of licensed and experimental vaccines in non-human primates. PMID- 22103428 TI - Evaluation of anti-nociceptive effect of epidural tramadol, tramadol-lidocaine and lidocaine in goats. AB - OBJECTIVE: To compare the anti-nociceptive effect of tramadol, a combination of tramadol-lidocaine, and lidocaine alone when administered in the epidural space. STUDY DESIGN: Experimental randomized cross-over study. ANIMALS: Seven healthy male goats, aged 9-11 months, weight 17.5-25.5 kg. METHODS: Treatments were lidocaine, 2.86 mg kg(-1), tramadol-lidocaine (1 mg kg(-1) and 2.46 mg kg(-1), respectively) and tramadol (1 mg kg(-1)) given into the epidural space. The volume of all treatments was 0.143 mL kg(-1). Nociception was tested by pin prick and by pressure from a haemostat clamp. Times to the onset and duration of anti nociception in the perineal region were recorded. Recumbency and ataxia were noted. Rectal temperature, heart rate and respiratory rate were recorded before and at 15 minute intervals for 2 hours after the administration of each treatment. Statistical comparison used one-way anova with a post hoc Duncan's test as a post hoc. Significance was taken as p < 0.05. RESULTS: Times (mean +/- SD) to onset of and duration of loss of sensation, respectively in minutes were; lidocaine, 3 +/- 1 and 85 +/- 11), tramadol-lidocaine 4 +/- 1 and 140 +/- 2; tramadol 12 +/- 1 and 235 +/- 18. Onset and duration times were significantly longer with tramadol than the other two treatments. Duration was significantly longer with tramadol-lidocaine than with lidocaine alone. With lidocaine treatment all goats were severely ataxic or recumbent, after tramadol-lidocaine mildly ataxic, and after tramadol not ataxic. Rectal temperature, heart and respiratory rates did not differ significantly from baseline after any treatment. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of tramadol-lidocaine given by epidural injection produced an anti-nociceptive effect in the perineal region, which was rapid in onset and had a longer duration of action than lidocaine alone. This combination might prove useful clinically to provide analgesia in goats for long-duration obstetrical and surgical procedures but surgical stimuli were not investigated in this study. PMID- 22103429 TI - Efficacy of FEIBA for acute bleeding and surgical haemostasis in haemophilia A patients with inhibitors: a multicentre registry in Turkey. AB - Long used in established industrialized nations to treat patients with haemophilia and inhibitors, factor eight inhibitor bypassing activity (FEIBA) has, in recent years, been introduced into more geographically diverse settings. Data are needed on how successfully FEIBA therapy has been implemented in new regions. To determine the efficacy and safety of FEIBA for the treatment of acute bleeding and surgical haemostasis in a newly industrialized country. A multicentre registry of haemophilia A patients with inhibitors receiving FEIBA treatment was established in Turkey. With a standardized case report form, data were collected retrospectively on: patient demographics; characteristics of acute bleeding episodes and surgical interventions; FEIBA regimen; and treatment outcomes. Thirty-seven patients received a total of 112 FEIBA treatment courses, 90 for acute bleeding and 22 for surgical haemostasis. The median FEIBA dose per infusion for acute bleeding was 50 IU kg(-1), and for surgery was 100 IU kg(-1). For both acute joint and muscle/soft tissue bleeding and in surgery, haemostasis was attained in a median of two FEIBA infusions. FEIBA was judged effective in 92% of treatment courses for acute bleeding, with a 95% confidence interval (CI) of 85-97%. Rates of haemostatic efficacy did not differ significantly between anatomical sites of acute bleeding. The haemostatic efficacy rate of FEIBA in surgery was 86% (CI, 65-97%). No thromboembolic complications or other adverse events occurred during any treatment course. FEIBA has been successfully integrated into clinical practice in Turkey, with rates of haemostatic efficacy comparable to those reported in countries with a longer history of FEIBA usage. PMID- 22103430 TI - Building blocks for peer success: lessons learned from a train-the-trainer program. AB - The National HIV/AIDS Strategy (NHAS) calls for a reduction in health disparities, a reduction in new HIV infections, and improved retention in HIV care and treatment. It acknowledges that HIV-positive peers can play an important role in supporting these aims. However, peer training must be comprehensive enough to equip peers with the knowledge and skills needed for this work. This article describes the development of a national train the trainer (TTT) model for HIV peer educators, and the results of its implementation and replication. A mixed methods evaluation identified who was trained locally as a result of TTT implementation, what aspects of the TTT were most useful to trainers in implementing local training sessions, and areas for improvement. Over the course of 1 year, 91 individuals were trained at 1 of 6 TTT sessions. These individuals then conducted 26 local training sessions for 272 peers. Factors that facilitated local replication training included the teach-back/feedback model, faculty modeling of facilitation styles, financial support for training logistics, and faculty support in designing and implementing the training. The model could be improved by providing instruction on how to incorporate peers as part of the training team. TTT programs that are easily replicable in the community will be an important asset in developing a peer workforce that can help implement the National AIDS Strategy. PMID- 22103432 TI - Noninvasive estimation of chronological and photoinduced skin damage using Raman spectroscopy and principal component analysis. AB - BACKGROUND: Skin aging can be attributed to endogenous and exogenous factors which modify the hydration and protein structure of the skin which can be measured using Raman spectroscopy. METHOD: This study included 21 healthy adult volunteers, aged 32-81 years, Raman spectra were obtained from sun-protected and sun-exposed skin, also three millimeter punch biopsies of sun-exposed skin were collected and analyzed. The Raman spectra were analyzed using principal component analysis and the results were correlated with clinical and histological findings. RESULTS: The principal component analysis of the Raman spectra shows that the first principal component (PC1) obtained from the sun-protected skin is related to the age of the subject, which can be taken as a measure of chronological aging, the second (PC2) and fourth (PC4) principal components obtained from Raman spectra of sun-exposed skin are related to the amount of solar elastosis and collagen, respectively. CONCLUSION: In this work a relationship was found between histological properties of photoaged skin and noninvasive measurements based on Raman and principal components analysis (PCA). These relationships can be used to assess noninvasively the photoinduced damage and chronological characteristics of skin. PMID- 22103431 TI - Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues. AB - Inhibition of GSL (glycosphingolipid) synthesis reduces Abeta (amyloid beta peptide) production in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway may regulate some aspects of Abeta production. It is not clear whether there is a causative relationship linking GSL synthesis inhibition, ERK phosphorylation and Abeta production. In the present study, we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that both constitutively express human wild-type APP (amyloid precursor protein) and process this to produce Abeta, with GSL-modulating agents to explore this relationship. We found that three related ceramide analogue GSL inhibitors, based on the PDMP (D-threo-1-phenyl-2 decanoylamino-3-morpholino-1-propanol) structure, reduced cellular Abeta production and in all cases this was correlated with inhibition of pERK (phosphorylated ERK) formation. Importantly, the L-threo enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared with the D-threo enantiomers) also reduced ERK phosphorylation to a similar extent without altering Abeta production. Inhibition of ERK activation using either PD98059 [2 (2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] or U0126 (1,4-diamino-2,3 dicyano-1,4-bis[2-aminophenylthio] butadiene) had no impact on Abeta production, and knockdown of endogenous GCS using small interfering RNA reduced cellular GSL levels without suppressing Abeta production or pERK formation. Our data suggest that the alteration in pERK levels following treatment with these ceramide analogues is not the principal mechanism involved in the inhibition of Abeta generation and that the ERK signalling pathway does not play a crucial role in processing APP through the amyloidogenic pathway. PMID- 22103433 TI - The impact of peer support training on mothers' attitudes towards and knowledge of breastfeeding. AB - While the benefits of breastfeeding are well established, few Scottish women exclusively breastfeed, as recommended nationally and internationally. Breastfeeding peer support can help mothers to breastfeed for longer, but the training peer supporters receive is variable and few studies have measured the effectiveness of peer supporter training. This study aimed to compare mothers' attitudes towards and knowledge of breastfeeding before and after undertaking Breastfeeding Network (BfN) peer supporter training. This study used a quasi experimental design to investigate levels of breastfeeding knowledge and attitudes in 28 women, immediately before and after the BfN peer supporter (Helper) training programme. Data were collected using the Infant Feeding Questionnaire. Mothers had high baseline scores for attitude (88.8%) and knowledge (76.4%). After training 78% of mothers improved their attitude scores. The mean difference in attitude scores was 4.9%, which was statistically significant (t = 4.44, P < 0.001). Ninety-six per cent of mothers had increased their knowledge scores. The mean difference in knowledge scores was 10.4%, which was statistically significant (t = 6.25, P < 0.001). This study provides evidence that the BfN's accredited peer support training can improve both breastfeeding knowledge and attitudes of breastfeeding mothers. Peer supporters who have undertaken this training are therefore suitably qualified to provide mothers with the support and information required to make informed choices in breastfeeding and to contribute to effective support and promotion of breastfeeding as suggested in the National Institute for Health and Clinical Excellence guideline on maternal and infant nutrition (PH11) and Scottish Government's Maternal and Infant Nutrition: A Framework for Action (2011). PMID- 22103434 TI - A time-varying effect model for intensive longitudinal data. AB - Understanding temporal change in human behavior and psychological processes is a central issue in the behavioral sciences. With technological advances, intensive longitudinal data (ILD) are increasingly generated by studies of human behavior that repeatedly administer assessments over time. ILD offer unique opportunities to describe temporal behavioral changes in detail and identify related environmental and psychosocial antecedents and consequences. Traditional analytical approaches impose strong parametric assumptions about the nature of change in the relationship between time-varying covariates and outcomes of interest. This article introduces time-varying effect models (TVEMs) that explicitly model changes in the association between ILD covariates and ILD outcomes over time in a flexible manner. In this article, we describe unique research questions that the TVEM addresses, outline the model-estimation procedure, share a SAS macro for implementing the model, demonstrate model utility with a simulated example, and illustrate model applications in ILD collected as part of a smoking-cessation study to explore the relationship between smoking urges and self-efficacy during the course of the pre- and postcessation period. PMID- 22103435 TI - Lack of irritative potential of nadifloxacin 1% when combined with other topical anti-acne agents. AB - BACKGROUND: Diverse options are available for the treatment of acne. Topical therapy is standard, especially in cases of mild to moderate acne, while the current treatments for acne vulgaris are topical keratolytics and topical antibiotics. Tolerability is a critical factor in patient compliance with topical acne therapies. The simultaneous use of more than one topical preparation with different active ingredients may cause increased irritation. However, the multifactorial aetiologies of acne, and the need to prevent development of bacterial resistance, require new acne-treatment combinations. Combining agents that target the different aetiological factors of acne can help increase efficacy and reduce response time. AIM: To compare the dermal irritation produced by an anti-acne cream containing 1% nadifloxacin with that produced by additional treatment with four different topical anti-acne products in a 21-day open application test in 40 healthy volunteers. METHODS: This was a randomized, double blind (observer-blind), single-centre, phase I clinical study with an intraindividual comparison. The topic anti-acne products (nadifloxacin, adapalene, benzoyl peroxide, azelaic acid and isotretinoin) were applied without occlusion, either alone or in combination with nadifloxacin, to the skin test areas. One test area was left untreated. RESULTS: Most of the mean irritation scores were 0, and all were < 1. CONCLUSIONS: Combined application of nadifloxacin with any of the other four topical anti-acne products did not lead to substantial intolerance reactions compared with the effects after application of the products alone. PMID- 22103436 TI - Towards personalized treatment: predictors of short-term HAQ response in recent onset active rheumatoid arthritis are different from predictors of rapid radiological progression. AB - OBJECTIVE: Personalized treatment depends on the treatment goals. Current prediction models to guide initial treatment choices focus on radiological damage progression. However, for some patients this outcome is less relevant, whereas short-term functional ability is relevant to all. Do these various treatment goals share the same predictors? METHODS: Data for 497 patients from the Dutch Behandel Strategieen (BeSt) study of treatment strategies for early rheumatoid arthritis (RA), randomized to initial monotherapy or combination therapy, were used. Predictors of short-term functional disability [Health Assessment Questionnaire (HAQ) score >= 1 after 3 months of treatment] were identified with logistic regression analyses. Predicted risks of a HAQ score >= 1 were determined for each treatment group and for each subpopulation. RESULTS: At baseline, 76% of patients had a HAQ score >= 1 (mean 1.7 +/- 0.5). After 3 months of treatment this score was achieved by 40% (mean HAQ score 1.5 +/- 0.5). Baseline HAQ score, pain, the Ritchie Articular Index (RAI), and treatment group were significant independent predictors for a HAQ score >= 1; the presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and baseline radiological damage were not. With cut-offs of 35% and 60%, the risk of a HAQ score >= 1 was high for 47% and low for 20% of the patients treated with initial monotherapy. Risks were markedly reduced in the combination therapy groups, also in unfavourable risk profiles. CONCLUSION: In recent-onset active RA, baseline HAQ score, pain, and initial treatment are predictors for a HAQ score >= 1 after 3 months. Known predictors of radiological damage were not predictive of short term functional disability. The choice of the best initial treatment thus depends on the relevance of various outcome measures for an individual patient. PMID- 22103437 TI - Polyphenol contents and antioxidant activity of Brassica nigra (L.) Koch. leaf extract. AB - Profound research has been done on the medicinal value of Brassica nigra (BN) seeds, and the leaves of the plant have been investigated in this study. The methanol extracts of the leaves were subjected to several in vitro studies. The antioxidant activity of methanol extract was demonstrated with a wide range of concentration, 10-500 ug mL(-1), and the antioxidant activity increased with the increase in concentration. Total phenol content was found to be 171.73 +/- 5.043 gallic acid equivalents and the total flavonoid content 7.45 +/- 0.0945 quercetin equivalents. Further quantification and identification of the compounds were done by HPTLC and GC-MS analyses. The predominant phenolic compounds determined by HPTLC were gallic acid, followed by quercetin, ferulic acid, caffeic acid and rutin. The free radical quenching property of BN leaf extract suggests the presence of bioactive natural compounds. PMID- 22103438 TI - Detection of Legionella by quantitative-polymerase chain reaction (qPCR) for monitoring and risk assessment. AB - BACKGROUND: Culture and quantitative polymerase chain reaction (qPCR) assays for the detection of Legionella were compared on samples from a residential area before and after two interventions. A total of 84 samples were collected from shower hoses and taps as first flush samples and at constant temperature. Samples were grouped according to the origin of the sample, a) circulation water b) water from empty apartments c) water from shower hoses. The aims were to investigate the usefulness of qPCR compared to culture for monitoring remedial actions for elimination of Legionella bacteria and as a tool for risk assessment. RESULTS: In water collected from the apartments Legionella spp were detected by qPCR in the concentration range from LOQ to 9.6*105GU/L while L. pneumophila were detected in a range from LOQ to 6.8*105 GU/L. By culturing, the legionellae were detected in the range from below detection limit (> 10 CFU/L) to 1.6*106 CFU/L. In circulating water and in first flush water from shower hoses, culture and qPCR showed the same tendencies. The overall correlation between the bacteria number detected by culture and the two developed qPCR assays (L. spp and L. pneumophila) was relatively poor (r2 = 0.31 for culture and Legionella spp. assay, r2 = 0.20 for culture and L. pneumophila assay). CONCLUSION: Detection by qPCR was suitable for monitoring changes in the concentration of Legionella but the precise determination of bacteria is difficult. Risk assessment by qPCR only on samples without any background information regarding treatment, timing, etc is dubious. However, the rapid detection by qPCR of high concentrations of Legionella - especially Legionella pneumophila - is valuable as an indicator of risk, although it may be false positive compared to culture results. On the other hand, the detection of a low number of bacteria by qPCR is a strong indication for the absence of risk. PMID- 22103439 TI - A meta-analysis to compare speech recognition in noise with bilateral cochlear implants and bimodal stimulation. AB - OBJECTIVE: This investigation quantified the relative benefits of binaural CI arrangements (i.e., bilateral, bimodal) for three binaural phenomena (i.e., binaural squelch, binaural summation, head-shadow effect) and sensitivity of two speech-recognition test paradigms (i.e., adaptive and fixed). DESIGN: A repeated measures meta-analytical approach was used to compare effect sizes between binaural CI arrangements for each of the three binaural-listening phenomena and between the two test paradigms. STUDY SAMPLE: A total of 95 effect sizes were calculated and analyzed from 42 peer-reviewed studies published between January 2000 and April 2011. RESULTS: Findings revealed significant effect sizes for both CI arrangements for the binaural phenomena of summation and head-shadow effect. A significant effect size for binaural squelch was determined only for bilateral CI users. Further, the two paradigms resulted in similar effect sizes for bilateral and bimodal users, with the exception of binaural squelch. Here, significant effect sizes were significant only in the fixed-testing paradigm. CONCLUSIONS: The average user of binaural CI arrangements realizes the binaural phenomena of summation and the head-shadow effect, but only the bilateral CI arrangement is afforded the advantage of binaural squelch. Statistically, listeners fit with bilateral CIs have a slight advantage in binaural performance over those using bimodal stimulation. PMID- 22103440 TI - Total hip replacement as a treatment option for capital physeal fractures in dogs and cats. AB - OBJECTIVES: To evaluate outcome of capital physeal fractures (CPFs) treated by total hip replacement (THR) in dogs and cats. STUDY DESIGN: Retrospective phase II nonrandomized efficacy study. ANIMALS: Dogs (n = 21), cats (n = 4). METHODS: Medical records (1991-2009) and radiographs of dogs and cats with CPF treated by THR were reviewed. Physical examination findings, radiographs, thigh circumference (TC), force plate gait analysis, and an owner questionnaire were reviewed. RESULTS: Signalment and median interval between CPF and THR of all 25 animals had no clinical correlation with post-THR outcome. Force plate gait analysis and TC were available for 12 dogs. No significant difference in TC or force plate analyses between the THR limb and the normal contralateral limb was identified. Owner questionnaires (13 dogs) revealed improvement after THR with minimal (n = 2) or no lameness (n = 11). CONCLUSION: Animals with CPF treated by THR did not have statistically significant differences in any subjective (21 dogs, 4 cats) or objective (12 dogs) variable when compared with the normal contralateral limb. PMID- 22103441 TI - When friends disappoint: boys' and girls' responses to transgressions of friendship expectations. AB - In this study, the prevailing view that girls are pervasively more skilled in their friendships than boys was challenged by examining whether girls respond more negatively than boys when a friend violates core friendship expectations. Fourth- and fifth-grade children (n = 267) responded to vignettes depicting transgressions involving a friend's betrayal, unreliability, or failure to provide support or help. Results indicated that girls were more troubled by the transgressions, more strongly endorsed various types of negative relationship interpretations of the friend's actions, and reported more anger and sadness than did boys. Girls also endorsed revenge goals and aggressive strategies just as much as boys. These findings lead to a more complex view of boys' and girls' friendship competencies. PMID- 22103442 TI - Pseudomonas aeruginosa pyocyanin causes airway goblet cell hyperplasia and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2. AB - The redox-active exotoxin pyocyanin (PCN) can be recovered in 100 uM concentrations in the sputa of bronchiectasis patients chronically infected with Pseudomonas aeruginosa (PA). However, the importance of PCN within bronchiectatic airways colonized by PA remains unrecognized. Recently, we have shown that PCN is required for chronic PA lung infection in mice, and that chronic instillation of PCN induces goblet cell hyperplasia (GCH), pulmonary fibrosis, emphysema and influx of immune cells in mouse airways. Many of these pathological features are strikingly similar to the mouse airways devoid of functional FoxA2, a transcriptional repressor of GCH and mucus biosynthesis. In this study, we postulate that PCN causes and exacerbates GCH and mucus hypersecretion in bronchiectatic airways chronically infected by PA by inactivating FoxA2. We demonstrate that PCN represses the expression of FoxA2 in mouse airways and in bronchial epithelial cells cultured at an air-liquid interface or conventionally, resulting in GCH, increased MUC5B mucin gene expression and mucus hypersecretion. Immunohistochemical and inhibitor studies indicate that PCN upregulates the expression of Stat6 and EGFR, both of which in turn repress the expression of FoxA2. These studies demonstrate that PCN induces GCH and mucus hypersecretion by inactivating FoxA2. PMID- 22103443 TI - Proteomic analysis of a pleistocene mammoth femur reveals more than one hundred ancient bone proteins. AB - We used high-sensitivity, high-resolution tandem mass spectrometry to shotgun sequence ancient protein remains extracted from a 43 000 year old woolly mammoth ( Mammuthus primigenius ) bone preserved in the Siberian permafrost. For the first time, 126 unique protein accessions, mostly low-abundance extracellular matrix and plasma proteins, were confidently identified by solid molecular evidence. Among the best characterized was the carrier protein serum albumin, presenting two single amino acid substitutions compared to extant African ( Loxodonta africana ) and Indian ( Elephas maximus ) elephants. Strong evidence was observed of amino acid modifications due to post-mortem hydrolytic and oxidative damage. A consistent subset of this permafrost bone proteome was also identified in more recent Columbian mammoth ( Mammuthus columbi ) samples from temperate latitudes, extending the potential of the approach described beyond subpolar environments. Mass spectrometry-based ancient protein sequencing offers new perspectives for future molecular phylogenetic inference and physiological studies on samples not amenable to ancient DNA investigation. This approach therefore represents a further step into the ongoing integration of different high-throughput technologies for identification of ancient biomolecules, unleashing the field of paleoproteomics. PMID- 22103444 TI - Suppression of EGFR autophosphorylation by FKBP12. AB - FK506 binding proteins (FKBPs) represent a subfamily of peptidyl prolyl cis/trans isomerases that can control receptor-mediated intracellular signaling. The prototypic PPIase FKBP12 functionally interacts with EGFR. FKBP12 was shown to inhibit EGF-induced EGFR autophosphorylation with all internal phosphorylation sites equally affected. The inhibition of EGFR catalytic activity is conducted by targeting the EGFR kinase domain. The change of intracellular FKBP12 levels resulted in a change of EGFR autophosphorylation level. Collectively, our results demonstrate that FKBP12 forms an endogenous inhibitor of EGFR phosphorylation directly involved in the control of cellular EGFR activity. PMID- 22103445 TI - Evaluation of spatial variability of soil arsenic adjacent to a disused cattle dip site, using model-based geostatistics. AB - This study investigated the spatial variability of total and phosphate extractable arsenic (As) concentrations in soil adjacent to a cattle-dip site, employing a linear mixed model-based geostatistical approach. The soil samples in the study area (n = 102 in 8.1 m(2)) were taken at the nodes of a 0.30 * 0.35 m grid. The results showed that total As concentration (0-0.2 m depth) and phosphate-extractable As concentration (at depths of 0-0.2, 0.2-0.4, and 0.4-0.6 m) in soil adjacent to the dip varied greatly. Both total and phosphate extractable soil As concentrations significantly (p = 0.004-0.048) increased toward the cattle-dip. Using the linear mixed model, we suggest that 5 samples are sufficient to assess a dip site for soil (As) contamination (95% confidence interval of +/-475.9 mg kg(-1)), but 15 samples (95% confidence interval of +/ 212.3 mg kg(-1)) is desirable baseline when the ultimate goal is to evaluate the effects of phytoremediation. Such guidelines on sampling requirements are crucial for the assessment of As contamination levels at other cattle-dip sites, and to determine the effect of phytoremediation on soil As. PMID- 22103446 TI - Evaluation of antidiabetic and antioxidant activity of Moringa oleifera in experimental diabetes. AB - BACKGROUND: Moringa oleifera, a widely cultivated species in India, is an exceptionally nutritious vegetable with a variety of potential uses in treating rheumatism, venomous bites, and microbial infections. In the present study, we investigated the antidiabetic and antioxidant effects of methanol extracts of M. oleifera pods (MOMtE) in streptozotocin (STZ)-induced diabetic albino rats. METHODS: Diabetic rats were treated with 150 or 300 mg/kg MOMtE for 21 days and the antidiabetic effects of the extract were evaluated by measuring changes in biochemical parameters in the serum and pancreatic tissue. Two phytoconstituents, namely quercetin and kaempferol, were isolated from the MOMtE extract and their structures were determined using nuclear magnetic resonance and infrared spectroscopy. RESULTS: The progression of diabetes was significantly reduced after MOMtE treatment. In treated rats, both doses of MOMtE induced a significant reduction in serum glucose and nitric oxide, with concomitant increases in serum insulin and protein levels. Furthermore, MOMtE treatment increased antioxidant levels in pancreatic tissue, with concomitant decreases in levels of thiobarbituric acid-reactive substances. Histologic examination of the pancreas from diabetic rats showed degenerative changes in beta-cells; MOMtE treatment significantly reversed the histoarchitectural damage to the islets cells. CONCLUSION: In conclusion, M. oleifera exerts protective effects against STZ induced diabetes. The MOMtE exhibited significant antidiabetic and antioxidant activity and active constituents may be isolated from the extract for evaluation in future clinical studies. PMID- 22103447 TI - Cardiovascular actions of leptin in the subfornical organ are abolished by diet induced obesity. AB - The subfornical organ (SFO), a sensory circumventricular organ lacking the normal blood-brain barrier with well documented roles in cardiovascular regulation, has recently been identified as a potential site at which the adipokine, leptin, may act to influence central autonomic pathways. Systemic and central leptin administration has been shown to increase blood pressure and it has been suggested that selective leptin resistance contributes to obesity-related hypertension. Given the relationship between obesity and hypertension, the present study aimed to investigate the cardiovascular consequences of the direct administration of leptin into the SFO of young lean rats and in the diet-induced obesity (DIO) rat model, which has been shown to be leptin-resistant. Leptin administration (500 fmol) directly into the SFO of young rats resulted in rapid decreases in blood pressure (BP) [mean area under the curve (AUC) = -677.8 +/- 167.1 mmHg*s; n = 9], without an effect on heart rate (mean AUC = -21.2 +/- 13.4 beats; n = 9), and these effects were found to be dose-related as microinjection of 5 pmol of leptin into the SFO had a larger effect on BP (mean AUC = -972.3 +/- 280.1 mmHg*s; n = 4). These BP effects were also shown to be site-specific as microinjection of leptin into non-SFO regions or into the ventricle was without effect on BP (non-SFO: mean AUC = -22.4 +/- 55.3 mmHg*s; n = 4; ventricle: mean AUC = 194.0 +/- 173.0 mmHg*s; n = 6). By contrast, microinjection of leptin into leptin-resistant DIO rats was without effect on BP (mean AUC = 205.2 +/- 75.1 mmHg*s; n = 4). These observations suggest that the SFO may be an important relay centre through which leptin, in normal weight, leptin responsive rats, acts to maintain BP within normal physiological limits through descending autonomic pathways involved in cardiovascular control and that, in obese, leptin-resistant, rats leptin no longer influences SFO neurones, resulting in an elevated BP, thus contributing to obesity-related hypertension. PMID- 22103448 TI - Charge-displacement analysis of the interaction in the ammonia-noble gas complexes. AB - We carry out an accurate ab initio study of the interaction between ammonia and the whole series of noble gas atoms and relate the results to those of high resolution scattering experiments that provide access to the average radial dependence of the interaction potential. The charge-displacement calculations show that charge transfer is a non-negligible, strongly anisotropic, component of the interaction, governing some basic features of the potential energy surfaces especially for the heavier systems. A comparison is made with the analogous binary complexes of H(2)O with the water-H(2) system (Belpassi, L.; et al. J. Am. Chem. Soc.2010, 132, 13046), supporting the conclusion that charge transfer plays a peculiarly special role in water's intermolecular interactions. PMID- 22103449 TI - Design of single-site Ti embedded highly hydrophilic silica thin films with macro mesoporous structures. AB - Single-site Ti-containing macroporous silica thin films with mesoporous frameworks were successfully prepared on quartz substrate with high transparency by using poly(methyl methacrylate) (PMMA) microspheres and organic surfactant as template of porous structures. The presence of mesoporous structure and the differences of macroporous structure of film surface were investigated by XRD and FE-SEM measurements. The local structure of Ti moieties embedded within silica matrixes were also confirmed by UV-vis investigations. It was found that the macroporous structure and the embedded single-site Ti moieties within mesoporous frameworks were quite effective for improvement of surface hydrophilicity, i.e., the water droplet was entirely spread on the film surface even before and after irradiation of UV light. PMID- 22103450 TI - Perceptions of Caribbean type 2 diabetes patients on self-monitoring of blood glucose. AB - CONTEXT: The views of type 2 diabetes (T2DM) patients have not been considered in the debate on the role of self-monitoring of blood glucose (SMBG) in the management of T2DM. OBJECTIVE: To assess the views of T2DM patients on SMBG. METHODS: Two previously trained research assistants used a structured pre-tested questionnaire to interview 416 T2DM patients practising SMBG in out-patient clinics in the privacy of the patients after they have consented to be interviewed. RESULTS: 79% of patients were unemployed with mean duration of diabetes of 11.8 +/- 0.5 year. 94% of patients did not have health insurance policies while 86% did not belong to any diabetes support group. Although 70% of the patients identified SMBG as expensive, 94% believed it assists glycaemic control, while 89% thought it was worth the expense. CONCLUSION: Caribbean T2DM patients believe SMBG was beneficial for the management of their diabetes and empowering them may reduce diabetes complications. PMID- 22103451 TI - Generalizability of WISC-IV index and subtest score profiles in children with traumatic brain injury. AB - The Wechsler Intelligence Scale for Children, 4th edition (WISC-IV) is often used to assess children with traumatic brain injury (TBI); although limited information is available regarding its psychometric properties in these children. Two recent reports suggest that the Perceptual Reasoning Index is not uniquely sensitive to TBI, which differs from the Perceptual Organization Index of the WISC-III. The current study examined WISC-IV profiles in two independently gathered samples of children with TBI. Examination of profiles indicated similarities between the current findings and those reported in other studies, in that the greatest deficits were present on the Processing Speed Index and its component subtests of Coding and Symbol Search, while the Perceptual Reasoning index score was comparable to the Verbal Comprehension Index. Also, no significant index or subtest score differences were present when the current sample was compared to the children with TBI reported by Allen, Thaler, Donohue and Mayfield (2010 ). The present findings are consistent with two prior studies of the WISC-IV in children with TBI, providing additional evidence for profile differences between the WISC-III and WISC-IV. The results also suggest that WISC IV profiles reported in prior studies are generalizable across TBI samples and study sites. PMID- 22103452 TI - Comparison of three different inhalant anesthetic agents (isoflurane, sevoflurane, desflurane) in red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE: To compare isoflurane, sevoflurane and desflurane for inhalant anesthesia in red-tailed hawks (Buteo jamaicensis) in terms of the speed and characteristics of induction; cardiovascular and respiratory parameters while anesthetized; and speed and quality of recovery. STUDY DESIGN: Prospective, cross over, randomized experimental study. ANIMALS: 12 healthy adult red-tailed hawks. METHODS: Anesthesia was induced with isoflurane, sevoflurane or desflurane in oxygen via face mask in a crossover, randomized design with a 1 week washout period between each treatment. Hawks were tracheally intubated, allowed to breathe spontaneously, and instrumented for cardiopulmonary monitoring. Data collected included heart rate, respiratory rate, end-tidal CO(2) , inspired and expired agent, SpO(2,) temperature, systolic blood pressure, time to intubation and time to recovery (tracking). Recovery was subjectively scored on a 4 point scale as well as a summary evaluation, by a single blinded observer. RESULTS: No significant difference in time to induction and time to extubation was noted with the administration of isoflurane, sevoflurane or desflurane. Time to the ability of the bird to follow a moving object with its eyes (tracking) was significantly faster with the administration of sevoflurane and desflurane. All recoveries were scored 1 or 2 and were assessed as good to excellent. No significant difference was noted in heart rate, blood pressure and temperature among the three inhalants. Administration of isoflurane resulted in lower respiratory rates. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, although isoflurane remains the most common inhaled anesthetic in avian practice, sevoflurane and desflurane both offer faster time to tracking, while similar changes in cardiopulmonary function were observed with each agent during anesthesia of healthy red-tailed hawks. PMID- 22103453 TI - Pre-operative flexion contracture determines the functional outcome of haemophilic arthropathy treated with total knee arthroplasty. AB - End-stage haemophiliac arthropathy can be successfully treated with total knee arthroplasty. However, the functional results may not be as good as anticipated and certain pre-op knee characteristics may alter the functional results. The purpose of this study was to evaluate the functional outcome of TKA in haemophilic patients with specific attention to final range of motion and residual flexion contracture of the joint. Twenty-one consecutive patients were retrospectively reviewed. The average age was 34 years with an average follow-up of 5.7 years. Functional status was evaluated with Hospital for Special Surgery Knee Score. Receiving Operating Characteristics analysis was used to determine the threshold of pre-operative flexion contracture degree to avoid residual knee contracture. The range of motion was increased in 16 joints and unchanged in three joints and decreased in the remaining two. Preoperative average range of motion was 37.6 degrees , improved to 57.1 degrees post-operatively. The average knee score increased from 27.85 (15-30) points pre-operatively to 79.42 (12-94) points at the last follow-up. The degree of pre-operative flexion contracture was found to be a good predictor for residual flexion contracture. (Specificity: 85.7%, sensitivity: 100%, cut-off: 27.5 degrees ). Total knee replacement improves the quality of life in patients with advanced haemophilic arthropathy. Statistical analysis revealed that pre-op flexion contracture of 27.5 degrees is an important threshold. Patients should be operated before that stage to gain maximum benefit with minimal gait abnormalities. PMID- 22103454 TI - Sexual dimorphism of sulcal length asymmetry in the cerebrum of adult cynomolgus monkeys (Macaca fascicularis). AB - The present study aimed to quantitatively clarify the gross anatomical asymmetry and sexual dimorphism of the cerebral hemispheres of cynomolgus monkeys. While the fronto-occipital length of the right and left cerebral hemispheres was not different between sexes, a statistically significant rightward asymmetry was detected in the cerebral width at the perisylvian region in females, but not in males (narrower width of the left side in the females). An asymmetry quotient of the sulcal lengths revealed a rightward asymmetry in the inferior occipital sulcus and a leftward asymmetry in the central and intraparietal sulci in both sexes. However, the laterality of the lengths of other sulci was different for males and females. The arcuate sulcus was directed rightward in males but there was no rightward bias in females. Interestingly, the principle sulcus and lateral fissure were left-lateralized in the males, but right-lateralized in the females. The results suggest that lateralization patterns are regionally and sexually different in the cerebrum of cynomolgus monkeys. The present results provide a reference for quantitatively evaluating the normality of the cerebral cortical morphology in cynomolgus monkeys. PMID- 22103456 TI - Alternations of phospholipid profile in placenta of streptozotocin-induced diabetic rat. AB - Phospholipids have important roles in many biological processes, but their role in fetal malformation in pregnancy in diabetes is unclear. Metabolic fingerprinting of placental phospholipids in pregnant streptozotocin-induced type 1 diabetic rats was performed using Fourier transform-ion cyclotron resonance mass spectrometry. Some of the fetuses from the pregnant diabetic rats exhibited ventricular septal defects. Alterations of phospholipid compositions in the diabetic rat placenta were detected. We suggest that these changes in phospholipids in the diabetic placenta might be involved in development of fetal malformation in a type 1 diabetic pregnancy. PMID- 22103455 TI - Early onset of fatty liver in growth-restricted rat fetuses and newborns. AB - Intrauterine growth-restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is "programmed" or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated "fatty liver" with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content, whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype. PMID- 22103457 TI - Hyperactivity induced by prenatal BrdU exposure across several experimental conditions. AB - Behavioral results are sometimes not reproducible even in the positive controls of developmental neurotoxicity (DNT) tests. Effects of several factors on the results should be considered. In the present paper, we examined the effects of strain-, gender-, and test-condition differences on BrdU-induced hyperactivity. The results showed that BrdU-induced hyperactivity was reproducible in two rat strains (SD and F344 rats), rodent species (rat and mouse), and both sexes. When the level of background sound in a test room was increased, the hyperactivity was persistent, resulting in no effect of background sound on BrdU-induced hyperactivity. Thus, we have demonstrated that the BrdU-animal model is a useful positive control via prenatal exposure to validate the entire DNT test process. PMID- 22103458 TI - Stage-specific changes in the levels of granulocyte-macrophage colony-stimulating factor and its receptor in the biological fluid and organ of mouse fetuses. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that has neurotrophic and neuroprotective functions. However, its function in the mid- to late-gestational fetus remains unclear. We used enzyme linked immunosorbent assay to analyze GM-CSF levels in cerebrospinal fluid (CSF), serum, and amniotic fluid of mouse fetuses. We also examined GM-CSF and receptor alpha (GM-CSFRalpha) levels in the fetal brain, liver, and placenta. GM-CSF peaked between embryonic day (E) 14 and E15 in the CSF. GM-CSF level was higher in the fetal serum than in the dam serum on E13 and decreased thereafter. GM-CSF and GM-CSFRalpha levels peaked between E13 and E15 in the brain. These results suggest that GM-CSF plays stage- and organ-specific roles in fetal development. PMID- 22103459 TI - Rare case of isolated levocardia with polysplenia including normally structured lung without cardiac anomaly. AB - Isolated levocardia (IL) is a rare type of situs inversus in which the heart is in the normal left-side position, but the abdominal viscera are in the dextroposition. Polysplenia is a congenital disorder affecting the asymmetric organs, including the heart, lungs, bronchi, liver, stomach, intestines, and spleen. In this report, we present a rare type satisfying the characteristics of both IL and polysplenia, confirmed by several imaging investigations, which revealed normally structured lungs and heart and the existence of the inferior vena cava (IVC), which runs on the left side, returns to the anterior-right side at the liver, and returns to the right atrium directly. Anatomical investigation and careful observation will make it possible to improve the prognosis of IL. PMID- 22103462 TI - Significance of the TGF-beta1/IL-6 axis in oral cancer. AB - The aim of the present study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments in oral cancer. The role of TGF-beta1 (transforming growth factor-beta1) and its predictive power in the prognosis of oral cancer has been identified. Human oral cancer cell lines, including SCC4 and SCC25, were selected for cellular experiments. Changes in tumour aggressiveness, responses to treatment and the signalling pathway responsible were investigated in vitro. Furthermore, 125 oral cancer tissue specimens were constructed into tissue microarray blocks for immunohistochemical analysis to correlate the expression of TGF-beta1 with clinical outcome. Using in vitro experiments, our results revealed that activated TGF-beta1 signalling resulted in more aggressive tumour growth, augmented the epithelial-mesenchymal transition and more resistance to treatment. Activated IL 6 (interleukin-6) signalling could be the mechanism underlying the effects of TGF beta1 on oral cancer. Regarding clinical data, the incidence of TGF-beta1 immunoreactivity in oral cancer specimens was significantly higher than in non malignant epithelium and positively linked to IL-6 staining. Furthermore, expression of TGF-beta1 was significantly correlated with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, the TGF-beta1/IL-6 axis had predictive power in the prognosis of oral cancer, and targeting TGF-beta1 could represent a promising treatment strategy. PMID- 22103463 TI - Different patterns of dermatological presentations in patients co-infected with human immunodeficiency virus and hepatitis C virus (HCV), and those infected with HCV alone. AB - BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same transmission routes. About 30% of HIV-positive patients are co-infected with HCV. Of the various HCV-related extrahepatic events, those involving the skin may be the first sign of infection. AIM: To specify the skin presentations in patients co-infected with HIV and HCV (co-infected patients; CP) and compare them with those found in patients with HCV mono-infection (mono-infected patients; MP). METHODS: This was a cross-sectional study, in which the studied population consisted of MP and CP from a tertiary hospital in the South of Brazil, who underwent complete skin examination and laboratory tests. RESULTS: In total, 201 patients were assessed, of whom 108 were CP, and 93 were MP. Pruritus tended to be more common in MP. MP also had significantly more dermatological conditions (mean of 5.2) than CP (mean of 4.5). In total, 104 different skin diseases were identified. There was a higher prevalence of infectious diseases and pigmentation disorders, such as verruca vulgaris and facial melasma, in CP, whereas trunk and facial telangiectasias, palmar erythema, and varicose veins were more common in MP. CONCLUSION: We found a high prevalence of skin conditions both in MP and in CP; however, the patterns of the dermatological conditions were different. CP were found to have significantly fewer skin lesions than MP, but had a higher prevalence of infectious and pigmentation disorders. By contrast, vascular conditions were more common in MP. PMID- 22103464 TI - Decisions about life-sustaining measures in children: in whose best interests? AB - As the community of physicians and nurses dedicated to the care of critically ill children has gained ever more well-developed skill sets, the decision to either continue or forego life-sustaining measures has become less time-sensitive. As a result, there is greater opportunity for careful consideration and discussion. The core principle in making decisions about whether to continue or forego life sustaining measures is the best interests of the child. However, there are many clinical situations wherein factors other than the child's best interests may influence treatment decisions. The present report seeks to examine the notion that in the arena of paediatric critical care medicine, the decision-making process regarding life-sustaining measures may place insufficient priority upon the child's best interests. We examine actual, de-identified clinical situations, encountered in the critical care arena in two categories: (i) cases that challenge the imperative to act in the child's best interests, and (ii) cases that compromise the ability of parents and caregivers to use child-centred, best interests approaches to decision-making. Clarity surrounding the implications of a clinical decision for the patient is essential. Decisions that are not focused squarely on the child's best interests may compromise the delivery of optimally ethical end-of-life care. CONCLUSION: The cases and analysis may benefit parents and caregivers as they struggle with the difficult ethical issues that accompany decisions to continue or forego life-sustaining measures in children. PMID- 22103465 TI - Cardiovascular assessment of asymptomatic patients with juvenile-onset localized and systemic scleroderma: 10 years prospective observation. AB - OBJECTIVES: The aim of the present study was non-invasive evaluation of the cardiovascular system in asymptomatic young adult patients with juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSS). METHODS: A group of 34 consecutive children with scleroderma were prospectively observed in the study. The control group (CG) consisted of 20 healthy subjects. In each subject 12-lead electrocardiographic, echocardiographic, ECG Holter, and ambulatory blood pressure monitoring examinations were performed at the baseline visit and after 10 years. Additionally, B-type natriuretic peptide (BNP) concentrations were measured after 10 years. RESULTS: Examinations were performed in 13 patients with JLS and 15 with JSS at the final visit. Two children had died (one from each group). Four patients were alive but refused the final visit. After 10 years, a higher prevalence of ventricular extrasystoles (p = 0.01) and an elevated pulmonary arterial pressure (JLS: p = 0.04, JSS: p = 0.03) were observed in both groups, but in comparison with the controls there was no significant difference at the final visit. In JLS patients more cases of left ventricle diastolic dysfunction, hypertension, and sinus tachycardia were diagnosed at the final visit (p <= 0.05). More atrioventricular block episodes in both groups of scleroderma patients were observed. Over the 10 years, arterial hypertension was diagnosed in three patients from the JLS group and in two with JSS. There were no significant differences in BNP concentrations at the final visit. CONCLUSIONS: The results of the present study show that juvenile scleroderma seems to be more benign than adult-onset disease. This observational study shows subclinical, not severe, cardiac abnormalities in adult patients with juvenile-onset disease. PMID- 22103466 TI - Electron transfer across modular oligo-p-phenylene bridges in Ru(bpy)2(bpy-ph(n) DQ)4+ (n = 1-5) dyads. Unusual effects of bridge elongation. AB - A series of dyads of general formula Ru(bpy)(2)(bpy-ph(n)-DQ)(4+) (n = 1-5), based on a Ru(II) polypyridine unit as photoexcitable donor, a set of oligo-p phenylene bridges with 1-5 modular units, and a cyclo-diquaternarized 2,2' bipyridine (DQ(2+)) as electron acceptor unit, have been synthesized. Their spectroscopic and photophysical properties have been investigated in CH(3)CN and CH(2)Cl(2) by time-resolved emission and absorption spectroscopy in the nanosecond and picosecond time scale. The experimental study has also been complemented with a computational investigation carried out on the whole series of dyads. The absorption spectra of the dyads show new spectroscopic transitions, in addition to those characteristic of the donor, bridge, and acceptor fragments. DFT calculations suggest the assignment of such bands as bridge-to-acceptor (pi ph(n)) -> (pi* DQ) charge-transfer transitions. This assignment is consistent with the solvatochromic and spectroelectrochemical behavior of the new bands. For all the dyads at room temperature in fluid solution, the typical (3)MLCT luminescence of the Ru(II) polypyridine unit is strongly (>90%) quenched, supporting the occurrence of an efficient intramolecular photoinduced electron transfer. The study has revealed, however, that the photophysical mechanism is actually more complex than presumed on the basis of a simple photoinduced electron-transfer scheme. For n = 1, very fast (few picoseconds) photoinduced electron transfer from the MLCT state localized on the substituted bpy ligand to the DQ unit has been observed, followed by slower interligand hopping and charge recombination. For n = 2-5, MLCT excited-state quenching takes place without transient detection of charge-separated product, indicating that charge recombination is faster than charge separation. This behavior can be rationalized in terms of the superexchange couplings expected through this type of bridges for the two processes. The kinetics of MLCT quenching in the dyads with n = 1-5 does not follow the usual exponential falloff with bridge length: after a regular decrease for n = 1-3, the rate constants become almost insensitive to bridge length for n = 3-5. The rationale of this uncommon behavior, as suggested by DFT calculations, lies in a switch in the MLCT quenching mechanism with increasing bridge length, from oxidative quenching by the DQ acceptor to reductive quenching by the bridge. PMID- 22103467 TI - Frequent detection of respiratory agents by multiplex PCR on oropharyngeal samples in Swedish school-attending adolescents. AB - BACKGROUND: Respiratory agents may be detected in the oropharynx of healthy individuals. The extent of this condition and the reasons behind it are largely unknown. The objective of this study was to determine the factors associated with the presence of respiratory agents in the oropharynx of adolescents healthy enough to attend school activities. METHODS: On a single day in December, samples from the posterior wall of the oropharynx of adolescents aged 10-15 y were obtained using cotton-tipped swabs. The samples were analyzed by real-time polymerase chain reaction (PCR) for the presence of 13 respiratory viruses and 2 bacteria (Mycoplasma pneumoniae and Chlamydophila pneumoniae). RESULTS: Out of the 232 adolescents sampled, 67 (29%) had any respiratory symptom. A positive PCR result was found in 50 individuals (22%). Human rhinovirus was the most commonly found agent. Respiratory agents were significantly more frequent in the younger age group (10-13 y) than in the older age group (14-15 y): 26% (38/148) vs 14% (12/84), respectively; p = 0.04. Cough was the only symptom that was more common among individuals with a positive PCR test than among those with a negative PCR test: 8/50 (16%) vs 11/182 (6%); p = 0.02. Family size and class size were not associated with the likelihood of a positive PCR test. CONCLUSIONS: The presence of respiratory agents in the oropharynx is a frequent finding among adolescents healthy enough to attend school activities. The high prevalence was found to be associated with young age, but not with the size of the family or class. PMID- 22103468 TI - Topographic relationship between frequency-doubling technology threshold values. AB - PURPOSE: To study the topographic relationship of retinal sensitivity evaluated by frequency-doubling perimetry (FDT) in healthy subjects and patients with glaucoma. METHODS: Hundred and thirty-four eyes from 134 subjects (72 patients with glaucoma and 62 healthy controls) were prospectively and consecutively selected. Only one eye of each subject was randomly selected for evaluation. All subjects underwent a full ophthalmic examination and a reliable FDT (full threshold C-20-5 algorithm). Pearson correlation coefficients between threshold values within the same hemifield were calculated. Maps of related points were plotted according to these correlation coefficients. RESULTS: In the control group, each FDT location strongly to moderately correlated with the other FDT locations in the same hemifield. In glaucoma subjects, only a few locations significantly correlated with other threshold values in the same hemifield. The strongest correlations were observed between neighbouring locations. The pairs of points with the strongest correlation corresponded to the inferior retinal regions. In general, perimetric maps showed the retinotopic distribution of ganglion cell axons in the retinal nerve fibre layer. CONCLUSIONS: The statistical correlations between the FDT threshold values in the same visual hemifield objectively highlight the structure-function relationship determined by the anatomic distribution of retinal nervous tissue. This structure is altered in patients with glaucoma. PMID- 22103469 TI - Early reherniation of disk material in eleven dogs with surgically treated thoracolumbar intervertebral disk extrusion. AB - OBJECTIVE: To report findings and outcomes of dogs with reherniation of nuclear material within 7 days of hemilaminectomy for acute thoracolumbar (TL) intervertebral disk extrusion. STUDY DESIGN: Retrospective case series. ANIMALS: Chondrodystrophic dogs (n = 11). METHODS: Dogs with acute neurologic decline within 1 week of surgical decompression for TL disk extrusion were identified. Advanced imaging was used to document extradural spinal cord compression at the previous surgery site. Ten dogs had a 2nd decompressive surgery to remove extruded nuclear material. RESULTS: All dogs had acute neurologic deterioration (average, 2 neurologic grades) 2-7 days after initial hemilaminectomy. Computed tomography (CT; n = 10) or myelography (n = 1) documented extradural spinal cord compression compatible with extruded disk material at the previous hemilaminectomy site. Dogs that had a 2nd surgical decompression improved neurologically within 24 hours and were paraparetic at discharge. The single dog that did not have decompressive surgery did not regain deep nociception during 185-day follow-up. CONCLUSIONS: Early reherniation at the site of previous hemilaminectomy can produce acute deterioration of neurologic function and should be investigated with diagnostic imaging. Repeat decompressive surgery can lead to functional recovery. PMID- 22103470 TI - Actin cytoskeleton remodelling by sex steroids in neurones. AB - Cell morphology and its interaction with the extracellular environment are integrated processes involving a number of intracellular controllers orchestrating cytoskeletal proteins and their interaction with the cell membrane and anchorage proteins. Sex steroids are effective regulators of cell morphology and tissue organisation, and recent evidence indicates that this is obtained through the regulation of the actin cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through the rapid, nonclassical signalling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterisation of the effects of sex steroids under physiological conditions, such as for the development of neurone/neurone interconnections and dendritic spine density. This is considered to be critical for gender-specific differences in brain function and dysfunction. Recent advancements in the characterisation of the molecular basis of the extranuclear signalling of sex steroids help to clarify the role of oestrogen and progesterone in the brain, and may turn out to be of relevance for clinical purposes. This review highlights the regulatory effects of oestrogens and progesterone on actin cytoskeleton and neurone morphology, as well as recent progresses in the characterisation of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system. PMID- 22103471 TI - Molecular screening of the CFTR gene in Mexican patients with congenital absence of the vas deferens. AB - BACKGROUND: In several populations CFTR mutations, as well as IVS8-Tn CFTR polymorphism, have been associated with congenital bilateral absence of the vas deferens (CBAVD) and idiopathic obstructive azoospermia diseases. However, the involvement of these mutations in infertility of Mexican males has not been elucidated. AIMS: We investigated whether CFTR mutations and IVS8-Tn(TG)m polymorphisms are associated with infertility in azoospermic Mexican patients. METHODS: Sixteen CBAVD and 33 idiopathic azoospermic cases were included. The CFTR gene was sequenced in all CBAVD cases. In the idiopathic azoospermic patients, the p.F508del, p.G542X, p.N1303K, p.S549N, p.I507del, and p.R117H mutations and those detected in our CBAVD cases were screened. RESULTS: The p.F508del, p.G85E, p.D1152H, and p.W1089X mutations were found in 3 CBAVD patients (18.8%). None of the 9 CFTR mutations screened for in idiopathic azoospermic were found; however, we documented a high frequency of the Gln1463Gln polymorphism in comparison with healthy controls (20% vs 6%; p=0.0029). CONCLUSIONS: These data showed that the CFTR mutations but not the IVS8-Tn polymorphism are involved in CBAVD etiology in a Mexican population. Nevertheless, other screening strategies should be used to rule out the implication of CFTR mutations in idiopathic azoospermic disease. PMID- 22103472 TI - Chemokine ligand Xenopus CXCLC (XCXCLC) regulates cell movements during early morphogenesis. AB - We cloned the gene for the CXC-type chemokine ligand, Xenopus CXCLC (XCXCLC), the transcripts of which were detected at the dorsal midline during the gastrula and neurula stages. XCXCLC overexpression resulted in the attraction of nearby mesodermal cells, and the excess of chemoattractant interfered with convergent and extension movements. The direction of the deep neural plate cells around the notoplate was also controlled by XCXCLC. Fluorescence signals for XCXCLC + enhanced green fluorescent protein derivatives accumulated around the notochord region. These results indicate that XCXCLC attracts adjacent cells to the midline region, so as to ensure accurate lateral-medial directional tissue convergence during gastrulation and neurulation. PMID- 22103473 TI - Influences of oxygen pressure on optical properties and interband electronic transitions in multiferroic bismuth ferrite nanocrystalline films grown by pulsed laser deposition. AB - Bismuth ferrite (BiFeO(3)) nanocrystalline films with the crystalline size of 27 40 nm have been grown on c-sapphire substrates under various oxygen pressures of 1 * 10(-4) to 1 Pa by pulsed laser deposition. The X-ray diffraction spectra show that the films are polycrystalline and present the pure rhombohedral phase. It was found that the Raman-active phonon mode E(TO1) shifts towards a higher energy side from 74 to 76 cm(-1) with increasing oxygen pressure, indicating a larger tensile stress in the films deposited at higher oxygen pressure. The X-ray photoelectron spectroscopy analysis suggests that the concentrations of both Fe(2+) ions and oxygen vacancies in the BiFeO(3) films increase with decreasing oxygen pressure. Moreover, the dielectric functions in the photon energy range of 0.47-6.5 eV have been extracted by fitting the transmittance spectra with the Tauc-Lorentz dispersion model. From the transmittance spectra, the fundamental absorption edge is observed to present a redshift trend with increasing the temperature from 8 to 300 K. Note that the optical band gap (E(g)) decreases with increasing the temperature due to the electron-phonon interactions associated with the interatomic distance in the BiFeO(3) films. However, the E(g) decreases from 2.88 to 2.78 eV with decreasing oxygen pressure at 8 K, which can be attributed to the increment of oxygen vacancies leading to the formation of some impurity states between the valence and conduction band. It can be concluded that the oxygen pressure during the film fabrication has the significant effects on microstructure, optical properties, and electronic band structure modification of the BiFeO(3) films. PMID- 22103474 TI - alpha-Particle irradiated zebrafish embryos rescued by bystander unirradiated zebrafish embryos. AB - We report data demonstrating that zebrafish embryos irradiated by alpha-particles can release a stress signal into the water, which can be communicated to the unirradiated zebrafish embryos sharing the same water medium, and then these unirradiated zebrafish embryos can release a feedback stress signal back to the irradiated embryos. The effects of radiation on the whole embryos were studied through quantification of apoptotic signals at 24 h post fertilization through staining with the vital dye acridine orange, followed by counting the stained cells under a microscope. We refer to this phenomenon as the "rescue effect", where the unirradiated embryos successfully helped the irradiated embryos mitigate the radiation induced DNA damages. The results showed that the number of apoptotic signals in the irradiated embryos was smaller when they were partnered with bystander unirradiated embryos in the same medium. The results also showed significantly fewer apoptotic signals in the irradiated embryos when the population of bystander embryos increased from 10 to 30, while keeping the population of irradiated embryos at 10. These data suggest that the stress communicated between the unirradiated zebrafish embryos and the irradiated embryos sharing the same medium will help "rescue" the irradiated embryos, and that the strength of the rescue effect depends on the number of rescuing bystander unirradiated embryos. PMID- 22103476 TI - Using infrared spectroscopy of cyanylated cysteine to map the membrane binding structure and orientation of the hybrid antimicrobial peptide CM15. AB - The synthetic antimicrobial peptide CM15, a hybrid of N-terminal sequences from cecropin and melittin peptides, has been shown to be extremely potent. Its mechanism of action has been thought to involve pore formation based on prior site-directed spin labeling studies. This study examines four single-site beta thiocyanatoalanine variants of CM15 in which the artificial amino acid side chain acts as a vibrational reporter of its local environment through the frequency and line shape of the unique CN stretching band in the infrared spectrum. Circular dichroism experiments indicate that the placements of the artificial side chain have only small perturbative effects on the membrane-bound secondary structure of the CM15 peptide. All variant peptides were placed in buffer solution, in contact with dodecylphosphatidylcholine micelles, and in contact with vesicles formed from Escherichia coli polar lipid extract. At each site, the CN stretching band reports a different behavior. Time-dependent attenuated total reflectance infrared spectra were also collected for each variant as it was allowed to remodel the E. coli lipid vesicles. The results of these experiments agree with the previously proposed formation of toroidal pores, in which each peptide finds itself in an increasingly homogeneous and curved local environment without apparent peptide-peptide interactions. This work also demonstrates the excellent sensitivity of the SCN stretching vibration to small changes in the peptide-lipid interfacial structure. PMID- 22103477 TI - Life without a cell membrane: challenging the specificity of bacterial endophytes within Bryopsis (Bryopsidales, Chlorophyta). AB - BACKGROUND: The siphonous green macroalga Bryopsis has some remarkable characteristics. Besides hosting a rich endophytic bacterial flora, Bryopsis also displays extraordinary wound repair and propagation mechanisms. This latter feature includes the formation of protoplasts which can survive in the absence of a cell membrane for several minutes before regenerating into new individuals. This transient 'life without a membrane' state, however, challenges the specificity of the endophytic bacterial communities present and raises the question whether these bacteria are generalists, which are repeatedly acquired from the environment, or if there is some specificity towards the Bryopsis host. RESULTS: To answer this question, we examined the temporal stability and the uniqueness of endobiotic bacterial communities within Bryopsis samples from the Mexican west coast after prolonged cultivation. DGGE analysis revealed that Bryopsis endophytic bacterial communities are rather stable and clearly distinct from the epiphytic and surrounding cultivation water bacterial communities. Although these endogenous communities consist of both facultative and obligate bacteria, results suggest that Bryopsis owns some intrinsic mechanisms to selectively maintain and/or attract specific bacteria after repeated wounding events in culture. CONCLUSIONS: This suggests that Bryopsis algae seem to master transient stages of life without a cell membrane well as they harbor specific- and possibly ecological significant--endophytic bacteria. PMID- 22103478 TI - Structure of (5'S)-8,5'-cyclo-2'-deoxyguanosine in DNA. AB - Diastereomeric 8,5'-cyclopurine 2'-deoxynucleosides, containing a covalent bond between the deoxyribose and the purine base, represent an important class of DNA damage induced by ionizing radiation. The 8,5'-cyclo-2'-deoxyguanosine lesion (cdG) has been recently reported to be a strong block of replication and highly mutagenic in Escherichia coli. The 8,5'-cyclopurine-2'-deoxyriboses are suspected to play a role in the etiology of neurodegeneration in xeroderma pigmentosum patients. These lesions cannot be repaired by base excision repair, but they are substrates for nucleotide excision repair. The structure of an oligodeoxynucleotide duplex containing a site-specific S-cdG lesion placed opposite dC in the complementary strand was obtained by molecular dynamics calculations restrained by distance and dihedral angle restraints obtained from NMR spectroscopy. The S-cdG deoxyribose exhibited the O4'-exo (west) pseudorotation. Significant perturbations were observed for the beta, gamma, and chi torsion angles of the S-cdG nucleoside. Watson-Crick base pairing was conserved at the S-cdG.dC pair. However, the O4'-exo pseudorotation of the S-cdG deoxyribose perturbed the helical twist and base pair stacking at the lesion site and the 5'-neighbor dC.dG base pair. Thermodynamic destabilization of the duplex measured by UV melting experiments correlated with base stacking and structural perturbations involving the modified S-cdG.dC and 3'- neighbor dT.dA base pairs. These perturbations may be responsible for both the genotoxicity of this lesion and its ability to be recognized by nucleotide excision repair. PMID- 22103479 TI - Another role for the VW molecule. AB - My comments on the implication of the vW molecule in down-regulating the immunogenicity of factor VIII. PMID- 22103480 TI - Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse. AB - OBJECTIVE: To describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight, mature healthy horses age 11.7 +/ 4.6 (mean +/- SD) years, weighing 557 +/- 54 kg. METHODS: Medetomidine (10 MUg kg(-1) ) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis. RESULTS: Pharmacokinetic analysis estimated that medetomidine peaked (8.86 +/- 3.87 ng mL(-1) ) at 6.4 +/- 2.7 minutes following administration and was last detected at 165 +/- 77 minutes post administration. Medetomidine had a clearance of 39.6 +/- 14.6 mL kg(-1) minute(-1) and a volume of distribution of 1854 +/- 565 mL kg(-1). The elimination half-life was 29.1 +/- 12.5 minutes. Glucose concentration reached a maximum of 176 +/- 46 mg dL(-1) approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 +/- 12 to 20 +/- 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound. CONCLUSION AND CLINICAL RELEVANCE: Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration. PMID- 22103481 TI - Embryonal tumor with abundant neuropil and true rosettes: a report of three cases of a rare tumor, with an unusual case showing rhabdomyoblastic and melanocytic differentiation. AB - Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is an increasingly recognized entity that belongs to the family of embryonal tumors of the CNS. The authors present three cases of this rare tumor that were encountered at King Hussein Cancer Center, Amman, Jordan. Discussion of the clinicopathological findings is presented along with a recent literature review. Sixteen-, 57- and 30-month-old children presented with tumors located in the pineal gland, the right fronto- parieto-temporal region and the cerebellum, respectively. The findings of hypocellular neuropil as well as the characteristic ependymoblastic rosettes were seen. In addition the third case showed an abnormal combination of patterns including melanocytic and rhabdomyoblastic differentiation. The tumors stained positively for synaptophysin in the neuropil and small cell component, while the ependymoblastic rosettes stained for vimentin only. Epithelial membrane antigen and CD99 were negative in all components. One of the cases showed tetraploidy of chromosome 2. All cases exhibited an aggressive course. This is a rare and recently recognized tumor with dismal outcome, and reporting of additional new cases should help in gaining more knowledge about it. PMID- 22103482 TI - A case of split notochord syndrome: an adult with a spinal endodermal cyst mimicking an intramedullary tumor. AB - Intraspinal endodermal cysts are very rare congenital cysts, usually composed of a thin-walled cyst the lining of which mimics gastrointestinal or respiratory epithelium. Diagnosis is usually established during the first or second decade of life. These cysts are frequently associated with vertebral or spinal cord abnormalies and dual malformation with mediastinal or abdominal cysts. Collectively, they are called split notochord syndrome. The authors describe their experience in the treatment of a 57-year-old man having an endodermal cyst mimicking an intramedullary tumor at the level of Th1-2. He was admitted to our institution for evaluation of an intraspinal mass diagnosed by MRI at a local hospital after experiencing temporary numbness and weakness of the lower left extremity. T1-weighted sagittal MRI demonstrated the lesion with signal intensity iso- to slightly hypointense to the spinal cord without enhancement after administration of gadolinium. Although T2-weighted sagittal images demonstrated as hyperintense to the spinal cord, axial images revealed a passage between the mass and subarachnoid space. We could not completely rule out the presence of an intramedullary tumor and undertook a laminectomy with a posterior approach. Histopathological analysis revealed an endodermal cyst and the authors found syringomyelia, which was clearly separated from the cyst in the preoperative sagittal MRI and intraoperative ultrasonography study. To the best of our knowledge, this is the first report in the English literature of a thoracic endodermal cyst requiring differential diagnosis from a spinal cord tumor. PMID- 22103483 TI - A pediatric intramedullary spinal cord tumor with unusual solid-cystic and papillary features: a case report. AB - Spinal cord tumors are rare in children. We report a novel case of pediatric intramedullary spinal cord tumor with unusual solid-cystic and papillary features. Clinically, the patient presented at the age of 3 years with motor deficit and urinary incontinence, and MRI demonstrated multilocular cystic lesions in the thoracic spine. Histologically the tumor consisted of solid, sheet like components and branching papillary structures, and immunohistochemistry demonstrated positive reactivity for epithelial membrane antigen, cytokeratins (7, AE1/3, CAM5.2), E-cadherin and transthyretin, and negativity for GFAP, S-100 protein, synaptophysin and neurofilament. These histological and immunohistochemical findings appeared to be unique, and were not compatible with the features of classical ependymoma or choroid plexus papilloma. The clinical behavior, characterized by relatively rapid tumor regrowth after surgical resection and a relatively high MIB-1 labeling index, suggest that this tumor might have had moderate malignant potential. This pediatric case appears to be particularly informative with regard to the tumor biology or tumorigenesis of intramedullary spinal cord tumor with unusual solid-cystic and papillary features. PMID- 22103485 TI - Advances in the cellular and molecular biology of angiogenesis. AB - Capillaries have been recognized for over a century as one of the most important components in regulating tissue oxygen transport, and their formation or angiogenesis a pivotal element of tissue remodelling during development and adaptation. Clinical interest stems from observations that both excessive and inadequate vascular growth plays a major role in human diseases, and novel developments in treatments for cancer and eye disease increasingly rely on anti angiogenic therapies. Although the discovery of VEGF (vascular endothelial growth factor) provided the first clue for specificity of signalling in endothelial cell activation, understanding the integrative response that drives angiogenesis requires a much broader perspective. The Advances in the Cellular and Molecular Biology of Angiogenesis meeting brought together researchers at the forefront of this rapidly moving field to provide an update on current understanding, and the most recent insights into molecular and cellular mechanisms of vascular growth. The plenary lecture highlighted the integrative nature of the angiogenic process, whereas invited contributions from basic and clinician scientists described fundamental mechanisms and disease-associated issues of blood vessel formation, grouped under a number of themes to aid discussion. These articles will appeal to academic, clinical and pharmaceutical scientists interested in the molecular and cellular basis of angiogenesis, their modulation or dysfunction in human diseases, and application of these findings towards translational medicine. PMID- 22103486 TI - The critical role of VEGF in skeletal muscle angiogenesis and blood flow. AB - VEGF (vascular endothelial growth factor) is well known as an important molecule in angiogenesis. Its inhibition is pursued as an anticancer therapy; its enhancement as therapy for tissue ischaemia. In the present paper, its role in skeletal muscle is explored, both at rest and after exercise. Muscle VEGF mRNA and protein are increased severalfold after heavy exercise. Whereas global VEGF knockout is embryonically lethal, muscle-specific knockout is not, providing models for studying its functional significance. Its deletion in adult mouse skeletal muscle: (i) reduces muscle capillarity by more than 50%, (ii) decreases exercise endurance time by approximately 80%, and (iii) abolishes the angiogenic response to exercise training. What causes VEGF to increase with exercise is not clear. Despite regulation by HIF (hypoxia-inducible factor), increased HIF on exercise, and PO2 falling to single digit values during exercise, muscle-specific HIF knockout does not impair performance or capillarity, leaving many unanswered questions. PMID- 22103487 TI - Inhibition of angiogenesis and the angiogenesis/invasion shift. AB - Angiogenesis has become a major target in cancer therapy. However, current therapeutic strategies have their limitations and raise several problems. In most tumours, anti-angiogenesis treatment targeting VEGF (vascular endothelial growth factor) has only limited overall survival benefit compared with conventional chemotherapy alone, and reveals several specific forms of resistance to anti-VEGF treatment. There is growing evidence that anti-VEGF treatment may induce tumour cell invasion by selecting highly invasive tumour cells or hypoxia-resistant cells, or by up-regulating angiogenic alternative pathways such as FGFs (fibroblast growth factors) or genes triggering new invasive programmes. We have identified new genes up-regulated during glioma growth on the chick CAM (chorioallantoic membrane). Our results indicate that anti-angiogenesis treatment in the experimental glioma model drives expression of critical genes which relate to disease aggressiveness in glioblastoma patients. We have identified a molecular mechanism in tumour cells that allows the switch from an angiogenic to invasive programme. Furthermore, we are focusing our research on alternative inhibitors that act, in part, independently of VEGF. These are endogenous molecules that play a role in the control of tumour growth and may constitute a starting point for further development of novel therapeutic or diagnostic tools. PMID- 22103488 TI - Class 3 semaphorins and their receptors in physiological and pathological angiogenesis. AB - Class 3 semaphorins (Sema3) are a family of secreted proteins that were originally identified as axon guidance factors mediating their signal transduction by forming complexes with neuropilins and plexins. However, the wide expression pattern of Sema3 suggested additional functions other than those associated with the nervous system, and indeed many studies have now indicated that Sema3 proteins and their receptors play a role in angiogenesis. The present review specifically focuses on recent evidence for this role in both physiological and pathological angiogenesis. PMID- 22103489 TI - Shear stress, tip cells and regulators of endothelial migration. AB - We have in recent years described several endothelial-specific genes that mediate cell migration. These include Robo4 (roundabout 4), CLEC14A (C-type lectin 14A) and ECSCR (endothelial cell-specific chemotaxis regulator) [formerly known as ECSM2 (endothelial cell-specific molecule 2)]. Loss of laminar shear stress induces Robo4 and CLEC14A expression and an endothelial 'tip cell' phenotype. Low shear stress is found not only at sites of vascular occlusion such as thrombosis and embolism, but also in the poorly structured vessels that populate solid tumours. The latter probably accounts for strong expression of Robo4 and CLEC14A on tumour vessels. The function of Robo4 has, in the past, aroused controversy. However, the recent identification of Unc5B as a Robo4 ligand has increased our understanding and we hypothesize that Robo4 function is context-dependent. ECSCR is another endothelial-specific protein that promotes filopodia formation and migration, but, in this case, expression is independent of shear stress. We discuss recent papers describing ECSCR, including intracellular signalling pathways, and briefly contrast these with signalling by Robo4. PMID- 22103490 TI - An unexpected tail of VEGF and PlGF in pre-eclampsia. AB - PET (pre-eclamptic toxaemia), characterized by pregnancy-related hypertension and proteinuria, due to widespread endothelial dysfunction, is a primary cause of maternal morbidity. Altered circulating factors, particularly the VEGF (vascular endothelial growth factor) family of proteins and their receptors, are thought to be key contributors to this disease. Plasma from patients with PET induces numerous cellular and physiological changes in endothelial cells, indicating the presence of a circulating imbalance of the normal plasma constituents. These have been narrowed down to macromolecules of the VEGF family of proteins and receptors. It has been shown that responses of endothelial cells in intact vessels to plasma from patients with pre-eclampsia is VEGF-dependent. It has recently been shown that this may be specific to the VEGF165b isoform, and blocked by addition of recombinant human PlGF (placental growth factor). Taken together with results that show that sVEGFR1 (soluble VEGF receptor 1) levels are insufficient to bind VEGF-A in human plasma from patients with pre-eclampsia, and that other circulating macromolecules bind, but do not inactivate, VEGF-A, this suggests that novel hypotheses involving altered bioavailability of VEGF isoforms resulting from reduced or bound PlGF, or increased sVEGFR1 increasing biological activity of circulating plasma, could be tested. This suggests that knowing how to alter the balance of VEGF family members could prevent endothelial activation, and potentially some symptoms, of pre-eclampsia. PMID- 22103491 TI - How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns. AB - Essential roles of NRP1 (neuropilin-1) in cardiovascular development and in neuronal axon targeting during embryogenesis are thought to be mediated primarily through binding of NRP1 to two unrelated types of ligands: the VEGF (vascular endothelial growth factor) family of angiogenic cytokines in the endothelium, and the class 3 semaphorins in neurons. A widely accepted mechanism for the role of NRP1 in the endothelium is VEGF binding to NRP1 and VEGFR2 (VEGF receptor 2) and VEGF-dependent formation of complexes or NRP1-VEGFR2 holoreceptors with enhanced signalling activity and biological function. However, although some basic features of this model are solidly based on biochemical and cellular data, others are open to question. Furthermore, a mechanistic account of NRP1 has to accommodate research which emphasizes the diversity of NRP1 functions in different cell types and particularly an emerging role in signalling by other growth factor ligands for RTKs (receptor tyrosine kinases) such as HGF (hepatocyte growth factor) and PDGF (platelet-derived growth factor). It is uncertain, however, whether the model of NRP1-RTK heterocomplex formation applies in all of these situations. In the light of these developments, the need to explain mechanistically the role of NRP1 in signalling is coming increasingly to the fore. The present article focuses on some of the most important unresolved questions concerning the mechanism(s) through which NRP1 acts, and highlights recent findings which are beginning to generate insights into these questions. PMID- 22103492 TI - Molecular control of angiopoietin signalling. AB - The angiopoietins act through the endothelial receptor tyrosine kinase Tie2 to regulate vessel maturation in angiogenesis and control quiescence and stability of established vessels. The activating ligand, Ang1 (angiopoietin-1), is constitutively expressed by perivascular cells, and the ability of endothelial cells to respond to the ligand is controlled at the level of the Ang1 receptor. This receptor interacts with the related protein Tie1 on the cell surface, and Tie1 inhibits Ang1 signalling through Tie2. The responsiveness of endothelium to Ang1 is determined by the relative levels of Tie2 and the inhibitory co-receptor Tie1 in the cells. Tie1 undergoes regulated ectodomain cleavage which is stimulated by a range of factors including VEGF (vascular endothelial growth factor), inflammatory cytokines and changes in shear stress. Ectodomain cleavage of Tie1 relieves inhibition of Tie2 and enhances Ang1 signalling. This mechanism regulates Ang1 signalling without requiring changes in the level of the ligand and allows Ang1 signalling to be co-ordinated with other signals in the cellular environment. Regulation of signalling at the level of receptor responsiveness may be an important adaptation in systems in which an activating ligand is normally present in excess or where the ligand provides a constitutive maintenance signal. PMID- 22103493 TI - Uses of the in vitro endothelial-fibroblast organotypic co-culture assay in angiogenesis research. AB - Angiogenesis is a complex process that involves multiple cellular events. In addition to receiving inputs from a range of stimulatory and inhibitory factors, endothelial cells undergoing angiogenesis make multiple interactions with the extracellular matrix and with other cell types in the stroma. Recreating angiogenesis in vitro is probably an impossible goal; however, a number of assays have been developed that recapitulate many of the key events of the process. These assays are indispensible tools for investigating the signalling pathways that control the formation of new blood vessels. In the present paper, we review the organotypic co-culture assay of angiogenesis - until recently, a comparatively underemployed assay, but one with a number of powerful advantages for angiogenesis research. We give a set of optimized protocols for its use, including protocols for siRNA (small interfering RNA)-based screens, and we discuss appropriate methods for obtaining quantitative data from the assay. PMID- 22103494 TI - PPARs and angiogenesis. AB - The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPARalpha, PPARbeta/delta and PPARgamma. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPARgamma, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPARgamma was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPARalpha, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPARalpha or PPARgamma, activation of PPARbeta/delta induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPARbeta/delta is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail. PMID- 22103495 TI - The role of RhoJ in endothelial cell biology and angiogenesis. AB - RhoJ is an endothelially expressed member of the Cdc42 (cell division cycle 42) subfamily of small Rho GTPases. It is expressed in both the developing mammalian vasculature and the vascular beds of a number of adult tissues, with its expression regulated by the endothelial transcription factor ERG (ETS-related gene). RhoJ has been shown to regulate endothelial motility, tubulogenesis and lumen formation in vitro, and modulates the vascularization of Matrigel plugs in vivo. Both vascular endothelial growth factor and semaphorin 3E have been found to affect its activation. RhoJ has been shown to be a focal-adhesion-localized Rho GTPase which can modulate focal adhesion number, actomyosin contractility and activity of Cdc42 and Rac1. The present review discusses the biology of RhoJ with a focus on recent reports of its role in endothelial cells and angiogenesis. PMID- 22103496 TI - New pathways and mechanisms regulating and responding to Delta-like ligand 4 Notch signalling in tumour angiogenesis. AB - Notch signalling is a key pathway controlling angiogenesis in normal tissues and tumours. This has become a major focus of development of anticancer therapy, but to develop this appropriately, we need further understanding of the mechanisms of regulation of Dll4 (Delta-like ligand 4), a key endothelial Notch ligand. Dll4 and VEGF (vascular endothelial growth factor) cross-talk, with VEGF up-regulation of Dll4 and Dll4 down-regulating VEGFR (VEGF receptor) signalling. Both are essential for normal angiogenesis, and blockade of one may produce compensatory changes in the other. The present review considers recent developments in the regulation of Dll4 expression and functions, its role as a mechanism of resistance to anti-angiogenic therapy, and methods needed to develop effective therapy against this target. PMID- 22103498 TI - Vascular remodelling in human skeletal muscle. AB - Exercise-induced angiogenesis in skeletal muscle involves both non-sprouting and sprouting angiogenesis and results from the integrated responses of multiple systems and stimuli. VEGF-A (vascular endothelial growth factor A) levels are increased in exercised muscle and have been demonstrated to be critical for exercise-induced capillary growth. Only limited information is available regarding the role of other angiogenic and angiostatic factors in exercise, but changes in the angiopoietin family following repetitive bouts of exercise occur in a pattern that is favourable for angiogenesis. Results from other angiogenic model systems, indicate that miRNAs (microRNAs) are important factors in the regulation of angiogenesis and thus to explore their role as regulators of exercise induced angiogenesis will be an important avenue of study in the future. ECM (extracellular matrix) remodelling and activation of MMPs (matrix metalloproteinases) are, to some extent, overlooked players in skeletal muscle adaptation. Degradation of ECM proteins liberates angiogenic factors from immobilized matrix stores and make cell migration possible. In fact, it is known that MMPs become activated by a single bout of exercise in humans, rapid interstitial changes occur long before any changes in gene transcription could result in protein synthesis and inhibition of MMP activity completely abolishes sprouting angiogenesis. A growing body of evidence suggests that circulating and resident progenitor cells, in addition to other cell types located in skeletal muscle tissue, participate in skeletal muscle angiogenesis by various mechanisms. However, more studies are needed before these can be confirmed as mechanisms of exercise-induced capillary growth. PMID- 22103497 TI - Is inflammation the cause of pre-eclampsia? AB - It has been proposed that either excessive inflammation or an imbalance in angiogenic factors cause pre-eclampsia. In the present review, the arguments for and against the role of inflammation and/or angiogenic imbalance as the cause of pre-eclampsia are discussed on the basis of the Bradford-Hill criteria for disease causation. Although both angiogenic imbalance and systemic inflammation are implicated in pre-eclampsia, the absence of temporality of inflammatory markers with pre-eclampsia challenges the concept that excessive inflammation is the cause of pre-eclampsia. In contrast, the elevation of anti-angiogenic factors that precede the clinical signs of pre-eclampsia fulfils the criterion of temporality. The second most important criterion is the dose-response relationship. Although such a relationship has not been proven between pro inflammatory cytokines and pre-eclampsia, high levels of anti-angiogenic factors have been shown to correlate with increased incidence and disease severity, hence satisfying this condition. Finally, as the removal of circulating sFlt-1 (soluble Fms-like tyrosine kinase receptor-1) from pre-eclamptic patients significantly improves the clinical outcome, it fulfils the Hill's experiment principle, which states that removal of the cause by an appropriate experimental regimen should ameliorate the condition. In contrast, treatment with high doses of corticosteroid fails to improve maternal outcome in pre-eclampsia, despite suppressing inflammation. Inflammation may enhance the pathology induced by the imbalance in the angiogenic factors, but does not by itself cause pre-eclampsia. Development of therapies based on the angiogenic and cytoprotective mechanisms seems more promising. PMID- 22103499 TI - In vivo shear stress response. AB - EC (endothelial cell) responses to shear stress generated by vascular perfusion play an important role in circulatory homoeostasis, whereas abnormal responses are implicated in vascular diseases such as hypertension and atherosclerosis. ECs subjected to high shear stress in vitro alter their morphology, function and gene expression. The molecular basis for mechanotransduction of a shear stress signal, and the identity of the sensing mechanisms, remain unclear with many candidates under investigation. Translating these findings in vivo has proved difficult. The role of VEGF (vascular endothelial growth factor) flow-dependent nitric oxide release in remodelling skeletal muscle microcirculation is established for elevated (activity, dilatation) and reduced (overload, ischaemia) shear stress, although their temporal relationship to angiogenesis varies. It is clear that growth factor levels may offer only a permissive environment, and alteration of receptor levels may be a viable therapeutic target. Angiogenesis in vivo appears to be a graded phenomenon, and capillary regression on withdrawal of stimulus may be rapid. Combinations of physiological angiogenic stimuli appear not to be additive. PMID- 22103500 TI - New insights into the plasticity of the endothelial phenotype. AB - The mammalian vascular system consists of two distinct, but closely related, networks: the blood vasculature (itself divided into arterial and venous networks) and the lymphatic vasculature. EC (endothelial cell) lineage specification has been proposed to be determined during embryonic development, after which the ECs are committed to their fate. However, increasing evidence suggests that ECs retain various degrees of plasticity, and have the ability to express characteristics of alternative cell lineages. Therapeutic control of endothelial plasticity will allow greater understanding of the genesis and treatment of several vascular diseases. PMID- 22103501 TI - To sprout or to split? VEGF, Notch and vascular morphogenesis. AB - Therapeutic angiogenesis is an attractive strategy to treat patients suffering from peripheral or coronary artery disease. VEGF (vascular endothelial growth factor-A) is the fundamental factor controlling vascular growth in both development and postnatal life. The interplay between the VEGF and Notch signalling pathway has been recently found to regulate the morphogenic events leading to the growth of new vessels by sprouting. Angiogenesis can also take place by an alternative process, i.e. intussusception or vascular splitting. However, little is known about its role in therapeutic angiogenesis and its molecular regulation. In the present article, we briefly review how VEGF dose determines the induction of normal or aberrant angiogenesis and the molecular regulation of sprouting angiogenesis by Notch signalling, and compare this process with intussusception. PMID- 22103502 TI - Angiogenic properties of the chemokine RANTES/CCL5. AB - Atherosclerosis is an inflammatory disease that is one of the leading causes of death in developed countries. This disease is defined by the formation of an atherosclerotic plaque, which is responsible for artery obstruction and affects the heart by causing myocardial infarction. The vascular wall is composed of three cell types and includes a monolayer of endothelial cells and is irrigated by a vasa vasorum. The formation of the vascular network from the vasa vasorum is a process involved in the destabilization of this plaque. Cellular and molecular approaches are studied by in vitro assay of activated endothelial cells and in in vivo models of neovascularization. Chemokines are a large family of small secreted proteins that have been shown to play a critical role in the regulation of angiogenesis during several pathophysiological processes such as ischaemia. Chemokines may exert their regulatory activity on angiogenesis directly by activating the vasa vasorum, or as a consequence of leucocyte infiltration through the endothelium, and/or by the induction of growth factor expression such as that of VEGF (vascular endothelial growth factor). The present review focuses on the angiogenic activity of the chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted)/CCL5 (CC chemokine ligand 5). RANTES/CCL5 is released by many cell types such as platelets or smooth muscle cells. This chemokine interacts with GPCRs (G-protein-coupled receptors) and GAG (glycosaminoglycan) chains bound to HSPGs (heparan sulfate proteoglycans). Many studies have demonstrated, using RANTES/CCL5 mutated on their GAG or GPCR-binding sites, the involvement of these chemokines in angiogenic process. In the present review, we discuss two controversial roles of RANTES/CCL5 in the angiogenic process. PMID- 22103503 TI - Taming of the wild vessel: promoting vessel stabilization for safe therapeutic angiogenesis. AB - VEGF (vascular endothelial growth factor) is the master regulator of blood vessel growth. However, it displayed substantial limitations when delivered as a single gene to restore blood flow in ischaemic conditions. Indeed, uncontrolled VEGF expression can easily induce aberrant vascular structures, and short-term expression leads to unstable vessels. Targeting the second stage of the angiogenic process, i.e. vascular maturation, is an attractive strategy to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations of VEGF-based gene therapy, briefly summarizes the current knowledge of the molecular and cellular regulation of vascular maturation, and describes recent pre-clinical evidence on how the maturation stage could be targeted to achieve therapeutic angiogenesis. PMID- 22103504 TI - Angiogenesis regulation by TGFbeta signalling: clues from an inherited vascular disease. AB - Studies of rare genetic diseases frequently reveal genes that are fundamental to life, and the familial vascular disorder HHT (hereditary haemorrhagic telangiectasia) is no exception. The majority of HHT patients are heterozygous for mutations in either the ENG (endoglin) or the ACVRL1 (activin receptor-like kinase 1) gene. Both genes are essential for angiogenesis during development and mice that are homozygous for mutations in Eng or Acvrl1 die in mid-gestation from vascular defects. Recent development of conditional mouse models in which the Eng or Acvrl1 gene can be depleted in later life have confirmed the importance of both genes in angiogenesis and in the maintenance of a normal vasculature. Endoglin protein is a co-receptor and ACVRL1 is a signalling receptor, both of which are expressed primarily in endothelial cells to regulate TGFbeta (transforming growth factor beta) signalling in the cardiovasculature. The role of ACVRL1 and endoglin in TGFbeta signalling during angiogenesis is now becoming clearer as interactions between these receptors and additional ligands of the TGFbeta superfamily, as well as synergistic relationships with other signalling pathways, are being uncovered. The present review aims to place these recent findings into the context of a better understanding of HHT and to summarize recent evidence that confirms the importance of endoglin and ACVRL1 in maintaining normal cardiovascular health. PMID- 22103505 TI - The emerging role of tetraspanin microdomains on endothelial cells. AB - Tetraspanins function as organizers of the cell surface by recruiting specific partner proteins into tetraspanin-enriched microdomains, which regulate processes such as cell adhesion, signalling and intracellular trafficking. Endothelial cells appear to express at least 23 of the 33 human tetraspanins, and a number of recent studies have demonstrated their importance in endothelial cell biology. Tetraspanin CD151 is essential for pathological angiogenesis, which may in part be due to regulation of its main partner proteins, the laminin-binding integrins alpha3beta1, alpha6beta1 and alpha6beta4. CD9 and CD151 are essential for leucocyte recruitment during an inflammatory response, through the formation of pre-assembled nano-platforms containing the adhesion molecules ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), which ultimately coalesce to form docking structures around captured leucocytes. Tetraspanin CD63 also facilitates leucocyte capture by promoting clustering of the adhesion molecule P-selectin. Finally, Tspan12 is required for blood vessel development in the eye, through regulation of Norrin-induced Frizzled-4 signalling, such that Tspan12 mutations can lead to human disease. Future studies on these and other endothelial tetraspanins are likely to provide further novel insights into angiogenesis and inflammation. PMID- 22103506 TI - Intravital two-photon microscopy of lymphatic vessel development and function using a transgenic Prox1 promoter-directed mOrange2 reporter mouse. AB - Lymphatic vessels, the second vascular system of higher vertebrates, are indispensable for fluid tissue homoeostasis, dietary fat resorption and immune surveillance. Not only are lymphatic vessels formed during fetal development, when the lymphatic endothelium differentiates and separates from blood endothelial cells, but also lymphangiogenesis occurs during adult life under conditions of inflammation, wound healing and tumour formation. Under all of these conditions, haemopoietic cells can exert instructive influences on lymph vessel growth and are essential for the vital separation of blood and lymphatic vessels. LECs (lymphatic endothelial cells) are characterized by expression of a number of unique genes that distinguish them from blood endothelium and can be utilized to drive reporter genes in a lymph endothelial-specific fashion. In the present paper, we describe the Prox1 (prospero homeobox protein 1) promoter driven expression of the fluorescent protein mOrange2, which allows the specific intravital visualization of lymph vessel growth and behaviour during mouse fetal development and in adult mice. PMID- 22103507 TI - Nuclear envelope disease and chromatin organization. AB - The fifth U.K. meeting on nuclear envelope disease and chromatin brought together international experts from across the field of nuclear envelope biology to discuss the advancements in a class of tissue-specific degenerative diseases called the laminopathies. Clinically, these range from relatively mild fat wasting disorders to the severe premature aging condition known as Hutchinson Gilford progeria syndrome. Since the first association of the nuclear envelope with human inherited disease in 1994, there has been an exponential increase in an unexpected variety of functions associated with nuclear envelope proteins, ranging from mechanical support and nucleocytoskeletal connections to regulation of chromatin organization and gene expression. This Biochemical Society Focused Meeting reinforced the functional complexity of nuclear-associated diseases, revealed new avenues to be investigated and highlighted the signalling pathways suitable as therapeutic targets. PMID- 22103508 TI - Clinical and genetic heterogeneity in laminopathies. AB - Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability. PMID- 22103509 TI - The LINC complex and human disease. AB - The LINC (linker of nucleoskeleton and cytoskeleton) complex is a proposed mechanical link tethering the nucleo- and cyto-skeleton via the NE (nuclear envelope). The LINC components emerin, lamin A/C, SUN1, SUN2, nesprin-1 and nesprin-2 interact with each other at the NE and also with other binding partners including actin filaments and B-type lamins. Besides the mechanostructural functions, the LINC complex is also involved in signalling pathways and gene regulation. Emerin was the first LINC component associated with a human disease, namely EDMD (Emery-Dreifuss muscular dystrophy). Later on, other components of the LINC complex, such as lamins A/C and small isoforms of nesprin-1 and nesprin 2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 46% of the EDMD patients can be linked to genes of LINC and non-LINC components, pointing to further genes involved in the pathology of EDMD. Obvious candidates are the LINC proteins SUN1 and SUN2. Recently, screening of binding partners of LINC components as candidates identified LUMA (TMEM43), encoding a binding partner of emerin and lamins, as a gene involved in atypical EDMD. Nevertheless, such mutations contribute only to a very small fraction of EDMD patients. EDMD-causing mutations in STA/EMD (encoding emerin) that disrupt emerin binding to Btf (Bcl-2-associated transcription factor), GCL (germ cell-less) and BAF (barrier to autointegration factor) provide the first glimpses into LINC being involved in gene regulation and thus opening new avenues for functional studies. Thus the association of LINC with human disease provides tools for understanding its functions within the cell. PMID- 22103510 TI - Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells. AB - Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor. PMID- 22103511 TI - The nuclear lamina and heterochromatin: a complex relationship. AB - In metazoan cells, the heterochromatin is generally localized at the nuclear periphery, whereas active genes are preferentially found in the nuclear interior. In the present paper, we review current evidence showing that components of the nuclear lamina interact directly with heterochromatin, which implicates the nuclear lamina in a mechanism of specific gene retention at the nuclear periphery and release to the nuclear interior upon gene activation. We also discuss recent data showing that mutations in lamin proteins affect gene positioning and expression, providing a potential mechanism for how these mutations lead to tissue-specific diseases. PMID- 22103512 TI - Cell autonomous and systemic factors in progeria development. AB - Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Nestor Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging. PMID- 22103513 TI - The role of DNA damage in laminopathy progeroid syndromes. AB - Progeroid laminopathies are characterized by the abnormal processing of lamin A, the appearance of misshapen nuclei, and the accumulation and persistence of DNA damage. In the present article, I consider the contribution of defective DNA damage pathways to the pathology of progeroid laminopathies. Defects in DNA repair pathways appear to be caused by a combination of factors. These include abnormal epigenetic modifications of chromatin that are required to recruit DNA repair pathways to sites of DNA damage, abnormal recruitment of DNA excision repair proteins to sites of DNA double-strand breaks, and unrepairable ROS (reactive oxygen species)-induced DNA damage. At least two of these defective processes offer the potential for novel therapeutic approaches. PMID- 22103514 TI - Nesprin-3: a versatile connector between the nucleus and the cytoskeleton. AB - The cytoskeleton is connected to the nuclear interior by LINC (linker of nucleoskeleton and cytoskeleton) complexes located in the nuclear envelope. These complexes consist of SUN proteins and nesprins present in the inner and outer nuclear membrane respectively. Whereas SUN proteins can bind the nuclear lamina, members of the nesprin protein family connect the nucleus to different components of the cytoskeleton. Nesprin-1 and -2 can establish a direct link with actin filaments, whereas nesprin-4 associates indirectly with microtubules through its interaction with kinesin-1. Nesprin-3 is the only family member known that can link the nuclear envelope to intermediate filaments. This indirect interaction is mediated by the binding of nesprin-3 to the cytoskeletal linker protein plectin. Furthermore, nesprin-3 can connect the nucleus to microtubules by its interactions with BPAG1 (bullous pemphigoid antigen 1) and MACF (microtubule actin cross-linking factor). In contrast with the active roles that nesprin-1, -2 and -4 have in actin- and microtubule-dependent nuclear positioning, the role of nesprin-3 is likely to be more passive. We suggest that it helps to stabilize the anchorage of the nucleus within the cytoplasm and maintain the structural integrity and shape of the nucleus. PMID- 22103515 TI - The role of nesprins as multifunctional organizers in the nucleus and the cytoskeleton. AB - Nesprins (nuclear envelope spectrin repeat proteins), also known as SYNE (synaptic nuclear envelope protein), MYNE (myocyte nuclear envelope protein), ENAPTIN and NUANCE, are proteins that are primarily components of the nuclear envelope. The nuclear envelope is a continuous membrane system composed of two lipid bilayers: an inner and an outer nuclear membrane. Nesprins are components of both nuclear membranes and reach into the nucleoplasm and the cytoplasm, where they undergo different interactions and have the potential to influence transcriptional processes and cytoskeletal activities. PMID- 22103516 TI - Keeping the LINC: the importance of nucleocytoskeletal coupling in intracellular force transmission and cellular function. AB - Providing a stable physical connection between the nucleus and the cytoskeleton is essential for a wide range of cellular functions and it could also participate in mechanosensing by transmitting intra- and extra-cellular mechanical stimuli via the cytoskeleton to the nucleus. Nesprins and SUN proteins, located at the nuclear envelope, form the LINC (linker of nucleoskeleton and cytoskeleton) complex that connects the nucleus to the cytoskeleton; underlying nuclear lamins contribute to anchoring LINC complex components at the nuclear envelope. Disruption of the LINC complex or loss of lamins can result in disturbed perinuclear actin and intermediate filament networks and causes severe functional defects, including impaired nuclear positioning, cell polarization and cell motility. Recent studies have identified the LINC complex as the major force transmitting element at the nuclear envelope and suggest that many of the aforementioned defects can be attributed to disturbed force transmission between the nucleus and the cytoskeleton. Thus mutations in nesprins, SUN proteins or lamins, which have been linked to muscular dystrophies and cardiomyopathies, may weaken or completely eliminate LINC complex function at the nuclear envelope and result in impaired intracellular force transmission, thereby disrupting critical cellular functions. PMID- 22103518 TI - Nuclear envelope influences on cell-cycle progression. AB - The nuclear envelope is a complex double membrane system that serves as a dynamic interface between the nuclear and cytoplasmic compartments. Among its many roles is to provide an anchor for gene regulatory proteins on its nucleoplasmic surface and for the cytoskeleton on its cytoplasmic surface. Both sets of anchors are proteins called NETs (nuclear envelope transmembrane proteins), embedded respectively in the inner or outer nuclear membranes. Several lines of evidence indicate that the nuclear envelope contributes to cell-cycle regulation. These contributions come from both inner and outer nuclear membrane NETs and appear to operate through several distinct mechanisms ranging from sequestration of gene regulatory proteins to activating kinase cascades. PMID- 22103517 TI - Evolvement of LEM proteins as chromatin tethers at the nuclear periphery. AB - The nuclear envelope in eukaryotic cells has important roles in chromatin organization. The inner nuclear membrane contains over 60 transmembrane proteins. LEM [LAP2 (lamina-associated polypeptide 2)/emerin/MAN1] domain-containing proteins of the inner nuclear membrane are involved in tethering chromatin to the nuclear envelope and affect gene expression. They contain a common structural, bihelical motif, the so-called LEM domain, which mediates binding to a conserved chromatin protein, BAF (barrier to autointegration factor). Interestingly, this domain is highly related to other bihelical motifs, termed HeH (helix-extension helix) and SAP {SAF (scaffold attachment factor)/acinus/PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)]} motifs, which are directly linked to DNA. In the present paper, we summarize evidence that the LEM motif evolved from the HeH and SAP domains concomitantly with BAF. In addition, we discuss the potential evolution of HeH/SAP and LEM domain containing proteins and their role in chromatin tethering and gene regulation from unicellular eukaryotes to mammals. PMID- 22103519 TI - Chromobility: the rapid movement of chromosomes in interphase nuclei. AB - There are an increasing number of studies reporting the movement of gene loci and whole chromosomes to new compartments within interphase nuclei. Some of the movements can be rapid, with relocation of parts of the genome within less than 15 min over a number of microns. Some of these studies have also revealed that the activity of motor proteins such as actin and myosin are responsible for these long-range movements of chromatin. Within the nuclear biology field, there remains some controversy over the presence of an active nuclear acto-myosin motor in interphase nuclei. However, both actin and myosin isoforms are localized to the nucleus, and there is a requirement for rapid and directed movements of genes and whole chromosomes and evidence for the involvement of motor proteins in this relocation. The presence of nuclear motors for chromatin movement is thus an important and timely debate to have. PMID- 22103520 TI - LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations. AB - Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases. PMID- 22103521 TI - Synthesis, transport and incorporation into the nuclear envelope of A-type lamins and inner nuclear membrane proteins. AB - The mammalian NE (nuclear envelope), which separates the nucleus from the cytoplasm, is a complex structure composed of nuclear pore complexes, the outer and inner nuclear membranes, the perinuclear space and the nuclear lamina (A- and B-type lamins). The NE is completely disassembled and reassembled at each cell division. In the present paper, we review recent advances in the understanding of the mechanisms implicated in the transport of inner nuclear membrane and nuclear lamina proteins from the endoplasmic reticulum to the nucleus in interphase cells and mitosis, with special attention to A-type lamins. PMID- 22103523 TI - Reproductive aging: insights from model organisms. AB - Aging was once thought to be the result of a general deterioration of tissues as opposed to their being under regulatory control. However, investigations in a number of model organisms have illustrated that aspects of aging are controlled by genetic mechanisms and are potentially manipulable, suggesting the possibility of treatment for age-related disorders. Reproductive decline is one aspect of aging. In model organisms and humans of both sexes, increasing age is associated with both a decline in the number of progeny and an increased incidence of defects. The cellular mechanisms of reproductive aging are not well understood, although a number of factors, both intrinsic and extrinsic to an organism's germline, may contribute to aging phenotypes. Recent work in a variety of organisms suggests that nuclear organization and nuclear envelope proteins may play a role in these processes. PMID- 22103522 TI - DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome. AB - A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3 related) checkpoints, and arresting cell-cycle progression. PMID- 22103524 TI - In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria. AB - Progeria, also known as HGPS (Hutchinson-Gilford progeria syndrome), is a rare fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (C1804T) of the gene encoding lamins A and C, LMNA, leading to the production of a truncated form of the protein called progerin. Owing to their unique potential to self renew and to differentiate into any cell types of the organism, pluripotent stem cells offer a unique tool to study molecular and cellular mechanisms related to this global and systemic disease. Recent studies have exploited this potential by generating human induced pluripotent stem cells from HGPS patients' fibroblasts displaying several phenotypic defects characteristic of HGPS such as nuclear abnormalities, progerin expression, altered DNA-repair mechanisms and premature senescence. Altogether, these findings provide new insights on the use of pluripotent stem cells for pathological modelling and may open original therapeutic perspectives for diseases that lack pre-clinical in vitro human models, such as HGPS. PMID- 22103525 TI - Defective DNA-damage repair induced by nuclear lamina dysfunction is a key mediator of smooth muscle cell aging. AB - Accumulation of DNA damage is a major driving force of normal cellular aging and has recently been demonstrated to hasten the development of vascular diseases such as atherosclerosis. VSMCs (vascular smooth muscle cells) are essential for vessel wall integrity and repair, and maintenance of their proliferative capacity is essential for vascular health. The signalling pathways that determine VSMC aging remain poorly defined; however, recent evidence implicates persistent DNA damage and the A-type nuclear lamins as key regulators of this process. In the present review, we discuss the importance of the nuclear lamina in the spatial organization of nuclear signalling events, including the DNA-damage response. In particular, we focus on the evidence suggesting that prelamin A accumulation interferes with nuclear spatial compartmentalization by disrupting chromatin organization and DNA-damage repair pathways to promote VSMC aging and senescence. PMID- 22103526 TI - Microtubule-associated nuclear envelope proteins in interphase and mitosis. AB - The LINC (linker of nucleoskeleton and cytoskeleton) complex forms a transcisternal bridge across the NE (nuclear envelope) that connects the cytoskeleton with the nuclear interior. This enables some proteins of the NE to communicate with the centrosome and the microtubule cytoskeleton. The position of the centrosome relative to the NE is of vital importance for many cell functions, such as cell migration and division, and centrosomal dislocation is a frequent phenotype in laminopathic disorders. Also in mitosis, a small group of transmembrane NE proteins associate with microtubules when they concentrate in a specific membrane domain associated with the mitotic spindle. The present review discusses structural and functional aspects of microtubule association with NE proteins and how this association may be maintained over the cell cycle. PMID- 22103527 TI - UnLINCing the nuclear envelope: towards an understanding of the physiological significance of nuclear positioning. AB - Appropriate tissue morphogenesis strictly requires the developmental regulation of different types of nuclear movements. LINC (linker of nucleoskeleton and cytoskeleton) complexes are macromolecular scaffolds that span the nuclear envelope and physically connect the nuclear interior to different cytoskeletal elements and molecular motors, thereby playing essential roles in nucleokinesis. Recent studies dedicated to the in vivo disruption of LINC complexes not only confirmed their widespread role in nuclear dynamics, but also led to a vigorous regain of interest in the physiological relevance of nuclear positioning within cells and syncitia. In the present paper, we review the results of LINC complex disruption in vivo across different organisms and the potential implications of observed phenotypes in human diseases. PMID- 22103528 TI - The nuclear envelope and its involvement in cellular stress responses. AB - The nuclear envelope is not only important for the structural integrity of the nucleus, but also involved in a number of cellular functions. It has been shown to be important for maintaining and controlling chromatin organization, sequestering transcription factors, replication, transcription and signalling. The nuclear envelope is thus important for development and differentiation, and some of its components are essential for cell viability. Among the many functions which are emerging for the nuclear envelope is its involvement in protecting the cell against different types of cellular stress. In the present paper, we review key findings which describe the roles of nuclear envelope components in responses to common types of stress conditions. PMID- 22103529 TI - The metagenomic basis of anammox metabolism in Candidatus 'Brocadia fulgida'. AB - Anammox (anaerobic ammonium oxidation) coupled to nitrite reduction is an important step in the nitrogen cycle and has been recognized as an important sink for fixed nitrogen in the ocean. Still little is known about the genomic blueprint of different anammox species. In the present article, we discuss the important genes of anammox metabolism in Candidatus 'Brocadia fulgida' that were retrieved via a metagenomic approach. PMID- 22103530 TI - The ultrastructure of the compartmentalized anaerobic ammonium-oxidizing bacteria is linked to their energy metabolism. AB - The most striking example of a complex prokaryotic intracytoplasmic organization can be found in the members of the phylum Planctomycetes. Among them are the anammox (anaerobic ammonium-oxidizing) bacteria, which possess a unique cell compartment with an unprecedented function in bacteria: the anammoxosome is a prokaryotic cell organelle evolved for energy metabolism. It is an independent entity, which is enclosed by a contiguous membrane. Several lines of evidence indicate its importance in the anammox reaction and the unusual subcellular organization may well be essential for the lifestyle of anammox bacteria. The present review summarizes our knowledge about the ultrastructure of anammox cells and the connection between the anammoxosome and the energy metabolism of the cell. In the future, much more research will be necessary to validate the current models and to answer questions on the functional cell biology of anammox bacteria. PMID- 22103531 TI - Anaerobic ammonium oxidation (anammox) in different natural ecosystems. AB - Anammox (anaerobic ammonium oxidation), which is a reaction that oxidizes ammonium to dinitrogen gas using nitrite as the electron acceptor under anoxic conditions, was an important discovery in the nitrogen cycle. The reaction is mediated by a specialized group of planctomycete-like bacteria that were first discovered in man-made ecosystems. Subsequently, many studies have reported on the ubiquitous distribution of anammox bacteria in various natural habitats, including anoxic marine sediments and water columns, freshwater sediments and water columns, terrestrial ecosystems and some special ecosystems, such as petroleum reservoirs. Previous studies have estimated that the anammox process is responsible for 50% of the marine nitrogen loss. Recently, the anammox process was reported to account for 9-40% and 4-37% of the nitrogen loss in inland lakes and agricultural soils respectively. These findings indicate the great potential for the anammox process to occur in freshwater and terrestrial ecosystems. The distribution of different anammox bacteria and their contribution to nitrogen loss have been described in different natural habitats, demonstrating that the anammox process is strongly influenced by the local environmental conditions. The present mini-review summarizes the current knowledge of the ecological distribution of anammox bacteria, their contribution to nitrogen loss in various natural ecosystems and the effects of major influential factors on the anammox process. PMID- 22103532 TI - Anammox bacteria in different compartments of recirculating aquaculture systems. AB - Strict environmental restrictions force the aquaculture industry to guarantee optimal water quality for fish production in a sustainable manner. The implementation of anammox (anaerobic ammonium oxidation) in biofilters would result in the conversion of both ammonium and nitrite (both toxic to aquatic animals) into harmless dinitrogen gas. Both marine and freshwater aquaculture systems contain populations of anammox bacteria. These bacteria are also present in the faeces of freshwater and marine fish. Interestingly, a new planctomycete species appears to be present in these recirculation systems too. Further exploitation of anammox bacteria in different compartments of aquaculture systems can lead to a more environmentally friendly aquaculture practice. PMID- 22103533 TI - Combined anaerobic ammonium and methane oxidation for nitrogen and methane removal. AB - Anammox (anaerobic ammonium oxidation) is an environment-friendly and cost efficient nitrogen-removal process currently applied to high-ammonium-loaded wastewaters such as anaerobic digester effluents. In these wastewaters, dissolved methane is also present and should be removed to prevent greenhouse gas emissions into the environment. Potentially, another recently discovered microbial pathway, n-damo (nitrite-dependent anaerobic methane oxidation) could be used for this purpose. In the present paper, we explore the feasibility of simultaneously removing methane and ammonium anaerobically, starting with granules from a full scale anammox bioreactor. We describe the development of a co-culture of anammox and n-damo bacteria using a medium containing methane, ammonium and nitrite. The results are discussed in the context of other recent studies on the application of anaerobic methane- and ammonia-oxidizing bacteria for wastewater treatment. PMID- 22103534 TI - Nitrifying and denitrifying pathways of methanotrophic bacteria. AB - Nitrous oxide, a potent greenhouse gas and ozone-depleting molecule, continues to accumulate in the atmosphere as a product of anthropogenic activities and land use change. Nitrogen oxides are intermediates of nitrification and denitrification and are released as terminal products under conditions such as high nitrogen load and low oxygen tension among other factors. The rapid completion and public availability of microbial genome sequences has revealed a high level of enzymatic redundancy in pathways terminating in nitrogen oxide metabolites, with few enzymes involved in returning nitrogen oxides to dinitrogen. The aerobic methanotrophic bacteria are particularly useful for discovering and analysing diverse mechanisms for nitrogen oxide production, as these microbes both nitrify (oxidize ammonia to nitrite) and denitrify (reduce nitrate/nitrite to nitrous oxide via nitric oxide), and yet do not rely on these pathways for growth. The fact that methanotrophs have a rich inventory for nitrogen oxide metabolism is, in part, a consequence of their evolutionary relatedness to ammonia-oxidizing bacteria. Furthermore, the ability of individual methanotrophic taxa to resist toxic intermediates of nitrogen metabolism affects the relative abundance of nitrogen oxides released into the environment, the composition of their community, and the balance between nitrogen and methane cycling. PMID- 22103535 TI - Nitrous oxide production by lithotrophic ammonia-oxidizing bacteria and implications for engineered nitrogen-removal systems. AB - Chemolithoautotrophic AOB (ammonia-oxidizing bacteria) form a crucial component in microbial nitrogen cycling in both natural and engineered systems. Under specific conditions, including transitions from anoxic to oxic conditions and/or excessive ammonia loading, and the presence of high nitrite (NO2-) concentrations, these bacteria are also documented to produce nitric oxide (NO) and nitrous oxide (N2O) gases. Essentially, ammonia oxidation in the presence of non-limiting substrate concentrations (ammonia and O2) is associated with N2O production. An exceptional scenario that leads to such conditions is the periodical switch between anoxic and oxic conditions, which is rather common in engineered nitrogen-removal systems. In particular, the recovery from, rather than imposition of, anoxic conditions has been demonstrated to result in N2O production. However, applied engineering perspectives, so far, have largely ignored the contribution of nitrification to N2O emissions in greenhouse gas inventories from wastewater-treatment plants. Recent field-scale measurements have revealed that nitrification-related N2O emissions are generally far higher than emissions assigned to heterotrophic denitrification. In the present paper, the metabolic pathways, which could potentially contribute to NO and N2O production by AOB have been conceptually reconstructed under conditions especially relevant to engineered nitrogen-removal systems. Taken together, the reconstructed pathways, field- and laboratory-scale results suggest that engineering designs that achieve low effluent aqueous nitrogen concentrations also minimize gaseous nitrogen emissions. PMID- 22103536 TI - Bacterial nitrate assimilation: gene distribution and regulation. AB - In the context of the global nitrogen cycle, the importance of inorganic nitrate for the nutrition and growth of marine and freshwater autotrophic phytoplankton has long been recognized. In contrast, the utilization of nitrate by heterotrophic bacteria has historically received less attention because the primary role of these organisms has classically been considered to be the decomposition and mineralization of dissolved and particulate organic nitrogen. In the pre-genome sequence era, it was known that some, but not all, heterotrophic bacteria were capable of growth on nitrate as a sole nitrogen source. However, examination of currently available prokaryotic genome sequences suggests that assimilatory nitrate reductase (Nas) systems are widespread phylogenetically in bacterial and archaeal heterotrophs. Until now, regulation of nitrate assimilation has been mainly studied in cyanobacteria. In contrast, in heterotrophic bacterial strains, the study of nitrate assimilation regulation has been limited to Rhodobacter capsulatus, Klebsiella oxytoca, Azotobacter vinelandii and Bacillus subtilis. In Gram-negative bacteria, the nas genes are subjected to dual control: ammonia repression by the general nitrogen regulatory (Ntr) system and specific nitrate or nitrite induction. The Ntr system is widely distributed in bacteria, whereas the nitrate/nitrite-specific control is variable depending on the organism. PMID- 22103537 TI - A haloarchaeal ferredoxin electron donor that plays an essential role in nitrate assimilation. AB - In the absence of ammonium, many organisms, including the halophilic archaeon Haloferax volcanii DS2 (DM3757), may assimilate inorganic nitrogen from nitrate or nitrite, using a ferredoxin-dependent assimilatory NO3-/NO2- reductase pathway. The small acidic ferredoxin Hv-Fd plays an essential role in the electron transfer cascade required for assimilatory nitrate and nitrite reduction by the cytoplasmic NarB- and NirA-type reductases respectively. UV-visible absorbance and EPR spectroscopic characterization of purified Hv-Fd demonstrate that this protein binds a single [2Fe-2S] cluster, and potentiometric titration reveals that the cluster shares similar redox properties with those present in plant-type ferredoxins. PMID- 22103538 TI - Metabolic adaptation of Pseudomonas pseudoalcaligenes CECT5344 to cyanide: role of malate-quinone oxidoreductases, aconitase and fumarase isoenzymes. AB - In general, the biodegradation of a toxic compound by a micro-organism requires the concurrence of, at least, two features in the biological system: first, the capability of the micro-organism to metabolize the toxic compound, and secondly, the capacity to resist its toxic effect. Pseudomonas pseudoalcaligenes CECT5344 is a bacterium used in the biodegradation of cyanide because it is capable to use it as a nitrogen source. The present review is mainly focused on the putative role of iron-containing enzymes of the tricarboxylic acid cycle in cyanide resistance by P. pseudoalcaligenes CECT5344. PMID- 22103539 TI - Role of Fur on cyanide tolerance of Pseudomonas pseudoalcaligenes CECT5344. AB - Pseudomonas pseudoalcaligenes CECT5344 can be used in cyanide bioremediation processes because it grows at pH 9.5 using 2.0 mM cyanide at the sole nitrogen source. Cyanide strongly binds to metals creating iron-deprivation conditions. The bacterium responds to the presence of cyanide by inducing several processes such as siderophore synthesis for iron capture, cyanide-insensitive respiration system and defence mechanisms against oxidative stress. Since high concentrations of cyanide cause iron deficiency and because iron is an essential nutrient, bacterial growth in the presence of cyanide requires an efficient iron uptake. Fur is a global transcription factor that regulates a diversity of biological processes such as iron homoeostasis, TCA (tricarboxylic acid) cycle metabolism and oxidative stress response. Fur's regulation of iron uptake and storage genes should play a significant role in the lives of these bacteria. In the present review, current knowledge of Fur is summarized. PMID- 22103540 TI - Dissimilatory sulfur cycling in oxygen minimum zones: an emerging metagenomics perspective. AB - Biological diversity in marine OMZs (oxygen minimum zones) is dominated by a complex community of bacteria and archaea whose anaerobic metabolisms mediate key steps in global nitrogen and carbon cycles. Molecular and physiological studies now confirm that OMZs also support diverse micro-organisms capable of utilizing inorganic sulfur compounds for energy metabolism. The present review focuses specifically on recent metagenomic data that have helped to identify the molecular basis for autotrophic sulfur oxidation with nitrate in the OMZ water column, as well as a cryptic role for heterotrophic sulfate reduction. Interpreted alongside marker gene surveys and process rate measurements, these data suggest an active sulfur cycle with potentially substantial roles in organic carbon input and mineralization and critical links to the OMZ nitrogen cycle. Furthermore, these studies have created a framework for comparing the genomic diversity and ecology of pelagic sulfur-metabolizing communities from diverse low oxygen regions. PMID- 22103541 TI - Physiological function and catalytic versatility of bacterial multihaem cytochromes c involved in nitrogen and sulfur cycling. AB - Bacterial MCCs (multihaem cytochromes c) represent widespread respiratory electron-transfer proteins. In addition, some of them convert substrates such as nitrite, hydroxylamine, nitric oxide, hydrazine, sulfite, thiosulfate or hydrogen peroxide. In many cases, only a single function is assigned to a specific MCC in database entries despite the fact that an MCC may accept various substrates, thus making it a multifunctional catalyst that can play diverse physiological roles in bacterial respiration, detoxification and stress defence mechanisms. The present article briefly reviews the structure, function and biogenesis of selected MCCs that catalyse key reactions in the biogeochemical nitrogen and sulfur cycles. PMID- 22103542 TI - Characterization of the active site and calcium binding in cytochrome c nitrite reductases. AB - The decahaem homodimeric cytochrome c nitrite reductase (NrfA) is expressed within the periplasm of a wide range of Gamma-, Delta- and Epsilon-proteobacteria and is responsible for the six-electron reduction of nitrite to ammonia. This allows nitrite to be used as a terminal electron acceptor, facilitating anaerobic respiration while allowing nitrogen to remain in a biologically available form. NrfA has also been reported to reduce nitric oxide (a reaction intermediate) and sulfite to ammonia and sulfide respectively, suggesting a potential secondary role as a detoxification enzyme. The protein sequences and crystal structures of NrfA from different bacteria and the closely related octahaem nitrite reductase from Thioalkalivibrio nitratireducens (TvNir) reveal that these enzymes are homologous. The NrfA proteins contain five covalently attached haem groups, four of which are bis-histidine-co-ordinated, with the proximal histidine being provided by the highly conserved CXXCH motif. These haems are responsible for intraprotein electron transfer. The remaining haem is the site for nitrite reduction, which is ligated by a novel lysine residue provided by a CXXCK haem binding motif. The TvNir nitrite reductase has five haems that are structurally similar to those of NrfA and three extra bis-histidine-coordinated haems that precede the NrfA conserved region. The present review compares the protein sequences and structures of NrfA and TvNir and discusses the subtle differences related to active-site architecture and Ca2+ binding that may have an impact on substrate reduction. PMID- 22103543 TI - The production and detoxification of a potent cytotoxin, nitric oxide, by pathogenic enteric bacteria. AB - The nitrogen cycle is based on several redox reactions that are mainly accomplished by prokaryotic organisms, some archaea and a few eukaryotes, which use these reactions for assimilatory, dissimilatory or respiratory purposes. One group is the Enterobacteriaceae family of Gammaproteobacteria, which have their natural habitats in soil, marine environments or the intestines of humans and other warm-blooded animals. Some of the genera are pathogenic and usually associated with intestinal infections. Our body possesses several physical and chemical defence mechanisms to prevent pathogenic enteric bacteria from invading the gastrointestinal tract. One response of the innate immune system is to activate macrophages, which produce the potent cytotoxin nitric oxide (NO). However, some pathogens have evolved the ability to detoxify NO to less toxic compounds, such as the neuropharmacological agent and greenhouse gas nitrous oxide (N2O), which enables them to overcome the host's attack. The same mechanisms may be used by bacteria producing NO endogenously as a by-product of anaerobic nitrate respiration. In the present review, we provide a brief introduction into the NO detoxification mechanisms of two members of the Enterobacteriaceae family: Escherichia coli and Salmonella enterica serovar Typhimurium. These are discussed as comparative non-pathogenic and pathogenic model systems in order to investigate the importance of detoxifying NO and producing N2O for the pathogenicity of enteric bacteria. PMID- 22103544 TI - The nitric oxide response in plant-associated endosymbiotic bacteria. AB - Nitric oxide (NO) is a gaseous signalling molecule which becomes very toxic due to its ability to react with multiple cellular targets in biological systems. Bacterial cells protect against NO through the expression of enzymes that detoxify this molecule by oxidizing it to nitrate or reducing it to nitrous oxide or ammonia. These enzymes are haemoglobins, c-type nitric oxide reductase, flavorubredoxins and the cytochrome c respiratory nitrite reductase. Expression of the genes encoding these enzymes is controlled by NO-sensitive regulatory proteins. The production of NO in rhizobia-legume symbiosis has been demonstrated recently. In functioning nodules, NO acts as a potent inhibitor of nitrogenase enzymes. These observations have led to the question of how rhizobia overcome the toxicity of NO. Several studies on the NO response have been undertaken in two non-dentrifying rhizobial species, Sinorhizobium meliloti and Rhizobium etli, and in a denitrifying species, Bradyrhizobium japonicum. In the present mini-review, current knowledge of the NO response in those legume-associated endosymbiotic bacteria is summarized. PMID- 22103545 TI - Denitrification in Sinorhizobium meliloti. AB - Denitrification is the complete reduction of nitrate or nitrite to N2, via the intermediates nitric oxide (NO) and nitrous oxide (N2O), and is coupled to energy conservation and growth under O2-limiting conditions. In Bradyrhizobium japonicum, this process occurs through the action of the napEDABC, nirK, norCBQD and nosRZDFYLX gene products. DNA sequences showing homology with nap, nirK, nor and nos genes have been found in the genome of the symbiotic plasmid pSymA of Sinorhizobium meliloti strain 1021. Whole-genome transcriptomic analyses have demonstrated that S. meliloti denitrification genes are induced under micro-oxic conditions. Furthermore, S. meliloti has also been shown to possess denitrifying activities in both free-living and symbiotic forms. Despite possessing and expressing the complete set of denitrification genes, S. meliloti is considered a partial denitrifier since it does not grow under anaerobic conditions with nitrate or nitrite as terminal electron acceptors. In the present paper, we show that, under micro-oxic conditions, S. meliloti is able to grow by using nitrate or nitrite as respiratory substrates, which indicates that, in contrast with anaerobic denitrifiers, O2 is necessary for denitrification by S. meliloti. Current knowledge of the regulation of S. meliloti denitrification genes is also included. PMID- 22103546 TI - A snapshot of a pathogenic bacterium mid-evolution: Neisseria meningitidis is becoming a nitric oxide-tolerant aerobe. AB - Members of the Neisseria genus typically display the ability to carry out denitrification of nitrite to nitrous oxide as an alternative to oxygen respiration when oxygen is depleted. The key enzymes nitrite and nitric oxide reductase are found across the Neisseria genus. Within Neisseria meningitidis, however, a number of research groups have found that a significant proportion of strains lack a functional nitrite reductase. It appears that N. meningitidis is on an evolutionary trajectory towards loss of the capacity to reduce nitrite. In the present paper, I propose that N. meningitidis is evolving to become a nitric oxide-tolerant aerobe in order to occupy an oxygen-rich niche close to host tissue (and hence oxygen perfusion). Other features of the genomic and functional specialization of N. meningitidis, such as possession of a polysaccharide capsule and various acquired reactive oxygen species-resistance mechanisms, support this proposition. The importance of oxygen availability more generally is discussed with reference to recent findings with other mucosal pathogens. PMID- 22103547 TI - Tied down: tethering redox proteins to the outer membrane in Neisseria and other genera. AB - Typically, the redox proteins of respiratory chains in Gram-negative bacteria are localized in the cytoplasmic membrane or in the periplasm. An alternative arrangement appears to be widespread within the betaproteobacterial genus Neisseria, wherein several redox proteins are covalently associated with the outer membrane. In the present paper, we discuss the structural properties of these outer membrane redox proteins and the functional consequences of this attachment. Several tethered outer membrane redox proteins of Neisseria contain a weakly conserved repeated structure between the covalent tether and the redox protein globular domain that should enable the redox cofactor-containing domain to extend from the outer membrane, across the periplasm and towards the inner membrane. It is argued that the constraints imposed on the movement and orientation of the globular domains by these tethers favours the formation of electron-transfer complexes for entropic reasons. The attachment to the outer membrane may also affect the exposure of the host to redox proteins with a moonlighting function in the host-microbe interaction, thus affecting the host response to Neisseria infection. We identify putative outer membrane redox proteins from a number of other bacterial genera outside Neisseria, and suggest that this organizational arrangement may be more common than previously recognized. PMID- 22103549 TI - Progression of IgA gammopathy to myeloma following infliximab treatment for pyoderma gangrenosum. AB - Pyoderma gangrenosum (PG) may be associated with inflammatory disorders and haematological conditions such as monoclonal gammopathy of uncertain significance (MGUS). We report the case of a 53-year old man who had PG and MGUS. After treatment with infliximab for the PG, he developed myeloma. The course of events in this case suggests that infliximab facilitated the progression from MGUS to myeloma. PMID- 22103550 TI - The youth form of the Motivators of and Barriers to Health-Smart Behaviors Inventory. AB - OBJECTIVE: To develop a youth form of the Motivators of and Barriers to Health Smart Behaviors Inventory (MB-HSBI-Youth) for use in identifying self-reported motivators of and barriers to the following health-promoting behaviors (called health-smart behaviors): eating a healthy breakfast, eating healthy foods and snacks, drinking healthy drinks, and engaging in physical activity. DESIGN: The MB-HSBI-Youth was developed through several research phases as part of a larger, multisite, and multicomponent study on modifying and preventing obesity in families. A critical aspect of the larger study was to identify the motivators of and barriers to the above-identified health-smart behaviors among African American, Asian American, Hispanic/Latino American, and non-Hispanic White American adults and youth. After preliminary research involving content validity, item analyses, and pilot testing, a pilot version of the MB-HSBI-Youth was administered to a national sample of 567 culturally diverse youth ranging from 9 to 17 years old. RESULTS: Factor analyses and internal consistency results revealed the existence of multiple subscales measuring motivators of and barriers to each of the above-specified health-smart behaviors. Scores on the MB-HSBI Youth correlated in expected directions with health self-efficacy scores and with ratings of the importance of health-related behavioral goals. CONCLUSION: The MB HSBI-Youth may be a useful and novel tool for developing assessment-based, culturally sensitive health promotion programs customized to be responsive to the motivators of and barriers to health-smart behaviors identified in target communities, particularly those communities whose members are mostly racial/ethnic minorities. PMID- 22103551 TI - Comprehensive Trail Making Test performance in children and adolescents with traumatic brain injury. AB - The sensitivity of the Trail Making Test to brain damage has been well established over many years, making it one of the most commonly used tests in clinical neuropsychological evaluations. The current study examined the validity of scores from a newer version of the Trail Making Test, the Comprehensive Trail Making Test (CTMT), in children and adolescents with traumatic brain injury (TBI). Participants included 242 children and adolescents, 121 with sustained TBI and 121 normal control participants, who were matched to the individuals with TBI on age and sex. Receiver operating characteristic analysis indicated that the CTMT composite index provided the best overall classification, with a correct classification rate of 79%. Differences between the TBI and control groups remained stable across age. These findings indicate that the CTMT is sensitive to TBI and overall demonstrates classification rates that are comparable with some other versions of the Trail Making Test. Whether the CTMT will exhibit similar classification accuracy in adults with TBI and for other neurological disorders awaits further investigation. PMID- 22103552 TI - Factor structure of the primary scales of the Inventory of Personality Organization in a nonclinical sample using exploratory structural equation modeling. AB - Using exploratory structural equation modeling and multiple regression, we examined the factor structure and criterion relations of the primary scales of the Inventory of Personality Organization (IPO; Kernberg & Clarkin, 1995) in a nonclinical sample. Participants (N = 1,260) completed the IPO and measures of self-concept clarity, defenses, affect and emotion regulation, and risky and self injurious behavior. In contrast to that of Lenzenweger, Clarkin, Kernberg, and Foelsch (2001), a 4-factor measurement model was derived with factors representing instability of sense of self and other, instability of goals, instability of behaviors, and psychosis. The 1st of these factors related most strongly to external measures of self-concept clarity, defenses, and affect, whereas the 3rd factor related most strongly to measures of risky behavior and self-injury. These results suggest that the IPO's factor structure does not conform to the hypothesized 3-factor model, although it does capture important elements of Kernberg's (1996) theory of personality organization, especially the central construct of representations of self and others. The results point to several areas in which the IPO might be refined to provide a more comprehensive and theoretically appropriate measure of the borderline personality organization construct. PMID- 22103553 TI - Spontaneously resolved posterior rosette cataract after sulcus-fixed phakic lens implantation. PMID- 22103554 TI - Graphene nanoplatelets outperforming platinum as the electrocatalyst in co bipyridine-mediated dye-sensitized solar cells. AB - Graphene nanoplatelets (GNP) in the form of thin semitransparent films on F-doped SnO2 (FTO) exhibit high electrocatalytic activity for the Co(bpy)3(3+/2+) redox couple in acetonitrile electrolyte solution. The GNP film is superior to the traditional electrocatalyst, that is, platinum, both in charge-transfer resistance (exchange current) and in electrochemical stability under prolonged potential cycling. The good electrochemical performance of GNP is readily applicable for dye-sensitized solar cells with Y123-sensitized TiO2 photoanodes and Co(bpy)3(3+/2+) as the redox shuttle. The dye-sensitized solar cell with GNP cathode is superior to that with the Pt-FTO cathode particularly in fill factor and in power conversion efficiency at higher illumination intensity. PMID- 22103555 TI - Interferon-gamma inducible protein 10 as a biomarker for active tuberculosis and latent tuberculosis infection in children: a case-control study. AB - BACKGROUND: Interferon-gamma (IFN-gamma) release assays (IGRAs) are suboptimally sensitive to diagnose tuberculosis (TB) and latent TB infection (LTBI) in young children. In this study we compared Mycobacterium tuberculosis antigen-stimulated IFN-gamma inducible protein 10 (IP-10) responses in children with active TB and LTBI to responses from children with non-tuberculous mycobacterial (NTM) lymphadenopathy and respiratory tract infection (RTI). We also assessed test agreement between IP-10 and the QuantiFERON((r))-TB Gold In-Tube (QFT-IT) test results, and investigated whether IP-10 release upon mitogen stimulation is associated with age. METHODS: We recruited 48 children (median age 54 months) diagnosed in Germany with either active TB (n = 11), LTBI (n = 14), NTM lymphadenopathy (n = 8), or common RTI (n = 15). IFN-gamma levels were measured using the QFT-IT. These plasma supernatants were used to determine IP-10 concentrations using an in-house enzyme-linked immunosorbent assay (ELISA). RESULTS: The median antigen-stimulated IP-10 levels in children with active TB, LTBI, NTM lymphadenopathy, and RTI were 12,702 pg/ml, 9109 pg/ml, 97 pg/ml, and 84 pg/ml, respectively. We observed a strong correlation between IP-10 and IFN gamma plasma concentration in children with active TB and LTBI (r(2) = 0.69). Overall agreement between IP-10 and QFT-IT assays was high (kappa = 0.95). IP-10 levels after mitogen stimulation showed no association with age. CONCLUSIONS: IP 10 and IFN-gamma were both induced with antigen stimulation in blood from children in the TB and LTBI groups, in contrast to the NTM and RTI groups. Compared to IFN-gamma the IP-10 levels were higher and IP-10 was released independently of age. IP-10 therefore may represent an additional biomarker in the paediatric population. PMID- 22103556 TI - Enhancement of electrical conductivity by changing phase morphology for composites consisting of polylactide and poly(epsilon-caprolactone) filled with acid-oxidized multiwalled carbon nanotubes. AB - Composites consisting of polylactide (PLA) and poly(epsilon-caprolactone) (PCL) filled with acid-oxidized multiwalled carbon nanotubes (A-MWCNTs) were prepared through melt compounding. Phase morphologies of PLA/PCL/A-MWCNT composites with different contents of filled A-MWCNTs and PCL compositions were mainly observed by scanning electron microscope. The results show that A-MWCNTs are selectively dispersed in the PCL phase, regardingless of PCL phase domain sizes. For PLA/PCL/A-MWCNT composites with fixed PLA/PCL ratio of 95/5, the dispersed PCL phase domain sizes in the PLA matrix decrease even though a small content of A MWCNTs is added, compared with PLA/PCL blend with the same composition, indicating that A-MWCNTs effectively prevent from coalescence of the dispersed PCL phase domains. With filling of 1.0 wt % A-MWCNTs, an interesting change of electrical conductivity for PLA/PCL/A-MWCNT composites is observed, in which the maximum conductivity is observed for PLA/PCL/A-MWCNT composite with PLA/PCL ratio of 60/40. The result is well-explained by the formed cocontinuous phase morphology and effective A-MWCNT content. PMID- 22103557 TI - Developmentally programmed, RNA-directed genome rearrangement in Tetrahymena. AB - Developmentally programmed genome rearrangement has been observed in a variety of eukaryotes from vertebrates to worms to protists, and it provides an interesting exception to the general rule of the constancy of the genome. DNA elimination in the ciliated protozoan Tetrahymena is one of the most well-characterized programmed genome rearrangement events. DNA elimination in the newly formed macronucleus of Tetrahymena is epigenetically regulated by the DNA sequence of the parental macronucleus. Dicer-produced, Piwi-associated small RNAs mediate this epigenetic regulation, probably through a whole-genome comparison of the germline micronucleus to the somatic macronucleus. However, a correlation between small RNAs and programmed genome rearrangement could not be detected in the worm Ascaris suum. Therefore, different types of eukaryotes may have developed unique solutions to perform genome rearrangement. PMID- 22103558 TI - Interest in newborn genetic testing: a survey of prospective parents and the general public. AB - PURPOSE: Newborn screening (NBS) panels continue to expand, yet there are too few data on public attitudes toward testing in the newborn period to indicate whether there is support for such testing. We measured interest in newborn testing for several autosomal recessive disorders and reasons for interest. METHODS: A cross sectional, pen and paper survey was administered to the general public and prospective parents attending prenatal classes in Eastern Canada between April and December, 2010. RESULTS: A total of 648 individuals completed surveys. Interest in newborn testing for inherited hearing loss, vision loss, and neurological disorders was high (over 80% would have their newborn tested). The attitudes of prospective parents and students were positive, but somewhat less so than members of the general public. Across all disorders, interest in testing was driven by the desire to be prepared for the birth of a child with a genetic disorder. Significantly more people would use the information from testing for fatal neurological disorders in future reproductive decisions than the information generated by newborn testing for inherited hearing or vision loss. CONCLUSION: Interest is high in newborn testing for a variety of conditions, including those for which no effective treatment exists. Findings lend support to the expansion of NBS panels to include those disorders currently lacking treatment and highlight the value of including the views of diverse stakeholders, including prospective parents, in screening policies. PMID- 22103559 TI - Bone mass development in patients with Duchenne and Becker muscular dystrophies: a 4-year clinical follow-up. AB - AIM: To investigate the longitudinal development of bone mass in patients with Duchenne and Becker muscular dystrophies and to study the impact of muscle strength and motor function on bone mass in these patients. METHODS: Eighteen patients with Duchenne muscular dystrophy (2.3-19.7 years at baseline) and six patients with the milder Becker muscular dystrophy (10.8-18.9 years at baseline) were followed during a 4-year period with respect to areal bone mineral density (BMD), motor function and muscle strength. RESULTS: Greater bone mineral accretion was observed in the Becker patient group compared with the age-related Duchenne group above 10 years of age, and the older patients with Duchenne experienced decreased femoral neck BMD during the study period. In the study group, significant correlations were found between BMD in the lower extremities and muscle function parameters. CONCLUSIONS: The differences in BMD between patients with Duchenne and Becker as well as between different bone measurement sites demonstrated in the present study point out the importance of preserving muscle strength and motor function in patients with muscular dystrophy. Moreover; it highlights the value of performing region-specific analysis of the bone quality in these patients. PMID- 22103560 TI - Investigation of local mercury deposition from a coal-fired power plant using mercury isotopes. AB - Coal combustion accounts for approximately two-thirds of global anthropogenic mercury (Hg) emissions. Enhanced deposition of Hg can occur close to coal-fired utility boilers (CFUBs), but it is difficult to link specific point sources with local deposition. Measurement of Hg stable isotope ratios in precipitation holds promise as a tool to assist in the identification of local Hg deposition related to anthropogenic emissions. We collected daily event precipitation samples in close proximity to a large CFUB in Crystal River, Florida. Precipitation samples collected in Crystal River were isotopically distinct and displayed large negative delta(202)Hg values (mean = -2.560/00, 1 SD = 1.100/00, n = 28). In contrast, precipitation samples collected at other sites in FL that were not greatly impacted by local coal combustion were characterized by delta(202)Hg values close to 00/00 (mean = 0.070/00, 1 SD = 0.170/00, n = 13). These results indicate that, depending on factors such as powdered coal isotopic composition and efficiency of Hg removal from flue gas, Hg deposited near CFUBs can be isotopically distinct. As this tool is further refined through future studies, Hg stable isotopes may eventually be used to quantify local deposition of Hg emitted by large CFUBs. PMID- 22103561 TI - Intraoperative ventilation: incidence and risk factors for receiving large tidal volumes during general anesthesia. AB - BACKGROUND: There is a growing concern of the potential injurious role of ventilatory over-distention in patients without lung injury. No formal guidelines exist for intraoperative ventilation settings, but the use of tidal volumes (VT) under 10 mL/kg predicted body weight (PBW) has been recommended in healthy patients. We explored the incidence and risk factors for receiving large tidal volumes (VT > 10 mL/kg PBW). METHODS: We performed a cross-sectional analysis of our prospectively collected perioperative electronic database for current intraoperative ventilation practices and risk factors for receiving large tidal volumes (VT > 10 mL/kg PBW). We included all adults undergoing prolonged (>= 4 h) elective abdominal surgery and collected demographic, preoperative (comorbidities), intraoperative (i.e. ventilatory settings, fluid administration) and postoperative (outcomes) information. We compared patients receiving exhaled tidal volumes > 10 mL/kg PBW with those that received 8-10 or < 8 mL/kg PBW with univariate and logistic regression analyses. RESULTS: Ventilatory settings were non-uniform in the 429 adults included in the analysis. 17.5% of all patients received VT > 10 mL/kg PBW. 34.0% of all obese patients (body mass index, BMI, >= 30), 51% of all patients with a height < 165 cm, and 34.6% of all female patients received VT > 10 mL/kg PBW. CONCLUSIONS: Ventilation with VT > 10 mL/kg PBW is still common, although poor correlation with PBW suggests it may be unintentional. BMI >= 30, female gender and height < 165 cm may predispose to receive large tidal volumes during general anesthesia. Further awareness of patients' height and PBW is needed to improve intraoperative ventilation practices. The impact on clinical outcome needs confirmation. PMID- 22103562 TI - Natural and synthetic antioxidant additives for improving the performance of new biolubricant formulations. AB - Knowledge of the oxidative stability of vegetable oils for lubricant applications is a key point, because vegetable oil oxidation potential is the main disadvantage for its use as a lubricant. Oil degradation after an oxidation process can seriously affect its lubricating function and increase wear. In this work, two different methods for evaluating the oxidation stability of lubricating vegetable oils, the oxidation onset temperature, characterized through DSC measurements (ASTM E 2009-08), and the pressure drop in the oxygen pressure vessel (ASTM D 942-02), have been used. Additionally, thermogravimetric analysis and FTIR studies have also been carried out. High-oleic sunflower (HOSO) and castor (CO) oils were selected and blended with natural ((+)-alpha-tocopherol (TCP), propyl gallate (PG), l-ascorbic acid 6-palmitate (AP)) or synthetic antioxidants (4,4'-methylenebis(2,6-di-tert-butylphenol) (MBP)), with the aim of formulating biodegradable vegetable-based lubricants according to REACH regulation. (1) The results showed that the most effective biodegradable antioxidant is PG, comparable to MBP, whereas lower effectiveness was obtained for TCP and AP. In relation to the methods tested, DSC measurements achieve accurate data more quickly for evaluating the oxidation stability of these basestocks, showing a linear correlation with the traditional method based on the oxygen bomb test. The empirical equation obtained depends on the mechanism involved in the antioxidant activity. PMID- 22103563 TI - Copper-catalyzed intramolecular hydroalkoxylation of alpha-(1-hydroxy-1-alkyl- and -aryl)methylallenoates by a 5-endo mode for preparation of 2-alkyl- and 2 aryl-2,5-dihydrofurans. AB - Ethyl alpha-(1-hydroxy-1-alkyl)methylallenoates and alpha-(1-hydroxy-1 aryl)methylallenoates containing not only electron-donating groups but also an electron-withdrawing group on the aryl group at the alpha-position have been shown to undergo an efficient and selective copper-catalyzed intramolecular hydroalkoxylation to give functionalized 3-ethoxycarbonyl-2-alkyl- and -aryl-2,5 dihydrofurans in good to excellent yields through a 5-endo mode. PMID- 22103564 TI - Survival and regeneration of deep-freeze preserved autologous cranial bones after cranioplasty. AB - BACKGROUND: After decompressive craniectomy, a deep-freeze-preserved autologous cranial bone graft can be used for cranioplasty to avoid immunoreaction against an artificial patch material. Autologous cranial bone grafts not only have better physical properties, such as heat conduction, compared to artificial patch materials, but they also have the advantages of a lower medical cost and satisfactory physical flexibility. The discussion over (99)Tc(m)-MDP SPECT static cranial bone tomography in the diagnosis of survival and regeneration in deep freeze preservation autologous cranial bones after cranioplasty is valuable. Objective. To investigate whether deep-freeze-preserved autologous cranial bone grafts could survive and regenerate after autologous reimplantation. METHODS: The method of cranial bone preservation involved removing the cranial graft and sealing it in a double-layer sterile plastic bag under sterile surgical conditions. On the day of the cranioplasty operation, the cranial bone graft was disinfected by immersing it in 3% povidone-iodine for 30 minutes. At short-term (2 weeks), medium-term (3 months), and long-term (12 months) postoperative follow up visits, (99)Tc(m)-MDP SPECT static cranial bone tomography was used to examine the reimplanted cranial bone. Results. There were no postoperative infections or seromas in all 16 cases. Two weeks following cranial bone graft reimplantation, the SPECT tomography showed some radioactivity uptake in the reimplanted cranial bone graft, which was lower than that in the cranial bone on the healthy side. At 3 months and 12 months after the operation, the radioactivity uptake in the reimplanted cranial bone graft was the same as that in the cranial bone on the healthy side. X-ray films showed blurred sutures in the reimplanted cranial bone graft at 12 months after surgery. CONCLUSION: Reimplanted deep-freeze-preserved autologous cranial bone can survive in the short term and regenerate in the medium and long terms. PMID- 22103565 TI - Operative outcomes and adjuvant treatment of purely third ventricle craniopharyngioma after a transcallosal approach. AB - We reviewed four surgical cases of purely third ventricle craniopharyngioma, focusing on surgical outcomes and adjuvant treatments. From 2002 to 2008, we performed surgical treatments, via a transcallosal transforaminal approach, on four patients. All were males, with a median age of 42 (36-45) years. Most patients complained of headaches, while two (50%) patients presented with visual disturbances, and one (25%) presented with an endocrinological disturbance. Patients' follow-up periods ranged from 1.6 to 8.6 years. We totally removed the tumor in each of the four patients. The tumors originated in the infundibulum of the third ventricular floor. The pituitary stalk was anatomically preserved. The histopathological findings showed the adamantinomatous type of craniopharyngioma in all patients. Postoperatively, two patients who had experienced visual disturbances showed improvement, and there was no aggravation. Two patients had intact pituitary functioning, while two needed complete hormone replacement. The patients experienced no surgery-related complications. Two patients experienced recurrences 4.5 and 1.6 years later. One patient received gamma knife surgery for the recurred lesion, which controlled the lesion well. Purely third ventricle craniopharyngioma showed good visual and endocrinological outcomes after surgery. Gamma knife surgery could be of help in the event of a recurred lesion. PMID- 22103566 TI - Study of effectiveness of mifepristone for glioma cell line growth suppression. AB - OBJECTIVE: Glioblastoma multiforme is a malignant primary brain tumour with very limited treatment options. Any addition to existing treatment options which can improve prognosis and life expectancy is useful. In our study, we look at the usefulness of anti-progestogen mifepristone in causing growth suppression of glioma cell lines in the laboratory. METHODS: We cultured five cell lines in the lab and exposed them to mifepristone in different doses for a total of 96 h. Five different doses of mifepristone were used. Progesterone and dexamethasone were also used as growth stimulants. Immunostaining was used to identify progesterone receptors (PRs) in the cell lines. RESULTS: U257/7 and IN1265 showed statistically significant growth suppression (36% and 11%, P = 0.001 and 0.03 respectively), maximal at 96 h. Growth suppression in U257/7 showed a dose response progression except with the lowest dose which was not explicable. The response of IN1265 was seen only with the highest dose of mifepristone. There was no significant growth stimulation with either dexamethasone or progesterone. None of the cell lines showed any significant positivity for PRs. CONCLUSION: We were able to produce enough growth suppression of glioma cell lines using mifepristone. This is in keeping with some of the published results in literature. This raises the possibility of using mifepristone in treating GBMs which have very limited treatment options. This, however, needs further work probably on primary glioma cultures first followed by in vivo studies before it can be used in patients. PMID- 22103567 TI - Double reduction of plastoquinone to plastoquinol in photosystem 1. AB - In Photosystem 1 (PS1), phylloquinone (PhQ) acts as a secondary electron acceptor from chlorophyll ec(3) and also as an electron donor to the iron-sulfur cluster F(X). PS1 possesses two virtually equivalent branches of electron transfer (ET) cofactors from P(700) to F(X), and the lifetime of the semiquinone intermediate displays biphasic kinetics, reflecting ET along the two different branches. PhQ in PS1 serves only as an intermediate in ET and is not normally fully reduced to the quinol form. This is in contrast to PS2, in which plastoquinone (PQ) is doubly reduced to plastoquinol (PQH(2)) as the terminal electron acceptor. We purified PS1 particles from the menD1 mutant of Chlamydomonas reinhardtii that cannot synthesize PhQ, resulting in replacement of PhQ by PQ in the quinone binding pocket. The magnitude of the stable flash-induced P(700)(+) signal of menD1 PS1, but not wild-type PS1, decreased during a train of laser flashes, as it was replaced by a ~30 ns back-reaction from the preceding radical pair (P(700)(+)A(0)(-)). We show that this process of photoinactivation is due to double reduction of PQ in the menD1 PS1 and have characterized the process. It is accelerated at lower pH, consistent with a rate-limiting protonation step. Moreover, a point mutation (PsaA-L722T) in the PhQ(A) site that accelerates ET to F(X) ~2-fold, likely by weakening the sole H-bond to PhQ(A), also accelerates the photoinactivation process. The addition of exogenous PhQ can restore activity to photoinactivated PS1 and confer resistance to further photoinactivation. This process also occurs with PS1 purified from the menB PhQ biosynthesis mutant of Synechocystis PCC 6803, demonstrating that it is a general phenomenon in both prokaryotic and eukaryotic PS1. PMID- 22103568 TI - Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements. AB - Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non-invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long-term effect of successful antiviral treatment, using LSM, in HCV infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P-value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P-value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment. PMID- 22103569 TI - Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs. AB - OBJECTIVE: To determine the effect of maropitant, an NK-1 receptor antagonist on the minimum alveolar concentration (MAC) of sevoflurane after intravenous and epidural administration to dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Seven, adult, spayed-female dogs (24.8 +/- 1.9 kg). METHODS: Each dog was anesthetized twice with sevoflurane in oxygen, with at least 10 days separating the anesthetic events. The minimum alveolar concentration (MAC) of sevoflurane was determined using the tail-clamp technique. During the first anesthetic event, the MAC of sevoflurane was determined initially and again after intravenous administration of maropitant (5 mg kg(-1)) and an infusion (150 MUg kg(-1) hour(-1)). During the second anesthetic event, an epidural catheter was advanced to the 4th lumbar vertebra and MAC was determined after administration of saline and maropitant (1 mg kg(-1)) epidurally. All MAC determinations were done in duplicate. The MAC values were adjusted to sea level and compared using student's t-test. RESULTS: The baseline MAC for sevoflurane was 2.08 +/- 0.25%. Intravenous maropitant decreased (p < 0.05) MAC by 16% (1.74 +/- 0.17%). In contrast, epidural administration of either saline or maropitant did not change (p > 0.05) the MAC (2.17 +/- 0.34% and 1.92 +/- 0.12%, respectively). CONCLUSION AND CLINICAL RELEVANCE: Maropitant decreased the MAC of sevoflurane when administered intravenously to dogs but not after epidural administration. PMID- 22103570 TI - Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany. AB - OBJECTIVES: Capillary electrophoresis mass spectrometry urinary proteome analysis for prostate cancer has been shown to be highly accurate in the detection of prostate cancer. The aim of the present study was to report our experience with routine application of this test in clinical practice and its cost-effectiveness. METHODS: The urinary proteome analysis for prostate cancer test was carried out in 211 patients in outpatient centers. In 184 of them, data about their follow up and the test results were available for analysis. Prostate cancer was detected in 49 cases. RESULTS: The test correctly recognized 42 out of 49 tumor patients, showing a sensitivity of 86% (95% confidence interval 73-94). Of 135 prostate cancer-negative patients, 79 had a negative urinary proteome analysis for prostate cancer test (specificity 59% [79/135 95% confidence interval 50-66]). Negative and positive predictive values were 92% (95% confidence interval 84-96) and 43% (95% confidence interval 33-53), respectively. A statistically significant (P<0.0005) improvement in terms of diagnostic accuracy was observed in comparison with serum prostate-specific antigen and percent-free prostate specific antigen. Whereas the urinary proteome analysis for prostate cancer test results agreed in 65.7% with follow-up reference results, prostate-specific antigen achieved 33.3% and percent-free prostate-specific antigen achieved 42.7%. Cost-effectiveness analysis showed that the urinary proteome analysis for prostate cancer strategy outperformed the biopsy approach as well as prostate specific antigen tests. CONCLUSIONS: The non-invasive urinary proteome analysis for prostate cancer test appears to be a helpful addition to prostate cancer diagnostics for patients with suspicious prostate-specific antigen and/or digital rectal examination. PMID- 22103571 TI - Sevoflurane vs. propofol in patients with coronary disease undergoing mitral surgery: a randomised study. AB - BACKGROUND: Myocardial ischemic damage is reduced by volatile anaesthetics in patients undergoing low-risk coronary artery bypass graft surgery; few and discordant results exist in other settings. We therefore performed a randomised controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery. METHODS: Patients with coronary artery disease undergoing mitral surgery were randomly allocated to receive either sevoflurane (50 patients) or propofol (50 patients) as main hypnotic. The primary endpoint of the study was peak post-operative cardiac troponin release defined as the maximum value among the post-operative values measured at intensive care unit arrival, 4 h later, on the first and second post operative day. RESULTS: There was no significant difference in post-operative peak troponin release, the median (25th-75th percentiles) values being 14.9 (10.1 22.1) ng/ml and 14.5 (8.8-17.6) ng/ml in the sevoflurane and propofol groups, respectively (P = 0.4). Fentanyl administration was different between the two groups: 1347 +/- 447 MUg in patients receiving sevoflurane and 1670 +/- 469 MUg in those receiving propofol, P = 0.002. The 1-year follow-up identified two patients who died in the propofol group (one myocardial infarction and one low cardiac output syndrome) and one in the sevoflurane group (myocardial infarction). CONCLUSION: In this study, patients with coronary artery disease undergoing mitral surgery did not benefit from the cardioprotective properties of halogenated anaesthetics. Sevoflurane anaesthesia was not associated to lower cardiac troponin release when compared with propofol anaesthesia. PMID- 22103572 TI - Q-switched ruby laser therapy and long-term follow-up evaluation of small to medium-sized congenital melanocytic naevi. PMID- 22103573 TI - Expression of autotaxin and acylglycerol kinase in proliferative vitreoretinal epiretinal membranes. AB - PURPOSE: Lysophosphatidic acid (LPA)/LPA(1) receptor pathway is involved in inflammation, angiogenesis and fibrosis. This study was conducted to analyse the expression of LPA-producing enzymes, autotaxin (ATX) and acylglycerol kinase (AGK) and LPA(1) receptor, in proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR) epiretinal membranes. METHODS: Nine active and 13 inactive membranes from patients with PDR and 21 membranes from patients with PVR were studied by immunohistochemistry. RESULTS: In PDR membranes, vascular endothelial cells expressed ATX and AGK in 16 and 19 membranes, respectively. Stromal cells expressed ATX and AGK in 19 and 22 membranes, respectively. Immunoreactivity for LPA(1) receptor was noted in vascular endothelial cells and stromal cells in the five membranes stained for LPA(1) receptor. Numbers of blood vessels and stromal cells expressing CD34, ATX and AGK were significantly higher in active membranes than in inactive membranes. Significant correlations were detected between number of blood vessels expressing the panendothelial cell marker CD34 and number of blood vessels and stromal cells expressing ATX and AGK. In PVR membranes, spindle-shaped myofibroblasts expressing alpha-smooth muscle actin co-expressed ATX, AGK and LPA(1) receptor. CONCLUSIONS: The LPA/LPA(1) receptor pathway may be involved in inflammatory, angiogenic and fibrotic responses in proliferative vitreoretinal disorders. PMID- 22103574 TI - Biocompatible magnetite/gold nanohybrid contrast agents via green chemistry for MRI and CT bioimaging. AB - Magnetite/gold (Fe(3)O(4)/Au) hybrid nanoparticles were synthesized from a single iron precursor (ferric chloride) through a green chemistry route using grape seed proanthocyanidin as the reducing agent. Structural and physicochemical characterization proved the nanohybrid to be crystalline, with spherical morphology and size ~35 nm. Magnetic resonance imaging and magnetization studies revealed that the Fe(3)O(4) component of the hybrid provided superparamagnetism, with dark T(2) contrast and high relaxivity (124.2 +/- 3.02 mM(-1) s(-1)). Phantom computed tomographic imaging demonstrated good X-ray contrast, which can be attributed to the presence of the nanogold component in the hybrid. Considering the potential application of this bimodal nanoconstruct for stem cell tracking and imaging, we have conducted compatibility studies on human Mesenchymal Stem Cells (hMSCs), wherein cell viability, apoptosis, and intracellular reactive oxygen species (ROS) generation due to the particle-cell interaction were asessed. It was noted that the material showed good biocompatibility even for high concentrations of 500 MUg/mL and up to 48 h incubation, with no apoptotic signals or ROS generation. Cellular uptake of the nanomaterial was visualized using confocal microscopy and prussian blue staining. The presence of the nanohybrids were clearly visualized in the intracytoplasmic region of the cell, which is desirable for efficient imaging of stem cells in addition to the cytocompatible nature of the hybrids. Our work is a good demonstrative example of the use of green aqueous chemistry through the employment of phytochemicals for the room temperature synthesis of complex hybrid nanomaterials with multimodal functionalities. PMID- 22103575 TI - Production of heterologous IgG antibody against Heymann nephritis antigen by injections of immune complexes. AB - Heterologous IgG antibody (ab) can be produced against Heymann nephritis (HN) antigen (ag) in rabbits by administering it in Freund's complete adjuvant. The developing abs reacted at high titre with rat kidney brush border (BB) regions of the renal proximal tubules in an indirect fluorescence ab test. A single IV injection of the heterologous ab into a susceptible strain of rat resulted in the localization of IgG ab to glomerular fixed ags, producing immune complex glomerular nephritis. The injected ab also reacted with the BB region of the renal proximal tubules. The aim of this experiment was to find out whether heterologous IgG ab against the HN ag can also be produced in recipient rabbits by injecting immune complexes (ICs) composed of a rat kidney tubular preparation [rat kidney fraction 3 (rKF3)] and donor rabbit-derived rabbit anti-rKF3 IgG ab. We found that anti-rKF3 IgG ab--against the BB region of the renal proximal tubules--could be induced in rabbits injected with ICs, and the resulting ab was able to initiate passive HN in rats. This was the first time a pathogenic IgG ab was produced against HN ag in rabbits without the use of adjuvant. Ab responses in recipient rabbits were achieved by ab information transfer. Recipient rabbits injected with the IC produced the same class of immunoglobulin with the same specificity against the target ag rKF3, as was present in the innoculum, namely rabbit anti-rKF3 IgG ab. PMID- 22103576 TI - Protective effects of kaerophyllin against liver fibrogenesis in rats. AB - BACKGROUND: We previously demonstrated that kaerophyllin, a lignan, isolated from a widely used traditional Chinese herb, Bupleurum scorzonerifolium, leading to the inhibition of hepatic stellate cells (HSCs) activation in vitro. This current study evaluated the in vivo role of kaerophyllin in protecting the liver against injury and fibrogenesis caused by thioacetamide (TAA) in rats and further explored the underlying mechanisms. MATERIALS AND METHODS: Liver fibrosis in Sprague-Dawley rats was induced by intraperitoneal injection of TAA (200 mg/kg) twice per week for 6 weeks. Animals were divided into five groups: vehicle control, TAA control, TAA + low dose kaerophyllin, TAA + high dose kaerophyllin and TAA + curcumin groups. Kaerophyllin (10 or 30 mg/kg) or curcumin (150 mg/mL) was given by gavage twice per day consecutively for 4 weeks starting 2 weeks after TAA injection. Rat HSCs were used to investigate the anti-inflammatory role of kaerophyllin against tumour necrosis factor alpha (TNF-alpha) in vitro. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression was knocked down in rat HSCs using PPAR-gamma small interfering RNAs. RESULTS: Kaerophyllin significantly protected liver from injury by reducing serum aspartate transaminase and alanine transaminase levels and by improving the histological architecture and fibrosis score. In addition, kaerophyllin suppressed inflammation by reducing the mRNA of TNF-alpha, interleukin-1beta (IL 1beta) and monocyte chemoattractant protein-1 (MCP-1) genes. In HSCs, kaerophyllin elevated PPAR-gamma activity and reduced TNF-alpha-stimulated mRNA levels of intracellular adhesion molecule-1 (ICAM-1), MCP-1 and IL-1beta genes, which were reversed by small interfering RNA knockdown of PPAR-gamma gene. CONCLUSIONS: Our results demonstrated that kaerophyllin protected the rat liver from TAA-caused injury and fibrogenesis by suppressing hepatic inflammation and inhibiting HSC activation, possibly through upregulation of PPAR-gamma expression. PMID- 22103577 TI - Stability and change in the first 10 years of marriage: does commitment confer benefits beyond the effects of satisfaction? AB - Although commitment is theoretically distinct from relationship satisfaction, empirical associations between the concepts are high. After drawing from classic definitions of commitment to distinguish between commitment as the desire for a relationship to persist versus the behavioral inclination to maintain the relationship, we predicted that the former component would function much like satisfaction, whereas the latter component would operate independently of satisfaction to stabilize couple relationships. Using satisfaction and commitment data collected over the first 4 years of marriage (N = 172 couples), we demonstrate that only behavioral inclinations to maintain the marriage are related to observed marital interaction behaviors, to reported steps taken toward dissolution, and to 11-year divorce rates, independent of satisfaction. Consistent with dyadic "weak-link"' conceptions of commitment, likelihood of divorce was found to increase as a function of the lower of the 2 partners' inclination to maintain the relationship. Commitment may stabilize declining intimate partnerships, particularly when it is conceptualized as the inclination to maintain the relationship. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22103578 TI - Threat and defense as goal regulation: from implicit goal conflict to anxious uncertainty, reactive approach motivation, and ideological extremism. AB - Four studies investigated a goal regulation view of anxious uncertainty threat (Gray & McNaughton, 2000) and ideological defense. Participants (N = 444) were randomly assigned to have achievement or relationship goals implicitly primed. The implicit goal primes were followed by randomly assigned achievement or relationship threats that have reliably caused generalized, reactive approach motivation and ideological defense in past research. The threats caused anxious uncertainty (Study 1), reactive approach motivation (Studies 2 and 3), and reactive ideological conviction (Study 4) only when threat-relevant goals had first been primed, but not when threat-irrelevant goals had first been primed. Reactive ideological conviction (Study 4) was eliminated if participants were given an opportunity to attribute their anxiety to a mundane source. Results support a goal regulation view of anxious uncertainty, threat, and defense with potential for integrating theories of defensive compensation. PMID- 22103579 TI - On the psychology of time in action: regulatory mode orientations and procrastination. AB - Six studies explored the relations of the regulatory modes of locomotion and assessment to individuals' tendency toward procrastination. Across academic and organizational contexts, and a variety of ways of assessing procrastination, the authors found assessment to be positively related to procrastination and locomotion to be negatively related to procrastination. Discussion considered implications of these findings to task environments that may instill the tendencies toward locomotion or assessment and to task requirements where timeliness and punctuality are (or are not) prioritized. PMID- 22103580 TI - Association of angiotensin converting enzyme (insertion/deletion) gene polymorphism with essential hypertension in northern Indian subjects. AB - OBJECTIVE: Essential hypertension is a multifactorial disease in which genetic and environmental factors play an important role. The renin-angiotensin system (RAS) is known to play a critical role in the homeostasis of blood pressure. Angiotensin-I converting enzyme (ACE) is a significant component of RAS, and an insertion/deletion (I/D) polymorphism in its gene has been implicated in predisposition to hypertension. The purpose of the current study is to investigate the association of I/D polymorphism of the ACE gene with essential hypertension in northern Indians. METHOD: Two hundred twenty-two patients with essential hypertension and 252 controls were recruited for the study. DNA samples were isolated from peripheral blood by using a kit. Polymerase chain reaction was used for genotyping. RESULT: All the genotypes and allele distribution in study subjects were in the Hardy-Weinberg equilibrium. There was a significant difference in the distribution of DD, II, and ID genotypes of ACE polymorphism in patients and controls. In the subjects having an I allele, the odds ratio is 2.08 [1.6-2.58] at 95% confidence interval, thus suggesting an association of ACE I/D gene polymorphism with essential hypertension. CONCLUSION: Our findings suggest that the I allele of ACE I/D polymorphism is associated with essential hypertension in our population. PMID- 22103581 TI - Highly efficient synthesis of graphene nanocomposites. AB - Graphene consists of a monolayer of sp(2) bonded carbon atoms and has attracted considerable interest over recent years due to its extreme mechanical, electrical, and thermal properties. Graphene nanocomposites have naturally begun to be studied to capitalize upon these properties. A range of complex chemical and physical processing methods have been devised that achieve isolated graphene sheets that attempt to prevent aggregation. Here we demonstrate that the simple casting of a polymer solution containing dispersed graphene oxide, followed by thermal reduction, can produce well-isolated monolayer reduced-graphene oxide. The presence of single layer reduced-graphene oxide is quantitatively demonstrated through transmission electron microscopy and selected area electron diffraction studies and the reduction is verified by thermogravimetric, X-ray photoelectron spectroscopy, infrared spectrum, and electrical conductivity studies. These findings provide a simple, environmentally benign and commercially viable process to produce reduced-graphene oxide reinforced polymers without complex manufacturing, dispersion or reduction processes. PMID- 22103582 TI - Distribution and air-sea exchange of current-use pesticides (CUPs) from East Asia to the high Arctic Ocean. AB - Surface seawater and marine boundary layer air samples were collected on the ice breaker R/V Xuelong (Snow Dragon) from the East China Sea to the high Arctic (33.23-84.5 degrees N) in July to September 2010 and have been analyzed for six current-use pesticides (CUPs): trifluralin, endosulfan, chlorothalonil, chlorpyrifos, dacthal, and dicofol. In all oceanic air samples, the six CUPs were detected, showing highest level (>100 pg/m(3)) in the Sea of Japan. Gaseous CUPs basically decreased from East Asia (between 36.6 and 45.1 degrees N) toward Bering and Chukchi Seas. The dissolved CUPs in ocean water ranged widely from 59). At screening, 88% of subjects reported current butalbital use; 68% had used butalbital for more than 6 weeks; and 82% reported satisfaction with butalbital. Across treatment groups, 28-29% of subjects took study medication within 15 minutes of migraine onset, 34-37% of subjects took study medication >15 minutes to 2 hours after onset, and 32-36% of subjects took study medication more than 2 hours after onset. This study did not detect a difference at the nominal 0.05 level in percent sustained pain-free between SumaRT/Nap (8%), BCM (6%), and placebo (3%). SumaRT/Nap was superior to BCM for pain free at 2, 4, 6, 8, 24, 48 hours (P<=.044); pain relief (mild or no pain) at 2, 4, 6, 8, 24, 48 hours (P<=.01); sustained pain relief 2-24 hours (P<.001); migraine free (pain free with no nausea, photophobia, or phonophobia) at 4, 6, 8, 24, 48 hours (P<=.046); and complete symptom free (migraine free with no neck/sinus pain) at 4, 6, 8, 48 hours (P<=.031). Adverse event incidence was similar for all treatments (10%, 12%, and 9% for placebo, SumaRT/Nap, and BCM, respectively). Nausea was the most frequent adverse event (2%, 2%, and <1% for placebo, SumaRT/Nap, and BCM, respectively). Five serious adverse events were reported by 3 subjects: viral meningitis and colon neoplasm (placebo); chest pain and hypertension 17 days postdose (SumaRT/Nap); and breast cancer (BCM). Investigators judged no serious adverse events related to study medication. CONCLUSIONS: This study primarily included subjects whose migraines significantly impacted their lives. Before the study, these subjects used butalbital-containing medications as part of their current migraine treatment regimen and were satisfied with it, suggesting they were butalbital responders who had found a workable treatment strategy for themselves. When treated with SumaRT/Nap versus BCM in this study, however, a significant proportion of subjects reported better treatment outcomes for themselves for both migraine pain and associated symptoms. Use of SumaRT/Nap was also associated with less rescue medication use and a longer time before use of rescue medication compared with both BCM and placebo. PMID- 22103636 TI - Participants' perceptions of research benefits in an African genetic epidemiology study. AB - BACKGROUND: Both the Council for International Organization of Medical Sciences and the Helsinki Declaration emphasize that the potential benefits of research should outweigh potential harms; consequently, some work has been conducted on participants' perception of benefits in therapeutic research. However, there appears to be very little work conducted with participants who have joined non therapeutic research. This work was done to evaluate participants' perception of benefits in a genetic epidemiological study by examining their perception of the potential benefits of enrollment. METHODS: In-depth interviews lasting between 45 and 60 minutes were conducted with a convenient sample of 25 ill patients and 25 healthy accompanying relatives enrolled in a genetic epidemiological study of tuberculosis. Recorded interviews were transcribed and analyzed using content analysis. RESULTS: Participants perceived that research was beneficial and some of the benefits included the generation of new knowledge, finding the cause of diseases, as well as the control, eradication and prevention of disease. Some thought that research was risky whilst others thought that the benefits outweighed the risks. CONCLUSION: Participants perceived research to be beneficial and most of them thought that, though it was risky, the benefits outweighed the risks. It is our view that researchers need to give serious consideration to participant's perception of benefits in designing their consent forms, to see to the fulfillment of achievable goals. PMID- 22103637 TI - Gender context of personalism in bioethics. AB - Personalism is one of the philosophical perspectives which hold that the reality in person and the human person has the highest intrinsic value. This paper makes reference to Louis Janssens' eight criteria in adequate consideration of the human person but further argues that there is need to consider people as situated agents especially within gender relational perspectives. The paper identifies gender as an important social construction that shapes the consideration of the human persons within socio-spatial spheres. The main crux of the paper is that there is a gender context of personalism and this has profound implications for bioethical agendas. Gender is part of the human condition, especially when we philosophically or sociologically engage the notion of equity and equality within the social system, because social realities in the relational perspective are not impartial, impersonal and equal. Gender does not determine morality but it plays a role in morality and expectations from moral agents. Women have been categorised as a sociological group because their integrity, freedom/autonomy and dignity (which are basic concerns of bioethics) are capable of being threatened. A gender perspective provides important incentives for moral theory which searches for possible conceptual imbalances or blind spots in ethical reflections. The paper refers to Sen's faces of gender inequality and expands on the notion that natality inequality is one of the fundamental levels of gender inequality, which in turn is the primary starting agenda in bioethics. The paper avers that the recognition of the fundamental importance of gender to the organization of social reality and the development of personal identities have important practical implications for bioethics. PMID- 22103638 TI - On euthanasia: exploring psychological meaning and attitudes in a sample of Mexican physicians and medical students. AB - Euthanasia has become the subject of ethical and political debate in many countries including Mexico. Since many physicians are deeply concerned about euthanasia, due to their crucial participation in its decision and implementation, it is important to know the psychological meaning that the term 'euthanasia' has for them, as well as their attitudes toward this practice. This study explores psychological meaning and attitudes toward euthanasia in 546 Mexican subjects, either medical students or physicians, who were divided into three groups: a) beginning students, b) advanced students, and c) physicians. We used the semantic networks technique, which analyzed the words the participants associated with the term 'euthanasia'. Positive psychological meaning, as well as positive attitudes, prevailed among advanced students and physicians when defining euthanasia, whereas both positive and negative psychological meaning together with more ambivalent attitudes toward euthanasia predominated in beginning students. The findings are discussed in the context of a current debate on a bill proposing active euthanasia in Mexico City. PMID- 22103639 TI - Guidelines for international service learning programs. PMID- 22103642 TI - HIV/AIDS--30 years later. PMID- 22103643 TI - Expanding the social communication model of pain: are adult attachment characteristics associated with observers' pain-related evaluations? AB - OBJECTIVE: Evaluations of another's pain can have important implications in medical, employment, and social settings. Influenced by the Social Communication Model of Pain, this vignette-based study investigated the potential influence of characteristics of the person being evaluated (viz., the coping strategy used by an individual with chronic pain depicted in a vignette) and characteristics of those making evaluations (viz., self-reported attachment anxiety and avoidance of the study participants). The main hypothesis was that participants higher in attachment avoidance would be more critical in their evaluations than those lower in attachment avoidance. METHOD: Undergraduate students (N = 267) read 1 of 2 vignettes about an individual experiencing chronic pain, provided ratings of this individual, and completed a measure of adult attachment. The vignettes varied in terms of the pain-related coping strategy (catastrophizing vs. distraction) described. RESULTS: Similar to past research, the catastrophizing vignette received more negative ratings than the distraction vignette (e.g., greater disability level), and female participants provided more positive ratings than male participants (e.g., greater deservingness of support). While the attachment variables were unrelated to some dependent variables, consistent with the main hypothesis, attachment avoidance was associated with lower ratings of perceived deservingness of support and desirability as a friend. CONCLUSIONS: The current findings suggest that chronic pain patients' coping styles influence evaluations made about them, and that evaluators' gender and attachment characteristics also have important effects on such evaluations. PMID- 22103644 TI - Highly parallel single-molecule amplification approach based on agarose droplet polymerase chain reaction for efficient and cost-effective aptamer selection. AB - We have developed a novel method for efficiently screening affinity ligands (aptamers) from a complex single-stranded DNA (ssDNA) library by employing single molecule emulsion polymerase chain reaction (PCR) based on the agarose droplet microfluidic technology. In a typical systematic evolution of ligands by exponential enrichment (SELEX) process, the enriched library is sequenced first, and tens to hundreds of aptamer candidates are analyzed via a bioinformatic approach. Possible candidates are then chemically synthesized, and their binding affinities are measured individually. Such a process is time-consuming, labor intensive, inefficient, and expensive. To address these problems, we have developed a highly efficient single-molecule approach for aptamer screening using our agarose droplet microfluidic technology. Statistically diluted ssDNA of the pre-enriched library evolved through conventional SELEX against cancer biomarker Shp2 protein was encapsulated into individual uniform agarose droplets for droplet PCR to generate clonal agarose beads. The binding capacity of amplified ssDNA from each clonal bead was then screened via high-throughput fluorescence cytometry. DNA clones with high binding capacity and low K(d) were chosen as the aptamer and can be directly used for downstream biomedical applications. We have identified an ssDNA aptamer that selectively recognizes Shp2 with a K(d) of 24.9 nM. Compared to a conventional sequencing-chemical synthesis-screening work flow, our approach avoids large-scale DNA sequencing and expensive, time-consuming DNA synthesis of large populations of DNA candidates. The agarose droplet microfluidic approach is thus highly efficient and cost-effective for molecular evolution approaches and will find wide application in molecular evolution technologies, including mRNA display, phage display, and so on. PMID- 22103645 TI - Inflammatory aneurysms of the ascending aorta: diagnosis and surgical treatment. AB - Inflammatory aortic aneurysms (IAAs) are rare and located mainly in the infra renal abdominal aorta. The ascending aorta has been typically spared from this process. We report on two cases of ascending aortic inflammatory aneurysms and describe the available literature on this rare entity. PMID- 22103646 TI - Electric impedance tomography for monitoring volume and size of the urinary bladder. AB - A novel non-invasive technique for monitoring fluid content in the human bladder is described. Specifically, a precommercial electric impedance tomograph (EIT) was applied to measure and visualize impedance changes in the lower torso due to changes in bladder volume. Preliminary measurements were conducted during routine urodynamic tests of nine male paraplegic patients, in whom a contrast agent was slowly infused into the bladder for diagnostic purposes. In some patients, a good correlation between bladder volume and EIT measurements was found, whereas in others the correlation was still good but inverted, presumably due to a poor electrode positioning. These preliminary results indicate that a sufficiently accurate finite element modeling of the impedance distribution in the abdomen, and proper electrode positioning aids, are important prerequisites to enable this technology to be used for routine measurement of bladder volume. PMID- 22103647 TI - Psychophysiological classification and staging of mental states during meditative practice. AB - The study of meditation offers a perfect setting for the study of a large variety of states of consciousness. Here, we present a classification paradigm that can be used for staging of individual meditation sessions into a variety of predefined mental states. We have measured 64 channels of the electroencephalogram (EEG) plus peripheral physiological measures in 49 participants with varying experiences in meditation practice. The data recorded in a meditation session of seven meditative tasks were analyzed with respect to EEG power spectral density measures plus peripheral measures. A multiclass linear discriminant analysis classifier was trained for classification of data epochs of the seven standard tasks. The classification results were verified using random partitions of the data. As an overall result, about 83% (+/-7%) of the epochs could be correctly classified to their originating task. The best classification method was then applied to individual meditation sessions, which allowed for staging of meditation states similarly to the staging possibility of sleep states. This study exemplarily demonstrates the possibility of developing an automatized staging tool that can be used for monitoring changes in the states of consciousness offline or online for training or therapeutic purpose. PMID- 22103648 TI - Improving local PCA in pseudo phase space for fetal heart rate estimation from single lead abdominal ECG. AB - This paper proposes an improved local principal component analysis (LPCA) in pseudo phase space for fetal heart rate estimation from a single lead abdominal ECG signal. The improved LPCA process can extract both the maternal ECG component and the fetal ECG component in an abdominal signal. The instantaneous fetal heart rate can then be estimated from the extracted fetal ECG waveform. Compared with the classical LPCA procedure and another single lead based fetal heart rate estimation method, our improved LPCA method has shown better robustness and efficiency in fetal heart estimation, testing with synthetic ECG signals and a real fetal ECG database from PhysioBank. For the real fetal ECG validating dataset of six long-duration recordings (obtained between the 22(nd) and 40(th) week of gestation), the average accuracy of the improved LPCA method is 84.1%. PMID- 22103649 TI - Bone loss of immediately loaded implants with implant-supported and tooth-implant supported fixed maxillary prostheses. AB - This 2-year study investigates the survival and crestal bone loss of immediately loaded implants used to support complete-arch implant-supported prostheses (ISPs) or tooth-implant-supported fixed prostheses (TISPs) in the maxilla. Six patients with 52 implants for the support of ISPs and seven patients with 22 implants and 24 abutment teeth for the support of TISPs were included. All implants were immediately loaded. The survival of the supporting implants and teeth was evaluated for up to 6 months after immediate loading. Bone loss around the implants was measured using panoramic radiographs. After the first year, TISPs showed less bone resorption (-0.04 mm from the reference level) than did ISPs ( 0.1 mm), while no difference was observed after the second year. Considering the number of pontics used for the prostheses, no significant difference was observed between ISPs and TISPs after both 1 and 2 years. Immediate loading could be a protocol of choice for both maxillary ISPs and TISPs. PMID- 22103650 TI - Pedicle-screw-based dynamic implants may increase posterior intervertebral disc bulging during flexion. AB - Abstract Posterior disc bulging may lead to nerve root compression and radicular pain, and in extreme cases to a local pressure on the dural sac and thus to back pain. Compared to when standing, posterior disc bulging is increased during extension and decreased during flexion, in an uninstrumented spine. The aim of this study was to determine the effect of a pedicle-screw-based dynamic implant on posterior disc bulging. A finite element model of the lumbosacral spine was used to calculate posterior disc bulging before and after implantation of a dynamic implant for different loading cases. The elastic modulus of the longitudinal rod was varied, and the influence of distraction of the bridged segment on disc bulging was also determined. In addition, the centre of rotation (CoR) was determined. Due to a dynamic implant, the magnitude of posterior disc bulging was reduced compared to that for "standing without an implant" during extension, lateral bending, and axial rotation. During flexion, however, disc bulging was usually increased. With increasing stiffness of the dynamic implant, the CoR moved towards the longitudinal rod. This posterior shift of the CoR led to a compression of the entire intervertebral disc during flexion and thus to an increase of disc bulging. PMID- 22103651 TI - Association between the PPARG gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. AB - BACKGROUND: The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma (PPARG) gene is suggested to associate with diabetic nephropathy. AIM: A meta-analysis was conducted to investigate the potential association of PPARG gene polymorphisms with susceptibility to diabetic nephropathy. METHODS: A comprehensive search of MEDLINE (1966 to June 2011) was conducted to identify published epidemiologic studies related to polymorphisms of the PPARG gene and diabetic nephropathy. A database search yielded 5 studies involving 2758 patients. Odds ratios (ORs) along with their 95% confidence intervals (CIs) were computed to compare the distribution of alleles and genotypes between cases and controls. RESULTS: The combined results based on all studies showed no significant difference in genotype distribution (Pro/Pro: OR. 1.42, 95% CI, 0.96 2.09); Pro/Ala: OR, 0.74, 95% CI, 0.50-1.10; Ala/Ala: OR, 0.85, 95% CI, 0.52 1.38) between cases and controls. After stratification for race, results were similar except that patients with diabetic nephropathy had a significantly higher frequency of Pro/Pro (OR, 1.82; 95% CI, 1.17-2.85) than controls among Asians. CONCLUSION: This meta-analysis suggests that the Pro12Ala polymorphism of the PPARG gene may be associated with diabetic nephropathy among Asians. PMID- 22103652 TI - Clinical outcome of pneumococcal meningitis during the emergence of pencillin resistant Streptococcus pneumoniae: an observational study. AB - BACKGROUND: Prior to the availability of generic third-generation cephalosporins, penicillins were widely used for treatment of pneumococcal meningitis in developing countries despite concerns about rising levels of penicillin resistance among pneumococcal isolates. We examined the impact of penicillin resistance on outcomes of pneumococcal meningitis over a ten year period in an infectious diseases hospital in Brazil. METHODS: Clinical presentation, antimicrobial therapy and outcomes were reviewed for 548 patients with culture confirmed pneumococcal meningitis from December, 1995, to November, 2005. Pneumococcal isolates from meningitis patients were defined as penicillin resistant if Minimum Inhibitory Concentrations for penicillin were greater than 0.06 MUg/ml. Proportional hazards regression was used to identify risk factors for fatal outcomes. RESULTS: During the ten-year period, ceftriaxone replaced ampicillin as first-line therapy for suspected bacterial meningitis. In hospital case-fatality for pneumococcal meningitis was 37%. Of 548 pneumococcal isolates from meningitis cases, 92 (17%) were resistant to penicillin. After controlling for age and severity of disease at admission, penicillin resistance was associated with higher case-fatality (Hazard Ratio [HR], 1.62; 95% Confidence Interval [CI], 1.08-2.43). Penicillin-resistance remained associated with higher case-fatality when initial therapy included ceftriaxone (HR, 1.68; 95% CI 1.02 2.76). CONCLUSIONS: Findings support the use of third generation cephalosporin antibiotics for treatment of suspected pneumococcal meningitis even at low prevalence of pneumococcal resistance to penicillins. PMID- 22103653 TI - Population screening for prostate cancer: an overview of available studies and meta-analysis. AB - The objective of the present review was to evaluate the effect of population based screening on the incidence of prostate cancer, prostate cancer tumor stage and grade, prostate cancer mortality, and overall mortality. A systematic review was carried out in April 2011, searching the Medline and Web of Science databases. The records were reviewed to identify comparative and randomized controlled trials evaluating the effect of screening on prostate cancer. Eight trials were identified containing personalized data on a screened versus a non screened cohort. Prostate-specific antigen and digital rectal examination were the main screening tools. Prostate-specific antigen threshold and screening interval was not uniform among the different trials. Screening was associated with a significant increase in prostate cancer detection (relative risk 1.55; P=0.002), and a significant shift towards more localized (relative risk 1.81; P=0.01) and more low-grade tumors (relative risk 2.32; P=0.001). In overall analysis, no significant effect on prostate cancer mortality (relative risk 0.88; P=0.18) and overall mortality (relative risk 0.90; P=0.27) in favor of screening was observed. An adjusted analysis excluding papers with short follow up, high prostate-specific antigen contamination in the non-screening group and low participation in the screening group was able to show a significant reduction in prostate cancer mortality of 24%. The ideal screening strategy is unclear. Screening is associated with better PC detection and this in a more localized stage and of less aggressive tumors. Excluding the main shortcomings in screening studies (short follow up, high prostate-specific antigen contamination in non screening group and low participation in screening group), screening is able to reduce prostate cancer mortality. PMID- 22103654 TI - Heterogeneous dehydrocoupling of amine-borane adducts by skeletal nickel catalysts. AB - Skeletal Ni, produced by the selective leaching of Al from a Ni/Al alloy, has been successfully employed in the catalytic dehydrogenation of various amine borane adducts. The combination of low cost and facile single-step synthesis make this system a potentially attractive alternative to the previously described precious metal and other first-row metal catalysts. The heterogeneous nature of the catalyst facilitates convenient product purification, and this is the first such system to be based on a first-row transition metal. Catalytic dehydrocoupling of Me(2)NH.BH(3) (1) and Et(2)NH.BH(3) (5) was demonstrated using 5 mol % skeletal Ni catalyst at 20 degrees C and produced [Me(2)N-BH(2)](2) (2) and [Et(2)N-BH(2)](2)/Et(2)N?BH(2) (6), respectively. The related adduct iPr(2)NH.BH(3) (7) was also dehydrogenated to afford iPr(2)N?BH(2) (8) but with significant catalyst deactivation. Catalytic dehydrocoupling of MeNH(2).BH(3) (9) was found to yield the cyclic triborazane [MeNH-BH(2)](3) (10) as the major product, whereas high molecular weight poly(methylaminoborane) [MeNH-BH(2)](n) (11) (M(w) = 78 000 Da, PDI = 1.52) was formed when stoichiometric quantities of Ni were used. Similar reactivity was also observed with NH(3).BH(3) (12), which produced cyclic oligomers and insoluble polymers, [NH(2)-BH(2)](x) (14), under catalytic and stoichiometric Ni loadings, respectively. Catalyst recycling was hindered by gradual poisoning. A study of possible catalyst poisons suggested that BH(3) was the most likely surface poison, in line with previous work on colloidal Rh catalysts. Catalytic dehydrogenation of amine-borane adducts using skeletal Cu and Fe was also explored. Skeletal Cu was found to be a less active dehydrogenation catalyst for amine-borane adducts but also yielded poly(methylaminoborane) under stoichiometric conditions on reaction with MeNH(2).BH(3) (9). Skeletal Fe was found to be completely inactive toward amine borane dehydrogenation. PMID- 22103655 TI - Oral vitamin D, still a viable treatment option for psoriasis. AB - Vitamin D as a topical treatment has become one of the mainstays for treatment of psoriasis vulgaris. Oral vitamin D on the other hand has for the most part become a forgotten option. But a review of the literature on oral vitamin D as a treatment for psoriasis reveals that this treatment is efficacious. The main side effect of this therapy is hypercalcemia, which appears to be easily monitored and avoidable with proper dosing and monitoring. The literature also suggests a correlation between low levels of serum vitamin D in this patient population associated with increased severity of disease involvement. In addition, oral vitamin D improves psoriatic arthropathy. Moreover, vitamin D has been proven to have many health benefits such as prevention of cancer, improved cardiovascular health among many others. Psoriatic patients as a population are at increased risk of developing adverse health complications such as cardiovascular disease, and oral vitamin D may prove to be of benefit in this population. Oral vitamin D is inexpensive and easily available. It is still a viable option and should not be forgotten as a possible treatment for psoriasis. PMID- 22103657 TI - Direct guanidinylation of aryl and heteroaryl halides via copper-catalyzed cross coupling reaction. AB - A modified Ullmann reaction using p-methoxybenzyl (PMB) guanidine as guanidinylation agent yielded various aryl and heteroaryl guanidines in good yields. PMID- 22103656 TI - Characterization of molecular interactions between ACP and halogenase domains in the Curacin A polyketide synthase. AB - Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are large multidomain proteins present in microorganisms that produce bioactive compounds. Curacin A is such a bioactive compound with potent anti-proliferative activity. During its biosynthesis the growing substrate is bound covalently to an acyl carrier protein (ACP) that is able to access catalytic sites of neighboring domains for chain elongation and modification. While ACP domains usually occur as monomers, the curacin A cluster codes for a triplet ACP (ACP(I)-ACP(II)-ACP(III)) within the CurA PKS module. We have determined the structure of the isolated holo ACP(I) and show that the ACPs are independent of each other within this tridomain system. In addition, we have determined the structure of the 3-hydroxyl-3 methylglutaryl-loaded holo-ACP(I), which is the substrate for the unique halogenase (Hal) domain embedded within the CurA module. We have identified the interaction surface of both proteins using mutagenesis and MALDI-based identification of product formation. Amino acids affecting product formation are located on helices II and III of ACP(I) and form a contiguous surface. Since the CurA Hal accepts substrate only when presented by one of the ACPs within the ACP(I)-ACP(II)-ACP(III) tridomain, our data provide insight into the specificity of the chlorination reaction. PMID- 22103658 TI - Preparation and characterization of the foam-stabilizing properties of cellulose ethyl cellulose complexes for use in foods. AB - Surface active cellulose particles have been prepared for use as foam stabilizing agents in foods. Various sources of cellulose were broken down by combinations of milling, acid dissolution and treatment with cellulase. The most efficient and simple method was hammer and freezer milling of dry crystalline alpha-cellulose (Tencel). The resultant Tencel particles were made partially hydrophobic through precipitation of ethyl cellulose (EC) onto them in acetone-water dispersions. The optimum ratio of EC to cellulose and the optimum solids concentration (C(x)) at which to form the complexes were 1:1 and C(x) ~ 1 wt %, respectively. Complexes combined at low concentrations (e.g., C(x) ~ 0.1 wt %) with caseins or whey proteins gave significant improvements in stability of foams and bubbles to coalescence and disproportionation compared to either component alone. As such, the complexes could be a useful ingredient in improving the quality of various food foams. PMID- 22103660 TI - A linear regression model to differentiate axial myopia from non-axial myopia. PMID- 22103661 TI - Family-based association study of chromosome 6p12.2-p21.1 migraine locus. AB - BACKGROUND: One of the genome-wide linkage studies performed in migraine has yielded a significant linkage of migraine (with and without aura) with markers located at 6p12.2-21.1. This locus (named MIGR3) has not been replicated in the only genome-wide association scan study performed to date or in previous genome wide linkage studies. OBJECTIVE: Our objective had been to replicate the MIGR3 locus performing a family-based association study. METHODS: A sample of 594 subjects belonging to 134 migraine families of diverse complexity underwent genotyping for the markers previously published as linked at 6p12.2-21.1 migraine locus. Family-based association test, under different models of inheritance, and also the model-free TDT analysis were performed. RESULTS: The best result was obtained with the D6S1650 marker under the additive model (rank [S observed] = 265.0; permuted P = .0006), using family-based association test program (HBAT subprogram). Similar results were obtained with the model-free TDTPHASE algorithm (P < .0001, corrected). Nominal significant P values were obtained for D6S1630, D6S452, and D6S257. After correction for multiple testing with the stratified false-discovery rate, all markers showed significant association (P < .0001). CONCLUSION: We corroborated that the MIGR3 locus at 6p12 is a genetic risk for migraine with and without aura. PMID- 22103662 TI - Core-extended terrylene diimide on the bay region: synthesis and optical and electrochemical properties. AB - Two novel core-extended terrylene diimides on the bay region (CETDIs) were synthesized via annulation of the four additional ethylene units or benzene units on the bay region of the terrylene diimide core. The optical and electrochemical properties of the two compounds were investigated. These CETDIs exhibited broad absorption spectra with high extinction coefficients, which span a wide range in the ultraviolet and visible spectrum from 300 to 700 nm. Furthermore, the redox process of the CETDIs increased from two waves to four waves, and the lowest unoccupied molecular orbital (LUMO) levels were enhanced from -4.00 to -3.59 eV. PMID- 22103663 TI - Prevalence of early and late stages of physiologic PVD in emmetropic elderly population. AB - PURPOSE: To investigate the early and late stages of posterior vitreous detachment (PVD) in the foveal area in correlation with age and gender. METHODS: Three hundred and thirty-five emmetropic eyes of 271 Caucasian patients (216 women/119 men) were examined by optical coherence tomography (OCT) and ultrasound (US). Eyes were classified into groups according to the patients age (up to 69.9; 70-74.9; 75-79.9; over 80 years) and to the clinical findings [Vitreous state: Detached in US; Detached in OCT; Foveal adhesion (FA); Attached vitreous]. RESULTS: The mean age was 76 +/- 8 ranging from 44 to 89 years in female and 72 +/- 10 ranging from 46 to 87 years in male subjects. The vitreous was attached in 32% of all eyes, 18.5% had FA, 18.5% were detached in OCT and 68% were detached in US. While prevalence of FA decreases with increasing age, OCT-diagnosed detachments did not change significantly with age. Between the ages of 70 and 75, an increase in PVD rates occurred. The prevalence of PVD was similar in both genders. Women were significantly older than men in the late-stage PVD in the eyes. CONCLUSION: The use of OCT and US enabled us to detect a partial or total PVD in 80% of the eyes. A sudden increase in late-stage PVD between the ages of 70 and 75 was observed, correlating with the reported age prevalence of various macular diseases. In contrast to myopics, both genders of elderly emmetropics have a similar prevalence of PVD. PMID- 22103664 TI - Cross-cultural validation of the CHO-KLAT and HAEMO-QoL-A in Canadian French. AB - Multi-site studies are necessary in the field of haemophilia to ensure adequate sample sizes. Quality of life (QoL) instruments need to be harmonized across languages and cultures to facilitate their inclusion. The purpose of this study was to adapt the Canadian Haemophilia Outcomes - Kids Life Assessment Tool (CHO KLAT((c))) and HAEMO-QoL-A((c)) to French for Canada. The CHO-KLAT and the HAEMO QoL-A are haemophilia-specific measures of QoL for boys and men respectively. Both measures originated in English, were translated into Canadian French by clinicians with expertise in haemophilia care, back-translated by expert translators and harmonized by a multi-disciplinary team. The harmonized versions were evaluated through a cognitive debriefing process with 6 boys with haemophilia, their parents and 10 men with haemophilia. The final versions were validated in a sample of 19 boys with haemophilia, 19 parents, and 22 men with haemophilia along with a generic QoL scale: the PedsQL for children; and the SF 36 for adults. The translation and cognitive debriefing processes resulted in a preliminary version that maintained the intent of the original questions. The validation study estimated the mean score for the child-reported CHO-KLAT at 71.9 (SD 10.4), and the adult-reported HAEMO-QoL-A at 79.1 (SD 21.3). The CHO-KLAT correlated 0.64 with the PedsQL and the HAEMO-QoL-A correlated 0.78 with the SF 36 physical component summary score. The French-Canadian version of the CHO-KLAT and HAEMO-QoL-A are valid. These measures are available for use in multi-site haemophilia trials and clinical practices to capture QoL data from French Canadians. PMID- 22103665 TI - Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan. AB - While it is generally recognized that misfolding of specific proteins can cause late-onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry-based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)-insoluble conformations during aging in Caenorhabditis elegans. SDS insoluble proteins extracted from young and aged C. elegans were chemically labeled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS-insoluble fraction in aged nematodes and were largely absent from a similar protein fraction in young nematodes. The SDS-insoluble fraction in aged animals contains a diverse range of proteins including a large number of ribosomal proteins. Gene ontology analysis revealed highly significant enrichments for energy production and translation functions. Expression of genes encoding insoluble proteins observed in aged nematodes was knocked down using RNAi, and effects on lifespan were measured. 41% of genes tested were shown to extend lifespan after RNAi treatment, compared with 18% in a control group of genes. These data indicate that genes encoding proteins that become insoluble with age are enriched for modifiers of lifespan. This demonstrates that proteomic approaches can be used to identify genes that modify lifespan. Finally, these observations indicate that the accumulation of insoluble proteins with diverse functions may be a general feature of aging. PMID- 22103666 TI - The effects of a harm reduction housing program on the viral loads of homeless individuals living with HIV/AIDS. AB - Although the advent of highly active antiretroviral therapies has increased survival rates for many individuals living with HIV/AIDS, chronically homeless individuals with the disease continue to experience poor clinical outcomes and high mortality rates in comparison to the general population living with HIV. Housing as a structural intervention for homeless people living with HIV/AIDS has been shown both to be feasible and to improve access to care. However, few studies report the impact of accessing stable housing on residents' viral load counts, even though viral load has been accepted as the best predictor of clinical prognosis for over a decade. The Open Door is a nonprofit agency that utilizes a harm reduction, housing first model of care to improve clinical outcomes for homeless people living with HIV. This article describes the first study that utilizes viral load to assess the effectiveness of a housing first approach. During the study period, we found that 69% of residents of The Open Door achieved undetectable viral loads, which far exceeds adherence rates ranging from 13 to 32% that were found in other studies of similar vulnerable populations. This finding supports the feasibility of this approach and its potential impact on reducing HIV morbidity, mortality, and secondary transmission. Given that the majority of the residents were active substance users during the study period and achieved undetectable viral loads, our findings also substantiate other studies demonstrating that substance users are able to maintain clinical adherence. PMID- 22103667 TI - Before and after endosomal escape: roles of stimuli-converting siRNA/polymer interactions in determining gene silencing efficiency. AB - Silencing the expression of a target gene by RNA interference (RNAi) shows promise as a potentially revolutionizing strategy for manipulating biological (pathological) pathways at the translational level. However, the lack of reliable, efficient, versatile, and safe means for the delivery of small interfering RNA (siRNA) molecules, which are large in molecular weight, negatively charged, and subject to degradation, has impeded their use in basic research and therapy. Polyplexes of siRNA and polymers are the predominant mode of siRNA delivery, but innovative synthetic strategies are needed to further evolve them to generate the desired biological and therapeutic effects. This Account focuses on the design of polymeric vehicles for siRNA delivery based on an understanding of the molecular interactions between siRNA and cationic polymers. Ideal siRNA/polymer polyplexes should address an inherent design dilemma for successful gene silencing: (1) Cationic polymers must form tight complexes with siRNA via attractive electrostatic interactions during circulation and cellular internalization and (2) siRNA must dissociate from its cationic carrier in the cytoplasm before they are loaded into RNA-induced silencing complex (RISC) and initiate gene silencing. The physicochemical properties of polymers, which dictate their molecular affinity to siRNA, can be programmed to be altered by intracellular stimuli, such as acidic pH in the endosome and cytosolic reducers, subsequently inducing the siRNA/polymer polyplex to disassemble. Specific design goals include the reduction of the cationic density and the molecular weight, the loss of branched structure, and changes in the hydrophilicity/hydrophobicity of the polymeric siRNA carriers, via acid responsive degradation and protonation processes within the endosome and glutathione (GSH)-mediated reduction in the cytoplasm, possibly in combination with gradual stimuli-independent hydrolysis. Acetals/ketals are acid-cleavable linkages that have been incorporated into polymeric materials for stimuli responsive gene and drug delivery. Tailoring the ketalization ratio and the molecular weight of ketalized branched PEI (K-BPEI) offers molecular control of the intracellular trafficking of siRNA/polymer polyplexes and, therefore, the gene silencing efficiency. The ketalization of linear PEI (K-LPEI) enhances gene silencing in vitro and in vivo by improving siRNA complexation with the polymer during circulation and cellular internalization, supplementing proton buffering efficiency of the polymer in the endosome, and facilitating siRNA dissociation from the polymer in the cytoplasm, in a serum-resistant manner. Spermine polymerization via ketalization and esterification for multistep intracellular degradations provides an additional polymeric platform for improved siRNA delivery and highly biocompatible gene silencing. The chemistry presented in this Account will help lay the foundation for the development of innovative and strategic approaches that advance RNAi technology. PMID- 22103668 TI - Expression of c-FLIP in malignant melanoma, and its relationship with the clinicopathological features of the disease. AB - BACKGROUND: Numerous molecular events have been associated with the development of malignant melanoma (MM). The cellular FLICE-like inhibitory protein (c-FLIP) was originally identified as an inhibitor of death-receptor signalling through competition with FADD-like interleukin-1beta-converting enzyme (FLICE; also known as caspase-8) for recruitment to the FAS-associated death domain (FADD), and it has been suggested recently that c-FLIP is required for the survival and proliferation of various cell types. Aim. To investigate the relationship of c FLIP expression with the clinicopathological features of MM. METHODS: Immunohistochemical staining with anti-c-FLIP antibody was performed on tissue samples taken from 77 MMs and 20 naevi. The proliferative cells were visualized by staining with Ki-67 antibody. Annexin V-propidium iodide labelling, a marker for chromatin condensation, was performed to observe the rate of cell apoptosis by flow cytometry. RESULTS: Expression of c-FLIP was increased in MM tissue compared with the matched pigmented naevi. The c-FLIP expression was significantly associated with the histological type and Clark level of MM, and correlated strongly with the Ki-67 labelling index. Downregulation of c-FLIP might increase apoptosis in MM cell lines. CONCLUSIONS: c-FLIP might play an important role in the obtaining of aggressive biological behaviours and be useful in predicting prognosis of patients with MM. PMID- 22103669 TI - Impact of the combined left ventricular systolic and renal dysfunction on one year outcomes after primary percutaneous coronary intervention. AB - BACKGROUND: The aim of this study was to assess the impact of combined left ventricular systolic dysfunction (LVSD) and renal dysfunction (RD) on 1-year overall mortality and major adverse cardiovascular events (MACEs) (comprising cardiovascular death, nonfatal renfarction, target vessel revascularization, and nonfatal stroke) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI). METHODS: One thousand three hundred ninety eight patients with first myocardial infarction, undergoing pPCI were divided into four groups according to the presence of LVSD (ejection fraction [EF] <40%) and/or baseline RD (estimated glomerular filtration rate <60 mL/min per m(2)): Group I (no LVSD and no RD); Group II (LVSD, no RD); Group III (RD, no LVSD); Group IV (LVSD + RD). RESULTS: One-year mortality rates in Groups I, II, III, and IV were 2.6%, 15.2%, 10.6%, and 34.2% and 1-year MACE rates were 5.7%, 19.5%, 17.1% and 35.7%, respectively. Patients in Groups II, III, and IV had an increased probability of 1-year overall mortality and MACE as compared to Group I. Overall mortality: Group II HR 2.1 (95% CI 1.1-4.2); Group III HR 2.1 (95% CI 1.1-4.1); Group IV HR 4.8 (95% CI 2.4-9.4); MACE: Group II HR 2.2 (95% CI 1.1-4.2); Group III HR 2.2 (95% CI 1.1-4.3); Group IV HR 5.1 (95% CI 2.6-10.1). The LVSD-RD combination was the strongest independent predictor for 1-year outcomes. CONCLUSIONS: The LVSD-RD combination is associated with an approximately five-fold increase in 1-year overall mortality and MACE after pPCI. The evaluation of the renal function in patients with LVSD represents a simple method which enables a more precise stratification of the risks related to the occurrence of adverse events in long-term patient follow-up. PMID- 22103670 TI - Electrodialytic membrane suppressors for ion chromatography make programmable buffer generators. AB - The use of buffer solutions is immensely important in a great variety of disciplines. The generation of continuous pH gradients in flow systems plays an important role in the chromatographic separation of proteins, high-throughput pK(a) determinations, etc. We demonstrate here that electrodialytic membrane suppressors used in ion chromatography can be used to generate buffers. The generated pH, computed from first principles, agrees well with measured values. We demonstrate the generation of phosphate and citrate buffers using a cation exchange membrane (CEM) -based anion suppressor and Tris and ethylenediamine buffers using an anion-exchange membrane (AEM) -based cation suppressor. Using a mixture of phosphate, citrate, and borate as the buffering ions and using a CEM suppressor, we demonstrate the generation of a highly reproducible (avg RSD 0.20%, n = 3), temporally linear (pH 3.0-11.9, r(2) > 0.9996), electrically controlled pH gradient. With butylamine and a large concentration (0.5 M) of added NaCl, we demonstrate a similar linear pH gradient of large range with a near-constant ionic strength. We believe that this approach will be of value for the generation of eluents in the separation of proteins and other biomolecules and in online process titrations. PMID- 22103672 TI - Optimal decision making in neural inhibition models. AB - In their influential Psychological Review article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the DDM and accomplish optimal decision making. Here we show that these conclusions depend on how the models handle negative activation values and (for the LCA) across-trial variability in response conservativeness. Negative neural activations are undesirable for both neurophysiological and mathematical reasons. However, when negative activations are truncated to 0, the equivalence to the DDM is lost. Simulations show that this concern has practical ramifications: the DDM generally outperforms truncated versions of the LCA and the FFI, and the parameter estimates from the neural models can no longer be mapped onto those of the DDM in a simple fashion. We show that for both models, truncation may be avoided by assuming a baseline activity for each accumulator. This solution allows the LCA to approximate the DDM and the FFI to be identical to the DDM. PMID- 22103673 TI - Neutrophil inhibition contributes to cardioprotection by postconditioning. AB - BACKGROUND: Postconditioning (postcon) reduces infarct size, myocardial superoxide ((*)O(2)) generation, and neutrophil (PMN) accumulation. It is unknown whether inhibition of PMNs influence cardioprotection by postcon. The present study tested the following hypotheses: (1) myocardial salvage by postcon is modified by inhibition of PMNs and (2) postcon directly inhibits PMN (*)O(2) generation. METHODS: For hypothesis 1, a deductive approach was used to determine infarct size in vivo with and without PMNs in rats, and for hypothesis 2, blood sampled from the anterior interventricular vein (AIV) in a canine model was used. Protocol 1: anesthetized rats, subjected to 30 min of coronary artery occlusion and 3 h of reperfusion, were randomized to control (n = 13), postcon (n = 13), PMN-depletion: (n = 9), and postcon in PMN-depleted rats (n = 9). Protocol 2: blood was sampled at baseline, 2 h and 24 h from the AIV, draining the area at risk (AAR) in anesthetized dogs with 60 min coronary occlusion +/- postcon; whole blood was analyzed for (*)O(2) by luminol-enhanced chemiluminescence. RESULTS: Postcon and PMN depletion reduced infarct size (42.6 +/- 2.1%, P < 0.05 vs. control, and 43.9 +/- 3.0%, P < 0.05 vs. control, respectively) vs. control (58.8 +/- 0.9%), with no further decrease with postcon in PMN-depleted rats (37.2 +/- 2.9%, P = 0.34 vs. postcon). PMN accumulation in AAR was less in postcon (21.2 +/ 0.3%, P < 0.05 vs. control) and PMN-depleted (9.4 +/- 0.3%, P < 0.05 vs. control) vs. control (30.5 +/- 1.2%), with a further decrease in the postcon + PMN depletion group (5.4 +/- 0.6%, P < 0.05 vs. control). In dogs, (*)O(2) release by PMNs increased at 2 h and 24 h of R, which was reduced to baseline levels by postcon. CONCLUSIONS: These data imply PMN involvement in cardioprotection by postconditioning. PMID- 22103674 TI - A fixed-dose combination of adapalene 0.1%-BPO 2.5% allows an early and sustained improvement in quality of life and patient treatment satisfaction in severe acne. AB - INTRODUCTION: Acne has a significant negative impact on quality of life (QoL): lack of self-confidence, depressive symptoms and suicidal thoughts. The objective was to assess the impact of an initial and continued therapy in severe acne patients through patient-related outcomes (PRO). METHODS: In two sequential double-blind randomized studies, patients received either adapalene 0.1% and benzoyl peroxide 2.5% (A-BPO) or vehicle, associated with doxycycline 100 mg for 12 weeks. Patients having obtained at least a good improvement according to investigator global assessment were re-randomized for a 24-week therapy with A BPO or vehicle. PROs were assessed using the Acne-QoL and a patient treatment satisfaction questionnaire. RESULTS: QoL was improved at week 12 in all domains with a significant difference for the Acne-symptoms domain (p < 0.001) in favor of the A-BPO regimen. Additional 24-week A-BPO treatment showed a sustained improvement, significant (p < 0.001) for all domains except for Acne-symptoms. In the vehicle arm, QoL significantly worsened for all domains (p < 0.03). At weeks 12 and 36, a significantly higher proportion of patients receiving A-BPO vs. vehicle reported high satisfaction for five out of six treatment satisfaction items. CONCLUSIONS: The early and sustained improvement of these PROs is correlated to the fast onset of action of A-BPO, the treatment effectiveness and a good safety profile. PMID- 22103675 TI - Successful pregnancy following low-dose hCG administration in addition to hMG in a patient with hypothalamic amenorrhea due to weight loss. AB - We describe successful ovulation induction with low-dose hCG administration in addition to hMG in a patient with refractory hypothalamic amenorrhea. A 24-year old woman with weight loss-related amenorrhea underwent ovulation induction and intracytoplasmic sperm injection (ICSI). Administration of exogenous gonadotropins was ineffective in ovulation induction. Supplementation with low dose hCG in order to increase luteinizing hormone (LH) activity in the late follicular phase produced late folliculogenesis and steroidogenesis, and ovulation was then successfully induced. This report reacknowledges the critical role that LH plays cooperatively with follicle-stimulating hormone in both folliculogenesis and steroidogenesis. PMID- 22103676 TI - Rapid magnetic solid-phase extraction based on magnetic multiwalled carbon nanotubes for the determination of polycyclic aromatic hydrocarbons in edible oils. AB - In this study, magnetic multiwalled carbon nanotubes were fabricated by a simple method and applied to magnetic solid-phase extraction (MSPE) of eight heavy molecular weight polycyclic aromatic hydrocarbons (PAHs) including chrysene, benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, indeno[1,2,3-cd]pyrene, dibenzo[a,h]anthracene and benzo[g,h,i]perylene from edible oil samples. Several parameters affecting the extraction efficiency were investigated, including the type and volume of desorption solvent, extraction and desorption time, washing solution and the amount of sorbent. Under the optimized conditions, a simple and effective method for the determination of PAHs in edible oils was developed by coupling with gas chromatography-mass spectrometry (GC-MS). The whole pretreatment process was rapid, and it can be accomplished within 10 min. The limits of quantitation for the target PAHs were found to be 0.34-2.9 ng/g. The recoveries in oil sample were in the range 87.8-122.3% with the RSDs less than 6.8% (intraday) and 9.6% (interday). This method was successfully applied to the analysis of PAHs in seven kinds of edible oils from local markets. PMID- 22103677 TI - An alternative approach for Mohs surgery using a combination of a flexible blade and the traditional scalpel. AB - BACKGROUND: Mohs surgery is a specialized surgical and pathological technique used for the removal of high-risk neoplasms. Previous reports show the ability of using a flexible blade for Mohs surgery. METHOD: We utilized a technique combining the traditional #15 blade and scalpel with a flexible blade to perform excisions for Mohs surgery. DISCUSSION: The use of the flexible blade alone in Mohs may yield jagged tissue peripheral edges after cutting on the cryostat. The classic technique with a scalpel excision often results in a deeper cut than desired, resulting in a larger defect. We modified both the traditional Mohs technique and the flexible blade by combining both. We have performed this method in approximately over 100 cases on the scalp, face and ears, preserving tissue, minimizing bleeding and avoiding alopecia. PMID- 22103678 TI - Hereditary thrombophilia, anti-beta2 glycoprotein 1 IgM, and anti-annexin V antibodies in recurrent pregnancy loss. AB - PROBLEM: We investigated the beta2-glycoprotein I and anti-annexin V antibodies as anti-phospholipid-cofactor antibodies; and factor V G1691A Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations as hereditary thrombophilia in recurrent pregnancy losses (RPL). METHOD OF STUDY: Study group consisted of 84 women with recurrent pregnancy loss and control group consisted of 84 women having at least one live birth. RESULTS: Methylenetetrahydrofolate reductase C677T homozygous mutation was detected in 28.5% of the study group and in 14.2% of the controls, and the difference was highly significant (P < 0.001). Heterozygous mutation of this gene was found in 64.3% of the study population and in 38.1% of the controls, and difference in heterozygous mutation frequency was also significant (P < 0.001). Both homozygous and heterozygous mutations of PT G20210A and factor V G1691A were not different between the groups. There was no significant difference in anti-annexin V levels and anti-beta2-gp 1 levels of the groups. CONCLUSION: We concluded that both homozygous and heterozygous mutations of MTHFR C677T were related with RPL in Caucasian women. PMID- 22103679 TI - Phase evolution, phase transition, raman spectra, infrared spectra, and microwave dielectric properties of low temperature firing (K(0.5x)Bi(1-0.5x))(Mo(x)V(1 x))O4 ceramics with scheelite related structure. AB - In the present work, the (K(0.5x)Bi(1-0.5x))(Mo(x)V(1-x))O(4) ceramics (0<=x <= 1.00) were prepared via the solid state reaction method and sintered at temperatures below 830 degrees C. At room temperature, the BiVO(4) scheelite monoclinic solid solution was formed in ceramic samples with x < 0.10. When x lies between 0.1-0.19, a BiVO(4) scheelite tetragonal phase was formed. The phase transition from scheelite monoclinic to scheelite tetragonal phase is a continuous, second order ferroelastic transition. High temperature X-ray diffraction results showed that this phase transition can also be induced at high temperatures about 62 degrees C for x = 0.09 sample, and has a monoclinic phase at room temperature. Two scheelite tetragonal phases, one being a BiVO(4) type and the other phase is a (K,Bi)(1/2)MoO(4) type, coexist in the compositional range 0.19 < x < 0.82. A pure (K,Bi)(1/2)MoO(4) tetragonal type solid solution can be obtained in the range 0.82 <= x <= 0.85. Between 0.88 <= x <= 1.0, a (K,Bi)(1/2)MoO(4) monoclinic solid solution region was observed. Excellent microwave dielectric performance with a relative dielectric permittivity around 78 and Qf value above 7800 GHz were achieved in ceramic samples near the ferroelastic phase boundary (at x = 0.09 and 0.10). PMID- 22103680 TI - Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study. AB - BACKGROUND: Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease. METHODS: 330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models. RESULTS: Using a nominal P <= 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified. CONCLUSIONS: No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers. PMID- 22103681 TI - Reaction of selenium dioxide with aromatic ketones in the presence of boron triflouride etherate: a protocol for the synthesis of triarylethanones. AB - An efficient regioselective protocol for the C-C bond formation by the unexpected alpha,alpha-diarylation of aromatic ketones with unactivated arenes in the presence of selenium dioxide and boron trifluoride etherate has been developed. The generality and functional tolerance of this protocol is demonstrated by the synthesis of a series of triarylethanones. PMID- 22103682 TI - Specific domains of nucleolin interact with Hdm2 and antagonize Hdm2-mediated p53 ubiquitination. AB - Nucleolin is an abundant multifunctional nucleolar protein with defined roles in ribosomal RNA processing, RNA polymerase I catalyzed transcription and the regulation of apoptosis. Earlier we reported that human nucleolin binds to the p53 antagonist human double minute 2 (Hdm2) as determined by reciprocal co immunoprecipitation assays using cell lysates. We also demonstrated that nucleolin antagonizes Hdm2-mediated degradation of p53. Here, we identify specific domains of nucleolin and Hdm2 proteins that support mutual interaction and investigate the implications of complex formation on p53 ubiquitination and protein levels. Our data indicate that the nucleolin N-terminus as well as the central RNA-binding domain (RBD) are predominantly involved in binding to Hdm2. The nucleolin RBD robustly bound to the NLS/NES (nuclear localization and export signals) domain of Hdm2 in vitro, while the N-terminus of nucleolin preferentially associated with the Hdm2 RING (really interesting new gene) domain expressed in cells. We further demonstrate that the C-terminal glycine-arginine rich domain of nucleolin serves as the predominant binding domain for direct interaction with p53. While overexpression of nucleolin or its various domains had no significant effect on Hdm2 auto-ubiquitination, the nucleolin RBD antagonized the Hdm2 E3 ligase activity against p53, leading to p53 stabilization. Conversely, the adjacent glycine-arginine rich domain of nucleolin interacted with p53 causing a modest stimulatory effect on p53 ubiquitination. These data suggest that changes in nucleolin conformation can alter the availabilities of such domains in vivo to modulate the overall impact of nucleolin on Hdm2 activity and hence on p53 stability. PMID- 22103683 TI - The association between corneal neovascularization and visual acuity: a systematic review. AB - PURPOSE: Corneal neovascularization (CNV) is thought to negatively influence visual acuity. New therapeutic options that offer a differentiated influence on the ingrowths or regression of either corneal blood or lymphatic vessels force us to re-evaluate the association between CNV and visual acuity. METHODS: A systematic review was conducted. Electronic databases were searched up to August 2009. Given the heterogeneity in study populations, interventions and measures of association, we were unable to undertake meta-analysis. The association between CNV and visual acuity was reported descriptively for each study. RESULTS: Eleven studies using either vascular endothelial growth factor inhibitor treatments (i.e. bevacizumab, Avastin((r)) ; Hoffmann-La Roche AG, Basel, Switzerland) or an antiangiogenic treatment based on IRS-1 modulation [Gene-Signal (GS) 101, Aganirsen((r)) ; GeneSignal, Evry (Paris), France] in a total of 131 patients (142 eyes) with corneal neovascularization were included. Ten of the eleven studies reported evidence of a statistically significant reduction in neovascularization following treatment. However, only four studies reported a statistically significant improvement in visual acuity following therapy. We found no studies that assessed the patient-level association between the change in neovascularization and visual acuity. CONCLUSION: This systematic review found that there is currently weak evidence to support the hypothesis that in patients with pathological neovascularization, a treatment-related reduction in neovascularization is associated with an increase in visual acuity. There is a need for future appropriately designed studies. PMID- 22103684 TI - Direct current electric stimulation in implant osseointegration: an experimental animal study with sheep. AB - In an effort to obtain a high-quality bone-implant interface, several methods involving alteration of surface morphological, physicochemical, and biochemical properties are being investigated. The aim of our study was to increase the osseointegration rate and quality and decrease the waiting period of dental implants before loading by using a microelectric implant stimulator device. It imitates microelectrical signals, which occur in bone fractures described in terms of piezoelectric theory. A single dental implant (Zimmer Dental), 3.7 mm in diameter, was inserted into the tibia of sheep bilaterally. Twenty-four dental implants were inserted into 12 sheep. Implant on the tibia of each sheep was stimulated with 7.5 MUA direct current (DC), while the other side did not receive any stimulation and served as a control. Animals were sacrificed 1, 2, and 3 months after implantation. Bone segments with implants were processed with unclassified method. The determination of new bone formation and osseointegration around the dental implants was investigated by means of undecalcified method, histomorphologically. No statistically significant difference in bone-to-implant contact (BIC) ratio, osteoblastic activity, and new bone formation was found between the stimulation group and the control group at the late phase of healing (4, 8, and 12 weeks). No evidence was found that electric stimulation with implanted 7.5 MUA DC is effective at late phase implant osseointegration on a sheep experimental model. PMID- 22103685 TI - Ultrasmall iron oxide nanoparticles for biomedical applications: improving the colloidal and magnetic properties. AB - A considerable increase in the saturation magnetization, M(s) (40%), and initial susceptibility of ultrasmall (<5 nm) iron oxide nanoparticles prepared by laser pyrolysis was obtained through an optimized acid treatment. Moreover, a significant enhancement in the colloidal properties, such as smaller aggregate sizes in aqueous media and increased surface charge densities, was found after this chemical protocol. The results are consistent with a reduction in nanoparticle surface disorder induced by a dissolution-recrystallization mechanism. PMID- 22103686 TI - House dust mite avoidance measures for perennial allergic rhinitis: an updated Cochrane systematic review. AB - BACKGROUND: To assess the benefits and harms of measures designed to reduce house dust mite (HDM) exposure in the management of house dust mite-sensitive allergic rhinitis. METHODS: Systematic review of randomized controlled trials was made, in which HDM control measures have been evaluated in comparison with placebo or other HDM avoidance measures, in patients with clinically proven allergic rhinitis. RESULTS: Nine trials involving 501 participants satisfied the inclusion criteria. These trials have investigated the effectiveness of bedroom environmental control programmes involving the use of HDM impermeable bedding covers (n = 4), acaricides (n = 2), high-efficiency particulate air filters (n = 2) and, using a factorial design, acaricide and HDM impermeable bedding covers in isolation and combination (n = 1). Seven of the nine trials reported that, when compared with control, the interventions studied resulted in significant reductions in HDM load. Of the interventions studied to date, acaricides appear to be the most promising, although the findings from these studies need to be interpreted with care because of their methodological limitations. House dust mite impermeable bedding as an isolated intervention is unlikely to offer benefit. CONCLUSIONS: Trials have tended to be small and of poor methodological quality, making it difficult to offer any definitive recommendations. Interventions that achieve substantial reductions in HDM load may offer some benefit in reducing rhinitis symptoms. Isolated use of HDM impermeable bedding is unlikely to prove effective. PMID- 22103687 TI - Comparison of muscle strength and in-vivo muscle morphology in young children with haemophilia and those of age-matched peers. AB - Recent advances in imaging have enhanced our understanding of the morphological adaptations of muscle in response to disease and altered use. Adaptation in muscle morphology has been linked to changes in muscle strength. To date, no studies have compared muscle morphology and strength in young children with haemophilia to that of typically developing children. This study explored differences in muscle strength and morphology between typically developing and age and size-matched boys aged 6-12 years with haemophilia and a history of recurrent haemorrhage in the ankle joint. Maximum muscle strength of the knee flexors (KF), extensors (KE), ankle dorsi (ADF) and plantar flexors (APF) was measured in 19 typically developing boys (Group 1) and 19 boys with haemophilia (Group 2). Ultrasound images of vastus lateralis (VL) and lateral gastrocnemius (LG) were recorded to determine muscle cross-sectional area (CSA), thickness, width, fascicle length and pennation angle. Muscle strength of the KE, ADF and APF were significantly (P < 0.05) lower in Group 2 when compared with Group 1. Muscle CSA and width of VL were significantly smaller and pennation angles significantly larger in Group 2 (P < 0.05). Muscle CSA and thickness of LG were significantly (P < 0.05) smaller in Group 2. Linear regression showed that LG muscle CSA and thickness were significant (P < 0.01) predictors of APF muscle strength. Following ankle joint bleeding in young boys with haemophilia, secondary adaptations in muscle strength and morphology were observed, suggesting that muscle function is more impaired than current clinical evaluations imply. PMID- 22103688 TI - Total synthesis of (+/-)-cephalosol. AB - A concise and efficient total synthesis of (+/-)-cephalosol has been completed (5 steps from known ester 5, 39% overall yield), featuring a Cu(II)-promoted haloisocoumarin formation and sequential Suzuki cross-coupling/intramolecular oxo Michael addition. PMID- 22103689 TI - Consumer-resource coupling in wet-dry tropical rivers. AB - 1. Despite implications for top-down and bottom-up control and the stability of food webs, understanding the links between consumers and their diets remains difficult, particularly in remote tropical locations where food resources are usually abundant and variable and seasonal hydrology produces alternating patterns of connectivity and isolation. 2. We used a large scale survey of freshwater biota from 67 sites in three catchments (Daly River, Northern Territory; Fitzroy River, Western Australia; and the Mitchell River, Queensland) in Australia's wet-dry tropics and analysed stable isotopes of carbon (delta(13) C) to search for broad patterns in resource use by consumers in conjunction with known and measured indices of connectivity, the duration of floodplain inundation, and dietary choices (i.e. stomach contents of fish). 3. Regression analysis of biofilm delta(13) C against consumer delta(13) C, as an indicator of reliance on local food sources (periphyton and detritus), varied depending on taxa and catchment. 4. The carbon isotope ratios of benthic invertebrates were tightly coupled to those of biofilm in all three catchments, suggesting assimilation of local resources by these largely nonmobile taxa. 5. Stable C isotope ratios of fish, however, were less well-linked to those of biofilm and varied by catchment according to hydrological connectivity; the perennially flowing Daly River with a long duration of floodplain inundation showed the least degree of coupling, the seasonally flowing Fitzroy River with an extremely short flood period showed the strongest coupling, and the Mitchell River was intermediate in connectivity, flood duration and consumer-resource coupling. 6. These findings highlight the high mobility of the fish community in these rivers, and how hydrological connectivity between habitats drives patterns of consumer resource coupling. PMID- 22103690 TI - Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity. AB - Naked mole-rats (Heterocephalus glaber), the longest-lived rodents, live 7-10 times longer than similarly sized mice and exhibit normal activities for approximately 75% of their lives. Little is known about the mechanisms that allow them to delay the aging process and live so long. Neuregulin-1 (NRG-1) signaling is critical for normal brain function during both development and adulthood. We hypothesized that long-lived species will maintain higher levels of NRG-1 and that this contributes to their sustained brain function and concomitant maintenance of normal activity. We monitored the levels of NRG-1 and its receptor ErbB4 in H. glaber at different ages ranging from 1 day to 26 years and found that levels of NRG-1 and ErbB4 were sustained throughout development and adulthood. In addition, we compared seven rodent species with widely divergent (4 32 year) maximum lifespan potential (MLSP) and found that at a physiologically equivalent age, the longer-lived rodents had higher levels of NRG-1 and ErbB4. Moreover, phylogenetic independent contrast analyses revealed that this significant strong correlation between MLSP and NRG-1 levels was independent of phylogeny. These results suggest that NRG-1 is an important factor contributing to divergent species MLSP through its role in maintaining neuronal integrity. PMID- 22103691 TI - Acetaminophen-induced nephrotoxicity in rats: protective role of Cardiospermum halicacabum. AB - CONTEXT: Nephrotoxicity induced by several synthetic drugs is a major problem of modern age. Medicinal plants and phytomedicine are the prime choice of research as they possess better activity and lesser side effects. OBJECTIVE: To investigate the protective effect of Cardiospermum halicacabum Linn. (Sapindaceae), methanol and petroleum ether extracts against acetaminophen induced nephrotoxicity in rats. MATERIALS AND METHODS: Nephrotoxicity was induced by the administration of acetaminophen suspension (750 mg/kg, p.o.) after the pretreatment with methanol extract (MECF) and petroleum ether extract (PEECF) of Cardiospermum halicacabum for 7 days. Forty-eight h after the acetaminophen administration estimations of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, total proteins, cholesterol, albumin level and histological analysis of kidney injuries were determined. RESULTS: In nephrotoxic animals, a significant (P < 0.01) elevation of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol and depletion of total proteins and albumin were observed. Pretreatment with MECF and PEECF (400 mg/kg) significantly (P < 0.01, P < 0.05) decreased serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol level and causes elevation of total protein and albumin level, though MECF produces better effect than PEECF in rats. Histopathological studies also confirm the protective effect of extracts. The protective effect of Cardiospermum halicacabum was associated with restoration of serum alkaline phosphate, creatinine, blood urea nitrogen, uric acid, cholesterol, total protein and albumin level. DISCUSSION AND CONCLUSIONS: Methanol and petroleum ether extracts of Cardiospermum halicacabum had a significant nephroprotective activity against acetaminophen-induced nephrotoxicity in rats. PMID- 22103692 TI - Reasons for living among older male Chinese residents of veterans' homes. AB - AIM: The purpose of this paper was to report a study of reasons for living among older male residents of veterans' homes in Taiwan. BACKGROUND: Suicide rates are high for older persons worldwide. Little is known about protective factors against suicide among elderly Chinese populations. METHOD: A qualitative descriptive design was used. Two veterans' homes, one government paid and one self-paid, were randomly selected from 18 institutions throughout Taiwan. Participants were 36 residents (>=65 years) who had expressed suicidal ideas in the past 6 months but had never shown suicidal behaviours. Data were collected in individual interviews from 2006 to 2007 and analysed by content analysis. RESULTS: Five major themes related to reasons for living were identified: fear of death, comparative improvement in health condition, maintaining self-dignity, family related concerns and concerns for staff. CONCLUSION: Fear of death, maintaining self-dignity and family related concerns are similar to reasons for living found in western studies, but not comparatively better health and concerns for staff. These differences may be due to our sample being veterans' home residents rather than community-dwelling elders and residents' perceived social support from staff. Since most healthcare providers are nurses and nurses' aides, they may consider promoting/maintaining older people's health, promoting their self-dignity, and strengthening relationships with family members and staff to strengthen protective factors against suicide in older Chinese/Asians. Given the aging population worldwide, nurses should become aware of protective factors related to suicide among older people to improve care for this population. PMID- 22103693 TI - Individual-specific transgenerational marking of fish populations based on a barium dual-isotope procedure. AB - The present study focuses on the development and evaluation of an individual specific transgenerational marking procedure using two enriched barium isotopes, (135)Ba and (137)Ba, mixed at a given and selectable molar ratio. The method is based on the deconvolution of the isotope patterns found in the sample into four molar contribution factors: natural xenon (Xe nat), natural barium (Ba nat), Ba135, and Ba137. The ratio of molar contributions between Ba137 and Ba135 is constant and independent of the contribution of natural barium in the sample. This procedure was tested in brown trout ( Salmo trutta ) kept in captivity. Trout were injected with three different Ba137/Ba135 isotopic signatures ca. 7 months and 7 days before spawning to compare the efficiency of the marking procedure at long and short term, respectively. The barium isotopic profiles were measured in the offspring by means of inductively coupled plasma mass spectrometry. Each of the three different isotopic signatures was unequivocally identified in the offspring in both whole eggs and larvae. For 9 month old offspring, the characteristic barium isotope signatures could also be detected in the otoliths even in the presence of a high and variable amount of barium of natural isotope abundance. In conclusion, it can be stated that the proposed dual isotope marking is inheritable and can be detected after both long-term and short term marking. Furthermore, the dual-isotope marking can be made individual specific, so that it allows identification of offspring from a single individual or a group of individuals within a given fish group. PMID- 22103694 TI - Human sensitivity to the magnitude and probability of a continuous causal relation in a video game. AB - Continuous causation, in which incremental changes in one variable cause incremental changes in another, has received little attention in the causal judgment literature. A video game was adapted for the study of continuous causality in order to examine the novel cues to causality that are present in these paradigms. The spatial proximity of an object to an "enemy detector" produced auditory responses as a function of the object's proximity. Participants' behavior was a function of the range of the effect's auditory sensitivity and the moment-to-moment likelihood of detection. This new paradigm provides a rich platform for examining the cues to causation encountered in the learning of continuous causal relations. PMID- 22103695 TI - Indirect object recognition: evidence for associative processes in recognition memory. AB - Rats' exploration of stimulus P (e.g., a domestic object) is reduced following either its direct exposure or its indirect exposure and is taken to indicate recognition memory. Procedures for demonstrating indirect object recognition involve an initial presentation of object P with stimulus X (and of an object Q with stimulus Y). On test, stimulus X is presented with objects P and Q and rats' exploration of Q exceeds their exploration of P. One interpretation here is that the presentation of stimulus X on test associatively activates the memory of object P, which diminishes exploration of P relative to Q. It is possible, instead, that performance is simply the result of a novel pattern of stimulation generated by the unfamiliar combination of X and Q. The authors modified this procedure to reduce the likelihood of such a process. Their procedure involved first the presentation of PX and QY before the presentation of stimulus X alone. During the test that followed, objects P and Q were presented but stimulus X was removed. The authors found that exploration of Q remained greater than that of P despite these modifications and discuss some theoretical implications of indirect, associative processes in recognition memory. PMID- 22103696 TI - Development of a measure of the patient-provider relationship in antenatal care and its importance in PMTCT. AB - The prevention of mother-to-child HIV transmission (PMTCT) is a complex challenge in heavily affected and resource-limited settings such as South Africa. Management of PMTCT requires a cascade of interventions that need to be addressed to effectively decrease the risk of HIV transmission to infants. This PMTCT cascade includes incremental components that can be shaped and influenced by the patient-provider relationship. The relationship that a pregnant woman has with her care providers may possibly affect decisions that she makes concerning her antenatal care and may, in turn, influence the quality of the care provided. A patient-provider relationship scale (PPRS) was developed in Pretoria, South Africa with two aims: first, to quantify the patient-provider relationship in an antenatal population in a resource-limited setting and provide preliminary evidence of its reliability and validity; and second, to determine whether the patient-provider relationship has an effect on PMTCT. The instrument was administrated in a cross-sectional pilot study to a group of women at discharge after delivery (n=192) at two major hospitals in South West Tshwane. Statistical analysis of the instrument showed high reliability (alpha=0.91) and preliminary evidence of its validity including significant associations with participants' attitudes regarding the functioning of the clinics and a single statement (the clinic staff "know me as a person," R=0.47, p<0.001) that has been shown previously to have a significant association with adherence to antiretroviral treatment. For HIV-positive participants, the PPRS was significantly associated with statements related to important components of the PMTCT cascade. In addition, those with substantially inadequate antenatal care (<=2 visits) and those who did not initiate highly active antiretroviral therapy, although eligible, had significantly poorer PPRS scores. The PPRS is a potentially useful, context-appropriate instrument that could have an important role in future research focused on improving PMTCT and decreasing the risk of HIV infection in children. PMID- 22103697 TI - Risk of placenta previa in second birth after first birth cesarean section: a population-based study and meta-analysis. AB - BACKGROUND: OBJECTIVE: To compare the risk of placenta previa at second birth among women who had a cesarean section (CS) at first birth with women who delivered vaginally. METHODS: Retrospective cohort study of 399,674 women who gave birth to a singleton first and second baby between April 2000 and February 2009 in England. Multiple logistic regression was used to adjust the estimates for maternal age, ethnicity, deprivation, placenta previa at first birth, inter birth interval and pregnancy complications. In addition, we conducted a meta analysis of the reported results in peer-reviewed articles since 1980. RESULTS: The rate of placenta previa at second birth for women with vaginal first births was 4.4 per 1000 births, compared to 8.7 per 1000 births for women with CS at first birth. After adjustment, CS at first birth remained associated with an increased risk of placenta previa (odds ratio = 1.60; 95% CI 1.44 to 1.76). In the meta-analysis of 37 previously published studies from 21 countries, the overall pooled random effects odds ratio was 2.20 (95% CI 1.96-2.46). Our results from the current study is consistent with those of the meta-analysis as the pooled odds ratio for the six population-based cohort studies that analyzed second births only was 1.51 (95% CI 1.39-1.65). CONCLUSIONS: There is an increased risk of placenta previa in the subsequent pregnancy after CS delivery at first birth, but the risk is lower than previously estimated. Given the placenta previa rate in England and the adjusted effect of previous CS, 359 deliveries by CS at first birth would result in one additional case of placenta previa in the next pregnancy. PMID- 22103698 TI - Crystal structure, electronic structure, and optical and photoluminescence properties of Eu(III) ion-doped Lu6Mo(W)O12. AB - Lu(6)WO(12) and Lu(6)MoO(12) doped with Eu(3+) ions have been prepared by using a citrate complexation route, followed by calcination at different temperatures. The morphology, structure, and optical and photoluminescence properties of the compounds were studied as a function of calcination temperature. Both compositions undergo transitions from a cubic to a hexagonal phase when the calcination temperature increases. All the compositions have strong absorption of near-UV light and show intense red luminescence under a near-UV excitation, which is related to the transfer of energy from the host lattices to dopant Eu(3+) ions. Density functional theory calculations have also been performed. The calculation reveals that hexagonal Lu(6)WO(12) and Lu(6)MoO(12) are indirect bandgap materials, and the near-UV excitations are due to the electronic transitions from the O-2p orbitals to W-5d and Mo-4d orbitals, respectively. The lattice parameters and bandgap energies of hexagonal Lu(6)WO(12) and Lu(6)MoO(12) were determined. PMID- 22103699 TI - Synthesis of hexadehydrotribenzo[a,e,i][12]annulenes by acetylene insertion into an open-chain precursor. AB - A simple synthesis of a hexadehydrotribenzo[a,e,i][12]annulene by insertion of acetylene into an open-chain diiodo precursor under Sonogashira coupling conditions has been developed and used to prepare a rigid three-armed star connector for testing as a building block for a two-dimensional hexagonal hydrogen-bonding array. PMID- 22103700 TI - Hospital discharge as experienced by family carers of people with dementia: a case for quality improvement. AB - To explore whether hospital discharge practices meets the needs of the family carer of a person with dementia. Qualitative methodology utilizing semistructured interviews with the primary family carer of a person with dementia after hospital discharge. Purposive sampling methods were used to recruit family carers within 2 months of discharge from hospitals in the state of Victoria, Australia. Twenty five family carers were interviewed. Key issues that families found problematic include: coordination of discharge planning, the ability of the staff to address family members' needs, poor engagement with family, and perceived lapses in care delivery. Findings suggest that a number of changes to hospital processes and health professionals' practices are needed in order to better meet the transitional needs of family carers of people with dementia. Considerations for practice to improve the quality of hospital discharge preparation for family carers of people with dementia are provided. PMID- 22103701 TI - Implementing a transitional care program for high-risk heart failure patients: findings from a community-based partnership between a certified home healthcare agency and regional hospital. AB - Provisions within the recently passed health reform law provide support for new approaches to reducing the high cost of care for clinically complex patients. This article describes the characteristics of a recent transitional care pilot initiative that aims to reduce hospital readmissions among high-risk heart failure patients. The program was designed and implemented through a joint collaboration between a Certified Home Healthcare Agency and regional hospital. As a preliminary assessment of the impact of this program on patient outcomes, we compare the odds of rehospitalization among patients who received the transitional care services (n = 223) and a similar group of patients who received usual home care services (n = 224). Analyses indicated that patients who received the transitional care services were significantly less likely to be readmitted to the hospital than the patients in the control group. Although preliminary, our findings suggest that providing transitional care services to high-risk heart failure patients can be an effective deterrent against patterns of rehospitalization. The opportunities and challenges associated with implementing this pilot program are discussed. PMID- 22103702 TI - Process improvement of pap smear tracking in a women's medicine center clinic in residency training. AB - Application of Six-Sigma methodology and Change Acceleration Process (CAP)/Work Out (WO) tools to track pap smear results in an outpatient clinic in a hospital based residency-training program. Observational study of impact of changes obtained through application of Six-Sigma principles in clinic process with particular attention to prevention of sentinel events. Using cohort analysis and applying Six-Sigma principles to an interactive electronic medical record Soarian workflow engine, we designed a system of timely accession and reporting of pap smear and pathology results. We compared manual processes from January 1, 2007 to February 28, 2008 to automated processes from March 1, 2008 to December 31, 2009. Using the Six-Sigma principles, CAP/WO tools, including "voice of the customer" and team focused approach, no outlier events went untracked. Applying the Soarian workflow engine to track prescribed 7 day turnaround time for completion, we identified 148 pap results in 3,936, 3 non-gynecological results in 15, and 41 surgical results in 246. We applied Six-Sigma principles to an outpatient clinic facilitating an interdisciplinary team approach to improve the clinic's reporting system. Through focused problem assessment, verification of process, and validation of outcomes, we improved patient care for pap smears and critical pathology. PMID- 22103703 TI - Continuity in home health care: is consistency in nursing personnel associated with better patient outcomes? AB - A growing body of evidence suggests that patients who receive coordinated and uninterrupted health care services have better outcomes, more efficient resource utilization, and lower costs of health care. However, limited research has considered whether attributes of continuity in home health care service delivery are associated with improved patient outcomes. The present study examines the relationship between one dimension of continuity of care, consistency in nursing personnel, and three patient outcomes: hospitalization, emergent care, and improvement in activities of daily living. Analyses of data from a large population of home health patients (N=59,854) suggest that greater consistency in nursing personnel decreases the probability of hospitalization and emergent care, and increases the likelihood of improved functioning in activities of daily living between admission and discharge from home health care. These results provide preliminary evidence that efforts to decrease dispersion of nursing personnel across a series of home visits to patients may lead to improved outcomes. The implications of these findings for clinical practice and further research are discussed in the paper. PMID- 22103704 TI - Prevalence and antimicrobial susceptibility of Campylobacter in broiler flocks in Japan. AB - Campylobacter was isolated from 67 (47.2%) of 142 broiler flocks between September 2009 and February 2010. The prevalence of Campylobacter in broiler flocks was significantly lower during January and February than it was from September to December. Campylobacter colonization was more common in flocks that were not provided with a disinfected water supply, which was consistent with the findings of a previous study. The prevalence of antimicrobial drug-resistant Campylobacter spp. was investigated, and the minimum inhibitory concentrations of eight antimicrobial agents were determined for 122 Campylobacter jejuni isolates and 46 Campylobacter coli isolates from broiler flocks between 2007 and 2010. In this study, 29.5% (36/122) of C. jejuni isolates and 41.3% (19/46) of C. coli isolates were resistant to enrofloxacin (ERFX), whereas all isolates were susceptible to erythromycin. Furthermore, the ERFX-resistant isolates were tested for susceptibility to other classes of antimicrobial agents, and 55.6% (20/36) of ERFX-resistant C. jejuni isolates and 47.4% (9/19) of ERFX-resistant C. coli isolates were resistant to at least one of aminobenzyl penicillin, dihydrostreptomycin and oxytetracycline. To avoid an impact of antimicrobial drug resistant Campylobacter spp. on the efficacy of antimicrobial treatment for human campylobacteriosis, prudent use of antimicrobial agents is a requisite. The use of antimicrobial agents should be accompanied by various approaches such as prevention of Campylobacter colonization in broiler flocks with the aim of lowering the occurrence of Campylobacter infection in humans. PMID- 22103705 TI - In silico design of robust bolalipid membranes. AB - The robustness of microorganisms used in industrial fermentations is essential for the efficiency and yield of the production process. A viable tool to increase the robustness is through engineering of the cell membrane and especially by incorporating lipids from species that survive under harsh conditions. Bolalipids are tetraether lipids found in Archaea bacteria, conferring stability to these bacteria by spanning across the cytoplasmic membrane. Here we report on in silico experiments to characterize and design optimal bolalipid membranes in terms of robustness. We use coarse-grained molecular dynamics simulations to study the structure, dynamics, and stability of membranes composed of model bolalipids, consisting of two dipalmitoylphosphatidylcholine (DPPC) lipids covalently linked together at either one or both tail ends. We find that bolalipid membranes differ substantially from a normal lipid membrane, with an increase in thickness and tail order, an increase in the gel-to-liquid crystalline phase transition temperature, and a decrease in diffusivity of the lipids. By changing the flexibility of the linker between the lipid tails, we furthermore show how the membrane properties can be controlled. A stiffer linker increases the ratio between spanning and looping conformations, rendering the membrane more rigid. Our study may help in designing artificial membranes, with tunable properties, able to function under extreme conditions. As an example, we show that incorporation of bolalipids makes the membrane more tolerant toward butanol. PMID- 22103706 TI - Self-regulation following prostatectomy: phase-specific self-efficacy beliefs for pelvic-floor exercise. AB - OBJECTIVE: Beliefs in one's ability to perform a task or behaviour successfully are described as self-efficacy beliefs (Bandura, 1977). Since individuals have to deal with differing demands during a behaviour-change process, they form phase specific self-efficacy beliefs directed at these respective challenges. The present study, based on the Health Action Process Approach (Schwarzer, 2001), examines the theoretical differentiation, relative importance, and differential effects of four phase-specific self-efficacy beliefs, including task self efficacy, preactional self-efficacy, maintenance self-efficacy, and recovery self efficacy. DESIGN: In a prospective longitudinal study, 112 prostatectomy-patients received questionnaires at 2 days, 2 weeks, 1 month, and 6 months post-surgery. METHODS: Participants provided data on phase-specific self-efficacies as well as phase indicators of health-behaviour change, that is, intentions, planning, and pelvic-floor exercise. Hierarchical regression analyses were conducted to test the study hypotheses. RESULTS: Task self-efficacy was not uniquely associated with intentions. Preactional self-efficacy was related to action planning. Maintenance self-efficacy did not predict behaviour. Recovery self-efficacy was associated with re-uptake of pelvic-floor exercise after relapses only. CONCLUSION: Findings underline the importance of differentiating between task self-efficacy and preactional self-efficacy during early phases of behaviour change as well as of considering the occurrence of relapses as a moderator of potential effects of recovery self-efficacy on the maintenance of behaviour change. Advanced knowledge on distinct, phase-specific self-efficacy beliefs may facilitate the design of effective tailored interventions for behaviour change. PMID- 22103707 TI - Altered position of the medial lingual nutritional foramina at different stages of alveolar ridge atrophy. AB - To determine the altered location of the medial lingual nutritional foramina in different stages of bone resorption, 55 cadaveric mandibles were selected for this study from a total of 1532. Prevalence, location of the foramen (lingual, cranial, labial), application of Atwood classification (grades 1-6), and macroanatomic dissections were tools of this examination. An increasing grade of atrophy leads to a shift in position of the medial lingual nutritional foramen. PMID- 22103708 TI - Heart rate limitation and cardiac unloading in sevoflurane post-conditioning. AB - BACKGROUND: Sevoflurane post-conditioning (SePost) has been found to alleviate ischemic myocardial reperfusion injury through the activation of prosurvival kinases. Lowered myocardial oxygen demand from reduced cardiac work may also contribute to cardioprotection, and is much less well-studied. Our aim was to examine the simultaneous effects of SePost on cardiac work (here, rate-pressure product, RPP) and myocardial infarct size in a porcine model. METHODS: Anesthetized 25 kg pigs were randomly allocated to two groups and underwent 45 min regional coronary artery balloon occlusion and subsequent 2 h reperfusion. SePost (n = 10) was given as sevoflurane 1.5-3% end-tidal concentration during reperfusion while controls (n = 12) were untreated. Aortic blood pressure was measured directly, while mixed-venous oxygen saturation and cardiac output were measured in the pulmonary artery. Cardiac work was determined as RPP. Post mortem, histologic myocardial infarct size (IS), and area at risk were determined in transverse heart slices after tetrazolium stain. RESULTS: Myocardial infarct size was reduced from (control) 55.0 (mean) +/- 13.6% (standard deviation) to 32.5 +/- 13.4% in group SePost (P = 0.0009). During reperfusion, SePost resulted in lower heart rate (P = 0.0003), cardiac output (P = 0.0123), mixed-venous oxygen saturation (P = 0.0103), blood pressure, and RPP (P < 0.0001). RPP was highly correlated to IS (P = 0.0055). CONCLUSION: SePost (1.5-3%) reduced infarct size after regional myocardial ischemia in vivo and reduced cardiac work was significantly correlated to myocardial salvage. PMID- 22103709 TI - Intramolecular [2 + 2] cycloaddition reactions of alkynyl ether derived ketenes. A convenient synthesis of donor-acceptor cyclobutanes. AB - Mild thermolysis of tert-butyl alkynyl ethers furnishes aldoketenes, which undergo facile [2 + 2] cycloaddition reactions with pendant di- and trisubstituted alkenes. A wide variety of cis-fused cyclobutanones are produced in moderate to high diastereoselectivity and good to excellent yields by this method, and free hydroxyl groups are tolerated in the ene-ynol ether starting materials. Enol-ynol ethers also undergo efficient reaction to produce donor acceptor cyclobutanes in high yields. PMID- 22103710 TI - Is hyperandrogenemia protective for fibrocystic breast disease in PCOS? AB - The aim of this study is to evaluate the fibrocystic breast disease rates and its association with different clinical, endocrine and metabolic parameters between main polycystic ovary syndrome (PCOS) phenotypes. One hundred thirty two consecutive women were included in the study. Body mass index, serum follicle stimulating hormone, luteinizing hormone (LH), progesterone, estradiol, testosterone, dehydroepiandrosterone sulphate, fasting glucose, low density lipoprotein (LDL-C), total cholesterol, high density lipoprotein, insulin, insulin sensitivity and fibrocystic breast disease rates were compared among different phenotypes of PCOS. Group 1: Polycystic ovaries (PCO)-anovulation (n = 32), Group 2: Hyperandrogenemia (HA)-anovulation (n = 28), Group 3: HA-PCO (n = 29), Group 4: HA-PCO-anovulation (n = 43). There were statistically significant differences between the different phenotype groups in terms of waist-hip ratio (p = 0.006), serum LDL-C (p = 0.008), LH (p = 0.002), estradiol (p = 0.022), fasting glucose (p = 0.001), progesterone (p = 0.007), free testosterone levels (p < 0.001) and Ferriman-Gallwey (FG) scores (p < 0.001). Different phenotype groups had significantly different fibrocystic breast disease rates. (p = 0.016). Higher free testosterone >3 pg/dl was protective for fibrocystic disease (RR = 0.316, 95:% CI 0.109-0.912, p = 0.033). Higher FG scores were more protective for fibrocystic disease (RR = 0.005, 95:% CI 0.001-0.042, p < 0.001). Group 3 ovulatory PCOS patients with PCO and hyperandrogenemia phenotype had lower risk to develop fibrocystic disease, while higher rates were observed in group 1 anovulatory-normoandrogenemic PCOS patients. Hyperandrogenemia is protective for fibrocystic diseases in PCOS. PMID- 22103711 TI - Emerging roles of anacardic acid and its derivatives: a pharmacological overview. AB - Anacardic acid (AA) is a bioactive phytochemical found in nutshell of Anacardium occidentale. Chemically, it is a mixture of several closely related organic compounds, each consisting of salicylic acid substituted with an alkyl chain. The traditional Ayurveda depicts nutshell oil as a medicinal remedy for alexeritic, amebicidal, gingivitis, malaria and syphilitic ulcers. However, the enduring research and emerging evidence suggests that AA could be a potent target molecule with bactericide, fungicide, insecticide, anti-termite and molluscicide properties and as a therapeutic agent in the treatment of the most serious pathophysiological disorders like cancer, oxidative damage, inflammation and obesity. Furthermore, AA was found to be a common inhibitor of several clinically targeted enzymes such as NFkappaB kinase, histone acetyltransferase (HATs), lipoxygenase (LOX-1), xanthine oxidase, tyrosinase and ureases. In view of this, we have made an effort to summarize the ongoing research on the therapeutical role of AA and its derivatives. The current MiniReview sheds light on the pharmacological applications, toxicity and allergic responses associated with AA and its derivatives. Although the available records are promising, much more detailed investigations into the therapeutical properties, particularly the anti cancer and anti-inflammatory activities, are urgently needed. We hope the present MiniReview will attract and encourage further research on elucidating and appreciating the possible curative properties of AA and its derivatives in the management of multifactorial diseases. PMID- 22103712 TI - Liquid deposition patterning of conducting polymer ink onto hard and soft flexible substrates via dip-pen nanolithography. AB - Ink formulations and protocols that enable the deposition and patterning of a conducting polymer (PEDOT:PSS) in the nanodomain have been developed. Significantly, we demonstrated the ability to pattern onto soft substrates such as silicone gum and polyethylene terephthalate (PET), which are materials of interest for low cost, flexible electronics. The deposition process and dimensions of the polymer patterns are found to be critically dependent on a number of parameters, including the pen design, ink properties, time after inking the pen, dwell time of the pen on the surface, and the nature of material substrate. By assessing these different parameters, an improved understanding of the ability to control the dimensions of individual PEDOT:PSS structures down to 600 nm in width and 10-80 nm in height within patterned arrays was obtained. This applicability of DPN for simple and nonreactive liquid deposition patterning of conducting polymers can lead to the fabrication of organic nanoelectronics or biosensors and complement the efforts of existing printing techniques such as inkjet and extrusion printing by scaling down conductive components to submicrometer and nanoscale dimensions. PMID- 22103713 TI - Novel effect of adenosine 5'-monophosphate on ameliorating hypertension and the metabolism of lipids and glucose in stroke-prone spontaneously hypertensive rats. AB - The aim of the study was to investigate the effects of adenosine 5'-monophosphate (AMP) in stroke-prone spontaneously hypertensive rats (SHRSP). Male rats (10 weeks old) were divided into three groups: a control group fed an AIN-93 M diet and two others fed supplemental AMP (17.5 and 87.5 mg/kg diet) for 3 weeks. AMP effectively improved hypertension, plasma triglyceride, and HDL-cholesterol, glucose, kidney function parameters, hepatic lipid, enhances plasma nitric oxide, and plasma adiponectin accompanied by the up-regulation of mRNA expression levels of the hepatic adiponectin receptor 2. Single and chronic oral administration of AMP affected the hepatic mRNA expression levels of genes involved in beta oxidation, fatty acid synthesis, and AMP-activated protein kinase. Furthermore, a single oral dose of AMP (40 mg/kg body weight) improved hypertension and hyperglycemia in SHRSP. In conclusion, AMP displays a novel effect in ameliorating metabolic-related diseases in SHRSP and could be beneficial as a functional food. PMID- 22103714 TI - Peptide-based cationic liposome-mediated gene delivery. AB - INTRODUCTION: As an important type of nonviral gene delivery vector, peptide based cationic liposomes have shown many advantages over other cationic liposomes, such as good biodegradability, excellent biocompatibility and targeting ability to cells, and great potential application in improving the delivery of gene therapeutics. AREAS COVERED: This article reviews the research progress on peptide-based cationic liposomes for gene delivery, including the structure characteristics of peptide lipids, the development of peptide cationic liposomes and three special types of peptide cationic liposomes: peptide-based Gemini lipids, lipitoids and lipids with cholesterol hydrophobic group. This review hopes to provide some suggestions on the design of peptide cationic lipids and insight into their development trend in the field of gene delivery. EXPERT OPINION: As peptide-based cationic liposomes still hold some limitations, future research needs to select suitable peptide heads and investigate the surface modification of peptide cationic liposomes, in order to facilitate targeting and reduce cytotoxicity. PMID- 22103715 TI - Tandem mass tag protein labeling for top-down identification and quantification. AB - Top-down mass spectrometry holds tremendous potential for characterization and quantification of intact proteins. So far, however, very few studies have combined top-down proteomics with protein quantification. In view of the success of isobaric mass tags in quantitative bottom-up proteomics, we applied the tandem mass tag (TMT) technology to label intact proteins and examined the feasibility to directly quantify TMT-labeled proteins. A top-down platform encompassing separation via ion-pair reversed-phase liquid chromatography using monolithic stationary phases coupled online to an LTQ-Orbitrap Velos electron-transfer dissociation (ETD) mass spectrometer (MS) was established to simultaneously identify and quantify TMT-labeled proteins. The TMT-labeled proteins were found to be readily dissociated under high-energy collision dissociation (HCD) activation. The liberated reporter ions delivered expected ratios over a wide dynamic range independent of the protein charge state. Furthermore, protein sequence tags generated either by low-energy HCD or ETD activation along with the intact protein mass information allow for confident identification of small proteins below 35 kDa. We conclude that the approach presented in this pilot study paves the way for further developments and numerous applications for straightforward, accurate, and multiplexed quantitative analysis in protein chemistry and proteomics. PMID- 22103716 TI - Aesthetic evaluation after non-invasive treatment for superficial basal cell carcinoma. AB - BACKGROUND: Cosmetic results following non-invasive treatments are difficult to compare. Although qualified objective scar assessment scales are available, they are not used in dermatological studies. Usually a 4-point scale is used in dermatological scars. The reproducibility of this method has never been evaluated. Moreover, significant specific scar characteristics are lacking. The patient and observer scar assessment scale (POSAS) is a scale qualified for the assessments of surgical scars. It has proven to be as reliable as the widely used Vancouver Scar Scale, but has the advantage that it includes the patient's opinion and specifies different scar characteristics. OBJECTIVE: Both methods were used to evaluate cosmetic results following non-invasive treatments of superficial basal cell carcinoma (BCC). METHODS: A total of 54 lesions following non-invasive treatment for BCC in 54 patients were evaluated with the traditional 4-point scale and the POSAS. RESULTS: The 4-point scale showed the best reproducibility and had an intra-class correlation coefficient (ICC) of 0.66 (95% CI: 0.52-0.77) for a single observer and 0.85 (95% CI: 0.77-0.91) for multiple observers. The ICC of the POSAS was 0.41 (95% CI: 0.21-0.58) for a single observer and 0.67 (95% CI: 0.45-0.81) for three observers. The scar characteristics, vascularity and pigmentation were most decisive for the overall opinion. CONCLUSION: The use of the 4-point scale is a valid method to compare scars of non-invasive dermatological treatments. Supplementary registering vascularity and pigmentation can be useful in future studies. PMID- 22103717 TI - Antidiabetic effect of polyphenols from brown alga Ecklonia kurome in genetically diabetic KK-A(y) mice. AB - CONTEXT: Prevalence of diabetes mellitus type 2 (DM-II) is increasing in Japan. Brown alga Ecklonia kurome Okamura (Laminariaceae) (kurome in Japanese) is rich in phlorotannins, a kind of polyphenol. Phlorotannins have been reported to possess various bioactivities; however, few studies have reported its effect on DM-II. OBJECTIVE: The present study was conducted to investigate the antidiabetic effect of polyphenols from E. kurome (KPP) on KK-A(y) mice, the animal model for human DM-II. MATERIALS AND METHODS: Inhibitory activities of KPP against alpha amylase and alpha-glucosidase in vitro, and effects on oral carbohydrate tolerance test in vivo were investigated. KK-A(y) mice were fed with 0.1% KPP containing water for 5 weeks. A glucose tolerance test was conducted at week 4 of the 5-week period. At the end of experiment, blood biochemical parameters, including blood glucose, insulin, glycoalbumin, and fructosamine were determined. Furthermore, the kidneys and pancreatic islets were histologically examined. RESULTS: KPP showed inhibitory activities on carbohydrate-hydrolyzing enzymes and decreased postprandial blood glucose levels. The body weight gain and blood glucose levels in the KPP group were lower than the control group during the experimental period. KPP improved glucose tolerance and decreased the fasting blood glucose and insulin levels, fructosamine and glycoalbumin levels compared with the control group. Furthermore, KPP contracted the pancreatic islet size and decreased renal mesangial matrix in KK-A(y) mice. DISCUSSION AND CONCLUSION: These results suggest that KPP is effective against DM-II and might provide a source of therapeutic agents for DM-II. PMID- 22103719 TI - BH3 under pressure: leaving the molecular diborane motif. AB - Molecular and crystalline structures of (BH(3))(n) have been theoretically studied in the pressure regime from 1 atm to 100 GPa. At lower pressures, crystals of the familiar molecular dimer are the structure of choice. At 1 atm, in addition to the well-characterized beta diborane structure, we suggest a new polymorph of B(2)H(6), fitting the diffraction lines observed in the very first X ray diffraction investigation of solid diborane, that of Mark and Pohland in 1925. We also find a number of metastable structures for oligomers of BH(3), including cyclic trimers, tetramers, and hexamers. While the higher oligomers as well as one-dimensional infinite chains (bent at the bridging hydrogens) are less stable than the dimer at ambient pressure, they are stabilized, for reasons of molecular compactness, by application of external pressure. Using periodic DFT calculations, we predict that near 4 GPa a molecular crystal constructed from discrete trimers replaces the beta diborane structure as the most stable phase and remains as such until 36 GPa. At higher pressures, a crystal of polymeric, one-dimensional chains is preferred, until at least 100 GPa. PMID- 22103718 TI - Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. AB - The thymus is the most rapidly aging tissue in the body, with progressive atrophy beginning as early as birth and not later than adolescence. Latent regenerative potential exists in the atrophic thymus, because certain stimuli can induce quantitative regrowth, but qualitative function of T lymphocytes produced by the regenerated organ has not been fully assessed. Using a genome-wide computational approach, we show that accelerated thymic aging is primarily a function of stromal cells, and that while overall cellularity of the thymus can be restored, many other aspects of thymic function cannot. Medullary islet complexity and tissue-restricted antigen expression decrease with age, representing potential mechanisms for age-related increases in autoimmune disease, but neither of these is restored by induced regrowth, suggesting that new T cells produced by the regrown thymus will probably include more autoreactive cells. Global analysis of stromal gene expression profiles implicates widespread changes in Wnt signaling as the most significant hallmark of degeneration, changes that once again persist even at peak regrowth. Consistent with the permanent nature of age-related molecular changes in stromal cells, induced thymic regrowth is not durable, with the regrown organ returning to an atrophic state within 2 weeks of reaching peak size. Our findings indicate that while quantitative regrowth of the thymus is achievable, the changes associated with aging persist, including potential negative implications for autoimmunity. PMID- 22103720 TI - You owe it to yourself: boosting retirement saving with a responsibility-based appeal. AB - Americans are not saving enough for retirement. Previous research suggests that this is due, in part, to people's tendency to think of the future self as more like another person than like the present self, making saving feel like giving money away rather than like investing in oneself. Using objective employer saving data, a field experiment capitalized on this phenomenon to increase saving. It compared the effectiveness of a novel message--one appealing to people's sense of "social" responsibility to their future selves--with a more traditional appeal to people's sense of rational self-interest. The social-responsibility-to-the-future self message resulted in larger increases in saving than the self-interest message, but only to the extent that people felt a strong "social" connection to their future selves. These results broaden our understanding of the psychology of moral responsibility and refine our understanding of the role of future-self continuity in fostering intertemporal patience. They further demonstrate how understanding conceptions of the self over time can suggest solutions to important and challenging policy problems. PMID- 22103721 TI - World War II and other historical influences on the formation of the Ergonomics Research Society. AB - Little has been written about wartime ergonomics and the role this played in prompting the need for a society dedicated to ergonomics within the UK, namely the formation of the Ergonomics Research Society (ERS) in early 1950. This article aims to fill this gap in our understanding of the history of ergonomics in the UK and provide further details of the types of research undertaken by wartime research groups and committees such as the Institute of Aviation Medicine, Medical Research Council Applied Psychology Unit and the Flying Personnel Research Committee. In addition, the role of societal developments such as wartime links with the USA, the post-war drive to increase productivity and collaboration with industry and the recommendations of government committees in stimulating the work of the ERS are described in detail. This article also offers some reflection on present-day ergonomics in the UK and how this contrasts with the past. STATEMENT OF RELEVANCE: This article will provide practitioners with a historical perspective on the development of ergonomics from its roots in the Second World War. These developments shed light on current trends and challenges within the discipline as a whole. PMID- 22103722 TI - Railway-controller-perceived competence in incidents and accidents. AB - Railway controllers play a pivotal role in service recovery of normal rail system operations when incidents and accidents occur. Those in this position must have sufficient competence to overcome task difficulties caused by accident uncertainties. This study adopts Taiwan's railway system as a case study to diagnose railway-controller-perceived competence when facing diverse tasks during incidents and accidents that are derived from a proposed conceptual model. Railway-controller-perceived competence is measured using the Rasch model. Analytical results indicate that working with an external rescue agency handling a rescue operation, explanations to the public, and communication with an external rescue agency are considered the most troublesome tasks. Additionally, railway-controller-perceived competence differs based on the work experience. This information will prove useful for rail system operators and government regulators when designing and regulating railway controller competence management systems. STATEMENT OF RELEVANCE: This study presents a systematic approach for examining the gap between railway-controller-perceived competence and task difficulties associated with incidents and accidents. The relevance of findings encompasses the effects of transportation ergonomics and railway issues on the problem-solving competence and decision-making skills of railway controllers, and the competence management system. PMID- 22103723 TI - Familiarity effects in the construction of facial-composite images using modern software systems. AB - We investigate the effect of target familiarity on the construction of facial composites, as used by law enforcement to locate criminal suspects. Two popular software construction methods were investigated. Participants were shown a target face that was either familiar or unfamiliar to them and constructed a composite of it from memory using a typical 'feature' system, involving selection of individual facial features, or one of the newer 'holistic' types, involving repeated selection and breeding from arrays of whole faces. This study found that composites constructed of a familiar face were named more successfully than composites of an unfamiliar face; also, naming of composites of internal and external features was equivalent for construction of unfamiliar targets, but internal features were better named than the external features for familiar targets. These findings applied to both systems, although benefit emerged for the holistic type due to more accurate construction of internal features and evidence for a whole-face advantage. STATEMENT OF RELEVANCE: This work is of relevance to practitioners who construct facial composites with witnesses to and victims of crime, as well as for software designers to help them improve the effectiveness of their composite systems. PMID- 22103724 TI - Factors affecting numerical typing performance of young adults in a hear-and-type task. AB - Numerical hear-and-type tasks, i.e. making immediate keypresses according to verbally presented numbers, possess both practical and theoretical importance but received relatively little attention. Effects of speech rates (500-ms vs. 1000-ms interval), urgency (urgent condition: performance-based monetary incentive plus time limit vs. non-urgent condition: flat-rate compensation) and finger strategies (single vs. multi-finger typing) on typing speed and accuracy were investigated. Fast speech rate and multi-finger typing produced more errors and slower typing speed. Urgency improved typing speed but decreased accuracy. Errors were almost doubled under urgent condition, while urgency effect on speed was similar to that of speech rate. Examination of error patterns did not fully support Salthouse's (1986) speculations about error-making mechanisms. The results implied that urgency could play a more important role in error-making than task demands. Numerical keyboard design and error detection could benefit from spatial incidence of errors found in this study. STATEMENT OF RELEVANCE: This study revealed that classic speculations about error-making mechanisms in alphabetical typing do not necessarily translate to numerical typing. Factors other than external task demands such as urgency can affect typing performance to a similar or greater extent. Investigations of intrinsic error-making factors in non-traditional typing tasks are encouraged. PMID- 22103725 TI - Performance in one-, two- and three-dimensional terminal aiming tasks. AB - Arm movement times were measured to targets with independent constraints (target sizes) in one, two or three directions (width, height and depth). In each case, modified forms of Fitts' law give a good fit to the data, with the best form being dependent on all constraints in the 'Weighted Euclidean' model of Accot, J. and Zhai, S., 2003. (Refining Fitts' law models for bivariate pointing. Proceedings of the SIGCHI conference on Human factors in computing systems CHI '03, 5-10 April 2003, Ft. Lauderdale, FL. New York: ACM Press, 193-200). The best predictor includes all the individual ratios of amplitude of movement to target dimension related to the various constraints, with the maximum portion of variance accounted for by the index of difficulty (ID) in the direction of motion. The suggestion by various authors that the maximum of the ID associated with the different constraints will determine the movement times is only partially successful. An explanation for the results is given in terms of control strategy and the form of target. STATEMENT OF RELEVANCE: In many tasks, workers move objects into limited spaces that allow only a single entry area. Termination of the movement may have constraints in one, two or three dimensions. Movement times for such tasks are important to predict industrial performance, and guide task designers in reducing physical constraints on performance. PMID- 22103726 TI - Physiologically acceptable resistance of an air purifying respirator. AB - Physiologically acceptable limits of inspiratory impediment for air purifying respirators (APRs) were sought.Measurements on 30 subjects included pressure in, and flow through, an APR, and respiratory and cardiovascular variables. Exercise with and without APR included ladder climbing, load lift and transfer, incremental running and endurance running, with endurance at 85% peak oxygen uptake. Resistance that did not alter minute ventilation (VE) was judged acceptable long-term. Acceptable short-term impediments were deduced from end exercise conditions. Proposed long-term limits are inspiratory work of breathing per tidal volume (WOBi/VT) <= 0.9 kPa and peak inspiratory pressure (P (i) peak) <=1.2 kPa. Proposed short-term limits are: for VE <=110 L min(-1), WOBi/VT <=1.3 kPa and P (i) peak <= 1.8 kPa; and for VE >130 L min(-1), WOBi/VT <=1.6 kPa. A design relation among VE, pressure-flow coefficients of an APR, and WOBi/VT is proposed. STATEMENT OF RELEVANCE: This work generalises results from one APR by considering the altered physiological parameters related to factors inhibiting exercise. Simple expressions are proposed to connect bench-test parameters to the relation between ventilation and work of breathing. Population-based recommendations recognise that those who need more air flow can also generate higher pressures. PMID- 22103727 TI - Field evaluation of a new prototype self-contained breathing apparatus. AB - Firefighters are required to use a self-contained breathing apparatus (SCBA) for respiratory protection when engaged in a variety of firefighting duties. While the SCBA provides crucial respiratory support and protection, it is also cumbersome and heavy, thus adding to the physical work performed by the firefighter. The purpose of the present study was to evaluate and compare the low profile SCBA prototype to a standard SCBA, as assessed by the objective and subjective measures of mobility and comfort, time of donning/doffing, as well as by acquiring user feedback on SCBA design features during field activities. The results of the present study indicated that the prototype SCBA was rated as a significant improvement over the standard SCBA in the areas of range of motion (ROM), mobility, comfort, induction of fatigue, interaction with protective clothing, and operability when worn over a standard firefighter ensemble, while performing a series of International Association of Fire Fighters Fire Ground Survival Program training exercises. STATEMENT OF RELEVANCE: A prototype SCBA was evaluated and compared with a standard SCBA, focusing on the objective and subjective measures of mobility and comfort during field activities. Feedback from end users was collected during the evaluation. The findings of the present study can be used for improving the system design and overall performance of new prototype SCBAs. PMID- 22103728 TI - The effect of school bag design and load on spinal posture during stair use by children. AB - Thirteen male children ascending and descending stairs with loads that equalled 0%, 10%, 15% and 20% of their body weight were the subject of our research: the boys were wearing an asymmetrical single-strap athletic bag or a symmetrical double-strap backpack during our experiments with them. The maximum spinal tilt to the loading side and to the support side, and the range of spinal motions, were obtained by using a motion analysis system. Our results showed that symmetry of spinal posture was observed both when they ascended staircase with all loads and descended in a backpack. When carrying an athletic bag with 15% and 20% of their body weight while ascending the staircase, the lateral spinal tilt to the supporting side was significantly increased. We concluded that a symmetrical backpack with a load not exceeding 20% or an asymmetrical single-strap athletic bag with a load not exceeding 10% should be recommended for school children in order to promote safer staircase use. STATEMENT OF RELEVANCE: Children carrying heavy school bags may develop spinal problems. This study suggested that when they are using stairs, a symmetrical backpack with a load within 20% body weight is acceptable for them. When they are carrying an asymmetrical single-strap athletic bag, the bag's weight should not exceed 10% of the body weight in order to avoid excessive spinal tilt. PMID- 22103729 TI - The vibration of inclined backrests: perception and discomfort of vibration applied parallel to the back in the z-axis of the body. AB - This study determined how backrest inclination and the frequency of vibration influence the perception and discomfort of vibration applied parallel to the back (vertical vibration when sitting upright, horizontal vibration when recumbent). Subjects experienced backrest vibration at frequencies in the range 2.5 to 25 Hz at vibration magnitudes up to 24 dB above threshold. Absolute thresholds, equivalent comfort contours, and the principal locations for feeling vibration were determined with four backrest inclinations: 0 degrees (upright), 30 degrees , 60 degrees and 90 degrees (recumbent). With all backrest inclinations, acceleration thresholds and equivalent comfort contours were similar and increased with increasing frequency at 6 dB per octave (i.e. velocity constant). It is concluded that backrest inclination has little effect on the frequency dependence of thresholds and equivalent comfort contours for vibration applied along the back, and that the W (d) frequency weighting in current standards is appropriate for evaluating z-axis vibration of the back at all backrest inclinations. STATEMENT OF RELEVANCE: To minimise the vibration discomfort of seated people, it is necessary to understand how discomfort varies with backrest inclination. It is concluded that the vibration on backrests can be measured using a pad between the backrest and the back, so that it reclines with the backrest, and the measured vibration evaluated without correcting for the backrest inclination. PMID- 22103730 TI - The vibration discomfort of standing persons: evaluation of random and transient motions. AB - The discomfort of standing people experiencing steady-state vibration can be predicted from the root-mean-square (rms) of the frequency-weighted acceleration, but alternative methods are advocated for evaluating motions containing transients. Using the method of magnitude estimation, 20 standing subjects estimated the discomfort caused by octave-bandwidth random vibrations at two centre frequencies (1 and 8 Hz) in each of three directions (fore-and-aft, lateral and vertical). For motions having seven different crest factors (i.e. the ratio of the peak to the rms value), the vibration magnitude required for similar discomfort, and a method predicting this equivalence, were determined. The rms method (with an exponent of 2) and the root-mean-quad method (exponent of 4) tended to, respectively, underestimate and overestimate the discomfort of high crest factor motions. The optimum evaluation method had an exponent of about 3.0 for 1-Hz motions and 3.5 for 8-Hz motions. Current standards do not provide reliable indications of when vibration discomfort can be predicted by an rms measure. STATEMENT OF RELEVANCE: Current standards recommend alternatives to the root-mean-square method (exponent of 2.0) for predicting the discomfort caused by transient vibration. The alternatives include the root-mean-quad or vibration dose value (exponent of 4.0) and peak values. An exponent of 2.0 underestimates, but an exponent of 4.0 slightly overestimates, the discomfort of transients experienced by standing people. Peak values are not appropriate. PMID- 22103733 TI - Introducing a semi-automatic method to simulate large numbers of forensic fingermarks for research on fingerprint identification. AB - Statistical research on fingerprint identification and the testing of automated fingerprint identification system (AFIS) performances require large numbers of forensic fingermarks. These fingermarks are rarely available. This study presents a semi-automatic method to create simulated fingermarks in large quantities that model minutiae features or images of forensic fingermarks. This method takes into account several aspects contributing to the variability of forensic fingermarks such as the number of minutiae, the finger region, and the elastic deformation of the skin. To investigate the applicability of the simulated fingermarks, fingermarks have been simulated with 5-12 minutiae originating from different finger regions for six fingers. An AFIS matching algorithm was used to obtain similarity scores for comparisons between the minutiae configurations of fingerprints and the minutiae configurations of simulated and forensic fingermarks. The results showed similar scores for both types of fingermarks suggesting that the simulated fingermarks are good substitutes for forensic fingermarks. PMID- 22103734 TI - Intestinal ischemia measured by intraluminal microdialysis. AB - OBJECTIVE: To evaluate the possibility of detecting intestinal ischemia by intraluminal microdialysis and comparing the ileum and colon. METHODS: The studies were performed on male Sprague-Dawley rats. In the first part of the study, microdialysis catheters were placed in the sigmoid part of the colon and in the subcutaneous adipose tissue. In the second part of the study, microdialysis catheters were placed in the lumen of the ileum and the colon. The infrarenal aorta was clamped proximal to the cranial mesenteric artery. Microdialysate levels of glucose, lactate, pyruvate and glycerol were measured. Intestinal specimens were removed at the end of the ischemic period for microscopic evaluation. RESULTS: Intraluminal microdialysis could detect early signs of ischemic injury in the ileum, as well as in the colon, with a marked increase of lactate, lactate/pyruvate ratio and glycerol. The increased levels of intraluminal glycerol showed a positive correlation to prolonged ischemia and to higher degrees of intestinal damage. CONCLUSION: Intraluminal measurement of glycerol is a good marker for intestinal ischemia. Intraluminal microdialysis in the colon is easily accessible through the rectum, and may prove to be a valuable clinical tool for diagnosing intestinal ischemia. PMID- 22103735 TI - Unexpected direct reduction mechanism for hydrogenation of ketones catalyzed by iron PNP pincer complexes. AB - The hydrogenation of ketones catalyzed by 2,6 bis(diisopropylphosphinomethyl)pyridine (PNP)-ligated iron pincer complexes was studied using the range-separated and dispersion-corrected omegaB97X-D functional in conjunction with the all-electron 6-31++G(d,p) basis set. A validated structural model in which the experimental isopropyl groups were replaced with methyl groups was employed for the computational study. Using this simplified model, the calculated total free energy barrier of a previously postulated mechanism with the insertion of ketone into the Fe-H bond is far too high to account for the observed catalytic reaction. Calculation results reveal that the solvent alcohol is not only a stabilizer of the dearomatized intermediate but also more importantly an assistant catalyst for the formation of trans (PNP)Fe(H)(2)(CO), the actual catalyst for hydrogenation of ketones. A direct reduction mechanism, which features the solvent-assisted formation of a trans dihydride complex trans-(PNP)Fe(H)(2)(CO), direct transfer of hydride to acetophenone from trans-(PNP)Fe(H)(2)(CO) for the formation of a hydrido alkoxo complex, and direct H(2) cleavage by hydrido alkoxo without the participation of the pincer ligand for the regeneration of trans-(PNP)Fe(H)(2)(CO), was predicted. PMID- 22103737 TI - Identification of Yersinia ruckeri from diseased salmonid fish by Fourier transform infrared spectroscopy. AB - Yersinia ruckeri is the causative agent of enteric redmouth disease (ERM), which mainly affects salmonid fish. Isolates of Y. ruckeri from diseased salmonid fish were obtained over a 6-year period from eight fish farms in the State of Baden Wurttemberg, Southwest Germany. The strains were characterized by biochemical methods and Fourier transform infrared spectroscopy (FT-IR) combined with artificial neural network analysis. These methods were complemented by 16S rDNA sequencing for several isolates. The set of strains from these fish farms included sorbitol-positive, gelatinase-positive and non-motile Y. ruckeri. These variants were differentiated with an advanced FT-IR module, which is part of a higher-ranking method including more than 200 well-defined Yersinia strains against a background of more than 1000 other Gram-negative isolates. Validation of the newly constructed method yielded 97.4% of Y. ruckeri identified correctly on the species level. Thus, the FT-IR analysis enables distinction of all Y. ruckeri from other Yersinia species (e.g. fish-borne Y. enterocolitica) and other Enterobacteriaceae typically misidentified because of similar biochemical reaction profiles, especially Hafnia alvei. The differentiation of sorbitol positive variants of Y. ruckeri using FT-IR was demonstrated. PMID- 22103736 TI - Overweight and obesity knowledge prior to pregnancy: a survey study. AB - BACKGROUND: Overweight and obesity are associated with increased risk for pregnancy complications. Knowledge about increased risks in overweight and obese women could contribute to successful prevention strategies and the aim of this study is to assess current levels of knowledge in a pregnant population. METHODS: Cross sectional survey of 412 consecutive unselected women in early pregnancy in Brisbane, Australia: 255 public women attending their first antenatal clinic visit and 157 women at private maternal fetal medicine clinics undergoing a routine ultrasound evaluation prior to 20 weeks gestation. The cohort was stratified according to pre pregnancy BMI (< 25.0 or >= 25.0). The main outcome measure was knowledge regarding the risks of overweight and obesity in pregnancy. RESULTS: Over 75% of respondents identified that obese women have an increased risk of overall complications, including gestational diabetes and hypertensive disorders of pregnancy compared to women of normal weight. More than 60% of women asserted that obesity would increase the risk of caesarean section and less than half identified an increased risk of adverse neonatal outcomes. Women were less likely to know about neonatal complications (19.7% did not know about the effect of obesity on these) than maternal complications (7.4%). Knowledge was similar amongst women recruited at the public hospital and those recruited whilst attending for an ultrasound scan at a private clinic. For most areas they were also similar between women of lower and higher BMI, but women with BMI < 25.0 were less likely to know that obesity was associated with increased rate of Caesarean section than those with higher BMI (16.8% versus 4.5%, P < 0.001). Higher educational status was associated with more knowledge of the risks of overweight and obesity in pregnancy. CONCLUSIONS: Many women correctly identify that overweight and obesity increases the overall risk of complications of pregnancy and childbirth. The increased risks of maternal complications associated with being obese are better known than the increased risk of neonatal complications. Maternal education status is a main determinant of the extent of knowledge and this should be considered when designing education campaigns. PMID- 22103738 TI - Coupled-channels quantum theory of electronic flux density in electronically adiabatic processes: application to the hydrogen molecule ion. AB - This article presents the results of the first quantum simulations of the electronic flux density (j(e)) by the "coupled-channels" (CC) theory, the fundamentals of which are presented in the previous article [Diestler, D. J. J. Phys. Chem. A 2012, DOI: 10.1021/jp207843z]. The principal advantage of the CC scheme is that it employs exclusively standard methods of quantum chemistry and quantum dynamics within the framework of the Born-Oppenheimer approximation (BOA). The CC theory goes beyond the BOA in that it yields a nonzero j(e) for electronically adiabatic processes, in contradistinction to the BOA itself, which always gives j(e) = 0. The CC is applied to oriented H(2)(+) vibrating in the electronic ground state ((2)Sigma(g)(+)), for which the nuclear and electronic flux densities evolve on a common time scale of about 22 fs per vibrational period. The system is chosen as a touchstone for the CC theory, because it is the only one for which highly accurate flux densities have been calculated numerically without invoking the BOA [Barth et al, Chem. Phys. Lett. 2009, 481, 118]. Good agreement between CC and accurate results supports the CC approach, another advantage of which is that it allows a transparent interpretation of the temporal and spatial properties of j(e). PMID- 22103739 TI - Analysis of the complete genome of Tembusu virus, a flavivirus isolated from ducks in China. AB - During investigations into the outbreak of duck viral infection in 2010 in China, with a severe drop in egg production, a flavivirus was isolated from the affected ducks. It was characterized as a Tembusu virus (TMUV). In this study, we obtained a complete genome sequence of Tembusu virus using RT-PCR and RACE techniques. TMUV genome is a singled-stranded RNA, with 10,990 nucleotides in length, and contains a single open reading frame (3410 amino acids) encoding 11 viral proteins with 5'and 3'non-translated regions (NTRs) of 142 and 618 nt, respectively. We characterized the open reading frame (ORF) with respect to gene sizes, cleavage sites and potential glycosylation sites. The different genomic regions of the virus were also compared with those of six other flaviviruses including Japanese encephalitis virus, West Nile virus (WNV), dengue-2 virus, yellow fever virus, tick-borne encephalitis virus (TBEV) and Bagaza virus. TMUV demonstrated the highest similarity to Bagaza virus. The result of entire ORF scanning shows that TMUV was close to Bagaza viruses in genetic relatedness. These data demonstrate that TMUV is a unique virus among the mosquito-borne flaviviruses and also provide a useful reference for a critically important study to determine why TMUV is a serious pathogen for ducks. PMID- 22103740 TI - Interview with quality leaders: Dr. Donna E. Shalala and Dr. Linda Burnes Bolton on the committee on the Robert Wood Johnson Foundation initiative on The Future of Nursing at the Institute of Medicine. Interviewed by Diane Storer Brown. AB - The Institute of Medicine released a consensus report in October 2010, titled The Future of Nursing (FON): Leading Change, Advancing Health, which concluded significant change was needed in nurses' roles, responsibilities, and education to meet the increased demand for care that will be created by health care reform and to advance improvements in America's increasingly complex health system (http://www.iom.edu/Reports/2010/The-Future-of-Nursing-Leading-Change-Advancing Health.aspx). Dr. Donna Shalala, Chair of the study, and Dr. Linda Burnes Bolton, Vice Chair of the study, spoke about the Future of Nursing (FON) at the Collaborative Alliance for Nursing Outcomes (CALNOC) conference to a predominately nursing and quality professional audience. This follow-up interview expands the discussion specifically for quality professionals, many of whom are nurses. PMID- 22103741 TI - Spherulites. PMID- 22103742 TI - Implant esthetic restoration in ridge deficiencies in cases of trauma: a case report. AB - The long-term success of implant therapy does not depend solely on osseointegration, but the gingival architecture surrounding the implant system. It becomes very important to restore the gingival tissues in the areas that enhance one's esthetics. The esthetic zone can be defined as any dentoalveolar area of esthetic concern to the patient. The anterior maxillary teeth in the esthetic zone usually extend from first premolar to first premolar, but in some individuals can extend as far distally as the first molar. The patients requiring esthetic reconstruction at the site of trauma pose a great problem in implant placement and prosthetic restoration as scar tissue interferes with the same. To be successful, an implant-supported restoration should meet biological, mechanical, and esthetic goals. The most challenging situation is when esthetics is of prime concern in deficient ridge cases. This clinical report presents problems faced during implant placement and the sequential procedure to rehabilitate with an implant that was esthetically harmonized at the site of trauma. PMID- 22103743 TI - Topical dose justification: benzoyl peroxide concentrations. AB - BACKGROUND: Benzoyl peroxide (BPO) is widely utilized in acne treatment as an alternative to antibiotics against which Propionibacterium acnes becomes more resistant. OBJECTIVE: This overview examines BPO dose justification. METHODS: PubMed, Embase(r) and Science Citation Index searches were conducted using the keywords "benzoyl peroxide" and "acne vulgaris". RESULTS: Limited experimental data are available. However, there appears no significant difference in the efficacy of concentrations from 2.5% to 10%. DISCUSSION: The extent of free fatty acids and the percutaneous penetration of BPO may not play a critical role in acne vulgaris. PMID- 22103744 TI - In situ surface-enhanced Raman spectroscopic studies of nafion adsorption on Au and Pt electrodes. AB - Understanding interactions between Nafion (perfluorosulfonic acid) and Pt catalysts is important for the development and deployment of proton exchange membrane fuel cells. However, study of such interactions is challenging and Nafion/Pt interfacial structure remains elusive. In this study, adsorption of Nafion ionomer on Au and Pt surfaces was investigated for the first time by in situ surface-enhanced Raman spectroscopy. The study is made possible by the use of uniform SiO(2)@Au core-shell particle arrays which provides very strong enhancement of Raman scattering. The high surface sensitivity offered by this approach yields insightful information on interfacial Nafion structure. Through spectral comparison of several model compounds, vibration assignments of SERS bands were made. The SER spectra suggest the direct interaction of sulfonate group with the metal surfaces, in accord with cyclic voltammetric results. Comparison of present SERS results with previous IR spectra was briefly made. PMID- 22103746 TI - Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models. AB - INTRODUCTION: The field of cardiac safety pharmacology has been experiencing exciting changes over the recent years. Drug induced arrhythmia of the torsade des pointes types has been the reason for the denial of approval of novel drug candidates. The aim of cardiac safety pharmacology is to detect undesirable pharmacodynamic drug effects within and above the therapeutic range. A special focus is on the identification of potential arrhythmogenic effects within the drug discovery chain. AREAS COVERED: Here, the authors discuss the relevance of induced pluripotent stem (iPS) cell derived cardiomyocytes for safety pharmacology. The technology of obtaining functional cardiomyocytes from somatic cells of healthy donors and patients with inherited diseases is the basis for diverse disease models in multi-level safety pharmacology screening. The reader will gain an overview of stem cell based technologies in cardiac safety pharmacology in cardiac and disease modeling by iPS cell derived cardiomyocytes from patients with an inherited cardiac syndrome. EXPERT OPINION: iPS cell derived cardiomyocytes - especially from patients with increased risk of cardiac arrhythmia - are on the verge of offering new options for drug testing. More reliable assays can be expected to predict the arrhythmogenic risk of drug candidates in humans. However, this technology is still new and extensive validation studies are due. PMID- 22103747 TI - Altered expression of COP9 signalosome proteins in preeclampsia. AB - OBJECTIVE: The presumptive factors that are released by the preeclamptic placenta to cause maternal disease are less well known. The constitutive photomorphogenic 9 (COP9) signalosome (CSN) complex, a multifunctional protein complex involved in modulating signal transduction, gene transcription, and protein stability in cells. Although the roles of most CSN components in early embryonic development have been studied, their role in preeclamptic human placentas is not known. Thus, this study was aimed to show the localization and the protein expression of CSN1 and CSN5 in normal and preeclamptic placenta. STUDY DESIGN: The distribution and the protein expression of CSN1 and CSN5 were analyzed in normal (n: 15) and preeclamptic (n: 15) human placenta by using immunohistochemistry (IHC) and Western blotting. RESULTS: CSN1 and CSN5 were mainly localized in the vascular endothelium, syncytiotrophoblast, stromal and Hofbauer cells in normal and preeclamptic placentas. However, a stronger immunoreactivity and protein expression for CSN1 and CSN5 were observed in preeclamptic placentas compared to normal term placentas. Western blotting of the tissue extracts confirmed the IHC results. CONCLUSIONS: Our results suggest that an increased level of CSN1 and CSN5 as an important part of the ubiquitin proteasome system (UPS) might be associated with the pathophysiology of preeclampsia. PMID- 22103748 TI - Underuse of antithrombotic therapy caused high incidence of ischemic stroke in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation is one of the most important causes of ischemic stroke. The purposes of this study were to recognize the incidence of ischemic stroke, the use of antithrombotic agents, the predictors of ischemic stroke, and prescription of warfarin during the three-years after atrial fibrillation was diagnosed. METHODS: This was a descriptive design and chart review study, comprised of 1211 subjects at two hospitals in Northern Taiwan who were aged >= 60 at their first diagnosis of atrial fibrillation. Chi-square and logistic regression were used for data analysis. RESULTS: The incidence of ischemic stroke was 46.2% during the three-years after atrial fibrillation was diagnosed, with 86.3% of those occurring in the first year. The prescription rate was 53.3% in antithrombotic therapy, which included 42.5% antiplatelet agents and 10.8% warfarin. The positive predictors of ischemic stroke were age >= 75 (odds ratio = 1.48) and a history of ischemic stroke (odds ratio = 3.19); the negative predictors were continued use of warfarin (odds ratio = 0.01), transient use of warfarin (odds ratio = 0.25), alternating use of warfarin and antiplatelet agents (odds ratio = 0.04), and use of antiplatelet agents alone (odds ratio = 0.13). The positive predictors of prescribing warfarin were a history of ischemic stroke (odds ratio = 2.32), thromboembolism (odds ratio = 31.06), mitral stenosis (odds ratio = 10.02), and mechanical valve replacement (odds ratio = 136.02). The negative predictor of prescribing warfarin was age >= 75 (odds ratio = 0.62). CONCLUSIONS: It is important in prevention of ischemic stroke to give antithrombotic therapy to newly diagnosed atrial fibrillation patients. Underuse of antithrombotic therapy and warfarin were more severe in our study than in Western countries. PMID- 22103749 TI - Antibiotic-resistant Propionibacterium acnes among acne patients in a regional skin centre in Hong Kong. AB - BACKGROUND: There has been no study on antibiotic-resistant Propionibacterium acnes in Hong Kong. OBJECTIVE: We investigated the prevalence and pattern of antibiotic-resistant P. acnes and to identify any associated factors for harbouring the resistant strains. METHODS: Culture and sensitivity testing of P. acnes to commonly used antibiotics were performed. Resistance to tetracycline was defined at a minimal inhibitory concentration (MIC) of 2 MUg/mL or more; erythromycin at an MIC of 0.5 MUg/mL or more; clindamycin at an MIC of 0.25 MUg/mL or more according to EUCAST. For breakpoints of doxycycline and minocycline, those with an MIC of 1 MUg/mL or more were defined as resistant strains. RESULTS: Among the 111 specimens collected from 111 patients, 86 strains of P. acnes were recovered, one from each specimen. Twenty-five specimens had no growth. Forty-seven (54.8%) strains were found to be resistant to one or more antibiotics. Forty-six (53.5%), 18 (20.9%), 14 (16.3%), 14(16.3%) and 14 (16.3%) strains were resistant to clindamycin (CL), erythromycin (EM), tetracycline (TET), doxycycline (DOX) and minocycline (MR) respectively. Ten strains (11.6%) had cross resistance between the MLS antibiotics (erythromycin or clindamycin), one strain (1.2%) had cross resistance among the cyclines and 14 strains (16.4%) had cross resistance between the MLS and cycline antibiotics. Binary logistic regression showed an association between MLS antibiotic resistance with an increased age whereas cycline resistance was associated with the duration of treatment. CONCLUSION: Antibiotic-resistant P. acnes is prevalent in Hong Kong. Dermatologists should be more vigilant in prescribing antibiotics for acne patients. PMID- 22103750 TI - Biological tissue diagnostics using needle biopsy and spray ionization mass spectrometry. AB - Needle biopsy is a routine medical procedure for examining tissue or biofluids for the presence of disease using standard methods of pathology. In this work, spray ionization directly from tissue in the biopsy needle is shown to provide highly specific molecular information through mass spectrometry analysis. The data are available within a minute after the tissue biopsy, a time scale that allows immediate medical decisions to be made. This method has been performed for tissues in a variety of organs including brain, liver, kidney, adrenal gland, stomach, and spinal cord. Amino acids, hormones, fatty acids, anesthetics, and phospholipids are detected from the tissues and identified using exact mass measurement and tandem mass spectrometry. Lipid profiles are rich in information and, as in imaging MS methods, they have the potential to serve to distinguish diseased from healthy tissue. Needle biopsies allow a crude form of depth profiling that is demonstrated with the analysis of tissue samples taken by a needle inserted into a porcine kidney at various depths. PMID- 22103751 TI - Isoflurane late preconditioning against myocardial stunning is associated with enhanced antioxidant defenses. AB - BACKGROUND: We tested the hypothesis that an upregulation of antioxidant proteins [Cu-Zn superoxide dismutase (SOD), Mn SOD, catalase, glutathione peroxidase, and glutathione peroxidase] plays a role in the delayed protection against myocardial stunning produced by isoflurane preconditioning (ISOPC). Findings were compared with late ischemic PC (IPC). METHODS: Fourteen mongrel dogs were chronically instrumented to measure coronary blood flow and myocardial wall thickening (WT) in conscious state. In Group 1, dogs underwent IPC, induced by a 10-min coronary artery occlusion (CAO); after 24 h of reperfusion, they were subjected to a second 10-min ischemia CAO-reperfusion. In Group 2 (ISOPC), dogs inhaled one minimum alveolar concentration (MAC) ISO (1.4% in O(2)) for 60 min, allowed to recover for 24 h, and then subjected to CAO ischemia-reperfusion. Recovery of WT following the initial 10-min CAO in Group 1 served as control response for both ISOPC and IPC. Expression and activity of antioxidant proteins were measured using Western blotting and spectrophotometric techniques, respectively. RESULTS: Two to three hours of reperfusion were required for recovery of WT following either ISOPC or IPC; in contrast, without PC, WT remained markedly reduced (30% below baseline) at this time point and required more than 6 h of reperfusion for recovery. Neither IPC nor ISOPC affected expression of Cu-Zn SOD, Mn SOD, or catalase. However, ISOPC increased activity of Mn SOD (+40%), catalase (+39%), glutathione peroxidase (+37%), and glutathione reductase (+93%) (P < 0.05); IPC had similar effects. CONCLUSION: ISOPC had powerful, delayed anti-stunning effect that was associated with an enhancement of endogenous antioxidant defenses. PMID- 22103752 TI - Myosin light chain 3f attenuates age-induced decline in contractile velocity in MHC type II single muscle fibers. AB - Aging is characterized by a progressive loss of muscle mass and impaired contractility (e.g., decline in force, velocity, and power). Although the slowing of contraction speed in aging muscle is well described, the underlying molecular mechanisms responsible for the decrement in speed are unknown. Myosin heavy chain (MHC) isoforms are the primary molecules determining contractile velocity; however, the contraction speed of single fibers within a given MHC isoform type is variable. Recent evidence proposes that the decline in shortening velocity (Vo) with aging is associated with a decrease in the relative content of essential myosin light chain 3f (MLC(3f) ) isoform. In the current study, we first evaluated the relative content of MLC(3f) isoform and Vo in adult and old rats. We then used recombinant adenovirus (rAd) gene transfer technology to increase MLC(3f) protein content in the MHC type II semimembranosus muscle (SM). We hypothesized that (i) aging would decrease the relative MLC(3f) content and Vo in type II fibers, and (ii) increasing the MLC(3f) content would restore the age-induced decline in Vo. We found that there was an age-related decrement in relative MLC(3f) content and Vo in MHC type II fibers. Increasing MLC(3f) content, as indicated by greater % MLC(3f) and MLC(3f) /MLC(2f) ratio, provided significant protection against age-induced decline in Vo without influencing fiber diameter, force generation, MHC isoform distribution, or causing cellular damage. To the best of our knowledge, these are the first data to demonstrate positive effects of MLC(3f) against slowing of contractile function in aged skeletal muscle. PMID- 22103753 TI - Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease. AB - CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in Egypt, in parallel with increasing obesity. NAFLD can lead to liver inflammation, fibrosis and cirrhosis. NAFLD appears tightly linked with metabolic syndrome (MetS). OBJECTIVE: Examine the impact of dietary fish oil on human patients with MetS and NAFLD. MATERIALS AND METHODS: One hundred and forty patients were enrolled in the current study and classified into two groups: patients with both MetS and NAFLD and patients with MetS alone. Sixty-four patients were treated with daily supplementation of 2 g of fish oil for 6 months. Markers of hyperlipidemia and oxidative stress, hydrogen peroxide (H(2)O(2)) and malondialdhyde (MDA), as well as proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), were analyzed. RESULTS: Patients without fish oil exhibited significant increases in triglycerides (TGs), low density lipoprotein (LDL), H(2)O(2) and MDA that were associated with significantly elevated TNF-alpha and IL-6 compared to controls. Furthermore, patients with both NAFLD and MetS showed significant increase in H(2)O(2), MDA, TNF-alpha and IL-6 levels compared with MetS group (p < 0.05). Treatment with fish oil reduced serum level of TG, LDL-cholesterol (LDL-C), H(2)O(2), MDA, TNF alpha and IL-6 levels in patients and did not affect the control levels. DISCUSSION AND CONCLUSION: Patients with NAFLD had bad lipid profile through a mechanism that involved developed redox imbalance, characterized by boosted free radical activity and lipid peroxidation enhancing the release of proinflammatory cytokines leading to increased MetS risk and liver damage. However, daily treatment of patients with fish oil for 6 months improved lipid profile and blocked the oxidative stress and cytokines release. PMID- 22103754 TI - Highly luminescent, electron-deficient bora-cyclophanes. AB - A highly luminescent conjugated organoboron macrocycle containing six Lewis acidic boron centers was synthesized. Comparison of the optical and electronic properties with those of a hexameric linear oligomer revealed important differences due to delocalization within the highly symmetric cyclic conjugated structure. Exposure of this unique electron-deficient bora-cyclophane to fluoride or cyanide results in amplified fluorescence quenching and can be exploited to switch between an electron-deficient macrocycle and a highly charged, electron rich borate cycle. PMID- 22103755 TI - Sex estimation from the mastoid process among North Indians. AB - Determination of sex from fragmentary crania is a critical problem in forensic anthropology. Osteometric analysis of mastoid can serve forensic anthropologists better in sex identification by virtue of the noticeable dimorphic characteristics. The present study aims to develop population-specific, sex differentiating anthropometric standards for the mastoid process of North Indian skulls. Eight parameters of the mastoid region were measured on 138 adult crania (M/F 104:34, 22-65 years) and analyzed using SPSS 16.0. All parameters showed significant sexual dimorphism (p < 0.000). In stepwise analysis, asterion mastoidale and mastoid breadth have provided an accuracy of 87%. Receiver operating characteristic curves were obtained for each variable to observe their overall performance in sex determination. Posterior end of incisura mastoidea depression of suprameatal triangle was found to be the best variable with maximum area under curve and highest predictive accuracy (82.6%). PMID- 22103756 TI - A slurry sampling method for the determination of iron and zinc in baby food by flame atomic absorption spectrometry. AB - A slurry sampling method is proposed for the determination of iron and zinc in baby food by flame atomic absorption spectrometry without sample digestion prior to analysis. The effect of slurry concentration (the ratio of solid sample to total slurry volume), different acids at various concentrations as diluent and the addition of dispersant on accuracy and precision were investigated. The samples were dried at 105 degrees C overnight and ground using an agate mortar. To obtain quantitative recoveries, 500 mg of sample was slurried in 20 ml of 0.05% Triton X-114 containing 0.1 M HNO(3), homogenised using a high-performance overhead disperser at 15,000 rpm for 5 min and directly aspirated into the flame. The accuracy of the method was tested by determination of analytes in various certified reference materials. The limits of detection of the method (N = 10; 3sigma) for iron and zinc were 5.5 and 3.4 ug g(-1), respectively, using a very dilute slurry of baby food, which gave a very low background signal. Finally, the proposed method was applied to the determination of iron and zinc in different baby food samples obtained from markets in Turkey. The range of iron and zinc content for the samples were 33-76 and 15-73 ug g(-1), respectively. PMID- 22103757 TI - A test of Bayesian observer models of processing in the Eriksen flanker task. AB - Two Bayesian observer models were recently proposed to account for data from the Eriksen flanker task, in which flanking items interfere with processing of a central target. One model assumes that interference stems from a perceptual bias to process nearby items as if they are compatible, and the other assumes that the interference is due to spatial uncertainty in the visual system (Yu, Dayan, & Cohen, 2009). Both models were shown to produce one aspect of the empirical data, the below-chance dip in accuracy for fast responses to incongruent trials. However, the models had not been fit to the full set of behavioral data from the flanker task, nor had they been contrasted with other models. The present study demonstrates that neither model can account for the behavioral data as well as a comparison spotlight-diffusion model. Both observer models missed key aspects of the data, challenging the validity of their underlying mechanisms. Analysis of a new hybrid model showed that the shortcomings of the observer models stem from their assumptions about visual processing, not the use of a Bayesian decision process. PMID- 22103758 TI - Action-specific effects in a social context: others' abilities influence perceived speed. AB - According to the action-specific account of perception, perceivers see the environment relative to their ability to perform the intended action. For example, in a modified version of the computer game Pong, balls that were easier to block looked to be moving slower than balls that were more difficult to block (Witt & Sugovic, 2010). It is unknown, however, if perception can be influenced by another person's abilities. In the current experiment, we examined whether another person's ability to block a ball influenced the observer's perception of ball speed. Participants played and observed others play the modified version of Pong where the task was to successfully block the ball with paddles that varied in size, and both the actor and observer estimated the speed of the ball. The results showed that both judged the ball to be moving faster when it was harder to block. However, the same effect of difficulty on speed estimates was not found when observers watched a computer play, suggesting the effect is specific to people and not to the task. These studies suggest that the environment can be perceived relative to another person's abilities. PMID- 22103759 TI - Implementation and optimization of smart infusion systems: are we reaping the safety benefits? AB - To address the high incidence of infusion errors, manufacturers have replaced the development of standard infusion pumps with smart pump systems. The implementation and ongoing optimization processes for smart pumps are more complex, as they require larger coordinated efforts with stakeholders throughout the medication process. If improper implementation/optimization processes are followed, hospitals invest in this technology while extracting minimal benefit. We assessed the processes hospitals employed when migrating from standard to smart infusion systems, and the extent to which they leveraged their investments from both a systems and resource perspective. Twenty-nine hospitals in Ontario, Canada, were surveyed that had either implemented smart pump systems or were in the process of implementing, representing a response rate of 69%. Results demonstrated that hospitals purchased smart pumps for reasons other than safety, did not involve a multidisciplinary team during implementation, made little effort to standardize drug concentrations or develop drug libraries and dosing limits, seldom monitored how nurses use the pumps, and failed to ensure wireless connectivity to upgrade protocols and download use data. Consequently, they are failing to realize the safety benefits these systems can provide. PMID- 22103760 TI - Nonprocessed adipose tissue graft in the treatment of peri-implant osseous defects in the rabbit's tibiae: a pilot study. AB - We hypothesized that a new technique using nonprocessed adipose tissue could regenerate bone around dental implants. Eighteen rabbits received 1 implant per tibia surrounded by a surgically created osseous defect. The defects were assigned for treatment into 3 groups: C, AT, and AB. The percentages of bone-to implant contact were 17.64% +/- 16.22% (AB), 3.54% +/- 7.08% (AT), and 12.71% +/- 10.11% (C) (rho = 0.25). The use of adipose tissue around surgically created peri implant osseous defects interferes with bone formation. PMID- 22103761 TI - New volatile strontium and barium imidazolate complexes for the deposition of group 2 metal oxides. AB - We report the synthesis, characterization, and experimental density function theory-derived properties of new volatile strontium and barium imidazolate complexes, which under atomic layer deposition conditions using ozone as a reagent can deposit crystalline strontium oxide at 375 degrees C. PMID- 22103762 TI - Industry funded clinical trials: bias and quality. AB - The quality of the clinical data supporting the development and ultimately the approval for medical use of new drugs is often challenged. Many share the perception that the business goals of the pharmaceutical industry overrule the best scientific efforts to accrue critical knowledge on a new molecule, in order to inform investment of resources, regulatory approvals and appropriate use by patients. Despite this common belief, few scientists have attempted to assess objectively the quality of industry funded (IF) clinical trials by measuring it and comparing it with non-industry funded (NIF) clinical trials in a data-driven fashion. Overall, the average quality of IF clinical research has been reported to be higher than the quality of NIF clinical research. PMID- 22103763 TI - Approaching charge balance in organic light-emitting diodes by tuning charge injection barriers with mixed monolayers. AB - Self-assembled monolayers (SAMs) of binary mixtures of 1-butylphosphonic acid and the trifluoromethyl-terminated analogue (4,4,4-trifluoro-1-butylphosphonic acid) were formed on ITO surfaces to tune the work function of ITO over a range of 5.0 to 5.75 eV by varying the mixing ratio of the two adsorbents. The mixed SAM modified ITO surfaces were used as the anode in the fabrication of OLED devices with a configuration of ITO/SAM/HTL/Alq3/MX/Al, where HTL was the NPB or BPAPF hole-transporting layer and MX was the LiF or Cs(2)CO(3) injection layer. It was shown that, depending on the HTL or MX used, the maximum device current and the maximum luminance efficiency occurred with anodes of different modifications because of a shift in the point of hole/electron carrier balance. This provides information on the charge balance in the device and points to the direction to improve the performance. PMID- 22103764 TI - Evaluating different fixation protocols for spectral cytopathology, part 1. AB - Spectral cytopathology (SCP) is a novel approach for disease diagnosis that utilizes infrared spectroscopy to interrogate the biochemical components of cellular samples and multivariate statistical methods, such as principal component analysis, to analyze and diagnose spectra. SCP has taken vast strides in its application for disease diagnosis over the past decade; however, fixation induced changes and sample handling methods are still not systematically understood. Conversely, fixation and staining methods in conventional cytopathology, typically involving protocols to maintain the morphology of cells, have been documented and widely accepted for nearly a century. For SCP, fixation procedures must preserve the biochemical composition of samples so that spectral changes significant to disease diagnosis are not masked. We report efforts to study the effects of fixation protocols commonly used in traditional cytopathology and SCP, including fixed and unfixed methods applied to exfoliated oral (buccal) mucosa cells. Data suggest that the length of time in fixative and duration of sample storage via desiccation contribute to minor spectral changes where spectra are nearly superimposable. These findings illustrate that changes influenced by fixation are negligible in comparison to changes induced by disease. PMID- 22103765 TI - Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C. AB - BACKGROUND/AIMS: Accuracy of transient elastography (TE) in hepatitis B virus (HBV) infection has not been well established. We aimed to compare the performances of TE for the assessment of liver fibrosis in patients with chronic HBV or hepatitis C virus (HCV) infection. A secondary analysis was performed to assess whether or not alanine aminotransferase (ALT) levels would impact on the accuracy of TE. METHODS: This cross-sectional study, carried out in a single centre, included treatment-naive patients with compensated chronic HBV or HCV infection, consecutively admitted between 2006 and 2008 for a liver biopsy and TE measurement on the same day. RESULTS: A total of 202 HBV patients and 363 HCV subjects were evaluated. Overall diagnostic accuracy of TE in the HBV group was comparable to that observed in HCV patients [area under the receiver-operating characteristics (AUROCs) 0.867 +/- 0.026 vs. 0.868 +/- 0.019 for predicting F >= 2, P = 0.975; 0.902 +/- 0.029 vs. 0.894 +/- 0.020 for F >= 3, P = 0.820; and 0.935 +/- 0.024 vs. 0.947 +/- 0.027 for F4, P = 0.740 respectively]. TE exhibited comparable accuracies, sensitivities, specificities, predictive values and likelihood ratios in HBV and HCV groups. AUROC analysis showed no influence of ALT levels on the performance of TE in HBV individuals. ALT-specific cut-off values did not exhibit significantly higher diagnostic performances for predicting fibrosis in HBV patients with elevated ALT. CONCLUSIONS: In HBV patients, TE measurement accurately predicts the absence or presence of significant fibrosis, advanced fibrosis or cirrhosis and shows similar performances as compared to HCV patients. The use of TE cut-off values adjusted to ALT level did not improve performances for estimating liver fibrosis in HBV patients. PMID- 22103766 TI - Evaluation of the liver protection and toxicity of Da-Huang-Zhe-Chong pill in rats. AB - CONTEXT: Da-Huang-Zhe-Chong pill (DHZCP), a classical traditional Chinese formula, consists of 12 crude drugs which have been widely used with significant therapeutic effects. Some drugs in this formula have toxicities that might result in some adverse effects of DHZCP. OBJECTIVE: The liver protection and toxicity of DHZCP were first evaluated against chronic carbon tetrachloride (CCl(4))-induced liver injury in rats. MATERIALS AND METHODS: The rats were treated by intraperitoneal injection of 10% CCl(4) for 12 weeks. At the end of week 4, DHZCP at doses of 44 g/kg (high-dose group) and 22 g/kg (low-dose group) was intragastrically administered to CCl(4)-treated rats, once a day for four weeks. At the end of weeks 8 and 12, the general status of the rats, histopathology of liver, serum alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL) levels were observed or determined and recorded. By correspondence analysis (CA) on biochemical markers and liver histopathological score (HS), the "dose-time-response" relationship of DHZCP on the hepatic injury rats was evaluated. RESULTS: The results showed that DHZCP exhibited a significant protective effect on liver injury by reversing the biochemical parameters and histopathological changes. However, this hepatoprotective effect may be weakened, or even be transferred to toxicity with the increase of the administration dose (44 g.kg(-1).d(-1)) and time (more than 2 months) of this formula. These results were consistent with the histopathological observation and the serum levels. DISCUSSION AND CONCLUSION: Administration of proper dose and time of DHZCP could well play its hepatoprotective effect and even treat hepatitis, but the safety on liver should be considered when large dose (44 g.kg(-1).d(-1)) DHZCP is used for long time (more than 2 months). We suggest that the administration dose and time of DHZCP in clinical use should not be increased and prolonged, and simultaneously liver function should be regularly monitored. PMID- 22103767 TI - The pathology of 'scale drop syndrome' in Asian seabass, Lates calcarifer Bloch, a first description. AB - This is the first pathological description of 'scale drop syndrome' (SDS) in Asian seabass, Lates calcarifer Bloch. Cumulative mortality was estimated at 40 50%. The vasculitis in all major organs including the skin and associated tissue necrosis was distinctive. The dermis overlying scale beds was often necrotic and associated with scale loss. Necrosis of splenic ellipsoids, renal glomeruli and choroid rete glands of eye were further hallmarks of a disease with systemic vascular involvement. The brain was not spared vascular damage, and the resulting multifocal encephalomalacia probably accounts for the spiral swimming behaviour in some affected fish. Other lesions included accentuated hepatic lobulation and gastric gland necrosis. Nuclear chromatin margination and karyolysis in hepatocytes, renal tubular epithelium and gastric and intestinal epithelium suggest specific targeting of cells. Basophilic cytoplasmic inclusions were present in spleen, kidney, liver, heart and choroid rete, but they were not prominent. Using transmission electron microscopy, two morphological forms of virions were observed: single- and double-enveloped hexagonal virions. Based on size and morphology, these virions resemble iridovirus or herpesvirus. The cause of SDS is unknown, but the pathological changes, especially the vasculitis, suggest an infectious aetiology, possibly viral. PMID- 22103768 TI - Coupled-channels quantum theory of electronic flux density in electronically adiabatic processes: fundamentals. AB - The Born-Oppenheimer (BO) description of electronically adiabatic molecular processes predicts a vanishing electronic flux density (j(e)), =1/2?dR[Delta(b) (x;R) - Delta(a) (x;R)] even though the electrons certainly move in response to the movement of the nuclei. This article, the first of a pair, proposes a quantum-mechanical "coupled-channels" (CC) theory that allows the approximate extraction of j(e) from the electronically adiabatic BO wave function . The CC theory is detailed for H(2)(+), in which case j(e) can be resolved into components associated with two channels alpha (=a,b), each of which corresponds to the "collision" of an "internal" atom alpha (proton a or b plus electron) with the other nucleus beta (proton b or a). The dynamical role of the electron, which accommodates itself instantaneously to the motion of the nuclei, is submerged in effective electronic probability (population) densities, Delta(alpha), associated with each channel (alpha). The Delta(alpha) densities are determined by the (time-independent) BO electronic energy eigenfunction, which depends parametrically on the configuration of the nuclei, the motion of which is governed by the usual BO nuclear Schrodinger equation. Intuitively appealing formal expressions for the electronic flux density are derived for H(2)(+). PMID- 22103769 TI - A comparative study on the impact of fresh variables on the success of frozen thawed embryo transfer cycles using 2PN sibling embryos in women with/without polycystic ovary syndrome. AB - AIMS: The aim of the present study was to identify the fresh variables that influence the frozen-thawed embryo transfer (FET) outcome using sibling two pronuclei (2PN) embryos in women with polycystic ovary syndrome (PCOS) and non PCOS women. MATERIAL & METHODS: Fifty-five FET cycles were performed using sibling embryos randomly cryopreserved at 2PN states and basal/cycle characteristics of fresh variables were compared between PCOS and non-PCOS groups according to the success in FET pregnancy: group A (pregnant PCOS); group B (not pregnant PCOS); group C (pregnant non-PCOS); group D (not pregnant non-PCOS). RESULTS: In PCOS patients, higher progesterone level on human chorionic gonadotropin (hCG) day was observed in group A than in group B (0.9 +/- 0.0 vs. 0.5 +/- 0.3, p = 0.004). In non-PCOS patients who achieved a pregnancy in the fresh cycle, a subsequent FET cycle using sibling 2PN embryos conferred a thirteen times increased chance of achieving pregnancy (OR 13.0; 95% CI, 2.3 74.1). Embryo quality and endometrial maturation were comparable between A and B or C and D. CONCLUSIONS: The success of the fresh embryo transfer (ET)was the most important predictor of pregnancy in FET cycles in the non-PCOS group. The relationship between serum progesterone on hCG day in the fresh cycle and the outcome of subsequent FET would benefit further evaluation in PCOS group. PMID- 22103770 TI - Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd:YAG laser. AB - BACKGROUND: Recently, tranexamic acid (TNA) containing oral medication has gained public attention, claiming for whitening effects. OBJECTIVE: This study was performed to evaluate the clinical efficacy and safety of oral TNA as an adjuvant to intense pulsed light (IPL) and laser treatment in melasma. METHODS: A total of 51 patients were included in the study. Patients who have been on oral TNA during IPL and laser treatments (group A) and those who were treated with only IPL and laser (group B) were analyzed (from winter to summer). Modified melasma area and severity index (mMASI) scores were blindly evaluated by two investigators using digital photographs taken at each visit. RESULTS: The mean modified MASI score decreased from 11.33 +/- 7.07 to 6.21 +/- 5.04 in group A and from 11.70 +/- 6.72 to 8.93 +/- 5.89 in group B (baseline vs. 2 weeks after the last treatment, p = 0.005). Modified MASI score right before and after IPL were more reduced in group A. No serious adverse effects were reported up to 8 months of oral TNA medication. CONCLUSION: Oral TNA may improve clinical efficacy in light- or laser based melasma treatment especially during the period of relative high sun exposure without serious adverse effects. PMID- 22103772 TI - Three-component coupling sequence for the regiospecific synthesis of substituted pyridines. AB - A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an alpha,beta-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II) mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control. PMID- 22103773 TI - Value of measuring serum vascular endothelial growth factor levels in diagnosing acute ischemic stroke. AB - BACKGROUND AND PURPOSE: It has previously been reported that serum levels of vascular endothelial growth factor are raised after acute ischemic stroke compared to healthy controls. The aim of this prospective study was to ascertain whether serum vascular endothelial growth factor measurements could be used to distinguish between acute ischemic stroke and common stroke mimics in the emergency room. METHODS: Blood samples were taken on arrival to hospital and daily for six-days, in 44 patients with suspected ischemic stroke (29 acute infarcts and 15 stroke mimics), arriving within 24 h of symptom onset. Vascular endothelial growth factor levels were measured by enzyme-linked immunoassay. The neurological deficit was recorded daily using the National Institute of Health Stroke Scale. Evaluation of infarct volumes was based on diffusion-weighted magnetic resonance imaging. RESULTS: Serum vascular endothelial growth factor levels were significantly raised in acute ischemic stroke patients on the day of symptom onset and at all other time points, compared to healthy controls (P < 0.01). The sensitivity and specificity of vascular endothelial growth factor for diagnosing acute ischemic stroke on admission to hospital were only 69% and 73%, respectively. Vascular endothelial growth factor levels were also elevated in four out of 15 stroke mimics, including three patients presenting with postictal paresis. CONCLUSIONS: Vascular endothelial growth factor has limited clinical utility in the diagnosis of acute ischemic stroke in the emergency room because levels are also raised in common stroke mimics. Further studies are required to establish the mechanism of vascular endothelial growth factor elevation in postictal paresis. PMID- 22103774 TI - Psychotherapy for social phobia: how do alliance and cognitive process interact to produce outcome? AB - The purpose of this study was to ascertain whether and how alliance and specific cognitive process may interact to influence outcome. Eighty social phobic patients were randomized to 10-week residential cognitive or interpersonal therapy, conducted mostly in groups. They completed process and outcome measures weekly. The ratings were analyzed with mixed models. It was found that initial patient-rated alliance predicted the course of social anxiety throughout therapy and that this effect was indirect through the cognitive process. However, this indirect effect did not interact with treatment. There was a trend toward an indirect effect of weekly variations in alliance rated by the individual therapist through weekly variations in subsequent cognitive process on weekly variations in subsequent social anxiety. Thus, the results support a facilitative rather than an active ingredient perspective on the role of alliance. PMID- 22103775 TI - Ethylene in organic synthesis: a new route to anticholenergic pyrrolidinoindolines, and other molecules with all carbon-quaternary centers via asymmetric hydrovinylation. AB - The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans. PMID- 22103776 TI - Aerosolized adenovirus-vectored vaccine as an alternative vaccine delivery method. AB - Conventional parenteral injection of vaccines is limited in its ability to induce locally-produced immune responses in the respiratory tract, and has logistical disadvantages in widespread vaccine administration. Recent studies suggest that intranasal delivery or vaccination in the respiratory tract with recombinant viral vectors can enhance immunogenicity and protection against respiratory diseases such as influenza and tuberculosis, and can offer more broad-based generalized protection by eliciting durable mucosal immune responses. Controlled aerosolization is a method to minimize vaccine particle size and ensure delivery to the lower respiratory tract. Here, we characterize the dynamics of aerosolization and show the effects of vaccine concentration on particle size, vector viability, and the actual delivered dose of an aerosolized adenoviral vector. In addition, we demonstrate that aerosol delivery of a recombinant adenoviral vaccine encoding H1N1 hemagglutinin is immunogenic and protects ferrets against homologous viral challenge. Overall, aerosol delivery offers comparable protection to intramuscular injection, and represents an attractive vaccine delivery method for broad-based immunization campaigns. PMID- 22103777 TI - U.S. Department of Health adverse event reporting policies for nursing homes. AB - The objectives of this study were to describe state policies for the frequency of adverse event reporting and follow-up that occurs in U.S. nursing homes, and to identify the health information technology used to facilitate these processes. The study was conducted using a mailed survey to the Departments of Health (DOH) in all 50 states, specifically the department that is responsible for the oversight and regulation of nursing home care. Thirty-two state DOH representatives participated. The primary variables examined were (1) which incidents were most commonly reported to state DOH and (2) whether or not they were followed up with a surveyor visit to the nursing home. There was wide variation in incident reporting processes across all states and lack of a standardized process. Abuse is the only adverse event that almost always is required to be reported to the state DOH and has the highest incidence of follow up with a surveyor visit. Improving and standardizing adverse event reporting systems is a necessary strategy to enhance patient safety in nursing homes. This study provides an important step by increasing our knowledge base of the current state of adverse event reporting policies and processes at the state level. PMID- 22103778 TI - Short stay and less pain after ambulatory anterior cruciate ligament (ACL) repair: COX-2 inhibitor versus glucocorticoid versus both combined. AB - BACKGROUND: Many studies have demonstrated that either COX-2 antagonists or glucocorticoids are efficient analgesics after orthopaedic surgery. We wanted to evaluate if the combination of these two drugs was better than one drug alone when added to paracetamol, local anaesthesia, and cryo-cuff for outpatient anterior crucial ligament (ACL) surgery. METHODS: In a double-blind design, 89 adult patients scheduled for day-case ACL repair in general anaesthesia were randomly assigned into three groups: The COXIB group (n = 30) received either 40 mg parecoxib iv or 120 mg etoricoxib orally 1 h before surgery. The STEROID group (n = 30) received 8 mg dexamethasone iv, and the combination group (Group COMBI, n = 29) received both. RESULTS: At 24 h, Group COMBI had significantly lower visual analogue scale (0-10 cm) scores during rest (2.1 +/- 1.3) (mean +/- standard deviation) and movement (4.2 +/- 2.5) when compared to both the COXIB group (P = 0.04) and the STEROID group (P = 0.035). The accumulated consumption of rescue opioids (5.2 +/- 4,5 mg morphine) was also significantly lower at 24 h compared to the other groups (P = 0.02). Mean time to discharge from hospital was about 3 h in all groups. The pain scores in the post-anaesthetic care unit, mobilization at 24 h and 7 days, and general level of satisfaction were similar between the groups. CONCLUSION: The combination of a COX-2 inhibitor and dexamethasone results in better pain relief 24 h after surgery in patients undergoing outpatient ACL surgery, compared to COX-2 inhibitor alone or dexamethasone alone. With a dedicated multimodal pain regime, most ACL patients may be discharged within 3 h. PMID- 22103779 TI - Bisphosphonate therapy for osteoporosis: combining optimal fracture risk reduction with patient preference. AB - OBJECTIVE: To review current use of bisphosphonates as first-line therapy for osteoporosis, with an emphasis on the importance of patient compliance and persistence. METHODS: The US National Library of Medicine was used to obtain the relevant information on current bisphosphonate treatment for osteoporosis management, and patient compliance and persistence with treatment. RESULTS: Bisphosphonates have demonstrated efficacy in fracture risk reduction, although differences may exist with respect to both onset of action and the site of fracture risk reduction. Good compliance and persistence with osteoporosis therapy is needed to reduce fracture risk, but currently the willingness of patients to conform to their prescribed course of treatment is suboptimal. Intermittent dosing schedules have been developed to facilitate ease of medication-taking in order to help improve rates of compliance and persistence. When primary care physicians provide patients with information about the established efficacy and safety of medications, as well as clarifying the crucial link between continued, consistent treatment and fracture risk reduction, patients are more likely to understand the importance of taking their medications consistently in order to maximize the effectiveness of the therapy. CONCLUSIONS: A therapy that provides vertebral and nonvertebral efficacy, is well-tolerated, and offers a flexible dosing regimen is likely to enhance patient compliance and persistence, and provide optimal fracture protection. Numerous studies have consistently demonstrated that medication compliance and persistence are well correlated with fracture risk reduction. PMID- 22103780 TI - Histologic and histomorphometric assessment of implants and periapical tissues when placed in the sockets of extracted teeth, teeth with periapical lesions, and healed lesions: a canine study. AB - Eighteen canine mandibular premolars were divided into 3 groups. In group 1, implants were inserted in periapical lesions. In group 2, implants were inserted when lesions were radiographically healed. In group 3 (control), implants were inserted immediately after extraction. There was no significant difference in average bone implant contact between the 3 groups. Considering the limitations of this study, immediate placement of dental implants in tooth sockets with periapical lesions should be proposed only under special circumstances. PMID- 22103781 TI - Fracture patterns on the infant porcine skull following severe blunt impact. AB - The objective of this study was to document patterns of fracture on infant porcine skulls aged 2-28 days (n = 57) because of a single, high energy blunt impact to the parietal bone with rigid (nondeformable) and compliant (deformable) interfaces. Fracture patterns were mapped using Geographic Information System software. For the same generated impact force, the rigid interface produced more fractures than the compliant interface for all ages. This study also showed that this increased level of impact energy versus an earlier study using a lower energy resulted in new sites of fracture initiation and also caused previously defined fractures that propagate into an adjacent bone. Several unique characteristics of bone and diastatic fracture were documented as a function of specimen age, impact energy, and interface. These data describe some baseline characteristics of skull fracture using an animal model that may help guide future studies from forensic case files. PMID- 22103782 TI - Low incidence and severity of oral mucositis in allogeneic stem cell transplantation after conditioning with treosulfan and fludarabine. PMID- 22103783 TI - Adaptive and qualitative changes in encoding strategy with experience: evidence from the test-expectancy paradigm. AB - Three experiments demonstrated learners' abilities to adaptively and qualitatively accommodate their encoding strategies to the demands of an upcoming test. Stimuli were word pairs. In Experiment 1, test expectancy was induced for either cued recall (of targets given cues) or free recall (of targets only) across 4 study-test cycles of the same test format, followed by a final critical cycle featuring either the expected or the unexpected test format. For final tests of both cued and free recall, participants who had expected that test format outperformed those who had not. This disordinal interaction, supported by recognition and self-report data, demonstrated not mere differences in effort based on anticipated test difficulty, but rather qualitative and appropriate differences in encoding strategies based on expected task demands. Participants also came to appropriately modulate metacognitive monitoring (Experiment 2) and study-time allocation (Experiment 3) across study-test cycles. Item and associative recognition performance, as well as self-report data, revealed shifts in encoding strategies across trials; these results were used to characterize and evaluate the different strategies that participants employed for cued versus free recall and to assess the optimality of participants' metacognitive control of encoding strategies. Taken together, these data illustrate a sophisticated form of metacognitive control, in which learners qualitatively shift encoding strategies to match the demands of anticipated tests. PMID- 22103784 TI - Neural correlates of creativity in analogical reasoning. AB - Brain-based evidence has implicated the frontal pole of the brain as important for analogical mapping. Separately, cognitive research has identified semantic distance as a key determinant of the creativity of analogical mapping (i.e., more distant analogies are generally more creative). Here, we used functional magnetic resonance imaging to assess brain activity during an analogy generation task in which we varied the semantic distance of analogical mapping (as derived quantitatively from a latent semantic analysis). Data indicated that activity within an a priori region of interest in left frontopolar cortex covaried parametrically with increasing semantic distance, even after removing effects of task difficulty. Results implicate increased recruitment of frontopolar cortex as a mechanism for integrating semantically distant information to generate solutions in creative analogical reasoning. PMID- 22103785 TI - The influence of forward and backward associative strength on false recognition. AB - In an experiment, I examined the influence of 2 associative factors on false memory in the Deese-Roediger-McDermott paradigm (Deese, 1959; Roediger & McDermott, 1995): the strength of the association from studied items to unstudied lure items (backward associative strength, or BAS) and the strength of the association from unstudied lure items to studied items (forward associative strength, or FAS). BAS and FAS were manipulated, and participants were asked to respond rapidly at retrieval or were allowed to respond in a self-paced manner in order to examine the contributions of automatic and controlled memory processes to lure errors. The results of this study demonstrated that both BAS and FAS influenced lure errors under speeded retrieval conditions and under self-paced retrieval conditions, as well as that lure errors generally increased when retrieval time increased. These results favor the explanation of false memory offered by global-matching models over those of activation-monitoring theory and fuzzy-trace theory. PMID- 22103786 TI - Tracking cognitive phases in analogical reasoning with event-related potentials. AB - Analogical reasoning consists of multiple phases. Four-term analogies (A:B::C:D) have an encoding period in which the A:B pair is evaluated prior to a mapping phase. The electrophysiological timing associated with analogical reasoning has remained unclear. We used event-related potentials to identify neural timing related to analogical reasoning relative to perceptual and semantic control conditions. Spatiotemporal principal-components analyses revealed differences primarily in left frontal electrodes during encoding and mapping phases of analogies relative to the other conditions. The timing of the activity differed depending upon the phase of the problem. During the encoding of A:B terms, analogies elicited a positive deflection compared to the control conditions between 400 and 1,200 ms, but for the mapping phase analogical processing elicited a negative deflection that occurred earlier and for a shorter time period, between 350 and 625 ms. These results provide neural and behavioral evidence that 4-term analogy problems involve a highly active evaluation phase of the A:B pair. PMID- 22103787 TI - Mixing metaphors in the cerebral hemispheres: what happens when careers collide? AB - Are processes of figurative comparison and figurative categorization different? An experiment combining alternative-sense and matched-sense metaphor priming with a divided visual field assessment technique sought to isolate processes of comparison and categorization in the 2 cerebral hemispheres. For target metaphors presented in the right visual field/left cerebral hemisphere (RVF/LH), only matched-sense primes were facilitative. Literal primes and alternative-sense primes had no effect on comprehension time compared to the unprimed baseline. The effects of matched-sense primes were additive with the rated conventionality of the targets. For target metaphors presented to the left visual field/right cerebral hemisphere (LVF/RH), matched-sense primes were again additively facilitative. However, alternative-sense primes, though facilitative overall, seemed to eliminate the preexisting advantages of conventional target metaphor senses in the LVF/RH in favor of metaphoric senses similar to those of the primes. These findings are consistent with tightly controlled categorical coding in the LH and coarse, flexible, context-dependent coding in the RH. PMID- 22103788 TI - Zeta potential time dependence reveals the swelling dynamics of wood cellulose nanofibrils. AB - In this paper, we present the swelling dynamics of individual wood cellulose nanofibrils (CNFs) following solvent substitution into various organic solvents and drying, by employing the time dependence of the zeta potential (zeta). We succeeded in smoothly redispersing the coaggregating CNFs dried in solvents, including acetone, acetonitrile, DMSO, ethanol, and t-butanol into water. zeta-t plots of the redispersed CNFs measured in a 1 mM KCl solution indicated different values of Deltazeta (volume fraction of hydration capacity), corresponding to the dielectric constant of the substituted solvents. Differential scanning calorimetry confirmed that the redispersed CNFs swell to different degrees, corresponding to Deltazeta. This swelling behavior is characterized by expansion of hemicelluloses, the amorphous polysaccharides located on the CNF surface, with a different degree of aggregation during drying. The specific swelling ratio, radius, and diameter of the CNFs in water were calculated using the values of zeta(0) and zeta(infinity) by introducing surface chemical analysis. The calculated diameters of the CNFs at t = 0 coincided well with the median diameters measured directly by transmission electron microscope. Swellability of hemicelluloses exponentially increased with the decrease in dielectric constant of solvent during drying. The analysis method combining zeta potential time dependence and a surface chemical approach proved useful for specifically evaluating the swelling dynamics of polymers on a bulk surface. PMID- 22103789 TI - Retroperitoneal laparoendoscopic single-site ureterolithotomy: a comparison with conventional laparoscopic surgery. AB - BACKGROUND AND PURPOSE: Laparoendoscopic single-site (LESS) surgery through the retroperitoneal approach has been seldom reported. We aimed to compare the feasibility and outcomes of LESS and conventional laparoscopic surgery via the retroperitoneal approach in the management of large, impacted ureteral stones. PATIENTS AND METHODS: From June 2010 to May 2011, LESS ureterolithotomy through the retroperitoneal approach was performed in 10 patients (the LESS group). Another 15 patients who underwent conventional retroperitoneal laparoscopic ureterolithotomy (the conventional laparoscopic group) by the same surgeon were involved and compared. The operative time, complications, and surgical outcomes were evaluated. RESULTS: All the operations were completed successfully, without conversion to conventional laparoscopic or open surgeries. The operative time of the LESS group and of the conventional laparoscopic group were 132.7+/-16.3 and 128.1+/-20.1 minutes, respectively (P=0.782). The estimated blood loss were 30.7+/-5.9 vs 28.0+/-4.5 mL (P=0.620). Duration of analgesia postoperatively was 2.0+/-0.8 vs 3.5+/-0.5 days (P=0.005). All targeted stones were successfully extracted without major complications. Postoperative urine leakage was noted in one patient in each group. Cosmetic results were superior in the LESS group according to both the study nurse's and the patients' assessments (8.5 vs 5.3; P=0.012, and 8.3 vs 5.6; P=0.025, respectively). All patients showed no obstructions or stricture formations on postoperative follow-up. CONCLUSIONS: In experienced hands, LESS for ureterolithotomy through the retroperitoneal approach is feasible and can acquire outcomes equal to those of conventional multiport laparoscopic surgery. Prospective long-term follow-up studies with a larger number of patients are needed to further evaluate its benefits. PMID- 22103790 TI - Hepatoprotection of emodin and Polygonum multiflorum against CCl(4)-induced liver injury. AB - CONTEXT: Polygonum multiflorum is known as a medicinal plant. It has been used as a folk medicine which showed antioxidative property. OBJECTIVE: Protective effects of the water extracts (w/v:1/10) from fresh P. multiflorum (WEP) on carbon tetrachloride (CCl(4))-induced liver damage in rats were investigated. MATERIALS AND METHODS: CCl(4) was used for inducing liver damage of SD rats, and WEP and emodin were fed for eight consecutive weeks. RESULTS: We found that emodin levels in fresh WEP was higher than that in ripening WEP. Rats were administered WEP and emodin, the main active compound, for 56 consecutive days. WEP significantly lowered the serum levels of hepatic enzyme markers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and reduced the generation of malonaldehyde. Treatment with WEP recovered glutathione S transferase and catalase activity in rats as compared to treatment with CCl(4) alone. In addition, serum tumor necrosis factor-alpha, an inflammatory marker, was found to decrease in rats treated with WEP. In histopathological evaluation, fatty degeneration and necrosis were found to be significantly decreased in the CCl(4) plus WEP treatment group. DISCUSSION AND CONCLUSION: WEP may be effective in attenuating liver damage by reducing lipid peroxidation as well as by positively modulating inflammation. PMID- 22103791 TI - The effect of follicular antimullerian hormone levels of non-obese, non hyperandrogenemic polycystic ovary syndrome patients on assisted reproduction outcome. AB - Our aim is to investigate the follicular fluid concentrations of antimullerian hormone and its effect on assisted reproductive technology (ART) outcome in non obese, non-hyperandrogenemic polycystic ovary syndrome patients. Subjects were categorized according to in vitro fertilization (IVF) indications: Group 1 PCOS (n:16), Group 2 male factor infertility (n:19) and Group 3 unexplained infertiliy patients (n:19). Follicular fluid antimullerian hormone levels (FF AMH) on the day of oocyte retrieval were analysed and ART outcome was studied. FF AMH levels in group 1, 2 and 3 were 35.70 ng/ml (median); 17.90 ng/ml (median); 17.90 ng/ml (median), respectively (p = 0.18). There were correlations between the FF AMH levels and follicle, oocyte, 2PN and embryo numbers in pathophysiology of polycystic ovary syndrome (PCOS) patients (p = 0.012; 0.024; 0.027; 0.013 respectively). There were no correlations between the FF AMHand ART outcome parameters in group 2 and 3. FF AMH levels were not different between the groups who were pregnant or not (p = 0.06). In conclusion there were no significant differences in terms of FF AMH levels in the three groups. FF AMH levels can predict the recovery of oocytes but not oocyte quality, embryo quality or pregnancy in non-obese non-hyperandrogenemic PCOS patient. PMID- 22103792 TI - Velocity map imaging and theoretical study of the Coulomb explosion of CH3I under intense femtosecond IR pulses. AB - The Coulomb explosion of CH(3)I in an intense (10-100 TW cm(-2)), ultrashort (50 fs) and nonresonant (804 nm) laser field has been studied experimentally and justified theoretically. Ion images have been recorded using the velocity map imaging (VMI) technique for different singly and multiply charged ion fragments, CH(3)(p+) (p = 1) and I(q+) (q <= 3), arising from different Coulomb explosion channels. The fragment kinetic energy distributions obtained from the measured images for these ion fragments show significantly lower energies than those expected considering only Coulomb repulsion forces. The experimental results have been rationalized in terms of one-dimensional wave packet calculations on ab initio potential energy curves of the different multiply charged species. The calculations reveal the existence of a potential energy barrier due to a bound minimum in the potential energy curve of the CH(3)I(2+) species and a strong stabilization with respect to the pure Coulombic repulsion for the higher charged CH(3)I(n+) (n = 3, 4) species. PMID- 22103793 TI - In situ trace analysis of oil in water with mid-infrared fiberoptic chemical sensors. AB - The determination of trace amounts of oil in water facilitates the forensic analysis on the presence and origin of oil in the aqueous environment. To this end, the present study focuses on direct sensing schemes for quantifying trace amounts of oil in water using mid-infrared (MIR) evanescent field absorption spectroscopy via fiberoptic chemical sensors. MIR transparent silver halide fibers were utilized as optical transducer for interrogating oil-in-water emulsions via the evanescent field emanating from the waveguide surface, and penetrating the surrounding aqueous environment by a couple of micrometers. Unmodified fibers and fibers surface-modified with grafted epoxidized polybutadiene layers enabled the direct detection of crude oil in a deionized water matrix at the ppm level to ppb concentration level, respectively. Thus, direct chemical sensing of crude oil IR signatures without any sample preparation as low as 46 ppb was achieved with a response time of a few seconds. PMID- 22103794 TI - The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis. AB - BACKGROUND: An association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognized. However, the disease course of IBD following liver transplantation (LT) for PSC remains ill-defined. AIMS AND METHODS: We aimed to assess the impact of IBD in patients that had undergone LT for PSC to help identify risk factors for flare and to assess the impact of IBD on graft survival. RESULTS: 110 patients underwent LT for PSC (Oct 1990-Aug 2009) at King's College Hospital. 74 (67%) patients had concurrent IBD and 36 had PSC alone prior to transplant. 39 patients developed IBD (flare of IBD and de-novo) post transplant. Cumulative risk for IBD at 1-, 2-, 5- and 10-years was 16%, 24%, 38% and 72% respectively. Flare of IBD occurred in 33 patients with a mean time to flare of 30 +/- 28 months. De-novo IBD occurred in 6 patients (all UC). Mean time to diagnosis was 29 +/- 25 months. Multivariate cox-regression analysis identified active IBD at time of LT as a significant predictor of graft failure post LT (HR 10, CI 3-39, P = 0.001) and smoking at time of transplantation and subsequent cessation predictive of recurrent IBD post transplantation (HR 17, 2 180, P = 0.02). CONCLUSION: In conclusion, smoking at time of LT was predictive of flare of IBD and active IBD at time of transplantation had a significant effect on graft survival. Medical therapy needs to be maximised in the pre-LT period. Patients with poorly controlled IBD refractory to medical therapy should be considered for colectomy at time of transplantation. PMID- 22103795 TI - Patient change processes in psychotherapy: development of a new scale. AB - There is considerable interest in understanding and augmenting the process of change in psychotherapy. In this study qualitative and quantitative analyses were used to examine patient processes associated with change in recorded psychotherapy sessions from the Christchurch Psychotherapy for Depression Study. The sample consisted of 177 outpatients with a primary diagnosis of major depressive disorder randomized to receive weekly therapy sessions of Cognitive Behavior Therapy or Interpersonal Psychotherapy. Qualitative analyses identified four main themes associated with patient change. From these themes a 10-item rating scale, the Patient Psychotherapy Process Scale (PPPS), was developed. Analyses indicated the PPPS is a reliable and valid measure of important patient change processes, with higher scores associated with a better response to psychotherapy. PMID- 22103796 TI - Parasite genomics and post-genomic activities: 21st century resources for the parasite immunologist. PMID- 22103797 TI - Prevalence and clinical picture of gastroesophageal prolapse in gastroesophageal reflux disease. AB - The prevalence of gastroesophageal (GE) mucosal prolapse in patients with gastroesophageal reflux disease (GERD) was investigated as well as the clinical profile and treatment outcome of these patients. Of the patients who were referred to our service between 1980 and 2008, those patients who received a complete diagnostic work-up, and were successively treated and followed up at our center with interviews, radiology studies, endoscopy, and, when indicated, esophageal manometry and pH recording were selected. The prevalence of GE prolapse in GERD patients was 13.5% (70/516) (40 males and 30 females with a median age of 48, interquartile range 38-57). All patients had dysphagia and reflux symptoms, and 98% (69/70) had epigastric or retrosternal pain. Belching decreased the intensity or resolved the pain in 70% (49/70) of the cases, gross esophagitis was documented in 90% (63/70) of the cases, and hiatus hernias were observed in 62% (43/70) of the cases. GE prolapse in GERD patients was accompanied by more severe pain (P < 0.05) usually associated with belching, more severe esophagitis, and dysphagia (P < 0.05). A fundoplication was offered to 100% of the patients and was accepted by 56% (39/70) (median follow up 60 months, interquartile range 54-72), which included two Collis-Nissen techniques for true short esophagus. Patients who did not accept surgery were medically treated (median follow up 60 months, interquartile range 21-72). Persistent pain was reported in 98% (30/31) of medical cases, belching was reported in 45% (14/31), and GERD symptoms and esophagitis were reported in 81% (25/31). After surgery, pain was resolved in 98% (38/39) of the operative cases, and 79% (31/39) of them were free of GERD symptoms and esophagitis. GE prolapse has a relatively low prevalence in GERD patients. It is characterized by epigastric or retrosternal pain, and the need to belch to attenuate or resolve the pain. The pain is allegedly a result of the mechanical consequences of prolapse of the gastric mucosa into the esophagus. PMID- 22103798 TI - Randomized comparison of synchronous CABG and carotid endarterectomy vs. isolated CABG in patients with asymptomatic carotid stenosis: the CABACS trial. AB - RATIONALE: High-grade carotid artery stenosis is present in 6-8% of patients undergoing coronary artery bypass graft surgery. Many cardiovascular surgeons advocate staged or synchronous carotid endarterectomy to reduce the high perioperative and long-term risk of stroke associated with multivessel disease. However, no randomized trial has assessed whether a combined synchronous or staged carotid endarterectomy confers any benefit compared with isolated coronary artery bypass grafting in these patients. AIMS: The objective of this study is to compare the safety and efficacy of isolated coronary artery bypass grafting vs. synchronous coronary artery bypass grafting and carotid endarterectomy in patients with asymptomatic high-grade carotid artery stenosis. DESIGN: Coronary Artery Bypass graft surgery in patients with Asymptomatic Carotid Stenosis (CABACS) is a randomized, controlled, open, multicenter, group sequential trial with two parallel arms and outcome adjudication by blinded observers. Patients with asymptomatic high-grade carotid stenosis scheduled for elective coronary artery bypass grafting will be assigned to either isolated coronary artery bypass grafting or synchronous coronary artery bypass grafting and carotid endarterectomy by 1 : 1 block-stratified randomization with three different stratification factors (age, gender, modified Rankin scale). STUDY: The trial started in December 2010 aiming at recruiting 1160 patients in 25 to 30 German cardiovascular centers. The composite primary efficacy end point is the number of strokes and deaths from any cause (whatever occurs first) within 30 days after operation. A 4.5% absolute difference (4% compared to 8.5%) in the 30-day rate of the above end points can be detected with >80% power. OUTCOMES: The results of this trial are expected to provide a basis for defining an evidence-based standard and will have a wide impact on managing this disease. PMID- 22103799 TI - A simple modification creates a great difference: new solid-base catalyst using methylated N-substituted SBA-15. AB - A simple modification, methylation of the nitrogen-substituted mesoporous silica SBA-15, enhances the basicity of a solid-base catalyst. The methyl group donates an electron to the nitrogen atom in the silica framework. This catalyst accelerates Knoevenagel condensation using benzaldehyde and diethyl malonate, which conventional solid-base catalysts reported to date cannot do. This report demonstrates a possible new type of base catalyst using nitrogen-substituted mesoporous silica materials. PMID- 22103800 TI - Improvement of skin surface texture by topical estradiol treatment in climacteric women. AB - BACKGROUND: Hormone replacement therapy (HRT) has been widely applied to climacteric women to improve various climacteric symptoms. Purpose of the present study is to reveal the effect of topical HRT with estradiol on skin surface texture (SST), a major determinant of skin appearance. METHODS: Estradiol 1.08 mg in gel was topically applied daily to the upper limbs of menopausal or ovariectomized women for 8 weeks. Thereafter, lower-dose estradiol 0.54 mg or placebo gel was applied for a further 16 weeks. Images of SST in the flexor forearm and cheek were captured by video microscope; fineness of texture as revealed by the number of ridges was calculated by image analysis. RESULTS: Increase in fineness of texture by topical HRT during 8 weeks was observed not only in the forearm, where estradiol was applied, but also in the cheek, an unapplied site. In women receiving topical estradiol, the fine texture tended to decline slightly but nonsignificantly during the consecutive 16-week low-dose HRT period whereas it was markedly declined in those receiving placebo gel. CONCLUSION: Topical HRT can improve age-associated decline of fineness of SST. PMID- 22103801 TI - Child abduction murder: the impact of forensic evidence on solvability. AB - This study examined 733 child abduction murders (CAMs) occurring from 1968 to 2002 to explore the influence of forensic evidence on case solvability in CAM investigations. It was hypothesized that the presence of forensic evidence connecting the offender to the crime would enhance case solvability in murder investigations of abducted children. This study examined the impact of CAM of different types of forensic evidence and the impact of the summed total of forensic evidence items on case solvability by controlling for victim age, victim race, victim gender, and victim-offender relationship. Time and distance theoretical predictors were also included. Binomial logistic regression models were used to determine whether forensic evidence was a critical solvability factor in murder investigations of abducted children. This research indicated that, while forensic evidence increased case solvability, the impact of forensic evidence on solvability was not as important as other solvability factors examined. PMID- 22103802 TI - Missing referents, psychotic symptoms, and discriminating the internal from the externalized. AB - The communicative efficacy of the speech of schizophrenia patients is compromised by the presence of references for which there are no referents. There is evidence that this kind of error is positively associated with the genetic substrate of schizophrenia. The present study was an effort to identify a cognitive process source of these errors by looking at their association with performance on an internal source memory task assessing the ability to remember what one has said out loud versus only thought. Their relationship to psychotic symptoms also was examined. A sample of 110 schizophrenic/schizoaffective outpatients, and 23 nonpsychiatric controls provided 10-min speech samples and completed a battery of memory tests. Patients' symptoms also were rated for severity. Patients performed more poorly than controls on the memory tests, and their speech contained much more frequent references without referents. Frequency of missing referents was associated with scores on the test of internal source memory, even after scores on tests of immediate memory, working memory, and external source memory were regressed out. Missing referents were also related to severity of hallucinations and delusions, and internal source memory performance was related to hallucinations. The findings of this study support the idea that missing referents, hallucinations, and delusions have some common process underpinnings. Impairment in internal source memory appears to be one such process. PMID- 22103803 TI - Higher-order structure in the trajectories of depression and anxiety following sudden involuntary unemployment. AB - Recent work on comorbidity finds evidence for hierarchical structure of mood and anxiety disorders and symptoms. This study tests whether a higher-order internalizing factor accounts for variation in depression and anxiety symptom severity and change over time in a sample experiencing a period of major life stress. Data on symptoms of depression, chronic worry, and social anxiety were collected five times across seven months from 426 individuals who had recently lost jobs. Growth models for each type of symptom found significant variation in individual trajectories. Slopes were highly correlated across symptom type, as were intercepts. Multilevel confirmatory factor analyses found evidence for a higher-order internalizing factor for both slopes and intercepts, reflective of comorbidity of depression and anxiety, with the internalizing factor accounting for 54% to 91% of the variance in slopes and intercepts of specific symptom sets, providing evidence for both a general common factor and domain-specific factors characterizing level and change in symptoms. Loadings on the higher order factors differed modestly for men and women, and when comparing African American and White participants, but did not differ by age, education, or history of depression. More distal factors including gender and history of depression were strongly associated with internalizing in the early weeks after job loss, but rates of change in internalizing were associated most strongly with reemployment. Findings suggest that stressors may contribute in different ways to the common internalizing factor as compared to variance in anxiety and depression that is independent of that factor. PMID- 22103804 TI - Elevated ambitions for fame among persons diagnosed with bipolar I disorder. AB - A growing body of evidence suggests that people with bipolar disorder are highly goal-oriented. Compared to other persons, they expend more effort to attain rewards and view goal pursuit as more important to their self-worth. Persons at risk for mania and those diagnosed with bipolar spectrum disorders have been shown to endorse highly ambitious life goals, such as becoming a multimillionaire or achieving fame. This study is the first examination of whether such elevated goals characterize persons diagnosed with bipolar I disorder. We also examined whether elevated ambitions predicted symptom change over time. Ninety-two persons with bipolar I disorder and 81 age- and sex-matched controls completed the Willingly Approached Set of Statistically Unlikely Pursuits, a measure of extremely high life ambitions. A subset of the bipolar participants completed a 3 month follow-up interview. Participants with bipolar disorder endorsed higher ambitions for popular fame than did controls; moreover, heightened ambitions for popular fame and financial success predicted increases in manic symptoms in those with bipolar disorder over the next three months. Discussion focuses on goal regulation in bipolar disorder. PMID- 22103805 TI - Celecoxib-induced erythema multiforme-type drug eruption with a positive patch test. PMID- 22103806 TI - Thymine dimer photoreversal in purine-containing trinucleotides. AB - Cyclobutane-pyrimidine dimer yields in UV-irradiated DNA are controlled by the equilibrium between forward and reverse photoreactions. Past studies have shown that dimer yields are suppressed at sites adjacent to a purine base, but the underlying causes are unclear. In order to investigate whether this suppression is the result of repair by electron transfer from a neighboring nucleobase, the yields and dynamics of the reverse reaction were studied using trinucleotides containing a cis-syn dimer (T<>T) flanked on the 5' or the 3' side by adenine or guanine. The probability of forming an excited state on T<>T or on the purine base was varied by tuning the irradiation wavelength between 240 and 280 nm. Cleavage quantum yields decrease by an order of magnitude over this wavelength range and are less than 1% at 280 nm, a wavelength that excites the purine base with more than 95% probability. Conditional quantum yields of cleavage for the trinucleotides given excitation of T<>T are similar in magnitude to the quantum yield of cleavage of unmodified T<>T. These results indicate that within experimental uncertainty all photoreversal in these single-stranded substrates is the result of direct electronic excitation of T<>T. Photolyase-like repair of T<>T due to electron transfer from an adjacent purine is negligible in these substrates. Instead, the observed variation in photoreversal quantum yields for adenine- versus guanine-flanked cis-syn dimer could be due to uncertainties in absorption cross sections or to a modest quenching effect by the purine on the excited state of T<>T. Pump-probe measurements reveal that the excited-state lifetimes of A or G in the dimer-containing trinucleotides are unperturbed by the neighboring dimer, indicating that electron transfer from purine base to T<>T is not competitive with rapid excited-state deactivation. Pump-probe measurements on unmodified T<>T in aqueous solution indicate that cleavage is most likely complete on a picosecond or subpicosecond time scale. PMID- 22103807 TI - eXframe: reusable framework for storage, analysis and visualization of genomics experiments. AB - BACKGROUND: Genome-wide experiments are routinely conducted to measure gene expression, DNA-protein interactions and epigenetic status. Structured metadata for these experiments is imperative for a complete understanding of experimental conditions, to enable consistent data processing and to allow retrieval, comparison, and integration of experimental results. Even though several repositories have been developed for genomics data, only a few provide annotation of samples and assays using controlled vocabularies. Moreover, many of them are tailored for a single type of technology or measurement and do not support the integration of multiple data types. RESULTS: We have developed eXframe - a reusable web-based framework for genomics experiments that provides 1) the ability to publish structured data compliant with accepted standards 2) support for multiple data types including microarrays and next generation sequencing 3) query, analysis and visualization integration tools (enabled by consistent processing of the raw data and annotation of samples) and is available as open source software. We present two case studies where this software is currently being used to build repositories of genomics experiments - one contains data from hematopoietic stem cells and another from Parkinson's disease patients. CONCLUSION: The web-based framework eXframe offers structured annotation of experiments as well as uniform processing and storage of molecular data from microarray and next generation sequencing platforms. The framework allows users to query and integrate information across species, technologies, measurement types and experimental conditions. Our framework is reusable and freely modifiable - other groups or institutions can deploy their own custom web-based repositories based on this software. It is interoperable with the most important data formats in this domain. We hope that other groups will not only use eXframe, but also contribute their own useful modifications. PMID- 22103808 TI - Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) of the myocardium by limb ischemia/reperfusion may mitigate cardiac damage, but its interaction with the anesthetic regimen is unknown. We tested whether RIPC is associated with differential effects depending on background anesthesia. Specifically, we hypothesized that RIPC during isoflurane anesthesia attenuates myocardial injury in patients undergoing coronary artery bypass graft (CABG) surgery, and that effects may be different during propofol anesthesia. METHODS: In a randomized, single-blinded, placebo-controlled prospective study, serum troponin I concentration (cTnI) (baseline, and 1, 6, 12, 24, 48, and 72 h postoperatively) were measured during isoflurane/sufentanil or propofol/sufentanil anesthesia with or without RIPC (three 5-min periods of intermittent left upper arm ischemia with 5 min reperfusion each) in non-diabetic patients (n = 72) with three-vessel coronary artery disease (ClinicalTrials.gov NCT01406678). RESULTS: RIPC during isoflurane anesthesia (n = 20) decreased the area under the cTnI time curve (cTnI AUC) (-50%, 190 +/- 105 ng/ml * 72 h vs. 383 +/- 262 ng/ml * 72 h, P = 0.004), and the peak (7.3 +/- 3.6 ng/ml vs. 11.8 +/- 5.5, P = 0.004) and serial (P < 0.041) postoperative cTnI when compared to isoflurane alone (n = 19). In contrast, RIPC during propofol anesthesia (n = 14) did not alter the cTnI AUC [263 +/- 157 ng/ml * 72 h vs. 372 +/- 376 ng/ml * 72 h (n = 19), P = 0.318] or peak postoperative cTnI (10.1 +/- 4.5 ng/ml vs. 12 +/- 8.2, P = 0.444). None of the patients experienced harm or side effects from the intermittent left arm ischemia. CONCLUSION: Thus, RIPC during isoflurane but not during propofol anesthesia decreased myocardial damage in patients undergoing CABG surgery. Accordingly, effects of RIPC evoked by upper limb ischemia/reperfusion depend on background anesthesia, with combined RIPC/isoflurane exerting greater beneficial effects under conditions studied. PMID- 22103809 TI - Surface derivatization strategy for combinatorial analysis of cell response to mixtures of protein domains. AB - We report a robust strategy for conjugating mixtures of two or more protein domains to nonfouling polyurethane surfaces. In our strategy, the carbamate groups of polyurethane are reacted with zirconium alkoxide from the vapor phase to give a surface-bound oxide that serves as a chemical layer that can be used to bond organics to the polymer substrate. A hydroxyalkylphosphonate monolayer was synthesized on this layer, which was then used to covalently bind primary amine groups in protein domains using chloroformate-derived cross-linking. The effectiveness of this synthesis strategy was gauged by using an ELISA to measure competitive, covalent bonding of cell-binding (III(9-10)) and fibronectin-binding (III(1-2)) domains of the cell adhesion protein fibronectin. Cell adhesion, spreading, and fibronectin matrix assembly were examined on surfaces conjugated with single domains, a 1:1 surface mixture of III(1-2) and III(9-10), and a recombinant protein "duplex" containing both domains in one fusion protein. The mixture performed as well as or better than the other surfaces in these assays. Our surface activation strategy is amenable to a wide range of polymer substrates and free amino group-containing protein fragments. As such, this technique may be used to create biologically specific materials through the immobilization of specific protein groups or mixtures thereof on a substrate surface. PMID- 22103810 TI - The new therapy schema of the various kinds of acne based on the mucosa-skin side effects of the retinoids. AB - The most common adverse effects of oral isotretinoin (>1/10) are: cheilitis, skin dryness, erythema, itching, scaling, bruising, skin atopy, conjunctivitis, dry eyes and eyelid inflammation. The aim of this work was to define an optimal dose regime of the oral isotretinoin allowing for effective reduction of sebum production and minimalization of adverse effects such as decreased skin moisturization, increase in TEWL and intensified erythema. The skin parameters were assessed using the MPA 5 diagnostic apparatus. Moisturization together with an increase in TEWL and erythema during treatment with isotretinoin seem to be crucial factors responsible for patient discomfort. The decrease in the pigment content in the skin during retinoid treatment is a favourable symptom, due to the frequent tendency of skin pigmentation disturbances in the sites after acne changes. On the basis of performed analyses it was concluded that the new therapy schema is the most advantageous form of isotretinoin dosing and it involves the use of a constant drug dose - 0.4-1.0 mg/kg body mass/day without modification during treatment. PMID- 22103811 TI - Robust analysis of the yeast proteome under 50 kDa by molecular-mass-based fractionation and top-down mass spectrometry. AB - As the process of top-down mass spectrometry continues to mature, we benchmark the next installment of an improving methodology that incorporates a tube-gel electrophoresis (TGE) device to separate intact proteins by molecular mass. Top down proteomics is accomplished in a robust fashion to yield the identification of hundreds of unique proteins, many of which correspond to multiple protein forms. The TGE platform separates 0-50 kDa proteins extracted from the yeast proteome into 12 fractions prior to automated nanocapillary LC-MS/MS in technical triplicate. The process may be completed in less than 72 h. From this study, 530 unique proteins and 1103 distinct protein species were identified and characterized, thus representing the highest coverage to date of the Saccharomyces cerevisiae proteome using top-down proteomics. The work signifies a significant step in the maturation of proteomics based on direct measurement and fragmentation of intact proteins. PMID- 22103812 TI - Platelet-activating factor (PAF) receptor binding activity of the roots of Enicosanthellum pulchrum. AB - CONTEXT: Enicosanthellum pulchrum (King) Heusden (Annonaceae) is a coniferous tree that is confined to mountain forests. The chemical constituents of this species have been studied previously; however, its biological activity has never been investigated before and is reported here for the first time. OBJECTIVE: The extracts, fractions and compounds from the roots of E. pulchrum were investigated for their inhibitory effects on platelet-activating factor (PAF) receptor binding to rabbit platelets using (3)H-PAF as a ligand. MATERIALS AND METHODS: The PAF receptor binding inhibitory effect using rabbit platelets was determined in vitro by measuring the difference between total amount of bound (3)H-PAF in the presence and the absence of excess unlabelled PAF. The compounds were isolated by bioassay-guided fractionation and their structures were elucidated by spectroscopic techniques. RESULTS AND DISCUSSION: Among the extracts tested, the ethyl acetate extract was the most active with 85.6% inhibition, while hexane and methanol extracts showed 40.2 and 42.5% inhibition, respectively. Fractionation of the ethyl acetate extract using vacuum liquid chromatography (VLC) yielded six fractions AEA(I--VI). Chromatography fraction AEA(VI) yielded a new compound, 1 (2',3',4'-trimethoxyphenyl)hexan-1-ol, while fraction AEA(III) afforded three compounds, namely liriodenine, cleistopholine and dehydroanonaine. 1-(2',3',4' Trimethoxyphenyl)hexan-1-ol, cleistopholine and dehydroanonaine showed relatively strong inhibition with IC(50) values of 26.6, 50.2 and 45.4 uM, respectively. CONCLUSION: The results suggest that these compounds could be responsible for the PAF antagonistic activity of the ethyl acetate extract of this plant. PMID- 22103813 TI - Sequence-dependent variation in the reactivity of 8-Oxo-7,8-dihydro-2' deoxyguanosine toward oxidation. AB - The goal of this study was to define the effect of DNA sequence on the reactivity of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) toward oxidation. To this end, we developed a quadrupole/time-of-flight (QTOF) mass spectrometric method to quantify the reactivity of site specifically modified oligodeoxyribonucleotides with two model oxidants: nitrosoperoxycarbonate (ONOOCO(2)(-)), a chemical mediator of inflammation, and photoactivated riboflavin, a classical one-electron oxidant widely studied in mutagenesis and charge transport in DNA. In contrast to previous observations with guanine [ Margolin , Y. , ( 2006 ) Nat. Chem. Biol. 2 , 365 ], sequence context did not affect the reactivity of ONOOCO(2)(-) with 8-oxodG, but photosensitized riboflavin showed a strong sequence preference in its reactivity with the following order (8-oxodG = O): COA ~ AOG > GOG >= COT > TOC > AOC. That the COA context was the most reactive was unexpected and suggests a new sequence context where mutation hotspots might occur. These results point to both sequence- and agent-specific effects on 8 oxodG oxidation. PMID- 22103814 TI - YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C. AB - BACKGROUND/AIMS: The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC). METHODS: YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation. RESULTS: Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24-48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression. CONCLUSIONS: A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis. PMID- 22103815 TI - Lateral augmentation of the maxilla and mandible using framework technique with allogeneic bone grafts. AB - This study aimed to evaluate the effectiveness of lateral ridge augmentation in 36 patients with severely atrophic alveolar ridge using allogeneic bone grafts in a framework technique. A thinned allogeneic cortical graft was screwed to the alveolar ridge, leaving a hollow space that was filled with particulated allogeneic cortical bone. Thirty-six patients who received surgical lateral block augmentation using allogeneic bone grafts were involved in this study. Implants were placed in a second session after a mean time of 6.3 months. The surgical technique and the reasons for failure of surgery in three patients are described. Additionally, properties of allogeneic bone grafts are reviewed. In 33 patients, dental implants were successfully installed and continued to be well maintained at the last follow-up (91.7% success). In three patients, dental implants could not be installed (8.3% failure) as the graft was lost because of wound dehiscence; however, repeat surgery was successfully carried out in all three. The use of allogeneic bone grafts in lateral ridge augmentation of the maxilla and mandible showed successful clinical results. It seems to be a reliable material for reconstructing a severely atrophic alveolar ridge. It presents a good alternative to autogenous bone regarding augmentation because it offers good ossification, less morbidity, unlimited availability and shorter duration of surgery, and lower costs. PMID- 22103816 TI - Potential role of decidual apoptosis in the pathogenesis of miscarriages. AB - To investigate the existence and the distribution of decidual apoptosis in normal pregnancies and miscarriages (spontaneous and recurrent), a comparative immunofluorescent tissue labelling of normal control (n = 12) and miscarried pregnancies (n = 24) was designed. Evaluation of the existence and distribution of decidual apoptosis in normal pregnancies and miscarriages, characterization of the apoptotic cell types and the involvement of caspase-dependent pathways was analyzed with TUNEL, anti-active caspase-3, anti-pancytokeratin and anti-CD45 antibodies. Normal decidua showed few apoptotic cells, whereas decidua from recurrent miscarriages had a significantly higher number of apoptotic cells preferentially localized to the sub-epithelial and periarteriolar regions, where the onset of decidualization occurs. Apoptosis occurred via a caspase-dependent pathway. Neither immune nor epithelial cells were positively stained for any apoptotic markers. The increased number of apoptotic cells, which are strictly restricted to the periarteriolar stroma particularly in recurrent miscarriages leads us to suggest that decidual apoptosis could result a series of cellular dysfunctions that may threaten the course of pregnancy. PMID- 22103817 TI - School-performance indicators and subjective health complaints: are there gender differences? AB - Although boys and girls are generally located in the same physical school environment, it may be experienced differently by, and have varying implications for, boys and girls. Girls like school more and achieve higher school marks, but they also perceive more school-related pressure. Based on a total sample of 8456 ninth grade pupils in Stockholm in 2004, this study uses multilevel linear regression to analyse differences between boys and girls with regard to a number of school-performance indicators (demands, motivation, teacher support and school marks) and their association with subjective health complaints. Results showed that girls perceive more demands, show greater academic motivation, perform better in school and report more emotional support from teachers than boys. In contrast, instrumental and appraisal support from teachers are more commonly reported by boys. Associations between school-performance indicators and subjective health complaints were slightly stronger for girls than for boys. Contextual variation in health complaints, especially between classes, was found only for girls. High achievement motivation and emotional teacher support in the school class was associated with better pupil health, suggesting that a positive climate in terms of motivation and support favours class health as a whole. PMID- 22103818 TI - What use are scientific nursing journals to nursing practice? PMID- 22103819 TI - Accreditation of midwife lactation consultants to perform infant tongue-tie release. AB - Infants with a tongue-tie or ankyloglossia have a short lingual frenulum, which can lead to problems with breastfeeding: attachment difficulties, nipple pain and damage, poor weight gain and eventually a reduction in milk supply. Trained clinicians can release the frenulum (frenotomy) in infants having difficulty with breastfeeding. Although traditionally performed by medical practitioners, we argue that this simple procedure is within the scope of practice of other clinicians. This paper outlines the process of setting up and maintaining credentialing for midwife lactation consultants (International Board Certified Lactation Consultants (IBCLCs)) to assess infant tongue-ties and perform frenotomy when appropriate at a tertiary maternity hospital. Since 2005, 11 midwives/IBCLCs have been credentialed to perform frenotomies at The Breastfeeding Education and Support Services at The Royal Women's Hospital in Melbourne, Australia. We believe that nurses/midwives/lactation consultants working in other settings could be trained to perform frenotomies, thus enabling faster resolution of breastfeeding problems. PMID- 22103820 TI - Developing risk management behaviours for nurses through medication incident analysis. AB - The aim of this study was to define risk management behaviours related to medication safety. Mixed methods were used to analyze 318 nursing related medication incidents reported in an Australian metropolitan hospital. Most incidents did not result in patient harm (93%). Omission of medications was the most frequent often related to patient absences from the unit or nurses failing to sign for medications. Thematic analysis resulted in the Medication Safety Subscales including 29 behavioural statements within three domains-administering medications, storage and management of medications, managing adverse events related to medications. The Medication Safety Subscales can be used by managers, educators and clinicians to reinforce the importance of medication safety. Early action by nurses may reduce patient injury. PMID- 22103821 TI - Hemodynamic and oxygenation changes in surgical intensive care unit patients with fever and fever lowering nursing interventions. AB - The purpose of this study was to determine the effects of fever and nursing interventions to lower fever on hemodynamic values and oxygenation in febrile (temperature greater than 38.3 degrees C) surgical intensive care unit patients. This retrospective study was conducted in 53 febrile patients out of 519 patients admitted to the surgical intensive care unit at a university hospital. Data were obtained from the medical records, laboratory files and nursing notes. Statistical analysis of the data was analyzed by repeated measures analysis of variance and a paired sample t-test. The average hourly urine output (F = 5.46; P = 0.002) and systolic blood pressure (F = 2.87; P = 0.03) were significantly lower after fever onset. Heart rate, respiratory rate, positive end-expiratory pressure settings and FiO(2) settings were unchanged after the development of fever. Diastolic blood pressure and oxygen saturation had non-statistically significant decreases. Nursing interventions for febrile patients consisted of medication administration (69.8%), ice (62.3%) and sponging with tepid water (62.3%). The present results showed that fever was associated with an increase in heart rate, decreased systolic arterial pressure, mean arterial pressure, oxygen saturation and hourly urine output. PMID- 22103822 TI - Understanding overweight adolescents' beliefs using the theory of planned behaviour. AB - This qualitative inquiry examined adolescents' experiences surrounding their beliefs towards being overweight. The purpose of this qualitative study was to understand behavioural, normative and control beliefs of overweight adolescents regarding losing weight, exercising and eating healthy. Purposive sampling was used to obtain 10 overweight adolescents between the ages of 13 and 19. The theory of planned behaviour was used as a theoretical framework for this study. An interview guide based on the Theory of Planned was used to conduct individual semistructured interviews. Content analysis showed that overweight adolescents exhibited positive attitudes in dealing with their weight status and valued their family's support and guidance in helping control their weight. Although friends were important to facilitate regular exercise, families, particularly mothers, were crucial in addressing healthy eating habits. Understanding the subtleties and complexities of living with childhood overweight might assist health professionals in creating more effective and developmentally sensitive interventions. PMID- 22103823 TI - The complementary and alternative medicine use among asthma and chronic obstructive pulmonary disease patients in the southern region of Turkey. AB - The aim of this descriptive study was to investigate the complementary and alternative medicine (CAM) applications and factors associated and its use among asthma and chronic obstructive pulmonary disease (COPD) patients in the southern region of Turkey. The study sample consisted of 197 patients. A percentage of 86.3 of asthma and COPD patients used at least one type of CAM. The most commonly used CAM methods are deep inhalation (51.8%), herb or herbal tea (46.7%), praying (41.1%) and applying vapour (36%). Patients generally use CAM methods for breathing comfortably, improving respiration, reducing dyspnoea, and relaxing. Patients frequently use CAM methods together with medical treatments, and they benefit from these methods without getting any harm. The rate of CAM usage is higher among patients who have a longer period of asthma and COPD and more than five symptoms of asthma and COPD. In conclusion, CAM is used commonly by asthma and COPD patients. The CAM usage rate is higher among patients who have a longer period of asthma and COPD and more than five symptoms of asthma and COPD. PMID- 22103824 TI - Mothers' experiences of pregnancy, labour and childbirth: a qualitative study in Northern Greece. AB - This qualitative study aims at describing the mothers' most positive and negative experiences during pregnancy, labour and childbirth, and at identifying the aspects of pregnancy monitoring and obstetric care that should be developed most urgently in the future. The sample consisted of 607 mothers. The data were analyzed using content analysis. Mothers who preferred vaginal delivery believe that they do not interfere with nature and, consequently, their convalescence is easier and faster. Those who selected Caesarean section stress that they feel much safer because the whole process is well organized and controlled. The mothers' experiences are closely related with their interaction with the health care professionals. Psychological support, good education and delivery preparation courses are some of the factors that could contribute to the improvement of maternal services. The basis of prenatal, intrapartum and postnatal care should be influenced by the women's experiences of pregnancy, labour and childbirth. PMID- 22103825 TI - Dying in a rural residential aged care facility: an action research and reflection project to improve end-of-life care to residents with a non-malignant disease. AB - This article describes a qualitative research project that explored issues around end-of-life care provided to residents dying from non-malignant diseases in two, rural Australian, residential aged care facilities. Reflective processes and action research were combined to work in collaboration with 14 aged nurses, associated staff and relatives of dying residents. Reflection featured in the research and included group reflection on practice stories, critical reflection during thematic analysis and reflection on action research cycles. Themes and subthemes emerged, indicating that aspects of end-of-life care needed further improvement. Major thematic concerns were prioritized for action and included the need for better pain management practices which will be discussed. Identifying these clinical issues was an important step in creating, implementing and evaluating actions. Participants reported varying degrees of success in attempting to improve end-of-life care. PMID- 22103826 TI - Self-efficacy associated with self-management behaviours and health status of South Koreans with chronic diseases. AB - Although prior research in Western societies has revealed an association between self-efficacy and both self-management behaviours and better health status, little is known about the applicability of this association in Korean populations. We examined the differences in self-management behaviours and health status among three groups according to the level of self-efficacy (high, moderate and low). We used a descriptive and correlational design, and administrated a questionnaire to 322 Korean patients with diabetes mellitus, hypertension or arthritis at three ambulatory clinics in a university medical centre. We performed the Pearson chi-square test to test for differences in proportions, and the Kruskall-Wallis and Mann-Whitney U-tests for non-parametric measures. The level of self-efficacy was associated with self-management behaviours (P < 0.05) and with better health status indices (P < 0.001) except fatigue (P < 0.277). The mean age (Mean +/- standard deviation, 53.71 +/- 12.60), the percentage of high level of education (62.4%) and the level of employment (51.4%) were significantly higher in high self-efficacy group than in low self-efficacy group or moderate self-efficacy group. Further study of the potential factors affecting any relationship between self-efficacy and fatigue is recommended. Self-efficacy enhancing interventions can be beneficial for Korean chronic patients to improve their self-management behaviours and health status. PMID- 22103827 TI - Assessment of quality of life and activities of daily living in Turkish patients with heart failure. AB - Heart failure is an entire clinical syndrome affecting many aspects of life, rather than merely a usual disease. This cross-sectional study was designed to assess heart failure patients' quality of life and activities of daily living (ADL). Seventy-five patients who applied to the cardiology department were included in the study. The data were obtained using the left ventricular dysfunction scale (LVD-36) and ADL scale. A statistically significant relationship was found between LVD-36 and ADL scores and New York Heart Association (NYHA) functional class, previous hospitalization, daily medication, age and education (P < 0.05). It was found that LVD-36 and ADL scores increase as the level of education increases and as the NYHA functional class, previous hospitalization, number of drugs taken daily and age decrease. The study found a statistically significantly negative relationship between quality of life and ADL (P < 0.05). In patients with heart failure, age, NYHA functional class, number of drugs taken daily independently affected the ADL scores. Additionally, in these patients, education, NYHA functional class, number of drugs taken daily and previous hospitalizations independently affected the quality of life. As the functional situation deteriorates and becomes severe, individual care, training, social support and consultation services for the patient and their family should be increased. PMID- 22103828 TI - Protecting and respecting military nurses. AB - There are data reported in psychological and sociological scientific literature concerning the physical and sexual abuse of members of the US Military Services with a focus on abuse of females. An extensive search of that literature found little evidence that military nurses had experienced physical or sexual abuse. An oral history project to collect accounts of wartime experiences of military nurses is currently ongoing from an institution in the western United States. A secondary analysis of data finds that project participants included almost no reports of such abuse. Rather, there were many reports that nurses were respected and protected from harm during the time of their military service. PMID- 22103829 TI - A comparison of nurses' perceptions of elective laparoscopic or elective open colorectal resections. AB - The purpose of this study was to develop an instrument to measure the perceived benefits nurses observe in the recovery of patients who have undergone elective laparoscopic colorectal resections vs. traditional open elective colorectal resections. Secondly, to determine if there are perceived differences in the intensity of nursing required to care for these patients. A twenty-three-point questionnaire was developed and distributed to 23 colorectal nurses working in a single tertiary referral hospital. There was an 83.6% response rate. The findings demonstrate that the participants believe there are significantly better outcomes for the laparoscopic patients in the postoperative period. These benefits include more rapid resumption of independence, decreased pain and fewer complications. The nurses also perceived less time and effort was required when caring for these patients. PMID- 22103830 TI - Reflections on the practice of facilitating group-based antenatal education: should a midwife wear a uniform in the hospital setting? AB - The first author of this paper, a Thai midwife, conducted a feminist action research project aimed at collaboratively developing a model for group-based antenatal education in Thailand. Should a midwife wear a uniform when facilitating midwife-led group-based antenatal education sessions in the hospital setting? This paper reports on a single example of reflection in and on midwifery practice that aimed to answer the guiding question. The practice and reflection occurred over a number of months at the beginning of the feminist action research project. The midwife should wear normal clothes when facilitating group-based antenatal education as a symbol of equality in power relationships within the group. When power relationships between women and the midwife are equalized, women are more able to take responsibility for their health as they are less likely to defer to the 'expert'. Reflection in and on practice is a powerful tool to allow the midwife to understand and change her own practice as required to meet those goals. Self-change is a critical first step because there can be no change in the way maternity care is provided without each midwife being willing to be self-aware and open to appropriate self-change. PMID- 22103831 TI - The Nef-infectivity enigma: mechanisms of enhanced lentiviral infection. AB - The Nef protein is an essential factor for lentiviral pathogenesis in humans and other simians. Despite a multitude of functions attributed to this protein, the exact role of Nef in disease progression remains unclear. One of its most intriguing functions is the ability of Nef to enhance the infectivity of viral particles. In this review we will discuss current insights in the mechanism of this well-known, yet poorly understood Nef effect. We will elaborate on effects of Nef, on both virion biogenesis and the early stage of the cellular infection, that might be involved in infectivity enhancement. In addition, we provide an overview of different HIV-1 Nef domains important for optimal infectivity and briefly discuss some possible sources of the frequent discrepancies in the field. Hereby we aim to contribute to a better understanding of this highly conserved and therapeutically attractive Nef function. PMID- 22103832 TI - Role of the CD4 down-modulation activity of Nef in HIV-1 infectivity. AB - The regulatory Nef protein of HIV-1/2 and SIV is required for high viral replication and disease progression, thus represents a very attractive therapeutic target. Because of the multi-functional nature of the Nef protein, it is unclear which of the several Nef activities are most crucial in vivo for the outcome of viral infection. Some findings indicate that the CD4 down-regulation activity of Nef is critical for viral infectivity as well as for progression to immunodeficiency. On the other hand, more recent evidences suggest that CD4 targeting and stimulation of infectivity are two separate functions of Nef. This controversial issue will be discussed here in the light of the latest findings. PMID- 22103834 TI - Nef performance in macrophages: the master orchestrator of viral persistence and spread. AB - Following transmission of human immunodeficiency virus (HIV) into a new host, cells of the monocyte/macrophage lineage play a central role in host invasion and viral replication. In particular, macrophages survive infection and support long standing viral replication, contributing to viral persistence within the host and representing a viral reservoir in vivo. On the other hand, HIV Nef protein is a small though versatile molecule that plays an unquestioned key role in viral pathogenesis. In macrophages, Nef is able to modulate cell surface receptor expression, to intersect intracellular signaling pathways and to augment the release of pro-inflammatory and chemotactic molecules. In addition, Nef can alter macrophage phagocytic capacity, autophagy machinery and metabolism. Altogether, these Nef activities support viral replication and persistence in this cell type while at the same time favor viral dissemination. Here, we will review the newest findings describing how monocytes/macrophages natural pathways are altered by Nef protein, highlighting how viral and host biology are perturbed in consequence. PMID- 22103833 TI - One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef. AB - The HIV-1, HIV-2 and SIV Nef protein are known to modulate the expression of several cell surface receptors and molecules to escape the immune system, to alter T cell activation, to enhance viral replication, infectivity and transmission and overall to ensure the optimal environment for infection outcome. Consistent and continuous efforts have been made over the years to characterize the modulation of expression of each of these molecules, in the hope that a better understanding of these processes essential for HIV infection and/or pathogenesis will eventually highlight new therapeutic targets. In this article we provide an extensive review of the knowledge gained so far on this important and evolving topic. PMID- 22103835 TI - Tetherin antagonism by primate lentiviral nef proteins. AB - The multifunctional Nef protein of primate lentiviruses is commonly considered an early viral factor that down-modulates various receptors from the cell surface and modulates several signaling pathways to facilitate viral immune evasion and to render the cell conducive for viral replication. However, Nef also acts during the late stages of infection, e.g. by increasing the infectivity of progeny virions. Just recently, it has become clear that many primate lentiviruses that have been detected in about 40 different monkey and ape species also use Nef to antagonize tetherin (BST2/CD317), a cellular factor that inhibits virus release by tethering nascent viral particles to the cell surface. Exceptions are some simian immunodeficiency viruses (SIVs) infecting Cercopithecus monkeys that employ their accessory Vpu protein to counteract the restriction by tetherin. Furthermore, pandemic HIV-1 group M strains switched from Nef to Vpu and HIV-2 group A isolates from Nef to Env after zoonotic transmission from chimpanzees and sooty mangabeys, respectively, to antagonize the tetherin restriction in humans. These evolutionary switches were most likely enforced by a deletion in the cytoplasmic domain of the human tetherin orthologue that confers resistance to Nef. Here, we summarize some of our current knowledge about Nef-mediated tetherin antagonism. PMID- 22103836 TI - The CD4C/HIV(Nef)transgenic model of AIDS. AB - CD4C/HIVNef Tg mice express HIV-1 Nef in relevant target cells through the regulatory sequences of the human CD4 gene. These mice develop a severe disease showing many characteristics of human AIDS. A summary of the results obtained with these Tg mice is presented. PMID- 22103837 TI - Interactions of the HIV/SIV pathogenicity factor Nef with SH3 domain-containing host cell proteins. AB - A bewildering number of host cell proteins associated with Nef can be found in the literature and in the public protein interaction databases. However, only in a few of these cases, including binding of Nef to certain Src homology-3 (SH3) domain proteins, is the interaction understood in any molecular detail or even known to be direct. Indeed, SH3 binding capacity by Nef is required for many of the other protein interactions to take place, suggesting that a large proportion of the latter is indirectly coupled to Nef via an SH3 protein. Accordingly, the proline-rich SH3 binding site, the "PxxP motif", is one of the key functional determinants of Nef. It is highly conserved among the lentiviral Nef proteins, and mutations disrupting it abrogate the majority of the known effects of Nef on host cell physiology. This review summarizes the current understanding as well as the outstanding gaps in our knowledge regarding the relevant SH3 protein partners and SH3-dependent cellular functions of Nef. The roles of these interactions in the pathogenesis of AIDS and their potential as targets for antiviral drug development are also discussed. PMID- 22103838 TI - Nef surfaces: where to interfere with function. AB - The HIV-1 Nef protein is an accessory protein of 24-27 kDa mass that mediates a multitude of effector functions in infected cells. Although not essentially required for viral replication, HIV-1 Nef exhibits stimulating potential towards disease progression to AIDS and is therefore considered a pathogenic factor in retroviridae. Here we correlate sequence conservation in HIV-1 Nef with surface hydrophobicity and functionality in protein-protein interaction to identify accessible substructures on the surface of Nef that might be suitable as pharmacological target sites. Recent advances in targeting of Nef by small molecular compounds that interfere with SH3 domain binding or MHC class I down regulation are discussed. Similarly, approaches for the use of larger molecules are introduced, such as tailored fusion proteins that simultaneously interact with multiple highly conserved sequence motifs of Nef. In addition, the design of a single domain antibody from llama that interferes with CD4 down-regulation activity and PAK2 binding is discussed. The flexibility in binding recognition is exemplarily shown for the modulation of RT-loop binding using engineered SH3 domains. The various considerations corroborate the potential of HIV-1 Nef as a promising target for the development of potent Nef inhibitors. PMID- 22103839 TI - Clinical utility of the AlphaFIM(r) instrument in stroke rehabilitation. AB - BACKGROUND: The AlphaFIM instrument is an assessment tool designed to facilitate discharge planning of stroke patients from acute care, by extrapolating overall functional status from performance in six key Functional Independence Measure (FIM) instrument items. AIM: To determine whether acute care AlphaFIM rating is correlated to stroke rehabilitation outcomes. METHODS: In this prospective observational study, data were analyzed from 891 patients referred for inpatient stroke rehabilitation through an Internet-based referral system. Simple linear and stepwise regression models determined correlations between rehabilitation ready AlphaFIM rating and rehabilitation outcomes (admission and discharge FIM ratings, FIM gain, FIM efficiency, and length of stay). Covariates including demographic data, stroke characteristics, medical history, cognitive deficits, and activity tolerance were included in the stepwise regressions. RESULTS: The AlphaFIM instrument was significant in predicting admission and discharge FIM ratings at rehabilitation (adjusted R2 0.40 and 0.28, respectively; P < 0.0001) and was weakly correlated with FIM gain and length of stay (adjusted R2 0.04 and 0.09, respectively; P < 0.0001), but not FIM efficiency. AlphaFIM rating was inversely related to FIM gain. Age, bowel incontinence, left hemiparesis, and previous infarcts were negative predictors of discharge FIM rating on stepwise regression. Intact executive function and physical activity tolerance of 30 to 60 mins were predictors of FIM gain. CONCLUSIONS: The AlphaFIM instrument is a valuable tool for triaging stroke patients from acute care to rehabilitation and predicts functional status at discharge from rehabilitation. Patients with low AlphaFIM ratings have the potential to make significant functional gains and should not be denied admission to inpatient rehabilitation programs. PMID- 22103840 TI - Photoluminescence of TiO2: effect of UV light and adsorbed molecules on surface band structure. AB - The photoluminescence (PL) of TiO(2) at 529.5 nm (2.34 eV) has been found to be a sensitive indicator of UV-induced band structure modification. As UV irradiation occurs, the positive surface potential changes and shifts the depth of the depletion layer. In addition, reversible band bending due to the adsorption of the electron-donor NH(3) and CO molecules has been observed in measurements combining PL with FTIR surface spectroscopy. It has been found that the O(2) molecule acts in two ways: as a reversibly adsorbed electron-acceptor molecule and as an irreversibly adsorbed molecule that heals natural oxygen vacancy defects in the near-surface region. PMID- 22103841 TI - Effect of long-term water immersion on the fracture toughness of denture base and reline resins. AB - PURPOSE: This study evaluated the fracture toughness (FT) of one denture base (Lucitone 550 - L) and four hard reline resins [Ufi Gel Hard (UH), Tokuyama Rebase II (TR), New Truliner (NT) and Kooliner (K)], and the effect of long-term water storage on this property. MATERIALS AND METHODS: Forty specimens (40 * 8 * 4 mm) of each material were made, and FT was assessed after polymerisation (control of reliners), after 48 +/- 2 h in water at 37 degrees C (control of denture base resin) and after storage in water at 37 degrees C for 7, 90 or 180 days (all materials). Data (MPa.m(1/2) ) were analysed by two-way anova and Games Howell test (p = 0.05). RESULTS: Resin L exhibited the highest FT mean values. After 180 days of storage, FT mean values of L (3.37), UH (1.53) and K (1.20) were higher than those of the other periods. FT mean values of NT decreased from control (1.63) to 7 days (1.30) and then remained constant. FT mean values of TR (1.13) were similar in all periods of analysis. CONCLUSION: The denture base resin L showed higher FT mean values than the reline resins. Long-term water storage increased the FT of L, UH and K, reduced the FT of NT and did not influence the FT of TR. PMID- 22103842 TI - Impacts of climate, host and landscape factors on Culicoides species in Scotland. AB - Culicoides biting midges (Diptera: Ceratopogonidae) vector a wide variety of internationally important arboviral pathogens of livestock and represent a widespread biting nuisance. This study investigated the influence of landscape, host and remotely-sensed climate factors on local abundance of livestock associated species in Scotland, within a hierarchical generalized linear model framework. The Culicoides obsoletus group and the Culicoides pulicaris group accounted for 56% and 41%, respectively, of adult females trapped. Culicoides impunctatus Goetghebuer and C. pulicaris s.s. Linnaeus were the most abundant and widespread species in the C. pulicaris group (accounting for 29% and 10%, respectively, of females trapped). Abundance models performed well for C. impunctatus, Culicoides deltus Edwards and Culicoides punctatus Meigen (adjusted R(2) : 0.59-0.70), but not for C. pulicaris s.s. (adjusted R(2) : 0.36) and the C. obsoletus group (adjusted R(2) : 0.08). Local-scale abundance patterns were best explained by models combining host, landscape and climate factors. The abundance of C. impunctatus was negatively associated with cattle density, but positively associated with pasture cover, consistent with this species' preference in the larval stage for lightly grazed, wet rush pasture. Predicted abundances of this species varied widely among farms even over short distances (less than a few km). Modelling approaches that may facilitate the more accurate prediction of local abundance patterns for a wider range of Culicoides species are discussed. PMID- 22103843 TI - Age of onset of marijuana use and executive function. AB - Marijuana (MJ) remains the most widely abused illicit substance in the United States, and in recent years, a decline in perceived risk of MJ use has been accompanied by a simultaneous increase in rates of use among adolescents. In this study, the authors hypothesized that chronic MJ smokers would perform cognitive tasks, specifically those that require executive function, more poorly than control subjects and that individuals who started smoking MJ regularly prior to age 16 (early onset) would have more difficulty than those who started after age 16 (late onset). Thirty-four chronic, heavy MJ smokers separated into early and late onset groups, and 28 non-MJ smoking controls completed a battery of neurocognitive measures. As hypothesized, MJ smokers performed more poorly than controls on several measures of executive function. Age of onset analyses revealed that these between-group differences were largely attributed to the early onset group, who were also shown to smoke twice as often and nearly 3 times as much MJ per week relative to the late onset smokers. Age of onset, frequency, and magnitude of MJ use were all shown to impact cognitive performance. Findings suggest that earlier MJ onset is related to poorer cognitive function and increased frequency and magnitude of MJ use relative to later MJ onset. Exposure to MJ during a period of neurodevelopmental vulnerability, such as adolescence, may result in altered brain development and enduring neuropsychological changes. PMID- 22103844 TI - Targeting mast cells and basophils in allergy and beyond: emerging concepts. AB - Since the times of P. Ehrlich, F. D. von Recklinghausen, and O.Westphal, the research on mast cells and basophils made significant progression towards the recognition of their involvement in antimicrobial functions and of their role in mobilizing inflammation in wound healing, allergy, and autoimmunity. However, the role of mast cells in normal physiology is still poorly understood. Only in recent years, these cells are increasingly recognized as important effectors in number of pathways related mostly to tissue remodeling. The mast cells are capable to orchestrate inflammatory reactions and angiogenesis, they are frequently present near pre-neoplastic epithelial cells, etc. Absolute mast cell deficiency, as in the cross of Min mice to the C57BL/6-KitWsh/Wsh mice, can have overreaching immunological consequences. PMID- 22103845 TI - Targeting cardiac mast cells: pharmacological modulation of the local renin angiotensin system. AB - Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3 receptors. Once activated, cardiac mast cells release a host of potent pro inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local renin-angiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3 receptor activation. PMID- 22103846 TI - Mast cells and basophils: trojan horses of conventional lin- stem/progenitor cell isolates. AB - Cancer microenvironment is increasingly recognized as an important factor affecting cancer onset and progression. Since Wirchow reported in 1863 that tumors contain inflammatory cells, the field shifted significantly forward, and immune cells residing in tumors appear to be attractive targets of cancer therapies. For some methods, such as stem/progenitor cell isolation from both cancer and healthy tissues, removal of contaminating immune cells is crucial to achieve consistent, reproducible and accurate results. Despite current methods of lineage negative selection accounts for removal of over 99 % of immune cells from stem/progenitor cell isolates, the vast majority of lineage antibody cocktails retain basophils, dendritic cells, and mast cells. Here we discuss the ability of the most commonly used lineage markers to bind to the plasma membrane of mast cells and/or basophils, and suggest alternatives, which may be used for negative selection of these cellular populations. Both, mast cells and basophils, were shown to participate actively in cancer-associated angiogenesis, tissue remodeling and recruitment of other immune cell types, including eosinophils, B cells, memory T cells and Treg cells. In turn, tumor-derived peptides and chemotactic factors are known to recruit and activate mast cells in neoplasias, resulting in altered tumor progression. Repeated findings of CD34+ populations of mast cells and basophils further highlight necessity of their separation from stem/progenitor cell isolates in both, preclinical experiments and clinical praxis. PMID- 22103847 TI - Mast cells in tissue healing: from skin to the gastrointestinal tract. AB - Mast cells are largely found at interfaces between the environment and the internal milieu. Early knowledge of the mast cell suggested a role predominantly associated with allergy and pathologic response to antigens, but more recent research has shown a myriad of functions is likely. Wound healing is a complex process of lysis and reconstitution controlled by a series of cell signalling proteins. Mast cells have been shown to play a significant role in the early inflammatory stage of wound healing and also influence proliferation and tissue remodelling in skin. Emerging work implicates the mast cell as a modulator of intestinal healing particularly following surgical anastomosis. The study of mast cells and wound healing involves the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addresses wound healing in skin and the gastrointestinal tract and specifically identifies data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration. PMID- 22103848 TI - IL-19 as a potential therapeutic in autoimmune and inflammatory diseases. AB - Interleukin-19 (IL-19) is a member of the IL-10 family of cytokines. The last ten years from the finding of IL-19, investigations underline the role of IL-19 in the immunological diseases. It is known that expression of IL-19 is increased in the epidermis of patients with psoriasis, which is a Th1 dominant disease. Increased concentration of IL-19 has also been found in the serum of patients with asthma, which is a Th2 dominant disease. There is an increasing body of data demonstrating that IL-19 is associated with the pathogenesis of both Th1 and Th2 dominant diseases. Regarding the role of IL-19 on the innate immunity and inflammation, interestingly, in vitro studies have shown that lipopolysaccharide can stimulate human monocytes and macrophages to upregulate the expression of IL 19. IL- 19 is upregulated in macrophages after infection and lessens inflammation by suppressing the production of tumor necrosis factor-alpha , IL-6 and IL-12, but not by inducing IL-10. In addition, IL-19-deficient mice are susceptible to experimental colitis induced by dextran sodium sulfate, a disease which is characterized by excessive inflammatory responses of local macrophages and epithelial cells to intestinal microflora. In this review, we discuss our current understanding of the role of IL-19 in autoimmune and inflammatory diseases. PMID- 22103849 TI - Interleukin-25: key regulator of inflammatory and autoimmune diseases. AB - Polarization of naive T cells in a certain functional direction is influenced not only by antigen type and concentration, but also by co-stimulatory signals, the local cytokine environment and transcription factors that activate or inhibit specific T cell lineage programs through positive or negative feedback loops. Interleukin-25 (IL-25) is a recently identified member of the IL-17 cytokine family. It has the ability to influence innate and adaptative immunity. Within the IL-17 family, IL-25 possesses the lowest degree of homology to IL- 17A, does not share common biological functions with other members of the IL-17 cytokine family, and instead has been been implicated in the promotion of Th2 immunity. IL 25 drives the expression of IL-4, IL-5, and IL-13, thereby contributing to allergic disease. Although our understanding of the biology of IL-25 is increasing, how IL-25 is regulated is still poor. On the other hand, recent studies have shown a novel anti-inflammatory role for IL-25 as a key factor in the attenuation of IL-17-mediated inflammation, such as in colitis, encephalomyelitis, and diabetes mellitus. Thus, IL-25 and IL-17, being members of the same cytokine family, seem to play opposing roles in the pathogenesis of autoimmune diseases. In this article, we review the dual roles of IL-25 in immune responses, the molecular basis for these effects, and the potential therapeutic implications. PMID- 22103850 TI - CD164 as a Basophil Activation Marker. AB - Introduction of flow cytometric technique to the research on basophil activation has led to significant achievements in allergy diagnosis in vitro. Most of the studies employing the flow cytometry used CD63 as a marker of basophil activation and only some of them used CD203c. Recently discovered basophil activation markers, including CD164, opened new possibilities for solving majority of current diagnostic needs. Use of allergen-induced CD164 upregulation in diagnosis of pollen allergy has been validated, and this encourages to further studies on other diagnostic usefulness of this marker. There are some hopeful data indicating that it might be useful in diagnosis of allergy caused by variety of other allergens, including drug allergens. Although CD164 upregulation as a marker of basophil activation is a promising and powerful diagnostic tool, it still requires a lot of both basic research and comparative studies with older and well known markers, in order to select the best of them. A research on basophil CD164 upregulation caused by various stimuli offers a good possibility to increase our knowledge of basophil's involvement in allergic inflammation. Moreover, this might trigger a variety of pharmacological studies with known and new anti-inflammatory drugs in the future. PMID- 22103851 TI - Mast cells as sources and targets of membrane vesicles. AB - In addition to being major effector cells in the elicitation of allergic responses, mast cells have been found to play a significant role in the establishment of innate and adaptive immune responses. This occurs, in part, by regulating the phenotype and function of immune cells such as T cells, B cells and dendritic cells, and by acting as antigen presenting cells. Indeed, mast cells have been found to be activated in various T cell-mediated inflammatory processes and to reside in close physical proximity to T cells. Such observations have led investigators to propose a functional relationship between these two cell populations. Mast cells can interact with other cells including T cells in several ways such as cell-cell interaction via membrane associated receptors, release of cytokines and chemokines or by heterotypic adhesion to activated T cells. In this review, we focus on a novel communication pathway between mast cells and other inflammatory cells that occurs by the release of or response to membrane vesicles. Membrane vesicles are circular fragments, released from the endosomal compartment as exosomes or shed from the cell plasma membrane as microparticles. Because their membrane orientation is the same as that of the donor cell, they can be considered to be miniature versions of a cell. Growing evidence indicates that microparticles play a pivotal role in cell to cell communication. The functional consequences of such membrane transfers include the induction, amplification and/or modulation of immune responses, as well as the acquisition of new functional properties by recipient cells. PMID- 22103852 TI - Autoimmunity-inducing metals (Hg, Au and Ag) modulate mast cell signaling, function and survival. AB - The three heavy metals, mercury, gold and silver commonly and specifically induce aberrant immunological responses leading to autoimmune disorders in genetically susceptible animals and humans. The disorders are characterized by autoantibody production, increases in serum IgG and IgE, polyclonal activation of B and T lymphocytes and renal immune complex deposition and glomerulonephritis. Mast cells play key roles in allergic and inflammatory reactions. A growing body of evidence suggests that mast cells are key players in innate and adaptive immunity and involved in autoimmune diseases. Mast cells are also direct targets for autoimmunity-inducing metals both in vitro and in vivo and play a role in the development of metal-induced autoimmune disorders. The three metals specifically modulate mast cell function, including degranulation and secretion of arachidonic acid metabolites and cytokines such as interleukin-4. Divergent signaling components, including mitogen-activated protein kinase activation, reactive oxygen and nitric oxide generation and Ca2+ influx are modulated by the metals. Furthermore, the metals have considerable impacts on mast cell survival, which also species seems to be involved in the development of metal-induced autoimmune disorders. In this review, we provide an overview of recent advances in our understanding of the impacts of the three metals on mast cell signaling, function and survival and their possible roles in the pathologies of metal-induced autoimmunity. PMID- 22103853 TI - PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases. AB - It is well established that mast cells play a key regulatory role in allergy and inflammation involving engagement of antigen with IgE bound to high-affinity IgE receptors (FcepsilonRI). The most aggressive efforts in regulating mast cell function have focused on selectively inhibiting cell activation and subsequent mediator synthesis and release, or alternatively, blocking the action of proinflammatory mediators in order to prevent or reduce disease severity. More recently, the goal for rationally designed pharmacotherapy has shifted focus to targeting and disrupting signaling pathways leading to inhibition of specific cell function(s). In this context, the PI-3K/PIP3/Akt pathway represents a potent target for pharmacologic intervention in mast cell-mediated inflammatory disorders. A pivotal component of this cascade is the activation of phosphatidylinositol-3-kinase (PI-3K) leading to a rise in intracellular levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 has broad effects on mast cell signaling and function as well as on proliferation and survival. We propose that PIP3 represents a potent target for developing therapeutic approaches to down regulate mast cell function and, in turn, reduce the severity of mast cell dependent disease. In this article we review approaches that have been taken to regulate the PI-3K pathway in mast cells. Moreover, we review a novel approach to target the signaling lipid, PIP3, and deplete intracellular levels of this phosphoinositol using a chimeric toxin composed of the FcepsilonRI binding region of IgE and the active subunit of the cytolethal distending toxin, CdtB, which we have recently demonstrated to function as a PIP3 phosphatase. PMID- 22103854 TI - Modulation of mast cell and basophil functions by benzene metabolites. AB - Benzene is a carcinogenic compound used in industrial manufacturing and a common environmental pollutant mostly derived from vehicle emissions and cigarette smoke. Benzene exposure is associated with a variety of clinical conditions ranging from hematologic diseases to chronic lung disorders. Beside its direct toxicity, benzene exerts multiple effects after being converted to reactive metabolites such as hydroquinone and benzoquinone. Mast cells and basophils are primary effector cells involved in the development of respiratory allergies such as rhinitis and bronchial asthma and they play an important role in innate immunity. Benzene and its metabolites can influence mast cell and basophil responses either directly or by interfering with other cells, such as T cells, macrophages and monocytes, which are functionally connected to mast cells and basophils. Hydroquinone and benzoquinone inhibit the release of preformed mediators, leukotriene synthesis and cytokine production in human basophils stimulated by IgE- and non IgE-mediated agonists. Furthermore, these metabolites reduce IgE-mediated degranulation of mast cells and the development of allergic lung inflammation in rats. Both in vitro and in vivo studies indicate that benzene metabolites alter biochemical and functional activities of other immunocompetent cells and may impair immune responses in the lung. These inhibitory effects of benzene metabolites are primarily mediated by interference with early transduction signals such as PI3 kinase. Together, currently available studies indicate that benzene metabolites interfere by multiple mechanisms with the role of basophils and mast cells in innate immunity and in chronic inflammation in the lung. PMID- 22103855 TI - Latent fingermark development on a range of porous substrates using ninhydrin analogs--a comparison with ninhydrin and 1,8-diazofluoren. AB - Three relatively new reagents for developing latent fingermarks on porous substrates, 1,2-indandione (IND), 5-methylthioninhydrin (5-MTN), and lawsone, are compared with the more widely used ninhydrin and 1,8-diazofluoren (DFO). Developed latent fingermark visualization on 10 different substrates comprising colored papers, cardboard, and cellophane rather than conventional printer and writing/notepad paper is assessed using latent fingermark deposits from 48 donors. Results show improved fluorescent fingermark visualization using IND compared with DFO on a range of colored cardboards and thick white paper, thus extending the range of substrates known to yield improved visualization with IND. Adding zinc chloride to IND failed to yield any further improvement in fluorescent fingermark visualization. 5-MTN (with and without zinc chloride posttreatment) showed no improvement in visualization compared with ninhydrin and DFO although visible fingermarks were developed. Lawsone produced fluorescent visible fingermarks only with white substrates, which were inferior to those produced with DFO. PMID- 22103856 TI - A phylogeny and molecular barcodes for Caenorhabditis, with numerous new species from rotting fruits. AB - BACKGROUND: The nematode Caenorhabditis elegans is a major laboratory model in biology. Only ten Caenorhabditis species were available in culture at the onset of this study. Many of them, like C. elegans, were mostly isolated from artificial compost heaps, and their more natural habitat was unknown. RESULTS: Caenorhabditis nematodes were found to be proliferating in rotten fruits, flowers and stems. By collecting a large worldwide set of such samples, 16 new Caenorhabditis species were discovered. We performed mating tests to establish biological species status and found some instances of semi-fertile or sterile hybrid progeny. We established barcodes for all species using ITS2 rDNA sequences. By obtaining sequence data for two rRNA and nine protein-coding genes, we determined the likely phylogenetic relationships among the 26 species in culture. The new species are part of two well-resolved sister clades that we call the Elegans super-group and the Drosophilae super-group. We further scored phenotypic characters such as reproductive mode, mating behavior and male tail morphology, and discuss their congruence with the phylogeny. A small space between rays 2 and 3 evolved once in the stem species of the Elegans super-group; a narrow fan and spiral copulation evolved once in the stem species of C. angaria, C. sp. 8 and C. sp. 12. Several other character changes occurred convergently. For example, hermaphroditism evolved three times independently in C. elegans, C. briggsae and C. sp. 11. Several species can co-occur in the same location or even the same fruit. At the global level, some species have a cosmopolitan distribution: C. briggsae is particularly widespread, while C. elegans and C. remanei are found mostly or exclusively in temperate regions, and C. brenneri and C. sp. 11 exclusively in tropical zones. Other species have limited distributions, for example C. sp. 5 appears to be restricted to China, C. sp. 7 to West Africa and C. sp. 8 to the Eastern United States. CONCLUSIONS: Caenorhabditis are "fruit worms", not soil nematodes. The 16 new species provide a resource and their phylogeny offers a framework for further studies into the evolution of genomic and phenotypic characters. PMID- 22103857 TI - Reproducibility of observables and coherent control in molecular photoionization: from continuous wave to ultrashort pulsed radiation. AB - One-photon single ionization of molecules has been at the focus of several discussions concerning the reconstruction of observables obtained with ultrashort pulses from those obtained from continuous wave radiation (and vice versa). A related controversy on the conditions and observables that allow for coherent control in one-photon processes has been recently revisited (Science 2006, 313, 1257; J. Chem. Phys. 2010, 133, 151101). Our benchmark to investigate these issues is photoionization of the hydrogen molecule, where the autoionization events are the time-dependent processes in field-free evolution that could serve as a target for coherent control. We show that the variation of one-photon ionization probabilities with pulse duration are solely due to spectral effects and thus cannot be coherently controlled. We then discuss for which observables and under which conditions phase control of autoionization dynamics is possible. PMID- 22103858 TI - Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer. AB - The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, clopidogrel, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is a classical cytochrome P450 (P450) dependent monooxygenation of its thiophene ring leading to 2-oxo-clopidogrel, a thiolactone metabolite. The second step was described as a P450-dependent oxidative opening of the thiolactone ring of 2-oxo-clopidogrel, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding thiol 4b. A very recent paper published in Nat. Med. (Bouman et al., (2011) 17, 110) reported that the second step of clopidogrel bioactivation was not catalyzed by P450 enzymes but by paraoxonase-1(PON-1) and that PON-1 was a major determinant of clopidogrel efficacy. The results described in the present article show that there are two metabolic pathways for the opening of the thiolactone ring of 2-oxo-clopidogrel. The major one, that was previously described, results from a P450-dependent redox bioactivation of 2-oxo-clopidogrel and leads to 4b cis, two previously reported thiol diastereomers bearing an exocyclic double bond. The second, minor one, results from a hydrolysis of 2-oxo clopidogrel, which seems to be dependent on PON-1, and leads to an isomer of 4b cis, 4b "endo", in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. These results were obtained from a detailed study of the metabolism of 2-oxo-clopidogrel by human liver microsomes and human sera and analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, either as such or after derivatization with 3'-methoxy phenacyl bromide or N-ethyl maleimide (NEM). These results also show that the major bioactive thiol isomer found in the plasma of clopidogrel-treated patients derives from 2-oxo-clopidogrel by the P450-dependent pathway. Finally, chemical experiments on 2-oxo-clopidogrel showed that this thiolactone is in equilibrium with its tautomer having a double bond inside the piperidine ring and that nucleophiles such as CH(3)O(-) preferentially react on the thioester function of this tautomer. This allowed us to understand why 4b cis has to be formed via an oxidative opening of 2-oxo-clopidogrel thiolactone, whereas a hydrolytic opening of this thiolactone ring leads to the "endo" thiol isomer 4b "endo". PMID- 22103859 TI - Locating the binding sites of folic acid with milk alpha- and beta-caseins. AB - We located the binding sites of folic acid with milk alpha- and beta-caseins at physiological conditions, using constant protein concentration and various folic acid contents. FTIR, UV-visible, and fluorescence spectroscopic methods as well as molecular modeling were used to analyze folic acid binding sites, the binding constant, and the effect of folic acid interaction on the stability and conformation of caseins. Structural analysis showed that folic acid binds caseins via both hydrophilic and hydrophobic contacts with overall binding constants of K(folic acid-alpha-caseins) = 4.8 (+/-0.6) * 10(4) M(-1) and K(folic acid-beta caseins) = 7.0 (+/-0.9) * 10(4) M(-1). The number of bound acid molecules per protein was 1.5 (+/-0.4) for alpha-casein and 1.4 (+/-0.3) for beta-casein complexes. Molecular modeling showed different binding sites for folic acid on alpha- and beta-caseins. The participation of several amino acids in folic acid protein complexes was observed, which was stabilized by hydrogen bonding network and the free binding energy of -7.7 kcal/mol (acid-alpha-casein) and -8.1 kcal/mol (acid-beta-casein). Folic acid complexation altered protein secondary structure by the reduction of alpha-helix from 35% (free alpha-casein) to 33% (acid-complex) and 32% (free beta-casein) to 26% (acid-complex) indicating a partial protein destabilization. Caseins might act as carriers for transportation of folic acid to target molecules. PMID- 22103860 TI - Yellowish discoloration of dialyzer. AB - A 43-year-old Chinese man with chronic viral hepatitis and end-stage renal disease, receiving conventional hemodialysis for 6 years, presented with general malaise and abdominal fullness. After 4.5 hours of hemodialysis, the hollow fibers of the dialyzer turned yellow. Biochemistry studies showed hyperbilirubinemia. The actual serum bilirubin (7.4 mg/dL) could be proved. Abdominal echography survey was negative. Hyperbilirubinemia was secondary to acute exacerbation of chronic viral hepatitis. Anuria and skin hyperpigmentation in uremia lack the tea-color urine and mask clinical jaundice in the presence of hyperbilirubinemia. Careful observation of dialyzer yellowish discoloration gave us timely discovery of patient's hyperbilirubinemia. PMID- 22103861 TI - Sex, price and preferences: accounting for unsafe sexual practices in prostitution markets. AB - Unsafe sexual practices are persistent in prostitution interactions: one in four contacts can be called unsafe. The determinants of this are still matter for debate. We account for the roles played by clients' preferences and the hypothetical price premium of unsafe sexual practices with the help of a large dataset of clients' self-reported commercial sexual transactions in Belgium and The Netherlands. Almost 25,000 reports were collected, representing the whole gamut of prostitution market segments. The first set of explanations consists of an analysis of the price-fixing elements of paid sex. With the help of the so called hedonic pricing method we test for the existence of a price incentive for unsafe sex. In accordance with the results from studies in some prostitution markets in the developing world, the study replicates a significant wage penalty for condom use of an estimated 7.2 per cent, confirmed in both multilevel and fixed-effects regressions. The second part of the analysis reconstructs the demand side basis of this wage penalty: the consistent preference of clients of prostitution for unsafe sex. This study is the first to document empirically clients' preference for intercourse without a condom, with the help of a multilevel ordinal regression. PMID- 22103862 TI - Toward the optimization of an e-tongue system using information visualization: a case study with perylene tetracarboxylic derivative films in the sensing units. AB - The wide variety of molecular architectures used in sensors and biosensors and the large amount of data generated with some principles of detection have motivated the use of computational methods, such as information visualization techniques, not only to handle the data but also to optimize sensing performance. In this study, we combine projection techniques with micro-Raman scattering and atomic force microscopy (AFM) to address critical issues related to practical applications of electronic tongues (e-tongues) based on impedance spectroscopy. Experimentally, we used sensing units made with thin films of a perylene derivative (AzoPTCD acronym), coating Pt interdigitated electrodes, to detect CuCl(2) (Cu(2+)), methylene blue (MB), and saccharose in aqueous solutions, which were selected due to their distinct molecular sizes and ionic character in solution. The AzoPTCD films were deposited from monolayers to 120 nm via Langmuir Blodgett (LB) and physical vapor deposition (PVD) techniques. Because the main aspects investigated were how the interdigitated electrodes are coated by thin films (architecture on e-tongue) and the film thickness, we decided to employ the same material for all sensing units. The capacitance data were projected into a 2D plot using the force scheme method, from which we could infer that at low analyte concentrations the electrical response of the units was determined by the film thickness. Concentrations at 10 MUM or higher could be distinguished with thinner films--tens of nanometers at most--which could withstand the impedance measurements, and without causing significant changes in the Raman signal for the AzoPTCD film-forming molecules. The sensitivity to the analytes appears to be related to adsorption on the film surface, as inferred from Raman spectroscopy data using MB as analyte and from the multidimensional projections. The analysis of the results presented may serve as a new route to select materials and molecular architectures for novel sensors and biosensors, in addition to suggesting ways to unravel the mechanisms behind the high sensitivity obtained in various sensors. PMID- 22103863 TI - Sensitive detection of microRNA with isothermal amplification and a single quantum-dot-based nanosensor. AB - MicroRNAs (miRNAs) play important roles in a wide range of biological processes, and their aberrant expressions are associated with various diseases. Here we develop a rapid, highly sensitive, and specific miRNA assay based on the two stage exponential amplification reaction (EXPAR) and a single-quantum-dot (QD) based nanosensor. The two-stage EXPAR involves two templates and two-stage amplification reactions under isothermal conditions. The first template enables the amplification of miRNA, and the second template enables the conversion of miRNA to the reporter oligonucleotide. Importantly, different miRNAs can be converted to the same reporter oligonucleotides, which can hybridize with the same set of capture and reporter probes to form sandwich hybrids. These sandwich hybrids can be assembled on the surface of 605 nm emission QDs (605QDs) to form the 605QD/reporter oligonucleotide/Cy5 complexes, where the 605QD functions as both a fluorescence resonance energy transfer donor and a target concentrator. Upon excitation with a wavelength of 488 nm, distinct Cy5 signals can be observed in the presence of target miRNA. This assay is highly sensitive and specific with a detection limit of 0.1 aM and can even discriminate single-nucleotide differences between miRNA family members. Moreover, in combination with the specific templates, this method can be applied for multiplex miRNA assay by simply using the same set of capture and reporter probes. This highly sensitive and specific assay has potential to become a promising miRNA quantification method in biomedical research and clinical diagnosis. PMID- 22103864 TI - Correlation between cardiac output and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex. AB - BACKGROUND: The aim of this study was to evaluate the correlation between cardiac output (CO) and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex in elderly patients. METHODS: Fifty elderly (>= 65 years) patients were enrolled in this study. During 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was acceleromyographically quantified. All patients initially received 1 mg/kg rocuronium followed by 0.2 mg/kg whenever the second twitch T2 of the train-of-four (TOF) response reappeared. CO was measured throughout the study using a FloTracTM/VigileoTM monitor. After completion of surgery and at the reappearance of T2, the time required for a bolus dose of 2 mg/kg sugammadex to facilitate recovery to a TOF ratio of 0.9 was recorded, and its correlation with CO was analysed. RESULTS: Adequate recovery of neuromuscular block was achieved after sugammadex in all patients. Mean CO at the time of reversal with sugammadex was 5.3 l/min (1.3), and recovery time to a TOF ratio of 0.9 was 173.4 s (54.8). A statistically significant inverse correlation was seen between the time to recovery to a TOF ratio of 0.9 and CO [reversal time (s) = 27.7.CO + 298.7, R(2) = 0.461, P < 0.0001]. CONCLUSIONS: The time to reach a TOF ratio of 0.9 following sugammadex is dependent on CO in elderly patients. PMID- 22103866 TI - Microvascular dysfunction: What have we learned from WISE? PMID- 22103868 TI - Nifedipine and telmisartan for the treatment of hypertension: the TALENT study. AB - A combination of two drugs as initial treatment in patients with a high or very high cardiovascular risk profile is recommended. Nifedipine extended release (GITS) is a calcium-channel antagonist known to be metabolically neutral, to mildly slow the development of atherosclerosis in hypertensive subjects and to significantly decrease cardiovascular risk in diabetic patients. Telmisartan is highly selective for the angiotensin receptor 1, it gives a greater improvement in glycemic and lipid control compared with irbesartan, and it proved its superiority in improving insulin sensitivity compared with eprosartan. The TALENT study was aimed to determine whether combining low-dose nifedipine GITS at and telmisartan reduced ambulatory and clinic blood pressure more than the two components in monotherapy in hypertensive patients at high cardiovascular risk. The study shows that combination treatment with nifedipine GITS and telmisartan provides a greater and earlier blood pressure reduction than the combination components in monotherapy. PMID- 22103869 TI - Tolvaptan for the treatment of hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. AB - Hyponatremia is prevalent in hospitalized patients and predicts a poor prognosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is perceived as one of the most frequent causes of hyponatremia. Traditionally, chronic hyponatremia has been treated with fluid restriction and demeclocycline. However, these treatment options have been unsatisfactory due to problems with treatment compliance and/or safety concerns. In recent years, several vasopressin receptor antagonists, the vaptans, were introduced into clinical practice. One of these vaptans - tolvaptan - is an oral vasopressin V2-receptor antagonist that induces free water excretion without increasing sodium excretion. Few studies have assessed the role of vaptans in treating hyponatremia in a population with only SIADH. Current data shows that vaptans may safely correct mild or moderate hyponatremia in patients with SIADH. However, further clinical trials are needed to determine the optimal dosing, proper monitoring and adequate precautions for the use of vaptans in this patient population. PMID- 22103870 TI - Uncontrolled hypertension: highlights and perspectives from the European Society of Hypertension Satellite Symposium. AB - The Padua ESH 2011 Satellite Symposium on uncontrolled hypertension was focused on why only a relatively small percentage of patients under treatment do not reach 'safe' blood pressure levels; the major reason being the modest use of combination therapy. It was also an occasion to discuss new pharmacological and nonpharmacological tools, some of which appear to be efficacious when even the 'appropriate' traditional therapeutic strategy fails to work. PMID- 22103871 TI - Methylene blue: potential use of an antique molecule in vasoplegic syndrome during cardiac surgery. AB - Vasoplegic syndrome is a common complication of cardiopulmonary bypass, appearing with an incidence ranging between 5 and 25%. It is characterized by significant hypotension, high or normal cardiac output and low systemic vascular resistance. This syndrome is hypothesized to be caused by the inflammation-mediated dysregulation of endothelial homeostasis and subsequent endothelial dysfunction. In vasoplegic syndrome, the inhibition of the nitric oxide/cyclic guanosine monophosphate pathway with concomitant administration with traditional ionotropes may represent a promising therapeutic option. Methylene blue, an inhibitor of nitric oxide synthase and guanylate cyclase, may contribute to the improvement of refractory hypotension associated with endothelial dysfunction in vasoplegia. In this article, we will update evidence on the potential therapeutic use of methylene blue in vasoplegic syndrome. PMID- 22103872 TI - Common arterial trunk: review of surgical strategies and future research. AB - Common arterial trunk is a congenital malformation that is relatively uncommon, representing 0.21-0.34% of congenital heart disease. Natural history, if not treated, leads to early death. Cardiac surgery has been modifying its natural course during the last 30 years by prolonging the lifespan of patients affected. Despite surgical mortality improvements over the last 10 years, morbidity still remains high, mainly due to the age of the patient, associated heart lesions, the evolution of truncal valve function and the type of conduit used for pulmonary artery reconstruction. Common arterial trunk disease still represents a significant challenge for cardiac surgeons and cardiologists regarding attempts to improve long-term outcomes and quality of life. Promising results may be achieved in the next 5 years by the tissue valve-engineering technology applied to search for the ideal conduit on the right ventricular outflow tract. This research has already started in many centers in order to reduce several unavoidable reinterventions nowadays. In this review, we will comment on the situation, focusing on the latest surgical innovations of the last 5 years. PMID- 22103873 TI - Contemporary management of pulmonary and systemic circulations after the Norwood procedure. AB - Hypoplastic left heart syndrome remains one of the most challenging pathologies in pediatric cardiac surgery. The surgical techniques, and anesthetic and intensive care management, have evolved over the last decades, which has resulted in improved outcomes. A central component in the postoperative management of hypoplastic left heart syndrome patients is to achieve an optimal balance between the pulmonary and systemic circulations. This article discusses the contemporary postoperative management of pulmonary and systemic circulations in detail. PMID- 22103874 TI - Pregnancy in women with Fontan physiology. AB - Advances in the care of patients with a univentricular heart have enabled the majority to survive well into adulthood. Consequently, an increasing number of women with Fontan palliation are contemplating pregnancy. This review summarizes physiologic modifications related to pregnancy in the setting of single-ventricle physiology, discusses potential maternal cardiovascular concerns and describes commonly encountered obstetrical and neonatal complications. Management issues are addressed, including counseling, anesthetic considerations and the need for multidisciplinary specialized care. PMID- 22103875 TI - Adiposity assessment: explaining the association between obesity, hypertension and stroke. AB - Obesity is associated with a greater prevalence of cardiovascular risk factors and a higher risk of cardiovascular events, and contributes to the rise in cardiovascular morbidity and mortality worldwide. Increased BMI is established as an independent risk factor for cardiovascular disease (CVD). Attention has recently been drawn to alternate measures of adiposity/obesity, such as waist circumference, waist-to-hip ratio and waist-to-height ratio, that provide information regarding body fat distribution. Although BMI is the established clinical measurement to estimate CVD risk associated with excess bodyweight, there is evidence suggesting that abdominal obesity could represent a better marker of CVD risk than BMI. It is now recognized that abdominally obese individuals tend to have higher blood pressure. A major cardiovascular risk factor associated with stroke is systemic hypertension followed closely by obesity. Clinical adiposity indices used to describe obesity linked with systemic hypertension and stroke incidence are reviewed in this article. In summary, BMI, waist circumference, waist-to-hip ratio and waist-to-height ratio measurements are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated with other cardiometabolic risk factors to refine cardiovascular risk stratification. PMID- 22103876 TI - Role of C-reactive protein in cerebrovascular disease: a critical review. AB - C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research. PMID- 22103877 TI - Renin-angiotensin system blockade and reduction of cardiovascular risk: future perspectives. AB - Treatment with renin-angiotensin system blockers (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) has shown clear benefits in distinct stages of cardiovascular disease. These treatments lower blood pressure and prevent the appearance of markers of subclinical disease (such as microalbuminuria), reduce cardiovascular and renal events in patients with subclinical lesions, and prolong survival in patients with clinical disease or organ dysfunction. Despite this unquestionable benefit, the residual risk in patients receiving these treatments often continues to be high and, consequently, strategies to reduce such risk are required. The present article reviews options that may help to reduce cardiovascular disease in such patients. They include efforts of primary prevention in healthy individuals, stricter therapeutic goals, comprehensive risk control, a more complete blocking of the renin-angiotensin system and the use of combinations of drugs with synergistic protective mechanisms. PMID- 22103878 TI - The proarrhythmic risk of cell therapy for cardiovascular diseases. AB - Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell-cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation. PMID- 22103881 TI - Clinical and genetic analysis for two Chinese siblings with 17alpha hydroxylase/17,20-lyase deficiency. AB - AIMS: 17alpha-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by impaired productions of gonadal steroids and cortisol, a subsequent elevation of adrenocorticotropic hormone, and accumulation of steroid precusors, which are shunted into the mineralocorticoid synthesis pathway. This disease is caused by mutations in the CYP17 gene. In this paper, we will describe the clinical features and genetic alterations on two female siblings of 46,XY and 46,XX from a family with complete 17OHD. METHODS: This study employed a spectrum of methods, including clinical, hormonal, radiological and genetic analyses. Blood samples from the siblings and their family members were taken for genetic tests. Genomic DNA was extracted from peripheral blood leukocytes, and coding sequence abnormalities of the CYP17 gene were assessed by polymerase chain reaction and direct sequencing analysis. RESULTS: Genetic analysis of the CYP17 gene revealed a homozygous mutation in the two siblings. The mutation is a microdeletion, located in exon 8, Asp487-Ser488-Phe489 deletion. This deletion may be a prevalent CYP17 mutation in the Chinese population. CONCLUSION: Our study showed that a possible founder effect may account for the recurrent mutation Asp487 Ser488-Phe489 deletion in Chinese patients with 17OHD. And genetic testing could provide a useful method for a definitive diagnosis of 17OHD. PMID- 22103880 TI - Too good to treat? Outcomes in patients not receiving thrombolysis due to mild deficits or rapidly improving symptoms. AB - INTRODUCTION: Among ischemic stroke patients arriving within the treatment window, rapidly improving symptoms or having a mild deficit (i.e. too good to treat) is a common reason for exclusion. Several studies have reported poor outcomes in this group. We addressed the question of early neurological deterioration in too good to treat patients in a larger prospective cohort study. METHODS: Admission and discharge information were collected prospectively in acute stroke patients who presented to the emergency room within three-hours from onset. The primary outcome measure was change in the National Institutes of Health Stroke Scale from baseline to discharge. Secondary outcomes were discharge National Institutes of Health Stroke Scale >4, not being discharged home, and discharge modified Rankin scale. RESULTS: Of 355 patients who presented within three-hours, 127 (35.8%) had too good to treat listed as the only reason for not receiving thrombolysis, with median admission National Institutes of Health Stroke Scale = 1 (range = 0 to 19). At discharge, seven (5.5%) showed a worsening of National Institutes of Health Stroke Scale >=1, and nine (7.1%) had a National Institutes of Health Stroke Scale >4. When excluding prior stroke (remaining n = 97), discharge status was even more benign: only five (5.2%) had a discharge National Institutes of Health Stroke Scale >4, and two (2.1%) patients were not discharged home. CONCLUSION: We found that a small proportion of patients deemed too good to treat will have early neurological deterioration, in contrast to other studies. Decisions about whether to treat mild stroke patients depend on the outcome measure chosen, particularly when considering discharge disposition among patients who have had prior stroke. The decision to thrombolyze may ultimately rest on the nature of the presentation and deficit. PMID- 22103882 TI - Eight-year results of site retention of anorganic bovine bone and anorganic bovine matrix. AB - The long-term fate of some biomaterials is still unknown, and the reports present in the literature are not conclusive as to whether these biomaterials are resorbed over time or not. Different reports can be found with regard to the resorption behavior of anorganic bovine bone (ABB). The aim of the present study was to provide a comparative histological and histomorphometrical evaluation, in the same patient, of 2 specimens retrieved from a sinus augmented with ABB and with anorganic bovine matrix added to a cell-binding peptide (PepGen P-15), respectively, after a healing period of 6 months and after 8 years of implant loading, to evaluate the resorption of both biomaterials. A unilateral sinus augmentation procedure with ABB (50%) and with PepGen P-15 (50%) was performed in a 54-year-old male patient. Two titanium dental implants with a sandblasted and acid-etched surface were inserted after 6 months. During this procedure, 2 tissue cores were retrieved from the sinus with a trephine, before implant insertion. After an additional 6 months, a fixed prosthetic restoration was fabricated. One of these implants, after a loading period of 8 years, fractured in the coronal portion and was removed. Both specimens, one retrieved after a 6-month healing period and the other after an 8-year loading period, were treated to obtain thin ground sections. In the 6-month specimen, the histomorphometry showed that the percentage of newly formed bone was 27.2% +/- 3.6%, marrow spaces 35.6% +/- 2.3%, residual ABB particles 25.1% +/- 1.2%, and residual PepGen P-15 particles 12.1% +/- 2.2%. In the 8-year specimen, the histomorphometry showed that the percentage of newly formed bone was 51.4% +/- 4.8%, marrow spaces 40% +/- 7.1%, residual ABB particles 6.2% +/- 0.7%, and residual PepGen P-15 particles 2.4% +/- 0.5%. Both biomaterials underwent significant resorption over the course of this study. PMID- 22103883 TI - Validity and reliability of the Oral Impacts on Daily Performance (OIDP) scale in the elderly population of Bosnia and Herzegovina. AB - OBJECTIVES: To adapt the Oral Impacts on Daily Performance (OIDP) index for elderly people in Bosnia and Herzegovina and test its validity, reliability and responsiveness to change. BACKGROUND: Clinical measures alone may not be adequate for assessing the oral health of individuals. Subjective oral health indicators tested within a particular cultural context may not be relevant across cultures. MATERIALS AND METHODS: The study population comprised 231 free-living adults aged 65 years or older. The OIDP was cross-culturally adapted from English into the Serbian language and its psychometric properties were tested. Data were collected using a clinical examination and a questionnaire containing the OIDP. RESULTS: In terms of reliability, Cronbach's alpha coefficient was 0.82 and the intraclass correlation coefficient 0.88. The very high correlation of OIDP with self-rated oral health (r = 0.78) verified criterion validity, while construct validity was demonstrated through its significant and graded associations with other subjective health measures. OIDP change scores on a treated subsample showed moderate effect size (0.59) and were associated with perceptions of oral health change, providing evidence for its responsiveness to change. CONCLUSION: The Bosnian version of the OIDP showed satisfactory validity, reliability and responsiveness to change confirming its appropriateness for use among older populations in Bosnia and Herzegovina. PMID- 22103884 TI - Water-soluble mitochondria-specific ytterbium complex with impressive NIR emission. AB - A water-soluble porphyrinato ytterbium complex linked with rhodamine B (Yb-2) showed mitochondria-specific subcellular localization and strong two-photon induced NIR emissions (lambda(em) = 650 nm, porphyrinate ligand pi -> pi* transition; lambda(em) = 1060 nm, Yb(III) (5)F(5/2) -> (5)F(7/2) transitions; sigma(2) = 375 GM in DMSO) with an impressive Yb(III) NIR emission quantum yield (1% at lambda(ex) = 340 nm; 2.5% at lambda(ex) = 430 nm) in aqueous solution. PMID- 22103885 TI - C-type natriuretic peptide forms in adult hyperthyroidism: correlation with thyroid hormones and markers of bone turnover. AB - CONTEXT: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown. OBJECTIVE: To determine the effect of restoring euthyroidism on plasma CNP forms and bone turnover markers (BTMs) in hyperthyroid adults. DESIGN AND SETTING: We performed a prospective observational study in 20 adults (19 women) with acquired hyperthyroidism before and during carbimazole treatment. INTERVENTION AND MAIN OUTCOMES: Blood levels of CNP, amino-terminal propeptide of CNP (NTproCNP), TH and BTMs - bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 amino-terminal propeptide and type 1 collagen C-telopeptide (CTx) - were measured before and during the first 6 months of carbimazole treatment and correlations determined. RESULTS: Both CNP and NTproCNP were significantly correlated with TH at baseline. As in children, decreases in CNP forms were closely associated with fall in TH. Significant associations were found between CNP forms and CTx. CONCLUSIONS: CNP production from tissues other than endochondral cartilage is responsive to TH. Strong temporal links with markers of bone resorption suggest that CNP may also participate in bone remodelling in the adult skeleton. PMID- 22103886 TI - It is with great pleasure that we offer in this issue the selected peer reviewed proceedings from the 12th national meeting of the Diabetes in Pregnancy Study Group. Introduction. PMID- 22103887 TI - Guidelines for assessment of and intervention with persons with disabilities. PMID- 22103888 TI - Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer. AB - BACKGROUND: There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor prognosis in patients with advanced cancers. We evaluated the relationships between clinical status, laboratory factors and progression free survival (PFS), and overall survival (OS) in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy. METHODS: We reviewed 402 patients with advanced gastric adenocarcinoma who received first-line palliative chemotherapy from June 2004 and December 2009. Various chemotherapy regimens were used. Eastern Cooperative Oncology Group performance status (ECOG PS), C-reactive protein (CRP), albumin, Glasgow prognostic score (GPS), and clinical factors were recorded immediately prior to first-line chemotherapy. Patients with both an elevated CRP (>1.0 mg/dL) and hypoalbuminemia (<3.5 mg/dL) were assigned a GPS of 2. Patients in whom only one of these biochemical abnormalities was present were assigned a GPS of 1, and patients with a normal CRP and albumin were assigned a score of 0. To evaluate the factors that affected PFS and OS, univariate and multivariate analyses were performed. RESULTS: According to multivariate analysis, the factors independently associated with PFS were ECOG PS (HR 1.37, 95% CI 1.02-1.84, P = 0.035), bone metastasis (HR 1.74, 95% CI 1.14-2.65, P = 0.009), and CRP elevation (HR 1.64, 95% CI 1.28-2.09, P = 0.001). The factors independently associated with OS were ECOG PS (HR 1.33, 95% CI 1.01-1.76, P = 0.037), bone metastasis (HR 1.61, 95% CI 1.08-2.39, P = 0.017), and GPS >= 1 (HR 1.76, 95% CI 1.41-2.19, P = 0.001). CONCLUSIONS: The results of this study showed that the presence of a systemic inflammatory response as evidenced by the CRP, GPS was significantly associated with shorter PFS and OS in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy. Bone metastasis and GPS were very useful indicator for survival in patients with recurrent or metastatic gastric cancer receiving palliative chemotherapy. PMID- 22103889 TI - Relationship between erythropoietin resistance index and left ventricular mass and function and cardiovascular events in patients on chronic hemodialysis. AB - The response to erythropoietin (EPO) treatment varies considerably in individual patients on chronic hemodialysis. The EPO resistance index (ERI) has been considered useful to assess the EPO resistance and can be easily calculated in the clinic. The aim of this study was to investigate the association between ERI and left ventricular mass (LVM) and function and to determine whether ERI was associated with cardiovascular events in patients on hemodialysis. This study was designed prospectively. Clinical, laboratory, and echocardiographic variables were assessed in 72 patients on hemodialysis. The ERI was determined as the weekly weight-adjusted dose of EPO (U/kg/week) divided by hemoglobin concentration (g/dL). Patients were divided into three groups by tertiles of ERI. Patients with higher tertiles of ERI had a higher LVM index and lower LV ejection fraction compared with those with lower tertiles of ERI (P = 0.019 and P = 0.030, respectively). The median follow-up period was 53 months. The Kaplan-Meier plot showed increased frequency of cardiovascular events in patients with higher tertiles of ERI, compared with those with lower tertiles of ERI (P = 0.011, log rank test). The multivariate Cox proportional hazard models showed that the ERI was the significant independent predictor of cardiovascular events (HR 3.00, 95% CI, 1.04-8.62, P = 0.042). Our data show that ERI was related with LVM index, LV systolic function and cardiovascular events in patients with hemodialysis. By monitoring of ERI, early identification of the EPO resistance may be helpful to predict the cardiovascular risk in hemodialysis patients. PMID- 22103890 TI - Supervised team management, with or without structured psychotherapy, in heavy users of a mental health service with borderline personality disorder: a two-year follow-up preliminary randomized study. AB - BACKGROUND: Individuals affected by severe Borderline Personality Disorder (BPD) are often heavy users of Mental Health Services (MHS). Short-term treatments currently used in BPD therapy are useful to target disruptive behaviors but they are less effective in reducing heavy MHS use. Therefore, alternative short-term treatments, less complex than long-term psychodynamic psychotherapies but specifically oriented to BPD core problems, need to be developed to reduce MHS overuse. This study aimed to evaluate the efficacy of adding Sequential Brief Adlerian Psychodynamic Psychotherapy (SB-APP) to Supervised Team Management (STM) in BPD treatment compared to STM alone in a naturalistic group of heavy MHS users with BPD. Effectiveness was evaluated 6 times along a two-year follow-up. METHODS: Thirty-five outpatients who met inclusion criteria were randomly assigned to two treatment groups (STM = 17; SB-APP = 18) and then compared. Clinical Global Impression (CGI) and CGI-modified (CGI-M) for BPD, Global Assessment of Functioning (GAF), State-Trait Anger Expression Inventory (STAXI), and Symptom Checklist-90 Revised (SCL-90-R) were administered at T1, T3, T6, T12, T18 and T24. At T12 the Working Alliance Inventory-Short Form (WAI-S) was also completed. At the one-year follow-up, SB-APP group did not receive any additional individual psychological support. MHS team was specifically trained in BPD treatment and had regular supervisions. RESULTS: All patients improved on CGI, GAF, and STAXI scores after 6 and 12 months, independently of treatment received. SB-APP group showed better outcome on impulsivity, suicide attempts, chronic feelings of emptiness, and disturbed relationships. We found a good stabilization at the one year follow-up, even after the interruption of brief psychotherapy in the SB-APP group. CONCLUSIONS: Although STM for BPD applied to heavy MHS users was effective in reducing symptoms and improving their global functioning, adding a time-limited and focused psychotherapy was found to achieve a better outcome. In particular, focusing treatment on patients' personality with a specific psychotherapeutic approach (i.e. SB-APP) seemed to be more effective than STM alone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT1356069. PMID- 22103891 TI - Investigation of the interaction between a bivalent aptamer and thrombin by AFM. AB - Aptamers are a new class of molecular probes for protein recognition, detection, and inhibition. Multivalent aptamer-protein binding through aptamer assembly has been currently developed as an effective way to achieve higher protein affinity and selectivity. In this study, the specific interaction between bivalent aptamer Bi-8S and thrombin has been measured directly and quantitatively by atomic force microscopy to investigate the unbinding dynamics and dissociation energy landscape of the multivalent interaction. Bivalent aptamer Bi-8S contains thrombin's two aptamers, 15apt and 27apt, which are linked by eight spacer phosphoramidites. The results revealed the sequential dissociation of the two aptamers. Moreover, the dynamic force spectroscopy data revealed that the 27apt's binding to the thrombin remains largely unaffected by the eight-spacer phosphoramidites within Bi-8S. In contrast, the eight-spacer phosphoramidites stabilized the 15apt-thrombin binding. PMID- 22103892 TI - Differentiating fragmented human and nonhuman long bone using osteon circularity. AB - Distinguishing between human and nonhuman bone is important in forensic anthropology and archeology when remains are fragmentary and DNA cannot be obtained. Histological examination of bone is affordable and practical in such situations. This study suggests using osteon circularity to distinguish human bone fragments and hypothesizes that osteons will more closely resemble a perfect circle in nonhumans than in humans. Standard histological methods were used, and circularity was determined using an image analysis program, where circularity was controlled for by Haversian canal measurements. Homogeneity was first tested for multiple variables within human and nonhuman samples. No significant differences were found between human sexes (p = 0.657) or among nonhuman species (p = 0.553). Significant differences were found among intraskeletal elements of both humans (p = 0.016) and nonhumans (p = 0.013) and between pooled samples of humans and nonhumans (p < 0.001). Results of this study indicate that osteon circularity can be used to distinguish between fragmented human and nonhuman long bone. PMID- 22103893 TI - Courtesy stigma: a hidden health concern among front-line service providers to sex workers. AB - Courtesy stigma, also referred to as 'stigma by association', involves public disapproval evoked as a consequence of associating with a stigmatised individual or group. While a small number of sociological studies have shown how courtesy stigma limits the social support and social opportunities available to family members of stigmatised individuals, there is a paucity of research examining courtesy stigma among the large network of people who provide health and social services to stigmatised groups. This article presents results from a mixed methods study of the workplace experiences of a purposive sample of workers in a non-profit organisation providing services to sex workers in Canada. The findings demonstrate that courtesy stigma plays a role in workplace health as it shapes both the workplace environment, including the range of resources made available to staff to carry out their work activities, as well as staff perceptions of others' support. At the same time, it was evident that some workers were more vulnerable to courtesy stigma than others depending on their social location. We discuss these results in light of the existing literature on courtesy stigma and conclude that it is an under-studied determinant of workplace health among care providers serving socially denigrated groups. PMID- 22103894 TI - Evolutionary relationships and diversification of barhl genes within retinal cell lineages. AB - BACKGROUND: Basic helix-loop-helix and homeodomain transcription factors have been shown to specify all different neuronal cell subtypes composing the vertebrate retina. The appearance of gene paralogs of such retina-specific transcription factors in lower vertebrates, with differently evolved function and/or conserved non-coding elements, might provide an important source for the generation of neuronal diversity within the vertebrate retinal architecture. In line with this hypothesis, we investigated the evolution of the homeobox Barhl family of transcription factors, barhl1 and barhl2, in the teleost and tetrapod lineages. In tetrapod barhl2, but not barhl1, is expressed in the retina and is important for amacrine cell specification. Zebrafish has three barhl paralogs: barhl1.1, barhl1.2 and barhl2, but their precise spatio-temporal retinal expression, as well as their function is yet unknown. RESULTS: Here we performed a meticulous expression pattern comparison of all known barhl fish paralogs and described a novel barhl paralog in medaka. Our detailed analysis of zebrafish barhl gene expression in wild type and mutant retinas revealed that only barhl1.2 and barhl2 are present in the retina. We also showed that these two paralogs are expressed in distinct neuronal lineages and are differently regulated by Atoh7, a key retinal-specific transcription factor. Finally, we found that the two retained medaka fish barhl paralogs, barhl1 and barhl2, are both expressed in the retina, in a pattern reminiscent of zebrafish barhl1.2 and barhl2 respectively. By performing phylogenetic and synteny analysis, we provide evidence that barhl retinal expression domain is an ancestral feature, probably lost in tetrapods due to functional redundancy. CONCLUSIONS: Functional differences among retained paralogs of key retina-specific transcription factors between teleosts and tetrapods might provide important clues for understanding their potential impact on the generation of retinal neuronal diversity. Intriguingly, within teleosts, retention of zebrafish barhl1.2 and its medaka ortholog barhl1 appears to correlate with the acquisition of distinct signalling mechanisms by the two genes within distinct retinal cell lineages. Our findings provide a starting point for the study of barhl gene evolution in relation to the generation of cell diversity in the vertebrate retina. PMID- 22103895 TI - Expression of the novel NUP98/PSIP1 fusion transcripts in myelodysplastic syndrome with t(9;11)(p22;p15). AB - OBJECTIVES: The t(9;11)(p22;p15) is a very rare but recurrent translocation in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) blast crisis. The translocation results in a fusion gene between NUP98 at 11p15 and PSIP1 encoding two transcriptional coactivators, p52 and p75, at 9p22. Here, we describe the first case of myelodysplastic syndrome (MDS) with t(9;11)(p22;p15). PATIENT: A 64 yr-old woman presented pancytopenia, trilineage dysplasia, and 9.2% blasts in the bone marrow, indicating the diagnosis of MDS. RESULTS: G-banding and spectral karyotyping showed 46,XX,t(9;11)(p22;p15)[20]. Reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing detected four types of NUP98/PSIP1-p52 and two types of NUP98/PSIP1-p75 fusion transcripts. Essentially, the NUP98 exon 12 or exon 11 by alternative splicing was fused in-frame with the PSIP1 exon 8. Real-time quantitative (RQ) PCR for NUP98/PSIP1/GAPDH demonstrated a 4-log decrease after cord blood transplantation and a 2-log increase at relapse. CONCLUSIONS: The fusion genes combining NUP98 exon 11/12 with PSIP1 exon 8, which have never been detected in other AML/CML cases, may be implicated in the pathogenesis of MDS. Furthermore, RQ-PCR for NUP98/PSIP1 could be useful to monitor minimal residual disease. PMID- 22103896 TI - Correlations of survivin expression with clinicomorphological parameters and hormonal receptor status in breast ductal carcinoma. AB - The antiapoptotic protein survivin is widely expressed in most human cancers, including carcinomas of the breast. It is rarely detected in corresponding normal adult tissues. Therefore, survivin comes into the limelight as a promising diagnostic biomarker and prognostic parameter. Immunohistochemically, we examined the expression of this protein in 126 cases of ductal breast carcinoma to determine the association with clinicomorphological parameters such as age of patients, grade, stage and size of the primary tumor, lymph node metastasis, vascular invasion as well as estrogen and progesterone status. In each section, the subcellular location of survivin antigen, the intensity of staining and the percentage of labeled cells were assessed. Overall, survivin was expressed in 111 cases (88.1%). The statistical analysis revealed a significant correlation between the nuclear location of survivin and tumor grade 3. Furthermore, a significant relation was also found between vascular invasion and nuclear and combined nuclear and cytoplasmic survivin expression, together with a higher intensity of immunoreaction. However, no significant correlations were shown with other clinicomorphological parameters, such as stage and size of the tumor, lymph node metastasis, estrogen and progesterone receptors and age. Our findings revealed that survivin was frequently overexpressed in carcinoma cells, where it was present in different subcellular compartments. The nuclear positivity of survivin or combined nuclear and cytoplasmic expression was shown to be a poor prognostic parameter in ductal breast carcinoma. PMID- 22103897 TI - Gemcitabine and cisplatin combination chemotherapy in triple negative metastatic breast cancer previously treated with a taxane/anthracycline chemotherapy; multicenter experience. AB - This study was aimed to establish clinical efficacy and tolerability of gemcitabine and cisplatin combination in patients with metastatic triple negative breast cancer progressing after anthracycline and taxane based chemotherapies.Thirty-three patients who were given cisplatin and gemcitabine for triple negative and metastatic breast cancer were evaluated retrospectively. A total of 141 cycles were administered with a median 4 cycles per patient. Median follow-up time was 14 months (range, 2-36 months). Objective response rate was 27.3%. Total clinical benefit of the combination was 48.4%. The estimated median progression free survival and median overall survival were 5 months and 14 months, respectively. The most common Grade 3 and 4 toxicity were neutropenia and thrombocytopenia observed in 10 (27.7%) and 9 (24.9%) patients, respectively. The combination of the gemcitabine and cisplatin after taxane/anthracycline is well tolerated and seems to be effective with acceptable toxicity profile. PMID- 22103898 TI - Gentiana asclepiadea and Armoracia rusticana can modulate the adaptive response induced by zeocin in human lymphocytes. AB - Zeocin is a member of bleomycin/phleomycin family of antibiotics isolated from Streptomyces verticullus. This unique radiomimetic antibiotic is known to bind to DNA and induce oxidative stress in different organisms producing predominantly single- and double- strand breaks, as well as a DNA base loss resulting in apurinic/apyrimidinic (AP) sites. The aim of this study was to induce an adaptive response (AR) by zeocin in freshly isolated human lymphocytes from blood and to observe whether plant extracts could modulate this response. The AR was evaluated by the comet assay. The optimal conditions for the AR induction and modulation were determined as: 2 h-intertreatment time (in PBS, at 4 degrees C) given after a priming dose (50 ug/ml) of zeocin treatment. Genotoxic impact of zeocin to lymphocytes was modulated by plant extracts isolated from Gentiana asclepiadea (methanolic and aqueous haulm extracts, 0.25 mg/ml) and Armoracia rusticana (methanolic root extract, 0.025 mg/ml). These extracts enhanced the AR and also decreased DNA damage caused by zeocin (after 0, 1 and 4 h-recovery time after the test dose of zeocin application) to more than 50%. These results support important position of plants containing many biologically active compounds in the field of pharmacology and medicine. PMID- 22103899 TI - Long-term trends in the development of the epidemiology of breast cancer in the Slovak and Czech Republic with reference to applied screening and international comparisons. AB - Breast cancer represents a major problem in oncology and epidemiology, especially because of the growing trends in its incidence, which are most pronounced in countries with historically low levels of incidence of this disease and because of the increasingly unfavorable mortality trends even in some countries where screening has been established. The purpose of this study is to analyse the incidence of breast cancer and resulting mortality in two neighbouring countries with national population-based cancer data in central Europe and to assess possible reasons for any differences discovered. The recorded increase in the incidence of breast cancer in the Slovak and Czech Republic is apparently the result of a westernizing lifestyle. In the Czech Republic the acceleration of the incidence of this disease recorded after 1991 was more pronounced than in the Slovak Republic, which may be influenced especially by the more pronounced increase in the number of mammograms but also by a higher prevalence of risk factors of the disease. After the year 1991 a stabilization of mortality was recorded in both countries. However, this stabilization is not satisfactory but is correlated with the unsatisfactory extent (in the case of the Slovak Republic still unorganized) of screening, with the low number (or unused) mammograms, with slow onset of anti-cancer therapy and with expenditures for health care below the European average. The existing situation with an unfavourable mortality trend in all age groups indicates the importance of implementing intervention measures. PMID- 22103900 TI - Microsomal epoxide hydrolase polymorphisms, cigarette smoking and prostate cancer risk in the Slovak population. AB - Polymorphisms in tobacco carcinogen metabolizing enzymes may generate interindividual variations towards the risk of developing prostate cancer. One of these enzymes is microsomal epoxide hydrolase (EPHX1) which metabolizes polycyclic aromatic hydrocarbons, or PAH, carcinogens found in cigarette smoke. The activity of this enzyme is affected by two polymorphisms, a substitution of Tyr113 by His in exon 3 and a substitution of His139 by Arg in exon 4. The aim of this study was to use a population-based case-control study to investigate whether or not such genetic polymorphisms in EPHX1 gene can modify the relationship between smoking status and the risk of developing prostate cancer. We used restriction fragment length polymorphism, or PCR-RFLP to determine EPHX1 genotypes in subjects comprising 194 patients with histologically verified prostate cancer and 305 healthy individuals as control. We found no overall association between prostate cancer risk and functional polymorphisms of EPHX1 gene in exon 3 and exon 4. We further analysed the association between the EPHX1 genotypes and smoking. Smokers carrying the exon 3 Tyr/Tyr and Tyr/His genotypes were at no significant risk compared to non-smokers with the "rapid" Tyr/Tyr genotype. By contrast, a significant interaction of smoking and the exon 4 polymorphism was present. PMID- 22103901 TI - Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status. AB - Promoter hypermethylation was shown to be involved in human cancerogenesis through silencing gene expression. Several studies were dedicated to explore the frequency and clinical significance of BRCA1 hypermethylation in sporadic breast cancer to identify a specific molecular and clinico-pathological phenotype. However the available data are limited and rather too heterogeneous. In this study we investigated the level of methylation in the promoter region of BRCA1 and its correlation with clinico-pathological and molecular characteristics in a group of 135 Bulgarian patients. Methylation specific PCR was applied to determine methylation status of tumor samples. Clinical impact of BRCA1 hypermethylation was estimated using standard statistical methods including Fisher's exact and the Chi-squared tests, the Kaplan-Meier method, the univariate and multivariate Cox proportional hazards regression model. We found that hypermethylation was present in 17.04% of the cases (23/135). Patients with hypermethylation in BRCA1 displayed favorable clinical status as their tumors were smaller in size (P = 0.066), lacked p53 gene mutations (P = 0.073) and were of lobular type (P = 0.046). The presence of hypermethylation was weakly associated with better overall survival (P = 0.2) with a hazard ratio of 0.47 (95% CI 0.14-1.54, P= 0.213). Our study provides the first data on the BRCA1 hypermethylation of Bulgarian patients and contributes to elucidation of its clinical significance in sporadic breast cancer. PMID- 22103902 TI - Characterization of adrenal metastatic cancer using FDG PET/CT. AB - The adrenal gland is a common location for metastasis from a primary tumor in another organ. This study evaluated the properties of adrenal lesions in cancer and non-cancer patients and investigated what variables may help predict adrenal metastasis. This retrospective study used 18fluorodeoxyglucose PET/CT on 371 patients with adrenal lesions (N = 260 with a primary tumor and N= 111 with an unknown primary tumor). Parameters such as the presence of a tumor, nodule, enlarged adrenal, maximum standardized uptake (SUVmax ratio) were evaluated. Univariate and multivariate analysis were used to identify variables that may predict risk of adrenal metastasis. Subjects with adrenal metastasis versus those without had a higher frequency of primary lung tumors (53.7% versus 28.6%, respectively; P<= 0.001) but a lower frequency of gastrointestinal cancer (9.3% versus 20.4%, respectively; P = 0.014). The frequency of other abnormalities including nodules and enlarged adrenals were similar between cancer and non cancer subjects. A higher proportion of subjects with adrenal metastasis regardless whether the primary tumor site in the lung, gastrointestinal track, or liver had SUVmax ratio > 2.5 versus those with no adrenal metastasis. In this cohort of subjects, the greatest proportion of subjects with adrenal metastasis was those with primary lung cancer. Univariate and multivariate analysis indicated that age, SUVmax ratio, and the presence of metastasis in multiple organs were independent variables for having adrenal metastasis. In this study, FDG PET/CT was useful in characterizing adrenal lesions including determining whether they were benign or malignant. This technology allowed us to identify characteristics that may useful in predicting adrenal metastasis and cancer severity. PMID- 22103903 TI - Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. AB - To know the incidence of epidermal growth factor receptor (EGFR) mutations in small cell lung cancer (SCLC) patients who received surgical resection in mainland China. xTAG technology was used to detect the EGFR exon 19 and exon 21 mutations of 40 patients with SCLC who received surgical treatment in Zhejiang Cancer Hospital from 1998 to 2010. 2 of 40 cases were found with mutations in exon 19 of the EGFR gene. The mutation in exon 19 of the EGFR gene is in a female and non smoking patient which pathology is SCLC combined adenocarcinoma, and the other is male and smoking patient which pathology is SCLC combined squamous cell carcinoma. The EGFR mutation is rare in SCLC patients, and EGFR mutation might occur more often in combined SCLCs than conventional patients. PMID- 22103904 TI - Silencing of EphA2 inhibits invasion of human gastric cancer SGC-7901 cells in vitro and in vivo. AB - Receptor tyrosine kinases (RTKs), the common products of transforming oncogenes, have been widely used as indicators in the genesis and progression of human tumors. Until now, the erythropoietin-producing human hepatocellular (Eph) receptors have been recognized as the largest family of RTKs. EphA2, one member of Eph receptors, locates on human chromosome 1p36.1 which is a hot region for cancer research. It has been reported that high EphA2 expression levels were correlated with the tumor metastasis and poor prognosis. Increased expression of EphA2 can promote tumor growth and enhance the metastatic potential. To further define the function of EphA2 in malignant invasion, we employed the small interference RNA (siRNA) technique to knockdown gene expression of EphA2 in the gastric cancer SGC-7901 cell. Our results showed that the expression of double stranded RNA led to the efficient and specific inhibition of endogenous EphA2 expression in SGC-7901 cells. Silencing of EphA2 expression inhibited cell proliferation, caused cell cycle arrest, and decreased cell invasion in vitro. In addition, intratumoral injection EphA2 siRNA plasmid suppressed the growth of SGC 7901 cells xenografts in nude mice. Furthermore, knockdown of EphA2 expression reduced the expression of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo. In conclusion, our findings demonstrate that silencing of EphA2 inhibits gastric cancer SGC-7901 cell proliferation, invasion and MMP-9 expression, which indicate that the specific inhibition of EphA2 may be a potential approach for gastric cancer therapy. PMID- 22103905 TI - Stereotactic radiotherapy (SBRT) as a sole or salvage therapy in non-small cell lung cancer patients. AB - The aim of this study is to present evaluation of treatment toxicity and the rate of local control in non-small cell lung cancer patients (NSCLC) treated with stereotactic body radiotherapy (SBRT). The analysis was performed on heterogenous group of 61 NSCLC patients, treated with SBRT between 2005 and 2008. It included 26 patients in clinical stage I, 5 in stage II, 22 in III and 8 in stage IV. In 30 patients SBRT was the only treatment, in 20 patients SBRT was a salvage therapy and in 11 patients SBRT was used as a boost after conventionally fractionated radiotherapy (CRT). The mean age was 67 yrs. Fifteen patients received chemotherapy in the course of treatment. Radiation doses were converted into Linear Quadratic Equivalent Dose at 2Gy per fraction (LQED2). The survival curves were plotted using Kaplan-Maier estimator and analyzed using log-rank test and Cox method. The LQED2 doses administered in stereotactic technique ranged from 8 Gy to 150 Gy and the fraction doses from 5 Gy to 24 Gy. The rate of 2 years local control correlated with LQED2: it was 81% in a group of patients who received over 110 Gy, compared to 51% and 33% in a group of patients who received 60-110 Gy and less than 30 Gy respectively. Prior radiotherapy and advanced clinical stage correlated with lower doses at SBRT and hence lower rate of local control. The tolerance of SBRT was satisfactory: there was no RTOG grade 3 - 4 toxicity. The results are consistent with findings of other authors and indicate that LQED2 doses delivered by SBRT in the treatment of NSCLC should be higher than 110 Gy whenever clinically feasible. SBRT used as a salvage therapy was less effective, because use of high doses was precluded due to consideration of normal tissue tolerance. PMID- 22103906 TI - Environment-responsive alkanol-based supramolecular solvents: characterization and potential as restricted access property and mixed-mode extractants. AB - Self-assembly, the process by which supramolecular solvents (SUPRAS) with an ordered structure are produced, provides unique opportunities to obtain tailored solvents with advanced functional features. In this work, environment-responsive (C(7)-C(14)) alkanol-based SUPRAS were synthesized and their potential for analytical extractions was assessed. The global composition of the solvent, the size of the coacervate droplets that form it, and the aqueous cavities of the inverted hexagonal arrangement of the alkanols can be tailored by controlling the environment [specifically, the tetrahydrofuran (THF):water ratio in the bulk solution] for alkanol self-assembly. Interestingly, supramolecular solvents are highly adaptive and the previous features can all be reversed by modifying the environment. The spontaneous self-assembly of these solvents followed predictable routes, and their composition and volume can be accurately predicted from equations derived in this work. The solvents were structurally elucidated by light and cryo-scanning electron microscopy. Extractive applications exploiting the molecular size-based restricted access properties of SUPRAS were developed and their ability to engage in mixed-mode mechanisms for solute solubilization was established. Thus, solutes of increasing molecular weight were extracted from food and environmental samples with recoveries dependent on vacuole size in the SUPRAS, while macromolecules such as proteins, carbohydrates, and humic acids were excluded. The ability of SUPRAS to establish hydrogen-bonding and dispersion interactions was exploited to extract carcinogenic chlorophenols (CCPs) from environmental waters, and a simple and fast method was developed with quantitation limits (e.g., 0.21-0.23 MUg.L(-1)) low enough to comply with legislation (e.g., maximum permitted levels for pentachlorophenol are in the range 0.4-1 MUg.L(-1)). PMID- 22103907 TI - Pegylated interferon alpha-2b plus ribavirin for Japanese chronic hepatitis C patients with normal alanine aminotransferase. AB - AIM: To investigate the efficacy and safety of a pegylated interferon (PEG-IFN) alpha-2b plus ribavirin (RBV) combination treatment for patients with chronic hepatitis C virus (HCV) infection who have persistently normal alanine aminotransferase (NALT). METHODS: This multicenter study included 989 patients with HCV genotype 1 (114 with NALT and 875 with elevated ALT) who received weight based doses of PEG-IFN alpha-2b plus RBV for 48 weeks. We compared the sustained viral response (SVR) rates of patients with NALT and elevated ALT who received at least 80% or more of the target dosage of PEG-IFN alpha-2b and 60% or more of the target RBV (minimum acceptable dosage). RESULTS: No significant difference was found in the overall SVR rate between the NALT (42.1%) and elevated ALT groups (37.3%). No significant difference in the SVR rates was found between NALT (63.3%) and elevated ALT group (61.6%) patients who received minimum acceptable dosage. Multivariate analysis showed that age (<65 years old) and total cholesterol (?220 mg/dL) were significantly independent positive factors associated with an SVR in the NALT group. Twenty-four weeks after treatment, an ALT increase above the normal range was observed for 34.0% (18 of 53) of the non responsive group of NALT patients. CONCLUSIONS: The efficacy and safety of PEG IFN alpha-2b plus RBV combination therapy for patients with chronic HCV infection are similar for patients with NALT and those with elevated ALT levels. These results indicate that patients with NALT should be considered for treatment with PEG-IFN alpha-2b plus RBV. PMID- 22103908 TI - The impact of maxillary osteotomy on speech outcomes in cleft lip and palate: an evidence-based approach to evaluating the literature. AB - Objective : To undertake a critical and systematic review of the literature on the impact of maxillary advancement on speech outcomes in order to identify current best evidence. Design and Main Outcome Measures : The following databases were searched: PubMed, CINAHL, and The Cochrane Controlled Trials Register. In addition, reference lists were hand searched for additional articles. Using a predefined framework and set criteria, evidence was evaluated using the assignment of levels of evidence (at least Level III on the evidence hierarchy), calculation of post-hoc power (>= 0.8), effect size (Cohen's d >= 0.5), and adaptation of the parameters as set out by The Cochrane Collaboration. Results : Of the 40 studies identified, the majority (68%) fell within Level III.ii, representing cohort-type studies and a fifth (20%) within Level IV, the weakest form of evidence. Power and effect size calculations were only possible in 9 studies for different speech outcomes, and only seven studies met the set criteria for best evidence. Accordingly, current best evidence for articulation exists only for a noncleft population, is conflicting for resonance and nasalance, and is mixed for velopharyngeal function depending on which instrumental measure is used. Conclusions : There is an obvious need for further prospective research in the field with strong speech methodology such as the undertaking of interrater and intrarater reliability, adequate follow-up, and sufficient sample sizes based on a priori power analyses. Methodologic issues are discussed and recommendations made. PMID- 22103909 TI - Long-lasting TMS motor threshold elevation in mild traumatic brain injury. AB - OBJECTIVES: Mild traumatic brain injury (mTBI) is very common, and part of the patients experience persistent symptoms. These may be caused by diffuse neuronal damage and could therefore affect cortical excitability. The motor threshold (MT), measured by transcranial magnetic stimulation (TMS), is a measure of cortical excitability and cortico-spinal tract integrity. MATERIALS AND METHODS: We used navigated TMS (nTMS) and electromyography to determine subjects' left hemisphere MTs. Nineteen subjects with mTBI (11 with persistent symptoms and eight fully recovered) and nine healthy controls were tested. The injuries had occurred on average 5 years earlier. All participants had normal brain MRIs, that is, no signs of injury. None used centrally acting medication. RESULTS: The mean MT in controls was 43.0% (SD 2.5) of maximum stimulator output. The mTBI subjects mean MT was 53.4% (SD 9.7), being higher than the controls' threshold. Subjective recovery did not correlate with MT. CONCLUSIONS: The results show chronic MT elevation in a sample of subjects with symptomatic or recovered mTBI. This suggests that mTBI may be compensated, although not fully recovered, years after the injury. While the cause for MT elevation cannot be concluded from these preliminary observations, possible explanations include decreased cortical excitability and impaired subcortical conduction. PMID- 22103910 TI - Topical grape seed proanthocyandin extract reduces sunburn cells and mutant p53 positive epidermal cell formation, and prevents depletion of Langerhans cells in an acute sunburn model. AB - OBJECTIVE: The purpose of this study was to investigate whether grape seed proanthocyanidin extract (GSPE) can provide photoprotection against ultraviolet (UV) irradiation. BACKGROUND DATA: Study has shown that GSPE is a natural oxidant, and is used in many fields such as ischemia-reperfusion injury, chronic pancreatitis, and even cancer. However, the effect of GSPE on UV irradiation is as yet unknown. METHODS: Cutaneous areas on the backs of normal volunteers were untreated or treated with GSPE solutions or vehicles 30 min before exposure to two minimal erythema doses (MED) of solar simulated radiation. Cutaneous areas at different sites were examined histologically for the number of sunburn cells, or immunohistochemically for Langerhans cells and mutant p53 epidermal cells. RESULTS: On histological and immunohistochemical examination, skin treated with GSPE before UV radiation showed fewer sunburn cells and mutant p53-positive epidermal cells and more Langerhans cells compared with skin treated with 2-MED UV radiation only (p<0.001, p<0.001, and p<0.01, respectively). CONCLUSIONS: GSPE may be a possible preventive agent for photoprotection. PMID- 22103911 TI - Report of depressive symptoms on waiting list and mortality after liver and kidney transplantation: a prospective cohort study. AB - BACKGROUND: Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation. Our objective is to determine whether report of depressive symptoms on waiting list predicts outcome of liver and kidney transplantation. METHODS: Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list. 339 were transplanted 6 months later on average, and followed prospectively. The main outcome measures were graft failure and mortality 18 months post-transplantation. RESULTS: Among the 339 patients, 51.6% reported depressive symptoms on waiting list, 16.5% had a graft failure and 7.4% died post-transplantation.Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation, independently from age, gender, current cigarette smoking, anxiety symptoms, main primary diagnosis, UNOS score, number of comorbid diagnoses and history of transplantation. Data were consistent for liver and kidney transplantations. Other baseline predictive factors were: for graft failure, the main primary diagnosis and a shorter length since this diagnosis, and for mortality, older age, male gender and the main primary diagnosis. CONCLUSION: Further studies are needed to understand the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation. PMID- 22103913 TI - Characterization of a novel PTEN mutation in MDA-MB-453 breast carcinoma cell line. AB - BACKGROUND: Cowden Syndrome (CS) patients with germ line point mutations in the PTEN gene are at high risk for developing breast cancer. It is believed that cells harboring these mutant PTEN alleles are predisposed to malignant conversion. This article will characterize the biochemical and biological properties of a mutant PTEN protein found in a commonly used metastatic breast cancer cell line. METHODS: The expression of PTEN in human breast carcinoma cell lines was evaluated by Western blotting analysis. Cell line MDA-MB-453 was selected for further analysis. Mutation analysis of the PTEN gene was carried out using DNA isolated from MDA-MB-453. Site-directed mutagenesis was used to generate a PTEN E307K mutant cDNA and ectopic expressed in PC3, U87MG, MCF7 and Pten(-/-) mouse embryo fibroblasts (MEFS). Histidine (His)-tagged PTEN fusion protein was generated in Sf9 baculovirus expression system. Lipid phosphatase and ubiquitination assays were carried out to characterize the biochemical properties of PTEN E307K mutant. The intracellular localization of PTEN E307K was determined by subcellular fractionation experiments. The ability of PTEN E307K to alter cell growth, migration and apoptosis was analyzed in multiple PTEN-null cell lines. RESULTS: We found a mutation in the PTEN gene at codon 307 in MDA-MB-453 cell line. The glutamate (E) to lysine (K) substitution rendered the mutant protein to migrate with a faster mobility on SDS-PAGE gels. Biochemically, the PTEN E307K mutant displayed similar lipid phosphatase and growth suppressing activities when compared to wild-type (WT) protein. However, the PTEN E307K mutant was present at higher levels in the membrane fraction and suppressed Akt activation to a greater extent than the WT protein. Additionally, the PTEN E307K mutant was polyubiquitinated to a greater extent by NEDD4-1 and displayed reduced nuclear localization. Finally, the PTEN E307K mutant failed to confer chemosensitivity to cisplatinum when re-expressed in Pten(-/-) MEFS. CONCLUSIONS: Mutation at codon 307 in PTEN C2 loop alters its subcellular distribution with greater membrane localization while being excluded from the cell nucleus. This mutation may predispose breast epithelial cells to malignant transformation. Also, tumor cells harboring this mutation may be less susceptible to the cytotoxic effects of chemotherapeutics. PMID- 22103914 TI - Preliminary report of the use of everolimus in a patient with progressive medullary thyroid carcinoma. PMID- 22103915 TI - Resonance frequency analysis of 208 Straumann dental implants during the healing period. AB - The most important prerequisite for the success of an osseointegrated dental implant is achievement and maintenance of implant stability. The aim of the study was to measure the 208 Straumann dental implant stability quotient (ISQ) values during the osseointegration period and determine the factors that affect implant stability. A total of 164 of the implants inserted were standard surface, and 44 of them were SLActive surface. To determine implant stability as ISQ values, measurements were performed at the stage of implant placement and healing periods by the Osstell mentor. The ISQ value ranges showed a significant increase during the healing period. Except for the initial measurement, the posterior maxilla had the lowest ISQ values, and there was no significant difference among anterior mandible, posterior mandible, and anterior maxilla (P < .05). Implant length did not have a significant influence on ISQ value (P > .05). The second measurement was significantly higher in men compared with women (P < .05). The second measurement was significantly higher than the others at 4.8 mm, and for the final measurement, there were no significant differences between 4.8 and 4.1 mm, which were higher than 3.3 mm (P < .05). When comparing sandblasted, large-grit, acid etched (SLA) and SLActive surface implants, there were no significant differences for insertion measurements, but for second measurements, SLActive was significantly higher (P = 0), and for the final measurement, there was no significant difference. It appears that repeated ISQ measurements of a specific implant have some diagnostic benefit, and the factors that affect implant stability during the healing period are presented. PMID- 22103916 TI - Focus on mitochondria dysfunction and dysregulation in heart failure: towards new therapeutic strategies to improve heart function. PMID- 22103917 TI - Proteomic remodeling of mitochondria in heart failure. AB - Heart failure (HF) is a common disease that has been attributed, in part, to deprivation of cardiac energy. As a result, the interplay between metabolism and adenosine triphosphate production is fundamental in determining the mechanisms driving the disease progression. Due to its central role in energy production, metabolism, calcium homeostasis, and oxidative stress, the mitochondrion has been suggested to play a pivotal role in the progression of the heart to failure. Nevertheless, the mitochondrion's specific role(s) and the proteins contributing to the development and progression of HF are not entirely clear. Thus, changes in mitochondrial proteomic make-up during HF have garnered great interest. With the continued development of advanced tools for assessing proteomic make-up, characterization of mitochondrial proteomic changes during disease states such as HF are being realized. These studies have begun to identify potential biomarkers of disease progression as well as protein targets that may provide an avenue for therapeutic intervention. The goal of this review is to highlight some of the changes in mitochondrial proteomic make-up that are associated with the development of HF in an effort to identify target axes and candidate proteins contributing to disease development. Results from a number of different HF models will be evaluated to gain insight into some of the similarities and differences in mitochondrial proteomic alterations associated with morphological and functional changes that result from the disease. Congest Heart Fail. PMID- 22103919 TI - Relationship between arterial impedance and concentric remodeling in patients with normal systolic function: impact on prevalence and survival. AB - Although concentric remodeling (CR) is associated with increased morbidity and mortality, little is known regarding the interaction of arterial impedance (IMP) on survival in CR. The authors evaluated 50,421 patients with normal systolic function to assess prevalence of CR and impact of CR and IMP on survival (mean follow-up, 3.9+/-2.3 years.) In 2636 patients with paired echocardiograms, the authors assessed the impact of IMP on mortality, based on maintaining a high or low IMP (> or <4.0 mm Hg/mL/m(2) ). CR occurred in 21% of patients and was associated with twice the mortality compared with patients with normal left ventricular (LV) structure (P<.0001). The prevalence of CR increased with increasing IMP (P<.001 for trend). In the paired cohort, CR patients with an IMP <4.0 had a mortality of 6.3%, with 58% converting to normal LV structure, whereas mortality was higher (10%; P<.0001) and conversion to normal LV structure was less frequent (46%; P<.001) in those whose IMP remained >=4.0. CR is prevalent and associated with high mortality and increases with higher IMP. Reducing IMP levels in CR is associated with lower mortality and greater conversion to normal LV structure. Studies are needed to determine whether reporting and targeting IMP is beneficial in CR. PMID- 22103920 TI - Pulmonary arterial elastance for estimating right ventricular afterload in systolic heart failure. AB - Assessment of right ventricular afterload in systolic heart failure seems mandatory as it plays an important role in predicting outcome. The purpose of this study is to estimate pulmonary vascular elastance as a reliable surrogate for right ventricular afterload in systolic heart failure. Forty-two patients with systolic heart failure (ejection fraction <35%) were studied by right heart catheterization. Pulmonary arterial elastance was calculated with three methods: Ea(PV) = (end-systolic pulmonary arterial pressure)/stroke volume; Ea*(PV) = (mean pulmonary arterial pressure - pulmonary capillary wedge pressure)/stroke volume; and PPSV = pulmonary arterial pulse pressure (systolic - diastolic)/stroke volume. These measures were compared with pulmonary vascular resistance ([mean pulmonary arterial pressure - pulmonary capillary wedge pressure]/CO). All estimates of pulmonary vascular elastance were significantly correlated with pulmonary vascular resistance (r=0.772, 0.569, and 0.935 for Ea(PV), Ea*(PV), and PPSV, respectively; P <.001). Pulmonary vascular elastance can easily be estimated by routine right heart catheterization in systolic heart failure and seems promising in assessment of right ventricular afterload. PMID- 22103918 TI - Mitochondrial protein phosphorylation as a regulatory modality: implications for mitochondrial dysfunction in heart failure. AB - Phosphorylation of mitochondrial proteins has been recognized for decades, and the regulation of pyruvate- and branched-chain alpha-ketoacid dehydrogenases by an atypical kinase/phosphatase cascade is well established. More recently, the development of new mass spectrometry-based technologies has led to the discovery of many novel phosphorylation sites on a variety of mitochondrial targets. The evidence suggests that the major classes of kinase and several phosphatases may be present at the mitochondrial outer membrane, intermembrane space, inner membrane, and matrix, but many questions remain to be answered as to the location, timing, and reversibility of these phosphorylation events and whether they are functionally relevant. The authors review phosphorylation as a mitochondrial regulatory strategy and highlight its possible role in the pathophysiology of cardiac hypertrophy and failure. PMID- 22103921 TI - Impact of congestive heart failure treatment on peripheral microvascular tissue oxygenation. AB - The authors evaluated peripheral tissue oxygenation during treatment of acutely decompensated congestive heart failure (CHF) to determine whether differences exist between patients who experienced adverse outcomes (AO), defined as death or readmission within 6 months, and patients who did not (non-AO). This prospective, observational study measured differential absorption spectroscopy-derived tissue hemoglobin oxygenation (S(t) O(2) ) in CHF patients from presentation through hospital discharge to determine whether differences between the AO and non-AO groups exist. Of 52 patients, 6 died and 27 were readmitted. In the non-AO group, S(t) O(2) increased from admission to discharge by 5.2% ( P<.01; 95% confidence interval, 1.7%-8.7%). No S(t) O(2) change occurred in the AO group (2.3%; P=.42; 95% CI, -2.2%-6.8%). Tissue oxygenation increased during inpatient treatment in CHF patients without future adverse outcomes, but was unchanged for those who later died or were readmitted. Lack of improvement may be associated with higher rates of death and readmission. PMID- 22103922 TI - Availability of data when heart failure patients are admitted to hospice. AB - Guidelines recommend hospice care for patients with advanced heart failure (HF) who are approaching end of life. However, little is known about the data available when HF patients are admitted to hospice. This pilot study surveyed the staff from 100 hospices in the United States and Canada about how frequently data were provided to or obtained by the hospice when admitting HF patients and how important they perceived the data. The survey response rate was 66%. Overall, data were less often provided or obtained than rated important (aggregate mean difference, P<.001, r=.75). Data important to prognostication or ongoing care were provided to or readily obtained by the hospices for blood pressure (50.0%), left ventricular ejection fraction (EF) (50.0%), edema (58.3%), HF medications, symptoms of dyspnea (63.2%), chest pain (57.2%), common comorbidities, and pacemaker (69.6%) or other devices (60.0%). Approximately half of the time, hospices reported that they rarely or never received information about medication intolerance. Significant amounts of clinically valid data are not provided to or obtained by hospice providers when admitting HF patients. Investigations are needed to corroborate these findings, understand information transfer at transitions in care, and to determine the impact of admission data on hospice care for HF patients. Congest Heart Fail. PMID- 22103923 TI - Open access to an outpatient intravenous diuresis program in a systolic heart failure disease management program. AB - In order to provide efficient utilization of resources in an outpatient setting for acute exacerbation of heart failure (HF), the authors piloted an open-access outpatient intravenous (IV) diuretic program (IVDP) to evaluate utilization in an HF disease management program (HFDMP), patient characteristics for users of the program, and safety. An outpatient HFDMP at Jackson Memorial Hospital in Miami, Florida, enrolling 577 patients 18 years and older with an ejection fraction <=40% was implemented. For symptoms or weight gain >=5 pounds, patients were eligible to use an open-access IVDP during clinic hours. A total of 130 HFDM patients (22.5%) used the IVDP. IVDP users were more likely to be diabetic, with lower body mass indices than non-IVDP users. New York Heart Association class IV patients and previously hospitalized patients were more likely to use the IVDP. There were no documented adverse reactions for patients receiving treatment and no difference in mortality between groups. This open-access outpatient IVDP model for patients with HF was readily utilized by the HFDMP participants and appears safe for use in this population. This unique model may provide alternative access for acute HF treatment. Congest Heart Fail. PMID- 22103924 TI - From bench to bedside: chromogranin B-a promising novel biomarker in heart failure. PMID- 22103925 TI - Iliac vessel wall thickness in menstrual and hormone treated and untreated postmenopausal women. AB - OBJECTIVE: To assess iliac vessel wall thickness in different groups of women. METHOD: Three groups of women were menopausal and were classified by hormone replacement therapy (HRT) (n = 32), atherosclerotic risk factors (n = 14) and an untreated group of postmenopausal women (n = 29), two groups of menstrual women, above 35 years (N = 35) and below 35 years (n = 16). In these groups of women, a 3.5 MHz ultrasound was used to assess the combined vessel wall thickness of the right iliac artery inner wall and vein outer wall. RESULTS: The iliac vessel wall thickness was found significantly high in the menopausal group of women possessing high risk factors for atherosclerosis (4.3 +/- 0.08 mm) and the untreated menopausal group of women (3.9 +/- 0.08 mm) compared to the other three groups (p < 0.0001) (Mann-Whitney U test). The vessel wall thickness of the HRT group was 2.96 +/- 0.09 mm, the older menstrual group 2.61 +/- 0.07 mm, and 2.0 +/- 0.06 mm in the young menstrual group. The HRT group had a significantly thicker iliac vessel wall compared to the young menstrual group (p < 0.001). CONCLUSION: These results confirm the significant impact of high risk factors, such as smoking, hyperlipidaemia and diabetes, on the vessel wall thickness due to accelerated atherosclerosis. This study also suggests that the oestrogenaemic state of a woman may affect the health of the vessel wall. PMID- 22103926 TI - Humor appreciation of captionless cartoons in obsessive-compulsive disorder. AB - BACKGROUND: It seems that the core neural regions and cognitive processes implicated in obsessive-compulsive disorder (OCD) pathophysiology may overlap with those involved in humor appreciation. However, to date, there have been no studies that have explored humor appreciation in OCD. The purpose of the present work was to investigate humor appreciation in a group of patients with OCD. METHODS: We examined 25 patients with OCD and 25 healthy controls, matched by age, education, and gender. We administered Penn's Humor Appreciation Test (PHAT), a computerized test comprising captionless cartoons by Mordillo. Each set of stimuli consisted of two almost identical drawings, one of which was funny due to the alteration of a detail in the cartoon, whereas the other was not funny. Severity of psychopathology was evaluated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). RESULTS: No significant effect for group, gender or group * gender interaction was found on the PHAT scores. In OCD patients, humor appreciation was not significantly associated with age of onset, duration of illness, and obsessions, but correlated significantly with compulsions. CONCLUSIONS: Humor appreciation, based on captionless cartoons in OCD, does not seem to be deficient compared to healthy subjects but may be related to illness characteristics. PMID- 22103927 TI - Stroke patients do not need to be inactive in the first two-weeks after stroke: results from a stroke unit focused on early rehabilitation. AB - BACKGROUND: Although stroke unit care with early rehabilitation is recommended for most stroke patients, the content of the treatment given to acute stroke patients differs a lot. AIM: The primary aim of this study was to describe the activity patterns of acute stroke patients managed in a stroke unit focused on early rehabilitation. METHODS: Patients admitted to the stroke unit at St. Olavs Hospital, Trondheim, with the diagnosis of stroke were asked to participate. Patients were eligible if they were less than 14 days post stroke and did not receive palliative care. Patients were observed every 10 mins from 8:00 am to 5:00 pm, and activity, location, and who helped them were recorded. RESULTS: A total of 117 patients (mean age 78.7 years; 56% male) were included. In total, patients spent 30.3% of time in bed, 46.4% of time in sitting out of bed, and 19.9% of time in higher motor activities such as transferring, standing, walking, or climbing stairs. Patients with mild, moderate, and severe stroke spent 79.5%, 59.2%, and 31.0% of observed time sitting out of bed or engaged in higher motor activities, respectively. CONCLUSION: This study shows that it is possible for acute stroke patients to spend most of the active day out of bed and to engage in higher motor activities up to 20% of the time. It also shows that it is feasible for severely affected stroke patients to stay out of bed in the early phase after stroke. PMID- 22103928 TI - Asymmetric Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne vinylcyclopropanes for bicyclo[3.3.0] compounds with a chiral quaternary carbon stereocenter and density functional theory study of the origins of enantioselectivity. AB - A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts. PMID- 22103929 TI - The chemoadjuvant potential of grape seed procyanidins on p53-related cell death in oral cancer cells. AB - BACKGROUND: To clarify the efficacy of grape seed procyanidin (GSP) on antiproliferative effects related to p53 functional status of oral squamous cell carcinoma (OSCC) for its chemoadjuvant potential. METHODS: We used GSP to investigate SCC-25 cells with wild-type p53 gene and OEC-M1 cells with mutant p53 gene for the assessment of antiproliferative effects including cell viability, cell cycle, apoptosis, migration and invasion potential, and alterations of associated oncoproteins involved in cellular and molecular events. RESULTS: The findings suggest that GSP on OEC-M1 cells leads to cell cycle arrest by increasing the expression of p21(Cip1) /p27(Kip1) protein without functioning mitochondria-mediated apoptosis, whereas GSP on SCC-25 cells inhibits cell proliferation via both G1-phase arrest and mitochondria-mediated apoptosis in a dose-dependent manner as a result of alterations of Bcl-2. GSP also inhibits the migration and invasion of both cells, which are associated with the suppression of matrix metalloproteinases (MMPs), MMP-2 and MMP-9. CONCLUSION: Antiproliferative effectiveness of GSP is closely associated with the p53 status of OSCC cells. GSP displays chemoadjuvant potential via cell cycle blockage and apoptotic induction. Our findings clearly suggest that GSP may play a role as a novel chemopreventive or therapeutic agent for OSCC. PMID- 22103930 TI - A test for carrion fly full siblings: a tool for detecting postmortem relocation of a corpse. AB - We propose a genetic test for full sibship for a pair of carrion flies that could reveal the postmortem relocation of a corpse. A carrion fly larva is sometimes left behind when a corpse is moved. The discovery of full sibling larvae of approximately the same developmental stage at two locations would strongly suggest that a corpse was moved between those two sites. Distributions of pairwise comparisons of relatedness (R) coefficients were generated using amplified fragment length polymorphism profiles for nine samples of laboratory generated full siblings as well as for a reference sample of nonfull sibling Phormia regina (Diptera: Calliphoridae). The mean relative R coefficient, a pairwise measure of the proportion of shared alleles, was 0.479 (+/-0.289 SD) for full siblings, close to the theoretical expectation of 0.5. A likelihood ratio (LR) test was based on observed distributions of R. R >0.55 corresponded to an LR >1000 favoring full sibship for that pair of individuals. PMID- 22103931 TI - Diversification of land plants: insights from a family-level phylogenetic analysis. AB - BACKGROUND: Some of the evolutionary history of land plants has been documented based on the fossil record and a few broad-scale phylogenetic analyses, especially focusing on angiosperms and ferns. Here, we reconstructed phylogenetic relationships among all 706 families of land plants using molecular data. We dated the phylogeny using multiple fossils and a molecular clock technique. Applying various tests of diversification that take into account topology, branch length, numbers of extant species as well as extinction, we evaluated diversification rates through time. We also compared these diversification profiles against the distribution of the climate modes of the Phanerozoic. RESULTS: We found evidence for the radiations of ferns and mosses in the shadow of angiosperms coinciding with the rather warm Cretaceous global climate. In contrast, gymnosperms and liverworts show a signature of declining diversification rates during geological time periods of cool global climate. CONCLUSIONS: This broad-scale phylogenetic analysis helps to reveal the successive waves of diversification that made up the diversity of land plants we see today. Both warm temperatures and wet climate may have been necessary for the rise of the diversity under a successive lineage replacement scenario. PMID- 22103932 TI - Drop-casted self-assembling graphene oxide membranes for scanning electron microscopy on wet and dense gaseous samples. AB - Graphene oxide sheets dispersed in water and many other solvents can spontaneously assemble into a surface film covering an evaporating droplet due to their amphiphilicity. Thus, graphene oxide membranes with controllable thickness suspended over an orifice have been directly fabricated using a simple drop-cast approach. Mechanical properties and electron transparency tests of these membranes show their use as electron transparent, but molecularly impenetrable, windows for environmental electron microscopy in liquids and dense gaseous media. The foreseeable, broader application of this drop-cast window methodology is the creation of access spots for electron probes to study isolated microsamples in their natural, undisrupted state within the interior of prefabricated devices (such as microfluidic chips or sealed containers of biological, chemically reactive, toxic, or forensic materials). PMID- 22103933 TI - Multiple phase inversion of emulsions stabilized by in situ surface activation of CaCO3 nanoparticles via adsorption of fatty acids. AB - The in situ surface activation of raw CaCO(3) nanoparticles by interaction with a series of sodium carboxylates of chain length between 6 and 12 as well as sodium 2-ethylhexylsulfosuccinate (AOT) was studied, and the impact of this on the stabilization and phase inversion of toluene-water emulsions was assessed. By using complementary experiments including measurement of particle zeta potentials, adsorption isotherms of amphiphile, and relevant contact angles, the mechanism of this activation was revealed. The results show that hydrophilic CaCO(3) nanoparticles can be surface activated by interaction with sodium carboxylates and AOT even if they are not surface-active themselves. Both the electrostatic interaction between the positive charges on particle surfaces and the negative charges of anionic amphiphile headgroups and the chain-chain interactions of the amphiphile result in monolayer adsorption of the amphiphile at the particle-water interface. This transforms the particles from hydrophilic to partially hydrophobic such that they become surface-active and stabilize oil in-water O/W(1) emulsions and induce O/W(1) -> water-in-oil W/O phase inversion, depending on the chain length of the carboxylate molecules. At high amphiphile concentration, bilayer or hemimicelle adsorption may occur at the particle-water surface, rendering particles hydrophilic again and causing their desorption from the oil-water interface. A second phase inversion, W/O -> O/W(2), may occur depending on the surface activity of the amphiphile. CaCO(3) nanoparticles can therefore be made good stabilizers of both O/W and W/O emulsions once surface activated by mixing with traces of suitable anionic amphiphile. PMID- 22103934 TI - 'It burdens me': the impact of stroke in central Aceh, Indonesia. AB - The complex primary and secondary consequences of stroke have often been equated with the concept of biographical disruption, although a number of mediating factors have been identified. However, the research to date is almost exclusively based in western contexts, despite the fact that stroke is increasing most rapidly in low-income and middle-income countries. This research explores the experience of stroke in the rural community of central Aceh, Indonesia. The participants included 11 stroke survivors and 18 carers, with data collected through in-depth interviews and photographic facilitated interviews, supported with participant observation over a nine month period. The participants discussed and illustrated the disruptive result of their stroke, but for most, their ability to maintain religious duties and contribute to their family resulted in a form of biographical continuity. Their strategies and challenges are discussed alongside the implications for care in this context. PMID- 22103935 TI - Effect of passive stretch on intracellular nitric oxide and superoxide activities in single skeletal muscle fibres: influence of ageing. AB - Skeletal muscle is repeatedly exposed to passive stretches due to the activation of antagonist muscles and to external forces. Stretch has multiple effects on muscle mass and function, but the initiating mechanisms and intracellular signals that modulate those processes are not well understood. Mechanical stretch applied to some cell types induces production of reactive oxygen species (ROS) and nitric oxide that modulate various cellular signalling pathways. The aim of this study was to assess whether intracellular activities of ROS and nitric oxide were modulated by passive stretches applied to single mature muscle fibres isolated from young and old mice. We developed a novel approach to apply passive stretch to single mature fibres from the flexor digitorum brevis muscle in culture and to monitor the activities of ROS and nitric oxide in situ by fluorescence microscopy. Passive stretch applied to single skeletal muscle fibres from young mice induced an increase in dihydroethidium oxidation (reflecting intracellular superoxide) with no increase in intracellular DAF-FM oxidation (reflecting nitric oxide activity) or CM-DCFH oxidation. In contrast, in fibres isolated from muscles of old mice passive stretch was found to induce an increase in intracellular nitric oxide activities with no change in DHE oxidation. PMID- 22103936 TI - Toxicity testing: the need for new maps for the future. PMID- 22103937 TI - Assessing the search for information on Three Rs methods, and their subsequent implementation: a national survey among scientists in the Netherlands. AB - A local survey conducted among scientists into the current practice of searching for information on Three Rs (i.e. Replacement, Reduction and Refinement) methods has highlighted the gap between the statutory requirement to apply Three Rs methods and the lack of criteria to search for them. To verify these findings on a national level, we conducted a survey among scientists throughout The Netherlands. Due to the low response rate, the results give an impression of opinions, rather than being representative of The Netherlands as a whole. The findings of both surveys complement each other, and indicate that there is room for improvement. Scientists perceive searching the literature for information on Three Rs methods to be a difficult task, and specific Three Rs search skills and knowledge of Three Rs databases are limited. Rather than using a literature search, many researchers obtain information on these methods through personal communication, which means that published information on possible Three Rs methods often remains unfound and unused. A solution might be to move beyond the direct search for information on Three Rs methods and choose another approach. One approach that seems rather appropriate is that of systematic review. This provides insight into the necessity for any new animal studies, as well as optimal implementation of available data and the prevention of unnecessary animal use in the future. PMID- 22103938 TI - An alternative gas-phase in vitro exposure system for toxicity testing: the interaction between nitrous oxide and A549 cells. AB - An original in vitro approach was adopted to expose cells to volatile agents. The anaesthetic nitrous oxide (N(2)O) was chosen as the model agent, and type II pneumocyte-like cells (A549 cells) were used as the target to represent the lungs. A time-lapse microscopy station was equipped with a manual gas mixer that allowed the generation of a mixture of N(2)O/air/CO(2) in the gas phase, to provide a uniform distribution of the volatile agent. The dissolution of N(2)O in the culture medium was monitored by gas chromatography-electron capture detection. Biochemical alterations, in terms of homocysteine accumulation, demonstrated that intracellular methionine synthase had been inactivated by N(2)O absorbed by the cells, a process that also occurs in vivo. Toll-like receptors, which are key molecules in inflammatory lung diseases, were also investigated at the molecular level. Our experiments indicated that biochemical and molecular alterations occurred in the cells, even under conditions where neither morphologic changes nor consistent alterations in cell proliferation were evident. This in vitro exposure system can be efficiently adopted for looking at the repeat-dose effects of volatile agents on respiratory tissues. Moreover, it could be of further benefit for identifying the wide range of specific cell targets, and for monitoring relevant endpoints in the cellular and molecular processes that occur during exposure to volatile compounds. PMID- 22103939 TI - Veterinary science student preferences for the source of dog cadavers used in anatomy teaching. AB - Live animals and cadavers are integral to veterinary education. In the year of this survey (2008), and in at least the five preceding years, cadavers obtained by euthanasia of healthy pound dogs and ex-racing greyhounds were dissected by students, during their veterinary anatomy classes at the University of Queensland School of Veterinary Science. Students may have ethical concerns about this. An alternative approach was to use donated dog cadavers. These are owned pet dogs that have died of natural causes or have been euthanised for medical reasons, and have been donated by their owners for the purposes of veterinary education. Veterinary students at the School were surveyed in 2008, in order to determine their preferences for cadaver source. Data from 406 questionnaires were analysed. Third-year and fifth-year veterinary students were more likely than first-year students to prefer pound-dog/greyhound cadavers over donated cadavers for anatomy dissection (p <= 0.002). Between 32% and 45% of the students had no preference for either source of cadaver. These findings are consistent with the hypothesis that veterinary students become more accepting of the euthanasia of unwanted healthy animals for education as they progress through the veterinary programme, in contexts such as the current study. This could occur due to increased acceptance of the euthanasia of healthy animals generally, a decline in moral development, desensitisation, and/or the belief that healthy animal cadavers offer a superior learning experience. PMID- 22103940 TI - Hallmarks of atopic skin mimicked in vitro by means of a skin disease model based on FLG knock-down. AB - Loss-of-function mutations in the filaggrin gene (FLG) are a strong predisposing factor for atopic dermatitis, although their relevance to the disease pathomechanism needs further elucidation. The generation of an in vitro model of atopic skin would not only permit further evaluation of the underlying pathogenetic mechanisms and the testing of new treatment options, but would also allow toxicological studies to be performed in a simple, rapid and inexpensive manner. In this study, we have knocked down FLG expression in human keratinocytes and created three-dimensional skin models, which we used to investigate the impact of FLG on epidermal maturation and on skin absorption and its response to irritation. Histopathological evaluation of the skin models showed impaired epidermal differentiation in the FLG knock-down model. In addition, skin irritation induced by an application of sodium dodecyl sulphate resulted in significantly higher lactate dehydrogenase leakage, and interleukin (IL)-6 and IL 8 levels, than in the control model. To assess the effect of filaggrin deficiency on skin absorption of topically applied agents, we quantified the percutaneous absorption of lipophilic and hydrophilic model drugs, finding clinical relevance only for lipophilic drugs. This study clearly demonstrates that important clinical characteristics of atopic skin can be mimicked by using in vitro skin models. The FLG knock-down construct is the first step toward an in vitro model that allows clinical and toxicological studies of atopic-like skin. PMID- 22103941 TI - A critical evaluation of the 2011 ECHA reports on compliance with the REACH and CLP regulations and on the use of alternatives to testing on animals for compliance with the REACH regulation. AB - On 30 June 2011, the European Chemicals Agency published two reports, one on the functioning of the REACH system, the other on the use of alternatives to animal testing in compliance with that system. The data presented are based on information gained during the first registration period under the REACH system, which included high production volume chemicals and substances of very high concern, which have the most extensive information requirements. A total of 25,460 registration dossiers were received, covering 3,400 existing, so-called 'phase-in', substances, and 900 new, so-called 'non-phase-in', substances. Data sharing and the joint submission of data are reported to have worked successfully. In the registration dossiers for these substances, results from new animal tests were included for less than 1% of all the endpoints; testing proposals (required for 'higher-tier' information requirements) were submitted for 711 in vivo tests involving vertebrate animals. The registrants mainly used old, existing experimental data, or options for the adaptation (waiving) of information requirements, before collecting new information. For predicting substance toxicity, 'read-across' was the second most-used approach, followed by 'weight-of-evidence'. In vitro toxicity tests played a minor role, and were only used when the respective test methods had gained the status of regulatory acceptance. All in all, a successful start to the REACH programme was reported, particularly since, in contrast to most predictions, it did not contribute to a significant increase in toxicity testing in animals. PMID- 22103942 TI - A regenerative approach for bone repair in congenital pseudarthrosis of the tibia associated or not associated with type 1 neurofibromatosis: correlation between laboratory findings and clinical outcome. AB - BACKGROUND AND AIMS: Congenital pseudarthrosis of the tibia (CPT) is a rare orthopedic disease presenting spontaneous fractures that do not heal. The treatment of CPT is characterized by repeated surgical procedures that often fail, with the inevitable outcome of severe disability and amputation. We tested the hypothesis that CPT may benefit from regenerative strategies based on mesenchymal stromal cells (MSC) combined with platelet-rich fibrin (PRF) as a source of growth factors. The aim of the study was to verify whether laboratory testing to assess the osteogenic properties of MSC and the osteo-inductive activity of PRF correlated with the clinical outcome. METHODS: Ten patients affected by refractory CPT were treated by using MSC derived from the iliac crest (IC-MSC), PRF and lyophilized bone. In six patients, CPT was associated with type 1 neurofibromatosis (NF1). Biochemical, functional and molecular assays were performed to assess the intrinsic osteogenic potential of IC-MSC (cells cultured with fetal calf serum) and the osteo-inductive properties of PRF (cells cultured with autologous serum). RESULTS: Bone consolidation was obtained in three patients who had CPT and NF1. In these patients, the IC-MSC exposed to autologous serum were able to form mineral nodules in vitro, while the mineralizing ability was totally abrogated in patients with a poor clinical outcome. CONCLUSIONS: Cell therapy may be a useful tool for the treatment of refractory CPT because it increases the opportunity to achieve effective bone tissue regeneration. Our data suggest that the presence of pro-osteogenic growth factors is an essential requirement for bone healing. PMID- 22103943 TI - New ways to count CD34. PMID- 22103944 TI - Anti-tumor cytotoxic T lymphocytes targeting solid tumors: ready for clinical trials. PMID- 22103946 TI - The structure, dynamics and movement patterns of the Australian sheep industry. AB - OBJECTIVE: To describe the structure of Australia's sheep industries and the movement of sheep to enable examination of the potential for animal movements to spread disease between farms. PROCEDURE: The structure, size, marketing and movement patterns of Australian sheep farms was determined through (i) review of data published by the Australian Bureau of Statistics and Australian Bureau of Agricultural and Resource Economics, (ii) interviews with producers and saleyard managers and (iii) expert opinion. RESULTS: Twelve geographic regions are described, based on the type and extent of sheep farming in each region. Five production sectors were identified within the Australian sheep industry, with the proportion of each varying between the geographic regions. Over the past 20 years, the industry has decreased in size and contracted from the northern and central areas of Australia. Movement of sheep onto the majority (79%) of properties was limited to the introduction of less than 50 stud rams annually, although cross-bred- and wether-based farms introduced up to 2000 sheep annually; 75% of sheep movements occurred over distances less than 200 km, but stud rams moved up to 500 km. An increasing percentage of movements off farms was direct to abattoirs and over 80% of sheep sold through saleyards were purchased by abattoirs. CONCLUSIONS: The majority of Australian sheep farms operate as self replacing enterprises and introduce few stock. In addition, most sheep movements occur over distances of less than 200 km and therefore sheep movements within Australia have only a limited potential to spread disease over larger distances. PMID- 22103947 TI - The important role that veterinary practitioners play. Letter to the editor. PMID- 22103948 TI - Determinants of permanent first incisor eruption in grazing Australian Angora goats. AB - OBJECTIVE: To investigate the effects of live weight, sex and other factors on deciduous (first incisor) loss and permanent first incisor development in Angora goats. DESIGN: Goats were part of a pen study on the effects of energy intake in Angora does during pregnancy and lactation on kid growth and development. The design was three levels of nutrition in mid-pregnancy * two levels of postnatal nutrition in 17 randomised blocks. METHODS: Conception times were calculated by using artificial insemination, with ultrasound examination 43 days after insemination. Does were fed different amounts of a formulated diet in their pens. After weaning, goats were grazed in sex groups. Deciduous first incisor loss and permanent first incisor development were recorded at 11 time points from 14 to 20 months of age. RESULTS: For each sex, the time for visible eruption and full development of permanent first incisor declined linearly with increased live weight by 5.9 and 5.4 days/kg live weight, respectively. The time to reach similar development stages for first permanent incisors eruption was 3 months longer for the lightest animals compared with the heaviest animals. Date of birth, birth weight, doe age, growth rates, mid-pregnancy and postnatal nutrition, parity, day of weaning and weaning weight had no detectable effect. CONCLUSIONS: The results explain much of the substantial range in reported first permanent incisor eruption dates for small ruminants and have application in ageing of goats, marketing of kids for meat, in the selection of animals for breeding flocks and in educational material. PMID- 22103949 TI - Hepatitis E virus genotype 3f in pigs in New Caledonia. AB - BACKGROUND: Hepatitis E virus (HEV) is highly prevalent in farm pigs worldwide and an increasing body of data from industrialised countries suggests that it is an agent of a porcine zoonosis. METHODS: We used in-house real-time reverse transcription polymerase chain reaction to study HEV infection in 4-26-week-old pigs on a pig farm in New Caledonia, Oceania, for which no data are available. RESULTS: HEV RNA was detected in faeces from 6 of 92 (6.5%) pigs tested and all were 9-16 weeks old. Phylogenetic analysis showed that the HEV open reading frame 1 and 2 sequences recovered in this study formed a single cluster among HEV genotype 3 subtype f. CONCLUSIONS: Our work shows for the first time that pigs are a reservoir for HEV in New Caledonia. Further studies are needed to assess the prevalence and phylogenetic relationships of HEV in pigs and humans in this French overseas collectivity. PMID- 22103950 TI - Thromboelastography in healthy, sick non-septic and septic neonatal foals. AB - OBJECTIVES: To evaluate citrated recalcified thromboelastography (TEG) in healthy newborn foals, and to determine intra-assay, inter-individual and intra individual (at 12 h, 24 h and 7 days after birth) variations. Additionally, to compare TEG variables, haematological values and conventional coagulation profiles from healthy, sick non-septic, and septic foals. DESIGN: Prospective study. METHODS: The study group comprised 18 healthy, 15 sick non-septic and 17 septic foals. Two citrated (3.2%; 1 : 9 anticoagulant : blood ratio) blood samples were submitted for haemostatic evaluation using a TEG analyser and conventional coagulation profile. TEG values (R time (R), K time (K), angle (alpha), maximum amplitude (MA) and G value (G)), complete blood count (CBC) and conventional coagulation profile (prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration (Fib) and antithrombin (AT)) were evaluated. Signalment, presenting complaint, sepsis scores, blood culture results and outcome were taken from the medical records of the sick foals. RESULTS: Mean values +/- SD for TEG variables in healthy neonatal foals were: R = 11.82 +/- 5.35 min, K = 3.06 +/- 1.34 min, alpha= 51.19 +/- 12.66 degrees, MA = 55.06 +/- 6.67 mm and G = 6361 +/- 1700 dyn/cm(2) . Mean coefficients of variation for intra-assay/inter-individual/intra-individual in healthy foals were: R = 3.5/45.2/43.1%; K = 5.3/58.7/28.7%; alpha= 1.5/24.7/11.9%; MA = 0.3/12.1/6.1%; G = 1.6/26.7/14.7%. Septic foals had significantly greater alpha, MA and G values than sick non-septic foals, and significantly greater MA and G than healthy foals, changes that are consistent with hypercoagulability. Weak correlations were detected between TEG variables and haematological or haemostatic values. CONCLUSIONS: TEG could be used to provide additional information about the haemostatic system in equine neonates. PMID- 22103951 TI - Localised Mycobacterium ulcerans infection in four dogs. AB - Localised infection caused by Mycobacterium ulcerans is described in two Kelpies, a Whippet and a Koolie domiciled on the Bellarine Peninsula, Victoria, Australia. The diagnosis was confirmed using real-time polymerase chain reaction (PCR) targeting the M. ulcerans-specific insertion sequence (IS2404) in DNA extracted from swabs of ulcerated lesions in all cases. Where available, molecular typing confirmed that three of the dogs were infected with a strain of M. ulcerans that was indistinguishable from a disease-causing strain in people and other animals in Victoria. One dog was still undergoing treatment at the time of writing, but the remaining three dogs were successfully treated with a combination of surgical debridement and medical therapy in one case, and medical therapy alone in the other two. Investigation of the home environs of three of the dogs using real time PCR revealed low amounts of M. ulcerans DNA in various environmental samples. Mycobacterium ulcerans infection should be included in the differential diagnoses of any ulcerated skin lesions in dogs that live in or visit endemic areas of Victoria and Queensland. PMID- 22103952 TI - Use of the harmonic scalpel for soft palate resection in dogs: a series of three cases. AB - Soft palate resection is performed to resect a redundant or diseased soft palate, often associated with brachycephalic airway obstructive syndrome (BAOS). Resection has been associated with numerous complications, including coughing, bleeding, pharyngeal oedema, respiratory obstruction and death. Traditionally, the surgery is performed by sharp dissection and suturing, but other reported techniques include the use of an electrothermal sealing device or a laser. Operative time for sharp dissection is approximately 12 min, but is shortened to around 5 min when using a laser, as the haemostatic properties of the instrument negates the need for post-resection oversewing. The successful use of a harmonic scalpel to resect redundant soft palates in three dogs is described. The resected soft palates were not oversewn and the surgical time was comparable with that for laser surgery. The first dog had a minor bleed 6 h postoperatively, possibly associated with suboptimal placement of the harmonic scalpel cutting jaws. The following two patients had no postoperative complications. The harmonic scalpel laparoscopic handpiece allowed excellent visualisation of the surgical field and rapid performance of the procedure. All three patients had markedly improved postoperative respiratory function. Cleaning and resterilisation permitted multiple reuse of the handpiece, making it cost-competitive with other surgical techniques. PMID- 22103953 TI - Deep fungal dermatitis caused by the Chrysosporium anamorph of Nannizziopsis vriesii in captive coastal bearded dragons (Pogona barbata). AB - Deep fungal dermatitis caused by the Chrysosporium anamorph of Nannizziopsis vriesii (CANV) was diagnosed in a group of coastal bearded dragons (Pogona barbata). The outbreak extended over a 6-month period, with four of six lizards from the same zoological outdoor enclosure succumbing to infection. A fifth case of dermatomycosis was identified in a pet lizard originally sourced from the wild. Diagnosis of infection with the CANV was based on similar clinical signs and histopathology in all animals and confirmed by culture and sequencing of the fungus from one animal. This is the first report of the CANV causing disease in a terrestrial reptile species in Australia and the first in the coastal bearded dragon. PMID- 22103954 TI - Osteosarcoma in a woma python (Aspidites ramsayi). AB - Osteosarcoma of the axial skeleton in an 18-month-old woma python (Aspidites ramsayi) is described. A subcutaneous mass overlying the costal arches enlarged progressively over a period of 5 months and, in that time, became ulcerated and more invasive of surrounding tissues. A punch biopsy of the lesion under general anaesthesia provided tissue for histopathology and diagnosis of low-grade osteosarcoma. PMID- 22103955 TI - Interpersonal pathoplasticity in the course of major depression. AB - OBJECTIVE: The identification of reliable predictors of course in major depressive disorder (MDD) has been difficult. Evidence suggests that the co occurrence of personality pathology is associated with longer time to MDD remission. Interpersonal pathoplasticity, the mutually influencing nonetiological relationship between psychopathology and interpersonal traits, offers an avenue for examining specific personality vulnerabilities that may be associated with depressive course. METHOD: This study examined 312 participants with and without a co-occurring personality disorder diagnosis who met criteria for a current MDD episode at baseline and who were followed for 10 years in the Collaborative Longitudinal Personality Disorders Study. RESULTS: Latent profile analysis (LPA) identified 6 interpersonal groups (extraverted, dominant, arrogant, cold, submissive, and unassuming), and circular statistical profile analysis confirmed group interpersonal distinctiveness. No significant differences between groups were found in comorbid Axis I disorders or baseline MDD severity. Chronicity and functioning analyses found significantly greater chronicity and poorer functioning in individuals with a submissive interpersonal style over 10 years. CONCLUSIONS: These findings support the relevance of interpersonal pathoplasticity in depressive course and that this heterogeneity has clinical significance. This study is the first to use LPA and circular profiles to examine interpersonal heterogeneity within a diagnostic group. The implications of these findings for therapeutic intervention, interpersonal functioning, and psychopathological course are discussed. PMID- 22103956 TI - Randomized trial of a broad preventive intervention for Mexican American adolescents. AB - OBJECTIVE: This randomized trial of a family-focused preventive intervention for Mexican American (MA) adolescents evaluated intervention effects on adolescent substance use, internalizing and externalizing symptoms, and school discipline and grade records in 8th grade, 1 year after completion of the intervention. The study also examined hypothesized mediators and moderators of intervention effects. METHOD: Stratified by language of program delivery (English vs. Spanish), the trial included a sample of 516 MA adolescents (50.8% female; M = 12.3 years, SD = 0.54) and at least one caregiver that were randomized to receive a low-dosage control group workshop or the 9-week group intervention that included parenting, adolescent coping, and conjoint family sessions. RESULTS: Positive program effects were found on all 5 outcomes at 1-year posttest but varied depending on whether adolescents, parents, or teachers reported on the outcome. Intervention effects were mediated by posttest changes in effective parenting, adolescent coping efficacy, adolescent school engagement, and family cohesion. The majority of intervention effects were moderated by language, with a larger number of significant effects for families who participated in Spanish. Intervention effects also were moderated by baseline levels of mediators and outcomes, with the majority showing stronger effects for families with poorer functioning at baseline. CONCLUSION: Findings not only support the efficacy of the intervention to decrease multiple problem outcomes for MA adolescents but also demonstrate differential effects for parents and adolescents receiving the intervention in Spanish vs. English, and depending on their baseline levels of functioning. PMID- 22103957 TI - Motivational interviewing (MINT) improves continuous positive airway pressure (CPAP) acceptance and adherence: a randomized controlled trial. AB - OBJECTIVE: Adherence to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA) is poor. We assessed the effectiveness of a motivational interviewing intervention (motivational interview nurse therapy [MINT]) in addition to best practice standard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA. METHOD: One hundred six Australian adults (69% male) with a new diagnosis of OSA and a clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders center. Participants were randomly assigned to receive either 3 sessions of a motivational interviewing intervention (MINT; n = 53; mean age = 55.4 years) or no intervention (control; n = 53; mean age = 57.74 years). The primary outcome was the difference between the groups in objective CPAP adherence at 1-month, 2-month, 3-month, and 12-month follow-ups. RESULTS: Fifty (94%) participants in the MINT group and 50 (94%) participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis. The number of hours of CPAP use per night in the MINT group at 3 months was 4.63 hr and was 3.16 hr in the control group (p = .005). This represents almost 50% better adherence in the MINT group relative to the control group. Patients in the MINT group were substantially more likely to accept CPAP treatment. CONCLUSIONS: MINT is a brief, manualized, effective intervention that improves CPAP acceptance and objective adherence rates compared to standard care alone. PMID- 22103958 TI - Why two smoking cessation agents work better than one: role of craving suppression. AB - OBJECTIVE: This research examined why smokers receiving combination medication for smoking cessation are more likely to quit smoking than are those who receive either single agent (monotherapy) or placebo. METHOD: Data were collected from 1,504 current smokers (58.2% women, 83.9% White; mean age = 44.67 years, SD = 11.08) participating in a cessation clinical trial who were randomized to 1 of 6 cessation pharmacotherapy conditions (placebo, nicotine patch, nicotine lozenge, bupropion, nicotine patch + nicotine lozenge, and bupropion + nicotine lozenge). Participants completed ecological momentary assessments 4 times a day, concerning 5 hypothesized mediators (negative affect, positive affect, craving, smoking expectations, and withdrawal) of pharmacotherapy effects. Medications were provided for 8-12 weeks post-quit along with 6 individual counseling sessions. Mediational paths were estimated via a novel Bayesian approach with estimation of multiple mediator models. RESULTS: Biochemically confirmed 8-week abstinence was the outcome variable, with the monotherapy and combination pharmacotherapy composites producing 45% (n = 689) and 54% (n = 478) abstinence rates, respectively. The univariate models suggested that the combination treatments produced higher abstinence rates than the monotherapies because of greater suppression of withdrawal, craving, and smoking expectations. However, multiple mediator models showed that the suppression of craving on the quit day produced the strongest mediational effects and could account for the mediational effects of other tested variables. CONCLUSION: Suppression of craving on the quit day significantly mediates the clinical effects of monotherapies and combination smoking pharmacotherapies, and the higher abstinence rates for combination therapy versus monotherapies appear primarily due to greater craving suppression. PMID- 22103959 TI - Rapamycin combined with donor immature dendritic cells promotes liver allograft survival in association with CD4(+) CD25(+) Foxp3(+) regulatory T cell expansion. AB - AIM: To determine whether donor immature dendritic cells (imDCs) combined with a short postoperative course of rapamycin (Rapa) has the ability to expand the CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells and prolong liver allograft survival. METHODS: Orthotopic liver transplantation (OLT) was performed from Lewis rats to Brown Norway recipients. Three days before transplantation, animals were injected intravenously with 2 * 10(6) donor bone marrow-derived imDCs. Recipient rats (the combined treated group) also received Rapa for 7 d after liver transplantation. Additional groups received either imDCs alone, Rapa alone, or saline alone. Every six recipients from each group were killed at 14 days, 28 days after OLT. The changes of CD4(+) CD25(+) Foxp3(+) Treg cells in peripheral blood and spleen, histological changes of liver grafts, and serum cytokine levels were investigated. The other six recipients were left in each group to observe the animal survival. RESULTS: Donor imDCs followed by a short postoperative course of Rapa induced long-term allograft survival. The percentage of CD4(+) CD25(+) Foxp3(+) Treg cells in CD4(+) T cells in the combination treatment group were significantly higher compared with the acute rejection group. Moreover, within the CD4(+) CD25(+) T cell population the combination treatment recipients maintained a higher incidence of Foxp3(+) T cells compared with the other groups. Despite the lower serum levels of interleukin (IL)-2, IL-12, and interferon-gamma in the combined treated group, the cytokine levels in the combined treated group at 7 days after OLT was nearly twice that at 3 days after OLT but decreased significantly compared with the other groups at 28 days after OLT. Serum IL-10 level in the combined treated group was higher than the other groups. CONCLUSIONS: A single imDC infusion followed by a short postoperative course of Rapa prolongs liver allograft survival and enhances the expansion of Treg cells. This optimal protocol may be a promising administration protocol for the peritransplant tolerance induction. PMID- 22103960 TI - Individual and neighborhood-level socioeconomic characteristics in relation to smoking prevalence among black and white adults in the Southeastern United States: a cross-sectional study. AB - BACKGROUND: Low individual-level socioeconomic status (SES) is associated with higher prevalence of cigarette smoking. Recent work has examined whether neighborhood-level SES may affect smoking behavior independently from individual level measures. However, few comparisons of neighborhood-level effects on smoking by race and gender are available. METHODS: Cross-sectional data from adults age 40-79 enrolled in the Southern Community Cohort Study from 2002-2009 (19, 561 black males; 27, 412 black females; 6, 231 white males; 11, 756 white females) were used in Robust Poisson regression models to estimate prevalence ratios (PRs) and 95% confidence intervals (CI) for current smoking in relation to individual level SES characteristics obtained via interview and neighborhood-level SES characteristics represented by demographic measures from US Census block groups matched to participant home addresses. RESULTS: Several neighborhood-level SES characteristics were modestly associated with increased smoking after adjustment for individual-level factors including lower percentage of adults with a college education and lower percentage of owner-occupied households among blacks but not whites; lower percentage of households with interest, dividends, or net rental income among white males; and lower percentage of employed adults among black females. CONCLUSIONS: Lower neighborhood-level SES is associated with increased smoking suggesting that cessation programs may benefit from targeting higher-risk neighborhoods as well as individuals. PMID- 22103961 TI - Absence of mutations in four genes encoding for congenital cataract and expressed in the human brain in Tunisian families with cataract and mental retardation. AB - BACKGROUND: To identify the genetic defect associated with autosomal recessive congenital cataract (ARCC), mental retardation (MR) and ARCC, MR and microcephaly present in most patients in four Tunisian consanguineous families. METHODS: We screened four genes implicated in congenital cataract by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. Among its three genes PAX6, PITX3 and HSF4 are expressed in human brain and one gene LIM2 encodes for the protein MP20 that interact with the protein galectin-3 expressed in human brain and plays a crucial role in its development. All genes were screened by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. RESULTS: We report no mutation in the four genes of congenital cataract and its flanking regions. Only variations that did not segregate with the studied phenotypes (ARCC associated to MR, ARCC associated with MR and microcephaly) are reported. We detected three intronic variations in PAX6 gene: IVS4 -274insG (intron 4), IVS12 -174G>A (intron12) in the four studied families and IVS4 -195G>A (intron 4) in two families. Two substitutions polymorphisms in PITX3 gene: c.439 C>T (exon 3) and c.930 C>A (exon4) in one family. One intronic variation in HSF4 gene: IVS7 +93C>T (intron 7) identified in one family. And three intronic substitutions in LIM2 gene identified in all four studied families: IVS2 -24A>G (intron 2), IVS4 +32C>T (intron 4) and c.*15A>C (3' downstream sequence). CONCLUSION: Although the role of the four studied genes: PAX6, PITX3, HSF4 and LIM2 in both ocular and central nervous system development, we report the absence of mutations in all studied genes in four families with phenotypes associating cataract, MR and microcephaly. PMID- 22103962 TI - Using DNA sequencers as stethoscopes. AB - A report on the Cold Spring Harbor Laboratory meeting on 'Personal Genomes', Cold Spring Harbor, New York, USA, 30 September to 2 October, 2011. PMID- 22103963 TI - Electrochemical behavior of titanium in artificial saliva: influence of pH. AB - Titanium is the most common material chosen for dental implants because it is highly corrosion resistant because it constantly reforms a protective passive film layer. The formation and composition of the passive film layer is dependent on the environmental conditions. If the stable oxide layer is damaged, the titanium surface underneath can corrode. The purpose of this study was to determine if basic corrosion of commercially pure titanium (CpTi) alloy in artificial saliva was affected by pH and to understand the corrosion kinetics/mechanisms of CpTi as a function of pH. In this study, titanium alloy discs were subjected to corrosion tests. Before the tests, all samples were cleaned and polished using standard metallographic preparation methods. Artificial saliva was used as the testing medium. The following pH values were tested: 3.0, 4.5, 6.0, 6.5, 7.5, and 9.0. Different pH values were achieved by adding lactic acid (acidic) or NaOH (basic) in appropriate amounts. Potentiodynamic curves indicated behavior change at each pH. In addition, the corrosion current density value determined from the potentiodynamic curve exhibited the poorest corrosion resistance for pH 7.5. The Nyquist plot (from the electrochemical impedance spectroscopy results) indicated that pH 7.5 had the poorest resistance. Scanning electron microscopy images indicated that pH levels of 6.5, 7.5, and 9.0 had considerable surface corrosion. The results showed that the media's pH significantly influenced the corrosion behavior of CpTi. The poor corrosion behavior at the neutral pHs invites some concerns and highlights the need for further study. PMID- 22103964 TI - Effects of in-vehicle warning information displays with or without spatial compatibility on driving behaviors and response performance. AB - A driving simulator study was conducted to evaluate the effects of five in vehicle warning information displays upon drivers' emergent response and decision performance. These displays include visual display, auditory displays with and without spatial compatibility, hybrid displays in both visual and auditory format with and without spatial compatibility. Thirty volunteer drivers were recruited to perform various tasks that involved driving, stimulus-response, divided attention and stress rating. Results show that for displays of single-modality, drivers benefited more when coping with visual display of warning information than auditory display with or without spatial compatibility. However, auditory display with spatial compatibility significantly improved drivers' performance in reacting to the divided attention task and making accurate S-R task decision. Drivers' best performance results were obtained for hybrid display with spatial compatibility. Hybrid displays enabled drivers to respond the fastest and achieve the best accuracy in both S-R and divided attention tasks. PMID- 22103965 TI - Prevention of abdominal wound infection (PROUD trial, DRKS00000390): study protocol for a randomized controlled trial. AB - BACKGROUND: Wound infection affects a considerable portion of patients after abdominal operations, increasing health care costs and postoperative morbidity and affecting quality of life. Antibacterial coating has been suggested as an effective measure to decrease postoperative wound infections after laparotomies. The INLINE metaanalysis has recently shown the superiority of a slowly absorbable continuous suture for abdominal closure; with PDS plus(r) such a suture has now been made available with triclosan antibacterial coating. METHODS/DESIGN: The PROUD trial is designed as a randomised, controlled, observer, surgeon and patient blinded multicenter superiority trial with two parallel groups and a primary endpoint of wound infection during 30 days after surgery. The intervention group will receive triclosan coated polydioxanone sutures, whereas the control group will receive the standard polydioxanone sutures; abdominal closure will otherwise be standardized in both groups. Statistical analysis is based on intention-to-treat population via binary logistic regression analysis, the total sample size of n=750 is sufficient to ensure alpha=5% and power=80%, an interim analysis will be carried out after data of 375 patients are available. DISCUSSION: The PROUD trial will yield robust data to determine the effectiveness of antibacterial coating in one of the standard sutures for abdominal closure and potentially lead to amendment of current guidelines. The exploration of clinically objective parameters as well as quality of life holds immediate relevance for clinical management and the pragmatic trial design ensures high external validity. TRIAL REGISTRATION: The trial protocol has been registered with the German Clinical Trials Register (DRKS00000390). PMID- 22103966 TI - Emerging point of care tests for influenza: innovation or status quo. AB - BACKGROUND: Point of care tests (POCTs) for influenza potentially offer earlier diagnosis, enabling specific treatment, infection control measures and greater patient convenience and satisfaction. Current POCTs have limited sensitivity, some cannot distinguish influenza types, none differentiate subtypes and are relatively expensive. AIMS: To identify and characterise influenza POCTs expected to be available for clinical use in the U.K. by mid-2013, highlighting those with potential benefits over existing tests. METHODS: Potential developers of influenza POCTs were identified through known manufacturers' websites, Medical Technology trade associations, the EuroScan International Network, an expert advisory group and by searching relevant online sources. Identified companies were asked to provide standard information on relevant technologies. RESULTS: Fifty-six companies were identified, and 29 (52%) responded, identifying 57 potentially relevant technologies. Of these, 40 (70%) were already available or had undetermined status and 5 (9%) were excluded as time to results took over 60 minutes. Of the remaining 12 emerging POCTs, 10 (83%) reportedly enabled differentiation of influenza types and eight differentiation of A subtypes. Nasopharyngeal swabs were the most commonly acceptable sample type; the sample volume ranging from 80 MUl to 1.4 ml. DISCUSSION: Most identified emerging influenza POCTs offered differentiation of influenza type and subtype. Tests claiming this capability include several incorporating reverse transcription polymerase chain reaction assays; though, these also had the longest time to result. However, whilst some identified POCTs exhibit high sensitivity and specificity, most lack published clinical data for assessment, and the overall costs of these technologies remains largely unknown. PMID- 22103967 TI - Protein identification using customized protein sequence databases derived from RNA-Seq data. AB - The standard shotgun proteomics data analysis strategy relies on searching MS/MS spectra against a context-independent protein sequence database derived from the complete genome sequence of an organism. Because transcriptome sequence analysis (RNA-Seq) promises an unbiased and comprehensive picture of the transcriptome, we reason that a sample-specific protein database derived from RNA-Seq data can better approximate the real protein pool in the sample and thus improve protein identification. In this study, we have developed a two-step strategy for building sample-specific protein databases from RNA-Seq data. First, the database size is reduced by eliminating unexpressed or lowly expressed genes according to transcript quantification. Second, high-quality nonsynonymous coding single nucleotide variations (SNVs) are identified based on RNA-Seq data, and corresponding protein variants are added to the database. Using RNA-Seq and shotgun proteomics data from two colorectal cancer cell lines SW480 and RKO, we demonstrated that customized protein sequence databases could significantly increase the sensitivity of peptide identification, reduce ambiguity in protein assembly, and enable the detection of known and novel peptide variants. Thus, sample-specific databases from RNA-Seq data can enable more sensitive and comprehensive protein discovery in shotgun proteomics studies. PMID- 22103968 TI - Treatment of refractory atopic blepharoconjunctivitis with topical tacrolimus 0.03% dermatologic ointment. AB - PURPOSE: To report a case of refractory atopic blepharoconjunctivitis (ABC) treated by using topical tacrolimus 0.03% dermatologic ointment. METHODS: A 73 year-old man with ABC was refractory to topical corticosteroid treatment. RESULTS: Topical tacrolimus 0.03% dermatologic ointment (Protopic; Astellas Pharma) was applied into the conjunctival fornix twice each day. Dramatic improvement of patient's symptoms was observed during the first week of therapy. Tacrolimus ointment treatment continued for 12 months. No drug-induced conjunctival hyperemia, ocular surface staining, or other adverse changes were noted secondary to the use of the topical tacrolimus ointment. CONCLUSIONS: Topical tacrolimus 0.03% dermatologic ointment appears to be an effective treatment for ABC that is refractory to conventional therapy. PMID- 22103973 TI - Review: Spatiotemporal dynamics of hCG/cAMP signaling and regulation of placental function. AB - The pregnancy hormone human chorionic gonadotropin (hCG) is essential to sustain early pregnancy and involved in regulation of progesterone production, decidualization, and cytotrophoblast differentiation. It binds to and activates the G-protein coupled luteinizing hormone/hCG-receptor, activating the cAMP/protein kinase A (PKA) pathway which results in the phosphorylation of specific intracellular target proteins. Specificity in cAMP signaling is ensured by generation of localized pools of cAMP controlled by phosphodiesterases and by discrete spatial and temporal activation of PKA in supramolecular signaling clusters inside the cell organized by A-kinase-anchoring proteins. Here we discuss spatiotemporal regulation of PKA signaling in response to hCG controlling placental function. PMID- 22103974 TI - Coexpression of hypoxia-inducible factor-2alpha, TWIST2, and SIP1 may correlate with invasion and metastasis of salivary adenoid cystic carcinoma. AB - BACKGROUND: Adenoid cystic carcinoma (ACC) of salivary gland is characterized by advanced local invasion and distant metastasis. Intratumoral hypoxia was reported to be associated with epithelial-mesenchymal transition (EMT) regulators. The purpose of this study was to evaluate the relationship between hypoxia-inducible factor (HIF)-2alpha, TWIST2, and SIP1 expression and the invasion and metastasis in ACC of salivary gland. METHOD: In vitro we first detected the expression of HIF-2alpha, TWIST2, and SIP1 in two ACC cell lines by Western blot and real-time RT-PCR. Then, in vivo, a retrospective investigation of 121 patients with ACC from Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University between 1996 and 2005 was carried out using immunohistochemistry to analyze the association between the expression of these three factors and clinical-pathological factors of patients. RESULTS: The protein and mRNA levels of HIF-2alpha, TWIST2, and SIP1 in the high-metastasis cell line (ACC-M) were much higher than those of the low-metastasis cell line (ACC-2). The positive expression of HIF-2alpha, TWIST2, and SIP1 (71.07%, 42.98%, and 38.02%, respectively) was associated with the perineural invasion, the local recurrence, and distant metastasis of patients with ACC (P < 0.05). The patients with the positive coexpression of the three factors had a lower survival rate than those with the negative expression (P < 0.05). CONCLUSION: It is proposed that the elevated expression of HIF-2alpha, TWIST2, and SIP1 can contribute to invasion and metastasis of ACC, and there might be some correlation between the hypoxia microenvironment and EMT in ACC. PMID- 22103975 TI - Histone H3 covalent modifications driving response of BCR-ABL1+ cells sensitive and resistant to imatinib to Aurora kinase inhibitor MK-0457. PMID- 22103976 TI - Use of natural radionuclides to determine the time range of the accidental melting of an orphan radioactive source in a steel recycling plant. AB - In the rare event that an orphan radioactive source is melted in an Electric Arc Furnace steel recycling plant, the radionuclides present are partitioned in the different products, by-products and waste. As a consequence of an unforeseen melting of a radiocesium source, cesium radioisotopes can be found in the dust, together with many natural radionuclides from the decay of radon and thoron, which are present in the atmosphere, picked up from the off-gas evacuation system and associated with the dust of the air filtration system ("baghouse"). In this work we verified that the activity concentration of 212Pb in this dust is essentially constant in a specific factory so that it is possible to use it to date back to the time of the accidental melting of the orphan radioactive source. The main features of this method are described below, together with the application to a particular case in which this method was used for dating the moment in which the dust was contaminated with 137Cs. PMID- 22103977 TI - Effect of Escherichia coli lipopolysaccharide on u-PA activity and u-PA and u-PAR RNA expression in a bovine mammary epithelial cell line. AB - It is well known that the plasminogen-activating (PA) system plays a key role in the bovine mammary gland during tissue remodelling. However, the modulation of the PA cascade after bacterial infections needs to be elucidated. This study examined the effects of Escherichia coli lipopolysaccharide (LPS) on cell viability, the modulation of cell-associated u-PA activity, and the regulation of u-PA and u-PA receptor (u-PAR) RNA expression using the BME-UV1 bovine mammary epithelial cell line. LPS did not affect cell viability, but induced an increase in u-PA activity, with the maximum response after 6 h of incubation. Moreover, u PA and u-PAR mRNA expression were both up-regulated in BME-UV1 cells after 3 h of incubation with LPS. These data indicated that E. coli LPS led to an increase in u-PA activity and RNA expression of u-PA and u-PAR in BME-UV1 cells, thus strengthening the role of the PA system during pathological processes. PMID- 22103978 TI - The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China. AB - PURPOSE: To evaluate the 7th edition of the International Union against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system for nasopharyngeal carcinoma (NPC) in patients treated with intensity-modulated radiotherapy. METHODS AND MATERIALS: We performed a retrospective data review from 512 patients with biopsy-proven, nonmetastatic NPC in our cancer center (South China) between January 2003 and December 2006. RESULTS: The local relapse free survival rates (LRFS) and disease failure-free survival rates (DFS) in the 6th edition system T1 and T2a stages were not significantly different (P=0.629 and P=0.820), while the LRFS and DFS of T1 and T2 using the 7th edition system were significantly different (P=0.019 and P=0.009). The LRFS and DFS between T2 and T3 in the 7th edition systems were lack of significance (P=0.874 and P=0.589). The total difference in distant metastasis-free survival rate and DFS between N0 and N3 was slightly larger using the 7th edition system than the 6th edition. The nodal dimension of a cervical lymph node was not a significant prognostic factor. CONCLUSIONS: We observed a better segregation of survival curves by using the 7th edition system. It seems reasonable to downstage T3 as T2 and reject nodal greatest dimension from the N-staging system in the future revised edition. PMID- 22103979 TI - A practical method of identifying data loss in 4DCT. AB - BACKGROUND AND PURPOSE: The design, testing and clinical implementation of a simple quality assurance tool which allows quick and accurate identification of regions of data loss and data interpolation in 4DCT data sets is reported. MATERIALS AND METHODS: A 4DCT model, dependent on gantry rotation time and pitch, was developed to allow an understanding of the data collection and reconstruction processes. To test this model, 4DCT scans of a phantom were acquired using a Siemens SOMATOM Sensation 40 slice CT scanner. A radio-opaque rod mounted under the couch top was present during the phantom scans. RESULTS: The model predicts that periodic regions of data loss occur when the respiration rate drops below a critical value. These results are verified by experimental data. Regions of data loss result in breaks in the imaged radio-opaque rod. CONCLUSIONS: Regions of data loss in 4DCT data sets can be difficult to detect. Mounting a radio-opaque rod under the couch top allows regions of data loss and data interpolation to be quickly assessed on a patient by patient basis. This quality assurance tool has been successfully implemented into clinical use. The results of this work have implications for quality assurance programmes for 4DCT scanning. PMID- 22103980 TI - Ovarian response to gonadotropins after laparoscopic salpingectomy for ectopic pregnancy. AB - OBJECTIVE: To evaluate whether laparoscopic salpingectomy compromises ovarian response in women undergoing controlled ovarian hyperstimulation in vitro fertilization (IVF). METHODS: In a retrospective study in Changsha, China, data from 76 women who underwent ovarian stimulation before and after laparoscopic salpingectomy for ectopic pregnancy were compared with those from 80 women who underwent 2 IVF cycles without surgical intervention between 2004 and 2009. RESULTS: There were no differences in basal serum follicle-stimulating hormone (FSH) or estradiol (E(2)); length of stimulation; or numbers of follicles, retrieved and fertilized oocytes, or high-quality embryos between the cycles before and after salpingectomy; however, initial and total doses of gonadotropins were significantly increased after surgery (P<0.05). IVF parameters were also comparable between the 2 cycles among women without surgical intervention, except for a significant increase in initial and total doses of gonadotropins at the second cycle (P<0.05). IVF parameters did not differ between the cycle subsequent to salpingectomy and the second cycle in women without surgical intervention. There were no significant differences between patients with unilateral and those with bilateral salpingectomy, nor between the operated and non-operated ovary in the same individual. CONCLUSION: Laparoscopic salpingectomy had no detrimental effect on ovarian response during IVF-embryo transfer treatment. PMID- 22103981 TI - Therapeutic riding followed by rhythmic auditory stimulation to improve balance and gait in a subject with orthopedic pathologies. AB - OBJECTIVES: The study objectives were to investigate the effect of therapeutic riding with a subject who had an orthopedic diagnosis. DESIGN: This is a single subject case report. LOCATION: The study was conducted at an equestrian facility with an indoor riding arena. SUBJECT: The subject was a 59-year-old woman with grade I spondylolisthesis at L4/L5 and multilevel lumbar spinal stenosis in central and foraminal canals. The subject had an anterior cervical fusion of C3 C7. EVALUATION: The subject has been ambulating with a straight cane due to her history of frequent falls. Gait, agility, strength, range of motion, and balance testing were performed. The subject had impairments of bilateral lower extremities with an ataxic gait pattern and was at risk for continued falls according to the balance measures. INTERVENTIONS: The intervention comprised therapeutic riding sessions 3 times a week for 20 minutes for 4 weeks. Each riding session was immediately followed by a 10-minute independent walking program with a metronome for rhythmic auditory stimulation. OUTCOME MEASURES: The outcome measures were as follows: Manual muscle testing and range of motion of the lower extremities, Gait Speed Test, Dynamic Gait Index, Four-Square Step Test, Chair Stand Test, Single Leg Stance. RESULTS: Improvements were seen in lower extremity strength and range of motion and balance. The subject improved on balance scores, placing her out of the risk for falls category. CONCLUSIONS: Therapeutic riding followed by rhythmic auditory stimulation improved lower extremity range of motion, strength, and balance with this subject. PMID- 22103982 TI - Detoxification in naturopathic medicine: a survey. AB - OBJECTIVES: This study sought to assess the use of clinical detoxification therapies used by licensed naturopathic doctors (NDs) in the United States. DESIGN: This was a qualitative, descriptive, online survey of a convenience sample of NDs. METHODS: An online survey was conducted of NDs who were licensed in the United States. Responses were analyzed descriptively regarding the use of clinical detoxification therapies. Respondents were recruited from a membership list provided by the American Association of Naturopathic Physicians, and from alumni e-mail lists of Council of Naturopathic Medical Education accredited naturopathic medical schools. RESULTS: Surveys were sent out to 1442 e-mail addresses (261 were returned to sender); a total of 196 respondents completed the survey (16.6%). Ninety-two percent (92%) of respondents reported using clinical detoxification therapies. Over 75% of respondents utilized detoxification therapies primarily to treat patients for environmental exposures, general cleansing/preventive medicine, gastrointestinal disorders, and autoimmune disease. Regarding methods used, >75% reported using dietary measures, reducing environmental exposures, and using botanicals as detoxification therapies. Eighty three percent (83%) of NDs surveyed reported using follow-up measurements to determine efficacy of detoxification therapies. The most common were patient symptom questionnaires (66%), patient medical histories (54%), and urinary provocative challenge testing (53%). CONCLUSIONS: The majority of NDs responding to this survey reported routine use of clinical detoxification therapies to treat a range of medical conditions utilizing multiple therapeutic approaches. Although the majority of NDs reported using some follow-up measurements after detoxification therapy, few of these are an objective means to determine treatment efficacy. Further research is needed in the field of complementary and alternative medicine clinical detoxification to determine the safety and efficacy of these approaches. PMID- 22103983 TI - Effect of fluoroethylene carbonate (FEC) on the performance and surface chemistry of Si-nanowire Li-ion battery anodes. AB - The effect of FEC as a co-solvent on the electrochemical performance and surface chemistry of silicon nanowire (SiNW) anodes was thoroughly investigated. Enhanced electrochemical performance was observed for SiNW anodes in alkyl carbonates electrolyte solutions containing fluoroethylene carbonate (FEC). Reduced irreversible capacity losses accompanied by enhanced and stable reversible capacities over prolonged cycling were achieved with FEC-containing electrolyte solutions. TEM studies provided evidence for the complete and incomplete lithiation of SiNW's in FEC-containing and FEC-free electrolyte solutions, respectively. Scanning electron microscopy (SEM) results proved the formation of much thinner and compact surface films on SiNW's in FEC-containing solutions. However, thicker surface films were identified for SiNW electrodes cycled in FEC free solutions. SiNW electrodes develop lower impedance in electrolyte solutions containing FEC in contrast to standard (FEC-free) solutions. The surface chemistry of SiNW electrodes cycled in FEC-modified and standard electrolytes were investigated using X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. The impact of FEC as a co-solvent on the electrochemical behavior of SiNW electrodes is discussed herein in light of the spectroscopic and microscopic studies. PMID- 22103984 TI - Acticoat and smith and nephew. PMID- 22103985 TI - Effect of 12-week isokinetic training on muscle strength in adult with healed thermal burn. AB - INTRODUCTION: Severe burns result in marked and prolonged skeletal muscle catabolism and weakness, which persist despite 'standard" rehabilitation programmes of occupational and physical therapy. Therefore, the objectives of this study were of twofold: to quantify the long-term effects of burns on leg muscle strength and to assess whether adults with thermal burn would benefit from the isokinetic training programme. MATERIALS AND METHODS: Burned adult patients, with 35-55% total body surface area (TBSA) burned, were assessed at 6 months after burn in respect to leg muscle strength at 150 degrees s(-1), using isokinetic dynamometry. Non-burned adults were assessed similarly, and served as controls. The burned adults participated in the resistance training programme 3 times weekly. The isokinetic exercise programme was begun with 60% of the average peak torque. Intensity of isokinetic exercise was increased from one set to five sets during the first through fifth sessions and remained at six sets for the remaining 6th to 24th sessions. Finally, a dose of 10 sets was applied for the 25th to the 36th sessions. Each set consisted of five repetitions of concentric contraction in angular velocities of 150 degrees s(-1) for knee extensors, and flexors. All exercise sessions were preceded by a 5-min warm-up period on the treadmill. RESULTS: Subjects with burns more than 35% of TBSA produced significantly less torque, work, and power in the quadriceps and hamstring than control subjects (20.5%, 15.2%, p<0.05). Three months after isokinetic programme, muscle strength further increased by 17.9%+/-10.1% compared to the baseline measurement for burned patients but continued to be below the concurrent age matched, non-burned adult. CONCLUSION: We found that adults with severe burns, relative to non-burned adults, had significantly lower peak torque as well as total work performance using the extensors and flexors muscles of the thigh. Participation in isokinetic training resulted in a greater improvement in extensor and flexor muscle strength in adults with held thermal burn compared to base line values. PMID- 22103986 TI - Differential expression of the immunoinflammatory response in trauma patients: burn vs. non-burn. AB - RATIONALE: Cytokines are central mediators of the immune-inflammatory response to injury and subsequent multiple organ dysfunction syndrome (MODS). Although previous studies evaluated cytokine levels after trauma, differences between patients with burn and non-burn trauma have not been assessed systematically. METHODS: A prospective database of trauma patients admitted between May 2004 and September 2007 to the burn or surgical intensive care units within 24 h of injury with an anticipated stay of at least 72 h was analyzed. Sequential clinical and laboratory parameters were collected in the first week, including multiplex analysis data for plasma levels of inflammatory cytokines (IL-6, and IL-8). Patients with known pre-injury coagulopathy were excluded. A Marshall score of 10 or greater was defined as MODS. RESULTS: A total of 179 patients were enrolled (67 burn and 112 non-burn). Plasma IL-6 and IL-8 levels were markedly elevated in both burn and non-burn patients compared to healthy volunteers. Burn subjects had higher levels of IL-6 and IL-8 than the non-burn on days 1 through 7 after injury. Subjects with burns and at least 30% total body surface area were older and had a lower injury severity score, a higher prevalence of MODS, and correspondingly higher mortality. Multivariate analysis of injury type, MODS, and time did not demonstrate an influence of MODS. CONCLUSIONS: Burns were associated with a greater and more sustained immune-inflammatory response than non-burn trauma as evidenced by elevated plasma IL-6 and IL-8 levels during the first week. There was no association between MODS and plasma cytokine levels. PMID- 22103987 TI - Urban compared with rural and remote burn hospitalisations in Western Australia. AB - AIM: To compare the incidence, temporal trends and cause of burn hospitalisations between urban, rural and remote regions in Western Australia, 1983-2008. METHODS: De-identified linked hospital morbidity and mortality records for all persons hospitalised for an index burn in Western Australia were analysed 1983-2008. Annual age-specific incidence and age standardised rates were estimated. Poisson regression analyses were used to estimate temporal trends in hospital admissions by urban, rural and remote region. RESULTS: Of 23,450 burn-related hospital admissions 1983-2008, 14,007 (59.7%) were in urban, 5442 (23.1%) rural and 4021 (17.2%) remote hospital regions. Hospitalisation rates were higher in rural (Incidence rate ratio (IRR), 95% CI: 1.5, 1.4-1.6) and remote (IRR, 95%C: 2.1, 2.0-2.2) regions compared to urban. Age-standardised rates of burn hospital admissions declined from 1983 to 2008 for each region with 26-year declines of 56% (95% CI: 51-60) for remote, 71% (95% CI: 68-73) for rural, and 9% (95% CI: 4 14) for admissions in urban regions. Scald was the most common cause for urban admissions while flame the most common cause for rural and remote burn admissions. CONCLUSIONS: Significant differences in the incidence, and cause of burn were identified between urban, rural and remote regions in Western Australia. PMID- 22103988 TI - Efficacy of enzymatic debridement of deeply burned hands. AB - BACKGROUND: The burned hand is a common and difficult to care-for entity in the field of burns. Due to the anatomy of the hand (important and delicate structures crowded in a small limited space without sub-dermal soft tissue), surgical debridement of the burned tissue is technically difficult and may cause considerable complications and, therefore, should be performed judiciously. Selective enzymatic debridement of the burn wound can preserve the spontaneous epithelialisation potential and reduce the added injury to the traumatised tissue added by a surgical debridement. OBJECTIVE: The aim of the study was to assess the implication of a selective enzymatic compound (Debrase((r)) - Ds) in the special field of deep hand burns, by comparing the actual burn area that required surgical coverage after enzymatic debridement to the burn area clinically judged to require skin grafting prior to debridement. MATERIALS AND METHODS: This was a retrospective data collection and analysis from 154 complete files of prospective, open-label study in 275 hospitalised, Ds-treated burn patients. RESULTS: A total of 69 hand burns diagnosed as 'deep' was analysed; 36% of the wounds required surgical intervention after enzymatic debridement; 28.6% of the total burned area estimated initially as deep was covered by skin graft (statistically significant p<0.001). CONCLUSION: Debridement of deep-hand burns with a selective enzymatic agent decreased the perceived full-thickness wound area and skin-graft use. PMID- 22103989 TI - Epidemiological studies of electrical injuries in Shaanxi province of China: a retrospective report of 383 cases. AB - A statistical survey was conducted at the Burn Unit of the Tangdu Hospital, Shaanxi, China, during the 10-year period from January 2000 to December 2009. In this retrospective study, 383 patients who admitted to our burn unit because of electrical trauma were included. Data including the patient's general condition, clinical presentation, complications and operation times was collected retrospectively and analyzed with epidemiological methods. Subjects in our collective were predominantly male (90.3%, n=346/383) and were composed by those who injured in work-related incidents (78.3%, n=300/383), rural individuals (58.2%, n=223/383) and students (9.4%, n=36/383). High voltage was directly correlated to severity clinical complications, and amputation. The percentage of myocardial impairment was 79.3% (n=92/116) among patients who suffered with electrical current through heart tissue. Along with the more developed east area of China, electrical injuries are becoming a growing concern of the developing West part in China as well. Electrical injuries induce serious tissue damage, need long hospital stay, and result in high rate of permanent disability and economic hardship for the afflicted families. A competent prevention program needs to be developed to address this problem. PMID- 22103990 TI - Epidemiology of severe burn among children in Newfoundland and Labrador, Canada. AB - PURPOSE: The objective of this study was to identify the epidemiologic characteristics of childhood burns in the province of Newfoundland and Labrador. METHODS: A population-based study was carried out on children aged 0-16 years who were hospitalized due to burns in Newfoundland and Labrador between April 1995 and March 2001. Hospital and mortality data were obtained from the provincial hospital admission database and Mortality System, respectively. The Newfoundland and Labrador population was considered as a whole and as two separate geographic areas. RESULTS: A total of 157 hospital admissions due to burns were identified during the study period. The rate of burns requiring hospitalization in the province was 22.3 per 100,000 person-years (P-Y). The rates for males and females was 27.7 and 16.6 per 100,000 P-Y, respectively (P=0.006). Infants (0-1 year) had the highest rate of burn (88.8 per 100,000 P-Y) followed by children aged 2-4 years (26.0 per 100,000 P-Y) (P<0.0001). Labrador, a region with high Aboriginal population (51.4 per 100,000 P-Y), had a higher rate of burn compared to Newfoundland (20.3 per 100,000 P-Y) (P<0.0001). Median age of patients with burns was 2 years for the island portion of the province and 9 years in Labrador (P<0.01). Overall, scald burn (52.2%) was the most frequent type of burn followed by flame (32.5%). In the island portion of the province, scald burn was the most common type of burn (56.4%), while in Labrador flame was the most frequent type (66.7%). Overall mortality rate due to burns was 0.9 per 100,000 P-Y. CONCLUSION: Age (infants) and sex (male) are factors associated with burn in Newfoundland and Labrador. Study results indicate a difference in the epidemiologic pattern of burn between the island portion of the province, Newfoundland, and mainland Labrador. It is recommended that preventive programs be directed towards high risk groups to reduce the incidence of burns. PMID- 22103991 TI - Clinical studies of the High-Intensity Narrow-Spectrum light Environmental Decontamination System (HINS-light EDS), for continuous disinfection in the burn unit inpatient and outpatient settings. AB - Infections are the leading cause of morbidity and mortality in burn patients and prevention of contamination from exogenous sources including the hospital environment is becoming increasingly emphasised. The High-Intensity Narrow Spectrum light Environmental Decontamination System (HINS-light EDS) is bactericidal yet safe for humans, allowing continuous disinfection of the environment surrounding burn patients. Environmental samples were collected from inpatient isolation rooms and the outpatient clinic in the burn unit, and comparisons were then made between the bacterial contamination levels observed with and without use of the HINS-light EDS. Over 1000 samples were taken. Inpatient studies, with sampling carried out at 0800 h, demonstrated a significant reduction in the average number of bacterial colonies following HINS light EDS use of between 27% and 75%, (p<0.05). There was more variation when samples were taken at times of increased activity in the room. Outpatient studies during clinics demonstrated a 61% efficacy in the reduction of bacterial contamination on surfaces throughout the room during the course of a clinic (p=0.02). The results demonstrate that use of the HINS-light EDS allows efficacious bacterial reductions over and above that achieved by standard cleaning and infection control measures in both inpatient and outpatient settings in the burn unit. PMID- 22103992 TI - Surgical treatment of 19 cases with vibrio necrotising fasciitis. AB - BACKGROUND: Necrotising fasciitis and sepsis caused by the infection of vibrio is a rare but dangerous clinical emergency, with a mortality of 50-100%. Early diagnosis and surgical treatment may improve the prognosis significantly. However, valid emergency operation indications are scarce and need to be explored, which will be helpful for the early recognition and selection of operational procedures in patients with vibrio necrotising fasciitis. METHODS: We retrospectively analysed the patients with vibrio necrotising fasciitis admitted to the emergency department of our hospital from July 2000 to June 2009. The surgical treatment strategy was summarised in order to provide clinical evidence for surgical treatment of vibrio necrotising fasciitis. RESULTS: A total of 19 cases of vibrio necrotising fasciitis were selected in our study. All the patients were living along the coast, and 68.4% had a history of chronic liver disease, 78.9% had a history of ethanol abuse, 52.6% had fever, 89.5% were complicated with septic shock and 31.6% progressed to multiple-organ dysfunction syndrome. Rapidly progressive local swelling and pain as well as skin superficial venous stasis were the early presentations of vibrio necrotising fasciitis, while skin ecchymosis, blisters or blood blisters, necrosis and subcutaneous crepitation were the presentations of the advanced stage. Seventeen patients received emergency incision and drainage, subcutaneous vein thrombosis, subcutaneous tissue necrosis, muscle and full-thickness necrosis observed in the operation, and necrotising fasciitis was confirmed by exploration or pathologic examination. Selective debridement and skin graft was performed to repair the wound after operation, and amputation was performed on two patients to close the wound. The average length of stay was 21.3 days (1-82 days), and eight patients died, with mortality being 42.1%. CONCLUSION: Rapidly progressive local damage and acute deterioration of the patients are the most distinctive clinical manifestations of vibrio necrotising fasciitis. Recognition of the signs of local skin and tissue damage in early stage is crucial for early diagnosis and surgical intervention. Emergency incision and drainage, combined with selective debridement and skin graft, could improve the prognosis of the patients, and preserve the integrity of the patient's limbs as much as possible. PMID- 22103993 TI - Association between infection early in life and mental disorders among youth in the community: a cross-sectional study. AB - BACKGROUND: The objective of this study was to examine the association between infection early in life and mental disorders among youth in the community. METHODS: Data were drawn from the MECA (Methods in Epidemiology of Child and Adolescent psychopathology), a community-based study of 1,285 youth in the United States conducted in 1992. Multiple logistic regression analyses were used to investigate the association between parent/caregiver-reported infection early in life and DSM/DISC diagnoses of mental disorders at ages 9-17. RESULTS: Infection early in life was associated with a significantly increased odds of major depression (OR = 3.9), social phobia (OR = 5.8), overanxious disorder (OR = 6.1), panic disorder (OR = 12.1), and oppositional defiant disorder (OR = 3.7). CONCLUSIONS: These findings are consistent with and extend previous results by providing new evidence suggesting a link between infection early in life and increased risk of depression and anxiety disorders among youth. These results should be considered preliminary. Replication of these findings with longitudinal epidemiologic data is needed. Possible mechanisms are discussed. PMID- 22103994 TI - Utility of clinical parameters to identify HIV infection in infants below ten weeks of age in South Africa: a prospective cohort study. AB - BACKGROUND: As HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa.HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings. RESULTS: 417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50(th) centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression. CONCLUSIONS: A combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere. PMID- 22103995 TI - Improved facial outcome assessment using a 3D anthropometric mask. AB - The capacity to process three-dimensional facial surfaces to objectively assess outcomes of craniomaxillofacial care is urgently required. Available surface registration techniques depart from conventional facial anthropometrics by not including anatomical relationship in their analysis. Current registrations rely on the manual selection of areas or points that have not moved during surgery, introducing subjectivity. An improved technique is proposed based on the concept of an anthropometric mask (AM) combined with robust superimposition. The AM is the equivalent to landmark definitions, as used in traditional anthropometrics, but described in a spatially dense way using (~10.000) quasi-landmarks. A robust superimposition is performed to align surface images facilitating accurate measurement of spatial differences between corresponding quasi-landmarks. The assessment describes magnitude and direction of change objectively and can be displayed graphically. The technique was applied to three patients, without any modification and prior knowledge: a 4-year-old boy with Treacher-Collins syndrome in a resting and smiling pose; surgical correction for hemimandibular hypoplasia; and mandibular hypoplasia with staged orthognathic procedures. Comparisons were made with a reported closest-point (CP) strategy. Contrasting outcomes were found where the CP strategy resulted in anatomical implausibility whilst the AM technique was parsimonious to expected differences. PMID- 22103996 TI - Osteomark: a surgical navigation system for oral and maxillofacial surgery. AB - The purpose of this project was to test a surgical navigation tool designed to help execute a surgical treatment plan. It consists of an electromagnetically tracked pencil that is used to mark bone intraoperatively. The device was tested on a precision block, an ex vivo pig mandible and during performance of six endoscopic vertical ramus osteotomies on pig cadavers. The difference between actual pencil position and that displayed by the computer was measured three times each at ten 2mm holes on the block (n=30 observations) and on the ex vivo mandible (n=11 measurements). Errors between planned and actual osteotomy locations for the cadaver procedures were measured. The mean distance between known and displayed locations was 1.55 +/- 0.72 mm on the precision block and 2.10 +/- 0.88 mm on the pig mandible. The error measured marking the same point on the block multiple (n=5) times was 0.58 +/- 0.37 mm. The mean error on the simulated osteotomies was 2.35 +/- 1.35 mm. Osteomark was simple to use and permitted localisation of holes and osteotomies with acceptable accuracy. In the future, the device and algorithms will be revised to further decrease error and the system will be tested on live animals. PMID- 22103997 TI - Squamous cell carcinoma of the oral cavity associated with graft-versus-host disease. PMID- 22103998 TI - The reliability of high resolution ultrasound in the identification of pus collections in head and neck swellings. AB - Head and neck swellings often present to oral and maxillofacial surgeons. It is often unclear whether a collection of pus is present. This information is essential for decisions regarding surgical intervention. Although ultrasound scanning (USS) is widely used to investigate the presence of a collection, the reliability and validity of this investigation in this context is uncertain. A retrospective review of 4000 consecutive head and neck USS reports over a 4 year period in the Cardiff University Health Board produced 43 cases in which ultrasound had been used to look for evidence of pus collection. The management and treatment outcome of these patients were reviewed and the data analysed. 36 of 43 patients had their swelling incised in theatre, and in 92% of these cases USS and clinical findings corresponded. Of the seven not taken to theatre, four were USS negative and three USS positive; in all seven cases the swelling resolved with antimicrobial therapy. Sensitivity and specificity of USS imaging to identify pus collection were very high, 96% and 82%, respectively. The evidence in this study indicates that USS is a very reliable diagnostic tool in the diagnosis of a collection as well as providing evidence that small collections of pus can resolve without surgical drainage. PMID- 22103999 TI - Masseter muscle fibre changes following reduction of masticatory function. AB - This study evaluated histological changes in masseter muscle fibres following reduced masticatory function by injection of botulinum toxin type A (BTX). Sixty 30-day-old Long-Evans male rats were randomly separated into four groups (15 per group): group I BTX masseter, 25U/ml (0.04ml each muscle) BTX was injected in bilateral masseter muscle whilst bilateral temporalis muscles received an equal amount of normal saline; group II BTX temporalis, 25U/ml (0.04ml each muscle) BTX was injected in bilateral temporalis muscle whilst bilateral masseter muscle received an equal amount of normal saline; group III BTX temporalis and masseter, bilateral temporalis and masseter were given 25U/ml (0.04ml each muscle) BTX; group IV normal saline (control), bilateral temporalis and masseter were given normal saline (0.04ml each muscle). After 45 days, the rats were killed, the muscles dissected and mean muscle mass recorded. The superficial masseter muscles were immunohistochemically analysed. Fibre sizes in group III were bigger than those in other groups. There was a small percentage of type IIa fibres in group III. Reduction in muscle fibre size and transition of muscle fibre subtypes from type IIa to IIx or IIb fibres may occur due to reduced masticatory function. PMID- 22104000 TI - Surgical treatment of macroglossia in patients with Beckwith-Wiedemann syndrome: a 20-year experience and review of the literature. AB - Macroglossia is observed in the majority of paediatric patients diagnosed with Beckwith-Wiedemann syndrome and surgical treatment may be indicated. A 20-year retrospective study was performed to evaluate all patients with Beckwith Wiedemann syndrome who underwent tongue reduction surgery at the authors' institution. A literature review was performed. Surgical treatment was indicated and carried out in 23 patients with a yearly average varying from 0 to 3 subjects. The mean follow-up time was 7 years. Primary indications for surgical treatment of macroglossia included significant tongue protrusion in 30% (n=7), and a combination of clinical problems in 70% (n=16). In all cases, the procedure was performed by the same surgeon using an anterior, V-shaped, wedge resection technique. Two patients had direct postoperative complications. No recurrence of macroglossia was observed in this study. Reported clinical outcome during follow up demonstrated a satisfactory resting tongue position in all patients. Review of the literature demonstrated variability in surgical indications and techniques, and postoperative outcome. The results of this study indicate that the anterior wedge resection is a simple, effective and safe technique in the surgical treatment of paediatric patients, diagnosed with Beckwith-Wiedemann syndrome, suffering from macroglossia. PMID- 22104001 TI - Research - why bother? PMID- 22104002 TI - Health-related quality of life in patients with hepatocellular carcinoma after hepatic resection, transcatheter arterial chemoembolization, radiofrequency ablation or no treatment. AB - BACKGROUND: Aim of this work was to compare quality of life (QoL) of patients affected by HCC and submitted to hepatic resection (HR), transarterial chemoembolization (TACE), radiofrequency ablation (RFA), or no treatment (NT). METHODS: Patients affected by HCC between 2001 and 2009 were considered for this study. Gender, diabetes, hepatitis status, Child grade, tumor size, and recurrence were analyzed. QoL was assessed before treatment and 3, 6, 12, and 24 months after, using a FACT-Hep questionnaire. P value was considered significant if <0.01 and highly significant if <0.001. RESULTS: Fourteen patients (27.45%) were treated with HR, 15 patients (29.41%) underwent TACE, RFA was performed in 9 patients (17.65%), and 13 patients (25.49%) were not treated. Physical well being, social/family well-being, emotional well-being, functional well-being and additional concerns 24 months after HR were significantly higher compared to all other treatments. CONCLUSIONS: Hepatic resection provides the best QoL at 24 months. RFA provides a worse QoL compared to HR, but a higher QoL compared to TACE or NT. PMID- 22104003 TI - Cardiac myxoma with oncocytic change--cardiac oncocytoma? AB - We report the case of an incidental cardiac myxoma that was remarkable for the presence of extensive oncocytic change, a feature that has not be reported previously. The oncocytes most likely represent part of a spectrum of degenerative changes present in the tumor, but the possibility that they are neoplastic is also discussed. PMID- 22104004 TI - Serum proteomics in patients with diagnosis of abdominal aortic aneurysm. AB - BACKGROUND: Molecular mechanisms underlying abdominal aneurysm (AAA) formation and rupture are not well understood. Early detection and repair of AAA may reduce the high mortality rates associated with rupture. Serum proteomics allows the detection of alterations in the expression of proteins, guiding further studies on these target molecules as potential markers. Analysis of proteomic profile of asymptomatic patients with AAA allows the identification of reliable predictors or markers of disease presence or progression. METHODS: A proteomics approach based on two-dimensional electrophoresis and mass spectrometry was used to compare serum proteomic profiles of patients with AAA who are candidates for surgical repair compared with healthy controls. We analyzed in parallel the proteomic profile of subjects with cardiac heart failure to discriminate these two pathologies, which show similar pattern of systemic inflammation process. RESULTS: We identified in AAA subjects four serum proteins that show altered expression profile and that could be specifically linked to AAA pathology. We discuss the role of our identified proteins with their possible implications in disease outcome. CONCLUSIONS: This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases. These results need to be validated in larger studies to find potential markers of AAA presence or progression to use in clinical settings. SUMMARY: A proteomics approach was used to compare serum proteomic profiles of patients with abdominal aortic aneurysm who are candidates for surgical repair compared with healthy controls. Four serum proteins showed altered expression profile that could be correlated with the pathology. This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases. PMID- 22104005 TI - Helicobacter species in the atherosclerotic plaques of patients with coronary artery disease. AB - INTRODUCTION: Several epidemiological studies have proposed an association between Helicobacter pylori infection and coronary artery disease. In the current study, we aimed to evaluate the prevalence and relevance of H. pylori infection, using polymerase chain reaction (PCR) methods, in the coronary arterial wall of Iranian patients who have already undergone coronary bypass grafting (CABG). METHODS: A total of 105 consecutive patients who underwent CABG at the Department of Cardiovascular Surgery of Baqiyatallah University of Medical Sciences were included in the study, and biopsy specimens from their coronary plaques were taken and analyzed using the PCR methods for detecting Helicobacter species (H Spp.). Fifty-three specimens from biopsies of the left internal mamillary artery in the same patients were also collected and tested. RESULTS: H. Spp. PCR test result was positive for 31 (29.5%) specimens from coronary artery atherosclerotic plaques. Serologic test results also showed 25 (23.8%) positive cases for H. pylrori immunoglobulin A (IgA) and 56 (53.3%) positive for anti-H. pylori immunoglobulin G. None of the specimens from the mamillary artery were positive for H Spp. genome when it was evaluated using PCR (P<.0001). Patients with positive test result for H. pylori IgA were significantly more likely to have higher total cholesterol and low-density lipoprotein (LDL) levels than IgA negative patients. CONCLUSION: H Spp. infection replication in the coronary arterial wall is associated with atherosclerotic plaque formation. Seropositivity for H. pylori IgA may also enhance blood values of total cholesterol and LDL in these patients. PMID- 22104006 TI - Cardiac hypertrophy in deceased users of anabolic androgenic steroids: an investigation of autopsy findings. AB - BACKGROUND: The use of anabolic androgenic steroids (AASs) has been associated with hypertrophy of the left cardiac ventricle (LVH) as diagnosed by echocardiography. Case reports suggest that AAS-related LVH may lead to sudden death. We performed an investigation of the gross cardiac pathological findings in deceased male AAS users in order to further elucidate the proposed role of AAS in cardiac hypertrophy. METHODS: Eighty-seven deceased males who tested positive for AAS at autopsy and 173 age-adjusted control deceased males without suspected AAS use were studied for cardiac hypertrophy. The AAS-positive subjects had been examined at any of the six departments of forensic medicine in Sweden during the period from 1989 to 2009. Data were assessed employing multivariate analyses controlling for body weight, height, age, bleeding after trauma, and the impact of weight training. RESULTS: The analysis of the logarithm of heart mass by multivariate statistics implied that strong correlations existed between body mass and heart mass (P<.00001), height and heart mass (P<.02), age and heart mass (P<.00001), and trauma (bleeding) and heart mass (P=.00001). After controlling for these factors, a significantly higher heart mass (P=.0001) was found among the AAS-positive males. CONCLUSION: Our findings suggest that use of AAS may lead to cardiac hypertrophy with a direct cardiotropic effect. PMID- 22104007 TI - Arrhythmogenic cardiomyopathy: from autopsy to genes and transgenic mice (SCVP Achievement Award Lecture, San Antonio, TX, February 27, 2011). AB - We present the history of arrhythmogenic cardiomyopathy since its discovery in the 1980s at autopsy of young subjects, who died suddenly during effort as a first manifestation of the disease and in whom the right ventricle was found as the source of lethal arrhythmias. Most of the contributions have come from the Padua as well as from the Paris and London schools. Investigations were then developed to arrive at the diagnosis, and these include electrocardiography, angiography, echocardiography, electroanatomic mapping, endomyocardial biopsy, and magnetic resonance imaging. Disqualification from sport activity and implantable cardioverter defibrillator proved to be life-saving. Genetic investigations have confirmed that arrhythmogenic cardiomyopathy is a hereditary Mendelian disease, either dominant or recessive, with mutations of genes encoding intercellular proteins (desmosome disease). The disease was recently reproduced in transgenic mice, with electrocardiographic and morphologic features overlapping the human disease. Cardiomyocyte cell death occurs with time as a genetically determined injury. The challenge now is to find ways to prevent onset and progression of the disease. PMID- 22104008 TI - Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A2A adenosine receptor. AB - Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. d-Amino acid conjugates were generally more potent than l-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles. PMID- 22104009 TI - Parkinsonian signs and symptoms in adults with a history of Sydenham's chorea. AB - BACKGROUND: Sydenham's chorea is associated with dysfunction of fronto-striatal circuits induced by cross-reactive antibodies to group A beta-hemolytic streptococcus. High susceptibility of extrapyramidal effects of neuroleptics in patients with Sydenham's chorea suggests underlying nigro-striatal dysfunction. OBJECTIVE: To study the presence of parkinsonism in patients with a history of Sydenham's Chorea. METHODS: We used the UFMG Sydenham's Chorea Rating Scale (USCRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) part III, respectively, to determine the presence of chorea and parkinsonian symptoms and signs in 25 adults with a history of previous Sydenham's Chorea currently without chorea or use of anti-choreic drugs. RESULTS: Bradykinesia was found in 64% of subjects. There was a statistically significant correlation between bradykinesia and hemichorea (-0.412; p = 0.036) and bradykinesia and generalized chorea (0.412; p = 0.036). There was no correlation between bradykinesia and use of anti choreic drugs. CONCLUSIONS: Bradykinesia is common in patients with Sydenham's Chorea in remission. This finding suggests an immune-mediated dysfunction of the nigro-striatal system. PMID- 22104010 TI - SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population. AB - BACKGROUND: Significant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene-gene and gene-environment interactions in association with PD was also attempted. METHODS: The SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype. RESULTS: Single-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 * 10(-04), intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 * 10(-04) and P = 4.23 * 10(-04) for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ~83 kb from intron 4 to the 3' end of SNCA (P = 1.29 * 10(-05)). CONCLUSIONS: Our findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions. PMID- 22104011 TI - No evidence of association between the LINGO4 gene and essential tremor in Chinese Han patients. AB - Essential tremor (ET) is shown an autosomal dominant mode of inheritance, with no disease-causing gene has been found. Genetic variations in the leucine-rich repeat and lg domain containing nogo receptor-interacting protein genes (LINGO1 and LINGO2) were reported to be associated with an increased risk of developing ET. To explore whether the LINGO4 gene (a homologous gene of the LINGO1 and the LINGO2 genes) plays a role in ET susceptibility, we performed genetic analysis of coding region of the LINGO4 gene in 100 patients with ET from Mainland China. Two nucleotide variants had been identified: (1) T > A transition (rs61746299), predicted to lead to the amino acid change Thr444Ser, and (2) C > T transition (rs1521179), located 12 bp downstream to the end of coding region. To evaluate whether these variants are related to ET susceptibility, we investigated a total of 150 Chinese Han ET patients (77 familial ET and 73 sporadic ET) and 300 sex, age and ethnicity matched normal controls. No significant differences in genotypic and allele distributions between patients and control subjects for rs61746299 and rs1521179 (p = 0.531 and p = 0.867 for genotypic distributions; p = 1.000 and p = 0.844 for allele distributions) were observed, suggesting variants in coding region of the LINGO4 gene may play litter or no role in the risk of ET susceptibility. PMID- 22104012 TI - Deep brain stimulation in early Parkinson's disease: enrollment experience from a pilot trial. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an accepted therapy for advanced Parkinson's disease (PD). In animal models, pharmacologic ablation and stimulation of the subthalamic nucleus have resulted in clinical improvement and, in some cases, improved survival of dopaminergic neurons. DBS has not been studied in the early stages of PD, but early application should be explored to evaluate safety, efficacy, and the potential to alter disease progression. METHODS: We are conducting a prospective, randomized, single-blind clinical trial of optimal drug therapy (ODT) compared to medication plus DBS (ODT + DBS) in subjects with Hoehn & Yahr Stage II idiopathic PD who are without motor fluctuations or dementia. We report here subject screening, enrollment, baseline characteristics, and adverse events. RESULTS: 30 subjects (average age 60 +/- 6.9 years, average duration of medicine 2.1 +/- 1.3 years, average UPDRS-III scores 14.9 on medication and 27.0 off medication) are enrolled in the ongoing study. Twelve of 15 subjects randomized to DBS experienced perioperative adverse events, the majority of which were related to the procedure or device and resolved without sequelae. Frequently reported adverse events included wound healing problems, headache, edema, and confusion. CONCLUSION: This report demonstrates that subjects with early stage PD can be successfully recruited, consented and retained in a long-term clinical trial of DBS. Our ongoing pilot investigation will provide important preliminary safety and tolerability data concerning the application of DBS in early stage PD. PMID- 22104013 TI - Deep brain stimulation in rapidly progressive Parkinson-dystonia syndrome due to mitochondrial disorder. PMID- 22104014 TI - Motor pathway excitability in ATP13A2 mutation carriers: a transcranial magnetic stimulation study. AB - OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) as markers of intracortical intrahemispheric inhibition/facilitation and the ipsilateral silent period (iSP) and paired-pulse interhemispheric inhibition (IHI) to probe interhemispheric motor interactions. RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical inhibition. In addition, some aspects of interhemispheric inhibition are increased in the presence of a single ATP13A2 mutation. PMID- 22104015 TI - Everolimus and long acting octreotide as a volume reducing treatment of polycystic livers (ELATE): study protocol for a randomized controlled trial. AB - BACKGROUND: Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients. METHODS/DESIGN: This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed. DISCUSSION: This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01157858. PMID- 22104016 TI - A point-of-purchase intervention featuring in-person supermarket education affects healthful food purchases. AB - OBJECTIVE: This study tested the efficacy of a multicomponent supermarket point of-purchase intervention featuring in-person nutrition education on the nutrient composition of food purchases. DESIGN: The design was a randomized trial comparing the intervention with usual care (no treatment). SETTING AND PARTICIPANTS: A supermarket in a socioeconomically diverse region of Phoenix, AZ. One hundred fifty-three adult shoppers were recruited onsite. INTERVENTION: The intervention consisted of brief shopping education by a nutrition educator and an explanation and promotion of a supermarket point-of-purchase healthful shopping program that included posted shelf signs identifying healthful foods, sample shopping lists, tips, and signage. MAIN OUTCOME MEASURES: Outcomes included purchases of total, saturated, and trans fat (grams/1,000 kcal), and fruits, vegetables, and dark-green/yellow vegetables (servings/1,000 kcal) derived through nutritional analysis of participant shopping baskets. ANALYSIS: Analysis of covariance compared the intervention and control groups on food purchasing patterns while adjusting for household income. RESULTS: The intervention resulted in greater purchasing of fruit and dark-green/yellow vegetables. No other group differences were observed. CONCLUSIONS AND IMPLICATIONS: Long-term evaluations of supermarket interventions should be conducted to improve the evidence base and to determine the potential for influence on food choices associated with decreased chronic disease incidence. PMID- 22104017 TI - [Infundibulo-hypophysitis in a girl: 10 years follow-up]. PMID- 22104018 TI - [Febrile seizures in the first year of life: Dravet spectrum epilepsy?]. AB - INTRODUCTION: Dravet syndrome is a drug resistant epilepsy which starts in the first year of life with febrile seizures, followed by cognitive impairment and epilepsy with multiple seizure types. Diagnosis has been typically made at the age of three to four years, but earlier diagnosis is now possible as clinical features are better recognised and molecular diagnosis is available. PATIENTS AND METHODS: We studied a series of 14 children with Dravet syndrome or Dravet spectrum epilepsy. A screening test, developed by other authors to distinguish the febrile seizures in Dravet syndrome from febrile seizures from other origin, was applied to the clinical features of the seizures occurring during the first year of life in our patients. RESULTS: Clinical suspicion of Dravet spectrum epilepsy was possible in 100% of children in our series. Moreover, taking into consideration only the first seizure, 79% of patients scored sufficiently to detect Dravet syndrome. CONCLUSIONS: Dravet syndrome can be recognised during the first year of life. It is important that physicians are made aware of these clinical criteria capable to distinguish febrile seizures in Dravet syndrome from febrile seizures of other origin, and set up a protocol to collect appropriate data regarding febrile seizures occurring in the first year of life. PMID- 22104019 TI - [Disseminated staphylococcal infection resembling Kawasaki disease]. PMID- 22104020 TI - [Urinary tract infections: antibiotic resistance and clinical follow up]. AB - The initial treatment of the urinary tract infections (UTI) is empirical and it is a priority to determine the antibiotic resistance of most common germs in a population. Furthermore, due to the suspicion of acute pyelonephritis the presence of renal scarring should be ruled out as this may lead to further complications. A retrospective longitudinal study was performed on all children under 14 years diagnosed with UTI from January 1 2009 to December 31 2009. The in vitro susceptibility to the most important urinary pathogens was analysed, along with the presence of scars, and a subsequent follow-up. The most frequently isolated bacteria were E. coli (80%), P. mirabilis (9.7%) and K. pneumoniae (4.2%). In the antibiogram, E coli showed a high sensitivity to fosfomycin (99.1%), cefotaxime (98.2%) cefuroxime (97.3%) and gentamicin (95.6%). The sensitivity obtained against amoxicillin-clavulanate was 83.2%, while that obtained against cotrimoxazole was 78.9%. Post-pyelonephritis scars were found in 19% of patients with febrile UTI, 17% out-patients and 20% of those admitted. PMID- 22104021 TI - [Photoxicity reaction due to methotrexate]. PMID- 22104022 TI - [Aetiology of bronchiolitis in hospitalised children in South-East Spain]. AB - BACKGROUND: Bronchiolitis is the most common respiratory disease in children under 2 years-old and a major cause of hospitalization in young children, especially during the winter. OBJECTIVES: To determine the prevalence and etiology of bronchiolitis in south-east of Spain. STUDY DESIGN: A prospective study was conducted during the bronchiolitis season (December-April). Children below 18 months-old admitted to the hospital for a first bronchiolitis episode were included. Nasopharyngeal aspirates were analysed by reverse transcription polymerase chain reaction (RT-PCR) respiratory syncytial virus. RESULTS: A total of 235 children were included during this period, and 235 RT-PCR were performed. A total of 287 viruses were detected in nasopharyngeal aspirates from 204 infants. Respiratory syncytial virus was the virus detected more frequently, followed by rhinovirus. Co-infections were found in the 36% of children. CONCLUSIONS: Respiratory viruses were detected in most of the children below 18 months-old hospitalised with bronchiolitis, and 36% of them showed a mixed infection. PMID- 22104023 TI - Multislice frozen phonon high angle annular dark-field image simulation study of Mo-V-Nb-Te-O complex oxidation catalyst "M1". AB - Multislice frozen phonon calculations were performed on a model structure of a complex oxide which has potential use as an ammoxidation catalyst. The structure has 11 cation sites in the framework, several of which exhibit mixed Mo/V substitution. In this paper the sensitivity of high-angle annular dark-field (HAADF) imaging to partial substitution of V for Mo in this structure is reported. While the relationship between the average V content in an atom column and the HAADF image intensity is not independent of thickness, it is a fairly weak function of thickness suggesting that HAADF STEM imaging in certain cases can provide a useful starting point for Rietveld refinements of mixed occupancy in complex materials. The thermal parameters of the various cations and oxygen anions in the model affect the amount of thermal diffuse scattering and therefore the intensity in the HAADF images. For complex materials where the structure has been derived via powder Rietveld refinement, the uncertainty in the thermal parameters may limit the accuracy of HAADF image simulations. With the current interest in quantitative microscopy, simulations need to accurately describe the electron scattering to the very high angles often subtended by a HAADF detector. For this system approximately 15% of the scattering occurs above 200 mrad at 200 kV. To simulate scattering to such high angles, very fine sampling of the projected potential is necessary which increases the computational cost of the simulation. PMID- 22104024 TI - Eosinophilic airway inflammation is increased in children with asthma and food allergies. AB - BACKGROUND: Asthma is associated with food allergies in a significant number of children, with evidence linking allergies to asthma severity and morbidity. In this study, we tested our hypothesis that the eosinophilic lower airway inflammation is higher in asthmatic children with food allergies. AIMS: The aims of the study were to compare the eosinophilic inflammatory markers in asthmatic children with and without food allergies. MATERIALS AND METHODS: Children with asthma, with (n = 22) and (n = 53) without food allergies were included. All subjects were classified according to the GINA guidelines (2009) and had received at least 3 months of anti-inflammatory therapy prior to testing. Fractional exhaled nitric oxide and sputum differential counts were performed using standard techniques. RESULTS: Children with asthma and food allergies had significantly higher fractional exhaled nitric oxide median (range) [(22.4 (6.1-86.9) vs. 10.3 (2.7-38.7) (p = 0.01)] and sputum eosinophil percentage [15.5 (5.0-53.0) vs. 2.0 (0-20) (p < 0.001)] compared with asthmatic children without allergies. CONCLUSION: These results suggest that the children with asthma and food allergies have increased eosinophilic inflammation of the airways. PMID- 22104025 TI - Waist circumference, waist-hip ratio and waist-height ratio percentiles and central obesity among Pakistani children aged five to twelve years. AB - BACKGROUND: Central obesity has been associated with the risk of cardiovascular and metabolic disease in children and anthropometric indices predictive of central obesity include waist circumference (WC), waist-hip ratio (WHR) and waist height ratio (WHtR). South Asian children have higher body fat distribution in the trunk region but the literature regarding WC and related indices is scarce in this region. The study was aimed to provide age- and gender-specific WC, WHR and WHtR smoothed percentiles, and to explore prevalence and correlates of central obesity, among Pakistani children aged five to twelve years. METHODS: A population-based cross-sectional study was conducted with a representative multistage random cluster sample of 1860 primary school children aged five to twelve years in Lahore, Pakistan. Smoothed percentile curves were constructed for WC, WHR and WHtR by the LMS method. Central obesity was defined as having both age- and gender-specific WC percentile >=90th and WHtR >=0.5. Chi-square test was used as the test of trend. Multivariate logistic regression was used to quantify the independent predictors of central obesity and adjusted odds ratios (aOR) with 95% CI were obtained. Linear regression was used to explore the independent determinants of WC and WHtR. Statistical significance was considered at P < 0.05. RESULTS: First ever age- and gender-specific smoothed WC, WHR and WHtR reference curves for Pakistani children aged five to twelve years are presented. WC increased with age among both boys and girls. Fiftieth WC percentile curves for Pakistani children were higher as compared to those for Hong Kong and British children, and were lower as compared to those for Iranian, German and Swiss children. WHR showed a plateau pattern among boys while plateau among girls until nine years of age and decreased afterwards. WHtR was age-independent among both boys and girls, and WHtR cut-off of >=0.5 for defining central obesity corresponded to 85th WHtR percentile irrespective of age and gender. Twelve percent children (95% CI 10.1-13.0) had a WC >=90th percentile and 16.5% children (95% CI 14.7-18.1) had a WHtR >=0.5 while 11% children (95% CI 8.9-11.6) had both WC >=90th percentile and WHtR >=0.5. Significant predictors of central obesity included higher grade, urban area with high socioeconomic status (SES), high income neighborhood and higher parental education. Children studying in higher grade (aOR 5.11, 95% CI 1.76-14.85) and those living in urban area with high SES (aOR 82.34, 95% CI 15.76-430.31) showed a significant independent association. Urban area with high SES and higher parental education showed a significant independent association with higher WC and higher WHtR while higher grade showed a significant independent association with higher WC. CONCLUSIONS: Comprehensive worldwide reference values are needed to define central obesity and the present study is the first one to report anthropometric indices predictive of central obesity for Pakistani school-aged children. Eleven percent children were centrally obese and strong predictors included higher grade, urban area with high SES and higher parental education. These findings support the need for developing a National strategy for childhood obesity and implementing targeted interventions, prioritizing the higher social class and involving communities. PMID- 22104026 TI - Local thermal therapy effects on menopausal symptoms and bone mineral density. AB - OBJECTIVES: The aim of this study was to evaluate the effects of local thermal therapy with far-infrared rays (FIR) on menopausal symptoms and bone mineral density (BMD) in postmenopausal women. SUBJECTS AND METHODS: A prospective randomized, controlled trial was conducted in female volunteers from communities in Northern Taiwan. The intervention group (n=22) received local thermal therapy with the help of FIR from an FIR emitter, for approximately 20 minutes per day, twice a week, for 20 sessions. They received the therapy on their backs while lying in a supine position. The control group (n=21) received no treatment. The primary outcome was the change in the Perceived Perimenopausal Disturbances Scale, designed for the measurement of menopause-related symptoms (MRS) before and after completion of treatment in a 10-week period. Secondary outcome parameters included serum levels of estradiol (E2) with osteocalcin (OC), and calcaneal BMD by quantitative ultrasound. RESULTS: After 10 weeks of intervention, MRS determined by the scale decreased in mean total scores and mean scores for vasomotor, musculoskeletal, urologic, reproductive, and psychologic domains (p<0.05), except for reproductive (sexuality-related) symptoms. In the control group, mean total scores and scores of each domain had no significant difference between baseline and follow-up examination after 10 weeks. There was no significant difference between the quantitative ultrasound parameters in the calcaneus, serum E2, and OC levels either at the baseline or in the changes from the baseline between the intervention and control groups of women (p>0.05). CONCLUSIONS: Local thermal therapy with FIR results in a significant reduction of MRS in postmenopausal women. Serum E2, OC levels, and calcaneal BMD showed no significant changes between the two groups. These results suggest that FIR local thermal therapy may be a potential alternative for the management of postmenopausal symptoms. PMID- 22104027 TI - A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol. AB - BACKGROUND: The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. METHODS/DESIGN: A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. DISCUSSION: This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence. PMID- 22104028 TI - Effect of single amino acid substitution on oxidative modifications of the Parkinson's disease-related protein, DJ-1. AB - Mutations in the gene encoding DJ-1 have been identified in patients with familial Parkinson's disease (PD) and are thought to inactivate a neuroprotective function. Oxidation of the sulfhydryl group to a sulfinic acid on cysteine residue C106 of DJ-1 yields the "2O " form, a variant of the protein with enhanced neuroprotective function. We hypothesized that some familial mutations disrupt DJ-1 activity by interfering with conversion of the protein to the 2O form. To address this hypothesis, we developed a novel quantitative mass spectrometry approach to measure relative changes in oxidation at specific sites in mutant DJ-1 as compared with the wild-type protein. Treatment of recombinant wild-type DJ-1 with a 10-fold molar excess of H(2)O(2) resulted in a robust oxidation of C106 to the sulfinic acid, whereas this modification was not detected in a sample of the familial PD mutant M26I exposed to identical conditions. Methionine oxidized isoforms of wild-type DJ-1 were depleted, presumably as a result of misfolding and aggregation, under conditions that normally promote conversion of the protein to the 2O form. These data suggest that the M26I familial substitution and methionine oxidation characteristic of sporadic PD may disrupt DJ-1 function by disfavoring a site-specific modification required for optimal neuroprotective activity. Our findings indicate that a single amino acid substitution can markedly alter a protein's ability to undergo oxidative modification, and they imply that stimulating the conversion of DJ-1 to the 2O form may be therapeutically beneficial in familial or sporadic PD. PMID- 22104029 TI - Feeding practices among children attending child welfare clinics in Ragama MOH area: a descriptive cross-sectional study. AB - BACKGROUND: Feeding during early childhood is important for normal physical and mental growth as well as for health in later life. Currently, Sri Lanka has adopted the WHO recommendation of exclusive breastfeeding for six months, followed by addition of complementary feeds thereafter, with continuation of breastfeeding up to or beyond two years. This study was conducted to evaluate the current feeding practices among Sri Lankan children during early childhood. METHODS: This study was a descriptive cross-sectional study conducted in the Ragama Medical Officer of Health (MOH) area. It was conducted between 10 August 2010 and 30 October 2010. Children between the ages of 24 and 60 months, attending child welfare clinics, were included in the study on consecutive basis. An interviewer-administered questionnaire was used to collect data regarding sociodemographic characteristics and feeding practices. RESULTS: There were 208 boys and 202 girls in the study population. Of them, 255 (62.2%) were exclusively breastfed up to 6 months. Younger children had a statistically significant, higher rate of exclusive breastfeeding compared to older children. Three hundred and fifty one (85.6%) children had received infant formula, and it was started before the age of 6 months in 61 children, and in 212 before one year. Sugar was added to infant formula in 330 (80.4%) children, and out of them 144 had sugar added within first year of life. Complementary foods were started before 4 months in 29 (7%) children. Of the 410 children, 294 (71.7%) were breastfed beyond 2 years and 41.6% of them were breastfed at regular intervals throughout the day. Three hundred and thirty eight (82.6%) children were receiving overnight feeding of either breast milk or infant formula even after 2 years. CONCLUSIONS: Though a high rate of exclusive breastfeeding was observed in this study population, there are many other issues related to feeding during the early years of life that need immediate intervention. Too early introduction of complementary food, using infant formula without an indication, adding sugar to infant formula, too frequent breastfeeding and overnight feeding of older children are among them. PMID- 22104030 TI - Physiological responses, rating of perceived exertion, and stride characteristics during walking on dry land and walking in water, both with and without a water current. AB - CONTEXT: Walking in water has been included in rehabilitation programs. However, there is a dearth of information regarding the influence of a water current on physiological responses, rating of perceived exertion (RPE), and stride characteristics of subjects while they walk in water. OBJECTIVE: To compare physiological responses, RPE, and stride characteristics of subjects walking in water (with and without a current) with those of subjects walking on dry land. DESIGN: Repeated measures. SETTING: University laboratory. PARTICIPANTS: 7 male adults (mean age = 21.6 y). INTERVENTION: Subjects walked on a treadmill on dry land and on an underwater treadmill immersed to the level of the xiphoid process. The walking speeds in water were set to be half of that on dry land. MAIN OUTCOME MEASURES: Oxygen consumption (VO2), respiratory-exchange ratio (RER), heart rate (HR), minute ventilation (VE), RPE (for breathing and legs, RPE-Br and RPE-Legs, respectively), systolic (SBP) and diastolic (DBP) blood pressures, and stride frequency (SF) were measured. In addition, stride length (SL) was calculated. RESULTS: There was no significant difference in the VO2, RER, HR, VE, RPE-Br, and RPE-Legs while walking in water with a current compared with walking on dry land (P > .05). Furthermore, VO2, RER, HR, VE, RPE-Br, RPE-Legs, SF, and SBP while walking in water were significantly higher with a water current than without (P < .05). CONCLUSIONS: These observations suggest that half the speed should be required to work at the similar metabolic costs and RPE while walking in water with a current, compared with walking on dry land. Furthermore, it was suggested that the physiological responses and RPE would be higher while walking in water with a current than without. PMID- 22104031 TI - Expression of vomeronasal receptors and related signaling molecules in the nasal cavity of a caudate amphibian (Plethodon shermani). AB - G-protein-coupled receptors are responsible for binding to chemosensory cues and initiating responses in vertebrate olfactory neurons. We investigated the genetic diversity and expression of one family of G-protein-coupled receptors in a terrestrial caudate amphibian (the red-legged salamander, Plethodon shermani). We used degenerate RT-PCR to isolate vomeronasal type 2 receptors (V2Rs)--including full-length sequences--and compared them with other vertebrate V2Rs with phylogenetic analyses. We also amplified a salamander Golf, a G-protein usually expressed in the main olfactory epithelium (MOE) of vertebrates, and an ion channel expressed in the rodent vomeronasal organ: trpc2. We then localized mRNA expression of V2Rs, trpc2, and Golf in the olfactory and vomeronasal epithelia with in situ hybridization. The mRNA transcripts of V2Rs and trpc2 were detected solely in the vomeronasal epithelium of P. shermani. Furthermore, there were differences in the density of cells that expressed particular subclasses of V2Rs: 2 probes showed sexually dimorphic expression, whereas a third did not. Although Golf mRNA was expressed primarily in the MOE, Golf transcripts also were found in the vomeronasal epithelium. Thus, some aspects of mRNA expression of vomeronasal receptors and related molecules differ between salamanders and frogs, and between salamanders and mice. PMID- 22104032 TI - Asthma, atopy and exhaled nitric oxide in a cohort of 6-yr-old New Zealand children. AB - BACKGROUND: Exhaled nitric oxide has been promoted as a non-invasive measure of airway inflammation, with clinical utility for the diagnosis and management of asthma. AIM: We studied associations between exhaled nitric oxide, asthma and atopy in a variety of clinically relevant phenotypes in a cohort of 6-yr-old children. METHOD: Asthma was defined using standard questionnaire criteria, atopy was measured using skin prick tests (SPT) and specific IgE to common allergens, and exhaled nitric oxide was measured using a chemiluminescence analyser according to American and European Thoracic Society criteria. RESULTS: Exhaled nitric oxide was strongly related to atopy and in particular to sensitization to house dust mites. Children with non-allergic asthma had no increase in exhaled nitric oxide compared with non-asthmatic children. Compared with children who never wheezed both late onset and persistent, wheezing was associated with increased FE(NO), while early transient wheezing was not. Elevated levels of exhaled nitric oxide amongst children with allergic asthma were almost entirely explained by their levels of specific IgE to aeroallergens, predominantly D pteronyssinus. CONCLUSION: Airway inflammation as measured by exhaled nitric oxide in young New Zealand children is related to their level of specific IgE to aeroallergens. This has implications for the utility of nitric oxide as a diagnostic and management tool in childhood asthma and for the importance of specific IgE as a marker of asthma severity. PMID- 22104033 TI - A double blind, randomised placebo controlled trial of topical 2% viscous lidocaine in improving oral intake in children with painful infectious mouth conditions. AB - BACKGROUND: Painful infectious mouth conditions are a common presentation to emergency departments. Although self limiting, painful ulcerative lesions and inflamed mucosa can decrease oral intake and can lead to dehydration. Oral analgesia is of limited efficacy and is often refused by the patient. Despite widespread use of oral 2% viscous lidocaine for many years, there is little evidence for its efficacy as an analgesic and in aiding oral intake in children with painful infectious mouth conditions. This study aims to establish the effectiveness of 2% viscous lidocaine in increasing oral intake in these children by comparing it with placebo. METHODS/DESIGN: This study is a randomised double blind placebo controlled trial of children between 6 months and 8 years of age with painful infectious mouth conditions defined as gingivostomatitis (herpetic or non herpetic), ulcerative pharyngitis, herpangina and hand foot and mouth disease as assessed by the treating clinician in association with a history of poor oral fluid intake. It will be conducted at a single tertiary paediatric emergency department in Melbourne Australia.20 patients have already been randomised to receive 2% lidocaine or placebo in a pilot study to determine the sample size in a preplanned adaptive design. A further 80 patients will be randomised to receive either 2% lidocaine or placebo. The placebo agent is identical to lidocaine in terms of appearance, flavour and smell. All clinical and research staff involved, patients and their parents will be blinded to treatment allocation.The primary endpoint is the amount of fluid ingested by each child, expressed in ml/kg, within 60 minutes from the time of administration of the study mixture. Secondary endpoints are the proportion of patients ingesting 5 ml/kg and 10 ml/kg at 30 and 60 minutes after drug administration and the incidence of adverse events. Longer term outcomes will include the proportion of patients requiring hospital admission and length of emergency department stay. DISCUSSION: This trial will define the role of 2% lidocaine in the treatment of painful infectious mouth conditions. TRIAL REGISTRATION: The trial is registered with the Australian and New Zealand Clinical Trials Registry- ACTRN12609000566235. PMID- 22104034 TI - Spatial distribution and temporal evolution of scattering centers by optical coherence tomography in the poly(L-lactide) backbone of a bioresorbable vascular scaffold. AB - BACKGROUND: Scattering centers (SC) are often observed with optical coherence tomography (OCT) in some struts of bioresorbable vascular scaffolds (BVS). These SC might be caused by crazes in the polymer during crimp-deployment (more frequent at inflection points) or by other processes, such as physiological loading or hydrolysis (eventually increasing with time). The spatial distribution and temporal evolution of SC in BVS might help to understand their meaning. METHODS AND RESULTS: Three patients were randomly selected from 12 imaged with Fourier-domain OCT at both baseline and 6 months in the ABSORB cohort B study (NCT00856856). Frame-by-frame analysis of the SC distribution was performed using spread-out vessel charts, and the results from baseline and 6 months were compared. A total of 4,328 struts were analyzed. At baseline and follow-up all SC appeared at inflection points. No significant difference was observed between baseline and 6 months in the number of SC struts (14.9 vs. 14.5%, P=0.754) or in the distribution of SC. The proportion and distribution of SC did not vary substantially among the patients analyzed. CONCLUSIONS: The SC observed in OCT imaging of the BVS are located exclusively at inflection points and do not increase with time. These findings strongly suggest that SC are caused by crazes in the polymer during crimp-deployment, ruling out any major role of hydrolysis or other time-dependent processes. PMID- 22104035 TI - Cardiac event risk in Japanese subjects estimated using gated myocardial perfusion imaging, in conjunction with diabetes mellitus and chronic kidney disease. AB - BACKGROUND: Cardiac event risk is estimated using quantitative gated myocardial perfusion imaging (MPI) and clinical background in patients with ischemic heart disease. The aim of the present study was to calculate major cardiac event risk and tabulate it in the Heart Risk Table for clinical use of risk stratification. METHODS AND RESULTS: Multivariate logistic regression was performed based on a multicenter prognostic database (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated Single-photon emission computed tomography [J-ACCESS investigation]) using MPI (n=2,395). The risk of major cardiac events (cardiac death, non-fatal myocardial infarction and heart failure requiring hospitalization) was estimated using age, ejection fraction (EF), estimated glomerular filtration rate (eGFR) and presence of diabetes mellitus (DM). Age matched standard eGFR was determined in 77 subjects. Major cardiac event risk was calculated using the equation: risk (%/3 years)=1/(1+Exp(-(-4.699 0.0151*eGFR+0.7998*DM+0.0582*age+0.697*SSS-0.0359*EF))*100, where SSS refers to summed stress scores. Risk was determined without eGFR (the initial version) and using the present formula with eGFR (revised version), with consistent results. DM and chronic kidney disease were major determinants of cardiac events. CONCLUSIONS: Cardiac event risk was estimated using MPI defect score and left ventricular EF in conjunction with eGFR and the presence of DM. The risk table might be used for risk evaluation in Japanese patients undergoing MPI. PMID- 22104036 TI - Intensive lipid-lowering therapy with statins for primary prevention. PMID- 22104037 TI - Comorbidities related to BMI category in children and adolescents: German/Austrian/Swiss Obesity Register APV compared to the German KiGGS Study. AB - PURPOSE: To assess cardiovascular risk factors in overweight or obese children and adolescents in Germany, Austria and Switzerland and to investigate the relationship to BMI category. METHODS: Data of 63,025 overweight or obese patients (APV population) were compared to normal-weight subjects from a representative study on health status of 14,298 children and adolescents in Germany (KiGGS survey). The weight status was assessed by BMI, and BMI-SDS values were cal-culated using national reference data. RESULTS: In normal-weight KiGGS subjects, mean BMI was 17.3 +/- 2.5 (BMI-SDS -0.1 +/- 0.8). In the overweight or obese APV population, mean BMI was 30.2 +/- 5.6 (BMI-SDS 2.5 +/- 0.6). In normal weight subjects blood pressure, total cholesterol, LDL-cholesterol, and triglycerides were elevated in 6.1, 8.6, 7.0 and 3.0%, respectively, and HDL cholesterol was reduced in 3.0%, whereas in overweight/obese subjects the percentages of abnormal values were 35.3, 13.8, 14.5, 13.6, and 10.1%, respectively. CONCLUSIONS: Cardiovascular risk is increased in obese children and adolescents. There is a strong need to monitor blood pressure and serum lipids in this group of patients. Our results emphasize the importance of prevention of obesity in order to reduce cardiovascular risk. PMID- 22104038 TI - Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking. AB - BACKGROUND: Smokers need effective support to maximise the chances of successful quit attempts. Current smoking cessation medications, such as nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, have been shown to be effective in clinical trials but are underused by smokers attempting to quit due to adverse effects, contraindications, low acceptability and/or high cost. Cytisine is a low-cost, plant-based alkaloid that has been sold as a smoking cessation aid in Eastern Europe for 50 years. A systematic review of trial evidence suggests that cytisine has a positive impact on both short- and long-term abstinence rates compared to placebo. However, the quality of the evidence is poor and insufficient for licensing purposes in many Western countries. A large, well-conducted placebo-controlled trial (n = 740) of cytisine for smoking cessation has recently been published and confirms the findings of earlier studies, with 12-month continuous abstinence rates of 8.4% in the cytisine group compared to 2.4% in the placebo group (Relative risk = 3.4, 95% confidence intervals 1.7-7.1). No research has yet been undertaken to determine the effectiveness of cytisine relative to that of NRT. METHODS/DESIGN: A single blind, randomised controlled, non-inferiority trial has been designed to determine whether cytisine is at least as effective as NRT in assisting smokers to remain abstinent for at least one month. Participants (n = 1,310) will be recruited through the national telephone-based Quitline service in New Zealand and randomised to receive a standard 25-day course of cytisine tablets (Tabex(r)) or usual care (eight weeks of NRT patch and/or gum or lozenge). Participants in both study arms will also receive a behavioural support programme comprising an average of three follow-up telephone calls delivered over an eight-week period by Quitline. The primary outcome is continuous abstinence from smoking at one month, defined as not smoking more than five cigarettes since quit date. Outcome data will also be collected at one week, two months and six months post-quit date. DISCUSSION: Cytisine appears to be effective compared with placebo, and given its (current) relative low cost may be an acceptable smoking cessation treatment for smokers, particularly those in low- and middle-income countries. Cytisine's 'natural' product status may also increase its acceptability and use among certain groups of smokers, such as indigenous people, smokers in countries where the use of natural medicines is widespread (e.g. China, India), and in those people who do not want to use NRT or anti-depressants to help them quit smoking. However it is important to ascertain the effectiveness of cytisine compared with that of existing cessation treatments. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12610000590066). PMID- 22104039 TI - Normal variation in thermal radiated temperature in cattle: implications for foot and-mouth disease detection. AB - BACKGROUND: Thermal imagers have been used in a number of disciplines to record animal surface temperatures and as a result detect temperature distributions and abnormalities requiring a particular course of action. Some work, with animals infected with foot-and-mouth disease virus, has suggested that the technique might be used to identify animals in the early stages of disease. In this study, images of 19 healthy cattle have been taken over an extended period to determine hoof and especially coronary band temperatures (a common site for the development of FMD lesions) and eye temperatures (as a surrogate for core body temperature) and to examine how these vary with time and ambient conditions. RESULTS: The results showed that under UK conditions an animal's hoof temperature varied from 10 degrees C to 36 degrees C and was primarily influenced by the ambient temperature and the animal's activity immediately prior to measurement. Eye temperatures were not affected by ambient temperature and are a useful indicator of core body temperature. CONCLUSIONS: Given the variation in temperature of the hooves of normal animals under various environmental conditions the use of a single threshold hoof temperature will be at best a modest predictive indicator of early FMD, even if ambient temperature is factored into the evaluation. PMID- 22104040 TI - Duration of electrically induced muscle cramp increased by increasing stimulation frequency. AB - CONTEXT: Electrically induced muscle cramps (EIMC) do not last long enough to study many cramp treatments. Increasing stimulation frequency lengthens cramp duration; it is unknown which frequency elicits the longest EIMC. OBJECTIVE: To determine which stimulation frequency elicits the longest EIMC and whether cramp duration and stimulation frequency are correlated. DESIGN: Randomized, crossover. SETTING: Laboratory. PARTICIPANTS: 20 participants (12 male, 8 female; age 20.7 +/- 0.6 y; height 174.9 +/- 1.9 cm; mass 76.6 +/- 2.2 kg) with a self-reported history of muscle cramps in their lower extremities within the 6 mo before the study. INTERVENTIONS: The dominant leg's tibial nerve was percutaneously stimulated with 2-s-duration electrical stimuli trains starting at a frequency of 4 Hz. After 1 min of rest, stimulation frequency increased in 2-Hz increments until a cramp occurred in the flexor hallucis brevis. The stimulation frequency at which a cramp occurred was termed cramp threshold frequency (TF). Cramp duration was determined using strict clinical criteria (loss of hallux rigidity and return of hallux neutral). On the next 4 consecutive days, participants were stimulated at 5, 10, 15, or 20 Hz above TF, and cramp duration was reassessed. MAIN OUTCOME MEASURES: Cramp TF and duration. RESULTS: Cramp TF was 16.9 +/- 5.1 Hz. Cramp duration was longer at 15 and 20 Hz above TF (77.9 +/- 37.6 s and 69.5 +/- 36.9 s, respectively) than at TF (40.8 +/- 34.0 s; P < .05). Cramp duration and TF were highly correlated (r = .90). CONCLUSIONS: Stimulating at 15 and 20 Hz above cramp TF produces the longest-lasting EIMC. PMID- 22104041 TI - Outcome in hip fracture patients related to anemia at admission and allogeneic blood transfusion: an analysis of 1262 surgically treated patients. AB - BACKGROUND: Anemia is more often seen in older patients. As the mean age of hip fracture patients is rising, anemia is common in this population. Allogeneic blood transfusion (ABT) and anemia have been pointed out as possible risk factors for poorer outcome in hip fracture patients. METHODS: In the timeframe 2005-2010, 1262 admissions for surgical treatment of a hip fracture in patients aged 65 years and older were recorded. Registration was prospective from 2008 on. Anemic and non-anemic patients (based on hemoglobin level at admission) were compared regarding clinical characteristics, mortality, delirium incidence, LOS, discharge to a nursing home and the 90-day readmission rate. Receiving an ABT, age, gender, ASA classification, type of fracture and anesthesia were used as possible confounders in multivariable regression analysis. RESULTS: The prevalence of anemia and the rate of ABT both were 42.5%. Anemic patients were more likely to be older and men and had more often a trochanteric fracture, a higher ASA score and received more often an ABT. In univariate analysis, the 3- and 12-month mortality rate, delirium incidence and discharge to a nursing home rate were significantly worse in preoperatively anemic patients.In multivariable regression analysis, anemia at admission was a significant risk factor for discharge to a nursing home and readmission < 90 days, but not for mortality. Indication for ABT, age and ASA classification were independent risk factors for mortality at all moments, only the mortality rate for the 3-12 month interval was not influenced by ABT. An indication for an ABT was the largest negative contributor to a longer LOS (OR 2.26, 95% CI 1.73-2.94) and the second largest for delirium (OR 1.67, 95% CI 1.28-2.20). CONCLUSIONS: This study has demonstrated that anemia at admission and postoperative anemia needing an ABT (PANT) were independent risk factors for worse outcome in hip fracture patients. In multivariable regression analysis, anemia as such had no effect on mortality, due to a rescue effect of PANT. In-hospital, 3- and 12-month mortality was negatively affected by PANT, with the main effect in the first 3 months postoperatively. PMID- 22104042 TI - Preventing pressure ulcers--Are pressure-redistributing support surfaces effective? A Cochrane systematic review and meta-analysis. AB - OBJECTIVES: To undertake a systematic review of the effectiveness of pressure redistributing support surfaces in the prevention of pressure ulcers. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Wound Group Specialised Register, The Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. The reference sections of included trials were searched for further trials. REVIEW METHODS: Randomised controlled trials and quasi-randomised trials, published or unpublished, which assessed the effects of support surfaces in preventing pressure ulcers (of any grade), in any patient group, in any setting compared to any other support surface, were sought. Two reviewers extracted and summarised details of eligible trials using a standardised form and assessed the methodological quality of each trial using the Cochrane risk of bias tool. RESULTS: Fifty-three eligible trials were identified with a total of 16,285 study participants. Overall the risk of bias in the included trials was high. Pooled analysis showed that: (i) foam alternatives to the standard hospital foam mattress reduce the incidence of pressure ulcers in people at risk (RR 0.40, 95% CI 0.21-0.74) and Australian standard medical sheepskins prevent pressure ulcers compared to standard care (RR 0.48, 95% CI 0.31-0.74). Pressure-redistributing overlays on the operating table compared to standard care reduce postoperative pressure ulcer incidence (RR 0.53, 95% CI 0.33 0.85). CONCLUSIONS: While there is good evidence that higher specification foam mattresses, sheepskins, and that some overlays in the operative setting are effective in preventing pressure ulcers, there is insufficient evidence to draw conclusions on the value of seat cushions, limb protectors and various constant low pressure devices. The relative merits of higher-tech constant low pressure and alternating pressure for prevention are unclear. More robust trials are required to address these research gaps. PMID- 22104043 TI - The impact of an intervention to improve patient participation in a surgical care unit: a quasi-experimental study. AB - BACKGROUND: Organizational changes in surgical care are requiring patients to become more responsible for their own care, both before and after surgery, and also during recovery. Involving patients in their care is vital to improving quality of care and patient safety. OBJECTIVE: The aim of this study was to investigate the impact of the 'Tell-us' card on patients' perceptions of quality of care, with a specific focus on patient participation. Another aim was to evaluate the use of the Tell-us card from the patients' perspective. DESIGN: A quasi-experimental design with an intervention group and control groups was used. The patient's self-written Tell-us card was introduced as the intervention. SETTING: The study was conducted in two surgical care units at a Swedish university hospital. PARTICIPANTS: A consecutive sample of patients admitted from the waiting list and from the emergency department was included (n=310). The inclusion criteria were surgical patients with a hospital stay of at least one day. Patients who were younger than 18 years, not able to speak or write in Swedish, or unable or unwilling to give informed consent to participate were excluded. METHODS: Quality of care was assessed using the questionnaire 'Quality from the Patient's Perspective'. The patients included in the intervention group were asked to write what was most important for them during the day or just before discharge on patient-written Tell-us cards. RESULTS: The use of the Tell us card resulted in significant improvements (5 out of 17 items) in patients' abilities to participate in decisions about their nursing and medical care. The patients found the Tell-us card more useful in their interaction with registered nurses and assistant nurses than with physicians. CONCLUSIONS: The use of the Tell-us card improved patients' participation in some areas of nursing and medical care in the surgical care units. The Tell-us card is an uncomplicated and inexpensive tool that could be an important step towards improved patient participation in the surgical care unit. More research is needed to evaluate the use of the Tell-us card in different hospital units and over a longer period of time. PMID- 22104044 TI - Massive pulmonary embolism in wife-caregiver of terminally ill patient with sarcoma. AB - We report a case of massive pulmonary embolism in a 63-year-old female caregiver of her terminally ill husband. Venous thromboembolism in family caregivers is a rare but a serious problem. Increased awareness and implementation of policies and guidelines to decrease potentially preventable venous thromboembolism are vital to help prevent unnecessary death, to increase patient safety, and to contain rising costs in health care. PMID- 22104045 TI - Designing research with hospice and palliative care populations. AB - Research in palliative care and hospice populations is important for improving quality of care, quality of life, and provider understanding of individuals at the end of life. However, this research involves many potential challenges. This review seeks to inform and assist researchers targeting to design studies targeting hospice and palliative care patients by presenting a thorough review of the published literature. This review covers English-language articles published from 1990 through 2009 listed in the PsycInfo, Medline, or CINAHL research databases under relevant keywords. Articles on pediatric hospice were not included. Issues discussed include study design, informed consent, and recruitment for participants. Synthesized recommendations for researchers in these populations are presented. PMID- 22104046 TI - Changes in spirituality and quality of life in patients undergoing radiation therapy. AB - PURPOSE: Investigations into the role of spirituality in cancer confirm the association of good spiritual well-being with many positive outcomes. This study aimed to evaluate potential changes in spirituality over the course of radiation therapy (RT). PATIENTS AND MATERIALS: The Functional Assessment of Chronic Illness Therapy-Spiritual questionnaire measuring spiritual well-being and quality of life (QOL) was administered to adult patients undergoing RT. Scores were compared using student t tests and chi-square analysis. RESULTS: Despite statistically significant declines in QOL measures such as physical well-being (P < .001) and overall well-being (P < .001), no significant changes were noted in spirituality for all comers. A significant increase in the Sp-12 spirituality measure (P = .001) was noted in patients with breast cancer, independent of age, gender, and purpose of treatment. Sp-12 scores were positively correlated with overall QOL scores (P < .001). PMID- 22104047 TI - Pyoderma gangrenosum associated with inflammatory bowel disease. Report of two cases with good response to infliximab. AB - Among the extraintestinal manifestations of inflammatory bowel disease (IBD), pyoderma gangrenosum (PG) often poses a therapeutic challenge. We describe two cases of PG associated with inflammatory bowel disease, who responded to treatment with Infliximab. PMID- 22104048 TI - Abatacept mechanism of action: concordance with its clinical profile. AB - The double and simultaneous molecular interaction between antigen-presentig cells (APC) and T lymphocytes is essential for the optimal activation of the immunological response and requires the participation of two membrane receptor groups. Abatacept is a fusion protein that selectively modulates one of these two ways, by binding to CD80 and CD86 receptors on APC. In this way, the drug inhibits T cell activation, selectively blocking the specific interaction of CD80/CD86 receptors to CD28 and, therefore, inhibiting T cell proliferation and B cell immunological response. This pharmacological action results in the normalization of inflammatory mediators in rheumatoid arthritis patients and in a safe and efficacious clinical response. Abatacept in combination with methotrexate prevents the progression of joint damage and improves physical function in rheumatoid arthritis patients. PMID- 22104049 TI - The evolution of a novel biomedical informatics curriculum for medical students. AB - Health information technology is an essential component of current medical practice, and federal initiatives to promote the further adoption of these technologies are under way. Therefore, it is increasingly important that medical students receive training in the use of these technologies and become familiar with the discipline of biomedical informatics (BMI), which seeks to maximize the utility of health information. In August 2007, the University of Arizona College of Medicine established a new four-year medical school campus in Phoenix. At the same time, a new BMI department was created by the Arizona State University on the same campus. One of the unique features of the new medical school curriculum was a significant focus on BMI, consisting of over 45 hours of required sequenced and integrated instruction in BMI topics. This article describes how the medical school curriculum was created, what BMI elements were contained within the curriculum, and how the instruction was provided. Evaluation of the curriculum included subjective and objective components and revealed significant differences both within group (pre- and posttraining) and across groups when compared with students without formal BMI training. Specifically, self-assessment of BMI ability increased after exposure to the curriculum, and students receiving the BMI curriculum were able to answer objective questions related to BMI content. Implications and lessons learned in the implementation are also discussed. PMID- 22104050 TI - Specialty choice and practice location of physician alumni of University of California premedical postbaccalaureate programs. AB - PURPOSE: To investigate the longer-term career outcomes, such as specialty choice and practice location, of underrepresented minority and disadvantaged students who finished a University of California postbaccalaureate (UCPB) premedical program. METHOD: The authors compared 303 UCPB alumni from the 1986-1987 to 2001 2002 cohorts who matriculated into medical school and could be matched to the 2008 American Medical Association Physician Masterfile with 586 randomly selected control physicians who graduated from the same medical schools in the same years as the UCPB alumni. Outcome variables included specialty, practice in a Health Professional Shortage Area (HPSA) or Medically Underserved Area (MUA), and practice in a California community with high concentrations of African American, Latino, or low-income residents. RESULTS: A greater percentage of UCPB alumni (161/303 [53.1%]) than control physicians (235/586 [40.1%]) were in primary care (P < .001). Although there were no differences between the two groups in the percentages of physicians working in HPSAs or MUAs, a greater percentage of UCPB alumni than control physicians working in California practiced in high-poverty communities (31/191 [16.2%] versus 22/252 [8.7%], P < .016), high-Latino communities (35/191 [18.3%] versus 22/252 [8.7%], P <. 01), and high-African American communities (57/191 [29.8%] versus 50/252 [19.8%], P <. 02). CONCLUSIONS: UCPB programs have enhanced the number of physicians entering primary care and working in disadvantaged California communities. However, many UCPB alumni practice in disadvantaged communities in California that are not federally designated as HPSAs or MUAs. PMID- 22104051 TI - Perspective: publication ethics and the emerging scientific workforce: understanding "plagiarism" in a global context. AB - English has long been the dominant language of scientific publication, and it is rapidly approaching near-complete hegemony. The majority of the scientists publishing in English-language journals are not native English speakers, however. This imbalance has important implications for training concerning ethics and enforcement of publication standards, particularly with respect to plagiarism. The authors suggest that lack of understanding of what constitutes plagiarism and the use of a linguistic support strategy known as "patchwriting" can lead to inadvertent misuse of source material by nonnative speakers writing in English as well as to unfounded accusations of intentional scientific misconduct on the part of these authors. They propose that a rational and well-informed dialogue about this issue is needed among editors, educators, administrators, and both native English-speaking and nonnative-English-speaking writers. They offer recommendations for creating environments in which such dialogue and training can occur. PMID- 22104052 TI - Women physicians: choosing a career in academic medicine. AB - PURPOSE: Despite recent efforts to understand the complex process of physician career development, the medical education community has a poor understanding of why, how, and when women physicians embark on careers in academic medicine. METHOD: In 2010, the authors phone-interviewed women physicians in academic medicine regarding why, how, and when they chose academic medicine careers. Project investigators first individually and then collectively analyzed transcripts to identify themes in the data. RESULTS: Through analyzing the transcripts of the 53 interviews, the investigators identified five themes related to why women choose careers in academic medicine: fit, aspects of the academic health center environment, people, exposure, and clinical medicine. They identified five themes related to how women make the decision to enter academic medicine: change in specialty, dissatisfaction with former career, emotionality, parental influence, and decision-making styles. The authors also identified four themes regarding when women decide to enter academic medicine: as a practicing physician, fellow, resident, or medical student. CONCLUSIONS: Choosing a career in academic medicine is greatly influenced by the environment in which one trains and by people-be they faculty, mentors, role models, or family. An interest in teaching is a primary reason women choose a career in academic medicine. Many women physicians entering academic medicine chose to do so after or during fellowship, which is when they became more aware of academic medicine as a possible career. For many women, choosing academic medicine was not necessarily an active, planned decision; rather, it was serendipitous or circumstantial. PMID- 22104053 TI - The Master of Science in clinical epidemiology degree program of the Perelman School of Medicine at the University of Pennsylvania: a model for clinical research training. AB - An innovative training program to provide clinical research training for clinicians was created in 1979 at the University of Pennsylvania School of Medicine, now the Perelman School of Medicine. The program's principal and continuing aim is to provide trainees mentored experiences and the training needed to become skilled independent investigators able to conduct clinical research and develop academic careers as independent clinical investigators.The authors identify the vision that led to the creation of the master of science in clinical epidemiology (MSCE) degree program and describe today's training program, including administration, oversight, participating faculty, and trainees. They also describe the program's core curriculum, elective options, seminars on ongoing research, training in the responsible conduct of research, professional development activities, and the development and completion of a closely mentored clinical research project.Approximately 35 new trainees enter the two- to three-year program annually. Funding is provided primarily by National Institutes of Health-funded training programs and supplemented by private industry, private foundations, and employee-based benefits. More than 500 individuals have received or are currently receiving training through the MSCE program. A large percentage of former trainees maintain full-time positions in academic medicine today.The authors identify some challenges that have been met and insights regarding funding, faculty, trainees, and curriculum. Ongoing challenges include recruiting trainees from some selected highly paid, procedure oriented specialties, maintaining sufficient mentors for the continually increasing numbers of trainees, and distinguishing applicants who truly desire a primary research career from others. PMID- 22104054 TI - The Center for Clinical Epidemiology and Biostatistics of the Perelman School of Medicine at the University of Pennsylvania: an organizational model for clinical research in a school of medicine. AB - A new model for the conduct of clinical research was established at the University of Pennsylvania (Penn) School of Medicine, now the Perelman School of Medicine, through the development of the interdepartmental Center for Clinical Epidemiology and Biostatistics in 1993 and the basic science Department of Biostatistics and Epidemiology in 1994. The authors describe the development and evolution of these novel structures.Five key objectives were achieved with these structures' creation: (1) Clinical faculty have the opportunity to be identified as both clinicians and epidemiologists, (2) nonclinical faculty have an academic "home," (3) clinical trainees are now educated in population medicine, which promotes its incorporation into their clinical practice, (4) population medicine and clinical medicine have become fully integrated, and (5) better epidemiologic research is conducted, informed by clinical insights.Today's center is the primary home for epidemiology and biostatistics at Penn, linking epidemiology, biostatistics, clinical medicine, and the health sciences. The center's core faculty manage their own research programs, conduct primary research in epidemiology and biostatistics, serve as members of collaborative research teams, manage cores and service centers that support research projects, and lead graduate training programs in epidemiology and biostatistics. The department provides an academic home and structure for faculty, provides primary research in epidemiology and biostatistics, supports the center's mission, and provides training in biostatistics. This organizational approach has wide applicability across schools of medicine in the United States and abroad and has been a model for many. PMID- 22104055 TI - ResearchMatch: a national registry to recruit volunteers for clinical research. AB - The authors designed ResearchMatch, a disease-neutral, Web-based recruitment registry to help match individuals who wish to participate in clinical research studies with researchers actively searching for volunteers throughout the United States. In this article, they describe ResearchMatch's stakeholders, workflow model, technical infrastructure, and, for the registry's first 19 months of operation, utilization metrics. Having launched volunteer registration tools in November 2009 and researcher registration tools in March 2010, ResearchMatch had, as of June 2011, registered 15,871 volunteer participants from all 50 states. The registry was created as a collaborative project for institutions in the Clinical and Translational Science Awards (CTSA) consortium. Also as of June 2011, a total of 751 researchers from 61 participating CTSA institutions had registered to use the tool to recruit participants into 540 active studies and trials. ResearchMatch has proven successful in connecting volunteers with researchers, and the authors are currently evaluating regulatory and workflow options to open access to researchers at non-CTSA institutions. PMID- 22104056 TI - Thinking about giving up clinical practice? A gender-stratified approach to understanding junior doctors' choices. AB - PURPOSE: This study examined the association between workplace factors and thinking about leaving clinical care by junior doctors (i.e., doctors in postgraduate training) in Germany, and used a gender-stratified approach to address the so-called feminization of medicine. METHOD: In this cross-sectional questionnaire study, 1,494 German junior doctors working in patient care in Bavaria in 2006-2007 were sent a questionnaire about considering leaving patient care (outcome variable). Logistic regression analyses were used to calculate the predictive influence of workplace factors on the outcome variable (adjusted odds ratio [aOR], 95% confidence interval [95% CI]). RESULTS: Of the 637 responding junior doctors, altogether 52% (men 49.3%, women 54.2%) had thought about leaving clinical practice. Support of colleagues and superiors (men aOR 2.70, 95% CI 1.20 6.04; women aOR 3.46, 95% CI 1.67-7.17), performance feedback (women aOR 1.88, 95% CI 1.23-3.14), the availability of postgraduate training possibilities (men aOR 4.74, 95% CI 1.53-14.69), overtime (women aOR 1.82, 95% CI 1.02-3.25), weekend duty (men aOR: 3.58, 95% CI 1.86-6.88), and the medical specialty were found to be significant predictors for thinking about leaving clinical practice for both men and women. CONCLUSIONS: Workplace factors predict the wish for leaving clinical care for junior doctors. Male and female junior doctors seem to have different priorities in the workplace, which should be addressed in order to retain them in patient care. PMID- 22104057 TI - A randomized trial to evaluate methodologies for engaging academic physicians in grateful patient fundraising. AB - PURPOSE: Donations from grateful patients can support medical education, research, and clinical programs. This study sought to compare the effectiveness of three approaches to educating physicians about grateful patient fundraising. METHOD: In 2010, the authors conducted a randomized trial at an academic health center to compare the effectiveness of three educational strategies that encouraged physicians to participate in grateful patient fundraising. The authors randomized physicians into an "e-mail arm," a "lecture arm," and a "coaching arm." All participants received weekly e-mail articles describing philanthropy processes and outcomes. Those in the lecture arm also attended a single, one-hour training session taught by a physician with prior fundraising success, and those in the "coaching arm" received personalized, one-on-one communications with development professionals. The intervention period was three months. The primary outcome was the number of "qualified referrals" (i.e., individuals capable of making a >=$25,000 gift) whose names participants provided to the development team during the three months of and three months following the intervention; dollars received was the secondary outcome. RESULTS: Participants in the e-mail arm (n = 14) generated 0 referrals and $0, those in the lecture arm (n = 18) generated three referrals and $0, and those in the coaching arm (n = 19) generated 41 referrals and $219,550 (five gifts). Of the 19 physicians in the coaching arm, 17 (89%) generated at least one qualified referral. CONCLUSIONS: A process in which development officers give one-on-one coaching to physicians can effectively enhance collaboration on grateful patient philanthropy. PMID- 22104058 TI - What "patient-centered care" requires in serious cultural conflict. AB - The medical community has hailed the recent movement to provide patient-centered care as a progressive step forward in meeting the needs of the very diverse patient population of the United States. Stakeholders in all arenas of U.S. medicine-professional organizations, public advocacy groups, hospital administration, medical school leadership, insurance carriers, and nursing-have embraced the focus on patient-centered care. But, although the community universally endorses the ideal of patient-centered care, the ethical obligations it entails have only just begun to be explored. One of the most difficult circumstances in which to provide patient-centered care is when there is a deep cultural conflict-that is, when the values and priorities of the patient and his or her family are in direct opposition to those of the clinical team. Given the mandate to provide care that is "culturally and linguistically appropriate," the author asks what obligations providers have to meet patient demands when doing so is inconvenient, challenging, or, at the extreme, offensive and contrary to clinical values. The author examines the tension that occurs when culturally sensitive patient-centered care disrupts the workflow of the service, requires acknowledging antithetical, unsupportable values, or entails discriminatory or ad hominem practices that constitute a personal insult or affront to the provider. The strategy the author has invoked for this analysis is to search for common values that might provide a bridge between patients and providers who are in deep cultural conflict. PMID- 22104059 TI - Toward "harder" medical humanities: moving beyond the "two cultures" dichotomy. AB - Using the current international debate surrounding the incorporation of medical humanities into medical curricula as a starting point, the authors address both the legitimacy and didactics of teaching medical humanities to medical students. They highlight the paradox of the increasing prevalence of medical humanities in medical curricula and the often critical reception humanities courses receive. The alleged lack of empirical evidence linking such courses with improved patient care cannot alone explain the criticism they engender. After a short overview of the debate surrounding medical humanities and their inclusion in outcomes-based education, the authors outline the medical humanities block, "The History, Theory, and Ethics of Medicine," which is part of the German medical curriculum. A model developed at Ulm University exemplifies the integrated inclusion of the heterogeneous aspects of medical culture into medical education. This model emphasizes a reflexive approach (i.e., understanding how the humanities are manifested in medicine) as an alternative to the currently dominant narrative approach (i.e., liberal arts, moral development, and/or mental retreat), which has gradually been limited to a quasi-"secular religion" for doctors. This model uses established concepts from science and cultural studies as the "instruments" for seminars and courses; paradigms, discourses, social systems, and cosmologies constitute the tools for teaching and learning about the historical, theoretical, and ethical dimensions of medicine. The authors argue that this approach both precludes the need to justify the medical humanities and overcomes the dichotomy that has heretofore existed between the two cultures of science and the humanities in medicine. PMID- 22104060 TI - Fostering and evaluating reflective capacity in medical education: developing the REFLECT rubric for assessing reflective writing. AB - PURPOSE: Reflective writing (RW) curriculum initiatives to promote reflective capacity are proliferating within medical education. The authors developed a new evaluative tool that can be effectively applied to assess students' reflective levels and assist with the process of providing individualized written feedback to guide reflective capacity promotion. METHOD: Following a comprehensive search and analysis of the literature, the authors developed an analytic rubric through repeated iterative cycles of development, including empiric testing and determination of interrater reliability, reevaluation and refinement, and redesign. Rubric iterations were applied in successive development phases to Warren Alpert Medical School of Brown University students' 2009 and 2010 RW narratives with determination of intraclass correlations (ICCs). RESULTS: The final rubric, the Reflection Evaluation for Learners' Enhanced Competencies Tool (REFLECT), consisted of four reflective capacity levels ranging from habitual action to critical reflection, with focused criteria for each level. The rubric also evaluated RW for transformative reflection and learning and confirmatory learning. ICC ranged from 0.376 to 0.748 for datasets and rater combinations and was 0.632 for the final REFLECT iteration analysis. CONCLUSIONS: The REFLECT is a rigorously developed, theory-informed analytic rubric, demonstrating adequate interrater reliability, face validity, feasibility, and acceptability. The REFLECT rubric is a reflective analysis innovation supporting development of a reflective clinician via formative assessment and enhanced crafting of faculty feedback to reflective narratives. PMID- 22104061 TI - Assessing gender equity in a large academic department of pediatrics. AB - PURPOSE: To determine the extent of gender inequity in a large academic pediatrics department and to demonstrate an assessment methodology other departments can use. METHOD: Using deidentified data, the authors evaluated all promotion track faculty in the University of Colorado School of Medicine's Department of Pediatrics in 2009 by five parameters: promotion, tenure, leadership roles, faculty retention, and salary. Outcome metrics included time to promotion and at rank; awards of tenure, time to tenure, and time tenured; departmental leadership positions in 2009; attrition rates from 2000 to 2009; and salary in academic year 2008-2009 compared with national benchmarks. RESULTS: Women constituted 54% (60/112) of assistant professors and 56% (39/70) of associate professors but only 23% (19/81) of professors. Average years to promotion at each rank and years at assistant and associate professor were identical for men and women; male professors held their rank six years longer. Only 18% (9/50) of tenured faculty were women. Men held 75% (18/24) of section head and 83% (6/7) of vice chair positions; women held 62% (13/21) of medical director positions. More women than men retired as associate professors and resigned/relocated as professors. Women's pay (98% of national median salary) was lower than men's (105% of median) across all ranks and specialties. CONCLUSIONS: These gender disparities were due in part to women's later start in academics and the resulting lag time in promotion. Differences in the awarding of tenure, assignment of leadership roles, faculty retention, and salary may also have played important roles. PMID- 22104062 TI - [Alzheimer disease and other dementia in France: Identification, management and neuroleptic use (2007-2009)]. AB - Numbers of patients with Alzheimer's disease or other dementia (ADD) are necessary for care organisation and indicators development as rates of neuroleptics prescription will have a negative risk-benefit balance. Among people of 60 years old and more covered by the general regime (11 millions, 80% of French people), patients with ADD were identified by at least one of the following criteria: long-term affection status for ADD (67.1% of the identified), refunds for Alzheimer medication (67.5%) or hospitalization for ADD (13.6%). In 2009, 353,482 patients were identified using the presence of one criterion in 2009 and 409,021 were identified the same year when criteria were selected over a period of 3 years (2007 to 2009) (prevalence 3.58%, 2.35 to 5.31% between French regions). By extrapolation, their number for whole France was 551,000. Among patients with ADD, 16% had at least three refunds for neuroleptic in 2009 (9.3 to 22.8% according to regions). Increased use of neuroleptic was associated with hospitalisation in a community hospital, the number of general practitioner consultation and an age between 60 and 75 years. At least one liberal psychiatrist consultation decreased the use. This study gives information among ADD patients management and supports prevention program for neuroleptics use. PMID- 22104063 TI - [What's new in immune-mediated neuropathies?]. AB - Many papers have been published in the field of immune-mediated neuropathies in 2010. Various topics have been covered: diagnostic criteria and clinical forms, pain and its risk factors, clinical evaluation and new immunological markers. Additionally, as nerve biopsy is still useful for evaluating patients with peripheral neuropathy, French and international guidelines have been published. This paper aims to summarize recent discoveries in the field of immune-mediated neuropathies. PMID- 22104064 TI - [Diagnostic profile of young-onset dementia before 65 years. Experience of a French Memory Referral Center]. AB - OBJECTIVE: The aim of the study was to compare the profiles of patients with young (age<=65 years) and late (age>65 years) onset of dementia in a memory clinic of a Memory Referral Center in Lyons (France), for the year 2008. METHODS: A total of 746 demented patients were evaluated using clinical, neuropsychological and imaging information. For each patient, diagnoses of the dementing disorder used clinical criteria at the first visit. We examined the distribution of patients diagnosis and differences in sex and education between the young-onset dementia (YOD) and the late-onset dementia (LOD) groups. RESULTS: From a total of 746 registered demented patients (300 men, 446 women), there were 91 patients (12.2%) with YOD (from 36.5 to 65 years) and 655 patients with LOD (from 66 to 92 years). Among the 91 YOD patients, the most frequent causes were Mild Cognitive Impairment (MCI) (18.7%), then Alzheimer's disease (AD), frontotemporal dementia and posterior cortical atrophy (14.3% each), followed by progressive aphasia (11.0%), dementia with Lewy bodies (DLD) (9.9%), semantic dementia (8.8%), other causes (3.3%), vascular dementia (2.2%), undetermined dementia (2.2%), AD+cerebrovascular disease (1.1%). Among the 655 LOD patients, AD was the most frequent cause of dementia (57.4%). Referred cases by a specialist doctor were 50.5% in the YOD group and 12.7% in the LOD group (P<0.0001). In the ACP group, 68.4% patients began before 65 years. CONCLUSION: The number of YOD in our memory clinic was four-fold the number of expected patients in France. The characteristics of the Referral Center explain the high frequency of rare dementia such as progressive aphasia (5.2% of overall number), semantic dementia (3.6%) and posterior cortical atrophy (2.5%). PMID- 22104065 TI - [Shifting paradigm in skull base surgery: Roots, current state of the art and future trends of endonasal endoscopic approaches]. AB - During the last two decades, endoscopic endonasal approach has completed the minimally invasive skull base surgery armamentarium. Endoscopic endonasal skull base surgery (EESBS) was initially developed in the field of pituitary adenomas, and gained an increasing place for the treatment of a wide variety of skull base pathologies, extending on the midline from crista galli process to the occipitocervical junction and laterally to the parasellar areas and petroclival apex. Until now, most studies are retrospective and lack sufficient methodological quality to confirm whether the endoscopic endonasal pituitary surgery has better results than the microsurgical trans-sphenoidal classical approach. The impressions of the expert teams show a trend toward better results for some pituitary adenomas with the endoscopic endonasal route, in terms of gross total resection rate and probably more comfortable postoperative course for the patient. Excepting intra- and suprasellar pituitary adenomas, EESBS seems useful for selected lesions extending onto the cavernous sinus and Meckel's cave but also for clival pathologies. Nevertheless, this infatuation toward endoscopic endonasal approaches has to be balanced with the critical issue of cerebrospinal fluid leaks, which constitutes actually the main limit of this approach. Through their experience and a review of the literature, the authors aim to present the state of the art of this approach as well as its limits. PMID- 22104066 TI - [Telemedicine and fibrinolysis in Franche-Comte]. AB - INTRODUCTION: The aim of our study was to compare the efficacy and safety of intravenous thrombolysis of cerebral ischemia as it has been established in a distant hospital (DH) through telemedicine tools or in neurovascular unit of the University Hospital of Besancon. METHOD: Our work was conducted retrospectively at the University Hospital of Besancon from 1 January 2003 to December 31, 2009. RESULTS: Fibrinolysis was introduced at the university hospital in 98/161 patients (61%) and a DH in remote 63/161 patients (39%). A favorable neurological outcome (Rankin 0/1) was observed in 27/98 patients (27.5%) treated at University Hospital and in 25/63 (39.5%) patients in a DH. There was no significant difference between the two subgroups. Symptomatic hemorrhagic transformation occurred in 5/98 (5%) patients treated at University Hospital and in 1/63 (1.5%) patients treated in DH. There was no significant difference between the two subgroups. CONCLUSION: Our study shows that fibrinolysis remotely using the tools of telemedicine has, from 2003 to 2009, in Franche-Comte deal effectively and without risk of a significant proportion of patients. PMID- 22104067 TI - Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. AB - BACKGROUND: Mean arterial blood pressure (MAP) targets are empirically chosen during cardiopulmonary bypass (CPB). We have previously shown that near-infrared spectroscopy (NIRS) can be used clinically for monitoring cerebral blood flow autoregulation. The hypothesis of this study was that real-time autoregulation monitoring using NIRS-based methods is more accurate for delineating the MAP at the lower limit of autoregulation (LLA) during CPB than empiric determinations based on age, preoperative history, and preoperative blood pressure. METHODS: Two hundred thirty-two patients undergoing coronary artery bypass graft and/or valve surgery with CPB underwent transcranial Doppler monitoring of the middle cerebral arteries and NIRS monitoring. A continuous, moving Pearson correlation coefficient was calculated between MAP and cerebral blood flow velocity and between MAP and NIRS data to generate mean velocity index and cerebral oximeter index. When autoregulated, there is no correlation between cerebral blood flow and MAP (i.e., mean velocity and cerebral oximetry indices approach 0); when MAP is below the LLA, mean velocity and cerebral oximetry indices approach 1. The LLA was defined as the MAP at which mean velocity index increased with declining MAP to >= 0.4. Linear regression was performed to assess the relation between preoperative systolic blood pressure, MAP, MAP in 10% decrements from baseline, and average cerebral oximetry index with MAP at the LLA. RESULTS: The MAP at the LLA was 66 mm Hg (95% prediction interval, 43 to 90 mm Hg) for the 225 patients in which this limit was observed. There was no relationship between preoperative MAP and the LLA (P = 0.829) after adjusting for age, gender, prior stroke, diabetes, and hypertension, but a cerebral oximetry index value of >0.5 was associated with the LLA (P = 0.022). The LLA could be identified with cerebral oximetry index in 219 (94.4%) patients. The mean difference in the LLA for mean velocity index versus cerebral oximetry index was -0.2 +/- 10.2 mm Hg (95% CI, 1.5 to 1.2 mm Hg). Preoperative systolic blood pressure was associated with a higher LLA (P = 0.046) but only for those with systolic blood pressure <= 160 mm Hg. CONCLUSIONS: There is a wide range of MAP at the LLA in patients during CPB, making estimation of this target difficult. Real-time monitoring of autoregulation with cerebral oximetry index may provide a more rational means for individualizing MAP during CPB. PMID- 22104068 TI - Factor XIII and tranexamic acid but not recombinant factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood. AB - BACKGROUND: Hyperfibrinolysis is a pathological state that often results in depletion of coagulation factors and platelets and can contribute to bleeding. Factor XIII (FXIII) and thrombin activatable fibrinolysis inhibitor have key roles in protecting clots against fibrinolysis. We tested the hypotheses that FXIII concentrate, prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), and tranexamic acid (TA) inhibit fibrinolysis to different degrees, and that platelets contribute to antifibrinolysis. METHODS: Hyperfibrinolysis was induced by addition of recombinant tissue plasminogen activator (r-tPA) (final concentration: 100 ng . mL(-1)) to citrated whole blood obtained from 13 healthy volunteers. To assess inhibition of fibrinolysis, we added to the assays FXIII A(2)B(2) (0.42 U . mL(-1)), PCC (0.42 U . mL(-1)), rFVIIa (final concentration: 1.6 MUg . mL(-1)), TA (final concentration: 0.33 mg . mL(-1)), or saline. Coagulation was analyzed by rotational thromboelastometry (ROTEM(r)) using the clot lysis index (CLI) after 45 and 60 minutes in extrinsically activated assays, with (FIBTEM(r)) and without (EXTEM(r)) inhibition of platelet function by cytochalasin D. RESULTS: After r-tPA-evoked fibrinolysis (CLI45: median 78%; 72/85.5, 25th/75th percentile), FXIII (90%; 82.5/96, P = 0.025), PCC (89%; 74/91, P = 0.0465), and TA (94%; 92/96, P = 0.001) but not rFVIIa (79%; 72/86.5, P = 1.0) significantly attenuated the decrease in CLI. Similarly, CLI60 increased only with FXIII (66%; 33/90.5, P = 0.017) and TA (90%; 89/92, P = 0.001) compared with r-tPA alone (21%; 7/59). After abolition of platelet function by cytochalasin D, only TA (95%; 89/97.5, P = 0.0025) and PCC (84%; 70.5/90, P = 0.0305) but not FXIII or rFVIIa significantly increased CLI45 and CLI60 (TA: 89%; 84.5/96, P = 0.01 and PCC: 55%; 29.5/60, P = 0.0405) compared with r-tPA alone (CLI45: 59%; 40.5/72.5 and CLI60: 10%; 0/30). CONCLUSION: In thromboelastometric assays using whole blood, only TA, FXIII, and PCC significantly inhibited r-tPA evoked hyperfibrinolysis whereas rFVIIa had no effect. We also found that the effects of exogenous FXIII were dependent on the presence of functional platelets. PMID- 22104069 TI - A meta-analysis of the use of nonsteroidal antiinflammatory drugs for pediatric postoperative pain. AB - BACKGROUND: Opioid side effects are a great concern during the postoperative period in children. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to effectively decrease postoperative pain, but their opioid-sparing effect is still controversial. In this present meta-analysis, we investigated the postoperative opioid-sparing effect of NSAIDs in children. METHODS: A comprehensive literature search was conducted to identify clinical trials using NSAIDs and opioids as perioperative analgesic compounds in children and infants. Outcomes measured were opioid consumption, pain intensity, postoperative nausea and vomiting (PONV), and urinary retention. All outcomes were studied during postanesthesia care unit (PACU) stay and the first 24 postoperative hours. Data from each trial were combined to calculate the pooled odds ratios (ORs) or standardized mean difference (SMD) and their 95% confidence interval. RESULTS: Twenty-seven randomized controlled studies were analyzed. Perioperative administration of NSAIDs decreased postoperative opioid requirement (both in the PACU and during the first 24 postoperative hours; SMD = -0.66 [-0.84, -0.48] and 0.83 [-1.11, -0.55], respectively), pain intensity in the PACU (SMD = -0.85 [ 1.24, -0.47]), and PONV during the first 24 postoperative hours (OR = 0.75 [0.57 0.99]). NSAIDs did not decrease pain intensity during the first 24 postoperative hours (OR = 0.56 [0.26-1.2]) and PONV during PACU stay (OR = 1.02 [0.73-1.44]). Subgroup analysis according to the timing of NSAID administration (intraoperative versus postoperative), type of surgery, or coadministration of paracetamol did not show any influence of these factors on the studied outcomes except the reduction of pain intensity and the incidence of PONV during the first 24 postoperative hours, which were influenced by the coadministration of paracetamol and the type of surgery, respectively. CONCLUSION: This meta-analysis shows that perioperative NSAID administration reduces opioid consumption and PONV during the postoperative period in children. PMID- 22104071 TI - A rare anatomical variation of the brachial plexus: single cord anomaly. AB - Anatomical variations of the brachial plexus may be important in regional anesthesia and upper limb procedures. A fused single cord of the brachial plexus, although considered rare, was discovered in 4 Indian male cadavers during the dissection of 90 brachial plexuses. All 4 cases demonstrated deviation from the usual pattern starting at the division of trunks continuing to the formation of cords. The location of these single cords was lateral to the axillary artery instead of the typical perivascular relationship. A fused single cord of brachial plexus might be more common than previously thought. The impact on the performance or success of blockade remains unknown. PMID- 22104070 TI - Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. AB - Virchow's triad is traditionally invoked to explain pathophysiologic mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Given the tissue-specific bleeding observed in hemophilia patients, it may be instructive to consider the principles of Virchow's triad when investigating mechanisms operant in hemostatic disorders as well. Blood composition (the function of circulating blood cells and plasma proteins) is the most well studied component of the triad. For example, increased levels of plasma procoagulant proteins such as prothrombin and fibrinogen are established risk factors for thrombosis, whereas deficiencies in plasma factors VIII and IX result in bleeding (hemophilia A and B, respectively). Vessel wall (cellular) components contribute adhesion molecules that recruit circulating leukocytes and platelets to sites of vascular damage, tissue factor, which provides a procoagulant signal of vascular breach, and a surface upon which coagulation complexes are assembled. Blood flow is often characterized by 2 key variables: shear rate and shear stress. Shear rate affects several aspects of coagulation, including transport rates of platelets and plasma proteins to and from the injury site, platelet activation, and the kinetics of fibrin monomer formation and polymerization. Shear stress modulates adhesion rates of platelets and expression of adhesion molecules and procoagulant activity on endothelial cells lining the blood vessels. That no one abnormality in any component of Virchow's triad fully predicts coagulopathy a priori suggests coagulopathies are complex, multifactorial, and interactive. In this review, we focus on contributions of blood composition, vascular cells, and blood flow to hemostasis and thrombosis, and suggest that cross-talk among the 3 components of Virchow's triad is necessary for hemostasis and determines propensity for thrombosis or bleeding. Investigative models that permit interplay among these components are necessary to understand the operant pathophysiology, and effectively treat and prevent thrombotic and bleeding disorders. PMID- 22104072 TI - The reliability and accuracy of a noncontact electrocardiograph system for screening purposes. AB - BACKGROUND: Electrocardiography (ECG) requires the application of electrodes to the skin and often necessitates undressing. Capacitively coupled electrodes embedded in a normal chair would be a rational alternative for ECG screening. We evaluated the reliability and accuracy of ECG electrodes imbedded in a chair cushion. METHODS: Two independent clinicians compared ECG recordings obtained using skin electrodes with recordings obtained using capacitively coupled electrodes that were embedded in a chair cushion in an anesthesiology premedication room, a cardiology outpatient ward, and a cardiology day ward. We analyzed the data to compare the sensitivity and specificity for the diagnosis of cardiac arrhythmias. RESULTS: ECG recordings were obtained from 107 patients. Heart rate was accurately measured using the capacitively coupled electrodes, but motion artifacts made the identification of P and T waves unreliable. Signal quality was poor for patients with low body weight, patients wearing clothing containing mixed fibers, and patients wearing sweaty shirts. CONCLUSIONS: Heart rate was accurately measured, and some cardiac arrhythmias were correctly diagnosed using capacitive ECG electrodes. Capacitive electrodes embedded into an examination chair are a promising tool for preoperative screening. Improved artifact reduction algorithms are needed before capacitive electrodes will replace skin electrodes. PMID- 22104073 TI - Oxytocin inhibits the membrane depolarization-induced increase in intracellular calcium in capsaicin sensitive sensory neurons: a peripheral mechanism of analgesic action. AB - BACKGROUND: Lumbar intrathecal injection of oxytocin produces antinociception in rats and analgesia in humans. Classically, oxytocin receptors couple to stimulatory G proteins, increase inositol-3-phosphate production, and result in neuronal excitation. Most work to date has focused on a spinal site of oxytocin to excite gamma-aminobutyric acid interneurons to produce analgesia. Here we ask whether oxytocin might also affect primary sensory afferents by modulating high voltage-gated calcium channels, such as it does in the brain. METHODS: Dorsal root ganglion cells from adult rats were acutely dissociated and cultured, and changes in intracellular calcium determined by fluorescent microscopy using an indicator dye. The effects of oxytocin alone and in the presence of transient depolarization from increased extracellular KCl concentration were determined, and the pharmacology of these effects were studied. Cells from injured dorsal root ganglion cells after spinal nerve ligation were also studied. RESULTS: Oxytocin produced a concentration-dependent inhibition of the increase in intracellular calcium from membrane depolarization, an effect blocked more efficiently by oxytocin- than vasopressin-receptor selective antagonists. Oxytocin-induced inhibition was present in cells responding to capsaicin, and when internal stores of calcium were depleted with thapsigargin. Oxytocin produced similar inhibition in cells from animals with spinal nerve ligation. CONCLUSIONS: These data suggest that oxytocin produces antinociception after intrathecal delivery in part by reducing excitatory neurotransmitter release from the central terminals of nociceptors. PMID- 22104074 TI - A heat map of superior cervical ganglion location relative to the common carotid artery bifurcation. AB - BACKGROUND: Determining the superior cervical ganglion's precise anatomical location for local anesthetic block, when stellate block is not feasible or is contraindicated, is difficult. METHODS: We dissected the superior cervical ganglion in 60 embalmed cadaveric specimens. Multiple regressions determined whether subject characteristics predicted the distance between the superior cervical ganglion and common carotid artery bifurcation and the superior cervical ganglion dimensional width and area. Based on these regressions, we mapped the ganglion and common carotid artery bifurcation using a pseudocolor statistical heat map. RESULTS: The statistical model significantly predicted the superior cervical ganglion-common carotid artery bifurcation distance (P = 0.01), and the superior cervical ganglion dimensional width (P = 0.02). CONCLUSION: This study determined that the common carotid artery bifurcation is a good landmark for localizing the superior cervical ganglion for anesthetic block. PMID- 22104075 TI - Esophageal guidewire-assisted nasogastric tube insertion in anesthetized and intubated patients: a prospective randomized controlled study. AB - BACKGROUND: Nasogastric tube (NGT) insertion is indicated almost routinely in patients undergoing abdominal surgery to decompress the stomach intraoperatively and postoperatively, and to allow postoperative tube feeding. NGTs are made of nonreinforced polymer plastic materials and are prone to kinking and coiling during insertion. This often poses difficulty in blind NGT placement or placement assisted by variously described techniques. We hypothesized that esophageal guidewire-assisted NGT insertion with manual forward laryngeal displacement can significantly improve the first-attempt success rate over the technique of head flexion and lateral neck pressure during its insertion in anesthetized and tracheally intubated patients. METHODS: Four hundred eighty adult patients presenting for abdominal surgery under general anesthesia with neuromuscular relaxation were randomized to an experimental technique of esophageal guidewire with manual forward displacement of the larynx (group 1) or a control technique of head flexion and lateral neck pressure (group 2) for insertion of the NGT. The success rates (and failure rate) of the first and second attempts (and overall) were assessed along with the incidence of coiling and kinking of the NGT, procedure-related nasal bleeding and pharyngeal bleeding, and the incidence of moderate and life-threatening complications. RESULTS: The first-attempt success rate was 99.2% in group 1 compared with 56.7% in group 2 (P < 0.001). Thus, the first-attempt failure rate was 0.8% in group 1 compared with 43.3% in group 2 (P < 0.001, absolute risk reduction of first-attempt failure rate = 42.5%, 95% confidence interval [CI] = 36.0%-49.9%; numbers needed to treat = 2, 95% CI = 2 3; relative risk reduction of first-attempt failure rate = 98.1%, 95% CI = 92.3% 99.5%). The median time required to insert the NGT was significantly shorter in group 1 (55 vs 60 seconds); P < 0.001, 95% CI for the difference in means = 3.2 to 6.8 seconds. The incidences of kinking/coiling, bleeding, and moderate injuries were significantly lower in group 1. CONCLUSIONS: Esophageal guidewire assisted insertion with manual forward laryngeal displacement technique most frequently resulted in correct positioning of the NGT in anesthetized and tracheally intubated patients after the first attempt. This technique is also associated with a lower incidence of procedure-related injuries and is less time consuming than conventional insertion techniques. PMID- 22104076 TI - A review of the impact of phenylephrine administration on maternal hemodynamics and maternal and neonatal outcomes in women undergoing cesarean delivery under spinal anesthesia. AB - Phenylephrine is effective for the management of spinal anesthesia-induced hypotension in parturients undergoing cesarean delivery under spinal anesthesia. While ephedrine was previously considered the vasopressor of choice in obstetric patients, phenylephrine is increasingly being used. This is largely due to studies suggesting improved fetal acid-base status with the use of phenylephrine as well as the low incidence of hypotension and its related side effects with prophylactic phenylephrine regimens. This review highlights the effects of phenylephrine compared with ephedrine on maternal hemodynamics (arterial blood pressure, heart rate, and cardiac output), and occurrence of intraoperative nausea and vomiting. The impact of the administration of phenylephrine as a bolus for the treatment of established hypotension compared with its administration as a prophylactic infusion is discussed. This article also reviews the impact of phenylephrine compared with ephedrine on uteroplacental perfusion, and fetal outcomes such as neonatal acid-base status and Apgar scores. The optimum dosing regimen for phenylephrine administration is also discussed. PMID- 22104077 TI - The effects of anesthetic technique on cancer recurrence in percutaneous radiofrequency ablation of small hepatocellular carcinoma. AB - BACKGROUND: Retrospective studies report that the benefit of regional anesthesia on cancer recurrence may depend on the specific tumor type. We compared the association between anesthetic technique and cancer recurrence in patients undergoing percutaneous radiofrequency ablation (RFA) of small hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed medical records of patients with small HCC treated with RFA between August 1999 and December 2008. Patients receiving epidural anesthesia were compared with a group given general anesthesia. The end points were recurrence-free survival and overall survival, which were assessed using the Kaplan-Meier technique and compared using a multivariate Cox proportional hazards regression model and an alternative model with inverse probability weights to adjust for propensity score. RESULTS: The hazard ratio for recurrence-free survival in the epidural anesthesia group compared with the general anesthesia group was 3.66 (95% confidence interval [CI], 2.59-5.15; P < 0.001) in the Cox regression model and 4.31 (95% CI, 2.24 8.29; P < 0.001) in the analysis adjusted for propensity score with inverse probability weights. The hazard ratio for overall survival in the epidural anesthesia group compared with the general anesthesia group was 0.77 (95% CI, 0.50-1.18; P = 0.232) in the Cox regression model and 1.26 (95% CI, 0.81-1.97; P = 0.312) in the analysis adjusted for propensity score with inverse probability weights. CONCLUSIONS: This retrospective analysis suggests that treatment of small HCC by RFA under general anesthesia is associated with reduced risk of cancer recurrence. No effect of anesthetic technique on overall survival is detected. Prospective, randomized trials to evaluate this association are warranted. PMID- 22104078 TI - SNP analysis of minimally evolved t(14;18)(q32;q21)-positive follicular lymphomas reveals a common copy-neutral loss of heterozygosity pattern. AB - Follicular lymphoma (FL) cases with a t(14;18)(q32;q21) and minimal or no additional karyotypic alterations, such as copy number gains and losses and/or chromosomal rearrangements, may exhibit pathologic features and a clinical behavior similar to those with more complex karyotypes. This study sought to investigate whether the copy-neutral loss of heterozygosity (cnLOH) profiles of these minimally evolved t(14;18)(q32;q21)-positive follicular lymphoma (MEV-FL) cases are similar to or different from the majority of FL cases with more karyotypic alterations. Affymetrix SNP 6.0 array analysis was applied to the tumor genomes of 23 MEV-FL biopsy samples to assess for the presence of cnLOH. These cases carried either a single or no chromosomal abnormality in addition to t(14;18)(q32;q21) as determined by karyotyping. We found that, although these MEV FL cases had simple karyotypes, they showed very similar cnLOH profiles as compared to cytogenetically complex cases. The most frequent regions affected by cnLOH were 1p (17%), 6p (17%), 12q (13%) and 16p (13%). Our study suggests that cnLOH alterations may serve as important contributors to the pathological and clinical manifestations of FL. PMID- 22104079 TI - Diffuse malignant peritoneal mesothelioma--an update on treatment. AB - Mesotheliomas are aggressive and lethal neoplasms arising from mesothelial cells lining the pleura, peritoneum, tunica vaginalis testis and pericardium. Malignant peritoneal mesothelioma accounts for about 30% of all mesotheliomas. Asbestos is the main known cause of the disease. Presenting symptoms in these patients include: ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting. Electron microscopy, immunohistochemistry, computed tomography scan, echotomography, magnetic resonance imaging, positron emission tomography and laparoscopy are used in diagnosis and follow-up. Chemotherapy alone is considered as a palliative treatment for these patients who are not eligible for radical surgery. The most promising non-surgical approach today in the management of peritoneal mesothelioma is the use of the combination chemotherapy regime of an antifolate (pemetrexed and raltitrexed) and a platinum based (cisplatin) agent with a median survival of about 12-14 months. Due to peritoneal confinement of malignant mesothelioma and low occurrence of metastasis, a locoregional approach consisting of cytoreductive surgery and perioperative intraperitoneal chemotherapy has been introduced as a curative treatment option over the last decade with an overall 5-year survival rate of 29 63%. In this locoregional approach, surgery can separate the adhesions and remove the bulky tumor, leaving microscopic residual tumors much more susceptible to the killing effect of chemotherapeutic drugs. Here in St. George hospital, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (using cisplatin and doxorubicin) resulted in significant survival advantage. This article describes how the prognosis of the disease has changed over the last decade. PMID- 22104080 TI - Microtubule stabilization triggers the plus-end accumulation of Kif18A/kinesin-8. AB - The precise control of spindle microtubule (MT) dynamics is essential for chromosome capture and alignment. Kif18A/kinesin-8, an essential regulator of kinetochore MT dynamics, accumulates at its plus-ends in metaphase but not prometaphase cells. The underlying mechanism of time-dependent and kinetochore MT specific plus-end accumulation of Kif18A is unknown. Here, we examined the factors required for the MT plus-end accumulation of Kif18A. In Eg5 inhibitor treated cells, Kif18A localized along the MTs in the monopolar spindle and rarely accumulated at their plus-ends, indicating that MT-kinetochore association was not sufficient to induce Kif18A accumulation. In contrast, taxol treatment triggered the rapid MT plus-end accumulation of Kif18A regardless of kinetochore association. Furthermore, Aurora B inhibitor-induced stabilization of the plus ends of kinetochore MTs promoted the plus-end accumulation of Kif18A. In the absence of Kif18A, treatment with taxol but not Eg5 inhibitor causes highly elongated mitotic MTs, suggesting the importance of plus-end accumulation for the MT length-controlling activity of Kif18A. Taken together, we propose that there is a mutual regulation of kinetochore MT plus-end dynamics and Kif18A accumulation, which may contribute to the highly regulated and ordered changes in kinetochore MT dynamics during chromosome congression and oscillation. PMID- 22104081 TI - Managing pregnancy with HIV, HELLP syndrome and low platelets. AB - Management of pregnancies with human immunodeficiency virus, haemolytic anaemia, elevated liver enzymes, low platelets (HELLP) syndrome, and low platelets presents complexities in investigations and treatments, because these conditions and their treatment affect the mother and baby. Low platelets in severe pre eclampsia, eclampsia and HELLP syndrome are relatively common, and should be detected early once the diagnosis of pre-eclampsia, HELLP syndrome, or both, are made. The mainstay of treatment is lowering of high blood pressure with rapid acting antihypertensive agents, prevention of convulsions or further seizures with MgSO(4), use of steroids for fetal lung maturity if necessary, followed by delivery of the baby. The use of high-dose steroids for the rapid recovery of maternal platelet counts is controversial, and should not be used routinely in women with HELLP syndrome. The use of platelet transfusion in women with severe pre-eclampsia, eclampsia and HELLP syndrome is a temporising measure, and should only be justified if the clinical circumstances warrant their use (e.g. before caesarean section when the woman has a low platelet count with evidence of bruising or bleeding from venepuncture sites). Low platelets may be an isolated finding in asymptomatic pregnant women and warrant the offer of a human immunodeficiency virus test, as it may be the first sign of this infection. Isolated low platelets may also indicate gestational thrombocytopaenia or idiothrombocytopaenic purpura. Gestational thrombocytopaenia is a benign condition and a diagnosis of exclusion. All clinicians should be aware that low platelets warrant further investigations because of the above-mentioned issues. PMID- 22104082 TI - Assembly of CeO2-TiO2 nanoparticles prepared in room temperature ionic liquid on graphene nanosheets for photocatalytic degradation of pollutants. AB - CeO(2)-TiO(2) nanoparticles were prepared by the sol-gel process using 2 hydroxylethylammonium formate as room-temperature ionic liquid and calcined at different temperatures (500-700 degrees C). CeO(2)-TiO(2)-graphene nanocomposites were prepared by hydrothermal reaction of graphene oxide with CeO(2)-TiO(2) nanoparticles in aqueous solution of ethanol. The photocatalysts were characterized by X-ray diffraction, BET surface area, diffuse reflectance spectroscopy, scanning electron microscopy, and Fourier transformed infrared techniques. The results demonstrate that the room-temperature ionic liquid inhibits the anatase-rutile phase transformation. This effect was promoted by addition of CeO(2) to TiO(2). The addition of graphene to CeO(2)-TiO(2) nanoparticles enhances electron transport and therefore impedes the charge recombination of excited TiO(2). The photodegradation results of the pollutants in aqueous medium under UV irradiation revealed that CeO(2)-TiO(2)-graphene nanocomposites exhibit much higher photocatalytic activity than CeO(2)-TiO(2) and pure TiO(2). The photocatalytic activity of CeO(2)-TiO(2)-graphene nanocomposites decreases with additional increasing of the graphene content. Moreover, comparison of the photocatalytic activities of CeO(2)-TiO(2)-graphene with the other CeO(2)-TiO(2)-carbon demonstrates that CeO(2)-TiO(2)-graphene nanocomposites have the highest photocatalytic activity due to their unique structure and electronic properties. Chemical oxygen demand for solutions of the pollutants gave a good idea about mineralization of them. PMID- 22104083 TI - Photoelectrocatalytic degradation of chlortetracycline using Ti/TiO2 nanostructured electrodes deposited by means of a Pulsed Laser Deposition process. AB - Ti/TiO(2) electrode was prepared by means of the Pulsed Laser Deposition method and used in a photoelectrocatalytic oxidation (PECO) process in order to degrade chlortetracycline (CTC). The deposited TiO(2) coatings were found to be of rutile structure. High treatment efficiency of CTC was achieved by the PECO process compared to the conventional electrochemical oxidation, direct photolysis and photocatalysis processes. Several factors such as current intensity, treatment time, UV lamp position and initial concentration of CTC were investigated. Using a 2(4) factorial matrix, the best performance for CTC degradation (74.3% of removal) was obtained at a current intensity of 0.5A during 120 min of treatment time and when the UV lamp was immersed in the solution in the presence of 25 mg L(-1) of CTC. The current intensity and treatment time were the main parameters influencing the degradation rate of CTC. Subsequently, a central composite design methodology has been investigated to determine the optimal experimental parameters for CTC degradation. The PECO process applied under optimal conditions (at current intensity of 0.39 A during 120 min with internal position of the UV lamp) is able to oxidize around 74.2 +/- 0.57%, of CTC. PMID- 22104084 TI - Import and spread of Panton-Valentine Leukocidin-positive Staphylococcus aureus through nasal carriage and skin infections in travelers returning from the tropics and subtropics. AB - BACKGROUND: Antibiotic-resistant Staphylococcus aureus is a globally emerging pathogen. Exchangeable virulence factors, such as Panton-Valentine leukocidin (PVL), have been proposed to drive this epidemic. We investigated whether skin infections and nasal colonization in travelers contribute to the global spread of such strains. METHODS: We conducted a case-control study of 38 returnees from the tropics and subtropics with S. aureus-positive skin and soft tissue infections (SSTIs) and 124 control patients with other travel-associated disorders. We collected information on travel characteristics, clinical outcomes of SSTIs, antibiotic sensitivity patterns, and genotypes of S. aureus strains isolated from skin lesions and the nares. RESULTS: S. aureus-positive SSTIs were associated with travel duration and purpose and were most common in returnees from Africa (odds ratio, 4.2; P = .005). PVL-positive (PVL(+)) S. aureus was frequent in the lesional and nasal isolates from travelers with SSTIs but could not be found in the nares of the control patients. The presence of PVL in S. aureus in travelers was associated with complicated disease, reduced antibiotic susceptibility, and secondary spread. The genotypes of PVL(+) S. aureus in returnees were reported to be endemic to the visited destination but rarely observed in Europe. CONCLUSIONS: Geographic variation in the risk of SSTIs in travelers supports a globally heterogeneous distribution of virulent S. aureus. Complicated SSTIs in returnees from nontemperate climates are associated with PVL(+) S. aureus and promote the emergence and spread of virulent and antibiotic resistant strains. We propose a network for the surveillance of imported S. aureus (www.staphtrav.eu). PMID- 22104085 TI - Reactivity and reactions to regulatory transparency in medicine, psychotherapy and counselling. AB - We explore how doctors, psychotherapists and counsellors in the U.K. react to regulatory transparency, drawing on qualitative research involving 51 semi structured interviews conducted during 2008-10. We use the concept of 'reactivity mechanisms' (Espeland & Sauder, 2007) to explain how regulatory transparency disrupts practices through simplifying and decontextualizing them, altering practitioners' reflexivity, leading to defensive forms of practice. We make an empirical contribution by exploring the impact of transparency on doctors compared with psychotherapists and counsellors, who represent an extreme case due to their uniquely complex practice, which is particularly affected by this form of regulation. We make a contribution to knowledge by developing a model of reactivity mechanisms, which explains how clinical professionals make sense of media and professional narratives about regulation in ways that produce emotional reactions and, in turn, defensive reactivity to transparency. PMID- 22104086 TI - Eicosanoid levels in the neocortex of drug-resistant epileptic patients submitted to epilepsy surgery. AB - There is an increasing body of evidence implicating eicosanoids (arachidonic acid metabolites) in the experimental generation of epileptic seizures and the development of epilepsy. Our purpose was to measure the synthesis of eicosanoids from the cyclooxygenase and lipoxygenase pathways in human brain neocortex tissue samples obtained from epileptic patients, and to compare them with non-epileptic control subjects. Epileptic neocortex specimens demonstrated a significant increase (P<0.001) in the levels of three eicosanoids derived from the cyclooxygenase pathway: Prostaglandin E(2) (PGE(2)), Thromboxane A(2) (TXA(2)), and Prostacyclin (PGI(2)), compared to controls. In the epileptic samples the level of TXA(2) was twice as much the levels of PGI(2), while in the control samples the levels of PGI(2) were slightly higher than TXA(2). Conversely, there were no detectable levels of eicosanoids derived from the lipoxygenase pathway: Leukotriene B(4) (LTB(4)) and Leukotriene C(4) (LTC(4)). The lack of leukotrienes synthesis illustrates that COX pathway is dominant in neocortex of epileptic patients. Our human data are consistent with the results obtained in experimental animal models of epilepsy. The important increase in PGE(2) and TXA(2) suggests that selective inhibition of prostanoid synthesis or blockage of prostanoid receptors might provide novel antiepileptic strategies in human epilepsy. PMID- 22104087 TI - Cerebral ketone metabolism during development and injury. AB - Cerebral metabolism of ketones is a normal part of the process of brain development. While the mature brain relies on glucose as a primary fuel source, metabolism of ketone bodies remains an alternative energy source under conditions of starvation. The neuroprotective properties of brain ketone metabolism make this alternative substrate a viable therapeutic option for various pathologies. Since the ability to revert to utilizing ketones as an alternative substrate is greatest in the younger post-weaned brain, this particular therapeutic approach remains an untapped resource particularly for pediatric pathological conditions. PMID- 22104088 TI - A new method to combine contrast-enhanced magnetic resonance imaging during live ultrasound of the breast using volume navigation technique: a study for evaluating feasibility, accuracy and reproducibility in healthy volunteers. AB - OBJECTIVES: To evaluate feasibility, accuracy and reproducibility of combined US MR of the breast using volume navigation technique. SUBJECTS AND METHODS: Five healthy females underwent bilateral contrast-enhanced MR (CE-MR) of the breast in supine position, after positioning three couples of markers on the breast. After CE-MR data uploading in the ultrasound (US) database, manual co-registration was obtained during live US of the breast by means of an electromagnetic transmitter positioned near the subject under examination and two electromagnetic sensors were mounted on the transducer bracket. Transmitter and sensors were connected to a position-sensing unit embedded in the US equipment allowing to track probe position and orientation within the electromagnetic field. Live US image were co registered to the previously loaded breast CE-MR volume by coupling markers. For each subject, two independent radiologists recorded the examination time and verified twice image alignment using five fixed checkpoints. Pair t Student test and Wilcoxon test were used for statistical analysis. RESULTS: In all subjects US and CE-MR images were successfully combined. The examination time was 10+/-2 vs. 9+/-4 min, respectively (p=0.642; NS). A total of one hundred measurements of images misalignment were performed: the measurements recorded between the two operators were 0.42+/-0.32 cm and 0.58+/-0.41 cm (p=0.161; NS), and 0.50+/-0.32 cm and 0.56+/-0.52 cm (p=0.928; NS), respectively. DISCUSSION: In our preliminary experience, volume navigation technique appears to be a accurate and reproducible method to combine CE-MR image during unilateral US of the breast. PMID- 22104089 TI - A longitudinal study of brain volume changes in normal aging. AB - PURPOSE: To evaluate the effect of normal aging on brain volumes and examine the effects of age and sex on the rates of changes in global and regional brain volumes. METHODS: A total of 199 normal subjects (65 females and 134 males, mean age=56.4 +/- 9.9 years, age range=38.1-82.9 years) were included in this study. Each subject was scanned twice, at an interval of about 2 years (range=1.5-2.3 years). Two-time-point percentage brain volume change (PBVC) was estimated with SIENA 2.6. RESULTS: The mean annualized PBVC was -0.23%/y. Analysis of covariance (ANCOVA) for annual brain volume changes revealed a main effect of age. There was no main effect of sex, nor was there a sex-by-age interaction. Voxel-wise analysis revealed a negative correlation between age and edge displacement values mainly in the periventricular region. CONCLUSIONS: The results of our study indicate that brain atrophy accelerates with increasing age and that there is no gender difference in the rate of brain atrophy. PMID- 22104090 TI - Investigation of renal lesions by diffusion-weighted magnetic resonance imaging applying intravoxel incoherent motion-derived parameters--initial experience. AB - PURPOSE: Usefulness of biexponentially fitted signal attenuation at different b values for differentiating the histological characteristics of renal tumors. MATERIALS AND METHODS: A total of 26 patients with 28 renal masses (histologically proven: 20 clear cell renal cell carcinomas [ccRCC], three transitional cell carcinomas, two oncocytomas, and one papillary RCC) and 30 volunteers with healthy kidneys were examined at 1.5 Tesla using an echo-planar DWI sequence. Using the IVIM model, we calculated the perfusion fraction f and the diffusion coefficient D. Furthermore, the ADC was obtained. These tumor parameters were compared to healthy renal tissue nonparametrically, and a receiver operating characteristic (ROC) analysis was performed. RESULTS: Healthy renal parenchyma showed higher ADC and D values (p<0.001) than ccRCC (ADC 1.95+/ 0.10 [SD] MUm2/ms, f 18.32+/-2.52%, and D 1.88+/-0.11 MUm2/ms versus ADC 1.45+/ 0.38 MUm2/ms, f 18.59+/-6.16%, and D 1.34+/-0.38 MUm2/ms). When detecting malignancies the area under the curve for D was higher than for ADC. The f values for ccRCC were higher (p<0.001) than for non-ccRCC (ADC 1.52+/-0.47 MUm2/ms, f 8.44+/-1.24%, and D 1.30+/-0.18 MUm2/ms). Both f and D correlated with ccRCC grading. CONCLUSION: IVIM imaging is able to provide reliable diffusion values in the human kidney and may enhance the accuracy of tumor diagnosis. The D value was the best parameter to distinguish renal tumors from healthy renal tissue. The f value is promising for determining the histological subgroups. PMID- 22104091 TI - High cholesterol feeding may induce tubular dysfunction resulting in hypomagnesemia. AB - BACKGROUND/AIMS: Hypomagnesemia may induce hypercholesterolemia, but the contrary has not been described yet. Thus, magnesium homeostasis was evaluated in rats fed a cholesterol-enriched diet for 8 days. This study has a relevant clinical application if hypomagnesemia, due to hypercholesterolemia, is confirmed in patients with long-term hypercholesterolemia. METHODS: Both hypercholesterolemic (HC) and normocholesterolemic rats (NC) were divided into sets of experiments to measure hemodynamic parameters, physiological data, maximum capacity to dilute urine (C(H)((2))(O)), variations (Delta) in [Ca(2+)](i) and the expression of transporter proteins. RESULTS: HC developed hypomagnesemia and showed high magnesuria in the absence of hemodynamic abnormalities. However, the urinary sodium excretion and C(H)((2))(O) in HC was similar to NC. On the other hand, the responses to angiotensin II by measuring Delta [Ca(2+)](i) were higher in the thick ascending limb of Henle's loop (TAL) of HC than NC. Moreover, high expression of the cotransporter NKCC2 was found in renal outer medulla fractions of HC. Taken together, the hypothesis of impairment in TAL was excluded. Actually, the expression of the epithelial Mg(2+) channel in renal cortical membrane fractions was reduced in HC. CONCLUSION: Impairment in distal convoluted tubule induced by hypercholesterolemia explains high magnesuria and hypomagnesemia observed in HC. PMID- 22104092 TI - Endogenous opioid peptide-mediated neurotransmission in central and pericentral nuclei of the inferior colliculus recruits MU1-opioid receptor to modulate post ictal antinociception. AB - BACKGROUND: The aim of the present work was to investigate the involvement of the MU1-endogenous opioid peptide receptor-mediated system in post-ictal antinociception. METHODS: Antinociceptive responses were determined by the tail flick test after pre-treatment with the selective MU1-opioid receptor antagonist naloxonazine, peripherally or centrally administered at different doses. RESULTS: Peripheral subchronic (24 h) pre-treatment with naloxonazine antagonised the antinociception elicited by tonic-clonic seizures. Acute (10 min) pre-treatment, however, did not have the same effect. In addition, microinjections of naloxonazine into the central, dorsal cortical and external cortical nuclei of the inferior colliculus antagonised tonic-clonic seizure-induced antinociception. Neither acute (10-min) peripheral pre-treatment with naloxonazine nor subchronic intramesencephalic blockade of MU1-opioid receptors resulted in consistent statistically significant differences in the severity of tonic-clonic seizures shown by Racine's index (1972), although the intracollicular specific antagonism of MU1-opioid receptor decreased the duration of seizures. CONCLUSION: MU1-Opioid receptors and the inferior colliculus have been implicated in several endogenous opioid peptide-mediated responses such as antinociception and convulsion. The present findings suggest the involvement of MU1-opiate receptors of central and pericentral nuclei of the inferior colliculus in the modulation of tonic-clonic seizures and in the organisation of post-ictal antinociception. PMID- 22104093 TI - Alkaline peroxide pretreatment of rapeseed straw for enhancing bioethanol production by Same Vessel Saccharification and Co-Fermentation. AB - Alkaline peroxide pretreatment of rapeseed straw was evaluated for conversion of cellulose and hemicellulose to fermentable sugars. After pretreatment, a liquid phase called pretreatment liquid and a solid phase were separated by filtration. The neutralized pretreatment liquids were used in a co-fermentation process, with Saccharomyces cerevisiae and Pichia stipitis. The solid fraction was used for simultaneous saccharification and co-fermentation process in the same vessel. The effects of various operating variables were investigated. Pretreatment with 5% (v/v) H(2)O(2) at 50 degrees C for 1h was found to be the optimal pretreatment combination with respect to overall ethanol production. At this condition, 5.73 g ethanol was obtained from pretreatment liquid and 14.07 g ethanol was produced by co-fermentation of solid fraction with P. stipitis. Optimum delignification was observed when 0.5 M MgSO(4) was included in the pretreatment mixture, and it resulted in 0.92% increase in ethanol production efficiency. PMID- 22104094 TI - Process model and economic analysis of ethanol production from sugar beet raw juice as part of the cleaner production concept. AB - The batch fermentation process of sugar beet processing intermediates by free yeast cells is the most widely used method in the Autonomous Province of Vojvodina for producing ethanol as fuel. In this study a process and cost model was developed for producing ethanol from raw juice. The model can be used to calculate capital investment costs, unit production costs and operating costs for a plant producing 44 million l of 99.6% pure ethanol annually. In the sensitivity analysis the influence of sugar beet and yeast price, as well as the influence of recycled biomass on process economics, ethanol production costs and project feasibility was examined. The results of this study clearly demonstrate that the raw material costs have a significant influence on the expenses for producing ethanol. Also, the optimal percentage of recycled biomass turned out to be in the range from 50% to 70%. PMID- 22104095 TI - Pilot-scale comparison of two hybrid-passive landfill leachate treatment systems operated in a cold climate. AB - Hybrid-passive landfill leachate treatment systems employ active pretreatment to remove dissolved inorganic constituents and decrease the oxygen demand of the leachate prior to treatment in a passive system. In a 1-year pilot-scale study, two passive treatment systems - a peat and wood shaving biological trickle filter and a sand and gravel constructed wetland - were installed to treat leachate from the Merrick Landfill in North Bay, Ontario, Canada. Leachate was pretreated in a fixed-film aerobic reactor, which provided reductions in COD (26%), and masses of ammonia (21%), Al (69%), Ca (57%), Fe (73%) and Sr (37%). A comparison of the performance of the hybrid-passive treatment systems indicated different extents of heterotrophic nitrification; the peat and wood shaving filter removed 49% of the ammonia and nitrified 29%, while the constructed wetland removed 99% of the ammonia and nitrified 90%. Hybrid-passive landfill leachate treatment was determined to be feasible in cold climates. PMID- 22104096 TI - Impact of reactor configuration on anammox process start-up: MBR versus SBR. AB - Anaerobic ammonium oxidation (anammox) is an energy saving biological nitrogen removal process which was limited to slow growth rate of anammox bacteria during start-up period. This study investigated the start-up of anammox process by a laboratory sequential batch reactor (SBR) for 218 days and subsequently modified the reactor as a membrane bioreactor (MBR) for 178 days. Modification of a SBR as MBR with installation of an external membrane module resulted in acceleration of specific anammox activity by 19 times. The acceleration of specific anammox activity with MBR was further confirmed by starting-up another MBR for a 242 day period. Molecular microbial analyses showed that Candidatus "Brocadia anammoxidans" and Candidatus "Kuenenia stuttgartiensis" were the dominant species in the inocula and biomass developed in the reactor. The start-up with MBR appeared to be more effective than SBR for the enrichment of anammox bacteria due to high sludge retention property of MBR configuration. PMID- 22104097 TI - High-solid anaerobic digestion of sewage sludge under mesophilic conditions: feasibility study. AB - Feasibility of high-solid anaerobic digestion of sewage sludge was investigated in single-stage completely stirred tank reactors at 35+/-1 degrees C. System stability and the effect of organic loading rate (OLR), sludge retention time (SRT) and total solid (TS) content on the performance of high-solid system was examined. Experimental results showed that, with the concentration of free ammonia nitrogen (FAN) lower than 600 mg l(-1), high-solid anaerobic digestion of sewage sludge could maintain satisfactory stability. Slight, moderate and significant inhibition was found with FAN concentration ranging from 250 to 400, 400 to 600 and 600 to 800 mg l(-1), respectively. The VFA/TA criteria could not foresee system instability in significant ammonia inhibition system by its traditional ratio grades. High-solid system could support higher OLR (4-6 times as high) and obtain similar methane yield and VS reduction as conventional low solid system at the same SRT, thus reach much higher volumetric methane production rate. PMID- 22104098 TI - Enhanced coproduction of hydrogen and methane from cornstalks by a three-stage anaerobic fermentation process integrated with alkaline hydrolysis. AB - A three-stage anaerobic fermentation process including H(2) fermentation I, H(2) fermentation II, methane fermentation was developed for the coproduction of hydrogen and methane from cornstalks. Hydrogen production from cornstalks using direct microbial conversion by Clostridium thermocellum 7072 was markedly enhanced in the two-stage thermophilic hydrogen fermentation process integrated with alkaline treatment. The highest total hydrogen yield from cornstalks in the two-stage fermentation process reached 74.4 mL/g-cornstalk. The hydrogen fermentation effluents and alkaline hydrolyzate were further used for methane fermentation by anaerobic granular sludge, and the total methane yield reached 205.8 mL/g-cornstalk. The total energy recovery in the three-stage anaerobic fermentation process integrated with alkaline hydrolysis reached 70.0%. PMID- 22104099 TI - Enhanced anoxic bioremediation of PAHs-contaminated sediment. AB - In this study, the biodegradation of 16 polycyclic aromatic hydrocarbons (PAHs) in marine sediment was investigated under three different anoxic conditions, i.e. sulfate-only, nitrate-only and mixed nitrate/sulfate as electron acceptors. All two-, three- and four-ring PAHs showed significant biodegradation with the removal efficiencies ranging from 42% to 77%, while five- and six-ring PAHs showed little degradation. The results illustrated that two- to three-ring PAHs could be degraded at a rate of 4.01*10(-2)-6.42*10(-2) d(-1) under nitrate reducing condition, faster than that of under sulfate-reducing condition. Biodegradation of two- and three-ring PAHs followed first-order model well with the rate constants of 1.62*10(-2)-6.42*10(-2) d(-1). The biodegradation of four ring PAHs followed the zero-order kinetic model with the rate constants of 1.26*10(-2)-2.22*10(-2) mg/kg/d. Molecular analysis indicated that nahAc gene increased by two orders of magnitude during the biodegradation and served as a good indicator of PAHs-degrading bacterial population and biodegradation process. PMID- 22104100 TI - Application of ultrafiltration and nanofiltration for recycling cellulase and concentrating glucose from enzymatic hydrolyzate of steam exploded wheat straw. AB - Application of combined ultrafiltration (UF) and nanofiltration (NF) was examined to recycle cellulase and concentrate glucose present in lignocellulosic hydrolyzate. With PES10 membrane operated at 25.6 l/m(2) h, 73.9% of cellulase protein present in the hydrolyzate suspension could be recovered while allowing free transmission of glucose. The permeate obtained from UF was then concentrated by NF. With NF270 membrane operated at 13.3 l/m(2) h, the glucose concentration in the ultrafiltered hydrolyzate increased from 30.2 to 110.2 g/l. Recycling cellulase by UF could reduce the hydrolysis cost of lignocellulosic feedstock, while concentrating glucose by NF could improve the fermentation efficiency of lignocellulosic hydrolyzate and lower the separation and purification cost of fermentative product. Therefore, the use of UF and NF for treating lignocellulosic hydrolyzate could be a promising approach in fermentative production of bioproducts and biofuels using lignocellulosic feedstock as substrate. PMID- 22104101 TI - Algae biodiesel has potential despite inconclusive results to date. AB - A meta-analysis of several published life cycle assessments of algae-to-energy systems was developed to better understand the environmental implications of deploying this technology at large scales. Taken together, results from these six studies seemed largely inconclusive because of differences in modeling assumptions and system boundaries. To overcome this, the models were normalized using a generic pathway for cultivating algae in open ponds, converting it into biodiesel, and processing the nonlipid fraction using anaerobic digestion. Meta analysis results suggest that algae-based biodiesel would result in energy consumption and greenhouse gas emissions on par with terrestrial alternatives such as corn ethanol and soy biodiesel. Net energy ratio and normalized greenhouse gas emissions were 1.4 MJ produced/MJ consumed and 0.19 kg CO(2) equivalent/km traveled, respectively. A scenario analysis underscores the extent to which breakthroughs in key technologies are needed before algae-derived fuels become an attractive alternative to conventional biofuels. PMID- 22104102 TI - Effect of steam explosion and microbial fermentation on cellulose and lignin degradation of corn stover. AB - In order to increase nutrient values of corn stover, effects of steam explosion (2.5 MPa, 200 s) and Aspergillus oryzae (A. oryzae) fermentation on cellulose and lignin degradation were studied. The results showed the contents of cellulose, hemicellulose and lignin in the exploded corn stover were 8.47%, 50.45% and 36.65% lower than that in the untreated one, respectively (P<0.05). The contents of cellulose and hemicellulose in the exploded and fermented corn stover (EFCS) were decreased by 24.36% and 69.90%, compared with the untreated one (P<0.05); decreased by 17.35% and 38.59%, compared with the exploded one (P<0.05). The scanning electron microscope observations demonstrated that the combined steam explosion and fermentation destructed corn stover. The activities of enzymes in EFCS were increased. The metabolic experiment showed that about 8% EFCS could be used to replace corn meal in broiler diets, which made EFCS become animal feedstuff possible. PMID- 22104103 TI - Establishment of a real-time, quantitative, and reproducible mouse model of Staphylococcus osteomyelitis using bioluminescence imaging. AB - Osteomyelitis remains a serious problem in the orthopedic field. There are only a few animal models in which the quantity and distribution of bacteria can be reproducibly traced. Here, we established a real-time quantitative mouse model of osteomyelitis using bioluminescence imaging (BLI) without sacrificing the animals. A bioluminescent strain of Staphylococcus aureus was inoculated into the femurs of mice. The bacterial photon intensity (PI) was then sequentially measured by BLI. Serological and histological analyses of the mice were performed. The mean PI peaked at 3 days, and stable signals were maintained for over 3 months after inoculation. The serum levels of interleukin-6, interleukin 1beta, and C-reactive protein were significantly higher in the infected mice than in the control mice on day 7. The serum monocyte chemotactic protein 1 level was also significantly higher in the infected group at 12 h than in the control group. A significantly higher proportion of granulocytes was detected in the peripheral blood of the infected group after day 7. Additionally, both acute and chronic histological manifestations were observed in the infected group. This model is useful for elucidating the pathophysiology of both acute and chronic osteomyelitis and to assess the effects of novel antibiotics or antibacterial implants. PMID- 22104104 TI - Poly-N-acetyl-beta-(1-6)-glucosamine is a target for protective immunity against Acinetobacter baumannii infections. AB - Acinetobacter baumannii has emerged as a highly troublesome, global pathogen. Treatment is complicated by high levels of antibiotic resistance, necessitating alternative means to prevent or treat A. baumannii infections. We evaluated an immunotherapeutic approach against A. baumannii, focusing on the surface polysaccharide poly-N-acetyl-beta-(1-6)-glucosamine (PNAG). We used a synthetic oligosaccharide of 9 monosaccharide units (9Glc-NH(2)) conjugated to tetanus toxoid (TT) to induce antibodies in rabbits. In the presence of complement and polymorphonuclear cells, antisera to 9Glc-NH(2)-TT mediated the killing of A. baumannii S1, a high-PNAG-producing strain, but not its isogenic PNAG-negative, in-frame deletion mutant strain, S1 Deltapga. Complementing the pgaABCD locus in trans in the shuttle vector pBAD18kan-ori, plasmid Deltapga-c, restored the high levels of killing mediated by antibody to PNAG observed with the wild-type S1 strain. No killing was observed when normal rabbit serum (NRS) or heat inactivated complement was used. Antiserum to 9Glc-NH(2)-TT was highly opsonic against an additional four unrelated multidrug-resistant clinical isolates of A. baumannii that synthesize various levels of surface PNAG. Using two clinically relevant models of A. baumannii infection in mice, pneumonia and bacteremia, antisera to 9Glc-NH(2)-TT significantly reduced levels of A. baumannii in the lungs or blood 2 and 24 h postinfection, respectively, compared to levels of control groups receiving NRS. This was true for all four A. baumannii strains tested. Overall, these results highlight the potential of PNAG as a vaccine component for active immunization or as a target for passive antibody immunotherapy. PMID- 22104105 TI - Synergistic interaction between Candida albicans and commensal oral streptococci in a novel in vitro mucosal model. AB - Candida albicans is a commensal colonizer of the gastrointestinal tract of humans, where it coexists with highly diverse bacterial communities. It is not clear whether this interaction limits or promotes the potential of C. albicans to become an opportunistic pathogen. Here we investigate the interaction between C. albicans and three species of streptococci from the viridans group, which are ubiquitous and abundant oral commensal bacteria. The ability of C. albicans to form biofilms with Streptococcus oralis, Streptococcus sanguinis, or Streptococcus gordonii was investigated using flow cell devices that allow abiotic biofilm formation under salivary flow. In addition, we designed a novel flow cell system that allows mucosal biofilm formation under conditions that mimic the environment in the oral and esophageal mucosae. It was observed that C. albicans and streptococci formed a synergistic partnership where C. albicans promoted the ability of streptococci to form biofilms on abiotic surfaces or on the surface of an oral mucosa analogue. The increased ability of streptococci to form biofilms in the presence of C. albicans could not be explained by a growth stimulatory effect since the streptococci were unaffected in their growth in planktonic coculture with C. albicans. Conversely, the presence of streptococci increased the ability of C. albicans to invade organotypic models of the oral and esophageal mucosae under conditions of salivary flow. Moreover, characterization of mucosal invasion by the biofilm microorganisms suggested that the esophageal mucosa is more permissive to invasion than the oral mucosa. In summary, C. albicans and commensal oral streptococci display a synergistic interaction with implications for the pathogenic potential of C. albicans in the upper gastrointestinal tract. PMID- 22104106 TI - Monoclonal antibodies neutralize Bacillus cereus Nhe enterotoxin by inhibiting ordered binding of its three exoprotein components. AB - The Nhe enterotoxin from Bacillus cereus is known to induce cytotoxicity on Vero and CaCo-2 cells by ordered binding of its single components NheA, NheB, and NheC. This study aimed to elucidate functional sites on NheB by identifying the epitopes of the neutralizing monoclonal antibodies 1E11 and 2B11. The binding regions of both antibodies were determined by using recombinant NheB fragments and synthetic peptides. The antigenic site of antibody 1E11 was located within the amino acids 321 to 341 of NheB, whereas reactivity of antibody 2B11 was dependent on the presence of amino acids 122 to 150 and on conformation. Both antibodies were able to bind simultaneously to NheB and did not interfere with target cell binding as shown by immunofluorescence microscopy. A set of neutralization assays revealed that antibody 2B11 most likely interfered with the interaction between NheB and NheC both on the epithelium cell surface and in solution. In contrast, antibody 1E11 inhibited association between NheA and cell bound NheB in a competitive manner, and effectively neutralized Nhe cytotoxicity on a variety of human cell lines. This distinct mechanism further supports that NheA is the key component during the Nhe mode of action and the C-terminal epitope recognized by antibody 1E11 points to an important functional region of NheB. PMID- 22104107 TI - Enhanced bacteremia in human factor H transgenic rats infected by Neisseria meningitidis. AB - Neisseria meningitidis binds the complement downregulating protein, factor H (fH), which enables the organism to evade host defenses. Two fH ligands, fHbp and NspA, are known to bind specifically to human fH. We developed a human fH transgenic infant rat model to investigate the effect of human fH on meningococcal bacteremia. At 18 h after intraperitoneal challenge with 560 CFU of group B strain H44/76, all 19 human fH-positive rats had positive blood cultures compared to 0 of 7 human fH-negative control littermates (P < 0.0001). Human fH positive infant rats also developed bacteremia after challenge with isogenic mutants of H44/76 in which genes encoding fHbp and NspA (DeltafHbp DeltaNspA mutant) or the lipooligosaccharide sialyltransferase (Deltalst mutant) had been inactivated. A fully encapsulated DeltafHbp DeltaNspA Deltalst mutant unable to sialylate lipooligosaccharide or bind human fH via the known fH ligands did not cause bacteremia, which argued against global susceptibility to bacteremia resulting from random integration of the transgene into the rat genome. In vitro, the wild-type and DeltafHbp DeltaNspA mutant strains were killed by as little as 20% wild-type infant rat serum. The addition of 3 MUg of human fH/ml permitted survival of the wild-type strain in up to 60% infant rat serum, whereas >=33 MUg of human fH/ml was required to rescue the DeltafHbp DeltaNspA mutant. The ability of meningococci lacking expression of fHbp and NspA to cause invasive disease in human fH transgenic rats and to survive in wild-type infant rat serum supplemented with human fH indicates an additional human fH-dependent mechanism of evasion of innate immunity. PMID- 22104108 TI - Anthrax edema toxin impairs clearance in mice. AB - The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo. We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo, ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection. PMID- 22104109 TI - Kinetics of humoral and memory B cell response induced by the Plasmodium falciparum 19-kilodalton merozoite surface protein 1 in mice. AB - The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP 1(19)) has been shown to regulate antibody (Ab)-mediated protective immunity to blood-stage malaria infection. But the serological memory to this antigen tends to be short-lived, and little is known of the mechanisms that regulate the formation of B cell memory to MSP-1(19) antigen. We studied the formation of B cell memory response after immunization with the recombinant 19-kDa Plasmodium falciparum merozoite surface protein 1 (PfMSP-1(19)). Immunization with PfMSP 1(19) resulted in delayed increase in germinal center (GC) B cell numbers. This poor GC reaction correlated with short-lived PfMSP-1(19)-specific antibodies in serum and the short life of PfMSP-1(19)-specific plasma cells and memory B cells (MBCs) in spleen and bone marrow. PfMSP-1(19)-specific MBCs were capable of producing antigen (Ag)-specific Ab-secreting cell (ASC) responses that were short lived following challenge immunization of the immune mice with antigen or transgenic Plasmodium berghei parasite expressing PfMSP-1(19) in place of native P. berghei MSP-1(19) at 8 weeks after the last immunization or following adoptive transfer into naive hosts. However, no protection was achieved in PfMSP-1(19) immune mice or recipient mice with PfMSP-1(19)-specific MBCs following challenge with transgenic P. berghei. Our findings suggest that PfMSP-1(19)-specific IgG production by short-lived plasma cells combined with the poor ability of the PfMSP-1(19)-induced MBCs to maintain the anamnestic IgG responses failed to contribute to protection against infection. PMID- 22104110 TI - An inside job: hacking into Janus kinase/signal transducer and activator of transcription signaling cascades by the intracellular protozoan Toxoplasma gondii. AB - The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype. PMID- 22104111 TI - Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps. AB - Neutrophils have recently been shown to release DNA-based extracellular traps that contribute to microbicidal killing and have also been implicated in autoimmunity. The role of neutrophil extracellular trap (NET) formation in the host response to nonbacterial pathogens has received much less attention. Here, we show that the protozoan pathogen Toxoplasma gondii elicits the production of NETs from human and mouse neutrophils. Tachyzoites of each of the three major parasite strain types were efficiently entrapped within NETs, resulting in decreased parasite viability. We also show that Toxoplasma activates a MEK extracellular signal-regulated kinase (ERK) pathway in neutrophils and that the inhibition of this pathway leads to decreased NET formation. To determine if Toxoplasma induced NET formation in vivo, we employed a mouse intranasal infection model. We found that the administration of tachyzoites by this route induced a rapid tissue recruitment of neutrophils with evidence of extracellular DNA release. Taken together, these data indicate a role for NETs in the host innate response to protozoan infection. We propose that NET formation limits infection by direct microbicidal effects on Toxoplasma as well as by interfering with the ability of the parasite to invade target host cells. PMID- 22104112 TI - Toll-like receptor 9-dependent activation of bone marrow-derived dendritic cells by URA5 DNA from Cryptococcus neoformans. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense against C. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using the URA5 gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bp URA5 gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5' 129-bp DNA fragment of URA5 and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that the C. neoformans URA5 gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif. PMID- 22104113 TI - Comparison of asymptomatic bacteriuria Escherichia coli isolates from healthy individuals versus those from hospital patients shows that long-term bladder colonization selects for attenuated virulence phenotypes. AB - Asymptomatic bacteriuria (ABU) is a condition where bacteria stably colonize the urinary tract, in a manner closely resembling commensalism at other mucosal sites. The patients carry >10(5) CFU/ml for extended periods of time and rarely develop symptoms. Contrasting the properties of ABU strains to those of uropathogenic isolates causing symptomatic infection is therefore highly relevant to understand mechanisms of bacterial adaptation. The prototype ABU strain Escherichia coli 83972 has a smaller genome than uropathogenic E. coli (UPEC) strains with deletions or point mutations in several virulence genes, suggesting that ABU strains undergo a programmed reductive evolution within human hosts. This study addressed if these observations can be generalized. Strains causing ABU in outpatients or hospitalized patients after catheterization or other invasive procedures were compared to commensal E. coli isolates from the intestinal flora of healthy individuals. Notably, clonal complex 73 (CC73) was a prominent phylogenetic lineage dominated by ABU isolates. ABU isolates from outpatients and hospitalized patients had a similar overall virulence gene repertoire, which distinguished them from many commensals, but typical UPEC virulence genes were less frequently attenuated in hospital strains than in outpatient strains or commensals. The decreased virulence potential of outpatient ABU isolates relative to that of ABU strains from hospitalized patients supports the hypothesis that loss of expression or decay of virulence genes facilitates long-term carriage and adaptation to host environments. PMID- 22104114 TI - A case report and brief review of the literature on bilateral retinal infarction following cardiopulmonary bypass for coronary artery bypass grafting. AB - Postoperative visual loss is a devastating perioperative complication. The commonest aetiologies are anterior ischaemic optic neuropathy (AION), posterior ischaemic optic neuropathy (PION), and central retinal artery occlusion (CRAO). These appear to be related to certain types of operation, most commonly spinal and cardiac bypass procedures; with the rest divided between: major trauma causing excessive blood loss; head/neck and nasal or sinus surgery; major vascular procedures (aortic aneurysm repair, aorto-bifemoral bypass); general surgery; urology; gynaecology; liposuction; liver transplantation and duration of surgery. The non-surgical risk factors are multifactorial: advanced age, prolonged postoperative anaemia, positioning (supine v prone), alteration of venous drainage of the retina, hypertension, smoking, atherosclerosis, hyperlipidaemia, diabetes, hypercoagulability, hypotension, blood loss and large volume resuscitation. Other important cardiac causes are septic emboli from bacterial endocarditis and emboli caused by atrial myxomata. The majority of AION cases occur during CPB followed by head/neck surgery and prone spine surgery. CPB is used to allow coronary artery bypass grafting on a motionless heart. It has many side-effects and complications associated with its use and we report here a case of bilateral retinal infarction during routine coronary artery bypass grafting in a young male patient with multiple risk factors for developing this complication despite steps to minimise its occurrence. PMID- 22104115 TI - Reliability of 2-dimensional video assessment of frontal-plane dynamic knee valgus during common athletic screening tasks. AB - CONTEXT: Two-dimensional (2D) video analysis of frontal-plane dynamic knee valgus during common athletic screening tasks has been purported to identify individuals who may be at high risk of suffering knee injuries such as anterior cruciate ligament tear or patellofemoral pain syndrome. Although the validity of 2D video analysis has been studied, the associated reliability and measurement error have not. OBJECTIVE: To assess the reliability and associated measurement error of a 2D video analysis of lower limb dynamic valgus. DESIGN: Reliability study. PARTICIPANTS: 20 recreationally active university students (10 women age 21.5 +/- 2.3 y, height 170.1 +/- 6.1 cm, weight 66.2 +/- 10.2 kg, and 10 men age 22.6 +/- 3.1 y, height 177.9 +/- 6.0 cm, weight 75.8 +/- 7.9 kg). MAIN OUTCOME MEASUREMENT: Within-day and between-days reliability and measurement-error values of 2D frontal-plane projection angle (FPPA) during common screening tasks. INTERVENTIONS: Participants performed single-leg squat and drop jump and single leg landings from a standard 28-cm step with standard 2D digital video camera assessment. RESULTS: Women demonstrated significantly higher FPPA in all tests except the left single-leg squat. Within-day ICCs showed good reliability and ranged from .59 to .88, and between-days ICCs were good to excellent, ranging from .72 to .91. Standard error of measurement and smallest detectable difference values ranged from 2.72 degrees to 3.01 degrees and 7.54 degrees to 8.93 degrees , respectively. CONCLUSIONS: 2D FPPA has previously been shown to be valid and has now also been shown to be a reliable measure of lower extremity dynamic knee valgus. Using the measurement error values presented along with previously published normative data, clinicians can now make informed judgments about individual performance and changes in performance resulting from interventions. PMID- 22104116 TI - Elevated levels of C-reactive protein as a risk factor for metabolic syndrome in Indians. AB - OBJECTIVE: Relationship of high sensitivity C-reactive protein (hsCRP) with metabolic syndrome (MetS) is well documented in many populations, but comprehensive data is lacking in Indian population. Thus, we set out to investigate the association of hsCRP levels with MetS and its features and the effect of obesity and insulin resistance on this association in urban Indians. METHODS: This is a cross-sectional study that included 9517 subjects comprising 4066 subjects with MetS. MetS was defined according to the modified National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) criteria for Asians. RESULTS: Median levels of hsCRP were considerably higher in individuals with MetS with higher levels in women compared to men. Among the features of MetS, waist circumference was most strongly correlated with hsCRP levels (r=0.28) and contributed maximally (beta=0.025mg/l lnhsCRP, P=7.4*10(-147)). Subjects with high risk hsCRP levels (>3mg/l) were at high risk of MetS (OR (95% CI)=1.65(1.41 1.92), P=1.7*10(-10)). Risk of MetS increased in a dose dependent manner from low risk to high risk hsCRP category with increase in BMI and HOMA-IR. CONCLUSIONS: Our findings suggest that hsCRP predicts the risk of MetS, independent of obesity and insulin resistance, and therefore, can be a valuable tool to aid the identification of individuals at risk of MetS. The study provides a lead for future investigation for effects of hsCRP, obesity, and insulin resistance on MetS in this population. PMID- 22104117 TI - The expression of IGFs and IGF binding proteins in human carotid atherosclerosis, and the possible role of IGF binding protein-1 in the regulation of smooth muscle cell proliferation. AB - OBJECTIVE: Proliferation of smooth muscle cells (SMCs) in the fibrous cap of atherosclerotic lesions has been proposed to be important for plaque stability. Since the insulin-like growth factor (IGF) system has been implicated to play a role in atherosclerosis and plaque stability, we investigated the expression of members of the IGF system in carotid plaques, in particular IGFBP-1 and its role in the regulation of SMC proliferation. METHODS AND RESULTS: Gene expression profiles of the IGF system in 164 human carotid plaques obtained from our Biobank of Karolinska Endarterectomies (BiKE) were analyzed. Expression of IGFBP-1 mRNA was significantly increased in carotid plaques compared with normal iliac arteries in contrast to IGF-1, IGF-2, and IGFBP-3 to IGFBP-6. The expression of IGFBP-1 mRNA correlated positively to that of CD163, CD68, IL-1beta, IL-6, TNFalpha, IGFBP-4 and IGFBP-5. Immunohistochemistry demonstrated co-localization of IGFBP-1 with SMCs and macrophages. In vitro studies showed that IL-1beta, IL-6 and TNFalpha stimulated IGFBP-1 mRNA expression in SMCs. IGFBP-1 stimulated SMC proliferation through ERK1/2 activation but independently of the IGF-1 receptor. In addition, IGFBP-1 modulated the effect of IGF-1 on SMC proliferation and ERK1/2 activation. CONCLUSIONS: Our results demonstrate that IGFBP-1 mRNA and protein is detected at increased levels in human carotid plaques, possibly as a consequence of plaque inflammation. IGFBP-1 affects SMC proliferation and may be involved in the regulation of plaque stability. PMID- 22104118 TI - Antibacterial activity of water-soluble extract from pine needles of Cedrus deodara. AB - The antibacterial activity of water-soluble extract from pine needles of Cedrus deodara (WEC) was evaluated on five food-borne bacteria, and its related mechanism was investigated by transmission electron microscope. In vitro antibacterial assay showed that WEC possesses a remarkable antibacterial activity against tested food-borne bacteria including Escherichia coli, Proteus vulgaris, Staphylococcus aureus, Bacillus subtilis and Bacillus cereus, with the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values in the ranges of 0.78-12.5 mg/ml and 1.56-25mg/ml, respectively. In a food system of fresh-squeezed tomato juice, WEC was observed to possess an effective capacity to control the total counts of viable bacteria. Shikimic acid was isolated from WEC and identified as the main antibacterial compound. All results of our study suggested that WEC might be a new potential source of natural antibacterial agents applicable to food. PMID- 22104119 TI - Effects of microencapsulated Allyl isothiocyanate (AITC) on the extension of the shelf-life of Kimchi. AB - Allyl isothiocyanate (AITC) is a well-recognized antimicrobial agent but, application of AITC to food systems is limited due to its high volatility and strong odor. This study was performed to overcome the volatility of AITC by encapsulation using gum Arabic and chitosan and to investigate the effect of microencapsulated AITC as a natural additive on the shelf-life and quality of Kimchi. AITC loaded microparticles were prepared using gum Arabic and chitosan and were added to Kimchi at various concentrations (0-0.02%, w/w). The titratable acidity, pH, microbial changes, and sensory test of Kimchi were examined for 15days at different fermentation temperatures (4 and 10 degrees C). The pH of Kimchi containing AITC microparticles was significantly higher than that of control and the higher the quantity of added AITC, the higher the pH became. The titratable acidity of Kimchi increased during storage especially, titratable acidity of control increased significantly higher than those of Kimchi with added AITC microparticles. The number of Leuconostoc and Lactobacillus species in Kimchi decreased with an increase in the concentration of AITC. The addition of AITC induced reduction of sour taste and improvement of the texture of Kimchi during fermentation. However, as the content of AITC increased, the scores of overall acceptability decreased due to the odor of AITC. These results indicate that addition of AITC (less than 0.1%) to Kimchi is an effective way of enhancing the shelf-life of Kimchi without reducing quality. PMID- 22104120 TI - Effect of Equisetum arvense and Stevia rebaudiana extracts on growth and mycotoxin production by Aspergillus flavus and Fusarium verticillioides in maize seeds as affected by water activity. AB - Cereals are a very important part of the human and animal diets. However, agricultural products can be contaminated by moulds and their mycotoxins. Plant extracts, particularly those of Equisetum arvense and Stevia rebaudiana have been reported previously to contain antioxidant compounds which may have antifungal properties. In this study, E. arvense and S. rebaudiana extracts were tested for their control of mycotoxigenic fungi in maize. The extracts were tested separately and as a mixture for their effect on growth of Aspergillus flavus and Fusarium verticillioides. Extracts were added to unsterilised inoculated maize at different water activity (a(w)) levels (0.85-0.95). Moulds were inoculated and incubated for 30 days. Results confirmed that the extract of E. arvense and a mixture 1:1 of Equisetum-Stevia may be effective for the inhibition of both growth of A. flavus and aflatoxin production at high water activity levels (pre harvest conditions). In general, growth of the F. verticillioides was reduced by the use of plant extracts, especially at 0.95 a(w). However, fumonisin presence was not significantly affected. E. arvense and S. rebaudiana extracts could be developed as an alternative treatment to control aflatoxigenic mycobiota in moist maize. PMID- 22104121 TI - Technological characterization of bacteriocin producing Lactococcus lactis strains employed to control Listeria monocytogenes in cottage cheese. AB - In recent years, there has been a particular focus on the application of antimicrobial compounds produced by lactic acid bacteria (LAB) as natural preservatives to control the growth of spoilage and pathogenic bacteria in food. Bacteriocins are antimicrobial peptides which can be added to foods in concentrated forms as food preservatives, e.g. additives, or they can be produced in situ by starters or protective cultures. In this study, twenty Lactococcus lactis bacteriocin producers previously isolated from Italian fermented foods were subjected to a variety of physical and biochemical tests in order to identify those with the greatest potential as starter cultures in cheese production. Of these, four strains isolated from cheese (one nisin Z producer, one nisin A producer and two lacticin 481 producers) which fulfilled the desired technological criteria were assessed for their ability to control Listeria monocytogenes. The subsequent application of these bacteriocinogenic strains as starter cultures in Cottage cheese established that the nisin A producing Lact. lactis 40FEL3, and to a lesser extent the lacticin 481 producers 32FL1 and 32FL3, successfully controlled the growth of the pathogen. This is the first study to directly compare the ability of nisin A, nisin Z and lacticin 481 producing strains to control listerial growth during the manufacture and storage of Cottage cheese. PMID- 22104122 TI - Risk assessment of staphylococcal poisoning due to consumption of informally marketed milk and home-made yoghurt in Debre Zeit, Ethiopia. AB - The objectives of the study were twofold: to prove that participatory risk assessment can be applied to informally-marketed foods, and to assess the risk of staphylococcal poisoning through consumption of raw milk and home-made yoghurt in Debre Zeit, Ethiopia. Rapid urban appraisals were combined with conventional interviews to identify and quantify formal and informal milk value chains and to collect information on consumers' food preparation and consumption behavior. Milk was sampled in 170 dairy farms and 5 milk collection centers and microbiological tests were conducted. Published data on milk fermentation in Ethiopia was combined with a growth model of Staphylococcus aureus to develop a stochastic risk model. The annual incidence rate of staphylococcal poisoning was estimated to be 20.0 (90% CI: 13.9-26.9) per 1000 people. When the effect of fermentation was removed from the model, the annual incidence rate increased to 315.8 (90% CI: 224.3-422.9) per 1000 people, showing the importance of traditional food preparation methods in risk mitigation; traditional milk fermentation reduced the risk by 93.7%. Improving the safety of milk and dairy products could be achieved through supporting appropriate traditional food preparation and consumption where an industrial risk mitigation system is not feasible. Participatory risk assessment was shown to be applicable to informal food value chain. PMID- 22104123 TI - Listeria monocytogenes inhibition by defatted mustard meal-based edible films. AB - An antimicrobial edible film was developed from defatted mustard meal (Sinapis alba) (DMM), a byproduct from the bio-fuel industry, without incorporating external antimicrobials and its antimicrobial activity against Listeria monocytogenes and physical properties were investigated. The DMM colloidal solution consisting of 184 g water, 14 g DMM, and 2g glycerol was homogenized and incubated at 37 degrees C for 0.2, 0.5, 24 or 48 h to prepare a film-forming solution. The pH of a portion of the film-forming solution (pH 5.5) was adjusted to 2.0 or 4.0. Films were formed by drying the film-forming solutions at 23 degrees C for 48 h. The film-forming solution incubated for 48 h inhibited L. monocytogenes in broth and on agar media. Antimicrobial effects of the film prepared from the 48 h-incubated solution increased with decrease in pH of the solution from 5.5 to 2.0. The film from the film forming solution incubated for 48 h (pH 2.0) initially inhibited more than 4.0 log CFU/g of L. monocytogenes inoculated on film-coated salmon. The film-coating retarded the growth of L. monocytogenes in smoked salmon at 5, 10, and 15 degrees C and the antimicrobial effect during storage was more noticeable when the coating was applied before inoculation than when it was applied after inoculation. The tensile strength, percentage elongation, solubility in watercxu, and water vapor permeability of the anti microbial film were 2.44 +/- 0.19 MPa, 6.40 +/- 1.13%, 3.19 +/- 0.90%, and 3.18 +/- 0.63 gmm/kPa hm(2), respectively. The antimicrobial DMM films have demonstrated a potential to be applied to foods as wraps or coatings to control the growth of L. monocytogenes. PMID- 22104124 TI - Cooperative effects in differentiation and proliferation between PDGF-BB and matrix derived synthetic peptides in human osteoblasts. AB - BACKGROUND: Enhancing osteogenic capabilities of bone matrix for the treatment of fractures and segmental defects using growth factors is an active area of research. Recently, synthetic peptides like AC- 100, TP508 or p-15 corresponding to biologically active sequences of matrix proteins have been proven to stimulate bone formation. The platelet-derived growth factor (PDGF) BB has been identified as an important paracrine factor in early bone healing. We hypothesized that the combined use of PDGF-BB with synthetic peptides could result in an increase in proliferation and calcification of osteoblast-like cells. METHODS: Osteoblast like cell cultures were treated with PDGF and synthetic peptides, singly and as combinations, and compared to non-treated control cell cultures. The cultures were evaluated at days 2, 5, and 10 in terms of cell proliferation, calcification and gene expression of alkaline phosphate, collagen I and osteocalcin. RESULTS: Experimental findings revealed that the addition of PDGF, p-15 and TP508 and combinations of PDGF/AC-100, PDGF/p-15 and PDGF/TP508 resulted in an increase in proliferating osteoblasts, especially in the first 5 days of cultivation. Proliferation did not significantly differ between single factors and factor combinations (p > 0.05). The onset of calcification in osteoblasts occurred earlier and was more distinct compared to the corresponding control or PDGF stimulation alone. Significant difference was found for the combined use of PDGF/p-15 and PDGF/AC-100 (p < 0.05). CONCLUSIONS: Our findings indicate that PDGF exhibits cooperative effects with synthetic peptides in differentiation and proliferation. These cooperative effects cause a significant early calcification of osteoblast-like cells (p < 0.05). We suggest the combination of synthetic peptides and PDGF as a potential clinical approach for accelerating bone healing or coating osteosynthesis materials. PMID- 22104125 TI - The relation between parental influence, body image, and eating behaviors in a nonclinical female sample. AB - The purpose of the current study is to create a comprehensive composite measure of parental influence based on previously developed measures to clarify the underlying dimensions of parental influence and to determine the degree to which parental influence relates to body image and dysfunctional weight concerns. Previously published literature was reviewed for measures of parental influence, and items from 22 measures were condensed and combined into a single questionnaire, which was completed by 367 female undergraduate psychology students. Two dimensions emerged from a principle components analysis: Direct Influence, which includes weight and eating related comments, and Modeling, which includes parental modeling of dieting and related behavior. Direct Influence and Modeling were significantly related to eating disturbance, such as drive for thinness and bulimic symptomatology. Overall, the results integrate the previous literature and clarify the underlying dimensions of parental influence. Further, this study provides directions for future research related to the development and maintenance of body image and eating disturbance. PMID- 22104126 TI - Weight status misperception among Mexican young adults. AB - Individuals who misperceive their body size are at risk for eating disorders, unhealthy weight control practices, and obesity-related diseases. This study assessed the prevalence and demographic, behavioral, and psychosocial correlates of agreement between perceived (self-reported) and actual (measured) body mass index categories in a sample of Mexican college applicants aged 18-20 years (N=3622; 52% female). Under two thirds (63.1%) accurately reported their weight status categories. Reporting accuracy was lower among overweight and obese participants. In multivariate analyses, overestimating was associated with female gender, younger age, lower level of parent education, and more hours of daily TV viewing; underestimating was associated with male gender and older age. In within gender analyses, overestimating was associated with hours of TV among men and underestimating was positively associated with depressive symptoms among women. This study adds to a growing international literature on body weight status misperception among adolescents and young adults. PMID- 22104127 TI - Management of deep infection after reverse total shoulder arthroplasty: a case series. AB - BACKGROUND: Reverse total shoulder arthroplasty (RSA) is being increasingly used in the treatment of disabling shoulder conditions. This study reports the management of deep infections after RSA. MATERIALS AND METHODS: Eight of 138 patients were treated for deep infection after the index procedure. A retrospective review was performed to identify risk factors, methods of management, and determine ultimate outcome. A minimum of 12-month follow-up was available in 7 of 8 patients. RESULTS: Six infections occurred in patients who had had previous shoulder surgery. The causative bacterial organism was identified in 6 patients. Deep infection occurred in 3 patients with diabetes mellitus. Antibiotic cement was used in all cases. Six patients were managed with irrigation and debridement and retention of components. Two patients with of Staphylococcus aureus infection ultimately required resection arthroplasty. Patients managed with irrigation and debridement, intravenous antibiotics, and retention of components demonstrated good pain relief and function, without evidence of radiographic loosening. Resection resulted in pain relief but poor functional outcomes. CONCLUSION: Limited literature is available regarding the management of deep infection in patients with RSA. Component removal after a RSA creates increased bone loss due to a cemented humeral component and glenoid baseplate with several large screws. Five of 7 patients with deep infection had undergone previous shoulder surgery. We recommend that patients should be managed with an initial irrigation and debridement, appropriate intravenous antibiotics, and component retention. PMID- 22104128 TI - Ulnar component surface finish influenced the outcome of primary Coonrad-Morrey total elbow arthroplasty. AB - BACKGROUND: Controversy remains regarding the mechanisms leading to ulnar loosening after elbow replacement. We therefore assessed the loosening rate of the ulnar component as a function of the surface finish of a commonly used implant design. MATERIALS AND METHODS: This study included 3 groups who received implants with 3 different surface finishes: sintered beads (278 components), polymethylmethacrylate precoating (219 components), and plasma-sprayed beads (205 components). RESULTS: The 3 groups who received the implants did not differ statistically in age, sex, or underlying diagnosis. The rates of mechanical failure for the sintered, precoated, and plasma-sprayed ulnar components were 6.8%, 12.8%, and 0%, respectively. The 7-year Kaplan-Meier survival rates free of mechanical failure were 93.1% for the sintered-beads group, 83.1% for the precoated group, and 100% for the plasma-sprayed group. Failed precoated ulnar components often failed early and exhibited typical features, including proximal debonding and severe focal or global osteolysis, sometimes leading to periprosthetic insufficiency fractures. CONCLUSION: Precoating the ulnar component with polymethylmethacrylate can lead to an increased rate of loosening and severe osteolysis. A plasma-sprayed ulnar component is associated with a very low mechanical failure rate with surveillance of less than 10 years. PMID- 22104129 TI - Regarding: Humeral head abrasion: an association with failed superior labrum anterior posterior repairs. PMID- 22104130 TI - Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. AB - The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4-10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (ABCB1, ABCG2, ABCC2, RFC1, PCFT, SLCO1B1, MTHFR, GGH, ATIC, MTR, and MTRR) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the ABCB1 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the ABCB1 3435CC genotype (p = 0.02). Similarly, patients with the ABCB1 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the ABCB1 2677GG/GA/GT genotypes (p = 0.04). The patients with the MTHFR 1298AA genotype had a significantly lower mean DAS28 than those with the MTHFR 1298AC/CC genotypes (p = 0.04). In conclusion, the ABCB1 3435C>T, ABCB1 2677G>A/T, and MTHFR 1298A>C polymorphisms influenced the efficacy of MTX monotherapy. PMID- 22104131 TI - Giant cell lesions of the jaws: does the level of vascularity and angiogenesis correlate with behavior? AB - PURPOSE: To compare vascularity and angiogenic activity in aggressive and nonaggressive giant cell lesions (GCLs) of the jaws. MATERIALS AND METHODS: This is a retrospective study of 14 GCLs treated at the University of California, San Francisco. Immunohistochemistry was used to determine of the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), CD34, and CD31. VEGF and bFGF expression in giant cells (GCs) and surrounding mononuclear stroma was classified into 1) high immunoreactivity (>50% staining) and 2) low immunoreactivity (<50% staining). CD31- and CD34-stained vessels were counted at 200* magnification. Clinical and radiographic records were reviewed to classify lesions as aggressive or nonaggressive. RESULTS: Of the lesions, 8 were aggressive and 6 were nonaggressive. High VEGF expression was found within the GCs in 4 of 8 aggressive lesions compared with 1 of 6 nonaggressive lesions. The stroma in both groups had low staining. High staining of the GCs for bFGF was found in 6 of 8 aggressive lesions compared with 3 of 6 nonaggressive lesions. The stroma of all aggressive cases showed high expression of bFGF compared with 3 of 6 nonaggressive cases. The aggressive group had a mean of 20.1 +/- 5.4 vessels/high-powered field (hpf) stained for CD31 compared with 11.5 +/- 5.6 vessels/hpf in the nonaggressive group. The aggressive group had 24.6 +/- 7.0 vessels/hpf stained with CD34 compared with 18.5 +/- 4.0 vessels/hpf in the nonaggressive group. CONCLUSIONS: The vascularity and level of angiogenesis within aggressive GCLs are higher than those in nonaggressive lesions. PMID- 22104132 TI - Effect of bimaxillary surgery on adaptive condylar head remodeling: metric analysis and image interpretation using cone-beam computed tomography volume superimposition. AB - PURPOSE: The aim of the present study was to use cone-beam computed tomography volume superimposition to investigate the effect of bimaxillary orthognathic surgery on condylar head remodeling. MATERIALS AND METHODS: Using a retrospective study design, 2 investigators evaluated the cone-beam computed tomography data of subjects who had undergone Le Fort I osteotomy and mandibular setback surgery. The predictor variable was time, grouped as preoperative versus postoperative. The outcome variables were the measurement changes of the condylar heads and the distribution of the condylar head remodeling signs. Paired t and chi(2) tests were performed for the purposes of the 2-dimensional metric analysis and the condylar head remodeling distribution. P < .05 was considered significant. RESULTS: The sample was composed of 22 adults (11 men and 11 women, age 20.3 +/- 3.2 years) diagnosed with skeletal Class III malocclusion. The intra- and interoperator reliabilities of the image interpretation showed substantial agreement, according to Cohen's kappa index. The condylar heights on the sagittal and coronal planes decreased after surgery. Bone resorption occurred predominantly in the anterior and superior areas on the sagittal plane, the superior and lateral areas on the coronal plane, and the anterolateral and posterolateral areas on the axial plane (P < .05). Bone formation was apparent only in the anteromedial area on the axial plane (P < .05). CONCLUSIONS: Bimaxillary orthognathic surgery caused a decrease in the condylar heights and condylar head remodeling. The cone-beam computed tomography volume superimposition method showed that the condylar head had undergone remodeling after bimaxillary surgery. PMID- 22104133 TI - Therapygenetics: moving towards personalized psychotherapy treatment. AB - New research suggests that genetic variation predicts response to cognitive behavior therapy (CBT) for the treatment of pediatric anxiety. We discuss this intriguing finding, review its implications for understanding the etiology of psychopathology, and suggest that psychosocial treatment research would strongly benefit from routinely assessing genetic variation in clinical trials. PMID- 22104134 TI - Cryptic introgression of Dasypyrum villosum parental DNA in wheat lines derived from intergeneric hybridization. AB - Cytogenetic and DNA molecular analyses have been carried out in 3 wheat introgression lines (ILs; CS*V58, CS*V59, and CS*V60) derived from Triticum aestivum cv. 'Chinese Spring' (CS) * Dasypyrum villosum(Dv) intergeneric hybridization. All lines, which showed several phenotypic differences compared to CS, had the same chromosome number (2n = 42) and structure as CS, and neither chromosomes nor chromatin from Dv were apparently added to their complement. However, Feulgen/DNA cytophotometry showed that there was more nuclear DNA in the lines than in the parental wheat (by 1.85%, 2.76%, and 1.26% in CS*V58, CS*V59, and CS*V60, respectively). Molecular investigation indicated the presence of Dv DNA in the ILs. AFLP analysis of genomic DNA from the ILs, CS, and Dv detected a total of 120 polymorphic bands, of which 7 (5.8%) were present in some or all the ILs and Dv but were absent in CS. PCR amplification, sequence analysis of amplicons, and Southern blot hybridization confirmed the presence of Dv-specific sequences in each of the ILs. These results indicate cryptic introgression of Dv DNA sequences into the genome of the ILs. Some implications of this finding are discussed. PMID- 22104135 TI - Determination of reactive oxygen species generated by phorbol 12-myristate 13 acetate-stimulated oral polymorphonuclear cells from healthy human volunteers without any dental problems. AB - Human oral polymorphonuclear cells (OPMNs) play an important role in the defence of oral cavity from bacteria by releasing reactive oxygen species (ROS). The purpose of the study is to determine ROS generated by OPMNs collected from healthy volunteers without any dental problems by applying a luminol analogue 8 amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt dependent chemiluminescence (CL) response in combination with radical and ROS scavengers. In the CL response induced by OPMNs primed with phorbol 12-myristate 13-acetate, 0.23 M 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, 12.5 U/ml of super oxide dismutase (SOD) as a superoxide anion (O(2)(.-)) scavenger, and 0.96 M dimethyl sulfoxide (DMSO) as a hydroxyl radical ((.)OH) scavenger inhibited the response by approximately 90%, 70%, and 60%, respectively. The inhibitory effects were obtained in a range of concentrations where viability of the OPMNs exposed to DMPO, SOD, and DMSO were more than 70%. Electron spin resonance-spin trapping analysis confirmed that at least O(2)(.-) and (.)OH were generated via primed OPMNs. Furthermore, the addition of both 12.5 U/ml of SOD and 0.96 M DMSO inhibited the CL response by more than 90%, which was in accordance with the inhibition rate obtained by the addition of DMPO. Therefore, it is suggested that around 90% of the CL response is induced by free radicals, and at least around 70% of the radicals are SOD-inhibitable, meaning that they are originally derived from O(2)(.-). In addition, some of the (.)OH are generated independently of O(2)(.-) because if all of the (.)OH were formed through dismutation of O(2)(.-), only 70% of the CL response would be inhibited by the combination of SOD and DMSO as was inhibited by SOD alone. The present study suggests that OPMNs in health individuals have an ability to generate free radicals, which consist mainly of O(2)(.-), (.)OH and possibly an intermediate ROS derived from O(2)(.-) and (.)OH. PMID- 22104136 TI - Comparisons of different regressions tools in measurement of antioxidant activity in green tea using near infrared spectroscopy. AB - To rapidly and efficiently measure antioxidant activity (AA) in green tea, near infrared (NIR) spectroscopy was employed with the help of a regression tool in this work. Three different linear and nonlinear regressions tools (i.e. partial least squares (PLS), back propagation artificial neural network (BP-ANN), and support vector machine regression (SVMR)), were systemically studied and compared in developing the model. The model was optimized by a leave-one-out cross validation, and its performance was tested according to root mean square error of prediction (RMSEP) and correlation coefficient (R(p)) in the prediction set. Experimental results showed that the performance of SVMR model was superior to the others, and the optimum results of the SVMR model were achieved as follow: RMSEP=0.02161 and R(p)=0.9691 in the prediction set. The overall results sufficiently demonstrate that the spectroscopy coupled with the SVMR regression tool has the potential to measure AA in green tea. PMID- 22104137 TI - Can background checks of long term care residents improve safety? PMID- 22104138 TI - The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion. AB - The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by D-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction. PMID- 22104139 TI - PTSD'S mediation of the relationships between trauma, depression, substance abuse, mental health, and physical health in individuals with severe mental illness: evaluating a comprehensive model. AB - OBJECTIVE: Following trauma exposure and PTSD, individuals with severe mental illness (SMI) frequently suffer a complex course of recovery complicated by reduced mental and physical health and increased substance abuse. The authors evaluated a theoretical PTSD-SMI model which theorizes that trauma, PTSD, depression, substance abuse, mental health, and physical health are interrelated and that PTSD mediates these relationships. METHOD: Participants were ethnoracially diverse individuals diagnosed with SMI (N=175) who were assessed for trauma exposure, severity of PTSD and depression, substance abuse, and overall mental and physical health functioning. Pearson's correlations were utilized to examine the relationships between study domains. The mediating effects of PTSD were assessed using regression coefficients and the Sobel test for mediation. RESULTS: A majority of participants with SMI (89%) reported trauma exposure and 41% reported meeting diagnostic criteria for PTSD. On average, participants were exposed to over four types of traumatic events. Trauma, severity of PTSD and depression, substance abuse, and overall mental and physical health functioning were significantly interrelated. PTSD partially mediated the relationships between trauma and severity of depression and between trauma and overall mental health; PTSD fully mediated the trauma and overall physical health relationship. DISCUSSION: Within an ethnoracially diverse SMI sample, trauma exposure and PTSD comorbidity were high and associated with severity of depression, substance abuse, overall mental health and physical health functioning. Supporting our theoretical PTSD-SMI model, PTSD mediated the adverse effects of trauma exposure on participants' current severity of depression and overall mental and physical health functioning. PMID- 22104140 TI - Five-year clinical course and outcome of schizophrenia in Ethiopia. AB - BACKGROUND: Findings from the WHO sponsored multicenter studies done a few decades ago, which reported favorable outcome of schizophrenia in developing countries both in 2 and 5 year follow-up studies, dominated the world view until recently. Emerging evidence from Low and Middle Income countries (LAMIC) started to challenge this long held view, also called 'dogma' by some authors. We reported the short-term follow-up which showed unfavorable outcome. We followed up the cohort further to determine the 5-year outcome of schizophrenia and to compare the results with the WHO reports. METHODS: Patients with schizophrenia (n=321) were identified systematically after screening 68378 adults, ages 15-49 years, in rural Ethiopia. The majority (74.9%) had chronic illness at entry and were treatment naive (89.6%). RESULTS: During 5-year follow-up, 96% had received treatment at least once although only about 6% had received antipsychotic treatments continuously. Forty five percent of participants were continuously symptomatic with 30.3% having had continuous psychotic episode. About 20% had experienced continuous remission. Being single (OR=3.41, 95% CI=1.08-10.82, P=0.037), on antipsychotic treatment for at least 50% of follow up time (OR=2.28, 95% CI=1.12-4.62, P=0.023), and having a diagnosis of paranoid subtype of schizophrenia (OR=3.68, 95% CI=1.30-10.44, P=0.014) were associated with longer period of remission CONCLUSION: The findings from this 5-year outcome were consistent with our previous short term report which was unfavorable. Treatment has been a consistent predictor of a favorable outcome. Therefore, ensuring availability of treatment and adherence is an essential pragmatic step to improve outcome in this setting. PMID- 22104141 TI - Infectious agents associated with schizophrenia: a meta-analysis. AB - Schizophrenia is a highly disabling and limiting disorder for patients and the possibility that infections by some microorganisms may be associated to its development may allow prevention and recovery. In the current study we have done a meta-analysis of studies that have assessed the possible association between detection of different infectious agents and schizophrenia. We report results that support the idea that there is a statistically significant association between schizophrenia and infection by Human Herpesvirus 2 (OR=1.34; CI 95%: 1.09 1.70; p=0.05), Borna Disease Virus (OR=2.03; CI 95%: 1.35-3.06; p<0.01), Human Endogenous Retrovirus W (OR=19.31; CI 95%: 6.74-55.29; p<0.001), Chlamydophila pneumoniae (OR=6.34; CI 95%: 2.83-14.19; p<0.001), Chlamydophila psittaci (OR=29.05; CI 95%: 8.91-94.70; p<0.001) and Toxoplasma gondii (OR=2.70; CI 95%: 1.34-4.42; p=0.005). The implications of these findings are discussed and further research options are also explicated. PMID- 22104142 TI - Lead diversification. Application to existing drug molecules: mifepristone 1 and antalarmin 8. AB - A series of C-H functionalisation plate-based chemical screens and other C-H activation protocols were developed for the chemical diversification of drug molecules. In this Letter, metalloporphyrin and other catalytic oxidation systems are described in addition to chlorination. Mifepristone and antalarmin are used as substrates. The products obtained and the biological data demonstrate the potential utility of this approach. PMID- 22104143 TI - Down-regulation of the human VEGF gene expression by perylene monoimide derivatives. AB - The proximal promoter region of the human vascular endothelial growth factor (VEGF) gene contains a guanine-rich strand that can act as a transcriptional silencer by forming an intramolecular G-quadruplex. In this study, we compared two perylene monoimide derivatives, PM1 and PM2, with the well-studied perylene diimide derivative, PIPER, and the well-studied porphyrin derivative, TmPyP(4), with regard to G-quadruplex formation, G-quadruplex binding selectivity, and human VEGF gene silencing in A549 lung cancer cells. The results show that these perylene derivatives can preferentially induce intramolecular G-quadruplex formation from a duplex containing the VEGF G-quadruplex motif in vitro. Incubating A549 lung cancer cells with these perylene derivatives, especially PM2, led to the reduction of both VEGF mRNA and VEGF protein. This study might provide the foundation for the rational design and development of new perylene derivatives as effective anti-angiogenesis agents for cancer therapy. PMID- 22104144 TI - Quinolinone-based agonists of S1P1: use of a N-scan SAR strategy to optimize in vitro and in vivo activity. AB - We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 MUM, 120% efficacy; 5: EC(50)=0.070 MUM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 MUM; 5: EC(50)=1.5 MUM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat. PMID- 22104145 TI - Synthesis and evaluation of potential inhibitors of human and Escherichia coli histidine triad nucleotide binding proteins. AB - Based on recent substrate specificity studies, a series of ribonucleotide based esters and carbamates were synthesized and screened as inhibitors of the phosphoramidases and acyl-AMP hydrolases, Escherichia coli Histidine Triad Nucleotide Binding Protein (ecHinT) and human Histidine Triad Nucleotide Binding Protein 1 (hHint1). Using our established phosphoramidase assay, K(i) values were determined. All compounds exhibited non-competitive inhibition profiles. The carbamate based inhibitors were shown to successfully suppress the Hint1 associated phenotype in E. coli, suggesting that they are permeable intracellular inhibitors of ecHinT. PMID- 22104146 TI - II. Novel HCV NS5B polymerase inhibitors: discovery of indole C2 acyl sulfonamides. AB - Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053MUM, replicon EC(50)=4.8MUM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039MUM, replicon EC(50)=0.011MUM) with >100-fold improved replicon activity. PMID- 22104147 TI - Design and combinatorial synthesis of a novel kinase-focused library using click chemistry-based fragment assembly. AB - Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3beta kinase. PMID- 22104148 TI - Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4 fluorophenyl)-4-substituted pyrazole derivatives. AB - As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system. A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. The CoMFA model provided a significant correlation of steric and electrostatic fields with the biological activity while the CoMSIA model could additionally shed light on the role of hydrogen bonding and hydrophobic features. The important features identified in the 3D-QSAR models have been used to propose new molecules whose activities are predicted higher than the existing systems. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents. PMID- 22104149 TI - Potent adjuvantic activity of a CCR1-agonistic bis-quinoline. AB - A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4 ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties. RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine alpha-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen. PMID- 22104150 TI - Synthesis and evaluation of novel prodrugs of caspase inhibitors. AB - A novel type of caspase inhibitor prodrug that improves systemic exposure after oral administration in rats has been designed. Such a prodrug, based on a 6,6a dihydrofuro[3,2-d]oxazol-5(3aH)-one motif, has the advantage of rapidly liberating the active inhibitor without producing any cleavage by-product. Prodrugs 6-8, are synthesised in a high yielding one-step transformation from the active parents with high diastereomeric excess. PMID- 22104151 TI - Synthesis, anticancer activity and apoptosis inducing ability of bisindole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates. AB - A series of bisindole-pyrrolobenzodiazepine conjugates (5a-f) linked through different alkane spacers was prepared and evaluated for their anticancer activity. All compounds exhibited significant anticancer potency and the most potent compounds 5b and 5e were taken up for detailed studies on MCF-7 cell line. Cell cycle effects were examined apart from investigating the inhibition of tubulin polymerization for compounds 2a, 2b, 5b and 5e at 2MUM. FACS analysis showed that at higher concentrations (4 and 8MUM) there was an increase of sub-G1 phase cells and decrease of G2/M phase cells, thus indicating that compounds 5b and 5e are effective in causing apoptosis in MCF-7 cells. It was also observed that compounds 5b and 5e showed the down regulation of histone deacetylase protein levels such as HDAC1, 2, 3, 8 and increase in the levels of p21, followed by apoptotic cell death. The apoptotic nature of these compounds was further evidenced by increased expression of cleaved-PARP and active caspase-7 in MCF-7 cells. PMID- 22104152 TI - Hoiamide D, a marine cyanobacteria-derived inhibitor of p53/MDM2 interaction. AB - Bioassay-guided fractionation of two cyanobacterial extracts from Papua New Guinea has yielded hoiamide D in both its carboxylic acid and conjugate base forms. Hoiamide D is a polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS)-derived natural product that features two consecutive thiazolines and a thiazole, as well as a modified isoleucine residue. Hoiamide D displayed inhibitory activity against p53/MDM2 interaction (EC(50)=4.5 MUM), an attractive target for anticancer drug development. PMID- 22104153 TI - Is removal of the primary tumor beneficial in breast cancer with synchronous metastases? - there may be more than one answer. PMID- 22104154 TI - Predictive value of serum bone sialoprotein in patients with bone metastasis of non-small cell lung cancer. AB - BACKGROUND: The purpose of this study was to evaluate the diagnostic and prognostic significance of serum bone sialoprotein (BSP) in patients with bone metastasis (BM) from non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 146 patients diagnosed with NSCLC and 110 healthy controls were enrolled in this study. The clinical characteristics including clinical stage, pathological type, smoking status, and ECOG performance status were obtained. The mean serum BSP was detected by sandwich ELISA. RESULTS: The mean serum BSP level in individuals with BM was significantly higher than those in non-BM NSCLC and controls (p < 0.001). Receiver operating characteristics (ROC) analysis showed that BSP discriminated patients with BM from non-BM NSCLC patients at the cutoff value of 33.56 ng/ml. Sensitivity and specificity were 77.8 and 81.1%, respectively. Kaplan-Meier analysis showed that subjects with higher BSP levels had a shorter BM-free period than those with lower BSP levels. Cox regression analysis revealed that the BSP level was a predictor for prognosis of BM from NSCLC. CONCLUSION: Serum BSP is a useful biomarker for the diagnosis of BM from NSCLC, and can be regarded as an independent factor for predicting the prognosis of BM from NSCLC. PMID- 22104155 TI - Polymorphic variant Ser128Arg of E-Selectin is associated with breast cancer risk and high grade tumors. AB - BACKGROUND: The present study aimed to evaluate the association between the E Selectin Ser128Arg polymorphism and breast cancer risk and clinicopathological characteristics of the patients. MATERIALS AND METHODS: The genotypes of 387 breast cancer patients and 252 healthy women who had no history of any malignancy were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a hospital-based Malaysian population. RESULTS: The frequency of the Arg allele was significantly (p = 0.030) higher in breast cancer patients than in healthy individuals. Women who were Ser/Arg heterozygotes (adjusted odds ratio (OR(adj)) = 1.607; 95% confidence interval (CI) = 1.008 2.564), and carriers of the Arg allele genotype (OR(adj) = 1.587; 95% CI = 1.037 2.430) or Arg allele (OR(adj) = 1.509; 95% CI = 1.040-2.189) showed a significantly increased risk of breast cancer. Patients who were carriers of the Arg allele genotype showed a significant association with poorly differentiated tumors (p = 0.002). CONCLUSION: The Ser128Arg polymorphism might confer an increased susceptibility to breast cancer and contribute to aggressive phenotypic characteristics. PMID- 22104156 TI - Feasibility of involved-field conformal radiotherapy for cervical and upper thoracic esophageal cancer. AB - BACKGROUND: The aim of this study was to investigate the feasibility of involved field irradiation (IFI) for the treatment of cervical and upper-thoracic esophageal cancer with concurrent chemoradiation. PATIENTS AND METHODS: 102 eligible patients with cervical or upper-thoracic esophageal cancer were treated with concurrent chemoradiation and randomized to either an IFI or elective nodal irradiation (ENI) group. RESULTS: Adverse events included infection (27.4 vs. 64.7%) and nausea (25.4 vs. 54.9%), with a statistically significant difference between the IFI and the ENI group (p = 0.008 and 0.028, respectively). No difference was seen for late radiation reaction. The cumulative incidence of local/regional failure (13.7 vs. 17.6%) and regional lymph failure (7.8 vs. 9.8%) showed no statistically significant difference between the IFI versus the ENI group (p = 0.837 and 0.837, respectively). A nodal out-field relapse rate of only 2% was seen in the IFI group. 3-year survival rates for the ENI and IFI group were 41.3 and 32.0%, respectively (p = 0.58), and 3-year local control rates were 85.7 and 80.1%, respectively (p = 0.34). CONCLUSION: IFI was acceptable for cervical and upper-thoracic esophageal cancer with a decrease in acute toxicities and no increase in lymph node failure. PMID- 22104157 TI - Primary tumor excision in stage IV breast cancer at diagnosis without influence on survival: a retrospective analysis and review of the literature. AB - BACKGROUND: Patients with synchronous metastastic breast cancer and intact primary tumor traditionally undergo systemic treatment. Surgical intervention at the primary site is typically reserved for palliation and often replaceable by radiation. Nevertheless, local surgery in metastatic breast cancer has become an issue of great controversy since retrospective studies published during the recent years suggested a slight benefit from an operative procedure. We evaluated the effect of surgery on long-term survival and progression-free survival in synchronous stage IV breast cancer. METHODS: We retrospectively reviewed the records of all breast cancer patients treated at our institution between 1986 and 2007. Information recorded for each patient included age, tumor characteristics, metastasis characteristics, therapy, progression-free survival, and overall survival. Survival data were compared between surgical and nonsurgical patients. RESULTS: 61 patients with synchronous metastastic breast cancer and intact primary tumor were analyzed. 26 patients (43%) received no primary site surgery and 35 (57%) patients had surgery. Overall survival and progression-free survival determined via the Kaplan-Meier method showed no significant difference between the surgery and the non-surgery group. CONCLUSION: In patients with metastatic breast cancer, the operation of the primary tumor did not influence overall survival or progression-free survival. PMID- 22104158 TI - Comparison of actual hospital costs versus DRG revenues for in-patient treatment of febrile neutropenia during adjuvant anthracycline plus/minus taxane-based chemotherapy for primary breast cancer. AB - BACKGROUND: In flat-rate reimbursement systems, the hospital's own costs should not exceed its revenues. In a cohort of primary breast cancer (pBC) patients, costs and reimbursement for febrile neutropenia (FN) were compared to verify cost coverage. METHODS: A prospective, observational study in pBC patients receiving adjuvant anthracycline +/- taxane-based chemotherapy calculated the costs per in patient FN episode. The correlating revenues were retrospectively analyzed from diagnosis-related group (DRG) invoices. The actual costs of the therapies were compared to the individual DRG revenues, and the results are presented from the provider's perspective. RESULTS: In 50 patients, n = 11 patients were treated for FN as in-patients. The hospital's overall treatment costs were ? 18,288, on average (O) ? 1663 per case (range ? 1139-2344); the overall DRG revenues were ? 23,593, O ? 2145 per case (range ? 1266-2660). In n = 8 cases, the DRGs were cost covering, and in n = 3 cases, a loss was observed, but overall resulting in a gain of O ? 482 per case and thus being cost covering for the provider. Inadequate DRG coding (n = 4/11; 36.4%) resulted in a preventable loss of O ? 1069/case. CONCLUSIONS: The costs of FN treatment vary substantially and DRG reimbursements do not necessarily reflect the provider's costs. Surprisingly, the in-patient treatment of FN here is overall more than cost covering if adequately coded. The main reasons are asymmetrical costs for this FN low-risk pBC group. These results emphasize the importance of correct medical coding to avoid potential losses. PMID- 22104159 TI - Positive response to trastuzumab in a case of HER2-overexpressing metastatic gastric cancer that presented as severe thrombocytopenia. AB - BACKGROUND: Trastuzumab, a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), has been shown to be active against metastatic gastric cancers that overexpress HER2. CASE REPORT: A 47-year-old man presented with a headache and visual disturbance. He was subsequently found to have an intracranial hemorrhage. Laboratory testing showed severe thrombocytopenia, and a bone marrow biopsy revealed aggregates of malignant tumor cells. Endoscopic biopsy of an ulcerative lesion of the gastric antrum confirmed signet ring cell carcinoma based on the results of H&E staining. Immunohistochemistry of the tumor cells revealed HER2 overexpression with an intensity of 3+, and silver in situ hybridization showed HER2 gene amplification. The patient was treated with trastuzumab because of the presence of severe thrombocytopenia. After 2 months of trastuzumab therapy, gastric wall thickening and ascites were diminished and thrombocytopenia was markedly improved. Trastuzumab was continued for an additional 3 months. CONCLUSION: This is the first report of a positive response to trastuzumab in a patient with HER2 overexpressing metastatic gastric cancer that was accompanied by bone marrow involvement and severe thrombocytopenia. This finding is of considerable relevance for difficult cases of metastatic gastric cancer that preclude the administration of aggressive antineoplastic regimens. PMID- 22104160 TI - Tumor lysis syndrome in a patient with merkel cell carcinoma and provoked pathologic sequence of acute kidney injury, reduced clearance of carboplatin and fatal pancytopenia. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare, highly malignant cancer of the skin primarily affecting the elderly, with a tendency for local recurrence and regional lymph node metastasis. It is very unusual for this kind of tumor to induce clinically apparent tumor lysis syndrome (TLS) which is a consequence of spontaneous cytolysis or massive tumor cell lysis, beginning a few hours after the initiation of treatment. CASE REPORT: We report here on a patient with metastatic MCC, who developed TLS following combination chemotherapy with carboplatin and etoposide. CONCLUSION: The evolving acute kidney injury (AKI) provoked a pathologic sequence of reduced renal clearance leading to protracted clearance of carboplatin and subsequent fatal pancytopenia. When AKI occurs in close association with the administration of carboplatin, the institution of rescue hemodialysis is recommended to decrease plasma carboplatin levels and avoid this lethal complication. PMID- 22104161 TI - Optic disc and choroidal metastasis from sporadic medullary thyroid carcinoma: case report and review of the literature. AB - BACKGROUND: Choroidal metastasis is a very rare clinical manifestation of thyroid cancer. Herein, we report on a patient with non-familial medullary thyroid carcinoma (MTC), who presented with choroidal metastasis. CASE REPORT: A 63-year old male patient with MTC presented with sudden loss of vision in his right eye for 1 month. The patient had a history of complete thyroidectomy and chemotherapy for disseminated MTC. Ophthalmological examination showed optic disc and choroidal metastases in the right eye and a small choroidal metastasis in the left eye. The patient was scheduled for external irradiation therapy for the ocular area but died 2 months after choroidal metastasis was diagnosed. CONCLUSIONS: Choroidal metastasis must be considered in MTC patients who develop loss of vision. This is a very rare clinical situation that generally occurs in the late advanced stages of the disease and carries a poor prognosis for these patients. PMID- 22104162 TI - Interdigitating dendritic cell sarcoma: case report with review of the literature. AB - BACKGROUND: Interdigitating dendritic cell sarcoma (IDCS) is an exceedingly rare tumor. The characteristics of IDCS and its optimal therapeutic approach have not been fully clarified. CASE REPORT: We report the case of a 53-year-old Chinese male patient presenting with a subcutaneous nodule in the right chest wall. The histological and immunohistochemical features of the nodule confirmed the diagnosis of IDCS. Complementary examination excluded other involvement of the tumor. The patient was alive without evidence of disease 1 year after tumor resection followed by radiotherapy. CONCLUSION: With regard to the literature, IDCS presents with a wide spectrum of clinical manifestations, and its correct diagnosis requires awareness of this rare disease and the use of appropriate markers. Surgery with curative potential might remain the first treatment option, and current data do not support adjuvant therapy. Systemic chemotherapy is mainly suggested for extensive disease while the long-term efficacy is unsatisfactory. The prognosis of IDCS seems to be associated with the initial stage of disease. PMID- 22104163 TI - Digestive complaints in patients with hematologic malignancies undergoing bone marrow transplantation. AB - The aim of this study was to assess the severity and frequency of complaints affecting the digestive system in 57 patients with hematological malignancies, who underwent allogeneic (Group I, n = 22) and autologous (Group II, n = 35) hematopoietic stem cell transplantation. Chemotherapy-related toxicities affecting the digestive system (mucositis, nausea/vomiting, diarrhea) were assessed according to the WHO scale for organ toxicity. Selection of the feeding route (oral or parenteral) depended on the tolerance to oral nutrition. Parenteral nutrition (PN) was introduced when oral intake represented <= 50% of the total energy requirement over 2 days. PN was started in the third 24-h period. 63.6% of patients undergoing allogeneic transplantation and 54.3% of patients undergoing autologous transplantation needed PN. Ailments affecting the digestive system began in both groups during the administration of conditioning chemotherapy and gradually decreased in the posttransplantation period. Mucositis grade 3/4 requiring PN was observed in 85% patients in Group I and 52.7% patients in Group II. In Group I, grade 3 diarrhea was observed only in patients requiring PN. Severe grade 3/4 organ toxicity from chemotherapy was the main indication for PN in patients undergoing hematopoietic stem cell transplantation. PMID- 22104164 TI - Occidental diffusion of cucumber (Cucumis sativus) 500-1300 CE: two routes to Europe. AB - BACKGROUND: The cucumber, Cucumis sativus, is one of the most widely consumed fruit vegetables the world over. The history of its dispersal to the Occident from its centre of origin, the Indian subcontinent, has been incorrectly understood for some time, due to the confusion of cucumbers with vegetable melons. Iconographic and literary evidence has shown that cucumber was absent in Roman times, up to 500 CE, but present in Europe by late medieval times, 1300. The objective of the present investigation was to determine more accurately when the cucumber arrived in Europe and by what route. FINDINGS AND CONCLUSIONS: The evidence for the movement of C. sativus westward is entirely lexicographical until the 10th century. Syriac, Persian and Byzantine Greek sources suggest the presence of cucumbers, to the east and north-east of the Mediterranean Sea (modern Iran, Iraq and Turkey), by the 6th or 7th century. Arabic medical writings suggest the presence of cucumbers in Spain as early as the mid-9th century and in Tunisia by the early 10th century. Descriptive evidence in Arabic establishes the presence of cucumbers in Andalusia by the second half of the 10th century. Latin translations from Arabic sources indicate the presence of cucumbers in southern Italy by the second half of the 11th century. These writings, together with lexicographical discrepancies in names of cucurbits in late medieval Latin writings, suggest that cucumber was introduced to Europe by two independent diffusions. One diffusion appears to have been overland from Persia into eastern and northern Europe and preceded the Islamic conquests. The other, subsequent diffusion into western and southern Europe, was probably by a mostly maritime route from Persia or the Indian subcontinent into Andalusia. PMID- 22104165 TI - Improved left ventricular mass quantification with partial voxel interpolation: in vivo and necropsy validation of a novel cardiac MRI segmentation algorithm. AB - BACKGROUND: Cardiac magnetic resonance (CMR) typically quantifies LV mass (LVM) by means of manual planimetry (MP), but this approach is time-consuming and does not account for partial voxel components--myocardium admixed with blood in a single voxel. Automated segmentation (AS) can account for partial voxels, but this has not been used for LVM quantification. This study used automated CMR segmentation to test the influence of partial voxels on quantification of LVM. METHODS AND RESULTS: LVM was quantified by AS and MP in 126 consecutive patients and 10 laboratory animals undergoing CMR. AS yielded both partial voxel (AS(PV)) and full voxel (AS(FV)) measurements. Methods were independently compared with LVM quantified on echocardiography (echo) and an ex vivo standard of LVM at necropsy. AS quantified LVM in all patients, yielding a 12-fold decrease in processing time versus MP (0:21+/-0:04 versus 4:18+/-1:02 minutes; P<0.001). AS(FV) mass (136+/-35 g) was slightly lower than MP (139+/-35; Delta=3+/-9 g, P<0.001). Both methods yielded similar proportions of patients with LV remodeling (P=0.73) and hypertrophy (P=1.00). Regarding partial voxel segmentation, AS(PV) yielded higher LVM (159+/-38 g) than MP (Delta=20+/-10 g) and AS(FV) (Delta=23+/ 6 g, both P<0.001), corresponding to relative increases of 14% and 17%. In multivariable analysis, magnitude of difference between AS(PV) and AS(FV) correlated with larger voxel size (partial r=0.37, P<0.001) even after controlling for LV chamber volume (r=0.28, P=0.002) and total LVM (r=0.19, P=0.03). Among patients, AS(PV) yielded better agreement with echo (Delta=20+/-25 g) than did AS(FV) (Delta=43+/-24 g) or MP (Delta=40+/-22 g, both P<0.001). Among laboratory animals, AS(PV) and ex vivo results were similar (Delta=1+/-3 g, P=0.3), whereas AS(FV) (6+/-3 g, P<0.001) and MP (4+/-5 g, P=0.02) yielded small but significant differences with LVM at necropsy. CONCLUSIONS: Automated segmentation of myocardial partial voxels yields a 14-17% increase in LVM versus full voxel segmentation, with increased differences correlated with lower spatial resolution. Partial voxel segmentation yields improved CMR agreement with echo and necropsy-verified LVM. PMID- 22104167 TI - Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence. AB - BACKGROUND: Anderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the SAR1B gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal SAR1B gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7). METHODS AND RESULTS: The patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the SAR1B gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes. CONCLUSIONS: This patient with AD/CMRD has a normal SAR1B gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine. PMID- 22104168 TI - A neuromuscular intervention for exercise-related medial leg pain. AB - CONTEXT: Exercise-related medial leg pain (ERMLP) is a common complaint among athletes, and efforts toward rehabilitation are often unsuccessful. OBJECTIVE: To evaluate the efficacy of a therapeutic intervention in ERMLP localized to soft tissue. DESIGN: A quasi-experimental, nonequivalent control-group study. SETTING: Athletic training facility. PATIENTS: 20 volunteer male and female athletes (18 22 y old) with ERMLP. Complete data were available for 13 participants. INTERVENTION: Treatment group (TRE, n = 7) received therapeutic intervention focused on relieving muscle hypertonicity in the deep compartment of the lower leg and restoring balance of the toe flexors and extensors. Control group (CON, n = 6) received no intervention. MAIN OUTCOME MEASURES: Self-reported pain intensity, pain threshold, and extensor hallucis longus to extensor digitorum brevis (EHL:EDB) electromyography ratio. RESULTS: There were no significant differences in age, duration of symptoms, or pain measures between the 2 groups at baseline. CON demonstrated no significant changes in any of the outcome measures in posttreatment testing, but significant between-groups differences were identified for pain during activity (CON mean = 6.5, 95% CI 5.05, 7.95; TRE mean = 3.5, 95% CI 1.67, 5.33; P = .01), change scores for pain during activity (CON mean = 0.33, 95% CI -1.25, 1.91; TRE mean = -3.43, 95% CI:-4.6, -2.25; P < .001), change scores in pressure threshold (CON mean = -0.25, 95% CI -0.74, 0.23; TRE mean = 0.72, 95% CI 0.22, 1.37; P = .006), and change in EHL:EDB ratios (CON mean = 0.05, 95% CI -0.22, 0.33; TRE mean = 1.07, 95% CI 0.75, 2.07; P < .046). CONCLUSION: Therapeutic interventions focused on restoring muscle balance appear to be effective in resolving ERMLP. PMID- 22104169 TI - Probing the mechanobiological properties of human embryonic stem cells in cardiac differentiation by optical tweezers. AB - Human embryonic stem cells (hESC) and hESC-derived cardiomyocytes (hESC-CM) hold great promise for the treatment of cardiovascular diseases. However the mechanobiological properties of hESC and hESC-CM remains elusive. In this paper, we examined the dynamic and static micromechanical properties of hESC and hESC CM, by manipulating via optical tweezers at the single-cell level. Theoretical approaches were developed to model the dynamic and static mechanical responses of cells during optical stretching. Our experiments showed that the mechanical stiffness of differentiated hESC-CM increased after cardiac differentiation. Such stiffening could associate with increasingly organized myofibrillar assembly that underlines the functional characteristics of hESC-CM. In summary, our findings lay the ground work for using hESC-CMs as models to study mechanical and contractile defects in heart diseases. PMID- 22104170 TI - An engineered pathway for glyoxylate metabolism in tobacco plants aimed to avoid the release of ammonia in photorespiration. AB - BACKGROUND: The photorespiratory nitrogen cycle in C3 plants involves an extensive diversion of carbon and nitrogen away from the direct pathways of assimilation. The liberated ammonia is re-assimilated, but up to 25% of the carbon may be released into the atmosphere as CO2. Because of the loss of CO2 and high energy costs, there has been considerable interest in attempts to decrease the flux through the cycle in C3 plants. Transgenic tobacco plants were generated that contained the genes gcl and hyi from E. coli encoding glyoxylate carboligase (EC 4.1.1.47) and hydroxypyruvate isomerase (EC 5.3.1.22) respectively, targeted to the peroxisomes. It was presumed that the two enzymes could work together and compete with the aminotransferases that convert glyoxylate to glycine, thus avoiding ammonia production in the photorespiratory nitrogen cycle. RESULTS: When grown in ambient air, but not in elevated CO2, the transgenic tobacco lines had a distinctive phenotype of necrotic lesions on the leaves. Three of the six lines chosen for a detailed study contained single copies of the gcl gene, two contained single copies of both the gcl and hyi genes and one line contained multiple copies of both gcl and hyi genes. The gcl protein was detected in the five transgenic lines containing single copies of the gcl gene but hyi protein was not detected in any of the transgenic lines. The content of soluble amino acids including glycine and serine, was generally increased in the transgenic lines growing in air, when compared to the wild type. The content of soluble sugars, glucose, fructose and sucrose in the shoot was decreased in transgenic lines growing in air, consistent with decreased carbon assimilation. CONCLUSIONS: Tobacco plants have been generated that produce bacterial glyoxylate carboligase but not hydroxypyruvate isomerase. The transgenic plants exhibit a stress response when exposed to air, suggesting that some glyoxylate is diverted away from conversion to glycine in a deleterious short-circuit of the photorespiratory nitrogen cycle. This diversion in metabolism gave rise to increased concentrations of amino acids, in particular glutamine and asparagine in the leaves and a decrease of soluble sugars. PMID- 22104171 TI - Matrix-associated autologous chondrocyte transplantation combined with iliac crest bone graft for reconstruction of talus necrosis due to villonodular synovitis. AB - We report the case of a 24-year-old driving instructor with osteonecrosis of the talus and a large articular cartilage and osseous defect. The cystic lesion was caused by villonodular synovitis. After magnetic resonance imaging detection and arthoscopic analysis, the defect was filled with a bone graft, followed by matrix associated autologous chondrocyte transplantation (MACT) combined with a total synovectomy. In general, lesions similar to the one described in this case are treated using osteochondral autografts, but in our case the osseous defect was too large to perform an osteochondral autograft. Our choice of treatment with an iliac crest bone graft combined with a MACT simultaneously has not yet been published, as far as we know. The patient returned to his former activities of daily living and sport activities, without restrictions or complaints, and with only a slight deficit in range of motion. Morphological and biochemical magnetic resonance imaging 12 months after surgery showed excellent bone healing with no intraosseous edema. The MACT resulted in a good clinical outcome, with 100% defect filling and excellent integration and surface and signal intensity of the cartilage repair tissue, and the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score increased from 47 to 79 points. PMID- 22104172 TI - Perceiving age and gender in unfamiliar faces: an fMRI study on face categorization. AB - Efficient processing of unfamiliar faces typically involves their categorization (e.g., into old vs. young or male vs. female). However, age and gender categorization may pose different perceptual demands. In the present study, we employed functional magnetic resonance imaging (fMRI) to compare the activity evoked during age vs. gender categorization of unfamiliar faces. In different blocks, participants performed age and gender classifications for old or young unfamiliar faces (50% female respectively). Both tasks elicited activations in the bilateral fusiform gyri (fusiform face area, FFA) and bilateral inferior occipital gyri (occipital face area, OFA). Importantly, the same stimuli elicited enhanced activation during gender as compared to age categorization. This enhancement was significant in the right FFA and the left OFA, and may be related to increased configural processing. Our findings replicate and extend recent work, and shows that the activation of core components of the face processing network is strongly dependent on task demands. PMID- 22104173 TI - Values of cardio-ankle vascular index (CAVI) between Amami islands and Kagoshima mainland among health checkup examinees. AB - AIM: To investigate the prevalence and geographical variation of high arterial stiffness in groups from the Amami islands (Amami) and Kagoshima mainland (mainland), Japan, using the cardio-ankle vascular index (CAVI) as a surrogate marker of arterial stiffness. METHODS: We recruited 4,523 health checkup examinees from Amami and 440 examinees from the mainland, with an age range of 40 69 years. The frequency of high arterial stiffness (CAVI>=9.0) was geographically compared between the regions, and both mean CAVI values were compared with those of the healthy Japanese population with less risk factors for coronary artery disease. Clinical, lifestyle, and regional factors for increased CAVI values were estimated by the multiple linear regression model. RESULTS: The frequency of high arterial stiffness on Amami was significantly lower than on the mainland. Mean CAVI values on Amami were similar in males and lower in females than in the healthy Japanese population, but those on the mainland were higher for both sexes. Age, systolic blood pressure, triglycerides, fasting blood glucose, and a history of hypertension and diabetes mellitus were positively related to increased CAVI values on Amami. The regional factor of Amami, compared with the mainland, was negatively related to increased CAVI values in both sexes after adjusting for traditional cardiovascular risk factors. CONCLUSION: CAVI values in Amami residents were significantly lower than in mainland residents, suggesting that environmental or genetic factors might have improved arterial stiffness in the Amami population. PMID- 22104174 TI - Activation of TGF-beta receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice. AB - AIM: Transforming growth factor-beta (TGF-beta) plays important role in atherogenesis via TGF-beta receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. METHODS: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n =8) was fed with chow diet, while in the atorvastatin group (ATV) (n =8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. RESULTS: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. CONCLUSION: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis. PMID- 22104175 TI - Formula diet is effective for the reduction and differentiation of visceral adipose tissue in Zucker fatty rats. AB - AIM: Formula diet (FD), which is used as a tool for calorie restriction, has beneficial effects on metabolic disorders in obese patients; however, the molecular mechanism is not fully understood. METHODS: Sixteen-week-old male Zucker Diabetic Fatty (ZDF) rats were divided into 3 groups (n= 10 each): calorie controlled low-fat diet [Control; 75 kcal/day, protein : fat : carbohydrate (P:F:C)=25:15: 60], calorie-restricted low-fat diet (CR-LFD; 56 kcal/day, P:F:C=25:15:60), and calorie-restricted FD (CR-FD; 56 kcal/day, P:F:C=50:14:36) group, and fed each diet for 4 weeks. Before the study, baseline data were obtained in 10 rats. After 4 weeks, body weight and epididymal fat weight were measured, and blood samples, mesenteric and subcutaneous adipose tissues were collected for analyses. Messenger RNA expression was evaluated by real-time PCR, and protein expression by Western blotting. RESULTS: The decrease in epididymal fat weight was significantly greater in the CR-FD group than in control and CR LFD groups, although changes in body weight were not different among groups. The decrease in fasting plasma glucose and increase in plasma adiponectin were greater in the CR-FD group than in the control group, but not in the CR-LFD group. The decrease in triglyceride and increase in HDL-cholesterol were greatest in the CR-FD group. Both mRNA and protein of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, adiponectin, lipoprotein lipase and PPARgamma were overexpressed in the CR-FD group, especially in mesenteric adipose tissue. CONCLUSIONS: FD may have beneficial effects on abdominal obesity and metabolic disorders by reducing visceral fat and improving glucose and lipid profiles, possibly through modulating adipose tissue function. PMID- 22104176 TI - Plasma levels of platelet-derived microparticles in patients with obstructive sleep apnea syndrome. AB - AIM: Obstructive sleep apnea syndrome (OSAS) has been associated with high cardiovascular morbidity and mortality, and patients suffer from repeated episodes of hypoxia. Platelet-derived microparticles (PDMPs) are released via platelet activation by various agonists, including inflammatory cytokines or high shear stress. Plasminogen activator inhibitor -1 (PAI-1) is a fibrinolytic marker and soluble fibrin (SF) is a coagulation activation marker. We examined plasma levels of PDMPs, PAI-1 and SF in patients with OSAS. We also examined the effects of continuous positive airway pressure (CPAP) on plasma levels of PDMPs. METHODS: Full polysomnography (PSG) monitoring was performed on 27 patients. The apneahypopnea index (AHI) of 5 events/h or less than 30 events/h indicated mild to moderate OSAS, and an AHI of 30 events/h or more indicated severe OSAS. Plasma levels of PDMPs were measured using an ELISA kit, and PAI and SF were determined by a latex immunoassay. In addition, the effects of CPAP treatment were studied in 7 patients. RESULT: The plasma level of PDMPs was significantly higher in patients with severe OSAS (15.8+/-10.4 U/mL) than normal controls (10.8+/-7.1 U/mL, p < 0.05) and patients with mild to moderate OSAS (9.2+/-3.5 U/mL, p < 0.05). The plasma levels of PDMPs correlated with the AHI (r = 0.39, p < 0.05). In addition, CPAP treatment decreased the plasma level of PDMPs (11.9+/-5.6 U/mL to 6.7+/-3.2 U/mL, p < 0.05). CONCLUSIONS: Patients with OSAS might be at increased cardiovascular risk due to elevated PDMPs. Moreover a decrease in the plasma level of PDMPs by treatment with CPAP might reduce cardiovascular risk. PMID- 22104177 TI - PSGL-1-expressing CD4 T cells induce endothelial cell apoptosis in perimenopausal women. AB - AIM: Menopause and subsequent estrogen deficiency correlate with the development of atherosclerosis and cardiovascular diseases in women. However, the relationship between estrogen deficiency and development of atherosclerosis with inflammatory infiltrates is not fully understood. We sought to determine whether perimenopausal women (PMW) exhibited T cell dysfunction related to the expression of adhesion molecules and accelerated endothelial cell (EC) apoptosis. METHODS: Fresh CD4 T cells were isolated from 48 PMW and 54 healthy control women with regular menstrual cycles (CW), and investigated cytotoxicity to ECs by apoptosis assay. The adhesion molecules on CD4 T cells were examined by flow cytometry. CD4 T cell rolling and adhesion on ECs were analyzed by adhesion assay under laminar flow. RESULTS: CD4 T cells from PMW with low estradiol levels induced significant EC apoptosis (P = 0.0152). Furthermore, cytotoxic CD4 T cells from PMW strongly expressed P-selectin glycoprotein ligand-1 (PSGL-1) and integrin beta2 (P < 0.0001 and P = 0.0285, respectively) but not L-selectin or integrin alphaM when compared to CD4 T cells from CW. Estradiol levels negatively correlated with only PSGL-1 expression (R = -0.781, P = 0.0002), and estradiol treatments inhibited both PSGL-1 expression (P = 0.0133) and T cell-induced EC apoptosis (P = 0.018). An estrogen receptor antagonist inhibited these effects of estradiol (P = 0.0355 and P = 0.0097, respectively). Moreover, PSGL-1 expression correlated with T cell adhesion to ECs under laminar flow conditions (R = 0.636, P = 0.0355) and with EC apoptosis (R = 0.614, P = 0.0196). PSGL-1 specific antibodies effectively suppressed T cell adhesion (P = 0.0057) and EC apoptosis (P = 0.001) indicating that CD4 T cell-mediated EC apoptosis depended on PSGL-1 adhesion in PMW. CONCLUSIONS: PSGL-1-expressing cytotoxic CD4 T cells are abundant in PMW with low estradiol levels may contribute to T cell-mediated atherosclerotic development. PMID- 22104178 TI - Circulating chemerin level is independently correlated with arterial stiffness. AB - AIM: Adipokines have been implicated in the pathogenesis of obesity and obesity related disorders, including atherosclerosis. Chemerin is a recently discovered adipokine which is closely correlated with various metabolic phenotypes in humans. We examined the association between circulating chemerin levels and arterial stiffness, as represented by the brachial ankle pulse wave velocity (baPWV). METHODS: Fifty-eight obese and 62 non-obese individuals participated in the study. We measured the serum chemerin and high sensitivity C-reactive protein (hsCRP) levels, and the homeostasis model assessment of insulin resistance (HOMA IR), as well as other cardiovascular risk factors. Vascular health was assessed by the baPWV and carotid intima-media thickness (IMT). RESULTS: The serum chemerin level was significantly increased in obese individuals compared with lean controls (120.14+/-19.43 ng/mL vs. 106.81+/-23.39 ng/mL, p = 0.001). The circulating chemerin level had a significant positive correlation with the body mass index, waist circumference, HOMA-IR, and low-density lipoprotein cholesterol, triglycerides, and hsCRP levels. The serum chemerin level was significantly associated with the baPWV (r= 0.280, p= 0.002), but not the carotid IMT (r= 0.065, p= 0.504). Multiple stepwise regression analysis showed that age (p < 0.001), waist circumference (p= 0.038), systolic blood pressure (p < 0.001), and serum fasting glucose (p= 0.003) and chemerin levels (p= 0.017) were definitive risk factors for arterial stiffness (r(2)=0.457). CONCLUSIONS: The circulating chemerin level was an independent risk factor for arterial stiffness even after adjusting for other cardiovascular risk factors. PMID- 22104179 TI - Visualizing protein partnerships in living cells and organisms. AB - In recent years, scientists have expanded their focus from cataloging genes to characterizing the multiple states of their translated products. One anticipated result is a dynamic map of the protein association networks and activities that occur within the cellular environment. While in vitro-derived network maps can illustrate which of a multitude of possible protein-protein associations could exist, they supply a falsely static picture lacking the subtleties of subcellular location (where) or cellular state (when). Generating protein association network maps that are informed by both subcellular location and cell state requires novel approaches that accurately characterize the state of protein associations in living cells and provide precise spatiotemporal resolution. In this review, we highlight recent advances in visualizing protein associations and networks under increasingly native conditions. These advances include second generation protein complementation assays (PCAs), chemical and photo-crosslinking techniques, and proximity-induced ligation approaches. The advances described focus on background reduction, signal optimization, rapid and reversible reporter assembly, decreased cytotoxicity, and minimal functional perturbation. Key breakthroughs have addressed many challenges and should expand the repertoire of tools useful for generating maps of protein interactions resolved in both time and space. PMID- 22104180 TI - Molecular imaging: sine labore nihil. PMID- 22104181 TI - In vitro and in vivo single-molecule fluorescence imaging of ribosome-catalyzed protein synthesis. AB - Combined with the availability of highly purified, fluorescently labeled in vitro translation systems, the advent of single-molecule fluorescence imaging has ushered in a new era in high-resolution mechanistic studies of ribosome-catalyzed protein synthesis, or translation. Together with ensemble biochemical investigations of translation and structural studies of functional ribosomal complexes, in vitro single-molecule fluorescence imaging of protein synthesis is providing unique mechanistic insight into this fundamental biological process. More recently, rapidly evolving breakthroughs in fluorescence-based molecular imaging in live cells with sub-diffraction-limit spatial resolution and ever increasing temporal resolution provide great promise for conducting mechanistic studies of translation and its regulation in living cells. Here we review the remarkable recent progress that has been made in these fields, highlight important mechanistic insights that have been gleaned from these studies thus far, and discuss what we envision lies ahead as these approaches continue to evolve and expand to address increasingly complex mechanistic and regulatory aspects of translation. PMID- 22104182 TI - Prevalence and risk factors for xerosis in the elderly: a cross-sectional epidemiological study in primary care. AB - BACKGROUND: Limited information is available concerning the prevalence and risk factors of xerosis in the elderly. OBJECTIVE: To establish the prevalence of xerosis and associated factors in elderly patients. METHODS: A national, multicenter, observational, cross-sectional study in patients aged 65 or older was performed. The data collected by general practitioners were demographics and medical history, including history of atopic disease. Xerosis was evaluated using the Overall Dry Skin score. RESULTS: 756 patients were included. The prevalence of xerosis was 55.6%. Xerosis was significantly associated with older age (OR: 1.48, 95% CI: 1.16-1.89), female sex (OR: 1.80, 95 CI%: 1.29-2.53), treatments that can potentially cause xerosis (OR: 2.21, 95 CI%: 1.54-3.17), itching during sweating (OR: 7.11, 95% CI: 3.90-12.95), a history of dry skin (OR: 2.89, 95% CI: 1.65-5.08) and a history of atopic dermatitis (OR: 3.60, 95% CI: 1.99-6.52). CONCLUSION: Xerosis is highly prevalent in the elderly. A history of atopy, especially atopic dermatitis, is associated with an increased risk of xerosis in the elderly. PMID- 22104183 TI - Methicillin-resistant Staphylococcus aureus expressing low-level methicillin resistance may not be detected by the VITEK2(r) system. AB - Low-level methicillin-resistant Staphylococcus aureus may be difficult to detect with the VITEK(r) 2 system (VK2). Here, we suggest that S. aureus exhibiting VK2 oxacillin MIC of 1 or 2 mg/L and a negative cefoxitin screen should be tested for the presence of mecA or its gene product. PMID- 22104184 TI - Clinical evidence for rapid transmission of Lyme disease following a tickbite. AB - Lyme disease transmission to humans by Ixodes ticks is thought to require at least 36-48 h of tick attachment. We describe 3 cases in which transmission of Borrelia burgdorferi, the spirochetal agent of Lyme disease, appears to have occurred in less than 24 h based on the degree of tick engorgement, clinical signs of acute infection, and immunologic evidence of acute Lyme disease. Health care providers and individuals exposed to ticks should be aware that transmission of Lyme disease may occur more rapidly than animal models suggest. A diagnosis of Lyme disease should not be ruled out based on a short tick attachment time in a subject with clinical evidence of B. burgdorferi infection. PMID- 22104185 TI - Coccidioidomycosis of cervical lymph nodes in an HIV-infected patient with immunologic reconstitution on potent HAART: a rare observation in a nonendemic area. AB - Coccidioidomycosis is caused by the dimorphic fungus Coccidioides immitis, which is endemic in southwestern United States. We report a case of coccidioidomycosis of cervical lymph nodes that occurred early after the introduction of highly active antiretroviral therapy during the phase of immune system recovery, demonstrating a rare disease in a nonendemic area. PMID- 22104186 TI - Fulminant gestational hepatitis due to primary herpes simplex type 2 infection: use of serum HSV polymerase chain reaction for noninvasive diagnosis. AB - Acute gestational hepatitis from herpes simplex virus (HSV) infection is a rare but potentially life-threatening condition. We present the first reported case of primary HSV type 2 hepatitis in a pregnant woman who was diagnosed by detection of HSV-2 viremia via real-time polymerase chain reaction. The patient was successfully treated with acyclovir and delivered a healthy infant. PMID- 22104187 TI - Evaluation of 3 different rapid automated systems for diagnosis of urinary tract infections. AB - Urinary tract infections (UTI) are one of the most common infections in both hospitalised and ambulant patients. Rapid diagnostic of UTIs is necessary to provide early information about the presence of bacteria and the indication to administer an antibiotic therapy. Here we report on a study comparing 3 different rapid automated systems with the semiquantitative plate culture reference method in a university hospital with a highly complex patient population. In total, 2230 urine samples were consecutively tested using the UroQuick (Alifax), the BACSYS 40i (Sysmex), and the UF-1000i (Sysmex) system. In comparison to the results obtained by culture techniques, the automated systems showed a sensitivity of 73.0-80.9% and a specificity ranging between 61.8% and 92.8%. Additionally, sensitivity and specificity for the most common UTI-causing microorganisms were analysed and showed that sensitivity and specificity correlate with the colony forming units of microorganisms in the urine, with a sensitivity of nearly 90% for Gram-negative rods, typical for community acquired UTIs, but a very low sensitivity for Gram-positive bacteria and yeasts. This led us to the conclusion that the currently available automated systems might be rather helpful to analyse a typical UTI in an ambulant patient population but not for rapid diagnosis of UTIs in a complex population of hospitalized patients. PMID- 22104188 TI - Diagnostic coding of abuse related fractures at two children's emergency departments. AB - OBJECTIVES: Pediatric fractures suspicious for abuse are often evaluated in emergency departments (ED), although corresponding diagnostic coding for possible abuse may be lacking. Thus, the primary objective of this study was to determine the proportion of fracture cases investigated in the ED for abuse that had corresponding International Classification of Diseases (ICD) codes documenting abuse suspicion. Additional objectives were to determine the proportion of these fractures with admission ICD abuse coding, and physician text diagnoses recording abuse suspicion in the ED and/or admission notes. Factors possibly associated with abuse-related ED ICD codes were also examined. METHODS: Children less than three years of age that presented primarily with a fracture to two large academic children's hospitals from 1997 to 2007 and were evaluated for suspicion of abuse by child protective services were included in this retrospective review. The main outcome measure was the proportion of the fracture cases that had abuse suspicion reflected in ED discharge ICD codes. RESULTS: Of the 216 eligible patients, only 23 (11.5%) patients had ED ICD codes that included the possibility of abuse. Forty-nine (22.7%) had the possibility for abuse documented by physicians as an ED discharge diagnosis. In addition, 53/149 (35.6%) of all admitted patients and 34/55 (61.8%) of confirmed abuse cases included abuse-related admission ICD coding. Female gender was found to be a factor associated with ED ICD abuse codes. CONCLUSION: Current standards of ICD coding result in a significant underestimate of the prevalence of children assessed in the ED and hospital wards for possible and confirmed abusive fracture(s). PMID- 22104189 TI - Abusive head trauma at a tertiary care children's hospital in Mexico City. A preliminary study. AB - OBJECTIVES: Determine the prevalence, clinical signs and symptoms, and demographic and family characteristics of children attending a tertiary care hospital in Mexico City, Mexico, to illustrate the characteristics of abusive head trauma among this population. METHODS: This is a cross-sectional descriptive study of infants and children under 5, who suffered head trauma and were admitted to the National Pediatrics Institute in Mexico City, a tertiary care referral center. We reviewed medical records and extracted data on clinical and neurological signs and symptoms, fundus, radiological (long bones, thorax, CAT scan), and laboratory tests. We administered a standardized questionnaire assessing child abuse and neglect to the parents of the children included in the study. RESULTS: One hundred and twenty children, under 5 presenting with head trauma, were recruited, 13 (11%) were considered abusive head trauma (AbHT) and 107 (89%) were diagnosed as accidental head injury (AcHI). The AbHT group comprised younger infants (mean age 8 months) and the AcHI group included toddlers about an average of 25 months. To account for this significant age difference, we performed a comparison of age matched cases. The children in the AbHT were more likely to be female, the result of the first unintended pregnancy and the children of younger mothers (17-19). Mothers in this group had attended fewer than 5 prenatal care visits and fathers had a history of alcohol abuse. Five (38%) of the 13 AbHT children did not survive their injuries and overall showed greater neurological and respiratory compromise, increased prothrombin time (PT), and lower hematocrit values. The most common intracranial injuries suffered by children in the AbHT group were subdural/epidural hematoma and parenchymal/subarachnoid hemorrhage. Retinal hemorrhage was the most frequent ocular injury. CONCLUSIONS: In a tertiary care children's hospital, 11% of the children presenting with head trauma, were considered of abusive origin. Unintended pregnancy among teen mothers and substance abuse in the father were associated with abusive head trauma in this descriptive study. PMID- 22104190 TI - A pilot study of the tolerability and effects of high-definition transcranial direct current stimulation (HD-tDCS) on pain perception. AB - Several brain stimulation technologies are beginning to evidence promise as pain treatments. However, traditional versions of 1 specific technique, transcranial direct current stimulation (tDCS), stimulate broad regions of cortex with poor spatial precision. A new tDCS design, called high definition tDCS (HD-tDCS), allows for focal delivery of the charge to discrete regions of the cortex. We sought to preliminarily test the safety and tolerability of the HD-tDCS technique as well as to evaluate whether HD-tDCS over the motor cortex would decrease pain and sensory experience. Twenty-four healthy adult volunteers underwent quantitative sensory testing before and after 20 minutes of real (n = 13) or sham (n = 11) 2 mA HD-tDCS over the motor cortex. No adverse events occurred and no side effects were reported. Real HD-tDCS was associated with significantly decreased heat and cold sensory thresholds, decreased thermal wind-up pain, and a marginal analgesic effect for cold pain thresholds. No significant effects were observed for mechanical pain thresholds or heat pain thresholds. HD-tDCS appears well tolerated, and produced changes in underlying cortex that are associated with changes in pain perception. Future studies are warranted to investigate HD tDCS in other applications, and to examine further its potential to affect pain perception. PERSPECTIVE: This article presents preliminary tolerability and efficacy data for a new focal brain stimulation technique called high definition transcranial direct current stimulation. This technique may have applications in the management of pain. PMID- 22104191 TI - Psychometric properties of the eating disorder inventory in clinical and nonclinical populations in Taiwan. AB - OBJECTIVE: To examine psychometric properties and investigate factor structures of the Mandarin Chinese version of the Eating Disorder Inventory (C-EDI). METHOD: The Mandarin C-EDI and other self-administered questionnaires were completed by a group of female eating disorder (ED) patients (n = 551) and a group of female nursing students (n = 751). Internal consistency, and convergent and discriminant validities were evaluated. Exploratory and confirmatory factor analyses were conducted to examine the construct validity of the Mandarin C-EDI. RESULTS: The Mandarin C-EDI had good internal consistency and convergent and discriminant validities. With a few exceptions, the original clinically derived eight EDI subscales were clearly identified and the factorial validity of the first-order eight-factor structure and the second-order two-factor structure showed an acceptable degree of fit to our empirical data in clinical patients. DISCUSSION: The findings suggest that the Mandarin C-EDI is a valid tool for clinical use in Taiwan. PMID- 22104192 TI - Control of immunopathology during Plasmodium infection by hepcidin. AB - Malaria is a major health problem affecting millions of people annually especially in underdeveloped countries. Mutations causing alterations in hemoglobin production or structure are known to afford protection against the development of severe forms of malaria. Not surprinsingly, these hemoglobin disorders are present at high frequency in areas where malaria is endemic, indicating a survival advantage for individuals carrying them. Despite many years of research, the exact mechanisms underlying the protection afforded by hemoglobinopathies against severe forms of malaria have not yet found a definitive answer. One feature of hemoglobinopathies, observed both in humans and mice, is the fact that individuals carrying these disorders express low levels of the hormone hepcidin that plays a major role in iron homeostasis. Hepcidin acts by binding to the iron exporter ferroportin and inducing its degradation. When hepcidin levels are low, ferroportin expression in cells is sustained leading to export of intracellular iron. Importantly, low intracellular iron content may affect activation of innate immune cells leading to diminished production of pro inflammatory cytokines. Notably, several lines of evidence support the notion that development of severe forms of malaria is dependent on immune-mediated damage, caused by unfettered immune responses. Herein the hypothesis that hemoglobinopathies afford protection against severe forms of malaria by limiting exacerbated immune activation, via a mechanism that involves low hepcidin expression, is discussed. PMID- 22104193 TI - Severe diarrhea-dehydration in infancy permanently alters auditory function. AB - Of the myriad etiologies of sensorineural hearing impairment, metabolic stress is rarely considered. I posit that severe dehydration in conjunction with hypoxia, at least during infancy, prompts permanent changes in the cochlea. In a population-based prospective study of otitis media, children without otitis were found to have at age 4-8 years, worse auditory thresholds if as an infant had been hospitalized for diarrhea-dehydration. What is more, stapedius reflex thresholds tended to be lower in children who had been hospitalized for diarrhea dehydration: that is, less acoustic energy for arousal or to be frightening. The hypothesis that the transient metabolic stress of dehydration with hypoxia prompts permanent sensorineural hearing impairment with reduced uncomfortable loudness thresholds, is both (1) consistent in an evolutionary sense with a subsequent survival advantage, and (2) subject to verification both by descriptive studies of children undergoing ECMO (ExtraCorporeal Membrane Oxygenation) or care for congenital diaphragmatic hernia, and by animal studies. PMID- 22104194 TI - [Nursing intervention in the family treatment plan for anorexia nervosa]. AB - One of the main nursing interventions in the treatment of eating disorders is family psycho-education, an essential aspect of mental health treatment. This article describes and analyses the difficulties families expressed in the performance of a treatment plan for patients hospitalised for anorexia nervosa (AN) in the adolescent Day Hospital of Mental Health, of the Corporacio Sanitaria Parc Tauli, during 2009. Data was also collected data on professional interventions, performed by the nurse assigned to this unit, in order to group and categorise them, and as an aid to nursing intervention. A total of 10 families of the 10 patients admitted with a diagnosis of AN were included in the study period. In all cases, the patients were young women who had received treatment before in an Outpatient Unit, with partial or no response to the treatment. The difficulties expressed by the families were grouped into five categories from content analysis: problems in preparing a balanced diet, problems as they are unable to handle the behaviour and emotions of the patient, problems because as there are no previous family eating habits, problems because there is no family control or supervision, and problems with the established guidelines. Specific individualised interventions are proposed for developing and promoting a nursing care plan, and assessing the results. PMID- 22104195 TI - Irradiation of light emitting diode at 850nm inhibits T cell-induced cytokine expression. AB - BACKGROUND: An anti-inflammatory effect of light obtained from light-emitting diodes (LEDs) has been discovered, however, limited ranges of wavelengths have been used and the action mechanism has been rarely demonstrated. OBJECTIVE: We sought to analyze the immunomodulatory effect of LED on Jurkat T cells and human T cells. METHODS: Jurkat T cells with/without stimulation were irradiated once or five times using seven ranges of LED wavelengths, from 415nm to 940nm. Cytotoxic effects were examined by an MTT assay. Changes in T cell-induced cytokines, including IL-2, IL-4, IL-10, IL-12 and IFN-gamma, and their upstream signaling molecules, ZAP-70 and PKCtheta, were examined by real-time PCR, ELISA, and Western blot analysis. The effect of the LED wavelength, whose effect was identified on Jurkat T cells, was also examined in human CD3+ T cells with/without stimulation and in Dermatophagoides farinae-induced atopic dermatitis (AD) NC/Nga mice. RESULTS: Lower doses of LED irradiation at 850nm inhibited T cell-derived cytokines without inducing cell death in both Jurkat T cells and human T cells. Repeated exposure resulted in a greater increase of inhibitory effects than that observed with a single exposure, and these effects were identified in the NC/Nga AD model. CONCLUSIONS: Although more remains to be clarified, these results may support the clinical application of LED for immune regulation. PMID- 22104197 TI - VEGF and PEDF secretion in ARPE-19 and fhRPE cells. PMID- 22104196 TI - Current status of the congenital myasthenic syndromes. AB - Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, and in the postsynaptic region of the motor endplate. The disease proteins identified to date include choline acetyltransferase (ChAT), the endplate species of acetylcholinesterase (AChE), beta2-laminin, the acetylcholine receptor (AChR), rapsyn, plectin, Na(v)1.4, the muscle specific protein kinase (MuSK), agrin, downstream of tyrosine kinase 7 (Dok-7), and glutamine-fructose-6-phosphate transaminase 1 (GFPT1). Myasthenic syndromes associated with centronuclear myopathies were recently recognized. Analysis of properties of expressed mutant proteins contributed to finding improved therapy for most CMS. Despite these advances, the molecular basis of some phenotypically characterized CMS remains elusive. Moreover, other types of CMS and disease genes likely exist and await discovery. PMID- 22104198 TI - No difference in gluteus medius activation in women with mild patellofemoral pain. AB - CONTEXT: The gluteus medius (Gmed) is proposed to consist of 3 functional subdivisions (anterior, middle, and posterior). Gmed weakness and dysfunction have been implicated in numerous lower extremity disorders, including patellofemoral pain syndrome (PFPS). PFPS is a knee condition that frequently occurs in females and is associated with activities such as squatting and stair climbing. There is a lack of evidence for the role of the subdivisions of the Gmed in females with and without PFPS. OBJECTIVE: To compare muscle activation in the 3 Gmed subdivisions during 4 weight-bearing exercises in women with and without PFPS. DESIGN: Single-session, repeated-measures observational study. SETTING: University research laboratory. PARTICIPANTS: Convenience sample of 12 women with PFPS and 12 age- and gender-matched asymptomatic controls. INTERVENTION: Participants performed 4 weight-bearing exercises (wall press, pelvic drop, step-up-and-over, and unilateral squat) 3 times while surface electromyography (sEMG) activity of the Gmed segments was recorded. MAIN OUTCOME MEASURES: sEMG muscle activity for each functional subdivision of the Gmed during each weight-bearing exercise was analyzed using a mixed between-within-subjects ANOVA (post hoc Bonferroni). RESULTS: No statistically significant differences in muscle activation were found between the PFPS and healthy participants (P = .97). Furthermore, there were no statistically significant differences between the exercises (P = .19) or muscle fibers (P = .36) independent of group analyzed. However, the activation of the subdivisions varied according to the exercise performed (P = .003). CONCLUSIONS: Similar levels of muscle activation were recorded in the Gmed subdivisions of the PFPS and healthy participants during the different exercises. This is the first study to examine all 3 Gmed subdivisions in PFPS. Future studies using larger sample sizes should also investigate onset and duration of muscle activation in all Gmed subdivisions in both healthy individuals and those with PFPS. PMID- 22104199 TI - Future perspectives of gastric cancer treatment: from bench to bedside. PMID- 22104200 TI - Constitutive activation of signal transducers and activators of transcription 3 correlates with better prognosis, cell proliferation and hypoxia-inducible factor 1alpha in human gastric cancer. AB - OBJECTIVE: We aimed to investigate the biological significance of signal transducers and activators of transcription 3 (STAT3) in gastric carcinoma. METHODS: Immunohistochemistry was performed on tissue array slides containing 285 gastric carcinoma specimens. The relationship between the nuclear expression of phospho-Tyr705-STAT3 (pSTAT3), an active form of STAT3, and prognosis, clinicopathological factors, proliferation, cell cycle regulators, apoptosis regulators, or angiogenesis-related proteins was evaluated. RESULTS: In nonneoplastic gastric mucosa, pSTAT3 was observed primarily in the nuclei of cells in the proliferative zone and intestinal metaplasia. In gastric carcinomas, nuclear STAT3 activation was observed in 36% of cases and was positively correlated with the Ki-67 labeling index and earlier tumor stage, whereas it was inversely correlated with lymphatic metastasis and distant metastasis (p< 0.05). Moreover, survival analyses showed that pSTAT3 expression was an independent prognostic factor of good survival. In addition, the expression of nuclear pSTAT3 positively correlated with that of cyclin D1, p21, p27, hypoxia-inducible factor 1alpha, or vascular endothelial growth factor (p< 0.05). CONCLUSIONS: STAT3 activation is an early event in gastric tumorigenesis and significantly correlates with better prognosis, proliferation and angiogenesis. Thus, STAT3 activation may be a valuable prognostic variable and therapeutic target in gastric carcinoma. PMID- 22104201 TI - Molecular pathology of gastric carcinoma. AB - Gastric carcinoma (GC) is a biologically heterogeneous disease involving numerous genetic and epigenetic alterations. A very small proportion of GCs can be caused by a specific germ-line mutation of the E-cadherin gene (CDH1). Sporadic GC is developed through multistep processes that begin with Helicobacter pylori-induced atrophic gastritis. Epstein-Barr virus is another infectious cause of GC, and the above two infection-associated GCs are characterized by global CpG island methylation in the promoter region of cancer-related genes. Mutations of tumor protein p53 (TP53) and beta-catenin (CTNNB1) genes occur early in the development of GC and contribute to gastric carcinogenesis. Furthermore, significant numbers of GCs show loss of Runx3 due to hemizygous deletion and hypermethylation of the promoter region. Aberrant Cdx2 expression has been shown in precancerous lesions as well as GC. However, it remains unclear whether Cdx2 plays an oncogenic role in gastric carcinogenesis. GC with microsatellite instability is also a well defined subset exhibiting distinctive clinicopathologic features. Targeted therapy against GC with ERBB2 amplification recently improved the prognosis of patients with advanced GC. In addition, epigenetic changes in GC could be attractive targets for cancer treatment with modulators. A genome-wide search has been undertaken to identify novel methylation-silenced genes in GC, which will help us understand the overall molecular features of GC and further provide novel opportunities in the treatment of GC. PMID- 22104202 TI - Fabrication and validation of autologous human oral mucosal epithelial cell sheets to prevent stenosis after esophageal endoscopic submucosal dissection. AB - OBJECTIVES: Human oral mucosal epithelial cells derived from 7 healthy volunteer donors were cultured in a clean room in a cell-processing center (CPC) according to good manufacturing practice guidelines. Cell culture and fabricated transplantable epithelial cell sheets were validated for treating ulcers after endoscopic mucosal dissection. METHODS: The clonal growth and morphology of the human oral mucosal epithelial cells seeded on temperature-responsive surfaces were observed. During the cultivation, sterilization tests were performed to validate the environment in the CPC. To validate the purity and morphology of fabricated epithelial cell sheets, cell sheets harvested from temperature responsive surfaces by temperature reduction were examined by histology and flow cytometry. RESULTS: Human oral mucosal epithelial cells were successfully cultured and harvested as continuous cell sheets from temperature-responsive culture inserts without any animal-derived materials. During the cultivations, the sterile environment in the CPC was confirmed. The results of histological and flow cytometry analysis showed the high reproducibility of stratification and the purity of the fabricated human oral mucosal epithelial cell sheets. CONCLUSIONS: The method for fabricating epithelial cell sheets shown in this study was suitable for the validation for clinical trials and suggested usability of the fabricated cell sheets. PMID- 22104203 TI - Operating room to bench for gastric cancer. AB - Gastric cancer is the most common cancer in Korea, with an age-standardized rate of 61.2 in males and 23.9 in females (in 2007), one of the highest in the world. Using a large gastric tissue depository and the extensive clinical experience gained from gastric cancer surgery, we work as a 'translational researcher' to apply basic research tools and results to the clinical field. We are also interested in providing answers to the questions in the operating room using the methods of basic research. I would like to introduce our research activities in this review paper. PMID- 22104204 TI - Robot-assisted surgery for gastric cancer: experience at our institute. AB - OBJECTIVE: The robot-assisted surgical system was developed for minimally invasive surgery and is thought to have the potential to overcome the shortcomings of laparoscopic surgery. We introduced this system for the treatment of gastric cancer in 2008. Here we report our initial experiences of robot assisted surgery using the da Vinci system. METHODS: A retrospective review of robot-assisted gastrectomy for gastric cancer patients was performed in our institute. The clinicopathological features and surgical outcomes were analyzed. Whereas the procedures of the gastrectomy were similar to those of the usual laparoscopic surgery, several aspects such as the port placement and the role of the assistant were modified from those for conventional laparoscopic surgery. RESULTS: From January 2008 to December 2010, 61 patients with gastric cancer underwent robot-assisted surgery. Gastrectomy was distal in 46 patients, total in 14, proximal in 1 and no operation was converted to the open procedure. D2 lymph node dissection was performed on 28 patients in the distal gastrectomy group and on 11 in the total gastrectomy group. Complications occurred in 2 cases (4%): these consisted of ruptured sutures and hemorrhage from the anastomotic site. CONCLUSIONS: This study demonstrated that robot-assisted gastrectomy using the da Vinci system can be applied safely and effectively for patients with gastric cancer. PMID- 22104205 TI - Future perspectives for the development of chemotherapy for advanced gastric cancer: Japanese and global status. AB - In Japan, gastric cancer is the second leading cause of cancer-related mortality after lung cancer. Many randomized trials of various chemotherapeutic regimens have been conducted, contributing to improved outcomes in patients with advanced gastric cancer (AGC). The standard regimen for AGC is a combination of S-1 and cisplatin in Japan. Recently, new drug development has focused on molecular target agents, and personalized therapy for AGC has just begun. In patients with human epidermal growth factor receptor 2-positive AGC, trastuzumab in combination with chemotherapy improves survival. Furthermore, abundant information about the heterogeneity and biological backgrounds of AGC patients has been compiled. New strategies for the development of personalized therapy should be studied in the future. PMID- 22104206 TI - The roles of surgical oncologists in the new era: minimally invasive surgery for early gastric cancer and adjuvant surgery for metastatic gastric cancer. AB - In the new era of technical development in surgery, operative devices, molecular targeting and chemotherapeutic agents, surgical oncologists have two main roles in the treatment of gastric cancer. One is to provide patients with minimally invasive surgery, including laparoscopy- or robot-assisted surgery in early gastric cancer patients, and the new concept of surgical intervention toward advanced and metastatic disease. Since recently, laparoscopy-assisted distal gastrectomy has become prevalent in Japan as a surgery which is minimally invasive for the patients and provides them with a good quality of life afterwards. However, the provision of advanced surgical techniques, including lymph node dissection and reconstruction, is more important for patient survival. The second role of surgical oncologists is to evaluate the significant values of the aggressive treatment which we term 'adjuvant surgery' for stage IV gastric cancer patients who have successfully responded to initial chemotherapy for curative intent. Stage IV gastric cancer patients are now being informed about the possibility of longer survival with the new chemotherapeutic and surgical strategic approach. PMID- 22104207 TI - Toll/interleukin-1 receptor member ST2 exhibits higher soluble levels in type 2 diabetes, especially when accompanied with left ventricular diastolic dysfunction. AB - BACKGROUND: Soluble ST2, a member of the of the Toll/IL-1 superfamily, is a novel biomarker with exceptional predictive value in heart failure and myocardial infarction- related mortality as well as in acute dyspneic states. Soluble ST2 is considered a decoy receptor of IL 33 that blocks the protective effects of the cytokine in atherosclerosis and cardiac remodeling. In the present study we investigated the differences in the levels of soluble ST2, BNP and hs-CRP between healthy controls and patients with type 2 diabetes with and without left ventricular diastolic dysfunction. A secondary aim was to investigate correlations between sST2 and other biomarkers of type 2 diabetes, such as HbA1c. METHODS: 158 volunteers were recruited and underwent a complete Doppler echocardiographic evaluation of both systolic & diastolic cardiac function. All subjects with ejection fraction<50% were excluded. The study population was divided in 4 groups as follows: A: 42 healthy controls, B: 18 subjects without diabetes with LVDD, C: 48 patients with type 2 diabetes without LVDD & D: 50 patients with type 2 diabetes & LVDD. ELISA technique was performed to measure sST2 levels. Statistical analysis was performed with Kruskal-Wallis & Mann Whitney test (continuous variables), chi squared & Fischer exact test (discrete variables), Spearman coefficient (univariate analysis) and step-wise backward method (multivariate analysis). RESULTS: Patients with type 2 diabetes with (p<0.001) or without LVDD (p=0.007) had higher serum ST2 levels compared to healthy controls, state found also for hs-CRP levels but not for the corresponding BNP levels (p=0.213 & p=0.207 respectively). Patients with type 2 diabetes & LVDD had higher serum ST2 in relation to diabetic patients without LVDD (p=0.001). In multivariate analysis HbA1c positively and independently correlated with sST2 levels in both groups of patients with type 2 diabetes. CONCLUSIONS: Patients with type 2 diabetes exhibit higher sST2 levels compared to healthy controls. The presence of LVDD in patients with type 2 diabetes is associated with even higher sST2 levels. A significant correlation between glycemic control and sST2 levels was also revealed. PMID- 22104208 TI - Mutations in the HIV-1 reverse transcriptase tryptophan repeat motif affect virion maturation and Gag-Pol packaging. AB - Our goal was to determine the contribution of HIV-1 reverse transcriptase tryptophan repeat motif residues to virion maturation. With the exception of W402A, we found none of the single substitution mutations exerted major impacts on virus assembly or processing. However, all mutants except for W410A exhibited significant decreases in virus-associated RT, presumably a result of unstable RT mutant degradation. Mutations W398A, W401A and W406A decreased the enhancement effect of efavirenz on PR-mediated Gag processing efficiency, which is in agreement with their destabilizing RT effects. Furthermore, combined double or triple W398, W401 and W406 mutations significantly affected virus processing and Gag-Pol packaging. Further analyses suggest that inefficient PR-mediated Gag cleavage partly accounts for the virion processing defect. Our results support the idea that in addition to playing a role in RT heterodimer stabilization, the RT Trp repeat motif in the Gag-Pol context is also involved in PR activation via Gag-Pol/Gag-Pol interaction. PMID- 22104209 TI - ADAR1 is a novel multi targeted anti-HIV-1 cellular protein. AB - We examined the antiviral activity of ADAR1 against HIV-1. Our results indicated that ADAR1 in a transfection system inhibited production of viral proteins and infectious HIV-1 in various cell lines including 293T, HeLa, Jurkat T and primary CD4+ T cells, and was active against a number of X4 and R5 HIV-1 of different clades. Further analysis showed that ADAR1 inhibited viral protein synthesis without any effect on viral RNA synthesis. Mutational analysis showed that ADAR1 introduced most of the A-to-G mutations in the rev RNA, in the region of RNA encoding for Rev Response Element (RRE) binding domain and in env RNA. These mutations inhibited the binding of rev to the RRE and inhibited transport of primary transcripts like gag, pol and env from nucleus to cytoplasm resulting in inhibition of viral protein synthesis without any effect on viral RNA synthesis. Furthermore, ADAR1 induced mutations in the env gene inhibited viral infectivity. PMID- 22104210 TI - HIV-1 Tat induces biochemical changes in the serum of mice. AB - The HIV-1 Tat protein is released by infected cells and has numerous biological activities which might contribute either to the impairment of the immune response or to viral dissemination and pathogenesis. To date, the effects of Tat protein on metabolites remain unclear. In this study, a metabolomic study on serum of HIV 1 Tat-induced ICR mice was performed to research the pathologic mechanism of Tat protein by using gas chromatography coupled to mass spectrometry (GC/MS). Clear separations among the HIV-1 Tat-induced mice and the inaTat-induced or control mice were observed by principal component analysis and partial least-squares discriminant analysis based on the GC/MS spectral data. Additionally, 16 significantly changed metabolites in HIV-1 Tat-induced mice were identified that are involved in multiple perturbed metabolic pathways, which contributed to the elucidation of the complex pathogenic mechanism of Tat protein and may shed new lights on future improvement of HIV-1 therapy. PMID- 22104211 TI - Determining novel functions of Arabidopsis 14-3-3 proteins in central metabolic processes. AB - BACKGROUND: 14-3-3 proteins are considered master regulators of many signal transduction cascades in eukaryotes. In plants, 14-3-3 proteins have major roles as regulators of nitrogen and carbon metabolism, conclusions based on the studies of a few specific 14-3-3 targets. RESULTS: In this study, extensive novel roles of 14-3-3 proteins in plant metabolism were determined through combining the parallel analyses of metabolites and enzyme activities in 14-3-3 overexpression and knockout plants with studies of protein-protein interactions. Decreases in the levels of sugars and nitrogen-containing-compounds and in the activities of known 14-3-3-interacting-enzymes were observed in 14-3-3 overexpression plants. Plants overexpressing 14-3-3 proteins also contained decreased levels of malate and citrate, which are intermediate compounds of the tricarboxylic acid (TCA) cycle. These modifications were related to the reduced activities of isocitrate dehydrogenase and malate dehydrogenase, which are key enzymes of TCA cycle. In addition, we demonstrated that 14-3-3 proteins interacted with one isocitrate dehydrogenase and two malate dehydrogenases. There were also changes in the levels of aromatic compounds and the activities of shikimate dehydrogenase, which participates in the biosynthesis of aromatic compounds. CONCLUSION: Taken together, our findings indicate that 14-3-3 proteins play roles as crucial tuners of multiple primary metabolic processes including TCA cycle and the shikimate pathway. PMID- 22104212 TI - Long-term balancing selection at the antiviral gene OAS1 in Central African chimpanzees. AB - Oligoadenylate synthetases (OAS) are interferon-induced enzymes that participate in the first line of defense against a wide range of viral infection in animals. Upon activation by viral double-stranded RNA, OAS synthesizes (2-5) oligoadenylates, which activate RNase L, leading to the nonspecific degradation of cellular and viral RNA. Some association studies in humans suggest that variation at one of the OAS genes, OAS1, could be influencing host susceptibility to viral infection. We assessed the diversity of OAS1 in hominoid primates with a focus on chimpanzees. We found that the OAS1 gene is extremely polymorphic in Central African chimpanzee and exhibits levels of silent and replacement diversity much higher than neutral regions of the chimpanzee genome. This level of variation strongly suggests that balancing selection is acting on OAS1, and indeed, this conclusion was validated by several tests of neutrality. We further demonstrated that balancing selection has been acting at this locus since the split between chimpanzees, humans, and gorillas (~8.6 Ma) and caused the persistence of two deeply divergent allelic lineages in Central African chimpanzees. These two groups of OAS1 alleles differ by a large number of amino acids (a.a.), including several a.a. putatively involved in RNA binding. It is therefore very likely that variation at the OAS1 locus affects the innate immune response of individuals to specific viral infection. Our data strongly suggest that interactions between viral RNA and OAS1 are responsible for the maintenance of ancestral polymorphisms at this locus for at least 13.2 My. PMID- 22104213 TI - Solid phase analytical derivatization of anthropogenic and natural phenolic estrogen mimics with pentafluoropyridine for gas chromatography-mass spectrometry. AB - A simple, low cost, fast and sensitive method is reported for the determination of the four endocrine disrupting chemicals (EDCs) 4-tert-butylphenol, 4-tert octylphenol, bisphenol A and 17beta-estradiol using pentafluoropyridine as the derivatizing reagent. These EDCs were determined by simultaneous extraction and derivatization in a solid phase analytical derivatization (SPAD) technique without the aid of any phase transfer catalyst (PTC) or an ion-pair mechanism. Recoveries of analytes as their tetrafluoropyridyl derivatives from water ranged from 71% for 4-tert-butylphenol to 106% for 17beta-estradiol; from urine they ranged from 61% for 17beta-estradiol to 91% for 4-tert-octylphenol; and from humic acids solution the ranged from 59% for 17beta-estradiol to 104% for 4-tert octylphenol in humic acid solutions. Calibration curves were constructed from a matrix of human male urine in the range 1-40 ng/mL and had coefficients of correlation greater than 0.99. For 4-tert-butylphenol, bisphenol A and 17beta estradiol the limits of quantitation were 5 ng/mL and for 4-tert-octylphenol it was 1 ng/mL. This method was applied to determine EDCs and detected 4-tert octylphenol, bisphenol A and 17beta-estradiol in concentrations comparable to those found in the literature. The method offers advantages in speed of analysis, reduced reagent and specificity of derivatization. PMID- 22104214 TI - Low cross-linked molecularly imprinted monolithic column prepared in molecular crowding conditions. AB - Molecular crowding is a new approach to promoting molecular imprinting more efficiently. In this work, this concept was applied to the preparation of low cross-linked imprinted polymers in the presence of an immobilised template for stabilizing binding sites and improving molecular recognition. An imprinted monolithic column was synthesized using a mixture of 2,4-diamino-6-methyl-1,3,5 triazine (template), 2,4-diamino-6-(methacryloyloxy) ethyl-1,3,5-triazine (polymerisable template), methacrylic acid, ethylene glycol dimethacrylate, and polystyrene (molecular crowding agent). Some polymerization factors, such as template-monomer molar ratio, the composition of the porogen and crosslinking density, on the imprinting effect of resulting MIP monolith were systematically investigated. The results indicated that the imprinted monolithic columns prepared in the presence of molecular crowding agent retained affinity and specificity for template even when prepared with a level of cross-linker as low as 9%. Moreover, a stoichiometric displacement model for retention was successfully applied to evaluate the interaction between the solute and the stationary phase. Compared with the low cross-linked MIP prepared by conventional polymerization, the molecular crowding-based low cross-linked monolithic MIPs showed higher selectivity. The results suggested that molecular crowding is a powerful strategy to increase the effect of molecular imprinting at a low level of crosslinker. PMID- 22104215 TI - New method for resolving the enantiomeric composition of 2-methyltetrols in atmospheric organic aerosols. AB - In order to facilitate the determination of the primary and secondary origin of atmospheric organic aerosols, a novel method involving chiral capillary gas chromatography coupled with mass spectrometry has been developed and validated. The method was focused on the analysis of 2-methylerythritol and 2 methylthreitol, considered to be tracers of secondary organic aerosols from the oxidation of atmospheric isoprene. The method was validated by performing various tests using authentic standards, including pure enantiomeric standards. The result showed that the analytical method itself does not affect the enantiomeric composition of the samples analyzed. The method was applied on atmospheric aerosols from a boreal forest collected in Aspvreten, Sweden and on laboratory samples obtained from liquid phase oxidation of isoprene and smog chamber experiments. Aerosol samples contained one enantiomer of 2-methylerythritol in significantly larger quantities than the others. In contrast, the liquid-phase oxidation of isoprene and its gas-phase oxidation in the smog chamber produced all enantiomers in equal quantities. The results obtained where the enantiomer fraction, EF, is larger than 0.50 suggest that 2-methyltetrols in atmospheric aerosols may also have biological origin. Information about the differences between enantiomer fractions obtained using this method brings new insights in the area of atmospheric aerosols. PMID- 22104216 TI - [Screening of metastasis-related microRNAs in the large-cell lung cancer cell lines with different metastastic potentials]. AB - BACKGROUND AND OBJECTIVE: MicroRNAs (miRNAs) regulate a wide range of cancer associated processes, including cell division, proliferation, cell cycle, apoptosis, angiogenesis, invasion, and metastasis. A microarray was performed to analyze metastasis-related miRNAs with different metastastic potentials and to further elucidate their mechanism in the large-cell lung cancer cell lines. METHODS: L9981 and NL9980 cells were harvested, and total RNA was extracted for CY3. RNA hybridization was then performed on the chip with marked miRNAs. MiRNAs with significantly different expression were selected through statistical analysis. A real-time polymerase chain reaction (PCR) was employed to validate the results of the microarray, and target genes were predicted using bioinformatics. RESULTS: Expressions of 22 miRNAs were significantly different in the L9981/NL9980 cell lines. Compared with the NL9980, 13 miRNAs were upregulated in the L9981 cell lines, whereas 9 miRNAs were downregulated. The result of miR 125a-3p expression based on real-time PCR was consistent with the microarray. Insulin-like growth factor 2 might be a target gene of miR-125a-3p. CONCLUSION: The metastatic miRNA profile in large-cell lung cancer was successfully screened out. PMID- 22104217 TI - [Effection and mechanism of radiosensitivity of non-small cell lung cancer cell line H358 following gefitinib treatment]. AB - BACKGROUND AND OBJECTIVE: The epidermal growth factor receptor (EGFR) is an important determinant of radioresponse, the elevated expression and activity of which frequently correlates with radioresistance in several cancers, including non-small-cell lung carcinoma (NSCLC). The molecular blockade of EGFR signaling is a promising therapeutic strategy for the enhancement of the cytotoxic effects of radiotherapy. The aims of the present study are to observe whether gefitinib, a selective EGFR tyrosine kinase inhibitor, can radiosensitize the NSCLC H358 cell line and to investigate the mechanism by which this drug restores the radiosensitivity of NSCLC cells. METHODS: NSCLC cell line H358 was divided into two groups, namely the X-ray and the gefitinib-interfering groups. The former was irradiated using X-ray only, and the latter was treated with 1 MUmol/L gefitinib 24 h before irradiation under the same conditions. The cells were tested using the clonogenic cell survival assay to identify the radiosensitivity of both groups. Immunostaining for confocal microscopy was used to observe nuclear gamma H2AX repair and EGFR foci after irradiation. Nuclear EGFR expression was detected using Western blot after radiotherapy. RESULTS: In the clonogenic cell survival assay, the survival fraction in the gefitinib-interfering group was lower than that in the X-ray group at different doses. Surviving fraction of 2 Gy (SF2) were 0.000,865 and 0.011,1 for the gefitinib-interfering and the X-ray groups, respectively. Sensivive enhancement ratio (SER) was 2.815. Immunostaining for confocal microscopy suggested that more nuclear gamma-H2AX foci are present in the gefitinib-interfering group than in the X-ray group. The nuclear gamma-H2AX foci also stayed longer in the gefitinib-interfering group. EGFR translocated into the nucleus within 1 h in X-ray group, but stayed in the cytoplasma in the gefitinib-interfering group. Western blot was tested using SPSS 13.0, P=0.042. CONCLUSION: Gefitinib, at the cellular level, radiosensitizes EGFR with NSCLC H358 by blocking EGFR nuclear translocation as one of its mechanisms. PMID- 22104218 TI - [Decorin protein is down-regulated in non-small cell lung cancer tissue and significantly associated with histological type]. AB - BACKGROUND AND OBJECTIVE: Decorin is a protein component of the extracellular matrix. It has been proven that decorin plaid an important role in matrix assembly. The protein is also capable of suppressing tumor cell growth. The aim of this study is to examine the protein levels of decorin in tissue samples of non-small cell lung cancer (NSCLC) patients and evaluate its potential clinical value. METHODS: Decorin protein levels in tumor tissues and corresponding normal tissues from 16 cases of lung squamous cell carcinoma (SCC) were determined by Western blot analysis. Fifty-one NSCLC samples, including both tumor and normal lung tissues, were examined by immunohistochemical (IHC) staining. RESULTS: Western blot results showed that decorin protein levels in 75.0% (12/16) of the SCC tumor tissues were lower than those of the corresponding normal lung tissues. IHC results showed that positively stained decorin was detected in only 11.8% of the tumor tissues, significantly lower than that observed in normal alveoli tissues (53.1%, P<0.001). In lung adenocarcinoma (ADC), almost no expression of decorin was observed, in contrast to squamous cell carcinoma (SCC) (P=0.006). CONCLUSION: Decreased levels of decorin in NSCLC tissue samples, particularly ADC cases, indicate that decorin could play a role in lung cancer carcinogenesis. PMID- 22104219 TI - [3.0T MR diffusion-weighted imaging: evaluating diagnosis potency of pulmonary solid benign lesions and malignant tumors and optimizing b value]. AB - BACKGROUND AND OBJECTIVE: Diffusion is caused by random translational molecular motion, also known as Brownian water motion. Diffusion-weighted imaging (DWI) is the only imaging method that can be used to evaluate the diffusion process in vivo. The aim of this study is to evaluate 3.0T magnetic resonance imaging (MRI) DWI with phased-array coil and the array spatial sensitivity encoding technique (ASSET) of diagnosis potency in the discrimination of pulmonary solid benign lesions and malignant tumors. This study also aims to optimize b value. METHODS: One hundred and sixteen patients with 120 lesions confirmed by pathology and clinical diagnosis underwent T2 weighted imaging (T2WI), T1 weighted imaging, T2WI fat suppression, and DWI (diffusion factors of 200 s/mm2, 500 s/mm2, 800 s/mm2, 1,000 s/mm2) examinations by ASSET with 3.0T MR. The signal intensity of DWI images and the apparent diffusion coefficient (ADC) values of the lesions were measured. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and ADC were compared among different b values. Receiver operating characteristic (ROC) curves were analyzed and the b values were optimized. RESULTS: Both the SNR and CNR significantly differed among varied b values (P<0.001, P=0.002). The ADC values of pulmonary solid benign lesions and malignant tumors were gradually reduced with increasing b value, and the differences were statistically significant (P<0.001, P<0.001). ROC analysis shows that the area under curve (AUC) values were 0.831, 0.876, 0.813, 0.785 (b=200 s/mm2, 500 s/mm2, 800 s/mm2, 1,000 s/mm2, respectively). The AUC with a b value of 500 s/mm2 was the largest. The optimal threshold of ADC was 1.473*10-3 mm2/s, and the sensitivity and specificity were 80% and 84%, respectively. CONCLUSION: 3.0T MR DWI with phased array coil and ASSET has moderate diagnosis potency in differentiating pulmonary solid benign lesions and malignant tumors. The optimal b value is 500 s/mm2. PMID- 22104220 TI - [Relationship between the genetic polymorphisms of phase I and II drug metabolizing enzymes, as well as the outcome of chemotherapy in advanced non small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Currently available studies on the polymorphisms of drug-metabolizing enzymes and their chemotherapeutic effects in non-small cell lung cancer are not consistent. In the present study, the relationship of the gene polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1), cytochrome P450 2D6 (CYP2D6), and glutathione S-transferase M1 (GSTM1) enzymes with chemotherapeutic effects were investigated. The effects of these relationships on the survival of advanced non-small cell lung cancer patients were also examined. METHODS: Four drug metabolism enzymes were genotyped in lung cancer patients by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. These patients were followed for five years. RESULTS: The chemotherapeutic effect on patients carrying B-type CYP1A1 and null-type GSTM1 was better than on those carrying other types (P<0.001). The chemotherapeutic effect on patients carrying A-type CYP1A1 was better than on those carrying the B and C types when non-platinum drugs were administered (P=0.041). The chemotherapeutic effect on patients carrying null-type GSTM1 was better than on those carrying the functional type when platinum drugs were administered (P=0.011). The four enzymes did not affect the overall survival (OS) of advanced non-small cell lung cancer patients (P>0.05). CONCLUSION: The chemotherapeutic effect on patients carrying A-type CYP1A1 was better than on those carrying the B and C types when non-platinum drugs were administered. The chemotherapeutic effect on patients carrying null-type GSTM1 was better than on those carrying the functional type when platinum drugs were administered. The four enzymes did not affect the OS of advanced non-small cell lung cancer patients. PMID- 22104221 TI - [Radiofrequency ablation for the treatment of lung neoplasms: a retrospective study of 329 cases]. AB - BACKGROUND AND OBJECTIVE: In recent years, radiofrequency ablation (RFA) has been increasingly utilized as a non-surgical treatment option for patients with primary and metastatic lung tumors. The aim of this study is to evaluate the safety and therapeutic effects of RFA among patients with pulmonary neoplasms. METHODS: Patients with lung tumors treated with RFA from October 1999 to July 2006 in this hospital were enrolled into the study. A total of 329 cases, 237 primary lung tumors and 92 metastatic tumors, were retrospectively analyzed and evaluated for complications, local progression, and overall survival after one, two, and five years after RFA. RESULTS: The complications of RFA with surgery included 63 (19.1%) patients with pneumothorax, 14 (4.2%) with hemoptysis (one death), 10 (3.0%) with hemothorax, 15 (4.5%) with pneumonia, and three (0.9%) with pericardial tamponade (one death). The mortality within 30 days was 0.6%. Needle tract tumors were observed in 6 patients (1.8%). The median time for progression was 21.6 months. The overall survival rates at one, two, and five years after RFA were 68.2%, 35.3% and 20.1%, respectively. Up to 78 (23.7%) patients with tumors that exceed 4 cm developed local progression, and a significant difference was found. No significant difference was found among patients with tumors less than 3 cm and among those with 3 cm-4 cm tumors. CONCLUSION: RFA is a well-tolerated, reliable, and safe method for the treatment of lung malignancies. PMID- 22104222 TI - [Advances of treatment of small cell lung cancer in 2011 American Society of Clinical Oncology Annual Meeting]. PMID- 22104223 TI - [Current status and future direction of multi-targeted drugs in the era of personalized therapy--overview of advances in multi-targeted therapy in non-small cell lung cancer]. AB - Multi-targeted tyrosine kinase inhibitors (TKIs) play important roles in the treatment of non-small cell lung cancer (NSCLC). Recently, results of several large phase III studies have been published, showing bittersweet efficacy of multi-targeted TKIs. In the era of personalized therapy, optimal use of multi targeted TKIs is worthy of further investigation. In this review, we summarized current clinical development and future direction of multi-targeted TKIs in NSCLC. PMID- 22104224 TI - [Research progress in non-small cell lung cancer with concomitant EML4-ALK fusion gene and EGFR gene mutation]. AB - Lung cancer is one of the most prevalence malignances, of which non-small cell lung cancer (NSCLC) account for 80%-85% of lung cancer. Molecular target therapy is one of the most popular and promising field of NSCLC treatment, and its hotspots includes EGFR (epidermal growth factor receptor), EML4-ALK (echinoderm microtubule associated protein like4-anaplastic lymphoma kinase), etc. Former researches indicated that EML4-ALK fusion and EGFR mutation were excluded mutually. However, cases of patients harbored concomitant EML4-ALK fusion gene and EGFR mutation have been reported continuously at recent. This review aims to summarize the incidence and molecular structure of EML4-ALK fusion gene and EGFR mutation, as well as clinical features of patients with the concomitant genes induced NSCLC. PMID- 22104225 TI - [Research advances on Th17 cells in tumor]. AB - The Th17 cells, identified recently as a novel CD4+ T cell lineage, are characteristic of their production of IL-17 and distinct from Th1 and Th2 lineages. Their involvement in autoimmune and chronic inflammation diseases has been well observed. Recent evidence suggests that Th17 cells are also involved in tumor immunology. However, it remains unclear that how these cells regulate immune responses to tumor growth. In this review, we summarize the most recent findings about the biologics of the Th17 cells in tumor development with a hope of providing new insights into future development of effective new cancer immunotherapies. PMID- 22104226 TI - [Advances of heterogeneity of EGFR in non-small cell lung cancer]. PMID- 22104227 TI - [Advances of precise radiotherapy for lung cancer]. AB - At present lung tumor radiation therapy has entered the accurate radiotherapy era. Precise radiotherapy includes intensity modulated radiotherapy (IMRT), image guided radiotherapy (IGRT) and stereotactic body radiotherapy (SBRT). During the process of implementing precise radiotherapy, these problems should be fully considered to ensure executing precise radiotherapy accurately: patient positioning, controlling of the lung tumor motion, selecting of image techniques, PTV margin, dose prescription and reporting, arrangement of beams, controlling of dose volume and treatment delivering. PMID- 22104228 TI - [Endobronchial hamartoma removed completely by bronchoscopic electrosurgical snaring: a case report]. PMID- 22104229 TI - [Preface for special issue on image quality and dose in digital era]. PMID- 22104230 TI - [Study of appropriate dosing in consideration of image quality and patient dose on the digital radiography]. AB - Recently about 90% of radiographs have been taken by the digital radiographic system in Japan, but the exposure dose of the patients are about ten-times different among the systems. We understood it by a surveytaken in 2007. We studied the visual evaluation with varying exposure doses using the image phantom of the lumber AP, lumber lateral and hip AP. Additionally we measured quantum efficiency (DQE) of the digital systems. We also studied the exposure index (EI) of IEC standard to see whether it is able to be the sensitivity index among the digital systems. DQE in 1.0 cycle/mm of CR, FPD (GOS), FPD (CsI, a-Se) became 0.2 0.25, 0.3, 0.5, respectively. Our results display that the dose reduction is relative to DQE. The visual evaluation results also show that dose reduction is possible among the systems. From these results, we are able to reduce the exposure dose of the patients at the clinical site. We also suggest that we manage the exposure dose using the E.I of the IEC standard. PMID- 22104231 TI - [Estimation of radiation dose and image quality of coronary 320-row area detector CT angiography by optimal prospective ECG-gated protocols for different heart rate]. AB - The purpose of this study is to estimate radiation dose and image quality of ECG gated coronary 320-area detector CT (ADCT) angiography which was acquired using the protocols that were considered as optimal methods for different heart rates (HR) in 1031 consecutive patients (M/F=580/451, 65 +/- 12 yr) without arrhythmias. We set up 5 protocols for 320-ADCT based on the relationship among heart rates, temporal resolution, gantry rotation speed, optimal reconstruction phase and slow filling phase on 64-multidetector-row computed tomography (MDCT), ie, 1) mid-diastolic (75% of RR) 1 beat scan (MD 1 beat, N=761(73.8%)) for HR <= 60, 2) mid-diastolic (75% of RR) 2 beat scan (MD 2 beat, N=135) for 61 <= HR <= 65, 3) end-systolic and mid-diastolic (37-80% of RR) 2 beat scan (ES-MD 2 beat, N=92) for 66 <= HR <= 75, 4) end-systolic (R+280-430 ms) 2 beat scan (ES 2 beat, N=21) for 76 <= HR <= 80, and 5) end-systolic (R+250-400 ms) 3 beat scan (ES 3 beat, N=22) for 81 <= HR <= 105. Image quality was classified into 3 categories (excellent (3 points), acceptable (2 points), and unacceptable (1 point)). Scanning time, DLP.e and image quality score were 1.4 +/- 0.1 s, 220 +/- 59 mGy.cm, 3.0 +/- 0.2 points in MD 1 beat, 2.2 +/- 0.2 s, 434 +/- 118 mGy.cm, 2.9 +/- 0.3 points in MD 2 beat, 2.1 +/- 0.2 s, 729 +/- 229 mGy.cm, 2.7 +/- 0.5 points in ES-MD 2 beat, 1.9 +/- 0.1 s, 432 +/- 148 mGy.cm, 2.2 +/- 0.6 points in ES 2 beat, and 2.4 +/- 0.2 s, 669 +/- 152 mGy.cm, 2.3 +/- 0.6 points in ES 3 beat respectively. In conclusion, the prospective ECG-gated scan protocol for coronary 320-ADCT angiography in any HR group was considered reasonable and proper for image quality and radiation dose. PMID- 22104232 TI - [Quantitative evaluation of low contrast detectability in a brain computed tomography: investigation for the effect of window width on recognition of hyperacute ischemic stroke]. AB - In diagnostic brain computed tomography (CT) imaging of hyperacute ischemic stroke, the recognition of subtle lesions is difficult and may be missed. The aim of this study was to evaluate quantitatively the effect of the window width on low contrast detectability by using digital phantom images intended for detection of hyperacute ischemic stroke, and clinical CT images. We first derived the digital phantom images by subtracting the simulated signal data (intensity=1-3 hounsfield units (HU), diameter=10-30 mm) from the water phantom images at various mAs values. Observer studies were then performed under the various window widths at 20, 40, 60, and 80 HU by using the 30 digital phantom images and the 30 water phantom images. In addition, observer studies on brain CT images with 30 abnormal cases and 30 normal cases were performed under the window widths at 20 and 80 HU. Studies were also performed under the simultaneous display of the set of brain CT images on each window width. As a result of evaluation by receiver operating characteristic analysis, narrowing of the window width can improve the low contrast detectability in CT images with noticeable noise, and can decrease the variation in the interpretation skills between observers in clinical CT images. Moreover, the interpretation accuracy was improved by displaying simultaneously the clinical CT image set on window widths at 20 and 80 HU. PMID- 22104233 TI - [Investigation of image quality identification utilizing physical image quality measurement in direct- and indirect-type of flat panel detectors and computed radiography]. AB - The purpose of this study was to investigate image quality identification methods among direct- and indirect-type flat panel detectors (FPDs) and a computed radiography (CR) system using two radiation qualities RQA3 and RQA5 defined in the IEC 61267 standard. For each system, the digital characteristic curve, the presampled modulation transfer function (MTF), and the normalized noise power spectrum (NNPS) were measured. Images for a burger phantom and a foot-bone phantom were processed by resolution identification utilizing two-dimensional Fourier transform, and then contrast-to-noise ratio (CNR) for each image was measured. For the RQA3, the direct FPD system indicated the highest DQE value, and for the RQA5 DQE value of indirect FPD system, it was a little higher than that of direct FPD system. The CNR results with the resolution identification displayed good accordance with the DQE results in both phantoms. From the DQE results, dose ratios for image quality identification were determined, and the CNRs of the dose-adjusted images were measured. The results for, the CNRs of all systems showed good coincidence. From these findings, they indicated that the DQE measurement is effective to determine the exposure parameters for equalizing the image quality of different types of radiographic systems. PMID- 22104234 TI - [Radiation reduction and image quality improvement with iterative reconstruction at multidetector-row computed tomography]. AB - The purpose of our study was to investigate the relationship between image quality and radiation dose for the filtered backprojection (FBP) with smooth kernel and the iterative reconstruction (iDose) based on image noise, image resolution, CT number, and low-contrast detectability. We used the Catphan phantom and scanned at 65, 45, 32, and 20 mAs on a 64-detector CT. Image reconstruction algorithm and kernel were employed FBP with standard (C type) and FBP with smooth (A type) kernel as images obtained at 20-65 mAs. Regarding to 20 45 mAs, we additionally reconstructed it using the iDose. After scanning, we measured image noise, full width at half maximum (FWHM), and CT number and assessed low-contrast detectability. Image noise acquired at iDose was 10.9, 11.1, and 11.2 HU corresponding to 45, 32, and 20 mAs, respectively. Compared to FBP with standard kernel, FBP with smooth kernel increased the image noise range from 6.7 HU at 65 mAs to 12.3 HU at 20 mAs with decreasing tube current-time product. Unlike iDose and FBP with standard kernel, there was a statistically significant difference between FBP with standard and smooth kernel with respect to image resolution (P=0.002). Reconstruction algorithm of the iDose resulted in the same or better image quality improvements despite a reduction in the radiation dose compared to the FBP with standard or with smooth kernel. From our findings, iDose facilitates the reduction in radiation dose while maintaining image quality. PMID- 22104235 TI - [Evaluation of calibration error for applying exposure index]. AB - Exposure indicators of digital radiography systems have been termed by manufacturers individually. The International Electrotechnical Commission (IEC) provided a concept of exposure index (EI) that unified the exposure indicators in order to recognize the deviations from the intended exposure. Although the IEC determined the calibration conditions between the exposure indicator and the air kerma at the detector surface, the tolerance was described was limited concerning the beam conditions. The purpose of this study is to evaluate the calibration error regarding the geometry and the added filtrations. The relative errors of calibrations based on the IEC condition were derived using the value of exposure indicators at EI value of 200, 500 and 1000 for field size of 10*10 cm, 20*20 cm, 30*30 cm and 43*43 cm, and source-image receptor distance (SID) of 100 cm, 120 cm, 150 cm and 200 cm. The beam qualities using added filtrations of 0.5 mm Cu+2 mm Al, 0.6 mm Cu and 21 mm Al were adjusted to RQA 5. The air kerma at the detector surface over the clinical use ranged from 0.18 to 26.3 uGy. Consequently, the relative errors for the calibrations were less than 6% at a field size of more than 10 * 10 cm and at SID of more than 100 cm with all added filtrations. PMID- 22104236 TI - [Optimization of X-ray conditions for full spine X-ray examinations in slot-scan digital radiography]. AB - The purpose of this study was to optimize X-ray conditions for full spine X-ray examinations in slot-scan digital radiography (SSDR). Follow-up of spinal deformities, such as scoliosis, typically involves many radiographs of the patient throughout childhood and adolescence. The Radiation doses for the full spine X-ray examination should be minimized. Recently, SSDR has been introduced for full spine as well as lower extremity examinations. This system utilizes slot scanning geometry to acquire the radiographic images. X-ray energy characteristics of direct amorphous Selenium (a-Se) digital fluoroscopy and short time X-ray tube loads of this system were investigated. Orthopedists evaluated the irradiation time for full spine radiographs in various conditions using an observer study. Patient doses were measured with radiophotoluminescence glass dosimeters, which were implanted in various tissue and organ positions within an anthropomorphic phantom. In the optimization of conditions for SSDR, patient doses are reduced by approximately 60% compared to default setting. PMID- 22104237 TI - [Reduction method of patients' radiation dose considering the size of field of view with a digital cine X-ray system loading a flat-panel detector]. AB - Angiographic equipment has tended toward using flat-panel detector (FPD). However, the radiation dose varies depending on the size of field of view (FOV) in the FPD. Although we were using 7 inch FOV in cardiac procedures, we examined a way to reduce the patients' radiation dose by using 8 inch FOV utilizing a digital zoom processing. We measured the absorbed dose rates at an interventional reference point (IRP) with 20 cm acrylic board to compare 8 inch FOV using a digital zoom processing with 7 inch FOV. Additionally we visually evaluated these phantom images. Result of comparison of absorbed dose rates at IRP, 8 inch FOV using a digital zoom processing was reduced more than 7 inch FOV (fluoroscopic 29.0% and digital cine 37.5%). These phantom images were of equivalent quality. The method to use 8 inch FOV utilizing a digital zoom processing technique in cardiac procedures is one of the effective radiation exposure reduction methods. PMID- 22104238 TI - [Characteristic evaluation and clinical usefulness of dose area product meter at radiography]. AB - Philips DigitalDiagnost, a digital radiographic system mounting flat panel detector (FPD), can display dose area data (DiDi dose) calculated by examination parameters. We evaluated its fundamental characteristics and compared the values of DiDi dose andactual measured data obtained by the area dose product meter (PD 4100L). Tendency of varied values of mAs, X-ray tube values and exposure area from both the area dose product meter and the DiDi dose were coincided. Further, in clinical images of chest PA 100 cases, chest lateral 50 cases and abdomen stand 25 cases, the determination coefficient was overly high as R(2)=0.99. Based on these results, it is clear that the DiDi dose can be treated the same as the area dose product meter. Under increasing of patient X-ray exposure dose is a concern in digital general radiography, this research indicates that maximum values of histogram obtained by DiDi dose contributes dose awareness for radiographer. PMID- 22104239 TI - [Optimization of radiographic conditions for computed tomography (CT) during hepatic angiography by interventional radiology-CT angio system]. AB - Many cases in which the skin complication are caused by increased exposure dose to skin by interventional radiology (IVR) are reported. Therefore, the decrease of patient exposure dose at IVR is important. Patient exposure dose by using IVR computed tomography (CT) unit is defined as the sum of exposure dose from both angiography and CT scanner. The dose decrease with the CT device was examined in this article. Since the images available during angiography have a high contrast compared to conventional CT scan, best applied standard deviation (SD) values are evaluated by using CT auto exposure control (CT-AEC). Although exposure dose decreased by varying SD values, contrast resolution was kept high. As a result, it became possible to adjust the dose from CT device to about a third by setting a proper CT-AEC value, which led to decrease of the total exposure dose. PMID- 22104240 TI - [Low-dose CT and image quality]. PMID- 22104241 TI - [Image quality of cone-beam CT]. PMID- 22104242 TI - [Fundamentals of relationship between physical image quality and radiation dose in digital radiography]. PMID- 22104243 TI - [Optimization of image quality and dose]. PMID- 22104244 TI - [Chest tomosynthesis]. PMID- 22104245 TI - [2011 report of training in Stanford University (abstract)]. PMID- 22104246 TI - [Standardization manual of X-ray protection summary]. PMID- 22104247 TI - Clinical implications of non-A-type NPM1 and FLT3 mutations in patients with normal karyotype acute myeloid leukemia. AB - Mutations in the nucleophosmin (NPM1) and fms-like tyrosine kinase-3 (FLT3) genes are the most commonly observed mutations in patients with normal-karyotype acute myeloid leukemia (AML-NK). We analyzed the prognostic effects and interactions of these mutations in 201 AML-NK patients. NPM1 and FLT3 mutations were found in 38.3 and 24.9% of AML-NK patients, respectively. NPM1 mutations (NPM1mut), especially in patients without FLT3 mutations (FLT3mut), were associated with a favorable outcome. However, NPM1mut did not affect survival. FLT3mut tended to be associated with a poor survival outcome. FLT3mut showed no prognostic effects in patients with A-type NPM1mut. However, FLT3mut were associated with a significantly worse prognosis in patients with non-A-type NPM1mut. The prognostic interaction between the NPM1 and FLT3 mutations was significant in patients with non-A-type NPM1mut. PMID- 22104248 TI - The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease. AB - Concurrent chemotherapy and radiotherapy (CRT) has become standard treatment for many patients with advanced head and neck squamous cell carcinoma (HNSCC). This has led to controversy concerning the role of neck dissection (ND) in this setting. The current debate is focused on N2-N3 disease and the ability of a clinical complete response to predict the absence of viable cells in the ND specimen. Proponents of a systematic planned ND argue that it improves regional control and possibly disease-specific survival. They assert that a clinical response does not predict the pathologic response, and that in the event of recurrence in the neck, a surgical salvage procedure is unlikely to succeed. Conversely, there are many arguments in favor of performing ND only for patients who have evidence of residual neck disease because of the very low probability of isolated neck recurrence following a complete response. Proponents argue that for complete responders, planned ND is associated with no survival benefit. As planned surgery will only benefit patients with residual disease in the neck alone, there is a high rate of unnecessary ND with its associated morbidity. Another question concerns the appropriate type of ND to be performed. Even if required after chemoradiation, selective ND is oncologically feasible with minimal morbidity. Lastly, robust data from a randomized trial demonstrating the superiority of one approach vs. the other are lacking. After conducting a review of recent literature on the subject, the authors conclude that planned ND is not necessary for patients with complete response because of the availability of improved diagnostic follow up modalities, and the increased sensitivity to CRT of HNSCC, particularly HPV associated tumors. PMID- 22104249 TI - Neck dissection field and lymph node density predict prognosis in patients with oral cavity cancer and pathological node metastases treated with adjuvant therapy. AB - Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy. We examined 309 pN+ patients who underwent levels I-III ND and 148 pN+ patients treated with levels I-V ND. The 5-year control and survival rates served as the main outcome measures. The 5-year rates for patients treated with levels I-III and I-V NDs were as follows: local control, 79%, 74% (p=0.0630); neck control, 81%, 68% (p=0.0014); distant metastasis, 21%, 36% (p=0.0003); disease-free survival (DFS), 59%, 43% (p=0.0001); disease-specific survival (DSS), 66%, 46% (p<0.0001); and overall survival (OS), 49%, 37% (p=0.0048), respectively. Multivariate analysis demonstrated that an LN density >=0.16 was an independent prognostic factor for 5 year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412-5.128]), distant metastases (0.001, 2.831 [1.520 5.270]), DFS (<0.001, 2.464 [1.571-3.866]), and DSS (0.036, 1.781 [1.040-3.052]) in levels I-III ND patients. An LN density >=0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654-14.344]), neck control (0.002, 24.738 [3.367-181.771]), DFS (<0.001, 4.151 [2.264-7.610]), DSS (<0.001, 3.791 [2.017-7.125]), and OS (<0.001, 2.806 [1.706-4.613]) in levels I-V ND patients. Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy. PMID- 22104250 TI - Clinical significance of molecular alterations in histologically negative surgical margins of head and neck cancer patients. AB - The development of locoregional recurrence is the main reason for treatment failure in head and neck squamous cell carcinomas (HNSCC) and the remaining of tumor cells in surgical margins is associated with recurrence. Surgical margins are considered negative based on histologic assessment of the pathological specimen. However, this method lacks sensitivity in identifying cells that already started malignant transformation but have not yet developed a pathologic phenotype. We investigated the usefulness of assessing the expression of PTHLH, EPCAM, MMP9, LGALS1 and MET for the detection of molecular alterations in histologically negative surgical margins and determine the correlation of these tumor-related alterations with clinical and prognostic parameters. Differential gene expression was determined by quantitative RT-PCR analyses in normal mucosa, HNSCC and negative margin samples. Thirty-eight percent of the histologically negative surgical margins examined were margin-positive for overexpression of at least one of the genes evaluated. Moreover, MMP9 and PTHLH overexpression in the surgical margins was associated with the development of second primary tumors (p=0.002) and lower rates of local control (log rank test p=0.022; HR=4.186; p=0.035), respectively. These findings demonstrate that the overexpression of tumor-related genes in histologically negative surgical margins is a frequent event. The use of qRT-PCR may be an useful tool in detecting actually negative HNSCC surgical margins and the overexpression of specific genes in these margins could be helpful in the identification of patients with a higher risk of developing second primary tumors and local recurrences, thus aiding the surgeon in the delineation of the HNSCC resection extent and helping in the planning of adjuvant therapy. PMID- 22104251 TI - Lymphatic mapping after previous breast surgery. AB - BACKGROUND: To assess the feasibility of lymphatic mapping and determine the lymphatic drainage pathways in patients previously treated with breast conserving therapy (BCT). METHODS: We included patients without current breast cancer that previously received BCT with sentinel node biopsy (SNB) and/or axillary lymph node dissection (ALND) for primary breast cancer. The study population consisted of 44 patients and was divided into two groups according to previous surgical treatment of the axilla: 22 patients after previous SNB and 22 patients after previous ALND. Standard lymphatic mapping was performed and the lymphatic drainage pattern was registered. Drainage located outside the ipsilateral axilla was recorded as aberrant. RESULTS: Lymphoscintigraphy revealed a drainage pattern in 17 of 44 patients (39%). The identification rate in the SNB-group was 41% and 36% in the ALND-group (P=0.760). 8 patients (18%) showed aberrant drainage, which tended to be more frequent in the ALND-group than in the SNB-group (27% versus 9%, P=0.122). Lymphatic drainage to the contralateral axilla was observed in 2 patients, both previously treated with ALND. CONCLUSIONS: Lymphatic mapping seems feasible after previous BCT with axillary treatment, in spite of a relatively low identification rate. Aberrant drainage tends to be more frequent after previous treatment with ALND. PMID- 22104252 TI - The role of transforming growth factor-alpha on mucin overproduction in eosinophilic chronic rhinosinusitis. AB - OBJECTIVES: Eosinophilic chronic rhinosinusitis (ECRS) is considered a refractory and intractable disease with thick mucus production, long-term nasal congestion, loss of sense of smell and intermittent acute exacerbations secondary to bacterial infections. In this study, we investigated which growth factor is deeply involved in the mucin overproduction in ECRS. METHOD: We employed fluorescence immunohistochemical analysis to evaluate whether or not TGF-alpha expression was upregulated in the nasal tissue of ECRS patients. We also examined MUC5AC transcription using a luciferase reporter plasmid in HM3-MUC5AC cells and A549 cells in order to assess the role of TGF-alpha in human epithelial cells. RESULTS: TGF-alpha immunoreactivity was found markedly increased in the submucosal tissue in the ECRS patient compared with that of a normal patient and with noneosinophilic CRS. TGF-alpha synergized with TNF-alpha to upregulate MUC5AC expression in human epithelial cells through the ERK signaling pathway. CONCLUSION: Our results demonstrated that TGF-alpha was highly expressed in the upper airway tract in ECRS patients and is deeply involved in mucus hypersecretion. PMID- 22104253 TI - The "sponge effect" hypothesis: an alternative explanation of the improvement in the waterholding capacity of meat with ageing. AB - Bovine M. semimembranosus from different sexes of cattle were held at temperatures ranging from 0 to 35 degrees C until rigor and aged for up to 9weeks. The waterholding capacity (WHC) of the beef increased with ageing as evidenced by the decline in drip loss measured gravimetrically, centrifugally and by pressure. Drip viscosity (P<0.01), meat protein extractability (P<0.05), spreadability (P<0.01) and compressibility also increased with ageing. Evidence of structural changes was seen in SDS-PAGE confirming the physical changes. Meat spreadability under pressure and WHC were higher in samples with inherently higher pH relative to lower pH. The outcome of this study supports a hypothesis that the increase in WHC with ageing is due to the breakdown in meat structure and the creation of "sponge effect", which disrupts the channels through which moisture is lost and physically entraps the free water in meat and reduce the amount that drips out. PMID- 22104254 TI - Production system and slaughter age effects on intramuscular fatty acids from young Tudanca bulls. AB - Thirty-three young bulls from Tudanca local breed were used to investigate the effect of two production systems (semi-extensive vs. intensive) and two slaughter ages (12 vs. 14months) on meat fatty acid (FA) composition. Longissimus thoracis from semi-extensive animals had a lower percentage of intramuscular fat (p<=0.001), saturated FAs (p<=0.05), trans-18:1 (p<=0.001), n-6/n-3 ratio (p<=0.001) and a higher percentage of branched chain FAs (p<=0.001), polyunsaturated FAs (p<=0.001) and conjugated linoleic acid (CLA) (p<=0.001). Few differences were observed in FA composition between slaughter ages. Hence, meat from semi-extensive animals slaughtered at 12 or 14months displayed a healthier FA profile from a consumer's point of view. PMID- 22104255 TI - Effects of respiratory-muscle exercise on spinal curvature. AB - DESIGN: Randomized controlled study. SETTING: Laboratory. PARTICIPANTS: 26 healthy swimmers randomly assigned to an exercise (n = 13; Ex) or control group (n = 13; Cont). INTERVENTION: The Ex group performed respiratory-muscle exercises for 10 min thrice a week for 4 wk. CONTEXT: Respiratory-muscle exercises are used not only in the rehabilitation of patients with respiratory disease but also in endurance training for athletes. Respiration involves the back and abdominal muscles. These muscles are 1 of the elements responsible for posture control, which is integral to injury prevention and physical performance. However, the effects of respiratory-muscle exercise on posture remain unclear. OBJECTIVE: To examine the potential of respiratory-muscle exercise for improving posture. MAIN OUTCOME MEASURES: Spinal curvature, pulmonary function, and trunk-muscle strength were measured for both the groups at baseline and after 4 wk. The data were compared between the Ex and Cont groups with Mann-Whitney U test and preintervention and postintervention within groups with a Wilcoxon signed rank sum test. RESULTS AND CONCLUSION: The spinal curvature was significantly different in the Ex group, indicating a decrease in the thoracic (-13.1%, P < .01) and lumbar (-17.7%, P < .05) angles. The Ex group presented with lower thoracic (-8.6%) and lumbar (-20.9%) angles at postexercise than the Cont group (P < .05). With respect to trunk-muscle strength, only trunk-flexion strength significantly increased from pretest to posttest in the Ex group (P < .05). For pulmonary function, forced vital capacity and forced expiratory volume in 1.0 s were significantly increased after 4 wk in the Ex group (P < .05). The results suggest that respiratory-muscle exercise straightened the spine, leading to good posture control, possibly because of contraction of abdominal muscles. PMID- 22104256 TI - [Effectiveness of an intervention to improve the compliance of hand hygiene in a tertiary hospital]. AB - OBJECTIVE: The aim of the study is to assess the effectiveness of an intervention to improve the compliance with hand hygiene (HH) and the detection of factors associated with non-compliance. METHODS: A before and after intervention study with two cross-sectional and direct observations of HH compliance was performed. The intervention was targeted at all the health workers and hospital departments directly related with patients and their healthcare environment. One hundred and sixty observation periods were included in each cross-sectional observation, accounting for a total of 5,245 observed opportunities of HH among 947 health workers. RESULTS: Hand hygiene compliance showed a significant increase of 7.7% (95% CI: 5.5-9.9; P<.001) with a pre-intervention and post-intervention HH compliance of 17.4% (95% CI: 16.0-18.9) and 25.5% (95% CI: 23.5-26.9), respectively. The following variables showed an independent association with the non-compliance of HH: morning shift (0.32; 95% CI: 0.24-0.42), being a nurse (OR: 0.44; 95%CI: 0.29-0.65), working in an intensive care unit (OR: 0.14: 95%CI: 0.10 0.18), non-use of gloves (OR:0.58: 95% CI:0.48-0.69), observed opportunities of HH arising after high risk contact (OR:0.30: 95% CI: 0.22-0.41) and after low risk contact (OR:0.43: 95% CI:0.32-0.58). CONCLUSIONS: The intervention has independently and significantly improved hand hygiene in the hospital. Multimodal strategies need to be designed in healthcare settings in order to increase HH compliance among health workers. PMID- 22104257 TI - [A triage system for evacuating critical patients before an eventual disaster]. PMID- 22104258 TI - Glucose before thiamine for Wernicke encephalopathy: a literature review. AB - BACKGROUND: The prevailing teaching in medical school curricula and in medical textbooks is that if thiamine deficiency is suspected, thiamine supplementation should be given before administering glucose. OBJECTIVE: We sought to evaluate the published evidence describing the commonly held belief that thiamine supplementation must be given before glucose in hypoglycemic patients to prevent Wernicke encephalopathy. METHODS: Articles were identified through computerized searches of MEDLINE and other online sources. Pertinent references were traced back to their sources and also included in the literature review. The quality and content of each article was evaluated by the authors using the American Academy of Emergency Medicine literature review guidelines. RESULTS: Nineteen papers were ultimately identified and evaluated. No evidence rose above the level of case report/series. There were 13 case reports/series, 4 animal studies, and 2 expert opinion articles. True clinical research about the question of whether or not a glucose load can precipitate acute onset of Wernicke encephalopathy is lacking. CONCLUSIONS: Mounting case report evidence suggests that prolonged glucose supplementation without the addition of thiamine can be a risk factor for the development of Wernicke encephalopathy. Based on our findings, a delay in giving glucose to hypoglycemic patients cannot be recommended at this time, although prompt thiamine supplementation after or concurrent with a return to normoglycemia is recommended. PMID- 22104259 TI - Echo enhancers could facilitate the sonographic diagnosis of tubo-ovarian abscesses. PMID- 22104260 TI - HLA-DQB1 genotypes and islet cell autoantibodies against GAD65 and IA-2 in relation to development of diabetes post partum in women with gestational diabetes mellitus. AB - AIMS: To study HLA-DQB1 genes and islet cell autoantibodies against glutamic acid decarboxylase 65 (GADA) and insulinoma antigen-2 (IA-2A) in relation to diabetes post partum in mothers with diagnosed gestational diabetes mellitus (GDM). METHODS: During 2003-2004, women undergoing a 75 g oral glucose tolerance test (OGTT) during pregnancy were invited to participate in the Mamma Study. Cut-off level defining GDM was a 2-h capillary blood glucose of 7.8 mmol/L. 1-2 years after delivery a 75 g OGTT was performed, GADA and IA-2A were measured and HLA DQB1 genes analysed. Data were available for 452 mothers with previous GDM and 168 randomly selected control subjects. RESULTS: HLA-DQB1*0602 was negatively associated with GDM (p=0.033) and with development of diabetes post partum (p=0.017), whereas high risk HLA were not associated with GDM or with diabetes. The presence of GADA post partum was positively associated with diabetes post partum (p=0.0009), but not with impaired glucose tolerance. CONCLUSIONS: Mothers with GDM and HLA-DQB1*0602 were less likely to develop diabetes after pregnancy, and type 1 diabetes associated high risk HLA genes did not predict type 1 diabetes post partum. Additionally, GADA were positively associated with diabetes development. PMID- 22104261 TI - Limb revascularization feasibility in diabetic patients with critical limb ischemia: results from a cohort of 344 consecutive unselected diabetic patients evaluated in 2009. AB - AIMS: To evaluate the feasibility of peripheral revascularization by angioplasty (PTA) or bypass grafting (BPG) in diabetic patients with critical limb ischemia (CLI). METHODS: All diabetic patients referred to our Diabetic Foot Centre for foot lesion or rest pain were assessed for the presence of CLI as assessed by the TASC criteria. All patients underwent angiography that was evaluated jointly by an interventional radiologist, a vascular surgeon and a diabetologist of the diabetic foot care team. RESULTS: During 2009, 344 diabetics were admitted because of CLI in a total of 360 limbs. PTA was performed in 308 (85.6%) limbs, and BPG was performed in 40 (11.1%) limbs in which PTA was not feasible. Revascularization could not be carried out in 12 (3.3%) limbs due to the lack of target vessel (9 limbs) or high surgical risk (3 limbs). According to the judgement of the vascular surgeon, BPG was anatomically feasible in 180 (58.4%) of the 308 limbs that underwent PTA. Therefore, considering also the 40 limbs that underwent BPG, surgical revascularization was judged anatomically possible in a total of 220 (61.1%) limbs. At 30 days, 19 (5.3%) above-the-ankle amputations were performed: 8 (66.7%) amputations were performed in the 12 non revascularized limbs, 8 (2.6%) amputations were performed in the 308 limbs treated with PTA and 3 (7.5%) amputations were performed in the 40 limbs treated with BPG. CONCLUSIONS: Revascularization by PTA is highly feasible in diabetics with CLI. The feasibility of revascularization by BPG is lower but nonetheless consistent. In centres where both revascularization procedures are available, it is possible to revascularize more than 96% of diabetics with CLI. PMID- 22104262 TI - Lower extremity muscle strength is reduced in people with type 2 diabetes, with and without polyneuropathy, and is associated with impaired mobility and reduced quality of life. AB - AIM: The purpose of the present study was to distinguish the effects of both diabetes mellitus type 2 (DM2) and diabetic polyneuropathy (DPN) on mobility, muscle strength and health related quality of life (HR-QoL). METHODS: DPN patients (n=98), DM2 patients without DPN (DC) (n=39) and healthy subjects (HC) (n=19) performed isometric and isokinetic lower limb muscle strength tests. Mobility was determined by a timed up and go test (TUGT), a 6 min walk test and the physical activity scale for the elderly questionnaire. HR-QoL was determined by the SF36 questionnaire. RESULTS: DPN patients had moderate polyneuropathy. In both DPN and DC patients leg muscle strength was reduced by 30-50% compared to HC. Muscle strength was correlated with mobility tests, and reduced muscle strength as well as impaired mobility were associated with a loss of HR-Qol (all p<0.05). We did not observe major differences in muscle strength, mobility (except for the TUGT, p<0.01) and HR-QoL between diabetic patients with and without DPN. CONCLUSION: DM2 patients, with and without DPN, have decreased maximal muscle strength in the lower limbs and impaired mobility. These abnormalities are associated with a loss of HR-QoL. The additional effect of moderate DPN was small in our patients. PMID- 22104263 TI - Impact of introducing HbA1c into the diagnostic criteria on prevalence and cardiovascular risk profiles of individuals with newly diagnosed diabetes in Japan: the Toranomon Hospital Health Management Center Study 2 (TOPICS 2). AB - OBJECTIVE: To evaluate the impact of HbA1c for diagnosis of diabetes and investigate whether cardiovascular risks profiles differ among individuals with diabetes diagnosed by HbA1c or fasting plasma glucose (FPG). METHODS: This cross sectional study involved 26,884 participants (30.6% women; aged 20-91 years) without known diabetes. Subjects were categorized into 4 groups according to the presence or absence of FPG >=7.0 mmol/L and/or HbA1c >=6.5%, which were American Diabetes Association criteria. Oral glucose tolerance test data were not available. RESULTS: Prevalence of undiagnosed diabetes was 3.6%. Of those individuals, 47.5% fulfilled both two criteria and 26.0% fulfilled only HbA1c criterion. Individuals with diabetes according to FPG >=7.0 mmol/L alone were characterized as having poorly controlled hypertension while those with HbA1c >=6.5% alone were characterized as older, female, and having lower blood pressure and gamma-glutamyltransferase values. Persons with newly diagnosed diabetes by HbA1c had low HDL cholesterol and high LDL or non-HDL cholesterol levels. CONCLUSIONS: Introducing HbA1c into the diagnosis allowed detection of many previously undiagnosed cases of diabetes in Japanese individuals. Those diagnosed by FPG were characterized by hypertension and those diagnosed by HbA1c had unfavorable lipid profiles, reflecting an atherosclerotic trait. PMID- 22104264 TI - Publicly-funded homebirth models in Australia. AB - BACKGROUND: Publicly-funded homebirth programs in Australia have been developed in the past decade mostly in isolation from each other and with limited published evaluations. There is also distinct lack of publicly available information about the development and characteristics of these programs. We instigated the National Publicly-funded Homebirth Consortium and conducted a preliminary survey of publicly-funded homebirth providers. AIM: To outline the development of publicly funded homebirth models in Australia. METHODS: Providers of publicly-funded homebirth programs in Australia were surveyed using an on-line survey in December 2010. Questions were about their development, use of policy and general operational issues. A descriptive analysis of the quantitative data and content analysis of the qualitative data was undertaken. FINDINGS: In total, 12 programs were identified and 10 contributed data to this paper. The service providers reported extensive multidisciplinary consultation and careful planning during development. There was a lack of consistency in data collection throughout the publicly-funded homebirth programs due to different databases, definitions and the use of different guidelines. DISCUSSION: Publicly-funded homebirth services followed different routes during their development, but essentially had safety and collaboration with stakeholders, including women and obstetricians, as central to their process. CONCLUSION: The National Publicly-funded Homebirth Consortium has facilitated a sharing of resources, processes of development and a linkage of homebirth services around the country. This analysis has provided information to assist future planning and developments in models of midwifery care. It is important that births of women booked to these programs are clearly identified when their data is incorporated into existing perinatal datasets. PMID- 22104265 TI - Why community compulsion became the solution - Reforming mental health law in Sweden. AB - The aim of this article is to understand how compulsory community care (CCC) has become a solution in mental health policy in so many different legal and social contexts during the last 20 years. The recent introduction of CCC in Sweden is used as a case in point, which is then contrasted against the processes in Norway, England/Wales and New York State. In Sweden, the issue of CCC was initiated following high-profile acts of violence. Contrary to several other states, there was agreement about the (lack of) evidence about its effectiveness. Rather than focusing on dangerousness, the government proposal about CCC was framed within an ideology of integrating the disabled. The new legislation allowed for a broad range of measures to control patients at the same time as it was presented as a means to protect positive rights for patients. Compared to previous legislation in Sweden, the scope of social control has remained largely the same, although the rationale has changed - from medical treatment via community treatment and rehabilitation, to reducing the risk of violence, and then shifting back to rehabilitation in the community. The Swedish approach to CCC is similar to Norway, while New York and England/Wales have followed different routes. Differences in ideology, social control and rights orientations can be understood with reference to the general welfare and care regimes that characterize the four states. PMID- 22104266 TI - Analyses of the secondary particle radiation and the DNA damage it causes to human keratinocytes. AB - High-energy protons, and high mass and energy ions, along with the secondary particles they produce, are the main contributors to the radiation hazard during space explorations. Skin, particularly the epidermis, consisting mainly of keratinocytes with potential for proliferation and malignant transformation, absorbs the majority of the radiation dose. Therefore, we used normal human keratinocytes to investigate and quantify the DNA damage caused by secondary radiation. Its manifestation depends on the presence of retinol in the serum-free media, and is regulated by phosphatidylinositol 3-kinases. We simulated the generation of secondary radiation after the impact of protons and iron ions on an aluminum shield. We also measured the intensity and the type of the resulting secondary particles at two sample locations; our findings agreed well with our predictions. We showed that secondary particles inflict DNA damage to different extents, depending on the type of primary radiation. Low-energy protons produce fewer secondary particles and cause less DNA damage than do high-energy protons. However, both generate fewer secondary particles and inflict less DNA damage than do high mass and energy ions. The majority of cells repaired the initial damage, as denoted by the presence of 53BPI foci, within the first 24 hours after exposure, but some cells maintained the 53BP1 foci longer. PMID- 22104267 TI - Improvement of chaperone activity of 2-Cys peroxiredoxin using gamma ray. AB - A typical 2-cysteine peroxiredoxin (2-Cys Prx) PaPrx can act alternatively as thioredoxin (Trx)-dependent peroxidase and molecular chaperone in Pseudomonas aeruginosa PAO1. In addition, the functional switch of PaPrx is regulated by its structural change which is dependently induced by stress conditions. In the present study, we examined the effect of gamma ray on structural modification related to chaperone activity of PaPrx. The structural change of PaPrx occupied with gamma ray irradiation (2 kGy) based on polyacrylamide gel electrophoresis (PAGE) analysis and the functional change also began. The enhanced chaperone activity was increased about 3-4 folds at 30 kGy gamma irradiation compared with nonirradiated PaPrx, while the peroxidase activity was significantly decreased. We also investigated the influence of the gamma ray on protein hydrophobicity as related to chaperone function. The exposure of hydrophobic domains reached a peak at 30 kGy gamma ray and then decreased dependently with increasing gamma irradiation. Our results suggest that highly enhanced chaperone activity could be adapted for use in bio-engineering systems and industrial applications such as enzyme stabilization during industrial process (inactivation protection), improvement of useful protein productivity (refolding and secretion) and industrial animal cell cultivation (stress protection). PMID- 22104268 TI - The development of classically and alternatively activated macrophages has different effects on the varied stages of radiation-induced pulmonary injury in mice. AB - The classical and alternative activation of macrophages has been proposed to play a role in radiation-induced pneumonitis and fibrosis, respectively. To test this hypothesis, the thoraces of C57BL/6 mice were irradiated with 12 Gy X-rays, and irradiated and control mice were euthanized at 1, 8, 12, 24 and 72 hours, and 2, 4, 8, 16 and 24 weeks after irradiation. The expression of inducible nitric oxide synthase (iNOS) and arginase type 1 (Arg-1) was evaluated at the mRNA and protein levels at different stages post-irradiation. We demonstrated that the enhanced mRNA and protein expression of iNOS occurred within the pneumonic stage, whereas the high levels of Arg-1 expression occurred within the fibrotic phase. Immunohistochemistry revealed that iNOS and Arg-1 were mainly expressed in macrophages. The expression of iNOS and Arg-1 may be associated with acute radiation pneumonitis and the development of radiation fibrosis, respectively. Although the function of macrophages cannot explain the whole process of radiation-induced pulmonary injury development, it may play an important regulatory role during this process. PMID- 22104269 TI - Systematic analyses of genes associated with radiosensitizing effect by celecoxib, a specific cyclooxygenase-2 inhibitor. AB - To investigate genes regulated by COX-2 or a COX-2 specific inhibitor, celecoxib, in irradiated cancer cells, we analyzed changes in gene expression using complementary DNA microarray following celecoxib or combined celecoxib and ionizing radiation (IR) treatment in a stable COX-2 knockdown A549 (AS) and a mock cell line (AN). Thirty-six genes were differentially expressed by COX-2 knockdown. Celecoxib changed the expressions of 40 and 69 genes in AN and AS cells, respectively. Twenty-seven genes were synchronously regulated by COX-2 and celecoxib. Among these, celecoxib regulated ras homolog gene family B and mitosin protein expression in a COX-2 dependent manner, especially in irradiated cells. In addition, we identified 11 genes that changed by more than 1.5 times the expected additive values after celecoxib and IR treatment. The current study may provide evidence that COX-2 or celecoxib regulates various intracellular functions in addition to their enzymatic activity regulation. We also identified candidate molecules that may be responsible for COX-2-dependent radiosensitization by celecoxib. PMID- 22104270 TI - Study of the response of superoxide dismutase in mouse organs to radon using a new large-scale facility for exposing small animals to radon. AB - We examined dose-dependent or dose rate-dependent changes of superoxide dismutase (SOD) activity using a new large-scale facility for exposing small animals to radon. Mice were exposed to radon at a concentration of 250, 500, 1000, 2000, or 4000 Bq/m(3) for 0.5, 1, 2, 4, or 8 days. When mice were exposed to radon at 2000 day*Bq/m(3), activation of SOD activities in plasma, liver, pancreas, heart, thymus, and kidney showed dose-rate effects. Our results also suggested that continuous exposure to radon increased SOD activity, but SOD activity transiently returned to normal levels at around 2 days. Moreover, we classified the organs into four groups (1. plasma, brain, lung; 2. heart, liver, pancreas, small intestine; 3. kidney, thymus; 4. stomach) based on changes in SOD activity. Thymus had the highest responsiveness and stomach had lowest. These data provide useful baseline measurements for future studies on radon effects. PMID- 22104271 TI - Expression of hypoxia-inducible factor 1alpha predicts clinical outcome after preoperative hyperthermo-chemoradiotherapy for locally advanced rectal cancer. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) is an intrinsic marker of tumor hypoxia. It has been considered that hypoxic conditions reduce radiosensitivity, but the role of HIF-1alpha in patients treated with preoperative therapy for rectal cancer is still unclear. The aim of this study was to evaluate the predictive value of tumor response to preoperative hyperthermo-chemoradiotherapy (HCRT) and the prognostic significance of HIF-1alpha expression in patients with locally advanced rectal cancer. Between 2003 and 2006, 50 patients with histologically proven rectal adenocarcinoma who underwent HCRT followed by surgery were investigated. HIF-1alpha expression was immunohistochemically evaluated using pre-treatment biopsies. The total radiation dose was 40-50 Gy and chemotherapy consisted of 5-FU and LV administered by continuous infusion on Day 1-5, Day 15-19, and Day 29-33 during radiotherapy. Hyperthermia treatment was performed for once a week for 2-5 sessions. The surgical operation was performed 8 weeks after HCRT and each resected specimen was graded by histological criteria of the Japanese Classification of Colorectal Carcinoma. The effects of HIF-1alpha on clinical outcomes were analyzed by univariate and multivariate analysis. Positive HIF-1alpha expression was recognized in 42.0% of samples (21/50). Resected specimens that showed pathological grades 1, 2, and 3 numbered 17, 24, and 9 cases, respectively. There were no significant differences between the HIF 1alpha-positive group and HIF-1alpha-negative group for pathological grading and pCR. Overall survival (OS) rate at 3 years in the HIF-1alpha-negative group was 85.2%, which was significantly better than the 60.6% in the HIF-1alpha-positive group. Recurrence-free survival (RFS) rate at 3 years in the HIF-1alpha-negative group was 82.8%, being significantly better than 47.6% in the HIF-1alpha-positive group. In addition, elevated HIF-1alpha expression was significantly correlated with recurrence-free survival and metastasis-free survival rate in multivariate analysis. HIF-1alpha expression might be predictive of recurrence-free survival and metastasis-free survival rate for rectal cancer patients treated with HCRT. PMID- 22104272 TI - Radioprotection of bone marrow hematopoiesis by CpG-oligodeoxynucleotides administered to mice after total-body irradiation. AB - CpG-oligodeoxynucleotide (ODN), a synthetic analog of bacteria DNA, has attracted attention because it activates cells of an adaptive immune system and the innate immune system. In this study, we investigated whether CpG-ODN has radioprotective effects, when administered after total-body irradiation (TBI). Mice were treated with 50 ug CpG-ODN via intraperitoneal injection (i.p) within 30 min, 24 h and 48 h after TBI. Our results showed that the survival rate was enhanced at various levels of TBI. The calculated dose reduction factor (DRF) was 1.2. Bone marrow cell count and bone marrow histological examination indicated that CpG-ODN minimized the bone marrow damage induced by TBI. The data of the white blood cell (WBC) count, exogenous (CFU-S) and endogenous (endoCFU-S) colony forming unit spleen count demonstrated that CpG-ODN reduced primitive hematopoietic stem cells damage and reconstituted hematopoiesis after TBI. Thus, we suggested that CpG-ODN had the potential to contribute to the improvement of the survival rate and limitation of myelosuppression induced by TBI. PMID- 22104273 TI - Effects of intensity-modulated radiotherapy on human oral microflora. AB - This study aimed to evaluate changes in the biodiversity of the oral microflora of patients with head and neck cancer treated with postoperative intensity modulated radiotherapy (IMRT) or conventional radiotherapy (CRT). Pooled dental plaque samples were collected during the radiation treatment from patients receiving IMRT (n = 13) and CRT (n = 12). Denaturing gradient gel electrophoresis (DGGE) was used to analyze the temporal variation of these plaque samples. The stimulated and unstimulated salivary flow rates were also compared between IMRT and CRT patients. Reductions in the severity of hyposalivation were observed in IMRT patients compared with CRT patients. We also observed that the temporal stability of the oral ecosystem was significantly higher in the IMRT group (69.96 +/- 7.82%) than in the CRT group (51.98 +/- 10.45%) (P < 0.05). The findings of the present study suggest that IMRT is more conducive to maintaining the relative stability of the oral ecosystem than CRT. PMID- 22104274 TI - Brachytherapy reirradiation with hyaluronate gel injection of paraaortic lymphnode metastasis of pancreatic cancer: paravertebral approach--a technical report with a case. AB - Paraaortic lymph nodal (PALN) recurrence is not a rare scenario of abdominal malignancies including pancreas cancer, even after radiotherapy. The role and indication of reirradiation is limited because it is often associated with significant late toxicity in the surrounding normal organs. We developed a new approach and technique of brachytherapy to overcome this difficult situation, with a paravertebral approach and hyaluronate gel injection (HGI). We encountered a patient with pancreatic cancer who developed PALN metastasis as in-field recurrence, 6 months after resection of pancreatic cancer with 50 Gy of preoperative radiotherapy. The applicator brachytherapy needles and gel injection needles were advanced by percutaneous paravertebral approach under local anesthesia, and by injection of a hyaluronate gel to separate the surrounding small intestines and the target. A single fraction of 18 Gy was delivered to the tumor (75.6 Gy equivalent in conventional schedule calculated with LQ model at alpha/beta = 3) and total estimated D2cc (the minimum dose to the most irradiated volume of 2 cc, calculated at alpha/beta = 2) in the small intestines was 61.6 GyE with HGI and 80.6 GyE without. No complications have been observed for six months. Three months later, FDG accumulation had disappeared, the tumor size was reduced, and serum CA-19-9 value decreased from 5150 U/mL to 36.6 U/mL (normal range < 37.5). Conclusively, the brachytherapy with the HGI procedure by paravertebral approach was thought safe and effective in reirradiation of PALN recurrence. PMID- 22104275 TI - Impact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the FIELD randomised trial. AB - BACKGROUND: Patients with the metabolic syndrome are more likely to develop type 2 diabetes and may have an increased risk of cardiovascular disease (CVD) events.We aimed to establish whether CVD event rates were influenced by the metabolic syndrome as defined by the World Health Organisation (WHO), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF) and to determine which component(s) of the metabolic syndrome (MS) conferred the highest cardiovascular risk in in 4900 patients with type 2 diabetes allocated to placebo in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. RESEARCH DESIGN AND METHODS: We determined the influence of MS variables, as defined by NCEP ATPIII, IDF and WHO, on CVD risk over 5 years, after adjustment for CVD, sex, HbA1c, creatinine, and age, and interactions between the MS variables in a Cox proportional-hazards model. RESULTS: About 80% had hypertension, and about half had other features of the metabolic syndrome (IDF, ATPIII). There was no difference in the prevalence of metabolic syndrome variables between those with and without CVD at study entry. The WHO definition identified those at higher CVD risk across both sexes, all ages, and in those without prior CVD, while the ATPIII definition predicted risk only in those aged over 65 years and in men but not in women. Patients meeting the IDF definition did not have higher risk than those without IDF MS.CVD risk was strongly influenced by prior CVD, sex, age (particularly in women), baseline HbA1c, renal dysfunction, hypertension, and dyslipidemia (low HDL-c, triglycerides > 1.7 mmol/L). The combination of low HDL c and marked hypertriglyceridemia (> 2.3 mmol/L) increased CVD risk by 41%. Baseline systolic blood pressure increased risk by 16% per 10 mmHg in those with no prior CVD, but had no effect in those with CVD. In those without prior CVD, increasing numbers of metabolic syndrome variables (excluding waist) escalated risk. CONCLUSION: Absence of the metabolic syndrome (by the WHO definition) identifies diabetes patients without prior CVD, who have a lower risk of future CVD events. Hypertension and dyslipidemia increase risk. PMID- 22104276 TI - Amphiphilic block copolymer-stabilized PtRu nanoparticles highly dispersed on multi-walled carbon nanotube for methanol oxidation. AB - We report a one-pot synthesis of amphiphilic block copolymer-stabilized PtRu nanoparticle modified multi-walled carbon nanotubes (MWCNTs) using RuCl(3).xH(2)O and H(2)PtCl(6).6H(2)O as ruthenium and platinum sources, and block copolymer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) as stabilizer agent. PtRu alloyed nanoparticles with an average diameter of 4.6nm are well decorated homogeneously on the exterior surfaces of the MWCNTs. The electrochemical catalytic activity for methanol oxidation of PtRu/MWCNTs and commercial PtRu/C (E-TEK) is comparatively investigated using cyclic voltammetry and chronoamperometry. It is revealed that the PtRu nanoparticle modified MWCNT samples display an enhanced electrochemical catalytic activity than commercial PtRu/C electrode. These results show that PtRu nanoparticles may find applications to fuel cells. PMID- 22104277 TI - Using colloid lithography to fabricate silicon nanopillar arrays on silicon substrates. AB - In this study, we partially grafted geminal silanol groups in the protecting organic shells on the surfaces of gold nanoparticles (AuNPs) and then assembled the alkyl-AuNP-Si(OH)(4) particles onto the surfaces of silicon (Si) wafers. The density of assembled AuNPs on the Si surface was adjusted by varying the geminal silanol group content on the AuNP surface; at its optimal content, it approached the high assembly density (0.0254 particles/nm(2)) of an AuNP assembled monolayer. Using reactive-ion etching (RIE) with the templates as masks, we transferred the patterned AuNP assemblies to form large-area, size-tunable, Si nanopillar arrays, the assembly density of which was controlled by the dimensions of the AuNPs. Using this colloidal lithography (CL) process, we could generate Si nanopillars having sub-10-nm diameters and high aspect ratios. The water contact angles of the high-aspect-ratio Si nanopillars approached 150 degrees . We used another fabrication process, involving electron beam lithography and oxygen plasma treatment, to generate hydrophilic 200-nm-resolution line patterns on a Si surface to assemble the AuNPs into 200-nm-resolution dense lines for use as an etching mask. Subsequent CL provided a patterned Si nanopillar array having a feature size of 200 nm on the Si surface. Using this approach, it was possible to pattern sub-10-nm Si nanopillar arrays having densities as high as 0.0232 nm(-2). PMID- 22104278 TI - Preparation and characterization of polystyrene/Ag core-shell microspheres--a bio inspired poly(dopamine) approach. AB - A facile and versatile method using a biopolymer as a chelating agent for silver ions and as a reducing agent for the formation of catalytic sites is proposed to prepare polystyrene (PS)/Ag core-shell microspheres. More specifically, the core shell microspheres were fabricated by electroless plating after the formation of poly(dopamine) (PDA) on the surface of PS microspheres through insitu spontaneous oxidative polymerization of dopamine. The PS-PDA microspheres were characterized by SEM, XPS, and TGA. The results showed that a uniform PDA layer was formed on the PS microsphere surface and the thickness of the PDA layer could be well controlled by varying the concentration of dopamine solution. The PDA layer was used as a chelating agent for silver ions, as a reducing agent for the formation of catalytic sites by reducing the silver ions into silver nanoparticles, and as an adhesion layer between the PS microspheres and silver layer. SEM and XRD results indicate that the diameter of the silver nanoparticles decreased with the increase in the thickness of the PDA layer. The silver nanoparticles could form a continuous and compact silver layer on the surface of the PS microspheres. Furthermore, the PS-PDA/Ag core-shell microspheres showed a good conductivity of 10S/cm and a low effective density of 1.8 g/cm(3), much lower than the corresponding values for block silver. Finally, hollow silver microspheres could be prepared by removing the PS core through calcination. SEM images showed that the hollow Ag microspheres remained unbroken and retained the spherical shape. PMID- 22104279 TI - Rheological and rheo-SALS investigation of the multi-lamellar vesicle formation in the C12E3/D2O system. AB - Usually in nonionic surfactant aqueous systems of the C(n)E(m) type, a lamellar phase occurs over a wide temperature and concentration range. For some C(n)E(m) surfactants, multi-lamellar vesicle (MLV) formation has been observed when the lamellar phase is subjected to shear flow. This communication reports the shear flow behavior at different shear rate values of a C(n)E(m) (where "n" is 12 and "m" is 3) aqueous system at 34 degrees C. The typical transient viscosity behavior of the shear-induced MLV formation in C(12)E(3)/D(2)O at 50 wt% of surfactant has been observed. The MLV formation is confirmed by time-resolved rheo-small angle light scattering (SALS) experiments. The experimental data show an intermediate structure that has been attributed to a multi-lamellar cylinders (MLCs). PMID- 22104280 TI - Nanotribological and nanomechanical properties of skin with and without cream treatment using atomic force microscopy and nanoindentation. AB - Various beauty care products involve surface interaction between the product and the skin surface they are applied to. Friction, adhesion and wear during sliding between the treated surface and the rubbing surfaces need to be optimized. Skin cream is used to improve skin health and create a smooth, soft, and flexible surface with moist perception by altering the surface roughness, friction, adhesion, elastic modulus, and surface charge of the skin surface. Rheology of skin cream as a function of cream thickness and strain rate and the binding interaction between skin cream and skin surface and operating environment are some of the important factors affecting the smooth feel and repair of the skin surface. Atomic force microscopy (AFM) and nanoindentation have recently become important tools for studying the micro/nanoscale properties of human hair, hair conditioner, skin, and skin cream. In this paper, we present an overview of the nanotribological and nanomechanical properties of skin with and without cream treatment as a function of operating environment. Relevant mechanisms are discussed. Next, the result of a triboelectrification study of skin with and without cream treatment is presented. Finally, an overview of attempts to develop a synthetic skin for research purposes is presented. PMID- 22104281 TI - Diversity of acquired beta-lactamases amongst Klebsiella pneumoniae in Greek hospitals. PMID- 22104282 TI - Effect of vinyl sulfone inhibitors of cysteine proteinases on Tritrichomonas foetus infection. AB - Tritrichomonas foetus is a sexually transmitted protozoon that causes genital inflammation and adverse pregnancy outcomes in cattle. Cysteine proteinases (CPs) released by T. foetus degrade immunoglobulin G (IgG) antibodies, complement component 3 and matrix proteins as well as inducing apoptosis of bovine genital epithelial cells. In this study, the efficacies of the vinyl sulfone CP inhibitors K11777 and WRR-483 were tested against CPs of T. foetus. The activity of secreted T. foetus CPs in culture supernatants was decreased in the presence of vinyl sulfone inhibitors. Inhibitor K11777 reduced the in vitro cytopathogenic effects of T. foetus in bovine foetal trophoblast cells, which are relevant target cells since this pathogen interferes with pregnancy. Pre-treatment of T. foetus prior to intravaginal inoculation diminished genital infection in a murine model. Therefore, vinyl sulfone CP inhibitors reduce several effects of T. foetus secreted CPs, including cytotoxicity on relevant target host cells and genital infection in a murine model. These inhibitors have potential as chemotherapeutic agents against bovine trichomoniasis. Generalisation to human trichomoniasis requires further study. PMID- 22104283 TI - Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, and its role in cancer biology has been widely studied. Many cancer therapies target angiogenesis, with a focus being on VEGF-mediated signaling such as antibodies to VEGF. However, it is difficult to predict the effects of VEGF neutralizing agents. We have developed a whole-body model of VEGF kinetics and transport under pathological conditions (in the presence of breast tumor). The model includes two major VEGF isoforms VEGF121 and VEGF165, receptors VEGFR1, VEGFR2 and co-receptors Neuropilin-1 and Neuropilin-2. We have added receptors on parenchymal cells (muscle fibers and tumor cells), and incorporated experimental data for the cell surface density of receptors on the endothelial cells, myocytes, and tumor cells. The model is applied to investigate the action of VEGF neutralizing agents (called "anti-VEGF") in the treatment of cancer. RESULTS: Through a sensitivity study, we examine how model parameters influence the level of free VEGF in the tumor, a measure of the response to VEGF-neutralizing drugs. We investigate the effects of systemic properties such as microvascular permeability and lymphatic flow, and of drug characteristics such as the clearance rate and binding affinity. We predict that increasing microvascular permeability in the tumor above 10-5 cm/s elicits the undesired effect of increasing tumor interstitial VEGF concentration beyond even the baseline level. We also examine the impact of the tumor microenvironment, including receptor expression and internalization, as well as VEGF secretion. We find that following anti-VEGF treatment, the concentration of free VEGF in the tumor can vary between 7 and 233 pM, with a dependence on both the density of VEGF receptors and co receptors and the rate of neuropilin internalization on tumor cells. Finally, we predict that free VEGF in the tumor is reduced following anti-VEGF treatment when VEGF121 comprises at least 25% of the VEGF secreted by tumor cells. CONCLUSIONS: This study explores the optimal drug characteristics required for an anti-VEGF agent to have a therapeutic effect and the tumor-specific properties that influence the response to therapy. Our model provides a framework for investigating the use of VEGF-neutralizing drugs for personalized medicine treatment strategies. PMID- 22104285 TI - Education matters. PMID- 22104284 TI - Poor outcomes in elderly kidney transplant recipients receiving alemtuzumab induction. AB - INTRODUCTION: Alemtuzumab and rabbit antithymocyte globulin (rATG) are being used with increasing frequency as induction agents in kidney transplantation. Using the US Renal Data Base System, we analyzed the safety profile of these agents in the elderly. METHODS: In a cohort of patients transplanted from January 2000 to July 2009 and followed through 2009, we assessed the effect of induction on allograft loss and death among elderly recipients. Recipients were censored at dates of allograft loss, death or the end of study. Independent associations between induction agents and allograft loss or death were examined using multivariate analysis with forward stepwise Cox regression. RESULTS: Among 130,402 patients with first transplants, 14,907 were age 65 years or older. 4,466 (30%), 3,049 (20.5%), 1,501 (10.1%), and 999 (6.7%) were induced with thymoglobulin, basiliximab, daclizumab, and alemtuzumab, respectively. After adjusting for baseline differences, induction with alemtuzumab was associated with an increased risk of graft loss and death, with an adjusted hazard ratio (AHR) of 1.26 (95% CI 1.08-1.48). Risk was also present at other age cutoffs [age >60 (AHR 1.16; 95% CI 1.03-1.31; p = 0.014), age >70 (AHR 1.43; 95% CI 1.13-1.81; p = 0.003) and age >75 (AHR 1.68; 95% CI 1.07-2.63; p = 0.024)]. CONCLUSIONS: In the elderly, alemtuzumab is associated with an escalating risk of death and graft loss in recipients of kidney transplantations. PMID- 22104286 TI - Caudal image contrast inversion in MPRAGE at 7 Tesla: problem and solution. AB - RATIONALE AND OBJECTIVES: The magnetization-prepared rapid-acquisition gradient echo (MPRAGE) sequence regularly shows caudal image contrast inversion at 7 T and therefore reduced clinical applicability. The investigators report the technical source of this problem and present a practical solution. MATERIALS AND METHODS: A total of 71 subjects were scanned using a 7-T whole-body magnetic resonance imaging system using a 32-channel transmit/receive head coil. In 39 subjects, 45 high-resolution T1 contrast image data sets were acquired with the standard MPRAGE sequence. A modified sequence with an adiabatic wideband uniform rate smooth truncation pulse for magnetization preparation was used for 45 further scans in 39 subjects. In total, seven subjects underwent scans with both sequences. The homogeneity of T1 contrast and the occurrence of caudal image contrast inversion were evaluated in consensus reading by two neuroradiologists. RESULTS: Caudal image contrast inversion was depicted in 19 acquisitions (42.2%) using the standard MPRAGE sequence. Using the adiabatic wideband uniform rate smooth truncation pulse for magnetization preparation, caudal image contrast inversion was depicted in only three acquisitions (6.7%). A chi(2) test showed a significant difference between the two preparation pulses (P < .001). CONCLUSIONS: Magnetization preparation with an adiabatic wideband uniform rate smooth truncation pulse in the MPRAGE sequence at 7 T can significantly reduce the occurrence of caudal image contrast inversion and improves signal homogeneity. PMID- 22104287 TI - Incidental aortic valve calcification on CT scans: significance for bicuspid and tricuspid valve disease. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the role of incidental aortic valve calcification on routine computed tomographic scans as a marker for stenosis, as assessed by echocardiography, in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve. MATERIALS AND METHODS: Computed tomographic and echocardiographic studies were retrospectively reviewed for 182 consecutive, unselected patients and 426 patients identified by a record search for "aortic valve calcification." Location and severity of valve calcification were correlated with aortic valve morphology and stenosis. Differences between subgroups were assessed using chi(2) or Fisher's exact tests. RESULTS: In unselected patients, calcification was present in 25.8% with tricuspid aortic valves (46 of 178) and 75% (three of four) with BAV. In patients selected for valve calcification, the average age of those with tricuspid aortic valves (n = 395) was 14.3 years older than those with BAV (n = 31). Patients with BAV were more likely to have severe calcification (87% vs 50%, P < .001), and if severe calcification was present, it was more likely to involve only the valve leaflets (41% vs 9%, P < .001) and result in aortic stenosis (85% vs 58%, P = .006). Patients aged < 60 years with severe calcification were more likely to have BAV (56% vs 7%; odds ratio, 7.9; 95% confidence interval, 3.4-18.7). CONCLUSIONS: Aortic valve calcification was found 14 years earlier in patients with BAV and was more severe and strongly linked to aortic stenosis. Valve calcification on computed tomographic scans should be considered a marker for BAV if found before the seventh decade. PMID- 22104288 TI - Hyperpolarized 3He magnetic resonance functional imaging semiautomated segmentation. AB - RATIONALE AND OBJECTIVES: To improve intra- and interobserver variability and enable the use of functional magnetic resonance imaging (MRI) for multicenter, multiobserver studies, we generated a semiautomated segmentation method for hyperpolarized helium-3 ((3)He) MRI. Therefore the objective of this study was to compare the reproducibility and spatial agreement of manual and semiautomated segmentation of (3)He MRI ventilation defect volume (VDV) and ventilation volume (VV) in subjects with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). MATERIALS AND METHODS: The multistep semiautomated segmentation method we developed employed hierarchical K-means clustering to classify (3)He MRI pixel intensity values into five user-determined clusters ranging from signal void to hyperintense. A seeded region-growing algorithm was also used to segment the (1)H MRI thoracic cavity for coregistration to the (3)He cluster-map, generating VDV and VV. RESULTS: We compared manual segmentation performed by an expert observer and semiautomated measurements of (3)He MRI VDV and observed strong significant correlations between the volumes generated using each method (asthma, n = 5, r = 0.89, P < .0001; COPD, n = 5, r = 0.84, P < .0001; CF, n = 5, r = 0.89, P < .0001). Semiautomated VDV had high interobserver reproducibility (coefficient of variation [CV] = 7%, intraclass correlation coefficient [ICC] = 0.96); intraobserver reproducibility was significantly higher for semiautomated (CV = 5%, ICC = 1.00) compared to manual VDV (CV = 12%, ICC = 0.98). Spatial agreement for VV determined using the Dice coefficient (D) was also high for all disease states (asthma, D = 0.95; COPD, D = 0.88; CF, D = 0.90). CONCLUSIONS: Semiautomated segmentation (3)He MRI provides excellent inter and intraobserver precision with high spatial and quantitative agreement with manual measurements enabling its use in longitudinal studies. PMID- 22104289 TI - Diagnostic performance of dual-time 18F-FDG PET in the diagnosis of pulmonary nodules: a meta-analysis. AB - RATIONALE AND OBJECTIVE: Perform a comprehensive meta-analysis evaluating the diagnostic performance of dual time point deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) in the diagnosis of pulmonary nodules. MATERIALS AND METHODS: MEDLINE, EMBASE, and PUBMED were queried between January 2000 and January 2011. Studies were included if they: 1) used dual time point FDG PET as a diagnostic test for pulmonary nodules, 2) used pathology or clinical follow-up as the reference standard, and 3) reported absolute number of true positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results or stated sufficient data to derive these values. Summary sensitivity (SN), summary specificity (SP), positive and negative likelihood ratios (LR+) and (LR-), and diagnostic odds ratio were calculated. Heterogeneity of the results was assessed using Forest plots and the value of inconsistency index (I(2)). RESULTS: Inclusion criteria were fulfilled by 10 articles with a total of 816 patients and 890 pulmonary nodules. The summary sensitivity was 85% (82%-89% at 95% confidence interval [CI]) and summary specificity was 77% (CI: 72%-81%), with a LR+ of 2.7 (CI: 1.4-5.2) and a LR- of 0.26 (CI: 0.14-0.49). Diagnostic odds ratio was 11 (CI: 3.8-32.2). Significant heterogeneity was found in the sensitivity (I(2) = 77%) and specificity (90.3%). CONCLUSION: Dual time point FDG PET demonstrates similar sensitivity and specificity to single time point FDG-PET in the diagnosis of pulmonary nodules. The additive value of the dual time point FDG-PET is questionable, primarily because of the significant overlap of benign and malignant nodule FDG-PET characteristics and lack of consensus criteria for quantitative thresholds to define nodules as malignant. PMID- 22104291 TI - I want it now! Neural correlates of hypersensitivity to immediate reward in hypomania. AB - BACKGROUND: Hypomania is associated with impulsive decision making and risk taking, characteristics that may arise from hypersensitivity to reward. To date, the neural dynamics underlying intertemporal reward processing have neither been characterized clinically nor in the general population. Taking vulnerability to hypomania as a surrogate model of impulsivity, we utilized event-related potentials to study the neural mechanisms of delay discounting. METHODS: In the first experiment, 32 participants completed an established Two Choice Impulsivity Paradigm in which free choice between immediate and delayed rewards was used to quantify impulsivity behaviorally. In the second experiment, electroencephalography was recorded while 32 separately recruited participants completed a speeded response task involving gains and losses of monetary incentives to be paid at three different delays after the experiment. RESULTS: In the first experiment, the hypomania-prone group made significantly more immediate choices than the control group. In the second experiment, the hypomania-prone group evidenced greater differentiation between delayed and immediate outcomes in early attention-sensitive (N1) and later reward-sensitive (feedback-related negativity) components. Proneness to hypomania was also associated with greater N1 amplitude to rewards per se. CONCLUSIONS: These results indicate steeper delay discounting in hypomania at multiple stages of information processing. The N1 modulation by valence and delay suggests an attentional bias to immediate rewards, which may drive subsequent cognitive appraisal of outcomes (feedback related negativity). These results highlight the early influence of attention on reward processing and provide support for reward dysregulation accounts of bipolar disorder. Potential implications for mindfulness training and other therapeutic interventions are highlighted. PMID- 22104290 TI - Design considerations for using PET as a response measure in single site and multicenter clinical trials. AB - RATIONALE AND OBJECTIVES: Positron emission tomography (PET) is used to evaluate response to therapy with increasing interest in having PET provide endpoints for clinical trials. Here we demonstrate impacts of PET measurement error and choice of quantification method on clinical trial design. MATERIALS AND METHODS: Sample size was calculated for two-arm randomized trials with percent change in (18)F fluorodeoxyglucose (FDG) PET uptake as an efficacy endpoint. Two methods of uptake quantification were considered: standardized uptake values (SUVs) and kinetic measures from dynamic imaging. Calculations assumed a 20 percentage point difference in treatment groups' average percent change, and yielded 80% power at alpha = 0.05. The range of precision (10%-40%) in PET uptake measures was based on review of the literature. The range of SUV sensitivities (50%-100%) relative to kinetic analyses was based on a study of 75 locally advanced breast cancer patients. RESULTS: Sample sizes increased from 8 to 126 as PET precision worsened from 10% to 40% at full measurement sensitivity to true change. In a subgroup with low initial FDG uptake, a sample size of 126 was required under 20% standard deviation using clinical SUVs. More sophisticated imaging quantification could reduce this sample size to 32. CONCLUSIONS: The dependence of sample size on measurement precision and the sensitivity of imaging measures to true change should be considered in single site and multicenter PET trials to avoid underpowered studies with inconclusive results. Sophisticated PET imaging methods that are more sensitive to changes in uptake may be advantageous in early studies with limited patient numbers. PMID- 22104292 TI - Effects of foot orthoses: How important is the practitioner? AB - Foot orthoses (FO) are commonly used in the treatment of numerous lower limb problems, pains and injuries. Whilst many studies report their positive effects, and most practitioners would confirm those findings, the available information appears to be anecdotal. As such, the exact mechanisms in which FO work are not fully understood. Therefore, a need exists to study the influence of the inter practitioner variability in the assessment of orthoses performance. This investigation is central to the understanding of the performance variations in custom-made foot orthoses (CFO). Eleven practitioners took part in the study. Each practitioner completed a clinical assessment of one subject, after which a pair of foot orthoses was manufactured based on casts of the subject's feet using a neutral non-weight bearing plaster cast. Ten trials per condition were recorded during which kinematic and kinetic data were collected. CFO did not have any systematic significant effects (p<0.05) on any kinetic except for the right-leg peak active force. In addition, systematic kinematic effects could be observed mainly for the sagittal plane for forefoot-to-hindfoot and hindfoot-to-tibia peak angles. The results from this study demonstrate that inter-practitioner variability is a major factor in orthotic intervention in treating a single patient and for a specific pathology. It is therefore strongly recommended to use caution when drawing general conclusions from research studies using custommade foot orthoses. The results suggest that CFO effects can differ between limbs. More importantly, their effects are also practitioner-dependant. Great caution should be used when comparing studies on CFO with different practitioners as conclusions could vastly differ. PMID- 22104293 TI - The jasmonate-responsive AP2/ERF transcription factors AaERF1 and AaERF2 positively regulate artemisinin biosynthesis in Artemisia annua L. AB - Plants of Artemisia annua produce artemisinin, a sesquiterpene lactone widely used in malaria treatment. Amorpha-4,11-diene synthase (ADS), a sesquiterpene synthase, and CYP71AV1, a P450 monooxygenase, are two key enzymes of the artemisinin biosynthesis pathway. Accumulation of artemisinin can be induced by the phytohormone jasmonate (JA). Here, we report the characterization of two JA responsive AP2 family transcription factors--AaERF1 and AaERF2--from A. annua L. Both genes were highly expressed in inflorescences and strongly induced by JA. Yeast one-hybrid and electrophoretic mobility shift assay (EMSA) showed that they were able to bind to the CRTDREHVCBF2 (CBF2) and RAV1AAT (RAA) motifs present in both ADS and CYP71AV1 promoters. Transient expression of either AaERF1 or AaERF2 in tobacco induced the promoter activities of ADS or CYP71AV1, and the transgenic A. annua plants overexpressing either transcription factor showed elevated transcript levels of both ADS and CYP71AV1, resulting in increased accumulation of artemisinin and artemisinic acid. By contrast, the contents of these two metabolites were reduced in the RNAi transgenic lines in which expression of AaERF1 or AaERF2 was suppressed. These results demonstrate that AaERF1 and AaERF2 are two positive regulators of artemisinin biosynthesis and are of great value in genetic engineering of artemisinin production. PMID- 22104294 TI - Modulation of peripheral inflammatory pain thresholds by M(1) and nicotinic receptor antagonists. AB - The study used the paw withdrawal test to investigate the role of the cholinergic system on the modulation of inflammatory pain induced by carrageenan (Cg) at the peripheral level, through activation of muscarinic and nicotinic receptors. Intraplantar administration of the specific M(1) receptor antagonist telenzepine (TEL; 6, 12 and 24 MUg/paw) caused a dose-dependent reduction in the nociceptive threshold induced by Cg (125 MUg/paw). This effect was not observed with increasing doses (4, 10 and 40 MUg) of other specific receptor antagonists: M(2) (dimethindene), M(3) (4-DAMP) and M(4) (tropicamide). The nicotinic antagonist mecamylamine (MEC; 25, 50 and 100 MUg/paw) also caused a dose-dependent reduction in the nociceptive threshold induced by Cg (125 MUg). To exclude a non-local effect, Cg (125 MUg) was injected into both hind paws, while TEL (12 MUg) and MEC (50 MUg) were administered only in the right paw. At these doses, the muscarinic antagonists increased inflammatory pain only in the treated right paw, suggesting a peripheral effect. In the presence of prostaglandin E(2) (1 MUg/paw), TEL (12 MUg) and MEC (50 MUg) did not reduce the nociceptive threshold, suggesting that this hyperalgesic agent does not induce the release of endogenous acetylcholine. These data suggest that muscarinic M(1) and nicotinic receptors participate in the modulation of endogenous cholinergic inflammatory pain at the peripheral level. PMID- 22104295 TI - Caffeine as an indicator for the quantification of untreated wastewater in karst systems. AB - Contamination from untreated wastewater leakage and related bacterial contamination poses a threat to drinking water quality. However, a quantification of the magnitude of leakage is difficult. The objective of this work is to provide a highly sensitive methodology for the estimation of the mass of untreated wastewater entering karst aquifers with rapid recharge. For this purpose a balance approach is adapted. It is based on the mass flow of caffeine in spring water, the load of caffeine in untreated wastewater and the daily water consumption per person in a spring catchment area. Caffeine is a source-specific indicator for wastewater, consumed and discharged in quantities allowing detection in a karst spring. The methodology was applied to estimate the amount of leaking and infiltrating wastewater to a well investigated karst aquifer on a daily basis. The calculated mean volume of untreated wastewater entering the aquifer was found to be 2.2 +/- 0.5 m(3) d(-1) (undiluted wastewater). It corresponds to approximately 0.4% of the total amount of wastewater within the spring catchment. PMID- 22104296 TI - Similarities in effluent organic matter characteristics from Connecticut wastewater treatment plants. AB - Effluent organic matter (EfOM) from five Connecticut (USA) municipal wastewater treatment plants was isolated with DAX8 (hydrophobic fraction) and XAD4 (transphilic fraction) resins. Isolate recoveries ranged from 18 to 42% of the total organic carbon for DAX8 resin and from 6 to 12% for XAD4 resin. Isolated EfOM was characterized by traditional organic geochemistry techniques. Weight averaged molecular weights of extracted EfOM by size exclusion chromatography were 450-670 Da with higher weights observed for the hydrophobic fractions than the transphilic fractions. Fluorescence characterization showed both humic- and fulvic-like fluorescence, as well as tryptophan- and tyrosine-like fluorescence, the latter not commonly observed for terrestrial organic matter. Fluorescence indices were between 1.5 and 1.9 with lower values observed for hydrophobic EfOM fractions than for transphilic fractions. Specific ultraviolet absorbance was measured between 0.8 and 3.0 L mg(-1)m(-1) with higher values for the hydrophobic EfOM fractions. Together these results indicated that isolated EfOM is similar in characteristics to microbially derived organic matter from natural aquatic systems. Little variation in EfOM characteristics was observed between the five wastewater treatment plants, suggesting that the characteristics of EfOM are similar, regardless of treatment plant design. PMID- 22104297 TI - Paratesticular endometriosis in a man with a prolonged hormonal therapy for prostatic carcinoma. AB - A rare case of paratesticular endometriosis in a 69-year-old male with prostatic carcinoma, who had a history of 9-year hormonal therapy, is presented. The lesion was a multilocular cyst, 5.2 cm * 3.1 cm * 3.0 cm in size, in the left paratestis. The cysts were lined by a single layer of cuboidal cells. A small number of glands were scattered in the underling stroma composed of closely packed small round or ovoid cells with scant cytoplasm resembling endometrial stromal cells, and abundant capillaries. Hemosiderin deposits were observed. Immunohistochemically, the lining cells of the cysts and glands were positive for CAM5.2, vimentin and calretinin, and were negative for CD10, estrogen and progesterone-receptors, indicating mesothelial profiles. The stromal cells expressed vimentin, estrogen- and progesterone-receptors and CD10. The findings indicated stromal endometriosis associated with the tunica vaginalis. Mullerian or endometriotic metaplasia and stromal cell hyperplasia under the influence of prolonged estrogen therapy may be the mechanism of this lesion. PMID- 22104298 TI - Effects of calisthenics and Pilates exercises on coordination and proprioception in adult women: a randomized controlled trial. AB - OBJECTIVE: To assess and compare the effects of 6 mo of Pilates and calisthenics on multijoint coordination and proprioception of the lower limbs at the 3rd and 6th mo of training. DESIGN: Randomized, controlled, assessor-blinded, repeated measures. SETTING: University research laboratory. PARTICIPANTS AND INTERVENTION: Healthy, sedentary, female participants age 25-50 y were recruited and randomly divided into 3 groups: a calisthenic exercise group (n = 34, mean age +/- SD 40 +/- 8 y, body-mass index [BMI] 31.04 +/- 4.83 kg/m2), a Pilates exercise group (n = 32, mean age +/- SD 37 +/- 8 y, BMI 31.04 +/- 4.83 kg/m2), and a control group (n = 41, mean age +/- SD 41 +/- 7 y, BMI 27.09 +/- 4.77 kg/m2). The calisthenics and Pilates groups underwent related training programs for 6 mo, while the controls had no specific training. MAIN OUTCOME MEASURES: Coordination and proprioception of the lower extremities with concentric and eccentric performances in the closed kinetic chain assessed with the monitored rehab functional squat system at baseline and at the 3rd and 6th mo of training. RESULTS: For the within-group comparison, coordinative concentric and eccentric deviation values were significantly decreased for both dominant and nondominant lower limbs at pretraining and at the 3rd and 6th mo posttraining in the calisthenics group (P < .05). In contrast, there was no improvement in the Pilates group throughout the training. However, for comparisons between groups, the baseline values of coordinative concentric and eccentric deviations were different in the calisthenics group than in Pilates and the controls (P < .05). There were no differences in the proprioception values of either visible or nonvisible movement in any group throughout the training (P > .05). CONCLUSIONS: It seems that calisthenic exercises are more likely to improve coordination of the lower extremity after 3 and 6 mo of training than Pilates exercises. Calisthenic exercises may be useful for individuals who require improved coordination. PMID- 22104299 TI - Verbal information about anesthesia before scheduled surgery - contents and patient satisfaction. AB - OBJECTIVE: The contents of information for patients before medical procedures are outlined by legislation and guidelines. The amount and form are less regulated. Our aim was to evaluate the contents of verbal information provided by anesthesiologists in a long-established preoperative clinic, and how satisfied patients are with it. METHODS: A questionnaire based on legislation and the DISCERN quality criteria for information on treatment choices was sent to patients who recently had anesthesia for elective hysterectomy in our hospital (n=372), and to the anesthesiologists involved (n=24). RESULTS: Preoperative information was regarded as sufficient by 82% of the patients and rated good by 65%. Information on the benefits of anesthesia, its risks, and effects on the quality of life was considered satisfactory by 74%, 49%, and 49%, respectively. Only 54% received enough information on lifestyle interventions to reduce their individual risks. Of the anesthesiologists, 33% had a policy to tell about risks on request only. CONCLUSION: Verbal information was highly appreciated by the patients, but only two-thirds rated its quality as good, and half were satisfied with the information concerning risks. PRACTICE IMPLICATIONS: More attention has to be focused on how to offer information on risks and self-help interventions to reduce them. PMID- 22104300 TI - Platinum(II) and palladium(II) complexes with (N,N') and (C,N,N')- ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities. AB - The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol] {where pzol represents pyrazole and R=H (1a), Me (1b) or Ph (1c)} with [MCl(2)(DMSO)(2)] (M=Pt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{kappa(2)-N,N'-{[1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol])}Cl(2)] {MM=PtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{kappa(3) C,N,N'-{[1-(CH(2))(2)NMe(2)}-3-(C(5)H(4))-5-Ph-pzol])}Cl] {M=Pt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC(50)=3 MUM) versus breast cancer cell lines (IC(50)>20 MUM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action. PMID- 22104301 TI - Coordination modes of tyrosinate-ligated catalase-type heme enzymes: magnetic circular dichroism studies of Plexaura homomalla allene oxide synthase, Mycobacterium avium ssp. paratuberculosis protein-2744c, and bovine liver catalase in their ferric and ferrous states. AB - Bovine liver catalase (BLC), catalase-related allene oxide synthase (cAOS) from Plexaura homomalla, and a recently isolated protein from the cattle pathogen Mycobacterium avium ssp. paratuberculosis (MAP-2744c (MAP)) are all tyrosinate ligated heme enzymes whose crystal structures have been reported. cAOS and MAP have low (<20%) sequence similarity to, and significantly different catalytic functions from, BLC. cAOS transforms 8R-hydroperoxy-eicosatetraenoic acid to an allene epoxide, whereas the MAP protein is a putative organic peroxide-dependent peroxidase. To elucidate factors influencing the functions of these and related heme proteins, we have investigated the heme iron coordination properties of these tyrosinate-ligated heme enzymes in their ferric and ferrous states using magnetic circular dichroism and UV-visible absorption spectroscopy. The MAP protein shows remarkable spectral similarities to cAOS and BLC in its native Fe(III) state, but clear differences from ferric proximal heme ligand His93Tyr Mb (myoglobin) mutant, which may be attributed to the presence of an Arg(+)-N(omega) H...-O-Tyr (proximal heme axial ligand) hydrogen bond in the first three heme proteins. Furthermore, the spectra of Fe(III)-CN-, Fe(III)-NO, Fe(II)-NO (except for five-coordinate MAP), Fe(II)-CO, and Fe(II)-O(2) states of cAOS and MAP, but not H93Y Mb, are also similar to the corresponding six-coordinate complexes of BLC, suggesting that a tyrosinate (Tyr-O-) is the heme axial ligand trans to the bound ligands in these complexes. The Arg(+)-N(omega)-H to -O-Tyr hydrogen bond would be expected to modulate the donor properties of the proximal tyrosinate oxyanion and, combined with the subtle differences in the catalytic site structures, affect the activities of cAOS, MAP and BLC. PMID- 22104302 TI - Detoxifying response in juvenile tench fed by selenium diet. AB - The effects of a selenium (Se) diet (1.0 mg Se kg-1) were investigated on growth, accumulation and antioxidant response in juvenile Tinca tinca at three endpoints (0, 4 and 8 weeks). Growth and condition factor (K>1.5) for both control (0.25 mg Se kg-1) and Se tench were not significantly affected. Se exposed fish exhibited the highest Se level in the kidney and the liver after 4 weeks. By feeding more Se the accumulation capacity of tench did not increase and a plateau, mainly for the liver, was thus reached. Se level remained almost constant in the muscle if compared to own control and for each endpoint. Superoxide dismutase activity in both tissues was not affected by Se supplementation and the higher catalase level in the kidney might support the hypothesis that the enzyme was adequate to remove the hydrogen peroxide production following Se exposure. However, supplemented diet with higher Se level could be critical for tench, as it may cause a lowering of glutathione peroxidase and glutathione reductase activities facilitating the onset of oxidative damage. The enhancement of thiol level and glutathione S transferase activity, mainly in the liver, could be the signals of the only protection against the oxidative damage induced by Se. PMID- 22104303 TI - Activity of tigecycline and comparators against skin and skin structure pathogens: global results of the Tigecycline evaluation and surveillance trial, 2004-2009. AB - BACKGROUND: This analysis from the global Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) reports on 24 784 isolates collected from integumentary culture sources between 2004 and 2009. METHODS: Minimum inhibitory concentrations (MICs) and susceptibility were determined according to the Clinical and Laboratory Standards Institute guidelines (US Food and Drug Administration breakpoints applied against tigecycline). RESULTS: All methicillin-resistant Staphylococcus aureus were susceptible to tigecycline, linezolid, and vancomycin. MIC(90)s for tigecycline against Enterococcus faecalis and Enterococcus faecium ranged between 0.12 mg/l and 0.25mg/l. Resistance to the carbapenems and tigecycline was low among the Enterobacteriaceae, with resistance at <= 2.0% between 2004 and 2009 for tigecycline against Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Enterobacter spp, and Serratia marcescens, for imipenem against E. coli and Enterobacter spp, and for meropenem against E. coli, Enterobacter spp, and S. marcescens. Against the Acinetobacter baumannii collected in 2009, resistance to amikacin, ceftazidime, levofloxacin, meropenem, and piperacillin-tazobactam was >30%; between 2004 and 2009 resistance to minocycline varied between 1.4% and 4.8%, and tigecycline MIC(90)s were <= 2mg/l. Against the Pseudomonas aeruginosa collected, MIC(90)s were greater than the susceptibility breakpoint for cefepime, ceftazidime, imipenem, levofloxacin, and meropenem. CONCLUSIONS: The problem of antimicrobial resistance is demonstrated by the data presented. T.E.S.T. continues to provide valuable information on antimicrobial resistance globally. PMID- 22104304 TI - Genetic population studies on 15 NGMTM STR loci in central Poland population. PMID- 22104305 TI - Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is associated with organ failure and it is often fatal condition. The main underlying diseases are infection, hematological malignancy and solid cancer. DIC is subclassified into overt DIC and non-overt DIC. The International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM) published the diagnostic criteria for DIC after several recent clinical trials. These diagnostic criteria are modified versions of the Japanese Ministry of Health, Labor and Welfare (JMHLW) criteria. The JAAM diagnostic criteria demonstrated excellent sensitivity for mortality but low specificity. The mechanisms of onset of DIC vary based on the underlying diseases, and depend on tissue factor, cytokines, etc. Early diagnosis and early treatment for DIC are important, and the use of hemostatic molecular markers is necessary to successfully make an early and rapid diagnosis. The mortality of DIC might be improved by the administration of recombinant activated protein C or recombinant thrombomodulin. Further investigation to improve the mortality of DIC is required, including new methods for diagnosing and treating the disease. PMID- 22104306 TI - Toll-like receptor--a potent driving force behind rheumatoid arthritis. AB - Toll like receptor (TLR), one of the key functions of innate immune system, can recognize not only exogenous pathogen-associated molecular patterns, namely PAMPs, but also endogenous molecules created upon tissue injury, sterile inflammation and degeneration. Endogenous TLR ligands are called as damage associated molecular patters (DAMPs), including endogenous molecules released by activated and necrotic cells, and extracellular matrix molecules. DAMPs are also known as alarmins. TLR research has brought about new insights in the rheumatic diseases. Previous reports suggest that TLRs and the signal pathways intensively contribute to the pathogenesis of rheumatoid arthritis (RA) and other arthritic conditions with interaction of various TLR ligands. Accumulated knowledge of TLR system is summarized to overlook TLRs and the signaling pathway in arthritis conditions, with special reference to RA. PMID- 22104307 TI - M2 macrophage/microglial cells induce activation of Stat3 in primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) is one of the most aggressive malignant lymphomas with a median survival of less than 20~40 months. Interest in signal transducer and activator of transcription 3 (Stat3) has increased during the past decade because Stat3 activation was found to contribute to tumor progression by inducing angiogenesis, immunosuppression, and metastasis. We previously demonstrated a significant correlation between Stat3 activation in tumor cells and infiltrating anti-inflammatory (M2) macrophages. Here, we focused on the phenotypes of infiltrating macrophages/microglial cells and Stat3 activation in PCNSL cells. The correlation of Stat3 activation or density of M2 macrophage infiltration with patient prognosis was also evaluated. We performed immunostaining for CD68, CD163, CD204, and pStat3 using paraffin-embedded PCNSL specimens obtained from 43 patients. CD163 and CD204 served as markers of the M2 phenotype. Dense infiltration of CD68(+) macrophages was found in all samples. High numbers of CD163(+) and CD204(+) M2 macrophages/microglial cells were observed in 29 and 25 cases, respectively. Stat3 activation in lymphoma cells was enhanced in the patients who showed denser infiltration of CD163(+) macrophages/microglial cells in tumor tissues. In vitro co-culture experiment to investigate cell-cell interactions between macrophages and lymphoma cells found that Stat3 in lymphoma cells was strongly activated by co-culture with macrophages. Numbers of CD68(+), CD163(+), and CD204(+) tumor-associated macrophages/microglial cells (TAMs) and Stat3 activation in lymphoma cells were not correlated with prognosis. However, because Stat3 involvement in tumor development was demonstrated in several malignant tumors, our present finding that cell-cell interactions of M2 macrophage/microglial cells with lymphoma cells induced Stat3 activation may provide novel insights into PCNSL pathogenesis. PMID- 22104308 TI - Clinical features and outcomes of 35 disseminated intravascular coagulation cases treated with recombinant human soluble thrombomodulin at a single institution. AB - Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome. PMID- 22104309 TI - Treatment outcome of adult Burkitt Lymphoma in Japanese patients with modified LMB protocol : a single center retrospective analysis. AB - The prognosis of adult Burkitt lymphoma (BL) has improved in western countries since the introduction of high-dose methotrexate (HD-MTX)-containing chemotherapy. Here we analyzed nine consecutive Japanese patients diagnosed with BL at our institution. All except for the three elderly (> 70 years) patients were treated with a regimen including 13 g/m(2) HD-MTX in total, divided into 3 cycles. The median follow-up period was 56 months (range 38-118). All the nine patients achieved complete remission and have not shown any disease progression, including the three elderly patients who received reduced doses or alternative treatments. These observations suggest that chemotherapy including 13 g/m(2) HD MTX in total is tolerable and effective in Japanese adult BL patients aged < 70 and that BL is curable even if developed in those who are > 70 years. PMID- 22104310 TI - A case of intravascular lymphoma complicated with Fournier's syndrome due to multidrug-resistant Pseudomonas aeruginosa. AB - Fournier's syndrome is the fulminant necrotizing fasciitis of the external genitalia. The occurrence of Fournier's syndrome in patients with hematologic malignancies has been reported. Here we report a case of an intravascular lymphoma complicated with Fournier's syndrome due to multidrug-resistant Pseudomonas aeruginosa (MDRP). A 71-year-old Japanese man received intensive chemotherapy for recurring intravascular lymphoma. Blood culture revealed MDRP, and physical examination led to the diagnosis of Fournier's syndrome. Aggressive treatment that comprised granulocyte transfusion, granulocyte stimulating factor, endotoxin filtration, appropriate antibiotic coverage, and aggressive surgical therapy was administered, and this lead to the successful recovery from sepsis and Fournier's syndrome. PMID- 22104311 TI - Enteropathy-associated T-cell lymphoma type II complicated by autoimmune hemolytic anemia. AB - A 74-year-old man was admitted to hospital because of persistent fever, diarrhea, and abdominal pain. CT scanning showed extensive wall thickening of the colon. He was transferred to our hospital because he further developed ascites and paraaortic lymph node swelling. On presentation, he was extremely emaciated with superficial lymph node swelling, ascitic signs, and leg edema. Histological image of a biopsied mesenteric lymph node demonstrated diffuse infiltration of large abnormal T cells. Surface antigen analysis of abnormal cells in the ascites revealed positivity for CD3, CD8, CD56, and weak positivity for CD103. Polymerase chain reaction analysis showed monoclonal rearrangement of the T cell receptor (TCR) gene. The subtype of TCR was alphabeta. A diagnosis of enteropathy associated T cell lymphoma (EATL) type II was made. The lymphoma involved the bone marrow. The patient also had severe hemolytic anemia with a positive Coomb's test result. An additional diagnosis for autoimmune hemolytic anemia (AIHA) was made, which was resistant to methylprednisolone therapy. We first treated him with only vincristine in addition to the steroid to avoid acute tumor lysis syndrome ; however, he died of septic shock that occurred soon after vincristine administration. To the best of our knowledge, this may be the first reported case of EATL complicated by AIHA. PMID- 22104312 TI - Local recurrence as immunoglobulin G4 (IgG4)-related disease 10 years after radiotherapy to ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue. AB - In 2000, a 48-year-old woman developed a left orbital mass with lacrimal gland involvement and then, in 2003, a right orbital mass with lacrimal gland involvement, both of which were diagnosed as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). She underwent 30 Gy external beam radiation to bilateral orbital lesions. The lymphoma cells in both lesions did not share the same clonality, as shown by amplification by polymerase chain reaction of the immunoglobulin heavy chain gene. Immunoglobulin light chain analysis by immunohistochemistry and messenger RNA in situ hybridization showed lambda chain monotype in the left orbital lesion but kappa chain monotype in the right orbital lesion. She developed recurrent left orbital mass with high uptake on fluorodeoxyglucose positron emission tomography fused with computed tomography in 2010, and excisional biopsy disclosed the formation of follicles and infiltration with immunoglobulin G4 (IgG4)-positive plasma cells mainly in interfollicular areas. The immunoglobulin light chain analysis showed the lambda chain and kappa chain bitype. With the immunohistopathological diagnosis of IgG4-related disease, the serum IgG4 level was found to show elevation at 376 mg/dL, and the patient chose observation. This is the first reported case of development of IgG4-related disease after bilataral orbital MALT lymphoma with external beam radiotherapy. PMID- 22104313 TI - Systemic follicular lymphoma with massive intestinal involvement with leukemic manifestation. AB - A 30-year-old man was referred to our hospital with leukocytosis and fecal occult blood. His white blood cell count was 30.2 * 10(9)/L with 79% small- to medium sized lymphocytes. Surface antigen analysis revealed that these lymphocytes were positive for CD19, CD20, CD10, and CD23, but negative for CD5. The lymphocytes infiltrated the bone marrow. On endoscopic examination of the duodenum and jejunum, many small polypoid lesions were observed. A histologic picture of a biopsied lesion showed diffuse infiltration of small- to medium-sized lymphocytes in the submucosal region. On immunohistochemistry, these lymphocytes were positive for CD20, BCL2, and CD10 (weakly). Polymerase chain reaction analysis of cells from peripheral blood, bone marrow, and intestinal lesion showed a fusion product of BCL2 and immunoglobulin heavy chain (IGH) genes. The fused BCL2/IGH gene was also demonstrated by fluorescence in situ hybridization in the same cell sources. Computed tomography scanning showed marked wall thickening throughout the small intestine and enlarged mesenteric lymph nodes. A diagnosis of follicular lymphoma with massive intestinal involvement in a leukemic state was made. After 6 courses of rituximab-combined CHOP chemotherapy, complete remission was obtained. PMID- 22104314 TI - Myelodysplastic syndrome of del 20q with plasma cell dysplasia. AB - Deletion of the long arm of chromosome 20 (del 20q) has been observed in patients with myelodysplastic syndrome (MDS) or myeloid malignancies. We experienced an MDS female case of del 20q accompanied by clusters of plasmacytic cells in bone marrow. Her bone marrow cells showed morphological abnormalities in three lineages and the chromosomal abnormality of 46, XX, del (20) (q11.2q13.3). Although the percentage of plasma cells was low in free cells, such cells showed nuclear abnormalities. In bone marrow clots, we also observed clusters of anti CD38 and anti-CD138 antibody-positive cells. According to the FAB or WHO classification, the diagnosis was unclear. Therefore, we were obliged to term this case as MDS with plasma cell dysplasia. This patient was considered to be a rare case of MDS related to abnormalities in myeloid and B-lymphoid cells. PMID- 22104315 TI - Mantle cell lymphoma superimposed on multicentric Castleman's disease. PMID- 22104316 TI - Lymph node lesion of acute infectious mononucleosis in the elderly : a case report. PMID- 22104317 TI - Control of Cr6+ emissions from gas metal arc welding using a silica precursor as a shielding gas additive. AB - Hexavalent chromium (Cr(6+)) emitted from welding poses serious health risks to workers exposed to welding fumes. In this study, tetramethylsilane (TMS) was added to shielding gas to control hazardous air pollutants produced during stainless steel welding. The silica precursor acted as an oxidation inhibitor when it decomposed in the high-temperature welding arc, limiting Cr(6+) formation. Additionally, a film of amorphous SiO(2) was deposited on fume particles to insulate them from oxidation. Experiments were conducted following the American Welding Society (AWS) method for fume generation and sampling in an AWS fume hood. The results showed that total shielding gas flow rate impacted the effectiveness of the TMS process. Increasing shielding gas flow rate led to increased reductions in Cr(6+) concentration when TMS was used. When 4.2% of a 30 lpm shielding gas flow was used as TMS carrier gas, Cr(6+) concentration in gas metal arc welding (GMAW) fumes was reduced to below the 2006 Occupational Safety and Health Administration standard (5 MUg m(-3)) and the efficiency was >90%. The process also increased fume particle size from a mode size of 20 nm under baseline conditions to 180-300 nm when TMS was added in all shielding gas flow rates tested. SiO(2) particles formed in the process scavenged nanosized fume particles through intercoagulation. Transmission electron microscopy imagery provided visual evidence of an amorphous film of SiO(2) on some fume particles along with the presence of amorphous SiO(2) agglomerates. These results demonstrate the ability of vapor phase silica precursors to increase welding fume particle size and minimize chromium oxidation, thereby preventing the formation of hexavalent chromium. PMID- 22104318 TI - Comparison of stochastic lung deposition fractions with experimental data. AB - Deposition fractions of inhaled particles predicted by different computational models vary with respect to physical and biological factors and mathematical modeling techniques. These models must be validated by comparison with available experimental data. Experimental data supplied by different deposition studies with surrogate airway models or lung casts were used in this study to evaluate the stochastic deposition model Inhalation, Deposition and Exhalation of Aerosols in the Lung at the airway generation level. Furthermore, different analytical equations derived for the three major deposition mechanisms, diffusion, impaction, and sedimentation, were applied to different cast or airway models to quantify their effect on calculated particle deposition fractions. The experimental results for ultrafine particles (0.00175 and 0.01) were found to be in close agreement with the stochastic model predictions; however, for coarse particles (3 and 8 MUm), experimental deposition fractions became higher with increasing flow rate. An overall fair agreement among the calculated deposition fractions for the different cast geometries was found. However, alternative deposition equations resulted in up to 300% variation in predicted deposition fractions, although all equations predicted the same trends as functions of particle diameter and breathing conditions. From this comparative study, it can be concluded that structural differences in lung morphologies among different individuals are responsible for the apparent variability in particle deposition in each generation. The use of different deposition equations yields varying deposition results caused primarily by (i) different lung morphometries employed in their derivation and the choice of the central bifurcation zone geometry, (ii) the assumption of specific flow profiles, and (iii) different methods used in the derivation of these equations. PMID- 22104319 TI - Estimating trends in quartz exposure in Swedish iron foundries--predicting past and present exposures. AB - BACKGROUND: Swedish foundries have a long tradition of legally required surveys in the workplace that, from the late 1960s onwards, included measurements of quartz. The availability of exposure data spanning almost 40 years presents a unique opportunity to study trends over that time and to evaluate the validity of exposure models based on data from shorter time spans. The aims of this study were (i) to investigate long-term trends in quartz exposure over time, (ii) using routinely collected quartz exposure measurements to develop a mathematical model that could predict both historical and current exposure patterns, and (iii) to validate this exposure model with up-to-date measurements from a targeted survey of the industry. METHODS: Eleven foundries, representative of the Swedish iron foundry industry, were divided into three groups based on the size of the companies, i.e. the number of employees. A database containing 2333 quartz exposure measurements for 11 different job descriptions was used to create three models that covered time periods which reflected different work conditions and production processes: a historical model (1968-1989), a development model (1990 2004), and a validation model (2005-2006). A linear mixed model for repeated measurements was used to investigate trends over time. In all mixed models, time period, company size, and job title were included as fixed (categorical) determinants of exposure. The within- and between-worker variances were considered to be random effects. A linear regression analysis was performed to investigate agreement between the models. The average exposure was estimated for each combination of job title and company size. RESULTS: A large reduction in exposure (51%) was seen between 1968 and 1974 and between 1975 and 1979 (28%). In later periods, quartz exposure was reduced by 8% per 5 years at best. In the first period, employees at smaller companies experienced ~50% higher exposure levels than those at large companies, but these differences became much smaller in later years. The furnace and ladle repair job were associated with the highest exposure, with 3.9-8.0 times the average exposure compared to the lowest exposed group. Without adjusting for this autonomous trend over time, predicting early historical exposures using our development model resulted in a statistically significant regression coefficient of 2.42 (R(2) = 0.81), indicating an underestimation of historical exposure levels. Similar patterns were seen for other historical time periods. Comparing our development model with our validation model resulted in a statistically significant regression coefficient of 0.31, indicating an overestimation of current exposure levels. CONCLUSION: To investigate long-term trends in quartz exposure over time, overall linear trends can be determined by using mixed model analysis. To create individual exposure measures to predict historical exposures, it is necessary to consider factors such as the time period, type of job, type of company, and company size. The mixed model analysis showed systematic changes in concentration levels, implying that extrapolation of exposure estimates outside the range of years covered by measurements may result in underestimation or overestimation of exposure. PMID- 22104320 TI - Perceptions of flatulence from bean consumption among adults in 3 feeding studies. AB - BACKGROUND: Many consumers avoid eating beans because they believe legume consumption will cause excessive intestinal gas or flatulence. An increasing body of research and the 2010 Dietary Guidelines for Americans supports the benefits of a plant-based diet, and legumes specifically, in the reduction of chronic disease risks. The purpose of the current research was to investigate the perception of increased flatulence and gastrointestinal discomfort among participants who consumed a 1/2 cup of beans daily for 8 or 12 weeks. METHODS: Participants in three studies to test the effects of beans on heart disease biomarkers completed the same weekly questionnaire to assess gastrointestinal discomfort issues such as increased flatulence, stool changes, and bloating. Studies 1 and 2 were randomized crossover trials. Participants consumed 1/2 cup of pinto beans, black-eyed peas, and canned carrots as control (n = 17) in Study 1 for three randomized 8-week phases. For Study 2, participants ate 1/2 cup baked beans or canned carrots as control (n = 29) for two randomized 8-week phases. Study 3 was a parallel arm trial with 40 subjects receiving 1/2 cup pinto beans and 40 consuming a control soup for 12 weeks. Changes in the frequency of perceived flatulence, stool characteristics, and bloating were the primary outcome measures. Chi-square distributions were examined for the presence or absence of symptoms and demographic characteristics to determine differences by gender, age, body mass index (BMI), and bean type. RESULTS: Less than 50% reported increased flatulence from eating pinto or baked beans during the first week of each trial, but only 19% had a flatulence increase with black-eyed peas. A small percentage (3-11%) reported increased flatulence across the three studies even on control diets without flatulence-producing components. CONCLUSIONS: People's concerns about excessive flatulence from eating beans may be exaggerated. Public health nutritionists should address the potential for gastrointestinal discomfort when increasing fiber intake from beans with clients. It is important to recognize there is individual variation in response to different bean types. PMID- 22104321 TI - Factor structure of self-regulation in preschoolers: testing models of a field based assessment for predicting early school readiness. AB - The importance of early self-regulatory skill has seen increased focus in the applied research literature given the implications of these skills for early school success. A three-factor latent structure of self-regulation consisting of compliance, cool executive control, and hot executive control was tested against alternative models and retained as best fitting. Tests of model equivalence indicated that the model held invariant across Head Start and private child-care samples. Partial invariance was supported for age and gender. In the validity model, because of a substantial amount of shared variance among latent factors, we included a second-order factor explaining the two types of executive control. Higher order executive control positively predicted teacher report of learning behaviors and social competence in the classroom. These findings are discussed in light of their practical and theoretical significance. PMID- 22104322 TI - An arteriovenous fistula model of intimal hyperplasia for evaluation of a nitinol U-Clip anastomosis. AB - OBJECTIVES: The aim of this study was to create an ovine arteriovenous fistula (AVF) model which would closely replicate a human forearm fistula and use this to quantify the degree of intimal hyperplasia in those created with the U-Clip compared to a conventional sutured anastomosis. MATERIALS AND METHODS: Twenty AVFs were created in 10 Border Leicester-Merino sheep between the superficial femoral artery and vein of each hind limb. On one side the U-Clip and on the other a continuous polypropylene suture was used to perform the anastomosis. The animals were sacrificed at 2 (n = 3), 4 (n = 4), 6 (n = 3) weeks and histological slices were taken of each AVF in cross section to determine the intimal media area per unit length (IMA/L). RESULTS: Intimal hyperplasia (IH) was observed at all time points with one AVF found occluded with thrombus at the time of harvest. The IMA/L was significantly lower in the U-Clip groups by 24% at 2 weeks, 32% at 4 weeks and 23% at 6 weeks (Two-way ANOVA, p = 0.019, observed power = 0.825, time or side p >= 0.766, type p = 0.001; Paired t-test, p < 0.001 between matched anastomotic types). Time taken to perform the anastomosis was similar between the two anastomotic techniques (Polypropylene 14(8-18) vs. U-Clip 15.3(11-23) min; p = 0.47). CONCLUSION: This ovine AVF model results in IH similar to that seen in a human AVF. The IH that occurs with the U-Clip is less than that of continuous polypropylene suture. PMID- 22104323 TI - Shared care in mental illness: A rapid review to inform implementation. AB - BACKGROUND: While integrated primary healthcare for the management of depression has been well researched, appropriate models of primary care for people with severe and persistent psychotic disorders are poorly understood. In 2010 the NSW (Australia) Health Department commissioned a review of the evidence on "shared care" models of ambulatory mental health services. This focussed on critical factors in the implementation of these models in clinical practice, with a view to providing policy direction. The review excluded evidence about dementia, substance use and personality disorders. METHODS: A rapid review involving a search for systematic reviews on The Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE). This was followed by a search for papers published since these systematic reviews on Medline and supplemented by limited iterative searching from reference lists. RESULTS: Shared care trials report improved mental and physical health outcomes in some clinical settings with improved social function, self management skills, service acceptability and reduced hospitalisation. Other benefits include improved access to specialist care, better engagement with and acceptability of mental health services. Limited economic evaluation shows significant set up costs, reduced patient costs and service savings often realised by other providers. Nevertheless these findings are not evident across all clinical groups. Gains require substantial cross organisational commitment, carefully designed and consistently delivered interventions, with attention to staff selection, training and supervision. Effective models incorporated linkages across various service levels, clinical monitoring within agreed treatment protocols, improved continuity and comprehensiveness of services. CONCLUSIONS: "Shared Care" models of mental health service delivery require attention to multiple levels (from organisational to individual clinicians), and complex service re-design. Re-evaluation of the roles of specialist mental health staff is a critical requirement. As expected, no one model of "shared" care fits diverse clinical groups. On the basis of the available evidence, we recommended a local trial that examined the process of implementation of core principles of shared care within primary care and specialist mental health clinical services. PMID- 22104324 TI - Phosphorus-nitrogen compounds. Part 23: syntheses, structural investigations, biological activities, and DNA interactions of new N/O spirocyclotriphosphazenes. AB - The Schiff base compounds (1 and 2) are synthesized by the condensation reactions of 2-furan-2-yl-methylamine with 2-hydroxy-3-methoxy- and 2-hydroxy-5-methoxy benzaldehydes and reduced with NaBH(4) to give the new N/O-donor-type ligands (3 and 4). The monospirocyclotriphosphazenes containing 1,3,2-oxazaphosphorine rings (5 and 6) are prepared from the reactions of N(3)P(3)Cl(6) with 3 and 4, respectively. The reactions of 5 and 6 with excess pyrrolidine, morpholine, and 1,4-dioxa-8-azaspiro [4,5] decane (DASD) produce tetrapyrrolidino (5a and 6a), morpholino (5b and 6b), and 1,4-dioxa-8-azaspiro [4,5] deca (5c and 6c) spirocyclotriphosphazenes. The structural investigations of the compounds are examined by (1)H, (13)C, (31)P NMR, DEPT, HSQC, and HMBC techniques. The solid state structures of 5, 5a, and 6 are determined using X-ray crystallography. The compounds 5a, 5b, 5c, 6a, 6b, and 6c are subjected to antimicrobial activity against six patojen bacteria and two yeast strains. In addition, interactions between these compounds and pBR322 plasmid DNA are presented by agarose gel electrophoresis. PMID- 22104325 TI - Preparation of low cost activated carbon from Myrtus communis and pomegranate and their efficient application for removal of Congo red from aqueous solution. AB - In this research, the potential applicability of activated carbon prepared from Myrtus communis (AC-MC) and pomegranate (AC-PG) as useful adsorbents for the removal of Congo red (CR) from aqueous solutions in batch method was investigated. The effects of pH, contact time, agitation time and amount of adsorbents on removal percentage of Congo red on both adsorbents were examined. Increase in pH up to 6 for AC-MC and pH 7 for AC-PG increase the adsorption percentage (capacity) and reach equilibrium within 30 min of contact time. Fitting the experimental data to conventional isotherm models like Freundlich, Langmuir, Tempkin and Dubinin-Radushkevich show that the experimental data fitted very well to the Freundlich isotherm for AC-MC and Langmuir isotherm for AC-PG. Fitting the experimental data to different kinetic models such as pseudo first order, pseudo second-order, Elovich and intraparticle diffusion mechanism showed the applicability of a pseudo second-order with involvement of intraparticle diffusion model for interpretation of experimental data for both adsorbents. The adsorption capacity of AC-PG and AC-MC for the removal of CR was found to be 19.231 and 10 mg g(-1). These results clearly indicate the efficiency of adsorbents as a low cost adsorbent for treatment of wastewater containing CR. PMID- 22104326 TI - Cadmium hydroxide nanowire loaded on activated carbon as efficient adsorbent for removal of Bromocresol Green. AB - In the present research, cadmium hydroxide nanowire loaded on activated carbon (Cd(OH)(2)-NW-AC) was synthesized and characterized. This new adsorbent was applied for the removal of Bromocresol Green (BCG) molecules from aqueous solutions. The influence of effective variables such as solution pH, contact time, initial BCG concentration, amount of Cd(OH)(2)-NW-AC and temperature on the adsorption efficiency of BCG in batch system was examined. During all experiments BCG contents were determined by UV-Vis spectrophotometer. Fitting the experimental data to different kinetic models including pseudo-first-order, pseudo-second-order, Elovich and intra-particle diffusion kinetic models show the suitability of the pseudo-second-order kinetic model to interpret in the experimental data. Equilibrium isotherm studies were examined by application of different conventional models such as Langmuir, Freundlich and Tempkin models to explain the experimental data. Based on considering R(2) value as criterion the adsorption data well fitted to Langmuir model with maximum adsorption capacity of 108.7 mg g(-1). Thermodynamic parameters (Gibb's free energy, entropy and enthalpy) of adsorption were calculated according to general procedure to take some information about the on-going adsorption process. The high negative value of Gibb's free energy and positive value of enthalpy show the feasibility and endothermic nature of adsorption process. PMID- 22104327 TI - Molecular structure, vibrational spectra, HOMO, LUMO and NMR studies of 1,2 dichloro-4-nitrobenzene and 2,3,5,6-tetrachloro-1-nitrobenzene based on density functional calculations. AB - The vibrational spectra of 1,2-dichloro-4-nitrobenzene (DCNB) and 2,3,5,6 tetrachloro-1-nitrobenzene (TCNB) were computed using B3LYP methodology with 6 31G* basis set. The solid phase FTIR and FT-Raman spectra were recorded in the region 4000-400 cm(-1) and 4000-50 cm(-1), respectively. A similarity was achieved between the observed and calculated frequencies by refinement of the scale factors. The HOMO and LUMO energies were calculated. (13)C and (1)H NMR chemical shifts results were also compared with the experimental values. PMID- 22104328 TI - Improvement in word recognition score with level is associated with hearing aid ownership among patients with hearing loss. AB - Market surveys consistently show that only 22% of those with hearing loss own hearing aids. This is often ascribed to cosmetics, but is it possible that patients apply a different auditory criterion than do audiologists and manufacturers? We tabulated hearing aid ownership in a survey of 1000 consecutive patients. We separated hearing loss cases, with one cohort in which word recognition in quiet could improve with gain (vs. 40 dB HL) and another without such improvement but nonetheless with audiometric thresholds within the manufacturer's fitting ranges. Overall, we found that exactly 22% of hearing loss patients in this sample owned hearing aids; the same finding has been reported in many previous, well-accepted surveys. However, while all patients in the two cohorts experienced difficulty in noise, patients in the cohort without word recognition improvement were found to own hearing aids at a rate of 0.3%, while those patients whose word recognition could increase with level were found to own hearing aids at a rate of 50%. Results also coherently fit a logistic model where shift of the word recognition performance curve by level corresponded to the likelihood of ownership. In addition to the common attribution of low hearing aid usage to patient denial, cosmetic issues, price, or social stigma, these results provide one alternative explanation based on measurable improvement in word recognition performance. PMID- 22104329 TI - Peliosis hepatis presenting as liver rupture in a vulnerable adult: a case report. AB - Liver rupture is a serious, life-threatening event that is commonly due to blunt abdominal trauma, which should be suspected in a patient who is unconscious or unable to communicate. We report an autopsy case of a 28-year-old woman with severe developmental delay who presented to the emergency department with hemoperitoneum due to massive liver rupture and subsequently died without a diagnosis. An autopsy performed by the hospital pathology department confirmed hemoperitoneum due to hepatic rupture. The case was then referred to the medical examiner to exclude a traumatic etiology. After review of the clinical data, radiological images, and gross and microscopic pathological features, a diagnosis of peliosis hepatis was established. This rare entity has been reported previously as a cause of spontaneous, nontraumatic liver rupture and is reported here to demonstrate its characteristic features and potential to present as fatal hepatic rupture in circumstances in which occult injury must be excluded. PMID- 22104330 TI - Secondary missile injury from lightning strike. AB - A 48-year-old-woman was struck dead by lightning on October 24, 2010, in Pretoria, South Africa. The cause of death was due to direct lightning strike. Examination showed secondary missile injury on her legs. This secondary missile (shrapnel) injury was caused by the lightning striking the concrete pavement next to her. Small pieces of concrete were located embedded within the shrapnel wounds. This case report represents the first documented case of secondary missile formation (shrapnel injury) due to lightning strike in the literature. PMID- 22104331 TI - Hallucinations and persecutory delusions in mefloquine-associated suicide. PMID- 22104332 TI - Fatal subarachnoid hemorrhage during sexual anal self-stimulation in a female: a case report. AB - Sudden death after sexual activity is a well-known entity, but it is rare in females. Herein we present a case of fatal, massive subarachnoid hemorrhage from a ruptured berry-shaped aneurysm, during sexual anal self-stimulation. A 39-year old woman was found dead on a couch, with the wooden handle of a spring twirl whisk inserted inside her anus and rectum as a dildo-like object. External examination was unremarkable with no signs of injuries. Intracranial examination showed a massive subarachnoid hemorrhage, up to 6 mm in thickness, especially around the brainstem and the inferior side of the brain. After removing the blood clots, the saccular aneurysm was found at the site of the bifurcation of the left internal carotid. In this case study, we underline the utility of forensic autopsy, as well as death scene investigation, in reconstructing the mechanism of death, as well as the dynamics of the event. PMID- 22104333 TI - Time course of acute neuroprotective effects of lidocaine evaluated by brain impedanciometry in the global ischemia model. AB - Voltage-activated sodium channels play a primary role during ischemic brain edema and thus are a pharmacological target for therapy. Lidocaine, a sodium channel blocker, was tested in male Sprague-Dawley rats anesthetized with thiobarbital (60 mg.kg(-1) i.p.) and perfused i.v. with Ringer's solution (n = 9) or lidocaine (0.75 mg.kg(-1), n = 9, or 1.5 mg.kg(-1), n = 6). Two tungsten microelectrodes were implanted in the cerebral cortex to register changes in tissue impedance in response to the voltage fall of a square wave electric pulse (100 MUA, 10 ms), before and after infusion of lidocaine or Ringer's solution and during global cerebral ischemia due to a respiratory arrest induced by D-tubocurarine. Lidocaine infusion under normoxic conditions did not change voltage values (Mann Whitney U = 51; p > 0.05). In animals infused with Ringer's solution, the voltage fall induced by global cerebral ischemia was fast for ~8 min at -8.0 +/- 2.3%.min(-1) followed by a slow decay at -0.96 +/- 0.17%.min(-1). The time constant of voltage decay (lambda) was 215.6 s (F = 547.4; p = 0.00000). Voltage values of lidocaine-infused animals were significantly higher than those of rats infused with Ringer's solution (U = 100; p = 0.000089). The decay rates were 4.97 +/- 1.36%.min(-1) (fast phase) and -1.04 +/- 0.3%.min(-1) (slow phase) with lambda = 672.5 s (+211.9%; p = 0.000000). These results suggest that lidocaine significantly reduced cerebral impedance, hence exerting a strong early anti edema effect probably by blocking voltage-activated sodium channels. PMID- 22104334 TI - Wood pellet fly ash and bottom ash as an effective liming agent and nutrient source for rye grass (Lolium perenne L.) and oats (Avena sativa). AB - Fly ash (FA) and bottom ash (BA) from a softwood pellet boiler were characterized and evaluated as soil amendments. In a greenhouse study, two plant species (rye grass, Lolium perenne L. and oats, Avena sativa) were grown in three different treatments (1% FA, 1% BA, non-amended control) of a silty loam soil. Total concentrations of plant nutrients Ca, K, Mg, P and Zn in both ashes were elevated compared to conventional wood ash. Concentrations of Cd, Cr, Pb, Se and Zn were found to be elevated in the FA relative to BA and the non-amended soil. At 28 d, oat above-ground biomass was found to be significantly greater in soil amended with FA. Potassium and Mo plant tissue concentrations were significantly increased by addition of either ash, and FA significantly increased Zn tissue concentrations. Cadmium and Hg tissue concentrations were elevated in some cases. As soil amendments, either pellet ash is an effective liming agent and nutrient source, but high concentrations of Cd and Zn in FA may preclude its use as an agricultural soil amendment in some jurisdictions. Lower ash application rates than those used in this study (i.e. <1%) may still provide sufficient nutrients and effective neutralization of soil acidity. PMID- 22104335 TI - Polychlorinated biphenyls in vacuum dust and blood of residents in 20 Wisconsin households. AB - Human exposure to PCBs is nearly universal in North America. While most exposure can be linked to consumption of contaminated fish, detection of PCBs in non-fish eating populations suggests that other routes of exposure including inhalation of PCB-laden particles or volatile congeners, ingestion of contaminated soil or dust, or dermal absorption following direct contact are also important. In an effort to assess the role of the residential environment as a source of exposure, vacuum dust was collected from the homes of 26 Wisconsin residents whose serum PCB levels had been measured approximately 2 years earlier. More than 60 congeners were detected in dust with all of the samples containing congeners 101, 110, 138 and 153. Total PCB levels ranged from 8.8 to 1186 ng g(-1) with levels being highest in vacuum dust from homes built between 1959 and 1970. Total PCB levels ranged from 0.05 to 8.34 MUg L(-1) in serum collected from the adults living in these households, with congeners 138, 153 and 180 predominating. Hexa- and hepta-chlorinated biphenyls comprised 73% of the total residues detected in serum. However, most of the residues found in dust were lower chlorinated congeners with tetra- and penta-chlorinated biphenyls being dominant. Following log transformation, a positive association was found between serum and house dust PCB levels. This association was stronger among infrequent consumers of Great Lake fish, but of borderline statistical significance. This exploratory study suggests that house dust may be a significant source of exposure to PCBs and supports the need for further investigations. PMID- 22104336 TI - The influence of diet on intra and inter-individual variability of urinary excretion of arsenic species in Italian healthy individuals. AB - To study the effect of eating foods with a high arsenic (As) content on the intra and inter-individual variability of urinary concentrations of the As species, daily urine samples were collected for 10 consecutive days from 12 healthy male subjects. A daily food diary was kept throughout the study period. Personal exposure to airborne As was measured once during the study. As(3), As(5), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and arsenobetaine were determined in all urine samples by inductive coupled plasma mass spectrometry, and the sum of As(3)+As(5)+MMA+DMA (iAs) by hydride generation-atomic absorption spectrophotometry. Exposure to airborne As was below the limit of detection in all samplings. As(3) was found in only 19.2% and As(5) in only 3.3% of the urine samples, whereas high urinary concentrations of arsenobetaine were observed. With the exception of arsenobetaine, expressed as a percentage, a significant inter individual variability was observed for all species of As, for iAs and for the MMA/DMA ratio (p<0.001). Instead, the intra-individual variability was significant only for the MMA/DMA ratio (p<0.001). Among foods with a high As content, only a heavy consumption of seafood was shown to influence inter individual variability of DMA%, arsenobetaine expressed as MUg g(-1) creatinine and iAs. In conclusion, even in populations with a high intake of organic As through foods, the finding of a significant inter-individual but no significant intra-individual variability of urinary species confirms the usefulness of urinary As speciation for biological monitoring of exposure to As. PMID- 22104337 TI - First assessment of population exposure to perfluorinated compounds in Flanders, Belgium. AB - With the objective to evaluate exposure of the population in Flanders (Belgium) to perfluorinated compounds (PFCs), we measured perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in settled dust in homes and offices, in a selection of food items from local origin, in drinking-water and in human serum. We complemented the data with results from a literature survey. Based on this dataset we calculated intake by children and adults from food, drinking-water, settled dust and soil, and air. Dietary exposure dominated overall intake. For adults, average dietary intake equalled 24.2 (P95 40.9) ng PFOS kg(-1) d(-1) and 6.1 (P95 9.6) ng PFOA kg(-1)d(-1), whereas for children the dietary intake was about 3 times higher. Predicted intake is high when compared to assessments in other countries, and to serum levels from Flanders, but comparable to the intakes published by The European Food Safety Authority (EFSA) in 2008. Intake of PFOS and PFOA remained below the Tolerable Daily Intake. PMID- 22104338 TI - Combined treatment with compression therapy and ablation of incompetent superficial and perforating veins reduces ulcer recurrence in patients with CEAP 5 venous disease. AB - OBJECTIVE: Patients with healed venous ulcers often experience recurrence of ulceration, despite the use of long-term compression therapy. This study examines the effect of closing incompetent superficial and/or perforating veins on ulcer recurrence rates in patients with CEAP 5 who have progressive lipodermatosclerosis and impending ulceration. METHODS: Endovenous ablation was performed on patients with CEAP 5 disease and incompetent superficial and/or perforator veins and increasing lipodermatosclerosis and/or progressive malleolar pain. A minimum of 3 months of compressive therapy was attempted before endovenous ablation of incompetent veins. Demographic data, risk factors, CEAP classification, procedural details, and postoperative status were all recorded. Patients underwent duplex ultrasound scans before ablation to assess for deep, superficial, and perforator venous incompetence as well as postoperatively to confirm successful ablation. RESULTS: Twenty-eight endovenous ablation procedures (superficial = 19; perforator = 9) were performed on 20 patients (limbs = 21). The mean patient age was 73 years old (range, 45-93 years) and the mean body mass index was 29.5 (18.9-58.4). Ninety-five percent of patients previously wore compression stockings (20-30 mm Hg = 9; 30-40 mm Hg = 10; none = 1) for a mean time of 23.3 months (range, 3-52 months) since the prior ulcer healed. Indications for venous ablation were increasing malleolar pain (55%) and/or lipodermatosclerosis (70%). Technical success rates for the ablation procedures were 100% for superficial veins and 89% for perforators (96.4% overall). All patients underwent closure of at least one incompetent vein. Postoperatively, 95% of patients were compliant with wearing compression stockings (20-30 mm Hg = 8; 30-40 mm Hg = 11; none = 1). Ulcer recurrence rates were 0% at 6 months and 4.8% at 12 and 18 months. These data compare with prior studies showing an ulcer recurrence rate up to 67% at 12 months with compression alone. CONCLUSION: Patients with CEAP 5 healed venous ulcers that undergo endovenous ablation of incompetent superficial and perforating veins and maintain compression have reduced ulcer recurrence rates compared with historical controls that are treated with compression alone. PMID- 22104339 TI - Radiofrequency thermal wire is a useful adjunct to treat chronic central venous occlusions. AB - Conventional techniques for central venous recanalization are successful in crossing most lesions but still fail in many patients. We used a radiofrequency wire in these failed cases. We report three patients with complicated central venous occlusions in whom conventional catheter and guidewire techniques were not successful and who were successfully treated using the PowerWire Radiofrequency Guidewire (Baylis Medical Company Inc, Montreal, QC, Canada). Occlusions were traversed using the radiofrequency wire, followed by angioplasty and stenting. The average length recanalized was 8.2 +/- 3.6 cm. One patient required repeat angioplasty at 4 months. All stents were patent at 12 to 15 months. The radiofrequency wire is valuable in the management of patients with refractory central venous occlusions. PMID- 22104340 TI - Preliminary intraobserver and interobserver variability in wall stress and rupture risk assessment of abdominal aortic aneurysms using a semiautomatic finite element model. AB - OBJECTIVE: We investigated the intraobserver and interobserver variability of using semiautomatic finite element analysis to calculate the von Mises stress and peak wall rupture risk (PWRR) in patients with an abdominal aortic aneurysm (AAA) in longitudinal studies. METHODS: Four independent observers made 3-dimensional (3D) reconstructions, with minimal manual adjustments, of small AAAs (<5.0 cm) in 17 patients and processed finite element analysis. We used semiautomatic diagnostic software with a finite element model (A4research, VASCOPS GmbH, Graz, Austria). The finite element method was used to calculate von Mises stress and PWRR, which are indicators for wall stress. The differences of each pair of measurements of von Mises stress and PWRR were plotted against their mean and the difference of the mean, according to Bland-Altman analysis. RESULTS: The intraobserver variability had an overall mean percentage difference of 6.86% +/- 6.46% for the von Mises stress and 7.70% +/- 6.26% for PWRR. The interobserver variability for the four observers showed an overall mean percentage difference of 7.09% +/- 6.16% for the von Mises stress and 9.47% +/- 8.18% for the PWRR measurement. No significant differences were found (P < .05), for the von Mises stress and PWRR for all observers. CONCLUSIONS: The von Mises stress and PWRR of small AAAs calculated in this semiautomatic finite element analysis program show good interobserver and intraobserver variability. It is suitable for clinical use to evaluate mechanical aortic wall characteristics and to compare it with other current methods such as maximum aortic diameter measurements. PMID- 22104341 TI - Efficacy of combined renal and mesenteric revascularization. AB - OBJECTIVE: Small numbers of patients have advanced renal and mesenteric vascular disease requiring treatment. Open surgical treatment has been considered high risk, and the advent of endovascular intervention has affected management. This study evaluated the safety and long-term efficacy of concomitant mesenteric and renal revascularization with open techniques. METHODS: Data from 90 consecutive patients who underwent mesenteric and renal revascularization during a 30-year period were analyzed. Early and late outcomes were evaluated over two intervals: 48 in period A (1978 to 1995), concomitant open renal and mesenteric revascularization (COR; n = 46) and sequential open renal and mesenteric revascularization (SOR; n = 2); 42 in period B (1996 to 2009), 22 COR, 4 SOR, 13 sequential hybrid open/endovascular repairs (SOER), and 3 sequential endovascular repairs (SER). RESULTS: There were 26 men and 64 women (median age, 67 years). Renal insufficiency was present in 24% and coronary artery disease (CAD) in 53%. Open surgical reconstruction was performed in 126 renal and 149 mesenteric arteries, with angioplasty/stenting in 15 and 8, respectively; 58 patients had concomitant aortic reconstruction (AR), and 9 had prior AR (8 in period A, 1 in period B). Hospital mortality was 8.8% overall; seven (14.5%) in period A and one (2.3%) in period B. Causes of early death were hemorrhage in three and multisystem organ failure in five. During a median follow-up of 4.5 years (range, 6 days-26.5 years), 11 patients progressed to hemodialysis (7 COR, 4 SOER), and 6 had recurrent mesenteric ischemia (4 COR, 1 SOER, 1 SER). Eight patients in period A and seven in period B required further procedures (9 renal, 9 mesenteric; 11 COR, 2 SOER, 1 SOR, 1 SER). Univariate analysis of COR patients showed CAD (P = .017) and prior AR (P = .035), but not concomitant AR (P = .366), predicted early death. Five-year survival for COR patients was 65% overall, but 74% in patients who survived the operation, with no difference between time periods (P = .55). CONCLUSIONS: Concomitant open mesenteric and renal revascularization is associated with low early mortality and good long-term durability in appropriately selected patients. It remains a viable procedure, especially in patients requiring concomitant aortic reconstruction. High-risk patients with CAD or prior aortic surgery should be considered for endovascular treatment, when anatomically feasible. PMID- 22104342 TI - Prospective intraindividual comparison of unenhanced magnetic resonance imaging vs contrast-enhanced computed tomography for the planning of endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: This study clarified whether unenhanced magnetic resonance imaging (MRI) is an alternative to contrast-enhanced computed tomography (CT) for aortoiliac arterial measurement before endovascular abdominal aortic aneurysm repair (EVAR). METHODS: The institutional review board approved this prospective study. Twenty patients being considered for EVAR underwent MRI using a steady state free-precession sequence in a 1.5-T system and contrast-enhanced CT within 4 weeks of each other. Two independent observers reviewed MRI and CT in random order using vessel analysis software and measured seven diameters, four lengths, and the angle of the aortoiliac arteries. The intermodality, interobserver, and intraobserver agreements were assessed for each measurement by intraclass correlation coefficients (ICCs) and the Altman-Bland method. Additionally, the observers independently recorded the number of bilateral renal arteries, decided EVAR suitability, and selected the main endograft on each modality. RESULTS: Intermodality ICCs for observers A and B showed ranges of 0.83 to 0.99 and 0.70 to 0.98; interobserver ICCs for MRI and CT showed ranges of 0.73 to 0.99 and 0.65 to 0.99; and intraobserver ICCs for MRI and CT showed ranges of 0.59 to 0.99 and 0.59 to 0.99. In intermodality, interobserver, and intraobserver comparisons, mean differences in diameters were included within the range -1 to +1 mm, excluding three of seven diameters on CT in interobserver comparison and one of seven on CT in intraobserver comparison. Mean differences in lengths were included within the range -5 to +5 mm, excluding one of four lengths in observer B in intermodality comparison and one of four on MRI and CT in interobserver comparison. All mean differences in angles were included within the range -5 degrees to +5 degrees . Both observers detected all 40 bilateral main renal arteries on MRI and CT. Of the 13 accessory renal arteries, observers A and B detected four (31%) and nine (69%), respectively, on MRI; in contrast, both observers detected 11 (85%) on CT. The observers independently determined that the same seven patients were suitable for EVAR on MRI and CT. Of the seven selected main endografts, seven and six diameters and five and six lengths agreed exactly between MRI and CT for observers A and B, respectively. CONCLUSIONS: Although contrast-enhanced CT remains the gold standard for preoperative EVAR planning, unenhanced MRI with steady-state free-precession sequence can be an alternative modality for patients with contraindications for CT, such as renal impairment, because the intermodality agreement for preoperative measurements is as good as interobserver and intraobserver agreement. PMID- 22104343 TI - Emergent endovascular treatment of a bleeding recurrent aortoenteric fistula as a "bridge" to definitive surgical repair. AB - We report the case of a 59-year-old man who developed a recurrent aortoenteric fistula (AEF) following previous aorto-bifemoral bypass grafting and subsequent AEF open repair with aorto-bifemoral graft excision and extra-anatomic reconstruction. The patient was treated emergently by means of endovascular plug deployment via a left brachial approach into the infrarenal aortic stump, obtaining recovery of hemodynamic stability. Five days later, he underwent elective relaparotomy, aortic plug removal, infrarenal aortic ligature, and duodenal repair. Endovascular strategies to rapidly stop bleeding associated with recurrent AEF may serve as a "bridge" to definitive open repair, as in the case discussed herein. Even if rare, recurrent AEF following previous prosthetic aortic graft excision and extra-anatomic revascularization represents a dreadful event. Since surgical treatment is technically demanding and time consuming in emergent settings, we present an "unconventional" endovascular option to obtain quick cessation of aortic bleeding. PMID- 22104344 TI - Gender-based outcomes after eversion carotid endarterectomy from 1998 to 2009. AB - BACKGROUND AND PURPOSE: Although the benefit of carotid endarterectomy (CEA) in reducing the risk of stroke in selected symptomatic and asymptomatic patients has been well documented, the higher incidence of adverse events after CEA for women than for men remains controversial. The purpose of this study was to analyze the effect of female gender on perioperative (30-day) and long-term outcomes after eversion CEA (eCEA). METHODS: Patients entered into a prospectively compiled computerized database of all primary consecutive eCEAs performed at our institution from September 1998 to December 2009 were analyzed. Endpoints were perioperative death and stroke, late carotid restenosis or occlusion, and long term freedom from stroke and survival rates. Long-term follow-up was obtained in 96.8% of patients (97.5% of the women). RESULTS: Among 1294 patients who underwent 1458 eCEAs under general anesthesia with continuous electroencephalographic monitoring and selective shunting, 409 (31.6%) were women (466 eCEAs). More women than men were over 80 years old (P = .001), and female patients were more likely to have arterial hypertension (P = .02) or hyperlipidemia (P = .006) than male patients. Preoperative statin medication (P = .01), contralateral carotid occlusion (P = .02), and shunting use (P = .03) were more frequent among female patients. No perioperative deaths occurred in the series as a whole, while the perioperative stroke risk (0.6% vs 0.5%), and the combined late carotid restenosis and occlusion rate (1.1% vs 0.4%) were comparable between female and male patients. The 7-year stroke-free survival and overall survival rates did not differ significantly between female and male patients (98.3% vs 98.8% and 87.2% vs 93.8%, respectively). CONCLUSIONS: This single-center university hospital study shows that although women have a different cardiovascular risk profile from men when they undergo eCEA, there is no evidence of a different gender effect on perioperative and long-term outcomes. PMID- 22104345 TI - Long-term results of a randomized controlled trial on ultrasound-guided foam sclerotherapy combined with saphenofemoral ligation vs standard surgery for varicose veins. AB - BACKGROUND: The long-term results of a prospective, randomized controlled trial in patients with primary varicose veins are reported. METHODS: Saphenofemoral ligation (SFL) was done in 73 patients (82 legs). In addition, 43 (23 women; age, 47) underwent stripping and multiple phlebectomies under general anesthesia (group S), and 39 (32 women; age, 49) had concurrent sclerotherapy under local anesthesia (group F). Assessments included CEAP C status, Venous Clinical Severity Score (VCSS), Venous Segmental Disease Score (VSDS), Aberdeen Varicose Vein Questionnaire (AVVQ), and 36-Item Short-Form (SF-36) scores. RESULTS: CEAP C was similar between groups (C(2-6)). In group S, 40% of legs required 25 additional foam sessions (mean volume, 11 mL). In group F, 47.5% of legs required 33 sessions (mean volume, 9 mL) The groups had equivalent preoperative VCSS scores and similar changes at 3 (P = .504) and 5 years (P = .484), as were the absolute VCSS scores at 3 (P = .313) and 5 years (P = .104; Mann-Whitney U). The VSDS score improved (median [interquartile range]) preoperatively vs 3 years (group S, 16.32 [14.7] vs 8.94 [11.51], P = .003; group F, 12.28 [10.37] vs 4.97 [6.19]; P < .0005, Wilcoxon). Above knee obliteration occurred in 17 of 26 (65.4%) for group S and in 16 of 33 (48.5%) for group F at 3 years, and in 14 (53.8%) and 19 (57.6%) at 5 years. AVVQ scores were similar before and at 3 years (P = .703) but significantly favored group S at 5 years (P = .015; Mann-Whitney U). The AVVQ also improved within both groups. The SF-36 mental summary score over 3 years deteriorated in group S (P = .04). However, the physical summary scores did not change between groups (S, P = .361; F, P = .889) or the mental score in group F (P = .285). Changes in the physical (P = .724) and mental (P = .354, Mann-Whitney U) scores did not differ between the groups due to treatment. CONCLUSION: At 3 and 5 years of follow-up, the treatment was equally effective in the surgical and foam groups, as demonstrated with VCSS, VSDS, and the SF-36 physical component score. At 5 years, the AVVQ was significantly better in the surgical group. The additional foam sessions were also similar. Because traditional surgery for varicose veins does not provide a definitive treatment, foam sclerotherapy could be offered as in a dental care treatment model: "treat as and when the problem appears." PMID- 22104346 TI - Knee-extension exercise's lack of immediate effect on maximal voluntary quadriceps torque and activation in individuals with anterior knee pain. AB - CONTEXT: Weight-bearing (WB) and non-weight-bearing (NWB) exercises are commonly used in rehabilitation programs for patients with anterior knee pain (AKP). OBJECTIVE: To determine the immediate effects of isolated WB or NWB knee extension exercises on quadriceps torque output and activation in individuals with AKP. DESIGN: A single-blind randomized controlled trial. SETTING: Laboratory. PARTICIPANTS: 30 subjects with self-reported AKP. INTERVENTIONS: Subjects performed a maximal voluntary isometric contraction (MVIC) of the quadriceps (knee at 90 degrees ). Maximal voluntary quadriceps activation was quantified using the central activation ratio (CAR): CAR = MVIC/(MVIC + superimposed burst torque). After baseline testing, subjects were randomized to 1 of 3 intervention groups: WB knee extension, NWB knee extension, or control. WB knee-extension exercise was performed as a sling-based exercise, and NWB knee extension exercise was performed on the Biodex dynamometer. Exercises were performed in 3 sets of 5 repetitions at approximately 55% MVIC. Measurements were obtained at 4 times: baseline and immediately and 15 and 30 min postexercise. MAIN OUTCOME MEASURES: Quadriceps torque output (MVIC: N.m/Kg) and quadriceps activation (CAR). RESULTS: No significant differences in the maximal voluntary quadriceps torque output (F2,27 = 0.592, P = .56) or activation (F2,27 = 0.069, P = .93) were observed among the 3 treatment groups. CONCLUSIONS: WB and NWB knee extension exercises did not acutely change quadriceps torque output or activation. It may be necessary to perform exercises over a number of sessions and incorporate other disinhibitory interventions (eg, cryotherapy) to observe acute changes in quadriceps torque and activation. PMID- 22104347 TI - IGF-1 induces hypoxia-inducible factor 1alpha-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells. AB - Glucose metabolism is essential for most mammalian neurons, and the passage of glucose across cell membranes is mainly facilitated by glucose transporter 3 (GLUT3). In ischemia/reperfusion injured brains, increase of IGF-1 secretion and GLUT3 up-regulation, are regarded as protective processes. Recent works have shown that various growth factors and cytokines including IGF-1 can stimulate HIF 1alpha expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. So, we hypothesized that HIF-1alpha might play important role in the process of IGF-1 induced GLUT3. Using echinomycin, a HIF-1 inhibitor, and HIF-1alpha siRNA, we demonstrated IGF-1 induced GLUT3 expression through HIF-1alpha in neuronal PC12 cells. Moreover, IGF-1 stimulated HIF-1alpha and GLUT3 protein expression through phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR dependent pathways. Analysis of GLUT3 promoter deletion sequences indicated that a putative hypoxia-response element (HRE) was critical in GLUT3 promoter activity when PC12 cells were treatment with CoCl(2) and IGF-1. In conclusion, we showed that the expression of GLUT3 in response to IGF-1 was dependent on PI-3-kinase and mTOR activity, and required the transcription factor HIF-1alpha. PMID- 22104348 TI - High-frequency stimulation of the temporoammonic pathway induces input-specific long-term potentiation in subicular bursting cells. AB - The subiculum (Sub) as a part of the hippocampal formation is thought to play a functional role in learning and memory. In addition to its major input from CA1 pyramidal cells, the subiculum receives input from the entorhinal cortex (EC) via the temporoammonic pathway. Thus far, synaptic plasticity in the subiculum was mainly investigated at CA1-Sub synapses. According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1-Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor dependent LTP that depends on the activation of a cAMP-PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC-Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca(2+) influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. Taken together, our data suggest that distinct, input specific mechanisms govern high frequency-induced LTP at subicular bursting cells' synapses. PMID- 22104349 TI - Incidence of cerebrospinal fluid leak following petrosectomy and analysis of avoidance techniques. AB - A cerebrospinal fluid (CSF) leak following skull base surgery can lead to meningitis, impaired wound healing, and often requires re-operation and/or CSF diversion. Thirty-two patients underwent a presigmoid, transpetrosal approach to skull base aneurysms and tumors. A vascularized temporalis muscle flap was utilized during the closure of the initial skull base reconstruction in 18 of the 32 patients. A temporary CSF diversion was utilized in 23 of the 32 patients. A permanent shunt was placed in eight patients. One patient developed a postoperative CSF leak from the contralateral ear due to a congenital abnormality in the middle ear. Another patient, who did not have a vascularized temporalis muscle flap reconstruction, developed a postoperative CSF leak in the context of an operation for recurrent tumor and prior radiation treatment. CSF diversion and vascularized temporalis muscle flaps are effective in preventing the development of postoperative CSF leaks following petrosectomy. PMID- 22104350 TI - Teratogenicity of the newer antiepileptic drugs--the Australian experience. AB - Data on the use in pregnancy of the new antiepileptic drugs (AED) are limited. We analysed data collected by the Australian Pregnancy Register to provide information on their relative teratogenicity. The database containing pregnancy outcomes from 1317 women with epilepsy (WWE) was examined for three widely used new AED in monotherapy in the first trimester--lamotrigine, levetiracetam and topiramate. This was compared with outcomes of pregnant WWE on monotherapy with three traditional AED, and with untreated women. The incidence of malformations associated with lamotrigine monotherapy was 12/231 (5.2%), with topiramate 1/31 (3.2%) and with levetiracetam 0/22 (0%). This compares with rates of 1/35 (2.9%) for phenytoin, 35/215 (16.3%) for valproate (VPA), 19/301 (6.3%) for carbamazepine and 6/116 (5.2%) for untreated women. There was no evidence of dose dependent risks of foetal malformation, except with VPA monotherapy. We conclude that the new AED appear no more teratogenic than traditional drugs in monotherapy. PMID- 22104351 TI - The comparison of ruthenium brachytherapy and simultaneous transpupillary thermotherapy of choroidal melanoma with brachytherapy alone. AB - PURPOSE: To compare the outcomes of combined treatment of choroidal melanoma with ruthenium brachytherapy (BT) simultaneously with transpupillary thermotherapy (TTT) and treatment with BT alone. METHODS AND MATERIALS: Two matched groups of patients, one treated with BT and simultaneous TTT (Group BT+TTT, n=63), the other treated with BT alone (Group BT, n=70) were analyzed retrospectively. The main outcome measures were rate of tumor regression, recurrences, enucleations, metastases, recurrence-free and overall survival rate, and visual acuity, assessed by Kaplan-Meier analysis. RESULTS: Patients were matched according to mean age (p=0.22), mean tumor thickness (6.4 vs. 6.25mm, range 2.5-10.8mm, p=0.59), and mean length of followup (42 vs. 34.4 months, range 3-109, p=0.052). Tumor largest basal diameter (13.0 vs. 12.9mm), tumor location, and mean radiation dose (apical 135 vs. 136Gy and scleral 1294 vs. 1438Gy) were also similar in both groups (p>0.1). Treatment with BT+TTT resulted in higher rate of tumor regression (63% vs. 49%, respectively, p=0.036), lower 5-year tumor recurrence rate (96% vs. 83%, p<0.034), and higher eye-globe preservation (98% vs. 87%, p<0.024) and recurrence-free survival rates (89% vs. 67%, p<0.017) than treatment with BT alone. There was no difference in complications (p>0.5), metastasis-free (93% vs. 81%, p>0.22) and overall survival rates (91% vs. 81%, p>0.39), or in visual outcomes. CONCLUSION: Combined treatment of choroidal melanoma with ruthenium BT and simultaneous TTT seems to provide higher local control, eye-globe preservation, and recurrence-free survival rates than treatment with BT alone and results in similar rates of metastases and overall survival. PMID- 22104352 TI - Experimental characterization of the dosimetric properties of a newly designed I Seed model AgX100 125I interstitial brachytherapy source. AB - PURPOSE: To measure the dosimetric properties of the Model AgX100 125I source for interstitial brachytherapy. METHODS AND MATERIALS: The photon energy spectrum emitted by the AgX100 source was measured using a high-resolution germanium spectrometer customized for low-energy brachytherapy source spectrometry. The dose distribution around the source was measured using the 1*1*1 mm3 lithium fluoride thermoluminescent dosimeters in water-equivalent solid phantoms. The dosimetric parameters needed for dose calculation using the American Association of Physicists in Medicine Task Group No. 43 (TG-43) formalism were determined and compared with the results of a Monte Carlo simulation by an independent research group and with the TG-43 consensus values of the well-established model 6711 source. RESULTS: It was found that (1) the photon energy spectrum emitted by the AgX100 source was nearly identical to that emitted by the model 6711, (2) the dose-rate constant determined by the photon spectrometry technique (0.957+/-0.037 cGy.h-1.U-1) and by the thermoluminescent dosimeter technique (0.995+/-0.066 cGy.h-1.U-1) was within 1.5% of the corresponding values determined for the model 6711 source, and (3) the radial dose function and the anisotropy function of the AgX100 source were also found to be similar to the consensus data established for the model 6711 source in the TG-43 update report. CONCLUSIONS: A comprehensive dosimetric characterization has been carried out for the model AgX100 125I source. The American Association of Physicists in Medicine TG-43 dosimetry parameters for this source has been determined from the experimental data. PMID- 22104353 TI - Tumor bed-to-skin distance using accelerated partial-breast irradiation with the strut-adjusted volume implant device. AB - PURPOSE: Because of the risk of skin toxicity with single dwell position, single lumen brachytherapy devices are sometimes contraindicated for tumor cavities 5 7mm from the skin surface. We discuss the use of multicatheter device to treat patients with tumor bed-to-skin distances <7mm. METHODS AND MATERIALS: We treated 117 patients with accelerated partial-breast irradiation brachytherapy: 77 single lumen and 40 multicatheter devices. A subset of 12 patients treated with SAVI((r)) had bed-to-skin spacing <7mm. All patients had Tis-2N0 ductal carcinoma with negative margins. A total dose of 34.0Gy in 10 fractions was delivered twice daily. Planning target volume was created using computed tomography-based three dimensional planning with a 1.0-cm expansion of the lumpectomy cavity. Skin dose was measured dosimetrically, with skin constraints <125% of the prescription. Toxicities were graded, and patients were assessed at various intervals. RESULTS: Of the patients treated with the multicatheter device, 0% (0/12) had their device pulled. At 2 weeks after treatment, fewer than 50% of the patients had skin toxicities of Grades 1-2, all of which resolved by 6 months. The cosmetic outcome was good to excellent at followup. CONCLUSIONS: Multicatheter devices permit well tolerated accelerated partial-breast irradiation in patients with tumor cavities near the skin surface for which the single-lumen device may not be appropriate. PMID- 22104354 TI - High-dose-rate and pulsed-dose-rate brachytherapy in palliative treatment of head and neck cancers. AB - PURPOSE: The main purpose of the study was to assess the results of high-dose rate brachytherapy (HDRBT) and pulsed-dose-rate brachytherapy (PDRBT) in the palliative treatment of patients with locally or regionally recurrent head and neck cancers. The detailed aims concerned the evaluation of these methods in the context of local control, survival, and complications rates in patients subgrouped by different parameters such as age, gender, primary and recurrent tumor localization, tumor size, treatment method (HDR/PDR), primary treatment method, and radiation dose applied. METHODS AND MATERIALS: PDRBT and HDRBT were used in 106 and 50 patients, respectively. In 8 patients, BT procedures were performed in combination with simultaneous chemotherapy. Sixteen patients were additionally treated with interstitial hyperthermia. All patients were regularly followed up within 6 months. Local control, complications, and survival were assessed. Materials included 156 patients with head and neck cancers treated palliatively with HDRBT and PDRBT in the Department of Otolaryngology of Poznan University of Medical Sciences and in the Department of Brachytherapy of Greater Poland Cancer Center from January 2002 to November 2008. RESULTS: Complete and partial remissions 6 months after finishing the treatment were achieved in 37.7% of patients, whereas survival rates 12 and 24 months after brachytherapy were estimated for 40% and 17%, respectively. The overall complications rate was 35%. CONCLUSIONS: Our results suggest that HDRBT and PDRBT constitute a safe alternative in the palliative treatment of patients with locally or regionally recurrent head and neck cancers with a relapse in a previously irradiated area, which were not qualified or rejected surgery. It gives a good palliative effect with acceptable complication rate. PMID- 22104355 TI - [Diagnosis and treatment of pelvic splenosis during exploration of infertility]. AB - Splenosis is the heterotopic autotransplantation of splenic tissue that usually follows traumatic splenectomy. Rare pelvic localizations are reported. We report here a case of a 36-year-old woman, followed for secondary infertility. On transvaginal ultrasound pelvic scanning hypervascular paracervical nodules were demonstrated. Pelvic splenosis was suspected regarding the patient's medical past (post-traumatic splenectomy). Surgical exploration and resection were decided considering the nodule localization, the risk during ovarian punction for IVF, and the hypothetical risk of bleeding at delivery. Generally, it is recommended to leave in place the splenic tissue, which may be immunologically functional. PMID- 22104356 TI - Local control with reduced-dose radiotherapy for low-risk rhabdomyosarcoma: a report from the Children's Oncology Group D9602 study. AB - PURPOSE: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study. METHODS AND MATERIALS: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies. RESULTS: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group. CONCLUSIONS: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved. PMID- 22104357 TI - Experience with carbon ion radiotherapy for WHO Grade 2 diffuse astrocytomas. AB - PURPOSE: To assess outcomes of carbon ion radiotherapy for diffuse astrocytomas in adults. METHODS AND MATERIALS: Between October 1994 and February 2002, 14 patients with diffuse astrocytoma, identified as eligible for carbon ion radiotherapy, were enrolled in a phase I/II clinical trial. Carbon ion radiotherapy was administered in 24 fractions over 6 weeks. The normal tissue morbidity was monitored carefully, and the carbon ion dose was escalated from 50.4 Gy equivalent (GyE) to 55.2 GyE. Patients were divided into two groups according to their carbon ion doses: a low-dose group in which 2 patients were irradiated with 46.2 GyE and 7 patients were irradiated with 50.4 GyE, and a high dose group in which 5 patients were irradiated with 55.2 GyE. RESULTS: Toxicities were within acceptable limits, and none of the patients developed Grade 3 or higher acute or late reactions. The median progression-free survival (PFS) time was 18 months for the low-dose group and 91 months for the high-dose group (p = 0.0030). The median overall survival (OS) time was 28 months for the low-dose group and not reached for the high-dose group (p = 0.0208). CONCLUSION: High-dose group patients showed significant improvement in PFS and OS rates compared to those in the low-dose group, and both dose groups showed acceptable toxicity. PMID- 22104358 TI - Effect of radiotherapy and chemotherapy on the risk of mucositis during intensity modulated radiation therapy for oropharyngeal cancer. AB - PURPOSE: To define the roles of radiotherapy and chemotherapy on the risk of Grade 3+ mucositis during intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer. METHODS AND MATERIALS: 164 consecutive patients treated with IMRT at two institutions in nonoverlapping treatment eras were selected. All patients were treated with a dose painting approach, three dose levels, and comprehensive bilateral neck treatment under the supervision of the same radiation oncologist. Ninety-three patients received concomitant chemotherapy (cCHT) and 14 received induction chemotherapy (iCHT). Individual information of the dose received by the oral mucosa (OM) was extracted as absolute cumulative dose-volume histogram (DVH), corrected for the elapsed treatment days and reported as weekly (w) DVH. Patients were seen weekly during treatment, and peak acute toxicity equal to or greater than confluent mucositis at any point during the course of IMRT was considered the endpoint. RESULTS: Overall, 129 patients (78.7%) reached the endpoint. The regions that best discriminated between patients with/without Grade 3+ mucositis were found at 10.1 Gy/w (V10.1) and 21 cc (D21), along the x-axis and y-axis of the OM-wDVH, respectively. On multivariate analysis, D21 (odds ratio [OR] = 1.016, 95% confidence interval [CI], 1.009-1.023, p < 0.001) and cCHT (OR = 4.118, 95% CI, 1.659-10.217, p = 0.002) were the only independent predictors. However, V10.1 and D21 were highly correlated (rho = 0.954, p < 0.001) and mutually interchangeable. cCHT would correspond to 88.4 cGy/w to at least 21 cc of OM. CONCLUSIONS: Radiotherapy and chemotherapy act independently in determining acute mucosal toxicity; cCHT increases the risk of mucosal Grade 3 toxicity ~4 times over radiation therapy alone, and it is equivalent to an extra ~6.2 Gy to 21 cc of OM over a 7-week course. PMID- 22104359 TI - The impact of extent and location of mediastinal lymph node involvement on survival in Stage III non-small cell lung cancer patients treated with definitive radiotherapy. AB - PURPOSE: Several surgical series have identified subcarinal, contralateral, and multilevel nodal involvement as predictors of poor overall survival in patients with Stage III non-small-cell lung cancer (NSCLC) treated with definitive resection. This retrospective study evaluates the impact of extent and location of mediastinal lymph node (LN) involvement on survival in patients with Stage III NSCLC treated with definitive radiotherapy. METHODS AND MATERIALS: We analyzed 106 consecutive patients with T1-4 N2-3 Stage III NSCLC treated with definitive radiotherapy at the University of Pennsylvania between January 2003 and February 2009. For this analysis, mediastinal LN stations were divided into four mutually exclusive groups: supraclavicular, ipsilateral mediastinum, contralateral mediastinum, and subcarinal. Patients' conditions were then analyzed according to the extent of involvement and location of mediastinal LN stations. RESULTS: The majority (88%) of patients received sequential or concurrent chemotherapy. The median follow-up time for survivors was 32.6 months. By multivariable Cox modeling, chemotherapy use (hazard ratio [HR]: 0.21 [95% confidence interval (CI): 0.07-0.63]) was associated with improved overall survival. Increasing primary tumor [18F]-fluoro-2-deoxy-glucose avidity (HR: 1.11 [CI: 1.06-1.19]), and subcarinal involvement (HR: 2.29 [CI: 1.11-4.73]) were significant negative predictors of overall survival. On univariate analysis, contralateral nodal involvement (HR: 0.70 [CI: 0.33-1.47]), supraclavicular nodal involvement (HR: 0.78 [CI: 0.38-1.67]), multilevel nodal involvement (HR: 0.97 [CI: 0.58-1.61]), and tumor size (HR: 1.04 [CI: 0.94-1.14]) did not predict for overall survival. Patients with subcarinal involvement also had lower rates of 2-year nodal control (51.2% vs. 74.9%, p = 0.047) and 2-year distant control (28.4% vs. 61.2%, p = 0.043). CONCLUSIONS: These data suggest that the factors that determine oncologic outcome in Stage III NSCLC patients treated with definitive radiotherapy are distinct from those observed in patients who undergo surgical resection. The ultimate efficacy of radiation in locally advanced NSCLC is dependent on the intrinsic biology of the tumor. PMID- 22104360 TI - Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. AB - BACKGROUND: Approximately two-thirds of patients with early-stage non-small-cell lung cancer (NSCLC) in The Netherlands currently undergo surgical resection. As an increasing number of fit patients have elected to undergo stereotactic ablative radiotherapy (SABR) in recent years, we studied outcomes after SABR in patients with potentially operable stage I NSCLC. METHODS AND MATERIALS: In an institutional prospective database collected since 2003, 25% of lung SABR cases (n = 177 patients) were found to be potentially operable when the following patients were excluded: those with (1) synchronous lung tumors or other malignancy, (2) prior high-dose radiotherapy/pneumonectomy, (3) chronic obstructive pulmonary disease with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease classification. (4) a performance score of >=3, and (5) other comorbidity precluding surgery. Study patients included 101 males and 76 females, with a median age of 76 years old, 60% of whom were staged as T1 and 40% of whom were T2. Median Charlson comorbidity score was 2 (range, 0-5). A SABR dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5, or 8 fractions, depending on tumor size and location. Follow-up chest computed tomography scans were obtained at 3, 6, and 12 months and yearly thereafter. RESULTS: Median follow-up was 31.5 months; and median overall survival (OS) was 61.5 months, with 1- and 3-year survival rates of 94.7% and 84.7%, respectively. OS rates at 3 years in patients with (n = 59) and without (n = 118) histological diagnosis did not differ significantly (96% versus 81%, respectively, p = 0.39). Post-SABR 30-day mortality was 0%, while predicted 30 day mortality for a lobectomy, derived using the Thoracoscore predictive model (Falcoz PE et al. J Thorac Cardiovasc Surg 2007;133:325-332), would have been 2.6%. Local control rates at 1 and 3 years were 98% and 93%, respectively. Regional and distant failure rates at 3 years were each 9.7%. Toxicity was mild, with grade >=3 radiation pneumonitis and rib fractures in 2% and 3%, respectively. CONCLUSIONS: Patients with potentially operable disease who underwent primary SABR had a median OS that exceeded 5 years. This finding supports ongoing randomized clinical trials comparing surgery and SABR in cases of operable stage I NSCLC. PMID- 22104361 TI - Whole abdominopelvic intensity-modulated radiation therapy for desmoplastic small round cell tumor after surgery. AB - PURPOSE: Desmoplastic small round cell tumor (DSCRT) is an uncommon pediatric tumor with a poor prognosis. Aggressive multimodality therapy is the current treatment approach; however. treatment toxicity is of concern. We report our results with whole abdominopelvic intensity-modulated radiation therapy (WAP IMRT) as a component of multimodality therapy for DSCRT at a single institution. MATERIALS/METHODS: Medical records of all patients with DSCRT who received WAP IMRT as part of definitive treatment at MD Anderson (2006-2010) were identified and reviewed. RESULTS: Eight patients with DSRCT received WAP-IMRT with a median follow-up of 15.2 months. All patients received multiple courses of chemotherapy followed by surgical debulking of intra-abdominal disease; seven also had intraoperative hyperthermic cisplatin. WAP-IMRT was delivered to a total dose of 30 Gy postoperatively; four patients received a simultaneous boost (6-10 Gy) to sites of gross residual disease. Seven patients received concurrent chemotherapy during WAP-IMRT. No Radiation Therapy Oncology Group Grade 4 nausea, vomiting, or diarrhea occurred during RT. Red-cell transfusions were given to two patients to maintain hemoglobin levels >10 g/dL. Grade 4 cytopenia requiring growth factor support occurred in only one patient; no other significant cytopenias were noted. WAP-IMRT resulted in 25% lower radiation doses to the lumbosacral vertebral bodies and pelvic bones than conventional RT plans. The median time to local or distant failure after WAP-IMRT was 8.73 months in seven patients. One patient who had completed RT 20 months before the last follow-up remains alive without evidence of disease. Five patients (63%) experienced treatment failure in the abdomen. Distant failure occurred in three patients (37.5%). CONCLUSIONS: WAP IMRT with concurrent radiosensitizing chemotherapy was well tolerated after aggressive surgery for DSCRT. Enhanced bone sparing with IMRT probably accounts for the low hematologic toxicity (vs. conventional WAP-RT). This modality should be considered as an additional local-regional control option for DSRCT. PMID- 22104362 TI - Matched cohort analysis of outcomes of definitive radiotherapy for prostate cancer in human immunodeficiency virus-positive patients. AB - PURPOSE: To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT). METHODS AND MATERIALS: A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months). RESULTS: The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3). CONCLUSIONS: Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population. PMID- 22104363 TI - Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation. AB - PURPOSE: To update the results of a clinical trial that assessed whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure and pulmonary-related mortality in subjects undergoing total body irradiation (TBI) in preparation for hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIALS: Updated records of the 55 subjects who were enrolled in this randomized controlled trial were analyzed. Twenty-eight patients received captopril, and 27 patients received placebo. Definitions of TBI HSCT-related chronic renal failure (and relapse) were the same as those in the 2007 analysis. Pulmonary-related mortality was based on clinical or autopsy findings of pulmonary failure or infection as the primary cause of death. Follow up data for overall and pulmonary-related mortality were supplemented by use of the National Death Index. RESULTS: The risk of TBI-HSCT-related chronic renal failure was lower in the captopril group (11% at 4 years) than in the placebo group (17% at 4 years), but this was not statistically significant (p > 0.2). Analysis of mortality was greatly extended by use of the National Death Index, and no patients were lost to follow-up for reasons other than death prior to 67 months. Patient survival was higher in the captopril group than in the placebo group, but this was not statistically significant (p > 0.2). The improvement in survival was influenced more by a decrease in pulmonary mortality (11% risk at 4 years in the captopril group vs. 26% in the placebo group, p = 0.15) than by a decrease in chronic renal failure. There was no adverse effect on relapse risk (p = 0.4). CONCLUSIONS: Captopril therapy produces no detectable adverse effects when given after TBI. Captopril therapy reduces overall and pulmonary-related mortality after radiation-based HSCT, and there is a trend toward mitigation of chronic renal failure. PMID- 22104364 TI - Young people's stories of self-harm: a narrative study. AB - This study explores the way in which adolescents who have engaged in self-harm make sense of their self-harm and its relationship to the events that have occurred in their lives. The six adolescents (aged between 13 and 18 years) who had been engaging in self-harm were invited to tell their life stories. The analysis explored both the content and the structure of these narratives in order to identify what they regarded to be key events in their lives and also what appeared to have been defended and less fully integrated features of their lives. A primary finding was that the adolescents perceive a severe lack of understanding from others about self-harm, which appeared to inhibit them from developing coherent narratives. They also found it difficult to discuss and integrate the difficulties behind their self-harm, giving narratives that were poorly integrated with little true resolution. One prominent story shared by this group was a story of self-harm as a way of directing their anger inwards. The findings highlight the importance for adolescents of access to conversations where difficult past events can be processed and understood within the context of a life story, and the implications for identity formation. PMID- 22104365 TI - Against the odds: foster carers' perceptions of family, commitment and belonging in successful placements. AB - This study examines carer attributes associated with placement stability for teenagers growing up in long term foster care, focusing on unexpected placement success. We explored experiences and perceptions relating to family, belonging and commitment in a group of foster carers providing a stable placement for a young person who had not been expected to settle. These placements showed positive outcome, despite factors in the child's history that might have predicted otherwise. Seven foster carers were interviewed following a semi structured guide, which covered their ideas about their relationship with the child in question, about the foster family, and the child's sense of belonging in foster and birth family. Analysis of carers' accounts of placements which had succeeded 'against the odds' revealed four major themes, described under the headings My Child--emotional bonding, the carers' enlarged view of family and their parental regard for the young person; Jam in the Sandwich--working within a 'compromised space' between Local Authority and birth family; Repair and Rebuild- the craft of fostering including managing the foster/birth family boundary; Sticking with It--resilience, tenacity and maintaining hopefulness. The carers' accounts offer pointers towards the ingredients of successful placements and prompt reflection on how these may be supported and promoted. They also highlight tensions inherent in the foster carer task relating to carers' parental functioning for young people in long-term foster care. PMID- 22104366 TI - The Incredible Years parenting program in Ireland: a qualitative analysis of the experience of disadvantaged parents. AB - Controlled trials demonstrate that parenting programs work, but less is known about the processes of change, contextual factors or intervention characteristics that influence trial outcomes. This qualitative study assessed the experiences of Irish parents involved in a randomized controlled trial of the Incredible Years BASIC parenting program, with a view to understanding how and why the program works, or does not work, within disadvantaged settings. Data from 33 parents of young children (aged 3-7 years) with conduct problems were collected by semi structured interviews and analysed using constructivist grounded theory. Emerging themes indicated that parents perceived the program to have produced positive changes through learning key parenting skills (e.g. positive attention, empathy and problem-solving skills) and through enhanced parental mood/confidence, derived primarily from gaining non-judgmental support from the group. Parents also experienced cultural, personal and environmental challenges in learning the new skills, including discomfort with praise and positive attention, conflict with their partner and parenting within an antisocial environment. Parents dropped out of the course for largely circumstantial reasons. These findings should help to inform the future implementation of this well-known parenting program both in Ireland and elsewhere. PMID- 22104367 TI - A reliability generalization meta-analysis of coefficient alpha for the Reynolds Adolescent Depression Scale. AB - The purpose of this study was to use a meta-analytic method known as reliability generalization to investigate the score reliability for a popular depression measure: The Reynolds Adolescent Depression Scale. We used the technique to provide an aggregate estimate of coefficient alpha across empirical studies that have employed the measure over time and across populations. Furthermore, we identified sample and demographic characteristics associated with variance in coefficient alpha. We discuss conditions associated with variability in coefficient alpha and alert researchers and practitioners to appropriate uses of the scale based on common reliability benchmarks. PMID- 22104368 TI - Gender-specific antitumor action of aspirin in a murine model of a T-cell lymphoma bearing host. AB - Aspirin is an anti-inflammatory drug demonstrated to possess a tremendous anticancer potential. As progression of some tumors is influenced by sex hormones, we investigated if the antineoplastic action of aspirin shows gender dependence. Using a murine model of T-cell lymphoma, the present investigation was undertaken to study if the antitumor actions of aspirin against lymphoma cells display gender dimorphism. The findings of the present investigation indicate that aspirin administration to male and female tumor-bearing hosts resulted in gender dependent differential tumor growth retardation. Such gender dichotomy of aspirin's antitumor action was associated with a differential impact on cell cycle progression and expression of cell survival regulatory molecules. Aspirin administration was also found to modulate crucial parameters of tumor microenvironment, including contents of glucose, lactate and cell growth regulatory cytokines, in a gender specific manner. Aspirin was found to reverse estrogen-dependent augmentation of tumor cell survival in vitro. Taken together the results of the present study suggest that the antineoplastic action of aspirin is gender-dependent and should be considered in designing of gender specific therapeutic applications of aspirin. PMID- 22104369 TI - Nonlinear changes in the activity of the oxygen-dependent demethylase system in Rhodococcus erythropolis cells in the presence of low and very low doses of formaldehyde. AB - The effect of exogenous, highly diluted formaldehyde on the rate of demethylation/re-methylation of veratric acid by the bacteria Rhodococcus erythropolis was studied using electrophoretic and microscopic techniques. The activity of 4-O-demethylase, responsible for accumulation of vanillic acid, and the levels of veratric and vanillic acids were determined using capillary electrophoresis. Formaldehyde was serially diluted at 1:100 ratios, and the total number of iterations was 20. After incubation of the successive dilutions of formaldehyde with the bacteria, demethylase activity oscillated in a sinusoidal manner. It was established using capillary electrophoresis that methylation of vanillic acid to veratric acid occurred at a double rate, as shown by the doubled fluctuation in the concentration of veratrate. There were also changes in the NADH oxidase activity, which is associated with methylation processes. Microscopic observations revealed the presence of numerous enlarged vacuoles in bacterial cells during the accumulation of large amounts of vanillic acid, and their disappearance together with a decrease in 4-O-demethylase activity. The presented results give evidence for the ability of living cells to detect the presence of submolecular concentrations of biological effectors in their environment and provide a basis for a scientific explanation of the law of hormesis and the therapeutic effect of homeopathic dilutions. PMID- 22104370 TI - Methodologies for assessing telemedicine: a systematic review of reviews. AB - BACKGROUND AND OBJECTIVES: Previous reviews have expressed concerns about the quality of telemedicine studies. There is debate about shortcomings and appropriate methodologies. The aim of this review of systematic reviews of telemedicine is to summarize methodologies used in telemedicine research, discuss knowledge gaps and recommendations and suggest methodological approaches for further research. METHODS: We conducted a review of systematic reviews of telemedicine according to a protocol listing explicit methods, selection criteria, data collection and quality assessment procedures. We included reviews where authors explicitly addressed and made recommendations for assessment methodologies. We did a qualitative analysis of the reviews included, sensitized by two broad methodological positions; positivist and naturalistic approaches. The analysis focused on methodologies used in the primary studies included in the reviews as reported by the review authors, and methodological recommendations made by the review authors. RESULTS: We identified 1593 titles/abstracts. We included 50 reviews that explicitly addressed assessment methodologies. One group of reviews recommended larger and more rigorously designed controlled studies to assess the impacts of telemedicine; a second group proposed standardisation of populations, and/or interventions and outcome measures to reduce heterogeneity and facilitate meta-analysis; a third group recommended combining quantitative and qualitative research methods; and others applying different naturalistic approaches including methodologies addressing mutual adaptations of services and users; politically driven action research and formative research aimed at collaboration to ensure capacity for improvement of services in natural settings. CONCLUSIONS: Larger and more rigorous studies are crucial for the production of evidence of effectiveness of unambiguous telemedicine services for pre defined outcome measures. Summative methodologies acknowledging telemedicine as complex innovations and outcomes as partly contingent on values, meanings and contexts are also important. So are formative, naturalistic methodologies that acknowledge telemedicine as ongoing collaborative achievements and engage with stakeholders, including patients to produce and conceptualise new and effective telemedicine innovations. PMID- 22104371 TI - Dopaminergic mechanisms of target detection - P300 event related potential and striatal dopamine. AB - The P300 is a cortically generated event related potential (ERP) widely used in neurophysiological research since it is related to cognitive functions and central information processing. Intracerebral recordings and functional neuroimaging studies have demonstrated that this potential is generated by various brain regions including frontal, temporal and parietal cortices. Regarding the neurochemical background, clinical and genetic investigations suggest that dopaminergic neurons could be involved in the generation of the P300. However, there is no direct evidence in vivo that P300 amplitudes and latencies are related to dopaminergic parameters. The aim of this study was to further elucidate dopaminergic aspects of the P300 ERP by combining neurophysiological and nuclear medicine assessments in vivo. Patients with a major depressive episode underwent both P300 recordings and dynamic [123I] IBZM SPECT for the evaluation of striatal dopamine D2/D3-receptor availability. There were statistically significant positive correlations of the striatal dopamine D2/D3-receptor status with P300 amplitudes and significant negative correlations with P300 latencies. Using this combined approach, the study presents direct evidence in vivo that the central dopaminergic system might play an important role in the generation of the P300 and that central dopaminergic activity could be involved in the modulation of P300 parameters. This association might be of relevance for the interpretation of P300 studies in psychiatric disorders. PMID- 22104372 TI - High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction. AB - BACKGROUND: Therapeutic irreversible electroporation (IRE) is an emerging technology for the non-thermal ablation of tumors. The technique involves delivering a series of unipolar electric pulses to permanently destabilize the plasma membrane of cancer cells through an increase in transmembrane potential, which leads to the development of a tissue lesion. Clinically, IRE requires the administration of paralytic agents to prevent muscle contractions during treatment that are associated with the delivery of electric pulses. This study shows that by applying high-frequency, bipolar bursts, muscle contractions can be eliminated during IRE without compromising the non-thermal mechanism of cell death. METHODS: A combination of analytical, numerical, and experimental techniques were performed to investigate high-frequency irreversible electroporation (H-FIRE). A theoretical model for determining transmembrane potential in response to arbitrary electric fields was used to identify optimal burst frequencies and amplitudes for in vivo treatments. A finite element model for predicting thermal damage based on the electric field distribution was used to design non-thermal protocols for in vivo experiments. H-FIRE was applied to the brain of rats, and muscle contractions were quantified via accelerometers placed at the cervicothoracic junction. MRI and histological evaluation was performed post-operatively to assess ablation. RESULTS: No visual or tactile evidence of muscle contraction was seen during H-FIRE at 250 kHz or 500 kHz, while all IRE protocols resulted in detectable muscle contractions at the cervicothoracic junction. H-FIRE produced ablative lesions in brain tissue that were characteristic in cellular morphology of non-thermal IRE treatments. Specifically, there was complete uniformity of tissue death within targeted areas, and a sharp transition zone was present between lesioned and normal brain. CONCLUSIONS: H-FIRE is a feasible technique for non-thermal tissue ablation that eliminates muscle contractions seen in IRE treatments performed with unipolar electric pulses. Therefore, it has the potential to be performed clinically without the administration of paralytic agents. PMID- 22104373 TI - Effective subthalamic nucleus deep brain stimulation sites may differ for tremor, bradykinesia and gait disturbances in Parkinson's disease. AB - BACKGROUND/AIMS: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD). This study investigates whether improvement for particular PD symptoms varies differentially with respect to stimulation location in the STN. METHODS: Ten PD patients treated with bilateral STN DBS were enrolled in the study. Each electrode contact was stimulated independently to assess for changes in tremor, bradykinesia, and gait. Electrode contacts were localized via MRI. A novel iterative volumetric analysis was used to search the contact space for stimulation regions corresponding to alleviation of specific symptoms. RESULTS: Tremor was best controlled with DBS applied to the more dorsal, anterior, and medial areas of the contact space. Improvement in bradykinesia was seen largely within the middle of the contact space. Gait improvement was observed with ventral contacts, likely bordering the ventral boundaries of the STN. CONCLUSION: The iterative volumetric analysis is a valuable tool in identifying anatomic regions responsive to DBS across a subject population treated for PD. In the subjects tested, overlapping efficacy for all symptoms was observed in the region of the STN, but anatomic variances in the responsiveness for tremor, bradykinesia, and gait were found. PMID- 22104374 TI - Spasmolytic effect of galetin 3,6-dimethyl ether, a flavonoid obtained from Piptadenia stipulacea (Benth) Ducke. AB - Piptadenia stipulacea (Benth) Ducke is a tree of the Caatinga, in Northeast Brazil, popularly known as "Jurema-branca", "Jurema malicia-da-serra", "Carcara" and "Calumbi". In folk medicine, a decoction or tincture of its bark and leaves are used to treat wounds and as healing agents. Galetin 3,6-dimethyl ether (FGAL) is a flavonoid isolated from the aerial components of Piptadenia stipulacea (Benth) Ducke. We decided to investigate a possible FGAL spasmolytic effect on preparations of both the guinea pig ileum and trachea, the rat uterus and the male rat aorta. FGAL inhibited oxytocin (IC(50) = 2.2 +/- 0.4 * 10(-5) M) and carbachol (CCh)-induced (IC(50) = 7.7 +/- 1.3 * 10(-5) M) phasic contractions in the rat uterus, but was more effective in the inhibition of the oxytocin-induced contractions. In the guinea pig ileum, FGAL equipotently inhibited CCh (IC(50) = 2.8 +/- 0.4 * 10(-5) M) and histamine-induced (IC(50) = 2.3 +/- 0.5 * 10(-5) M) phasic contractions. FGAL equipotently and concentration-dependently relaxed guinea pig trachea preparations pre-contracted with CCh, both in the absence (EC(50) = 0.8 +/- 0.1 * 10(-5) M) and presence (EC(50) = 1.0 +/- 0.1 * 10(-5) M) of a functional epithelium. FGAL also relaxed preparations of the rat aorta pre contracted with phenylephrine in both the absence (EC(50) = 5.0 +/- 1.1 * 10(-6) M) and presence (EC(50) = 5.4 +/- 1.2 * 10(-6) M) of a functional endothelium. FGAL shows a non-selective spasmolytic effect on each of the smooth muscle preparations we have tested, but with a greater effect on those from the rat aorta. The relaxant effect on preparations of both the guinea pig trachea and the rat aorta seems to not involve the epithelium or endothelium-derived relaxing factors. PMID- 22104375 TI - Role of calcium in contractile responses of calf cardiac vein during cooling. AB - The effects of cooling (to 28 degrees C) were studied on the responses induced by carbachol (10(-9) - 3 * 10(-4) M) and serotonin (5-HT, 10(-8) - 3 * 10(-4) M) in calf cardiac vein preparations and the role of calcium ions in these effects were analyzed. Ring preparations of veins obtained from calf hearts were suspended in organ baths containing 25 mL of Krebs-Henseleit solution, maintained at 37 degrees C and continuously gassed with 95%O(2)-5%CO(2). After a resting period, preparations were contracted with carbachol (10(-9) - 3 times; 10(-4) M) and 5-HT (10(-8) - 3 times; 10(-4) M) at 37 degrees C. The same protocol was repeated at 28 degrees C after the preparations were allowed to equilibrate at this temperature for 60 min. In order to analyze the role of calcium ions (Ca(2+)) in the cooling-induced vascular response, concentration-response curves to carbachol and 5-HT were obtained in the presence of verapamil (10(-6) M), caffeine (3 times; 10(-4) M), and Ca(2+ )free medium in the presence of EGTA at 28 degrees C. During cooling to 28 degrees C, the EC(50) values, to carbachol and 5-HT were significantly higher than at 37 degrees C. Cooling to 28 degrees C in the presence of verapamil, caffeine or Ca(2+ )free medium in the presence of EGTA increased the EC(50) values, to both carbachol and 5-HT. These results suggest that Ca(2+) plays an essential role in the cooling-induced changes of calf cardiac vein preparations treated with carbachol and 5-HT. PMID- 22104376 TI - Spasmolytic effect of citral and extracts of Cymbopogon citratus on isolated rabbit ileum. AB - Cymbopogon citratus, commonly known as lemongrass, has been shown to have antioxidant, antimicrobial and chemo-protective properties. Citral, a monoterpenoid, is the major constituent of C. citratus that gives off a lemony scent and is postulated to be responsible for most of its actions. In addition, C. citratus has been traditionally used to treat gastrointestinal discomforts, however, the scientific evidence for this is still lacking. Thus, the aim of the present study was to investigate the effect of the extracts of various parts of C. citratus (leaves, stems and roots) and citral on the visceral smooth muscle activity of rabbit ileum. The effect of the test substances were tested on the spontaneous contraction, acetylcholine (ACh)- and KCl-induced contractions. Citral at doses between 0.061 mM to 15.6 mM and the extract of leaves at doses between 0.001 mg/mL to 1 mg/mL significantly reduced the spontaneous, ACh- and KCl-induced ileal contractions. When the ileum was incubated in K(+)-rich-Ca(2+) free Tyrode's solution, it showed only minute contractions. However, the strength of contraction was increased with the addition of increasing concentrations of CaCl(2). The presence of citral almost abolished the effect of adding CaCl(2), while the leaf extract shifted the calcium concentration-response curve to the right, suggesting a calcium antagonistic effect. These results were similar to that elicited by verapamil, a known calcium channel blocker. In addition, the spasmolytic effect of citral was observed to be reduced by the nitric oxide synthase inhibitor, L-NAME. In conclusion, citral and the leaf extract of C. citratus exhibited spasmolytic activity and it appeared that they may act as calcium antagonists. Furthermore, the relaxant effect of citral, but not that of the leaf extract may be mediated by nitric oxide suggesting the presence of other chemical components in the leaf extract other than citral. PMID- 22104377 TI - The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media. AB - The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention. PMID- 22104378 TI - Schizophrenia in later life. PMID- 22104379 TI - Formaldehyde and tobacco smoke as alkylating agents: the formation of N methylenvaline in pathologists and in plastic laminate workers. AB - OBJECTIVE: Aim of this study was to investigate the relationships between the concentration of formaldehyde in air and the alkylation of hemoglobin to form a terminal N-methylenvaline residue in three occupationally exposed groups: a) technicians of pathology wards, b) workers of the plastic laminates industry, and c) a control group. All subjects recruited in this study were also tested on their smoking habits. METHODS: Formaldehyde adsorbed on passive air samplers was quantified by HPLC with UV detection (360 nm), cotinine was quantified by GC-MS. Terminal hemoglobin N-methylenvaline was determined by treating globine under reducing conditions with pentafluorophenyl isothiocyanate to yield a derivative, subsequently detected by GC-MS. One-way analysis of variance was performed to compare among the three groups the biomarkers considered in this study. RESULTS: For air-FA and N-methylenvaline a difference between the three groups was detected (p < 0.0001) and a significant higher concentration in the two professionally exposed groups was proved. Mean values for FA (MUg/m(3)): group a) 188.6, group b) 210.1, and group c) 41.4; mean values for N-methylenvaline (nmol/g of globin): group a) 377.9, group b) 342.8, and group c) 144.8. Conversely, the comparison between the two professionally exposed groups, a) vs b), does not show any significant difference highlighting similar exposition to FA and, consequently, similar biological response. Tobacco smoke proves to have a minor impact on the formation of N-methylenvaline molecular adduct. CONCLUSIONS: A positive correlation was demonstrated between professional exposition to air formaldehyde and hemoglobin alkylation to form N-methylenvaline molecular adduct in two occupationally exposed groups of subjects considered in the present study. In comparison with occupational exposition, tobacco smoke proved to have a minor impact on the formation of N-methylenvaline molecular adduct. PMID- 22104380 TI - The relationship between obesity, insulin and arsenic methylation capability in Taiwan adolescents. AB - PURPOSE: This study evaluated the arsenic methylation profile of adolescents and explored the influence of body mass index (BMI) on the arsenic methylation profile of adolescents in an area of Taiwan with no-obvious arsenic exposure. METHODS: This study evaluated 202 normal weight students and 101 obese students from eight elementary schools, recruited from September 2009 to December 2009. Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA(5+)) and dimethylarsinic acid (DMA(5+)) were determined by a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. RESULTS: Urinary total arsenic was significantly decreased with increasing BMI, indicating that obese children may retain higher levels of arsenic in the body, as compared to normal weight children. Participants with obesity accompanied by high insulin levels had higher inorganic arsenic, significantly higher MMA percentage and significantly lower DMA percentage than those with obesity and low insulin levels. It seems children with obesity and high insulin levels had lower arsenic methylation capacity than those with obesity and low insulin. CONCLUSIONS: This is the first study to demonstrate that total urinary arsenic is negatively associated with the BMI in adolescents in Taiwan, adjusted for age and sex. Obese adolescents with high insulin levels had significantly higher MMA% and significantly lower DMA% than obese adolescents with low insulin. PMID- 22104381 TI - Using 14C and 3H to delineate a recharge 'window' into the Perth Basin aquifers, North Gnangara groundwater system, Western Australia. AB - The Gnangara Mound and the underlying Perth Basin aquifers are the largest source of groundwater for the southwest of Australia, supplying between 35 and 50% of Perth's potable water (2009-2010). However, declining health of wetlands on the Mound coupled with the reduction in groundwater levels from increased irrigation demands and drier climatic conditions means this resource is experiencing increased pressures. The northern Gnangara is an area where the Yarragadee aquifer occurs at shallow depths (~50 m) and is in direct contact with the superficial aquifer, suggesting the possibility of direct recharge into a generally confined aquifer. Environmental isotopes ((14)C and (3)H) and hydrochemical modelling were used to assess the presence of a recharge 'window' as well as understand the groundwater residence time within different aquifers. Forty-nine groundwater samples were collected from depths ranging from 11 to 311 m below ground surface. The isotopic variation observed in the superficial aquifer was found to be controlled by the different lithologies present, i.e. quartz-rich Bassendean Sand and carbonate-rich sediments of the Ascot Formation. Rainfall recharge into the Bassendean Sand inherits its dissolved inorganic carbon from the soil CO(2). Organic matter throughout the soil profile is degraded by oxidation leading to anoxic/acidic groundwater, which if in contact with the Ascot Formation leads to enhanced dissolution of carbonates. Hydrochemical mass balance modelling showed that carbonate dissolution could contribute 1-2 mmol kg(-1) of carbon to groundwaters recharged through the Ascot Formation. The corrected groundwater residence times of the Yarragadee aquifer in the northern part of the study area ranged from 23 to 35 ka, while waters in the southeastern corner ranged from sub-modern to 2 ka. Groundwater ages increase with distance radiating from the recharge 'window'. This study delineates a recharge 'window' into the commonly presumed confined aquifers of the Perth Basin, highlighting the need for appropriate sustainable management. PMID- 22104382 TI - Effects of temple particles on inflammation and endothelial cell response. AB - To pray in temples is a regular activity in Buddhism and Taoism societies, yet few studies investigated the effects of particles from incense-burning in temples. The objectives of this study are to examine particle size and polycyclic aromatic hydrocarbon (PAH) effects of particles on coronary artery endothelial cell. We used two micro-orifice uniform deposit impactors to collect 11 sets of particles at a Chinese temple in Yi-Lan, Taiwan. 16 PAHs were determined by a high-resolution gas chomatograph/high-resolution mass spectrometer. Human coronary artery endothelial cells were exposed to particle extracts in three size ranges: PM(0.1) (diameters less than 0.1 MUm), PM(1.0-0.1) (diameters between 1.0 and 0.1 MUm), and PM(10-1.0) (diameters between 10 and 1.0 MUm) at 50 MUg/mL for 4h, and interleukin-6 (IL-6), endothelin-1 (ET-1), and nitric oxide (NO) concentrations in the medium were measured. We found that PM(1.0-0.1) stimulation resulted in significantly higher IL-6 and ET-1 production than PM(0.1) and PM(10 1.0). PM(1.0-0.1) also significantly reduced HCAEA cells to synthesize NO. Naphthalene, acenaphthylene, acenaphthene and anthracene of PM(1.0-0.1) were highly correlated with NO reduction. This study found that size and composition of temple particles were both important factors in inducing cytokine production and reducing NO formation in human coronary artery endothelial cell cultures. PMID- 22104383 TI - How does climate change influence Arctic mercury? AB - Recent studies have shown that climate change is already having significant impacts on many aspects of transport pathways, speciation and cycling of mercury within Arctic ecosystems. For example, the extensive loss of sea-ice in the Arctic Ocean and the concurrent shift from greater proportions of perennial to annual types have been shown to promote changes in primary productivity, shift foodweb structures, alter mercury methylation and demethylation rates, and influence mercury distribution and transport across the ocean-sea-ice-atmosphere interface (bottom-up processes). In addition, changes in animal social behavior associated with changing sea-ice regimes can affect dietary exposure to mercury (top-down processes). In this review, we address these and other possible ramifications of climate variability on mercury cycling, processes and exposure by applying recent literature to the following nine questions; 1) What impact has climate change had on Arctic physical characteristics and processes? 2) How do rising temperatures affect atmospheric mercury chemistry? 3) Will a decrease in sea-ice coverage have an impact on the amount of atmospheric mercury deposited to or emitted from the Arctic Ocean, and if so, how? 4) Does climate affect air surface mercury flux, and riverine mercury fluxes, in Arctic freshwater and terrestrial systems, and if so, how? 5) How does climate change affect mercury methylation/demethylation in different compartments in the Arctic Ocean and freshwater systems? 6) How will climate change alter the structure and dynamics of freshwater food webs, and thereby affect the bioaccumulation of mercury? 7) How will climate change alter the structure and dynamics of marine food webs, and thereby affect the bioaccumulation of marine mercury? 8) What are the likely mercury emissions from melting glaciers and thawing permafrost under climate change scenarios? and 9) What can be learned from current mass balance inventories of mercury in the Arctic? The review finishes with several conclusions and recommendations. PMID- 22104384 TI - Quantification of Legionella pneumophila by real-time quantitative PCR from samples with humic acid and ferric ion. AB - This study determined and overcame the influences of humic acid (HA) and/or ferric ion (Fe) on quantification of Legionella pneumophila by real-time quantitative PCR (qPCR). Four commonly used DNA isolation methods, QiAamp DNA Mini Kit (Q), Q with Sepharose 4B gel column (Q/G), freeze-thaw/phenol-chloroform lysis (FT-PC), and FT-PC/G, were adopted to isolate L. pneumophila DNA from samples containing Fe alone (0-30 mg l(-1)) or Fe/HA (0/0-3/100 mg l(-1)). Among the four DNA isolation methods, Q removed HA effectively and obtained the greatest DNA yield regardless of Fe and HA concentration (P<0.05). For samples containing Fe (0.3-3 mg l(-1)) or Fe/HA (0.3/10-3/100 mg l(-1)), qPCR inhibition was found in all isolated DNA, especially in those obtained by Q/G and FT-PC/G. DNA dilution at either 10 or 100 folds reduced qPCR inhibition and increased cell recovery (P<0.05). Under 10-fold dilution, Q acquired the highest concentrations of L. pneumophila determined by qPCR. Consequently, Q with post 10-fold dilution is suggested prior to qPCR for quantifying L. pneumophila from water containing Fe (<= 3 mg l(-1)) or Fe/HA (<= 3/100 mg l(-1)). PMID- 22104385 TI - Stable isotopes and mercury in a model estuarine fish: multibasin comparisons with water quality, community structure, and available prey base. AB - Stable-isotope ratios (delta(13)C and delta(15)N) and mercury in a model predator, and associated prey community assessments were used to make inferences regarding food web relationships and how these relationships are influenced by habitat variability and anthropogenic factors. Although interconnected, the three major basins of the Indian River Lagoon system on the Atlantic coast of Florida comprise noticeably different available habitat types with spatially distinct faunal communities and available prey for spotted seatrout, Cynoscion nebulosus, a model predatory fish species. Water quality, degree of urbanization, human population density, and levels of nitrogen enrichment clearly differ between these representative estuarine basins. The differences can influence feeding ecology and therefore result in different mercury concentrations and different stable-isotope signatures of spotted seatrout between basins. Mercury concentrations in spotted seatrout were greatest in Mosquito Lagoon (ML) and least in the Indian River Lagoon proper (IRL), although concentrations were low for all basins. Spotted seatrout from IRL were carbon-depleted and nitrogen enriched compared with those from the other basins; this suggests either that the fish's primary source of carbon in IRL is an algae- or phytoplankton-based food web or that the pathway through the food web is shorter there. The delta(15)N values of IRL spotted seatrout were greater than those in the Banana River Lagoon or ML, suggesting slightly different trophic positioning of fish in these basins. The greater delta(15)N values in IRL spotted seatrout may also reflect the greater human population density and resultant anthropogenic inputs (e.g., observed higher total nitrogen levels) in IRL compared with the other more pristine basins examined. Understanding species' responses to broad-scale habitat heterogeneity in estuaries and knowing basin-specific differences in stable isotopes, mercury, prey communities, and comprehensive food web relationships will be useful in the future for long-term monitoring of impacts of anthropogenic disturbances and of recovery from restoration efforts. PMID- 22104386 TI - The exposure data landscape for manufactured chemicals. AB - The U.S. Environmental Protection Agency is developing chemical screening and prioritization programs to evaluate environmental chemicals for potential risk to human health in a rapid and efficient manner. As part of these efforts, it is important to catalog available information on chemical toxicity and exposure from widely dispersed sources. The main objective of this analysis is to define important aspects of the exposure space and to catalog the available exposure information for chemicals being considered for analysis as part of the U.S. EPA ToxCastTM screening and prioritization program. Publicly available exposure data have been extracted into ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from >600 public sources. We use data from ACToR to assess the exposure data landscape for environmental chemicals. Of the roughly 100,000 chemicals that have at least limited toxicity information available, less than one-fifth also have exposure information - and for most of these the information is of limited utility (e.g., production volume). Readily accessible data on concentrations in exposure-related media are only available for a much smaller fraction. Among these, the largest number of chemicals is measured in water with over 1150 unique compounds, followed by 788 substances measured in soil, and 670 in air. These small numbers clearly reflect a focus of resources on those substances previously identified as possibly posing a hazard to human health. Exposure to a much broader number of chemicals will need to be measured in order to fully realize the envisioned goal of using exposure information to guide toxicity testing. PMID- 22104387 TI - Population genetics of beneficial heritable symbionts. AB - Most species of insects are infected with heritable, facultative symbionts. Such symbionts first appear within a host lineage as a result of lateral transfer from other host species. Although some facultative symbionts are reproductive parasites and thus adversely affect the transmission of host nuclear genes, there is growing evidence that many are beneficial to their hosts by, for example, conferring protection from natural enemies. The origin, spread, and maintenance of such symbionts bears many similarities to, as well as important differences from, the process of adaptive evolution by beneficial nuclear mutations. The time is ripe for the development of a coherent theory of the 'population genetics' of beneficial heritable symbionts. PMID- 22104388 TI - Emergency physician perspectives on child passenger safety: a national survey of attitudes and practices. AB - OBJECTIVE: To understand attitudes and self-reported practices of pediatric and general emergency physicians regarding child passenger safety. METHODS: We conducted a cross-sectional mailed national survey of 600 pediatric emergency medicine (PEM) physicians and 600 emergency medicine (EM) physicians who provide clinical care in the United States randomly sampled from the American Medical Association Physician Masterfile. Survey questions explored attitudes related to the role of the physician and the emergency department (ED) in child passenger safety and self-reported frequency of performing specific child passenger safety practices. RESULTS: Responses were received from 638 of 1000 (64%) eligible physicians with a valid mailing address. Surveys were completed by 367 PEM and 271 EM physicians. Regardless of their training background, emergency physicians overwhelmingly agreed that it is their role to educate parents about child passenger safety (95% PEM vs 82% EM) and that they can make a difference in how parents restrain their child (92% PEM vs 93% EM). Physicians were similar in their views that the most appropriate person to provide child passenger safety information in their ED was a nurse/midlevel provider followed by a physician. Self-report of child passenger safety practices in response to 2 hypothetical scenarios showed physicians infrequently provide best-practice safety recommendations to families. CONCLUSIONS: Emergency physicians are supportive of the ED as a setting to promote child passenger safety, yet do not consistently promote child passenger safety themselves. Differences between PEM and EM physicians' attitudes toward child passenger safety may necessitate different approaches on injury prevention in general and pediatric EDs. PMID- 22104389 TI - Prognostic factors for and prognostic value of mesenteric lymph node involvement in advanced-stage ovarian cancer. AB - AIM OF THIS STUDY: To determine the prognosis of and prognostic factors for mesenteric node involvement in patients undergoing a bowel resection at the time of debulking surgery for primary treatment of advanced-stage ovarian cancer (ASOC). METHODS: A retrospective review of patients treated between 2005 and 2008 for ASOC and undergoing initial and interval debulking surgery with bowel resection (whatever the bowel segment). The characteristics and prognostic impact of mesenteric node involvement were studied. RESULTS: During the study period, 52 patients underwent debulking surgery for ASOC with bowel resection. Eighteen and 34 patients underwent initial or interval debulking surgery respectively. The most frequent site of the bowel resection was the rectosigmoid colon (38 patients; 73%) and 12 patients had resection of at least 2 intestinal segments. All patients had a complete macroscopic resection of peritoneal disease. Nineteen patients (37%) had mesenteric node involvement with a median of 4 involved nodes (range, 1-12). The degree of involvement of the intestinal wall and retroperitoneal node involvement (pelvic or para-aortic) had no impact on the risk of mesenteric node involvement. Overall survival and the location of recurrent disease were similar in patients with or without spread to mesenteric nodes. CONCLUSIONS: This study suggests that mesenteric node involvement is frequent in patients undergoing bowel resection in ASOC. Such spread does not appear to have an impact on patient survival. Modifying peroperative (particularly the extent of the mesocolon resection) or postoperative management is therefore unnecessary. PMID- 22104390 TI - Autologous blood injection to treat achilles tendinopathy? A randomized controlled trial. AB - CONTEXT: Achilles tendinopathy is a common and often debilitating condition, and autologous blood injection is a promising treatment option. OBJECTIVE: To determine whether autologous blood injection added to standard management was effective in alleviating symptoms of Achilles tendinopathy. DESIGN: A prospective randomized controlled trial. SETTING: Private sports medicine clinic. PATIENTS: 33 patients (18 women, 15 men) of mean age 50 y (SD 9) with 40 cases of Achilles tendinopathy of mean duration of 11 mo (SD 7). INTERVENTION: Participants were randomized to blind peritendinous autologous blood injection added to standard treatment (eccentric-loading exercises) or standard treatment alone for 12 wk. MAIN OUTCOME MEASURE: Victorian Institute of Sport Assessment for Achilles (VISA A) score and ratings of discomfort during and after the injection were measured at baseline and 6 and 12 wk. Analytically derived effect-size thresholds of 5 (small) and 15 (moderate) VISA-A units were used as the reference values for clinical inference. RESULTS: Improvements in VISA-A of 7.7 units (95%CL: +/- 6.7) and 8.7 units (+/- 8.8) were observed in the treatment and control groups, respectively, at 6 wk relative to baseline, with no clear effect of blood injection. At 12 wk VISA-A score improved to 18.9 units (+/- 7.4) in the treatment group, revealing a blood-injection effect of 9.6 units (+/- 11.5), relative to a comparatively unchanged condition in control (9.4 units; +/- 9.0). Predictors of response to treatment were unremarkable, and a 21% rate of postinjection flare was the only noteworthy side effect. CONCLUSIONS: There is some evidence for small short-term symptomatic improvements with the addition of autologous blood injection to standard treatment for Achilles tendinopathy, although double-blinded studies with longer follow-up and larger sample size are required. PMID- 22104391 TI - Arthroscopic treatment of synovial chondromatosis at the knee posterior septum using a trans-septal approach: report of two cases. AB - Synovial chondromatosis of the knee joint rarely develops in the posterior septum. Such cases are difficult to treat arthroscopically since the posterior septum is not readily accessible via standard portals. We report two cases of localized synovial chondromatosis in the posterior septum. We used a posterior trans-septal portal to arthroscopically remove the loose bodies and perform a concomitant synovectomy. The two cases were followed-up for 24 and 16 months after surgery, respectively, and the patients were found to be pain-free, have a full range of knee motion and showed no evidence of recurrence. A posterior trans septal portal may be essential in some cases for treatment of synovial chondromatosis at the posterior septum. PMID- 22104392 TI - Personality and perceived need for mental health care among primary care patients. AB - BACKGROUND: Although there are many forms of effective, evidence-based treatments available to patients with mood and anxiety disorders, many do not seek any help. Certain personality characteristics are associated with increased use of mental health services. The objective of this study is to examine whether personality traits are also related to patients' perceived need for (specific types of) mental health care. METHODS: Cross-sectional data were derived from the Netherlands Study of Depression and Anxiety (NESDA). A total of 762 patients recruited from general practices, and who had been diagnosed with one or more DSM IV diagnoses of anxiety and/or depression were included. Perceived need for mental health care was assessed with the Perceived Need for Care Questionnaire (PNCQ) and personality traits were assessed with the NEO-Five Factor Inventory (NEO-FFI). RESULTS: We found indications that personality traits, in particular neuroticism and openness to experience, have an impact on care needs. Patients with higher scores on these traits were more likely to have a perceived need for care, irrespective of whether or not this need was met. Extraversion, agreeableness and conscientiousness were largely unrelated to perceived need for care. CONCLUSIONS: Regardless of the severity of anxiety and depression, personality is associated with need for care. This seems to be true for neuroticism, openness to experience, agreeableness and conscientiousness. Associations with these domains were found for various types of treatment. These findings suggest that patients with different levels of personality traits need different treatments. PMID- 22104393 TI - Effects of cyclin-dependent kinase 8 specific siRNA on the proliferation and apoptosis of colon cancer cells. AB - BACKGROUND: To investigate the expression of cyclin-dependent kinase 8 (CDK8) and beta-catenin in colon cancer and evaluate the role of CDK8 in the proliferation, apoptosis and cell cycle progression of colon cancer cells, especially in HCT116 cell line. METHODS: Colon cancer cell line HCT116 was transfected with small interfering RNA (siRNA) targeting on CDK8. After CDK8-siRNA transfection, mRNA and protein expression levels of CDK8 and beta-catenin were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot assay in HCT116 cells. Cell proliferation was measured by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide Methylthiazolyl tetrazolium (MTT) assay, and cell cycle distribution and apoptosis were analyzed by flow cytometry analysis (FACS). CDK8 and beta-catenin protein levels were also examined by real-time PCR and immunohistochemistry (IHC) in colon cancer tissues and adjacent normal tissues. RESULTS: After CDK8 specific siRNA transfection, mRNA and protein expression levels of CDK8 and beta-catenin in HCT116 cells were noticeably decreased (P < 0.05). CDK8 specific siRNA transfection inhibited HCT116 cells' proliferation and facilitated their apoptosis significantly (P < 0.05). In addition, the proportion of HCT116 cells in the G0/G1 phase was remarkably increased after CDK8-siRNA transfection (P < 0.05). The expression levels of CDK8 and beta-catenin in adjacent normal tissues were lower than in tumor tissues (P < 0.05). Moreover, the expression of CDK8 was correlated with the expression of beta-catenin in both tumor and adjacent normal tissues (P < 0.05). CONCLUSIONS: CDK8 and beta-catenin were expressed in colon cancer at a high frequency. CDK8 specific siRNA transfection down-regulated the expression of CDK8 in colon cancer cells, which was also associated with a decrease in the expression of beta-catenin Moreover, CDK8 specific siRNA inhibited the proliferation of colon cancer cells, promoted their apoptosis and arrested these cells in the G0/G1 phase. Interference of CDK8 might be an effective strategy through beta-catenin regulation of colon cancer. PMID- 22104394 TI - Staged gamma knife radiosurgery for large cerebral arteriovenous malformations. AB - BACKGROUND: We present our experience over a 10-year period of staged radiosurgery for large arteriovenous malformations (AVMs) including patient outcomes and methods. METHODS: From July 2000 to December 2010, 80 patients with AVMs were treated with gamma knife radiosurgery (GKS) at our institution; of these patients, 5 were treated for large AVMs with staged GKS (volumes >20 cm(3)). The mean interval between treatments was 10 months (range 7-16). The mean dose for the margin used was 18.0 Gy (range 16-20). The mean volume treated was 37.2 cm(3) (range 22-50). The mean total follow-up was 76.5 months (range 42 120). RESULTS: Two patients had complete obliteration of the AVM nidus. One patient had 95% obliteration (31 months after radiosurgery), one had 90% obliteration (38 months after radiosurgery), and one had less than 50% obliteration at 53 months with a 16-month interval between staged treatments. CONCLUSIONS: Staged radiosurgery is an effective and safe method for the treatment of large AVMs. We report achieving higher marginal doses with staging in planned intervals of 6-9 months between staged treatments. It appears that the longer the wait between treatments, the less likely it is that complete obliteration will be achieved. PMID- 22104395 TI - Cross-border movement and women's health: how to capture the data. AB - INTRODUCTION: The movement of women across international borders is occurring at greater rates than ever before, yet the relationship between migration and women's health has been under-explored. One reason may be difficulty measuring migration variables including country of birth, length of time in country, immigration status, language ability, and ethnicity. A range of social, environmental, cultural, and medical characteristics associated with the pre-, during- and post-migration phases are also important to consider. The objective of this paper is to present challenges and solutions in measuring migration and related variables via survey-like questionnaires administered to international migrant women. METHODS: The development, validation, and translation of two questionnaires subsequently applied in studies of migrant women during pregnancy, birth and postpartum were used as case examples to highlight related measurement issues. RESULTS: Challenges: (1) Measuring socio-cultural, medical and environmental variables across the pre-during-post migration phases (since questions must be framed so that data relating to each phase of migration are captured); (2) Obtaining data for complex patterns of migration (i.e., multiple movements between multiple destinations); and (3) answering long questions across a time continuum.Solutions: (1) Using interviewer-assisted rather than self administered questions; (2) Adding probes and explanations to 'walk' participants through their migration experiences; (3) Identifying variables (e.g., trafficking) better captured using non-questionnaire data collection methods or better not collected (e.g., ethnicity) due to extreme variations in meaning. CONCLUSION: Carefully constructed and translated survey questionnaires are practical tools for the collection of a breadth of migrant data. These data, including detailed accounts of countries lived in, length of time in those countries, immigration status, change in status, language fluency, and health insurance eligibility offer rich descriptions of the population under study and make research findings with regards to migration more interpretable. Analyses by a range of migration indicators are facilitated through survey-like questionnaire data of this type. PMID- 22104396 TI - Intestinal Tritrichomonas suis (=T. foetus) infection in Japanese cats. AB - Tritrichomonas suis (=T. foetus) has recently been reported to be a causative agent of chronic large-bowel diarrhea in cats. While the disease was previously attributed to Pentatrichomonas hominis, the etiologic agent for feline trichomonal diarrhea was identified as T. suis. Although feline trichomonosis due to T. suis has been reported at prevalences ranging from 14 to 31% in Europe and the U.S., no reports of the pathogen have been published to date in Japan. In 2008, however, we encountered a case of feline trichomonosis at the Veterinary Teaching Hospital of Hokkaido University. The parasite was identified as T. suis by nested PCR amplification of partial internal transcribed spacer region 1 and 5.8S ribosomal RNA gene sequences with T. suis-specific primers and DNA sequencing of the amplified products. We then conducted surveys for feline trichomonosis in three different animal hospitals using either cultivation and/or PCR-based assays. The results revealed that 13 of 147 samples (8.8%) were positive for T. suis, and that 5 of the 13 infected cats, which ranged between 1 month and 7.5 years-old, showed chronic diarrhea. Seven of the infected cats were purebred and 6 were mixed breed. These findings suggested that feline trichomonosis is prevalent in Japan, and that T. suis may play a role as a causative agent of feline chronic diarrhea. PMID- 22104397 TI - A case of canine multiple inflammatory colorectal polyps treated by endoscopic polypectomy and argon plasma coagulation. AB - Endoscopic polypectomy and argon plasma coagulation (APC) were performed in a refractory case of inflammatory colorectal polyps in a 7-year-old male Miniature Dachshund. Colonoscopic examination revealed a large sessile polyp and multiple diffuse small polyps, localized to the descending colon and rectum. The case showed a poor therapeutic response to prednisolone and cyclosporine. Under anesthesia, piecemeal resections were performed by polypectomy. APC was carried out to cauterize the polyp remnants. After treatment, reduction of the lesions and the improvement in clinical signs were observed, without recurrence of lesions for at least 10 months. Endoscopic treatment by polypectomy and APC is suggested to be a therapeutic option for refractory cases of inflammatory colorectal polyps in dogs. PMID- 22104398 TI - Different A-type natriuretic peptide level in five strains of mice. AB - Atrial (A-type) natriuretic peptide (ANP) is vasodilative hormone involved in the regulation of blood pressure and volume homeostasis. In this study, we examined the differences of the auricular and plasma ANP distribution by immunohistochemistry, ultrastructural morphometry, and radioimmunoassay in five strains of mice. The ANP-immunoreactivities of the auricle were most intense in ICR, and moderate in C57BL/6J and C3H/HeN, and weakest in BALB/cA and DBA/2Cr. The number of ANP-granules was greatest in ICR followed by C57BL, C3H or BALB/c, and DBA/2 mice, in this order. The auricular ANP content was highest in ICR, but the plasma ANP concentration was comparable in all strains. The present study demonstrates that there are differences in the ANP circulating system between five strains. PMID- 22104399 TI - Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma. AB - BACKGROUND: JC virus (JCV) infection is a prerequisite for development of progressive multifocal leukoencephalopathy (PML). We previously described the development of a novel, two-step enzyme-linked immunosorbent assay (ELISA) that detects anti-JCV antibodies in human serum or plasma, and the potential clinical utility of anti-JCV antibody status for PML risk stratification. OBJECTIVES: To validate the anti-JCV antibody ELISA at multiple clinical laboratories in order to demonstrate the robustness of the method. STUDY DESIGN: Analytical validation of the ELISA was performed at four laboratories by evaluation of intra- and inter assay precision, analytical specificity and sensitivity, matrix interference, robustness, sample and reagent stability. RESULTS: Analytical validation demonstrated that the assay is sensitive, specific, and precise. The assay sensitivity was estimated at 1.7ng/mL using a humanized anti-JCV monoclonal antibody control. The sensitivity to detect JCV infection was estimated to be 97.5%. The specificity of the assay to discriminate JCV-specific antibodies from antibodies directed to BK virus, a related polyomavirus, was also demonstrated. The inter- and intra-assay precision was <=6.0% and 9.8% for the screening step and 2.6% and 11.3% for the confirmation step. Results obtained for plasma and serum were highly congruent, and assay robustness was demonstrated by the highly concordant results generated by four laboratories testing a common panel of 100 blinded samples. CONCLUSIONS: The novel, two-step ELISA to detect anti-JCV antibodies in human serum and plasma is robust, and assay performance is consistent and reproducible in multiple laboratories, making it suitable to support testing for global clinical studies. PMID- 22104400 TI - Interaction of the CdSe quantum dots with plant cell walls. AB - There is an increasing application of quantum dots (QDs) in plant science, as markers for the cells or their cell walls (CWs). In a plant cell the CW is a first target place for external agents. We studied interaction of CdSe QDs with CWs isolated from a conifer -Picea omorika (Panc) Purkyne branch. Binding of CdSe QDs was followed by using fluorescence microscopy, fluorescence and FT-IR spectroscopy. The aim of the study was to see whether the QDs induce structural changes in the CW, as well as to find out which kind of interactions between QDs and CWs occur and to which particular constituent polymers QDs preferably bind. The isolated CW is an appropriate object for study of the interactions with nanoparticles. The results show that in the CW, CdSe predominantly binds to cellulose, via OH groups and to lignin, via the conjugated CC/C-C chains. The differences in interaction of wet and dry CWs with QDs/chloroform were also studied. In the reaction of the dry CW sample with QDs/chloroform, hydrophobic interactions are dominant. When water was added after QDs/chloroform, hydrophilic interactions enable a partial reconstruction of the CC chains. The results have an implication on the use of the QDs in plant bio-imaging. PMID- 22104401 TI - Osmotic repulsion force due to adsorbed surfactants. AB - When considering interaction forces in surfactant-stabilized colloidal dispersions a factor that has been rarely discussed is the possible effect of osmotic force due to overlapping adsorbed surfactant monolayers. In the present work, the osmotic repulsion force is built-in on the basis of DLVO mechanics and based on Fischer's consideration of the analogous situation for adsorbed polymer layers on solid surfaces [E.W. Fischer, Kolloid Zeitschrift 160 (1958) 120-141] and on Langmuir's earlier concept of osmotic pressure excess due to overlapping adsorption layers [I. Langmuir, J. Chem. Phys. 6 (1938) 873-896]. The advanced method for calculation of the net repulsion force in overlapping surfactant monolayers is developed and applied to real adsorbed surfactant systems. We show that the value of disjoining pressure can reach values as high as 8 MPa for the condition of fully overlapping surfactant adsorption layers, based on the calculation of the first virial term of the general expression for osmotic pressure. Thus, we have shown that osmotic forces can be substantial at distances of close interfacial approach, and that they can easily be of the same or greater order of magnitude than the forces that have been more conventionally considered. PMID- 22104402 TI - Expression of P-glycoprotein and multidrug resistance-associated protein on human brain-microvascular endothelial cells with electromagnetic stimulation. AB - This study investigates the effect of electromagnetic field (EMF) on the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) on human brain-microvascular endothelial cells (HBMECs). A monolayer of HBMECs was cocultured with human astrocytes for developing apical/basolateral membrane properties. The results revealed that an increase in the frequency of an EMF enhanced the endocytotic uptake of calcein-AM. Probenecid demonstrated a stronger inhibition to the efflux pumps than verapamil under the exposure to an EMF. The expressed quantities of P-gp and MRP1 after transcytosis of saquinavir were higher than those of azidothymidine, suggesting that the former induced a stronger drug resistance than the latter. In addition, an EMF with 750 Hz could effectively inhibit the expression of P-gp and MRP1. An appropriate exposure to an EMF can be efficient to deliver antiretroviral drugs into the brain via reducing the expressed efflux transporters on HBMECs. PMID- 22104403 TI - Synthesis and characterization of N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride for potential application in gene delivery. AB - A series of N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride (HTCC) samples with various degrees of quaternization ranging from 12.4 to 43.7% was synthesized. The structures and properties of HTCC were investigated by FT-IR, (1)H NMR, conductometric titration and XRD analysis. It was found that HTCC had a more amorphous structure than chitosan. HTCC samples showed significantly lower cytotoxicity than polyethyleneimine in HepG2 and HeLa cell lines. The samples spontaneously formed complexes with pGL3 luciferase plasmid. These complexes had desirable particle sizes (160-300 nm) and zeta potentials (10.8-18.7 mV) when the weight ratios of HTCC to plasmid altered in the range of 3:1-20:1. In vitro gene transfection results indicated that HTCC had significantly high transfection efficiency compared with chitosan for delivering pGL3 luciferase plasmid to HeLa cells. The results suggest that HTCC could be a promising non-viral vector for safe and efficient DNA delivery. PMID- 22104404 TI - Elastin-like polypeptide modified liposomes for enhancing cellular uptake into tumor cells. AB - Polyethylene glycol-modified (PEGylated) liposomes have been widely used because of their long circulation time, but they have a major drawback of limited cellular uptake. In this study, liposomes modified with a thermosensitive biopolymer, elastin-like polypeptide (ELP), were prepared to enhance cellular uptake in tumor cells. Synthesized ELP exhibited an inverse transition temperature (T(t)) of 40 degrees C in serum with hyperthermia treatment and contained a lysine residue for conjugation with 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine-N-[poly(ethylene-glycol)]-hydroxy succinamide, PEG MW 2000 (DSPE-PEG2000-NHS). ELP was covalently conjugated with liposomes encapsulating a high concentration of doxorubicin (Dox). Size and drug release properties of liposomes were investigated over a range of temperatures. ELP-modified liposomes tended to aggregate but did not show temperature-triggered release by phase transition of ELP molecules. Cellular uptake efficiency of liposomes was evaluated under normothermic and hyperthermic condition. Dox accumulation from liposomes was determined by flow cytometry and confocal microscopy. Higher internalization occurred in the ELP-modified liposomes than in ELP-unmodified liposomes. The results suggest that dehydration of ELP molecules on the liposomal surface can induce efficient cellular uptake, which can improve existing chemotherapeutic efficacy. PMID- 22104405 TI - Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 4: a change of the surface properties during degradation process and the corresponding in vitro cellular response. AB - The surface properties of PLGA/HAp core-shell nanoparticles loaded with clindamycin obtained by an ultrasonic processing method and their changes under the simulated physiological conditions during the degradation process (when the morphology is changed starting from the nanospheres, over micrometer-sized plate like films to a porous network) were investigated. The dynamic change of the surface properties of this material obtained in a water environment showed an increase of the surface area (up to 70 m(2)/g) and an improved wettability (estimated water contact angle was in the range between 40 degrees and 60 degrees ) suggesting the possibility for its good interaction with cells. The in vitro tests are in a good correlation with this hypothesis, showing a high level of cytocompatibility of the material with the mouse L929 and human lung MRC-5 fibroblasts. The fibroblasts were able to achieve the contact with the material's surface and to attach onto it. The significance of HAp, as the bioceramic phase within the PLGA/HAp core-shell nanoparticles, may be brought into relationship with its role in improving the surface properties of PLGA/HAp obtained during the degradation process. These properties are closely related to the bioactivity and biocompatibility of this material, which are highly relevant for its biomedical application. PMID- 22104406 TI - Calcium entry into pollen tubes. AB - Growing pollen tubes require calcium to maintain a tip-focused cytosolic gradient and as a constituent of the constantly expanding cell wall. Advances in cell and molecular biology as well as electrophysiology implicate several candidate channels and receptors in the flow of calcium into the cell. In this review we discuss the channels that have been identified and consider the role of the growing tip cell wall acting as a sink for calcium thus accounting for differences in oscillatory phase between influx measured on the outside of the cell and changes in tip concentration inside the cell. We also briefly draw attention to uptake mechanisms that restrict and shape the calcium signature in the growing pollen tube. PMID- 22104407 TI - Long noncoding RNA: unveiling hidden layer of gene regulatory networks. AB - Long noncoding RNAs (lncRNAs) are increasingly recognized as functional regulatory components in eukaryotic gene regulation. Distinct classes of lncRNAs have been identified in eukaryotes and they play roles in various regulatory networks. Previously characterized lncRNAs include primary transcripts for small regulatory RNAs. In the era of deep sequencing, new classes of lncRNAs have emerged as potent regulatory components in gene regulation. Recent studies showed that many lncRNAs are potent cis- and trans-regulators of gene activity and they can function as scaffolds for chromatin-modifying complexes. Furthermore, differential expressions of lncRNAs suggest that transcription of lncRNAs can modulate gene activity during development and in response to external stimuli. Here, we summarize our current understanding on potential roles of lncRNAs in plants. PMID- 22104408 TI - Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic target. AB - Inflammation is established as a contributor to cerebrovascular disease. Risk factors for stroke include many conditions associated with chronic or acute inflammation, and inflammatory changes in the brain after cerebrovascular events contribute to outcome in experimental studies, with growing evidence from clinical research. The brain is extremely susceptible to inflammatory challenge, but resident glia, endothelial cells and neurones can all mount a pronounced inflammatory response to infection or injury. Recent discoveries highlight the importance of peripherally-derived immune cells and inflammatory molecules in various central nervous system disorders, including stroke. The inflammatory cytokine, interleukin-1 (IL-1), plays a pivotal role in both local and systemic inflammation, and is a key driver of peripheral and central immune responses to infection or injury. Inhibition of IL-1 has beneficial effects in a variety of experimental paradigms of acute brain injury and is a promising clinical target in stroke. We propose that blockade of IL-1 could be therapeutically useful in several diseases which are risk factors for stroke, and there is already considerable pre-clinical and clinical evidence that inhibition of IL-1 by IL-1 receptor antagonist may be valuable in the management of acute stroke. PMID- 22104409 TI - Palliative care as a human right: update. PMID- 22104410 TI - An open trial of aripiprazole for the treatment of delirium in hospitalized cancer patients. AB - OBJECTIVE: The purpose of this study was to examine the efficacy and safety of aripiprazole in the treatment of delirium in hospitalized cancer patients, and to examine differential responses based on delirium subtypes. METHOD: We conducted an analysis of 21 hospitalized cancer patients at Memorial Sloan-Kettering Cancer Center (MSKCC) who had been evaluated and treated for delirium with aripiprazole, using an MSKCC Institutional Review Board (IRB) approved Clinical Delirium Database. Measures used were the Memorial Delirium Assessment Scale (MDAS), the Karnofsky Scale of Performance Status (KPS), and side effect rating at baseline (T1), 2-3 days (T2), and 4-7 days (T3). All measurements were integrated into the routine clinical care of patients. Doses of aripiprazole were adjusted based on clinical response. RESULTS: Patients treated for delirium with aripiprazole experienced significant improvement and resolution of delirium, with MDAS scores declining from a mean of 18.0 at baseline (T1) to mean of 10.8 at T2 and a mean of 8.3 at T3. KPS scores improved from 28.1 at baseline (T1) to 35.2 at T2 and 41 at T3. Delirium resolved (based on MDAS < 10) in 52.4% of cases at T2 and in 76.2% at T3. The mean dosage of aripiprazole required was 18.3 mg (range of 5-30) daily at T3. In our cohort of patients with hypoactive delirium, we observed a delirium resolution rate of 100% compared to the cohort of patients with hyperactive delirium (58.3% rate of delirium resolution). MDAS scores improved from 15.6 at T1 to 5.7 at T3 in hypoactive delirium and from 19.9 at T1 to 10.2 at T3 in hyperactive delirium. In patients with pre-morbid cognitive deficits and the hyperactive subtype of delirium, we observed a more limited treatment response to aripiprazole treatment for delirium. There were no clinically significant side effects noted. SIGNIFICANCE OF RESULTS: Aripiprazole is effective and safe in the treatment of delirium in hospitalized cancer patients. These preliminary finding suggest that aripiprazole may be most effective in resolving delirium of the hypoactive subtype. PMID- 22104411 TI - Responding to patient anger: development and evaluation of an oncology communication skills training module. AB - OBJECTIVE: The purpose of this study was to develop a communication skills training (CST) module for oncology healthcare professionals on how to more effectively respond to patient anger. We also sought to evaluate the module in terms of participant self-efficacy and satisfaction. METHOD: The development of this module was based on a systematic review of the literature and followed the Comskil model previously used for other doctor-patient CST. Using an anonymous 5 point Likert scale, participants rated their pre-post self-efficacy in responding to patient anger as well as their satisfaction with the course. Data were analyzed using a paired sample t test. RESULTS: During the academic years 2006 2009, 275 oncology healthcare professionals participated in a CST that focused on responding to patient anger. Participants' confidence in responding to patient anger increased significantly (p < 0.001) after attending the workshop. They also agreed or strongly agreed to five out of six items assessing course satisfaction 92-97% of the time. SIGNIFICANCE OF RESULTS: We have developed a CST module on how to respond to patient anger, which is both effective and useful. Training healthcare professionals to respond more effectively to patient anger may have a positive impact on the patient-physician relationship. PMID- 22104412 TI - Planning with parents for seriously ill children: preliminary results on the development of the parental engagement scale. AB - OBJECTIVE: The objective of this study was to develop a clinically relevant tool to assess parental engagement in decision making and planning for seriously ill children during palliative care consultations. Although little is known about the structure and process of planning meetings between parents and providers, less is known about the nature of parental engagement as it relates to decision making ability in pediatric end-of-life care. Using attachment and caregiving as a framework, this study clarified important dimensions of parental engagement. METHOD: Using a multi-phase, template-matching technique, both literature and pediatric palliative care consultation data were analyzed, iteratively reviewed, matched, and categorized to create a measure of parental engagement. The attachment paradigm serves as the theoretical framework for the study, which focuses on parental engagement in decision making as a caregiving system function. Attachment and related literatures as well as coping and pediatric palliative care literatures were used in the initial conceptual sampling phase. RESULTS: The study yielded two groups of findings. The first set of findings centered on the findings of the literature and consultation template-matching phases of the work. These two phases yielded a conceptual model of parental engagement as a psychobehavioral complex consisting of three dimensions: information-centered dialogue, insightful participation, and achievement of a collaboratively agreed-upon plan. The final phases consisted of creation of a 9 point Parental Engagement Scale, scoring of the consultations, and establishment of initial inter- rater reliability at .80. Psychometric testing continues. SIGNIFICANCE OF RESULTS: Parental engagement in decision making is a critical area for study and intervention. If we can support parents in their caregiving executive functions while understanding the psychological and emotional underpinnings of the caregiving system and parental engagement itself, we can move inquiry forward in understanding parental needs for intervention during this most profoundly challenging time. PMID- 22104413 TI - Perspectives of staff providing care at the end of life for people with progressive long-term neurological conditions. AB - OBJECTIVE: This article examines the views and opinions of staff from a larger study exploring the palliative and end-of-life care needs of patients with progressive long-term neurological conditions (PLTNC). METHOD: Eighty staff, in a range of professions from three types of care services provided to people with PLTNC in England, took part in 14 focus groups and 3 individual interviews. Sites included six long-term residential neurological care centers, an inpatient service at an urban hospice, and a multi-disciplinary outpatient service for people with Huntington's disease. RESULTS: Findings show a concordance between the views of staff from across the three types of participating services. Staff placed particular emphasis on teamwork, support from community-based resources, and developing rapport with patients in order to provide high quality palliative and end-of-life care. All staff perceived that identifying the dying phase was a particular challenge, sometimes resulting in patients being admitted to hospital at the end of life in contravention of their expressed advance wishes for place of death. SIGNIFICANCE OF RESULTS: This article adds to a small body of literature that seeks staff views and opinions about the rewards and challenges of providing palliative and end-of-life care to people with complex needs arising from long-term conditions. Although this article focuses primarily on the challenges of caring for people with neurological conditions, many issues reported are of wider relevance for the delivery of palliative and end-of-life care in other conditions. PMID- 22104414 TI - The impact of a palliative care unit on mortality rate and length of stay for medical intensive care unit patients. AB - OBJECTIVE: This study evaluates the impact of a 10-bed inpatient palliative care unit (PCU) on medical intensive care unit (MICU) mortality and length of stay (LOS) for terminally ill patients following the opening of an inpatient PCU. We hypothesized that MICU mortality and LOS would be reduced through the creation of a more appropriate location of care for critically ill MICU patients who were dying. METHOD: We performed a retrospective electronic database review of all MICU discharges from January 1, 2006 through December 31, 2009 (5,035 cases). Data collected included MICU mortality, MICU LOS, and mean age. The PCU opened on January 1, 2008. We compared location of death for MICU patients during the 2 year period before and the 2-year period after the opening of the PCU. RESULTS: Our data showed that the mean MICU mortality and MICU LOS both significantly decreased following the opening of the PCU, from 21 to 15.8% (p = 0.003), and from 4.6 to 4.0 days (p = 0.014), respectively. SIGNIFICANCE OF RESULTS: The creation of an inpatient PCU resulted in a statistically significant reduction in both MICU mortality rate and MICU LOS, as terminally ill patients were transitioned out of the MICU to the PCU for end-of-life care. Our data support the hypothesis that a dedicated inpatient PCU, capable of providing care to patients requiring mechanical ventilation or vasoactive agents, can protect terminally ill patients from an ICU death, while providing more appropriate care to dying patients and their loved ones. PMID- 22104415 TI - Depression and anxiety in palliative care inpatients compared with those receiving palliative care at home. AB - OBJECTIVE: This study compared the prevalence of anxiety and depression as measured on the Hospital Anxiety and Depression Scale (HADS) in palliative care patients being treated at home with those being treated as inpatients. METHOD: The participants were palliative care patients being treated at home (n = 46) and palliative care inpatients (n = 46). Subjects were assessed for functionality on the Karnofsky Performance Status Scale (KPS) and anxiety and depression were measured on the HADS. RESULTS: The results showed that ~20% of all patients were depressed and anxious as measured on the HADS, regardless of the cutoff criteria. There was no significant difference in depression and anxiety between the two groups when socioeconomic status and functionality were controlled for. Functionality, as measured on the KPS, was uniquely a predictor of depression, and younger patients were shown to have greater anxiety. SIGNIFICANCE OF RESULTS: The results suggest that home-based palliative care patients and palliative care inpatients should receive equal psychological support, and that clinicians need to be aware of the psychological vulnerability of younger and less-functional patients. The prevalence of depression and anxiety indicates that all palliative care patients should be screened for psychological distress, to identify those who need further assessment and treatment. PMID- 22104416 TI - Palliative medicine consultation impacts DNR designation and length of stay for terminal medical MICU patients. AB - OBJECTIVE: The purpose of this study was to assess the impact of a palliative medicine consultation on medical intensive care unit (MICU) and hospital length of stay, Do Not Resuscitate (DNR) designation, and location of death for MICU patients who died during hospitalization. METHOD: A comparison of two retrospective cohorts in a 17-bed MICU in a tertiary care university-affiliated hospital was conducted. Patients admitted to the MICU between January 1, 2003 and June 30, 2004 (N = 515) were compared to MICU patients who had had a palliative medicine consultation between January 1, 2005 and June 1, 2009 (N = 693). To control for disease severity, only patients in both cohorts who died during their hospitalization were considered for this study. RESULTS: Palliative medicine consultation reduced time until death during the entire hospitalization (log-rank test, p < 0.01). Time from MICU admission until death was also reduced (log-rank test, p < 0.01), further demonstrating the impact of the palliative care consultation on the duration of dying for hospitalized patients. The intervention group contained a significantly higher percentage of patients with a DNR designation at death than did the control group (86% vs. 68%, chi2 test, p < 0.0001). SIGNIFICANCE OF RESULTS: Palliative medicine consultation is associated with an increased rate of DNR designation and reduced time until death. Patients in the intervention group were also more likely to die outside the MICU as compared to controls in the usual care group. PMID- 22104417 TI - Posttraumatic stress disorder at the end of life: extant research and proposed psychosocial treatment approach. AB - According to some estimates, 84% of people experience a traumatic event during their lives (Vrana & Lauterbach, 1994), and 15% to 24% then develop posttraumatic stress disorder (PTSD). Many carry with them lasting effects of trauma as they age and enter the last phase of life. PTSD manifests in unique ways at the end of life, possibly disrupting factors associated with a positive dying process, including social support, medical communication, life review, and acceptance of death. Terminally ill people with PTSD may suffer more emotional distress, lower quality of life, and poorer medical prognosis than those without PTSD. Unfortunately, healthcare providers may not be trained to address this issue. This article reviews the literature concerning how PTSD may affect the end of life and proposes an intervention model based on a palliative care philosophy. PMID- 22104418 TI - The spiritual strength story in end-of-life care: two case studies. AB - In this article I analyze two brief case studies to propose that a "spiritual strength story" has five defining characteristics: (1) it is brief; (2) it is ontological; (3) it uses symbols and metaphors; (4) it is a "big story" or meta narrative with a positive spiritual and/or religious focus that informs other narrative data; and (5) most conspicuously of all, it repeats. Cultivating awareness of the "spiritual strength" narrative type can help to improve the quality of inter-professional patient-centered care teamwork and understanding, especially in regard to the reflexive, embodied, and relational aspects of palliative and end-of-life care. PMID- 22104419 TI - "Doctor, what did I do to deserve this?". PMID- 22104420 TI - Dying in the social media: when palliative care meets Facebook. PMID- 22104421 TI - A fight to beyond death. PMID- 22104422 TI - Sensitivity of discharge diagnosis ICD-9 codes for pediatric venous thromboembolism is greater than specificity, but still suboptimal for surveillance and clinical research. PMID- 22104423 TI - Serum 25(OH)-vitamin D level in children: is there a need to change the reference range based on 2011 Institute of Medicine report? PMID- 22104424 TI - Extracorporeal shock wave treatment improves incisional wound healing in diabetic rats. AB - Impaired wound healing in surgical patients with diabetes increases the incidence of infection, prolongs hospitalization, and even increases the rate of mortality. Low-energy extracorporeal shock wave treatment (ESWT) was reported to accelerate chronic wound healing by promoting revascularization and tissue regeneration; however, it is not known if ESWT could also improve healing of acute surgical incisional wounds in diabetes. In this study, using a rat model of diabetes, we investigated the effect of low-energy ESWT on collagen content in wound tissues and its efficacy in incisional wound healing. A single dorsal incisional wound was inflicted in streptozotocin-induced diabetic rats, and they received ESWT at different time post-wounding. Rats were sacrificed on days 7 and 14 post wounding. Wound breaking strength, hydroxyproline content, histological characteristics and the expression of transforming growth factor beta 1 (TGF beta1) were analyzed. As a result, the wound breaking strength was significantly enhanced and the hydroxyproline content in wound tissues was increased at each time point examined. The number of fibroblasts was signicantly increased, and the new collagen fibers were more abundant at the wound site after ESWT. Furthermore, the expression of TGF-beta1 was up-regulated after ESWT on day 7 post-wounding. These results suggest that low-energy ESWT can increase collagen content, enhance wound breaking strength and improve the healing of incisional wound in diabetic rats. The increased collagen content may be attributed, at least in part, to the up-regulation of TGF-beta1 expression in wound tissues. PMID- 22104425 TI - High lateral portal for sparing the infrapatellar fat-pad during ACL reconstruction. AB - During arthroscopic ACL reconstruction, intra-articular visualization can be compromised by the interposition of the infrapatellar fat pad (IPFP) between the scope and the notch. In this technical note, we describe our technique of using lateral higher arthroscopic portal, starting arthroscopy with the resection of the ligamentum mucosum and performing the tibial tunnel in 40 degrees of knee flexion to optimise the intra-articular view without IPFP debridement. This technique was performed in 112 consecutive arthroscopic ACL reconstructions and compared to that in the previous 112 cases in which a conventional method was used. The use of this technique was associated with a shorter operative time and no increase in the difficulty in performing associated meniscal procedures. PMID- 22104426 TI - Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection. AB - Infectious mononucleosis (IM) is one of the representative, usually benign, acute diseases associated with primary Epstein-Barr virus (EBV) infection. IM is generally self-limiting and is characterized mostly by transient fever, lymphadenopathy and hepatosplenomegaly. However, very rarely primary EBV infection results in severe or fatal conditions such as hemophagocytic lymphohistiocytosis together with fulminant hepatitis designated as severe or fatal IM or EBV-associated hemophagocytic lymphohistiocytosis alone. In addition, chronic EBV-associated diseases include Burkitt's lymphoma, undifferentiated nasopharyngeal carcinoma, Hodgkin lymphoma, T-cell lymphoproliferative disorder (LPD)/lymphoma, natural killer-cell LPD including leukemia or lymphoma, gastric carcinoma, pyothorax-associated lymphoma and senile B-cell LPD as well as chronic active EBV infection and LPD/lymphoma in patients with immunodeficiency. The number of chronic life-threatening diseases linked to the EBV infection is increasingly reported and many of these diseases have a poor prognosis. This review will focus on the historical, pathogenetic, diagnostic, therapeutic and prophylactic issues of EBV-associated life-threatening diseases. PMID- 22104427 TI - H1N1 influenza: the trigger of diabetic ketoacidosis in a young woman with ketosis-prone diabetes. AB - In this study, the authors report a case of new-onset ketosis-prone diabetes in a 21-year-old Chinese woman with H1N1 influenza, who presented with fever, polyuria and loss of appetite for 3 days before admission. She was hospitalized and diagnosed with acute-onset diabetic ketoacidosis for the first time. Her diabetes associated antibodies were negative. Interestingly, she had an unexplained fever and her white blood cell count was low at admission and remained low for several days. She was believed to have a viral infection, which was found to be H1N1 influenza infection. The literature regarding virus infection and diabetic ketoacidosis is reviewed. The precipitating factors, symptomatology, pathophysiology and management of ketosis-prone diabetes are discussed in the current case report. PMID- 22104428 TI - Bullous dermatosis associated with vancomycin extravasation. AB - Cutaneous side effects related to vancomycin therapy have been reported including histamine-related reactions, linear IgA bullous dermatosis, Stevens-Johnson syndrome, maculopapular rash and drug rash with eosinophilia and systemic symptoms. In all instances, these reports were due to the systemic administration of vancomycin and subsequent immunological reactions to the medication. Drug extravasation into soft tissues can result in a variety of clinical outcomes usually related to physiochemical properties of the drug extravasated and its diluents or pharmacologic effects on the vasculature and tissue. The authors report a patient who experienced vancomycin extravasation that resulted in a localized bullous eruption resembling linear IgA bullous dermatosis, a phenomenon not previously described in the literature. PMID- 22104429 TI - Bioprosthetic tricuspid valve stenosis in end-stage renal failure. AB - Outcome of bioprosthetic valve replacement in the tricuspid position in patients with kidney failure is unknown. The authors describe a case of accelerated bioprosthetic tricuspid valve calcification leading to critical stenosis in a patient on chronic dialysis and with poorly controlled hyperparathyroidism. He required a second valve replacement in less than 3 years from the initial tricuspid replacement surgery. Both renal failure and its associated hyperparathyroidism have been implicated in native heart valve calcification. This case suggests that bioprosthetic valves could also be at risk for rapid calcification; more frequent monitoring of prosthetic valve function may be necessary. PMID- 22104430 TI - Evaluation of cerebrospinal fluid adenosine deaminase activity for the differential diagnosis of tuberculous and nontuberculous meningitis. AB - INTRODUCTION: The diagnosis value of adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) has been well documented. However, the cutoff point of CSF ADA has not been fully assessed. In the current study, the authors set to calculate the cutoff points of ADA and monitor the changes of CSF ADA activities in patients with TBM after antitubercular therapy. METHODS: CSF ADA activity in patients with different types of meningitis was measured by Trinder enzyme-coupled assay. RESULTS: The mean CSF ADA values in the patients with TBM, bacterial meningitis, viral meningitis, cryptococcal meningitis and noninfectious neurologic disorders were 14.1 +/- 5.4, 9.6 +/- 5.5, 4.3 +/- 2.5, 7.8 +/- 3.4 and 2.6 +/- 1.3 U/L, respectively. CSF ADA activity was significantly higher in TBM compared with patients with non-TBM (P < 0.05). Moreover, the best cutoff point for differentiating between TBM and non-TBM was 9.5 U/L. In addition, CSF ADA activity was decreased in patients with TBM after antitubercular therapy in a time-dependent manner. CONCLUSIONS: The determination of ADA with a cutoff value of 9.5 U/L in CSF is a useful aid for the differential diagnosis of TBM and non TBM. Moreover, dynamic monitoring of CSF ADA activity may be an indicator for evaluating antitubercular therapy in TBM. PMID- 22104431 TI - Azygous continuation of the inferior vena cava with anomalous hepatic vein drainage. AB - A 62-year-old woman was referred for evaluation of hypoxemia. Despite a resting SaO(2) of 89%, she was otherwise asymptomatic. The arterial blood gas on room air demonstrated a pO(2) of 58 mm Hg. Two shunt studies confirmed a shunt fraction of 25%. Echocardiogram with agitated saline demonstrated bubbles in the left atrium. Nuclear perfusion study revealed no uptake over the kidneys or brain. Computed tomography of the chest and cardiac magnetic resonance imaging confirmed the presence of a large shunt (azygous continuation of the inferior vena cava [ACIVC] with anomalous hepatic vein drainage). A large shunt fraction dictates either significant cardiac septal defect or an extracardiac shunt. The finding of ACIVC should prompt consideration of other vascular or cardiac abnormalities. The true incidence of isolated ACIVC is not known, as limited ACIVC may remain asymptomatic. However, the spectrum of vascular, cardiac and somatic abnormalities that may accompany ACIVC is quite varied. PMID- 22104432 TI - Effect of obstructive sleep apnea on heart rate, heart rate recovery and QTc and P-wave dispersion in newly diagnosed untreated patients. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is associated with autonomic dysfunction, whereas increased heart rate (HR), HR recovery time (HRR 1), QT-corrected interval (QTc) and P-wave dispersion (Pd) are associated with cardiovascular events. The aim of the current investigation was to clarify the influence of OSAS severity on these cardiac parameters. METHODS: Ninety newly diagnosed and untreated patients with OSAS underwent overnight polysomnography and cardiopulmonary exercise testing, including HRR-1, echocardiography, 24-hour Holter electrocardiography, surface electrocardiogram (ECG) and measurement of several metabolic parameters. The patients were divided into the following 4 groups: 26 with apnea-hypopnea index (AHI) <5, 20 with 5 <= AHI <15, 20 with 15 <= AHI <30 and 24 with AHI >=30. QTc and Pd were calculated in all leads of the surface ECG. Mean HR was measured using 24-hour Holter ECG, and HRR-1 was measured using cardiopulmonary exercise testing. RESULTS: QTc was increased in patients with moderate-to-severe OSAS. Pd was significantly increased in patients with OSAS compared with those without OSAS. In addition, Pd was correlated with AHI and associated with the severity of disease. Mean HRs over a period of 24 hours during wakefulness and sleep correlated significantly with AHI and the lowest SpO2 in patients with OSAS, whereas HRR-1 was inversely correlated with the severity of OSAS, as expressed by AHI. CONCLUSION: We showed that HR, Pd, HRR 1 and QT-corrected time are correlated with OSAS severity. Further studies are required in order to investigate the prognostic effect of HRR-1, Pd, HR and QTc in OSAS. PMID- 22104433 TI - Estimation of stature from the foot and its segments in a sub-adult female population of North India. AB - BACKGROUND: Establishing personal identity is one of the main concerns in forensic investigations. Estimation of stature forms a basic domain of the investigation process in unknown and co-mingled human remains in forensic anthropology case work. The objective of the present study was to set up standards for estimation of stature from the foot and its segments in a sub-adult female population. METHODS: The sample for the study constituted 149 young females from the Northern part of India. The participants were aged between 13 and 18 years. Besides stature, seven anthropometric measurements that included length of the foot from each toe (T1, T2, T3, T4, and T5 respectively), foot breadth at ball (BBAL) and foot breadth at heel (BHEL) were measured on both feet in each participant using standard methods and techniques. RESULTS: The results indicated that statistically significant differences (p < 0.05) between left and right feet occur in both the foot breadth measurements (BBAL and BHEL). Foot length measurements (T1 to T5 lengths) did not show any statistically significant bilateral asymmetry. The correlation between stature and all the foot measurements was found to be positive and statistically significant (p-value < 0.001). Linear regression models and multiple regression models were derived for estimation of stature from the measurements of the foot. The present study indicates that anthropometric measurements of foot and its segments are valuable in the estimation of stature. Foot length measurements estimate stature with greater accuracy when compared to foot breadth measurements. CONCLUSIONS: The present study concluded that foot measurements have a strong relationship with stature in the sub-adult female population of North India. Hence, the stature of an individual can be successfully estimated from the foot and its segments using different regression models derived in the study. The regression models derived in the study may be applied successfully for the estimation of stature in sub adult females, whenever foot remains are brought for forensic examination. Stepwise multiple regression models tend to estimate stature more accurately than linear regression models in female sub-adults. PMID- 22104434 TI - Pathological outcomes of men eligible for active surveillance after undergoing radical prostatectomy: are results predictable? AB - INTRODUCTION: To analyze pathological results in patients with prostate cancer eligible for active surveillance (AS) after radical prostatectomy and available prediction systems. METHODS: A retrospective analysis was performed of 612 patients who underwent radical prostatectomy during a 14-year period. Subsequently, we selected those patients who would have been eligible for AS according to 2 different published criteria. Group AS-A matched the following criteria: <=T2a; Gleason Score <=6; and prostate-specific antigen <10 ng/mL, while group AS-B applied to different criteria: <=T2a; Gleason Score <7; and prostate-specific antigen <=15 ng/mL. Pathological outcomes were compared with results of the 2001 Partin tables. RESULTS: Altogether, 125 (20.4%) patients were included in group AS-A and 159 (25.9%) in group AS-B. We detected 32 cases of >pT2c (25.6%) for group AS-A and 47 cases (29.6%) for AS-B, respectively. Gleason score upgrading was recorded in 34.4% (AS-A) and 38.3% (AS-B). Results of the Partin tables showed good discrimination among patients at risk for positive lymph nodes but limited discrimination for organ-confined disease, seminal vesicle. CONCLUSIONS: Overall >25% of patients eligible for AS showed either upstaging or Gleason score upgrading, which could not be measured with the examined predictive tools. Patients should be informed about the risks of inaccurate preoperative diagnostic. PMID- 22104435 TI - Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4 tetrahydro-beta-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1. AB - New substituted (1-thioxo-1,2,3,4-tetrahydro-beta-carbolin-9-yl)acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6 methoxy-1-thioxo-1,2,3,4-tetrahydro-beta-carbolin-9-yl)acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC(50)=0.15MUM) with clinically used epalrestat (IC(50)=0.1MUM). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-beta carbolin-9-yl)acetic acid (7t), which showed strong inhibitory effect (IC(50)=0.17MUM) and very high selectivity for AKR1B1 against AKR1A1 (311:1) and AKR1B10 (253:1) compared with epalrestat. PMID- 22104436 TI - Modification of HIV-1 reverse transcriptase and integrase activity by gold(III) complexes in direct biochemical assays. AB - Gold(I) and gold(III) complexes have been previously investigated for potential biomedical applications including as anti-HIV agents. The oxidising nature of some gold(III) complexes yields well-documented cellular toxicity in cell-based assays but the effect in direct biochemical assays has not been fully investigated. In this study, gold(III) complexes were evaluated in HIV-1 reverse transcriptase and HIV-1 integrase biochemical assays. The gold(III) tetrachlorides KAuCl(4) and HAuCl(4) yielded sub-micromolar IC(50)'s of 0.947 and 0.983MUM in the direct HIV-1 RT assay, respectively, while IC(50)'s ranging from 0.461 to 8.796MUM were obtained for seven selected gold(III) complexes. The gold(III) tetrachlorides were also effective inhibitors of integrase enzymatic activity with >80% inhibition obtained at a single dose evaluation of 10MUM. RT inhibition was decreased in the presence of a reducing agent (10mM DTT) and against the M184V HIV-1 RT mutant, while none of the gold(III) complexes were effective inhibitors in cell-based antiviral assays (SI values <5.95). Taken together, the findings of this study demonstrate that gold(III) complexes modify HIV-1 enzyme activity in direct biochemical assays, most likely through protein oxidation. PMID- 22104437 TI - Resin-based investigation of acyl carrier protein interaction networks in Escherichia coli. AB - Protein-protein interactions play an integral role in metabolic regulation. Elucidation of these networks is complicated by the changing identity of the proteins themselves. Here we demonstrate a resin-based technique that leverages the unique tools for acyl carrier protein (ACP) modification with non hydrolyzable linkages. ACPs from Escherichia coli and Shewanella oneidensis MR-1 are bound to Affigel-15 with varying acyl groups attached and introduced to proteomic samples. Isolation of these binding partners is followed by MudPIT analysis to identify each interactome with the variable of ACP-tethered substrates. These techniques allow for investigation of protein interaction networks with the changing identity of a given protein target. PMID- 22104438 TI - Target identification of bioactive compounds. AB - To fully understand the regulation of cellular events, functional analysis of each protein involved in the regulatory systems is required. Among a variety of methods to uncover protein function, chemical genetics is a remarkable approach in which small molecular compounds are used as probes to elucidate protein functions within signaling pathways. However, identifying the target of small molecular bioactive compounds isolated by cell-based assays represents a crucial hurdle that must be overcome before chemical genetic studies can commence. A variety of methods and technologies for identifying target proteins have been reported. This review therefore aims to describe approaches for identifying these molecular targets. PMID- 22104439 TI - Subthalamic deep brain stimulation in Parkinson's disease under different anesthetic modalities: a comparative cohort study. AB - BACKGROUND: The efficacy and feasibility of bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease (PD) under general anesthesia (GA) has not been evaluated. OBJECTIVE: We compared the outcome of patients under GA with those who were operated on under local anesthesia (LA). MATERIAL AND METHODS: Thirty-three patients were assigned to the GA group (desflurane) and 19 patients were assigned to the LA group. Microelectrode recording (MER) was performed in both groups. The surgical outcomes of the patients were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) after at least 12 months after surgery. RESULTS: Postoperatively, there was no significant difference on the UPDRS scores in either groups. A significant deterioration in cognitive function in the GA group was observed (p = 0.017). The recorded electrode coordinates, the average tracts for the MER, and STN depth were comparable in both groups. The overall incidence of adverse effects did not show any difference except that the incidence of sialorrhea and dysarthria was significantly higher in the GA group. CONCLUSION: Desflurane GA was shown to be a good alternative anesthetic method for PD patients undergoing DBS. Although the motor outcomes were comparable, a significant cognitive decline may be seen in the GA group with a higher occurrence of stimulation side effects. PMID- 22104441 TI - Are sleep education programs successful? The case for improved and consistent research efforts. AB - Sleep duration and quality are associated with a range of neuropsychological and psychosocial outcomes in children and adolescents but community awareness of this is low. A small body of literature on sleep education programs in children and adolescents delivered through school-based programs is attempting to address this. A review of the literature found only 8 studies and 4 pilot studies in abstract form. This paper presents these sleep education programs and evaluates their effectiveness. In general, findings suggest that when sleep knowledge was measured it was increased in most programs. However this did not necessarily equate to sleep behaviour change such as increased sleep duration or improved sleep hygiene. Reasons for this are discussed and may include motivation and readiness to change, salience to the individual, delivery, content, time allocation, or methodological underpinnings. This paper attempts to understand this and assess how best to improve future sleep education programs from a theoretical perspective. Specifically, it considers the theory of planned behaviour which may assist in ensuring maximum efficacy for the current and future development of sleep education programs. PMID- 22104442 TI - [Cardiac output by pulse contour analysis and fluid responsiveness: more complex than you expect]. PMID- 22104443 TI - [French Society of Anaesthesia and Intensive Care. Guidelines on perioperative venous thromboembolism prophylaxis. Update 2011. Short text]. PMID- 22104444 TI - Structure and function of membrane-integral receptors. PMID- 22104445 TI - Keeping kinetochores on track. AB - The multiple functions of kinetochores are reflected in their complex composition, with over a hundred different proteins, which self-associate in several functional subcomplexes. Most of these kinetochore proteins were identified over the last 10-12 years using a combination of genetic, cell biological, biochemical, and bioinformatic approaches in various model organisms. The key challenge since then has been to determine the structural architecture of kinetochores, define the functions of its different subcomponents, and understand its regulation, both in response to the rapid changes in microtubule dynamics or to sense erroneous attachments for spindle checkpoint signalling. Here, we present some of the key advances obtained in the last six years on the biology of kinetochores, both through our work and through the work of many other groups studying this exciting structure. PMID- 22104446 TI - Posterior glenohumeral thermal capsulorraphy, capsular imbrication and labral repair with complication of adhesive capsulitis: a modified rehabilitation approach. AB - BACKGROUND: Isolated atraumatic posterior glenohumeral instability is rare. Use of thermal capsulorraphy for glenohumeral instability is considered controversial. This case study describes a modified rehabilitation protocol for a patient who underwent a multistep arthroscopic procedure for isolated posterior glenohumeral instability with a postoperative complication of adhesive capsulitis. CASE DESCRIPTION: A 30-y-old man with a 15-y history of bilateral posterior glenohumeral instability related to generalized hypermobility underwent right-shoulder arthroscopy consisting of a combined posterior labral repair, capsular imbrication, and thermal capsulorraphy. A gunslinger orthosis was prescribed for 6 wk of immobilization. Adhesive capsulitis was diagnosed at the 5 wk postoperative visit and immobilization was discontinued. A modified treatment protocol was devised to address both the surgical procedures performed and the adhesive capsulitis. Residual symptoms resolved with release of an adhesion while stretching 10 months postoperatively. OUTCOMES: Scores of 5 shoulder-assessment tools improved from poor to excellent/good with subjective report of a very good outcome. DISCUSSION: The complication of adhesive capsulitis required an individualized treatment protocol. In contrast to the standard protocol, our modified approach allowed more time to be spent in each phase of the program, was aggressive with restoring range of motion (ROM) without excessively stressing the posterior capsule, and allowed the patient to progress to activities that were tolerated regardless of protocol phase. Shoulder stiffness or frank adhesive capsulitis after stabilization, as in this case, requires a more aggressive modification to prevent permanent ROM limitations. Conversely, patients with early rapid gains in ROM must be protected from overstretching the repaired tissue with a program that allows functional motion to be incorporated over a longer time frame. This study indicates the use of thermal capsulorraphy as a viable surgical modality when it is used judiciously with the proper postoperative restrictions and rehabilitation. PMID- 22104447 TI - Primary human monocyte differentiation regulated by Nigella sativa pressed oil. AB - BACKGROUND: Oxidized low density lipoprotein plays an important role in development of foam cells in atherosclerosis. The study was focused on regulation of primary human monocyte growth and CD11b expression in presence of Nigella sativa oil. METHODS: Primary human monocytes were isolated from whole blood and grown at 37 degrees C and 5% CO2 saturation for five days prior to treatment with Nigella sativa oil. The cells were plated and washed before treatment with ox-LDL (10 MUg/ml) as positive control and combined treatment of ox-LDL (10 MUg/ml) and (140 ng/ml) Nigella sativa oil. The growth progression was monitored every 24 hours for 3 days. RESULTS: Macrophages showed reduced growth in comparison to monocytes 24 hours after treatment with Nigella sativa oil. The mean cell diameter was significantly different between untreated and treated condition in monocytes and macrophages (p < 0.001). Similarly, intracellular lipid accumulation was hindered in combined treatment with Nigella sativa oil. This was further supported by cell surface expression analysis, where CD11b was markedly reduced in cells treated with combination oxLDL and Nigella sativa oil compared to oxLDL alone. More cells differentiated into macrophage-like cells when monocytes were supplemented with oxidized LDL alone. CONCLUSIONS: The finding provides preliminary evidence on regulation of cell growth and differentiation in monocyte and monocyte-derived macrophages by Nigella sativa oil. Further investigations need to be conducted to explain its mechanism in human monocyte. PMID- 22104448 TI - Cerebral microbleeds: histopathological correlation of neuroimaging. AB - BACKGROUND: In recent years, there has been a growing interest in cerebral microbleeds (CMBs) and their role in cerebrovascular disease. A few studies have investigated the histopathological correlation between CMBs and neuroimaging findings. We conducted a systematic review in an attempt to characterize the pathological and radiological correlation. METHODS: A systematic literature search was conducted for studies in which CMBs were characterized histopathologically and correlated with MRI findings. RESULTS: Five studies met the inclusion criteria, with a total of 18 patients. Hemosiderin deposition was reported in 42 CMBs (49%), while 16 CMBs (19%) were described as old hematomas which stained for iron, 13 (15%) had no associated specific pathology, 11 (13%) contained intact erythrocytes, 1 (1%) was due to vascular pseudocalcification, 1 (1%) was a microaneurysm and 1 (1%) was a distended dissected vessel. Lipofibrohyalinosis was the most prominent associated vascular finding. Amyloid angiopathy was present primarily in patients with dementia. CONCLUSIONS: Although histopathological associations have been observed using MRI in patients with CMBs, the findings have yet to be validated and further research is warranted. PMID- 22104449 TI - Altered expression of NFY-C and RORA in colorectal adenocarcinomas. AB - NFY-C, a subunit of the transcription factor NFY, binds to the promoters of several eukaryotic genes, including cell cycle-related genes. RORA is a steroid hormone receptor implicated in a range of important cellular processes. We evaluated the expression of NFY-C and RORA in colorectal adenocarcinomas and normal colonic tissue. NFY-C expression was elevated in adenocarcinomas. Moreover, NFY-C mRNA levels correlated with time to disease progression, while NFY-C protein expression was significantly higher in metastatic disease. RORA expression was downregulated in CRC adenocarcinomas compared to normal controls and correlated with time to disease progression. The role of NFY-C and RORA in CRC merits further investigation. PMID- 22104450 TI - Update on the clinical management of atrial fibrillation: guidelines and beyond. AB - In clinical practice, atrial fibrillation (AF) is the most commonly encountered arrhythmia. With the aging of the US population, the number of patients with AF that physicians encounter will increase. Atrial fibrillation management involves a combination of rate- and rhythm-control strategies with thromboprophylaxis, a complicated endeavor given side effect profiles of treatments, patient comorbidities, and anticoagulation treatment requirements. Early treatment discontinuation and poor compliance with anticoagulation treatment are frequent and result in increased mortality, a 5-fold increased risk of ischemic stroke, decreased health-related quality of life, and decreased exercise capacity. In 2006, the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) provided guidelines for the management of patients with AF. Recently, the ACC Foundation, AHA, and Heart Rhythm Society released updates to these guidelines (January and February 2011). This article aims to assist physicians in improving the management of patients with AF by focusing on the main components of therapy as reflected in the guidelines, and by providing an update on new US Food and Drug Administration-approved treatments. PMID- 22104451 TI - Single-pill triple-combination therapy: an alternative to multiple-drug treatment of hypertension. AB - Hypertension (HTN) affects an estimated 76.4 million US adults. Despite improvements in blood pressure (BP) control rates and the availability of effective antihypertensive agents, only 50% of these individuals achieve BP control. It is now recognized that many patients will require >= 2 antihypertensive agents to achieve BP control. Both the current US and reappraisal of the 2007 European guidelines include dual-combination regimens among recommended treatments for initial HTN therapy. For patients requiring 3 drugs, the combination of agents with complementary mechanisms of action (ie, renin-angiotensin-aldosterone system blocker, calcium channel blocker, and diuretic) has been recognized as rational and effective. Three single-pill triple drug combinations have recently been approved for use in HTN in the United States: valsartan (VAL)/amlodipine (AML)/hydrochlorothiazide (HCTZ); olmesartan medoxomil (OM)/AML/HCTZ; and aliskiren (ALI)/VAL/HCTZ. Triple-combination regimens have resulted in a greater proportion of patients achieving BP control compared with dual-combination regimens, with significantly lower BP levels documented after only 2 weeks at maximum doses. Single-pill combinations offer convenience to address barriers to BP control such as poor adherence to therapy and therapeutic inertia. Additional benefits of combining antihypertensive agents from different classes include improved efficacy, safety, and reduction of cardiovascular risk. In patients with essential HTN for whom dual therapy is inadequate, single-pill triple-drug therapy can offer a simplified and effective treatment strategy. PMID- 22104452 TI - Adult congenital heart disease and pulmonary arterial hypertension: the Texas Adult Congenital Heart Program experience. AB - Congenital heart disease (CHD) is a common structural defect of the heart or major blood vessels. Patients with adult congenital heart disease (ACHD) have medical needs that are distinct from those of pediatric patients with CHD, and the transition into adult health care is important for management of the patient with ACHD. A large proportion of patients with CHD develop diseases and complications associated with the long-term stress of intracardiac shunts. Pulmonary arterial hypertension (PAH) is a significant complication of some CHD lesions. The treatment of these patients remains challenging due to their combined heart and lung disease, and multidisciplinary care is ofen necessitated for a variety of secondary conditions. A number of treatment options are available for the management of PAH associated with CHD, including prostanoids, phosphodiesterase type-5 inhibitors, and endothelin receptor antagonists. This article discusses the diagnosis and management of such ACHD patients with PAH. PMID- 22104453 TI - Hypertension and antihypertensive therapy in Hispanics and Mexican Americans living in the United States. AB - Hypertension is a major independent risk factor for cardiovascular diseases, which are the most frequent cause of death worldwide. In addition, the risk of hypertension has been associated with racial and/or ethnic background. Hispanics are the largest and fastest-growing minority population in the United States, currently comprising about 16.3% (50.5 million) of the total population; these numbers will continue to increase into the next 10 years. The rate of uncontrolled hypertension in Hispanics significantly exceeds the rates observed among non-Hispanic blacks and whites. The reasons for these racial and ethnic differences in blood pressure control may include factors such as lack of access to health care, low socioeconomic status, language barriers, degree of acculturation, poor doctor-patient communication, and genetic factors. This article provides an up-to-date summary of epidemiological and treatment aspects of high blood pressure in the US Hispanic population. Because Mexican Americans constitute approximately 66% of US Hispanics, data sources that focus on Mexican Americans are also discussed. PMID- 22104454 TI - Review: a single-pill combination of telmisartan plus amlodipine for the treatment of hypertension. AB - Despite an increased proportion of patients with hypertension achieving recommended blood pressure (BP) targets, BP control remains suboptimal in many patients. A range of combination therapies utilizing medications with differing mechanisms of action have been shown to provide superior BP-lowering efficacy than monotherapy with individual components. Single-pill combinations deliver improved convenience and may help to improve patient compliance. A single-pill combination of the angiotensin receptor blocker (ARB) telmisartan and the calcium channel blocker (CCB) amlodipine has recently been approved in 4 different doses (telmisartan/amlodipine 40 mg/5 mg, 40 mg/10 mg, 80 mg/5 mg, and 80 mg/10 mg) for antihypertensive use in the United States. In an 8-week clinical study (N = 1461), these combinations were superior to monotherapy with telmisartan or with amlodipine with respect to the primary endpoint, change in diastolic BP (DBP) from baseline (mean baseline BP, 153.2 [+/- 12.1]/101.7 [+/- 4.3] mm Hg) to study end (placebo-corrected reductions of 10.3, 14.0, 12.0, and 13.9 mm Hg, respectively), as well as in multiple secondary endpoints, including change in systolic BP (SBP), DBP response, SBP response, BP control (< 140/< 90 mm Hg), and DBP control (< 90 mm Hg). The telmisartan plus amlodipine combinations were well tolerated, with the incidence of adverse events similar to placebo; the incidence of peripheral edema was lower with the 40 mg/10 mg and 80 mg/10 mg combinations than with amlodipine 10 mg alone. In another study (N = 858), the highest-dose combination (80 mg/10 mg) demonstrated superior BP-lowering efficacy than same dose monotherapy with either telmisartan or amlodipine in patients with severe hypertension (SBP >= 180 and DBP >= 95 mm Hg). Single-pill telmisartan plus amlodipine combination therapy appears to be an effective and well-tolerated treatment as initial therapy for patients likely to require > 1 antihypertensive agent to reach BP targets. PMID- 22104455 TI - Impact of combination therapy with amlodipine and atorvastatin on plasma adiponectin levels in hypertensive patients with coronary artery disease: combination therapy and adiponectin. AB - BACKGROUND: In many countries, combination therapy with amlodipine and atorvastatin is indicated for the treatment of patients with hypertension and hypercholesterolemia. The aim of this study was to investigate the impact of this combination therapy on plasma adiponectin levels. HYPOTHESIS: Combination therapy with amlodipine and atorvastatin would increase plasma adiponectin levels. METHODS: A total of 25 patients with coronary artery disease and concomitant hypertension and hypercholesterolemia were evaluated. The combination of amlodipine and atorvastatin in 8 different dosage strengths were flexibly titrated over a period of 14 weeks. Lipid profile and plasma adiponectin were measured. Brachial flow-mediated dilation (FMD) was determined by vascular ultrasound. RESULTS: As compared with baseline, combination therapy with amlodipine and atorvastatin significantly reduced systolic and diastolic blood pressure, total cholesterol, and low-density lipoprotein cholesterol (all P < 0.05). Furthermore, there were significant increases in adiponectin levels (mean [95% confidence interval (CI)], 12.1 [10.7-13.7] vs 8.1 [6.5-10.0] MUg/mL; P < 0.001) and brachial FMD (4.4 +/- 0.6% vs 5.6 +/- 0.5%; P = 0.046) over 14 weeks of treatment. The change in adiponectin levels correlated significantly with the changes in diastolic blood pressure (r = -0.49; P = 0.014) and FMD (r = 0.55; P = 0.007). CONCLUSION: The results of this study indicate that along with its antihypertensive and cholesterol-lowering effects, combination therapy with amlodipine and atorvastatin appears to increase plasma adiponectin levels and improve endothelial function. PMID- 22104456 TI - Relative importance of comorbid psychological symptoms in patients with depressive symptoms following phase II cardiac rehabilitation. AB - BACKGROUND: Previous research has demonstrated a high prevalence of psychological risk factors in patients with coronary heart disease (CHD), as well as the benefits of cardiac rehabilitation (CR) on psychological distress (PD) in showing its potential to improve mortality. We examined the impact of CR on mortality by anxiety and/or hostility symptoms in a large population of CHD patients with symptoms of depression following CR. PATIENTS AND METHODS: We studied 538 patients with CHD who had completed formal CR. Using a validated questionnaire, symptoms of PD were obtained in 3 domains: anxiety, hostility, and depression. Subjects were divided into 3 groups: nondepressed (n = 502), depression alone (n = 14), and depression with anxiety and/or hostility (n = 22). A multivariate analysis for mortality was performed using a composite PD score (PD = sum of scores for anxiety, depression, and hostility). Subjects were analyzed by total mortality over 3-year follow-up by the National Death Index. RESULTS: Mortality was significantly higher in the group with depressive symptoms compared with those without depressive symptoms (19% vs 3%; P < 0.0001). The comorbid depressed group had a slight trend toward higher mortality (22.7% [5 of 22 patients] vs 14% [2 of 14 patients]; P = 0.52). After adjusting for age, body mass index (BMI), ejection fraction, exercise tolerance, and sex using Cox proportional regression, the number of psychiatric comorbidities (ie, depression, anxiety, and hostility), as well as the sum of their raw scores, were significantly associated with increased mortality. However, this effect disappeared after adjusting for depression score (comorbidity hazard ratio, 1.7; 95% confidence interval, 1.0-2.8 vs comorbidity hazard ratio, 1.2; 95% confidence interval, 0.4-3.7 after adjusting). CONCLUSION: Psychological distress is an independent predictor of mortality in stable CHD patients following CR; although anxiety and hostility may also modulate this effect, the overall impact seems to be mostly mediated through depression. Patients with persistent depression following CR may need further intervention. PMID- 22104457 TI - Evaluating the risk-benefit profile of the direct-acting P2Y(12) inhibitor ticagrelor in acute coronary syndromes. AB - Ticagrelor is a direct-acting, oral, reversibly binding P2Y(12) receptor antagonist. As a cyclopentyltriazolopyrimidine, ticagrelor represents a new chemical class of agents that do not require metabolic activation and have consistent ability to inhibit platelet aggregation. The phase 3 PLATelet Inhibition and Patient Outcomes (PLATO) trial (NCT00391872) evaluated ticagrelor compared with clopidogrel in 18 624 patients with acute coronary syndromes (ACS), and demonstrated a significant reduction in the risk of death from vascular causes/myocardial infarction (MI)/stroke with ticagrelor (9.8% vs 11.7% with clopidogrel [hazard ratio, 0.84; 95% confidence interval, 0.77-0.92]; P < 0.001) without a significant increase in PLATO-defined major bleeding (11.6% vs 11.2%, respectively; P = 0.43). Myocardial infarction and death from vascular causes were separately significantly reduced, and death from any cause and stent thrombosis reductions achieved nominal statistical significance. Ticagrelor showed benefit over clopidogrel in almost all patient subgroups, including patients who had previously received clopidogrel, patients with both planned invasive or noninvasive treatment, patients with ST-segment elevation MI (STEMI) referred for primary percutaneous coronary intervention, patients with non-STEMI, and patients who underwent bypass surgery. Hence, the PLATO population reflected specifically those patients who would ordinarily receive thienopyridine-based antiplatelet therapy in a clinical setting. Although there are limitations in directly translating trial findings to clinical practice, the findings of PLATO suggest that for every 1000 ACS patients admitted to hospital, using ticagrelor instead of clopidogrel for 12 months would result in 14 fewer deaths or 11 fewer MIs. This review places the PLATO data in context, and assesses the role that ticagrelor may play in treating patients with ACS. PMID- 22104458 TI - Strategies for venous thromboembolism prophylaxis programs. AB - Prevention of venous thromboembolism (VTE) is often overlooked in clinical practice, despite being a frequent and serious complication of various medical conditions and surgical procedures. The need to reduce hospital-acquired VTE is becoming increasingly recognized in the United States, and various quality improvement initiatives have been developed. Prevention of VTE through evidence based, practice-informed pathways includes assessing the patient's risk of VTE and provision of VTE at different stages: at admission, during hospitalization, and after hospital discharge. A multidisciplinary approach, involving physicians working with pharmacists, nurses, and other staff, can ensure that VTE prevention is routinely addressed. Patients admitted to hospitals should undergo VTE risk assessment, and the appropriate dose, type, and duration of medication should be administered with regular monitoring for VTE events and bleeding complications. Venous thromboembolism risk assessment should continue throughout hospitalization with appropriate prophylaxis when necessary. Patients may need to continue anticoagulation into the outpatient setting to achieve adequate prophylaxis duration. Useful approaches to ensure successful transition of care include patient education and support, with the accurate and timely transfer of information from the hospital to the primary care physician. Various strategies and tools are available to help physicians establish good VTE practices at each stage, including risk assessment models, reminders, clinical decision support systems, educational programs, and online resources, such as those from the Society of Hospital Medicine. Effective use of these strategies by physicians, with the engagement and support of nurses and pharmacists, should help to improve current practices and to reduce the considerable burden of VTE. PMID- 22104459 TI - Updating the role of natriuretic peptide levels in cardiovascular disease. AB - Heart disease affects 1 in 3 individuals in the United States, and the prevalence of heart failure (HF) is increasing exponentially. Although our understanding of the disease progression of congestive HF (CHF) has advanced, refining the areas of diagnosis, risk stratification, prognosis, and treatment is still needed. The natriuretic peptides, specifically B-type natriuretic peptide (BNP) and N terminal pro-B-type natriuretic peptide (NT-proBNP), have shown promise in clinical practice. Brain natriuretic peptide is released from cardiac ventricular myocytes in response to volume or pressure overload. Rapid measurement of plasma BNP or NT-proBNP has been shown to increase the diagnostic accuracy of HF exacerbations. A cutoff value of 100 pg/mL has a sensitivity and specificity of 90% and 73%, respectively, according to the Breathing Not Properly Study. In addition, BNP and NT-proBNP have been considered independent predictors of adverse outcome. One study calculated a 35% increase in risk of death due to HF for every 100-pg/mL increase in BNP level. Lastly, natriuretic peptides have been known to decrease following medical therapy of HF, suggesting the role of their measurement in monitoring inpatient disease progression and outpatient medical programs. The future of natriuretic peptides lies in risk stratification in other cardiac diseases, such as acute coronary syndrome, and possibly determining severity of valvular disease. Although there is substantial work done in elucidating the power of natriuretic peptides in clinical practice, more research is necessary to reach a consensus regarding how to appropriately utilize them in treatment regimens. PMID- 22104460 TI - Intensive glycemic control and cardiovascular disease: are there patients who may benefit? AB - Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Recent major publications, such as the Action to Control Cardiovascular Risk in Diabetes trial, the Advance in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial, and the Veterans Affairs Diabetes Trial, found that intensive glucose control in patients with T2DM did not reduce CVD outcomes. However, in this article, we review observational studies and clinical trials that, on aggregate, indicate how glucose lowering appears to reduce risks of CVD in certain subgroups, but can be harmful in other individuals. Based on available evidence, we suggest that younger patients with a shorter duration of T2DM, without CVD, and with few comorbid conditions may experience the greatest cardiovascular benefit from intensive glucose control. In contrast, more aggressive glucose lowering in older patients with a longer duration of T2DM, a history of CVD, and/or multiple comorbidities does not translate to reduced cardiovascular events, and may cause harm. The target goal and therapeutic strategy for intensive glucose control should be established for each individual after a careful review of his or her medical and psychosocial history, and should not reflect a "one-size-fits-all" approach. PMID- 22104461 TI - A critical assessment of opioid treatment adherence using urine drug testing in chronic pain management. AB - OBJECTIVE: To determine the current status of performing urine drug tests (UDTs) for monitoring chronic pain therapy, with an emphasis on their use in opioid treatment and the need for improved physician education about UDTs. RESULTS: Although opioids are commonly used in the treatment of chronic pain, their use is associated with an increased risk for drug abuse, addiction, diversion, and overdose in chronic pain patients. Thus, adherence with opioid therapy is central to optimal chronic pain management. Patient observation (ie, early refills, pill counts, etc.) is the least effective method of assessing opioid medication adherence. Urine drug tests, such as point-of-care (POC) tests and laboratory urine tests (LUTs) employing gas chromatography/mass spectrometry or liquid chromatography mass spectrometry and liquid chromatography tandem mass spectrometry, have recently been used. Point-of-care immunoassays are commonly used to assess treatment adherence, especially in primary care. However, POC tests are less specific and less sensitive than LUTs and are more likely to give false-negative or false-positive results, increasing the risk of excluding a patient from therapy due to an erroneous diagnosis. In contrast, LUTs provide quantitative measurement of a wider range of medications and their metabolites, and represent a more precise tool for monitoring drug adherence. They are, however, more difficult to interpret and more expensive. Physicians are generally unaware of the relative merits of POC tests and LUTs, their implementation, and interpretation of adherence data. CONCLUSION: Despite the acknowledged utility of UDTs, there is a critical need for physician education on the use of different UDTs for adherence monitoring because early detection of opioid nonadherence is key to optimal chronic pain management. PMID- 22104462 TI - Chronic pain: reducing costs through early implementation of adherence testing and recognition of opioid misuse. AB - OBJECTIVE: To review the literature on costs associated with chronic pain therapy and to identify key contributing factors. Also, to assess the potential cost saving benefits of monitoring pain treatment adherence using urine drug tests (UDTs), emphasizing their use in opioid therapy. RESULTS: Reduced productivity, compensation costs, and treatment of comorbid conditions related to chronic pain contribute to the substantial financial burden of chronic pain management in the United States. The growing use of opioids for chronic pain increases the risk for drug nonadherence and associated drug abuse, potential addiction, and aberrant drug-related behaviors (ADRBs). Treatment of drug abuse increases health care costs; opioid abusers are 25 times more likely to require hospitalization than nonopioid abusers. Early detection of patient nonadherence using UDTs could significantly reduce costs of chronic pain therapy by allowing the physician to identify and treat patients' ADRBs related to controlled substances and drug addiction and abuse problems. Adherence in chronic pain may be determined by point-of-care (POC) tests, and more sensitive laboratory urine tests employing gas chromatography/mass spectrometry with high-performance liquid chromatography tests (LUTs). Cost-benefit studies suggest that the cost of LUTs to optimize adherence may reduce costs associated with nonadherence, such as inpatient clinical care and patient self-release. Current estimates indicate that appropriate use of LUTs could produce decreases up to 14.8-fold in the cost of chronic pain therapy. CONCLUSIONS: The cost benefits of UDTs can only be fully realized if physicians know how to define and detect various types of drug abuse, addiction, and diversion. Physicians should be educated on the proper implementation of POC tests and LUTs, and interpretation of adherence data. Early monitoring of drug adherence using POC tests and follow-up LUTs may provide substantial cost savings associated with health care issues incurred in nonadherent chronic pain patients, especially those taking opioid therapy. PMID- 22104463 TI - Coanalgesics for chronic pain therapy: a narrative review. AB - Chronic pain is inadequately treated in many patients, which has led clinicians and researchers to investigate new indications for existing medications with pain relieving or adjuvant properties. These medications are known as coanalgesics. This review provides an evidence-based overview of select coanalgesics that are used in clinical practice for a variety of neuropathic and musculoskeletal pain disorders. The coanalgesics include antidepressants, anticonvulsants, topical agents, skeletal muscle relaxants, and antispasmodic agents. An update on emergent treatments and uses is also presented. The goals of this article are to highlight coanalgesic treatment options that are currently available for patients with chronic pain as well as provide guidelines for their use in clinical practice. PMID- 22104464 TI - Treatment and prophylaxis of gout flare in the clinic: an office-based approach to gout management. AB - Gout is an often-overlooked and undertreated inflammatory arthritis that is most frequently managed in the primary care office. Its initial clinical presentation may include acute-onset pain that is most typically associated with the big toe (podagra) or knee. Most patients with gout can be successfully treated from the primary care physician's office with little or no need for referral to a rheumatology practice. Prompt recognition, diagnosis, and management can greatly improve the lives of patients with gout. Patient education is important; addressing modifiable risk factors promptly after initial presentation can arrest the development of serious debilitating effects and improve, or occasionally replace, pharmacologic intervention. This article will discuss the epidemiology, pathophysiology, and diagnosis of gout, as well as management of the acute flare and management of chronic gout with urate-lowering therapy, including prophylaxis. PMID- 22104465 TI - Evolution of treatment for diabetic nephropathy: historical progression from RAAS inhibition and onward. AB - The past 2 decades have brought rapid advances in treatment options for chronic kidney disease; however, even with the best treatment, the decline of renal function and progression to end-stage renal disease (ESRD) continues in a significant number of patients. The prognosis of patients with diabetes and ESRD is grim, with < 50% of patients surviving beyond 5 years after diagnosis. Therefore, early recognition and optimal use of available interventions are essential, and research into newer therapeutic targets is needed. This article will review recent advances in our understanding of renal pathophysiology, summarize the evidence to date supporting current treatment options for diabetic nephropathy, and highlight new options that lie on the horizon for the treatment of diabetic kidney disease. PMID- 22104466 TI - Diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide compared with placebo for the treatment of osteoarthritis: pooled safety results. AB - Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2-selective inhibitors are frequently recommended for management of osteoarthritis (OA). However, serious gastrointestinal and cardiovascular systemic adverse events (AEs) are associated with oral NSAIDs and can be treatment limiting. The efficacy of diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide (TDiclo) has been established as superior to placebo and comparable with oral NSAIDs in the management of OA. This study characterizes the safety and tolerability profile of TDiclo compared with placebo through a pooled analysis of data from 1252 patients in 7 randomized controlled trials across 61 centers in the United States and 97 centers in Canada. Patients received TDiclo (n = 911) or placebo (n = 341) for 4 to 12 weeks for management of OA of the hand or knee. The most frequently reported AE was dry skin, occurring in 33.0% of patients receiving TDiclo and 5.0% of patients receiving placebo (P < 0.001). Dyspepsia was the most common gastrointestinal reaction, reported by 7.7% of patients receiving TDiclo and 2.9% of patients receiving placebo (P = 0.002). Changes in vital signs and laboratory assessments of hepatic and renal function were similar between the 2 groups; TDiclo did not increase mean blood pressure, nor was it associated with hypertension. The rate of serious AEs favored placebo in both groups (0.9% for TDiclo vs 1.5% for placebo; P = 0.358), as did the rate of severe AEs (4.4% vs 7.6%; P = 0.023). The most common reason for study discontinuation was dry skin (2.5% vs 0.3%). Results from this analysis suggest that TDiclo is well tolerated in a large population and may offer an alternative to oral NSAID therapy for OA of the knee or hand, particularly for patients at increased risk for serious systemic AEs. Larger head-to-head, long-term, multicenter trials would be beneficial to further evaluate safety data comparing both topical and oral NSAIDs. PMID- 22104467 TI - The pharmacologic basis for clinical differences among GLP-1 receptor agonists and DPP-4 inhibitors. AB - The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP 4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4% 1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP 4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors. PMID- 22104468 TI - Transient receptor potential vanilloid type 1 and pain development. AB - Transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated cation channel, is a polymodal nocitransducer widely expressed within pain transmitting/modulating areas of the peripheral and central nervous system. TRPV1 is both activated and sensitized by inflammatory endogenous mediators during inflammatory pain conditions and appears to be up regulated in neuropathic pain conditions. Owing to its role as pain integrator, its widespread expression in pain neuraxis and its involvement in pain development TRPV1 offers an exciting opportunity for therapeutic interventions in pain management. In particular, its supraspinal expression within the antinociceptive descending pathway, which includes periaqueductal grey (PAG) and rostral ventromedial medulla (RVM), represents an endogenous switch for extinguishing pain in pathological conditions. PMID- 22104469 TI - Progressive hearing loss after completion of cisplatin chemotherapy is common and more pronounced in children without spontaneous otoacoustic emissions before chemotherapy. AB - OBJECTIVE: High frequency hearing loss following cisplatin chemotherapy is frequent in children and often necessitates the fitting of hearing aids. During therapy, hearing is usually monitored. Post-therapeutic follow-up does not routinely include monitoring of hearing, although there are indications that hearing thresholds can decline after therapy. METHODS: Pure-tone audiograms taken from 27 children (17 males, 10 females) treated with cisplatin at Muenster university hospital (mean age 9.84 years, standard deviation 3.67 years) including an audiological follow-up at least 6 months after therapy, were analyzed retrospectively. RESULTS: In follow-up tests after completion of therapy, 24.1% of all ears showed an increase in mean high frequency hearing thresholds (4-8 kHz). Post-therapeutic hearing deterioration was significant at 4 kHz and significantly more pronounced in children without measurable spontaneous otoacoustic emissions (SOAE) before therapy. Post-therapeutic hearing deterioration did not occur in ears with normal pure tone thresholds (<= 10dB at all frequencies) after cisplatin therapy. No correlation was found between post therapeutic hearing deterioration and cranial irradiation. CONCLUSIONS: Cisplatin chemotherapy follow-up should include audiological monitoring in all children with elevated pure tone thresholds after therapy. Routine SOAE measurements taken as part of baseline audiometry before the start of chemotherapy can be taken into consideration. PMID- 22104470 TI - Screening for pre-school and school-age hearing problems: European Consensus Statement. AB - OBJECTIVES: To formulate consensus statement and policies on structured hearing screening programs in pre-school and school-age children in Europe. This consensus will be brought before the European Union's Member States as a working and effective program with recommendations for adoption. METHODS: A distinguished panel of experts discussed hearing screening of pre-school and school-age children during the 10th Congress of European Federation of Audiology Societies (EFAS), held in Warsaw, Poland, on June 22, 2011. The panel included experts in audiology, otolaryngology, communication disorders, speech language pathology, education and biomedical engineering. RESULTS: Consensus was reached on thirteen points. Key elements of the consensus, as described herein, are: (1) defining the role of pre-school and school screening programs in the identification and treatment of hearing problems; (2) identifying the target population; (3) recognizing the need for a quality control system in screening programs. CONCLUSIONS: The European Consensus Statement on Hearing Screening of Pre-school and School-age Children will encourage the appropriate authorities of the various countries involved to initiate hearing screening programs of pre-school and school-age children. PMID- 22104471 TI - Cerebral perfusion pressure and intracranial pressure are not surrogates for brain tissue oxygenation in traumatic brain injury. AB - OBJECTIVE: Utilization of brain tissue oxygenation (pBtO(2)) is an important but controversial variable in the treatment of traumatic brain injury (TBI). We evaluated the correlation between pBtO(2)/CPP and pBtO(2)/ICP and determined the parameter most closely related to survival. METHODS: Consecutive, adult patients with severe TBI and pBtO(2) monitors were retrospectively identified. Time indexed measurements of pBtO(2), CPP and ICP were collected and correlation coefficients were determined. Patients were then stratified according to survival and pBtO(2), CPP and ICP values were compared between groups. RESULTS: There were 4169 time-indexed data points (i.e., pBtO(2) with respective CPP and ICP values) in 15 patients. The cohort consisted of a mean age of 37+/-17 years, ISS of 27+/ 7 and GCS of 4.5+/-1.5. Survival was 53% (8/15). In a normal regression models, neither the ICP (p=0.58) nor the CPP (p=0.71) predict pBtO(2) significantly. There was a significant difference in pBtO(2) in survivors (31.5+/-3.1 vs. 25.2+/ 4.8, p=0.010) but not in CPP or ICP. Survivors had a lower proportion of time with pBtO(2)<25 mmHg [20% (3.4-44.6) vs. 40% (16.2-89), p=0.049]. In contrast, survivors had a greater proportion of time with CPP<70 and no difference in the proportion of time with and ICP>20. CONCLUSIONS: CPP and ICP should not be used as surrogates for pBtO(2) since cerebral oxygenation varies independently of cerebral hemodynamics and pressures. Brain tissue oxygen monitoring in patients with TBI provides unique information regarding cerebral oxygenation the utility of which remains to be fully described. SIGNIFICANCE: CPP and ICP are not surrogates for pBtO(2). Brain tissue oxygenation monitoring provides unique information for the treatment of traumatically injured patients. PMID- 22104472 TI - Intra-operative monitoring of lower extremity motor-evoked potentials by direct cortical stimulation. AB - OBJECTIVE: Motor-evoked potentials (MEPs) are commonly recorded from upper extremity muscles, whereas lower-extremity MEP (LE-MEP) monitoring has not been adequately established. The goal of the study was to develop a MEP monitoring method using direct cortical stimulation (DCS) for predicting motor deficits of lower extremities. METHODS: Intra-operative LE-MEP monitoring was performed in 22 patients. After craniotomy, a subdural electrode was placed on the cortex so that the optimal contact was positioned 2 cm lateral from the midline on the motor cortex. The electrodes for stimulation consisted of a cathode at Fpz and an anode at the optimal contact site on the motor cortex. After stimulation was performed with short trains of five stimuli, LE-MEPs were recorded from the lower-limb muscles. RESULTS: LE-MEPs were consistently recorded in all patients. Disappearance or amplitude reduction of MEP waveforms was observed in five patients, but the MEP waveforms had recovered and remained at the control level by dural closure, and no permanent motor deficit was observed in any patient. CONCLUSIONS: We accomplished LE-MEP recording during supratentorial surgery using monopolar DCS with a subdural electrode placed on the convex side of the motor cortex. SIGNIFICANCE: A useful method of intra-operative LE-MEP recording was described. PMID- 22104473 TI - Universal screening for meticillin-resistant Staphylococcus aureus in acute care: risk factors and outcome from a multicentre study. AB - BACKGROUND: A Health Technology Assessment (HTA) model on effectiveness of meticillin-resistant Staphylococcus aureus (MRSA) screening in Scotland suggested that universal screening using chromogenic agar was the preferred option in terms of effectiveness and cost. AIM: To test the model's validity through a one-year pilot-study. METHOD: A large one-year prospective cohort study of MRSA screening was carried out in six acute hospitals in NHS Scotland, incorporating 81,438 admissions. Outcomes (MRSA colonization and infection rates) were subjected to multivariable analyses, and trends before and after implementation of screening were compared. FINDINGS: The initial colonization prevalence of 5.5% decreased to 3.5% by month 12 of the study (P < 0.0001). Colonization was associated with the number of admissions per patient, specialty of admission, age, and source of admission (home, other hospital or care home). Around 2% of all admissions with no prior history of MRSA infection or colonization tested positive. Those who were screen positive on admission and not previously known positive were 12 times more likely than those who screened negative to develop infection, increasing to 18 times if they were both screen positive and previously known positive. MRSA infections (7.5 per 1000 inpatient-days overall) also reduced significantly over the study year (P = 0.0209). CONCLUSION: The risk factors identified for colonization and infection indicate that a universal clinical risk assessment may have a role in MRSA screening. PMID- 22104474 TI - A two-stage algorithm for Clostridium difficile including PCR: can we replace the toxin EIA? AB - A two step, three-test algorithm for Clostridium difficile infection (CDI) was reviewed. Stool samples were tested by enzyme immunoassays for C. difficile common antigen glutamate dehydrogenase (G) and toxin A/B (T). Samples with discordant results were tested by polymerase chain reaction detecting the toxin B gene (P). The algorithm quickly identified patients with detectable toxin A/B, whereas a large group of patients excreting toxigenic C. difficile but with toxin A/B production below detection level (G(+)T(-)P(+)) was identified separately. The average white blood cell count in patients with a G(+)T(+) result was higher than in those with a G(+)T(-)P(+) result. PMID- 22104475 TI - Unexpected absence of meticillin-resistant Staphylococcus aureus nasal carriage by healthcare workers in a tertiary hospital in Kenya. AB - Healthcare workers (HCWs) are a major reservoir of meticillin-resistant Staphylococcus aureus (MRSA). A cross-sectional study was conducted between July and December 2010 to determine the prevalence of nasal carriage of MRSA at the Aga Khan University Hospital Nairobi. Nasal swabs were taken from 246 randomly selected HCWs. MRSA was identified using both phenotypic and genotypic methods. The prevalence of MRSA carriage was 0% [95% confidence interval (CI): 0-1.5%] whereas that of meticillin-susceptible Staphylococcus aureus was 18.3% (95% CI: 14.0-23.6%). Given the absence of MRSA in our hospital, screening HCWs should be limited to an outbreak setting. PMID- 22104476 TI - A suggestive diagnosis of uterine arteriovenous fistula based on ultrasonography and hysteroscopy. PMID- 22104477 TI - Maternal serum protein S forms in pregnancies complicated by intrauterine growth restriction. AB - OBJECTIVES: The clinical relevance of protein S deficiency in pregnant women remains controversial. Major debate exists regarding which parameter (total protein S antigen, free protein S antigen or functional protein S) should be evaluated in order to define protein S deficiency. The present study aimed to identify which of these parameters correlate with intrauterine growth restriction (IUGR). STUDY DESIGN: A retrospective case-control study of women with IUGR (n=27) and healthy controls (n=123) in the third trimester of pregnancy. RESULTS: The maternal serum of women in the IUGR group had significantly lower levels of functional and free protein S compared with the control group: 54.07 +/- 24.72% vs 65.20 +/- 17.95% (p<0.005) and 42.88 +/- 11.01% vs 56.64 +/- 13.30% (p<0.0001), respectively. No significant correlation was found between total protein S and IUGR. CONCLUSIONS: Levels of functional and free protein S are correlated with IUGR. PMID- 22104478 TI - Toluidine blue staining in the diagnosis of endometrial pathologies: a preliminary study before chromohysteroscopy. AB - OBJECTIVE: To assess the efficacy of toluidine blue (TBlue) staining in the detection of endometrial premalignant or malignant lesions in uterine specimens obtained from hysterectomies. We hoped that the results of this preliminary study would help us in our future studies which may be on chromohysteroscopy. STUDY DESIGN: We developed an endometrium staining technique in which TBlue solution was used as a vital dye. The study enrolled 50 patients. Of these, 20 patients known to have a premalign or malign lesion of the uterus constituted the study group and 30 patients were recruited as the control group who were operated for leiomyoma of the uterus. Immediately after hysterectomy, all specimens were dyed with TBlue solution and a frozen section procedure was performed on the positively stained areas. The pre- and post-operative histopathological diagnoses of the participants were compared and the reliability of the new method was calculated. RESULTS: The sensitivity of TBlue staining in the determination of endometrial pathologies was 100% (95%, CI 0.83-1) with a specificity of 90% (95%, CI 0.74-0.96). As a diagnostic test, the positive predictive value (PPV) was 87% with a negative predictive value (NPV) of 100%. The positive likelihood ratio (+LR) was 10 (95%, CI 3.41-29.2). CONCLUSIONS: Our preliminary results demonstrated that TBlue staining of endometrium is a reliable and highly sensitive technique that may be used in the frozen section examination of uterine specimens if a malignancy is suspected. Moreover, TBlue staining of endometrium may prove useful in hysteroscopy, although the technique, interpretation, and indications require further studies. PMID- 22104479 TI - The surgical rectus sheath block for post-operative analgesia: a modern approach to an established technique. AB - OBJECTIVE: To describe the surgical rectus sheath block for post-operative pain relief following major gynaecological surgery. TECHNIQUE: Local anaesthetic (20 ml 0.25% bupivacaine bilaterally) is administered under direct vision to the rectus sheath space at the time of closure of the anterior abdominal wall. STUDY DESIGN: We conducted a retrospective case note review of 98 consecutive patients undergoing major gynaecological surgery for benign or malignant disease who received either standard subcutaneous infiltration of the wound with local anaesthetic (LA, n=51) or the surgical rectus sheath block (n=47) for post operative pain relief. MAIN OUTCOME MEASURES: (1) Pain scores on waking, (2) duration of morphine-based patient controlled analgesia (PCA), (3) quantity of morphine used during the first 48 post-operative hours and (4) length of post operative stay. RESULTS: The groups were similar in age, the range of procedures performed and the type of pathology observed. Patients who received the surgical rectus sheath block had lower pain scores on waking [0 (0-1) vs. 2 (1-3), p<0.001], required less morphine post-operatively [12 mg (9-26) vs. 36 mg (30 48), p<0.001], had their PCAs discontinued earlier [24h (18-34) vs. 37 h (28-48), p<0.001] and went home earlier [4 days (3-4) vs. 5 days post-op (4-8), p<0.001] [median (interquartile range)] than patients receiving standard subcutaneous local anaesthetic into the wound. CONCLUSIONS: The surgical rectus sheath block appears to provide effective post-operative analgesia for patients undergoing major gynaecological surgery. A randomised controlled clinical trial is required to assess its efficacy further. PMID- 22104480 TI - Road traffic crashes and prescribed methadone and buprenorphine: a French registry-based case-control study. AB - BACKGROUND: Opioids have been shown to impair psychomotor and cognitive functioning in healthy volunteers with no history of opioid abuse. Few or no significant effects have been found in opioid-dependant patients in experimental or driving simulation studies. The risk of road traffic crash among patients under buprenorphine or methadone has not been subject to epidemiological investigation so far. The objective was to investigate the association between the risk of being responsible for a road traffic crash and the use of buprenorphine and methadone. METHODS: Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Case-control analysis comparing responsible versus non responsible drivers was conducted. RESULTS: 72,685 drivers involved in an injurious crash in France over the July 2005-May 2008 period, were identified by their national health care number. The 196 drivers exposed to buprenorphine or methadone on the day of crash were young, essentially males, with an important co-consumption of other substances (alcohol and benzodiazepines). Injured drivers exposed to buprenorphine or methadone on the day of crash, had an increased risk of being responsible for the crash (odds ratio (OR)=2.02, 95% confidence interval (CI): 1.40 and 2.91). CONCLUSIONS: Users of methadone and buprenorphine were at increased risk of being responsible for injurious road traffic crashes. The increased risk could be explained by the combined effect of risky behaviors and treatments. PMID- 22104481 TI - Isolation, identification and characterization of a novel triazophos-degrading Bacillus sp. (TAP-1). AB - A novel triazophos-degrading Bacillus sp., TAP-1, was isolated from sewage sludge in a wastewater treating system of organophosphorus pesticide produced by Funong Group Co. in Jianou, Fujian, southeastern China. The isolate is a gram-positive and rod-shaped bacterium capable of hydrolyzing insecticide triazophos and was identified as a strain of Bacillus using polyphasic taxonomy combined with analysis of the morphological and physio-biochemical properties. TAP-1 could degrade triazophos through co-metabolism. When fed with nutrients such as yeast extract, peptone and glucose, TAP-1 could degrade 98.5% of TAP in the medium (100 mg/l) within 5 days. The optimal pH and temperature for the degradation were 6.5 8 and 32 degrees C, respectively. An enzyme distribution experiment showed that the enzyme responsible for TAP degradation appeared to be intracellular. PMID- 22104482 TI - Physical and rehabilitation medicine (PRM) care pathways: "stroke patients". AB - This document is part of a series of documents designed by the French Physical and Rehabilitation Medicine Society (SOFMER) and the French Federation of PRM (FEDMER). These documents describe the needs for a specific type of patients; PRM care objectives, human and material resources to be implemented, chronology as well as expected outcomes. "Care pathways in PRM" is a short document designed to enable the reader (physicians, decision-maker, administrator, lawyer or finance manager) to quickly apprehend the needs of these patients and the available therapeutic care structures for proper organization and pricing of these activities. Stroke patients are divided into four categories according to the severity of the impairments, each one being treated according to the same six parameters according to the International Classification of Functioning, Disability and Health (WHO), while taking into account personal and environmental factors that could influence the needs of these patients. PMID- 22104483 TI - [Cholelithiasis in infants, children and adolescents]. AB - The prevalence of cholelithiasis is estimated within 0.13% and 2% of children under 19 years of age. Pigment stones are the commonest type of gallstones in children, without recognizable predisposing factors in infants or secondary to a predisposing disease such as chronic hemolysis and ileal disease in children. In adolescents, idiopathic cholesterol gallstones accounts for the majority, such as in adults. Gallbladder stones are found in 80 to 90% of cases and common bile duct stones in 10 to 20% of cases. When common bile duct stones are found, a choledocal cyst with anomalous pancreatobiliary duct junction needs to be excluded. Magnetic resonance cholangiopancreatography should be performed in first line. Cholecystectomy is not indicated for silent gallstones, except in children with a predisposing disease such as chronic hemolysis. Treatment of common bile duct stones includes interventional radiologic, endoscopic or surgical procedures. Stone extraction may be performed at endoscopic retrograde cholangiopancreatography with or without sphincterotomy, combined with laparoscopic cholecystectomy. In children without a predisposing disease or no residual gallstones indicating a cholescystectomy, conservative management (percutaneous cholangiography with biliary drainage) may be proposed in specialised centers, especially for infants. A hepaticojejunostomy is indicated in cases of choledocal cyst with anomalous pancreatobiliary duct junctions. PMID- 22104484 TI - Using actigraphy versus polysomnography in the clinical assessment of chronic insomnia (retrospective analysis of 27 patients). AB - AIM: The current study was conducted in order to investigate whether several different methods of characterizing sleep and insomnia symptoms produce different diagnoses. METHOD: To this aim, we performed a retrospective study in order to compare the outcome of the assessment obtained using actigraphy with that obtained using polysomnography (PSG) in 27 outpatients complaining of chronic insomnia. Subjects were recruited from a database consisting of patients referred to the sleep centre of the Hotel-Dieu Hospital (Paris) complaining of chronic insomnia. Patients were divided into different groups with regard to type of insomnia. RESULTS: As far as type of insomnia was concerned, the comparison between actigraphy and PSG showed quite a good contingency coefficient value (C=0.64). CONCLUSION: Although this was a preliminary and retrospective study, our results seemed to indicate that actigraphy and PSG were able to lead to a similar output particularly with regard to type of insomnia. Beyond PSG, actigraphy might have a clinical utility in assessing sleep disorders in adults complaining of chronic insomnia. PMID- 22104485 TI - [Ovarian-vein thrombosis]. PMID- 22104486 TI - [Thyroid cancer screening: is it useful?]. AB - Differentiated thyroid cancer has a good overall prognosis, however, unfavourable evolution may be observed in cases discovered at an advanced stage. Thyroid cancer incidence has increased in occidental countries over the last 20 years without any significant change in mortality. This has been partially related to changes in diagnostic procedures with an increased detection of small cancers. Indeed, microcarcinomas (less than 10mm diameter), frequently incidentally discovered are now, the most frequent form of thyroid cancer, representing around 40 % of cases. Their prognosis is excellent and the benefit of their surgical management remains to be demonstrated. Unexpectedly, the proportion of large thyroid cancer at diagnosis has remained stable representing around 20 % of cases. These forms are responsible of most of the thyroid cancer specific mortality and an intensification of their clinical screening is necessary. By contrast, a systematic ultrasonographic screening of thyroid nodules should increase the proportion of small thyroid cancers without evidence of an earlier diagnosis of advanced forms and the ratio cost-benefit of such a strategy should be properly evaluated. PMID- 22104487 TI - Mechanical ventilation during acute lung injury: current recommendations and new concepts. AB - Despite a very large body of investigations, no effective pharmacological therapies have been found to cure acute lung injury. Hence, supportive care with mechanical ventilation remains the cornerstone of treatment. However, several experimental and clinical studies showed that mechanical ventilation, especially at high tidal volumes and pressures, can cause or aggravate ALI. Therefore, current clinical recommendations are developed with the aim of avoiding ventilator-induced lung injury (VILI) by limiting tidal volume and distending ventilatory pressure according to the results of the ARDS Network trial, which has been to date the only intervention that has showed success in decreasing mortality in patients with ALI/ARDS. In the past decade, a very large body of investigations has determined significant achievements on the pathophysiological knowledge of VILI. Therefore, new perspectives, which will be reviewed in this article, have been defined in terms of the efficiency and efficacy of recognizing, monitoring and treating VILI, which will eventually lead to further significant improvement of outcome in patients with ARDS. PMID- 22104488 TI - [The drug and human: pharmakon to the modern drug]. PMID- 22104489 TI - 2.5-year-olds use cross-situational consistency to learn verbs under referential uncertainty. AB - Recent evidence shows that children can use cross-situational statistics to learn new object labels under referential ambiguity (e.g., Smith & Yu, 2008). Such evidence has been interpreted as support for proposals that statistical information about word-referent co-occurrence plays a powerful role in word learning. But object labels represent only a fraction of the vocabulary children acquire, and arguably represent the simplest case of word learning based on observations of world scenes. Here we extended the study of cross-situational word learning to a new segment of the vocabulary, action verbs, to permit a stronger test of the role of statistical information in word learning. In two experiments, on each trial 2.5-year-olds encountered two novel intransitive (e.g., "She's pimming!"; Experiment 1) or transitive verbs (e.g., "She's pimming her toy!"; Experiment 2) while viewing two action events. The consistency with which each verb accompanied each action provided the only source of information about the intended referent of each verb. The 2.5-year-olds used cross situational consistency in verb learning, but also showed significant limits on their ability to do so as the sentences and scenes became slightly more complex. These findings help to define the role of cross-situational observation in word learning. PMID- 22104490 TI - The comprehension of anomalous sentences: evidence from structural priming. AB - We report three experiments investigating how people process anomalous sentences, in particular those in which the anomaly is associated with the verb. We contrast two accounts for the processing of such anomalous sentences: a syntactic account, in which the representations constructed for anomalous sentences are similar in nature to the ones constructed for well-formed sentences; and a semantic account, in which the representations constructed for anomalous sentences are erroneous, or altogether missing, and interpretation is achieved on the basis of semantic representations instead. To distinguish between these accounts, we used structural priming. First, we ruled out the possibility that anomaly per se influences the magnitude of the priming effect: Prime sentences with morphologically incorrect verbs produced similarly enhanced priming (lexical boost) to sentences with the same correct verbs (Exp. 1). Second, we found that prime sentences with a novel verb (Exp. 2) or a semantically and syntactically incongruent verb (Exp. 3) produced a priming effect, which was the same as that produced by well-formed sentences. In accord with the syntactic account, we conclude that the syntactic representations of anomalous sentences are similar to those constructed for well-formed sentences. Our results furthermore suggest that lexically-independent syntactic information is robust enough to produce well formed syntactic representations during processing without requiring aid from lexically-based syntactic information. PMID- 22104492 TI - Symptomatic and asymptomatic candidiasis in a pediatric intensive care unit. AB - INTRODUCTION: This study aimed to examine the incidence, epidemiology, and clinical characteristics of symptomatic and asymptomatic candidiasis in a pediatric intensive care unit (PICU), and to determine the risk factors associated with symptomatic candidiasis. METHODS: This retrospective study included 67 patients from a 7-bed PICU in a tertiary care hospital that had Candida-positive cultures between April 2007 and July 2009. Demographic and clinical characteristics of the patients, Candida isolates, antimicrobial and antifungal treatments, and previously identified risk factors for symptomatic candidiasis were recorded, and symptomatic and asymptomatic patients were compared. RESULTS: In all, 36 (53.7%) of the patients with Candida-positive cultures had asymptomatic candidiasis and 31 (46.3%) had symptomatic candidiasis. Candida albicans was the most common Candida sp. in the asymptomatic patients (n = 20, 55.6%), versus Candida parapsilosis in the symptomatic patients (n = 15, 48.4%). The incidence of central venous catheter indwelling, blood transfusion, parenteral nutrition, and surgery was higher in the symptomatic patient group than in the asymptomatic patient group (P < 0.5). Surgery was the only independent predictor of symptomatic candidiasis according to forward stepwise multivariate logistic regression analysis (OR: 6.1; 95% CI: 1.798-20.692). CONCLUSION: Surgery was the only risk factor significantly associated with symptomatic candidiasis and non-albicans Candida species were more common among the patients with symptomatic candidiasis. While treating symptomatic candidiasis in any PICU an increase in the incidence of non-albicans candidiasis should be considered. PMID- 22104493 TI - Evaluation of various cardiac autonomic indices in patients with familial Mediterranean fever on colchicine treatment. AB - BACKGROUND: Familial Mediterranean fever (FMF) is characterized by sporadic, acute attacks of fever and serositis. Cardiovascular involvement is one of the leading cause of morbidity and mortality among FMF patients. Herein, we aimed to evaluate cardiac autonomic functions in FMF patients without overt cardiac symptoms. METHODS: We enrolled 38 patients (20 female; mean age 34.4 +/- 10.2 years) with FMF and 34 healthy subjects (18 female; mean age 33.2 +/- 9.3 years). All participants underwent 24-hour Holter recording. Heart rate recovery (HRR) indices were calculated by subtracting first, second, and third minute heart rates from maximal heart rate. All patients underwent heart rate variability (HRV), heart rate turbulance (HRT) and QT dispersion analysis. The mean FMF duration was 9.8 +/- 4.2 years. RESULTS: Both groups were similar with regard to baseline characteristics. Mean HRR1 (p=0.001), HRR2 (p=0.003) and HRR3 (p<0.001) were significantly lower in FMF group. SDNN (standard deviation of all NN intervals), SDANN (SD of the 5 min mean RR intervals), RMSSD (root square of successive differences in RR interval), and PNN50 (proportion of differences in successive NN intervals >50 ms) and high-frequency (HF) components were significantly decreased, but low frequency (LF) and LF/HF were significantly higher in FMF patients. HRT onset and slope were significantly less negative in FMF patients. Also, QTd was significantly higher in FMF patients (p<0.001). CONCLUSION: Patients with FMF showed delayed recovery of heart rate and abnormal HRV and HRT parameters with respect to normal subjects. Cardiac autonomic functions might be involved in FMF patients even in patients without cardiac symptoms. PMID- 22104494 TI - An allosteric coagonist model for propofol effects on alpha1beta2gamma2L gamma aminobutyric acid type A receptors. AB - BACKGROUND: Propofol produces its major actions via gamma-aminobutyric acid type A (GABA(A)) receptors. At low concentrations, propofol enhances agonist stimulated GABA(A) receptor activity, and high propofol concentrations directly activate receptors. Etomidate produces similar effects, and there is convincing evidence that a single class of etomidate sites mediate both agonist modulation and direct GABA(A) receptor activation. It is unknown if the propofol binding site(s) on GABA(A) receptors that modulate agonist-induced activity also mediate direct activation. METHODS: GABA(A) alpha1beta2gamma2L receptors were heterologously expressed in Xenopus oocytes and activity was quantified using voltage clamp electrophysiology. We tested whether propofol and etomidate display the same linkage between agonist modulation and direct activation of GABA(A) receptors by identifying equiefficacious drug solutions for direct activation. We then determined whether these drug solutions produce equal modulation of GABA induced receptor activity. We also measured propofol-dependent direct activation and modulation of low GABA responses. Allosteric coagonist models similar to that established for etomidate, but with variable numbers of propofol sites, were fitted to combined data. RESULTS: Solutions of 19 MUM propofol and 10 MUM etomidate were found to equally activate GABA(A) receptors. These two drug solutions also produced indistinguishable modulation of GABA-induced receptor activity. Combined electrophysiological data behaved in a manner consistent with allosteric coagonist models with more than one propofol site. The best fit was observed when the model assumed three equivalent propofol sites. CONCLUSIONS: Our results support the hypothesis that propofol, like etomidate, acts at GABA(A) receptor sites mediating both GABA modulation and direct activation. PMID- 22104495 TI - Protection against Fas-induced fulminant hepatic failure in liver specific integrin linked kinase knockout mice. AB - BACKGROUND: Programmed cell death or apoptosis is an essential process for tissue homeostasis. Hepatocyte apoptosis is a common mechanism to many forms of liver disease. This study was undertaken to test the role of ILK in hepatocyte survival and response to injury using a Jo-2-induced apoptosis model. METHODS: For survival experiments, ILK KO and WT mice received a single intraperitoneal injection of the agonistic anti-Fas monoclonal antibody Jo-2 at the lethal dose (0.4 MUg/g body weight) or sublethal dose (0.16 MUg/g body weight). For further mechanistic studies sublethal dose of Fas monoclonal antibody was chosen. RESULTS: There was 100% mortality in the WT mice as compared to 50% in the KO mice. We also found that hepatocyte specific ILK KO mice (integrin linked kinase) died much later than WT mice after challenge with a lethal dose of Fas agonist Jo 2. At sublethal dose of Jo-2, there was 20% mortality in KO mice with minimal apoptosis whereas WT mice developed extensive apoptosis and liver injury leading to 70% mortality due to liver failure at 12 h. Proteins known to be associated with cell survival/death were differentially expressed in the 2 groups. In ILK KO mice there was downregulation of proapoptotic genes and upregulation of antiapoptotic genes. CONCLUSIONS: Mechanistic insights revealed that pro-survival pathways such as Akt, ERK1/2, and NFkB signaling were upregulated in the ILK KO mice. Inhibition of only NFkB and ERK1/2 signaling led to an increase in the susceptibility of ILK KO hepatocytes to Jo-2-induced apoptosis. These studies suggest that ILK elimination from hepatocytes protects against Jo-2 induced apoptosis by upregulating survival pathways. FAK decrease may also play a role in this process. The results presented show that the signaling effects of ILK related to these functions are mediated in part mediated through NFkB and ERK1/2 signaling. PMID- 22104496 TI - [18F]DPA-714, [18F]PBR111 and [18F]FEDAA1106-selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls. AB - Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [(18)F]DPA-714, [(18)F]PBR111 and [(18)F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer. This note also includes the quality control data of the validation batches for the manufacturing qualification of clinical production of [(18)F]DPA 714. PMID- 22104497 TI - Synchrotron imaging and diffraction to investigate internal features of stable tearing fracture phenomenon in metallic specimens. AB - In situ synchrotron imaging and diffraction on beamline 1-ID-C at the Advanced Photon Source (APS) has been used to investigate the internal features present during the stable tearing fracture phenomenon in low-constraint metallic specimens. The results that are obtained from this investigation show that the internal features are identifiable with these techniques, and this initial investigation lays the groundwork for future, more in-depth investigations with some improvements to the methods. PMID- 22104498 TI - Development of a 125I source for its application in bone densitometry. AB - This paper describes a method for the preparation of (125)I sources for their use in bone densitometer. The process consists of preparation of silver pellets of size ~2.5 mm (phi) * 0.6 mm (l) by 'Cold die compaction technique', palladium coating of the silver pellets, adsorption of (125)I on the palladium coated silver pellets and encapsulation source matrix in a titanium capsule [ 3 mm (phi) * 10 mm(l)] using Nd:YAG laser. The texture and morphology of the source matrix were examined by SEM and EDS analyses. Encapsulated sources containing (125)I activity up to ~1.85 GBq (50 mCi) were prepared. Quality control tests that were necessary before application were performed and gave satisfactory results. PMID- 22104499 TI - Ambient and personal dose assessment of a container inspection site using a mobile X-ray system. AB - Ambient monitor and phantom studies of absorbed and effective doses by TLDs were carried out in a non-intrusive inspection station for containers, Terminal I, of Taichung harbor, Taiwan. The doses from the X-ray scan in the control room and driver waiting room, located outside of the radiation control area, were quite small and could not be distinguished from the natural background radiation. The doses in the driver cab and the inspector cab of the X-ray scan car were also within background radiation levels. The protection wall, a 40-cm thick concrete barrier, can effectively attenuate the intensity of the primary X-ray scan. The possible effective dose of a person in the container or trailer is about 3.15 +/- 0.23 MUSv/scan and 2.31 +/- 0.38 MUSv/scan. This dose is below the annual background dose. If someone was to be scanned by the X-ray, the effective dose would be at an acceptable level. PMID- 22104500 TI - Improved methods to determine radionuclidic purity of F-18 compounds. AB - Current revisions of monographs for F-18 pharmaceuticals in the European Pharmacopoeia (Ph. Eur.) (Ph. Eur., 2011) call for a radionuclidic purity (RNP) of or better than 99.9%. However, the current method is not sufficient nor effective for testing this required RNP level. We present a theoretical model leading to a practical procedure for a simple test of RNP for F-18 compounds that tells whether or not the sample is pure with a statistical confidence of 97.5% (P=0.975). PMID- 22104501 TI - Detection efficiency of a disk shaped detector with a critical detection angle for particles with a finite range emitted by a point-like source. AB - Detection efficiency of a circular detector for particles with a finite range, emitted from a point-like source was investigated, taking a critical detection angle into account. Particles emitted from the source lose some of their energy in the surrounding medium, before entering the detector material. Incident-energy dependence of the critical detection angle was taken into account. The part of the detector exposed to the particles impacting at angles greater than the critical angle (with respect to the detector surface), was determined. Several different cases were investigated, depending on the radius of the detector and the position of the detector with respect to the source. Detection probability expressions were derived for each of the cases. Results obtained using these expressions were compared with Monte Carlo calculations. PMID- 22104502 TI - Intercomparison of gamma ray scattering and transmission techniques for fluid fluid and fluid-air interface levels detection and density measurements. AB - This paper focuses on the fluid-fluid, fluid-air interface level detection and density determination by gamma scattering method and intercomparison with transmission (gammatography) technique. The Monte Carlo (MC) numerical simulation of the scattering phenomena is done using the MCNP code. The obtained accuracies and resolution of the level detections and density measurements are higher in case of gamma scattering method compared to transmission method. PMID- 22104503 TI - Reconstruction of the relief of an investigated object with scanning X-ray fluorescence microanalysis and Monte Carlo simulations of surface effects. AB - This paper describes surface effects in microscopic X-ray fluorescence analysis, including the Monte Carlo simulations of the production and the detection of characteristic radiation. A new data analysis technique is also introduced. It enables us to make improved calculations of element concentrations and to determine the shape of the surface in an analyzed spot. Finally, reliefs of two scanned objects are presented. Good results were achieved, especially for a metallic object containing chemical elements only measurable with X-ray fluorescence analysis. PMID- 22104504 TI - Risk factors for equine laminitis: a systematic review with quality appraisal of published evidence. AB - Epidemiological studies into the risk factors for naturally-occurring equine laminitis are limited. There are a small number of such studies, although the results are inconsistent and remain disputed. The reasons for the conflicting results remain unclear. The aim of this review was to critically evaluate previous research in order to identify publications which provide the best evidence of risk factors for naturally-occurring equine laminitis. A systematic review of English language publications was conducted using MEDLINE (1950-2010), CAB Direct (1910-2010) and IVIS (1997-2010). Additional publications were included by searching bibliographies. Search terms included laminitis, equine, risk factors and epidemiology. Publications which compared a case population to a control population and made inferences about parameters as risk factors for naturally-occurring equine laminitis were included. Information was extracted using predefined data fields, including 18 study quality indicators. In total, 17 publications were fully appraised. Six were considered to provide the most reliable information about risk factors for naturally-occurring laminitis. Information on signalment was well researched and there was good evidence for an association with chronic laminitis and increasing age. There remain inconsistent results for many other horse-level risk factors including gender, breed and bodyweight. Previous publications estimating risk factors for equine laminitis were of reasonable quality, although they were limited in the number and scope of the risk factors studied. High-quality, evidence-based studies are needed to identify further risk factors and to establish consensus over previously identified risk factors for different equine populations. PMID- 22104505 TI - Canine and feline intracranial meningiomas: an updated review. AB - Meningiomas are the most common primary brain tumours in dogs and cats. There are several morphological phenotypes of this extra-axial neoplasm and they show predilections for certain anatomical locations. There have been a number of attempts to apply the current World Health Organization (WHO) classification for human meningiomas to dogs and cats and to obtain a universal classification scheme for domestic animals. Recently, certain enzymes involved in tumour growth have been recognised as biological markers and have been related to degrees of malignancy. The secondary effects of meningiomas have also been investigated, and vascular endothelial growth factor and peritumoural oedema have been reported to reduce survival rate. Breed and age predisposition are recognised in both dogs and cats and the presenting clinical signs are quite consistent. Magnetic resonance imaging and computed tomography are the techniques of choice for the presumptive diagnosis of meningiomas in domestic animals but advanced imaging techniques are constantly being developed and applied. Treatment methods for meningiomas involve a combination of de-bulking surgery, chemotherapy and radiotherapy, and detailed accounts of several treatment protocols have been reported. PMID- 22104506 TI - Effects of porcine circovirus type 2 on expression of mRNA associated with endogenous antigen processing and presentation in pulmonary alveolar macrophages and circulating T lymphocytes in piglets. AB - Pulmonary alveolar macrophages (PAMs) are the major target cells of porcine circovirus type 2 (PCV2). This study examined cellular immunity and expression of molecules associated with endogenous antigen processing and presentation in porcine PAMs for 28 days following infection with PCV2. The numbers of total T cells and T lymphocyte subpopulations were measured by flow cytometry (FCM). The expression of mRNA of large multifunctional peptidase 7 (LMP7), ubiquitin specific protease (UBP), heat shock proteins 70 and 90 (HSP70 and HSP90), major histocompatibility class I (MHC-I), beta(2)-microglobulin, glucose-regulated protein 94 (GRP94), calnexin and calreticulin of PAMs from PCV2 infected and control pigs were determined by real-time reverse transcriptase PCR. The absolute numbers of total T cells, T helper (Th) cells, cytotoxic T cells and gammadelta T cells, but not memory/activated Th cells, decreased following PCV2 infection. There was decreased expression of LMP7 mRNA at 3days postinfection (DPI), whereas expression of UBP and calreticulin mRNA was increased at 3 DPI, expression of HSP90 and beta(2)-microglobulin mRNA was increased at 3 and 7 DPI and expression of GRP94 mRNA was increased at 14 DPI. PAMs from PCV2-infected piglets had lower surface expression of CD80/CD86 at 7 and 14 DPI and MHC-II at 7 DPI. These findings suggest that there are alterations in cellular immune function and in the endogenous antigen presentation capacity of PAMs in PCV2-infected piglets. PMID- 22104507 TI - Genotyping of exercise-induced collapse in Labrador retrievers using an allele specific PCR. AB - Exercise-induced collapse (EIC) is an autosomal recessive disorder in Labrador retrievers. In this study, an allele-specific PCR was developed to detect the point mutation G767T in exon 6 of canine DNM1, previously shown to be responsible for canine EIC. Of 133 Labrador retrievers tested in Japan, 6 (4.5%) were homozygous (EIC) and 50 (37.6%) were heterozygous (carriers) for the G767T mutation. PMID- 22104508 TI - Vertical head and trunk movement adaptations of sound horses trotting in a circle on a hard surface. AB - Trotting a horse in circles is a standard and important part of the subjective equine lameness examination, yet objective data on this form of locomotion are sparse. The aim of this study was to investigate the effect of trotting in a circle on head and trunk movement symmetry. Vertical movements of the head, withers, os sacrum and left and right tuber coxae were measured using inertial sensors as 12 sound horses were trotted on a hard surface in a straight line and in a circle on both reins. Seven asymmetry measures and hip hike were calculated for each horse for at least nine strides of comparable stride duration across the three conditions (deviation on horse level <=3.7% stride duration). Trotting in a circle introduced systematic changes to the movement pattern of all five body landmarks, affecting most asymmetry measures. On average the asymmetry magnitude was comparable for midline locations between reins and for the tuber coxae on opposite reins with few exceptions, although individual horses showed unsystematic differences between the two reins. The results from this study showed that the thresholds for objective discrimination between lame and non-lame horses will need adjustment on the circle due to the observed asymmetry bias. PMID- 22104509 TI - Utility of the assessment of echogenicity in the identification of symptomatic carotid artery atheroma plaques in ischemic stroke patients. AB - BACKGROUND AND PURPOSE: Echogenicity of atheroma carotid plaques is related to a higher risk of stroke. Clinical and subjective ultrasound criteria are used to identify symptomatic plaques, but the standardized grayscale median (GSM) value may be an objective tool for this diagnosis. Our aim was to analyze the utility of assessing the echogenicity of atheroma carotid plaques in the identification of symptomatic plaques. METHODS: Observational prospective study with inclusion of acute noncardioembolic anterior cerebral circulation ischemic stroke patients. Only patients with bilateral atheroma plaques were included. Echogenicity of plaques was measured by a digital and standardized grayscale system in carotid ultrasound B-mode (longitudinal projection) conducted within the first week after admission. RESULTS: Sixty-six patients were included and 132 plaques were examined. Symptomatic atheroma plaques were less echogenic than asymptomatic ones (GSM 20.0 vs. 29.0; p = 0.002). A ROC curve analysis showed the predictive value of GSM with an AUC of 0.707 (95% CI 0.592-0.823; p = 0.002) and pointed to a value of 24.4 as the optimal cut-off level to identify a plaque as symptomatic (74% sensitivity; 67% specificity). This GSM cut-off point remained significantly associated with a high probability of symptomatic plaque even after the inclusion of the degree of carotid stenosis (either >70% or >50%) in the multivariate logistic regression models. CONCLUSIONS: The assessment of echogenicity of atheroma carotid plaques by the GSM value combined with clinical characteristics and stenosis degree may be useful in the identification of symptomatic plaques. PMID- 22104510 TI - Changes in motor function induced by chronic motor cortex stimulation in post stroke pain patients. AB - BACKGROUND: In well-designed multicenter studies, the protocol of continuing motor cortex stimulation (MCS) temporarily for 3-6 weeks was employed with rehabilitation therapy, and these studies showed some recovery of motor weakness in post-stroke patients. OBJECTIVES: We aimed to clarify the effects of long-term MCS and the optimal stimulation conditions to improve motor weakness in post stroke patients. METHODS: We applied chronic MCS in 6 post-stroke pain patients with motor weakness. We then examined the correlation between the duration of daily MCS applied over 6 months and motor function assessed on the basis of the Fugl-Meyer Assessment (FMA) score of the patients. RESULTS: In the 6 patients with motor weakness, the FMA score of the upper extremity increased in 4 patients who underwent daily MCS for less than 4 h. On the other hand, 2 patients who continued excessive MCS to control their complicating post-stroke pain showed decreased FMA scores and worsened motor function owing to their increased rigidity and/or spasticity. These 2 patients recovered their motor function after their daily MCS was restricted to less than 4 h. CONCLUSIONS: These findings indicate that MCS could be a new therapeutic approach to improving motor performance after stroke by attenuating rigidity and/or spasticity. However, it may be important to define the appropriate number of hours and conditions of daily MCS. PMID- 22104511 TI - Extraparenchymal neurocysticercosis. PMID- 22104512 TI - Time to direct COM candidates away from the MCAT? PMID- 22104513 TI - Treatment of adults with attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a clinically important neuropsychiatric developmental disorder that affects children, adolescents, and adults. The disorder is characterized by core symptoms of inattention, hyperactivity, distractibility, impulsivity, and impaired executive functioning. It is estimated that 2% to 5% of the adult population in the United States has ADHD. Adults with ADHD are at an increased risk for experiencing comorbid psychiatric disorders, including mood disorders, anxiety disorders, and substance use disorders. The authors provide a brief clinical overview of ADHD and the treatment of adults with this disorder. PMID- 22104514 TI - Osteopathic medical students' beliefs about osteopathic manipulative treatment at 4 colleges of osteopathic medicine. AB - CONTEXT: Osteopathic manipulative treatment (OMT) is a distinctive and foundational aspect of osteopathic medicine. Several studies have reported a decline in the use of OMT by practicing osteopathic physicians, but the reasons for this decline have not been fully investigated. OBJECTIVE: To investigate osteopathic medical students' attitudes and beliefs regarding osteopathic philosophy, including OMT. METHODS: A self-administered, 21-item, electronic questionnaire developed specifically for the current study was distributed to first- and second-year osteopathic medical students at 4 colleges of osteopathic medicine. The questionnaire contained items addressing student attitudes toward osteopathic philosophy, including OMT; perceptions of osteopathic predoctoral education; and plans for integrating OMT into future practice. RESULTS: Of 1478 questionnaires sent, 491 students completed the questionnaire for an overall response rate of 33%. Analysis of student responses revealed that a majority of first- and second-year osteopathic medical students (95%-76%, depending on the question asked) expressed agreement with osteopathic philosophy. Students who reported prior exposure to OMT had higher levels of agreement with osteopathic philosophy statements (P<.04) and with the intention to use OMT (P<.02) than students with no prior exposure. However, students who were drawn to an osteopathic medical school by the desire to become a physician regardless of degree reported lower levels of agreement with osteopathic philosophy and the intention to use OMT. Students' levels of agreement with osteopathic philosophy and intention to use OMT varied significantly based on the school that they attended, their current year of study, and whether or not they were participating in clinical rotations. CONCLUSION: The reason why a student decided to study osteopathic medicine was strongly associated with the level of agreement with osteopathic philosophy and the intention to use OMT in future practice. Prior experience receiving OMT, the medical school that a student attends, and the current year of study appear to be related to the students' levels of agreement with osteopathic philosophy and intention to use OMT. PMID- 22104515 TI - Rethinking the model of osteoarthritis: a clinical viewpoint. AB - The prevailing model of joint degeneration based on age-related, genetic, and familial factors implies inevitable progression and limited palliation from manual therapy. This model is presented to primary care physicians and the public on Web sites and in resource texts and is implicit in many published research articles. The author presents a synthesized model of the progression of osteoarthritis, combining radiographic, histologic, and clinical evidence. The revised model suggests that the progression of primary osteoarthritis is divided into an initial reversible arthrosis phase and a later arthritis phase, with both phases linked to accepted histologic and radiographic observations. The revised model also suggests a number of novel concepts, including the influence of dominance bias and laterality. The author concludes that a small change in understanding could translate into important changes in the therapeutic management of osteoarthritis, with implications for government public health policy. PMID- 22104516 TI - Carotid body tumor as a reversible cause of syncope. AB - The causes of syncope are diverse and extensive; carotid body tumors are an extremely rare cause of syncope. These rare neoplasms represent less than 0.5% of all head and neck tumors. The authors present a case of a woman with syncope who was found to have a right-sided carotid body tumor. After surgical resection was performed, she did not have any additional syncopal or near-syncopal events. The authors provide a review of the literature on the natural history, presentation, and preferred management of carotid body tumors. With modern diagnostic tools and treatment options, most patients with this diagnosis can expect to recover fully. PMID- 22104517 TI - Emphysematous cystitis. PMID- 22104518 TI - Multiplex quantification of lamprey specific bile acid derivatives in environmental water using UHPLC-MS/MS. AB - Larval and adult sea lampreys (Petromyzon marinus) release bile salts and acids into the surrounding aquatic environment. Some of these bile salts and acids, such as petromyzonol sulfate (PZS), 3-keto petromyzonol sulfate (3k PZS), petromyzonamine disulfate (PADS), petromyzosterol disulfate (PSDS), and 3-keto allocholic acid (3k ACA), may function as pheromones. To examine the release and distribution patterns of these metabolites, which this study has termed bile acid derivatives, we developed a novel UHPLC-MS/MS method that was characterized by simple sample preparation, baseline separation, and short analysis time for all studied compounds. These five analytes were separated in 7 min using a reversed phase C18 column containing 1.7 MUm particles and a gradient elution at pH 8.9. Once separated, the analytes were subjected to electrospray ionization-mass spectrometry (negative ion mode) and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) using the multiple reaction monitoring (MRM) mode. Deuterated 3k PZS ([(2)H(5)]3k PZS) was added as the internal standard (IS) to the sample prior to solid phase extraction (SPE). Among the three types of SPE sorbent tested, mixed-mode cation-exchange and reversed-phase sorbent for bases (MAX) and acids (MCX), and reversed-phase C18 sorbent (Sep-pak), the best recoveries (84.1-99.7%) were obtained with MCX cartridges. The calibration curves of all five analytes were linear between 0.15 and 1200 ng/mL, with R(2)>=0.9997. This method had a precision of relative standard deviation (RSD) <=9.9% and an accuracy of deviation (DEV) >=92.5%. The developed method was successfully used to quantify bile acid derivatives found in streams where lampreys spawn (SD<1.4) and water conditioned with male sea lampreys (SD<4.8). Utilizing this method provides a routine analysis of lamprey bile acid derivatives and may prove useful for sea lamprey population estimates in future studies and applications. PMID- 22104519 TI - Modified emergency department thoracotomy for postablation cardiac tamponade. AB - Cardiac dysrhythmias are a common problem in the United States. Radiofrequency ablation is being used more frequently as a treatment for these diagnoses. Although rare, serious complications such as cardiac tamponade have been reported as a result of ablation procedures. Traditionally, emergency department (ED) thoracotomy has been reserved for cases of traumatic arrest only. We report a case of a successful modified ED thoracotomy in a patient with postablation cardiac tamponade and subsequent obstructive shock who failed intravenous fluid resuscitation, pressor administration, and multiple attempts at pericardiocentesis. In this case, a modified approach was used to incise the pericardium. Although this was associated with large blood loss, we believed that using the traditional method of completely removing the pericardium would have resulted in uncontrolled hemorrhage. Instead, our method led to successful resuscitation of the patient until definitive care was available. A smaller pericardial incision than is traditionally used during ED thoracotomy deserves further consideration and research to determine whether and when it may be most useful as a temporizing treatment of cardiac tamponade when other methods have failed. PMID- 22104520 TI - Preterm prelabor rupture of membranes and fetal survival after minimally invasive fetal surgery: a systematic review of the literature. AB - OBJECTIVE: Iatrogenic preterm prelabor rupture of membranes (iPPROM; <37 weeks of gestation) is a major complication of fetal surgery. Little information is available about risk factors and incidence. METHODS: We systematically reviewed reported iPPROM rates, gestational age at delivery and fetal survival after representative minimally invasive antenatal procedures. RESULTS: A total of 1,146, 36 and 194 cases with mean iPPROM rates of 27, 31 and 26% were included for placental laser in twin-twin transfusion syndrome, shunting in lower urinary tract obstruction and interventions for twin-reversed arterial perfusion, respectively. In the statistical analysis, the maximum diameter of the instrument predicted iPPROM rate and was significantly related to gestational age at birth as well as fetal survival. Information on duration of the respective procedures was scarce and did not allow for meaningful analysis. CONCLUSIONS: iPPROM occurs in about 30% of cases treated by minimally invasive fetal surgery. The maximum diameter of the instrument explains iPPROM rate, gestational age at birth and fetal survival. Great variations in the reporting of iPPROM make data analysis difficult. PMID- 22104521 TI - Comparison of real-time in vivo spectral and vector velocity estimation. AB - The purpose of this study is to show whether a newly introduced vector flow method is equal to conventional spectral estimation. Thirty-two common carotid arteries of 16 healthy volunteers were scanned using a BK Medical ProFocus scanner (DK-2730, Herlev, Denmark) and a linear transducer at 5 MHz. A triplex imaging sequence yields both the conventional velocity spectrum and a two dimensional vector velocity image. Several clinical parameters were estimated and compared for the two methods: Flow angle, peak systole velocity (PS), end diastole velocity (ED) and resistive index (RI). With a paired t-test, the spectral and vector angles did not differ significantly (p = 0.658), whereas PS (p = 0.034), ED (p = 0.004) and RI (p < 0.0001) differed significantly. Vector flow can measure the angle for spectral angle correction, thus eliminating the bias from the radiologist performing the angle setting with spectral estimation. The flow angle limitation in velocity estimation is also eliminated, so that flow at any angle can be measured. PMID- 22104522 TI - Ultrasound for high altitude research. AB - This review describes ultrasound techniques of potential use to high altitude researchers and discusses technical issues related to using ultrasound for high altitude research. Ultrasound allows portable, noninvasive evaluation of many physiologic parameters of interest to high altitude researchers. We discuss techniques that have been extensively used and emerging techniques that can be used to assess parameters of particular interest to high altitude researchers. We do not provide a definitive description of all ultrasound scanning methods but references to instructive sources are included. Potential drawbacks of ultrasound use, such as the need for sometimes extensive training and the potential for interobserver variation, are discussed and strategies for mitigating these are suggested. This review is meant to encourage other high altitude researchers to consider using ultrasound, either as a primary investigative modality or as an adjunct for monitoring parameters of interest in studies of physiology, altitude illness, or therapeutics. PMID- 22104523 TI - Automatic bone localization and fracture detection from volumetric ultrasound images using 3-D local phase features. AB - This article presents a novel method for bone segmentation from three-dimensional (3-D) ultrasound images that derives intensity-invariant 3-D local image phase measures that are then employed for extracting ridge-like features similar to those that occur at soft tissue/bone interfaces. The main contributions in this article include: (1) the extension of our previously proposed phase-symmetry based bone surface extraction from two-dimensional (2-D) to 3-D images using 3-D Log-Gabor filters; (2) the design of a new framework for accuracy evaluation based on using computed tomography as a gold standard that allows the assessment of surface localization accuracy across the entire 3-D surface; (3) the quantitative validation of accuracy of our 3-D phase-processing approach on both intact and fractured bone surfaces using phantoms and ex vivo 3-D ultrasound scans; and (4) the qualitative validation obtained by scanning emergency room patients with distal radius and pelvis fractures. We show a 41% improvement in surface localization error over the previous 2-D phase symmetry method. The results demonstrate clearly visible segmentations of bone surfaces with a localization accuracy of <0.6 mm and mean errors in estimating fracture displacements below 0.6 mm. The results show that the proposed method is successful even for situations when the bone surface response is weak due to shadowing from muscle and fascia interfaces above the bone, which is a situation where the 2-D method fails. PMID- 22104524 TI - Splenic Doppler impedance indices estimate splenic congestion in patients with right-sided or congestive heart failure. AB - Splenic Doppler impedance indices are measurements of splenic congestion in chronic liver disease. It is not known whether they can also assess splenic congestion in patients affected by right-sided or congestive heart failure. We analyzed splanchnic hemodynamics with Doppler ultrasound and systemic hemodynamics with right-sided heart catheterization in patients with heart failure. Splenic pulsatility index (PI) was higher in patients with heart failure (48 patients) compared with healthy subjects (39 patients) (1.19 +/- 0.41 vs. 0.73 +/- 0.11, p < 0.0001) and was related to hepatic vein diameter (p = 0.02). Splenic PI was not related to systemic arterial pressure, cardiac output, systemic vascular resistance or splenic arterial resistance, whereas it was related to right atrial mean pressure (p = 0.0003) and to right ventricle end diastolic pressure (p = 0.011) (34 patients). In conclusion, splenic PI is a measurement of splenic congestion caused by an increase in venous outflow resistance. It can estimate splenic congestion in patients with right-sided or congestive heart failure. PMID- 22104525 TI - Ultrasound measurement of subcutaneous adipose tissue thickness accurately predicts total and segmental body fat of young adults. AB - This study evaluated the ability of ultrasound measurement of subcutaneous adiposity to accurately determine whole body and segmental body fat in young adults aged 18-29 years. Subcutaneous adipose tissue (SAT) thickness was measured by ultrasound at five body sites in 135 subjects (83 men, 52 women) and compared with the corresponding segmental fat mass measured by dual energy X-ray absorptiometry (DXA). Ultrasound measures of SAT thickness were strongly correlated to segmental fat mass and total percentage (%) body fat (r = 0.697 0.907, p < 0.01). Prediction equations generated using quantile regression found SAT thickness at the abdomen and thigh to accurately predict % body fat in men (standard error of the estimate, SEE = 1.9%, 95% limits of agreement (LoA); -3.6% to +3.8%) and SAT thickness at the abdomen and medial calf to accurately predict % body fat in women (SEE = 3.0%, LoA; -6.5% to +5.4%). These data indicate that ultrasound measurement of SAT thickness proportionally reflects segmental fat mass and accurately predicts % body fat in young adults. PMID- 22104526 TI - Ultrasound assessment of the rotator cuff cable: comparison between young and elderly asymptomatic volunteers and interobserver reproducibility. AB - Our aim was to characterize rotator cable ultrasound appearance in shoulders of different-aged asymptomatic volunteers, also estimating interobserver reproducibility. We studied 83 shoulders in 42 young volunteers (mean age 26 +/- 7.0 years, range 21-35 years) and 66 shoulders in 36 elderly volunteers (65-81 years, 73 +/- 4.9 years), noting rotator cable visibility and its minimum thickness and width. Interobserver reproducibility was tested in elderly volunteers by two blinded observers. chi(2), U Mann-Whitney, t-test, Bland Altman, and kappa statistics were used. Rotator cable was less frequently detected in younger than elderly volunteers (25/83 vs. 36/66 shoulders; p = 0.002). Young subjects had thicker (1.5 +/- 0.2 mm, range 1.3-1.8 mm vs. 1.1 +/- 0.1 mm, 0.9-1.3 mm; p < 0.001) and wider rotator cable (5.8 +/- 0.7 mm, 4.5-7.1 mm vs. 4.0 +/- 1.2 mm, 2.5-7.1 mm; p < 0.001) than elderly volunteers. Thickness and width reproducibility index were 89% and 94%, respectively; kappa = 0.87. Ultrasound demonstrated different rotator cable consistency in younger and elderly asymptomatic patients, with high interobserver reproducibility. PMID- 22104527 TI - Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors. AB - Sensations generated by intense focused ultrasound (iFU) can occur cutaneously and/or at depth, in contrast to other forms of stimulation (e.g., heat, electricity), whose action usually occurs only at the skin surface, or mechanical stimulation (e.g., von Frey hairs, calibrated forceps, tourniquets) that compress and thus stimulate all tissue. Previous work on iFU stimulation has led to the hypothesis that the tactile basis of iFU stimulation should correlate with the density of mechanoreceptors at the site of iFU stimulation. Here we tested that hypothesis, correlating a "two-point" neurological examination-a standard measure of superficial mechanoreceptor density-with the intensity of superficially applied iFU necessary to generate sensations with high sensitivity and specificity. We applied iFU at 1.1 MHz for 0.1 s to the fingertip pads of 17 test subjects in a blinded fashion and escalated intensities until they consistently observed iFU-induced sensations. Most test subjects achieved high values of sensitivity and specificity, doing so at values of spatially and temporally averaged intensity measuring <100 W/cm(2). Moreover, the test subjects' sensitivity to iFU stimulation correlated with the density of mechanoreceptors as determined by a standard two-point discrimination neurological examination, consistent with earlier hypotheses. PMID- 22104528 TI - First application of axial speed of sound to follow up injured equine tendons. AB - Ultrasonography is an established technique to follow up injured tendons, although the lesions' echogenicity tends to become normal before the tendon is ready to sustain the stresses imposed by exercise. Normalized axial speed of sound (SOS) has been found to correlate with an injured tendon's stiffness; therefore, the purpose of this study was to establish whether SOS would be a useful tool in tendon injury follow-up. Axial SOS was measured in 11 equine superficial digital flexor tendons during a 15-week follow-up period and compared with an ultrasonographic grading system. SOS significantly decreased 2 weeks after the surgical induction of a core lesion, showing a minimum between 7 and 10 weeks; ultrasonographic grade showed a minimum at 3 weeks and increased thereafter. The ultrasonographic grading at 15 weeks was correlated to normalized SOS. These results suggest that axial SOS provides complementary information to ultrasonography that could be of clinical interest. PMID- 22104529 TI - Propagation characteristics of photomechanical waves and their application to gene delivery into deep tissue. AB - Targeted gene transfection can be achieved by the use of photomechanical waves (PMWs) generated by irradiating a solid material with high-power nanosecond laser pulses. To examine the treatable tissue depth, we investigated propagation characteristics of PMWs and depth-dependent properties of gene transfection with different laser fluences and spot diameters. Pressure characteristics of PMWs were measured at different propagation distances using tissue phantoms and their propagation was imaged by shadowgraphing. Phantoms with various thicknesses were placed on rat dorsal skin that had been injected with plasmid DNA coding for a reporter gene and three pulses of PMWs were applied from the top of each phantom. Significant gene expression was observed in the skin even under a 15-mm-thick tissue phantom and the depth-dependent relationships between PMW parameters and gene expression level were revealed. The data obtained will be useful for determining appropriate laser parameters for PMW-based gene transfer into deep located tissue. PMID- 22104530 TI - Effect of a novel segmentation algorithm on radiologists' diagnosis of breast masses using ultrasound imaging. AB - We investigated the effect of using a novel segmentation algorithm on radiologists' sensitivity and specificity for discriminating malignant masses from benign masses using ultrasound. Five-hundred ten conventional ultrasound images were processed by a novel segmentation algorithm. Five radiologists were invited to analyze the original and computerized images independently. Performances of radiologists with or without computer aid were evaluated by receiver operating characteristic (ROC) curve analysis. The masses became more obvious after being processed by the segmentation algorithm. Without using the algorithm, the areas under the ROC curve (Az) of the five radiologists ranged from 0.70~0.84. Using the algorithm, the Az increased significantly (range, 0.79~0.88; p < 0.001). The proposed segmentation algorithm could improve the radiologists' diagnosis performance by reducing the image speckles and extracting the mass margin characteristics. PMID- 22104531 TI - Vascular effects of microbubble-enhanced, pulsed, focused ultrasound on liver blood perfusion. AB - The purpose of this study was to investigate the vascular effects of microbubble enhanced pulsed high-pressure ultrasound on liver blood perfusion. In the presence of circulating lipid-shell microbubbles, a focused ultrasound transducer was used to transcutaneously treat eight livers of healthy rabbits for perfusion analysis and to treat three livers with the abdomen open for histologic analysis. Twenty-two livers treated with the ultrasound only (n = 11) or microbubbles only (n = 11) served as the controls. The focused ultrasound was operated at a frequency of 1.22 MHz with a peak negative pressure of 4.6 MPa. The liver blood perfusion was estimated by performing contrast-enhanced ultrasound and gray-scale quantification on the livers before and after treatment. A temporary, nonenhanced region occurred in all of the experimental livers. The regional contrast gray scale values of the experimental group dropped significantly from 88.4 before treatment to 2.7 after treatment. The liver perfusion also demonstrated a gradual recovery over a 60-min period. The liver perfusion of the control groups remained the same after treatment. We found microvascular rupture, hemorrhage and swelling hepatocytes upon histologic examination of the experimental group. Regional liver blood perfusion can be temporarily blocked by microbubble-enhanced focused ultrasound with high-pressure amplitude. These vascular effects can be explained as acute microvascular injury of the liver and may have clinical implications. PMID- 22104532 TI - Would gestational age and presence of brain anomalies affect interobserver reliability of fetal head biometry? Using off-line analysis of 3-D dataset. AB - The objective was to assess interobserver reliability of fetal head biometry using archived three-dimensional (3-D) volumes and the impact of gestational age and presence of brain anomalies on examiners' performance. Seventy nine 3-D volume datasets of fetal head were examined: 27 were normal and 52 had brain abnormalities. Off-line analysis was done by three fetal medicine experts (E1, E2 and E2), all were blinded to history and patient details. Measurements of the biparietal diameter (BPD), head circumference (HC), lateral ventricle (Vp) and transcerebellar diameter (TCD) were compared between examiners and to two dimensional (2-D) measurements. Comparisons were made at two gestational age groups (<=22 and >22 weeks) and in presence and absence of brain anomalies. The intraclass coefficient showed a significantly high level of measurement agreement between 3-D examiners and 2-D, with values >0.9 throughout (p < 0.001). Bias was evident between 3-D examiners. E2 produced smaller measurements. The mean percentage difference between this examiner and the other two in BPD, HC, Vp and TCD measurements was significant, of 1.6%, 1%, 4.9% and 1.8%, respectively. E1 measured statistically larger for HC and TCD. E3 measured significantly larger for only BPD. The presence of anomalies was of no influence on the 3-D examiners' performance except for E3 who showed bias in BPD measurements only in cases with brain anomalies. Unlike other examiners, bias of E2 was only seen at gestational age group <=22 weeks. Limits of agreement in measurements between observers were narrow for all parameters but were widest for the Vp measurements, being +/-23% of the mean difference. Despite the above bias, the actual mean difference between examiners was small and unlikely to be of any clinical significance. Off line measurement of fetal head biometry using 3-D volumes is reliable. In our study, presence of brain anomalies was unlikely to influence the reproducibility of measurements. Gestational age seemed to be of an impact on examiners' bias. Among experts this bias may be of no clinical significance. PMID- 22104533 TI - Acoustic radiation force impulse imaging of human prostates: initial in vivo demonstration. AB - Reliably detecting prostate cancer (PCa) has been a challenge for current imaging modalities. Acoustic radiation force impulse (ARFI) imaging is an elasticity imaging method that uses remotely generated, focused acoustic beams to probe tissue stiffness. A previous study on excised human prostates demonstrated ARFI images portray various prostatic structures and has the potential to guide prostate needle biopsy with improved sampling accuracy. The goal of this study is to demonstrate the feasibility of ARFI imaging to portray internal structures and PCa in the human prostate in vivo. Custom ARFI imaging sequences were designed and implemented using a modified Siemens AntaresTM scanner with a three dimensional (3-D) wobbler, end-firing, trans-cavity transducer, EV9F4. Nineteen patients were consented and imaged immediately preceding surgical prostatectomy. Pathologies and anatomic structures were identified in histologic slides by a pathologist blinded to ARFI data and were then registered with structures found in ARFI images. The results demonstrated that when PCa is visible, it generally appears as bilaterally asymmetric stiff structures; benign prostatic hyperplasia (BPH) appears heterogeneous with a nodular texture; the verumontanum and ejaculatory ducts appears softer compared with surrounding tissue, which form a unique 'V' shape; and the boundary of the transitional zone (TZ) forms a stiff rim separating the TZ from the peripheral zone (PZ). These characteristic appearances of prostatic structures are consistent with those found in our previous study of prostate ARFI imaging on excised human prostates. Compared with the matched B-mode images, ARFI images, in general, portray prostate structures with higher contrast. With the end-firing transducer used for this study, ARFI depth penetration was limited to 22 mm. Image contrast and resolution were decreased as compared with the previous ex vivo study due to the small transducer aperture. Even with these limitations, this study suggests ARFI imaging holds promise for guidance of targeted prostate needle biopsy and focal therapy, as well as aiding assessment of changes during watchful waiting/active surveillance. PMID- 22104534 TI - Activation of microbubbles by short-pulsed ultrasound enhances the cytotoxic effect of cis-diamminedichloroplatinum (II) in a canine thyroid adenocarcinoma cell line in vitro. AB - Ultrasound targeted microbubble destruction has succeeded in delivering drugs and genes. This study was designed to explore characteristics of ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. Canine thyroid adenocarcinoma cells were exposed to short-pulsed diagnostic ultrasound in the presence of cis-diamminedichloroplatinum (II) (cisplatin) and ultrasound contrast agent Sonazoid((r)) microbubbles. The cytotoxic effect of cisplatin was enhanced by short-pulsed diagnostic ultrasound and microbubbles. Incubation time with microbubbles influenced the cytotoxic effect of cisplatin. However, exposure duration did not affect the cytotoxic effect of cisplatin. Therefore, short pulsed diagnostic ultrasound may activate microbubbles near cells and deliver cisplatin into cells. In addition, activation of microbubbles may be concluded in a short time. Our results suggest that short exposure duration could be potentially sufficient to induce efficient drug delivery by ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. PMID- 22104535 TI - A pilot study to assess markers of renal damage in the rodent kidney after exposure to 7 MHz ultrasound pulse sequences designed to cause microbubble translation and disruption. AB - Acoustic radiation force has been proposed as a mechanism to enhance microbubble concentration for therapeutic and molecular imaging applications. It is hypothesized that once microbubbles are localized, bursting them with acoustic pressure could result in local drug delivery. It is known that low-frequency, high-amplitude acoustic energy combined with cavitation nuclei can result in bioeffects. However, little is known about the bioeffects potential of acoustic parameters involved in radiation force and microbubble destruction pulse sequences applied at higher frequencies. In this pilot study, rat kidneys are exposed to high-duty cycle, low-amplitude pulse sequences known to cause substantial bubble translation due to radiation force, as well as high-amplitude short pulse sequences known to cause microbubble destruction. Both studies are performed at 7 MHz on a clinical ultrasound system, and implemented in three dimensions (3-D) for entire kidney exposure. Analysis of biomarkers of renal injury and renal histopathology indicate that there was no significant renal damage due to these ultrasound parameters in conjunction with microbubbles within the study group. PMID- 22104536 TI - Thermally-mediated ultrasound-induced contraction of equine muscular arteries in vitro and an investigation of the associated cellular mechanisms. AB - We have previously shown that MHz frequency ultrasound causes contraction of the carotid artery in vitro. We now extend this investigation to equine mesenteric arteries and investigate the cellular mechanisms. In vitro exposure of the large lateral cecal mesenteric artery to 4-min periods of 3.2 MHz continuous wave ultrasound at acoustic powers up to 145 mW induced reversible repeatable contraction. The magnitude of the response was linearly dependent on acoustic power and, at 145 mW, the mean increase in wall stress was 0.020 +/- 0.017 mN/mm(2) (n = 34). These results are consistent with our previous study and the effect was hypothesised to be thermally mediated. A 2 degrees C temperature rise produced an increase in intracellular calcium, measured by Fluo-4 fluorescence. Inhibition of the inward-rectifier potassium ion channel with BaCl(2) (4 MUM) increased the response to ultrasound by 55% +/- 49%, indicating a similar electrophysiologic basis to the response to mild hyperthermia. In small mesenteric arteries (0.5-1.0 mm diameter) mounted in a perfusion myograph, neither ultrasound exposure nor heating produced measureable vasoconstriction or a rise in intracellular calcium and we conclude that temperature-sensitive channels are absent or inactive in these small vessels. It, therefore, appears that response of blood vessels to ultrasound depends not only on the thermal properties of the vessels and surrounding tissues but also on the electrophysiology of the smooth muscle cells. PMID- 22104537 TI - The effect of the cold pressor test on a visually evoked cerebral blood flow velocity response. AB - We investigated the hypothesis that during tonic pain stimulus, neurovascular coupling (NVC) decreases, measuring visually evoked cerebral blood flow velocity response (VEFR) during cold pressor test (CPT) in healthy human subjects as a test. VEFR was calculated as a relative increase in blood flow velocity in the posterior cerebral artery from average values during the last 5 s of the stimulus OFF period to average values during the last 10 s of the stimulus-ON period. Three consecutive experimental phases were compared: basal, CPT and recovery. During CPT, end-diastolic and mean VEFR increased from 20.2 to 23.6% (p < 0.05) and from 17.5 to 20.0% (p < 0.05), respectively. In recovery phase, end-diastolic and mean VEFR decreased to 17.7% and 15.5%, respectively. Both values were statistically significantly different from CPT phase (p < 0.05). Compared with the basal phase, only end-diastolic VEFR was statistically significantly different in the recovery phase (p < 0.05). Our results are consistent with the assumption that there is a change in the activity of NVC during CPT because of the modulatory influence of subcortical structures activated during tonic pain. Contrary to our expectations, the combined effect of such influences increases rather than decreases NVC. PMID- 22104538 TI - Impact of propagating and standing waves on cavitation appearance. AB - Standing waves play a significant role in the appearance of cavitation phenomena. The goal of this study was to investigate the effect that the relation between standing and propagating waves in a focused field has on acoustic bubble cloud formation. Measurements of the cavitation signals were performed on five different configurations of a hemispheric phased array transducer (230 kHz) representing a wide range of relations between propagating and standing waves. The results show that configurations with a larger propagating component induce bubble clouds at lower pressures than configurations with a larger standing component. PMID- 22104539 TI - Differences in biomarkers in patients with heart failure with a reduced vs a preserved left ventricular ejection fraction. AB - BACKGROUND: The differences in concentrations of biomarkers between heart failure (HF) patients with a preserved left ventricular ejection fraction (LVEF), or HF PEF, and patients with HF with reduced LVEF (HF-REF) have yet to be defined. The objectives of this study were to compare the concentrations and correlation of biomarkers of inflammation, extracellular matrix (ECM) turnover and neurohormonal activation between these populations. METHODS: We performed a cross-sectional study of 29 subjects with symptomatic HF-REF (LVEF = 25.6 +/- 5.1%) and 29 subjects with symptomatic HF-PEF (LVEF = 63.3 +/- 5.3%). Concentrations of N terminal proB-type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), procollagen type III amino-terminal peptide (PIIINP), matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of MMP (TIMP)-1 were measured. RESULTS: Although NT-proBNP and PIIINP concentrations were higher in patients with HF-REF compared with patients with HF-PEF (both P < 0.05), the only significant difference between the groups remaining after adjusting for possible confounding variables was NT-proBNP (P = 0.02). In patients with HF-REF, NT proBNP correlated with PIIINP (P < 0.05), TIMP-1 (P < 0.05), and MMP-2 (P = 0.002), while PIIINP correlated with TIMP-1 (P < 0.05) and MMP-2 (P < 0.0001). In patients with a HF-PEF, only high sensitivity C-reactive protein correlated significantly with MMP-2 (P = 0.002). CONCLUSIONS: Patients with HF-REF or HF-PEF presenting similar symptoms and functional limitations exhibit similar concentrations of biomarkers of ECM and inflammation. However, patients with HF REF exhibit significantly higher NT-proBNP concentrations than patients with HF PEF. The differences in the correlations observed between the biomarkers between these 2 populations suggest some heterogeneity and differences in the mechanisms related to the release or clearance of biomarkers in HF-REF vs HF-PEF. PMID- 22104540 TI - Effects of whole body vibration in patients with chronic obstructive pulmonary disease--a randomized controlled trial. AB - INTRODUCTION: To date endurance and strength training are established and evidence-based exercise methods in patients with chronic obstructive pulmonary disease (COPD). There is an unmet need for further research in new and complementary exercise modalities. Additional whole body vibration training during pulmonary rehabilitation may be such a new approach that has not yet been investigated in patients with COPD. METHODS: Eighty-two patients (65 +/- 9 yrs, FEV(1) pred. 38 +/- 11%, female 51%) with COPD in GOLD stage III to IV assessed for a 3-week inpatient multidisciplinary rehabilitation program were on top randomly assigned to one of two intervention groups: (1) 3 * 3 min of bilateral dynamic squat exercises on a side-alternating vibration platform at 24-26 Hz three times per week (WBV) and (2) a control group (CON) with the same amount of exercise time without WBV. RESULTS: Thirty-six patients completed the study in each group. The improvement in 6-min walking distance was significantly higher in the WBV-group when compared to the CON-group (WBV: 64 +/- 59 m, CON: 37 +/- 52 m with a between-group difference of 27 m [95% CI, 1-53], p = 0.046). The time required for a sit-to-stand test also decreased more markedly in the WBV-group than in the CON-group (WBV: -4.0 +/- 4.8 s, CON: -2.0 +/- 3.1 s with a between group difference of -1.9 s [95% CI, -4.0 to 0.1], p = 0.067). Improvements in health-related quality of life were similar in both groups. CONCLUSIONS: WBV training seems to be a promising new exercise modality for patients with COPD and may enhance the effects of a multidisciplinary rehabilitation program. PMID- 22104541 TI - Targeting EGFR in non-small-cell lung cancer: lessons, experiences, strategies. AB - Cancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment. Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies. This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response. PMID- 22104542 TI - Factors influencing exercise performance in thoracic cancer. AB - BACKGROUND: Patients with incurable thoracic cancer often complain of a reduced ability to exercise, but the cause of this has been little studied. Thus, we have explored how various physiological and psychological factors relate to exercise performance in this group. METHODS: Inspiratory muscle strength, peripheral muscle power, lung function and mastery over breathlessness were assessed using sniff nasal inspiratory pressure, leg extensor power, simple spirometry and the mastery domain of the Chronic Respiratory Disease Questionnaire respectively. Exercise performance was assessed using the Incremental Shuttle Walking Test (ISWT) during which patients wore a K4 b(2) system permitting measurement of resting and breakpoint heart rate, minute ventilation (VE) and oxygen uptake (VO(2)). Relationships between ISWT distance and the four factors were determined using correlation and beta regression coefficients. RESULTS: Forty-one patients (21 male, mean (SD) age 64 (8) years) walked a median [IQR] of 320 [250-430] metres and reached a mean (SD) of 76 (10), 77 (25), and 48 (14) of their percent predicted maximum heart rate, VO(2), and VE respectively. Exercise performance was significantly associated only with inspiratory muscle strength (r = 0.42, P < 0.01) and peripheral muscle power (r = 0.39, P = 0.01). These factors were also significant determinants of exercise performance (beta coefficients [95%CI] 1.77 [0.53, 3.01] and 1.22 [0.31, 2.14] respectively). CONCLUSION: Of the factors examined, only inspiratory and peripheral muscle performance were significantly related to and predictive of exercise performance. Rehabilitation interventions which include inspiratory and peripheral muscle training are worth exploring further in this group of patients with thoracic cancer. PMID- 22104543 TI - Snoring and cognitive development in infancy. AB - OBJECTIVE: This study aimed to assess the influence of snoring and sleep duration on developmental outcomes in 6 month old infants. METHODS: As part of a longitudinal study of snoring in infancy, we identified 16 children (13 males) who commenced snoring shortly after birth and continued to snore frequently (>= 3 nights/week) at 6 months of age and 88 healthy infant controls who were reported never to snore in the absence of a cold (36 males). Infants were assessed at 6 months of age with the Bayley Scales of Infant and Toddler Development Edition III, and parents completed demographic, sleep, and developmental surveys. RESULTS: Cognitive development was reduced in infants who snored frequently (mean=95.3; SD=4.3) from the first month of life compared to control infants (mean=100.6; SD=3.9) (F [1, 99]=23.8, p<.01; eta(p)(2)=.21). CONCLUSION: Snoring during the first 6 months of life was associated with lower cognitive development scores. It is unknown whether these infants will continue to snore through childhood and, if so, whether the associated neurocognitive deficits will become worse with time. PMID- 22104544 TI - Heart rate increment in the diagnosis of obstructive sleep apnoea in an older population. AB - OBJECTIVE: To evaluate the ability of the heart rate power spectral density of the very low frequency component expressed as a percentage of the total power spectral band (%VLFI) to diagnose obstructive sleep apnoea (OSA) in the elderly. PATIENTS AND METHODS: Eight hundred and thirty-two subjects aged 68.5+/-0.8 years were selected from the participants of a 7-year cross-sectional study on the association between OSA and vascular morbidity-mortality. All subjects underwent electrocardiogram Holter monitoring and an at-home polysomnogram to measure the apnoea/hypopnoea index (AHI). OSA was assessed as an AHI>15. RESULTS: The very low, the low frequency powers, and the %VLFI increased in subjects with OSA and were correlated with the autonomic arousal index and AHI (p<0.0001). A %VLFI of 2.4% and 4% demonstrated a sensitivity of 62% and 69% and a specificity of 45% and 44% to predict OSA in the population. CONCLUSION: The %VLFI did not provide a high level of diagnostic sensitivity and specificity at different degrees of OSA severity in an elderly healthy population. The ability for prediction was lower in mild cases and in women. These findings suggest that the ageing-related changes in the autonomic nervous system reduce the applicability of HRV to diagnose OSA in older populations. PMID- 22104545 TI - Human papillomavirus infection in oral papillary and verrucous lesions is a prognostic indicator of malignant transformation. AB - BACKGROUND: Recent studies have demonstrated an increase in the incidence of HPV associated oral squamous cell carcinoma. The aim of this study was to investigate the presentation of HPV in verrucous and papillary lesions of the oral mucosa and the relationship with the prognosis of the patients. METHODS: Fifty-three biopsy specimens from 31 patients were investigated by polymerase chain reaction using a consensus primer directed to the HPV L1 gene; this was followed by a confirmatory in situ hybridization to identify the HPV types. RESULT: Fifteen tumor biopsies (28.3%) were positive for the HPV L1 gene, but only 8 specimens (15.1%) were found to be positive using in situ hybridization. The positive rates of HPV L1 gene were 58.8% and 13.9% in malignant and benign verrucous lesions, respectively. HPV infection is independently associated with malignant transformation and disease-specific survival. CONCLUSION: The presence of HPV infection is relatively low; however, the clinical outcome of patients with HPV positive papillary and verrucous lesions was poor. PMID- 22104546 TI - Immune activation resulting from NKG2D/ligand interaction promotes atherosclerosis. AB - BACKGROUND: The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood. METHODS AND RESULTS: Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions. CONCLUSIONS: The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease. PMID- 22104547 TI - Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. AB - BACKGROUND: More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association. METHODS AND RESULTS: A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4-2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5-2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4-2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results. CONCLUSIONS: The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa-related stroke. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00093015. PMID- 22104548 TI - Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. AB - BACKGROUND: Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. METHODS AND RESULTS: We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17-0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38-0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20-0.44; P<0.001). CONCLUSIONS: UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study. PMID- 22104549 TI - Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex >=120 milliseconds. AB - BACKGROUND: Left ventricular (LV) pacing alone may theoretically avoid deleterious effects of right ventricular pacing. METHODS AND RESULTS: In a multicenter, double-blind, crossover trial, we compared the effects of LV and biventricular (BiV) pacing on exercise tolerance and LV remodeling in patients with an LV ejection fraction <=35%, QRS >=120 milliseconds, and symptoms of heart failure. A total of 211 patients were recruited from 11 centers. After a run-in period of 2 to 8 weeks, 121 qualifying patients were randomized to LV followed by BiV pacing or vice versa for consecutive 6-month periods. The greatest improvement in New York Heart Association class and 6-minute walk test occurred during the run-in phase before randomization. Exercise duration at 75% of peak Vo(2) (primary outcome) increased from 9.3+/-6.4 to 14.0+/-11.9 and 14.3+/-12.5 minutes with LV and BiV pacing, respectively, with no difference between groups (P=0.4327). LV ejection fraction improved from 24.4+/-6.3% to 31.9+/-10.8% and 30.9+/-9.8% with LV and BiV pacing, respectively, with no difference between groups (P=0.4530). Reductions in LV end-systolic volume were likewise similar (P=0.6788). The proportion of clinical responders (>=20% increase in exercise duration) to LV and BiV pacing was 48.0% and 55.1% (P=0.1615). Positive remodeling responses (>=15% reduction in LV end-systolic volume) were observed in 46.7% and 55.4% (P=0.0881). Overall, 30.6% of LV nonresponders improved with BiV and 17.1% of BiV nonresponders improved with LV pacing. CONCLUSION: LV pacing is not superior to BiV pacing. However, nonresponders to BiV pacing may respond favorably to LV pacing, suggesting a potential role as tiered therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00901212. PMID- 22104550 TI - Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial. AB - BACKGROUND: We sought to separately examine the effects of either weight loss or diets varying in protein content and glycemic index without further changes in body weight on cardiovascular risk factors within the Diet, Obesity, and Genes study (DiOGenes). METHODS AND RESULTS: DiOGenes is a pan-European controlled dietary intervention study in 932 overweight adults who first lost body weight on an 8-week low-calorie diet and were then randomized to 1 of 5 ad libitum diets for 26 weeks. The diets were either high or low protein or high or low glycemic index in 4 combinations or control. Weight loss (-11.23 kg; 95% confidence interval, -11.54 to -10.92; P<0.001) reduced high-sensitivity C-reactive protein (-1.15 mg/L; 95% confidence interval, -1.30 to -0.41; P<0.001), low- and high density lipoprotein cholesterol, triglycerides, and blood pressure. During the 26 week weight maintenance period in the intention-to-treat analysis, the further decrease of high-sensitivity C-reactive protein blood levels was -0.46 mg/L greater (95% confidence interval, -0.79 to -0.13) in the groups assigned to low glycemic-index diets than in those on high-glycemic-index diets (P<0.001). Groups on low-protein diets achieved a -0.25 mg/L greater reduction in high-sensitivity C-reactive protein (95% confidence interval, -0.59 to -0.17) than those on high protein diets (P<0.001), whereas lipid profiles and blood pressure were not differently affected. CONCLUSIONS: This large-scale intervention study clearly separates weight loss from dietary composition-related effects. Low-glycemic index carbohydrates and, to a lesser extent, low-protein intake may specifically reduce low-grade inflammation and associated comorbidities in overweight/obese adults. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00390637. PMID- 22104551 TI - The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure. AB - BACKGROUND: Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging. METHODS AND RESULTS: This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced apex beat, rales, heart murmur, and increased jugular vein pressure) showed independent diagnostic value (c-statistic 0.83). NT-proBNP was the most powerful supplementary diagnostic test, increasing the c-statistic to 0.86 and resulting in net reclassification improvement of 69% (P<0.0001). A simplified diagnostic rule was applied to 2 external validation datasets, resulting in c- statistics of 0.95 and 0.88, confirming the results. CONCLUSIONS: In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure. PMID- 22104552 TI - Survival after open versus endovascular thoracic aortic aneurysm repair in an observational study of the Medicare population. AB - BACKGROUND: The goal of this study was to describe short- and long-term survival of patients with descending thoracic aortic aneurysms (TAAs) after open and endovascular repair (TEVAR). METHODS AND RESULTS: Using Medicare claims from 1998 to 2007, we analyzed patients who underwent repair of intact and ruptured TAA, identified from a combination of procedural and diagnostic International Classification of Disease, ninth revision, codes. Our main outcome measure was mortality, defined as perioperative mortality (death occurring before hospital discharge or within 30 days), and 5-year survival, from life-table analysis. We examined outcomes across repair type (open repair or TEVAR) in crude, adjusted (for age, sex, race, procedure year, and Charlson comorbidity score), and propensity-matched cohorts. Overall, we studied 12 573 Medicare patients who underwent open repair and 2732 patients who underwent TEVAR. Perioperative mortality was lower in patients undergoing TEVAR compared with open repair for both intact (6.1% versus 7.1%; P=0.07) and ruptured (28% versus 46%; P<0.0001) TAA. However, patients with intact TAA selected for TEVAR had significantly worse survival than open patients at 1 year (87% for open, 82% for TEVAR; P=0.001) and 5 years (72% for open; 62% for TEVAR; P=0.001). Furthermore, in adjusted and propensity-matched cohorts, patients selected for TEVAR had worse 5-year survival than patients selected for open repair. CONCLUSIONS: Although perioperative mortality is lower with TEVAR, Medicare patients selected for TEVAR have worse long-term survival than patients selected for open repair. The results of this observational study suggest that higher-risk patients are being offered TEVAR and that some do not benefit on the basis of long-term survival. Future work is needed to identify TEVAR candidates unlikely to benefit from repair. PMID- 22104553 TI - Matrix metalloproteinase-10 effectively reduces infarct size in experimental stroke by enhancing fibrinolysis via a thrombin-activatable fibrinolysis inhibitor-mediated mechanism. AB - BACKGROUND: The fibrinolytic and matrix metalloproteinase (MMP) systems cooperate in thrombus dissolution and extracellular matrix proteolysis. The plasminogen/plasmin system activates MMPs, and some MMPs have been involved in the dissolution of fibrin by targeting fibrin(ogen) directly or by collaborating with plasmin. MMP-10 has been implicated in inflammatory/thrombotic processes and vascular integrity, but whether MMP-10 could have a profibrinolytic effect and represent a promising thrombolytic agent is unknown. METHODS AND RESULTS: The effect of MMP-10 on fibrinolysis was studied in vitro and in vivo, in MMP-10-null mice (Mmp10(-/-)), with the use of 2 different murine models of arterial thrombosis: laser-induced carotid injury and ischemic stroke. In vitro, we showed that MMP-10 was capable of enhancing tissue plasminogen activator-induced fibrinolysis via a thrombin-activatable fibrinolysis inhibitor inactivation mediated mechanism. In vivo, delayed fibrinolysis observed after photochemical carotid injury in Mmp10(-/-) mice was reversed by active recombinant human MMP 10. In a thrombin-induced stroke model, the reperfusion and the infarct size in sham or tissue plasminogen activator-treated animals were severely impaired in Mmp10(-/-) mice. In this model, administration of active MMP-10 to wild-type animals significantly reduced blood reperfusion time and infarct size to the same extent as tissue plasminogen activator and was associated with shorter bleeding time and no intracranial hemorrhage. This effect was not observed in thrombin activatable fibrinolysis inhibitor-deficient mice, suggesting thrombin activatable fibrinolysis inhibitor inactivation as one of the mechanisms involved in the MMP-10 profibrinolytic effect. CONCLUSIONS: A novel profibrinolytic role for MMP-10 in experimental ischemic stroke is described, opening new pathways for innovative fibrinolytic strategies in arterial thrombosis. PMID- 22104555 TI - A cross-sectional investigation of the suicidal spectrum: typologies of suicidality based on ambivalence about living and dying. AB - OBJECTIVE: The aim of this study was to determine the validity of assigning suicidal individuals into differing typologies of suicidality based on their reported wish to live and wish to die. METHODS: One hundred five inpatients who reported suicidal ideation in the previous 48 hours completed a battery of assessments during inpatient psychiatric hospitalization. An algorithm was used to assign participants into 1 of 3 typologies of suicide: wish to live, ambivalent, or wish to die. Discriminant function analysis and group classification were used to predict group membership, followed by multiple analysis of variance and follow-up contrasts to measure between-group differences. MAIN RESULTS: Group classification resulted in 76% accuracy for predicting typology of suicidality based on scores from suicide-specific measures. Self-perceived risk of suicide and hopelessness were the strongest variables at differentiating between the 3 groups. Patients in the wish to die typology were less likely to report having never made a suicide attempt. CONCLUSIONS: Creating typologies of suicidality may prove useful to clinicians seeking to better differentiate among suicidal patients within a limited period of assessment. PMID- 22104554 TI - Combined lifestyle factors and cardiovascular disease mortality in Chinese men and women: the Singapore Chinese health study. AB - BACKGROUND: Lifestyle factors directly influence cardiovascular disease (CVD) risk, yet little research has examined the association of combined lifestyle factors with CVD mortality, especially in Asian populations. METHODS AND RESULTS: We examined the association of 6 combined lifestyle factors (dietary pattern, physical activity, alcohol intake, usual sleep, smoking status, and body mass index) with CVD mortality in 50 466 (44 056 without a history of diabetes mellitus, CVD, or cancer and 6410 with diabetes mellitus or history of clinical CVD) Chinese men and women in Singapore who were 45 to 74 years of age during enrollment in the Singapore Chinese Health Study in 1993 to 1998 and followed up through 2009. Each lifestyle factor was independently associated with CVD mortality. When combined, there was a strong, monotonic decrease in age- and sex standardized CVD mortality rates with an increasing number of protective lifestyle factors. Relative to participants with no protective lifestyle factors, the hazard ratios of CVD mortality for 1, 2, 3, 4, and 5 to 6 protective lifestyle factors were 0.60 (95% confidence interval, 0.45-0.84), 0.50 (95% confidence interval, 0.38-0.67), 0.40 (95% confidence interval, 0.30-0.53), 0.32 (95% confidence interval, 0.24-0.43), and 0.24 (95% confidence interval, 0.17 0.34), respectively, among those without a history of diabetes mellitus, CVD, or cancer (P for trend <0.0001). A parallel graded inverse association was observed in participants with a history of CVD or diabetes mellitus at baseline. Results were consistent for coronary heart disease and cerebrovascular disease mortality. CONCLUSION: An increasing number of protective lifestyle factors is associated with a marked decreased risk of coronary heart disease, cerebrovascular disease, and overall CVD mortality in Chinese men and women. PMID- 22104556 TI - Performance of the 6-item Kessler scale for measuring serious mental illness in Hong Kong. AB - BACKGROUND: The 6-item Kessler scale (K6) promises to be a valuable epidemiological tool for assessing serious mental illness (SMI) in communities with limited resources for psychiatric research and treatment. Its performance in Chinese community has not been studied with reference to clinically assessed SMI. METHOD: From a representative telephone-based population survey (n = 3014) that administered the K6, 153 participants were readministered the K6 and, on the same day, interviewed face-to-face by clinicians using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Axis I Disorder. Predictive indicators such as McNemar chi(2), area under receiver operating characteristic curve and stratum-specific likelihood ratios were used to investigate the concordance between the K6 and clinical status of SMI, individual-level predicted probabilities of having SMI, and the weighted prevalence of SMI in the community. RESULT: The K6 exhibited high internal consistency and test-retest reliability. Factor analysis revealed 2 correlating components composed of depression and anxiety. Matching of K6 caseness and SMI status showed that at the cutoff of 12/13, the area under receiver operating characteristic curve was moderate (0.69). The K6 had high specificity and was a stronger screen-out than screen-in tool for SMI. The weighted prevalence estimate of SMI in Hong Kong was 6.5%. A person scoring 13 or above on the K6 has a probability of at least 22.2% of having SMI. CONCLUSION: The Chinese K6 is reliable and generates the likelihood of SMI with substantial concordance with face-to-face clinical interviews in Hong Kong. It is a valuable tool for screening SMI, behavioral risk factor surveillance, and community epidemiological surveys. PMID- 22104557 TI - Impact of comorbid migraine on the clinical course of bipolar disorder. AB - BACKGROUND: Recent evidence suggests an association between migraine and bipolar disorder (BD), although the impact of this association in the clinical course of BD is relatively unknown. OBJECTIVE: This study aimed to compare 2 groups of individuals with BD (with vs without comorbid migraine) and evaluate differences in severity of clinical course. METHODS: Three hundred thirty-nine adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined bipolar I or II disorder were enrolled and divided into 2 groups: with and without comorbid migraine. Demographic and clinical data were obtained using standardized interviews. RESULTS: Patients with comorbid migraines had more mood episodes, especially those with depressive polarity. In addition, comorbid migraine was associated with a higher prevalence of psychiatric and general medical comorbidities. Differences between the 2 groups in number of lifetime hospitalizations for depression/mania, rates of rapid cycling, and history of suicide attempts were not observed after Bonferroni correction. CONCLUSIONS: Comorbid migraine seems to be associated with poor outcomes in BD. Additional studies should be conducted to investigate shared vulnerabilities and pathophysiologic mechanisms as well as treatment optimization of both illnesses. PMID- 22104558 TI - Clinical data integration of distributed data sources using Health Level Seven (HL7) v3-RIM mapping. AB - BACKGROUND: Health information exchange and health information integration has become one of the top priorities for healthcare systems across institutions and hospitals. Most organizations and establishments implement health information exchange and integration in order to support meaningful information retrieval among their disparate healthcare systems. The challenges that prevent efficient health information integration for heterogeneous data sources are the lack of a common standard to support mapping across distributed data sources and the numerous and diverse healthcare domains. Health Level Seven (HL7) is a standards development organization which creates standards, but is itself not the standard. They create the Reference Information Model. RIM is developed by HL7's technical committees. It is a standardized abstract representation of HL7 data across all the domains of health care. In this article, we aim to present a design and a prototype implementation of HL7 v3-RIM mapping for information integration of distributed clinical data sources. The implementation enables the user to retrieve and search information that has been integrated using HL7 v3-RIM technology from disparate health care systems. METHOD AND RESULTS: We designed and developed a prototype implementation of HL7 v3-RIM mapping function to integrate distributed clinical data sources using R-MIM classes from HL7 v3-RIM as a global view along with a collaborative centralized web-based mapping tool to tackle the evolution of both global and local schemas. Our prototype was implemented and integrated with a Clinical Database management Systems CDMS as a plug-in module. We tested the prototype system with some use case scenarios for distributed clinical data sources across several legacy CDMS. The results have been effective in improving information delivery, completing tasks that would have been otherwise difficult to accomplish, and reducing the time required to finish tasks which are used in collaborative information retrieval and sharing with other systems. CONCLUSIONS: We created a prototype implementation of HL7 v3 RIM mapping for information integration between distributed clinical data sources to promote collaborative healthcare and translational research. The prototype has effectively and efficiently ensured the accuracy of the information and knowledge extractions for systems that have been integrated. PMID- 22104559 TI - Fatigue's effect on eversion force sense in individuals with and without functional ankle instability. AB - CONTEXT: Force sense (FS), the proprioceptive ability to detect muscle-force generation, has been shown to be impaired in individuals with functional ankle instability (FAI). Fatigue can also impair FS in healthy individuals, but it is unknown how fatigue affects FS in individuals with FAI. OBJECTIVE: To assess the effect of fatigue on ankle-eversion force-sense error in individuals with and without FAI. DESIGN: Case control with repeated measures. SETTING: Sports medicine research laboratory. PARTICIPANTS: 32 individuals with FAI and 32 individuals with no ankle sprains or instability in their lifetime. FAI subjects had a history of >=1 lateral ankle sprain and giving-way >=1 episode per month. INTERVENTIONS: Three eversion FS trials were captured per load (10% and 30% of maximal voluntary isometric contraction) using a load cell before and after a concentric eversion fatigue protocol. MAIN OUTCOME MEASURES: Trial error was the difference between the target and reproduction forces. Constant error (CE), absolute error (AE), and variable error (VE) were calculated from 3 trial errors. A Group * Fatigue * Load repeated-measures ANOVA was performed for each error. RESULTS: There were no significant 3-way interactions or 2-way interactions involving group (all P > .05). CE and AE had a significant 2-way interaction between load and fatigue (CE: F1,62 = 8.704, P = .004; AE: F1,62 = 4.024, P = .049), and VE had a significant main effect for fatigue (F1,62 = 5.130, P = .027), all of which indicated increased FS error with fatigue at 10% load. However, at 30% load only VE increased with fatigue. The FAI group had greater error as measured by AE (F1,62 = 4.571, P = .036) but not CE or VE (P > .05). CONCLUSIONS: Greater AE indicates that FAI individuals are less accurate in their force production. Fatigue impaired force sense in all subjects equally. These deficits provide evidence of impaired proprioception with fatigue and in individuals with FAI. PMID- 22104560 TI - Population-based study of incidence and clinical characteristics of rheumatic fever in Abruzzo, central Italy, 2000-2009. AB - OBJECTIVE: To investigate the incidence and describe the characteristics of acute rheumatic fever (ARF) in the pediatric population in a community-based healthcare delivery system of the central Italy region of Abruzzo during 2000-2009. STUDY DESIGN: A retrospective study was conducted in Abruzzo to identify patients aged <18 years with a diagnosis of ARF between January 1, 2000, and December 31, 2009. Each patient's age, sex, date of diagnosis, age at disease presentation, and fulfilled Jones criteria were recorded. RESULTS: A total of 88 patients meeting the Jones criteria for the diagnosis of ARF were identified, with arthritis in 59.1% of the patients, carditis in 48.9%, erythema marginatum in 11.4%, 5.7% with chorea, and 4.6% with subcutaneous nodules. Residual chronic rheumatic heart disease was present in 44.3% of the children. Age at diagnosis ranged from 2.5 to 17 years (average, 8.7 +/- 4.0 years). Twelve children (13.6%) were under age 5 years. The overall incidence rate of ARF was 4.1/100 000. The lowest incidence rate was documented in the year 2000 (2.26/100 000), and the highest in 2006 (5.58/100 000). CONCLUSION: Our data indicate that ARF has not disappeared in industrialized countries and still causes significant residual rheumatic heart disease. Pediatricians should routinely consider the diagnoses of streptococcal pharyngitis and ARF to reduce long-term morbidity and mortality. PMID- 22104561 TI - Developmental neuroplasticity after cochlear implantation. AB - Cortical development is dependent on stimulus-driven learning. The absence of sensory input from birth, as occurs in congenital deafness, affects normal growth and connectivity needed to form a functional sensory system, resulting in deficits in oral language learning. Cochlear implants bypass cochlear damage by directly stimulating the auditory nerve and brain, making it possible to avoid many of the deleterious effects of sensory deprivation. Congenitally deaf animals and children who receive implants provide a platform to examine the characteristics of cortical plasticity in the auditory system. In this review, we discuss the existence of time limits for, and mechanistic constraints on, sensitive periods for cochlear implantation and describe the effects of multimodal and cognitive reorganization that result from long-term auditory deprivation. PMID- 22104562 TI - The radiation issue in cardiology: the time for action is now. AB - The "radiation issue" is the need to consider possible deterministic effects (e.g., skin injuries) and long-term cancer risks due to ionizing radiation in the risk-benefit assessment of diagnostic or therapeutic testing. Although there are currently no data showing that high-dose medical studies have actually increased the incidence of cancer, the "linear-no threshold" model in radioprotection assumes that no safe dose exists; all doses add up in determining cancer risks; and the risk increases linearly with increasing radiation dose. The possibility of deterministic effects should also be considered when skin or lens doses may be over the threshold. Cardiologists have a special mission to avoid unjustified or non-optimized use of radiation, since they are responsible for 45% of the entire cumulative effective dose of 3.0 mSv (similar to the radiological risk of 150 chest x-rays) per head per year to the US population from all medical sources except radiotherapy. In addition, interventional cardiologists have an exposure per head per year two to three times higher than that of radiologists. The most active and experienced interventional cardiologists in high volume cath labs have an annual exposure equivalent to around 5 mSv per head and a professional lifetime attributable to excess cancer risk on the order of magnitude of 1 in 100. Cardiologists are the contemporary radiologists but sometimes imperfectly aware of the radiological dose of the examination they prescribe or practice, which can range from the equivalent of 1-60 mSv around a reference dose average of 10-15 mSv for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multi-detector coronary angiography, or a myocardial perfusion imaging scintigraphy. A good cardiologist cannot be afraid of life-saving radiation, but must be afraid of radiation unawareness and negligence. PMID- 22104563 TI - Single-incision versus standard multiport laparoscopic colectomy: a multicenter, case-controlled comparison. AB - OBJECTIVE: The aim of this study was to compare single-incision laparoscopic colectomy (SILC) to multiport laparoscopic colectomy (MLC) when performed by experienced laparoscopic surgeons. BACKGROUND: Recent case reports and single institution series have demonstrated the feasibility of SILC. Few comparative studies for MLC and SILC have been reported. METHODS: Patients from 5 institutions undergoing SILC were entered into an IRB approved database from November 2008 to March 2010. SILC patients were matched with those undergoing MLC for gender, age, disease, surgery, BMI, and surgeon. The primary endpoint was length of stay and secondary endpoints included operative time, conversion, complications and postoperative pain scores. RESULTS: Three hundred thirty patients (SILC = 165, MLC = 165) were evaluated. Operative time (135 +/- 45 min vs. 133 +/- 56 min; P = 0.85) and length of stay (4.6 +/- 1.6 vs. 4.3 +/- 1.4; P = 0.35) were not significantly different. Maximum postoperative day one pain scores were significantly less for SILC (4.9 vs. 5.6; P = 0.005). Eighteen (11%) patients undergoing SILC were converted to multiport laparoscopy. There was no statistical difference between groups for conversions to laparotomy, complications, re-operations, or re-admissions. CONCLUSIONS: SILC is feasible when performed on select patients by surgeons with extensive laparoscopic experience. Outcomes were similar to MLC, except for a reduction in peak pain score on the first postoperative day. Prospective randomized trials should be performed before incorporation of this technology into routine surgical care. PMID- 22104564 TI - Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. AB - OBJECTIVE: To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFNalpha-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC). BACKGROUND: Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC. METHODS: Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNalpha-2b treatment or observation alone. The primary endpoint of this study was RFS. RESULTS: A total of 268 patients were enrolled with 133 in the IFNalpha-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFNalpha 2b and control arms were 42.2 (95% confidence interval [CI], 28.1-87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFNalpha-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNalpha-2b only temporarily suppressed viral replication during treatment period. CONCLUSIONS: In this study, adjuvant IFNalpha-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565. PMID- 22104565 TI - Microvascular blood flow changes in the small intestinal wall during conventional negative pressure wound therapy and negative pressure wound therapy using a protective disc over the intestines in laparostomy. AB - OBJECTIVES: Blood flow changes in the intestines during conventional negative pressure wound therapy (NPWT), and NPWT using a protective disc over the intestines in laparostomy. BACKGROUND: Higher closure rates of the open abdomen have been reported with NPWT compared with other kinds of wound management. However, the method has been associated with increased development of fistulae. We have compared the changes in blood flow in the intestinal wall using conventional NPWT and NWPT with a protective disc between the intestines and the vacuum source. METHODS: Midline incisions were made in 10 pigs and either conventional NPWT or NPWT with a disc over the intestines was applied. The microvascular blood flow was measured in the intestinal wall before and after the application of topical negative pressures of -50, -70, and -120 mmHg, using laser Doppler velocimetry. RESULTS: The blood flow was significantly decreased (by 24%) after the application of conventional NPWT at -50 mmHg, compared with a slight decrease (2%) after the application of NWPT with a protective disc (P < 0.05). The blood flow was significantly decreased (by 54%) after the application of conventional NPWT at -120 mmHg, compared with a slight decrease (17%) after application of NPWT using a protective disc (P < 0.001). CONCLUSIONS: Inserting a disc between the intestines and the vacuum source in NPWT protects the intestines from ischemia. The decreased blood flow in the intestinal wall may induce ischemia, which could promote the development of intestinal fistulae. PMID- 22104566 TI - The effects of multiple pre- and perinatal risk factors on the occurrence of cerebral palsy. A Norwegian register based study. AB - AIMS: To examine the effects of multiple risk factors on cerebral palsy (CP). MATERIALS/METHODS: For 176,591 Norwegian infants born 1996-98 and surviving the early neonatal period, data on a number of potential pre- and perinatal risk factors (RFs) for CP were available in the Medical Birth Registry of Norway. For 241 children with CP detailed clinical data were available in the Norwegian CP registry. RESULTS: In children born at term, 31% had no RF, and none had five or more, while in children born preterm, 9% had no RF in addition to prematurity (p < 0.001 vs. term), and 5% had five or more (p < 0.02 vs. term). In both groups, few children shared the same combination of RFs. Interdependent sequences were more often observed among children born preterm than at term (p < 0.001 vs. term). The most detrimental effect was observed for the combination of maternal disease and low 5-min Apgar score, registered in 11.2% of children with CP. The combination of maternal disease and premature birth had an interaction contrast ratio of 9.25 (CI: 3.56; 14.94), which may be consistent with biological interaction. CONCLUSIONS: The majority of children with CP born at term most likely had an antenatal or single cause, suggesting individual susceptibility to an injury. The majority of children born preterm, had combinations or sequences of antenatal and perinatal risk factors as the most likely cause of CP. PMID- 22104567 TI - IL-4 and TNF-alpha polymorphisms are associated with risk of multiple superficial tumors or carcinoma in situ development. AB - INTRODUCTION: This study evaluates the influence of clinicopathological characteristics, bacillus Calmette-Guerin (BCG) therapeutic schedule [maintenance (mBCG) or induction (iBCG)], and TNF-alpha and IL-4 polymorphisms on the outcome of non-muscle-invasive bladder cancer patients treated with BCG. MATERIAL AND METHODS: DNA was extracted from 125 bladder cancer patients treated with BCG; TNF 308G/A and IL4-590C/T polymorphisms were genotyped. RESULTS: The TNF-308A allele carriers had an increased risk of developing multiple tumors (OR: 2.80, p = 0.031). However, IL4-590 T carriers also had an increased risk of developing multiple and carcinoma in situ tumors (OR: 2.52, p = 0.033). For these polymorphisms, no association was found with BCG treatment outcome. When treated with iBCG, patients with multiple tumors had shorter recurrence-free survival (RFS) compared with those with a single tumor (p = 0.004); nevertheless, patients with multifocal tumors have improved RFS when treated with mBCG. CONCLUSIONS: Overall, the results suggest that multiple tumors and/or carcinoma in situ development are associated with the IL4-590C/T and TNF-308G/A polymorphisms, and emphasize the effectiveness of the mBCG schedule. PMID- 22104568 TI - Cognitive behavior therapy for chronic subjective dizziness: a randomized, controlled trial. AB - PURPOSE: The aim of this study was to evaluate the effects of a brief cognitive behavior therapy (CBT) intervention on the physical symptoms, illness-related disability, and psychologic distress of patients with chronic subjective dizziness. MATERIALS AND METHODS: Forty-one patients with chronic subjective dizziness referred by a neurootologic clinic were randomly assigned to immediate treatment or a wait-list control. Three weekly treatment sessions based on the CBT model of panic disorder, adapted for patients with dizziness, were administered by a clinical psychologist. Treatment included psychoeducation, behavioral experiments, exposure to feared stimuli, and attentional refocusing. Outcomes were measured on the Dizziness Handicap Inventory and the Depression, Anxiety and Stress Scales. Two further measures developed for this study; the Dizziness Symptoms Inventory and the Safety Behaviours Inventory were used to measure physical symptoms and safety behaviors. RESULTS: The intervention was associated with significant reductions in disability on the Dizziness Handicap Inventory, reduced dizziness and related physical symptoms on the Dizziness Symptoms Inventory, and reduced avoidance and safety behaviors as measured by the Safety Behaviours Inventory. Pre- to posteffect sizes ranged from 0.98 to 1.15. There was no change in psychologic outcomes measured on the Depression, Anxiety and Stress Scales. CONCLUSIONS: A 3-session psychologic intervention based on the CBT model can produce significant improvements in dizziness-related symptoms, disability, and functional impairment among patients with chronic subjective dizziness. This suggests that treatment of this condition may be reasonably simple and cost-effective for most of the patients. PMID- 22104569 TI - Are stroke occurrence and outcome related to weather parameters? Results from a population-based study in northern portugal. AB - BACKGROUND: Changes in meteorological parameters have been associated with cardiovascular mortality and stroke. The high incidence of stroke in Portugal may be modelled by short- or long-term weather changes whose effect may be different across stroke types and severity. METHODS: Data include all patients with a first ever-in-a-lifetime stroke registered in a population of 86,023 residents in the city of Porto from October 1998 to September 2000. Specific stroke types were considered and ischaemic stroke (IS) subtype was defined according to the Oxfordshire Community Stroke Projet classification and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Information on daily temperature, humidity and air pressure was obtained from the National Meteorological Office. The Poisson distribution was used to model the daily number of events as a function of each weather parameter measured over different hazard periods, and the binomial model to contrast effects across subgroups. Differential effects of meteorological parameters and hazard periods upon stroke occurrence and outcome were analysed in a stepwise model. RESULTS: Among the 462 patients registered, 19.6% had a primary intracerebral haemorrhage (PICH) and 75.3% an IS. Among patients with IS, 21.6% were total anterior circulation infarcts (TACIs), 19.8% partial anterior circulation infarcts (PACIs), 19.5% posterior circulation infarcts (POCIs) and 39.1% were lacunar infarcts (LACIs). The aetiology of IS was large artery atherosclerosis in 6.9%, cardioembolism in 23.3% and small artery occlusion in 35.6%. The incidence of PICH increased by 11.8% (95% CI: 3.8-20.4%) for each degree drop in the diurnal temperature range in the preceding day. The incidence of IS increased by 3.9% (95% CI: 1.6-6.3%) and cardioembolic IS by 5.0% (95% CI: 0.2-10.1%) for a 1 degrees C drop in minimum temperature in the same hazard period. The incidence of TACIs followed the IS pattern while for PACIs and POCIs there were stronger effects of longer hazard periods and no association was found for LACIs. The relative risk of a fatal versus a non-fatal stroke increased by 15.5% (95% CI: 6.1-25.4%) for a 1 degrees C drop in maximum temperature over the previous day. CONCLUSIONS: Outdoor temperature and related meteorological parameters are associated with stroke occurrence and severity. The different hazard periods for temperature effects and the absence of association with LACIs may explain the heterogeneous effects of weather on stroke occurrence found in community-based and hospital admission studies. Emergency services should be aware that specific weather conditions are more likely to prompt calls for more severe strokes. PMID- 22104570 TI - [Short-long-short sequences as trigger for ventricular tachycardia]. PMID- 22104571 TI - [Novel mutation in long QT syndrome in a patient with prior diagnosis of epilepsy]. AB - Congenital long QT syndrome (LQTS) can present as syncope or seizures, secondary to polymorphic ventricular tachycardia, mimicking a primary seizure disorder. In patients treated with an implantable cardioverter-defibrillator (ICD), the recurrence of arrhythmias with subsequent frequent therapeutic shocks may cause adverse reactions, which can be psychogenic. We report the case of a 22-year-old woman with syncope and seizures who was diagnosed in childhood as epileptic and in whom LQTS was diagnosed only in adulthood. Beta-blocker therapy failed and an ICD was implanted. However, as arrhythmias persisted, left cardiac sympathetic denervation was performed. After surgery, three-month follow-up showed a significant reduction in arrhythmias. The genetic study identified a heterozygous mutation, c.1817 C>T p.S606F, on the KCNH2 gene that has not previously been reported in the literature. We also report the rare occurrence of an electrical storm in the course of H1N1 infection. This case illustrates the difficulties in the diagnosis and treatment of LQTS. The possibility of a common genetic basis for arrhythmic diseases and epilepsy is discussed. PMID- 22104572 TI - The ARCAD advanced colorectal cancer database--open for business. PMID- 22104573 TI - Lung malignancies after Hodgkin lymphoma: disease characteristics, detection methods and clinical outcome. AB - BACKGROUND: Hodgkin lymphoma (HL) survivors have an increased risk of secondary malignancies. We analyzed outcomes in patients with lung cancers following HL treatment. PATIENTS AND METHODS: Cases of thoracic malignancies were retrospectively identified from a multi-institutional database of 1976 patients treated for HL from 1969 to 2007. Data regarding risk factors, disease characteristics and outcomes were obtained from medical records. RESULTS: Lung malignancies were identified in 55 patients a median of 19.5 years after initial HL therapy. Thirty-one patients (56%) had a >10 pack-year history of tobacco use, 48 (87%) received thoracic irradiation and 26 (47%) received alkylating chemotherapy. Of the 42 patients with known stage at lung cancer diagnosis, 23 (55%) were stage IV and 5 (12%) were stage III. The method of lung cancer detection was known for 35 patients; of these, 12 (34%) were detected incidentally. Median survival time after diagnosis was 10 months for all 55 patients. Median survival time for patients with incidentally detected tumors has not been reached with a median follow-up of 39 months. CONCLUSIONS: Lung malignancies diagnosed in patients successfully treated for HL generally have a dismal prognosis. However, a subset of patients diagnosed incidentally may have potentially curable disease. PMID- 22104574 TI - Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). AB - BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7 2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for >=35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ~20 years after quitting. PMID- 22104575 TI - Evaluation of glomerular filtration rate estimation by Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae in oncology patients. AB - BACKGROUND: The aim was to evaluate the accuracy of Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae as a substitute for the gold standard measure of glomerular filtration rate (GFR) using chromium 51 EDTA. PATIENTS AND METHODS: Retrospective analysis of GFR measurements in oncology patients from a University Teaching Hospital over 3 years was carried out. Bias and precision of estimates of GFR were compared with measured GFR. RESULTS: Six hundred and sixty patients with measured GFR (median 90 ml/min, range 23-179 ml/min) were identified. Cockcroft-Gault produced the smallest bias (median percentage error -1.4%) and highest precision (median absolute percentage error 14.0%) and was the most accurate for carboplatin dosing. For patients>30% over their ideal body weight (IBW), using IBW+30% in the Cockcroft-Gault formula was more precise than using actual body weight or IBW. The Wright formula was most accurate for patients aged 70+years and patients with a body mass index (BMI)>=30 but overestimated GFR when GFR<50 ml/min. CONCLUSIONS: When measured GFR is unavailable, we advise estimating GFR using the Cockcroft-Gault formula and using IBW+30% for patients weighing>30% over their IBW. If the GFR is >=50 ml/min and the patient is >70 years and/or BMI>=30, the Wright formula gives the best estimate of GFR. PMID- 22104576 TI - 153Samarium-EDTMP administration followed by hematopoietic stem cell support for bone metastases in osteosarcoma patients. AB - BACKGROUND: Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months. PATIENTS AND METHODS: Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion. RESULTS: The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months. CONCLUSIONS: Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients. PMID- 22104577 TI - Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost-utility analysis. AB - BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5 year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of ?11,822/QALY for TAX 323 and ?6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of ?50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions. PMID- 22104578 TI - Understanding the deafened brain: implications for cochlear implant rehabilitation. AB - The cochlear implant (CI), by enabling oral communication in severely to profoundly deaf subjects, is one of the major medical advances over the last fifty years. Despite the globally very satisfactory results, individual outcomes vary considerably. The objective of this review is to describe the various factors influencing the results of CI rehabilitation with particular emphasis on the better understanding of neurocognitive mechanisms provided by functional brain imaging. The following aspects will be discussed: 1. Peripheral predictors such as the degree of preservation of nerve structures and the positioning of the electrode array. 2. The duration of auditory deprivation whose influence on brain reorganization is now becoming more clearly understood. 3. The age of initiation of hearing rehabilitation in subjects with pre-lingual deafness influencing the possibility of physiological maturation of nerve structures. 4. The concepts of sensitive period, decoupling and cross-modality. 5. In post-lingually deaf adults, brain plasticity can allow adaptation to the disability induced by deafness, subsequently potentiating CI rehabilitation, particularly as a result of audiovisual interactions. 6. Several studies provide concordant evidence that implanted patients present different phonological analysis and primary linguistic capacities. The results of CI rehabilitation are dependent on factors situated between the cochlea and cortical associative areas. The importance of higher cognitive influences on the functional results of cochlear implantation justify adaptation of coding strategies, as well as global cognitive management of deaf patients by utilising brain plasticity capacities. PMID- 22104579 TI - Two cases of temporal bone metastases as presenting sign of lung cancer. AB - OBJECTIVE: To report the clinical and radiological features of temporal bone metastases and their association with primary lung cancer. CASE REPORTS: Both patients complained of headache, cochlear signs or cranial nerve palsy. Computed tomography of the petrous temporal bones and magnetic resonance imaging showed an osteolytic lesion of the temporal bone. The preoperative work-up was completed by chest, abdomen and pelvis computed tomography and positron emission tomography. Bronchoscopic biopsies confirmed the diagnosis of lung cancer. DISCUSSION/CONCLUSION: The discovery of an osteolytic lesion of the temporal bone requires an aetiological work-up, including the search for a lung tumour based on the hypothesis of temporal bone metastasis. Positron emission tomography should now be performed in the context of such lesions. Management consists of palliative chemotherapy and analgesic radiotherapy. PMID- 22104580 TI - Salvage surgery after radiotherapy for oropharyngeal cancer. Treatment complications and oncological results. AB - AIMS: Surgery is the only available curative treatment option following failure of radiation therapy for oropharyngeal cancer. This study was designed to analyse the postoperative morbidity and survival rate in patents undergoing salvage surgery. MATERIAL AND METHODS: Single-centre retrospective study in a tertiary referral centre. RESULTS: One hundred and five patients were included, with tumour recurrence in 72 cases, and disease progression in 33 cases, despite radiotherapy. Seventy-seven tumours were located in the tonsillar fossa or glossotonsillar sulcus. Ninety-four tumours were classified as rT2-T3 and 83 were classified as rN0. Segmental mandibulectomy was performed in 77 cases. Cervical lymph node dissection was performed in 96 cases. Pharyngeal reconstruction was performed with a myocutaneous flap in 90 cases. Forty-one local complications were observed, including 12 orocutaneous fistulae and/or neck abscesses, associated with carotid artery rupture in three cases. Twenty patients experienced general complications. The mean decannulation and feeding times were 20 and 30 days, respectively. The 5-year disease-free survival was 21%. On univariate analysis, survival was poorer in patients with disease progression (P=0.01); survival was also correlated with tumour site (P=0.02), rT status (P=0.03), rN (P=0.048), and quality of resection (P=0.04). On multivariate analysis, tumour size (P=0.03) and the interval between the end of radiotherapy and surgery (P=0.02) were the two main prognostic factors for survival. CONCLUSION: The results of this study confirm the high local complication rate of salvage surgery for oropharyngeal cancer and the poor overall survival. PMID- 22104581 TI - Isolated hydatid cyst of the neck: an unusual site. AB - INTRODUCTION: Head and neck hydatid disease is rare, even in countries in which echinococcosis is endemic and accounts for 1% of all human echinococcosis sites. The purpose of this report is to describe the epidemiology, clinical features, complementary investigations and treatment of head and neck hydatid disease in the light of a case report and a review of the literature. CASE REPORT: The authors report the case of a 40-year-old man, who presented with a right supraclavicular mass that had been growing for six months. Neck ultrasound initially suggested a type I unilocular hydatid cyst according to Gharbi's classification. Neck exploration was then performed, revealing a hydatid cyst. DISCUSSION/CONCLUSION: Isolated hydatid cyst of the neck is exceptional, but should be considered in the presence of any cystic mass of the neck in endemic regions. Ultrasound facilitates diagnostic and therapeutic procedures in order to ensure complete surgical resection. Prevention remains the essential treatment. PMID- 22104582 TI - Botulinum toxin in the treatment of post-radiosurgical neck contracture in head and neck cancer: a novel approach. AB - Neck pain affects a third of patients following head-and-neck cancer treatment, whether by radiation therapy or surgery. It is a disabling condition and the associated muscle contractures impair cervical motion. Type-A botulinum toxin is an analgesic and muscle relaxant, able to improve patients' quality of life. We here report our experience with botulinum toxin in post-radiosurgical neck contracture. PATIENTS AND METHODS: A single-center pilot study was run from January 2007 to July 2008, respecting the Declaration of Helsinki. All patients in complete remission from head-and-neck cancer with post-radiosurgical neck contracture impairing neck motion were included. Pain and functional impairment were assessed on a neck-function disability scale before and 1 month after botulinum toxin injection. Efficacy duration was measured. Complications at the injection site or related to drug diffusion were investigated. RESULTS: Nine consecutive patients (six male, three female; mean age, 61 years [range, 52-73 years]) were included. In six patients, the sternocleidomastoid muscle was injected and the muscular pedicle of a pectoralis major flap in three. Mean cervical disability score fell significantly from 33 to 23 (P=0.01). There were no complications. Efficacy was seen at a mean 6 days, and analgesia and muscle relaxation lasted for a mean 19 days. CONCLUSION: In post-radiosurgical neck contracture, botulinum toxin injection is a simple and easy procedure able to improve neck motion and reduce neck pain in head-and-neck cancer patients. A phase-II prospective study to determine injection sites and dosage should help bear out these preliminary findings. PMID- 22104583 TI - Medical information prior to invasive medical procedures in otorhinolaryngology head and neck surgery in France. AB - Based on a review of the medical literature (PubMed database, keywords: medical information, informed consent), the authors analyse the main medicolegal aspects concerning the patient information that must be provided in France prior to any invasive diagnostic or therapeutic medical procedures in otorhinolaryngology head and neck surgery, as well as the patient's perception and recall of the information provided, the quality of the information provided and problems encountered in providing this information. In the light of this review, several solutions are recommended to improve this essential phase prior to obtaining the patient's informed consent. PMID- 22104584 TI - Antimicrobial resistance of Actinobacillus pleuropneumoniae isolated from swine. AB - The aim of this retrospective study was to evaluate the antimicrobial resistance rates and the trend in resistance of Actinobacillus pleuropneumoniae isolated from pigs in Italy from 1994 to 2009. A total of 992 A. pleuropneumoniae isolates were tested for their susceptibility to a panel of antimicrobial agents in a disk diffusion method. Resistance to 7 drugs (amoxicillin, amoxicillin/clavulanic acid, ampicillin, cefquinome, cotrimoxazole, penicillin G and tilmicosin) showed a significant increasing trend over the time, while for 2 drugs (gentamycin and marbofloxacin) a significant decrease was observed. Resistance to the remaining 14 antimicrobial agents tested did not change significantly over the study period. Most of the isolates retained high susceptibility to antimicrobials usually effective against A. pleuropneumoniae such as amphenicols, fluoroquinolones and ceftiofur. However, high rates of resistance were observed for potentiated sulfa drugs, tetracyclines and penicillins which are currently recommended antimicrobials for pig pleuropneumonia therapy. Our results suggest the importance of continued monitoring of A. pleuropneumoniae clinical isolates in order to choose the most appropriate treatment of infections and to control the increase of resistance to currently used antimicrobials. PMID- 22104585 TI - Mechanism of male gamete motility in araphid pennate diatoms from the genus Tabularia (Bacillariophyta). AB - During sexual reproduction, araphid pennate diatoms of the genus Tabularia (Kutzing) D. M. Williams and Round released male gametes directly into the medium, sometimes at a considerable distance from the female gametes. This raised the question of how male gametes, suspended in water, manage to reach female ones, given that no locomotive organelles have been described in gametes of pennate diatoms. Optical microscopic investigation revealed cytoplasmic projections produced by male gametes of Tabularia tabulata (C. A. Agardh) Snoeijs and T. fasciculata (C. A. Agardh) D. M. Williams and Round. Morphology and behavior of these projections is consistent with pseudopodia, however, which specific type of pseudopodia they may be, remains inconclusive. The growth and retraction of the pseudopodia coincided with gamete motility and so we postulate that it explains the otherwise apparent random movement of male gametes. Spinning, shuffling and chaotic patterns of motility were documented. In theory, gamete mobility increases the probability of gamete encounter thus enhancing the probability of syngamy. This is the first known case where cytoplasmic projections have been described in diatom gametes, and possibly in mature gametes in general. PMID- 22104586 TI - Cytoskeleton organization during the cell cycle in two stramenopile microalgae, Ochromonas danica (Chrysophyceae) and Heterosigma akashiwo (Raphidophyceae), with special reference to F-actin organization and its role in cytokinesis. AB - F-actin organization during the cell cycle was investigated in two stramenopile microalgae, Ochromonas danica (Chrysophyceae; UTEX LB1298) and Heterosigma akashiwo (Raphidophyceae; NIES-6) using FITC-phalloidin. In the interphase cell of O. danica, F-actin bundles were localized forming a network structure in the cortical region, which converged from the anterior region to the posterior, whereas in the interphase cell of H. akashiwo, F-actin bundles were observed forming a network structure in the cortical region without any polarity. In both O. danica and H. akashiwo, at the initial stage of mitosis the cortical F-actin disappeared, and then during cytokinesis assembly of an actin-based ring-like structure occurred in the cell cortex in the plane of cytokinesis. The ring-like structure initiated from aster-like structures was composed of F-actin in both O. danica and H. akashiwo. Different from animal cells, later stages of cytokinesis of O. danica seemed to be promoted by microtubules, although the early stages of cytokinesis progressed with a constriction of the ring-like structure, whereas cytokinesis of H. akashiwo was apparently completed by constriction of the cell mediated by the F-actin ring, as in animal cells. PMID- 22104588 TI - Developing a sociology of normal substance use. PMID- 22104589 TI - Drug prohibition: it's broke, now go and fix it. PMID- 22104590 TI - The social context of controlled drug use amongst young people in a slum area in Makassar, Indonesia. AB - BACKGROUND: There are few studies exploring the social context of controlled drug use amongst young people in Indonesia. This qualitative study examines the experience of young people in a slum area (lorong) in Makassar, eastern Indonesia, who use drugs but are not drug dependent and who employ various forms of self regulation to control their use. METHODS: Semi-structured interviews were conducted with eight controlled drug users. RESULTS: The study found that whilst controlled drug users lived in a drug risk environment, they were not deeply embedded in the street culture, risk-taking practises and drug scene within their locality. Their employment, albeit in the informal economy and in low-paid jobs, facilitated their perspective that the status of rewa (a local construct of masculinity) and gaul (being sociable and up-to-date) could and should be accomplished through conventional means such as jobs and halal (legitimate) income. Their employment generated both direct benefit (legitimate income) and indirect benefit, including meaningful activities, structured time, positive identity and wider social networks (bridging social capital). This enabled them to have a stake in mainstream society and provided an incentive to control drug use. All factors which are protective against escalation into problematic drug use. CONCLUSION: The study showed the importance of sociological concepts of direct and indirect benefits of employment and of social capital in understanding the social context of controlled drug use amongst young people in the lorong. Additionally, drug policy should be more cognizant of the social vulnerability in the lorong and of the need to increase access to employment amongst young people in order to potentially decrease the likelihood of problematic drug use. PMID- 22104591 TI - The inside-out transobturator male sling for the surgical treatment of stress urinary incontinence after radical prostatectomy: midterm results of a single center prospective study. AB - BACKGROUND: Transobturator slings are currently promoted for the treatment of stress urinary incontinence (SUI) after radical prostatectomy (RP), but data on outcome remain limited. OBJECTIVE: To assess, at midterm, the efficacy and safety of the inside-out transobturator male sling for treating post-RP SUI and to determine factors associated with failure. DESIGN, SETTING, AND PARTICIPANTS: Prospective one-center trial involving 173 consecutive patients without detrusor overactivity, treated between 2006 and 2011 for SUI following RP. INTERVENTION: Placement of an inside-out transobturator sling. MEASUREMENTS: Baseline and follow-up evaluations included uroflowmetry and continence and quality-of-life (QoL) questionnaires. Cure was defined as no pad use and improvement as a number of pads per day reduced by >=50% and two or fewer pads. Complications were recorded, and factors associated with treatment failure were evaluated. RESULTS AND LIMITATIONS: Preoperatively, 21%, 35%, and 44% of the patients were using two, three to five, and more than five pads per day, respectively. After a median follow-up of 24 mo (range: 12-60 mo), 49% were cured, 35% improved, and 16% not improved. QoL was enhanced (p<0.001), and 72% of patients were moderately to completely satisfied with the procedure. Maximum flow rates were slightly reduced (p=0.004); postvoid residual volumes were similar (p=0.097). Complications were urinary retention after catheter removal (15%), perineal/scrotal hematoma (9%), pain lasting >6 mo (3%), and sling infection (2%); all were managed conservatively. Severe SUI before sling surgery was not associated with a worse outcome, whereas obesity and a history of pelvic irradiation or bladder neck stenosis were independent risk factors of failure, with risk ratios of 7.9 (95% confidence interval [CI], 3.3-18.9), 3.3 (95% CI, 1.4-7.8), and 2.6 (95% CI, 1.1 6.5), respectively. CONCLUSIONS: The inside-out transobturator male sling is an efficient and safe treatment for post-RP SUI at midterm. Patients with prior pelvic irradiation may not be suitable candidates. PMID- 22104592 TI - Prediction of prostate cancer risk: the role of prostate volume and digital rectal examination in the ERSPC risk calculators. AB - BACKGROUND: The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS). OBJECTIVE: Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV. DESIGN, SETTING, AND PARTICIPANTS: For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010 2011 as participants in ERSPC Rotterdam. MEASUREMENTS: Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60 cm3) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage>T2b and/or Gleason score>=7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study. RESULTS AND LIMITATIONS: Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p=0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p=0.0075) in the relatively small validation cohort. Further validation is required. CONCLUSIONS: An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners. PMID- 22104593 TI - Prostate-specific antigen and long-term prediction of prostate cancer incidence and mortality in the general population. AB - BACKGROUND: It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the general population. OBJECTIVE: Determine whether baseline PSA levels predict long-term risk of PCa incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: We examined 4383 men aged 20-94 yr from the Danish general population in the prospective Copenhagen City Heart Study. PSA was measured in plasma samples obtained in 1981-1983. MEASUREMENTS: PCa incidence and mortality as a function of baseline PSA was assessed using Kaplan-Meier plots of cumulative incidence and competing risk subhazard ratios. RESULTS AND LIMITATIONS: During 28 yr of follow-up, 170 men developed PCa, and 94 men died from PCa. Median follow-up was 18 yr (range: 0.5-28 yr). For PCa incidence, the subhazard ratio was 3.0 (95% confidence interval [CI], 1.9-4.6) for a PSA level of 1.01-2.00 ng/ml, 6.8 (95% CI, 4.2-11) for PSA 2.01-3.00 ng/ml, 6.6 (95% CI, 3.4-13) for PSA 3.01-4.00 ng/ml, 16 (95% CI, 10.4-25) for PSA 4.01-10.00 ng/ml, and 57 (95% CI, 32-104) for PSA >10.00 ng/ml versus 0.01-1.00 ng/ml. For PCa mortality, corresponding subhazard ratios were 2.2 (95% CI, 1.3-3.9), 5.1 (95% CI, 2.8-9.0), 4.2 (95% CI, 1.8-10), 7.0 (95% CI, 3.8-14), and 14 (95% CI, 6.0 32). For men with PSA levels of 0.01-1.00 ng/ml, the absolute 10-yr risk of PCa was 0.6% for ages <45 yr, 0.7% for ages 45-49 yr, 1.1% for ages 50-54 yr, 1.2% for ages 55-59 yr, 1.3% for ages 60-64 yr, 1.1% for ages 65-69 yr, 1.3% for ages 70-74 yr, and 1.5% for ages >=75 yr; corresponding values for PSA levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively. CONCLUSIONS: Stepwise increases in PSA at first date of testing predicted a 3-57-fold increased risk of PCa, a 2-16-fold increased risk of PCa mortality, and a 35-88% absolute 10-yr risk of PCa in men with PSA levels >10.00 ng/ml. Equally important, the absolute 10-yr risk of PCa in men with PSA levels 0.01-1.00 ng/ml was only 0.6-1.5%. PMID- 22104594 TI - Differential operator in seizure detection. AB - Differential operators can detect significant changes in signals. This has been utilized to enhance the contrast of the seizure signatures in depth EEG or ECoG. We have actually taken normalized exponential of absolute value of single or double derivative of epileptic ECoG. This in short we call differential filtering. Windowed variance operation has been performed to automatically detect seizure onset on differentially filtered signal. A novel method for determining the duration of seizure has also been proposed. Since all operations take only linear time, the whole method is extremely fast. Seven empirical parameters have been introduced whose patient specific thresholding brings down the rate of false detection to a bare minimum. Results of implementation of the methods on the ECoG data of four epileptic patients have been reported with an ROC curve analysis. High value of the area under the ROC curve indicates excellent detection performance. PMID- 22104595 TI - [Validity of a maternal alcohol consumption questionnaire in detecting prenatal exposure]. AB - INTRODUCTION: Ethanol consumption by pregnant women can produce severe effects in the foetus and the newborn, mainly in neurological and weight-height development, and are included in the term FASD (Fetal Alcohol Spectrum Disorder). Questionnaires are the most used screening method to detect prenatal exposure, but a previous population study questioned its reliability. The objective of this study was to compare alcohol prenatal exposure detection by questionnaire compared with biomarkers in meconium. METHODOLOGY: Sixty two meconium samples from mothers who denied alcohol consumption during pregnancy by questionnaire were analysed. The objective analysis was made by determination of FAEEs (fatty acid ethyl esters) as exposure biomarkers in meconium as biological matrix. RESULTS: In the meconium from 10 of 62 newborns from non-alcohol consuming mothers by questionnaire (16.12%) FAEE values were positive (>= 2 nmol/g). DISCUSSION: Questionnaires as a screening method during pregnancy are not a reliable tool. It is necessary to identify prenatal exposure to alcohol as soon as possible by biomarkers analysis in biological matrices from the newborn or the mother. The early detection will allow these patients to benefit from follow up and treatment to reach the best possible neurological development. PMID- 22104596 TI - [Invasive infection due to Blastoschizomyces capitatus]. PMID- 22104597 TI - [New X linked mental retardation syndrome]. AB - INTRODUCTION: Researching inherited mental retardation, from a diagnostic and aetiological point of view, is a great challenge. A particular type of mental retardation is the one linked to the X chromosome which is classified under syndromic and non-syndromic types, according to the presence or absence of a specific physical, neurological or metabolic pattern associated with mental retardation. PATIENTS AND METHOD: Five generations of a family have been studied with eight males suffering from mental retardation. Six of these males were clinically tested using anthropometric indicators and genetic tests: high resolution karyotypes, fragile X research, linkage and MID1 and PQBP1 gene studies. RESULTS: Along with mental retardation, the clinical study showed a pattern of microcephaly, micrognathia, osteoarticular and genital anomalies, short stature and other less frequent malformations. The linkage study mapped the possible causal gene of this mental retardation syndrome and multiple congenital abnormalities in the Xp11.23-q21.32 segment, with a LOD score of 2. As far as we know, a medical profile, similar to the one these patients have, linked to this X segment has not been described. CONCLUSIONS: We suspect that this family has a "new syndrome" of mental retardation and multiple congenital anomalies linked to the X chromosome. PMID- 22104598 TI - [Delayed presentation of hypertrophic pyloric stenosis in infants: an unusual case]. PMID- 22104600 TI - Fermentation, Isolation, Structure, and antidiabetic activity of NFAT-133 produced by Streptomyces strain PM0324667. AB - Type-2 diabetes is mediated by defects in either insulin secretion or insulin action. In an effort to identify extracts that may stimulate glucose uptake, similar to insulin, a high throughput-screening assay for measuring glucose uptake in skeletal muscle cells was established. During the screening studies to discover novel antidiabetic compounds from microbial resources a Streptomyces strain PM0324667 (MTCC 5543, the Strain accession number at Institute of Microbial Technology, Chandigarh, India), an isolate from arid soil was identified which expressed a secondary metabolite that induced glucose uptake in L6 skeletal muscle cells. By employing bioactivity guided fractionation techniques, a tri-substituted simple aromatic compound with anti-diabetic potential was isolated. It was characterized based on MS and 2D NMR spectral data and identified as NFAT-133 which is a known immunosuppressive agent that inhibits NFAT-dependent transcription in vitro. Our investigations revealed the antidiabetic potential of NFAT-133. The compound induced glucose uptake in differentiated L6 myotubes with an EC50 of 6.3 +/- 1.8 MUM without activating the peroxisome proliferator-activated receptor-gamma. Further, NFAT-133 was also efficacious in vivo in diabetic animals and reduced systemic glucose levels. Thus it is a potential lead compound which can be considered for development as a therapeutic for the treatment of type-2 diabetes. We have reported herewith the isolation of the producer microbe, fermentation, purification, in vitro, and in vivo antidiabetic activity of the compound. PMID- 22104601 TI - Photo-induced bleaching of sensory rhodopsin II (phoborhodopsin) from Halobacterium salinarum by hydroxylamine: identification of the responsible intermediates. AB - Sensory rhodopsin II from Halobacterium salinarum (HsSRII) is a retinal protein in which retinal binds to a specific lysine residue through a Schiff base. Here, we investigated the photobleaching of HsSRII in the presence of hydroxylamine. For identification of intermediate(s) attacked by hydroxylamine, we employed the flash-induced bleaching method. In order to change the concentration of intermediates, such as M- and O-intermediates, experiments were performed under varying flashlight intensities and concentrations of azide that accelerated only the M-decay. We found the proportional relationship between the bleaching rate and area under the concentration-time curve of M, indicating a preferential attack of hydroxylamine on M. Since hydroxylamine is a water-soluble reagent, we hypothesize that for M, hydrophilicity or water-accessibility increases specifically in the moiety of Schiff base. Thus, hydroxylamine bleaching rates may be an indication of conformational changes near the Schiff base. We also considered the possibility that azide may induce a small conformational change around the Schiff base. We compared the hydroxylamine susceptibility between HsSRII and NpSRII (SRII from Natronomonas pharaonis) and found that the M of HsSRII is about three times more susceptible than that of the stable NpSRII. In addition, long illumination to HsSRII easily produced M-like photoproduct, P370. We thus infer that the instability of HsSRII under illumination may be related to this increase of hydrophilicity at M and P370. PMID- 22104602 TI - Anthropogenic climate change and allergen exposure: The role of plant biology. AB - Accumulation of anthropogenic gases, particularly CO(2), is likely to have 2 fundamental effects on plant biology. The first is an indirect effect through Earth's increasing average surface temperatures, with subsequent effects on other aspects of climate, such as rainfall and extreme weather events. The second is a direct effect caused by CO(2)-induced stimulation of photosynthesis and plant growth. Both effects are likely to alter a number of fundamental aspects of plant biology and human health, including aerobiology and allergic diseases, respectively. This review highlights the current and projected effect of increasing CO(2) and climate change in the context of plants and allergen exposure, emphasizing direct effects on plant physiologic parameters (eg, pollen production) and indirect effects (eg, fungal sporulation) related to diverse biotic and abiotic interactions. Overall, the review assumes that future global mitigation efforts will be limited and suggests a number of key research areas that will assist in adapting to the ongoing challenges to public health associated with increased allergen exposure. PMID- 22104604 TI - Identification of a new major dog allergen highly cross-reactive with Fel d 4 in a population of cat- and dog-sensitized patients. PMID- 22104603 TI - Asthma in Head Start children: effects of the Breathmobile program and family communication on asthma outcomes. AB - BACKGROUND: Asthma morbidity and mortality rates are high among young inner-city children. Lack of routine primary care provider visits, poor access to care, and poor patient-physician communication might be contributing factors. OBJECTIVE: This study evaluated the effects of providing Breathmobile services only, a Facilitated Asthma Communication Intervention (FACI) only, or both Breathmobile plus FACI on asthma outcomes relative to standard care. METHODS: Children with asthma (n = 322; mean age, 4 years; 53% male; 97% African American) were recruited from Head Start programs in Baltimore City and randomized into 4 groups. Outcome measures included symptom-free days (SFDs), urgent care use (emergency department visits and hospitalizations), and medication use (courses of oral steroids and proportion taking an asthma controller medication), as reported by caregivers at baseline, 6-month, and 12-month assessments. Generalized estimating equations models were conducted to examine the differential treatment effects of the Breathmobile and FACI compared with standard care. RESULTS: Children in the combined treatment group (Breathmobile plus FACI) had an increase of 1.7 (6.6%) SFDs that was not maintained at 12 months. In intent-to-treat analyses the FACI-only group had an increase in the number of emergency department visits at 6 months, which was not present at 12 months or in the post hoc as-treated analyses. No significant differences were found between the intervention groups compared with those receiving standard care on all other outcome measures. CONCLUSIONS: Other than a slight improvement in SFDs at 6 months in the Breathmobile plus FACI group, the intervention components did not result in any significant improvements in asthma management or asthma morbidity. PMID- 22104605 TI - In situ imaging of honeybee (Apis mellifera) venom components from aqueous and aluminum hydroxide-adsorbed venom immunotherapy preparations. AB - BACKGROUND: Treatment with aqueous and aluminum hydroxide (Al[OH](3))-adsorbed purified honeybee (Apis mellifera) venom (HBV) preparations can reduce the incidence of side effects associated with venom immunotherapy. OBJECTIVE: The aim of the present study was to assess these purified HBV immunotherapy preparations in situ. METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize the distribution of HBV components. The preparations were administered on the back legs of naive Wistar rats. The rats were killed, and cryosectioned tissue sections were subjected to hematoxylin and eosin staining and MALDI-MSI analyses. RESULTS: Low-density maps of tissue distribution of HBV peptides, such as secapin, mast cell degranulating peptide, and melittin (Api m 4) were detected in the tissue after administration of HBV immunotherapy preparations. In addition, release of biogenic amines, cytokines, and leukotrienes was observed, and the distribution of HBV allergens, such as Api m 1 and Api m 2, was shown. At the 24-hour time point, the major HBV allergen Api m 1 was still detected at the site of Al(OH)(3)-adsorbed HVB injection, whereas in the case of aqueous HBV preparation, all the allergens, as well as most of the biogenic amines, were cleared at the 24-hour time point. CONCLUSION: The present study shows that the majority of low-molecular-weight HBV components are rapidly removed from the site of venom immunotherapy administration. Furthermore, Al(OH)(3)-adsorbed HBV preparation demonstrated a depot effect, prolonging the availability of bee venom allergens at the site of administration. PMID- 22104606 TI - Changes in thymic regulatory T-cell maturation from birth to puberty: differences in atopic children. AB - BACKGROUND: Characterization of regulatory immune pathways is a research priority for both the pathogenesis of allergic disease and potential therapeutic strategies. OBJECTIVE: The thymus is a rich source of regulatory T (Treg) cells, which offers a novel opportunity to document the maturation of these pathways beyond limited studies on small volumes of peripheral blood available from young children. METHODS: Thymus tissue was collected from children undergoing cardiac surgery (age, 1 week to 14 years), and skin prick testing was performed from 12 months of age. The ontogeny of Treg cell maturation and function was examined in atopic (n = 20) and nonatopic (n = 20) children by assessing their phenotype, enumeration, proliferation, and suppressive ability. RESULTS: Age-related changes in the thymic cytokine milieu paralleled the changes seen in peripheral immune function. Specifically, the thymic microenvironment is similarly T(H)2 skewed during the early postnatal period, and this undergoes age-related suppression as the T(H)1 (IFN-gamma) response increased. We detected CD4(+)CD25(+)CD127(lo/-) forkhead box protein 3 (FOXP3)-positive Treg cells in the neonatal thymus. These cells suppressed the proliferative response to allogeneic stimulation of CD4(+)CD25(-) T cells dose dependently. In nonatopic children Treg cell turnover and suppressive function increased with age and paralleled the increase in global thymic FOXP3 mRNA expression, whereas in atopic children Treg cell maturation was significantly delayed compared with that seen in age-matched nonatopic children. CONCLUSION: These data suggest that the developmental changes in the thymus parallel the recognized changes in peripheral blood responses. There is also a developmental delay in the function of thymic regulatory cells in atopic compared with nonatopic children. These differences are fundamental to understanding early events that lead to immune dysregulation and might predispose to allergic disease. PMID- 22104608 TI - Monitoring of thyroid function in patients who exhibit IgE against thyroperoxidase while taking omalizumab? PMID- 22104609 TI - Traffic-related air pollution and development of allergic sensitization in children during the first 8 years of life. AB - BACKGROUND: The role of exposure to air pollution in the development of allergic sensitization remains unclear. OBJECTIVE: We sought to assess the development of sensitization until school age related to longitudinal exposure to air pollution from road traffic. METHODS: More than 2500 children in the birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) from Stockholm, Sweden, were followed with repeated questionnaires and blood sampling until 8 years of age. Outdoor concentrations of nitrogen oxides, as a marker of exhaust particles, and particles with an aerodynamic diameter of less than 10 MUm (PM(10)), mainly representing road dust, were assigned to residential, day care, and school addresses by using dispersion models. Time-weighted average exposures were linked to levels of IgE against common inhalant and food allergens at 4 and 8 years of age. RESULTS: Air pollution exposure during the first year of life was associated with an increased risk of pollen sensitization at 4 years of age (odds ratio, 1.83; 95% confidence interval, 1.02-3.28) for a 5th to 95th difference in exposure to nitrogen oxides. At 8 years, there was no general increase in the risk of sensitization; however, the risk of food sensitization was increased, particularly among children free of sensitization at 4 years of age (odds ratio, 2.30; 95% confidence interval, 1.10-4.82). Results were similar by using PM(10). No associations between air pollution exposure after the first year of life and sensitization were seen. CONCLUSION: Traffic-related air pollution exposure does not seem to increase the overall risk of sensitization to common inhalant and food allergens up to school age, but sensitization to certain allergens might be related to exposure during infancy. PMID- 22104610 TI - Adherence to inhaled corticosteroids: an ancillary study of the Childhood Asthma Management Program clinical trial. AB - BACKGROUND: Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited. OBJECTIVE: We sought to compare subjective and objective measurements of children's adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes. METHODS: In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 MUg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The kappa statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes. RESULTS: Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (kappa = 0.00; 95% CI, -0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes. CONCLUSION: Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment. PMID- 22104611 TI - Abnormal shortened diastolic time length at increasing heart rates in patients with abnormal exercise-induced increase in pulmonary artery pressure. AB - BACKGROUND: The degree of pulmonary hypertension is not independently related to the severity of left ventricular systolic dysfunction but is frequently associated with diastolic filling abnormalities. The aim of this study was to assess diastolic times at increasing heart rates in normal and in patients with and without abnormal exercise-induced increase in pulmonary artery pressure (PASP). METHODS: We enrolled 109 patients (78 males, age 62 +/- 13 years) referred for exercise stress echocardiography and 16 controls. The PASP was derived from the tricuspid Doppler tracing. A cut-off value of PASP >= 50 mmHg at peak stress was considered as indicative of abnormal increase in PASP. Diastolic times and the diastolic/systolic time ratio were recorded by a precordial cutaneous force sensor based on a linear accelerometer. RESULTS: At baseline, PASP was 30 +/- 5 mmHg in patients and 25 +/- 4 in controls. At peak stress the PASP was normal in 95 patients (Group 1); 14 patients (Group 2) showed an abnormal increase in PASP (from 35 +/- 4 to 62 +/- 12 mmHg; P < 0.01). At 100 bpm, an abnormal (< 1) diastolic/systolic time ratio was found in 0/16 (0%) controls, in 12/93 (13%) Group 1 and 7/14 (50%) Group 2 patients (p < 0.05 between groups). CONCLUSION: The first and second heart sound vibrations non invasively monitored by a force sensor are useful for continuously assessing diastolic time during exercise. Exercise-induced abnormal PASP was associated with reduced diastolic time at heart rates beyond 100 beats per minute. PMID- 22104612 TI - The role of hyaluronic acid in atherosclerosis and intimal hyperplasia. AB - Atherosclerosis is a chronic inflammatory condition of the blood vessel wall that can lead to arterial narrowing and subsequent vascular compromise. Although there are a variety of open and endovascular procedures used to alleviate the obstructions caused by atherosclerotic plaque, blood vessel instrumentation itself can lead to renarrowing of the vessel lumen through intimal hyperplasia, wound contracture, or a combination of the two. While the cell types involved in both atherosclerosis and vessel renarrowing after surgical intervention are largely characterized, current research has shown that components of the extracellular matrix are also important in the pathogenesis of the aforementioned processes. One such component is hyaluronic acid (HA). The objective of this review, therefore, is to examine the involvement of HA in these pathologic processes. Literature on the structure and function of HA was reviewed, with particular attention given to the role of HA in the processes of atherogenesis, intimal hyperplasia, and wound contracture after blood vessel instrumentation. HA interacts with vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and platelets to promote atherogenesis. In particular, VSMCs manufacture large amounts of HA that form "cable-like" structures important for leukocyte adhesion and rolling. Additionally, transmigration of leukocytes across the EC layer is mediated by HA. Platelets cleave large molecules of HA into fragments that up regulate leukocyte production of chemokines and cytokines. HA also has a role in both intimal hyperplasia and wound contracture, the two processes most responsible for vessel renarrowing after vascular instrumentation. HA has a complex, and sometimes conflicting, role in the pathologic processes of atherogenesis and vessel wall renarrowing after surgical intervention. PMID- 22104613 TI - Risk factors for coronary artery bypass graft chest surgical site infections in New York State, 2008. AB - BACKGROUND: All hospitals in New York State (NYS) are required to report surgical site infections (SSIs) occurring after coronary artery bypass graft surgery. This report describes the risk adjustment method used by NYS for reporting hospital SSI rates, and additional methods used to explore remaining differences in infection rates. METHODS: All patients undergoing coronary artery bypass graft surgery in NYS in 2008 were monitored for chest SSI following the National Healthcare Safety Network protocol. The NYS Cardiac Surgery Reporting System and a survey of hospital infection prevention practices provided additional risk information. Models were developed to standardize hospital-specific infection rates and to assess additional risk factors and practices. RESULTS: The National Healthcare Safety Network risk score based on duration of surgery, American Society of Anesthesiologists score, and wound class were not highly predictive of chest SSIs. The addition of diabetes, obesity, end-stage renal disease, sex, chronic obstructive pulmonary disease, and Medicaid payer to the model improved the discrimination between procedures that resulted in SSI and those that did not by 25%. Hospital-reported infection prevention practices were not significantly related to SSI rates. CONCLUSIONS: Additional risk factors collected using a secondary database improved the prediction of SSIs, however, there remained unexplained variation in rates between hospitals. PMID- 22104614 TI - Application of spatial and non-spatial data analysis in determination of the factors that impact municipal solid waste generation rates in Turkey. AB - In studies focusing on the factors that impact solid waste generation habits and rates, the potential spatial dependency in solid waste generation data is not considered in relating the waste generation rates to its determinants. In this study, spatial dependency is taken into account in determination of the significant socio-economic and climatic factors that may be of importance for the municipal solid waste (MSW) generation rates in different provinces of Turkey. Simultaneous spatial autoregression (SAR) and geographically weighted regression (GWR) models are used for the spatial data analyses. Similar to ordinary least squares regression (OLSR), regression coefficients are global in SAR model. In other words, the effect of a given independent variable on a dependent variable is valid for the whole country. Unlike OLSR or SAR, GWR reveals the local impact of a given factor (or independent variable) on the waste generation rates of different provinces. Results show that provinces within closer neighborhoods have similar MSW generation rates. On the other hand, this spatial autocorrelation is not very high for the exploratory variables considered in the study. OLSR and SAR models have similar regression coefficients. GWR is useful to indicate the local determinants of MSW generation rates. GWR model can be utilized to plan waste management activities at local scale including waste minimization, collection, treatment, and disposal. At global scale, the MSW generation rates in Turkey are significantly related to unemployment rate and asphalt-paved roads ratio. Yet, significances of these variables may diminish at local scale for some provinces. At local scale, different factors may be important in affecting MSW generation rates. PMID- 22104615 TI - Recovery of solid fuel from municipal solid waste by hydrothermal treatment using subcritical water. AB - Hydrothermal treatments using subcritical water (HTSW) such as that at 234 degrees C and 3MPa (LT condition) and 295 degrees C and 8MPa (HT condition) were investigated to recover solid fuel from municipal solid waste (MSW). Printing paper, dog food (DF), wooden chopsticks, and mixed plastic film and sheets of polyethylene, polypropylene, and polystyrene were prepared as model MSW components, in which polyvinylchloride (PVC) powder and sodium chloride were used to simulate Cl sources. While more than 75% of carbon in paper, DF, and wood was recovered as char under both LT and HT conditions, plastics did not degrade under either LT or HT conditions. The heating value (HV) of obtained char was 13,886 27,544 kJ/kg and was comparable to that of brown coal and lignite. Higher formation of fixed carbon and greater oxygen dissociation during HTSW were thought to improve the HV of char. Cl atoms added as PVC powder and sodium chloride to raw material remained in char after HTSW. However, most Cl originating from PVC was found to converse into soluble Cl compounds during HTSW under the HT condition and could be removed by washing. From these results, the merit of HTSW as a method of recovering solid fuel from MSW is considered to produce char with minimal carbon loss without a drying process prior to HTSW. In addition, Cl originating from PVC decomposes into soluble Cl compound under the HT condition. The combination of HTSW under the HT condition and char washing might improve the quality of char as alternative fuel. PMID- 22104617 TI - Fluorescence excitation-emission matrix combined with regional integration analysis to characterize the composition and transformation of humic and fulvic acids from landfill at different stabilization stages. AB - Fluorescence excitation-emission matrix spectroscopy (EEMs) combined with fluorescence regional integration (FRI) analysis was used to investigate the composition and transformation of humic acid (HA) and fulvic acid (FA) from landfill. The EEMs of HAs at different landfill ages were characterized by two typical fluorescence chromophores with Ex/Em pairs at Ex=420-470 nm/Em=490-530 nm and Ex=345-375 nm/Em=450-465 nm. EEMs of FA were featured by other two distinctly different fluorophores with Ex/Em pairs at Ex=315-335 nm/Em=420-440 nm and Ex=255 275 nm/Em=425-455 nm. The results show that HA extracted from the refuse disposed in the year of 1989 was formed by connecting small-condensed aromatic structures with protein-like chains. Compared with HA extracted from the refuse disposed in the year of 1992, HA extracted from the refuse of 1996 had a higher fluorescence intensity and lower r(()(B)(,)(A)()) (the ratio of the fluorescence intensities of peak B and peak A) value. It contained low molar mass components, low aromatic condensation degree, and more easily oxidized substituents. This indicates that the landfill time strongly affects the EEMs characteristics of HA, and that the humification degree of HA increases with the landfill time. A red shift to a longer wavelength region and an increase of fluorescence intensity were observed when the concentration of HA was increased, suggesting that concentration had a great influence on the fluorescence characteristics of HAs. pH (2-12) also had significant effects on the fluorescence intensity, although it exerted no effect on the peak position of fluorescence of HA and FA. The results of FRI show that increasing concentration lead to more interactions among various structure components and that small molecular weight units tend to aggregate or be masked into more complicated and larger structures. The pH influence on the fluorescence intensity of HA seems mainly through molecular configuration, while the fluorescence intensity change with pH may be due to various substituents of FA. PMID- 22104618 TI - Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303). AB - CONTEXT: Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. OBJECTIVES: We evaluated HRQOL with the EuroQol (EQ-5DTM) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. METHODS: A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. RESULTS: Mean index scores remained stable (0.78 at baseline [n=267], 0.79 at eight weeks [n=186], P=0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P=0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P=0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. CONCLUSION: Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration. PMID- 22104619 TI - The lack of standard definitions in the supportive and palliative oncology literature. AB - CONTEXT: Multiple organizations have raised concerns about the lack of standard definitions for terminology in the supportive and palliative oncology literature. OBJECTIVES: We aimed to determine 1) the frequency of 10 commonly used terms in the supportive and palliative oncology literature, 2) the proportion of articles that provided definitions for each term, and 3) how each term was defined. METHODS: We systematically searched MEDLINE, PubMed, PsycINFO, the Cochrane Library, Embase, ISI Web of Science, and Cumulative Index to Nursing and Allied Health Literature for original studies, review articles, and systematic reviews related to palliative care and cancer in the first six months of 2004 and 2009. We counted the number of occurrences for "palliative care," "supportive care," "best supportive care," "hospice care," "terminal care," "end-of-life," "terminally ill," "goals of care," "actively dying," and "transition of care" in each article, reviewed them for the presence of definitions, and documented the journal characteristics. RESULTS: Among the 1213 articles found, 678 (56%) were from 2009. "Palliative care" and "end-of-life" were the most frequently used terms. "Palliative care," "end-of-life," and "terminally ill" appeared more frequently in palliative care journals, whereas "supportive care" and "best supportive care" were used more often in oncology journals (P<0.001). Among 35 of 601 (6%) articles with a definition for "palliative care," there were 16 different variations (21 of 35 articles used the World Health Organization definition). "Hospice care" had 13 definitions among 13 of 151 (9%) articles. "Supportive care" and other terms were rarely defined (less than 5% of articles that used the term). CONCLUSION: Our findings highlight the lack of definitional clarity for many important terms in the supportive and palliative oncology literature. Standard definitions are needed to improve administrative, clinical, and research operations. PMID- 22104620 TI - Influence of stroke localization on autonomic activation, immunodepression, and post-stroke infection. AB - BACKGROUND AND PURPOSE: Experimental and clinical data suggest that overactivation of the sympathetic nerve system (SNS) is an essential mediator of stroke-induced immunodepression, which in turn increases susceptibility to post stroke infections. In a post hoc analysis of the PANTHERIS (Preventive Antibacterial Treatment in Acute Stroke) trial, we investigated the impact of distinct lesion patterns on SNS activation, immunodepression, and frequency of post-stroke infections. METHODS: Stroke volume, stress hormone levels, and immune function were determined on day 1 after stroke onset. Stroke localization was graded using the Alberta Stroke Programme Early CT score (ASPECTS). In univariate analysis, we investigated the impact of clinical (National Institutes of Health Stroke Scale, NIHSS) and imaging stroke characteristics (lesion volume, lateralization, localization grading) on autonomous nervous system activity (norepinephrine, cortisol), immune competence (monocytic HLA-DR expression), and the frequency of post-stroke infections. In a logistic regression model, we tested for independent factors that might increase susceptibility to post-stroke infections. RESULTS: In a single-factor analysis, large stroke volume, lesions affecting distinct regions of the MCA cortex, and SNS activation (elevated norepinephrine levels) were associated with an impaired immune function (reduced mHLA-DR expression) and a higher susceptibility to post-stroke infections. Multivariate analysis identified increased levels of norepinephrine and infarction of the anterior MCA cortex as independent risk factors of post-stroke infections. Neither stroke severity nor stroke volume was independently associated with post-stroke infections. CONCLUSIONS: Apart from sympathetic activation, our data suggest that ischemic lesion in the anterior MCA cortex may be a major determinant of stroke-associated infection. This finding has to be confirmed in larger prospective studies. PMID- 22104621 TI - A modified technique and simplified laboratory procedure for ocular prosthesis fabrication. AB - PURPOSE: In many cases dentist tries to satisfy the patient with stock prosthesis that comes in standard sizes, shapes and colors. However, most of the patients complain of discomfort even after appropriate adjustment because of insufficient adaptation to underlying soft tissues. The rehabilitation of a patient with loss of eye as a result of congenital defect, pathology or accidental trauma is a challenge in terms of re-establishment of the esthetics of the patient. The purpose of this technical procedure is to provide a well fitting prosthesis to the patient, reducing the number of laboratory steps and appointments for fabrication of ocular prosthesis. METHOD: A suitable stock eye shell was modified to fit the eye socket, followed by relining with low fusing compound and making a final impression with polyvinyl siloxane impression material. The impression was poured in die stone, flasking procedure was accomplished. After dewaxing, molten wax was flown in the lower half of the flask followed by repositioning of the upper half. The flask was reopened, the stock eye shell along with the hardened wax on tissue surface was tried in the patient's eye. Finally processing was done. CONCLUSION: This technique describes an impression procedure, followed by a wax pattern try-in in the same appointment and also the detailed laboratory procedure for fabrication of the ocular prosthesis, taking into consideration positioning of iris as a result enhancing the esthetic appearance of the patient. PMID- 22104622 TI - Effect of acetyl resin retentive arms on the retentive force of circumferential clasps: an in vitro study. AB - PURPOSE: To compare and to evaluate the stability of the retentive force of cobalt-chromium (Co-Cr) circumferential clasps (control) to those with an acetyl resin retentive arm. METHODS: Sixteen specimens with a couple of circumferential clasps were made using Co-Cr over a metal model providing 0.25 mm undercuts. Eight specimens were fabricated without the anterior retentive arm, which was made later using acetyl resin (Dental D). Insertion and removal simulation test was performed through 7250 cycles. The retentive force was recorded in Newtons (N) for periods corresponding to 0, 1, 2, 3, 4, and 5 years. The data were subjected to ANOVA and Tukey test to compare periods and to Student's t test to compare groups (alpha=0.05). RESULTS: Mean (SD) is presented for Co-Cr and resin groups, respectively: 8.09(3.05) and 2.79(1.57) in period 0; 10.48(4.25) and 3.32(1.92) in 1 year; 10.09(4.15) and 3.47(1.81) in 2 years; 9.87(4.30) and 3.46(1.87) in 3 years; 9.46(3.93) and 3.27(1.59) in 4 years; 9.63(3.79) and 3.41(1.59) in 5 years. There were significant differences for Co-Cr between periods of 0 and 1 (p<0.001), 0 and 2 (p<0.01) and 0 and 3 (p<0.05). In the resin group, no significant differences were found between periods (p>0.05). Comparisons between the groups showed statistical differences for all tested periods: 0 (p=0.0012), 1 (p=0.0013), 2 (p=0.0019), 3 (p=0.0031), 4 (p=0.0027) and 5 years (p=0.0014). CONCLUSIONS: Acetyl resin retentive arms, even if only in the anterior clasps, can significantly reduce the retentive force, but this force remained stable after 5 years of simulated use. PMID- 22104623 TI - Evaluation of the structural behavior of three and four implant-supported fixed prosthetic restorations by finite element analysis. AB - PURPOSE: There is much controversy about the minimum number of implants and maximum cantilever length in mandible prosthetic restoration. Finite elements analysis of three and four implant-supported prostheses was performed to determine the stresses in the superstructure, implants and cortical bone and, therefore, the failure prediction for each restoration. METHODS: An edentulous mandible was modeled from CT scan images. Two finite element models of three and four implant-supported prostheses with cantilever lengths of 10 and 15 mm were created. Occlusal loads in different parts of the superstructure were applied and shear and normal stresses were calculated. RESULTS: Two failure criteria were analyzed: the von Mises criterion for isotropic materials (superstructure and implants) and the Tsai-Wu criterion for transversely isotropic material (cortical bone). Both criteria predict failure in the three implant-supported prosthesis for all cases analyzed. The same applies for the four-implant prosthesis of 15 mm cantilever length. However, four implants and a cantilever length of 10mm passed the failure criteria and were considered safe. CONCLUSIONS: The results from the patient analyzed showed that fixed support prostheses on three implants are not recommended from a structural point of view because they do not adequately support occlusal loads. Excessive stress in the superstructure and the cortical bone can be expected, which would anticipate the failure of the restoration. Fixed support prostheses on four implants with a cantilever length of 10mm properly resist occlusal loading. PMID- 22104624 TI - Newly designed gustatory test based on the number of chewing strokes required for recognition of the taste. AB - PURPOSE: The purpose of this study was to examine the usefulness of a new gustatory test based on the progress of mastication by counting the number of chewing strokes required for recognizing tastes. METHODS: Thirty-nine subjects (20 males and 19 females, 25.3+/-6.4 years old) without missing teeth were selected. Four types of newly designed test materials made from 15% gelatine were prepared, containing sucrose, sodium chloride, tartaric acid, or quinine hydrochloride. Five or six concentrations, representing weak to strong tastes, were prepared for each tastant. Subjects were instructed to chew the food, and the number of chewing strokes necessary to recognize the taste was counted. RESULTS: Female subjects recognized the sweet taste more accurately than male subjects (Friedman test: p<0.05). For each tastant of the test materials, the average number of chewing strokes (recognition threshold) was approximately 10. The frequency of correct responses and the average number of chewing strokes tended to be higher and lower, respectively, as the concentration of the taste in the test material increased (Kruskal-Wallis test: sweet p<0.01, salty p<0.01, sour p<0.01 and bitter p<0.01). CONCLUSIONS: Using the newly designed test materials, counting the number of chewing strokes necessary for recognizing the taste would be a useful index of a new gustatory test to investigate taste sensation. PMID- 22104625 TI - Determinants of blood lead levels in children: a cross-sectional study in the Canary Islands (Spain). AB - The adverse effects of lead exposure on children are well known. Low blood lead levels (BLL) produce neurodevelopmental delay and cognitive disorders. However, since BLL thresholds for adverse effects on children's health are not known, the children population at risk of excessive lead exposure still has to be identified. This study was aimed at evaluating BLL in a children population of Gran Canaria (Canary Islands, Spain). Up to our knowledge, this is the first study to report on BLL in this population. Lead was identified and quantified in blood samples of 120 children, by means of Graphite furnace atomic absorption spectrometry (GFAAS). Lead was undetected in 80% of samples; BLL was 1 to 5 MUg/dl in 15% of samples, and higher than 5 MUg/dl in more than 4% of samples. BLL values in the evaluated children were low and similar to those described for other populations in Western countries. However, samples with the highest contamination (those in percentile 95) reached BLLs as high as 5.2 MUg/dl. Positive associations were found between BLL and recent immigration (children adopted from non-western countries), and between BLL and parental smoking in children with low weight at birth. Since lead exposure in childhood may be a causative factor in adverse health trends - especially those involving the neurological system - and since threshold values for adverse lead effects are unknown, our finding that around 20% of the studied children had BLL higher than 1 MUg/dl are of concern. Enhancing preventive measures for reducing lead exposure in children from the Canary Islands deserves further study. PMID- 22104626 TI - Factors associated with rehospitalizations of very low birthweight infants: impact of a transition home support and education program. AB - OBJECTIVE: To determine the effects of a transition-home education and support program, BPD, and health insurance type on VLBW infant rehospitalizations at 3 and 7 months corrected age. It was hypothesized that the transition-home program would be associated with decreased rehospitalizations between Phase 1 and 2, and public health insurance and BPD would be associated with increased rehospitalizations. METHODS: 274 infants with birth weight <1500 g were enrolled in two successive years of a transition-home program (Phase 1-start-up) and (Phase 2-full implementation) and followed to 7 months CA. RESULTS: The Phase 2 rehospitalization rates were lower but not statistically significant at both 3 months (20% and 15%; p=0.246), and 7 months (24% and 17%; p=0.171). Infants with public insurance had twice as many rehospitalizations by 3 months (28% versus 11%; p=0.018) in Phase 1. In regression analyses the intervention effects did not achieve significance for the cohort at 3 months (OR=0.63; CI=0.33 to 1.20) or 7 months (OR=0.61; CI=0.33 to 1.13). BPD and public insurance did not reach significance in the models whereas siblings were significantly associated with increased odds of rehospitalization. In subgroup analyses for infants on pubic health insurance the intervention significantly decreased the odds of rehospitalization between Phase 1 and 2(OR=0.43; CI=0.19 to 0.96) at 3 months. CONCLUSIONS: Our findings suggest that a transition-home program may be beneficial to reduce the rehospitalization rate for VLBW infants, and infants on public insurance may derive greater benefit. PMID- 22104627 TI - Spatial analysis of the distribution of endometriosis in northwestern Italy. AB - OBJECTIVE: The aim of this study is to estimate the incidence of endometriosis in a northwestern region of Italy. The potential sources of geographical variations in the incidence of endometriosis within the region are discussed. METHODS: The patients selected were women between 18 and 45 years of age, born and residing in Piedmont who had undergone medical or surgical treatment for endometriosis between 2000 and 2005. The data were obtained from official hospital discharge records. RESULTS: The number of women contributed to the study was 3,929. The age standardized incidence rate of endometriosis was 81.8/100,000 patient-years (95% CI 79.1-84.2). The distribution of relative risks showed some areas with an increased rate of around 30% (southern and central Piedmont), while for other areas the disease risk was lower (southwestern Piedmont). These areas have greater exposure to environmental risk due to the presence of chemical pollutants. CONCLUSION: In order to achieve reliable data and good management of the disease, there is great need for national registers, as well as networks of excellence for the treatment of endometriosis. Our findings suggest that environmental factors may be associated with the development of the disease, but the observed results need to be cautiously interpreted in the context of ineligible biases. PMID- 22104628 TI - Application of proteomics to the study of polycystic ovary syndrome. AB - BACKGROUND: Clinical proteomics consists of qualitative and quantitative profiling of proteins present in clinical specimens such as body fluids or tissues, with the aim of discovering novel proteins and cellular pathways associated with the disease of interest. AIM: To review the proteomic studies conducted to date that addressed different aspects of the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Descriptive review of studies that applied proteomic techniques to the study of PCOS. Published articles were identified using the Entrez-PubMed online search facilities. RESULTS: Most studies conducted to date focused on protein variations in plasma and different target tissues. Plasma proteomics analysis revealed that PCOS associates changes in protein expression in several acute-phase response proteins. Moreover, some of these molecules play major roles in iron metabolism and low-grade chronic inflammation. Studies using omental adipose tissue from morbidly obese women with or without PCOS revealed differences in abundance of proteins that may be involved in lipid and glucose metabolism, oxidative stress processes, and adipocyte differentiation. Moreover, identification of differentially expressed proteins in ovarian tissue, granulosa cells or T lymphocites may help to characterize more clearly some aspects of this disorder. CONCLUSIONS: Although the application of proteomic techniques to the study of PCOS is in its early infancy, studies conducted to date highlight its heterogeneous nature. Aside from androgen excess, several pathways related to intermediate metabolism, oxidative stress processes, inflammation and iron metabolism appear to be involved in the pathophysiology of PCOS. PMID- 22104629 TI - Electrochemical detection of DNA hybridization using metallacarborane unit. AB - The evaluation of novel electrochemically active label for electrochemical detection of DNA hybridization is presented. Metallacarborane units modified with iron, cobalt or chromium were investigated. The value of redox potential and relatively strong current signal facilitate usage of Fe-carborane as marker covalently attached to the ssDNA. In electrochemical genosensor the sequence complementary to UL55 gene was labeled and used as a target for biosensor device. Interactions were investigated using electrochemical and piezoelectric methods. Obtained results confirm usefulness of the designed label in electrochemical detection of DNA hybridization. PMID- 22104630 TI - Trends in cancer mortality rates among migrants in Australia: 1981-2007. AB - BACKGROUND: Previous studies have shown that migrants have lower cancer mortality rates compared to the Australian-born population, particularly for colorectal and breast cancers, which are associated with an affluent lifestyle. This study seeks to update knowledge in this field by examining mortality from colorectal, stomach, lung, melanoma, breast and bladder cancers, as well as all cancers combined between 1981 and 2007. METHODS: Data were obtained from the Australian Bureau of Statistics. Average annual age and sex-standardised mortality rates were calculated for each region of birth, period of death registration and cancer site. RESULTS: Generally, mortality rates declined over the study period for most conditions for the majority of migrant groups. Notable exceptions included migrants from South Eastern Europe and Eastern Europe who experienced a significant increase in mortality due to all cancers combined and Australian-born individuals who recorded a significant increase in mortality due to melanoma of the skin. Migrants generally had more favourable cancer mortality outcomes, particularly for colorectal cancer and melanoma. Migrants from Southern Europe, South Eastern Europe, Chinese Asia and Southern Asia had the greatest advantage. However, migrants displayed higher rates of stomach, lung and bladder cancers than the Australian-born population. CONCLUSION: The migrant advantage can in part be explained by the protective effects of diet, lifestyle and reproductive behaviours. Possible explanations for why some migrants display greater mortality from stomach and bladder cancer include the consumption of abrasive, salted and preserved foods and higher rates of smoking. Greater emphasis should be placed on targeting at-risk migrant groups through screening and education programs at migrant resource centres and community groups. The study calls for further research to explain the observed trends, which has the potential to uncover important risk and protective factors. PMID- 22104632 TI - Pain indicators in brain-injured critical care adults: an integrative review. AB - INTRODUCTION: Health professionals are confronted with the difficulty of adequately evaluating pain in critically ill, brain-injured patients, as these patients are often unable to self-report. In addition, their confused and stereotyped behaviours may change their responses to pain; the indicators and descriptors generally used to evaluate pain in the critically ill may therefore not be appropriate for brain-injured patients. AIM: The aim of this integrative review was to identify clinically measurable and observable pain indicators and descriptors for brain-injured, critically ill adults. METHOD: A search of electronic databases (Medline, CINAHL, Embase) combined with cross-referencing was performed. Articles were included if they described pain indicators in critically ill adults and included brain-injured patients in their population. RESULTS: Seven articles met the inclusion criteria. They were critically appraised for their quality and their relevance for the population of brain injured patients. Behavioural pain indicators such as facial expressions, body movements and muscle tension were found in all of the articles. However, the descriptions of the indicators differ from one article to another. The intensity and nature of behavioural pain responses vary according to the level of consciousness. Changes in physiological parameters have also been reported, but these results are inconclusive. CONCLUSION: Additional research is needed to identify and better describe pain indicators that are specific to brain-injured patients in the ICU. Studies with large samples, different brain injury diagnoses and various levels of consciousness are warranted. PMID- 22104633 TI - Bench-to-beside review: acute-on-chronic liver failure - linking the gut, liver and systemic circulation. AB - The concept of acute-on-chronic liver failure (ACLF) was introduced recently to describe a subset of patients with chronic liver disease presenting with profound deterioration of liver function and rapidly evolving multi-organ failure. ACLF is frequently accompanied by the development of severe inflammatory response syndrome and has a high mortality. To date, treatment options are limited and exclusively supportive. Over the last few years, some insights have been generated in the pathophysiology of ACLF. A key role for the interaction of innate immune dysfunction, enhanced bacterial translocation from the gut, and circulatory dysfunction has been proposed. In this respect, therapeutic strategies have been examined, with variable success, in experimental studies in animals and humans. This review focuses on potentially relevant pathophysiological elements in the development of ACLF and points out promising treatment modalities in ACLF. PMID- 22104634 TI - A randomized open comparison of long-acting injectable risperidone and treatment as usual for prevention of relapse, rehospitalization, and urgent care referral in community-treated patients with rapid cycling bipolar disorder. AB - OBJECTIVE: To compare adjunctive long-acting injectable risperidone plus treatment as usual (RLAI+TAU) versus TAU alone for relapse, rehospitalization, and urgent care events in patients with bipolar disorder in routine care settings. METHODS: This was a 12-month randomized open comparison of RLAI+TAU (n = 20) and TAU alone (n = 25) in adults with rapid cycling, Mini International Neuropsychiatric Interview-confirmed bipolar I/II disorder and 4 or more illness relapses in the preceding 12 months. Clinical outcome was assessed every 2 weeks using the Longitudinal Interval Follow-up Evaluation instrument. Psychopathology and quality of life were assessed monthly using the Young Mania Rating Scale, Montgomery-Asberg Depression Rating Scale, Quick Inventory of Depressive Symptoms Self Report 16 and Quality of Life, Enjoyment, and Satisfaction Questionnaire. Relapse was defined using symptom severity, necessary clinical adjustment of medications, and urgent care referrals. Relapse rates and duration were calculated per person per year of follow-up. All treatments were provided by community-based clinicians. RESULTS: There were no significant between-groups differences in the total number or duration of relapse events (any cause) or in the number of manic or depressive relapses. Thirteen of 14 urgent care events (hospitalization, emergency department visit, intensive outpatient, or respite care referral) occurred with TAU alone (92.3%). Urgent care referral (P < 0.04) and necessary medication change rates (P = 0.01) were significantly lower in the RLAI+TAU group. There were no significant between-groups differences in the duration of follow-up, hospitalization rates, or psychopathology over time. CONCLUSIONS: Rates of any-cause relapse may not differ significantly between RLAI+TAU and TAU alone; however, RLAI may reduce the need for urgent care referrals or the frequency of medication adjustments to prevent relapse in community-treated patients with rapid cycling bipolar disorder. Additional investigation is warranted. PMID- 22104635 TI - Aripiprazole improves olanzapine-associated obsessive compulsive symptoms in schizophrenia. AB - Many schizophrenic patients have comorbid obsessive-compulsive syndromes (OCS) frequently associated with antiserotonergic second-generation antipsychotics such as clozapine and olanzapine. Whereas cognitive behavioral therapy and antiobsessive antidepressants brought up inconsistent results, pharmacological add-on strategies were able to alleviate OCS. One suggestive agent for antiobsessive add-on treatment is aripiprazole, a partial agonist at dopamine and serotonin receptors. Here, we summarize the course of a patient with paranoid schizophrenia. She developed OCS during long-term treatment with olanzapine at 20 mg/d over a period of 10 years. Baseline assessment showed severe obsessions (Yale Brown Obsessive Compulsive Scale (YBOCS) subscale score : 13) and compulsions (YBOCS subscale score : 10), whereas the psychotic syndrome was compensated (Positive and Negative Syndrome Scale, 11/17/28). The combination with aripiprazole (15 mg/) over a period of 12 weeks resulted in a marked improvement of OCS (YBOCS, 8/3) and some further improvement of the psychotic symptoms (Positive and Negative Syndrome Scale, 9/13/27). This observation points toward an antiobsessive potency of aripiprazole in combination with olanzapine, quite similar to approaches involving clozapine. Hence, the proposed strategy should be further evaluated in prospective controlled trials. PMID- 22104636 TI - The efficacy of low-dose aripiprazole treatment for trichotillomania. AB - This case report describes a 20-year-old man with trichotillomania (TTM). The patient was first treated with paroxetine and carbocisteine without response. Following the addition of aripiprazole (3 mg/d) to the other medications, the TTM was fully alleviated. After stopping treatment, 1.5 to 3.0 mg/d of aripiprazole alone improved TMM symptoms upon recurrence. These findings indicate that further investigation of low-dose aripiprazole for the treatment of TTM is warranted. PMID- 22104637 TI - Delayed-onset obsessive-compulsive symptoms after brain infarctions treated with paroxetine. AB - A 68-year-old woman showed obsessive thought that she could not remember the names of people or items that she saw. She repeatedly asked her husband to recall names of unspecified people and checked the garbage to find the names of items. The patient had a history of cerebral infarctions in the left middle cerebral artery regions 2 and 15 months before the emergence of her symptoms. A magnetic resonance imaging examination showed signs of an old infarction in the left basal ganglia and ischemic signs in the right temporal lobe. Her obsessive-compulsive symptoms relating to words were successfully treated with a serotonin selective reuptake inhibitor, paroxetine, at the dose of 40 mg/d. Her scores on the Yale Brown Obsessive Compulsive Scale reduced from 31 to 8 points after this treatment. This case may suggest therapeutic modulation of language-related cortical activity elicited by paroxetine. PMID- 22104638 TI - Oxcarbazepine-responsive paroxysmal kinesigenic dyskinesia in Wilson disease. AB - A 22-year-old man presented with a 2-year history of tremor of the upper limbs associated to behavioral disorders. A magnetic resonance imaging of the brain showed hyperintensity in the right frontoparietal region, basal ganglia, particularly in the caudate nucleus, midbrain, and pons in T2 sequences, fluid attenuated inversion recovery, and diffusion. Serum ceruloplasmin levels were 4 mg/dL (range, 20-45 mg/dL), and 24-hour urine cooper excretion was increased up to 223 ug (10-40 ug/24 hours). Slit lamp examination demonstrated the presence of a Kayser-Fleischer ring and penicillamine treatment started. Four months later, he developed episodes of paroxysmal dystonic posturing of his left arm, which increased in frequency reaching 2 or 3 attacks per hour. They were triggered by voluntary movements and forced him to adopt an abnormal flexion of the left forearm over the left bicep and were preceded by a tightening sensation of the left forearm muscles. Episodes completely remitted with oxcarbazepine. PMID- 22104639 TI - Ex vivo effects of flavonoids extracted from Artemisia herba alba on cytokines and nitric oxide production in Algerian patients with Adamantiades-Behcet's disease. AB - BACKGROUND: Adamantiades-Behcet's disease (ABD) is a chronic multisystemic inflammation with unknown pathophysiology. This disorder is associated with a dysregulation of the cytokine network that hyperactivates neutrophils and macrophages. In this study, we investigate the modulatory effects of flavonoid compounds extracted from Algerian medicinal plant Artemisia herba alba on Th1 and Th2 cytokines and nitric oxide production. METHODS: The modulatory effects of flavonoids extracted from Artemisia herba alba on cytokines and nitric oxide production by peripheral blood mononuclear cells isolated from Algerian ABD patients and healthy controls were respectively measured by means of ELISA assays and Griess modified method. RESULTS: Our results show that flavonoids significantly reduce the production of interleukin-12, the key effector of T helper 1 (Th1) cells and nitric oxide in a dose-dependent manner in Adamantiades Behcet's disease. In contrast, the production of IL-4, the key marker of Th2 cells was increased. CONCLUSION: This study suggests that in vitro supplementation with flavonoids extracted from Artemisia herba alba could have potential immuno-modulatory effects characterised by a down-regulation and up regulation of Th1 and Th2 cytokines, respectively. Moreover, flavonoids may prevent nitric oxide induced damages. PMID- 22104640 TI - Persistent hyperglycemia at 24-48 h in acute hyperglycemic stroke patients is not associated with a worse functional outcome. AB - BACKGROUND: Recently, it was shown that the relation between admission glucose and functional outcome after ischemic stroke is described by a J-shaped curve, with a glucose range of 3.7-7.3 mmol/l associated with a favorable outcome. We tested the hypothesis that persistence of hyperglycemia above this threshold at 24-48 h after stroke onset impairs 3-month functional outcome. METHODS: We analyzed all patients with glucose >7.3 mmol/l on admission from the Acute STroke Registry and Analysis of Lausanne (ASTRAL). Patients were divided into two groups according to their subacute glucose level at 24-48 h after last well-being time (group 1: <=7.3 mmol/l, group 2: >7.3 mmol/l). A favorable functional outcome was defined as a modified Rankin Score (mRS) <=2 at 3 months. A multiple logistic regression analysis of multiple demographic, clinical, laboratory and neuroimaging covariates was performed to assess predictors of an unfavorable outcome. RESULTS: A total of 1,984 patients with ischemic stroke were admitted between January 1, 2003 and October 20, 2009, within 24 h after last well-being time. In the 421 patients (21.2%) with admission glucose >7.3 mmol/l, the proportion of patients with a favorable outcome was not statistically significantly different between the two groups (59.2 vs. 48.7%, respectively). In multiple logistic regression analysis, unfavorable outcome was significantly associated with age (odds ratio, OR: 1.06, 95% confidence interval, 95% CI: 1.03 1.08 for every 10-year increase), National Institute of Health Stroke Score, NIHSS score, on admission (OR: 1.16, 95% CI: 1.11-1.21), prehospital mRS (OR: 12.63, 95% CI: 2.61-61.10 for patients with score >0), antidiabetic drug usage (OR: 0.36, 95% CI: 0.15-0.86) and glucose on admission (OR: 1.16, 95% CI: 1.02 1.31 for every 1 mmol/l increase). No association was found between persistent hyperglycemia at 24-28 h and outcome in either diabetics or nondiabetics. CONCLUSIONS: In ischemic stroke patients with acute hyperglycemia, persistent hyperglycemia (>7.3 mmol/l) at 24-48 h after stroke onset is not associated with a worse functional outcome at 3 months whether the patient was previously diabetic or not. PMID- 22104641 TI - Noise-induced duodenal lesions: a light and electron microscopy study of the lesions of the rat duodenal mucosa exposed to low frequency noise. AB - BACKGROUND AND AIMS: Non-auditory effects of noise, including digestive disorders have long being reported. Low frequency noise (LFN) is considered to be responsible to most of non-auditory effects of noise and is widely spread in modern societies. Only a few studies were designed to evaluate these noise induced digestive alterations. The pathogenesis of duodenal ulcers and erosions is complex and noise may be an environmental co-factor. The aim of the present study was to investigate the morphological injury of LFN-exposed duodenal mucosa. MATERIALS AND METHODS: Five groups of Wistar rats were exposed to continuous LFN, during increasing periods, since 1 to 13 weeks. A control group was kept in silence. Duodenal specimens were studied using light microscopy (LM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: We disclosed several changes in LFN-exposed rats: on LM, mucosa showed superficial erosions of the epithelial layer, degeneration, picnosis and cell death, with no inflammation. On SEM, epithelium presented displacement of cells and unequal distribution of microvilli, with coalescence and fusion. On TEM, microvilli were irregularly distributed, damaged and fragmented. The terminal web was destroyed. Morphological alterations occurred early, after just 1 week of LFN-exposure, persisted with longer noise exposition and did not suffer any evolution. Changes were similar among all LFN-exposed groups. CONCLUSIONS: LFN-exposed duodenal mucosa develops destruction of microvilli and terminal web, leading to cellular death and development of superficial erosions. These lesions of cytoskeleton structures could explain why cells with actinic and tubulinic structures like cilia and microvilli present severe destruction after LFN-exposure. These erosions are similar to those seen in dyspeptic patients. PMID- 22104642 TI - Modulation transfer function and optical quality after bilateral implantation of a +3.00 D versus a +4.00 D multifocal intraocular lens. AB - PURPOSE: To determine whether the improvement in intermediate vision after bilateral implantation of an aspheric multifocal intraocular lens (IOL) with a +3.00 diopter (D) addition (add) occurs at the expense of optical quality compared with the previous model with a +4.00 D add. SETTING: Department of Ophthalmology, University of Sao Paulo, Sao Paulo, Brazil. DESIGN: Prospective randomized double-masked comparative clinical trial. METHODS: One year after bilateral implantation of Acrysof Restor SN6AD1 +3.00 D IOLs or Acrysof Restor SN6AD3 +4.00 D IOLs, optical quality was evaluated by analyzing the in vivo modulation transfer function (MTF) and point-spread function (expressed as Strehl ratio). The Strehl ratio and MTF curve with a 4.0 pupil and a 6.0 mm pupil were measured by dynamic retinoscopy aberrometry. The uncorrected and corrected distance visual acuities at 4 m, uncorrected and distance-corrected near visual acuities at 40 cm, and uncorrected and distance-corrected intermediate visual acuities at 50 cm, 60 cm, and 70 cm were measured. RESULTS: Both IOL groups comprised 40 eyes of 20 patients. One year postoperatively, there were no statistically significant between-group differences in the MTF or Strehl ratio with either pupil size. There were no statistically significant between-group differences in distance or near visual acuity. Intermediate visual acuity was significantly better in the +3.00 D IOL group. CONCLUSION: Results indicate that the improvement in intermediate vision in eyes with the aspheric multifocal + 3.00 D add IOL occurred without decreasing optical quality over that with the previous version IOL with a +4.00 D add. PMID- 22104643 TI - Risk factors for vitreous complications in resident-performed phacoemulsification surgery. AB - PURPOSE: To identify risk factors for intraoperative vitreous complications in resident-performed phacoemulsification surgery. SETTING: Two urban public county hospitals. DESIGN: Case series. METHODS: Phacoemulsification cataract surgeries performed by residents between January 4, 2005, and January 8, 2008, were retrospectively reviewed. Clinical characteristics of patients with and without intraoperative vitreous complications were compared and independent factors associated with vitreous complications identified using univariate and multivariate analysis. RESULTS: Of 2434 cases meeting inclusion criteria, there were 92 vitreous complications (3.8%). On univariate analysis, significant preoperative risk factors for vitreous complications included older age (P=.020), poor preoperative corrected distance visual acuity (CDVA) (P=.007), left eye (P=.043), history of trauma (P=.045), prior pars plana vitrectomy (P=.034), dementia (P=.020), phacodonesis (P=.014), zonule dehiscence (P<.0001), posterior polar cataract (P=.037), white/mature cataract (P=.005), dense nuclear sclerotic cataract (P=.0006), and poor red reflex (P=.002). Factors that remained significant on multivariate analysis were older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05), poor preoperative CDVA (OR, 1.52; 95% CI, 1.14-2.03), left eye (OR, 1.63; 95% CI, 1.05-2.51), prior pars plana vitrectomy (OR, 1.88; 95% CI, 1.01-3.51), dementia (OR, 3.65; 95% CI, 1.20-11.17), and zonule dehiscence (OR, 8.55; 95% CI, 3.92-18.63). CONCLUSION: Elements of the preoperative history and examination can identify patients at higher risk for intraoperative complications during resident-performed phacoemulsification surgery. PMID- 22104644 TI - Transepithelial corneal collagen crosslinking: bilateral study. AB - PURPOSE: To evaluate the efficacy of transepithelial collagen crosslinking (CXL) in patients with bilateral progressive keratoconus. SETTING: Outpatient ophthalmic clinic. DESIGN: Cohort study. METHODS: Patients with a history of bilateral progressive keratoconus were recruited. The worst eye was treated with transepithelial CXL, while the fellow eye was left untreated as a control. Transepithelial CXL was performed by applying an enhanced riboflavin solution (riboflavin 0.1%, dextrane T500 with trometamol [Tris-hydroxymethyl aminomethane] and EDTA [ethylenediaminetetraacetic] sodium salt) on the intact corneal epithelium for 30 minutes before irradiation with ultraviolet A (370 nm at 3 mW/cm(2)) for 30 minutes. Follow-up was 18 months in all eyes. RESULTS: The study enrolled 20 patients. Transient hyperemia and mild foreign-body sensation occurred in 8 eyes (40%) after treatment; both resolved after 24 hours. In treated eyes, there were statistically significant improvements in uncorrected and corrected visual acuity and topography-derived keratometry, cone apex power, and higher-order aberrations (P<.05). In untreated control eyes, there was a general trend toward worsening of these parameters. No complications were reported. CONCLUSIONS: Transepithelial CXL treatment appeared to halt keratoconus progression, with a statistically significant improvement in visual and topographic parameters. The treatment was safe and well tolerated. Its noninvasive nature makes it potentially useful in cases in which epithelial debridement is ideally avoided, such as pediatric cases, uncooperative patients, and thin corneas with thicknesses nearing 380 MUm. PMID- 22104645 TI - High-performance bioanode based on the composite of CNTs-immobilized mediator and silk film-immobilized glucose oxidase for glucose/O2 biofuel cells. AB - A high-performance bioanode based on the composite of carbon nanotubes (CNTs) immobilized mediator and silk film (SF)-immobilized glucose oxidase (GOD) was developed for glucose/O(2) biofuel cell (BFC). Ferrocenecarboxaldehyde (Fc) was used as the mediator and covalently immobilized on the ethylenediamine (EDA) functionalized CNTs (CNTs-EDA). GOD was cross-linked on the SF with glutaraldehyde (GA) as the cross-linking agent. The resulting electrode (CNTs Fc/SF-GOD/glassy carbon (GC) electrode) exhibited good catalytic activity towards glucose oxidation and excellent stability. For the assembled glucose/O(2) BFC with the CNTs-Fc/SF-GOD/GC electrode as the bioanode and a commercial E-TEK Pt/C modified GC electrode as the cathode, the open circuit potential is 0.48 V and the maximum power density of 50.70 MUW cm(-2) can be achieved at 0.15 V. PMID- 22104646 TI - Antigen-specific T cell phenotyping microarrays using grating coupled surface plasmon resonance imaging and surface plasmon coupled emission. AB - The circulating population of peripheral T lymphocytes obtained from a blood sample can provide a large amount of information about an individual's medical status and history. Recent evidence indicates that the detection and functional characterization of antigen-specific T cell subsets within the circulating population may provide a diagnostic indicator of disease and has the potential to predict an individual's response to therapy. In this report, a microarray detection platform that combines grating-coupled surface plasmon resonance imaging (GCSPRI) and grating-coupled surface plasmon coupled emission (SPCE) fluorescence detection modalities were used to detect and characterize CD4(+) T cells. The microspot regions of interest (ROIs) printed on the array consisted of immobilized antibodies or peptide loaded MHC monomers (p/MHC) as T cell capture ligands mixed with additional antibodies as cytokine capture ligands covalently bound to the surface of a corrugated gold sensor chip. Using optimized parameters, an unlabeled influenza peptide reactive T cell clone could be detected at a frequency of 0.1% in a mixed T cell sample using GCSPRI. Additionally, after cell binding was quantified, differential TH1 cytokine secretion patterns from a T cell clone cultured under TH1 or TH2 inducing conditions was detected using an SPCE fluorescence based assay. Differences in the secretion patterns of 3 cytokines, characteristic of the inducing conditions, indicated that differences were a consequence of the functional status of the captured cells. A dual mode GCSPRI/SPCE assay can provide a rapid, high content T cell screening/characterization tool that is useful for diagnosing disease, evaluating vaccination efficacy, or assessing responses to immunotherapeutics. PMID- 22104647 TI - Contribution of potassium ion and split modes of G-quadruplex to the sensitivity and selectivity of label-free sensor toward DNA detection using fluorescence. AB - In recent years, bioanalytical technology based on G-quadruplex has been paid significant attention due to its versatility and stimulus-responsive reconfiguration. Notwithstanding, several key issues for template-directed reassembly of G-quadruplex have not been resolved: what is the key factor for determining the sensitivity and selectivity of split G-quadruplex probes toward target DNA. Therefore, in this study, we designed three pairs of split G quadruplex probes and investigated the sensitivity and selectivity of these systems in terms of potassium ion concentration and split modes of G-quadruplex. Due to its simplicity and sensitivity, N-methyl-mesoporphyrin (NMM) as fluorescence probes was used to monitor the target-directed reassembling process of G-quadruplex. A G-quadruplex sequence derived from the c-Myc promoter was split into "symmetric" probes, where each fragment contained two runs of guanine residues (2+2), or into "asymmetric" fragments each containing (3+1 or 1+3) runs of guanine residues. In all three cases, the sensitivity of target detection was highly dependent on the thermodynamic stability of the hybrid structure, which can be modulated by potassium ion concentrations. Using a combination of CD, fluorescence, and UV spectroscopy, we found that increasing potassium concentrations can increase the sensitivity of target detection, but can decrease the selectivity of discriminating cognate versus mismatched "target" DNA. The previous argument that asymmetrically split probes were always better than symmetrically split probes in terms of selectivity was not plausible anymore. These results demonstrate how the sensitivities and selectivity of split probes to mutations can be optimized by tuning the thermodynamic stability of the three way junction complex. PMID- 22104648 TI - Mediatorless sugar/oxygen enzymatic fuel cells based on gold nanoparticle modified electrodes. AB - We report on the fabrication and characterisation of a gold-nanoparticle (AuNP) based mediatorless sugar/oxygen biofuel cell (BFC) operating in neutral sugar containing buffers and human physiological fluids, such as blood and plasma. First, Corynascus thermophilus cellobiose dehydrogenase (CtCDH) and Myrothecium verrucaria bilirubin oxidase (MvBOx), used as anodic and cathodic bioelements, respectively, were immobilised on gold electrodes modified with 20 nm AuNPs. Detailed characterisation and optimisation of a new CDH/AuNP-based bioanode were performed and the following fundamental parameters were obtained: (i) the redox potential of the haem-containing centre of the enzyme was measured to be 75 mV vs. NHE, (ii) the surface coverage of CtCDH was found to be 0.65 pmol cm(-2) corresponding to a sub-monolayer coverage of the thiol-modified AuNPs by the enzyme, (iii) a turnover number for CtCDH immobilised on thiol-modified AuNPs was calculated to be ca. 0.5 s(-1), and (iv) the maximal current densities as high as 40 MUA cm(-2) were registered in sugar-containing neutral buffers. Second, both biomodified electrodes, namely the CtCDH/AuNP-based bioanode and the MvBOx/AuNP based biocathode, were combined into a functional BFC and the designed biodevices were carefully investigated. The following characteristics of the mediator-, separator- and membrane-less, miniature BFC were obtained: in phosphate buffer; an open-circuit voltage of 0.68 V, a maximum power density of 15 MUW cm(-2) at a cell voltage of 0.52 V and in human blood; an open-circuit voltage of 0.65 V, a maximum power density of 3 MUW cm(-2) at a cell voltage of 0.45 V, respectively. The estimated half-lives of the biodevices were found to be >12, <8, and <2 h in a sugar-containing buffer, human plasma, and blood, respectively. The basic characteristics of mediatorless sugar/oxygen BFCs were significantly improved compared with previously designed biodevices, because of the usage of three dimensional AuNP-modified electrodes. PMID- 22104649 TI - Acoustic wave immunosensing of a meningococcal antigen using gold nanoparticle enhanced mass sensitivity. AB - Bacterial meningitis is an infection of the thin membranes covering the brain and spinal cord by a number of microorganisms including Neisseria meningitidis, which can lead to permanent neurological damage in the event of late diagnosis. Given the quick onset and severity of the disease, there is a clear need for a rapid, sensitive and specific diagnostic technique. Here, we describe the development and evaluation of an acoustic wave sensor, the quartz crystal microbalance (QCM), as a rapid immunosensor employing antibodies against the cell surface outer membrane protein 85 (OMP85) of N. meningitidis as an immobilized selective layer. These antibodies were directionally orientated as receptors by thin film deposition of structured polyvinylidene fluoride and Protein A. The sensitivity of this QCM immunosensor was further increased by conjugation of the OMP85 antigen to 50 nm gold nanoparticles providing reproducible detection of the target down to 300 ng/mL. Subsequent treatment of the QCM surface with an acidic glycine solution regenerated the immunosensor allowing each crystal to be used several times. PMID- 22104650 TI - A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women. AB - OBJECTIVE: To test whether a synonymous single nucleotide polymorphism (A->G; rs700518) in the CYP19A1 gene, which encodes the enzyme aromatase, is associated with an increased risk for hypertension of midlife women. METHODS: In a cross sectional study, 639 midlife women were recruited. Eligible women had their blood pressure, weight and height measured, and donated a blood sample for hormone and genetic analyses. The participants also completed a detailed study survey. Women were grouped according to their genotype, blood pressure measurements, and medical history. The data were analyzed using logistic and linear regression models. The study had 80% power to detect small differences in mean systolic blood pressure (SBP; 4.5 mmHg) and diastolic blood pressure (DBP; 3 mmHg). RESULTS: The selected polymorphism was significantly associated with hypertension and SBP in unadjusted analyses. Interestingly, women with hypertension were more likely to be homozygous for the A allele (AA) compared to women who were not categorized as having hypertension. Further, the mean SBP was significantly higher for women who were homozygous for the A allele when compared to women carrying the other genotypes (AG or GG). The unadjusted association between DBP values and genotype was of borderline statistical significance (p=0.07). However, after adjustment for potential confounders (age, race, body mass index (BMI), smoking and physical activity), the associations between genotype and hypertension/blood pressure were attenuated and not statistically significant. CONCLUSION: The rs700518 polymorphism in the CYP19A1 is not associated with hypertension in our sample of midlife women. Other factors, including race and BMI, appear to play a greater role. PMID- 22104651 TI - Absolute reliability of five clinical tests for assessing hamstring flexibility in professional futsal players. AB - OBJECTIVES: To examine the absolute reliability of five methods for estimating hamstring flexibility in professional futsal players. DESIGN: Absolute reliability laboratory study (k=4). METHODS: A total of 46 male futsal players (172.9+/-4.5 cm; 69.7+/-7.5 Kg) completed the study. All participants performed each measurement test twice in a randomized order on four different occasions. Absolute reliability was examined through typical percentage error, percentage change in the mean and intraclass correlations (ICC) as well as their respective confidence limits. RESULTS: The findings showed high reliability for the sit and reach test (SRT) (4.48% typical error; 0.84% change in the mean, 0.95 ICC), toe touch test (TT) (5.89% typical error; 2.31% change in the mean, 0.89 ICC) and back-saver sit and reach test (BSSR) (3.73% typical error; 0.51% change in the mean, 0.97 ICC) compared to the passive straight leg raise test (PSLR) (7.6% typical error; 8.86% change in the mean, 0.77 ICC) and modified sit and reach test (MSR) (11.87% typical error; 7.64% change in the mean, 0.84 ICC) which showed moderate reliability. CONCLUSIONS: An observed change larger than 6.72%, 7.55% and 5.59% for baseline SRT, TT and BSSR scores respectively would indicate that a real improvement in hamstring flexibility has occurred. In addition, the clinical reliability of PSLR and MSR are questioned and should be re-evaluated in future research studies. PMID- 22104652 TI - Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy in Calabria: clinical, immunological and genetic patterns. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal- dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1), is a very rare disease. Diagnosis requires the presence of at least two of three major clinical features: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. DESIGN: In this study, we analyzed Autoimmune Regulator (AIRE) gene mutations and genotype-phenotype correlation in APECED patients originating from Calabria, a region in the south of Italy. PATIENTS AND METHODS: Four patients and their first-degree relatives were evaluated for clinical manifestations, autoantibody presence and AIRE gene mutations. RESULTS: Three patients carried a homozygous W78R mutation on exon 2, typical of patients with APECED from Apulia; the fourth patient had a homozygous R203X mutation on exon 5, typical of APECED patients from Sicily. Clinical disease expression showed wide variability. Analysis of relatives allowed the identification of 6 heterozygotes, none of whom showed major findings of APECED. CONCLUSIONS: No AIRE gene mutations specific to Calabria were found in patients with APS-1, but mutations similar to those in patients from Apulia and Sicily. Heterozygosity for AIRE gene mutation is not associated with major findings of APECED. PMID- 22104653 TI - Septoplasty in conjunction with cosmetic rhinoplasty. AB - This article discusses the intimate relationship that the form of the nasal septum and the esthetics of the nose have with one another and that alterations of either can significantly affect the other. Surgeons from several specialties perform surgical alterations of the external and internal nose; however, many of the advancements have been kept within the literature of their respective fields. It would be wise for rhinoplasty surgeons to have solid understanding of the form and function of the nose so that they may bridge the gaps of their specialty and provide the best possible care for their patients. PMID- 22104654 TI - Nasal tip modifications. AB - Rhinoplasty remains a challenging art but is now systematized at least in part by recent understanding of the supporting mechanisms and how they may be manipulated to control the nasal tip. Nasal tip control is the key to a successful, aesthetically pleasing, rhinoplasty result with preservation of nasal function. PMID- 22104655 TI - Challenges to the traditional exposure paradigm: variability in exposure therapy for contamination fears. AB - BACKGROUND AND OBJECTIVES: Traditional models and methods of exposure therapy utilize a fear hierarchy, whereby patients complete sets of exposures in a graduated manner, with the goal of fear habituation within and between sessions. In the current experiment, we examined whether this typical exposure paradigm was necessary to achieve clinical improvement. METHOD: Fifty undergraduate participants scoring in the top quartile of a self-report measure of contamination fears were randomly assigned to one of two groups: blocked and constant exposure (BC Group) and random and variable exposure (RV Group). Both groups completed three weekly sessions of exposure treatment, with subjective and psychophysiological indices of fear recorded throughout. Subjective, behavioral, and psychophysiological dependent measures were evaluated by an independent assessor at pre-treatment (PRE), post-treatment (POST), and two-week follow-up (2WFU). RESULTS: Both the BC Group and RV Group exhibited decreases in subjective fear from PRE to POST and 2WFU, with no significant differences between groups. Partialing group, greater variability in subjective fear during exposure predicted lower subjective fear at 2WFU. LIMITATIONS: Despite significant findings for subjective fear, behavioral and psychophysiological findings were limited. Follow-up studies should investigate questions regarding traditional exposure within a clinical group. CONCLUSIONS: These results support the notion that traditional exposure is sufficient, but not necessary, to produce clinical improvement in contamination-related fears. There may be benefits to variability in fear level during exposure, and evaluation of emotion variability during exposure therapy for other anxiety disorders is warranted. PMID- 22104656 TI - Admixture analysis of the diagnostic subtypes of social anxiety disorder: implications for the DSM-V. AB - BACKGROUND AND OBJECTIVES: Much controversy exists regarding diagnostic subtypes of social anxiety disorder (SAD). The present study used admixture analysis to examine whether individuals with generalized and nongeneralized SAD belong to the same or different populations of origin. This can inform diagnostic subtyping of SAD in the forthcoming DSM-V. METHODS: Treatment-seeking individuals with generalized SAD (n = 154) and nongeneralized SAD (n = 48) completed a battery of questionnaires. Based on participants' responses to the Liebowitz Social Anxiety Scale (LSAS), we estimated log likelihood and chi-square goodness-of-fit for models with 1, 2, 3, or 4 populations of origin, and compared models using forward stepwise estimation and maximum likelihood ratio tests. RESULTS: Admixture analyses suggested that the two diagnostic subtypes of SAD belong to the same underlying population of origin. In addition, observable differences in depression, general anxiety, and comorbidity were no longer significant when controlling for social anxiety severity. LIMITATIONS: Our sample was recruited in the U.S. and was a treatment-seeking sample. Future studies should examine whether our results generalize to different cultures, and community samples. CONCLUSIONS: Support for qualitative differences between SAD subtypes was not found. Rather, our findings support the notion that the diagnostic subtypes of SAD differ quantitatively, and that SAD exists on a continuum of severity. This finding informs diagnostic subtyping of SAD in the forthcoming DSM-V. PMID- 22104657 TI - Imagery in the aftermath of viewing a traumatic film: using cognitive tasks to modulate the development of involuntary memory. AB - BACKGROUND AND OBJECTIVES: Involuntary autobiographical memories that spring unbidden into conscious awareness form part of everyday experience. In psychopathology, involuntary memories can be associated with significant distress. However, the cognitive mechanisms associated with the development of involuntary memories require further investigation and understanding. Since involuntary autobiographical memories are image-based, we tested predictions that visuospatial (but not other) established cognitive tasks could disrupt their consolidation when completed post-encoding. METHODS: In Experiment 1, participants watched a stressful film then immediately completed a visuospatial task (complex pattern tapping), a control-task (verbal task) or no-task. Involuntary memories of the film were recorded for 1-week. In Experiment 2, the cognitive tasks were administered 30-min post-film. RESULTS: Compared to both control and no-task conditions, completing a visuospatial task post-film reduced the frequency of later involuntary memories (Expts 1 and 2) but did not affect voluntary memory performance on a recognition task (Expt 2). LIMITATIONS: Voluntary memory was assessed using a verbal recognition task and a broader range of memory tasks could be used. The relative difficulty of the cognitive tasks used was not directly established. CONCLUSIONS: An established visuospatial task after encoding of a stressful experience selectively interferes with sensory perceptual information processing and may therefore prevent the development of involuntary autobiographical memories. PMID- 22104658 TI - Does 'Yuck' mean 'Eek'? Fear responses in children after a disgust manipulation. AB - BACKGROUND AND OBJECTIVES: Disgust is a basic emotion that is thought to play a role in the development of animal phobias. This study was conducted to test whether experimentally induced disgust also results in higher levels of fear and interpretation bias. METHODS: Children aged 9-13 years (N=94) were asked to inspect a set of specimen characteristic of a novel animal and requested to form themselves an impression of it based on those characteristics. Half of the children were given a set of disgust-eliciting products in relation to the animal, whereas the other half received a set of neutral materials. RESULTS: The main results indicated that children in the disgust specimen group exhibited an increase in fear towards the novel animal and a stronger inclination to interpret ambiguous situations involving this animal in a more negative way as compared to children in the neutral specimen group. CONCLUSION: These findings confirm that disgust has a fear-promoting effect. PMID- 22104659 TI - Think Effectively About Mood Swings (TEAMS): a case series of cognitive behavioural therapy for bipolar disorders. AB - BACKGROUND AND OBJECTIVES: An integrative cognitive model for bipolar disorder proposes that multiple and extreme appraisals of changes in internal state and their reciprocal impact on behaviour, physiology and the environment provide the core mechanism in maintaining and escalating bipolar symptoms (Mansell, Morrison, Reid, Lowens, & Tai, 2007a). METHODS: A case series of cognitive-behavioural therapy (CBT) based on this model, known as the TEAMS approach (Think Effectively About Mood Swings), with seven participants was conducted. An A-B direct replication design with multiple baseline and follow-up assessments at one, three and six months was used. Treatment involved 12 sessions of CBT with an emphasis on addressing extreme positive and negative appraisals of internal state change. RESULTS: Improvements were reported for symptoms, functioning, cognitions and self-critical processes with large effect sizes on a range of measures, especially depression, at end of therapy and one-month follow-up. Five participants also showed clinically significant change in depression at both time points. CONCLUSIONS: This study provides preliminary evidence for the feasibility, acceptability and efficacy of CBT based on this model which warrants further evaluation. PMID- 22104660 TI - Assessing dog fear: evaluating the psychometric properties of the Dog Phobia Questionnaire. AB - BACKGROUND AND OBJECTIVES: The Dog Phobia Questionnaire (DPQ; Hong & Zinbarg, 1999) is a 27-item self-report questionnaire designed to assess symptoms of dog phobia. The present study investigated the psychometric properties of the DPQ. METHOD: Study 1 explored the factor structure, internal consistency, and convergent and discriminant validity of the DPQ using an undergraduate sample (N = 174). Study 2 assessed the extent to which DPQ scores correlated with subjective fear ratings and avoidance during a behavioral approach test (BAT) with a live dog using undergraduate and community participants (N = 91), and the extent to which DPQ scores differed for individuals with (n = 15) versus without (n = 66) a clinically significant specific phobia of dogs. Study 3 evaluated the test-retest reliability of the DPQ using an undergraduate sample (N = 31). RESULTS: A principal components exploratory factor analysis suggested a one factor solution. Internal consistency was high. DPQ scores were more highly correlated with measures assessing dog fear than measures assessing other types of fears. Test-retest reliability was high. DPQ scores correlated with fear responding and avoidance during the BAT. Participants with a specific phobia of dogs reported higher DPQ scores than those without a specific phobia of dogs. LIMITATIONS: The present study included undergraduate students and community participants; future research with a clinical sample is recommended. CONCLUSIONS: The DPQ may be a useful tool for measuring the severity of fear in dog phobic individuals. Implications for the theoretical assumptions underlying the development of the DPQ are discussed. PMID- 22104662 TI - Living organ donation: the effect of message frame on an altruistic behaviour. AB - OBJECTIVE: This experimental study investigates the impact of message frame and risk perceptions upon willingness to consider living organ donation. DESIGN: A 2 (gain vs. loss) by 2 (liver vs. kidney) by 2 (involved vs. not involved) between group study was conducted. METHOD: Eighty-seven participants completed a questionnaire after reading a vignette designed to invite participants to consider living kidney or liver donation. RESULTS: Within a gain frame scenario, willingness to donate was significantly higher when the risk of donating was lower. CONCLUSION: The results have important implications for the generalizability of framing theories and the promotion of living organ donation. PMID- 22104663 TI - Factor analysis of the Beck Depression Inventory-II with patients with chronic fatigue syndrome. AB - This study examined the properties of the Beck Depression Inventory-II (BDI-II) in a sample of 111 patients with chronic fatigue syndrome (CFS). Exploratory factor analysis identified two factors. The mean score for the Somatic-Affective factor was significantly higher than the Cognitive factor. Convergent and discriminant validity were assessed for BDI-II total score, the two factor scores, and the BDI for Primary Care (BDI-PC). The BDI-PC and Cognitive factor demonstrated superior validity. Results suggest patients endorse BDI-II somatic items that overlap with CFS symptoms at a high rate. Factor scores should be evaluated separately, or the BDI-PC should be utilized with this population. PMID- 22104664 TI - Investigating the therapeutic potential of a heritage-object focused intervention: a qualitative study. AB - This study explores the therapeutic potential of heritage-object handling in nurse-patient encounters with women facing cancer. Ten women participated in an object-focused conversation with a nurse specialist. Sessions were audio-tape recorded and transcribed. Kleinian theory framed the analysis to reveal the individual ways women 'used' the object in the session. Professionally observed heritage-object handling provides an aid to discussion with patients and has potential as an assessment platform for therapeutic work or as an intervention approach in its own right. Further longitudinal controlled trials are needed to evaluate such benefits, particularly given the depth of the talk revealed in this study. PMID- 22104665 TI - Temperament and character properties of male psoriasis patients. AB - Personality properties have an effect on the onset and triggering of psoriasis. The current study aimed to examine the personality of psoriasis patients in relation to the severity of the illness. Psoriasis and healthy participants completed the Beck Depression Inventory, Beck Anxiety Inventory, Maudsley Obsessive Compulsive Inventory, Temperament and Character Inventory. Severity of psoriasis was evaluated by the PASI. MANCOVA results revealed significantly higher Novelty Seeking, Harm Avoidance, Reward Dependence and Self-Transcendence scores for psoriasis group. Severity of PASI was predicted by harm avoidance and reward dependence. Personality properties should be evaluated while planning therapeutic interventions for psoriasis patients. PMID- 22104666 TI - Early stenosis of Medtronic Mosaic bioprosthesis in the aortic position. PMID- 22104668 TI - A novel detection method of non-small cell lung cancer using multiplexed bead based serum biomarker profiling. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) is the leading cause of cancer related mortality. Development of an early diagnosis method may improve survivals. We aimed to develop a new diagnostic model for NSCLC using serum biomarkers. METHODS: We set up a patient group diagnosed with NSCLC (n = 122) and a healthy control group (n = 225). Thirty serum analytes were selected on the basis of previous studies and a literature search. An antibody-bead array of 30 markers was constructed using the Luminex bead array platform (Luminex Inc, Austin, Tex) and was analyzed. Each marker was ranked by importance using the random forest method and then selected. Using selected markers, multivariate classification algorithms were constructed and were validated by application to independent validation cohort of 21 NSCLC and 28 control subjects. RESULTS: There was no difference in demographics between patients and the control population except for age (64.8 +/- 10.0 for patients vs 53.0 +/- 7.6 years for the control group). Among the 30 serum proteins, 23 showed a difference between the 2 groups (12 increased and 11 decreased in the patient group). We found the highest accuracy of multivariate classification algorithms when using the 5 highest ranked biomarkers (A1AT, CYFRA 21-1, IGF-1, RANTES, AFP). When we applied the algorithms on a validation cohort, each method recognized the patients from the controls with high accuracy (89.8% with random forest, 91.8% with support vector machine, 88.2% with linear discriminant analysis, and 90.5% with logistic regression). CONCLUSIONS: We confirmed that a new diagnostic method using 5 serum biomarkers profiling constructed by multivariate classification algorithms could distinguish NSCLC from healthy controls with high accuracy. PMID- 22104669 TI - Quality, not volume, determines outcome of coronary artery bypass surgery in a university-based community hospital network. AB - OBJECTIVES: The present study examined the relationship between hospital and surgeon coronary artery bypass grafting procedural volume, mortality, morbidity, and National Quality Forum care processes in a university-based community hospital quality improvement program. METHODS: The study population consisted of 2218 consecutive patients undergoing isolated coronary artery bypass grafting from 2007 to 2009 in a university-based quality improvement program that emphasizes involvement of all surgeons in the academic quality endeavor. The endpoints included operative mortality, major morbidity, and National Quality Forum-endorsed process measures as defined by the Society of Thoracic Surgeons. The procedural volume was analyzed as a categorical and continuous variable using general estimating equations, which accounted for clustering effects and which were adjusted for Society of Thoracic Surgeons risk scores and the propensity for operation in a low- versus high-volume program. RESULTS: The annual program volume ranged from 67 to 292 (median, 136; interquartile range, 88-224) and surgeon volume from 1 to 124 (median, 58; interquartile range, 30-89). The mortality rate among the hospitals was 0.47% to 2.23% (0.8% overall), and the observed/expected mortality ranged from 0 to 1.20 (0.41 overall). When comparing low-volume (<200 cases/year) and high-volume centers, no difference was found in the mortality (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.46-2.54, P = .85), morbidity (OR, 1.34; 95% CI, 0.73-2.43), or any of the medication process measures. No difference was found in mortality (OR, 1.59; 95% CI, 0.81-3.13; P = .18), morbidity (OR, 1.20; 95% CI, 0.86-1.66; P = .28), or medication failure (OR, 0.57, 95% CI, 0.3-1.10; P = .10) between the high- and low-volume surgeons (<87). After adjustment for both the Society of Thoracic Surgeons risk score and the propensity score, no association was found for either hospital or surgeon volume with mortality or morbidity. However, a lack of compliance with National Quality Forum measures was highly predictive of morbidity (OR, 1.51; 95% CI, 1.18 1.93; P = .001), regardless of volume, even after adjustment for predicted risk. CONCLUSIONS: In the setting of a university-based community hospital quality improvement program, excellent surgical results can consistently be obtained even in relatively low-volume programs. The surgical outcomes were not associated with program or surgeon volume, but were directly correlated with the focus on quality as manifested by compliance with evidence-based quality standards. Meaningful university affiliation might represent a new quality paradigm for cardiac surgery in the community hospital setting. PMID- 22104670 TI - Remote ischemic preconditioning for renal protection in children undergoing surgery for complex congenital heart disease: what do we know now and where do we go next? PMID- 22104672 TI - Does the mitral valve prosthesis adversely affect the hemodynamic performance of the aortic valve prosthesis in patients with double valve replacement? AB - OBJECTIVE: This study was undertaken to examine the possible adverse effect of the mitral valve prosthesis on the hemodynamic performance of the aortic valve prosthesis in patients who have undergone double valve replacement. METHODS: Patients who underwent double valve replacement were matched for age, body surface area, left ventricular function, and size and type of aortic valve prosthesis with patients who underwent isolated aortic valve replacement. Two types of prosthetic valves were examined: the St Jude Medical mechanical valve (St Jude Medical, St Paul, Minn) and the Hancock II bioprosthesis (Medtronic Inc, Minneapolis, Minn). Five patients for each size and type of aortic valve prosthesis in the double valve replacement group were matched at 1:2 with patients in the isolated aortic valve replacement group. Only valve sizes 21 to 27 were matched. Hemodynamic assessment of the aortic valve prosthesis was performed by transthoracic echocardiogram before hospital discharge. RESULTS: Matched patients had similar clinical profiles. There were no differences in the systolic gradients, effective aortic valve areas, or flow velocity across the aortic valve prostheses after isolated aortic valve replacement or double valve replacement. CONCLUSIONS: Early after surgery, the hemodynamic performance of aortic valve prostheses was not affected by the presence of mitral valve prostheses in patients who underwent combined aortic and mitral valve replacement. PMID- 22104674 TI - Repair of giant paraesophageal hernias routinely produces improvement in respiratory function. AB - OBJECTIVE: Assessment of the clinical impact of giant paraesophageal hernias have historically focused on upper gastrointestinal symptoms. This study assesses the effect of paraesophageal hernia repair on respiratory function. METHODS: All patients undergoing repair of giant paraesophageal hernia were prospectively entered into a database approved by the institutional review board. Patients had symptoms documented preoperatively, including dyspnea. Pulmonary function tests (PFTs) were done preoperatively and repeated a median of 106 days after repair (range, 16-660 days). RESULTS: Preoperative and postoperative PFTs were obtained in 120 unselected patients treated for paraesophageal hernia between 2000 and 2010. Patients' median age was 74 years (range, 45-91 years), 74 (62%) were female, and median body mass index was 28.0 (range, 16.8-46.6). Median length of stay was 4 days (range, 3-10 days), and perioperative mortality was zero. Hernias were classified as type II in 3 (3%) patients, III in 92 (77%), and IV in 25 (21%). Percent of intrathoracic stomach was assigned from preoperative contrast studies and grouped as less than 50% (n = 6; 5%), 50% to 74% (n = 35; 29%), 75% to 99% (n = 29; 24%), and 100% (n = 50; 42%). Preoperative symptoms included heartburn 71 (59%), early satiety 65 (54%), dyspnea 63 (52%), chest pain 48 (40%), dysphagia 56 (47%), regurgitation 47 (39%), and anemia 44 (37%). PFTs significantly improved after paraesophageal hernia repair (mean volume change, percent reference change): forced vital capacity +0.30 L,+10.3%pred; FEV(1) +0.23 L,+10.4%pred (all P < .001); diffusion capacity of the lung for carbon monoxide +0.58 mL . mm Hg(-1) . min(-1) (P = .004), and +2.9%pred (P = .002). Greater improvements were documented in older patients with significant subjective respiratory symptoms and higher percent of intrathoracic stomach (P < .01). CONCLUSIONS: Paraesophageal hernia has a significant effect on respiratory function, which is largely underappreciated. This study demonstrates that these repairs can be done safely and supports routine consideration for elective repair; older patients with borderline respiratory function may achieve substantial improvements in their respiratory status and quality of life. PMID- 22104675 TI - Long-term implications of emergency versus elective proximal aortic surgery in patients with Marfan syndrome in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium Registry. AB - OBJECTIVE: Patients with Marfan syndrome with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of patients with Marfan syndrome who survive emergency versus elective proximal aortic surgery. METHODS: The Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Registry is a National Institutes of Health-funded multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergency (n = 47) or elective (n = 147) status at the time of surgery. RESULTS: Patients in the emergency group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), the emergency group had a higher incidence of chronic dissection of the distal aorta and significantly larger diameters in distal aortic segments than elective patients. Patients in the emergency group had undergone more operations (1.31 vs 1.11 procedures/patient; P = .01) and had lower activity scores on a health-related quality of life survey. CONCLUSIONS: For patients with Marfan syndrome, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to the status of the distal aorta, need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for patients with Marfan syndrome. PMID- 22104677 TI - Robotic lobectomy for non-small cell lung cancer (NSCLC): long-term oncologic results. AB - OBJECTIVE(S): We evaluated a large series of patients undergoing robotic lobectomy for the treatment of early-stage non-small cell lung cancer (NSCLC) to assess long-term oncologic efficacy. METHODS: A multi-institutional retrospective review of patients undergoing robotic lobectomy for NSCLC was performed. Robotic lobectomy was performed in a manner consistent with the Cancer and Leukemia Group B (CALGB) consensus video-assisted thoracic surgery (VATS) lobectomy technique using a robotic surgical system. Perioperative outcomes and long-term follow-up were recorded prospectively, and survival was calculated from the date of surgery to last follow-up. RESULTS: From November 2002 through May 2010, a total of 325 consecutive patients underwent robotic lobectomy for early-stage NSCLC at 3 institutions. The median age of patients was 66 years (range, 30-87 years), and 37% (120) were female. The majority were in clinical stage I (IA, 247; IB, 63). Conversion rate to thoracotomy was 8% (27/325). Overall morbidity rate was 25.2% (82/325), and major complication rate was 3.7% (12/325). There was 1 in-hospital death (0.3%), and the median length of stay was 5 days (range, 2-28 days). Pathologic stage distribution was 54% (176) IA, 22% (72) IB, 13% (41) IIA, 5% (15) IIB, and 6% (21) IIIA. With a median follow-up of 27 months, overall 5-year survival was 80% (95% confidence intervals [CI] = 73-88), and by pathologic stage, 91% (CI = 83-99) for stage IA, 88% (CI = 77-98) for stage IB, and 49% (CI = 24-74) for all patients with stage II disease. Overall 3-year survival for patients with stage IIIA disease was 43% (CI = 16-69). CONCLUSIONS: Robotic lobectomy for early-stage NSCLC can be performed with low morbidity and mortality. Long-term stage-specific survival is acceptable and consistent with prior results for VATS and thoracotomy. PMID- 22104678 TI - Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study. AB - OBJECTIVES: The present multicenter study compared the usefulness of the solid tumor size with that of the whole tumor size on preoperative high-resolution computed tomography for predicting pathologic high-grade malignancy (positive lymphatic, vascular, or pleural invasion) and the prognosis of clinical stage IA lung adenocarcinoma. METHODS: We performed high-resolution computed tomography and F-18 fluorodeoxyglucose-positron emission tomography/computed tomography before curative surgical resection in 502 patients with clinical stage IA lung adenocarcinoma. The revised maximum standardized uptake values on F-18 fluorodeoxyglucose-positron emission tomography/computed tomography were used to correct interinstitutional discrepancies. The whole and solid tumor sizes on high resolution computed tomography were then analyzed in relation to surgical results. RESULTS: The mean whole and solid tumor size was 1.97 +/- 0.59 cm and 1.20 +/- 0.88 cm, respectively. The receiver operating characteristics area under the curve for the whole and solid tumor sizes used to identify high-grade malignancy were 0.590 and 0.829, respectively. Multiple logistic regression analyses demonstrated solid tumor size (P < .001) and maximum standardized uptake values of the tumor (P < .001) as independent variables for the prediction of high-grade malignancy. Multivariate Cox analysis of disease-free survival demonstrated the former (hazard ratio, 2.30; 95% confidence interval, 1.46-3.63; P < .001) and latter (hazard ratio, 1.08; 95% confidence interval, 1.00-1.17; P = .05) as independent prognostic factors. CONCLUSIONS: The solid tumor size on high resolution computed tomography and maximum standardized uptake values on positron emission tomography/computed tomography have greater predictive value for high grade malignancy and prognosis in clinical stage IA lung adenocarcinoma than that of whole tumor size. PMID- 22104679 TI - Decreasing prevalence but increasing importance of left ventricular dysfunction and reoperative surgery in prediction of mortality in coronary artery bypass surgery: trends over 18 years. AB - OBJECTIVES: The number of patients referred for coronary artery bypass grafting (CABG) has fallen, whereas their risk profile appears to be increasing. We evaluated changes in the predictors of hospital mortality among patients undergoing CABG during a span of 18 years. METHODS: Data were collected prospectively for all patients undergoing isolated CABG (n=23,445) from 1991 to 2008. To examine the effect of time on patients' risk profiles and outcomes, we divided patients into 3 time cohorts (1991-1996, n=8280; 1997-2002, n=9801; 2003 2008, n=5364). We used multivariable logistic regression model to identify predictors of mortality in the entire cohort and in each time cohort. RESULTS: Hospital mortality declined from 2.4% (1991-1996) to 1.2% (2003-2008; P<.0001). Urgent or emergency surgery, left ventricular dysfunction, reoperative CABG, increased age, female gender, hypertension, cardiogenic shock, congestive heart failure, peripheral vascular disease, left main disease, and earlier year of operation (1991-1996) were independent predictors of hospital mortality. The prevalence of most risk factors for mortality increased over the 18-year period of this study. In contrast, the prevalence of severe left ventricular dysfunction and reoperative CABG decreased significantly; however, their associated odds of mortality increased with time. CONCLUSIONS: Whereas the prevalence of most risk factors increased with time, left ventricular dysfunction and reoperative CABG became significantly less common. However, the odds of mortality associated with these 2 predictors increased, indicating that although they occur less commonly, these 2 risk factors paradoxically play an increasingly important role in determining patient outcomes. PMID- 22104680 TI - A novel reconstruction of the left superior vena cava. PMID- 22104681 TI - Pentacuspid aortic valve causing severe aortic regurgitation. PMID- 22104683 TI - Is completion lobectomy merited for unanticipated nodal metastases after radical segmentectomy for cT1 N0 M0/pN1-2 non-small cell lung cancer? AB - OBJECTIVE: To examine the role of radical segmentectomy, defined as a segmentectomy with extensive hilar/mediastinal lymph node dissection and a sufficient surgical margin, for local control in cT1 N0 M0/pN1-2 non-small cell lung cancer (NSCLC), we examined the following: (1) whether metastases were observed in specimens additionally resected by completion lobectomy undertaken after segmentectomy because of pN1-2 disease and (2) prognostic outcome in patients whose operations were completed with segmentectomy regardless of pN1-2. METHODS: Of 275 patients with cT1 N0 M0 NSCLC who were scheduled to undergo radical segmentectomy, 15 (6%) had a diagnosis of pN1 or N2 disease. Of these patients, 10 were additionally treated with completion lobectomy, whereas the operations of the remaining 5 were completed with segmentectomy. RESULTS: None of the 10 patients who underwent completion lobectomy showed residual metastases in the specimens additionally resected by completion lobectomy. Two of the 5 patients whose operations were completed with segmentectomy, regardless of N1 or N2 disease, had tumor recurrence, but their first recurrence was not local. CONCLUSIONS: Radical segmentectomy, with extensive hilar/mediastinal lymph node dissection and a sufficient surgical margin, may play a role in local control in patients with cT1 N0 M0/pN1-2 NSCLC. PMID- 22104684 TI - Is there a benefit of awake thoracoscopic surgery in patients with secondary spontaneous pneumothorax? AB - OBJECTIVES: The purpose of the present study was to retrospectively compare the outcomes of video-assisted thoracic surgery in awake and anesthetized patients in the treatment of secondary spontaneous pneumothorax. METHODS: A total of 57 consecutive patients who underwent video-assisted thoracic surgery for secondary spontaneous pneumothorax was retrospectively analyzed. Of these patients, 15 underwent surgery under epidural and/or local anesthesia (ELA) and 42 under general anesthesia. Using propensity score matching, we identified comparable patient groups: the ELA group and general anesthesia group (n = 8 each). We compared the duration of operating room stay, operating time, postoperative hematologic data on postoperative day 1, postoperative complications, duration of hospital stay, and the incidence of hospital death between the ELA and general anesthesia groups. RESULTS: After propensity score matching, the duration of operating room stay was significantly shorter in the ELA group (P = .006). The incidence of postoperative respiratory complications, including pneumonia and acute respiratory distress syndrome, was lower in the ELA group (P = .02). The duration of postoperative hospital stay and the incidence of hospital death were not different between the 2 groups. CONCLUSIONS: The ELA group had a lower incidence of postoperative respiratory complications. Awake video-assisted thoracic surgery can be performed with an acceptable overall morbidity for patients with secondary spontaneous pneumothorax. PMID- 22104685 TI - Valve-sparing aortic root repair without down-sizing of the annulus. AB - OBJECTIVES: The study was conducted to evaluate the intermediate results after patient-tailored aortic root repair with replacement of isolated sinuses adjusted to the existing aortic annulus diameter rather than annulus downsizing. METHODS: Between 2000 and 2009, 236 patients with aortic root disease underwent patient tailored restoration of the aortic root according to its anatomopathologic condition with repair of 1, 2, or all 3 sinuses in 73, 94, and 69 patients, respectively. Concomitant cusp repair was performed in 106 patients. Insufficiency grades of 0/1+, 2+, 3+, and 4+ were presented in 59, 74, 74, and 29 patients, respectively. All data were collected prospectively and intention-to treat analysis was performed. RESULTS: Valve repair was successful in all but 6 patients. At the most recent clinical and echocardiographic follow-up of the remaining patients, which averaged 43 +/- 24 months (range, 0.3-115 months), 216 patients showed no or slight aortic regurgitation (grade 0/1+) and 10 patients showed grade 2+. Another 4 patients had grade 3+ regurgitation and underwent aortic valve replacement. The actuarial freedom from aortic regurgitation grade 3+ or more at 8 years was 95.2%. Multivariate logistic regression analysis identified cusp repair as the independent risk factor for an aortic regurgitation grade of 2+ or more with an odds ratio of 10.9 (95% confidence interval, 2.5 47.7; P = .002). The association between aortic annulus size and functional results after repair could not be demonstrated. CONCLUSIONS: Aortic root repair with replacement of isolated sinuses adjusted to the existing aortic annulus leads to excellent, durable results and can be recommended. Cusp disease is a leading aspect affecting functional results of repair. Therefore, establishment of reproducible cusp repair techniques is of utmost importance for further development of reconstructive aortic valve surgery. PMID- 22104686 TI - Factors determining successful computed tomography-guided localization of lung nodules. AB - OBJECTIVES: To investigate the factors related to the successful computed tomography-guided nodule localization for subsequent nodule excision. METHODS: We retrospectively reviewed the medical records for 181 patients who had undergone computed tomography-guided nodule localization using hook wire and subsequent video-assisted thoracic surgery resection for lung nodules. The demographic factors, nodule factors, and technical factors were reviewed to determine what affects effective nodule localization for video-assisted thoracic surgery resection using both univariate and multivariate models. RESULTS: A total of 174 patients were included in our study. Successful localization was accomplished in 166 patients (95%). Univariate analysis implicated patient age, nodule solidity, zonal location, and a sufficient distance between the hook wire tip and pleural surface as significant factors for successful localization. Multivariate analysis focused on the distance between the wire tip and pleural surface as the sole independent factor for successful localization (P = .012). CONCLUSIONS: The distance between the hook wire tip and pleural surface was the major significant factor for successful computed tomography-guided nodule localization for subsequent video-assisted thoracic surgery resection. Thus, the localization of a hook wire adjacent to a target nodule with sufficient depth from the pleural surface is crucial to the success of the procedure. PMID- 22104687 TI - Wedge bronchoplastic lobectomy for non-small cell lung cancer as an alternative to sleeve lobectomy. AB - OBJECTIVES: Sleeve lobectomy was introduced for patients with lung cancer whose pulmonary reserve was inadequate for pneumonectomy. However, the safety and survival benefits of wedge bronchoplastic lobectomy as an alternative to sleeve lobectomy have not been thoroughly studied. This study was performed to evaluate the safety and oncologic results of wedge bronchoplastic lobectomy for lung cancer. METHODS: We retrospectively analyzed 191 patients who underwent wedge bronchoplastic lobectomy and mediastinal lymph node dissection from 2001 to 2009. RESULTS: There were 174 male patients with a mean age of 61.8 +/- 8.2 years. The median follow-up duration was 28 months. Nine patients showed severe postoperative complications: bronchopleural fistulas (n = 3), necrosis at the bronchoplasty site (n = 1), or obstruction (n = 5). The operative mortality rate was 3.7%. Local and regional recurrences were reported in 17 and 12 patients, respectively. The 5-year overall survival was 62.8%. The 5-year overall survival was 68.6% in N0, 64.4% in N1, and 52.6% in N2 (P = .09). The 5-year overall freedoms from local recurrence and locoregional recurrence were 85.3% and 78.9%, respectively, which did not differ by nodal status. A multivariate analysis showed that positive N1 and N2 nodes were risk factors (P = .036 and P = .042, respectively) for overall survival after wedge bronchoplastic lobectomy. CONCLUSIONS: Wedge bronchoplastic lobectomy for lung cancer is a safe and feasible procedure that does not compromise oncologic principles. It can be considered an appropriate alternative to sleeve lobectomy and pneumonectomy, regardless of nodal status. PMID- 22104688 TI - Choosing an appropriate length of loop type ureteral stent using direct ureteral length measurement. AB - PURPOSE: The ureteral stent is now a fundamental part of many urological procedures. To decrease ureteral stent-related symptoms, loop type ureteral stent was developed. However the most important factor to decrease urinary symptoms is choosing the optimal length of a ureteral stent. We investigated the relationship between the actual ureteral length and the loop type ureteral stent position. MATERIALS AND METHODS: A total of 226 loop type polyurethane ureteral stents (156 patients) were inserted with four options for stent length (20, 22, 24 and 26 cm). The ureteral length was measured using a ruled 5-Fr ureteral catheter. The appropriateness of stent position was defined into three groups based on kidney ureter-bladder films. RESULTS: Nine stents (3.9%) migrated, 171 stents (75.7%) were in the appropriate position and 46 stents (19.5%) were overlong. The rate of migration rate and overlong stents closely correlated with the ureteral length when the proximal end of the stent was in the renal pelvis. CONCLUSIONS: It is appropriate to choose a loop type ureteral stent that is the same or 1 cm less than the length of the ureter when the proximal end of the stent will be in the renal pelvis. PMID- 22104689 TI - Assessment of pulmonary veins after atrio-pericardial anastomosis by cardiovascular magnetic resonance. AB - BACKGROUND: The atrio-pericardial anastomosis (APA) uses a pericardial pouch to create a large communication between the left atrium and the pulmonary venous contributaries in order to avoid direct suturing of the pulmonary veins during the repair of congenital cardiac malformations. Post-operative imaging is routinely performed by echocardiography but cardiovascular magnetic resonance (CMR) offers excellent anatomical imaging and quantitative information about pulmonary blood flow. We sought to compare the diagnostic value of echocardiography and CMR for assessing pulmonary vein anatomy after the APA. METHODS: This retrospective study evaluated all consecutive patients between October 1998 and January 2010 after either a primary or secondary APA followed by post-repair CMR. RESULTS: Of 103 patients who had an APA, 31 patients had an analyzable CMR study. The average time to CMR was 24.6 +/- 32.5 months post repair. Echocardiographic findings were confirmed by CMR in 12 patients. There was incomplete imaging by echocardiography in 7 patients and underestimation of pulmonary vein restenosis in 12, when compared to CMR. In total, 19/31 patients (61%) from our cohort had significant stenosis following the APA as assessed by CMR. Our data suggest that at least 18% (19/103) of all patients had significant obstruction post-repair. CONCLUSIONS: Echocardiography incompletely imaged or underestimated the severity of obstruction in patients compared with CMR. Pulmonary vein stenosis remains a sizable complication after repair, even using the APA. PMID- 22104690 TI - Wrangling for microRNAs provokes much crosstalk. AB - Levels of transcripts sharing microRNA response elements are co-regulated. These RNA-RNA interactions imply that combinations of microRNAs modulate cell-specific transcript networks. PMID- 22104691 TI - A new image-based stroke registry containing quantitative magnetic resonance imaging data. AB - BACKGROUND: Conventional stroke registries contain alphanumeric text-based data on the clinical status of stroke patients, but this format captures imaging data in a very limited form. There is a need for a new type of stroke registry to capture both text- and image-based data. METHODS AND RESULTS: We designed a next generation stroke registry containing quantitative magnetic resonance imaging (MRI) data, 'DUIH_SRegI', developed a supporting software package, 'Image_QNA', and performed experiments to assess the feasibility and utility of the system. Image_QNA enabled the mapping of stroke-related lesions on MR onto a standard brain template and the storage of this extracted imaging data in a visual database. Interuser and intrauser variability of the lesion mapping procedure was low. We compared the results from the semi automatic lesion registration using Image_QNA with automatic lesion registration using SPM5 (Statistical Parametric Mapping version 5), a well-regarded standard neuroscience software package, in terms of lesion location, size and shape, and found Image_QNA to be superior. We assessed the clinical usefulness of an image-based registry by studying 47 consecutive patients with first-ever lacunar infarcts in the corona radiata. We used the enriched dataset comprised of both image-based and alphanumeric databases to show that diffusion MR lesions overlapped in a more posterolateral brain location for patients with high NIH Stroke Scale scores (>=4) than for patients with low scores (<=3). In April 2009, we launched the first prospective image-based acute (<=1 week) stroke registry at our institution. The registered data include high signal intensity ischemic lesions on diffusion, T(2)-weighted, or fluid attenuation inversion recovery MRIs, and low signal intensity hemorrhagic lesions on gradient-echo MRIs. An interim analysis at 6 months showed that the time requirement for the lesion registration (183 consecutive patients, 3,226 MR slices with visible stroke-related lesions) was acceptable at about 1 h of labor per patient by a trained assistant with physician oversight. CONCLUSIONS: We have developed a novel image-based stroke registry, with database functions that allow the formulation and testing of intuitive, image-based hypotheses in a manner not easily achievable with conventional alphanumeric stroke registries. PMID- 22104692 TI - Intrathecal baclofen therapy for severe spasticity: analysis on a series of 112 consecutive patients and future prospectives. AB - OBJECTIVE: Intrathecal baclofen therapy (ITB) is a well-known treatment for spasticity. Despite this fact, several topics have to be still discussed: new indications and screening tools, appropriate surgical timing and complicance avoidance. METHODS: A total of 112 consecutive patients all with a severe, progressive and refractory to medical therapy spasticity from different causes were treated using ITB, after a bolus test. Every patient was assessed by means of Modified Ashworth Scale (MAS), Penn spasm frequency scale (SFS) and Visual Analog Scale for pain. Since available, a Gait analysis was also performed. RESULTS: There were 63 males (56%) and 49 females (44%). Seventy-four (66%) had a quadriparesis, 34 (30.4%) had a paraparesis and 4 (3.6%) were hemiplegic. Among these patients 77 (68.7%) were non ambulatory, while 35 (31.3%) were ambulatory. These patients suffered from spasticity due to many different diseases. Mean follow-up was 55 months. The mean Modified Ashworth score decreased from 4.5+/ 0.5 preoperatively to 1.2+/-0.4 on chronic intrathecal baclofen. Daily baclofen dose varied between 23 and 500 mcg. Drug-induced complications and catheter related problems occurred, respectively in 7 (6.3%) and 10 patients (8.9%). CONCLUSIONS: Although ITB is a well known and good treatment option in the management of severe spasticity, because of the different goals and subgroups of patients treated, a variety of techniques are needed to evaluate the benefits of this therapy. New indications, effects of ITB on central nervous system and cognitive functions needs yet to be fully clarified. PMID- 22104693 TI - Subclinical Charcot-Marie-Tooth disease type 1A in an ex-professional cyclist. PMID- 22104694 TI - Necrotizing vasculitis revealed in a case of multiple mononeuropathy after a 14 year course of spontaneous remissions and relapses. PMID- 22104695 TI - Giant solitary cystic schwannoma of the cervical spine: a case report. PMID- 22104696 TI - Castleman's disease of the sacral spine. PMID- 22104697 TI - Usefulness of thallium-201 SPECT for prediction of early progression in low-grade astrocytomas diagnosed by stereotactic biopsy. AB - OBJECTIVE: To establish the value of thallium-201 single-photon emission computed tomography ((201)Tl-SPECT) as a predictor of early progression in low-grade astrocytomas (LGAs). METHODS: We studied 57 consecutive patients who underwent 201 Tl-SPECT before stereotactic biopsy (n=33) or surgical resection (n=24). The value of radiologic and histopathological variables ((201)Tl index and MIB-1 index) in predicting progression free survival (PFS) was examined in each group of patients. RESULTS: During a median follow up of 55 months (range, 11-101), progression of the primary lesion was identified in 46 patients (80.7%). Based on Cox's proportional hazards model, the increased thallium uptake was associated with a short PFS in both biopsy and resection groups, whereas the MIB-1 index was significant only in the resection group. Considering the cut-off value, (201)Tl index>1.7 was statistically significant for reduced PFS in the biopsy group; however, MIB-1 index was not directly related to the PFS at any level. For the surgical resection group, both a (201)Tl index>1.9 and a MIB-1 index>6% were associated with short PFS. CONCLUSION: (201)Tl SPECT may play a role in prediction of early tumor progression not only in resected LGAs, but also in biopsy-proven LGAs. Therefore, we suggest that patients with LGAs established from biopsy should be considered as high-risk groups for early progression if the tumor shows a high (201)Tl uptake, even if the tumor demonstrates low proliferative activity on histopathologic examination. PMID- 22104698 TI - Resveratrol inhibited GH3 cell growth and decreased prolactin level via estrogen receptors. AB - AIMS: Pituitary prolactinoma is one of the estrogen-related tumors, some anti estrogen compounds have suppressive effects on prolactinoma. Previous studies have suggested that resveratrol, a phytoestrogen, displays anti-estrogen and anti tumor characteristics. Therefore, We determined whether resveratrol could inhibit the cell proliferation and decrease prolactin level in prolactinoma cell line, and identify the signaling pathways that mediate the effects of resveratrol. MAIN METHODS: Prolactinoma cell line, GH3 cells were treated with resveratrol. Changes in proliferation, cell cycle, and apoptosis were assessed. The level of prolactin was assayed by Western blot or EIA. Expression of total Rb (retinoblastoma protein), phosphorylated Rb (pRb) and cyclin D3 were measured by Western blot. The changes of estrogen receptors and their roles in the effects of resveratrol were also determined. KEY FINDINGS: We report that resveratrol had a dose dependent inhibitory effect on GH3 cell proliferation. Inhibitory effects of resveratrol persisted, even on removal of resveratrol. The growth-inhibitory effect of resveratrol was accompanied by decreased expression of cyclin D3 and pRb. In addition, resveratrol induced G0/G1 cell cycle block and apoptosis. Furthermore, resveratrol suppressed intracellular levels and release of prolactin. Finally, we show that two types of estrogen receptor were involved in the different effects of resveratrol. SIGNIFICANCE: Taken together, we demonstrate that resveratrol could inhibit prolactinoma cell proliferation, induce cell cycle block and apoptosis, and decrease prolactin production and release, and estrogen receptors mediate its antitumor effects. And thus, these results lead us to propose developing resveratrol as a novel therapeutic agent for treatment of prolactinoma. PMID- 22104699 TI - Interactions between hypoxia and sewage-derived contaminants on gene expression in fish embryos. AB - Fish embryos were used to evaluate the interaction among common environmental and chemical stressors found in urban coastal environments, namely hypoxia, aryl hydrocarbon receptor (AhR) agonists, and estrogenic compounds. At the molecular level, the systems responding to these stressors share common response factors, and evidence exists for cross-talk between them. Biomarkers of exposure to these stressors, cytochrome P4501a (Cyp1a), estrogen receptor alpha (ERalpha), brain cytochrome P450 aromatase (Cyp19a2 or AromB), and hypoxia inducible factor 1 alpha (Hif-1alpha) mRNA expression were examined using qRT-PCR simultaneously in embryos of two well studied species, the Atlantic killifish, Fundulus heteroclitus, and the zebrafish Danio rerio. Embryos of both species were exposed to the model Cyp1a inducer beta-naphthoflavone (BNF) or 17-beta estradiol (E2) under either normoxic or hypoxic (5% oxygen atmosphere) conditions and harvested prior to hatch at 9 days post fertilization (dpf) for the killifish, and 48h post fertilization (hpf) for the zebrafish. BNF significantly induced Cyp1a expression in embryos of both species with killifish embryos being more responsive (700 fold>control) than zebrafish embryos (7-100-fold>control). AromB was also significantly influenced by treatment, but to a lesser extent, with mean expression levels increased by less than two-fold over control values in response to E2, and in one case upregulated by BNF. ERalpha and Hif-1alpha were constitutively expressed in embryos of both species, but expression was unaffected by exposure to either BNF or E2. Hypoxic conditions downregulated AromB expression strongly in killifish but not in zebrafish embryos. The impact of hypoxia on expression of other genes in either species was inconsistent, although an interactive effect between hypoxia and BNF on several of the genes evaluated was observed. These data are the first to examine expression patterns of these important environmental response genes together in embryos of two important model fish species. The results support the use of Cyp1a expression as a biomarker of AhR agonists in fish embryos, and indicate that AromB may be more responsive than ERalpha to estrogenic chemicals at this stage in development. Hif 1alpha expression was not found to be a good biomarker of hypoxic exposure in either killifish or zebrafish embryos. The interaction observed between BNF and co-exposure to hypoxia warrants further investigation. Finally killifish embryos are generally more sensitive than zebrafish embryos at this stage of development supporting their use in environmental assessments. PMID- 22104700 TI - Firearm related injuries amongst children: estimates from the nationwide emergency department sample. AB - OBJECTIVE: The objective of this study is to provide estimates of firearm related injuries in children seeking care in hospital based emergency departments. METHODS: The Nationwide Emergency Department Sample (NEDS) for the year 2008 was used for the current study. All ED visits occurring amongst children aged less than or equal to 18 years and that had an External Cause of Injury (E-Code) for any of the firearm related injuries were selected for analysis. RESULTS: A total of 14,831 ED visits (in children) in the United States had a firearm injury. The average age of the ED visits was 15.9 years. Males constituted a predominant proportion of all ED visits (89.2%). A total of 494 patients died in the emergency departments (3.4% of all ED visits) whilst 323 died following in patient admission into the same hospital (6% of all inpatient admissions). The most frequently documented firearms were assaults by firearms and explosives (55% of all ED visits), accidents caused by firearms and air gun missiles (33.6%), and injuries by firearms that were undetermined (7.4%). The average charge for each ED visit was $3642 (25th percentile is $1146, median is $2003, and 75th percentile is $4404). The mean charge for those visits that resulted in in patient admission into the same hospital was $70,164 (25th percentile is $16,704, median is $36,111, and 75th percentile is $74,165) and the total charges for the entire United States was about $371.33 million. CONCLUSIONS: The current study used the largest all-payer hospital based emergency department dataset to provide national estimates of firearm related injuries amongst children in the United States during the year 2008 and highlights the public health impact of such injuries. PMID- 22104701 TI - The regional association of rising type 2 diabetes incidence with magnesium in drinking water among young adults. AB - The incidence of type 2 diabetes is increasing among Finnish young adults. A slightly increased risk in men was found in the north-east and western part of the country. The higher risk areas in women were found in the western coastal area and in eastern Finland. The present register-based study aimed to evaluate the regional association of the incidence of type 2 diabetes among young adults with the concentration of magnesium in local ground water. The association was evaluated using Bayesian modeling of geo-referenced data aggregated into a regular 10 km * 10 km grid cells. No marked association was found, although suggestive findings were detected for magnesium in well water and diabetes in young adult women. The results of this register-based study did not completely rule out the association of well water magnesium with the geographical variation of type 2 diabetes. The incidence of type 2 diabetes was much higher among individuals aged 40 or over. These suggestive findings indicate that the association between magnesium and type 2 diabetes would also be worth examining among individuals over 40 years of age. PMID- 22104702 TI - A description of the nutritional status and quality of life of Australian gynaecological cancer patients over time. AB - PURPOSE OF THE RESEARCH: To describe the quality of life, nutritional status and physical activity of women with gynaecological cancer over three time points. METHODS AND SAMPLE: Women referred to a major gynaecological cancer service in Sydney for initial treatment were invited to complete validated questionnaires at baseline, three and six months after diagnosis. Quality of life was assessed using the 36-item Short Form Health Survey (SF36) and the Symptom Distress Scale. Nutritional status was assessed using the Patient Generated-Subjective Global Assessment and physical activity was assessed using the International Physical Activity Questionnaire short form. Effect sizes corrected for correlation were calculated using Cohen's d and Friedman's test was used to compare scores. Complete case analysis was used. KEY RESULTS: Forty women were recruited and twenty-three (58%) completed assessment measures for all three time points. No important clinical or demographic differences existed between women who completed all measures and those who did not. Over the duration of the study, the number of well-nourished women increased from 16 to 21, while the number of malnourished women decreased from 7 to 2. Improvements in SF36 scores were seen in all aspects except general health, which declined (p>0.05). Statistically significant (p<0.05) improvements were seen for role physical, vitality, social functioning and role emotional. The median number of minutes of physical activity per week was highest at diagnosis and declined after that. CONCLUSIONS: This study indicates the importance of assessing nutritional status at diagnosis for women with gynaecological cancer. PMID- 22104703 TI - Changes in serum runt-related transcription factor 2 levels after a 6-month treatment with recombinant human parathyroid hormone in patients with osteoporosis. AB - BACKGROUND: The mechanisms regulating the anabolic response of the skeleton for recombinant human PTH (1- 34) [rhPTH (1-34)] administration has not been fully elucidated. AIM: The aim of this study was to evaluate the effect of rhPTH (1-34) on serum levels of runt-related transcription factor 2 (Runx2) in women with osteoporosis. METHODS: Sixty post-menopausal women with osteoporosis (EO group) and 45 control subjects (NC group) were enrolled in this study. The EO group received daily injection of 20 MUg rhPTH (1-34) plus oral 500 mg elemental calcium and 400 IU vitamin D3 for 6 months. Runx2 and Matrix metalloproteinase 13 (MMP-13) were measured with commercially available enzyme-linked immunosorbent assay kits. Bone mineral density (BMD) was also measured before and 6 months after rhPTH (1-34) treatment. RESULTS: Serum total Ca2+, phosphate, and bone specific alkaline phosphatase were significantly increased (p<0.05 or p<0.01), and the lumbar spine BMD (LS-BMD) was also increased by 4% in patients with osteoporosis after treatment with rhPTH (1-34) (p<0.05). On the contrary, serum Runx2 and MMP-13 were significantly decreased at post treatment (13.1% and 36.6%, respectively, p<0.05 and p<0.01). At baseline, serum Runx2 positively correlated with MMP-13 (r=0.74, p<0.01), the correction remained after adjusting for age and body mass index. CONCLUSION: The daily injection of rhPTH (1-34) was able to stimulate bone formation. The therapy of 20 MUg rhPTH (1- 34) for 6 months resulted in decrease of serum Runx2 and MMP-13. These changes might reflect the increase of active osteoblasts and the better bone homeostasis. PMID- 22104704 TI - Anticipatory guidance is failing due to North American lifestyles. PMID- 22104705 TI - Trabecular juvenile ossifying fibroma with aneurysmal bone cyst: a rare presentation. AB - Juvenile ossifying fibroma is an uncommon, benign, bone-forming neoplasm that is distinguished from other fibro-osseous lesions primarily by its age of onset, clinical presentation, and potential behavior. It mainly occurs in juveniles and has a slight male predilection and more aggressive behavior than a common ossifying fibroma. There are 2 distinct histopathological variants of this lesion: (1) psammomatoid pattern and (2) trabecular pattern. An aneurysmal bone cyst may occur in association with other bone lesions, such as fibrous dysplasia, ossifying fibroma, and giant cell lesion. The clinical management and prognosis of juvenile ossifying fibroma is somewhat uncertain, and this tumor has high rates of recurrence. Such behavior may be related to younger patient age and the concurrent development of aneurysmal bone cyst. The purpose of this paper was to report a case of trabecular juvenile ossifying fibroma in a 9-year-old girl associated with an aneurysmal bone cyst, presenting an aggressive behavior, and causing significant facial asymmetry. PMID- 22104706 TI - Maternal beliefs and motivations for first dental visit by low-income Mexican American children in California. AB - PURPOSE: The purpose of this study was to examine Mexican American immigrant caregivers' beliefs and motivations surrounding the first dental visit for their young children (median age=5-years-old). METHODS: Qualitative interviews were conducted among a convenience sample of 48 low-income, Mexican American mothers about their young children's oral health. Transcripts were independently read, coded, and thematically analyzed. RESULTS: Half (51%) of first dental visits were for parent-initiated reasons, including: for pain or visible dental problems; for parent's proactive desire to get a checkup; or to avoid future dental problems. The other half was initiated by external prompts, especially pediatrician recommendations and school requirements. Once a child went to the dentist for his/her first visit, 94% continued with regular checkups. The mean age for a first dental visit was 3-years-old. Three parents reported cases in which dentists discouraged visits for symptomatic children before they were 3-years old. CONCLUSIONS: The low-income, urban Mexican American parents interviewed take their children to their first dental visit when they are approximately 3-years old, much later than the recommended 1-year-old first visit for this at-risk population. Physicians are well positioned to play an important role in prompting first dental visits. PMID- 22104707 TI - Pulp canal obliteration following trauma to primary incisors: a 9-year clinical study. AB - PURPOSE: The purpose of this study was to determine the occurrence of pulp canal obliteration (PCO) in traumatized primary maxillary central incisors and its association with secondary pulp necrosis, type of trauma, and further incidence of trauma. METHODS: A retrospective descriptive study on 112 traumatized teeth was carried out (9-year follow-up) using the clinical and radiographic data from 82 patient charts at the Traumatized Patient Care Program of the Universidade Federal de Santa Catarina. RESULTS: A total of approximately 54% of the teeth exhibited PCO; in approximately 58% of these cases, obliteration was diagnosed within 12 months following the trauma. An association between PCO and crown discoloration was confirmed (P<.001). PCO was not significantly associated with patient gender, age, type of trauma, or recurrence of trauma. There were no cases of secondary pulp necrosis. CONCLUSIONS: The findings of the present study reveal that the occurrence of PCO in traumatized primary teeth was high, while the type and recurrence of trauma were not risk factors for the development of PCO. Moreover, there was no association between PCO and secondary pulp necrosis. PMID- 22104708 TI - Effectiveness of an oral health program in improving the knowledge and competencies of head start staff. AB - PURPOSE: Head Start and Early Head Start (HS/EHS) programs have partnered with the American Academy of Pediatric Dentistry to promote oral health and increase access to dental homes. Preparing HS/EHS staff for issues related to pediatric oral health promises to improve effectiveness of this collaboration. This paper's purpose was to describe the Columbia Head Start Oral Health Program (C HSOHP) and changes in HS/EHS staff pediatric oral health knowledge and competencies after participating in C-HSOHP. METHODS: Four HS/EHS grantees in New York City engaged in the 2008-09 C-HSOHP. A convenience sample of 61 staff completed pre- and postself assessments of knowledge and competencies. RESULTS: Significant paired mean improvements were found for staff-reported level of preparation to explain dental issues during pregnancy, the tooth decay process, and preparing parents for their child's first dental visit. Significant improvements were found in staff confidence in teaching parents about children's oral health issues, referring for pediatric dental services, and talking to a dentist about a concern. CONCLUSIONS: The Columbia Head Start Oral Health Program was effective in improving Head Start/Early Head Start staff self confidence and self-perceived preparedness in teaching parents about oral health, applying oral health knowledge to HS/EHS programs, communicating with dental professionals, and improving access to pediatric dental services. PMID- 22104709 TI - Oral care for special needs patients: a survey of Nebraska general dentists. AB - PURPOSE: The purpose of this survey was to assess the attitudes, behavior, and demographics of general dentists in Nebraska regarding their providing oral health care to patients with special health care needs (PSHCN). METHODS: A 14 item questionnaire and accompanying cover letter were sent to 800 licensed general dentists in Nebraska. The survey asked for the dentists' demographic information and questions about their PSCHN. Responses to the questionnaire were tabulated, and percent frequency distributions for responses to each item were computed. RESULTS: Of the 800 surveys sent, 371 (approximately 46%) were returned. Solo practitioners were more likely to report seeing PSCHN (P<.001). Most respondents see all ages, but approximately 10% see only PSCHN over 18-years old. The most common reasons given to improve the practitioners' ability to care for PSCHN were improved reimbursement (approximately 35%) and more continuing education (approximately 36%). CONCLUSIONS: These data indicate that most general dentists surveyed in Nebraska see special needs patients of all ages. The most common reasons for not seeing more special needs patients were the level of the patient's disease, the patient's behavior, and insufficient training/experience. PMID- 22104710 TI - Reducing the pain of intranasal drug administration. AB - PURPOSE: The purpose of this research study was to develop a score to assess intranasal (IN) drug administration discomfort and then assess 3 different approaches to reduce the pain associated with the administration of an IN citrate study solution. METHODS: After Institutional Review Board approval and with informed consent, volunteers intranasally received 0.3 M solution of citrate, on 4 different days. In stage 1, the citrate was administered via syringe or by aerosol. Stage 2 compared the IN citrate before and 60 seconds after 2% lidocaine was given. Stage 3 compared the IN citrate to an IN mixture of 2% lidocaine and citrate. A placebo of IN saline was also used on one occasion. The degree of pain, burning, and unpleasant taste was recorded using a scale of 1 to 10 to give an overall intranasal discomfort score (INDS). RESULTS: The citrate proved significantly more unpleasant and painful than the placebo saline. The mean INDS was 12.1, which was significantly higher following IN citrate compared to saline. Lidocaine, both pretreatment and mixed, significantly reduced the INDS. CONCLUSIONS: The intranasal discomfort score appeared reproducible for assessing painful intranasal drug administration. The addition of lidocaine appeared to reduce the discomfort of intranasal citrate in adult volunteers. PMID- 22104711 TI - Beyond word recognition: understanding pediatric oral health literacy. AB - PURPOSE: Parental oral health literacy is proposed to be an indicator of children's oral health. The purpose of this study was to test if word recognition, commonly used to assess health literacy, is an adequate measure of pediatric oral health literacy. This study evaluated 3 aspects of oral health literacy and parent-reported child oral health. METHODS: A 3-part pediatric oral health literacy inventory was created to assess parents' word recognition, vocabulary knowledge, and comprehension of 35 terms used in pediatric dentistry. The inventory was administered to 45 English-speaking parents of children enrolled in Head Start. RESULTS: Parents' ability to read dental terms was not associated with vocabulary knowledge (r=0.29, P<.06) or comprehension (r=0.28, P>.06) of the terms. Vocabulary knowledge was strongly associated with comprehension (r=0.80, P<.001). Parent-reported child oral health status was not associated with word recognition, vocabulary knowledge, or comprehension; however parents reporting either excellent or fair/poor ratings had higher scores on all components of the inventory. CONCLUSIONS: Word recognition is an inadequate indicator of comprehension of pediatric oral health concepts; pediatric oral health literacy is a multifaceted construct. Parents with adequate reading ability may have difficulty understanding oral health information. PMID- 22104712 TI - Continued care of children seen in an emergency department for dental trauma. AB - PURPOSE: The purpose of this retrospective study was to determine the rate of continuing care for dental trauma patients seen after-hours in a hospital emergency department (ED) and identify predictors for and barriers to seeking continuing care. METHODS: Records of 856 patients treated at Nationwide Children's Hospital (NCH) ED for dental trauma between September 2003 and December 2007, were screened for avulsion, luxation, and intrusion injuries. A qualifying cohort (QC) of 175 patients was included based on injury and root development. A quality assurance survey was conducted with 96 parents of these patients to determine barriers and predictors for follow-up treatment. RESULTS: Patients averaged 2.5 follow-up visits at NCH. The most commonly reported barriers to receiving treatment were: having to miss school (21%), taking time off of work (17%), and costs associated with dental care (13%). No statistical significance (P=.22) was found between number of follow-up visits and the patient retaining the injured tooth. The number of follow-up visits was not significantly different between patients with private and public insurance. CONCLUSIONS: School, work, and costs associated with ongoing trauma management affect follow up compliance irrespective of payment source. PMID- 22104713 TI - Management of idiopathic gingival fibromatosis: report of a case and literature review. AB - Gingival hyperplasia is a rare condition and is of importance for cosmetic and mechanical reasons. Idiopathic gingival fibromatosis, a benign, slow-growing proliferation of the gingival tissues, is genetically heterogeneous. The enlargement is most intense during the eruption of the primary and permanent teeth, and minimal or nondetectable growth is observed in adults. The genetic aspect, clinical feature, histopathology, immunohistochemistry, and treatment aspects are reviewed. The purpose of this paper was to report a case of idiopathic gingival fibromatosis in a 13-year-old female who had a negative family history for a similar type of gingival enlargement. The diagnosis was established through history, clinical examination, and histopathology using both hematoxylin and eosin and Van Giesen stain (a special stain for collagen). Surgical treatment, which included both gingivectomy and gingivoplasty, was carried out. The case showed remarkable esthetic and functional improvement. The patient returned after a year and showed no recurrence. PMID- 22104714 TI - Adenomatoid odontogenic tumor: an uncommon location. AB - Adenomatoid odontogenic tumor is an uncommon tumor of odontogenic origin. It is usually located in the anterior region of the maxilla associated with impacted canines. The purpose of this paper was to present a case of adenomatoid odontogenic tumor in a 14-year-old girl with unusual clinical manifestations involving an impacted mandibular lateral incisor as well as its treatment follow up. PMID- 22104715 TI - Axenfeld-Rieger syndrome: dentofacial manifestation and oral rehabilitation considerations. AB - Axenfeld-Rieger syndrome is a rare genetic disorder characterized by ocular and dental abnormalities. This case demonstrates a comprehensive review of the syndrome's clinical and dental features and describes a case of a 13-year-old boy presenting with it. The patient showed severe hypodontia, microdontia, and short roots. Different treatment options are discussed. Early diagnosis and an interdisciplinary approach are necessary to provide the best short- and long-term treatment plans, as well as treatment and follow-up for individuals with the syndrome. PMID- 22104716 TI - Atypical case of oral lichen planus in a pediatric patient: clinical presentation and management. AB - Lichen planus (LP) is a mucocutaneous disease of unknown etiology that is relatively common in adults but rarely present in childhood. LP has been documented in dental and medical literature; however, there are few cases with oral involvement in children. The purpose of this paper was to report an unusual case of oral lichen planus involving the upper lip in a 7-year-old girl. A diagnosis was made based on clinical examination and histopathology features. The treatment consisted of topical corticosteroid and intralesional injection. After treatment with an intralesional corticosteroid, a complete re- mission of lesions involving the lip was observed. The 3-year follow-up, however, revealed asymptomatic lichenoid bilaterally affecting the buccal mucosa. The patient is currently under regular review. PMID- 22104717 TI - NH4+ enrichment and UV radiation interact to affect the photosynthesis and nitrogen uptake of Gracilaria lemaneiformis (Rhodophyta). AB - Solar ultraviolet radiation (UVR, 280-400 nm) is known to inhibit the photosynthesis of macroalgae, whereas nitrogen availability may alter the sensitivity of the algae to UVR. Here, we show that UV-B (280-315 nm) significantly reduced the net photosynthetic rate of Gracilaria lemaneiformis. This inhibition was alleviated by enrichment with ammonia, which also caused a decrease in dark respiration. The presence of both UV-A (315-400 nm) and UV-B stimulated the accumulation of UV-absorbing compounds. However, this stimulation was not affected by enrichment with ammonia. The content of phycoerythrin (PE) was increased by the enrichment of ammonia only in the absence of UVR. Ammonia uptake and the activity of nitrate reductase were repressed by UVR. However, exposure to UVR had an insignificant effect on the rate of nitrate uptake. In conclusion, increased PE content associated with ammonia enrichment played a protective role against UVR in this alga, and UVR differentially affected the uptake of nitrate and ammonia. PMID- 22104718 TI - Microbiological and physicochemical analysis of the coastal waters of southern Brazil. AB - The aim of this study was to assess the impact of sewage discharge on coastal waters by evaluating the influence of physicochemical parameters on the presence of enteric microorganisms in seawater samples collected from 11 beaches in Florianopolis, Santa Catarina, Brazil, over a one-year period (August 2009 to July 2010). Samples were assessed for the presence of human adenoviruses (HAdV), polyomavirus (JCPyV), hepatitis A virus (HAV), and noroviruses (HuNoV GI and GII). Escherichia coli and physicochemical parameters (salinity, temperature, pH and dissolved oxygen) were also evaluated. From the 132 samples analyzed, 55% were positive for HAdV, 51.5% for HAV, 7.5% for HuNoV GI, 4.5% for HuNoV GII, and 3% for JCPyV. E. coli levels ranged from 8 to 1325 CFU/100mL at all sites. The overall results highlight the problem of sewage discharge into coastal waters and confirm that there is no correlation between viral presence and bacterial contamination. PMID- 22104719 TI - Sponges as sentinels: patterns of spatial and intra-individual variation in trace metal concentration. AB - If sponges are to be effective biomonitors we require a better understanding of the spatial scales over which metals vary in these organisms. We determined how concentration of Cd, Zn, Cu, Pb, Hg and Se varied over four spatial scales for two common estuarine sponge species in the Sydney region. We examined variability with a fully nested sampling design; between coastal lakes, within coastal lakes, between sponges and within sponges. Calculation of variance components confirmed that 'within-sponge' variation in Cd, Zn, Cu, Pb and Se concentrations were low (1-14%) relative to the two largest spatial scales (49-98%) examined. In contrast, Hg concentrations exhibited marked variability 'between-sponges' and were below detection at one location. There was little evidence that sponge size was a good predictor of metal concentration. Taken together, these outcomes confirm that fragments of these sponges could be successfully transplanted and therefore show promise as biomonitors of metal contamination. PMID- 22104720 TI - Algae biofuels: versatility for the future of bioenergy. AB - The world continues to increase its energy use, brought about by an expanding population and a desire for a greater standard of living. This energy use coupled with the realization of the impact of carbon dioxide on the climate, has led us to reanalyze the potential of plant-based biofuels. Of the potential sources of biofuels the most efficient producers of biomass are the photosynthetic microalgae and cyanobacteria. These versatile organisms can be used for the production of bioethanol, biodiesel, biohydrogen, and biogas. In fact, one of the most economic methods for algal biofuels production may be the combined biorefinery approach where multiple biofuels are produced from one biomass source. PMID- 22104721 TI - Metabolomics-assisted synthetic biology. AB - As the world progresses from a fossil-fuel based economy to a more sustainable one, synthetic biology will become increasingly important for the production of high-value fine chemicals as well as low-value commodities in bulk. The integration of metabolomics and fluxomics within synthetic biology projects will be vital at all levels, including the initial design of the pathways to be generated, through to the optimisation of those pathways so that more efficient conversion of low-cost starting materials into highly desirable products can be achieved. This review highlights these areas and details the most important and exciting advances being made in this area. PMID- 22104722 TI - Structural damages in adsorbed vaccines affected by freezing. AB - This study was planned to evaluate structural damages in adsorbed vaccines affected by freezing using scanning electron microscopy and X-ray analysis of the elements. Randomly selected 42 vials of eight different types of WHO pre qualified adsorbed freeze-sensitive vaccines from 10 manufacturers were included in the study. Vaccines were kept at 5 degrees C. Selected numbers of vials from each type were then exposed to -25 degrees C for 24 h periods. All samples were evaluated for their structure using scanning electron microscopy, X-ray analysis of the elements and precipitation time. Scanning electron microscopy of vaccines affected by freezing showed either smooth or rough surfaced conglomerates associated with phosphate content of the precipitate. These vaccines precipitated 2-15 times faster compared to non-frozen samples. Non-frozen samples showed uniform flocculent structure either dense or dispersed. X-ray analysis of precipitates in frozen samples confirmed that the precipitate is mainly aluminium clutters. Scanning electron microscopy confirmed that the lattice structure of bonds between adsorbent and the antigen is broken and aluminium forms conglomerates that grow in size and weight. The precipitation time of vaccines affected by freezing is 4.5 times faster on average compared to non-frozen samples. These facts form the basis of the "shake test". PMID- 22104723 TI - Do journals publishing in the field of urology endorse reporting guidelines? A survey of author instructions. AB - INTRODUCTION: Reporting guidelines aim to ensure adequate and complete reporting of clinical studies and are an indispensable tool to translate scientific results into clinical practice. The extent to which reporting guidelines are incorporated into the author instructions of journals publishing in the field of urology remained unclear. MATERIALS AND METHODS: We assessed the author instructions of uro-nephrological journals indexed in 'Journal Citation Reports 2009'. Two authors independently assessed the author guidelines. We evaluated additional information including whether a journal was published by or in association with a medical association. Discrepancies were resolved by re-checking the respective author instructions and by discussion with a third author. RESULTS: The recommendations of the International Committee of Journal Editors were endorsed by 32 journals (58.2%) but were mentioned in 12 (37.5%) only to give general advice about manuscript preparation. Fourteen journals (25.5%) mentioned at least one reporting guideline, with CONSORT the most frequently cited. Journals with high impact factors were more likely to endorse CONSORT (p < 0.009). Other reporting guidelines were mentioned by <6% of the journals. CONCLUSION: All key stakeholders involved in the publication process should more frequently promote the awareness and use of reporting guidelines. PMID- 22104725 TI - A world in a grain of sand: human history from genetic data. AB - Genome-wide genotypes and sequences are enriching our understanding of the past 50,000 years of human history and providing insights into earlier periods largely inaccessible to mitochondrial DNA and Y-chromosomal studies.To see a world in a grain of sand ...William Blake, Auguries of Innocence. PMID- 22104726 TI - Correlation between macular thickness and glaucomatous visual fields. AB - PURPOSE: The purpose of the study was to establish whether predictable structural relationships exist between macular thickness parameters and anatomically related visual field (VF) defects. PATIENTS AND METHODS: The optical coherence tomography (OCT) macular scans and automated VFs of 127 eyes of 127 glaucoma patients were examined retrospectively. The macular scan parameters recorded included the superior inner and outer sectors and the inferior inner and outer sectors. For the VFs, the threshold sensitivities of the central 4*4 points were recorded. The 16 points were grouped into superior outer, superior inner, inferior inner, and inferior outer rows, and the mean of each row was calculated. The OCT macular scan sectors and the VF rows were compared using the Spearman correlation. RESULTS: Statistically significant structural relationships between each macular parameter and its anatomically related VF defect were noted in this study. Highest correlations were found between the inferior outer macular thickness and the superior outer VF region, the inferior inner macular and the superior inner VF region, the superior inner macula and the inferior inner VF region, and the superior outer macula and the inferior outer VF region. CONCLUSIONS: As a predictable and significant structural relationship exists between macular thickness and VF defects, macular scan OCT should be studied further and considered more carefully in the diagnosis and management of glaucoma. PMID- 22104727 TI - Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. AB - Multidrug resistance is a major obstacle in the treatment of gastric cancer. The underlying mechanisms of this phenomenon have not been well understood. Accumulating evidence indicates that Stat3 plays an important role in tumorigenesis of various primary cancers and cancer cell lines by upregulating cell survival proteins and downregulating tumor suppressors. We propose that the Stat3 pathway is also involved in acquired drug resistance of gastric cancer. To test this hypothesis, we investigated the expression and activation of Stat3 in drug resistant gastric cancer cell lines. Western blotting and real-time reverse transcription-PCR determined that Stat3 and its target genes were overactivated and/or overexpressed in drug resistant cells. Inhibition of Stat3 function resulted in significant decreases in cisplatin resistance and enhanced apoptosis in drug resistant cells. The levels of Stat3 target oncogenes such as Bcl-2 and c Myc were decreased with DPP, a Stat3 inhibitor, treatment, while the expression of tumor suppressor p53 was increased. Interestingly, the vacuolar ATPase, a proton pump which interferes the uptake of therapeutic drugs, was down regulated by Stat3 inhibition. In conclusion, these data supported the hypothesis that interruption of Stat3 signaling could reverse resistance to chemotherapy agents in human gastric cancer cells. PMID- 22104728 TI - IFN-gamma combined with targeting of XIAP leads to increased apoptosis sensitisation of TRAIL resistant pancreatic carcinoma cells. AB - The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a specific and potent inducer of apoptosis in cancer cells, but the resistance of many tumour cells to TRAIL still represents a major hurdle for the clinical treatment of tumours with TRAIL. As apoptosis is regulated by the balance of activities of several anti-apoptotic factors and pro-apoptotic factors, we analysed the relative contribution of the two sides and found that down regulation of Bcl-x(L) and in particular XIAP, but not c-Flip, sensitised the TRAIL resistant pancreatic cancer cell line Panc-1. A combination of both XIAP and Bcl-x(L) knock-downs showed no substantial added benefit indicating that both act in the same pathway. Notably, the degree of sensitisation by silencing of anti-apoptotic genes was further elevated by concomitantly increasing the pro apoptotic potential in Panc-1 cells through over-expression of TRAIL-R1 or IFN gamma-mediated increases in caspase-8 levels. Similar sensitisation effects were obtained for another TRAIL-resistant pancreatic tumour cell line, AsPC-1. Our findings demonstrate that modulation of the balance between anti- and pro apoptotic pathways from both sides by inhibition of apoptosis-antagonists and stimulation of pro-apoptotic factors provides the best way to enhance the anti tumourigenic effect of TRAIL. PMID- 22104730 TI - Monocyte differentiation induced by co-culture with tumor cells involves RGD dependent cell adhesion to extracellular matrix. AB - Macrophages that infiltrate tumor tissues, or tumor-associated macrophages (TAMs), affect the malignant behaviors of tumor cells. In this study, we attempted to induce monocytes to differentiate into TAM-like cells producing matrix metalloproteinases (MMPs) by co-culture with tumor cells. When human monocytes were co-cultured for 3-7 days with tumor cell lines, monocytes differentiated to produce MMP-9, accompanied by morphological changes. The in vitro cell invasion of MKN1 human gastric carcinoma cells into Matrigel membranes was promoted in the presence of differentiated monocytes, and the enhancement of cell invasion by differentiated monocytes was correlated with their MMP-9 productivity. The addition of an RGD (Arg-Gly-Asp) peptide to the culture significantly inhibited monocyte differentiation. The MMP-9 production from monocytes was diminished by the depletion of fibronectin from the conditioned media with gelatin-Sepharose, and potentiated by culturing them in fibronectin coated plates. These results suggest that cell adhesion to the extracellular matrix plays a crucial role in monocyte differentiation into TAM-like cells. PMID- 22104731 TI - Laboratory methods for evaluating the wear of denture teeth and their correlation with clinical results. AB - OBJECTIVE: To correlate different laboratory wear simulation protocols for three denture tooth materials with clinical wear results of the same materials. METHODS: Three denture tooth materials were evaluated for which clinical wear data of posterior denture teeth were available: DCL (double cross-linked PMMA with organic fillers; Ivoclar Vivadent), experimental material EM (double cross linked PMMA with organic fillers; Ivoclar Vivadent), and NFC (PMMA with inorganic nanofillers, Candulor). The clinical data on the three denture tooth materials (10 subjects for each material) came from clinical studies conducted at three different locations. The investigators sent the impressions to one center where they were analyzed with the same methodology and by the same operator. Four different wear simulation protocols were evaluated in a chewing simulator (Willytec) with integrated thermocycling (5 degrees C/55 degrees C) and 8 specimens for each group: (A) molar denture tooth against premolar denture tooth with 1 mm sliding, lifting, 5 kg load; (B) standardized conical ceramic stylus (O2.3 mm); (C) standardized ball-shaped ceramic stylus (O6 mm); (D) standardized conical stylus (O2.3 mm) cut with a special bur from the denture tooth material to be tested. For the protocols B, C and D, the stylus slid under a load of 3 kg for 3 mm on the flat specimen without lifting. All the tests were run for 100,000 chewing cycles. The maximum vertical wear of the material and stylus was quantified on replicas of improved white stone with the etkon es1 scanner and the match 3-D software. RESULTS: The ranking of the materials according to mean clinical vertical wear after 1 year was as follows: DCL=EM>NFC. The ranking of the materials according to the mean vertical wear was as follows (ANOVA post hoc Tukey B, p<0.05): group A: NFC>DCL=EM; group B: NFC>DCL>EM; group C: NFC>DCL=EM; group D: DCL=EM>NFC. SIGNIFICANCE: Only the results of the experimental setup with standardized antagonists of the same denture tooth material against flat specimens were similar to the clinical wear results with a comparable relative difference in mean vertical wear between the materials. When evaluating denture teeth for wear in the laboratory, a protocol should be applied that matches the clinical wear results. PMID- 22104729 TI - Recent trends in antibody-based oncologic imaging. AB - Antibodies, with their unmatched ability for selective binding to any target, are considered as potentially the most specific probes for imaging. Their clinical utility, however, has been limited chiefly due to their slow clearance from the circulation, longer retention in non-targeted tissues and the extensive optimization required for each antibody-tracer. The development of newer contrast agents, combined with improved conjugation strategies and novel engineered forms of antibodies (diabodies, minibodies, single chain variable fragments, and nanobodies), have triggered a new wave of antibody-based imaging approaches. Apart from their conventional use with nuclear imaging probes, antibodies and their modified forms are increasingly being employed with non-radioisotopic contrast agents (MRI and ultrasound) as well as newer imaging modalities, such as quantum dots, near infra red (NIR) probes, nanoshells and surface enhanced Raman spectroscopy (SERS). The review article discusses new developments in the usage of antibodies and their modified forms in conjunction with probes of various imaging modalities such as nuclear imaging, optical imaging, ultrasound, MRI, SERS and nanoshells in preclinical and clinical studies on the diagnosis, prognosis and therapeutic responses of cancer. PMID- 22104732 TI - Influence of tooth mobility on critical stresses in all-ceramic inlay-retained fixed dental prostheses: a finite element study. AB - OBJECTIVES: Inlay-retained fixed partial dentures are conservative prosthetic restorations. Their failure resistance is influenced by the stress distribution that depends on the material properties as well as the loading conditions. Finite element analysis provides the ability to estimate the loading capacity by simulating the stress distribution in all-ceramic dental restorations. The null hypothesis of this study was that tooth mobility or tooth bearing condition significantly influences the stress distribution and therefore the failure resistance of all-ceramic inlay-retained fixed dental prostheses. Therefore, the stress distribution under different loading and bearing conditions of the teeth was analyzed using the finite element method. METHODS: Three different bearing conditions, one fixed and two flexible were chosen to simulate tooth mobility. The flexible models were constrained with spring elements to a virtual center of rotation. In addition, loading conditions were varied. RESULTS: The influence of tooth mobility on the stress distribution depended on the degree of modeled tooth mobility, as well as the loading conditions. The maximum first principal stresses differed significantly in magnitude and location depending on the modeled bearing condition and the simulated load case. The maximum difference between fixed and flexible model was more than 100%. SIGNIFICANCE: Tooth mobility and occlusal loading conditions have to be considered in finite element analyses as the simulated stress distribution is strongly influenced by these factors. PMID- 22104733 TI - New vistas in opioid control of pain. AB - The MU-opioid receptors mainly contribute to the control of pain transmission, while a number of splice variants may have different physiological roles. In fact, some MU-opioid receptor agonists show distinct antinociceptive properties probably mediated via splice variants insensitive to traditional MU-opioid receptor agonists. These atypical MU-opioid receptor agonists are extremely effective against morphine-resistant interactive pain and lack the psychological dependence liability. MU-Opioid receptor splice variants specific for these atypical agonists may be the target for better analgesics effective against morphine-resistant interactive pain and lacking psychological dependence liability. PMID- 22104734 TI - Are individual differences in rates of aging greater at older ages? AB - Although differences among people are frequently assumed to increase with age, cross-sectional comparisons of measures of brain structure and measures of cognitive functioning often reveal similar magnitudes of between-person variability across most of adulthood. The phenomenon of nearly constant variability despite systematically lower means with increased age suggests that individual differences in rates of aging may be relatively small, particularly compared with the individual differences apparent at any age. The current study examined between-person variability in cross-sectional means and in short-term longitudinal changes in 5 cognitive abilities at different ages in adulthood. The variability in both level and change in cognitive performance was found to be similar among healthy adults from 25 to 75 years of age in all 5 cognitive abilities. Furthermore, the correlations between scores at the first and second occasions were very high, and nearly the same magnitude at all ages. The results indicate that between-person differences in short-term cognitive changes are not inevitably greater among healthy older adults than among young adults. PMID- 22104735 TI - Utility of p16, Ki-67, and HPV test in diagnosis of cervical intraepithelial neoplasia and atrophy in women older than 50 years with 3- to 7-year follow-up. AB - BACKGROUND: Differentiating cervical intraepithelial neoplasia (CIN) from atrophy in postmenopausal women based on morphology alone is challenging. p16 and Ki-67 help distinguish CIN2/3 from atrophy. The goal of this study is to further characterize the utility of p16, Ki-67, and human papillomavirus (HPV) tests in women older than 50 years, particularly in CIN1. DESIGN: The authors retrospectively identified cervical specimens from three, 1-year time periods. Included were cases from women older than 50 years with benign diagnoses, atrophy, and CIN. Slides were stained with p16 and Ki-67 and graded as positive or negative. Medical records were reviewed for cytology, HPV test, and histopathologic diagnoses from the time of biopsy to 2010. RESULTS: A total of 97 cervical samples were included. In all, 34 (74%) CIN1 cases were negative for p16 and Ki-67. Of CIN1 cases with positive HPV tests, only 1/10 (10%) had positive p16 staining versus 2/2 (100%) of CIN2/3 cases. Of 39 women with CIN1 who had follow-up data available, 4 (10%) had subsequent histologic progression to CIN2/3 and none developed invasive disease. CONCLUSIONS: In our study, the majority of cases (74%) diagnosed as CIN1 in women >= 50 years are negative for p16 and Ki-67 and do not progress to high-grade dysplasia during 3- to 7-year follow-up. A combination of morphology, p16, and Ki-67 on cervical specimens in women older than 50 years, and furthermore, use of these stains on Pap tests in combination with HPV testing may help distinguish CIN from atrophy and reduce unnecessary invasive follow-up testing. PMID- 22104736 TI - Colonic involvement in Fabry disease. PMID- 22104737 TI - Anesthetic management of vaginal delivery in a parturient with hemochromatosis induced end-organ failure. AB - The vast majority of females affected by hemochromatosis are asymptomatic during childbearing years. We were able to provide effective obstetric anesthesia care to a 35-year-old woman with severe hemochromatosis. She had systolic heart failure with a left ventricular ejection fraction of 15%, severe pulmonary hypertension, mitral insufficiency, a history of ventricular tachycardia, cirrhosis, obstructive sleep apnea, gestational diabetes, and severe scoliosis. A multidisciplinary approach was used to stabilize her heart failure and prepare her for childbirth. An arterial line and epidural analgesic were placed before induction of labor. Vaginal delivery was accomplished with passive decent of the fetus and forceps assistance. We discuss hemochromatosis and its implications for the parturient. PMID- 22104738 TI - Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria. AB - A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations. PMID- 22104739 TI - Protamine-1 and -2 polymorphisms and gene expression in male infertility: an Italian study. AB - BACKGROUND: Correct histone/protamine replacement is an important stage in chromatin condensation during spermiogenesis in humans. There are two types of protamines: protamine 1 (P1) and the protamine 2 family (P2, P3, and P4), coded by the genes PRM1 and PRM2. AIM: We analyze the sequences and gene expression of PRM1 and PRM2 and their relationship with defective spermatogenesis. MATERIALS AND METHODS: Sequence analysis was carried out on 163 patients attending our laboratory for analysis of seminal fluid. Patients were divided into three groups: normozoospermic (53), teratozoospermic (60), and azoospermic (50). Gene expression was analyzed in seven patients with azoospermia and one with cryptozoospermia. RESULTS: Seven single nuclotide polymorphisms (SNP) were identified: G54A, G102T and C230A for PRM1, and C246T, G288C, G298C and C373A for PRM2. For C230A, the CA genotype was present in 38% of teratozoospermic vs 55% of normozoospermic and 64% of azoospermic patients; for C373A, CA was found in 37% of teratozoospermic vs 47% of normozoospermic and 64% of azoospermic patients. In contrast, for G298C, GC was more common in the teratozoospermic (63%) than in the normozoospermic (49%) or azoospermic (48%) groups. These differences could suggest a greater susceptibility of these patients to abnormal sperm morphology. In five patients the levels of transcripts were reduced with respect to the control. CONCLUSION: These data suggest that premeiotic arrest is associated with extremely reduced protamine expression. New studies of both PRM1 and PRM2 and their mRNA expression could help us better understand the molecular mechanisms underlying the protamine transcription and translation processes. PMID- 22104740 TI - Racial discrimination, mood disorders, and cardiovascular disease among black americans. AB - PURPOSE: To examine associations between racial discrimination, mood disorders, and cardiovascular disease (CVD) among Black Americans. METHODS: Weighted logistic regression analyses were performed on a nationally representative sample of Black Americans (n = 5022) in the National Survey of American Life (NSAL; 2001 2003). Racial discrimination and CVD were assessed via self-report. Mood disorder was measured with the World Health Organization Composite International Diagnostic Interview. RESULTS: Model-adjusted risk ratios (RRs) revealed that participants with a history of mood disorder had greater risk of CVD (RR, 1.28; 95% confidence interval (CI), 1.12-1.45). This relationship was found specifically among those younger than 50 years of age (RR, 1.56; 95% CI, 1.27 1.91). There was a significant interaction between racial discrimination and mood disorder in predicting CVD in the total (F = 2.86, 3 df, p = .047) and younger sample (F = 2.98, 3 df, p = .047). Participants with a history of mood disorder who reported high levels of racial discrimination had the greatest risk of CVD. CONCLUSIONS: The association between racial discrimination and CVD is moderated by history of mood disorder. Future studies may examine pathways through which racial discrimination and mood disorders impact CVD risk among Black Americans. PMID- 22104741 TI - Family planning choices in couples using contraception without knowing they are infertile: should newly-wed men undergo a routine spermiogram? AB - INTRODUCTION: Newly-weds choose to use contraception either to spend the first years of their marriage more freely, because of economic reasons or because of the increase in working career women. We studied the reasons for infertility and the rate of contraception use in the first years of marriage among couples with primary infertility and evaluated the use of a spermiogram as a screening test in newly-wed men. SUBJECTS AND METHODS: In this cross-sectional study, 302 couples with primary infertility who were treated at our infertility clinic were included in the study. The couples were divided into 2 groups: group 1 (infertile couples who have used contraception) consisted of 67 couples and group 2 (infertile couples who did not use contraception) consisted of 235 couples. RESULTS: Sixty seven (22.5%) infertile couples stated that they had used no contraception in the first years of their marriage. In group 1, 35.8% of couples were diagnosed as having unexplained infertility, while 28.4% of them had male factor, 31.3% female factor and 4.5% a combination of male and female factor infertility. Sixteen men with male factor infertility used coitus interruptus (3-36 months) or condoms (6 12 months) unnecessarily. CONCLUSIONS: Infertility counseling in the early days of marriage and a spermiogram performed at that time could be beneficial for the newly-wed couples even if they do not want a child at the time. To perform a spermiogram as a screening test in all newly-wed men should be discussed. PMID- 22104742 TI - Reconstruction of the unknown optimization cost functions from experimental recordings during static multi-finger prehension. AB - The goal of the research is to reconstruct the unknown cost (objective) function(s) presumably used by the neural controller for sharing the total force among individual fingers in multifinger prehension. The cost function was determined from experimental data by applying the recently developed Analytical Inverse Optimization (ANIO) method (Terekhov et al. 2010). The core of the ANIO method is the Theorem of Uniqueness that specifies conditions for unique (with some restrictions) estimation of the objective functions. In the experiment, subjects (n = 8) grasped an instrumented handle and maintained it at rest in the air with various external torques, loads, and target grasping forces applied to the object. The experimental data recorded from 80 trials showed a tendency to lie on a 2-dimensional hyperplane in the 4-dimensional finger-force space. Because the constraints in each trial were different, such a propensity is a manifestation of a neural mechanism (not the task mechanics). In agreement with the Lagrange principle for the inverse optimization, the plane of experimental observations was close to the plane resulting from the direct optimization. The latter plane was determined using the ANIO method. The unknown cost function was reconstructed successfully for each performer, as well as for the group data. The cost functions were found to be quadratic with nonzero linear terms. The cost functions obtained with the ANIO method yielded more accurate results than other optimization methods. The ANIO method has an evident potential for addressing the problem of optimization in motor control. PMID- 22104743 TI - A national evaluation of Safe Schools/Healthy Students: outcomes and influences. AB - The Safe Schools/Healthy Students (SS/HS) Initiative has awarded over $2 billion in grants to more than 350 school districts in partnership with local mental health, law enforcement, and juvenile justice agencies. To estimate the impact of grantee characteristics, grant operations, and near-term outcomes in reducing violence and substance use, promoting mental health, and enhancing school safety, logged odds ratios (LORs) were calculated contrasting Year 3 with Baseline performance from grantee-provided data on seven outcome measures. After comparing grantee performance across outcomes and outcomes across grantees, the LORs were entered as dependent variables in a series of meta-regressions in which grantee characteristics, grant operations, and near-term outcomes were tested after controlling for pre-grant characteristics. Findings indicate that the SS/HS Initiative significantly improved most outcomes, that within-grantee performance varied greatly by outcome, and that random-effects meta-regression appreciably decreased the variance available for modeling. The approach demonstrates that the SS/HS Initiative is effective and that locally collected performance data can be used to estimate grantee success in improving youth outcomes. PMID- 22104745 TI - Update in biliary endoscopy. AB - Biliary endoscopy has seen the development of several new techniques in the last few years. Its current role includes direct diagnostic imaging, tissue sampling, early diagnosis and palliation of biliary tumors. Relatively new methods for biliary stones management are electrohydraulic lithotripsy combined with choledochoscope guidance and laser lithotripsy. Intraductal ultrasound, confocal laser endomicroscopy and optical coherence tomography are emerging, purely diagnostic endoscopic tools in biliary endoscopy. Cytological examinations such as digital imaging analysis and fluorescence in situ hybridization have the potential of becoming very important in the early diagnosis of biliary tumors. Direct visualization of the biliary mucosa and tissue sampling can be done with the last generation of cholangioscopes. All these tools are promising, especially for the 'undetermined biliary strictures'. Improvements in quality of life, survival and biliary drainage in patients with non-operable cholangiocarcinoma have been reported after the application of both photodynamic therapy and high dose rate intraluminal brachytherapy. Drug-eluting stents with incorporated anti tumor agents designed to improve patency and reduce the risk of tumor ingrowth have already been tested, and other stents are under investigation as well. PMID- 22104744 TI - Genome-wide patterns of genetic variation in sweet and grain sorghum (Sorghum bicolor). AB - BACKGROUND: Sorghum (Sorghum bicolor) is globally produced as a source of food, feed, fiber and fuel. Grain and sweet sorghums differ in a number of important traits, including stem sugar and juice accumulation, plant height as well as grain and biomass production. The first whole genome sequence of a grain sorghum is available, but additional genome sequences are required to study genome-wide and intraspecific variation for dissecting the genetic basis of these important traits and for tailor-designed breeding of this important C4 crop. RESULTS: We resequenced two sweet and one grain sorghum inbred lines, and identified a set of nearly 1,500 genes differentiating sweet and grain sorghum. These genes fall into ten major metabolic pathways involved in sugar and starch metabolisms, lignin and coumarin biosynthesis, nucleic acid metabolism, stress responses and DNA damage repair. In addition, we uncovered 1,057,018 SNPs, 99,948 indels of 1 to 10 bp in length and 16,487 presence/absence variations as well as 17,111 copy number variations. The majority of the large-effect SNPs, indels and presence/absence variations resided in the genes containing leucine rich repeats, PPR repeats and disease resistance R genes possessing diverse biological functions or under diversifying selection, but were absent in genes that are essential for life. CONCLUSIONS: This is a first report of the identification of genome-wide patterns of genetic variation in sorghum. High-density SNP and indel markers reported here will be a valuable resource for future gene-phenotype studies and the molecular breeding of this important crop and related species. PMID- 22104746 TI - Update lecture: benign diseases of the exocrine pancreas. AB - A brief overview on the physiology and regulation of digestive enzyme secretion by the exocrine pancreas is presented. Knowledge about the physiology of the exocrine pancreas should help for a better understanding of the pathophysiology of both acute and chronic pancreatitis. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes, which leads to intracellular activation of trypsinogen, is still regarded as a key step in pathophysiology. The role of activation by cathepsins and the role of autoactivation of trypsinogen are still under debate. Studies on genetic alterations in various forms of human chronic pancreatitis can be interpreted that an imbalance between protease inhibitors and active proteases plays a key role. Toxic Ca(2+) signals by excessive liberation from the endoplasmic reticulum may play another role. The mortality of necrotizing pancreatitis is still high. Early mortality is caused by a systemic inflammatory response syndrome with or without concomitant infection of necrosis; late mortality by multi-organ failure syndrome due to sepsis. Therapy of necroses should be performed as late as possible. A step-up approach using CT-guided and/or transgastric endoscopic necrosectomy seems to be superior to a primary surgical approach. A brief overview of the German S3 guidelines, not yet published, regarding diagnosis and treatment of chronic pancreatitis is presented. PMID- 22104747 TI - Capsule endoscopy and Crohn's disease. AB - Capsule endoscopy has been shown to detect small bowel inflammatory changes better than any other imaging modality. Selection criteria have been optimized to increase the yield of capsule endoscopy in patients suspected of having Crohn's disease. Capsule endoscopy allows for earlier diagnosis of Crohn's disease of the small bowel and improved diagnosis of colitis in patients where it is unclear if they suffer from Crohn's or ulcerative colitis. A test capsule is available to assess for small bowel strictures and thus avoid capsule retention. It is envisioned that the manner in which we treat Crohn's disease in the future will change, based on earlier diagnosis and treatment aimed at mucosal healing rather than symptom improvement. PMID- 22104748 TI - Radiological imaging of the small bowel. AB - Recently introduced endoscopy-based imaging methods such as double-balloon endoscopy or wireless capsule endoscopy can visualize the complete small bowel. These approaches are quite invasive diagnostic methods. Therefore, radiological small bowel imaging is also still considered as the primary imaging approach to diagnose pathological changes of the small bowel. In this review article the most important small bowel imaging modalities such as conventional fluoroscopy, computed tomography, magnetic resonance imaging and ultrasound are discussed. Additionally the most important diseases, which can affect the small bowel, are evaluated and the optimal imaging modalities are pointed out, respectively. PMID- 22104749 TI - Therapeutic double-balloon enteroscopy: a binational, three-center experience. AB - BACKGROUND/AIMS: There are few reports focusing on therapeutic small bowel endoscopy. The aim of this study was to analyze the results of therapeutic small bowel endoscopy in a large cohort of patients. METHODS: A retrospective study of a prospectively collected database comprising all patients undergoing diagnostic and therapeutic small bowel endoscopy in three centers. RESULTS: A total of 614 double-balloon enteroscopies were performed in 534 patients. The most common pathological findings were angiodysplasias and vascular lesions (n = 98, 18%), mucosal ulcers and erosions (n = 95, 17.8%), polyps and tumors (including patients with familiar polyposis syndrome such as Peutz-Jeghers syndrome, familiar adenomatous polyps syndrome, neurofibromatosis, adenocarcinoma, neuroendocrine tumors and gastrointestinal stromal tumors) (n = 52, 9.7%), and strictures (Crohn's disease, ischemia, tumors) (n = 12, 2.2%). The mean duration of therapeutic small bowel enteroscopy was 67 min (range 30-115) compared to 50 min (range 25-105) for diagnostic procedures (p < 0.05). A therapeutic small bowel endoscopy was performed in 121 patients (22%). Therapeutic procedures included argon plasma coagulation of vascular lesions (n = 73), polypectomy (n = 49), mucosectomy (n = 5), stricture dilation (n = 7), foreign body extraction (n = 7), injection of fibrin glue (n = 10), and clip placement (n = 5). There were a total of 5 complications (0.9%; paralytic ileus, n = 2, pancreatitis, n = 1, bleeding n = 2). No perforations or deaths occurred. CONCLUSION: Endoscopists performing double-balloon enteroscopy should be trained and prepared to provide therapeutic interventions for small bowel disorders including argon plasma coagulation, injection, hemoclipping, polypectomy, mucosectomy and foreign body extraction. Therapeutic small bowel endoscopy, albeit associated with complications in about 1% of cases, can be considered a relatively safe procedure. PMID- 22104750 TI - Endoscopic surveillance in Crohn's disease and ulcerative colitis: who needs what and when? AB - Crohn's disease and ulcerative colitis are chronic inflammatory diseases resulting from an inappropriate innate and adaptive immune response towards commensal microbiota. Patients with Crohn's disease and ulcerative colitis carry an increased risk of developing colon cancer and/or small bowel carcinoma, respectively. The colorectal cancer risks of ulcerative colitis and Crohn's disease with comparable surface area involvement and disease duration are very similar. Early disease onset, disease extent, severity of inflammation, a family history of sporadic colorectal cancer, efficacy and duration of medical therapy, coexisting primary cholangitis and mucosal dysplasia are all risk factors for colorectal cancer. Regular endoscopic surveillance is endorsed by leading professional societies and outlined in guidelines and consensus statements. The yield of endoscopic surveillance, particularly to detect dysplasia, can be improved with chromoendoscopy with methylene blue dye spray-targeted biopsies, autofluorescence plus high-resolution endoscopy, chromoendoscopy-guided confocal laser microscopy and confocal laser microscopy in combination with narrow band imaging and high-resolution endoscopy. Proper bowel preparation, complete, careful inspection of the entire colon, a minimum withdrawal time and adherence to recommended management guidelines ensure a high-quality study and improve surveillance. Dysplasia can be graded by the Vienna or Riddell classification. Colectomy is recommended for patients with flat high-grade dysplasia confirmed by an expert gastrointestinal pathologist. PMID- 22104751 TI - Colonoscopic surveillance in inflammatory bowel disease: state of the art reduction of biopsies. AB - Longstanding colitis in inflammatory bowel disease (IBD) is associated with an increased risk for intraepithelial neoplasia (IN). White light endoscopy (WLE) with 40-50 random biopsies has been promoted for surveillance but may miss a significant proportion of lesions. In addition, the yield of random biopsies to detect IN is low, and random biopsies are expensive, labor-intensive and distract from scrutinizing the colon. Chromoendoscopy with targeted biopsies has proven its superiority over WLE in multiple randomized trials. It has been incorporated into many national and international guidelines. Virtual chromoendoscopy techniques carry the potential to provide contrast enhancement without spraying color onto the mucosa. However, trials using virtual chromoendoscopy techniques have failed to show enhanced detection of IN compared to WLE so far. Autofluorescence imaging has the potential to serve as a red-flag technique for macroscopic detection of IN by screening large mucosal areas in IBD. Confocal laser endomicroscopy (CLE) is able to provide intravital microscopic diagnosis on a cellular level. In a first study, CLE had a high accuracy for prediction of neoplasia. Together, all these modern endoscopy approaches aim at overcoming shortcomings of WLE in a move towards abandoning untargeted random biopsies for targeted, 'smart' biopsies. Future efforts to optimize endoscopic surveillance in inflammatory colitis should aim at identifying patients at high risk of developing IN, tailor individual surveillance intervals, use red-flag techniques for IN detection and may even predict response to tailored therapy. PMID- 22104752 TI - Primary sclerosing cholangitis: diagnostic and therapeutic problems. AB - Progressive destruction of bile ducts in primary sclerosing cholangitis (PSC) may lead to end-stage liver disease, portal hypertension and liver failure. The diagnosis of PSC is made by characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts observed by cholangiography. Magnetic resonance cholangiography is considered to have comparable accuracy to endoscopic retrograde cholangiography (ERC) in the diagnosis of PSC, but its accuracy is limited in early stages of PSC. Up to 60% of patients with PSC develop a dominant stricture of the intra- or extrahepatic biliary tree. Patients may present with jaundice, pruritus or ascending cholangitis. Therefore, in patients with an increase in serum bilirubin and/or worsening pruritus, progressive bile duct dilation on imaging studies and/or cholangitis seen via ERC, it is recommended to exclude a dominant stricture. However, in a considerable number of patients without symptoms, a dominant stricture can be detected on the cholangiogram. The cholangiographic findings and the clinical presentation make it difficult to distinguish PSC from cholangiocarcinoma. The accuracy in the distinction between these two conditions is still rather disappointing, despite the combined use of imaging, endoscopic biopsy, and cytology. Medical, endoscopic, and surgical therapies aim to slow the progression of the disease. It is generally agreed upon that patients with symptoms from dominant strictures like cholangitis, jaundice, pruritus or worsening biochemical indices are candidates for endoscopic therapy. Although the best therapeutic endoscopic approach for these patients is still under discussion, a number of reports have documented clinical and radiographic improvement in patients following endoscopic dilation with or without placement of a biliary stent. Furthermore, indirect evidence by retrospective studies suggests that endoscopic therapy may improve survival. PMID- 22104753 TI - Technicalities of colonoscopy: endoscopic microscopy - where are we heading? AB - Confocal laser endomicroscopy (CLE) is a new endoscopic imaging tool enabling in vivo histology during ongoing endoscopy. Basically, three different patterns can be seen in the colon: normal, neoplastic and inflammatory mucosa. Several pilot studies have shown an excellent correlation with classical histology. However, what could be the future indications of CLE? (1) Differentiating neoplastic from inflammatory changes constitutes a promising diagnostic tool in screening for dysplasia in ulcerative colitis. This can help to further increase the efficacy of chromoendoscopy in dysplasia detection and reduce the number of biopsies. The possibility to differentiate sporadic adenoma from dysplasia-associated lesion or mass could have an immediate impact on patient management. (2) The diagnosis of collagenous colitis depends on multiple random biopsies. Case series have shown that CLE can guide the endoscopist to take more representative biopsies to make the diagnosis. Large prospective trials are needed to confirm this finding. (3) An interesting clinical application is graft-versus-host disease (GVHD). A pilot study showed that it was possible to predict the presence of GVHD in 14/19 patients with GVHD out of 35 patients who were referred for diarrhea after stem cell transplantation. (4) CLE for standard polyp surveillance is probably redundant since it will not change patient management at this stage. Moreover, it can currently not differentiate between classical hyperplastic and sessile serrated adenomas. (5) Future additional technological improvements of the system with faster Z-scanning, deeper light penetration and 3D reconstruction will help to improve the quality of CLE. Reports on in vivo molecular imaging and assessment of physiological changes provide a promising glance at the future possibilities of CLE imaging. PMID- 22104754 TI - Colonoscopy screening: status in Europe. AB - Europe has made significant progress in recent years by introducing population based screening programs for colorectal cancer. Due to excellent evidence-based results on the basis of large prospective randomized trials, mass screening using the fecal occult blood test is currently the procedure of choice. Endoscopy-based programs do afford quality insurance programs which are outlined in the recommendations of the European Commission. PMID- 22104755 TI - Colon cancer screening: which non-invasive filter tests? AB - The following non-invasive stool tests for colorectal cancer (CRC) screening exist: guaiac or immunochemical fecal occult blood testing (FOBT), genetic stool tests and the M2-PK. Currently the most widely used tests are guaiac-based (gFOBT). Several randomized controlled trials have shown that gFOBT are able to achieve a reduction in CRC-related mortality. This reduction is achieved by detecting asymptomatic cancers at an early stage with a better prognosis. However, gFOBT have a low sensitivity for colorectal adenomas and are thus unlikely to be able to reduce the incidence of CRC. Furthermore, gFOBT are not specific for human blood and can be influenced by external factors. Immunochemical tests (iFOBT) only detect human blood in the stool. In two recent randomized studies from the Netherlands comparing guaiac and immunochemical tests in the asymptomatic population, iFOBT were found to detect more cancers than gFOBT. Furthermore, iFOBT were able to detect more advanced adenomas thus having the potential to be able to reduce the incidence of CRC as well as CRC-related mortality. In the recently released European CRC screening guidelines, iFOBT are considered the screening test of choice. Several questions remain however. It is currently unknown what the optimal cut-off value for an iFOBT to be considered positive should be and what the number of stool samples is that are required. Genetic stool tests detect mutations in stool that can be found in CRC. The original test testing for 21 genetic changes was found to be superior to gFOBT for the detection of cancers. However, the sensitivity was moderate (51.6%) and the sensitivity for advanced adenomas was low. In the meantime the test has been modified improving DNA extraction and reducing the number of mutations tested for as well as including a methylation marker. The efficacy of the modified test in the screening population is unknown. M2-PK is an isomer of the enzyme pyruvate kinase that is involved in glycolysis. Studies have found a good sensitivity for cancers, a low sensitivity for advanced adenomas with a specificity of around 80%. Further studies in the screening population are required. PMID- 22104756 TI - The missed colorectal cancer problem. AB - BACKGROUND/AIMS: Colonoscopy is currently regarded as the gold standard for the detection of polyps and cancers in the colon and rectum, and is the preferred method of screening for colorectal cancer in Europe and the USA. However, evidence shows that polyps and other lesions can be missed during colonoscopy due to several reasons. METHODS: An unsystematic review of the literature concerning the issues of missed colorectal cancers and interval cancers during colonoscopy was performed and the most important articles described. RESULTS: According to the literature there are various reasons for interval and/or missed colorectal cancers: incomplete bowel cleaning, incomplete colonoscopy, short withdrawal time, incomplete resection of adenomas, rapid tumor progression, sessile serrated adenomas and the examiner him- or herself. CONCLUSION: For the minimization of missed neoplasias and even cancers it is necessary to perform screening colonoscopy after an optimal bowel preparation. Furthermore, colonoscopy should be performed in an 'optimal setting' with adequate withdrawal time and complete resection of all polypoid lesions by experienced examiners followed by an adequate histological work-up including the knowledge about sessile serrated adenomas. PMID- 22104757 TI - Paternal involvement in Multisystemic Therapy: effects on adolescent outcomes and maternal depression. AB - The association between paternal involvement in therapy, adolescent outcomes and maternal depression was examined within the context of Multisystemic Therapy (MST), an empirically supported, family- and community-based treatment for antisocial adolescents. Ninety-nine families were recruited from five mental health agencies providing MST. We compared families with paternal involvement in therapy (PIT) to families with no paternal involvement in therapy (NPIT) in pre post change in adolescents' externalizing and internalizing behaviours and also in maternal depression. There was a significant reduction in both groups in externalizing and internalizing behaviours. However, the magnitude of improvement was significantly greater for the PIT families. Both groups saw a significant reduction in maternal depression but no significant group differences were found. Results suggest that if possible, paternal figures should be encouraged to actively participate in therapy, as adolescents outcomes are enhanced when mothers and paternal figures participate in MST together. PMID- 22104758 TI - Co-development of internalizing and externalizing problem behaviors: causal direction and common vulnerability. AB - Latent growth curve modeling was used to study the co-development of internalizing and externalizing problems in a sample of 2844 Korean fourth graders followed over four years. The project integrated two major theoretical viewpoints positing developmental mechanism: directional model and common vulnerability model. Findings suggest that (a) boys and girls follow different developmental trajectories in both domains in early adolescence; (b) bidirectional progression from initial levels of each domain to the developmental pattern of the other domain emerged among boys, while only unidirectional progression from externalizing to internalizing problem emerged among girls; and (c) all risk factors are not equally risky across domain and gender; parental violence was a common cross-domain risk factor for boys, whereas affiliation with delinquent friends was a common cross-domain risk factor for girls. Implications for future research and intervention were discussed. PMID- 22104759 TI - Pain and quality of life (QoL) in elderly: the Turkish experience. AB - PURPOSE: The aims of this study were to evaluate the effects of demographic and clinical determinants on pain and to investigate the possible risk factors that disrupt QoL. MATERIALS AND METHODS: The design of this research was a prospective study performed in tertiary care hospital-based physical medicine and rehabilitation departments. A comprehensive geriatric pain assessment (Geriatric Pain Scale, GPS) and health-related quality of life (HR-QOL) assessment (Nottingham Health Profile, NHP) were performed. RESULTS: Of the 275 patients, 76% were female and 59.6% were older than 70 years of age. Two hundred seventy four patients (99.7%) had various levels of pain. The mean age of the patent group was 72.77 +/- 5.7 (min: 65, max: 96) years. The overall GPS was 60.41 +/- 22 (min: 0, max: 99.9), and the total NHP score was 49.01 +/- 22.4 (min: 0, max: 100). Correlation analyses showed that for the total GPS score, female gender, lower education, and economic status were significant determinants of higher levels of pain. The multiple linear regression analysis showed that the NHP, GPS, Self-Reported Disability Index (SRDI), and Geriatric Depression Scale (GDS) were significant determinants of poorer HR-QOL. CONCLUSIONS: There was a high prevalence of pain and being female, having low income, having low social support, having a higher rate of disability with related multiple comorbidities, and depression as related factors of HR-QOL. Strengthening these negative predictors of HR-QOL might enhance the efficiency of pain therapies in this population. PMID- 22104760 TI - Influence of mechanical stimulation in the development of a medial equivalent tissue-engineered vascular construct using a gelatin-g-vinyl acetate co-polymer scaffold. AB - Vascular regeneration in the area of small diameter (<6 mm) vessels via the tissue-engineering approach has been in focus for some time now. In this study, we report the development and evaluation of a tissue-engineered medial equivalent using gelatin-g-vinyl acetate co-polymer (GeVAc) as the scaffold material. GeVAc was synthesized by co-polymerizing gelatin and vinyl acetate monomer in the presence of AIBN as the initiator and subjected to physico-chemical characterization. A porous 3-D scaffold with open interconnected pores was then produced from GeVAc. The scaffold is non-cytotoxic with good smooth muscle cell proliferative capacity and high cell viability. Influence of smooth muscle cell phenotype in response to these scaffolds has been studied under mechanical stimulation. It was found that the cell-seeded tubular GeVAc constructs under mechanical stimulation preferentially supported the contractile phenotype of smooth muscle cells, as evidenced by the elevated expression of contractile protein markers such as alpha-SMA, calponin and SM22alpha. The mechanical properties and the ECM secretion were also increased on applying the mechanical stimulation. Hence, the results showed the promising potential of the GeVAc scaffolds in the regeneration of the medial equivalent tissue-engineered vascular construct. PMID- 22104761 TI - Genetically encoded neural activity indicators. AB - Recording activity from identified populations of neurons is a central goal of neuroscience. Changes in membrane depolarization, particularly action potentials, are the most important features of neural physiology to extract, although ions, neurotransmitters, neuromodulators, second messengers, and the activation state of specific proteins are also crucial. Modern fluorescence microscopy provides the basis for such activity mapping, through multi-photon imaging and other optical schemes. Probes remain the rate-limiting step for progress in this field: they should be bright and photostable, and ideally come in multiple colors. Only protein-based reagents permit chronic imaging from genetically specified cells. Here we review recent progress in the design, optimization and deployment of genetically encoded indicators for calcium ions (a proxy for action potentials), membrane potential, and neurotransmitters. We highlight seminal experiments, and present an outlook for future progress. PMID- 22104762 TI - Update on the use of cinacalcet in the management of primary hyperparathyroidism. AB - Cinacalcet is an allosteric modulator of the calcium sensing receptor acting to sensitize this receptor to the extracellular calcium. Cinacalcet has been shown to be effective in reducing or normalizing serum calcium levels in several groups of patients with primary hyperparathyroidism (PHPT), including patients with mild to moderate PHPT, intractable PHPT, and parathyroid carcinoma, and in PHPT as a part of multiple endocrine neoplasia type 1. Cinacalcet slightly reduces PTH levels and has no effects on bone mineral density. Cinacalcet at low doses is well tolerated, but side effects are more frequent and severe when relatively high doses are needed to control hypercalcemia. Cinacalcet may be of benefit in a wide spectrum of PHPT severity, offering a novel therapeutic option for the control of hypercalcemia in PHPT patients who are not able to undergo parathyroidectomy. To what extent the reduction of serum calcium particularly in patients with mild to moderate hypercalcemia, translates into a clinical benefit is currently unknown. Moreover, there are no data as to whether long-term treatment with cinacalcet can prevent the complications of PHPT. Finally, more data are needed on the long-term safety of cinacalcet, particularly at the renal level. PMID- 22104763 TI - Biotreatment of Cr(VI) contaminated waters by sulphate reducing bacteria fed with ethanol. AB - Biological treatment of Cr(VI) contaminated waters was performed in fixed bed reactors inoculated with SRB (sulphate-reducing bacteria) growing on ethanol. Treatment efficiency was evaluated by checking chemical abatement of Cr(VI) and by ecotoxicological tests using the nematode Caenorhabditis elegans. A preliminary comparison between ethanol and lactate was performed, denoting that using ethanol, the same values of final sulphate abatement were obtained. In addition ethanol showed to be a substrate more competitive than lactate in kinetic terms. Fixed bed column reactors were continuously fed with a solution containing sulphates (3 g L(-1)), ethanol (1.5 g L(-1)) and Cr(VI) (50 mg L(-1)). At steady state the column inoculated with SRB removed 65 +/- 5% of sulphate and 95 +/- 5% of chromium. Bioactive removal mechanisms predominated over biosorption. Diminution of Cr(VI) toxicity was assessed by using the nematode C. elegans as a test organism showing that the survival of nematodes was 20% in the presence of the untreated influent and raised up to 53% when the nematodes were exposed to the treated effluent. PMID- 22104764 TI - Distribution and mass balance of hexavalent and trivalent chromium in a subsurface, horizontal flow (SF-h) constructed wetland operating as post treatment of textile wastewater for water reuse. AB - In this study, during a two-year period, we investigated the fate of hexavalent and trivalent chromium in a full-scale subsurface horizontal flow constructed wetland planted with Phragmites australis. The reed bed operated as post treatment of the effluent wastewater from an activated sludge plant serving the textile industrial district and the city of Prato (Italy). Chromium speciation was performed in influent and effluent wastewater and in water-suspended solids, at different depths and distances from the inlet; plants were also analyzed for total chromium along the same longitudinal profile. Removals of hexavalent and trivalent chromium equal to 72% and 26%, respectively were achieved. The mean hexavalent chromium outlet concentration was 1.6 +/- 0.9 MUg l(-1) and complied with the Italian legal limits for water reuse. Chromium in water-suspended solids was in the trivalent form, thus indicating that its removal from wastewater was obtained by the reduction of hexavalent chromium to the trivalent form, followed by accumulation of the latter inside the reed bed. Chromium in water-suspended solids was significantly affected by the distance from the inlet. Chromium concentrations in the different plant organs followed the same trend of suspended solids along the longitudinal profile and were much lower than those found in the solid material, evidencing a low metal accumulation in P. australis. PMID- 22104765 TI - Effects of potassium ferrate on extracellular polymeric substances (EPS) and physicochemical properties of excess activated sludge. AB - The activated sludge process of wastewater results in the generation of a considerable amount of excess activated sludge. In many wastewater treatment plants, the bottleneck of the sludge handling system is the dewatering operation. This paper investigated the effect of potassium ferrate pretreatment on the physicochemical properties of the excess activated sludge at various dosages of potassium ferrate. The particle size, extracellular polymeric substances (EPS) content and chemical components, and sludge disintegration degree were measured to explain the observed changes of physicochemical properties. It was expected that potassium ferrate could enhance the filterability and dewaterability of the sludge. However, the results showed that potassium ferrate had a negative effect on the filterability by measuring the capillary suction time (CST), but improved the settleability and dewaterability extent by determining the water content in the dewatered cake, although the flocs size reduced slightly. Loosely bound EPS (LB-EPS) content, polysaccharides (PS) and proteins (PN) contents in LB-EPS all increased with increasing the amount of potassium ferrate. However, Tightly bound EPS (TB-EPS) content, PS and PN contents in TB-EPS did not changed significantly at first, and decreased slightly under higher dosage of potassium ferrate. EPS, especially LB-EPS played more important role in the observed changes of the settleability and filterability than the sludge particle size. PMID- 22104766 TI - Optimization of magnetic powdered activated carbon for aqueous Hg(II) removal and magnetic recovery. AB - Activated carbon is known to adsorb aqueous Hg(II). MPAC (magnetic powdered activated carbon) has the potential to remove aqueous Hg to less than 0.2 MUg/L while being magnetically recoverable. Magnetic recapture allows simple sorbent separation from the waste stream while an isolated waste potentially allows for mercury recycling. MPAC Hg-removal performance is verified by mercury mass balance, calculated by quantifying adsorbed, volatilized, and residual aqueous mercury. The batch reactor contained a sealed mercury-carbon contact chamber with mixing and constant N(2) (g) headspace flow to an oxidizing trap. Mercury adsorption was performed using spiked ultrapure water (100 MUg/L Hg). Mercury concentrations were obtained using EPA method 245.1 and cold vapor atomic absorption spectroscopy. MPAC synthesis was optimized for Hg removal and sorbent recovery according to the variables: C:Fe, thermal oxidation temperature and time. The 3:1 C:Fe preserved most of the original sorbent surface area. As indicated by XRD patterns, thermal oxidation reduced the amorphous characteristic of the iron oxides but did not improve sorbent recovery and damaged porosity at higher oxidation temperatures. Therefore, the optimal synthesis variables, 3:1 C:Fe mass ratio without thermal oxidation, which can achieve 92.5% (+/- 8.3%) sorbent recovery and 96.3% (+/- 9%) Hg removal. The mass balance has been closed to within approximately +/- 15%. PMID- 22104767 TI - A dual-cathode electro-Fenton oxidation coupled with anodic oxidation system used for 4-nitrophenol degradation. AB - The degradation of 4-nitrophenol was investigated using a novel electrochemical oxidation system, in which the anodic oxidation at Ti/SnO(2)-Sb(2)O(5)-IrO(2) electrode and the electro-Fenton oxidation with two cathodes were involved. In this system, gas diffusion electrode (GDE) was used to generate H(2)O(2) by O(2) reduction and graphite electrode was employed for the reduction of Fe(3+) regenerating Fe(2+). When the potential values of GDE and graphite cathode were controlled at -0.80 and -0.10 V/SCE respectively, the optimum Fe(2+) concentration for 4-nitrophenol degradation was about 0.10mM, much lower than the concentration of 0.25 mM obtained in the single-cathode system. Due to the combination of electro-Fenton oxidation and anodic oxidation, an effective degradation and a high mineralization current efficiency (MCE) were achieved. After 600 min treatment, 74.5% of the original TOC was removed by the dual cathode oxidation system. Moreover, it was confirmed that 57.0% of the original nitrogen could be removed in gaseous form from the simulated wastewater. These results indicate that this electrochemical oxidation process might provide an alternative for the degradation of organic pollutants. PMID- 22104768 TI - Evaluation of arsenic immobilization in red mud by CO2 or waste acid acidification combined ferrous (Fe2+) treatment. AB - Arsenic was detected in a red mud (RM) produced during alumina production from bauxite known as the Bayer process. The transporting RM was a mixture of RM solid phase (RMsf) and RM liquid phase (RMlf). The mass content of RMsf in RM is about 30-40%. The alkalinities concentrations in the RMlf were in a range of 37.2 * 10(3)mg/l to 51.5 * 10(3)mg/l. Acidification by CO(2) or waste acid (WA) combined with ferrous (Fe(2+)) treatment was evaluated for arsenic immobilization in the RM. The aqueous arsenic concentration in the RMlf decreased from 6.1mg/l to 0.5mg/l and 0.06 mg/l with the addition of CO(2) and WA, respectively. Ferrous was then added to decrease the aqueous arsenic concentration to be lower than 0.05 mg/l. The cost-effective dosages of CO(2) or WA were 80.1g/l or 26.7 g/l, and the corresponding dosages of ferrous were both 6g/l. A 2(3) full factorial design was employed to evaluate the importance of chemical components of the RM in the cost of arsenic immobilization. High concentrations of arsenic and alkalinities in the RM will increase the cost while the effects of alumina contents varied during the different acidifications. Dissolvable arsenic in the RMsf was 8.2% and 9.5% after the CO(2) and WA combined ferrous treatments, respectively. PMID- 22104769 TI - Mobilization of metals during treatment of contaminated soils by modified Fenton's reagent using different chelating agents. AB - Changes in pH and redox conditions and the application of chelating agents when applying in situ chemical oxidation (ISCO) for remediation of contaminated sites can cause mobilization of metals to the groundwater above threshold limit values. The mechanisms causing the mobilization are not fully understood and have only been investigated in few studies. The present work investigated the mobilization of 9 metals from two very different contaminated soils in bench and pilot tests during treatment with modified Fenton's reagent (MFR) and found significant mobilization of Cu and Pb to the water in mg/l levels. Also Fe, As, Mn, Ni, Zn, Mg, and Ca mobilization was observed. These findings were confirmed in a pilot test where concentrations of Cu and Pb up to 52.2 and 33.7 mg/l were observed, respectively. Overall, the chelating agents tested (EDTA, citrate and pyrophosphate) did not seem to increase mobilization of metals compared to treatment with only hydrogen peroxide and iron. The results strongly indicate that the mobilization is caused by hydrogen peroxide and reactive species including oxidants and reductants formed with MFR. Based on these results, the use of chelating agents for ISCO will not cause an increase in metal mobilization. PMID- 22104770 TI - Enrichment of anammox bacteria from three sludge sources for the startup of monosodium glutamate industrial wastewater treatment system. AB - Three activated sludges from a landfill leachate treatment plant (S1), a municipal sewage treatment plant (S2) and a monosodium glutamate (MSG) wastewater treatment plant (S3) were used as inocula to enrich anaerobic ammonium oxidation (anammox) bacteria for the startup of MSG industrial wastewater treatment system. After 360 days of cultivation using MSG wastewater, obvious anammox activity was observed in all three cultures. The maximum specific anammox activities of cultures S1, S2 and S3 were 0.11 kg N kg(-1) VSS day(-1), 0.09 kg N kg(-1) VSS day(-1) and 0.16 kg N kg(-1) VSS day(-1), respectively. Brownish-red anammox granules having diameters in the range of 0.2-1.0mm were visible in cultures S1 and S2, and large red granules having diameters in the range of 0.5-2.5mm were formed in culture S3 after 420 days of cultivation. Phylogenetic analysis of 16S rRNA genes showed that Kuenenia organisms were the dominant anammox species in all three cultures. The copy numbers of 16S rRNA genes of anammox bacteria in cultures S1, S2 and S3 were 6.8 * 10(7) copies mL(-1), 9.4 * 10(7) copies mL(-1) and 7.5 * 10(8) copies mL(-1), respectively. The results of this study demonstrated that anammox cultivation from conventional activated sludges was highly possible using MSG wastewater. Thus the anammox process has possibility of applying to the nitrogen removal from MSG wastewater. PMID- 22104951 TI - Comparing age of cystic fibrosis diagnosis and treatment initiation after newborn screening with two common strategies. AB - BACKGROUND: Newborn screening (NBS) for CF has become widespread, although there are multiple strategies. Little is known about outcomes such as age of diagnosis after different NBS methods. METHODS: We used the U.S. Cystic Fibrosis Foundation Patient Registry to identify infants with CF born between 2001 and 2008 in states that utilized NBS. We compared ages at diagnosis, genotyping, sweat test, and first visit to a CF Centre between states that used serial immunoreactive trypsinogen (IRT/IRT) levels and states that used IRT and DNA analysis (IRT/DNA). RESULTS: We identified 1288 infants with CF. Compared to infants born in IRT/IRT states, infants born in IRT/DNA states were younger at the time of diagnosis (median 2.3 weeks versus 4.0 weeks in IRT/IRT states, p<0.001), genotyping (0.7 weeks versus 5.3 weeks, p<0.001), and initial CF Centre visit (5.9 weeks versus 7.7 weeks, p=0.008). CONCLUSIONS: Although there is room to improve outcomes with both strategies, infants born in IRT/DNA states have treatment initiated at a younger age than infants born in IRT/IRT states. PMID- 22104952 TI - Employment and work disability in adults with cystic fibrosis. AB - BACKGROUND: As a result of prolonged survival, more patients with cystic fibrosis (CF) participate in the labour force. The aim of this study was to evaluate their education, occupation levels and risk factors for work disability. METHOD: 207 patients answered a self-administered questionnaire about their educational level and work status. Independently, medical records were reviewed for illness severity indicators. RESULTS: 39 patients (19%) were students, 117 (57%) were in the labour force, 13 (6%) were seeking employment and 38 (18%) were inactive. CF patients had a higher educational level and were more likely to hold skilled jobs and to work part time than the general population. FEV1 and educational level were the strongest predictive factors of disability. CONCLUSION: Many CF patients have access to professional life. Their higher educational levels improve the chances of attaining employment, which highlights the need for career counselling. Working part time helps to maintain employment despite declining health. PMID- 22104953 TI - [((18)F)-fluorodeoxyglucose PET/CT in cervix cancer: lymph node assessment and prognostic/predictive value of primary tumour analysis]. AB - PURPOSE: In cervix carcinoma: (a) to evaluate the ability of ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET) in the lymph node detection; (b) to investigate the prognostic and predictive value of the primary cervical PET parameters. PATIENTS AND METHODS: Ninety patients treated for cervix carcinoma and evaluated initially by MRI and FGD PET were included. The performances of FDG-PET for lymph node detection (relatively to the lymph node dissection) have been described (sensitivity, specificity, positive predictive value and negative predictive value). PET tumour parameters analyzed were: maximum standard uptake value (SUVmax), the volume and the maximum diameter. The prognostic and predictive values of these parameters were investigated. The tumour response was evaluated on surgical specimens. RESULTS: PET detected the cervical tumour with a sensitivity of 97% (mean values: SUVmax=15.8, volume=27 mm(3), maximum diameter=47). For the detection of the lymph nodes, the values of sensibility, specificity, positive predictive value and negative predictive value were: 86, 56, 69 and 78% in the pelvic, and 90, 67, 50 and 95% for the para aortic area, respectively. The SUVmax was correlated with histologic response (P=0.04). The frequency of partial histological response was significantly higher for tumour SUVmax>10.9 (P=0.017). The maximum PET diameter and pathologic response had an impact on disease-free survival and overall survival in multivariate analysis (P<0.05). CONCLUSION: PET has high sensitivity in detecting pelvic and para-aortic lymph nodes. Some primary cervical tumour PET parameters are useful as prognostic and predictive factors. PMID- 22104954 TI - Treatment of odontogenic pain in a correctional setting. AB - Odontogenic pain, or toothache, is highly prevalent in correctional facilities. When there is no dental sick call because the dental clinic is closed or the facility has no dental clinic, it is critical that midlevel providers and physicians triage and manage these patients until a dentist can resolve the problem. This article explores the etiology and diagnosis of toothache, presents the authors' opinion of the standard of care for managing these patients, and makes three recommendations: (a) access to timely and definitive dental treatment should be available to all inmates experiencing dental pain, (b) antibiotic use should be limited to patients with frank infection, and (c) progress of patients awaiting a dental appointment should be monitored with frequency consistent with the differential diagnosis. PMID- 22104955 TI - The experiences of providing children's palliative care education in undergraduate nursing programmes--a discussion of some practical issues. AB - Despite recent proliferation of palliative care services for children, and the fact that the needs of these children and their families are enshrined in current policy directives, the challenges of providing education for nurses within this area of practice is largely underexplored. This paper examines some of the key issues facing nurse educators who are involved in the delivery of palliative care content in undergraduate children's nursing programmes. Drawing on the extensive experiences of two nurse educators in children's palliative care education, research and practice, key issues which should be considered by those involved in curriculum development and delivery will be outlined. Such issues include ambiguity in terminology and resultant lack of conceptual clarity, the limited evidence base to underpin practice and education, the complexities of teaching sensitive topics to large groups and limited teaching expertise to deliver the content. Suggestions for addressing such issues will be outlined. PMID- 22104956 TI - Promoting mental health concepts in a doctor of nursing practice curriculum: an integrated and global approach. AB - Mental health disorders represent a significant burden across all nations with the vast majority of people being undiagnosed and/or undertreated. There is an urgent need to address these mental health disparities and to implement strategies that will improve appropriate diagnosis and treatment at both the local and international level. Two solutions will be discussed in this paper. First, an integrated care model which has the potential to decrease fragmentation of care and barriers to appropriate treatment. Second, the training and education of nurses in basic mental health competencies. This paper argues that nurses are well positioned to help meet the growing need for mental health care in a variety of health care settings. This paper will describe an educational workshop that was part of a plan to incorporate mental health concepts across a Doctor of Nursing Practice curriculum. It is believed that the underlying concepts of this educational model are transferrable to other countries and can serve as a template for improving the ability to identify, treat, and manage mental health care. PMID- 22104957 TI - Narrow-band imaging flexible cystoscopy in the detection of clinically unconfirmed positive urine cytology. AB - INTRODUCTION: The objective of this study was to investigate the value of narrow band imaging (NBI) cystoscopy in the detection of patients with positive voided urine cytology (VUC) who have no evidence of disease after standard initial investigations. PATIENTS AND METHODS: Between February 2009 and December 2010, 12 patients with positive or suspicious VUC but no regular endoscopic evidence of cancer were investigated with NBI flexible cystoscopy. All the specimens were biopsied both under NBI and white light imaging (WLI). Random biopsies of bladder and prostatic urethra were performed in cases without suspect lesions. RESULTS: Fourteen NBI cystoscopies were carried out in 12 patients. Non-muscle-invasive bladder cancer was diagnosed in 5 of 12 (42%) patients on the first NBI. One patient had carcinoma in situ diagnosed on repeat NBI 3 months later. The sensitivity and specificity in diagnosing unconfirmed positive VUC was 78 and 91% for NBI vs. 50 and 80% for WLI. CONCLUSIONS: NBI cystoscopy significantly improves detection of unconfirmed positive VUC over WLI. It should be carried out early in the investigation of such patients before random biopsies and ureteroscopy. PMID- 22104958 TI - Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia. AB - Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia. PMID- 22104959 TI - Temporally resolved electrocardiogram-triggered diffusion-weighted imaging of the human kidney: correlation between intravoxel incoherent motion parameters and renal blood flow at different time points of the cardiac cycle. AB - PURPOSE: To evaluate the influence of pulsatile blood flow on apparent diffusion coefficients (ADC) and the fraction of pseudodiffusion (F(P)) in the human kidney. MATERIALS AND METHODS: The kidneys of 6 healthy volunteers were examined by a 3-T magnetic resonance scanner. Electrocardiogram (ECG)-gated and respiratory-triggered diffusion-weighted imaging (DWI) and phase-contrast flow measurements were performed. Flow imaging of renal arteries was carried out to quantify the dependence of renal blood flow on the cardiac cycle. ECG-triggered DWI was acquired in the coronal plane with 16 b values in the range of 0 s/mm(2) and 750 s/mm(2) at the time of minimum (MIN) (20 milliseconds after R wave) and maximum renal blood flow (MAX) (197 +/- 24 milliseconds after R wave). The diffusion coefficients were calculated using the monoexponential approach as well as the biexponential intravoxel incoherent motion model and correlated to phase contrast flow measurements. RESULTS: Flow imaging showed pulsatile renal blood flow depending on the cardiac cycle. The mean flow velocity at MIN was 45 cm/s as compared with 61 cm/s at MAX. F(p) at MIN (0.29) was significantly lower than at MAX (0.40) (P = 0.001). Similarly, ADC(mono), derived from the monoexponential model, also showed a significant difference (P < 0.001) between MIN (ADC(mono) = 2.14 +/- 0.08 * 10(-3) mm(2)/s) and MAX (ADC(mono) = 2.37 +/- 0.04 * 10(-3) mm(2)/s). The correlation between renal blood flow and F(p) (r = 0.85) as well as ADC(mono) (r = 0.67) was statistically significant. CONCLUSION: Temporally resolved ECG-gated DWI enables for the determination of the diffusion coefficients at different time points of the cardiac cycle. ADC(mono) and FP vary significantly among acquisitions at minimum (diastole) and maximum (systole) renal blood flow. Temporally resolved ECG-gated DWI might therefore serve as a novel technique for the assessment of pulsatility in the human kidney. PMID- 22104960 TI - Cerebral computed tomography angiography using a low tube voltage (80 kVp) and a moderate concentration of iodine contrast material: a quantitative and qualitative comparison with conventional computed tomography angiography. AB - OBJECTIVE: To investigate the feasibility of an 80-kVp protocol using a moderate concentration contrast material (MC-CM) for cerebral computed tomography angiography by comparison with a conventional 120-kVp protocol using a high concentration contrast material (HC-CM). MATERIALS AND METHODS: Attenuation values and signal-to-noise ratios (SNRs) were determined in a head phantom for 2 tube voltages (80 and 120 kVp) and 2 different iodine concentration contrast materials (HC-CM and MC-CM). Among 90 consecutive patients, 45 patients were scanned with 120 kVp and 150 mAs(eff) after administration of 70 mL of HC-CM (370 mg iodine [mgI]/mL), whereas the other 45 patients were scanned with 80 kVp and 370 mAs(eff) after administration of 70 mL of MC-CM (300 mgI/mL). The Hounsfield units (HU) of the internal carotid artery T junction, SNR, contrast-to-noise ratio (CNR), subjective degree of arterial enhancement, image noise, sharpness of the cerebral arterial boundary, and overall diagnostic image quality were compared between the 2 groups. RESULTS: The mean attenuation of the internal carotid artery T junction, SNR, and CNR was significantly higher in the 80 kVp with MC-CM group (379.2, 33.7, and 31.1 HU, respectively) than in the 120 kVp with HC-CM group (282.2, 31.1, and 27.2 HU, respectively). The 80-kVp protocol resulted in significantly higher score in arterial enhancement, sharpness of the cerebral arteries, and overall diagnostic image quality. The effective dose of 80 kVp (0.7 mSv) was 22.2% lower than that of 120 kVp (0.9 mSv). CONCLUSIONS: The use of 80 kVp with MC-CM improved arterial enhancement, SNR, and CNR and provided superior quality images using a smaller amount of iodine and a lower radiation dose than the conventional protocol of 120 kVp with HC-CM. PMID- 22104961 TI - Detection of small metastatic brain tumors: comparison of 3D contrast-enhanced whole-brain black-blood imaging and MP-RAGE imaging. AB - OBJECTIVE: Early and accurate diagnosis of small metastatic brain tumors may affect outcomes and treatment strategies. For this reason, 3-dimensional (3D) thin-section imaging is preferred. However, with conventional contrast-enhanced (CE) 3D imaging, such as magnetization-prepared rapid gradient echo (MP-RAGE), many visually enhanced vessels may mimic small metastatic tumors, hindering tumor detection. CE black-blood single-slab 3D turbo-spin echo imaging (BB-ssTSE) was recently developed, which uses variable refocusing flip angles and flow sensitizing gradient schemes, to enhance metastatic brain tumors while selectively suppressing blood vessels. The purpose of this work was to investigate the efficiency of the proposed CE BB-ssTSE in detecting small metastatic brain tumors as compared with conventional MP-RAGE. MATERIALS AND METHODS: Numerical comparisons of MP-RAGE and BB-ssTSE were performed by simulation studies to investigate the signal/contrast behaviors of flowing blood and stationary CE tumors. For in vivo studies, we enrolled 35 patients (18 women; mean age, 58.1 years) with breast or lung cancer who underwent brain magnetic resonance imaging. After administering a double dose of contrast medium, whole brain 2-dimensional T1-weighted imaging followed by high-resolution isotropic 3D BB-ssTSE and MP-RAGE was performed at 3.0 T. Two reviewers independently evaluated the presence of metastatic brain tumors using: (1) MP-RAGE; (2) BB ssTSE; and (3) MP-RAGE + BB-ssTSE sequentially in 3 review sessions, 2 weeks apart. The lesions were classified by size into 2 groups: large (>=5 mm) and small (<5 mm). Both reviewers marked all tumors detected at each session. Another reviewer combined the results of the 2 reviewers and compared the detection rates of metastatic brain tumors between BB-ssTSE and MP-RAGE by using follow-up imaging. Intraclass correlation coefficients between the 2 reviewers were measured. RESULTS: Numerical simulations showed that the proposed BB-ssTSE effectively attenuated the signal intensity of flowing blood over the entire echo train, resulting in CE tumor-to-white matter contrast comparable with conventional MP-RAGE. The combined evaluation of MP-RAGE + BB-ssTSE showed 242 tumors in 28 patients. Of these, 153 lesions were <5 mm. MP-RAGE found 111 small metastatic brain tumors, BB-ssTSE found 150, and MP-RAGE + BB-ssTSE found 153. Significantly, more small tumors were detected by BB-ssTSE than MP-RAGE (P = 0.001, Wilcoxon signed-rank test). All large tumors were detected similarly by both MP-RAGE and BB-ssTSE. By combined results for MP-RAGE + BB-ssTSE, sensitivities for detection of small metastatic tumors were 72.5% for MP-RAGE and 98.0% for BB-ssTSE (P < 0.0001, McNemar test). Intraclass correlation coefficients between the 2 reviewers were 0.826 for MP-RAGE and 0.954 for BB ssTSE. CONCLUSION: Compared with conventional MP-RAGE, the proposed CE BB-ssTSE imaging, which enhances tumors while selectively suppressing blood vessels, leads to significantly better detection of small metastatic brain tumors <5 mm. PMID- 22104962 TI - Quantitative mapping of tumor vascularity using volumetric contrast-enhanced ultrasound. AB - OBJECTIVE: The goal of this research project was to develop a volumetric strategy for real-time monitoring and characterization of tumor blood flow using microbubble contrast agents and ultrasound (US) imaging. MATERIALS AND METHODS: Volumetric contrast-enhanced US (VCEUS) imaging was implemented on a SONIX RP US system (Ultrasonix Medical Corp, Richmond, BC) equipped with a broadband 4DL14 5/38 probe. Using a microbubble-sensitive harmonic imaging mode (transducer transmits at 5 MHz and receives at 10 MHz), acquisition of postscan-converted VCEUS data was achieved at a volume rate of 1 Hz. After microbubble infusion, custom data processing software was used to derive microbubble time-intensity curve-specific parameters, namely, blood volume (IPK), transit time (T1/2PK), flow rate (SPK), and tumor perfusion (AUC). RESULTS: Using a preclinical breast cancer animal model, it is shown that millimeter-sized deviations in transducer positioning can have profound implications on US-based blood flow estimators, with errors ranging from 6.4% to 40.3% and dependent on both degree of misalignment (offset) and particular blood flow estimator. These errors indicate that VCEUS imaging should be considered in tumor analyses, because they incorporate the entire mass and not just a representative planar cross-section. After administration of an antiangiogenic therapeutic drug (bevacizumab), tumor growth was significantly retarded compared with control tumors (P > 0.03) and reflects observed changes in VCEUS-based blood flow measurements. Analysis of immunohistologic data revealed no differences in intratumoral necrosis levels (P = 0.70), but a significant difference was found when comparing microvessel density counts in control with therapy group tumors (P = 0.05). CONCLUSIONS: VCEUS imaging was shown to be a promising modality for monitoring changes in tumor blood flow. Preliminary experimental results are encouraging, and this imaging modality may prove clinically feasible for detecting and monitoring the early antitumor effects in response to cancer drug therapy. PMID- 22104963 TI - Toxicity of metal oxide nanoparticles in immune cells of the sea urchin. AB - The potential toxicity of stannum dioxide (SnO2), cerium dioxide (CeO2) and iron oxide (Fe3O4) nanoparticles (NPs) in the marine environment was investigated using the sea urchin, Paracentrotus lividus, as an in vivo model. We found that 5 days after force-feeding of NPs in aqueous solutions, the three NPs presented different toxicity degrees, depending on the considered biomarkers. We examined: 1) the presence of the NPs in the coelomic fluid and the uptake into the immune cells (coelomocytes); 2) the cholinesterase activity and the expression of the stress-related proteins HSC70 and GRP78; 3) the morphological changes affecting cellular compartments, such as the endoplasmic reticulum (ER) and lysosomes. By Environmental Scanning Electron Microscope (ESEM) analysis, coupled with Energy Dispersive X-ray Spectroscopy (EDS) we found that NPs were uptaken inside coelomocytes. The cholinesterases activity, a well known marker of blood intoxication in vertebrates, was greatly reduced in specimens exposed to NPs. We found that levels of stress proteins were down-regulated, matching the observed ER and lysosomes morphological alterations. In conclusion, this is the first study which utilizes the sea urchin as a model organism for biomonitoring the biological impact of NPs and supports the efficacy of the selected biomarkers. PMID- 22104964 TI - Transforming growth factor-beta is required for vasculogenic mimicry formation in glioma cell line U251MG. AB - Both vasculogenic mimicry (VM) and transforming growth factor-beta (TGFbeta) are positively correlated with malignancy in glioma. Accordingly, we supposed that TGFbeta might be related with VM, and aimed to detect whether TGFbeta could influence VM formation in two glioma cell lines U251MG and SHG44, which were different in malignancy. We found that the VM-positive U251MG had a significantly higher TGFbeta expression than the VM-negative SHG44. Downregulating TGFbeta in U251MG by RNAi technology resulted in a significantly impaired VM formation, which could be rescued by rhTGFbeta. However, adding rhTGFbeta could not induce VM in SHG44. To investigate the possible mechanism, we detected the changes of some VM-related genes including EphA2, VE-cadherin, MMP-2, MMP-9, MT1-MMP and LAMC2 by RT-PCR and found that MT1-MMP transcript was affected by TGFbeta expression. Gelatin zymography showed a declined MMP-2 activity in the TGFbeta inhibited cells. Further studies showed that MT1-MMP inhibition impaired VM formation in U251MG. Moreover, TGFbeta induced MT1-MMP expression and VM formation in a dose-dependent manner. These findings indicated us that TGFbeta was required for VM formation in U251MG. MT1-MMP was correlated with TGFbeta induced VM formation. Thus, TGFbeta might be a potential target for VM inhibition in glioma. PMID- 22104965 TI - How, when and why proteins collapse: the relation to folding. AB - Unfolded proteins under strongly denaturing conditions are highly expanded. However, when the conditions are more close to native, an unfolded protein may collapse to a compact globular structure distinct from the folded state. This transition is akin to the coil-globule transition of homopolymers. Single molecule FRET experiments have been particularly conducive in revealing the collapsed state under conditions of coexistence with the folded state. The collapse can be even more readily observed in natively unfolded proteins. Time resolved studies, using FRET and small-angle scattering, have shown that the collapse transition is a very fast event, probably occurring on the submicrosecond time scale. The forces driving collapse are likely to involve both hydrophobic and backbone interactions. The loss of configurational entropy during collapse makes the unfolded state less stable compared to the folded state, thus facilitating folding. PMID- 22104966 TI - [Hormone replacement therapy after endometrial cancer: an opportunity to supervise!]. PMID- 22104967 TI - [Prevention of lymphoceles and gynaecologic cancers]. AB - Lymphoceles are the most frequent complications following systematic lymphadenectomy in gynaecologic cancers. Some of them may have clinical significance with high morbidity. Through a review of literature, we describe surgical methods (way of surgery, lymphadenectomy type, sentinel lymph node, peritonization, drainages, lymphostasis, surgical patch) and medical methods (somatostatin analogs and nutrition treatment) which could prevent lymphoceles formation after pelvic and lumboaortic lymphadenectomy. PMID- 22104968 TI - [Residentship in obsterics and gynaecology in Dijon]. PMID- 22104969 TI - A test to identify cyanide origin by isotope ratio mass spectrometry for forensic investigation. AB - Cyanide is one of the common poisons in murders. When cyanide has been used, to identify the origin of cyanide may be necessary in the forensic investigation. We have examined the possibility of distinguishing different commercial cyanide samples through the delta(13)C and delta(15)N values and developed a protocol for the isotope analysis of cyanide extracted from several matrices as food and medicine. Several cyanide precipitates were tested for the isotope analysis. The results show that cupric ferrocyanide Cu(2)[Fe(CN)(6)] is the most appropriate precipitate for the analysis. Thirteen batches of KCN and nine batches of NaCN chemicals were randomly chosen from different suppliers. The cyanides were converted to cupric ferrocyanide and then analysed by isotope ratio mass spectrometry coupled to elemental analysis (EA-IRMS). The isotopic signature of the commercial samples varied from -51.96 to -25.77 0/00 for delta(13)C and from 4.51 to +3.81 0/00 for delta(15)N, highlighting the potential of applying EA-IRMS technique to identify cyanide from different batches and sources. The influence of the cyanide extraction and isolation from spiked matrix on the isotopic analysis was also studied. Three matrices: orange juice, yogurt drink and a medicine were tested. In many cases, the isotopic analysis results obtained from the original cyanides precipitates and those isolated from the matrices showed a good accordance, especially for delta(15)N. In some matrices, the (13)C analysis was interfered by co-precipitates. With carefully elaborated working protocol, determining the isotope ratio of N and C in cyanide by EA-IRMS is a promising method for forensic investigations. PMID- 22104970 TI - Synthesis of novel cinnamanilides as potential immunosuppressive agents. AB - A series of new cinnamanilides (6-40) were synthesized and their immunosuppressive activity and cytotoxicity were evaluated. Most of the cinnamanilides showed good immunosuppressive activity. Among the synthesized compounds, (Z)-N-(4-bromophenyl)-2-methoxy-3-(4-methoxyphenyl)acrylamide (37) and (Z)-2-methoxy-3-(4-methoxyphenyl)-N-p-tolylacrylamide (38) exhibited potent immunosuppressive activity (IC(50) = 1.77 +/- 0.33 and 0.94 +/- 0.13 MUM) without significant cytotoxicity. PMID- 22104971 TI - Disubstituted quinazoline derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA. AB - A series of 2,4-disubstituted quinazoline derivatives found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time.Their interactions with telomeric G-quadruplex DNA were evaluated by using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR), and molecular modeling. Our results showed that these derivatives could well recognize G quadruplex and have high selectivity toward G-quadruplex over duplex DNA. The structure-activity relationships (SARs) study revealed that the disubstitution of quinazoline and the length of the amide side chain were important for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the quinazoline derivatives and their cellular effects were studied. PMID- 22104972 TI - Discovery of novel selective inhibitors of Staphylococcus aureus beta-ketoacyl acyl carrier protein synthase III. AB - beta-Ketoacyl-acyl carrier protein synthase III (KAS III) is a condensing enzyme in bacterial fatty acid synthesis and a potential target while designing novel antibiotics. In our previous report, we discovered the lead compound YKAs3003, which serves as an inhibitor of Escherichia coli KAS III (ecKAS III), and determined a reliable pharmacophore map from in silico screening. In this study, we determined two pharmacophore maps from receptor-oriented pharmacophore-based in silico screening of the x-ray structure of Staphylococcus aureus KAS III (saKAS III) to identify potent saKAS III inhibitors. We discovered a new potential inhibitor (6) with broad-spectrum antimicrobial activity and 0.8 nM binding affinity for saKAS III, proving the reliability of our pharmacophore map. Using optimization procedures, we identified three new antimicrobial saKAS III inhibitors: 6c (2,4-dichloro-benzoic acid (2,3,4-trihydroxy-benzylidene) hydrazide), 6e (4-[(3-chloro-pyrazin-2-yl)-hydrazonomethyl]-benzene-1,3-diol), and 6 (4-[(5-trifluoromethyl-pyridin-2-yl)-hydrazonomethyl]-benzene-1,3-diol). All three inhibitors have a novel 4-hydrazonomethyl-benzene-1,3-diol core structure. These inhibitors exhibited high binding affinity to saKAS III and highly selective antimicrobial activities against S. aureus and methicillin resistant S. aureus, with minimal inhibitory concentration values of 1-2 MUg/mL. PMID- 22104973 TI - Sulfur and selenium derivatives of quinazoline and pyrido[2,3-d]pyrimidine: synthesis and study of their potential cytotoxic activity in vitro. AB - The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido[2,3-d]pyrimidine are described. The synthesized compounds were screened in vitro against four tumoral cell lines - leukemia (CCRF CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) - and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI(50) values below 10MUM for eleven and ten compounds, respectively. Two compounds (2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF 7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases. PMID- 22104974 TI - Neuroanatomical correlates of cognitive performance in late life. AB - BACKGROUND/AIM: While a number of studies examined the neuroanatomical correlates of cognitive function in older adults, the results have been inconsistent. Examination of a large epidemiologically acquired sample with high-resolution magnetic resonance imaging has the potential to enhance the evidence in this field. METHODS: The participants were 326 non-demented elderly adults undergoing a battery of neuropsychological tests and brain magnetic resonance imaging scans. Regression analyses were performed to examine the correlation between voxel-based grey matter (GM) volume and four cognitive domain scores. RESULTS: Positive correlations were observed between specific GM volumes and cognitive domains, i.e. bilateral temporal lobes and hippocampi with language; bilateral temporal, parietal, and occipital lobes with processing speed; and bilateral frontal, temporal, parietal, and occipital lobes with executive function. The positive correlation between verbal memory performance and GM volume in the bilateral medial temporal lobes was not significant after correction for age. CONCLUSION: Our findings suggest that the location of GM correlates of cognitive tests is largely consistent with the conventional understanding of the neuroanatomical basis of cognition. However, the lack of hemispheric predominance in these GM correlates, and the extensively positive correlation between GM volume and cognitive performance, perhaps reflects the characteristics of the ageing brain. PMID- 22104975 TI - Dangerous dining: health and safety in the New York City restaurant industry. AB - OBJECTIVE: We characterized the health and safety conditions of New York City restaurant workers, a population comprising largely of immigrants and people of color. METHODS: We conducted an anonymous questionnaire survey of 502 New York City restaurant workers, addressing working conditions, benefits, demographic factors, psychosocial exposures, and medical symptoms and conditions. RESULTS: Restaurant workers reported fast-paced, repetitive, and physically demanding jobs that sometimes involve chemical exposures. Despite their youth, they experience a high prevalence of musculoskeletal and traumatic injuries. Few receive job benefits despite significant symptoms. Job-related injuries are positively associated with practices that pose a danger to consumers. CONCLUSIONS: New York City restaurant workers have stressful jobs, experience significant injury, and illness but receive few job benefits. A healthier work organization and greater access to benefits for restaurant workers would improve their health and public health. PMID- 22104976 TI - Effects of psychosocial work factors on lifestyle changes: a cohort study. AB - OBJECTIVE: To evaluate the effect of the demand-control-support model, the effort reward imbalance model, and emotional demands on smoking, alcohol consumption, physical activity, and body mass index. METHODS: This is a 2-year prospective cohort study of 3224 public sector employees. Measures were assessed with questionnaires. Multiple regression analyses were used to predict changes in lifestyle factors. RESULTS: Low reward predicted smoking, low-decision latitude predicted being inactive, and high demands predicted high-alcohol consumption but only for men at follow-up even after controlling for potential confounders. There were no other significant findings in the expected direction except for some of the confounders. CONCLUSIONS: We found only limited and inconsistent support for the hypothesis that a poor psychosocial work environment is associated with an adverse lifestyle. PMID- 22104977 TI - Seven-year trends in employee health habits from a comprehensive workplace health promotion program at Vanderbilt University. AB - OBJECTIVE: To assess long-term changes in health risks for employees participating in Vanderbilt University's incentive-based worksite wellness program. METHODS: Descriptive longitudinal trends were examined for employees' health risk profiles for the period of 2003 to 2009. RESULTS: The majority of risk factors improved over time with the most consistent change occurring in physical activity. The proportion of employees exercising one or more days per week increased from 72.7% in 2003 to 83.4% in 2009. Positive annual, monotonic changes were also observed in percentage for nonsmokers and seat belt usage. Although the largest improvements occurred between the first two years, improvements continued without significant regression toward baseline. CONCLUSIONS: This 7-year evaluation, with high participation and large sample size, provides robust estimates of health improvements that can be achieved through a voluntary incentive-based wellness program. PMID- 22104978 TI - Meeting the challenges of implementing an intervention to promote work ability and health-related quality of life at construction worksites: a process evaluation. AB - OBJECTIVE: To evaluate the process of a prevention program among construction workers. METHODS: The program consisted of training sessions of a physical therapist and an empowerment trainer, and a Rest-Break Tool. Data on seven process items were collected by means of questionnaires and interviews. RESULTS: Recruiting construction companies to participate was difficult. The therapists and trainer largely provided the training sessions as intended, but the Rest Break Tool was poorly implemented. Construction workers (n = 171) showed high reach (84%) and moderate attendance rates (three of four sessions). Sixty-four percent of the construction workers recommended the overall program to colleagues. Company size, economic recession, engagement of the management, and intervention year influenced dose delivered and satisfaction. CONCLUSIONS: The study showed a successful reach, dose and fidelity, and moderate satisfaction. Furthermore, contextual factors played an important role during the implementation. PMID- 22104979 TI - Time spent in physical activity and sedentary behaviors on the working day: the American time use survey. AB - OBJECTIVE: To determine time spent on the working day in sleep, work, sedentary behaviors, and light-, moderate-, and vigorous-intensity behaviors by occupation intensity. METHODS: Data came from 30,758 working respondents to the 2003 to 2009 American Time Use Survey. Mean +/- SEM time spent in work, sedentary behaviors, light-, moderate-, and vigorous-intensity activities, and sleep were computed by occupations classified as sedentary, light, moderate, and vigorous intensity. RESULTS: On average, approximately 32% of the 24-hour day was spent sleeping and approximately 31% was spent at work. Time spent in sedentary behaviors outside of work was higher, and light-intensity time was lower, with higher levels of intensity-defined occupation. CONCLUSIONS: Those employed in sedentary occupations were sedentary for approximately 11 hours per day, leaving little time to achieve recommended levels of physical activity for overall health. PMID- 22104980 TI - Perceived psychological pressure at work, social class, and risk of stroke: a 30 year follow-up in Copenhagen male study. AB - OBJECTIVE: Investigate if the association between perceived psychological work pressure and risk of stroke is modified by socioeconomic status. METHODS: Thirty year follow-up of 4943 middle-aged men without cardiovascular disease. RESULTS: In the higher social classes (I, II, and III), perceived regular exposure to psychological work pressure was common and a significant predictor of stroke; almost 10% of the stroke events could be attributed to this exposure in the higher social classes; among lower social classes (IV and V), perceived psychological pressure was no predictor at all. CONCLUSIONS: Regular psychological work pressure is a highly prevalent and independent risk factor for stroke among men in higher social classes. In contrast, no association to stroke risk was found among low social class men. PMID- 22104981 TI - Efficacy and tolerability of armodafinil: effect on clinical condition late in the shift and overall functioning of patients with excessive sleepiness associated with shift work disorder. AB - OBJECTIVE: This study examined the effect of armodafinil on late-in-shift clinical condition, wakefulness, and overall functioning of patients with shift work disorder. METHODS: Patients with clinically diagnosed shift work disorder received armodafinil or placebo on nights worked for 6 weeks. Patients included in the study experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale >=6) and were functionally impaired (Global Assessment of Functioning <70). Efficacy was determined by improvements in clinical condition (Clinical Global Impression-Change), late-in-the-shift Karolinska Sleepiness Scale score, and overall Global Assessment of Functioning score. Tolerability was assessed. RESULTS: Patients receiving armodafinil showed significant improvements in late-in-shift clinical condition, wakefulness, and global functioning, compared to placebo at final visit. Armodafinil was generally well tolerated. CONCLUSIONS: Armodafinil improved clinical condition and wakefulness late in the night shift of patients with shift work disorder. Overall patient functioning was also improved. PMID- 22104982 TI - Relationship between hyposalivation and acute respiratory infection in dental outpatients. AB - BACKGROUND: Hyposalivation may affect respiratory disease because the mouth serves as the entrance to the respiratory apparatus, as well as to the digestive tract. Patients with acute respiratory infection generally have a favorable prognosis and a short natural course. However, in cases in which the host has lowered resistance, such as in elderly patients, the infection may develop into pneumonia. OBJECTIVES: A prospective study was performed to examine the relationship between hyposalivation, which is common in elderly patients, and acute respiratory infection, which tends to become severe in elderly patients. METHODS: The subjects were 323 male and female patients >=40 years old who lived in Utsunomiya City and surrounding areas and regularly visited the Department of Dentistry and Oral Surgery, Tochigi National Hospital. A 6-month follow-up survey was performed to examine development of acute respiratory infection. Age, sex, and known risk factors were also investigated. Hyposalivation was defined as a saliva production (saliva secretion rate) of <=0.6 ml/min. Multivariate analysis adjusted for age and sex was performed to examine potential risk factors associated with the development of acute respiratory infection. RESULTS: Data were analyzed for 278 subjects who completed the follow-up survey. The incidence of acute respiratory infection was 60.4%, while hyposalivation was present in 96 subjects (35.5%). Multivariate analysis showed that the incidence of acute respiratory infection was higher in subjects with hyposalivation than in those without hyposalivation (adjusted odds ratio 1.761, p = 0.048). CONCLUSION: The results of this study suggest that hyposalivation may be a risk factor for acute respiratory infection. This also suggests that improvement of hyposalivation might prevent acute respiratory infection. PMID- 22104983 TI - Non-laser capture microscopy approach for the microdissection of discrete mouse brain regions for total RNA isolation and downstream next-generation sequencing and gene expression profiling. AB - As technological platforms, approaches such as next-generation sequencing, microarray, and qRT-PCR have great promise for expanding our understanding of the breadth of molecular regulation. Newer approaches such as high-resolution RNA sequencing (RNA-Seq)(1) provides new and expansive information about tissue- or state-specific expression such as relative transcript levels, alternative splicing, and micro RNAs(2-4). Prospects for employing the RNA-Seq method in comparative whole transcriptome profiling(5) within discrete tissues or between phenotypically distinct groups of individuals affords new avenues for elucidating molecular mechanisms involved in both normal and abnormal physiological states. Recently, whole transcriptome profiling has been performed on human brain tissue, identifying gene expression differences associated with disease progression(6). However, the use of next-generation sequencing has yet to be more widely integrated into mammalian studies. Gene expression studies in mouse models have reported distinct profiles within various brain nuclei using laser capture microscopy (LCM) for sample excision(7,8). While LCM affords sample collection with single-cell and discrete brain region precision, the relatively low total RNA yields from the LCM approach can be prohibitive to RNA-Seq and other profiling approaches in mouse brain tissues and may require sub-optimal sample amplification steps. Here, a protocol is presented for microdissection and total RNA extraction from discrete mouse brain regions. Set-diameter tissue corers are used to isolate 13 tissues from 750-MUm serial coronal sections of an individual mouse brain. Tissue micropunch samples are immediately frozen and archived. Total RNA is obtained from the samples using magnetic bead-enabled total RNA isolation technology. Resulting RNA samples have adequate yield and quality for use in downstream expression profiling. This microdissection strategy provides a viable option to existing sample collection strategies for obtaining total RNA from discrete brain regions, opening possibilities for new gene expression discoveries. PMID- 22104984 TI - Drug therapy: a new standard for thyroid cancer? PMID- 22104985 TI - Pulmonary arterial hypertension in a Kartagener syndrome patient: treatment with beraprost sodium. PMID- 22104986 TI - Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension. PMID- 22104987 TI - Impact of right ventricular pacing on patients with Chagas cardiomyopathy with chronic systolic heart failure. PMID- 22104988 TI - Rare coronary anomaly: common origin of major coronary arteries from the right sinus of Valsalva and a small ramus branch originating from the left sinus of Valsalva. PMID- 22104989 TI - Cardiac apical aneurysm secondary to ibuprofen-induced type 1-Kounis syndrome. PMID- 22104990 TI - Red cell distrubition width (RDW): a novel risk factor for cardiovascular disease. PMID- 22104991 TI - Clinical pearls regarding Prinzmetal's angina complicated by cardiac arrest- management during therapeutic hypothermia. PMID- 22104992 TI - When the prosthetic valve slips into the left ventricle, it would be better to have a cardiac surgeon as a friend! PMID- 22104993 TI - Ostial coronary stenoses after radiation therapy. PMID- 22104994 TI - Copeptin for rapid rule out of acute myocardial infarction in emergency department. AB - BACKGROUND: Copeptin, in combination with conventional troponin (cTn), has been suggested as a means of rapid rule out of the diagnosis of acute myocardial infarction (AMI). This study aims to assess the value of copeptin for rule out of AMI, according to the pre-test probability (PTP). METHODS: In a prospective multicentric study, we enrolled patients presenting into emergency departments with chest pain <6h, copeptin was measured, and PTP was quoted. The discharge diagnosis was adjudicated by 2 independent experts using all available data, including cTnI. RESULTS: 317 patients were included: 148 (46%) had low, 110 (35%) moderate and 59 (19%) high PTP. Final diagnosis was AMI in 45 patients (14%). Median copeptin level was higher in AMI patients compared with that in patients having other diagnoses (23.2 vs. 9.9 pmol/L, p=0.01). A copeptin level >=10.7 pmol/L in combination with cTnI detected AMI with higher sensitivity than for cTnI alone (98 [87-100] vs. 71 [55-83] %, p=0.001), whatever the PTP. The negative predictive value of the combination copeptin+cTnI was increased, compared to that of cTnI alone (99 [97-100] vs. 95 [92-97] %, p<0.05). CONCLUSIONS: In triage of chest pain patients, the additional use of copeptin with conventional cTnI might allow a rapid and reliable rule out of the diagnosis of AMI regardless of the PTP. PMID- 22104995 TI - Comparison of the reliability and validity of four contemporary risk stratification schemes to predict thromboembolism in non-anticoagulated patients with atrial fibrillation. AB - BACKGROUND: The risk of thromboembolic (TE) complications in atrial fibrillation (AF) patients is not homogeneous. Risk schemes can help target anticoagulant therapy for patients at highest risk of TE complications. OBJECTIVES: To test the predictive ability of 4 risk schemes: The Framingham, the 8th ACCP, the ACC/AHA/ESC 2006, and the CHA2DS2-VASc. METHODS: 186 patients with non-valvular AF and off anticoagulant therapy were included. All subjects who experienced a stroke, transient ischemic attack, or peripheral embolism were identified. Each schema was divided into low, intermediate, and high-risk categories. Discrimination was assessed via the c-statistic. RESULTS: We identified 10 TE events that occurred during 668 person-years off anticoagulation therapy. All risk schemes had fair discriminating ability (c-statistic ranged from 0.59 [for CHA2DS2-VASc] to 0.73 [for Framingham]). The proportion of patients assigned to individual risk categories varied widely across schemes. CHA2DS2-VASc categorized the fewest patients into low and intermediate-risk categories, whereas the Framingham schema assigned the highest patients into low-risk strata. There were no TE events in the low and intermediate-risk categories using CHA2DS2-VASc, whereas the most schemes assigned patients into intermediate-risk category had a event rate ranging from 2.5 (ACC/AHA/ESC and 8th ACCP schemes) to 6% (Framingham). The negative predictive value of TE events was of 100% for the no high-risk patients using CHA2DS2-VASc. CONCLUSIONS: Compared to ACC/AHA/ESC, 8th ACCP, and Framingham, CHA2DS2-VASc risk stratification schema may be better in discriminating between patients at a low and intermediate risk of TE complications. PMID- 22104996 TI - Characterisation of IL-22 and interferon-gamma-inducible chemokines in human carotid plaque. PMID- 22104997 TI - Asymptomatic embolized HELEX PFO closure device: catheter based retrieval and value of routine echocardiography the following day. PMID- 22104998 TI - C-reactive protein and endothelial dysfunction: the clinicians should have in mind diurnal variations. PMID- 22104999 TI - Interaction of anemia and decrease in renal function on survival of patients with heart failure. PMID- 22105000 TI - Persistent superior exercise performance and quality of life long-term after arterial switch operation compared to that after atrial redirection. AB - BACKGROUND: In the end of the last century arterial switch operation (ASO) replaced atrial redirection according to Senning or Mustard as the surgical technique for infants with transposition of the great arteries (TGA). Better survival with the new technique has been shown. However, exercise performance and quality of life have not yet been compared directly. METHODS AND RESULTS: All consecutive patients aged sixteen years or older that had undergone ASO for TGA at our institution and had performed a cardiopulmonary exercise test as part of their routine follow-up were included into the study. Those twenty-eight patients (20 male, median age 18.8 years) were matched for age and gender with twenty eight patients (20 male, median age 18.9 years) who underwent atrial redirection in the same surgical period at our institution. Peak oxygen uptake was higher in patients after ASO (median 38.1 [quartiles 30.3; 44.5] ml/kg/min vs. 29.8 [23.5; 33.9] ml/kg/min; p<.0001) representing 92.0% predicted and 66.1% predicted (p<.0001), respectively. In addition, patients after ASO presented a better ventilatory efficiency ( [Formula: see text] slope, p=.029), ventilatory threshold (p=.006), peak O2 pulse (p=.0001), and oxygen saturation (p=.016), as well as a superior blood pressure (p=.046) response to exercise. Self-estimated quality of life was rather good in both groups but with better results in the physical functioning and general health domains in patients after ASO. CONCLUSIONS: Adolescents and young adults with TGA still have an improved exercise performance and quality of life in the long-term follow-up after ASO than those patients after atrial redirection. PMID- 22105001 TI - Good luck!! from left atrial appendage. PMID- 22105002 TI - High-grade transitional cell carcinoma of the pediatric bladder. AB - Transitional cell carcinoma of the bladder is extremely rare in the first decade of life. We present the case of a 5-year-old male with gross hematuria found to have high-grade transitional cell carcinoma of the bladder. To our knowledge this is the first such reported case in this age group. PMID- 22105003 TI - Re: Abdulhannan P, Stahlschmidt J, Subramaniam R. Multicystic dysplastic kidney disease and hypertension: clinical and pathological correlation. J Pediatr Urol 2011;7: 566-8. PMID- 22105004 TI - Commentary to 'The modern staged repair of classic bladder exstrophy: a detailed postoperative management strategy for primary bladder closure'. PMID- 22105005 TI - Bony abnormalities in classic bladder exstrophy: the urologist's perspective. AB - INTRODUCTION: As the primary practitioner managing patients with classic bladder exstrophy (CBE), it is incumbent upon the pediatric urologist to understand the associated orthopedic anomalies and their management. METHODS: A Pubmed search was performed with the keyword exstrophy. Resulting literature pertaining to orthopedics and published references were reviewed. RESULTS: Anatomic changes to the bony pelvis include outward rotation, acetabular retroversion with compensatory femoral anteversion, anterior pubic shortening, and pubic diastasis. Imaging options have improved, which impacts surgical planning. Surgical approach, including type of osteotomy and method of pubic approximation, is evolving. Most centers employ immobilization after surgery, with external fixation, Bryant's traction, Buck's traction, and spica casting being the most common methods. Orthopedic complications range from minor pin-site infections to neurologic and vascular compromise. Most experts agree osteotomy aids bladder closure beyond 72 h of life, but effect on continence remains controversial. Although no significant orthopedic benefit has been expounded, it may be too early to appreciate improvement in frequency or severity of osteoarthritis or hip dysplasia. CONCLUSION: While orthopedic surgeons remain vital to managing exstrophy patients, knowledge of the anatomy, imaging, surgical approaches, and immobilization enable effective communication with parents and other physicians, improving care for these complicated patients. PMID- 22105006 TI - [Treatment of recurrent Clostridium difficile diarrhoea using sequential therapy with vancomycin followed by rifaximin]. PMID- 22105007 TI - Synthesis, characterization and biomedical properties of UV-cured polyurethane acrylates containing a phosphorylcholine structure. AB - In order to develop a simple, economical and rapid approach to incorporate 2 methacryloyloxyethyl phosphorylcholine (MPC) with other monomers without any solvent, we prepared a series of ultraviolet cured poly(urethane acrylate) (PUA) membranes containing different MPC content. Their chemical structure and surface properties were investigated by FT-IR, XPS, water swelling ratio and water contact angle measurement, while the biocompatibilities were evaluated through fibrinogen adsorptions, platelet adhesion and plasma recalcification time determination. The results demonstrate that the phosphorylcholine (PC) groups were successfully introduced into the PUA system by the UV-curing approach and the all PC-containing membranes showed better biocompatibility than those without PC moiety. The UV-curing method is potentially to be applied in the coating of medical devices which require biocompatibility and manufacturing efficiency. PMID- 22105008 TI - Sex-related differences of patient-controlled epidural analgesia for postoperative pain. AB - Gender differences in pain modulation are evident but data are rare with regard to perioperative regional analgesia. The aim of the present analysis was to assess gender-related differences in pain ratings, analgesic consumption, and adverse events in a large group of patients treated with patient-controlled epidural analgesia (PCEA) after major surgery. Data from 14,988 adult patients (6506 women; 8482 men) receiving a PCEA between January 1998 and December 2009 were examined. Demographic data and postoperative measurements assessed by the Acute Pain Service, including total PCEA consumption, pain scores, and complications, were analyzed by using PASW Statistics (18.0; SPSS Inc, Chicago, IL, USA). Beyond standard descriptive analyses, gender-related differences were investigated using a stepwise multivariate analysis of variances. Postoperative pain scores during rest and movement were almost equal between men and women. However, women showed lower total PCEA consumption consistently throughout the 5 day observation period (relative reduction by 1.7%-10.2% compared to men; P=0.00). Total PCEA consumption did not interact with surgical site (abdomen, thorax, extremity) (P=0.379) or age (<50, 50-75, >75 years; P=0.330), but was influenced by body mass index (P=0.017) and vomiting (P=0.011). Furthermore, motor blockade was greater in females compared to males (P=0.000). In patients treated with PCEA, gender differences in numeric rating scale scores exist but are not clinically relevant. However, reduced total PCEA consumption in women might be a consequence of an increased incidence of motor blockade and vomiting; the latter point towards an opioid-free PCEA solution in female patients at high risk for vomiting. PMID- 22105009 TI - Are we neglecting spinal reorganization following nerve damage? PMID- 22105010 TI - Investigating dose-dependent effects of placebo analgesia: a psychophysiological approach. AB - Investigating dose-dependent effects of placebo analgesia (PA) in laboratory subjects undergoing pain testing, we evaluated 2 hypotheses: (1) greater expectancy for relief produces greater PA, and (2) cued expectancy for relief triggered by a predictive cue leads to more enhanced analgesia than does passive expectancy (no predictive cue). We used conditioning procedures in which 84 subjects experienced reduced stimulation intensity following the application of purported analgesic creams to the 2 experimental fingers, while the control finger received the same levels of stimulation as in the baseline block. The dose of placebos was manipulated by creating 2 levels of expectations for relief. The form of expectation (cued vs uncued) was also manipulated by a predictive cue specifying the next finger to be stimulated. Subjective reports and psychophysiological responses served as critical indicators for evaluating impacts of the placebo manipulation on subsequent pain processing. The dose dependent PA was unambiguously demonstrated by the predicted ordering of the 3 fingers (ie, manipulated expectation levels) in terms of both response sensitivity and average response magnitude, in mixed-effects analysis of 3 outcome indicators (evoked potential, skin conductance response, pain report). Greater expectation for relief led to both (1) greater reductions in the average dependent variable slope (response sensitivity) as a function of stimulus intensity, and (2) greater reductions in average response magnitude. Unexpectedly, uncued expectation led to a slightly larger PA than did cued expectation. The study provided clear evidence that PA can occur in a "dose" dependent manner, mediated by the levels of expectancy for pain relief. PMID- 22105011 TI - Thermodynamic and structural study of phenanthroline derivative ruthenium complex/DNA interactions: probing partial intercalation and binding properties. AB - The binding of [Ru(PDTA-H(2))(phen)]Cl (PDTA = propylene-1,2-diaminetetra-acetic acid; phen = 1,10 phenanthroline) with ctDNA (=calf thymus DNA) has been investigated through intrinsic and induced circular dichroism, UV-visible absorption and fluorescence spectroscopies, steady-state fluorescence, thermal denaturation technique, viscosity and electrochemical measurements. The latter indicate that the cathodic and anodic peak potentials of the ruthenium complex shift to more positive values on increasing the DNA concentration, this behavior being a direct consequence of the interaction of both the reduced and oxidized form with DNA binding. From spectrophotometric titration experiments, the equilibrium binding constant and the number of monomer units of the polymer involved in the binding of one ruthenium molecule (site size) have been quantified. The intrinsic circular dichroism (CD) spectra show an unwinding and a conformational change of the DNA helix upon interaction of the ruthenium complex. Quenching process, thermal denaturation experiments and induced circular dichroism (ICD) are consistent with a partial intercalative binding mode. PMID- 22105012 TI - On the possible roles of N-terminal His-rich domains of Cu,Zn SODs of some Gram negative bacteria. AB - The Cu,Zn superoxide dismutases (Cu,Zn SOD) isolated from some Gram-negative bacteria possess a His-rich N-terminal metal binding extension. The N-terminal domain of Haemophilus ducreyi Cu,Zn SOD has been previously proposed to play a copper(II)-, and may be a zinc(II)-chaperoning role under metal ion starvation, and to behave as a temporary (low activity) superoxide dismutating center if copper(II) is available. The N-terminal extension of Cu,Zn SOD from Actinobacillus pleuropneumoniae starts with an analogous sequence (HxDHxH), but contains considerably fewer metal binding sites. In order to study the possibility of the generalization of the above mentioned functions over all Gram negative bacteria possessing His-rich N-terminal extension, here we report thermodynamic and solution structural analysis of the copper(II) and zinc(II) complexes of a peptide corresponding to the first eight amino acids (HADHDHKK NH(2), L) of the enzyme isolated from A. pleuropneumoniae. In equimolar solutions of Cu(II)/Zn(II) and the peptide the MH(2)L complexes are dominant in the neutral pH-range. L has extraordinary copper(II) sequestering capacity (K(D,Cu)=7.4*10( 13)M at pH 7.4), which is provided only by non-amide (side chain) donors. The central ion in CuH(2)L is coordinated by four nitrogens {NH(2),3N(im)} in the equatorial plane. In ZnH(2)L the peptide binds to zinc(II) through a {NH(2),2N(im),COO(-)} donor set, and its zinc binding affinity is relatively modest (K(D,Zn)=4.8*10(-7)M at pH 7.4). Consequently, the presented data do support a general chaperoning role of the N-terminal His-rich region of Gram negative bacteria in copper(II) uptake, but do not confirm similar function for zinc(II). Interestingly, the complex CuH(2)L has very high SOD-like activity, which may further support the multifunctional role of the copper(II)-bound N terminal His-rich domain of Cu,Zn SODs of Gram-negative bacteria. The proposed structure for the MH(2)L complexes has been verified by semiempirical quantum chemical calculations (PM6), too. PMID- 22105013 TI - Ultrasound assisted lipase catalyzed synthesis of poly-6-hydroxyhexanoate. AB - Ultrasonic irradiation greatly improved the Candida antarctica lipase B mediated ring opening polymerization of epsilon-caprolactone to poly-6-hydroxyhexanoate in the ionic liquid 1-ethyl-3-methylimidazolium tetraflouroborate. Compared to the conventional nonsonicated reaction, sonication improved the monomer conversion by 63% and afforded a polymer product of a narrower molecular weight distribution and a higher degree of crystallinity. Under sonication, the polydispersity index of the product was ~1.44 compared to a value of ~2.55 for the product of the conventional reaction. With sonication, nearly 75% of the monomer was converted to product, but the conversion was only ~16% for the reaction carried out conventionally. Compared to conventional operation, sonication enhanced the rate of polymer propagation by >2-fold and the turnover number of the lipase by >3 fold. PMID- 22105014 TI - In vivo liver endocytosis followed by purification of liver cells by liver perfusion. AB - The liver is the metabolic center of the mammalian body and serves as a filter for the blood. The basic architecture of the liver is illustrated in figure 1 in which more than 85% of the liver mass is composed of hepatocytes and the remaining 15% of the cellular mass is composed of Kupffer cells (KCs), stellate cells (HSCs), and sinusoidal endothelial cells (SECs). SECs form the blood vessel walls within the liver and contain specialized morphology called fenestrae within in the cytoplasm. Fenestration of the cytoplasm is the appearance of holes (~100 MUm) within the cells so that the SECs act as a sieve in which most chylomicrons, chylomicron remnants and macromolecules, but not cells, pass through to the hepatocytes and HSCs (1) (Fig. 1). Due to the lack of a basement membrane, the gap between the SECs and hepatocytes form the Space of Disse. HSCs occupy this space and play a prominent role in regulation and response to injury, storage of retinoic acid and immunoregulation of the liver (2). SECs are among the most endocytically active cells of the body displaying an array of scavenger receptors on their cell surface (3). These include SR-A, Stabilin-1 and Stabilin 2. Generally, small colloidal particles less than 230 nm and macromolecules in buffer phase are taken up by SECs, whereas, large particles and cellular debris is endocytosed (phagocytosed) by KCs (4). Thus, the bulk clearance of extracellular material such as the glycosaminoglycans from blood is largely dependent on the health and endocytic functions of SECs (5,6). For example, an increase in blood hyaluronan levels is indicative of liver disease ranging from mild to more severe forms (7). With the exception of one report (8), there are no immortalized SEC cell lines in existence. Even this immortalized cell line is de differentiated in that it does not express scavenger receptors that are present on primary SECs (our data, not shown). All cell biological studies must be performed on primary cells obtained freshly from the animal. Unfortunately, SECs dedifferentiate under standard culture conditions and must be used within 1 or 2 days upon isolation from the animal. Differentiation of SECs is marked by the expression of Stabilin-2 or HARE receptor (9) , CD31, and the presence of cytoplasmic fenestration (1). Differentiation of SECs can be extended by the addition of VEGF in culture media or by culturing cells in hepatocyte conditioned medium (10,11). In this report, we will demonstrate the endocytic activity of SECs in the intact organ using radio-labeled heparin for hyaluronan for the SEC specific Stabilin-2 receptor. We will then purify hepatocytes and SECs from the perfused liver to measure endocytosis. PMID- 22105015 TI - Prospective randomized study on the efficacy of blue light in the treatment of psoriasis vulgaris. AB - BACKGROUND: Blue light has no known toxic effects on human skin, but reduces the proliferative capacity of keratinocytes in vitro. We therefore investigated the efficacy of blue light in the treatment of psoriasis vulgaris (PV). METHODS: Forty patients with mild to moderate PV and bilateral plaques were assigned to two groups. Group 1 (n = 20) received irradiation at home with blue light (light emitting diode, LED, emission maximum: 420 nm) once daily for 4 weeks. In parallel, group 2 (n = 20) performed irradiations with another blue light device (LED emission maximum: 453 nm). The contralateral control plaques remained untreated in both groups. RESULTS: Thirty-seven patients completed the trial. The main study parameter, the difference of Local Psoriasis Severity Index (LPSI) scores of the irradiated plaques compared to the control plaques, showed statistically significant improvement after 4 weeks of treatment in both groups [group 1 (420 nm): n = 17, p = 0.04; group 2 (453 nm): n = 20, p = 0.04]. Accordingly, plaque status as assessed by both the physicians and the patients improved continuously during the 4 weeks of treatment and steadily declined thereafter. CONCLUSION: Blue light appears to be a promising treatment modality in PV that warrants further evaluation in larger studies. PMID- 22105016 TI - Interactive visibility retargeting in VR using conformal visualization. AB - In Virtual Reality, immersive systems such as the CAVE provide an important tool for the collaborative exploration of large 3D data. Unlike head-mounted displays, these systems are often only partially immersive due to space, access, or cost constraints. The resulting loss of visual information becomes a major obstacle for critical tasks that need to utilize the users' entire field of vision. We have developed a conformal visualization technique that establishes a conformal mapping between the full 360 degrees field of view and the display geometry of a given visualization system. The mapping is provably angle-preserving and has the desirable property of preserving shapes locally, which is important for identifying shape-based features in the visual data. We apply the conformal visualization to both forward and backward rendering pipelines in a variety of retargeting scenarios, including CAVEs and angled arrangements of flat panel displays. In contrast to image-based retargeting approaches, our technique constructs accurate stereoscopic images that are free of resampling artifacts. Our user study shows that on the visual polyp detection task in Immersive Virtual Colonoscopy, conformal visualization leads to improved sensitivity at comparable examination times against the traditional rendering approach. We also develop a novel user interface based on the interactive recreation of the conformal mapping and the real-time regeneration of the view direction correspondence. PMID- 22105017 TI - Body image and psychological distress after prophylactic mastectomy and breast reconstruction in genetically predisposed women: a prospective long-term follow up study. AB - PURPOSE: To explore the course of psychological distress and body image at long term follow-up (6-9 years) after prophylactic mastectomy and breast reconstruction (PM/BR) in women at risk for hereditary breast cancer, and to identify pre-PM risk factors for poor body image on the long-term. METHODS: Psychological distress (general and breast cancer specific) and body image (general and breast specific) were assessed in 36 high-risk women before PM (T0), at 6 months (T1) and 6-9 years (T2) after PM/BR. Investigated predictive variables (assessed at T0) for long-term body image (assessed at T2) included psychological distress, body image and coping styles. RESULTS: Breast cancer specific and general distress significantly decreased from T0 to T1 as well as from T1 to T2. Problems regarding breast related and general body image were significantly higher at T1 than at T0. Subsequently, breast related body image scores significantly decreased from T1 to T2, while the decrease in general body image scores were not significant. Active coping and seeking social support were predictive of lower scores (i.e. less problems) on breast related and general body image at long-term follow-up. Furthermore, higher scores on general body image before PM/BR were predictive for increased general body image scores at long-term follow-up. CONCLUSION: Our findings indicate that psychological distress is decreased after PM/BR, at the cost of persistent problems regarding body image. Exploration of coping styles and body image perception before PM/BR may help to identify vulnerable women who may benefit from additional support. PMID- 22105018 TI - Quality indicators for testicular cancer: a population-based study. AB - PURPOSE: This study aimed at developing and measuring an indicator set to monitor the quality of testicular cancer care, to make comparisons over time and to support quality improvement for all practitioners and centres involved in the care of testicular cancer patients. METHODS: Quality indicators were identified from a systematic literature search and from the 2010 Belgian evidence-based clinical practice guidelines. The selection process involved an expert panel evaluating reliability, relevance, interpretability and actionability of each indicator. The quality indicators were pilot tested using the Belgian Cancer Registry (BCR) data linked with claims data for 1307 men with testicular cancer diagnosed between 2001 and 2006. The variability between centres was displayed using funnel plots. RESULTS: Of the 12 finally selected indicators, 5 were fully and 1 was partly measurable, while 2 indicators were measurable using proxy information. Five-year relative survival was 97%, 95% and 76% for pStage I-III, respectively. Overall 5-year survival slightly improved from 91% in 2001 to 94% in 2004. Between 2004 and 2006, 14 of 97 centres performed >=10 orchidectomies. Large variability was found between centres. The nine centres with a 5-year observed survival below the lower limit treated less than 20 patients between 2001 and 2006. CONCLUSIONS: The present study demonstrates the feasibility to develop a multidisciplinary set of quality indicators for testicular cancer. Using national cancer registry data linked to claims data, eight indicators were measurable, showing a mixed picture of the quality of care for testicular cancer patients in Belgium. PMID- 22105019 TI - Preadmission beta-blockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Neurogenic stunned myocardium (NSM) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on disease course. The presumed cause is catecholamine surge at the time of aneurysm rupture. Beta-blockers, which reduce the impact of the catecholamine surge, may decrease the risk of developing NSM. METHODS: A chart review of 234 consecutive patients admitted to the Oregon Health and Science University Neurosurgery service between March 6, 2008 and June 23, 2010 with a diagnosis of aneurysmal SAH was performed. This group was further subdivided by patients who received echocardiograms on admission, by gender, and by the prehospital administration of beta-blockers. RESULTS: One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed NSM (13.8%). None of the 22 patients taking prehospital beta-blockers developed NSM. Using the Fisher exact test to compare the 2 groups, patients who were administered prehospital beta blockers were significantly less likely to develop stunning compared to those who were not (P = .04). After correcting for other variables using multiple logistic regression analysis, the previous use of beta-blockers was still found to be significantly associated with a decreased incidence of NSM after SAH (P = .049). There was no significant difference in hospital length of stay, peribleed stroke, vasospasm, or death. Of the 18 patients with stunning, 15 were women, 5 of whom were on estrogen supplementation. The mean peak troponin elevation of women who developed NSM on estrogen supplementation was significantly higher than for those who were not (mean peak troponin 9.97 +/- 2.01 mg/dL; P < .001). CONCLUSION: Prehospital beta-blockers are associated with decreased risk of developing NSM in patients with aSAH. Estrogen may play an additional role in shaping the degree of NSM in women. PMID- 22105020 TI - Pediatrics: Measuring pediatric BMD-the bar raised but the glass half full. AB - Extensive reference data sets of pediatric bone density measurements are now available, together with equations to translate BMD into relevant Z-scores and correct for abnormal stature. So now is the right time to ask: are you thinking about bone density in children correctly? PMID- 22105021 TI - Diabetes: insulin signal meets SIRT1 at AKT. PMID- 22105022 TI - Species discrimination of Radix Bupleuri through the simultaneous determination of ten saikosaponins by high performance liquid chromatography with evaporative light scattering detection and electrospray ionization mass spectrometry. AB - A simple, rapid and robust high performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) method was established for the species discrimination and quality evaluation of Radix Bupleuri through the simultaneous determination of ten saikosaponins, namely saikosaponin-a, -b(1), -b(2), -b(3), b(4), -c, -d, -g, -h, and -i. These compounds were chromatographed on an Ascentis((r)) Express C18 column with a gradient elution of acetonitrile and water containing 0.1% acetic acid at a flow rate of 1.0 mL/min. Saikosaponins were monitored by ELSD, which was operated at a 50 degrees C drift tube temperature and 3.0 bar nebulizer gas (N(2)) pressure. The developed method was validated with respect to linearity, intra- and inter-day accuracy and precision, limit of quantification (LOQ), recovery, robustness and stability, thereby showing good precision and accuracy, with intra- and inter-assay coefficients of variation less than 15% at all concentrations. Furthermore, a high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) method was developed to certify the existence of ten saikosaponins, as well as to confirm the reliability of ELSD. The extraction conditions of saikosaponins from Radix Bupleuri were also optimized by investigating the effect of extraction methods (sonication, reflux and maceration) and various solvents on the extraction efficiencies for saikosaponins. Sonication with 70% methanol for 40 min was found to be simple and effective for extraction of major saikosaponins. This analytical method was applied to determine saikosaponin profiles in 20 real samples consisting of four Bupleurum species, namely B. falcatum, B. chinense, B. sibiricum and the poisonous B. longiradiatum. It was found that three major saikosaponin-a, -c and -d were the major constituents in B. falcatum, B. chinense, and B. longiradiatum, while one major saikosaponin (saikosaponin-c) was not identified from B. sibiricum. In addition, no saikosaponin-b(3) was detected in B. longiradiatum samples, indicating that the toxic B. longiradiatum may be tentatively distinguished from officially listed Bupleurum species (B. falcatum and B. chinense) based on their saikosaponin profiles. Overall the simultaneous determination of ten saikosaponins in Radix Bupleuri was shown to be a promising tool to adopt for the discrimination and quality control of closely related Bupleurum species. PMID- 22105023 TI - A LC-MS/MS methodology to determine furaltadone residues in the macroalgae Ulva lactuca. AB - Presently, the rise of new contaminants in the environment has widened the scope of pharmaceutical analyses as to face the demanding new challenges. An increasing tendency for the interconnection and overlap of research fields, such as ecology and biochemistry, is intensifying the demand for new methodologies to be applied to the survey of drugs in unconventional matrices. Integrated in this group are macrophytes, such as the green macroalgae Ulva lactuca, which are under study as to ascertain their ability as indicators of contamination for many substances. Nonetheless, methodologies for extraction and determination of drugs in such matrices are scarce and new studies on the subject are pressing. A new methodology for the determination of the antibiotic furaltadone in U. lactuca by liquid chromatography-tandem mass spectrometric (LC-MS/MS) procedure was developed, optimized and validated following the guidelines of the EC Decision 2002/657. The calibration curves showed linearity above 0.99 (R(2)). The relative standard deviations obtained for repeatability, expressed as CV, were between 15.3 and 20.5 and for reproducibility 25.3 and 28.2 whereas accuracy was in the interval of 88.9-95.5 (%). The limit of decision (CCalpha) and the detection capability (CCbeta) were respectively 5.57 MUg kg(-1) and 10.97 MUg kg(-1). The method was successfully applied to experimental samples. PMID- 22105024 TI - The Nicotiana attenuata LECTIN RECEPTOR KINASE 1 is involved in the perception of insect feeding. AB - The Nicotiana attenuata LECTIN RECEPTOR KINASE 1 (LecRK1) has been recently identified as a component of the mechanism used by plants to suppress the Manduca sexta-triggered accumulation of salicylic acid (SA). The suppression of the SA burst by LecRK1 allows for the unfettered induction of jasmonic acid (JA) mediated defense responses against M. sexta herbivory. LecRK1 contains a multi domain extracellular region composed of a G-type Lectin domain and a PAN-AP domain separated by a variable sequence with low similarity to an EGF domain. The LecRK1 intracellular region is composed of a single domain structure with predicted Ser/Thr protein kinase activity. The multi-domain structure of the extracellular region of LecRK1 adds a level of complexity in terms of the potential ligands that this receptor protein could recognize. PMID- 22105025 TI - Detecting autophagy in Arabidopsis roots by membrane-permeable cysteine protease inhibitor E-64d and endocytosis tracer FM4-64. AB - Autophagy is the process by which cells degrade their own components in lysosomes or vacuoles. Autophagy in tobacco BY-2 cells cultured in sucrose-free medium takes place in formed, autolysosomes in the presence of a cysteine protease inhibitor. The autolysosomes in BY-2 cells are located in the endocytotic pathway and thus can be stained with fluorescent endocytosis marker FM4-64. In the present study, in order to detect autophagy in the root cells of Arabidopsis, we incubated root tips from Arabidopsis seedlings in culture medium containing the membrane-permeable cysteine protease inhibitor E-64d and FM4-64, and examined whether autolysosomes stained with FM4-64 are accumulated. The results suggest that autophagy accompanying the formation of autolysosomes also occurs in Arabidopsis root cells. Such autophagy appeared to occur constitutively in the root cells in nutrient-sufficient culture medium. Even in atg5 mutants in which an autophagy-related gene is disrupted, accumulation of the structures stained with FM4-64, which likely correspond to autolysosomes, was seen although at lower level than in wild type roots. PMID- 22105026 TI - EARLY RESPONSIVE to DEHYDRATION 15, a new transcription factor that integrates stress signaling pathways. AB - The Early Responsive to Dehydration (ERD) genes are defined as those genes that are rapidly activated during drought stress. The encoded proteins show a great structural and functional diversity, with a particular class of proteins acting as connectors of stress response pathways. Recent studies have shown that ERD15 proteins from different species of plants operate in cross-talk among different response pathways. In this mini-review, we show the recent progress on the functional role of this diverse family of proteins and demonstrate that a soybean ERD15 homolog can act as a connector in stress response pathways that trigger a programmed cell death signal. PMID- 22105027 TI - UV-B signaling in maize: transcriptomic and metabolomic studies at different irradiation times. AB - Plants have evolved adaptations to environmental factors, including UV-B present in solar radiation. Deployment of specific adaptive phenotypes to avoid or repair UV-B damage requires physiological and developmental acclimation to variable UV-B fluence. To gain a better understanding of the events in UV-B acclimation, we have analyzed a 5min to 6h time course of transcriptome and metabolome responses in irradiated and shielded leaves and in immature maize ears to unravel the systemic physiological and developmental responses in exposed and shielded organs. Within 10 min of UV-B exposure, transcripts are changed not only in irradiated leaves, but also in shielded tissues. The number of UV-B-regulated transcripts rapidly increases with exposure length. Interestingly, after 10 min of exposure, the overlap in transcriptome changes in irradiated and shielded organs is significant; while, after 6h of UV-B, most transcripts are specific for each tissue under study. We suggest that early events in all tissues may be elicited by common signaling pathways, while at longer exposure times responses become more organ-specific. Our working hypothesis is that mobile signaling molecules are generated in irradiated organs to elicit the initial responses. We found several metabolites that rapidly change after different treatments during the timecourse; myoinositol is one candidate metabolite based on its rapid modulation in all organs. There is also support from RNA profiling: after 1h UV B, transcripts for myoinositol-1-phosphate synthase are decreased in both irradiated and shielded leaves suggesting downregulation of biogenesis. PMID- 22105028 TI - Serine/threonine protein phosphatases: multi-purpose enzymes in control of defense mechanisms. AB - Depending on the threat to a plant, different pattern recognition receptors, such as receptor-like kinases, identify the stress and trigger action by appropriate defense response development. The plant immunity system primary response to these challenges is rapid accumulation of phytohormones, such as ethylene (ET), salicylic acid (SA), and jasmonic acid (JA) and its derivatives. These phytohormones induce further signal transduction and appropriate defenses against biotic threats. Phytohormones play crucial roles not only in the initiation of diverse downstream signaling events in plant defense but also in the activation of effective defenses through an essential process called signaling pathway crosstalk, a mechanism involved in transduction signals between two or more distinct, "linear signal transduction pathways simultaneously activated in the same cell." PMID- 22105029 TI - The phosphorylation state of chloroplast transit peptides regulates preprotein import. AB - Import of nuclear encoded proteins into chloroplast is an essential and well regulated mechanism. The cytosolic kinases STY8, STY17 and STY46 have been shown to phosphorylate chloroplast preprotein transit peptides advantaging the binding of a 14-3-3 dimer. Analyses of sty8 sty17 sty46 mutant plants revealed a role for the kinases in chloroplast differentiation, possibly due to lack of transit peptide phosphorylation. Moreover we could show that not only phosphorylation but also transit peptide dephosphorylation appears to be required for the fine regulation of the back-transport of nuclear encoded proteins to the chloroplast. PMID- 22105030 TI - Progress on trichome development regulated by phytohormone signaling. AB - Trichomes are specialized structures that develop from epidermal cells in the aerial parts of plants, and are an excellent model system to study all aspects of cell differentiation including cell fate determination, cell cycle regulation, cell polarity and cell expansion. The development of the trichome is a process of integration of both external signals and endogenous developmental programs. During recent years, molecular analysis of trichome development at different stages has been well studied, and through the mutant phenotypes and the function of corresponding genes, the underlying mechanism has been revealed in a first glimpse. This paper offers a mini-view on this integration process with emphasis on the effects of plant hormone signaling on trichome development in plants through GLABROUS INFLORESCENCE STEMS (GIS) family and subfamily genes. PMID- 22105031 TI - PhEXPA1, a Petunia hybrida expansin, is involved in cell wall metabolism and in plant architecture specification. AB - Expansins are wall-loosening proteins that induce wall stress relaxation and irreversible wall extension in a pH-dependent manner. Despite a substantial body of work has been performed on the characterization of many expansins genes in different plant species, the knowledge about their precise biological roles during plant development remains scarce. To yield insights into the expansion process in Petunia hybrida, PhEXPA1, an expansin gene preferentially expressed in petal limb, has been characterized. The constitutive overexpression of PhEXPA1 significantly increased expansin activity, cells size and organ dimensions. Moreover, 35S::PhEXPA1 transgenic plants exhibited an altered cell wall polymer composition and a precocious timing of axillary meristem development compared with wild-type plants. These findings supported a previous hypothesis that expansins are not merely structural proteins involved in plant cell wall metabolism but they also take part in many plant development processes. Here, to support this expansins dual role, we discuss about differential cell wall-related genes expressed in PhEXPA1 expression mutants and gradients of altered petunia branching pattern. PMID- 22105032 TI - Herbivore induced plant volatiles: their role in plant defense for pest management. AB - Plants respond to herbivory through different defensive mechanisms. The induction of volatile emission is one of the important and immediate response of plants to herbivory. Herbivore-induced plant volatiles (HIPVs) are involved in plant communication with natural enemies of the insect herbivores, neighboring plants, and different parts of the damaged plant. Release of a wide variety of HIPVs in response to herbivore damage and their role in plant-plant, plant-carnivore and intraplant communications represents a new facet of the complex interactions among different trophic levels. HIPVs are released from leaves, flowers, and fruits into the atmosphere or into the soil from roots in response to herbivore attack. Moreover, HIPVs act as feeding and/or oviposition deterrents to insect pests. HIPVs also mediate the interactions between the plants and the microorganisms. This review presents an overview of HIPVs emitted by plants, their role in plant defense against herbivores and their implications for pest management. PMID- 22105033 TI - Qualitative difference between "bulb" membranes and other vacuolar membranes. AB - "Bulb" is a mobile and complex structure appearing in vacuolar membrane of plant cell. We recently reported new fluorescent marker lines for bulbs and bulb-less mutants. We tried multicolor visualization of vacuolar membrane to show distinct segregation of bulb-positive protein (gammaTIP or AtVAM3) and bulb-negative protein (AtRab75). Unexpectedly, GFP-AtRab75 resulted to localize in bulb under the condition of co-expression with TagRFP-AtVAM3. The signal intensities of GFP AtRab75 and TagRFP-AtVAM3 were quantified and compared. The result indicates that TagRFP-AtVAM3 is concentrated in bulb than GFP-AtRab75. PMID- 22105034 TI - Distinct antimicrobial activities in aphid galls on Pistacia atlantica. AB - Gall-formers are parasitic organisms that manipulate plant traits for their own benefit. Galls have been shown to protect their inhabitants from natural enemies such as predators and parasitoids by various chemical and mechanical means. Much less attention, however, has been given to the possibility of defense against microbial pathogens in the humid and nutrient-rich gall environment. We found that the large, cauliflower-shaped, galls induced by the aphid Slavum wertheimae on buds of Pistacia atlantica trees express antibacterial and antifungal activities distinct from those found in leaves. Antibacterial activity was especially profound against Bacillus spp (a genus of many known insect pathogen) and against Pseudomonas aeruginosa (a known plant pathogen). Antifungal activity was also demonstrated against multiple filamentous fungi. Our results provide evidence for the protective antimicrobial role of galls. This remarkable antibacterial and antifungal activity in the galls of S. wertheimae may be of agricultural and pharmaceutical value. PMID- 22105035 TI - Meta-analysis of the expression profiles of the Arabidopsis ESCRT machinery. AB - The Endosomal Sorting Complex Required for Transport (ESCRT) machinery is a set of multi-protein complexes that are well conserved among all eukaryotes and mediate a remarkable array of cellular processes including late endosome/multivesicular body (MVB) formation, retroviral particle release, and membrane abscission during cytokinesis. While the molecular mechanisms underlying ESCRT function have been relatively well characterized in yeasts and mammals, far less is known about ESCRT in plants. In this study, we utilized publicly available microarray, massively parallel signature sequencing (MPSS) and proteome data sets in order to survey the expression profiles of many of the components of the Arabidopsis thaliana ESCRT machinery. Overall, the results indicate that ESCRT expression in Arabidopsis is highly dynamic across a wide range of organs, tissues and treatments, consistent with the complex interplay that likely exists between the spatial and temporal regulation of the ESCRT machinery and the diverse array of roles that ESCRT participates in during plant growth and development. PMID- 22105036 TI - [Theories in complementary medicine- "standstill" or "still: but slowly: progressing"?]. PMID- 22105037 TI - Phytodolor(r) in musculoskeletal disorders: re-analysis and meta-analysis. AB - BACKGROUND: Treatment of rheumatic or musculoskeletal disorders (MD) is multi disciplinary and includes herbal analgesics. Although already reviewed, no quantitative evaluation of efficacy and safety of the herbal combination Phytodolor(r) (STW1) is available. METHODS: We searched in databases and contacted authors and the manufacturer to identify randomized controlled trials (RCTs) examining STW1 in patients with MD. We made a reanalysis of raw data of eligible published and unpublished RCTs and pooled the results for meta-analysis according to Cochrane guidelines and intention-to-treat. Primary outcome measure was patient global assessment of efficacy, secondary outcome measure was pain at rest and on movement. Results were stratified according to treatment groups. RESULTS: Patient data of 11 RCTs were eligible for pooling. In the entire population, STW1 was significantly superior compared to placebo in patients' global assessment of efficacy (group difference for rating very good/good: 20%; placebo 48.9% and STW1 69.1%; p < 0.001; OR 0.43; 95% CI 0.28-0.65) and in the subpopulation 'other rheumatic diseases' (placebo 45.4%; STW1 72.3%; p < 0.001; OR 0.32; 95% CI 0.2-0.52), but not in the subpopulation 'gonarthrosis'. STW1 did not differ significantly compared to non-steroidal anti-inflammatory drugs (NSAIDs), neither in the entire population nor the subpopulations. Similar results were found for pain at rest and on movement. No serious adverse events (AE) but minor AE were reported (placebo 8.1%; STW1 14.2%; NSAIDs 18.9%). CONCLUSION: According to the analysed data, STW1 showed a better pain reduction than placebo in patients with pain due to MD, probably equivalent to NSAIDs, and was well tolerated. PMID- 22105038 TI - Traditional Chinese medicine in cancer care: a review of case reports published in Chinese literature. AB - BACKGROUND: Traditional Chinese Medicine (TCM) is widely used for cancer treatment in China. Many support its use in treatment for cancer, yet scientific evidence for the effect of TCM needs to be established. MATERIAL AND METHODS: In this review case reports on cancer patients treated by TCM therapies are included. Search runs were conducted in 4 main Chinese databases till December 2009. RESULTS: A total of 716 reports involving 1,198 cancer patients were identified and summarized. Top 5 of the reported cancers treated with TCM were lung cancer (14.44%; 173 patients), leukemia (14.11%; 169 patients), stomach cancer (10.85%; 130 patients), liver cancer (10.18%; 122 patients) and esophageal cancer (7.35%; 88 patients). In the majority of cases (66.44%; 772) combined treatments of Chinese and conventional medicine were applied. The use of herbal medicine was highly prevalent (98.50%; 1,168 patients), and the typical administration was an individually tailored treatment according to the pattern differentiation of symptoms (74.21%; 889 patients); the use of acupuncture was relatively rare (1.8%; 22 patients). Symptom improvement was the most frequently reported outcome (84.72%; 1,015 patients). Only 15 studies (2.1%) were structurally reported. Detailed information on patients' demography, pathologically confirmed diagnosis and safety was given in 275 (22.95%), 692 (57.76%) and 10 (0.83%) reports, respectively. CONCLUSION: The amount of information from case reports of TCM therapies in cancer is rich and can be valuable for the preliminary evaluation of TCM and for the planning of further clinical trials in cancer treatment. However, the quality of the reports was generally poor and we recommend that case reports should be published in a structured manner. PMID- 22105039 TI - Effectiveness of a herbal formula in women with menopausal syndrome. AB - BACKGROUND: Lady 4 is a combination of 4 natural components (evening primrose oil, damiana, ginseng, royal jelly) with a known history of traditional use for menopausal symptoms. OBJECTIVE: To study efficacy and safety of Lady 4 in women suffering from menopausal syndrome. METHODS: 120 women with menopausal symptoms were randomised into an experimental group treated with 2 capsules of Lady 4 daily and a control group treated with placebo. The outcome was measured by the Menopause Rating Scale II (MRS-II). RESULTS: There was a statistically significant improvement in the MRS-II score in both groups after 2 and 4 weeks of treatment, but the improvement was significantly better in the Lady 4 group (p < 0.001). 86.7% in the Lady 4 group and 56.7% in the placebo group rated the therapy success as 'much improved' or 'very much improved'. CONCLUSION: Lady 4 may be beneficial in the treatment of menopausal syndrome and can be used as a safe natural promoter of health and well-being in women during the menopausal transition. PMID- 22105040 TI - [Clinical research on anthroposophic medicine:update of a health technology assessment report and status quo]. AB - BACKGROUND AND OBJECTIVE: In 2005 a Health Technology Assessment (HTA) report analyzed efficacy, effectiveness, safety, utilization and costs of Anthroposophic Medicine (AM). After a recent referendum of the 'Swiss Population pro Complementary Medicine' (May 2009) this HTA report was updated. DESIGN: Update of the HTA report by a systematic review. METHODS: Methods corresponded to the existing HTA report and the guidelines of the Swiss Federal Office of Public Health. For clinical studies four databases and a specialized journal were searched, and extensive expert consultations were used. Studies were selected according to predefined inclusion criteria, data were extracted, and methodological quality was assessed individually. RESULTS: 70 new clinical studies were found. Altogether, 265 clinical studies investigated efficacy and effectiveness of AM: 38 randomized controlled trials, 36 prospective and 49 retrospective non-randomized controlled trials as well as 90 prospective and 52 retrospective trials without control groups. They investigated a wide spectrum of AM treatments in a multitude of diseases; the whole AM system in 38 trials, non pharmacological therapies in 10 trials, AM mistletoe products in cancer therapy in 133 trials, and other AM medication treatments in 84 trials. Most studies showed a positive result for AM. Methodological quality differed substantially; some studies showed major limitations, others were reasonably well conducted. Trials with better quality still showed a positive result. External validity was usually high. Side effects or other risks were rare and usually described to be mild or moderate. Studies regarding safety showed a good tolerability altogether. CONCLUSION: Trials of varying design and quality in a variety of diseases predominantly describe good clinical outcomes for AM, only marginal side effects, high satisfaction of patients with regard to results and safety and presumably slightly less costs. Further high-quality evaluations are desirable. PMID- 22105042 TI - Latest publications you should not miss. PMID- 22105041 TI - Brain ischemia and hypometabolism treated by ozone therapy. AB - BACKGROUND: Radiation-induced brain injury (RBI) and low-perfusion brain syndromes are mediated by ischemia and hypometabolism and have limited treatment options. Ozone therapy as treatment in vascular diseases has been described, but the effects on brain tissue have not been well documented. CASE REPORT: We describe a 75-year-old patient with vascular risk factors and meningioma who was treated with stereotactic radiosurgery. 14 months later the patient presented with progressive clinical impairment despite the use of acetylsalicylic acid and corticosteroids. Clinical and imaging evaluations before/after ozone therapy were done by magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT), and positron emission tomography (PET); performance status assessment was done using Barthel Index and World Health Organization/Eastern Cooperative Oncology Group Scale (WHO/ECOG Scale). Ozone therapy was performed by autohemotransfusion. RESULTS: Basal images showed brain areas with ischemia and hypometabolism compatible with ischemic processes and/or RBI. There were no changes in MRI or CT scan images following ozone therapy. However, improvements in brain perfusion and metabolism were demonstrable with SPECT and PET; they correlated with clinical development and performance status scales. CONCLUSION: This report supports our previous works about the effect of ozone therapy in cerebral blood flow, and it suggests the use of ozone therapy in ischemic and hypometabolic brain syndromes such as stroke or RBI. PMID- 22105043 TI - Supply-side and demand-side cost sharing in deregulated social health insurance: which is more effective? AB - Microeconomic theory predicts that if patients are fully insured and providers are paid fee-for-service, utilization of medical services exceeds the efficient level ('moral hazard effect'). In Switzerland, both demand-side and supply-side cost sharing have been introduced to mitigate this problem. Analyzing a panel dataset of about 160,000 adults, we find both types of cost sharing to be effective in curtailing the use of medical services. However, when moral hazard mitigation is traded off against risk selection, the minimum-deductible, supply side cost sharing option ranks first, followed by the medium-deductible demand side alternative, making the supply-side option somewhat more effective. PMID- 22105044 TI - Microsurgical free flap transfer in previously irradiated and operated necks: feasibility and safety. AB - OBJECTIVES: Microsurgery is difficult to perform in necks that have been previously irradiated and operated upon because of the limited availability of recipient vessels. The objective of this study was to clarify the feasibility and safety of performing microsurgery in necks that are scarred and fibrous owing to previous treatment. METHODS: Twenty patients whose necks were previously irradiated and operated upon and who underwent free tissue transfer were included in this study. All patients had been previously administered an average of 60.7 (range, 30-95)Gy of radiotherapy. Thirteen patients had undergone hemilateral neck dissections, 5 patients had undergone bilateral neck dissections, 8 patients had undergone (pharyngo)laryngectomies, and 10 patients had undergone prior flap transfer. The success rate of microsurgery and the selection of recipient vessels were examined. RESULTS: All recipient vessels could be adopted in the neck field without vessel grafting. One patient developed necrosis of the flap, which was salvaged with retransfer of another flap after trimming the same cervical vessels. For the remaining 19 patients, free tissue transfers were successful. CONCLUSIONS: Suitable recipient vessels are residual and available even in the previously irradiated and operated neck field. When performed properly, free tissue transfer in the previously treated neck is not as risky a surgery as was generally believed. PMID- 22105045 TI - Hip artroplasty: a transient reason not to be pregnant. AB - Metal implants corrode and release metal ions, cobalt and chromium, which, in turn, may cause systemic toxicity, mostly in the first few months from implantation of metal-on-metal hip arthroplasty. At the time of delivery, the placenta reduces the passage of cobalt and chromium ions released from metal-on metal prosthesis. From a biomechanical view point, hip replacement should not be considered a contraindication for pregnancy or for spontaneous delivery, and does not seem to have any negative effects in terms of risk of dislocation, loosening, fracture, or revision surgery, neither negative effects on clinical and functional outcomes. The long-term biological consequences of exposure to Co-Cr particles and ions remain largely unknown. PMID- 22105046 TI - Changing practices in the surgical management of hyperparathyroidism - a 10-year review. AB - AIM: Parathyroid surgery has undergone a paradigm shift over the last decade, with a move from traditional bilateral neck exploration to minimally invasive parathyroidectomy (MIP), and increasing reliance on pre- and intra-operative localization of overactive glands. We aimed to assess changing surgical practices and their impact on the management of parathyroid disease in a tertiary referral centre in the West of Ireland. METHODS: A retrospective cohort analysis of those patients undergoing a surgical intervention for parathyroid disease in the period between 1999 and 2009 in our centre was carried out. Data was analysed using PASW (v18) software. RESULTS: 248 procedures were performed, increasing from an annual rate of 6 in 1999 to 45 in 2009. 129 procedures were completed by minimally invasive means, following the introduction of MIP in 2003. Single-gland disease accounted for 87% of cases (n = 216) with carcinomas in 2 patients (0.8%). Pre operative localization had disappointing diagnostic value, with high false negative rates for both ultrasound (37.3%) and Sestamibi Scanning (35.81%). Intra operative adjuncts were more helpful, with intra-operative Parathyroid hormone monitoring facilitating curative resection of adenomas in 94.03% at 10 min. Median length of post-operative stay has significantly decreased from 6 days in 1999 to 1 night only in 2009 (p < 0.01, ANOVA). Those patients undergoing MIP had shorter stay than the open group (1.71 days -v-4.73, p = 0.003,t-test). CONCLUSION: The practice in our centre has shifted to a less invasive approach. Increased utilisation of intra-operative adjuncts has facilitated this change, and resulted in favourable changes in length of stay, extent of dissection, and number of patients treated. PMID- 22105047 TI - Effects of a combined resistance-plyometric training program on muscular strength, running economy, and Vo2peak in division I female soccer players. AB - Resistance and plyometric training programs have demonstrated consistent improvements in running economy (RE) in trained and untrained adults in the absence of improvements in maximal oxygen consumption. The purpose of this study was to investigate the effect of a 10-week combined resistance-plyometric training program on the RE and V[Combining Dot Above]O2max in female soccer players. Fifteen Division 1A female soccer players (age 19.0 +/- 0.7 years; height 1.67 +/- 0.1 m; weight 61.7 +/- 8.1 kg) performed a treadmill test for V[Combining Dot Above]O2max and RE at the end of a competitive season (PRE) and after a 10-week training program (POST). Isometric strength was measured in knee flexion and extension. Resistance training was conducted 2 d.wk on nonconsecutive days; plyometric training was conducted separately on different nonconsecutive days. Eleven subjects were included in the PRE-POST analysis (age 19.0 +/- 0.8 years; height 1.67 +/- 0.5 m; weight 59.9 +/- 6.7 kg). Descriptive statistics were compared using analysis of variance with repeated measures with a Bonferroni adjustment, and significance was set at p < 0.05. A significant increase occurred after training in the V[Combining Dot Above]O2peak (10.5%; p = 0.008), time to fatigue (6.9%; p = 0.017), and interpolated maximal speed (3.6%; p = 0.016), despite there being a decrease in the maximal respiratory exchange ratio (2.9%; p = 0.001). There was no significant change in the RE at 9 km.h; however, there was a significant decrease in the percentage of the V[Combining Dot Above]O2peak at 9 km.h (-5.6%; p = 0.02). Maximal isometric strength of knee flexors and extensors did not change. The results suggest a plyometric-agility training program may increase the V[Combining Dot Above]O2peak in female soccer players; however, the effect on RE was equivocal. PMID- 22105048 TI - Reproducibility and concurrent validity of hip joint angle test for estimating hamstring flexibility in recreationally active young men. AB - The purposes of this study were twofold: (a) to examine the test-retest reproducibility and concurrent validity of the horizontal hip joint angle test (H HJA) and vertical hip joint angle test (V-HJA) for estimating hamstring flexibility measured with an inclinometer during the passive straight-leg raise test (PSLR) and (b) to determine whether the H-HJA cutoff scores may be used for V-HJA for the detection of short hamstring flexibility in active recreationally young adults. Fifty young men underwent the H-HJA, V-HJA, and PSLR on the right and left legs 3 times in a randomized order with a 4-week interval between trials under a controlled laboratory environment. Reproducibility was examined using coefficient of variation (CV) and intraclass correlation coefficient (ICC3,1) and their respective confidence limits. Regression and kappa correlation analyses were performed to examine the association of H-HJA and V-HJA with the PSLR test, and the 95% limits of agreement between H-HJA and V-HJA were calculated to check if there were differences in the raising scores. The results demonstrated acceptable reproducibility measures for the H-HJA (4.12% CV; 0.93 ICC), V-HJA (4.99% CV; 0.92 ICC), and PSLR (4.83% CV; 0.88 ICC). The H-HJA (R = 0.62) and V HJA (R = 0.63) results were significantly associated with those of the PSLR. The 95% limits of agreement between the H-HJA and V-HJA reported systematic bias (+7.12 cm) and a wide 95% random error ( +/-13.72 cm). This study concluded that the test-retest reproducibility of the H-HJA, V-HJA, and PSLR is acceptable and that the validity of H-HJA and V-HJA is moderate. Furthermore, the H-HJA cutoff scores should not be used for V-HJA for the detection of short hamstring muscles in young adults. PMID- 22105049 TI - Modeling and relationship of respiratory exchange ratio to athletic performance. AB - Previous research has related the results of tests of maximum aerobic capacity to performance for endurance athletes. These results are often only able to predict the running velocity of races such as the marathon. This investigation sought to determine the absolute V[Combining Dot Above]O2 at various respiratory exchange ratio (RER) values (0.85, 0.90, 0.95, 1.0, 1.05, and 1.10) by using a third-order polynomial regression to model the physiological responses for V[Combining Dot Above]O2 and RER obtained from an assessment of maximum aerobic capacity. The V[Combining Dot Above]O2 determined was subsequently correlated to race performance. The participants in the study were selected from a population of National Collegiate Athletic Association Division 1 crosscountry runners (male n = 7, female n = 7, age 20.5 +/- 0.9 years; height 170.3 +/- 8.2 cm; weight 59.7 +/- 8.7 kg; V[Combining Dot Above]O2max 57.0 +/- 7.8 ml O2.kg.min). Third-order regression analysis resulted in strong curve fitting between the variables (r = 0.949 +/- 0.03). Partial correlations (controlled for weight) were used to assess the relationship between oxygen consumption at the desired points of RER and race performance. The partial correlations revealed that the absolute oxygen consumptions at all RER points of interest were significantly correlated to race performance (r > 0.740, p < 0.01). There was a significant difference in the strength of the correlations for the points RER 0.95 (t = 2.68957, p = 0.01), 1.0 (t = 2.18516, p = 0.03), and 1.05 (t = 1.85668, p = 0.04) and the correlations found for RER 0.85. After converting the oxygen consumption at the RER points to estimated horizontal running speeds, only the estimate at RER 1.05 was not statistically different from the actual speed achieved in the culminating XC race. It can be suggested based upon these results that coaches of collegiate crosscountry runners who engage in metabolic testing of athletes examine the estimated running pace at RER 1.05 to gain an insight into a runner's potential. PMID- 22105050 TI - Prior eccentric exercise reduces v[combining dot above]o2peak and ventilatory threshold but does not alter movement economy during cycling exercise. AB - Exercise-induced muscle damage (EIMD) has been shown to reduce force production and result in delayed-onset soreness and pain in the damaged muscle(s). Cycling in the presence of EIMD reduces peak power output and time-trial performance. However, its effect on peak aerobic capacity has not been widely studied. The purpose of this study was to examine the impact of EIMD targeted specifically to the quadriceps muscle group on peak oxygen consumption (V[Combining Dot Above]O2peak) during cycling. Ten participants (4 men, 6 women) completed a V[Combining Dot Above]O2peak test on a cycle ergometer before and 48 hours after performing 24 eccentric contractions with their right and left quadriceps with a weight equal to 120% of 1-repetition maximal concentric strength (1RM). The EIMD was assessed using 1RM, and muscle soreness was assessed using a 100-mm visual analog scale. The presence of EIMD was confirmed by a 9% reduction in 1RM (p = 0.0001) and increased ratings of soreness from 2.4 +/- 2.1 to 24.6 +/- 10.8 mm (p = 0.001). The V[Combining Dot Above]O2peak was reduced from 46.2 +/- 9.7 to 41.8 +/- 10.7 ml.kg.min (10%; p = 0.01) with participants terminating exercise at lower heart rates 191 +/- 9 vs. 186 +/- 10 b.min (p = 0.02) and power output 248 +/- 79 vs. 238 +/- 81 W (p = 0.02) after EIMD. Additionally, ventilatory threshold decreased from 34.2 +/- 7.8 to 30.5 +/- 8.5 ml.kg.min (11%; p = 0.031). Despite the reduction in V[Combining Dot Above]O2peak, cycling economy (p = 0.17) did not differ pre-EIMD and post-EIMD. These findings indicate that EIMD reduced peak aerobic exercise capacity to an extent that could result in meaningful reductions in exercise performance. The reduction is likely attributable to a combination of reduced strength, earlier accumulation of lactic acid, and heightened muscle pain during exercise. PMID- 22105051 TI - Occlusion training increases muscular strength in division IA football players. AB - The purpose of this study was to investigate the effectiveness of 4 weeks of low intensity resistance training with blood-flow occlusion on upper and lower body muscular hypertrophy and muscular strength in National Collegiate Athletic Association Division IA football players. There were 32 subjects (average age 19.2 +/- 1.8 years) who were randomized to an occlusion group or control group. The athletes performed 4 sets of bench press and squat in the following manner with or without occlusion: 30 repetitions of 20% predetermined 1 repetition maximum (1RM), followed by 3 sets of 20 repetitions at 20% 1RM. Each set was separated by 45 seconds. The training duration was 3 times per week, after the completion of regular off-season strength training. Data collected included health history, resting blood pressure, pretraining and posttraining bench press and squat 1RM, upper and lower chest girths, upper and lower arm girths, thigh girth, height, and body mass. The increases in bench press and squat 1RM (7.0 and 8.0%, respectively), upper and lower chest girths (3 and 3%, respectively), and left upper arm girth were significantly greater in the experiment group (p < 0.05). Occlusion training could provide additional benefits to traditional strength training to improve muscular hypertrophy and muscular strength in collegiate athletes. PMID- 22105052 TI - The components of the jumps in expert and intermediate water polo players. AB - The aim of this study is to show the different multifactorial structure of jump capacity in expert and intermediate water polo players, using the principal component analysis (PCA) and multiple regression. We adopted the Teknotrain3, an instrument that enabled us to measure maximal height out of the water and dynamic components such as force, velocity, and power. The experts showed high levels of power (t = 2.75, p < 0.04) and velocity (t = 4.4, p < 0.007) with a considerable maximal height (mh) (t = 2.73, p < 0.04), whereas the intermediate players showed only an average velocity and mh and an inverse relation between power, velocity, and temporal variability in jumps, r = -0.89 (p <0.01) and r = -0.94 (p < 0.01). The intermediate players need a physical preparation of resistance training aimed at developing rapid rate of force development (RFD) and the maximal dynamic force and power and reducing temporal variability. PMID- 22105053 TI - Cardiovascular responses to isometric hand grip vs. relaxed hand grip in sustained cycling efforts. AB - Peripheral isometric contractions may lead to enhanced performance. Previous research using hand grip protocols indicates increased stabilization and peak power outputs. Research is lacking with the grip vs. no-grip protocol during sustained efforts. The purpose of this study is to determine cardiovascular reactions (i.e., heart rate [HR], blood pressure [BP], and rate pressure product [RPP]) during sustained cycling via an isometric and relaxed hand grip. Nine (n = 9) recreational cyclists participated in this study. After signing a medical and physical readiness questionnaire, the subjects were randomly assigned to 1 of 2 different protocols. Preexercising values of the HR (beats per minute), BP (miilimeters of mercury), height (centimeters), weight (kilograms), and age (years) were assessed before testing. A Monark bicycle ergometer was used for testing. Grip was substantiated through the use of a hand grip dynamometer at 20 kg of tension. Protocol 1 used an isometric "Hand Grip" scenario at 150 W for 20 minutes. Protocol 2 used a "Relaxed Hand Grip" at the same power and time. During the 20-minute exercise test, HR (POLAR), BP (stethoscope and sphygmomanometer), and calculated RPP (HR * systolic BP [SPB]/100) were recorded every minute. Statistical measures included mean and SDs between protocols, and dependent samples t-tests were used to examine differences between grip and no-grip protocols. At an alpha of <=0.05, SBP did show a significant increase when using no grip, 161.4 (5.1) mm Hg vs. grip, 154.1 (6.6) mm Hg. However, rate pressure product and heart rate showed no significant differences between protocols. Our data suggested that the use of an isometric hand grip is transient and diminishes over time. PMID- 22105054 TI - Nutritional, physiological, and perceptual responses during a summer ultraendurance cycling event. AB - Despite the rapid growth of mass participation road cycling, little is known about the dietary, metabolic, and behavioral responses of ultraendurance cyclists. This investigation describes physiological responses, perceptual ratings, energy balance, and macronutrient intake of 42 men (mean +/- SD; age, 38 +/- 6 years; height, 179.7 +/- 7.1 cm; body mass, 85.85 +/- 14.79 kg) and 6 women (age, 41 +/- 4 years; height, 168.0 +/- 2.9 cm; body mass, 67.32 +/- 7.21 kg) during a summer 164-km road cycling event. Measurements were recorded 1 day before, and on the Event Day (10.5 hours) at the start (0 km), at 2 aid stations (52 and 97 km), and at the finish line (164 km). The ambient temperature was >39.0 degrees C during the final 2 hours of exercise. The mean finish times for men (9.1 +/- 1.2 hours) and women (9.0 +/- 0.2 hours) were similar, as were mean gastrointestinal temperature (TGI), 4 hydration biomarkers, and 5 perceptual (e.g., thermal, thirst, pain) ratings. Male cyclists consumed enough fluids on the Event Day (5.91 +/- 2.38 L; 49% water) to maintain body mass within 0.76 kg, start to finish, despite a sweat loss of 1.13 +/- 0.54 L.h(-1) and calculated energy expenditure of 3,115 kcal.10.5.h(-1). However, men voluntarily underconsumed food energy (deficit of 2,594 kcal, 10.9 MJ) and specific macronutrients (carbohydrates, 106 +/- 48 g; protein, 8 +/- 7 g; and sodium, 852 +/- 531 mg) between 0530 and 1400 hours. Also, a few men exhibited extreme final values (i.e., urine specific gravity of 1.035-1.038, n = 5; body mass loss >4 kg, n = 2; T(GI), 39.4 and 40.2 degrees C). We concluded that these findings provide information regarding energy consumption, macronutrient intake, hydration status, and the physiological stresses that are unique to ultraendurance exercise in a hot environment. PMID- 22105055 TI - Characterization of the differences in strength and power between different levels of competition in rugby union athletes. AB - Levels of strength and power have been used to effectively discriminate between different levels of competition; however, there is limited literature in rugby union athletes. To assess the difference in strength and power between levels of competition, 112 rugby union players, including 43 professionals, 19 semiprofessionals, 32 academy level, and 18 high school level athletes, were assessed for bench press and box squat strength, and bench throw, and jump squat power. High school athletes were not assessed for jump squat power. Raw data along with data normalized to body mass with a derived power exponent were log transformed and analyzed. With the exception of box squat and bench press strength between professional and semiprofessional athletes, higher level athletes produced greater absolute and relative strength and power outputs than did lower level athletes (4-51%; small to very large effect sizes). Lower level athletes should strive to attain greater levels of strength and power in an attempt to reach or to be physically prepared for the next level of competition. Furthermore, the ability to produce high levels of power, rather than strength, may be a better determinate of playing ability between professional and semiprofessional athletes. PMID- 22105056 TI - Online video-based resistance training improves the physical capacity of junior basketball athletes. AB - Junior basketball athletes require a well-designed resistance training program to improve their physical development. Lack of expert supervision and resistance training in junior development pathways may be overcome by implementing an online video-based program. The aim of this study was to compare the magnitude of improvement (change) in physical performance and strength and functional movement patterns of junior basketball athletes using either a fully supervised or an online video-based resistance training program. Thirty-eight junior basketball athletes (males, n = 17; age, 14 +/- 1 year; height, 1.79 +/- 0.10 m; mass, 67 +/ 12 kg; females, n = 21; age, 15 +/- 1 year; height, 1.70 +/- 0.07 m; mass, 62 +/ 8 kg) were randomly assigned into a supervised resistance training group (SG, n = 13), video training group (VG, n = 13) or control group (CG, n = 12) and participated in a 6-week controlled experimental trial. Pre- and posttesting included measures of physical performance (20-m sprint, step-in vertical jump, agility, sit and reach, line drill, and Yo-Yo intermittent recovery level 1), strength (15 s push-up and pull-up), and functional movement screening (FMS). Both SG and VG achieved 3-5% +/- 2-4% (mean +/- 90% confidence limits) greater improvements in several physical performance measures (vertical jump height, 20-m sprint time, and Yo-Yo endurance performance) and a 28 +/- 21% greater improvement in push-up strength compared with the CG. The SG attained substantially larger gains in FMS scores over both the VG (12 +/- 10%) and CG (13 +/- 8%). Video-based training appears to be a viable option to improve physical performance and strength in junior basketball athletes. Qualified supervision is recommended to improve functional movement patterns in junior athletes. PMID- 22105057 TI - Automated quantification of mitral inflow and aortic outflow stroke volumes by three-dimensional real-time volume color-flow Doppler transthoracic echocardiography: comparison with pulsed-wave Doppler and cardiac magnetic resonance imaging. AB - BACKGROUND: The aim of this study was to compare the feasibility, accuracy, and reproducibility of automated quantification of mitral inflow and aortic stroke volumes (SVs) using real-time three-dimensional volume color-flow Doppler transthoracic echocardiography (RT-VCFD), with cardiac magnetic resonance (CMR) imaging as the reference method. METHODS: In 44 patients (86% of the screened patients) without valvular disease, RT-VCFD, CMR left ventricular short-axis cines and aortic phase-contrast flow measurement and two-dimensional (2D) transthoracic echocardiography (TTE) were performed. Dedicated software was used to automatically measure mitral inflow and aortic SVs with RT-VCFD. CMR total SV was calculated using planimetry of short-axis slices and aortic SV by phase contrast imaging. SVs by 2D TTE were computed in the conventional manner. RESULTS: The mean age of the included patients was 40 +/- 16 years, and the mean left ventricular ejection fraction was 61 +/- 9%. Automated flow measurements were feasible in all study patients. Mitral inflow SV by 2D TTE and RT-VCFD were 85.0 +/- 21.5 and 94.5 +/- 22.0 mL, respectively, while total SV by CMR was 95.6 +/- 22.7 mL (P < .001, analysis of variance). On post hoc analysis, mitral inflow SV by RT-VCFD was not different from the CMR value (P = .99), while SV on 2D TTE was underestimated (P = .001). The respective aortic SVs were 82.8 +/- 22.3, 94.2 +/- 22.3, and 93.4 +/- 24.6 mL (P < .001). On post hoc analysis, aortic SV by RT VCFD was not different from the CMR value (P = .99), while SV on 2D TTE was underestimated (P = .006). The interobserver variability for SV measurements was significantly worse for 2D TTE compared with RT-VCFD. CONCLUSIONS: RT-VCFD imaging with an automated quantification algorithm is feasible, accurate, and reproducible for the measurement of mitral inflow and aortic SVs and is superior to manual 2D TTE-based measurements. The rapid and automated measurements make this technique practical in the clinical setting to measure and report SVs routinely where the acoustic window will allow it, which was 86% in our study. PMID- 22105058 TI - [The financial and learning and growth perspectives of the balanced scorecard in public institutions: application in the clinical laboratory]. PMID- 22105059 TI - [As simple as recalling the consequences! Intentional memory as a health resource in the prevention of traffic accident risk]. PMID- 22105060 TI - [Epidemiology and risk factors associated with religious pilgrimage to Saudi Arabia. Results of a prospective cohort 2008-2009]. AB - INTRODUCTION: Religious pilgrimage to Saudi Arabia, or Hajj, is a basic tenet of the Islamic doctrine and, after Ramadan, annually represents the largest human concentration (with up to 5% of from the EU) around the world. Such a gathering entails health risks. METHODS: A prospective observational study was conducted of a cohort of pilgrims attended for pre-travel preventive activities in the North Metropolitan International Health Unit (Santa Coloma de Gramenet, Barcelona, Spain) from 2009-2010. RESULTS: A total of 193 pilgrims were assessed and 135 (69.9%) were men. Their mean age (SD) was 37.1 (16.9) years. Among the pilgrims, 176 (91.2%) were immigrants, mainly from Pakistan (54.9%), Morocco (29%), Bangladesh (4.1%) or other countries (7.2%). The pilgrims stayed in Saudi Arabia a mean (SD) of 16.3 (9.2) days. Eighty (41.5%) opted for the 1 month-long pilgrimage (Hajj) and 113 (58.5%) for the shorter Umra. One or more pathological antecedent was recorded in 29 (15%). Vaccination coverage was >75% for tetanus diphtheria, pneumococcal and quadrivalent meningitis but was only 70.4% for influenza. After returning, 41 (13.5%) pilgrims reported some health problem; of these, 61% were respiratory tract symptoms. The risk factors independently correlated with the presence of diseases was the number of days in Saudi Arabia (OR=1.06; 95% CI: 1.01-1.11) and taking part in the Hajj compared with the Umra (OR=1.08; 95% CI: 1.07-1.12). CONCLUSIONS: Religious pilgrims from Spain to Saudi Arabia are mainly young and healthy. Those with longer stays abroad contracted a higher number of diseases. PMID- 22105061 TI - Comparison of buprenorphine treatment for opioid dependence in 3 settings. AB - Although use of buprenorphine in the treatment of opioid dependence is expected to continue to increase, little is known about the optimal setting for providing the medical and psychosocial care required with buprenorphine pharmacotherapy. OBJECTIVE: This study compared buprenorphine therapy delivered in 3 distinct treatment settings: an opioid treatment program (OTP) offering individual counseling, a group counseling program utilizing the manualized Matrix Model (MMM) of cognitive-behavioral treatment, and a private clinic setting mirroring standard medical management for buprenorphine treatment provided specifically at a psychiatrist's private practice (primary care setting). METHOD: Participants were inducted on buprenorphine and provided with treatment over a 52-week study duration. All participants were scheduled for weekly treatment visits for the first 6 study weeks and 2 sites reduced treatment to monthly visits for dispensing of medication and psychosocial counseling. Outcomes include opioid use, participant retention in treatment, and treatment participation. RESULTS: Participants presenting for treatment at the sites differed only by race/ethnicity and opioid use did not differ by site. Retention differed by treatment site, with the number of participants who stayed in the study until the end of 20 weeks significantly associated with treatment site. The mean number of minutes spent in each individual counseling session also differed by site. Although no difference in opioid use by treatment site was found, results document a significant association between opioid use and buprenorphine dose. DISCUSSION: These results show some differences by treatment site, although the similarity and relative ease in which the sites were able to recruit participants for treatment with buprenorphine, and minor implementation problems reported suggests the feasibility of treatment with buprenorphine across various treatment settings. CONCLUSION: Similar rates of continued opioid use across study sites and few qualitative reports of problems indicates that treatment with buprenorphine and associated psychosocial counseling are safe and relatively easy to implement in a variety of treatment settings. PMID- 22105062 TI - Prescription opioid misuse: characteristics of earliest and most recent memory of hydromorphone use. AB - OBJECTIVES: Prescription opioid use is highly prevalent and a major physician concern. However, little is known about how individuals initiate into use of these medications or how they use them later in life. Hydromorphone is a medication of particular interest given its subjective similarities to heroin and tendency to be misused by illicit opioid users. The purpose of this study was to evaluate the characteristics of initial, and more recent, hydromorphone use occasions as remembered by a population of individuals in treatment for their opioid use. METHODS: Seventy-eight clients enrolled in low-threshold methadone maintenance treatment were interviewed regarding their earliest and most recent uses of hydromorphone. RESULTS: Hydromorphone was first used after trying many different substances (eg, tobacco, alcohol, hallucinogens, powder cocaine). Two thirds of the sample reported initially using hydromorphone without a prescription. Participants who initially used hydromorphone without a prescription reported using for different reasons (ie, to get high, curiosity vs manage pain), via different routes of administration (ie, injection vs orally), and were more likely to co-use other substances, than those whose earliest hydromorphone use was prescribed. However, these 2 subgroups did not differ greatly during their most recent use occasion (ie, the majority reported using to avoid withdrawal, via injection; almost 50% reported co-use with other substances). CONCLUSIONS: There was considerable variability in characteristics of hydromorphone use initiation among individuals enrolled in low-threshold methadone maintenance treatment. However, later use of hydromorphone was remarkably consistent across individuals and shares many characteristics previously documented for heroin use. Additional investigations into hydromorphone are warranted, particularly given previous findings regarding the prevalence of nonmedical use of this drug and its similarities to heroin. PMID- 22105063 TI - Condom use during last sexual contact and last 30 days in two samples of Caribbean military personnel. AB - Condom use during last sexual contact is a survey measure that may be used to inform monitoring and evaluation indicators of recent condom use in populations at risk for HIV infection and other sexually transmitted infections, such as the uniformed services. The authors tested for differences in condom use measures that were fielded within separate Biological and Behavioral Surveillance Surveys conducted in the armed forces of two separate nations: the Dominican Republic and Belize. Both surveys included measures of condom use during last sexual contact with specified partners and both surveys included the Risk Behavior Assessment (RBA), which measures specific sexual acts and condom use frequency during a specified time period. In both samples, more than 40% of respondents who reported condom use during last sexual contact with a regular partner also reported engaging in unprotected sex when screened with the RBA. Furthermore, more than 60% of respondents who reported condom use during last sexual encounter with a commercial sex worker also reported engaging in unprotected sex when screened with the RBA. The results carry implications for monitoring and evaluation indicators of large-scale HIV prevention programs. The authors recommend that, when feasible, more in-depth instruments such as the RBA be considered to measure recent condom use in populations of uniformed services personnel. PMID- 22105064 TI - Depression, anxiety, and symptom profiles among female and male victims of sexual violence. AB - Sexual violence is a serious public health problem that has been associated with negative mental and physical health outcomes. Few existing studies have examined the prevalence and patterns of adverse mental health among victims of sexual violence using data from nationally representative samples of U.S. adults. The main objectives of this study were to identify patterns in the associations between sexual violence victimization and depression and anxiety (DA) symptoms using data from the sexual violence and DA Behavioral Risk Factor Surveillance System (BRFSS) modules. Stratified multivariate logistic regression models were conducted to test the associations between sexual violence victimization and DA controlling for demographic characteristics. Multiple stratified MANOVA models were used to detect the effect of sexual violence victimization on DA symptoms while controlling for key demographic characteristics. Among all 61,187 participants, more than 5% (n = 3,240) were victims of sexual violence, out of which 18.82% reported being diagnosed with depression, 8.37% reported an anxiety disorder, and 28.28% reported being diagnosed with DA disorder. Victims of sexual violence reported significantly higher number of days when they had trouble concentrating, sleep difficulties, poor appetite, little interest or pleasure in activities, blamed themselves for personal failure, felt depressed, and had little energy. The present study highlights the importance of collecting nationally representative data from victims of sexual violence and extends previous findings from clinically based studies. This study also serves as an example of an analytic approach that addresses a public health priority area by drawing on data from multiple topic-specific BRFSS modules. PMID- 22105065 TI - Preliminary findings exploring the social determinants of Black males' lay health perspectives. AB - The unequal discussion of Black males' health is a pressing social problem. This study addressed Black males' lay perspectives regarding their health, illness, and mortality, with attention to the determinants of men's health, prevention, lifestyle, and opportunities for health promotion using an exploratory/qualitative research methodology. Participants were 68 Black males aged 15 to 68 years, with an average age of 44 years (SD = 14.5). The narratives represented a complex interplay of biopsychosocial factors, ranging from intrapersonal attitudes, interpersonal experiences to discussions about community and public policy injustices. Five prominent themes emerged: (a) lack of chronic disease awareness, (b) fatalism, (c) fear and anxiety of academic-medical settings, (d) hyperactive masculinity fatigue, and (e) the gay-straight divide. The term Tired Black Male Health syndrome was coined in the forum. Implications of these findings are discussed in the context of culturally relevant strategies for improving Black male community health engagement. PMID- 22105066 TI - Are men more intuitive when it comes to eating and physical activity? AB - The purpose of this study was to determine where men fall on the motivation continuum based on intuitive eating status and if motivation for physical activity and intuitive eating are correlated. Results indicate that being an intuitive eater was associated with a lower body mass index. In terms of demographic variables, as age increased, intuitive eating status decreased and body mass index increased. Men scored high on the antidieting and self-care subscales of the Intuitive Eating Scale. Men who were classified as intuitive eaters scored higher on the external and introjected regulation of the Behavioral Regulation in Exercise Questionnaire but no significant differences were reported by eating status and the identified and intrinsic motivation subscales. Intuitive eating holds promise as a weight management and weight loss tool for men. Intuitive eating may also influence initial motivation for physical activity for men. PMID- 22105067 TI - Depression over the adult life course for African American men: toward a framework for research and practice. AB - Rarely are within-group differences among African American men explored in the context of mental health and well-being. Though current conceptual and empirical studies on depression among African American men exists, these studies do not offer a framework that considers how this disorder manifests over the adult life course for African American men. The purpose of this article is to examine the use of an adult life course perspective in understanding the complexity of depression for African American men. The proposed framework underscores six social determinants of depression (socioeconomic status, stressors, racial and masculine identity, kinship and social support, self-esteem and mastery, and access to quality health care) to initiate dialogue about the risk and protective factors that initiate, prolong, and exacerbate depression for African American men. The framework presented here is meant to stimulate discussion about the social determinants that influence depression for African American men to and through adulthood. Implications for the utility and applicability of the framework for researchers and health professionals who work with African American men are discussed. PMID- 22105068 TI - Delivery of bioactive molecules to the mitochondrial genome using a membrane fusing, liposome-based carrier, DF-MITO-Porter. AB - Mitochondrial dysfunction has been implicated in a variety of human diseases. It is now well accepted that mutations and defects in the mitochondrial genome form the basis of these diseases. Therefore, mitochondrial gene therapy and diagnosis would be expected to have great medical benefits. To achieve such a strategy, it will be necessary to deliver therapeutic agents into mitochondria in living cells. We report here on an approach to accomplish this via the use of a Dual Function (DF)-MITO-Porter, aimed at the mitochondrial genome, so-called mitochondrial DNA (mtDNA). The DF-MITO-Porter, a nano carrier for mitochondrial delivery, has the ability to penetrate the endosomal and mitochondrial membranes via step-wise membrane fusion. We first constructed a DF-MITO-Porter encapsulating DNase I protein as a bioactive cargo. It was expected that mtDNA would be digested, when the DNase I was delivered to the mitochondria. We observed the intracellular trafficking of the carriers, and then measured mitochondrial activity and mtDNA-levels after the delivery of DNase I by the DF MITO-Porter. The findings confirm that the DF-MITO-Porter effectively delivered the DNase I into the mitochondria, and provides a demonstration of its potential use in therapies that are selective for the mitochondrial genome. PMID- 22105069 TI - Mutagenesis of human immunodeficiency virus reverse transcriptase p51 subunit defines residues contributing to vinylogous urea inhibition of ribonuclease H activity. AB - The vinylogous urea, NSC727447, was proposed to allosterically inhibit ribonuclease H (RNase H) activity of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) by interacting with the thumb subdomain of its non catalytic p51 subunit. Proximity of the p51 thumb to the p66 RNase H domain implied that inhibitor binding altered active site geometry, whereas protein footprinting suggested a contribution from alpha-helix I residues Cys-280 and Lys 281. To more thoroughly characterize the vinylogous urea binding site, horizontal alanine scanning mutagenesis between p51 residues Lys-275 and Thr-286 (comprising alpha-helix I and portions of the neighboring alphaH/alphaI and alphaI/alphaJ connecting loops) was combined with a limited vertical scan of Cys-280. A contribution from Cys-280 was strengthened by our observation that all substitutions at this position rendered selectively mutated, reconstituted p66/p51 heterodimers ~45-fold less sensitive to inhibition. An ~19-fold reduced IC(50) for p51 mutant T286A coupled with a 2-8-fold increased IC(50) when intervening residues were substituted supports our original proposal of p51 alpha helix I as the vinylogous urea binding site. In contrast to these allosteric inhibitors, mutant enzymes retained equivalent sensitivity to the natural product alpha-hydroxytropolone inhibitor manicol, which x-ray crystallography has demonstrated functions by chelating divalent metal at the p66 RNase H active site. Finally, reduced DNA strand-transfer activity together with increased vinylogous urea sensitivity of p66/p51 heterodimers containing short p51 C terminal deletions suggests an additional role for the p51 C terminus in nucleic acid binding that is compromised by inhibitor binding. PMID- 22105070 TI - Histidine 66 in Escherichia coli elongation factor tu selectively stabilizes aminoacyl-tRNAs. AB - The universally conserved His-66 of elongation factor Tu (EF-Tu) stacks on the side chain of the esterified Phe of Phe-tRNA(Phe). The affinities of eight aminoacyl-tRNAs were differentially destabilized by the introduction of the H66A mutation into Escherichia coli EF-Tu, whereas Ala-tRNA(Ala) and Gly-tRNA(Gly) were unaffected. The H66F and H66W proteins each show a different pattern of binding of 10 different aminoacyl-tRNAs, clearly showing that this position is critical in establishing the specificity of EF-Tu for different esterified amino acids. However, the H66A mutation does not greatly affect the ability of the ternary complex to bind ribosomes, hydrolyze GTP, or form dipeptide, suggesting that this residue does not directly participate in ribosomal decoding. Selective mutation of His-66 may improve the ability of certain unnatural amino acids to be incorporated by the ribosome. PMID- 22105071 TI - Identification of molecular determinants from Moloney leukemia virus 10 homolog (MOV10) protein for virion packaging and anti-HIV-1 activity. AB - Discovery of novel antiretroviral mechanism is essential for the design of innovative antiretroviral therapy. Recently, we and others reported that ectopic expression of Moloney leukemia virus 10 (MOV10) protein strongly inhibits retrovirus replication. MOV10, a putative RNA helicase, can be packaged into HIV 1 virions by binding to the nucleocapsid (NC) region of Gag and inhibit viral replication at a postentry step. Here, we report critical determinants for MOV10 virion packaging and antiviral activity. MOV10 has 1,003 amino acids and seven helicase motifs. We found that MOV10 packaging requires the NC basic linker, and Gag binds to the N-terminal amino acids 261-305 region of MOV10. Our predicted MOV10 three-dimensional structure model indicates that the Gag binding region is located in a structurally exposed domain, which spans amino acids 93-305 and is Cys-His-rich. Simultaneous mutation of residues Cys-188, Cys-195, His-199, His 201, and His-202 in this domain significantly compromised MOV10 anti-HIV-1 activity. Notably, although MOV10-Gag interaction is required, it is not sufficient for MOV10 packaging, which also requires its C-terminal all but one of seven helicase motifs. Moreover, we have mapped the minimal MOV10 antiviral region to amino acids 99-949, indicating that nearly all MOV10 residues are required for its antiviral activity. Mutations of residues Cys-947, Pro-948, and Phe-949 at the C terminus of this region completely disrupted MOV10 anti-HIV-1 activity. Taken together, we have identified two critical MOV10 packaging determinants and eight other critical residues for anti-HIV-1 activity. These results provide a molecular basis for further understanding the MOV10 antiretroviral mechanism. PMID- 22105072 TI - Class II ADP-ribosylation factors are required for efficient secretion of dengue viruses. AB - Identification and characterization of virus-host interactions are very important steps toward a better understanding of the molecular mechanisms responsible for disease progression and pathogenesis. To date, very few cellular factors involved in the life cycle of flaviviruses, which are important human pathogens, have been described. In this study, we demonstrate a crucial role for class II Arf proteins (Arf4 and Arf5) in the dengue flavivirus life cycle. We show that simultaneous depletion of Arf4 and Arf5 blocks recombinant subviral particle secretion for all four dengue serotypes. Immunostaining analysis suggests that class II Arf proteins are required at an early pre-Golgi step for dengue virus secretion. Using a horseradish peroxidase protein fused to a signal peptide, we show that class II Arfs act specifically on dengue virus secretion without altering the secretion of proteins through the constitutive secretory pathway. Co immunoprecipitation data demonstrate that the dengue prM glycoprotein interacts with class II Arf proteins but not through its C-terminal VXPX motif. Finally, experiments performed with replication-competent dengue and yellow fever viruses demonstrate that the depletion of class II Arfs inhibits virus secretion, thus confirming their implication in the virus life cycle, although data obtained with West Nile virus pointed out the differences in virus-host interactions among flaviviruses. Our findings shed new light on a molecular mechanism used by dengue viruses during the late stages of the life cycle and demonstrate a novel function for class II Arf proteins. PMID- 22105073 TI - Activation of PDE10 and PDE11 phosphodiesterases. AB - The most recently identified cyclic nucleotide phosphodiesterases, PDE10 and PDE11, contain a tandem of so-called GAF domains in their N-terminal regulatory regions. In PDE2 and PDE5, the GAF domains mediate cGMP stimulation; however, their function in PDE10 and PDE11 remains controversial. Although the GAF domains of PDE10 mediate cAMP-induced stimulation of chimeric adenylyl cyclases, cAMP binding did not stimulate the PDE10 holoenzyme. Comparable data about cGMP and the PDE11 GAF domains exist. Here, we identified synthetic ligands for the GAF domains of PDE10 and PDE11 to reduce interference of the GAF ligand with the catalytic reaction of PDE. With these ligands, GAF-mediated stimulation of the PDE10 and PDE11 holoenzymes is demonstrated for the first time. Furthermore, PDE10 is shown to be activated by cAMP, which paradoxically results in potent competitive inhibition of cGMP turnover by cAMP. PDE11, albeit susceptible to GAF dependent stimulation, is not activated by the native cyclic nucleotides cAMP and cGMP. In summary, PDE11 can be stimulated by GAF domain ligands, but its native ligand remains to be identified, and PDE10 is the only PDE activated by cAMP. PMID- 22105074 TI - Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation. AB - Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important roles in insulin secretion through their receptors, GLP1R and GIPR. Although GLP-1 and GIP are attractive candidates for treatment of type 2 diabetes and obesity, little is known regarding the molecular interaction of these peptides with the heptahelical core domain of their receptors. These core domains are important not only for specific ligand binding but also for ligand induced receptor activation. Here, using chimeric and point-mutated GLP1R/GIPR, we determined that evolutionarily conserved amino acid residues such as Ile(196) at transmembrane helix 2, Leu(232) and Met(233) at extracellular loop 1, and Asn(302) at extracellular loop 2 of GLP1R are responsible for interaction with ligand and receptor activation. Application of chimeric GLP-1/GIP peptides together with molecular modeling suggests that His(1) of GLP-1 interacts with Asn(302) of GLP1R and that Thr(7) of GLP-1 has close contact with a binding pocket formed by Ile(196), Leu(232), and Met(233) of GLP1R. This study may provide critical clues for the development of peptide and/or nonpeptide agonists acting at GLP1R. PMID- 22105075 TI - Action of protein disulfide isomerase on proinsulin exit from endoplasmic reticulum of pancreatic beta-cells. AB - For insulin synthesis, the proinsulin precursor is translated at the endoplasmic reticulum (ER), folds to include its three native disulfide bonds, and is exported to secretory granules for processing and secretion. Protein disulfide isomerase (PDI) has long been assumed to assist proinsulin in this process. Herein we have examined the effect of PDI knockdown (PDI-KD) in beta-cells. The data establish that upon PDI-KD, oxidation of proinsulin to form native disulfide bonds is unimpaired and in fact enhanced. This is accompanied by improved proinsulin exit from the ER and increased total insulin secretion, with no evidence of ER stress. We provide evidence for direct physical interaction between PDI and proinsulin in the ER of pancreatic beta-cells, in a manner requiring the catalytic activity of PDI. In beta-cells after PDI-KD, enhanced export is selective for proinsulin over other secretory proteins, but the same effect is observed for recombinant proinsulin trafficking upon PDI-KD in heterologous cells. We hypothesize that PDI exhibits unfoldase activity for proinsulin, increasing retention of proinsulin within the ER of pancreatic beta cells. PMID- 22105076 TI - The ethylmalonyl-CoA pathway is used in place of the glyoxylate cycle by Methylobacterium extorquens AM1 during growth on acetate. AB - Acetyl-CoA assimilation was extensively studied in organisms harboring the glyoxylate cycle. In this study, we analyzed the metabolism of the facultative methylotroph Methylobacterium extorquens AM1, which lacks isocitrate lyase, the key enzyme in the glyoxylate cycle, during growth on acetate. MS/MS-based proteomic analysis revealed that the protein repertoire of M. extorquens AM1 grown on acetate is similar to that of cells grown on methanol and includes enzymes of the ethylmalonyl-CoA (EMC) pathway that were recently shown to operate during growth on methanol. Dynamic 13C labeling experiments indicate the presence of distinct entry points for acetate: the EMC pathway and the TCA cycle. 13C steady-state metabolic flux analysis showed that oxidation of acetyl-CoA occurs predominantly via the TCA cycle and that assimilation occurs via the EMC pathway. Furthermore, acetyl-CoA condenses with the EMC pathway product glyoxylate, resulting in malate formation. The latter, also formed by the TCA cycle, is converted to phosphoglycerate by a reaction sequence that is reversed with respect to the serine cycle. Thus, the results obtained in this study reveal the utilization of common pathways during the growth of M. extorquens AM1 on C1 and C2 compounds, but with a major redirection of flux within the central metabolism. Furthermore, our results indicate that the metabolic flux distribution is highly complex in this model methylotroph during growth on acetate and is fundamentally different from organisms using the glyoxylate cycle. PMID- 22105077 TI - Intra-membrane oligomerization and extra-membrane oligomerization of amyloid-beta peptide are competing processes as a result of distinct patterns of motif interplay. AB - Soluble oligomers of amyloid-beta peptide (Abeta) are emerging as the primary neurotoxic species in Alzheimer disease, however, whether the membrane is among their direct targets that mediate the downstream adverse effects remains elusive. Herein, we show that multiple soluble oligomeric Abeta preparations, including Abeta-derived diffusible ligand, protofibril, and zinc-induced Abeta oligomer, exhibit much weaker capability to insert into the membrane than Abeta monomer. Abeta monomers prefer incorporating into membrane rather than oligomerizing in solution, and such preference can be reversed by the aggregation-boosting factor, zinc ion. Further analyses indicate that the membrane-embedded oligomers of Abeta are derived from rapid assembly of inserted monomers but not due to the insertion of soluble Abeta oligomers. By comparing the behavior of a panel of Abeta truncation variants, we demonstrate that the intra- and extra-membrane oligomerization are mutually exclusive processes that proceed through distinct motif interplay, both of which require the action of amino acids 37-40/42 to overcome the auto-inhibitory interaction between amino acids 29-36 and the N terminal portion albeit via different mechanisms. These results indicate that intra- and extra-membrane oligomerization of Abeta are competing processes and emphasize a critical regulation of membrane on the behavior of Abeta monomer and soluble oligomers, which may determine distinct neurotoxic mechanisms. PMID- 22105078 TI - Alternative splicing regulates kv3.1 polarized targeting to adjust maximal spiking frequency. AB - Synaptic inputs received at dendrites are converted into digital outputs encoded by action potentials generated at the axon initial segment in most neurons. Here, we report that alternative splicing regulates polarized targeting of Kv3.1 voltage-gated potassium (Kv) channels to adjust the input-output relationship. The spiking frequency of cultured hippocampal neurons correlated with the level of endogenous Kv3 channels. Expression of axonal Kv3.1b, the longer form of Kv3.1 splice variants, effectively converted slow-spiking young neurons to fast-spiking ones; this was not the case for Kv1.2 or Kv4.2 channel constructs. Despite having identical biophysical properties as Kv3.1b, dendritic Kv3.1a was significantly less effective at increasing the maximal firing frequency. This suggests a possible role of channel targeting in regulating spiking frequency. Mutagenesis studies suggest the electrostatic repulsion between the Kv3.1b N/C termini, created by its C-terminal splice domain, unmasks the Kv3.1b axonal targeting motif. Kv3.1b axonal targeting increased the maximal spiking frequency in response to prolonged depolarization. This finding was further supported by the results of local application of channel blockers and computer simulations. Taken together, our studies have demonstrated that alternative splicing controls neuronal firing rates by regulating the polarized targeting of Kv3.1 channels. PMID- 22105079 TI - Three-dimensional printing (3DP) of neonatal head phantom for ultrasound: thermocouple embedding and simulation of bone. AB - A neonatal head phantom, comprising of an ellipsoidal geometry and including a circular aperture for simulating the fontanel was designed and fabricated, in order to allow an objective assessment of thermal rise in tissues during trans cranial ultrasonic scanning of pre-term neonates. The precise position of a series of thermocouples was determined on the basis of finite-element analysis, which identified crucial target points for the thermal monitoring within the phantom geometry. Three-Dimensional Printing (3DP) was employed for the manufacture of the skull phantom, which was subsequently filled with dedicated brain-mimic material. A novel 3DP material combination was found to be able to mimic the acoustic properties of neonatal skull bone. Similarly, variations of a standard recipe for tissue mimic were examined, until one was found to mimic the brain of an infant. A specific strategy was successfully pursued to embed a thermocouple within the 3DP skull phantom during the manufacturing process. An in process machine vision system was used to assess the correct position of the deposited thermocouple inside the fabricated skull phantom. An external silicone made skin-like covering completed the phantom and was manufactured through a Direct Rapid Tooling (DRT) technique. PMID- 22105080 TI - Quantitative analysis of synaptic vesicle pool replenishment in cultured cerebellar granule neurons using FM dyes. AB - After neurotransmitter release in central nerve terminals, SVs are rapidly retrieved by endocytosis. Retrieved SVs are then refilled with neurotransmitter and rejoin the recycling pool, defined as SVs that are available for exocytosis(1,2). The recycling pool can generally be subdivided into two distinct pools - the readily releasable pool (RRP) and the reserve pool (RP). As their names imply, the RRP consists of SVs that are immediately available for fusion while RP SVs are released only during intense stimulation(1,2). It is important to have a reliable assay that reports the differential replenishment of these SV pools in order to understand 1) how SVs traffic after different modes of endocytosis (such as clathrin-dependent endocytosis and activity-dependent bulk endocytosis) and 2) the mechanisms controlling the mobilisation of both the RRP and RP in response to different stimuli. FM dyes are routinely employed to quantitatively report SV turnover in central nerve terminals(3-8). They have a hydrophobic hydrocarbon tail that allows reversible partitioning in the lipid bilayer, and a hydrophilic head group that blocks passage across membranes. The dyes have little fluorescence in aqueous solution, but their quantum yield increases dramatically when partitioned in membrane(9). Thus FM dyes are ideal fluorescent probes for tracking actively recycling SVs. The standard protocol for use of FM dye is as follows. First they are applied to neurons and are taken up during endocytosis (Figure 1). After non-internalised dye is washed away from the plasma membrane, recycled SVs redistribute within the recycling pool. These SVs are then depleted using unloading stimuli (Figure 1). Since FM dye labelling of SVs is quantal(10), the resulting fluorescence drop is proportional to the amount of vesicles released. Thus, the recycling and fusion of SVs generated from the previous round of endocytosis can be reliably quantified. Here, we present a protocol that has been modified to obtain two additional elements of information. Firstly, sequential unloading stimuli are used to differentially unload the RRP and the RP, to allow quantification of the replenishment of specific SV pools. Secondly, each nerve terminal undergoes the protocol twice. Thus, the response of the same nerve terminal at S1 can be compared against the presence of a test substance at phase S2 (Figure 2), providing an internal control. This is important, since the extent of SV recycling across different nerve terminals is highly variable(11). Any adherent primary neuronal cultures may be used for this protocol, however the plating density, solutions and stimulation conditions are optimised for cerebellar granule neurons (CGNs)(12,13). PMID- 22105081 TI - Parasitism by Oestrus ovis: influence of sheep breed and nematode infections. AB - Previous studies showed that Santa Ines (SI) hair sheep were more resistant to gastrointestinal nematode infections (GIN) than Ile de France (IF) sheep. The present experiment aimed to evaluate if that reported resistance difference against GIN also occurred against Oestrus ovis infestation and also to evaluate the influence of O. ovis infestation on the gastrointestinal nematodes (GIN) infections. SI (n=12) and IF (n=12) young male lambs were weaned at 2 months of age and moved to a paddock (0.3 ha) with Brachiaria decumbens grass, where they also received concentrate ration. The animals were kept together during the experimental period (September to early December 2009). Fecal and blood samples were taken from all animals every 2 weeks and body weight and nasal discharge score (oestrosis clinic signs) were recorded on the same occasion. In early December 2009, all lambs were sacrificed and O. ovis larvae and GIN were recovered, counted and identified according to the larval stage. All animals were infested by different larval instars of O. ovis without any statistical difference between breeds (P>0.05). The SI lambs had an average of 24.8 larvae, and the intensity of infection ranged between 14 and 39 larvae, while the IF lambs showed an average of 23.5 larvae with the minimum and maximum from 11 to 36 larvae, respectively. SI lambs presented the lowest nematode fecal egg counts (FECs) and the lowest mean numbers of Haemonchus contortus, Trichostrongylus colubriformis and Strongyloides papillosus, however, there was no significant differences between group means (P>0.05). Inverse relationship between numbers of O. ovis larvae and gastrointestinal nematodes was observed in both breeds. SI sheep showed a significant increase in blood eosinophils and total IgE serum levels and these variables were negatively correlated with nematode FEC. A negative correlation was observed between total IgE serum level and H. contortus burden in both breeds. In conclusion, there was no breed difference regarding O. ovis infestation and in each breed, animals with more nasal bot fly larvae tended to display smaller worm burden. PMID- 22105082 TI - Subolesin/akirin orthologs from Ornithodoros spp. soft ticks: cloning, RNAi gene silencing and protective effect of the recombinant proteins. AB - Subolesin/akirin is a well characterized protective antigen highly conserved across vector species and thus potentially useful for the development of a broad spectrum vaccine for the control of arthropod infestations including hard ticks, mosquitoes, sand flies and the poultry red mite Dermanyssus gallinae. Soft ticks could be also targeted by this vaccine if proved that the soft tick subolesin orthologs are conserved and induce protective immune responses too. However, to date no soft tick subolesin orthologs have been fully characterized nor tested as recombinant antigens in vaccination trials. The objectives of the present work were to clone and characterize the subolesin orthologs from two important vector species of soft ticks as Ornithodoros erraticus and O. moubata, to evaluate the effect of subolesin gene silencing by RNAi, and to test the protective value of the recombinant antigens in vaccination trials. The obtained results demonstrate that both soft tick subolesins are highly conserved showing more than 69% and 74% identity with those of hard ticks in their nucleotide and amino acid sequences, respectively. Additionally, we demonstrate that both soft ticks possess fully operative RNAi machinery, and that subolesin gene silencing by dsRNA injection inhibits oviposition indicating the involvement of subolesin in tick reproduction. Finally, vaccination with the recombinant soft tick subolesins induced a partial protective effect resulting in the reduction of the oviposition rate. These preliminary results encourage further studies on the use of recombinant subolesins as vaccines for the control of soft tick infestations, either alone or in combination with other specific molecules. PMID- 22105083 TI - Toxoplasma gondii in foxes and rodents from the German Federal States of Brandenburg and Saxony-Anhalt: seroprevalence and genotypes. AB - Data on the genotypes of Toxoplasma gondii circulating in wildlife are scarce. In the present study, foxes and rodents from two Federal States in Central or Eastern Germany were examined for T. gondii infections. Body fluids were collected at necropsy or fluids were obtained from frozen tissues of naturally exposed red foxes (Vulpes vulpes), voles (Microtus arvalis), shrews (Neomys anomalus) and a striped field mouse (Apodemus agrarius) and tested for T. gondii by serology. DNA isolated from tissues of seropositive foxes and all the rodents was examined by PCR. In the German Federal States of Brandenburg and Saxony Anhalt 152/204 (74.5%) and 149/176 (84.7%) of foxes, respectively, but none of the rodents (0/72) had antibodies to T. gondii. Only 28/152 (18.4%) and 20/149 (13.4%) of seropositive foxes from Brandenburg and Saxony-Anhalt, respectively, but none of the rodents tested PCR-positive for T. gondii. The complete T. gondii genotype could be determined for twelve samples using nine PCR-restriction fragment length polymorphism (PCR-RFLP) markers (newSAG2, SAG3, BTUB, GRA6, c22 8, c29-2, PK1, L358 and Apico). In addition to T. gondii clonal type II (Apico II) and type II (Apico I), type III and T. gondii genotypes showing non-canonical allele patterns were observed in foxes. This suggests that, while T. gondii type II prevails in foxes, other genotypes circulate in wildlife. The population structure of T. gondii in Germany may be more diverse than previously thought. PMID- 22105084 TI - Human evolution: pathogen influence on human genetic variation. PMID- 22105085 TI - Gene regulation: RNAi gets stuck into transcription. PMID- 22105086 TI - Body and self in dolphins. AB - In keeping with recent views of consciousness of self as represented in the body in action, empirical studies are reviewed that demonstrate a bottlenose dolphin's (Tursiops truncatus) conscious awareness of its own body and body parts, implying a representational "body image" system. Additional work reviewed demonstrates an advanced capability of dolphins for motor imitation of self-produced behaviors and of behaviors of others, including imitation of human actions, supporting hypotheses that dolphins have a sense of agency and ownership of their actions and may implicitly attribute those levels of self-awareness to others. Possibly, a mirror-neuron system, or its functional equivalent to that described in monkeys and humans, may mediate both self-awareness and awareness of others. PMID- 22105087 TI - MicroRNA and colorectal cancer. AB - Colorectal cancer is still the third most common cancer in the world. Its carcinogenesis has been extensively studied at a molecular point of view, and has recently entered the era of microRNAs, a class small non-coding RNAs that post transcriptionally regulate gene expression and control various cellular mechanisms. Because they control biological processes that are implicated in carcinogenesis (as developmental transitions, organ morphology, apoptosis and cell proliferation), microRNAs have been linked to cancer development, and these molecules have been recently studied as new potential biomarkers to better characterise tumour prognosis and to predict response to the different active chemotherapy. This review summarizes the potential roles of microRNAs as potential biomarkers for colorectal cancer diagnosis, prognosis and drug-response prediction. Through the literature there is evidence that some microRNA could be used as biomarkers in colorectal cancer; however, there are some discrepancies amongst the different studies. These differences could partially due to heterogeneity between the different series associated with tumour stage, tumour location, genetic background of the tumours and technical issues. More progress is needed before microRNAs can be used in clinical practice. Accumulation of further data will allow to determine the most relevant microRNAs as biomarkers and also to better understand their role in colorectal carcinogenesis. PMID- 22105089 TI - [Study of the right ventricle using magnetic resonance imaging]. AB - Magnetic resonance (MR) imaging has proven efficacy in the study of the heart. Its clinical applications are directed primarily at the study of the left ventricle, and the right ventricle is relegated to the background. This article reviews the anatomy and physiology of the right ventricle, as well as the manifestations of most common diseases affecting this chamber of the heart: infarction, cardiomyopathy, masses, and right heart failure. Knowing the distinctive features of the right ventricle with respect to the left and the particularities of the MR imaging protocol results in better technical performance in cases in which the reason for the examination or imaging findings point to the right ventricle. The importance of the right ventricle in the management of cardiopulmonary disease is growing and MR imaging can provide clinicians with the support they need. PMID- 22105091 TI - Maturation of visual evoked potentials across adolescence. AB - Adolescence represents the period of transition from childhood to adulthood and is characterized by significant changes in brain structure and function. We studied changes in the functional visual processing in the brain across adolescence. Visual evoked potentials (VEPs) to three types of pattern reversal checkerboard stimuli were measured in 90 adolescents (10-18 years) and 10 adults. Across adolescence, the N75 and P100 VEP peaks decreased in size while the N135 peak increased slightly in size. The latency of VEP peaks showed no reliable change across adolescence. The results suggest that even very basic visual sensory function continues to develop throughout adolescence. The results indicate significant changes in visual parvocellular and magnocellular pathways across adolescence. PMID- 22105092 TI - Genetics of temporal lobe epilepsy. AB - The most common partial epilepsy, temporal lobe epilepsy (TLE) consists of a heterogeneous group of seizure disorders originating in the temporal lobe. TLE had been thought to develop as a result of acquired structural problems in the temporal lobe. During the past two decades, there has been growing evidence of the important influence of genetic factors, and familial and non-lesional TLE have been increasingly described. Here, we focus on the genetics of TLE and review related genes which have been studied recently. Although its molecular mechanisms are still poorly understood, TLE genetics is a fertile field, awaiting more research. PMID- 22105093 TI - Inhibition and dispersal of Agrobacterium tumefaciens biofilms by a small diffusible Pseudomonas aeruginosa exoproduct(s). AB - Environmental biofilms often contain mixed populations of different species. In these dense communities, competition between biofilm residents for limited nutrients such as iron can be fierce, leading to the evolution of competitive factors that affect the ability of competitors to grow or form biofilms. We have discovered a compound(s) present in the conditioned culture fluids of Pseudomonas aeruginosa that disperses and inhibits the formation of biofilms produced by the facultative plant pathogen Agrobacterium tumefaciens. The inhibitory activity is strongly induced when P. aeruginosa is cultivated in iron-limited conditions, but it does not function through iron sequestration. In addition, the production of the biofilm inhibitory activity is not regulated by the global iron regulatory protein Fur, the iron-responsive extracytoplasmic function sigma factor PvdS, or three of the recognized P. aeruginosa quorum-sensing systems. In addition, the compound(s) responsible for the inhibition and dispersal of A. tumefaciens biofilm formation is likely distinct from the recently identified P. aeruginosa dispersal factor, cis-2-decenoic acid (CDA), as dialysis of the culture fluids showed that the inhibitory compound was larger than CDA and culture fluids that dispersed and inhibited biofilm formation by A. tumefaciens had no effect on biofilm formation by P. aeruginosa. PMID- 22105094 TI - Quenching of the triplet state of Safranine-O by aliphatic amines in AOT reverse micelles studied by transient absorption spectroscopy. AB - The photophysics of Safranine-O (3,6-diamino-2,7-dimethyl-5 phenyl phenazinium chloride) (SfH(+)Cl(-)) was investigated in reverse micelles (RMs) of AOT (sodium bis(2-ethylhexyl)sulfosuccinate) with special emphasis on the triplet state processes. The triplet is formed in its monoprotonated form, independently of the pH of the water used to prepare the RMs. While the intersystem crossing quantum yields in RMs are similar to those in organic solvents, the triplet lifetime is much longer. Since the pH in the water pool of AOT RMs is close to 5 and the triplet state of the dye is subjected to proton quenching, the long lifetime indicates that the dye resides in a region where it cannot be reached by protons during its lifetime. All the measurements indicate that the dye is localized in the interface, sensing a medium of micropolarity similar to EtOH : water (3:1) mixtures. The quenching by aliphatic amines was also investigated. While the quenching by the hydrophobic tributylamine is similar to that in methanol, the hydro-soluble triethanolamine is one order of magnitude more effective in RMs than in homogeneous solution. In the latter case the quenching process is interpreted by a very fast intramicellar quenching, the overall kinetics being controlled by the exchange of amine molecules between RMs. Semireduced dye is formed in the quenching process in RMs in the di-protonated state with a comparable quantum yield to the monoprotonated state formed in homogeneous solvents. The results point to the advantage of the reverse micellar system for the generation of active radicals for the initiation of vinyl polymerization, since a much lower concentration of amine can be employed with similar quantum yields. PMID- 22105095 TI - Age-related changes in the elastic tissue of the human aorta. AB - BACKGROUND: Age-related arterial alterations affecting cells, matrix and biomolecules are the main culprit for initiation and progression of cardiovascular disease. The objective of this study is to gain further insights into the complex mechanism of elastic tissue ageing in human aortic blood vessels. METHODS: One hundred and nineteen human aortic tissue samples were collected from adult patients (101 males, 18 females; age 40-86 years) undergoing coronary artery bypass grafting. Overall extracellular matrix architecture was examined by multiphoton laser scanning microscopy and histology. Matrix metalloproteinases 2 and 9, corresponding tissue inhibitors 1 and 2 as well as desmosine were determined. mRNA levels of tropoelastin were assessed by quantitative RT-PCR. RESULTS: Age-related destruction of the vascular elastic laminas as well as a loss of interlamina cross-links were observed by laser scanning microscopy. These results were confirmed by histology indicating increasing interlamina gaps. There were no significant differences in matrix turnover or desmosine content. A steady decrease in tropoelastin mRNA by about 50% per 10 years of age increase was observed. CONCLUSIONS: Our findings indicate that ageing is accompanied by a destruction of the elastic vascular structure. However, tropoelastin expression analysis suggests that elastogenesis occurs throughout life with constantly decreasing levels. PMID- 22105096 TI - Telemedicine use among burn centers in the United States: a survey. AB - Telemedicine has been increasingly used in a host of settings for over 20 years. Burns are well suited for evaluation by either synchronous ("interactive") video or asynchronous digital ("store and forward") imagery, but little information is available about telemedicine use in burn care. The authors surveyed U.S. burn center directors to assess their current use of, and interest in, telemedicine in clinical burn treatment. With Institutional Review Board approval, a web-based survey (surveymonkey.com) was created and sent to directors of 126 burn centers in the United States. Questions measured the use of telemedicine by burn centers and burn directors' attitudes toward telemedicine. Surveys were returned from 50 centers (40%). Directors of 42 units (84%) reported using telemedicine; 37 use it routinely. Interactive video communication was used by 18 centers, store and forward by 38 centers, and remote access to patient data by home computer or personal digital assistant in 41 centers. Uses included remote evaluation of acute burns for consultation, for help in determining the need for transfer, or for remote clinic follow-up. Users identified some problems with current telemedicine usage, including Health Insurance Portability and Accountability Act/compliance, licensure, and billing/collection issues. Importantly, 40 respondents (80%) indicated that they would like programming on telemedicine to be available at American Burn Association's annual meetings. Use of telemedicine is fairly widespread among U.S. burn centers, with volume and type of usage varying widely. Significant interest in learning more about telemedicine suggests strongly that telemedicine should be included in the annual program at the American Burn Association. PMID- 22105097 TI - Ubiquitin and stromal cell-derived factor-1alpha in bronchoalveolar lavage fluid after burn and inhalation injury. AB - The objective of the study was to determine whether the CXC chemokine receptor (CXCR) 4 ligands ubiquitin and stromal cell-derived factor (SDF)-1alpha are detectable in bronchoalveolar lavage fluid (BALF) after burn and inhalation injury and whether their concentrations in BALF are associated with injury severity, physiological variables, or clinical outcomes. BALF was obtained on hospital admission from 51 patients (48 +/- 18 years) with burn (TBSA: 23 +/- 24%) and inhalation injury (controls: 10 healthy volunteers, 42 +/- 8 years). BALF was analyzed for total protein and for ubiquitin and SDF-1alpha by enzyme linked immunosorbent assay. Ubiquitin/SDF-1alpha levels were normalized to total BALF protein content. The extent of inhalation injury was determined during bronchoscopy using a standardized scoring system. Percent TBSA, Baux scores, revised Baux scores, and clinical variables were documented. Ubiquitin and SDF 1alpha were detectable in 40% of normal BALF specimens. After injury, ubiquitin was detectable in 90% (P < .01 vs control) and SDF-1alpha in 10% of the specimens (P < .05 vs control). While SDF-1alpha levels were reduced in patients (P < .01), ubiquitin levels were increased (P < .01). Ubiquitin concentrations correlated inversely with grade of inhalation injury, revised Baux scores, and resuscitation fluid requirements (Spearman correlation coefficients [r]: -.3, -.33, and -.45, respectively). Ubiquitin levels correlated positively with arterial oxygenation at the time of bronchoscopy (r: .35). BALF levels of CXCR4 agonists are differentially regulated after burn and inhalation injury. Increases in BALF ubiquitin after inhalation injury may maintain CXCR4-mediated lung protection and repair processes. The finding that BALF ubiquitin decreased with higher grades of inhalation injury may provide a biological correlate for an insufficient local inflammatory response after severe inhalation injury. PMID- 22105098 TI - Bilaminar co-culture of primary rat cortical neurons and glia. AB - This video will guide you through the process of culturing rat cortical neurons in the presence of a glial feeder layer, a system known as a bilaminar or co culture model. This system is suitable for a variety of experimental needs requiring either a glass or plastic growth substrate and can also be used for culture of other types of neurons. Rat cortical neurons obtained from the late embryonic stage (E17) are plated on glass coverslips or tissue culture dishes facing a feeder layer of glia grown on dishes or plastic coverslips (known as Thermanox), respectively. The choice between the two configurations depends on the specific experimental technique used, which may require, or not, that neurons are grown on glass (e.g. calcium imaging versus Western blot). The glial feeder layer, an astroglia-enriched secondary culture of mixed glia, is separately prepared from the cortices of newborn rat pups (P2-4) prior to the neuronal dissection. A major advantage of this culture system as compared to a culture of neurons only is the support of neuronal growth, survival, and differentiation provided by trophic factors secreted from the glial feeder layer, which more accurately resembles the brain environment in vivo. Furthermore, the co-culture can be used to study neuronal-glial interactions(1). At the same time, glia contamination in the neuronal layer is prevented by different means (low density culture, addition of mitotic inhibitors, lack of serum and use of optimized culture medium) leading to a virtually pure neuronal layer, comparable to other established methods(1-3). Neurons can be easily separated from the glial layer at any time during culture and used for different experimental applications ranging from electrophysiology(4), cellular and molecular biology(5-8), biochemistry(5), imaging and microscopy(4,6,7,9,10). The primary neurons extend axons and dendrites to form functional synapses(11), a process which is not observed in neuronal cell lines, although some cell lines do extend processes. A detailed protocol of culturing rat hippocampal neurons using this co-culture system has been described previously(4,12,13). Here we detail a modified protocol suited for cortical neurons. As approximately 20x10(6) cells are recovered from each rat embryo, this method is particularly useful for experiments requiring large numbers of neurons (but not concerned about a highly homogenous neuronal population). The preparation of neurons and glia needs to be planned in a time specific manner. We will provide the step-by-step protocol for culturing rat cortical neurons as well as culturing glial cells to support the neurons. PMID- 22105099 TI - Bicycle accidents - do we only see the tip of the iceberg? A prospective multi centre study in a large German city combining medical and police data. AB - INTRODUCTION: Bicycles are becoming increasingly popular. In Munster, a German town with a population of 273,000, bicycles were the main method of transportation in 2009, used more often (37.8%) than cars (36.4%). Each day in Munster, bicycles are used around 450,000 times. In 1982, they were only used around 270,000 times a day. However, the increased use of bicycles has also led to an increased number of bicycle accidents. METHODS: Between February 2009 and January 2010, data on bicycle-accidents leading to injuries were collected by the Police of Munster and in all emergency units of the six hospitals in Munster. A systematic acquisition of technical data from the police and the medical data from the hospitals were combined anonymously. None of the forms contained personal data of patients involved, except for patient age and sex as well as time and place of bicycle accidents to match the questionnaires. The data were entered into a central database (MS Access for input/MySQL for data retrieval). RESULTS: 2250 patients were included in this study. For each of these patients either a patient record or a hospital record or a police record or a combination of any of these different records existed in our database. In total, 1767 patients received medical treatment at a hospital and 484 people included in the study did not go to a hospital. Three fatalities occurred as a result of bicycle accidents. Considering reasons for hospital admission, traumatic brain injuries were the leading cause (25.7%). However, the largest resource consumption was attributed to fractures of the upper extremities (36.8%) and lower extremities (29.9%) with major surgery. DISCUSSION: Bicycle accidents occur more frequently than indicated by police records. The results of the Munster Bicycle Study have shown that the actual number of bicycle accidents exceeds the officially reported number by nearly two times. Since bicycle helmets cannot prevent accidents it is recommended not only to focus on helmet use as the only injury prevention method. Other factors, such as weather, pavement and default of traffic, roadworthiness of the bicycles or alcohol/drug abuse also affect the accident rates. PMID- 22105100 TI - Objective sound wave amplitude measurement generated by a tuning fork. An analysis of its use as a diagnostic tool in suspected femoral neck fractures. AB - INTRODUCTION: Hip injuries are becoming a more common problem as the elderly population increases and their management represents a significant proportion of health care costs. Diagnosis of a fracture based on clinical assessment and plain films is not always conclusive and further investigations for such occult fractures, such as magnetic resonance imaging (MRI), are sometimes required which are expensive and may be difficult to access. Disruption to the conduction of a sound wave travelling through a fractured bone is a concept that has been used to diagnose fractures. PATIENTS AND METHODS: In our study we used a tuning fork with frequency of 128 Hz to objectively measure the reduction in sound amplitude in fractured and non-fractured hips. We looked at the feasibility of using this test as a diagnostic tool for neck of femur fractures. RESULTS: A total of 20 patients was included in the study, using MRI scan as the standard for comparison of diagnostic findings. Informed consent was obtained from the patients. There was a significant difference in the amplitude reduction of the sound waves when comparing normal to fractured hips. This was 0.9 in normal hips, compared to 0.31 and 0.18 in intra-capsular and extra-capsular fractures, respectively. Our test was 80% accurate at diagnosing neck of femur fractures. CONCLUSION: In conclusion this test may be used as a diagnostic test or screening tool in the assessment of occult hip fractures. PMID- 22105101 TI - The clinical value of 3-T magnetic resonance myelography in far lateral disk herniation. AB - STUDY DESIGN: Prospective study of 30 patients suspected of suffering from far lateral lumbar disk herniation. OBJECTIVE: To assess the diagnostic and clinical value of a new technique 3-T magnetic resonance myelography (MRM) in patients with far lateral disk herniation. SUMMARY OF BACKGROUND DATA: No studies have reported regarding the usefulness of MRM images in assessing far lateral disk nor correlated it with clinical outcomes. METHODS: We evaluated 3-T MRM of 30 patients, whom we suspected of suffering from far lateral disk herniation. Using an assessment scale, 5 observers independently examined the images. We analyzed observer agreement and the accentuation of each image. RESULTS: We found complete match and observer agreement for 3-T MRM for diagnosing far lateral disk herniation. Furthermore, 3-T MRM revealed the disease's severity on the basis of the nerve root exit zone angle differences. CONCLUSIONS: MRM is an appropriate diagnostic tool and reduces the chance of misdiagnosis in far lateral disk herniation. Furthermore, through the use of this technique, we can evaluate postoperative clinical outcomes. PMID- 22105102 TI - Influence of a thread wire saw guide and spinal cord protector device in "en bloc" vertebrectomies. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of the study was to describe and compare the surgical outcomes between the use of a new auto static spinal cord and thread wire guiding device and the traditional scalpel technique for en bloc vertebrectomies using only the posterior approach. SUMMARY OF BACKGROUND DATA: As en bloc vertebrectomy has become more accepted as the ideal treatment for selected cases of spine tumors, its high morbidity has to be kept in mind. Uneven cutting surfaces and high risk of spinal cord lesions are among the problems. Although some modifications of the technique and development of new devices to minimize the risks have been reported, there are still some pitfalls associated with them. METHODS: Twenty-five patients, divided into 2 groups, were retrospectively reviewed. Patients in group 1 (G1) were operated using the device, and the patients in group 2 (G2) underwent en bloc vertebrectomy by the traditional scalpel technique. The surgical time, amount of blood loss based on the total volume of blood transfusion during surgery, and the rate of complication were compared. RESULTS: No differences regarding sex, age, and preoperative status occurred. The mean operative time was 294 and 388 minutes and the mean volume of transfused blood was 37 and 53 mL/kg for G1 and G2, respectively. These differences were not statistically significant. CONCLUSIONS: Patient selection and surgical experience are the best outcome predictors. However, methods to reduce the risks of neural lesions, surgical time, and blood loss should always be applied, specially dealing with highly morbid and demanding procedures in the spine. PMID- 22105103 TI - Comparison of isocentric C-arm 3-dimensional navigation and conventional fluoroscopy for C1 lateral mass and C2 pedicle screw placement for atlantoaxial instability. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of the study was to compare the precision of C1 lateral mass and C2 pedicle (C1LM-C2P) screw fixation for atlantoaxial instability using the isocentric C-arm 3-dimensional (Iso-C 3D) navigation versus conventional fluoroscopy. SUMMARY OF BACKGROUND DATA: The Iso-C 3D navigation has been widely used in spinal surgeries in recent years. The advantages of this navigation system compared with conventional fluoroscopy in C1LM-C2P screw fixation for atlantoaxial instability are not known. METHODS: Twenty-four patients diagnosed with atlantoaxial instability were treated with C1LM-C2P screw fixation in this study. The navigation group included 12 patients and the other 12 patients were in the conventional fluoroscopy group. The clinical and radiographic results were recorded and compared between the 2 groups. Patients were followed up with clinical examination and radiographs at a mean of 10.8 months. RESULTS: There were no significant differences between groups in the mean age, gender, and causes of atlantoaxial instability. Operative time was 130 +/- 5.4 minutes in the navigation group versus 145 +/- 6.5 minutes in the conventional fluoroscopy group. The mean blood loss in the navigation group was 304.2 +/- 47.9 mL relative to 462.5 +/- 55.4 mL in the conventional fluoroscopy group. The radiation time was significantly reduced using 3D navigation (47.5 +/- 1.5 s vs. 64.0 +/- 3.0 s). 95.8% (46/48) of 3D navigated screws and 83.3% (40/48) of fluoroscopy screws had no pedicle perforation. Each patient showed evidence of solid fusion after 6 months on cervical plain radiographies. CONCLUSION: On comparing the 2 imaging techniques, it was found that using Iso-C 3D navigation can significantly improve the accuracy of screw placement and decrease intraoperative fluoroscopic time and blood loss. This study demonstrates that Iso-C 3D navigation is a safe and effective means of guiding C1LM-C2P screw fixation for atlantoaxial instability. PMID- 22105104 TI - Upregulation of intervertebral disc-cell matrix synthesis by pulsed electromagnetic field is mediated by bone morphogenetic proteins. AB - STUDY DESIGN: An in vitro study on the effects of pulsed electromagnetic field (PEMF) on intervertebral disc-cell matrix synthesis. OBJECTIVES: The objective of the study was to determine whether (1) PEMF can upregulate intervertebral disc cell matrix synthesis and (2) any upregulation obtained is through transforming growth factor (TGF)-beta or bone morphogenetic proteins (BMPs). SUMMARY OF BACKGROUND DATA: PEMF has been reported to produce cell proliferation, enhance cell function, and upregulate matrix synthesis in cell types such as osteoblasts, chondroblasts, endothelial cells, and fibroblasts through the upregulation of several growth factors. PEMF has been used clinically in the treatment of delayed bone union. However, PEMF has never been tested on human intervertebral disc cells. METHODS: The PEMF signal used was similar to that used in the clinical treatment of delayed fracture healing. Human disc cells were treated with PEMF for 8 hours per day for 3 days. Quantitative real-time polymerase chain reaction was performed to determine mRNA expression levels of aggrecan, collagen-2, TGF beta, BMP-2, and BMP-7. Sulfated glycosaminoglycan synthesis was analyzed using the dimethylmethylene blue (DMMB) method. Western blot analysis was performed to determine the protein levels of TGF-beta, BMP-2, and BMP-7. To determine whether any action of PEMF was through BMP, recombinant human Noggin was used at a dose of 100 ng/mL to block BMP. RESULTS: PEMF could upregulate intervertebral disc cell matrix synthesis. BMP-7 was markedly upregulated by PEMF and was upregulated much more than BMP-2. TGF-beta was not upregulated by PEMF. The effect of PEMF on disc-cell matrix was entirely inhibited in the presence of Noggin. CONCLUSIONS: PEMF acts through BMPs to upregulate intervertebral disc-cell matrix synthesis. PMID- 22105105 TI - Biomechanical stability according to different configurations of screws and rods. AB - STUDY DESIGN: Comparison of biomechanical strength according to 2 different configurations of screws and rods. OBJECTIVE: To compare the biomechanical strength of different configurations of screws and rods composed of the same material and of the same size. SUMMARY OF BACKGROUND DATA: Many complications related to instrumentation have been reported. The incidence of metallic failure would differ according to the materials and configurations of the assembly of the screws and rods used. However, to our knowledge, the biomechanical effects of implant assembly rods and screws with different configurations and different contours have not been reported. METHODS: Biomechanical testing was conducted to compare top tightening (TT) screw-rod configuration with side tightening (ST) screw-rod configuration. All tests were conducted using a hydraulic all-purpose testing machine. All data were acquired at a rate of 10 Hz. Both screw systems used spinal rods of 6 mm diameter and were made of TiAl4V ELI material. Among 5 types of tests, 3 were conducted on the basis of American Society for Testing and Materials (ASTM) F 1798 to 97 and F1717-10. The other 2 tests were conducted for comparing the characteristics between TT and ST pedicle screws according to modified methods from ASTM F 1717-10 and ASTM F 1798-97. All results including axial gripping capacity and yield forces were obtained using the same methods on the basis of the mentioned ASTM standards. RESULTS: In the axial gripping capacity test, the mean axial gripping capacity of the TT screw-rod configuration was 3332 +/- 118 N and that of ST was 2222 +/- 147 N in straight rods (P = 0.019). In 15-degree contoured rods, TT was 2988 +/- 199 N and ST was 2116 +/- 423 N (P = 0.014). In 30-degree contoured rods, TT was 2227 +/- 408 N and ST was 1814 +/- 285 N (P = 0.009). In the pulling-out test, the pulling-out force of ST was 8695 +/- 1616 N and that of TT was 6106 +/- 195 N (P = 0.014). In the rod pushing test, the failure force of ST was 4131 +/- 205 N and that of TT was 5639 +/- 105 N. In the compressive fatigue test, the maximum load was 145 N in ST and 119 N in TT. In the cycle fatigue test, the fatigue strength of ST was higher than that of TT. In the rod-pushing test, the failure force of ST was 4131 +/- 205 N and that of TT was 5639 +/- 105 N (P=0.046). CONCLUSIONS: Two different configurations of rod-screw systems found statistically significant differences with axial gripping, pulling out, and fatigue failures. ST constructs improved fixation stability over TT constructs. It was concluded that ST configuration may reduce complications related to implantation. PMID- 22105106 TI - Mid-term follow-up of clinical and radiologic outcomes in cervical total disk replacement (Mobi-C): incidence of heterotopic ossification and risk factors. AB - INTRODUCTION: Cervical arthroplasty has been shown to have successful, short-term and long-term radiologic and clinical outcomes. The incidence of and predisposing factors for heterotopic ossification (HO) have not been determined. We retrospectively assessed the intermediate-term clinical and radiologic outcomes, especially the incidence of HO and its risk factors. METHODS: Our patient population consisted of 75 patients (85 levels) with cervical disk herniation. Mean follow-up was 40 months, with a minimum follow-up of 24 months. The numeric rating scale scores of neck and arm pain, the neck disability index, and Odom criteria were measured preoperatively and at 24 months postoperatively. Cervical overall lordosis, segmental lordosis, and range of motion at the operative level were evaluated immediately after surgery and at 1, 3, 6, 12, and 24 months postoperatively. The incidence and location of HO were evaluated at 12 and 24 months postoperatively. Univariate and multivariate logistic regression analyses were performed to determine the risk factors for HO. RESULTS: The mean numeric rating scale scores and neck disability index scores decreased significantly over 24 months. According to Odom criteria, this represented an overall success rate of 86.7%. Mean segmental lordosis and motion increased and then decreased until 24 months. HO occurred in 67 levels at 12 months postoperatively, increasing to 80 levels at 24 months. The multivariate logistic regression test showed a statistically significant difference when using a different surgical technique (P = 0.049). CONCLUSIONS: Intermediate follow-up of cervical arthroplasty showed good clinical outcomes, although there was a trend toward reduction in alignment and motion at 24 months. The overall HO occurrence was 94.1% at 24 months. In our study, the most important factor affecting HO was the different surgical techniques. PMID- 22105107 TI - Modified double-door laminoplasty in managing multilevel cervical spondylotic myelopathy: surgical outcome in 520 patients and technique description. AB - STUDY DESIGN: This is a prospective study on surgical outcomes of double-door laminoplasty in patients with cervical spondylotic myelopathy (CSM). OBJECTIVE: The purpose of this study was to report the efficacy and safety of modified double-door laminoplasty in a large series of patients with CSM. SUMMARY OF BACKGROUND DATA: Laminoplasty is an established procedure for the decompression of multisegmental CSM. However, no report has described the clinical outcomes of laminoplasty for a large number of patients with CSM (>500 patients). METHODS: Between April 1995 and December 2006, 520 consecutive patients (331 male and 189 female) with CSM who underwent double-door laminoplasty and were followed-up for more than 1 year were enrolled in this study. The mean age was 62.2 years (23 to 93 y), and the mean duration of disease was 20.1 +/- 32.0 months. The severity of myelopathy before and after surgery was evaluated according to a scoring system proposed by the Japanese Orthopedic Association for cervical myelopathy (JOA score). Functional improvement was expressed by the recovery rate (RR) of the JOA score. RESULTS: The average surgery time for laminoplasty was 75.2 +/- 23.3 minutes, and the average blood loss was 72.6 +/- 84.6 mL. The average follow-up period was 33.3 +/- 15.7 months. The mean JOA score was 10.4 +/- 2.8 points preoperatively and 13.6 +/- 2.5 points at final follow-up. The mean RR was 51.2 +/- 2 9.0%. On the basis of RR, we found that the conditions of 493 patients (94.8%) improved (RR, >1%), 20 patients (3.8%) showed no change (RR, 0%), and 7 patients (1.3%) in worse condition (RR, < 0%). The 7 patients deteriorated for reasons (lumbar spinal canal stenosis and cerebral infarction) that were unrelated to CSM. CONCLUSIONS: Modified double-door laminoplasty is a safe, reliable, and effective procedure for patients with CSM. PMID- 22105108 TI - Gastroesophageal reflux disease--from reflux episodes to mucosal inflammation. AB - Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation. PMID- 22105109 TI - MRI in Crohn's disease--current and future clinical applications. AB - Crohn's disease is a chronic, disabling disease that, over time, can lead to irreversible bowel damage. MRI can be used to diagnose and assess the activity, severity and complications of Crohn's disease; however, the role of MRI in therapeutic monitoring of changes in disease-related intestinal damage is still to be defined. Objective, validated MRI-based scores have been developed to assess the activity of Crohn's disease; these indices are based on the extent and severity of intestinal inflammation, postoperative recurrence and perianal disease. MRI is accurate, safe, reproducible and can allow repeated evaluations of patients without radiation exposure. Evidence that MRI might be valuable in the therapeutic monitoring of patients with Crohn's disease is increasing and, in combination with endoscopy and surgical history, this imaging technique could enable clinicians to assess Crohn's-disease-related intestinal damage. MRI could, therefore, have a crucial role in a future 'damage-driven' treatment paradigm--in which imaging is used to monitor intestinal damage and medication use is targeted to prevent the accumulation of further damage. This damage-driven therapeutic approach could potentially change the course of Crohn's disease. PMID- 22105110 TI - Androgen receptor co-activators in the regulation of cellular events in prostate cancer. AB - OBJECTIVES: Androgen receptor (AR) action in benign and malignant tissue is potentiated by a number of co-regulatory proteins that may interact with one or more receptor domains. With improvement of research methodologies, it became possible to detect a number of co-activators whose expression is increased in prostate cancer tissue. METHODS: Manuscripts describing prostate cancer-relevant regulation of cellular events by co-activators are selected and summarized. RESULTS: AR co-activators may regulate histone modification, proteasomal degradation, chaperones, sumoylation, chromatin remodeling, and cytoskeleton. Some of them (TIF-2) are up-regulated by androgens, whereas the expression of others increases during androgen ablation (p300, CBP, and Tip60). Most co-factors are important for the stimulation of cellular proliferation, although in some cases (ART-27), they act as tumor suppressors and are deleted in prostate cancer tissue. In addition to stimulating AR, some co-activators suppress apoptosis in prostate cancer cells that do not express the AR (p300 and SRC-3). It was recently shown that the inhibition of p300 slows down proliferation, stimulates apoptosis, and inhibits migration and invasion. CONCLUSIONS: Co-factors whose down-regulation results in the alterations of multiple cellular functions may be valid targets for novel therapies in advanced prostate cancer. PMID- 22105111 TI - Outbreak of leptospirosis among triathlon participants in Langau, Austria, 2010. AB - We report on the first documented outbreak of leptospirosis in Austria. In July 2010, four cases of serologically confirmed leptospirosis occurred in athletes after a triathlon held in Langau. Heavy rains preceded the triathlon (rainfall: 22 mm). The index case (Patient A) was a 41-year-old previously healthy male, who was admitted to hospital A on July 8 with a four-day history of fever up to 40 degrees C that began 14 days after attending the triathlon event. On July 7, patient B, a 42-year-old male, was admitted to the same hospital, with signs and symptoms of kidney failure. Hemodialysis was performed every other day for 3 weeks. While the serum drawn on the day of admission was negative for antibodies against Leptospira, a specimen from July 28 tested positive with Leptospira interrogans. On July 11, patient C, a 40-year-old male, was admitted to hospital B for nephritis. On July 14, patient D, a 44-year-old male, was admitted to hospital C with a ten days history of intermittent fever, mild dry cough and headache. Our report underlines that in Austria recreational users of bodies of freshwater must be aware of an existing risk of contracting leptospirosis, particularly after heavy rains. The suppressive influence of a triathlon on the immune system is well documented and therefore an outbreak in this population group can be seen as a sensitive indicator concerning possible risk for the general population. PMID- 22105112 TI - N-terminal pro-B-type natriuretic peptide and long-term mortality in non ischaemic cardiomyopathy. AB - AIM: The inactive N-terminal fragment of B-type natriuretic peptide is a strong predictor of mortality among patients with acute and chronic heart failure secondary to ischaemic heart disease. Its prognostic utility in patients with non ischaemic heart disease is not well established. We therefore assessed the relationship of N-terminal proBNP levels and long-term mortality in patients with non-ischaemic cardiomyopathy. METHODS: N-terminal proBNP was measured in serum samples of 156 patients who presented to a single academic centre with worsening heart failure secondary to non-ischaemic cardiomyopathy. The rate of death from all causes was determined after a mean follow-up of 8.9 years. RESULTS: Multivariate analyses, using Cox proportional hazards models, established NT proBNP and left ventricular diastolic diameter as predictors for cardiac mortality with estimated hazard ratios of 2.76 (95% confidence interval: 1.53, 4.98) and 1.06 (95% confidence interval: 1.02, 1.10), respectively. CONCLUSION: This to date longest-term analysis of N-terminal proBNP and mortality in patients with proven non-ischaemic cardiomyopathy confirms this cardiac-specific biomarker as powerful, independent risk predictor. It is a superior prognostic determinant to New York Heart Association functional class and left ventricular ejection fraction. PMID- 22105113 TI - Comparative study of frequency of different lymphocytes subpopulation in peripheral blood of patients with prostate cancer and benign prostatic hyperplasia. AB - PURPOSE: Benign prostatic hyperplasia (BPH) and prostate cancer (PC) are the most common urologic diseases among men over fifty and, until recently, they were considered to be caused by the impaired immune response. Despite many studies designed to investigate T-cell-based antitumor immunity, the role of innate immune cells in BPH and PC is still poorly understood. In this study the frequency of different leukocytes subpopulation in peripheral blood of BPH, PC patients and in healthy volunteers was analysed and compared. METHODS: In a cross sectional study 60 subjects were enrolled (20 patients with BPH or with PC and 20 healthy volunteers). Peripheral blood mononuclear cells (PBMC) were isolated and the percentage of T lymphocytes, natural killer (NK) and NKT cells, as well as subsets of T lymphocytes [CD3(+)CD56(-)CD4(+), T(regs) (CD4(+)CD25(+)FoxP3(+)) and CD3(+)CD56(-)CD8(+)] and NK cells (CD3(-)CD56(+dim) and CD3(-)CD56(+bright)) were analysed by flow cytometry. Intracellular content of interleukin-4 (IL-4) and interferon gamma (IFNgamma in T lymphocytes, NK and NKT cells were also detected. RESULTS: The percentage of T lymphocytes and their subsets in peripheral blood lymphocytes did not differ among investigated groups, while the frequency of Tregs was the highest in PC patients. The percentage of NK cell and their subsets did not differ among investigated groups. Negative correlation between PSA value, percentage of T lymphocytes and NK cells was observed only in PC patients. Highly positive correlation between the PSA value and the percentage of Tregs was found in PC patients. CONCLUSION: Different frequencies in distinctly lymphocyte subpopulation in peripheral blood of healthy men, BPH and PC patients could be responsible for occurrence and progression of prostatic hyperplasia or tumour. Due to the ability of tumours to suppress the cognate T cell immune response, the cells of innate immunity (NKT and Tregs) may be playing a key role in the immunopathogenesis of PC and BPH. PMID- 22105114 TI - Principles of an enhanced MBR-process with mechanical cleaning. AB - Up to date, different physical and chemical cleaning protocols are necessary to limit membrane fouling in membrane bioreactors. This paper deals with a mechanical cleaning process, which aims at the avoidance of hypochlorite and other critical chemicals in MBR with submerged flat sheet modules. The process basically consists of the addition of plastic particles into the loop circulation within submerged membrane modules. Investigations of two pilot plants are presented: Pilot plant 1 is equipped with a 10 m(2) membrane module and operated with a translucent model suspension; pilot plant 2 is equipped with four 50 m(2) membrane modules and operated with pretreated sewage. Results of pilot plant 1 show that the establishment of a fluidised bed with regular particle distribution is possible for a variety of particles. Particles with maximum densities of 1.05 g/cm(3) and between 3 and 5 mm diameter form a stable fluidised bed almost regardless of activated sludge concentration, viscosity and reactor geometry. Particles with densities between 1.05 g/cm(3) and 1.2 g/cm(3) form a stable fluidised bed, if the velocity at the reactor bottom is sufficiently high. Activities within pilot plant 2 focused on plant optimisation and the development of an adequate particle retention system. PMID- 22105115 TI - Evaluation of sludge properties in a pilot-scale UASB reactor for sewage treatment in a temperate region. AB - In this study, continuous operation of a pilot-scale upflow anaerobic sludge blanket (UASB) reactor for sewage treatment was conducted for 630 days to investigate the physical and microbial characteristics of the retained sludge. The UASB reactor with a working volume of 20.2 m(3) was operated at ambient temperature (16-29 degrees C) and seeded with digested sludge. After 180 days of operation, when the sewage temperature had dropped to 20 degrees C or lower, the removal efficiency of both total suspended solids (TSS) and total biochemical oxygen demand (BOD) deteriorated due to washout of retained sludge. At low temperature, the cellulose concentration of the UASB sludge increased owing to the rate limitation of the hydrolytic reaction of suspended solids in the sewage. However, after an improvement in sludge retention (settleability and concentration) in the UASB reactor, the process performance stabilized and gave sufficient results (68% of TSS removal, 75% of total BOD removal) at an hydraulic retention time (HRT) of 9.7 h. The methanogenic activity of the retained sludge significantly increased after day 246 due to the accumulation of Methanosaeta and Methanobacterium following the improvement in sludge retention in the UASB reactor. Acid-forming bacteria from phylum Bacteroidetes were detected at high frequency; thus, these bacteria may have an important role in suspended solids degradation. PMID- 22105116 TI - Performance evaluation of the BioCAST technology: a new multi-zone wastewater treatment system. AB - A new wastewater treatment technology, called BioCAST, has been designed and developed for high rate and simultaneous removal of organic carbonaceous compounds as well as nitrogen and phosphorus, along with reduced sludge generation. The treatment system has two interlinked reactors containing four independent zones with different environmental conditions of aerobic, microaerophilic, anoxic and anaerobic for the biological treatment of wastewater, as well as two clarification zones and a filtration unit for solid-liquid separation. The treatment system contains suspended as well as fixed-film microorganisms. The performance evaluation of the BioCAST system was carried out at organic loading rates of 0.95 to 1.86 kg/m(3) d, and nitrogen and phosphorus loading rates of 0.02 to 0.08 kg/m(3) d and 0.014 to 0.02 kg/m(3) d, respectively. The results demonstrated high removal efficiencies of carbon and nitrogen throughout the operation period, reaching 98.9 and 98.3%, respectively. Phosphorus removal efficiency was lower than 50% during the first 160 days of operation but it increased with the increase of nitrogen loading rate above 0.05 kg/m(3) day and concomitant reduction of C/N ratio below 15. Phosphorus removal efficiency reached 94.1%, producing an effluent concentration of 1.4 mg/L after 225 days of operation. The overall biomass yield based on the consumed COD was 3.7%. PMID- 22105117 TI - Study of impacts of floods on the water quality in an arid zone: the case of the Tarim River in Northwest China. AB - This paper presents the results of the study undertaken at the Tarim River Basin in Northwest China to analyze impacts of flooding on water quality. It was shown that irregular rainfall was the cause of flash floods that affected many ecosystems and eroded soils. Simulation results and the existence of relationships between flood volume and flood peak allowed potential model application that included flood peak estimation. The analysis of water pollution through sample sediment was helped by spectroscopy techniques and it was found that the flood was the main cause of many chemical elements in water. The floods affected the quality of water in the Tarim River where it was slightly basic with pH = 8.1 before flooding and acidic with pH = 6.9 after flooding. PMID- 22105118 TI - Water matrix effect on UV photodegradation of perfluorooctanoic acid. AB - The widespread detection of perfluorinated compounds (PFCs) in the water environment has been a concern for the last several years, while effluents from wastewater treatment facilities are the major sources of these compounds. Even advanced oxidation technologies (AOTs) are not useful for mineralization of the compounds due to their very high stability. Photochemical techniques using particularly vacuum UV (VUV) have been found to be very promising in this regard. But the use of VUV in UV-based AOTs has still not progressed much. Moreover, the impact of water quality on PFCs photomineralization is unknown. This investigation aimed to assess photomineralization potentials of perfluorooctanoic acid (PFOA) in ultrapure water (UPW), tap water (TW), surface water and treated wastewater effluent using a reactor setup enabling maximum utilization of VUV emission of low pressure lamp in laboratory batch experiments. Neya River water (NRW) and the Nakahama Wastewater Treatment Plant Effluent (NWWTPE) represented surface water and treated wastewater effluent respectively. Also, tests were carried out in 50% diluted NRW and NWWTPE. PFOA photomineralization in terms of PFOA removal, defluorination and total organic carbon (TOC) removal are discussed. The usefulness of the method for PFOA mineralization in organic-rich wastewaters, and further research needs are also highlighted. PMID- 22105119 TI - Resource recovery from source separated domestic waste(water) streams; full scale results. AB - A major fraction of nutrients emitted from households are originally present in only 1% of total wastewater volume. New sanitation concepts enable the recovery and reuse of these nutrients from feces and urine. Two possible sanitation concepts are presented, with varying degree of source separation leading to various recovery products. Separate vacuum collection and transport followed by anaerobic treatment of concentrated black water (BW) demonstrated on a scale of 32 houses preserve 7.6 g/N/p/d and 0.63 gP/p/d amounting to respectively 69 and 48% of the theoretically produced N and P in the household, and 95% of the retained P was shown to be recoverable via struvite precipitation. Reuse of the anaerobic sludge in agriculture can substantially increase the P recovery. Energy recovery in the form of biogas from anaerobic digestion of concentrated BW, fits well in new concepts of sustainable, zero energy buildings. Nutrient recovery from separately collected urine lowers the percentage of nutrient recovery in comparison with BW but can, on the other hand, often be implemented in existing sanitation concepts. Theoretically 11gN/p/d and 1.0 g P/p/d are produced with urine, of which 38-63 and 34-61% were recovered in practice on a scale of 8-160 inhabitants in Sweden. New sanitation concepts with resource recovery and reuse are being demonstrated worldwide and more and more experience is being gained. PMID- 22105120 TI - Multicriteria decision-aid method to evaluate the performance of stormwater infiltration systems over the time. AB - Nowadays, stormwater infiltration systems are frequently used because of their ability to reduce flows and volumes in downstream sewers, decrease overflows in surface waters and make it possible to recharge groundwater. Moreover, they come in various forms with different uses. Despite these advantages the long term sustainability of these systems is questionable and their real performances have to be assessed taking into account various and sometimes conflicting aspects. To address this problem a decision support system is proposed. It is based on a multicriteria method built to help managers to evaluate the performance of an existing infiltration system at different stages of its lifespan and identify whether it performs correctly or not, according to environmental, socio-economic, technical and sanitary aspects. The paper presents successively: the performance indicators and the way they were built, the multicriteria method to identify if the system works properly and a case study. PMID- 22105121 TI - Anaerobic degradation of palm oil mill effluent (POME). AB - The biodegradation characteristics of palm oil mill effluent (POME) and the related microbial community were studied in both actual sequential anaerobic ponds in Malaysia and enrichment cultures. The significant degradation of the POME was observed in the second pond, in which the temperature was 35-37 degrees C. In this pond, biodegradation of major long chain fatty acids (LCFA), such as palmitic acid (C16:0) and oleic acid (C18:1), was also confirmed. The enrichment culture experiment was conducted with different feeding substrates, i.e. POME, C16:0 and C18:1, at 35 degrees C. Good recovery of methane indicated biodegradation of feeds in the POME and C16:0 enrichments. The methane production rate of the C18:1 enrichment was slower than other substrates and inhibition of methanogenesis was frequently observed. Denaturing gradient gel electrophoresis (DGGE) analyses indicated the existence of LCFA-degrading bacteria, such as the genus Syntrophus and Syntorophomonas, in all enrichment cultures operated at 35 degrees C. Anaerobic degradation of the POME under mesophilic conditions was stably processed as compared with thermophilic conditions. PMID- 22105122 TI - Nitrification processes in scrubbing liquid of an exhaust air treatment system of a large-scale pig housing facility. AB - The use of multi-staged exhaust air treatment systems is an effective method of substantially reducing the emission of ammonia, dust particles and odorous substances. Wet filter walls are able to absorb large amounts of ammonia when scrubbing fluid containing sulphuric acid is used. In addition, due to their large surface areas and the permanent supply of oxygen and nutrients, wet filter walls provide a basis for the development of biofilms containing nitrogen converting bacteria. Cyclic nitrification processes could be observed in a two stage exhaust air treatment system, which had been converted to function as a regulated process control system (elutriation at kappa = 20 mS cm(-1); pH 6.5 6.8). With this system, the sulphuric acid requirement was periodically reduced every 6-8 weeks to less than 1 kg H(2)SO(4) per fattening place and year. There was an increased formation of nitrous oxide gas during nitrification after the wet filter stage. Electron-microscopic images of the biofilm growing on the wet filter wall showed aggregates of possible ammonium-oxidising and nitrite oxidising bacteria. PMID- 22105123 TI - Achieving and maintaining of short-cut nitrification in a cyclic activated sludge system. AB - A lab-scale Cyclic Activated Sludge Technology (CAST) system was operated more than 5 months to evaluate the effects of the operation mode on nitrogen removal performance and investigate a feasible method for achieving short-cut nitrification in the system. Results showed that nitrogen was removed by conventional biological nitrification and denitrification in traditional operation mode (fill/aeration 2 h, settle 1 h, decant 1 h), whereas short-cut nitrification and denitrification was the main nitrogen removal pathway in modified operation mode and the nitrogen removal performance was enhanced. Short cut nitrification was successfully achieved in CAST system at 17 +/- 1 degrees C by adjusting operation conditions and the average total nitrogen removal efficiency increased by 11.4% compared to traditional mode. It was assumed that low dissolved oxygen (<1.0 mg/L) limitation combined with free ammonia (0.28-0.34 mg/L) inhibition on nitrite-oxidizing bacteria caused nitrite accumulation in modified mode. During maintaining period of short-cut nitrification, preset aeration time enhanced ammonium-oxidizing bacteria dominance. It was also found that low DO could result in overgrowth of filamentous microorganisms and poor sludge settleability. The pH variation could provide effective information for controlling aeration duration in modified mode. However, no evident breakpoint appeared on pH and DO profiles in traditional mode. PMID- 22105124 TI - The effect of Ce doped in Ti/SnO(2)-Sb(2)O(3)/SnO(2)-Sb(2)O(3)-CeO(2) electrode and its electro-catalytic performance in caprolactam wastewater. AB - Ti/SnO(2)-Sb(2)O(3)/SnO(2)-Sb(2)O(3)-CeO(2) anodes were prepared by brush coating with high temperature oxidation. The anodes were characterized by X-ray diffractometer (XRD), scanning electron microscope and cyclic voltammetry. The surface of the electrode shows more compact and exist shallower mud cracks than the others by coating with 1% Ce to the surface of Ti/SnO(2)-Sb(2)O(3) electrode. The XRD patterns show that as-prepared electrodes are SnO(2) and TiO(2). The electrode with 1% Ce dopant shows the highest efficiency in the electrolysis of caprolactam wastewater. The oxygen evolution potential is about 1.75 V, the removal rate of chemical oxygen demand is 50%, and the biochemical oxygen demand is 353 mg/L for 5 h at a current of 0.12 A. PMID- 22105125 TI - Maize mono-digestion efficiency: results from laboratory tests. AB - A laboratory experimental campaign was carried out in order to assess the optimal configuration for the anaerobic digestion of a mixture of sweet corn and ensiled maize. Batch hydrolysis tests were conducted at 35 and 55 degrees C and at four different particle sizes (2, 5, 20 and 50 mm) obtained by manual chopping and sieving. Chemical pre-treatment by 24 h incubation at various acid and alkaline pH was also considered for its potential to increase the maize methane yield. Results suggest that the hydrolytic phase proceeds significantly faster under thermophilic conditions. Significant differences in the solubilization rate were also observed when comparing coarse (20-50 mm) with fine (2-5 mm) particles, while 2 and 5 mm particles were solubilized at similar rates. No advantages from the chemical pre-treatment, in terms of solubilization efficiency and biomethanization potential were observed. According to these preliminary results, a two-stage semi-continuous laboratory plant consisting of a thermophilic hydrolytic reactor followed by a mesophilic methanogenic reactor was operated for 110 days. Steady state loading parameters were: influent concentration (maize mixture diluted in tap water) of 46 g VS/L, hydraulic retention time of 31 d, organic loading rate of 1.5 g VS/L/d. Alkalinity was dosed to the methanogenic reactor to avoid pH drops. Collected data allowed the average biodegradation efficiency to be estimated at around 60-65%. PMID- 22105126 TI - Removal of contaminants and pathogens from secondary effluents using intermittent sand filters. AB - Intermittent infiltration percolation of wastewater through unsaturated sand bed is an extensive treatment technique aimed at eliminating organic matter, oxidizing ammonium and removing pathogens. The main purpose of this study was to determine the depuration efficiencies of a sand filter to remove contaminants from secondary wastewater effluents. Elimination of pathogenic bacteria (total and faecal coliforms, streptococci) and their relationship with the filter depth were investigated. Results showed a high capacity of infiltration percolation process to treat secondary effluents. Total elimination of suspended solids was obtained. Mean removal rate of BOD(5) and COD was more than 97 and more than 81%, respectively. Other water quality parameters such as NH(4)-N, TKN and PO(4)-P showed significant reduction except NO(3)-N which increased significantly in the filtered water. Efficiency of pathogenic bacteria removal was shown to mainly depend on the filter depth. Average reductions of 2.35 log total coliforms, 2.47 log faecal coliforms and 2.11 log faecal streptococci were obtained. The experimental study has shown the influence of the temperature on the output purification of infiltration percolation process. PMID- 22105127 TI - Integrating the implementation of the European Union Water Framework Directive and Floods Directive in Ireland. AB - Water Framework Directive (WFD) statutory authorities and stakeholders in Ireland are now challenged with the issue of how the proposed programmes of measures in the newly required River Basin Management Plans - designed to protect and restore good ecology by reverting as closely as possible back to natural conditions - are to be implemented in a way that concurrently complies with other existing and emerging intersecting European Union legislation, such as the Floods Directive (FD). The WFD is driven largely by ecological considerations, whereas the FD and other legislation are more geared towards protecting physical property and mitigating public safety risks. Thus many of the same waterbodies, especially heavily modified waterbodies, arguably have somewhat competing policy objectives put upon them. This paper explores the means by which Ireland might best achieve the highest degrees of cost effectiveness, economic efficiency and institutional durability in pursuing the common and overarching objective of the WFD and FD - to ensure Irish waterways are put to their highest valued uses. PMID- 22105128 TI - Retention of 2,4,6-trinitrotoluene and heavy metals from industrial waste water by using the low cost adsorbent pine bark in a batch experiment. AB - Pine bark is a low cost sorbent originating from the forest industry. In recent years, it has been found to show promise as an adsorbent for metals and organic substances in contaminated water, especially landfill leachates and storm water. This study aims to investigate if pine bark can replace commercial adsorbents such as active carbon. An industrial effluent, collected from a treatment plant of a demilitarization factory, was diluted to form concentration ranges of contaminants and shaken with pine bark for 24 hours. Metals (e.g. Pb, Zn, Cd, As and Ni) and explosives, e.g., 2,4,6-trinitrotoluene (TNT), were analysed before and after treatment. The aim of the experiment was twofold; firstly, it was to investigate whether metals are efficiently removed in the presence of explosives and secondly, if adsorption of explosive substances to pine bark was possible. Langmuir and Freundlich isotherms were used to describe the adsorption process where this was possible. It was found that metal uptake was possible in the presence of TNT and other explosive contaminants. The uptake of TNT was satisfactory with up to 80% of the TNT adsorbed by pine bark. PMID- 22105129 TI - Phenol adsorption by activated carbon produced from spent coffee grounds. AB - The present work highlights the preparation of activated carbons (ACs) using spent coffee grounds, an agricultural residue, as carbon precursor and two different activating agents: water vapor (ACW) and K(2)CO(3) (ACK). These ACs presented the microporous nature and high surface area (620-950 m(2) g(-1)). The carbons, as well as a commercial activated carbon (CAC) used as reference, were evaluated as phenol adsorbent showing high adsorption capacity (~150 mg g(-1)). The investigation of the pH solution in the phenol adsorption was also performed. The different activating agents led to AC with distinct morphological properties, surface area and chemical composition, although similar phenol adsorption capacity was verified for both prepared carbons. The production of activated carbons from spent coffee grounds resulted in promising adsorbents for phenol removal while giving a noble destination to the residue. PMID- 22105130 TI - The effect of sulfide and ammonia on cassava fermentation for ethanol production in an ethanol-methane coupled system. AB - An ethanol-methane coupled system was proposed to resolve wastewater pollution in cassava ethanol production. The wastewater originated from ethanol distillation is treated with two-stage anaerobic digestion and then recycled for medium preparation for the next batch ethanol fermentation, thus eliminating wastewater discharge and saving fresh water. The constituents of the two-stage anaerobic digestion effluent were complex which influenced the ethanol fermentation performance. This paper aimed to study the effect of two constituents in the effluent, i.e. sulfide and ammonia, on cassava-based ethanol fermentation performance. It was found that sulfide reduced the consumption rate of total sugar by significantly inhibiting the growth of Saccharomyces cerevisiae, but the total consumption amount of total sugar at the end of fermentation was not influenced. S. cerevisiae produced more glycerol and less ethanol at the end of fermentation containing higher concentration of sodium sulfide. Ethanol fermentation performance could be hardly influenced by the sulfide in the two stage effluent because of the very low concentration. More glycerol was produced while final ethanol concentration was reduced when the level of ammonia in the two-stage effluent was higher. PMID- 22105131 TI - A distillery by-product as an external carbon source for enhancing denitrification in mainstream and sidestream treatment processes. AB - The use of fusel oil as an 'alternative' carbon source for denitrification in the mainstream and sidestream treatment processes was studied. Research comprised two kinds of batch experiments as well as acclimation of process biomass to external carbon sources. In the conventional nitrate utilization rate (NUR) measurements (one-phase experiments with non-acclimated biomass), the NUR with fusel oil was 1.4-1.7 g N/(kg VSS.h which was comparable to NUR with ethanol and with slowly biodegradable fraction of the settled wastewater. When fusel oil was added at the beginning of the anoxic phase, preceded by an anaerobic phase (in two-phase experiments with non-acclimated biomass), the NURs of 2.5-2.9 g N/(kg VSS.h) were comparable to the tests without the addition of any external carbon sources. The addition of fusel oil and ethanol resulted in a significant enhancement of the denitrification efficiency in lab-scale sequencing batch reactors treating sludge reject water. The NURs continuously increased from below 1 g N/(kg VSS.h) to over 10 g N/(kg VSS.h) over the entire 4-week operational period, indicating gradual acclimation to the substrate. The overall total N removal efficiency reached ~90%. PMID- 22105132 TI - Modelling of an EGSB treating sugarcane vinasse using first-order variable kinetics. AB - An expanded granular sludge bed (EGSB) anaerobic reactor treating sugar cane vinasse was modelled using a simple model with two steps (acidogenesis and methanogenesis), two populations, two substrates and completely mixed conditions. A first-order kinetic equation for both steps with time-variant kinetic coefficients was used. An observer system was used to estimate the evolution of kinetic constants over time. The model was validated by comparing methane flow predictions with experimental values. An estimation of evolution of populations of microorganisms was also performed. This approach allows calculation of specific kinetic constants that reflect biological activity of microorganisms. Variation of specific kinetic constants reflects the influence of the fraction of raw vinasse in the feed. High salt concentrations in the reactor may have inhibited the process. PMID- 22105133 TI - Floating treatment wetlands for domestic wastewater treatment. AB - Floating islands are a form of treatment wetland characterized by a mat of synthetic matrix at the water surface into which macrophytes can be planted and through which water passes. We evaluated two matrix materials for treating domestic wastewater, recycled plastic and recycled carpet fibers, for chemical oxygen demand (COD) and nitrogen removal. These materials were compared to pea gravel or open water (control). Experiments were conducted in laboratory scale columns fed with synthetic wastewater containing COD, organic and inorganic nitrogen, and mineral salts. Columns were unplanted, naturally inoculated, and operated in batch mode with continuous recirculation and aeration. COD was efficiently removed in all systems examined (>90% removal). Ammonia was efficiently removed by nitrification. Removal of total dissolved N was ~50% by day 28, by which time most remaining nitrogen was present as NO(3)-N. Complete removal of NO(3)-N by denitrification was accomplished by dosing columns with molasses. Microbial communities of interest were visualized with denaturing gradient gel electrophoresis (DGGE) by targeting specific functional genes. Shifts in the denitrifying community were observed post-molasses addition, when nitrate levels decreased. The conditioning time for reliable nitrification was determined to be approximately three months. These results suggest that floating treatment wetlands are a viable alternative for domestic wastewater treatment. PMID- 22105134 TI - Removal of typical endocrine disrupting chemicals by membrane bioreactor: in comparison with sequencing batch reactor. AB - The removal of endocrine disrupting chemicals (EDCs) by a laboratory-scale membrane bioreactor (MBR) fed with synthetic sewage was evaluated and moreover, compared with that by a sequencing batch reactor (SBR) operated under same conditions in parallel. Eight kinds of typical EDCs, including 17beta-estradiol (E2), estrone (E1), estriol (E3), 17alpha-ethynilestradiol (EE2), 4-octylphenol (4-OP), 4-nonylphenol (4-NP), bisphenol A (BPA) and nonylphenol ethoxylates (NPnEO), were spiked into the feed. Their concentrations in influent, effluent and supernatant were determined by gas chromatography-mass spectrometry method. The overall estrogenecity was evaluated as 17beta-estradiol equivalent quantity (EEQ), determined via yeast estrogen screen (YES) assay. E2, E3, BPA and 4-OP were well removed by both MBR and SBR, with removal rates more than 95% and no significant differences between the two reactors. However, with regard to the other four EDCs, of which the removal rates were lower, MBR performed better. Comparison between supernatant and effluent of the two reactors indicated that membrane separation of sludge and effluent, compared with sedimentation, can relatively improve elimination of target EDCs and total estrogenecity. By applying different solids retention times (SRTs) (5, 10, 20 and 40 d) to the MBR, 10 and 5 d were found to be the lower critical SRTs for efficient target EDCs and EEQ removal, respectively. PMID- 22105135 TI - New insights in the dihydroxybenzenes-driven Fenton reaction: electrochemical study of interaction between dihydroxybenzenes and Fe(III). AB - It has been reported that the dihydroxybenzene (DHB) driven Fenton reaction is more efficient to degrade recalcitrant substrates than the simple Fenton reaction. The enhanced reactivity of the DHB driven Fenton reaction is not clear, but it could be explained by the formation of oxidant species different from the ones formed by classical Fenton reaction or by the shift of the redox potential of the complex formed by DHB and Fe(III). The redox reaction between Fe(III) and the DHBs 1,2-dihydroxybenzene (catechol, CAT), 2,3-dihydroxybenzoic acid (2,3 DHBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), and 1,2-dihydroxy-3,5 benzenedisulfonate (TIRON) was studied by cyclic voltammetry to better understand the enhanced reactivity of the DHB driven Fenton reaction. It was determined that the amount of Fe(II) produced by the redox reaction between Fe(III) and DHBs was insufficient to explain the enhanced reactivity. Cyclic voltammograms (CV) of the DHBs/Fe(III) systems show a quasi-reversible or irreversible behavior and also shifting and splitting the anodic peaks. This effect can be related to DHBs oxidation by Fe(III), but not to a real interaction. PMID- 22105136 TI - Water management in cities of the future using emission control strategies for priority hazardous substances. AB - Cities of the future face challenges with respect to the quantity and quality of water resources, and multiple managerial options need to be considered in order to safeguard urban surface water quality. In a recently completed project on 'Source control options for reducing emissions of Priority Pollutants' (ScorePP), seven emission control strategies (ECSs) were developed and tested within a semi hypothetical case city (SHCC) to evaluate their potential to reduce the emission of selected European priority hazardous substances (PHSs) to surface waters. The ECSs included (1) business-as-usual, (2) full implementation of relevant European (EU) directives, (3) ECS2 in combination with voluntary options for household, municipalities and industry, (4) ECS2 combined with industrial treatment and best available technologies (BAT), (5) ECS2 in combination with stormwater and combined sewer overflow treatment, (6) ECS2 in combination with advanced wastewater treatment, and (7) combinations of ECS3-6. The SHCC approach was chosen to facilitate transparency, to allow compensating for data gaps and to decrease the level of uncertainty in the results. The selected PHSs: cadmium (Cd), hexachlorobenzene (HCB), nonylphenol (NP) and pentabromodiphenyl ether (PBDE) differ in their uses and environmental fate and therefore accumulate in surface waters to differing extents in response to the application of alternative ECS. To achieve the required reduction in PHS levels in urban waters the full implementation of existing EU regulation is prioritised and feasible combinations of managerial and technological options (source control and treatment) can be highly relevant for mitigating releases. PMID- 22105137 TI - Hydrochemical evaluation of surface water quality and pollution source apportionment in the Luan River basin, China. AB - In the context of rapid economic growth in China, hydrochemical characteristics of stream water quality are being influenced by a variety of natural and anthropogenic inputs. We determined 10 hydrochemical parameters of the surface water at 29 monitoring sites in the Luan River basin of northern China during 2007-2009. Water quality hydrochemistry was evaluated using fuzzy comprehensive analysis based on the National Surface Water Environmental Quality Standards of China. Our results showed that 14 sites were classified as 'meeting standard (MS)' while the other 15 sites were classified 'non-meeting standard (NS)'. According to principal component analysis, four potential pollution sources were identified that explained 80.6% of the total variance among these MS sites, and three potential pollution sources that explained 78.3% of the total variance among these NS sites. Furthermore, multi-linear regression of the absolute principal component scores was used to estimate contributions from identified pollution sources. Most water pollution variables were influenced primarily by municipal sewage and non-point pollution in MS sites. In NS sites, chemical industry wastewater pollution dominated. Pollution in the main stream was more serious than that in the small tributaries. Our findings provide useful information for developing better pollution control strategies for the Luan River. PMID- 22105138 TI - Effective degradation of para-chloronitrobenzene through a sequential treatment using zero-valent iron reduction and Fenton oxidation. AB - In this study, zero-valent iron (ZVI) was used to pretreat para chloronitrobenzene (p-CNB), and the major product was para-chloroaniline (p-CAN). By adding H(2)O(2) directly, further p-CAN degradation can be attributed to Fenton oxidation because ferrous ions (Fe(2+)) released during the ZVI corrosion could be used as an activator for H(2)O(2) decomposition. In the reduction process, the reduction efficiency of p-CNB as well as Fe(2+) concentration increased with increasing iron dosage and decreasing solution pH. Under the optimal conditions, 25 mg L(-1) of p-CNB could be transformed in 3 h when initial solution pH was 3.0 and ZVI dosage was 2.0 g L(-1). A sufficient amount of Fe(2+) (50.4 mg L(-1)) was obtained after the above reaction to activate H(2)O(2). In the Fenton process, the oxidization of p-CAN was also more effective in acidic conditions and it increased with increasing H(2)O(2) concentration. The control experiments showed that the sequential treatment was more effective than Fenton oxidation alone in treating p-CNB wastewater since the removal rate of total organic carbon (TOC) was improved by about 34%. It suggested that the amino function group is more susceptible to oxidative radical attack than the nitro function group. Therefore, sequential treatment using zero-valent iron reduction followed by Fenton oxidation is a promising method for p-CNB degradation. PMID- 22105139 TI - Molecular properties of hybrid macromolecular antioxidants: dextran hydrophobically modified by sterically hindered phenols. AB - The conformation properties of clinically relevant hybrid macromolecular antioxidants (dextran hydrophobically modified by sterically hindered phenols) in aqueous solution were characterized by a combination of dynamic light scattering (DLS), size exclusion chromatography (SEC), and small-angle neutron scattering (SANS). We were able to split and analyze separately two different types of polydispersity -polydispersity over molecular weights and the one over substitution degree. The properties of the hybrid macromolecules are determined by the number of hydrophobic antioxidants in a single molecule. An insertion of hydrophobic groups into a hydrophilic chain changes the conformation of a single conjugate macromolecule. We have established that with the increasing of a number of hydrophobic antioxidant groups, a conformational transition occurs where a single conjugate undergoes a transition from a Gaussian coil conformation to a more compact structure. PMID- 22105140 TI - Do planning and visual integration difficulties underpin motor dysfunction in autism? A kinematic study of young children with autism. AB - This paper examines the upper-limb movement kinematics of young children (3-7 years) with high-functioning autism using a point-to-point movement paradigm. Consistent with prior findings in older children, a difference in movement preparation was found in the autism group (n = 11) relative to typically developing children. In contrast to typically developing children, the presence of a visual distractor in the movement task did not appear to impact on early movement planning or execution in children with autism, suggesting that this group were not considering all available environmental cues to modulate movement. The findings from this study are consistent with the possibility that autism is associated with a difficulty using visual information to prime alternative movements in a responsive way to environmental demands. PMID- 22105141 TI - Exploring the relationship between autism spectrum disorder and epilepsy using latent class cluster analysis. AB - Epilepsy co-occurs frequently in autism spectrum disorders (ASD). Understanding this co-occurrence requires a better understanding of the ASD-epilepsy phenotype (or phenotypes). To address this, we conducted latent class cluster analysis (LCCA) on an ASD dataset (N = 577) which included 64 individuals with epilepsy. We identified a 5-cluster solution with one cluster showing a high rate of epilepsy (29%), earlier age at first recognition, and high rates of repetitive object use and unusual sensory interests. We also conducted LCCA on an ASD epilepsy subset from the overall dataset (N = 64) which yielded three clusters, the largest of which had impairments in language and motor development; the remaining clusters, while not as developmentally impaired were characterized by different levels of repetitive and sensory behaviors. PMID- 22105142 TI - Predicting the academic achievement of gifted students with autism spectrum disorder. AB - We are not well informed regarding the ability-achievement relationship for twice exceptional individuals (very high cognitive ability and a diagnosed disability, e.g., autism spectrum disorder [ASD]). The research question for this investigation (N = 59) focused on the predictability of achievement among variables related to ability and education in a twice-exceptional sample of students (cognitive ability of 120 [91st percentile], or above, and diagnosed with ASD). We determined that WISC-IV Working Memory and Processing Speed Indices were both significantly positively correlated with achievement in math, reading, and written language. WISC Perceptual Reasoning Index was uniquely predictive of Oral Language test scores. Unexpected findings were that ASD diagnosis, Verbal Comprehension Index, and forms of academic acceleration were not related to the dependent variables. PMID- 22105143 TI - Normal rates of neuroradiological findings in children with high functioning autism. AB - Magnetic resonance imaging (MRI) has been used to analyze highly specific volumetric and morphological features of the brains of individuals with autism spectrum disorder (ASD). To date, there are few comprehensive studies examining the prevalence of neuroradiologic findings seen on routine MRI scans in children with ASD. This study examined the prevalence of neuroradiologic findings in children with high functioning ASD, and compared these rates to those in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and children who are typically developing (TD). Results showed that approximately 90% of children had normal MRI scans. There was no significant effect of diagnosis on the total number of neuroradiological findings or the number of specific brain findings. Implications and future research directions are discussed. PMID- 22105144 TI - Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD. AB - BACKGROUND: Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. METHODS: We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-alpha], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. RESULTS: Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R(2) = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. CONCLUSION: Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD. PMID- 22105146 TI - Clinical implications of ERbeta methylation on sporadic breast cancers in Chinese women. AB - Estrogens play a key role in the genesis and progression of breast cancer, activating two estrogen receptors, alpha and beta (ERalpha and ERbeta). We have previously observed that ERalpha methylation occurs in high frequency and may be one of the mechanisms of ERalpha expression silence in a subset of Chinese sporadic breast cancers. However, the ERbeta promoter methylation status and the relationship between clinicopathological characteristics and ERbeta methylation in sporadic breast cancer are still unknown, especially in Chinese women. This study acted to determine the methylation status of the ERbeta promoter and its correlation with clinicopathological features of sporadic breast cancers in Chinese women, and lay a foundation for the management of breast cancer. In total, 178 cases with sporadic breast cancers were enrolled in the study. ERbeta methylation was determined using a methylation-specific polymerase chain reaction (MSP). In general, ERbeta promoter methylation was found in 44.9% (80/178) of breast tumor samples, significantly higher than the benign breast hyperplasia (44.9% vs. 14.3%, X(2) = 4.986, P = 0.026). A total of 58% (40/69) of ERbeta negative tumors got methylation compared with 36.7% (40/109) of ERbeta-positive cases being methylated (X(2) = 7.728, P = 0.005). The levels of ERbeta protein expression diminished with the frequency of ERbeta methylation (r = -0.249, P < 0.0001). In addition, we observed a strong correlation between ERalpha promoter and ERbeta promoter methylation (odds ratio 2.054, 95% confidence interval 1.086 3.886, P = 0.026), and the triple-negative tumors showed a significantly higher methylation rate of ERbeta. This study presents, for what we believe to be the first time, that ERbeta methylation is also a frequent event in breast cancer and maybe also one of the mechanisms of ERbeta expression silence in a subset of Chinese sporadic breast cancers. Epigenetic alteration of the ERbeta gene may play an important role in the pathogenesis of breast cancer. PMID- 22105147 TI - Role of the recently identified dysadherin in E-cadherin adhesion molecule downregulation in head and neck cancer. AB - Dysadherin is a cancer-related cell membrane glycoprotein, recently identified, playing an important role in tumor progression and metastasis. In the present minireview article, we are focusing on the role of dysadherin in E-cadherin downregulation, the various expression patterns of the molecule in head and neck cancer as well as its potential role as a molecular target for future applications in diagnosis, clinical routine and prognosis of the disease. PMID- 22105148 TI - Mechanisms of Apoptin-induced cell death. AB - Apoptin, a 13.6-kD protein encoded by chicken anemia virus, is paid more and more attention, since it selectively induces apoptosis in tumor cells while abolishes cytotoxic effect in normal cells. In addition, Apoptin shows different localization in tumor cells and normal cells: it predominantly accumulates in nucleus of tumor cells, whereas in normal cells, it is detected mainly in cytoplasm. There are various mechanisms implicated in the program of Apoptin mediated cell death. Up to now, the interpretations have been recognized including that the particular domains control nucleocytoplasmic shuttling of Apoptin, phosphorylation on specific residue and varies relevant signaling contribute to Apoptin's activity, and the partners interacted with Apoptin regulate activity or subcellular localization of Apoptin. In this review, we make a comprehensive survey of the existing evidence about mechanisms of Apoptin's action, which might provide scientific basis to make progress in novel targeted tumor therapy. PMID- 22105150 TI - Letter to the Editor. PMID- 22105149 TI - Progestogen levels, progesterone receptor gene polymorphisms, and mammographic density changes: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study. AB - OBJECTIVE: Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestinv Interventions trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of posttreatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density. METHODS: We measured the percent mammographic density and serum progestogen levels in 280 Postmenopausal Estrogen/Progestin Interventions trial participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how an increase in progestogen levels and PGR genetic variation influenced mammographic density change after EPT. RESULTS: The increase in posttreatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P trend = 0.044). Compared with women in the lowest quartile of serum progestogen level, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P = 0.046). We did not find a strong indication that genetic variation in PGR was associated with mammographic density increase or modified the association with serum progestogen; however, confidence in these null findings is constrained by our small sample size. CONCLUSIONS: Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density. PMID- 22105151 TI - JoAnn E. Manson, MD, DrPH, NCMP 2011-2012 NAMS President. PMID- 22105152 TI - The Chinese Utian Quality of Life Scale for women around menopause: translation and psychometric testing. AB - OBJECTIVE: Chinese-language scales for assessing quality of life in women around menopause are rare. This study was conducted to evaluate the psychometric properties of a Chinese-language version of the Utian Quality of Life Scale (UQOL C). METHODS: A sample of women (n = 434) between 41 and 60 years old was recruited from an obstetrics/gynecology outpatient department in Taipei. After translating the instrument, we conducted psychometric testing, which included internal consistency, test-retest reliability, and construct validity. Construct validity of the UQOL-C was examined by testing the correlations between the UQOL C and the 36-item Short-Form Health Survey Taiwan version and between the UQOL-C and the Greene Climacteric Scale Chinese version. RESULTS: The Chinese translation captured the content of the original tool. The reliability coefficients (Cronbach alpha) for the quality of life domains measured were as follows: 0.86, overall; 0.85, occupational; 0.70, health-related; 0.66, emotional; and 0.61, sexual. The test-retest reliability of the UQOL-C was satisfactory (r = 0.88-0.91, P < 0.001). The construct validity of the UQOL-C was confirmed through significant correlations between scores on (1) the UQOL-C and the 36-item Short-Form Health Survey Taiwan version (r = 0.15-0.59, P < 0.01) and (2) the UQOL-C and the Greene Climacteric Scale Chinese version (r = -0.10 to 0.56, P < 0.05). CONCLUSIONS: The UQOL-C was shown to be reliable and valid with this sample of women between 41 and 60 years old. The low Cronbach alpha values of the UQOL-C emotional and sexual domains suggested that the reliability of these two domains required further studies. PMID- 22105153 TI - Computer-assisted gait analysis of the dog: comparison of two surgical techniques for the ruptured cranial cruciate ligament. AB - OBJECTIVES: To compare the improvement in degree of lameness following surgical repair of cranial cruciate ligament rupture in dogs using computer-assisted gait analysis. METHODS: Two groups of 14 dogs were used. One group was treated by a capsular-fascial imbrication method, and the other group by tibial plateau levelling osteotomy (TPLO). All dogs underwent gait analysis prior to surgery, as well as at four days, four weeks, and four months after surgery. Symmetry indices of vertical ground reaction forces as well as vertical ground reaction forces in % body weight, joint angles and certain gait cycle parameters were evaluated. RESULTS: Four months after surgery, the degree of lameness expressed as symmetry index for peak vertical force for the TPLO group (5.83%) was not significantly different to the capsular-fascial imbrication group (19.05%). Within the TPLO group, there was a significantly increased ability to extend the stifle joint four months after surgery. The stifle motion pattern of the capsular-fascial imbrication group as well as the range-of-motion in both groups showed very little change at the time of the last gait analysis. The complication rate was greater in the TPLO group than in the capsular-fascial group. CLINICAL SIGNIFICANCE: In conclusion the results suggest that the TPLO method leads to a faster recovery and improved limb function in comparison to the capsular-fascial imbrication method four months after surgery. Further analyses are needed to determine if the TPLO method is superior concerning long-term joint stability. PMID- 22105154 TI - Sepsis leads to a reduced antigen-specific primary antibody response. AB - Immunosuppression, impaired cytokine production and high susceptibility to secondary infections are characteristic for septic patients, and for mice after induction of polymicrobial septic peritonitis by sublethal cecal ligation and puncture (CLP). Here, we demonstrate that CLP markedly altered subsequent B-cell responses. Total IgG and IgM levels, as well as the memory B-cell response, were increased in septic mice, but antigen-specific primary antibody production was strongly impaired. We found that two days after CLP, CD11b(+) splenocytes were activated as demonstrated by the increased expression of activation markers, expression of arginase and production of NO by immature myeloid cells. The in vivo clearance of a bacterial infection was not impaired. DCs demonstrated reduced IL-12 production and altered antigen presentation, resulting in decreased proliferation but enhanced IFN-gamma production by CD4(+) cells. CD4(+) T cells from mice immunized on day 2 after CLP showed reduced Th1 and Th2 cytokine production. In addition, there was an increase in Treg cells. Interestingly, levels of immature B cells decreased but levels of mature B cells increased two days after CLP. However, adoptive transfer of naive CD4(+) T cells, naive B cells, or naive DCs did not rescue the antigen-specific antibody response. PMID- 22105155 TI - Proteotoxic stress of cancer: implication of the heat-shock response in oncogenesis. AB - Organisms frequently encounter a wide variety of proteotoxic stressors. The heat shock response, an ancient cytoprotective mechanism, has evolved to augment organismal survival and longevity in the face of proteotoxic stress from without and within. These broadly recognized beneficial effects, ironically, contrast sharply with its emerging role as a culprit in the pathogenesis of cancers. Here, we present an overview of the normal biology of the heat-shock response and highlight its implications in oncogenic processes, including the proteotoxic stress phenotype of cancer; the function of this stress response in helping cancer survive and adapt to proteotoxic stress; and perturbation of proteome homeostasis in cancer as a potential therapeutic avenue. PMID- 22105156 TI - FMRI as a measure of cognition related brain circuitry in schizophrenia. AB - Functional magnetic resonance imaging (fMRI) has played a prominent role in the quest to identify the brain systems responsible for cognitive dysfunction in schizophrenia. This chapter describes the evolution of these research efforts, which have alternated between efforts to localize specific cognitive impairments to work trying to understand broader network dysfunction. After a concise summary of localization efforts, the remainder of the chapter describes how different groups of scientists have developed and tested broader network theories. This includes a description of both task-activation and resting state studies, and involves a wide array of analytic techniques. The chapter closes with an understanding of how current default-mode and task-positive network theories grew out of these earlier resting-state and task-activation approaches, and provides some recommendations about future directions. PMID- 22105157 TI - Hypertension: Does the timing of antihypertensive agents affect clinical outcomes in patients with chronic kidney disease? PMID- 22105158 TI - Hemodialysis: Long weekend hemodialysis intervals--killing fields? PMID- 22105159 TI - Chronic kidney disease: Use of drug-eluting stents in older patients with CKD. PMID- 22105160 TI - Preventive effect of Terminalia bellirica on obesity and metabolic disorders in spontaneously obese type 2 diabetic model mice. AB - Visceral obesity induces insulin resistance and is recognized as an important risk factor for metabolic syndrome (MS). Therefore, inhibition of lipid absorption from the intestine is regarded as an effective way of preventing MS. Terminalia bellirica is extensively used in Ayurvedic medicine in India and neighboring countries, and the fruit of this plant has been reported to have hypoglycemic and hypolipidemic effects. In this study, we investigated the preventive effect of a hot water extract of T. bellirica fruit (TB) on obesity and various metabolic disorders, and explored its molecular mechanisms and active ingredients. TB treatment had a preventive effect on obesity, insulin resistance, and hyperlipidemia in spontaneously obese type 2 diabetic TSOD mice. To clarify the molecular mechanisms of TB in preventing obesity, we investigated the inhibitory effect on lipid absorption. TB suppressed absorption of triacylglycerol in an olive oil loading test (in vivo) and showed a strong inhibitory effect on pancreatic lipase activity (in vitro). Furthermore, a search for the active ingredients in TB revealed that gallic acid is the component primarily responsible for the inhibition of pancreatic lipase activity. Thus, our findings indicate that TB could be useful in preventing MS. The mechanisms probably involve suppression of the absorption of meal-derived lipids mediated by gallic acid. PMID- 22105161 TI - Behavioral assessment of manual dexterity in non-human primates. AB - The corticospinal (CS) tract is the anatomical support of the exquisite motor ability to skillfully manipulate small objects, a prerogative mainly of primates(1). In case of lesion affecting the CS projection system at its origin (lesion of motor cortical areas) or along its trajectory (cervical cord lesion), there is a dramatic loss of manual dexterity (hand paralysis), as seen in some tetraplegic or hemiplegic patients. Although there is some spontaneous functional recovery after such lesion, it remains very limited in the adult. Various therapeutic strategies are presently proposed (e.g. cell therapy, neutralization of inhibitory axonal growth molecules, application of growth factors, etc), which are mostly developed in rodents. However, before clinical application, it is often recommended to test the feasibility, efficacy, and security of the treatment in non-human primates. This is especially true when the goal is to restore manual dexterity after a lesion of the central nervous system, as the organization of the motor system of rodents is different from that of primates(1,2). Macaque monkeys are illustrated here as a suitable behavioral model to quantify manual dexterity in primates, to reflect the deficits resulting from lesion of the motor cortex or cervical cord for instance, measure the extent of spontaneous functional recovery and, when a treatment is applied, evaluate how much it can enhance the functional recovery. The behavioral assessment of manual dexterity is based on four distinct, complementary, reach and grasp manual tasks (use of precision grip to grasp pellets), requiring an initial training of adult macaque monkeys. The preparation of the animals is demonstrated, as well as the positioning with respect to the behavioral set-up. The performance of a typical monkey is illustrated for each task. The collection and analysis of relevant parameters reflecting precise hand manipulation, as well as the control of force, are explained and demonstrated with representative results. These data are placed then in a broader context, showing how the behavioral data can be exploited to investigate the impact of a spinal cord lesion or of a lesion of the motor cortex and to what extent a treatment may enhance the spontaneous functional recovery, by comparing different groups of monkeys (treated versus sham treated for instance). Advantages and limitations of the behavioral tests are discussed. The present behavioral approach is in line with previous reports emphasizing the pertinence of the non-human primate model in the context of nervous system diseases(2,3). PMID- 22105162 TI - Palliative care quality indicators in Italy. What do we evaluate? AB - PURPOSE: In recent years, the number of palliative service providers has increased significantly. This expansion necessitates an evaluation in order to provide the basis for quality improvement of the care. Policymakers, managers of palliative care programs, and others committed to the improvement of end-of-life care need methods and criteria to measure and evaluate the care delivered. As quality measurement is expensive and difficult to undertake, it is fundamental that quality measures evaluate the right things. Quality evaluation in Italy is supported by health authorities who have developed some indicators of palliative care. The aims of this study were to give an overview of these indicators. METHODS: We analyzed all palliative care indicators developed by Italian national authorities from 2000 to the present. These indicators have been divided into three different levels of analysis (structure, process, and outcome). Subsequently, two reviewers have independently compared their degree of concordance with domains, and guidelines developed by the NCP for palliative care and after careful discussion an expert panel has elaborated a final consensus document. RESULTS: Most of the quality indicators analyzed deal with the structure and process of palliative care, however they miss outcomes and do not cover domains mainly concerned with spiritual, ethical, cultural, or existential aspects of care. CONCLUSIONS: More attention should be paid to the development of outcome indicators of palliative care. The attempt to identify a group of indicators which cover every domain of palliative care represents a challenge for the future in terms of finding new cognitive models more oriented toward subjectivity. PMID- 22105163 TI - Head-to-head comparisons of quality of life instruments for young adult survivors of childhood cancer. AB - PURPOSE: Few studies examine the relevance of health-related quality of life (HRQOL) instruments for young adult survivors of childhood cancer (YASCC). This study compared the psychometric properties of two survivor-specific instruments, the Quality of Life-Cancer Survivor (QOL-CS) and Quality of Life in Adult Cancer Survivor (QLACS). METHODS: Data from 151 YASCC who enrolled in cancer/tumor registries of two medical centers were used. We examined construct validity by conducting confirmatory factor analysis using indices of chi-square statistic, comparative fit index, and root mean square error of approximation. We examined convergent/discriminant validity by comparing Pearson's correlation coefficients of homogeneous (e.g., physical functioning and pain) of both instruments versus heterogeneous domains (e.g., physical and psychological functioning). We assessed known-groups validity by examining the extent to which HRQOL differed by late effects and comorbid conditions and calculated relative validity (RV) defined as contrasting F-statistics of individual domains to the domain with the lowest F statistic. Superior known-groups validity is observed if a domain of one instrument demonstrates a higher RV than other domains of the instruments. RESULTS: YASCC data cannot replicate the constructs both instruments intend to measure, suggesting poor construct validity. Correlations of between-homogeneous and between-heterogeneous domains of both instruments were not discernible, suggesting poor convergent/discriminant validity. Both instruments were equally able to differentiate HRQOL between YASCC with and without late effects and comorbid conditions, suggesting similar known-groups validity. CONCLUSIONS: Neither instrument is superior. Item response theory is suggested to select high quality items from different instruments to improve HRQOL measure for YASCC. PMID- 22105164 TI - A new medical therapy for Cushing disease? AB - Members of the ErbB family of cell surface tyrosine kinase receptors are important targets for cancer treatment because they frequently contribute to the pathogenesis of malignancy. In this issue of the JCI, Fukuoka et al. generate data that suggest that using a tyrosine kinase inhibitor (TKI) against epidermal growth factor receptor (EGFR; also known as ErbB1) may be a novel approach for treating patients with hypercortisolemia due to pituitary corticotroph adenomas (Cushing disease). While surgical resection remains the cornerstone of treatment for individuals with such tumors, this study suggests that TKIs could perhaps be used to reduce tumor size prior to surgery or to treat recurrent disease after surgery. PMID- 22105165 TI - Perception of sound and gravity by TMC1 and TMC2. AB - Central to our ability to hear and sense gravity is a cellular process known as mechanotransduction, which is initiated by the opening of mechanosensitive cation channels located near the tips of the stereocilia of auditory and vestibular inner ear hair cells. The molecular identity of the mechanotransduction channels has eluded researchers despite intensive investigations over the years. In this issue of the JCI, Kawashima et al. report their results obtained using mice with targeted deletion of both transmembrane channel-like 1 (Tmc1) and Tmc2. The use of inner ear hair cells isolated from these mice provided a nearly perfect system for testing the mechanotransduction channels without disrupting functions of other accessory proteins needed in the complicated molecular apparatus, and it allowed the authors to show that the proteins encoded by these genes are integral components of the mechanotransduction complex. PMID- 22105166 TI - Another VCP interactor: NF is enough. AB - Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin 1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1. PMID- 22105167 TI - On the origin of the liver. AB - While it has been well established that the fetal liver originates from foregut endoderm, the identity of the mechanisms that maintain liver mass under both basal and injury conditions remains controversial. Dramatically different models have been proposed based on the experimental design employed. In this issue of the JCI, Malato and colleagues report their elegant new model for genetic lineage tracing of mature mouse hepatocytes using an adenoassociated virus-driven Cre recombinase. They show convincingly that maintenance of liver mass during normal turnover or in response to mild injury is achieved by mature hepatocytes, rather than cholangiocytes or specialized progenitor cells, as has been suggested by others. PMID- 22105168 TI - In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish. AB - Oxidative modification of LDL is an early pathological event in the development of atherosclerosis. Oxidation events such as malondialdehyde (MDA) formation may produce specific, immunogenic epitopes. Indeed, antibodies to MDA-derived epitopes are widely used in atherosclerosis research and have been demonstrated to enable cardiovascular imaging. In this study, we engineered a transgenic zebrafish with temperature-inducible expression of an EGFP-labeled single-chain human monoclonal antibody, IK17, which binds to MDA-LDL, and used optically transparent zebrafish larvae for imaging studies. Feeding a high-cholesterol diet (HCD) supplemented with a red fluorescent lipid marker to the transgenic zebrafish resulted in vascular lipid accumulation, quantified in live animals using confocal microscopy. After heat shock-induced expression of IK17-EGFP, we measured the time course of vascular accumulation of IK17-specific MDA epitopes. Treatment with either an antioxidant or a regression diet resulted in reduced IK17 binding to vascular lesions. Interestingly, homogenates of IK17-EGFP expressing larvae bound to MDA-LDL and inhibited MDA-LDL binding to macrophages. Moreover, sustained expression of IK17-EGFP effectively prevented HCD-induced lipid accumulation in the vascular wall, suggesting that the antibody itself may have therapeutic effects. Thus, we conclude that HCD-fed zebrafish larvae with conditional expression of EGFP-labeled oxidation-specific antibodies afford an efficient method of testing dietary and/or other therapeutic antioxidant strategies that may ultimately be applied to humans. PMID- 22105169 TI - EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. AB - Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease. PMID- 22105170 TI - Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. AB - The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans. PMID- 22105171 TI - Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. AB - Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1(+/-) mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation. PMID- 22105172 TI - Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. AB - Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes. PMID- 22105173 TI - Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. AB - Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1-infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood. PMID- 22105174 TI - Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. AB - Advanced human thyroid cancers, particularly those that are refractory to treatment with radioiodine (RAI), have a high prevalence of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations. However, the degree to which these cancers are dependent on BRAF expression is still unclear. To address this question, we generated mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas (BRAF(V600E)) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAF(V600E), the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAF(V600E) expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAF(V600E) rapidly induced hypothyroidism and virtually abolished thyroid-specific gene expression and RAI incorporation, all of which were restored to near basal levels upon discontinuation of dox. Treatment of mice with these cancers with small molecule inhibitors of either MEK or mutant BRAF reduced their proliferative index and partially restored thyroid-specific gene expression. Strikingly, treatment with the MAPK pathway inhibitors rendered the tumor cells susceptible to a therapeutic dose of RAI. Our data show that thyroid tumors carrying BRAF(V600E) mutations are exquisitely dependent on the oncoprotein for viability and that genetic or pharmacological inhibition of its expression or activity is associated with tumor regression and restoration of RAI uptake in vivo in mice. These findings have potentially significant clinical ramifications. PMID- 22105175 TI - Mechanotransduction in mouse inner ear hair cells requires transmembrane channel like genes. AB - Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1(Delta) mice) were deaf and those with a deletion of Tmc2 (Tmc2(Delta) mice) were phenotypically normal, Tmc1(Delta)Tmc2(Delta) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1(Delta)Tmc2(Delta) mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations. PMID- 22105176 TI - Slowing down with age: lung DCs do it too. AB - Decline in immune function with age has been attributed to defects or alterations in both the innate and the adaptive immune system. In this issue of the JCI, Zhao and coworkers provide evidence for a novel mechanism of immune dysfunction in aging mice. They show that migration of respiratory DCs from the site of virus replication to the draining lymph nodes in response to infection with several different respiratory viruses is markedly diminished with increasing age. The impaired DC migration was a result of increased levels of the lipid mediator prostaglandin D(2) (PGD(2)) in the respiratory tract with age and could be partially reversed by blockade of PGD(2) synthesis or action. PMID- 22105177 TI - Increasing echogenicity of diffuse circumferential thickening ("macaroni sign") of the carotid artery wall with decreasing inflammatory activity of Takayasu arteritis. AB - We report a case of sonographic follow-up showing brightening of the diffuse circumferential thickening (halo) of the carotid artery wall (the so-called "macaroni sign") in a patient with decreasing inflammatory activity of Takayasu arteritis over a 6-month period. Sonographic follow-up in patients with Takayasu arteritis may be a useful complementary tool for evaluation of inflammatory activity. Besides a reduction of halo diameter, an increase in wall echogenicity appears to be a sign of decreasing inflammation. PMID- 22105179 TI - Diverse effects of dimethyl sulfoxide (DMSO) on the differentiation potential of human embryonic stem cells. AB - In vitro disease modeling using pluripotent stem cells can be a fast track screening tool for toxicological testing of candidate drug molecules. Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents in drug screening. In the present investigation, we exposed 14- to 21-day-old embryoid bodies (EBs) to three different concentrations of DMSO [0.01% (low dose), 0.1% (medium dose) and 1.0% (high dose)] to identify the safest dose that could effectively be used as solvent. We found that DMSO treatment substantially altered the morphology and attachment of cells in concurrence with a significant reduction in cell viability in a dose-dependent manner. Gene expression studies revealed a selective downregulation of key markers associated with stemness (Oct-4, Sox-2, Nanog and Rex-1); ectoderm (Nestin, TuJ1, NEFH and Keratin-15); mesoderm (HAND-1, MEF-2C, GATA-4 and cardiac-actin); and endoderm (SOX-17, HNF-3beta, GATA-6 and albumin), indicating an aberrant and untimely differentiation trajectory. Furthermore, immunocytochemistry, flow cytometry and histological analyses demonstrated substantial decrease in the levels of albumin and CK-18 proteins coupled with a massive reduction in the number of cells positive for PAS staining, implicating reduced deposits of glycogen. Our study advocates for the first time that DMSO exposure not only affects the phenotypic characteristics but also induces significant alteration in gene expression, protein content and functionality of the differentiated hepatic cells. Overall, our experiments warrant that hESC based assays can provide timely alerts about the outcome of widespread applications of DMSO as drug solvent, cryoprotectant and differentiating agent. PMID- 22105178 TI - Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells. AB - Endothelial dysfunction precedes cardiovascular disease and is accompanied by mitochondrial dysfunction. Here we tested the hypothesis that diesel exhaust particulate extracts (DEPEs), prepared from a truck run at different speeds and engine loads, would inhibit genomic estrogen receptor activation of nuclear respiratory factor-1 (NRF-1) transcription in human umbilical vein endothelial cells (HUVECs). Additionally, we examined how DEPEs affect NRF-1-regulated TFAM expression and, in turn, Tfam-regulated mtDNA-encoded cytochrome c oxidase subunit I (COI, MTCO1) and NADH dehydrogenase subunit I (NDI) expression as well as cell proliferation and viability. We report that 17beta-estradiol (E(2)), 4 hydroxytamoxifen (4-OHT), and raloxifene increased NRF-1 transcription in HUVECs in an ER-dependent manner. DEPEs inhibited NRF-1 transcription, and this suppression was not ablated by concomitant treatment with E(2), 4-OHT, or raloxifene, indicating that the effect was not due to inhibition of ER activity. While E(2) increased HUVEC proliferation and viability, DEPEs inhibited viability but not proliferation. Resveratrol increased NRF-1 transcription in an ER dependent manner in HUVECs, and ablated DEPE inhibition of basal NRF-1 expression. Given that NRF-1 is a key nuclear transcription factor regulating genes involved in mitochondrial activity and biogenesis, these data suggest that DEPEs may adversely affect mitochondrial function leading to endothelial dysfunction and resveratrol may block these effects. PMID- 22105180 TI - Gastroesophageal reflux and voice changes: objective assessment of voice quality and impact of antireflux therapy. AB - BACKGROUND AND AIM: Voice-related complaints are the most common extraesophageal manifestation of gastroesophageal reflux disease (GERD). The aim of this study was to compare objectively measured voice parameters in normal subjects and patients with GERD and to assess the impact of antireflux surgery on these parameters in patients with reflux disease. METHODS: Normal subjects and patients with reflux symptoms were asked to read a standardized, phonetically balanced text while the impedance across vocal cords was recorded using electroglottography. Irregularity in the voice frequency (CFx) and amplitude (CAx) as well as irregularity of the closed phase ratio of vocal cords (CQx) were calculated. These 3 voice parameters were compared between the normal subjects and patients with gastroesophageal reflux. In a subgroup of GERD patients who underwent antireflux surgery, electroglottography was repeated 3 months or later after surgery and the voice parameters were compared with preoperative values. RESULTS: There were 55 normal subjects and 32 patients with GERD. Compared with normal subjects, GERD patients had a significantly higher irregularity in both voice frequency (P=0.04) and amplitude (P=0.03). The CQx did not differ significantly between the 2 groups (P=0.18). In 16 GERD patients who underwent surgery, a significant improvement in postoperative values was observed for both voice frequency (CFx: 48.4 vs. 30.4, P=0.002) and amplitude (CAx: 25.9 vs. 9.3, P=0.004). CONCLUSIONS: There are measurable alterations in voice quality in patients with GERD when compared with normal subjects. Antireflux surgery improves the irregularity in both amplitude and frequency of voice in patients with reflux disease. PMID- 22105181 TI - Plasma ribavirin trough concentrations during treatment of chronic hepatitis C in genotype-1 patients. AB - GOALS: To investigate the correlation between virological response and plasma ribavirin trough concentrations (RBV Ctrough) during the full period of chronic hepatitis C (CHC) treatment. STUDY: Multicenter prospective cohort study. Total 119 patients with CHC genotype-1 were treated with peginterferon alfa-2a (pegIFN) and RBV for 48 weeks. RBV quantification was carried out at week 4 (W4), W8, W12, W16, W24, W32, and W40 of treatment. RESULTS: The mean RBV Ctrough value during treatment was 2.5+/-0.9 mg/L in total patients. At no time point of treatment were patients with RBV Ctrough average correlated with early and sustained virological response (SVR), but those with RBV Ctrough >=5 mg/L (95th percentile) at any time point (22/119, 18%) were correlated with SVR (P=0.02). Such high RBV Ctrough values were found from the second to the fourth months of treatment in 73% of these patients (16/22), and this was independently associated with SVR (odds ratio=3.6, 95% confidence interval:1.02-13.2, P=0.04). CONCLUSION: Our data do not support RBV plasma monitoring as a tool to optimize treatment in patients with CHC genotype-1, but show that a high RBV plasma concentration could improve SVR rates. PMID- 22105182 TI - Coronary artery stents and antiplatelet therapy in patients with cirrhosis. AB - GOALS: To describe our experience with coronary artery stenting and antiplatelet therapy in cirrhotic patients and compare rates of bleeding with a control group. BACKGROUND: Although there are data on cardiac evaluation and perioperative cardiac risk in cirrhotic patients, there is a paucity of information on outcomes in cirrhotic patients with coronary artery stents. Cirrhotic patients may be at increased risk for complications, including gastrointestinal bleeding as a result of antiplatelet therapy prescribed after stenting. STUDY: We performed a retrospective study of complications in cirrhotics that received a coronary artery stent followed by clopidogrel and aspirin prescribed to prevent stent occlusion. Cirrhotics with stents were compared with an age and sex-matched control group with cirrhosis without stents and not on aspirin. RESULTS: Among 423 cirrhotic patients who underwent liver transplant evaluation, 16 patients (3.8%) received a stent of which 9 underwent liver transplant. Two patients with varices (12.5%) in the stent group had fatal variceal bleeding and 2 controls (6.3%) had nonfatal variceal bleeding during follow-up while on antiplatelet therapy (P=0.86). There were no significant differences in transfusion requirements between the 9 liver transplant recipients with stents compared with the control group, P=0.69 for packed red blood cells. CONCLUSIONS: In our experience, it is safe for cirrhotic patients without varices to receive a coronary artery stent and for cirrhotic patients with coronary artery stents to be considered for liver transplantation. Larger prospective studies are needed to confirm these results and evaluate the risk of bleeding in cirrhotics with varices who receive coronary artery stents and antiplatelet therapy. PMID- 22105183 TI - Non-Hodgkin's lymphoma involving the ileocecal region: a single-institution analysis of 46 cases in a Chinese population. AB - BACKGROUND AND GOALS: Non-Hodgkin's lymphoma (NHL) involving the ileocecal region is a rare occurrence. Optimal management and treatment outcomes of ileocecal NHL have not been well defined. STUDY: In this study, clinical characteristics, treatment outcomes, and prognostic factors of 46 Chinese patients with ileocecal NHL were retrospectively analyzed. RESULTS: Among 46 patients, the median age of these patients was 46 years and 84.8% of them were male. Twenty-four cases (52.2%) had early-stage disease (stage I/II1/II2) and 35 (76.1%) cases were of B cell origin. Higher incidence of fever (P=0.001) and intestinal perforation (P=0.038) at onset was observed in T-cell lymphomas. Surgical emergencies occurred in 13 patients, including 8 patients who were receiving chemotherapy. Patients with T-cell advanced ileocecal NHL (stage IIE/IV) suffered more surgical emergencies during chemotherapy than others (P=0.005). The 5-year overall survival and progression-free survival rates for these 46 patients were 64.2% and 49.3%, respectively. Early-stage cases undergoing radical resection before chemotherapy had a prolonged 5-year progression-free survival rate (P=0.01). In multivariate analysis, both advanced stage and T-cell phenotype were identified as independent prognostic factors for poor survival. CONCLUSIONS: Radical resection before chemotherapy should be considered in early-stage ileocecal NHL to achieve a better survival. Palliative resection of the primary lesion before chemotherapy may be necessary in T-cell advanced cases to avoid surgical emergencies during chemotherapy. Owing to the small sample number in this study, a prospective analysis with larger sample number is highly necessary. PMID- 22105184 TI - High HBV-DNA titer in surrounding liver rather than in hepatocellular carcinoma tissue predisposes to recurrence after curative surgical resection. AB - GOALS: In this study the authors intended to investigate the relationship between intrahepatic hepatitis B virus (HBV)-DNA concentrations and posthepatectomy recurrence of HBV-associated hepatocellular carcinoma (HCC). BACKGROUND: High HBV DNA level is strongly associated with HCC development in chronic HBV infection and considered to be a risk factor of HCC recurrence. STUDY: A total of 109 patients with HBV-associated HCC who underwent curative surgical resection were followed up every 3 to 6 months for a median of 82 months. Intrahepatic total HBV DNA titer was measured in HCC and surrounding liver tissues using a TaqMan probe based real-time polymerase chain reaction method. HBV-DNA titers in HCC and surrounding liver were compared in accordance with patients' clinical, radiologic, and histopathological characteristics. The relationships between HBV DNA titers in HCC or surrounding liver tissues and cumulative HCC recurrence rates were determined. RESULTS: Of the 109 patients, 67 (62%) showed posthepatectomy recurrence of HCC. In all patients, total HBV-DNA titers were significantly higher in HCCs than in surrounding liver tissues (P=0.019). HCC recurred more frequently in patients with higher than those with lower HBV-DNA titers in surrounding liver tissues (P=0.009). In contrast, the HCC recurrence rates were similar in patients with higher and those with lower HBV-DNA titers in HCC specimens (P=0.301). Multivariate analysis showed that tumor size >5 cm (P=0.008), the presence of portal vein thrombus (P=0.001), and high HBV-DNA titer in surrounding liver tissues (P=0.002) were independent risk factors for posthepatectomy HCC recurrence in patients with HBV-associated HCC. CONCLUSIONS: In patients with HBV-associated HCC, high HBV-DNA titer in surrounding liver rather than in the HCC itself is associated with posthepatectomy HCC recurrence after curative surgical resection. PMID- 22105185 TI - Meiotic segregation and interchromosomal effects in a rare (1:2:10) complex chromosomal rearrangement. AB - PURPOSE: Complex chromosomal rearrangements (CCR) are rare rearrangements involving more than two chromosomes and more than two breakpoints. CCR are associated with male infertility as a result of the disruption of spermatogenesis due to complex meiotic configurations and the production of chromosomally abnormal sperm. We examined a carrier of a t(1:2:10) CCR in order to determine the patterns of segregation and any presence of an interchromosomal effect (ICE). METHODS: Centromeric, locus specific and telomeric probes (Vysis, USA) were used for the study. On ~1,000 sperm nuclei from the reciprocal translocation carrier, dual color Fluorescence in situ hybridization (FISH) was performed on each of the involved chromosomes to determine the patterns of segregation. FISH was also performed on chromosome 13, 18, 21, X and Y to determine any ICE. RESULTS: We observed abnormal chromosome complements in 24.3%, 19.5% and 15.8% of sperm for chromosomes 2, 10 and 1, respectively. There was a significantly increased rate of ICEs for chromosomes 13 and 21 when compared with controls. CONCLUSIONS: CCR may present a lower risk for producing unbalanced chromosomes than other studies have indicated. CCRs may be at an increased risk for ICE especially among acrocentric chromosomes. PMID- 22105186 TI - Impact of freezing and thawing of human ovarian tissue on follicular growth after long-term xenotransplantation. AB - PURPOSE: To assess follicular growth after xenografting in order to understand how freezing and/or grafting may affect follicular development. METHODS: Human ovarian biopsies were used for fresh and frozen-thawed xenografting to SCID mice. After xenotransplantation, follicular morphology and proportion, oocyte and follicle diameter, and quantitative and qualitative parameters of antral follicles were analyzed. RESULTS: The proportion of growing follicles was significantly higher in grafted than non-grafted ovarian tissue. Follicular growth to the antral stage was observed and there was no significant difference in oocyte or follicle diameter in fresh or frozen-thawed grafts. Although no significant difference was observed in antral area or zona pellucida thickness, the theca layer in antral follicles from frozen-thawed grafted tissue was found to be significantly thinner than in fresh grafts. CONCLUSION: Antral follicles obtained after grafting of frozen-thawed human ovarian tissue showed a thinner theca cell layer compared to those from fresh grafts, which could affect follicular development and function. Further studies are nevertheless warranted to confirm the identity of theca cells and assess if they retain the ability to respond to luteinizing hormone and produce androgens. PMID- 22105188 TI - ChemComm: a new era. PMID- 22105187 TI - Potassium ion-mediated non-covalent bonded coordination polymers. AB - Crystal structures and vibrational spectra of three related network-forming coordination complexes have been studied. Two novel thermodynamically stable pseudo-polymorphic solvated rhodium chloro compounds, [cis-RhCl(4)(DMSO kappaS)(2)K](n), 1, and [cis-RhCl(4)(DMSO-kappaS)(2)K.3H(2)O](n), 2, and one metastable compound [trans-RhCl(4)(DMSO-kappaS)(2)K.0.25H(2)O](n), 3, crystallize at ambient temperature in the orthorhombic space group P2(1)2(1)2(1) for 1, and the monoclinic space groups P2(1)/n and P2(1)/c for 2 and 3, respectively. All three structures contain [RhCl(4)(DMSO-kappaS)(2)](-) complexes in which the rhodium(III) ions bind to two dimethyl sulfoxide (DMSO) sulfur atoms and four chloride ions in distorted octahedral coordination geometries. The complexes are connected in networks via potassium ions interacting with the Cl(-) and the DMSO oxygen atoms. As the sum of Shannon ionic radii of K(+) and Cl(-) exceeds the K Cl distances in compounds under study, these compounds can be described as Rh-Cl K coordination polymers with non-covalent bonding, which is not common in these systems, forming 1- and 2-D networks for 1/2 and 3, respectively. The 2-D network with nano-layered sheets for compound 3 was also confirmed by TEM images. Further evaluation of the bonding in the cis- and trans-[RhCl(4)(DMSO-kappaS)(2)](-) entities was obtained by recording Raman and FT-IR absorption spectra and assigning the vibrational frequencies with the support of force-field calculations. The force field study of complexes reveals the strong domination of trans-effect (DMSO-kappaS > Cl) over the effect of non-covalent bonding in coordination polymeric structures. The comparison of calculated RhCl, RhS and SO stretching force constants showed evidence of K(+)-ligand interactions whereas direct experimental evidences of K(+)-Cl(-) interaction were not obtained because of strong overlap of the corresponding spectral region with that where lattice modes and Rh-ligand bendings appear. PMID- 22105190 TI - Editorial: TBME Letters special issue on multiscale modeling and analysis in computational biology and medicine--part-2. PMID- 22105191 TI - Editorial: What biomedical engineers can do to impact multiscale modeling (TBME Letters special issue on multiscale modeling and analysis in computational biology and medicine: part-2). PMID- 22105192 TI - Dystrophin Dp71: the smallest but multifunctional product of the Duchenne muscular dystrophy gene. AB - Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As full-length dystrophin does in skeletal muscle, Dp71 associates with dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and accessory proteins to form the dystrophin-associated protein complex (DAPC) in non-muscle tissues. Although it has been nearly 20 years since the discovery of Dp71, its study has become relevant only recently due to its direct involvement with the two main DMD non-muscular phenotypes: cognitive impairment and abnormal retinal physiology. In this review, we describe the historical background of Dp71 and the experimental models developed for its study. Additionally, we present and discuss the experimental evidence supporting the participation of Dp71 in different cellular processes, including cell adhesion, water homeostasis, cell division, and nuclear architecture. The functional diversity of Dp71 is attributed to the formation of Dp71-containing DAPC in numerous cell types and different subcellular compartments, including in plasma membrane and nucleus, as well as to the capability of Dp71-containing DAPC to work as the scaffold for proper clustering and anchoring of structural and signaling proteins to the plasma membrane and of nuclear envelope proteins to the inner nuclear membrane. PMID- 22105193 TI - Colchicine for the prevention of postoperative atrial fibrillation: a new indication for a very old drug? PMID- 22105194 TI - Alcohol and the heart: does raising high-density lipoprotein matter? PMID- 22105195 TI - The incretin axis in cardiovascular disease. PMID- 22105196 TI - Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. AB - BACKGROUND: High blood pressure (BP) is a risk factor for cerebrovascular disease, including stroke. Little is known about the importance of BP on the progression of microvascular disease of the brain, which has been associated with functional decline in mobility and cognition in older people. METHODS AND RESULTS: This was a prospective cohort of subjects 75 to 89 years of age to determine relations among vascular risk factors, white matter hyperintensity volume, and functional status. Ninety-nine subjects were enrolled through the use of a balanced 3*3 matrix stratified by age and mobility performance, and 72 subjects completed all sets of baseline and follow-up studies at 2 years. Subjects were excluded if there were medications or systemic or neurological diseases that could compromise mobility. Ambulatory and clinic BP monitoring, magnetic resonance imaging, gait studies, and neuropsychological testing were performed at baseline and after 24 months. Brain classification into normal white matter and T2-hyperintense white matter hyperintensity volume was performed with semiautomated segmentation. Quantitative measures of mobility and cognitive function were obtained longitudinally. Increased ambulatory systolic BP, but not clinic systolic BP, from baseline to 24 month follow-up was associated with increased white matter hyperintensity volume over that same period, as well as measures of executive function/processing speed. Similar associations were observed for 24-hour BP, awake BP, and sleep BP but not for the surge between the sleep and awake time at the 24-month time point. CONCLUSIONS: These data demonstrate for the first time the importance of 24-hour systolic BP in the progression of brain white matter hyperintensity volume burden associated with impairment of cognitive function in older people. The 24-hour systolic BP may be a potential target for intervention in the elderly to reduce vascular disease of the brain and impairment of function. PMID- 22105197 TI - How to interpret elevated cardiac troponin levels. PMID- 22105198 TI - Running from her past: a case of rapidly progressive dyspnea on exertion. PMID- 22105199 TI - Cerebral abscess due to persistent left superior vena cava draining into the left atrium. PMID- 22105200 TI - Complete transposition of the atrioventricular valves associated with left ventricular apical hypoplasia. PMID- 22105201 TI - Heart failure with preserved ejection fraction. PMID- 22105203 TI - Letter by Naimer regarding article, "Duration of treatment with nonsteroidal anti inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study". PMID- 22105204 TI - Letter by Alla et al regarding article, "Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study". PMID- 22105205 TI - Letter by Altman and Gonzalez regarding article, "Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study". PMID- 22105206 TI - Osteochondral autograft transfer for the treatment of osteochondritis dissecans of the medial femoral condyle in dogs. AB - OBJECTIVE: To describe the clinical application of osteochondral autograft transfer procedure for the treatment of osteochondritis dissecans (OCD) of the canine medial femoral condyle and to report clinical and force plate outcomes. METHODS: Osteochondral autograft transfer (OATSTM Arthrex, Naples FL, USA) instrumentation was employed in six stifle joints of five dogs. Clinical examination was performed preoperatively and at two to three weeks, six to eight weeks, 12-18 weeks and at >22 months postoperatively. Radiography and arthroscopy were performed preoperatively and 12-18 weeks postoperatively. The follow-up examinations performed at 22 to 56 months included radiography, questionnaire completion with the owner, and force plate gait evaluation. RESULTS: Articular surface reconstruction was radiographically (for 6 stifle joints) and arthroscopically (for 5 stifle joints) maintained at 12-18 weeks. Subjectively assessed lameness resolved in five out of six stifles by the 12 to 18 week reassessment. Morbidity included lateral patellar luxation at seven weeks and cranial cruciate ligament rupture at 11 months postoperatively. At the >22 month re-evaluation examination, subjectively-assessed lameness and signs of discomfort were minimal. Owner perceptions of outcome were positive; force plate assessment of gait indicated that weight bearing on three out of six OAT implanted limbs was less than the contralateral limb, but these comparisons were not evaluated statistically. A progression in the development of osteophytes was radiographically evident. CLINICAL SIGNIFICANCE: The OAT procedure can reconstruct medial femoral condyle OCD defects in dogs. Long-term lameness and progressive osteophytosis may occur but can be associated with other pathology such as cruciate ligament insufficiency. PMID- 22105208 TI - Diagnostic yield of repeat catheter angiography in patients with catheter and computed tomography angiography negative subarachnoid hemorrhage. AB - BACKGROUND: The yield of repeat catheter angiography in patients with subarachnoid hemorrhage (SAH) who have negative initial catheter and computed tomography (CT) angiograms is not well understood. OBJECTIVE: To determine the yield of repeat catheter angiography in a prospective cohort of patients with SAH and negative initial catheter and CT angiograms. METHODS: From January 1, 2005, until September 1, 2010, we instituted a prospective protocol in which patients with SAH documented by noncontrast CT (NCCT) or cerebrospinal fluid (CSF) xanthochromia and negative initial catheter and CT angiograms were evaluated with repeat catheter angiography 7 days and 3 months after presentation to assess for causative vascular abnormalities. RESULTS: Seventy-two patients were included, with a mean age of 53.1 years (median, 53.5 years; range, 19-88 years). Forty-six patients were female (63.9%) and 26 male (36.1%). Thirty-nine patients had nonperimesencephalic SAH (54.2%), 29 patients had perimesencephalic SAH (40.3%), and 4 patients had CSF xanthochromia (5.5%). The first repeat catheter angiogram performed 7 days after presentation demonstrated a causative vascular abnormality in 3 patients (yield of 4.2%), 2 of which had nonperimesencephalic SAH (yield of 5.1%), and 1 had perimesencephalic SAH (yield of 3.4%). The second repeat catheter angiogram performed in 43 patients (59.7%) did not demonstrate any causative vascular abnormalities. No causative abnormalities were found in patients with CSF xanthochromia. CONCLUSION: Repeat catheter angiography performed 7 days after presentation is valuable in the evaluation of patients with SAH who have negative initial catheter and CT angiograms, demonstrating a causative vascular abnormality in 4.2% of patients. PMID- 22105209 TI - A simplified method for administration of intra-arterial nicardipine for vasospasm with cervical catheter infusion. AB - BACKGROUND: Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Nicardipine has previously been used to treat vasospasm through superselective intracranial microcatheter injections. OBJECTIVE: To evaluate a simple method of treatment of vasospasm with slow infusion of nicardipine from a cervical catheter. METHODS: Twenty-seven patients with symptomatic vasospasm were treated over 4 years with cervical catheter infusions. Nicardipine was infused at 20 mg/h for 30 to 60 minutes. Angioplasty was used in severe cases at the operator's discretion. Outcome at discharge and follow-up was evaluated with Glasgow Outcome Scale. RESULTS: Twenty-seven patients (17 women, 12 men) received intra-arterial therapy for vasospasm. Vasospasm treatment was done at a mean post-hemorrhage date of 7.2 days (range, 4 15 days). They underwent 48 sessions of treatment (mean, 1.8 per patient) in 72 separate arterial territories. Twelve patients underwent multiple treatments. The mean dose used per session was 19.2 mg (range, 5-50 mg). Four patients underwent angioplasty for severe vasospasm. Twenty-two patients (81.5%) had clinical improvement after the infusion. Angiographic improvement was seen in 86.1% of the vessels analyzed, which had moderate or severe spasm before infusion. Overall, 17 patients (62.9%) had good outcome (Glasgow Outcome Scale score, 4 and 5) at discharge, 11 had poor outcome, and 1 patient died. Follow-up was available in 19 patients, and 18 were doing well (Glasgow Outcome Scale score, 4 and 5). CONCLUSION: Intra-arterial nicardipine is an effective and safe treatment for cerebral vasospasm. In most patients, infusion can be performed from the cervical catheter, with microcatheter infusion and angioplasty reserved for the more severe and resistant cases. PMID- 22105212 TI - White matter disease: A novel approach to treatment of neuromyelitis optica. PMID- 22105211 TI - Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. AB - Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies. PMID- 22105213 TI - Stroke: Obesity is associated with a decreased risk of major vascular events after ischemic stroke. PMID- 22105214 TI - Stroke: Multiparameter MRI could be used as a biomarker to guide acute treatment of stroke. PMID- 22105215 TI - Multiple sclerosis: Teriflunomide shows promise for MS treatment in phase III trial. PMID- 22105216 TI - Retrospective evaluation of a decision support system for controlled mechanical ventilation. AB - Management of mechanical ventilation in intensive care patients is complicated by conflicting clinical goals. Decision support systems (DSS) may support clinicians in finding the correct balance. The objective of this study was to evaluate a computerized model-based DSS for its advice on inspired oxygen fraction, tidal volume and respiratory frequency. The DSS was retrospectively evaluated in 16 intensive care patient cases, with physiological models fitted to the retrospective data and then used to simulate patient response to changes in therapy. Sensitivity of the DSS's advice to variations in cardiac output (CO) was evaluated. Compared to the baseline ventilator settings set as part of routine clinical care, the system suggested lower tidal volumes and inspired oxygen fraction, but higher frequency, with all suggestions and the model simulated outcome comparing well with the respiratory goals of the Acute Respiratory Distress Syndrome Network from 2000. Changes in advice with CO variation of about 20% were negligible except in cases of high oxygen consumption. Results suggest that the DSS provides clinically relevant and rational advice on therapy in agreement with current 'best practice', and that the advice is robust to variation in CO. PMID- 22105217 TI - Ice-Cap: a method for growing Arabidopsis and tomato plants in 96-well plates for high-throughput genotyping. AB - It is becoming common for plant scientists to develop projects that require the genotyping of large numbers of plants. The first step in any genotyping project is to collect a tissue sample from each individual plant. The traditional approach to this task is to sample plants one-at-a-time. If one wishes to genotype hundreds or thousands of individuals, however, using this strategy results in a significant bottleneck in the genotyping pipeline. The Ice-Cap method that we describe here provides a high-throughput solution to this challenge by allowing one scientist to collect tissue from several thousand seedlings in a single day (1,2). This level of throughput is made possible by the fact that tissue is harvested from plants 96-at-a-time, rather than one-at-a time. The Ice-Cap method provides an integrated platform for performing seedling growth, tissue harvest, and DNA extraction. The basis for Ice-Cap is the growth of seedlings in a stacked pair of 96-well plates. The wells of the upper plate contain plugs of agar growth media on which individual seedlings germinate. The roots grow down through the agar media, exit the upper plate through a hole, and pass into a lower plate containing water. To harvest tissue for DNA extraction, the water in the lower plate containing root tissue is rapidly frozen while the seedlings in the upper plate remain at room temperature. The upper plate is then peeled away from the lower plate, yielding one plate with 96 root tissue samples frozen in ice and one plate with 96 viable seedlings. The technique is named "Ice Cap" because it uses ice to capture the root tissue. The 96-well plate containing the seedlings can then wrapped in foil and transferred to low temperature. This process suspends further growth of the seedlings, but does not affect their viability. Once genotype analysis has been completed, seedlings with the desired genotype can be transferred from the 96-well plate to soil for further propagation. We have demonstrated the utility of the Ice-Cap method using Arabidopsis thaliana, tomato, and rice seedlings. We expect that the method should also be applicable to other species of plants with seeds small enough to fit into the wells of 96-well plates. PMID- 22105219 TI - NMDA receptor glycine modulatory site in the ventral tegmental area regulates the acquisition, retrieval, and reconsolidation of cocaine reward memory. AB - RATIONALE AND OBJECTIVES: Accumulating clinical and preclinical studies have shown that the memories of the rewarding effects of drugs and their paired cues may contribute to relapse and persistent cocaine use. Glutaminergic actions in the ventral tegmental area (VTA) have been shown to regulate the rewarding effect of drugs and conditioned responses to drug-associated cues, but the role of the VTA in the acquisition, retrieval, and reconsolidation of cocaine cues is not yet known. METHODS: In the present study, we used 7-chlorothiokynurenic acid (7 CTKA), an N-methyl-D-aspartate (NMDA) receptor glycine modulatory site antagonist with no rewarding effects, to examine the role of the NMDA receptor glycine modulatory site in the acquisition, retrieval, and reconsolidation of cocaine related reward memory using the conditioned place preference (CPP) paradigm. RESULTS: Separate groups of Sprague-Dawley rats were trained to acquire cocaine induced CPP. Vehicle or 7-CTKA was microinjected into the VTA or substantia nigra (SN) (5 MUg/MUl) at different time points: 10 min before each CPP training session (acquisition), 10 min before the reactivation of CPP (retrieval), and immediately after the reactivation of CPP (reconsolidation). Cocaine-induced CPP was retested 24 h and 1 and 2 weeks after 7-CTKA administration. 7-CTKA microinjected into the VTA, but not SN, significantly impaired the acquisition, retrieval, and reconsolidation of cocaine-induced CPP without affecting cocaine induced locomotion. CONCLUSIONS: Our findings suggest that the NMDA receptor glycine modulatory site in the VTA plays a major role in cocaine reward memory, and NMDA receptor glycine site antagonists may be potential pharmacotherapies for the management of relapse. PMID- 22105220 TI - Effects of chronic polybrominated diphenyl ether exposure on gonadal development in the northern leopard frog, Rana pipiens. AB - Polybrominated diphenyl ethers (PBDEs) are bioaccumulative, persistent organic pollutants used as flame retardants in consumer goods. Concentrations of PBDEs in North American wildlife have been increasing for decades and been shown to have estrogenic effects on sexual development. No studies, however, have examined the effects of PBDEs on the sexual development of North American frogs at ecologically relevant concentrations. This study examined the effects of five dietary concentrations of DE-71 (0, 1.1, 6.1, 71.4, and 634 ng SigmaPBDEs/g diet), a technical PBDE mixture, on the gonadal development of the northern leopard frog, Rana pipiens. Tadpoles were exposed chronically from the time they became free-swimming until metamorphosis. Frogs were killed either at metamorphic climax or 10 weeks after completing metamorphosis, processed for histology, and examined for alterations in sexual development. The experimental group exposed to PBDEs at 1.1 ng/g had a significantly larger proportion of females compared with the expected 50:50 sex ratio. At 10 weeks post-metamorphosis, male frogs exposed to 6.1 and 71.4 ng/g had significantly smaller testes, but all other measure of gonadal development tested showed no effects. No intersex or increased incidence of gonadal abnormality were detected. These findings indicate that PBDEs may disrupt sexual differentiation in frogs at low, environmentally relevant concentrations. PMID- 22105221 TI - Preferential cell response to anisotropic electro-spun fibrous scaffolds under tension-free conditions. AB - Anisotropic alignment of collagen fibres in musculoskeletal tissues is responsible for the resistance to mechanical loading, whilst in cornea is responsible for transparency. Herein, we evaluated the response of tenocytes, osteoblasts and corneal fibroblasts to the topographies created through electro spinning and solvent casting. We also evaluated the influence of topography on mechanical properties. At day 14, human osteoblasts seeded on aligned orientated electro-spun mats exhibited the lowest metabolic activity (P < 0.001). At day 5 and at day 7, no significant difference was observed in metabolic activity of human corneal fibroblasts and bovine tenocytes respectively seeded on different scaffold conformations (P > 0.05). Osteoblasts and corneal fibroblasts aligned parallel to the direction of the aligned orientated electro-spun mats, whilst tenocytes aligned perpendicular to the aligned orientated electro-spun mats. Mechanical evaluation demonstrated that aligned orientated electro-spun fibres exhibited significant higher stress at break values than their random aligned counterparts (P < 0.006) and random orientated electro-spun fibres exhibited significant higher strain at break values than the aligned orientated scaffolds (P < 0.006). While maintaining fibre structure, we also developed a co-deposition method of spraying and electro-spinning, which enables the incorporation of microspheres within the three-dimensional structure of the scaffold. PMID- 22105222 TI - Pharmacological activity of ibuprofen released from mesoporous silica. AB - Novel drug delivery systems (DDS) to improve the pharmacokinetic profile of hydrophobic drugs following oral administration are an area of keen interest in drug research. An ideal DDS should not adversely affect drug activity, be capable of delivering a therapeutic dose of drug, and allow homogenous drug loading and drug release. Mesoporous silica has been proposed for this application, with ibuprofen employed as the model drug. It was hypothesised that mesoporous silica MCM-41 is capable of delivering a pharmacologically therapeutic dose of ibuprofen. Ibuprofen-loaded MCM-41 can be prepared reproducibly at a drug to carrier ratio of 30% (wt/wt). The release profile was seen to be 90% within 2 h. Initial assessment of COX-1 inhibitory activity suggests the absence of adverse effects attributable to drug-carrier interaction. The results of this study provide further evidence in support of the proposed use of mesoporous silica in drug delivery. PMID- 22105223 TI - In vivo lamellar bone formation in fibre coated MgCHA-PCL-composite scaffolds. AB - Bio-inspired materials with controlled topography have gained increasing interest in regenerative medicine, because of their ability to reproduce the physical features of natural extracellular matrix, thus amplifying certain biological responses both in vitro and in vivo, such as contact guidance and differentiation. However, information on the ability to adapt this high cell potential to 3D scaffolds, effective to be implanted in clinical bone defect, is still missing. Here, we examine the pattern of bone tissue generated within the implant in an ectopic model, seeding bone marrow progenitor cells onto PCL-MgCHA scaffolds. This composite material presented a porous structure with micro/nanostructured surfaces obtained by combining phase inversion/salt leaching and electrospinning techniques. Histological analysis of grafts harvested after 1 2-6 months from implantation highlights an extent of lamellar bone tissue within interconnected pores of fibre coated PCL-MgCHA composites, whereas uncoated scaffolds displayed sparse deposition of bone. Pure PCL scaffolds did not reveal any trace of bone for the overall 6 months of observation. In conclusion, we show that a structural modification in scaffold design is able to enhance bone regeneration possibly mimicking some physiological cues of the natural tissue. PMID- 22105224 TI - Preparation and characterization of ketoprofen-loaded microspheres for embolization. AB - To deliver drug locally and relieve the syndrome of pain after uterine artery embolization, N-[tris (hydroxymethyl) methyl] acrylamide-gelatin microspheres were prepared based on inverse suspension polymerization and then separated into a number of subgroups (150-350, 350-560, 560-710, 710-1,000, and 1,000-1,430 MUm) by wet-sieving. The microspheres were dried by lyophilization or by washing with anhydrous ethanol. And ketoprofen was loaded by soaking dried blank microspheres into concentrated ketoprofen ethanol solution. The ketoprofen loading level in different subgroups of microspheres was measured and found higher when the microspheres were dried by lyophilization. Equilibrium water content and mean diameters of microspheres decreased after drug loading, especially in subgroups with larger size. The microspheres went through the catheter without any difficulty. Compression and relaxation tests were performed on microspheres before lyophilization, embosphereTM, microspheres after lyophilization and ketoprofen loading microspheres. The Young's moduli were 54.74, 64.19, 98.15, and 120.44 kPa, respectively. The release of ketoprofen from microspheres in different subgroups was studied by using the USPII method and T-cell apparatus, respectively. The results indicate that the release rate of ketoprofen depends upon the diameter of microspheres, the type of dissolution apparatus and the flow rate of media in the case that T-cell apparatus was applied. The CH50 test shows that the activation of complement by ketoprofen-loaded microspheres was lower than by blank ones. PMID- 22105225 TI - Design and synthesis of dual-ligand modified chitosan as a liver targeting vector. AB - Vector plays an important role in hepatic targeted drug delivery system. In this study, a novel material as a liver targeting vector, dual-ligand modified chitosan (GCGA) composed of chitosan (CTS), glycyrrhetinic acid (GA) and lactobionic acid (LA), was designed and synthesized by an orthogonal experiment with two-step synthesis under mild conditions. The synthesized final product was characterized and confirmed by FTIR and (1)H-NMR spectroscopy, and DS of GA and LA in CTS were measured to be 13.77 and 16.74 mol% using (1)H-NMR, respectively. The cytotoxicity of CTS and GCGA was concentration dependent which was inverse proportion to the cell viability by MTT assay using L929 cell line, and inhibitory concentration 50% (IC50) was 0.2 mg/ml for GCGA. The in vitro targeting efficiency and the in vitro cellular uptake were investigated. Compared with CTS NPs and GA-CTS NPs, GCGA NPs showed good cell specificity to BEL-7402 cells via the dual-ligand-receptor-mediated recognition, leading to a higher affinity to BEL-7402 cells. The results suggested that GCGA described here has the potential to be used as an effective vector for hepatic targeted drug therapy. PMID- 22105226 TI - Preparation and analysis of chemically gradient functional bioceramic coating formed by pulsed laser deposition. AB - Bioactive ceramic coatings based on calcium phosphates yield better functionality in the human body for a variety of metallic implant devices including orthopaedic and dental prostheses. In the present study chemically and hence functionally gradient bioceramic coating was obtained by pulsed laser deposition method. Calcium phosphate bioactive ceramic coatings based on hydroxyapatite (HA) and tricalcium phosphate (TCP) were deposited over titanium substrate to produce gradation in physico-chemical characteristics and in vitro dissolution behaviour. Sintered targets of HA and alpha-TCP were deposited in a multi target laser deposition system. The obtained deposits were characterized by X-ray diffraction, fourier transform infrared spectroscopy, scanning electron microscopy and energy dispersive X-ray analysis. Inductively coupled plasma spectroscopy was used to estimate the in vitro dissolution behaviour of coatings. The variation in mechanical property of the gradient layer was evaluated through scratch test and micro-indentation hardness. The bioactivity was examined in vitro with respect to the ability of HA layer to form on the surface as a result of contact with simulated body fluid. It could be inferred that chemically gradient functional bioceramic coating can be produced by laser deposition of multiple sintered targets with variable chemical composition. PMID- 22105227 TI - Wear degradation of long-term in vivo exposed alumina-on-alumina hip joints: linking nanometer-scale phenomena to macroscopic joint design. AB - The wear behavior of alumina femoral heads was examined at follow-up periods between 7.7 and 10.7 years. Four head retrievals of the same size (28 mm in diameter) were divided into two groups with different design characteristics. Systematically using scanning electron and atomic force microscopy procedures, wear characteristics could be classified on the entire heads according to five zones with increasing degrees of wear damage (Grade 1-5), in addition to one zone of stripe wear (Grade SW). The stripe wear zone showed quite different topographical features as compared to frictionally worn zones. Furthermore, hip implants designed with different clearances are shown to lead to different wear patterns on the femoral head surface, the smaller the clearance the wider the worn surface area. Cathodoluminescence piezo-spectroscopy provided information about the residual stress state in surfaces worn to different degrees and helped clarifying the wear mechanisms on the microscopic scale. PMID- 22105228 TI - Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma. AB - Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm). CONCLUSION: Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels. PMID- 22105229 TI - Early remodeling processes as predictors of diastolic function 5 years after reperfused acute myocardial infarction and intracoronary progenitor cell application. AB - AIMS: Ischemia-induced left ventricular (LV) diastolic dysfunction (DD) is increasingly recognized as a therapeutic challenge. While DD during acute myocardial infarction (AMI) determines patients' prognosis, it is unknown how LV remodeling after AMI affects the development of DD. Therefore, we aimed to identify AMI characteristics, which determine diastolic function after 5 years. METHODS AND RESULTS: 41 patients with reperfused AMI and intracoronary infusion of progenitor cells were included into the present analysis of the TOPCARE-AMI trial. At 5-year follow-up, we determined LV diastolic function including LV filling index (E/E') by echocardiography. Diastolic function was normal in 21 patients (DD class 0), impaired in 14 patients (DD class 1) and pseudonormal in 6 patients (DD class 2). E/E' increased from DD class 0 to 2 (6.6 +/- 1.3 vs. 9.0 +/- 2.4 vs. 12.1 +/- 6.2; p < 0.01). E/E' correlated with the maximal creatine kinase activity during AMI (CKMB(max) r = 0.73, p < 0.01), the change in end diastolic or end-systolic LV volumes between AMI and 4 months (?LVEDV r = 0.67, p < 0.01; ?LVESV r = 0.58, p < 0.01), ejection fraction at 5 years (r = -0.47, p < 0.01) and NT-proBNP serum levels at 5 years (r = 0.37, p < 0.05). Multivariate analysis revealed CKMB(max) (beta = 0.56, p < 0.01) and ?LVEDV (beta = 0.38, p < 0.01) as independent predictors for E/E' 5 years after AMI. CONCLUSION: Adverse early remodeling processes (reflected by LV dilatation between infarction and 4 months) determine long-term diastolic function in patients after reperfused AMI and progenitor cell therapy. PMID- 22105230 TI - Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry. AB - BACKGROUND: Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). AIM: To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. METHODS: A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index <=2 together with complete steroid withdrawal and response as a decrease of >=3 from the baseline score. RESULTS: A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the AdacolumnTM system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. CONCLUSIONS: In clinical practice, apheresis allows long term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines. PMID- 22105233 TI - A message from the new ChemComm chair. PMID- 22105232 TI - A common computational process in cueing and conjunction search tasks. AB - The question of whether Posner's beam is the same as Treisman's glue is addressed to construct a computational model that integrates both target and cue information. The cueing and conjunction search tasks are conducted to analyze a common process that may be underlying the tasks. The dynamic interaction between target and cue information produces attentional benefit- and cost-based in the cueing task. Furthermore, the search order for target candidates in a conjunction search task is determined through the integration of target and cue information, which is basically the same as in the cueing task. Our simulations suggest that consistency (or validity) is considered as a computational process that may be commonly involved in the both tasks. PMID- 22105231 TI - Decrease in alpha-fetoprotein levels predicts reduced incidence of hepatocellular carcinoma in patients with hepatitis C virus infection receiving interferon therapy: a single center study. AB - BACKGROUND: Increasing evidence suggests the efficacy of interferon therapy for hepatitis C in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to identify predictive markers for the risk of HCC incidence in chronic hepatitis C patients receiving interferon therapy. METHODS: A total of 382 patients were treated with standard interferon or pegylated interferon in combination with ribavirin for chronic hepatitis C in a single center and evaluated for variables predictive of HCC incidence. RESULTS: Incidence rates of HCC after interferon therapy were 6.6% at 5 years and 13.4% at 8 years. Non sustained virological response (non-SVR) to antiviral therapy was an independent predictor for incidence of HCC in the total study population. Among 197 non-SVR patients, independent predictive factors were an average alpha-fetoprotein (AFP) integration value >=10 ng/mL and male gender. Even in patients whose AFP levels before interferon therapy were >=10 ng/mL, reduction of average AFP integration value to <10 ng/mL by treatment was strongly associated with a reduced incidence of HCC. This was significant compared to patients with average AFP integration values of >=10 ng/mL (P = 0.009). CONCLUSIONS: Achieving sustained virological response (SVR) by interferon therapy reduces the incidence of HCC in hepatitis C patients treated with interferon. Among non-SVR patients, a decrease in the AFP integration value by interferon therapy closely correlates with reduced risk of HCC incidence after treatment. PMID- 22105234 TI - Correction of craniodorsal coxofemoral luxation in cats and small breed dogs using a modified Knowles technique with the braided polyblend TightRope systems. AB - OBJECTIVES: To report the surgical technique and short-term radiographic and functional outcome data for a series of client owned, small breed dogs and cats treated for traumatic craniodorsal coxofemoral luxation using open reduction and internal fixation with the Arthrex Mini TightRope (mTR) and TightRope (TR) systems. METHODS: Data were collected retrospectively from the clinical case records, including the initial clinical and radiographic findings, surgical technique, and postoperative short-term clinical and radiographic data. Functional data collected after the six weeks reassessment were obtained via owner questionnaire. RESULTS: Four cats (mTR = 4) and five small breed dogs (mean weight 15 kg; TR = 4, mTR = 1) were included. Median time to postoperative weight bearing was one day. Median lameness score at six weeks postoperatively was 0 out of 5. Coxofemoral joint congruity was radiographically confirmed at the six weeks postoperative visit. Telephone follow-up (at a median of 16 weeks) revealed all animals had returned to their previous level of activity. Complications were minor, and limited to postoperative swelling (n = 1). CLINICAL SIGNIFICANCE: Clinical use of the Arthrex Mini TightRope and TightRope systems can be recommended for traumatic craniodorsal coxofemoral luxation in this novel application as short-term results are at least comparable to existing surgical techniques. Long-term follow-up studies are needed. PMID- 22105235 TI - Bordetella pertussis IgG and IgA antibodies seroprevalence among 1-35 y-old population: the role of subclinical pertussis infection. AB - OBJECTIVE: To determine age-dependent pertussis specific IgG and IgA antibodies seroprevalence in apparently healthy subjects. METHODS: A total of 595 healthy 1 35-y-old individuals divided into 5 different age groups were selected from Sari district. Antipertussis IgG and IgA antibodies levels were measured quantitatively by ELISA method. Positive sera for IgA and also IgG titer >=150 were considered for recent pertussis infection. RESULTS: High seroprevelence levels (72% and 71%) were observed among preschool (<7 y) children. After decreasing the seroprevelence rates significally to lowest level (54.4%) among school aged (7-11 y), the rates increased again to the highest levels of 60% and 73% at adulthood (P = 0.03 and P = 0.003). In total, 1.55% of study subjects were IgA positive, and 5.7% showed high IgG titers. CONCLUSIONS: The present study reveals, vaccine induced immunity has decreased among school-aged children and natural pertussis infection is common among adolescent and young adults. Also, asymptomatic/sub-clinical recent pertussis infection was prevalent among studied population. These findings necessitate developing new strategies to reduce and control pertussis infection in Iran. PMID- 22105236 TI - Predicting response to growth hormone treatment. AB - Despite extensive experience over the past 25 y in managing growth failure with growth hormone (rhGH), predicting treatment efficacy in individual children remains a challenge. In this paper, the authors present the methods that are currently available to clinicians for predicting the growth response, and other more sophisticated techniques which have the potential to pave the way for individualised therapy in the future. PMID- 22105237 TI - Radioguided exploration facilitates surgical cytoreduction of neuroendocrine tumors. AB - INTRODUCTION: Radioguided exploration (RGS) can be an important tool to direct the cytoreduction of neuroendocrine tumors (NETs). The selection of the proper radiolabeled isotope, the dose, and the time interval between isotope injection and exploration are the major factors that lead to the successful use of this technique. METHODS: Data on 43 patients who underwent RGS of their NET at our facility (Ochsner Medical Center-Kenner) was collected. These cases were reviewed to determine the optimal radiopharmaceutical, dose, and interval between injection and exploration. RESULTS: The isotopes used were (99)technetium sulfur colloid in three patients, (123)I metaiodobenzylguanidine ((123)I-MIBG) in six patients, and (111)In-pentreotide in 30 abdominal NET patients and in four patients undergoing neck and mediastinum explorations. In 29 of 30 (111)In pentreotide-guided abdominal explorations (five of which were re-explorations, all successful), the gamma detector was determined to be "helpful". In the four neck and mediastinum explorations, the gamma probe was deemed "essential" for completing a quick, safe, and minimally invasive procedure. (123)I-MIBG injection, in contrast, was useful in only one patient. The optimal dose and interval between injection and exploration of (111)In-pentreotide were discovered to be 6 mCi injected 7 days prior to the planned exploration. CONCLUSION: Radioguided exploration is a useful tool to guide the cytoreduction of NETs. The correct choice of radiopharmaceutical, its dose, and the interval between injection and exploration are critical for obtaining optimal results. PMID- 22105238 TI - Bone: Finding that osteoclasts repel osteoblast activity through Sema4D reveals novel target for bone-boosting therapies. PMID- 22105240 TI - Chlamydia-induced ReA: immune imbalances and persistent pathogens. AB - Reactive arthritis (ReA), an inflammatory arthritic condition that is commonly associated with Chlamydia infections, represents a significant health burden, yet is poorly understood. The enigma of this disease is reflected in its problematic name and in its ill-defined pathogenesis. The existence of persistent pathogens in the arthritic joint is acknowledged, but their relevance remains elusive. Progress is being made in understanding the underlying mechanisms of ReA, whereby an imbalance between type 1 and type 2 immune responses seems to be critical in determining susceptibility to disease. Such an imbalance occurs prior to the initiation of an adaptive immune response, suggesting that innate cellular and molecular mechanisms in ReA should be prioritized as fruitful areas for investigation. PMID- 22105245 TI - Comment on "Pre- and intra-operative mediastinal staging in non-small-cell lung cancer". PMID- 22105244 TI - Hand osteoarthritis--a heterogeneous disorder. AB - Hand osteoarthritis (OA) is a prevalent disorder. Hand OA is not one single disease, but a heterogeneous group of disorders. Radiographic signs of hand OA, such as osteophytes or joint space narrowing, can be found in up to 81% of the elderly population. Several hand OA subsets--such as nodal interphalangeal OA, thumb base OA and erosive OA--can be discriminated. Furthermore, the experience of symptoms and the course of the disease differ between patients. Studies that used well-defined study populations with longitudinal follow-up have shown that similarities and differences can be observed in the pathogenesis, epidemiology and risk factors of the various hand OA subsets. Erosive OA in particular, characterized by erosive lesions on radiographical images, has a higher clinical burden and worse outcome than nonerosive hand OA. Imaging modalities (such as ultrasonography) have increased our knowledge of the role of inflammation of the disease. Our understanding of the heterogeneous nature of hand OA can eventually lead to increased knowledge of the pathogenesis of, and ultimately new treatment modalities for, this complex disease. PMID- 22105247 TI - The year in review: it's time to find a way. PMID- 22105246 TI - Cross-modal multivariate pattern analysis. AB - Multivariate pattern analysis (MVPA) is an increasingly popular method of analyzing functional magnetic resonance imaging (fMRI) data(1-4). Typically, the method is used to identify a subject's perceptual experience from neural activity in certain regions of the brain. For instance, it has been employed to predict the orientation of visual gratings a subject perceives from activity in early visual cortices(5) or, analogously, the content of speech from activity in early auditory cortices(6). Here, we present an extension of the classical MVPA paradigm, according to which perceptual stimuli are not predicted within, but across sensory systems. Specifically, the method we describe addresses the question of whether stimuli that evoke memory associations in modalities other than the one through which they are presented induce content-specific activity patterns in the sensory cortices of those other modalities. For instance, seeing a muted video clip of a glass vase shattering on the ground automatically triggers in most observers an auditory image of the associated sound; is the experience of this image in the "mind's ear" correlated with a specific neural activity pattern in early auditory cortices? Furthermore, is this activity pattern distinct from the pattern that could be observed if the subject were, instead, watching a video clip of a howling dog? In two previous studies(7,8), we were able to predict sound- and touch-implying video clips based on neural activity in early auditory and somatosensory cortices, respectively. Our results are in line with a neuroarchitectural framework proposed by Damasio(9,10), according to which the experience of mental images that are based on memories - such as hearing the shattering sound of a vase in the "mind's ear" upon seeing the corresponding video clip - is supported by the re-construction of content specific neural activity patterns in early sensory cortices. PMID- 22105248 TI - Can ovarian cancer screening save lives? The question remains unanswered. PMID- 22105249 TI - Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. AB - OBJECTIVE: To estimate the effect of ultrasonographic screening on stage at detection and long-term disease-specific survival of women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women aged 50 years and older and women aged 25 years and older with a documented family history of ovarian cancer. From 1987 to 2011, 37,293 women received annual ultrasonographic screening. Women with abnormal screens underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Forty-seven invasive epithelial ovarian cancers and 15 epithelial ovarian tumors of low malignant potential were detected. No women with low malignant potential tumors experienced recurrent disease. Stage distribution for invasive epithelial cancers was: stage I, 22 (47%); stage II, 11 (23%); stage III, 14 (30%), and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean, 5.8 years). The 5-year survival rate for invasive epithelial ovarian cancers detected by screening was: stage I, 95%+/-4.8%; stage II, 77.1%+/-14.5%; and stage III, 76.2%+/-12.1%. The 5 year survival rate for all women with invasive epithelial ovarian cancer detected by screening as well as interval cancers was 74.8%+/-6.6% compared with 53.7%+/ 2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001). CONCLUSION: Annual ultrasonographic screening of asymptomatic women achieved increased detection of early-stage ovarian cancer cases and an increase in 5-year disease-specific survival rate for women with ovarian cancer. LEVEL OF EVIDENCE: II. PMID- 22105250 TI - The clinical meaning of a cervical intraepithelial neoplasia grade 1 biopsy. AB - OBJECTIVE: To determine whether the diagnosis of cervical intraepithelial neoplasia (CIN) grade 1 increases the risk of CIN 3 above what is observed for human papillomavirus (HPV) infection. METHODS: Using data from the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) triage study, we compared the 2-year cumulative risk of CIN 3 for women with an enrollment diagnosis of CIN 1 (n=594) (median age 23 years) compared with those with negative histology or no biopsy taken at colposcopy ("no CIN 1," n=570) (median age 24 years). Baseline cervical specimens were tested for carcinogenic HPV by a clinical HPV test and HPV genotypes by polymerase chain reaction. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of association of enrollment status, including CIN 1 compared with no CIN 1 diagnosis, with 2-year worst outcomes of CIN 3. RESULTS: The two-year risks of CIN 3 were 10.3% (95% CI 7.9-13.0) for women with CIN 1, 7.3% (95% CI 4.6-10.9) for negative histology, and 6.4% (95% CI 3.8-9.9) for women referred to colposcopy and no biopsies were taken (P=.1). The 2-year risks of CIN 3 for women positive for HPV16, HPV18, or other carcinogenic HPV genotypes were 19.1%, 13.9%, and 5.7%, respectively, and did not differ significantly by the baseline cytology interpretation (ASCUS or LSIL). Taking HPV genotypes into account, having a CIN 1 (compared with no CIN 1) was not a risk factor for developing CIN 3 (OR 0.99, 95% CI 0.54-1.8). CONCLUSION: A CIN 1 diagnosis does not represent a significant risk factor for CIN 3 above the risk attributed to its molecular cause, genotype-specific HPV infection. LEVEL OF EVIDENCE: II. PMID- 22105251 TI - Transversus abdominis plane infiltration and quality of recovery after laparoscopic hysterectomy: a randomized controlled trial. AB - OBJECTIVE: To examine the effect of a preoperative transversus abdominis plane infiltration on postoperative quality of recovery and analgesia in patients undergoing laparoscopic hysterectomy. METHODS: The study was a randomized, double blinded, placebo-controlled trial. Seventy-five healthy women were randomized to receive a preoperative infiltration with 0.5% ropivacaine, 0.25% ropivacaine, or saline. Postoperative quality of recovery score (QoR-40), pain, and opioid consumption were assessed up to 24 hours after the surgical procedure. Data were analyzed using Kruskal-Wallis test. Post hoc pair-wise comparisons were made using Dunn test. P<.05 was required to reject the null hypothesis. RESULTS: Sixty six patients completed the study. Patients' baseline characteristics and surgical factors were not different between groups. The ropivacaine group experienced a better quality recovery and less postoperative pain than the saline group. The median difference (99.2% confidence interval) in global recovery scores at 24 hours after surgery was 28 (QoR score 4-39, P=.001) for ropivacaine 0.5% and 28 (QoR score 10-43, P<.001) for ropivacaine 0.25% compared with saline, respectively. The 0.5% ropivacaine group also had less pain, lower opioid consumption, and faster postanesthesia care unit discharge than the saline group. Linear regression demonstrated an inverse relationship between opioid consumption and global quality of recovery at 24 hours (P<.001). CONCLUSION: The transversus abdominis plane infiltration improves quality of recovery. There was an inverse linear relationship between postoperative opioid consumption and quality of recovery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01074229. LEVEL OF EVIDENCE: I. PMID- 22105252 TI - Mode of delivery in nulliparous women and neonatal intracranial injury. AB - OBJECTIVE: To compare neonatal neurologic complication rates of cesarean deliveries, forceps-assisted vaginal deliveries, and vacuum-assisted vaginal deliveries. METHODS: Data on singleton live births at 34 weeks or greater gestation born to nulliparous women from 1995 to 2003 in New York City were linked to hospital discharge data. Any diagnosis of neonatal subdural hemorrhage, intraventricular hemorrhage, seizures, scalp laceration or cephalohematoma, fracture, facial nerve palsy, brachial plexus injury, or 5-minute Apgar score of less than 7 was considered significant. Multivariable logistic regression was used to estimate associations between delivery mode and these neonatal morbidities. RESULTS: Forceps-assisted vaginal deliveries were associated with significantly fewer seizures and 5-minute Apgar scores less than 7 compared with vacuum-assisted vaginal deliveries and cesarean deliveries. Cesarean deliveries were linked to less subdural hemorrhages compared with forceps-assisted vaginal deliveries or vacuum-assisted vaginal deliveries. When seizure, intraventricular hemorrhage, and subdural hemorrhage were examined collectively to best predict neurologic outcome, forceps-assisted vaginal deliveries had an overall reduced risk compared with both vacuum-assisted vaginal deliveries (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.40-0.90) and cesarean deliveries (OR 0.68, 95% CI 0.48-0.97). The number needed to treat to prevent one case of severe neurologic morbidity is 509 for forceps-assisted vaginal deliveries compared with vacuum assisted vaginal deliveries and 559 for forceps-assisted vaginal deliveries compared with cesarean deliveries. CONCLUSION: Compared with vacuum-assisted vaginal delivery or cesarean delivery, a forceps-assisted vaginal delivery is associated with a reduced risk of adverse neonatal neurologic outcomes. LEVEL OF EVIDENCE: II. PMID- 22105253 TI - Intrapartum management of premature rupture of membranes: effect on cesarean delivery rate. AB - OBJECTIVE: To estimate whether it is possible to define clinically a subgroup of women who have so high a cesarean delivery rate as to avoid spontaneous onset of labor or induced labor. METHODS: We conducted a retrospective cohort study (October 2005 to January 2010) on a data set of women who had premature rupture of membranes (PROM) at greater than 24 weeks of gestation, a singleton pregnancy, and a viable fetus without congenital anomalies. Patients were treated in a common way regarding indications for delivery. The primary outcome was cesarean delivery. RESULTS: We identified 1,026 women (comprising 7.9% of all deliveries) who had PROM and met the inclusion criteria. There were 404 with preterm deliveries. One hundred thirty-seven (13.4%) had a contraindication to either labor or vaginal delivery. For women with induction (n=355), vaginal delivery occurred in 82%, whereas for those with spontaneous labor (n=534), vaginal delivery occurred in 87% (P=.03). No clinically defined subgroup had an observed cesarean delivery rate greater than 27%, and in most subgroups, it was lower, even when we built in multiple risk factors, including gestational age less than 34 weeks, chorioamnionitis, abruption, and nulliparity. CONCLUSION: In the absence of a contraindication to labor or to vaginal delivery, the likelihood of vaginal delivery after PROM, with either spontaneous or induced labor, is high, even when we included multiple risk factors for cesarean delivery. LEVEL OF EVIDENCE: II. PMID- 22105254 TI - Oral misoprostol for labor augmentation: a randomized controlled trial. AB - OBJECTIVE: To estimate the efficacy of oral misoprostol for labor augmentation. METHODS: We performed a randomized, controlled trial comparing intravenous oxytocin to a 75-microgram dose of oral misoprostol. Women in spontaneous labor were eligible if they had cervical dilation of 4-8 cm and required labor augmentation. Primary outcome was the incidence of uterine tachysystole, hypertonus, or both. Secondary outcomes included labor durations, presence of nonreassuring fetal heart rate, mode of delivery, and select maternal and neonatal outcomes. RESULTS: Three hundred fifty women were randomized, 176 (50%) to oral misoprostol and 174 (50%) to intravenous oxytocin. Whereas the admission to study drug interval was significantly shorter in women randomized to misoprostol (median 330 minutes [252, 408] compared with 402 minutes [330, 492]; P<.001), there was no difference in the time interval between initiation of augmentation and delivery: 306 (150, 534) minutes in the misoprostol group compared with 276 (162, 462) in the oxytocin group (P=.29). Women in the misoprostol group were more likely to experience uterine tachysystole, hypertonus, or tachysystole and hypertonus compared with those in the oxytocin group (76% compared with 64%, respectively; P=.02). This increase was secondary to uterine hypertonus as the incidence of tachysystole did not differ between groups (P=.74). Women in the misoprostol arm were no more likely to experience a nonreassuring fetal heart rate (P=.20) or require a cesarean delivery for this indication (P=.78). There were no significant differences in maternal or neonatal outcomes. CONCLUSION: Oral misoprostol is an effective agent for augmentation of labor. CLINICAL TRIAL REGISTRATION: : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00906347. LEVEL OF EVIDENCE: I. PMID- 22105255 TI - Morbidity of appendectomy and cholecystectomy in pregnant and nonpregnant women. AB - OBJECTIVE: To use the data from the American College of Surgeons (ACS) National Surgical Quality Improvement Program to estimate major postoperative morbidity after 1) appendectomy in pregnant compared with nonpregnant women; and 2) cholecystectomy in pregnant compared with nonpregnant women. METHODS: We selected a cohort of reproductive-aged women undergoing appendectomy and cholecystectomy between 2005 and 2009 from the data files of the ACS National Surgical Quality Improvement Program. Outcomes in pregnant women were compared with those in nonpregnant women. The primary outcome was composite 30-day major postoperative complications. Pregnancy-specific complications were not assessed and thus not addressed. RESULTS: Pregnant and nonpregnant women had similar composite 30-day major morbidity after appendectomy (3.9% [33 of 857] compared with 3.1% [593 of 19,172], P=.212) and cholecystectomy (1.8% [eight of 436] compared with 1.8% [584 of 32,479], P=.954). Pregnant women were more likely to have preoperative systemic infections before each procedure. In logistic regression analysis, pregnancy status was not predictive of increased postoperative morbidity for appendectomy (adjusted odds ratio 1.26, 95% confidence interval 0.87-1.82). CONCLUSION: Pregnancy does not increase the occurrence of postoperative maternal morbidity related to appendectomy and cholecystectomy. LEVEL OF EVIDENCE: II. PMID- 22105256 TI - Trends in bilateral oophorectomy at the time of hysterectomy for benign disease. AB - OBJECTIVE: To identify patient characteristics associated with bilateral oophorectomy or removal of remaining ovary at the time of benign hysterectomy, and to estimate trends in the performance of oophorectomy from 2001 to 2006. METHODS: This was a cross-sectional analysis using the New York State Department of Health Statewide Planning and Research Cooperative System. Women aged 18 years or older undergoing hysterectomies for benign gynecologic conditions were included. We evaluated factors associated with oophorectomy on both univariable and multivariable analyses and assessed for changes in performance of oophorectomy over the course of the study. RESULTS: Forty-seven percent of 144,877 hysterectomies included oophorectomy. Women who underwent oophorectomy were older and were more likely to have a family history of breast or ovarian cancer, a personal history of breast cancer, ovarian cysts, or endometriosis. Women who underwent vaginal or laparoscopic hysterectomy or had uterine prolapse were less likely to undergo oophorectomy. Both race and insurance status were associated with performance of oophorectomy. From 2001 to 2006, there was an 8% absolute decrease in the performance of oophorectomy at the time of benign hysterectomy for women of all ages, with a 10.4% decrease in women aged younger than 55 (P for trend <.001). CONCLUSION: Age, route of hysterectomy, and concomitant gynecologic diagnoses influence oophorectomy rate. From 2001 to 2006, a significant decrease in the performance of oophorectomy at the time of benign hysterectomy was noted in women aged younger than 55 years. Recent studies of complications of hormone therapy and prophylactic oophorectomy may have influenced patients' and physicians' decision-making, leading to lower oophorectomy rates. LEVEL OF EVIDENCE: II. PMID- 22105257 TI - Five-year follow-up after comparing bipolar endometrial ablation with hydrothermablation for menorrhagia. AB - OBJECTIVE: To evaluate the results of a previous study comparing bipolar radiofrequency endometrial ablation with hydrothermablation for the treatment of menorrhagia at 5-year follow-up. METHOD: A double-blind, randomized, controlled trial was performed in a large teaching hospital in the Netherlands between March 2005 and August 2007. One-hundred sixty women with menorrhagia were randomly allocated to bipolar ablation or hydrothermablation. The results of follow-up at 12 months were previously reported. At 4-5 years of follow-up, a questionnaire was sent to all the participants to register amenorrhea rates, reinterventions, and patient satisfaction. RESULTS: At 5-year follow-up, response rates were 90% and 83% in the bipolar group and hydrotherm group, respectively. Amenorrhea rates were 55.4% and 35.3% in the bipolar group and the hydrotherm group, respectively (relative risk [RR] 1.5, 95% confidence interval [CI] 1.05-2.3). The number of surgical reinterventions was 11 compared with 23 (RR 0.43, 95% CI 0.23-0.80). Overall, more women were satisfied in the bipolar group compared with the hydrotherm group. CONCLUSION: After treatment, bipolar radiofrequency endometrial ablation system is more effective at 5 years than hydrothermablation in the treatment of menorrhagia. LEVEL OF EVIDENCE: II. PMID- 22105259 TI - The diagnosis and natural history of false preterm labor. AB - OBJECTIVE: To estimate the natural history of pregnancies in women who present with preterm labor symptoms and who are sent home with a diagnosis of false labor. METHODS: A prospective observational study of women with singletons and intact membranes who presented to triage between 24 0/7 and 33 6/7 weeks of gestation with preterm labor symptoms and cervical dilation less than 2 cm was conducted. Women sent home with a diagnosis of false preterm labor were analyzed against a comparable general obstetric population delivered during the same time period. The primary outcome was delivery before 37 weeks of gestation. Secondary outcomes included the interval between presentation and delivery, as well as maternal and neonatal outcomes. RESULTS: Of the 843 women who met inclusion criteria, 690 (82%) were sent home with a diagnosis of false preterm labor and 153 (18%) were admitted to labor and delivery. When analyzed compared with a comparable general obstetric population, women sent home had a similar rate of birth before 34 weeks of gestation (2% compared with 1%, P=.28) but a higher rate of birth between 34 and 36 weeks of gestation (5% compared with 2%, P<.001). There was no difference in neonatal mortality (0% compared with 0.3%, P=.18). Women with cervical dilation of 1 cm at discharge were more likely to deliver before 34 weeks of gestation compared with nondilated women (5% compared with 1%, P=.02); however, 89% of the 1-cm group delivered more than 21 days after presentation. CONCLUSION: Women sent home with a diagnosis of false preterm labor are not at increased risk for early preterm birth or neonatal mortality; however, they are at increased risk for late preterm birth. LEVEL OF EVIDENCE: II. PMID- 22105258 TI - Clinical subtypes of premenstrual syndrome and responses to sertraline treatment. AB - OBJECTIVE: To estimate response of diagnosis and symptom-based subtypes to sertraline treatment. METHODS: This was a secondary data analysis for women who were diagnosed with premenstrual syndrome (PMS) or premenstrual dysphoric disorder and treated in three National Institutes of Health-supported clinical trials (N=447). Three PMS subtypes were identified based on predominance of psychological, physical, or both symptom types. Scores for each symptom and a total premenstrual score at baseline and endpoint were calculated from daily symptom diaries. Change from baseline after three treated menstrual cycles (or endpoint if sooner) was estimated using linear regression models adjusted for baseline severity. RESULTS: The PMS and premenstrual dysphoric disorder diagnoses improved similarly with sertraline relative to placebo, whereas symptom-based subtypes had differential responses to treatment. The mixed symptom subtype had the strongest response to sertraline relative to placebo (Daily Symptom Rating difference 33.80; 95% confidence interval [CI] 17.16-50.44; P<.001), and the physical symptom subtype had the poorest response to sertraline (Daily Symptom Rating difference 9.50; 95% CI -16.29 to 35.28; P=.470). Results based on clinical improvement (50% decrease from baseline) indicated that 8.3 participants in the mixed symptom subtype, 3.9 in the psychological subtype, and 7.1 in the physical subtype are needed to observe one woman in the subtype who would achieve clinical improvement. CONCLUSION: The PMS and premenstrual dysphoric disorder diagnoses have similar response to sertraline treatment, but symptom-based subtypes have significantly different responses to this treatment. Mixed and psychological symptom subtypes improved whereas the physical symptom subtype did not improve significantly. Identifying the patient's predominant symptoms and their severity is important for individualized treatment and a possible response to a selective serotonin reuptake inhibitor. LEVEL OF EVIDENCE: II. PMID- 22105261 TI - Impaired fetal growth and low plasma volume in adult life. AB - OBJECTIVE: To estimate whether normotensive women who were born small for gestational age have low plasma volume in adult life, which is associated with later chronic hypertension. METHODS: In 280 normotensive women with a history of hypertension in pregnancy, we recorded recalled gestational age and weight at birth and measured plasma volume (I-human serum albumin indicator dilution method). To correct for possible confounders, we recorded recent obstetric history and measured in each individual all constituents of the metabolic syndrome (World Health Organization criteria), sex hormones (progesterone and estradiol), renal function, and cardiac performance at rest (echocardiography). We estimated daily activity level with a validated questionnaire (Short Questionnaire to Assess Health-enhancing physical activity). We studied the relation between women's own birth weight centile and her adult plasma volume (mL) and adjusted for the effects of confounding variables using multiple linear regression analysis. RESULTS: Birth weight correlated positively with adult plasma volume (P<.001). Linear regression analysis demonstrated that each 10 centile change in birth weight is associated with an average change of 46.6 mL (95% confidence interval [CI] 30.8-62.3) in adult plasma volume. This association persisted after adjustment for confounding factors (current body surface area, mean arterial pressure, total vascular resistance, glomerular filtration rate, and a total 24 hours of sodium output). After adjustment, each 10 centile change in birth weight was associated with an average change of 32.1 mL (95% CI 19.6 44.6) in adult plasma volume. Birth centile contributes 14% to the variation in total adult plasma volume. CONCLUSION: Impaired fetal growth is associated with low plasma volume in adult life. LEVEL OF EVIDENCE: II. PMID- 22105262 TI - Management of very early fetal anemia resulting from red-cell alloimmunization before 20 weeks of gestation. AB - OBJECTIVE: To evaluate the results of management of very early fetal anemia (before 20 weeks of gestation) in cases of red-cell alloimmunization. METHODS: Retrospective study of the outcome of all in utero transfusions performed before 20 weeks of gestation and all pregnancies requiring an in utero transfusion before 20 weeks in our reference center from January 1990 through August 2011 in cases with severe alloimmunization. RESULTS: Twenty-five in utero transfusions were performed in 18 pregnancies in 16 patients during the study period. A vascular access was performed successfully in 22 of the 24 cases in which it was attempted. An intraperitoneal transfusion was necessary in two cases. Two in utero deaths attributable to the intravascular procedure occurred during attempts before 18 weeks of gestation and another, not associated with a transfusion, at 29 weeks. The overall survival rate was 83.3% (compared with 88.0% when the first in utero transfusion took place before 22 weeks). The risk of fetal loss for each transfusion was 8.0% before 20 weeks and 6.3% before 22 weeks. An intraperitoneal transfusion at 17 2/7 weeks allowed one fetus to survive until the first intravascular in utero transfusion could take place at 18 2/7 weeks. CONCLUSION: Fetal anemia before 20 weeks remains at high risk of lethal complications compared with later gestational ages. Technical difficulties in a vascular access are mainly encountered before 18 weeks of gestation. At an earlier gestational age, intraperitoneal transfusion may gain the days necessary to perform an intravascular transfusion more safely. LEVEL OF EVIDENCE: III. PMID- 22105260 TI - Increasing maternal body mass index and characteristics of the second stage of labor. AB - OBJECTIVE: To evaluate the length of the second stage of labor in relation to increasing maternal prepregnancy body mass index (BMI) among nulliparous parturient women, and to determine whether route of delivery differs among obese, overweight, and normal-weight women reaching the second stage of labor. METHODS: We performed a secondary analysis of a multicenter trial of fetal pulse oximetry conducted among 5,341 nulliparous women who were induced or labored spontaneously at 36 weeks or more of gestation. Normal weight was defined as BMI of 18.5-24.9 kg/m, overweight was a BMI of 25.0-29.9 kg/m, and obese was a BMI of 30 or higher. RESULTS: Of the 5,341 women, 97% had prepregnancy BMI recorded. Of these, 3,739 had BMIs of 18.5 or higher and reached the second stage of labor. Increasing maternal BMI was not associated with second stage duration: normal weight, 1.1 hour; overweight, 1.1 hour; and obese, 1.0 hours (P=.13). Among women who reached the second stage, as BMI increased, so did the likelihood that the woman had undergone induction of labor. Even so, the lack of association between second-stage duration and BMI did not vary by method of labor onset (P=.84). The rate of cesarean delivery in the second stage did not differ by increasing BMI (normal weight 7.1%, overweight 9.6%, obese 6.9%, P=.17). CONCLUSION: Among nulliparous women who reach the second stage of labor, increasing maternal BMI is not associated with a longer second stage or an increased risk of cesarean delivery. LEVEL OF EVIDENCE: II. PMID- 22105264 TI - Identification of six loci associated with pelvic organ prolapse using genome wide association analysis. AB - OBJECTIVE: There is evidence that both environmental and genetic factors contribute to pelvic organ prolapse. We conducted a genome-wide association study to investigate whether common genetic variants modify the risk of pelvic organ prolapse. METHODS: We recruited women who had been evaluated and treated for pelvic organ prolapse at the University of Utah from 1996 to 2008 and their affected female relatives. Those in the case group were genotyped on the Illumina 550K platform. We genetically matched 2,976 white control participants available from Illumina as the control group. Association tests were adjusted for related participants using two different software programs: EMMAX and Genie. Confirmation of findings was performed in a cohort of Dutch women (n=76) with recurrent pelvic organ prolapse and family history of pelvic organ prolapse. RESULTS: The Utah study sample included 115 case group participants treated for pelvic organ prolapse, in most case group participants with surgery (n=78) or repeat surgery (n=35). Results from association analyses using EMMAX software identified five single-nucleotide polymorphisms (SNPs) significantly associated with pelvic organ prolapse (P<1*10). Independent association analysis with Genie software identified three of the same SNPs and one additional SNP. The six SNPs were located at 4q21 (rs1455311), 8q24 (rs1036819), 9q22 (rs430794), 15q11 (rs8027714), 20p13 (rs1810636), and 21q22 (rs2236479). Nominally significant findings (P<.05) or findings trending toward significance (P<.1) were observed for five of the six SNPs in the Dutch cohort. CONCLUSION: Six SNPs have been identified that are significantly associated with pelvic organ prolapse in high risk familial case group participants and that provide evidence for a genetic contribution to pelvic organ prolapse. LEVEL OF EVIDENCE: II. PMID- 22105263 TI - Continuation rates and complications of intrauterine contraception in women diagnosed with bipolar disorder. AB - OBJECTIVE: To estimate continuation rates, complications, and psychiatric hospitalizations among women with bipolar disorder using levonorgestrel-releasing or copper-containing intrauterine devices (IUDs) as compared with those using depot medroxyprogesterone acetate or sterilization for birth control. METHODS: Data for this cohort study were obtained from a nationwide health insurance claims database on an employed, commercially insured population. Women aged 18-44 years with a prior diagnosis of bipolar disorder (n=849) who were using the levonorgestrel intrauterine system, a copper-containing IUD, depot medroxyprogesterone acetate, or sterilization were evaluated. Outcomes included continuation rates over a 12-month interval, infectious and noninfectious complications, and hospitalizations for bipolar disorder or depression. RESULTS: Women using an IUD were more likely than those using depot medroxyprogesterone acetate to continue the method for at least 12 months (copper-containing IUD, 86%; levonorgestrel intrauterine system, 87%). In comparison, only 31% of those who initiated depot medroxyprogesterone acetate received three more injections during the next year (P<.001). No significant differences were noted in infectious or noninfectious complications by contraceptive type. Finally, no differences were observed in the number of hospitalizations for bipolar disorder or depression among the four contraceptive groups. CONCLUSION: More women with bipolar disorder continued using IUDs at one year than women using depot medroxyprogesterone acetate. The rates of complications and psychiatric hospitalizations were not different among women using an IUD, depot medroxyprogesterone acetate, or sterilization. LEVEL OF EVIDENCE: II. PMID- 22105265 TI - Optical coherence tomography compared with colposcopy for assessment of vaginal epithelial damage: a randomized controlled trial. AB - OBJECTIVE: Colposcopy has been used to detect epithelial damage with vaginal microbicides. In animal models, optical coherence tomography provided increased sensitivity over colposcopy in detecting epithelial injury. This randomized, double-blinded, clinical study compared optical coherence tomography to colposcopy for the evaluation of epithelial injury in women using placebo or nonoxynol-9. METHODS: Thirty women aged 18-45 were randomized to use hydroxyethyl cellulose placebo or nonoxynol-9 vaginal gel twice daily for 5.5 days. Imaging with colposcopy and optical coherence tomography was performed before product use, after the last dose, and 1 week later. Colposcopy was graded using standard criteria. Optical coherence tomography images were scored for epithelial integrity based on a published scoring system and were measured for epithelial thickness. RESULTS: Colposcopy findings, optical coherence tomography scores, and epithelial thicknesses were similar between treatment groups at baseline. After treatment, there were significant differences between the nonoxynol-9 (1.37) and control group (1.15) optical coherence tomography scores (P<.001), indicating epithelial injury, and there was epithelial thinning in the nonoxynol-9 group (237 micrometers) compared with the control group (292 micrometers; P=.008). There were no significant posttreatment colposcopic differences in epithelial disruption between treatment groups, with only increased erythema noted after nonoxynol-9 use (P=.02). CONCLUSION: Optical coherence tomography detected epithelial disruption and thinning not identified by colposcopy. Vaginal epithelial thickness, a measure previously available only through biopsy, decreased after nonoxynol-9 use, a finding that may contribute to increased susceptibility to human immunodeficiency virus after frequent use. Optical coherence tomography shows promise for the noninvasive clinical assessment of vaginal epithelial damage. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry, www.umin.ac.jp/ctr/index.htm, R000006186. LEVEL OF EVIDENCE: I. PMID- 22105267 TI - Type of attending obstetrician call schedule and changes in labor management and outcome. AB - OBJECTIVE: To estimate whether a night-float call schedule for attending obstetricians is associated with different labor management or obstetric outcomes compared with a traditional call schedule. METHODS: A chart review was performed for all women admitted for labor and delivery during two 3-month periods. One period occurred immediately before a single group of generalist obstetricians changed from a traditional call schedule to a night-float call schedule, whereas the second 3-month period occurred immediately after this change. A control group of women who were managed during the same 6-month time period by a group of generalist obstetricians at the same institution who did not alter their traditional call schedule was also identified. Data on labor management and perinatal outcomes were collected. RESULTS: Change to a night-float call schedule was associated with a decreased use of induction of labor (30% to 16.7%, P=.02). Physicians also were more likely to use oxytocin augmentation (57.5% to 75.0%, P=.01) and less likely to manually extract the placenta (5.0% to 0%, P=.02) or perform an episiotomy (10.1% to 2.6%, P=.04). There were fewer observed third degree and fourth-degree lacerations (10.3% to 3.3%, P=.045) and fewer neonates born with an umbilical artery pH less than 7.10 (9.3% to 2.2%, P=.03). CONCLUSION: A night-float call schedule was associated with both a reduction in obstetric interventions, such as labor induction and episiotomy, and improvement of particular obstetric outcomes, such as the frequency of perineal lacerations. LEVEL OF EVIDENCE: II. PMID- 22105266 TI - Interferon gamma release assay compared with the tuberculin skin test for latent tuberculosis detection in pregnancy. AB - OBJECTIVE: To estimate agreement and correlation between the tuberculin skin test and an interferon gamma release assay for detecting latent tuberculosis (TB) infection in pregnant women. METHODS: We conducted a cross-sectional study of pregnant women initiating prenatal care at a university-affiliated public hospital between January 5, 2009, and March 15, 2010. Eligible women received a questionnaire about TB history and risk factors as well as the tuberculin skin test and phlebotomy for the interferon gamma release assay. Agreement and correlation between tests were estimated, and different cutoffs for interferon gamma release assay positivity were used to assess effect on agreement. Furthermore, predictors of test positivity and test discordance were evaluated using multivariable analysis. RESULTS: Of the 220 enrolled women, 199 (90.5%) returned for tuberculin skin test evaluation. Over 70% were Hispanic and 65% were born in a country with high TB prevalence. Agreement between the tuberculin skin test and interferon gamma release assay was 77.39 (kappa=0.26). This agreement was not significantly changed using different cutoffs for the assay. Birth bacille Calmette-Guerin vaccination was associated with tuberculin skin test positivity (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.4-13.48, P=.01), but not interferon gamma release assay positivity. There were no statistically significant predictors of the tuberculin skin test and interferon gamma release assay result discordance; however, birth in a high-prevalence country was marginally associated with tuberculin skin test-positive and interferon gamma release assay-negative results (OR 2.94, 95% CI 0.86-9.97 P=.08). CONCLUSION: Comparing the tuberculin skin test and interferon gamma release assay results in pregnancy, concordance and agreement were poor. Given that much is still unknown about the performance of interferon gamma release assays in pregnancy, further research is necessary before the tuberculin skin test is abandoned for screening of latent TB infection in pregnancy. LEVEL OF EVIDENCE: III. PMID- 22105268 TI - Lethal fetal anomalies: why the big void? PMID- 22105269 TI - Gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) represents a heterogeneous group of metabolic disorders, which result in varying degrees of maternal hyperglycemia and pregnancy-associated risk. The frequency of GDM is rising globally and may also increase further as less-stringent criteria for the diagnosis are potentially adopted. The additional burden placed on the health care system by increasing cases of GDM requires consideration of diagnostic approaches and currently used treatment strategies. Debate continues to surround both the diagnosis and treatment of GDM despite several recent large-scale studies addressing these controversial issues. As many now have come to reassess their approach to the management of GDM, we provide information in this review to help guide this process. The goal for each health care practitioner should continue to be to provide optimum care for women discovered to have carbohydrate intolerance during pregnancy. PMID- 22105270 TI - Antenatal dietary interventions in obese pregnant women to restrict gestational weight gain to Institute of Medicine recommendations: a meta-analysis. AB - OBJECTIVE: To estimate whether antenatal dietary interventions restrict maternal weight gain in obese pregnant women without compromising newborn birth weight. DATA SOURCES: PubMed and Cochrane Controlled Trials Register were searched using free-text search terms: pregnancy, obesity, overweight, dietary intervention, lifestyle, and randomis(z)ed controlled trial through March 2011 in a similar search strategy to that used in a previous systematic review. METHODS OF STUDY SELECTION: We included randomized controlled trials in which antenatal dietary intervention was provided to pregnant women who were overweight or obese at booking. We extracted 263 abstracts or reports, from which 39 full-text articles were reviewed. TABULATION, INTEGRATION, AND RESULTS: Four randomized controlled trials were identified involving 537 women. The results suggested that there was a significant pool treatment effect (z=11.58, P<.001), because antenatal dietary intervention programs were effective in reducing the total gestational weight gain by 6.5 kg. Despite this, antenatal dietary interventions did not alter newborn birth weight (z=0.18, P=.859). CONCLUSION: Antenatal dietary interventions in obese pregnant women can reduce maternal weight gain in pregnancy without an effect on newborn birth weight. PMID- 22105271 TI - Nomenclature for pregnancy outcomes: time for a change. AB - Traditionally, obstetricians have grouped together all pregnancy losses before the mid-second trimester as spontaneous abortions. However, this nomenclature is arbitrary, outdated, and not clinically useful. Using this system, miscarriages due to genetic abnormalities, fetal deaths associated with abnormal placental growth and development, and spontaneous preterm births of liveborn fetuses at previable gestations are lumped together in a single category. In addition, the term abortion is fraught with emotional connotations for families suffering the loss of a pregnancy. Thus, whereas the existing classification for pregnancy loss has served a somewhat pragmatic role, it ignores precepts of developmental biology and the clinical realities of these adverse pregnancy outcomes. In this article, we propose a more useful nomenclature for pregnancy loss and preterm births that is informative and is based on developmental periods in gestation and shared pathophysiology. PMID- 22105272 TI - Informed consent and the use of transvaginal synthetic mesh. AB - In 2008 and again in July of this year, the U.S. Food and Drug Administration (FDA) issued safety communications regarding the use of transvaginally placed surgical mesh. These FDA communications have been the subject of much discussion in the literature. One issue raised by these communications and in the medical literature is the matter of informed consent. Informed consent is an established bioethical principle in modern health care, but it is evolving. The legal interpretations of informed consent are also in flux. A review of contemporary ethical and legal elements of informed consent is presented as it relates to the use of medical innovation, with a focus on transvaginally placed surgical mesh. PMID- 22105273 TI - Society for Women's Health Oversight: establishing equality in the profession of obstetrics and gynecology. PMID- 22105275 TI - Comparing postcesarean infectious complication rates using two different skin preparations. PMID- 22105276 TI - Safe maternal positioning during labor and delivery. PMID- 22105278 TI - Postpartum sterilization with the titanium clip: a systematic review. PMID- 22105280 TI - Selective serotonin reuptake inhibitors and risk for major congenital anomalies. PMID- 22105282 TI - How to stop the relentless rise in cesarean deliveries. PMID- 22105284 TI - How to stop the relentless rise in cesarean deliveries. PMID- 22105286 TI - How to stop the relentless rise in cesarean deliveries. PMID- 22105287 TI - How to stop the relentless rise in cesarean deliveries. PMID- 22105293 TI - Committee Opinion no. 512: health care for transgender individuals. AB - Transgender individuals face harassment, discrimination, and rejection within our society. Lack of awareness, knowledge, and sensitivity in health care communities eventually leads to inadequate access to, underutilization of, and disparities within the health care system for this population. Although the care for these patients is often managed by a specialty team, obstetrician-gynecologists should be prepared to assist or refer transgender individuals with routine treatment and screening as well as hormonal and surgical therapies. The American College of Obstetricians and Gynecologists opposes discrimination on the basis of gender identity and urges public and private health insurance plans to cover the treatment of gender identity disorder. PMID- 22105294 TI - Committee Opinion no. 513: vaginal placement of synthetic mesh for pelvic organ prolapse. AB - Since 2004, use of synthetic mesh has increased in vaginal surgery for the treatment of pelvic organ prolapse. However, concerns exist about the safety and efficacy of transvaginally placed mesh. Based on the currently available limited data, although many patients undergoing mesh-augmented vaginal repairs heal well without problems, there seems to be a small but significant group of patients who experience permanent and life-altering sequelae, including pain and dyspareunia, from the use of vaginal mesh. The American College of Obstetricians and Gynecologists and the American Urogynecologic Society provide background information on the use of vaginally placed mesh for the treatment of pelvic organ prolapse and offer recommendations for practice. PMID- 22105295 TI - Committee Opinion no. 514: emergent therapy for acute-onset, severe hypertension with preeclampsia or eclampsia. AB - Acute-onset, persistent (lasting 15 minutes or more), severe systolic (greater than or equal to 160 mm Hg) or severe diastolic hypertension (greater than or equal to 110 mm Hg) or both in pregnant or postpartum women with preeclampsia or eclampsia constitutes a hypertensive emergency. Severe systolic hypertension may be the most important predictor of cerebral hemorrhage and infarction in these patients and if not treated expeditiously can result in maternal death. Intravenous labetalol and hydralazine are both considered first-line drugs for the management of acute, severe hypertension in this clinical setting. Close maternal and fetal monitoring by the physician and nursing staff are advised. Order sets for the use of labetalol and hydralazine for the initial management of acute, severe hypertension in pregnant or postpartum women with preeclampsia or eclampsia have been developed. PMID- 22105296 TI - Patient Safety Checklist no. 3: scheduling planned cesarean delivery. PMID- 22105297 TI - Patient Safety Checklist no. 4: preoperative planned cesarean delivery. PMID- 22105298 TI - Patient Safety Checklist no. 5: scheduling induction of labor. PMID- 22105299 TI - A luminescent bacterium assay of fusaric acid produced by Fusarium proliferatum from banana. AB - Fusarium proliferatum was isolated as a major pathogen causing the Fusarium disease in harvested banana fruit. One of its major compounds, fusaric acid, was identified by high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS). Because the light intensity of the luminescent bacterium Vibrio qinghaiensis sp. Nov. Q67 can be inhibited by fusaric acid, the fusaric acid content of F. proliferatum was assessed and compared by both the HPLC and luminescent bacterium methods. Although both methods afforded almost similar values of fusaric acid, the latter indicated slightly lower content than the former. Czapek medium was more suitable for the growth of F. proliferatum and fusaric acid production than modified Richard medium, with an optimum pH of approximately 7.0. However, no significant (P < 0.05) correlation was obtained between the fusaric acid production and growth of mycelia of F. proliferatum. The study suggests that the bioevaluation by use of the luminescent bacterium was effective in monitoring fusaric acid production by F. proliferatum without expensive equipment. PMID- 22105300 TI - Zirconium arsenate-modified silica nanoparticles for specific capture of phosphopeptides and direct analysis by matrix-assisted laser desorption/ionization mass spectrometry. AB - In this paper, we report, as far as we are aware, the first use of zirconium arsenate-modified silica nanoparticles (ZrAs-SNPs) for specific capture of phosphopeptides, followed by matrix-assisted laser desorption/ionization mass spectrometric (MALDI MS) analysis. Under the optimized enrichment conditions, the efficiency and specificity of ZrAs-SNPs were evaluated with tryptic digests of four standard proteins (alpha-casein, beta-casein, ovalbumin, and bovine serum albumin) and compared with those of titanium arsenate-modified silica nanoparticles (TiAs-SNPs). The results showed that more selective enrichment of multiply phosphorylated peptides was observed with ZrAs-SNPs than with TiAs-SNPs whereas TiAs-SNPs resulted in slightly better recovery of singly phosphorylated peptides. ZrAs-SNPs were chosen for direct capture of phosphopeptides from diluted human serum of healthy and adenocarcinoma individuals. Our experimental profiling of serum phosphopeptides revealed that the level of phosphorylated fibrinogen peptide A was up-regulated in the serum of adenocarcinoma patients in comparison with healthy adults. This suggests the possibility of using ZrAs-SNPs for discovery of biomarkers of the pathogenesis process of tumors. PMID- 22105301 TI - Expansion of Tfh-like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88-deficient mice. AB - The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88(-/-) mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4(+) T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4(+) T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88(-/-) mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1- and ICOS-dependent manner. PMID- 22105303 TI - Homogentisate 1,2 dioxygenase is expressed in human osteoarticular cells: implications in alkaptonuria. AB - Alkaptonuria (AKU) results from defective homogentisate1,2-dioxygenase (HGD), causing degenerative arthropathy. The deposition of ochronotic pigment in joints is so far attributed to homogentisic acid produced by the liver, circulating in the blood and accumulating locally. Human normal and AKU osteoarticular cells were tested for HGD gene expression by RT-PCR, mono- and 2D-Western blotting. HGD gene expression was revealed in chondrocytes, synoviocytes, osteoblasts. Furthermore, HGD expression was confirmed by Western blotting, that also revealed the presence of five enzymatic molecular species. Our findings indicate that AKU osteoarticular cells produce the ochronotic pigment in loco and this may strongly contribute to induction of ochronotic arthropathy. PMID- 22105304 TI - Perineural cysts resembling complex cystic adnexal masses on transvaginal sonography. AB - Perineural cysts may be discovered incidentally on pelvic sonography and can easily mimic more common gynecologic masses. We report the complex cystic adnexal mass like appearance of these incidentally noted cysts which mimicked malignancy on sonography in a postmenopausal female, with stage I breast cancer and vaginal spotting. PMID- 22105305 TI - Fractional deuteration applied to biomolecular solid-state NMR spectroscopy. AB - Solid-state Nuclear Magnetic Resonance can provide detailed insight into structural and dynamical aspects of complex biomolecules. With increasing molecular size, advanced approaches for spectral simplification and the detection of medium to long-range contacts become of critical relevance. We have analyzed the protonation pattern of a membrane-embedded ion channel that was obtained from bacterial expression using protonated precursors and D(2)O medium. We find an overall reduction of 50% in protein protonation. High levels of deuteration at H(alpha) and H(beta) positions reduce spectral congestion in ((1)H,(13)C,(15)N) correlation experiments and generate a transfer profile in longitudinal mixing schemes that can be tuned to specific resonance frequencies. At the same time, residual protons are predominantly found at amino-acid side-chain positions enhancing the prospects for obtaining side-chain resonance assignments and for detecting medium to long-range contacts. Fractional deuteration thus provides a powerful means to aid the structural analysis of complex biomolecules by solid state NMR. PMID- 22105306 TI - Intentions versus unintended discursive consequences: reflections upon Sherbino et al.'s commentary on "Flower Power". PMID- 22105307 TI - 1H, 13C and 15N resonance assignment of the anticodon binding domain of human lysyl aminoacyl tRNA synthetase. AB - Human lysyl aminoacyl tRNA synthetase (hLysRS) is a multi-functional aminoacyl tRNA synthetase which is primarily involved in protein biosynthesis as well as crucial processes ranging from proinflammatory response to signal transduction. One important, non-canonical function of hLysRS is to target tRNA(Lys,3), the HIV 1 reverse transcription primer molecule, for uptake and packaging into new HIV-1 particles. Since the anticodon binding (ACB) domain of hLysRS is required for proper recognition of its cognate tRNA, NMR studies of the ACB domain are being conducted to enhance our understanding of how hLysRS interacts with these RNAs during protein biosysnthesis as well as HIV-1 viral packaging. Here, we report the backbone and side chain NMR resonance assignments of the uniformly (15)N-, (13)C-labeled ACB domain of hLysRS. PMID- 22105308 TI - The validity of ankle-brachial index for the differential diagnosis of peripheral arterial disease and lumbar spinal stenosis in patients with atypical claudication. AB - PURPOSE: Claudication is a typical symptom of peripheral arterial disease (PAD) and lumbar spinal stenosis (LSS). Differential diagnosis of PAD and LSS is often difficult due to the subjective natures of symptoms and atypical signs. The authors aimed to determine the usefulness of ankle-brachial index (ABI) measurement for the differential diagnosis of PAD and LSS when the etiology of claudication is uncertain. METHODS: Forty-two consecutive patients who had been referred by spine surgeons to a lower extremity vascular surgeon for atypical claudication were retrospectively analyzed. Atypical claudication was defined as claudication not caused by PAD, as determined by clinical manifestations, or by LSS, as determined by MR imaging. A final diagnosis of PAD was established by CT angiography (CTA) and of LSS by excluding PAD. Diagnostic validity of ABI for PAD in atypical presentation was assessed. RESULTS: Sixty-two legs of 42 atypical claudication patients were analyzed. Mean patient age was 65.8 +/- 8.2 years (38 85) and 29 (69.0%) had diabetes mellitus. Mean ABI was 0.73 +/- 0.14 (0.53-0.94) in the PAD group and 0.92 +/- 0.18 (0.52-1.10) in the LSS group (P < 0.001). Of the 33 legs with a low ABI (ABI < 0.9), 29 legs were diagnosed as true positives for PAD by CTA and 4 were false positives, and of the 29 legs with a high ABI, 5 were false negatives and 24 were true negatives. The sensitivity and specificity of ABI for the diagnosis of PAD in patients with atypical claudication were 85.3 and 85.7%, respectively, and its positive and negative predictive values were 87.9 and 82.8%. CONCLUSIONS: ABI is a recommended screening test for the differential diagnosis of lower leg claudication when clinical symptoms are atypical. PMID- 22105309 TI - Anterior osteotomy and percutaneous in situ contouring for correction of rigid posttraumatic T12-L1 malunion. PMID- 22105310 TI - A comparative study of axis-line-distance technique and Cobb method on assessing the curative effect on scoliosis. AB - PURPOSE: To compare the axis-line-distance technique (ALDT) and Cobb method for therapeutic evaluation of scoliosis. METHODS: Fifty-seven patients with scoliosis were treated in our hospital, 47 underwent conservative bracing therapy and 10 underwent surgery. Based on 171 full-spine X-ray images obtained from these 57 cases before treatment, during conservative treatment or surgery, and at final follow-up after removing the brace or after surgery, two radiologists independently measured and calculated the correction rate during treatment and at final follow-up and the rate of correction loss after treatment with the ALDT and Cobb methods. Paired t-test and correlation analysis were performed. RESULTS: Based on the ALDT, the lateral deviations of the apical vertebrae before treatment, during treatment, and at final follow-up were 31 +/- 14 mm, 16 +/- 8 mm, and 20 +/- 8 mm, respectively; the correction rates during treatment and at final follow-up were 48.7 +/- 21.2% and 37.6 +/- 14.2%, respectively, and the rate of correction loss after treatment was 11.3 +/- 6.5%. The Cobb angles of scoliosis before treatment, during treatment, and at final follow-up were 34 +/- 14 degrees , 19 +/- 7 degrees , and 22 +/- 6 degrees , respectively; the correction rates during treatment and at final follow-up were 44.4 +/- 17.3% and 33.9 +/- 14.4%, respectively, and the rate of correction loss after treatment was 11.4 +/- 4.3%. Calculation of the correction rate during treatment differed significantly between the two radiologists when using the Cobb method (P < 0.05); their calculations of the correction rate and rate of correction loss were not different (P > 0.05). The measurement data of the two radiologists using the Cobb method showed a weak to moderate correlation (r = 0.49, 0.57, and 0.51, respectively). When using the ALDT, there were no significant differences between the radiologists in their measurements of the correction rate during and after treatment (P > 0.05) or in the rate of correction loss. The measurement data of the two radiologists using the ALDT showed a good to excellent correlation (r = 0.92, 0.93, and 0.90, respectively). CONCLUSION: The ALDT is better than the Cobb method for therapeutic evaluation of scoliosis during treatment and at follow-up visits. PMID- 22105311 TI - Cardioprotective and hepatoprotective effects of ellagitannins from European oak bark (Quercus petraea L.) extract in rats. AB - BACKGROUND: Red wine contains many potentially bioactive polyphenols including resveratrol, catechins, anthocyanins and flavonoids as well as tannins derived from oak during maturation. This study examined the effects of a mixture of ellagitannins from oak bark (Quercus petraea L.) on cardiovascular, metabolic and liver changes in high-carbohydrate, high-fat diet-fed rats and in Spontaneously Hypertensive Rats (SHR). METHODS: First, 8-week-old male Wistar rats were divided into four groups and given either cornstarch diet, cornstarch diet + oak bark extract (0.5 mL/kg food), high-carbohydrate, high-fat diet or high-carbohydrate, high-fat diet + oak bark extract (0.5 mL/kg food) for 16 weeks. Oak bark extract was added to the diets for last 8 weeks of the feeding period. Secondly, SHR aged 42 weeks fed on standard chow diet were divided into two groups with and without oak bark extract treatment for 12 weeks (0.5 mL/kg food). RESULTS: The high carbohydrate, high-fat diet induced signs of metabolic syndrome along with cardiovascular remodelling and non-alcoholic steatohepatitis. Oak bark extract attenuated the signs of metabolic syndrome in high-carbohydrate, high-fat diet fed rats and improved the structure and function of the heart and the liver. SHR after oak bark extract treatment for 12 weeks showed lower systolic blood pressure, lower cardiac fibrosis and cardiac stiffness and improved vascular reactivity. CONCLUSIONS: Oak bark extract containing ellagitannins improved cardiovascular, metabolic and liver parameters in these rat models of human disease, suggesting that part of the benefits attributed to red wine may be produced by these ellagitannins. PMID- 22105312 TI - Effect of docosahexaenoic acid on hypoxia/reoxygenation injury in human coronary arterial smooth muscle cells. AB - PURPOSE: Hypoxia and reoxygenation (H/R) occur in a wide variety of important clinical conditions such as myocardial infarction. H/R injury is a complex phenomenon involving not only intracellular damage processes but also an injurious inflammatory response. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has long been proved to be protective against several types of cardiovascular disease. However, its beneficial effect during H/R is inconclusive. In this study, we employed an in vitro model to examine whether DHA is protective against H/R-induced cell damage in human coronary artery smooth muscle cells (HCASMCs). METHODS: HCASMCs in the absence or presence of DHA (1, 3, 10, and 30 MUM) were subjected to control or H/R treatment using a modular incubator chamber to create hypoxic condition. Cell viability was evaluated by MTT assay. Spectrophotometric and spectrofluorometric assays were used to measure the generation of nitric oxide (NO) and reactive oxygen species (ROS), respectively. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay. Intracellular calcium mobilization was estimated microfluorimetrically using calcium indicator dye, fura 2-acetomethyl ester. RESULTS: Hypoxia/reoxygenation caused significant injury in cultured HCASMCs. DHA at low concentrations (1, 3, and 10 MUM) did not afford protection, whereas at 30 MUM, it caused deleterious effects, presumably by enhancing the production of NO, ROS, IL-1beta, and IL-6 and altering the intracellular calcium dynamics. CONCLUSIONS: Our results do not support the protective function of DHA in H/R injured coronary arterial smooth muscle cells. PMID- 22105313 TI - Surgical management of first caudal nerve root foraminal compression secondary to intervertebral disc disease in a Cocker Spaniel. AB - A nine-year-old spayed female Cocker Spaniel was investigated for an eight week history of licking and rubbing at the tail base, dullness, and signs of pain on manipulation of the tail. Left-sided intraforaminal compression of the first caudal nerve root due to intervertebral disc disease was diagnosed by radiographic, computed tomography, and magnetic resonance imaging examinations. The dog was nonresponsive to conservative medical therapy. A decompressive left sided first-second caudal (Cd1-Cd2) foraminotomy was performed. Postoperative computed tomography confirmed surgical decompression of the involved nerve root. At the one month follow-up examination there was marked improvement in clinical signs. At two months, clinical signs were completely resolved and there was not any evidence of recurrence twelve months after surgery. Intervertebral disc disease should be considered as a differential diagnosis in dogs with discomfort at the tail base or signs of pain on manipulation of the tail. Surgical decompression may be indicated for management of these cases. This is the first report of diagnosis and surgical management of caudal intervertebral disc disease by foraminotomy in the dog. Surgical decompression by foraminotomy may therefore be a treatment option for this condition. PMID- 22105314 TI - Fate of triclosan and triclocarban in soil columns with and without biosolids surface application. AB - The leaching and transformation behaviors of triclosan (TCS) and triclocarban (TCC) in soil columns (20 cm high, 4 cm in diameter) packed with an agricultural soil (Roxana very fine sandy loam) with and without biosolids surface application were investigated. The column leachates and soil samples were analyzed for TCS, TCC, and their transformation products. Significantly more TCS was transformed compared with TCC. Surface application of biosolids significantly retarded their transformation. Downward movement of TCS and TCC occurred within a 10-cm soil depth. Methyl-TCS was not detectable in the leachates but was detected in the top 5-cm soil layer, with more appearing in the biosolids-applied soil. At the end of the column study, carbanilide (CBA) was the only detectable TCC reductive dechlorination product in the soil. No TCC reductive dechlorination products were detectable in the leachates. Detection of 3,4-dichloroaniline (3,4-DCA) and 4 chloroaniline (4-CA) suggested the occurrence of TCC hydrolysis. Rapid leaching of 4-CA through the soil column was observed. The 3,4-DCA was detected throughout the entire 20-cm depth of the soil column but not in the leachates. The fact that only small percentages of the transformed TCS and TCC appeared, after a 101-d column study, in the forms of the products analyzed suggested that either the investigated transformation pathways were minor pathways or further rapid transformation of those products had occurred. PMID- 22105315 TI - Fundamentals and application of ordered molecular assemblies to affinity biosensing. AB - Organization of biomolecules in two/three dimensional assemblies has recently aroused much interest in nanobiotechnology. In this context, the development of techniques for controlling spatial arrangement and orientation of the desired molecules to generate highly-ordered nanostructures in the form of a mono/multi layer is considered highly significant. The studies of monolayer films to date have focused on three distinct methods of preparation: (i) the Langmuir-Blodgett (LB) technique, involving the transfer of a monolayer assembled at the gas-liquid interface; (ii) self-assembly at the liquid-solid interface, based on spontaneous adsorption of desired molecules from a solution directly onto a solid surface; and (iii) Layer-by-layer (LBL) self-assembly at a liquid-solid interface, based on inter-layer electrostatic attractions for fabrication of multilayers. A variety of monolayers have been utilized to fabricate biomolecular electronic devices including biosensors. The composition of a monolayer based matrix has been found to influence the activity(ies) of biomolecule(s). We present comprehensive and critical analysis of ordered molecular assemblies formed by LB and self-assembly with potential applications to affinity biosensing. This critical review on fundamentals and application of ordered molecular assemblies to affinity biosensing is likely to benefit researchers working in this as well as related fields of research (401 references). PMID- 22105316 TI - Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity. AB - Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G(1) as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G(1) regulated viral replication in HBV transfected cells. We also observed that cyclin G(1) expression was up-regulated in HBV-infected patients, and cyclin G(1) levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G(1) specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53 mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells. CONCLUSION: miR-122 down-regulates its target cyclin G(1) , and thus interrupts the interaction between cyclin G(1) and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis. PMID- 22105317 TI - Genetics: POP goes the smooth muscle contractile protein. PMID- 22105318 TI - Chemotherapy for bladder cancer in patients with impaired renal function. AB - Carcinoma of the bladder is a common, chemosensitive malignancy. The value of chemotherapy for transitional cell carcinoma (the commonest malignant bladder histology in the developed world) has been demonstrated in both the palliative and the neoadjuvant settings, with survival benefits in both scenarios being achieved with cisplatin-based regimens. Conventional drug treatment is, therefore, dependent on adequate renal function, but renal impairment is a common confounding factor in patients with bladder cancer, due in part to obstruction of the urinary tract and in part to comorbidity in an elderly population. A recent consensus statement deems patients with impaired renal function unsuitable for cisplatin treatment, but the limited available evidence does not support the exclusion of cisplatin in patients with moderate renal impairment. The literature on which to base alternative, non-cisplatin-based chemotherapy is inadequate, but the perception that carboplatin-based combinations are inferior to cisplatin based combinations is probably incorrect. Trials are needed to specifically examine chemotherapy in patients with bladder cancer and renal impairment. PMID- 22105319 TI - Prostate cancer: Targeting SSX cancer-testis antigens for immunotherapy. PMID- 22105321 TI - Sexual dysfunction: Shock therapy can improve erectile function. PMID- 22105323 TI - Prostate cancer: Focal cryotherapy--results of a COLD search. PMID- 22105324 TI - BPH: Untangling LUTS, BPH and renal function. PMID- 22105327 TI - Revealing neural circuit topography in multi-color. AB - Neural circuits are organized into functional topographic maps. In order to visualize complex circuit architecture we developed an approach to reliably label the global patterning of multiple topographic projections. The cerebellum is an ideal model to study the orderly arrangement of neural circuits. For example, the compartmental organization of spinocerebellar mossy fibers has proven to be an indispensable system for studying mossy fiber patterning. We recently showed that wheat germ agglutinin (WGA) conjugated to Alexa 555 and 488 can be used for tracing spinocerebellar mossy fiber projections in developing and adult mice (Reeber et al. 2011). We found three major properties that make the WGA-Alexa tracers desirable tools for labeling neural projections. First, Alexa fluorophores are intense and their brightness allows for wholemount imaging directly after tracing. Second, WGA-Alexa tracers label the entire trajectory of developing and adult neural projections. Third, WGA-Alexa tracers are rapidly transported in both retrograde and anterograde directions. Here, we describe in detail how to prepare the tracers and other required tools, how to perform the surgery for spinocerebellar tracing and how best to image traced projections in three dimensions. In summary, we provide a step-by-step tracing protocol that will be useful for deciphering the organization and connectivity of functional maps not only in the cerebellum but also in the cortex, brainstem, and spinal cord. PMID- 22105328 TI - Calcium supplementation, vitamin K status and cardiovascular disease: an additional point. PMID- 22105329 TI - Half of the T-cell repertoire combinatorial diversity is genetically determined in humans and humanized mice. AB - In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human beta chain of the T-cell receptor (hTRBV) in NOD.SCID.gammac(-/-) (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.1+1.2 and BV6-J1.1+1.2 rearrangements. Finally, comparison of CD3(-) and CD3(+) thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined. PMID- 22105330 TI - Agreement between retinal nerve fiber layer measures from Spectralis and Cirrus spectral domain OCT. AB - PURPOSE: An assessment of the retinal nerve fiber layer (RNFL) provides important information on the health of the optic nerve. There are several non-invasive technologies, including spectral domain optical coherence tomography (SD OCT), that can be used for in vivo imaging and quantification of the RNFL, but often there is disagreement in RNFL thickness between clinical instruments. The purpose of this study was to investigate the influence of scan centration, ocular magnification, and segmentation on the degree of agreement of RNFL thickness measures by two SD OCT instruments. METHODS: RNFL scans were acquired from 45 normal eyes using two commercially available SD OCT systems. Agreement between RNFL thickness measures was determined using each instrument's algorithm for segmentation and a custom algorithm for segmentation. The custom algorithm included ocular biometry measures to compute the transverse scaling for each eye. Major retinal vessels were identified and removed from RNFL measures in 1:1 scaled images. Transverse scaling was also used to compute the RNFL area for each scan. RESULTS: Instrument-derived global RNFL thickness measured from the two instruments correlated well (R(2) = 0.70, p < 0.01) but with significant differences between instruments (mean of 6.7 MUm; 95% limits of agreement of 16.0 MUm to -2.5 MUm, intraclass correlation coefficient = 0.62). For recentered scans with custom RNFL segmentation, the mean difference was reduced to 0.1 MUm (95% limits of agreement 6.1 to -5.8 MUm, intraclass correlation coefficient = 0.92). Global RNFL thickness was related to axial length (R = 0.24, p < 0.01), whereas global RNFL area measures were not (R(2) = 0.004, p = 0.66). Major retinal vasculature accounted for 11.3 +/- 1.6% (Cirrus) or 11.8 +/- 1.4% (Spectralis) of the RNFL thickness/area measures. CONCLUSIONS: Sources of disagreement in RNFL measures between SD-OCT instruments can be attributed to the location of the scan path and differences in their retinal layer segmentation algorithms. In normal eyes, the major retinal vasculature accounts for a significant percentage of the RNFL and is similar between instruments. With incorporation of an individual's ocular biometry, RNFL area measures are independent of axial length, with either instrument. PMID- 22105331 TI - Does atropine use increase intraocular pressure in myopic children? AB - PURPOSE: Because pupillary dilation caused by muscarinic antagonists is a predisposing factor for glaucoma, we examined the effects of long-term atropine treatment for myopia on intraocular pressure (IOP) and studied the risk factors of elevated IOP among myopic children. METHODS: A retrospective chart review was conducted in 621 myopic children (aged 6 to 15 years) whose spherical equivalent refractive error ranged from -1.00 to -6.00 D in each eye and who had received atropine therapy. For all children, we collected their complete ocular examination data and IOP measurements beginning in 2008. We then calculated the cumulative dose and the duration of atropine therapy in the 3 years before the date of recruitment to quantitatively assess the effects of atropine therapy on IOP. RESULTS: Four hundred eighty-nine children who received atropine therapy were classified as the "treatment" group, whereas 132 children who did not receive atropine therapy were classified as "reference" group. Statistical analyses did not find any relation between the dose or duration of atropine therapy and the risk of having elevated IOP. However, the age of the myopic children and the spherical equivalent values were positively associated with the risk of having elevated IOP irrespective of whether they had been treated with atropine or not. CONCLUSIONS: Topical atropine therapy for up to 3 years seemed to be safe in myopic children; neither the cumulative dose nor the duration of atropine therapy was statistically associated with the risk of having elevated IOP. However, the safety of longer atropine therapy still needs more study. Clinicians should be careful to monitor the changes in IOP among older myopic children or myopic children with more severe myopia. PMID- 22105332 TI - Role of NMO-IgG in distinguishing the type of optic neuritis. AB - PURPOSE: To emphasize the importance of neuromyelitis optica (NMO)-immunoglobulin G (IgG) antibodies testing in patients with typical optic neuritis (ON) refractory to steroid treatment. METHODS: Two patients were evaluated with ON refractory to steroid therapy and poor visual acuity; they were tested for NMO IgG antibodies. RESULTS: Brain magnetic resonance imaging was normal in both patients. The serum and cerebrospinal fluid were positive for NMO-IgG antibodies. Magnetic resonance imaging of the cervical and thoracic spine revealed lesions longer than three vertebral segments and the diagnosis of NMO was confirmed. Treatment with plasma exchange and immunosuppressive therapy resulted in marked improvement of visual acuity. This improvement was sustained. CONCLUSIONS: The testing for NMO-IgG antibodies is important for distinguishing ON in NMO from multiple sclerosis in cases of ON refractory to steroid treatment. These cases suggest that testing for NMO-IgG antibodies should be performed in comparative trials on a larger series. PMID- 22105333 TI - Algorithm for correcting the keratometric estimation error in normal eyes.. AB - PURPOSE: To obtain an accurate algorithm for calculating the keratometric index that minimizes the errors in the calculation of corneal power assuming only a single corneal surface in the range of corneal curvatures of the normal population. METHODS: Corneal power was calculated by using the classical keratometric index and also by using the Gaussian equation. Differences between types of calculation of corneal power were determined and modeled by regression analysis. RESULTS: We proposed two options for the selection of the most appropriate keratometric index (n(k)) value for each specific case. First was the use of specific linear equations (depending on the ratio of the anterior to the posterior curvature, k ratio) according to the value of the central radius of curvature of the anterior corneal surface (r(1c)) in 0.1 mm steps and the theoretical eye model considered. The second was the use of a general simplified equation only requiring r(1c) (Gullstrand eye model, n(k) = -0.0064286r(1c) + 1.37688; Le Grand eye model, n(k) = -0.0063804r(1c) + 1.37806). CONCLUSIONS: The generalization of the keratometric index (n(k)) value is not an appropriate approximation for the estimation of the corneal power and it can lead to significant errors. We proposed a new algorithm depending on r(1c), with a maximal associated error in the calculation of the corneal power of 0.5 D and without requiring knowledge of the posterior corneal curvature. PMID- 22105335 TI - No Colavita effect: equal auditory and visual processing in people with one eye. AB - Previous research has shown that people with one eye have enhanced spatial vision implying intra-modal compensation for their loss of binocularity. The current experiments investigate whether monocular blindness from unilateral eye enucleation may lead to cross-modal sensory compensation for the loss of one eye. We measured speeded detection and discrimination of audiovisual targets presented as a stream of paired objects and familiar sounds in a group of individuals with monocular enucleation compared to controls viewing binocularly or monocularly. In Experiment 1, participants detected the presence of auditory, visual or audiovisual targets. All participant groups were equally able to detect the targets. In Experiment 2, participants discriminated between the visual, auditory or bimodal (audiovisual) targets. Both control groups showed the Colavita effect, that is, preferential processing of visual over auditory information for the bimodal stimuli. The monocular enucleation group, however, showed no Colavita effect, and further, they demonstrated equal processing of visual and auditory stimuli. This finding suggests a lack of visual dominance and equivalent auditory and visual processing in people with one eye. This may be an adaptive form of sensory compensation for the loss of one eye and could result from recruitment of deafferented visual cortical areas by inputs from other senses. PMID- 22105336 TI - Perceived size change induced by audiovisual temporal delays. AB - The retinal image of an object does not contain information about its actual size. Size must instead be inferred from extraretinal cues for which distance information makes an essential contribution. Asynchronies in the arrival time across visual and auditory sensory components of an audiovisual event can reliably cue its distance, although this cue has been largely neglected in vision research. Here we demonstrate that audio-visual asynchronies can produce a shift in the apparent size of an object and attribute this shift to a change in perceived distance. In the present study participants were asked to match the perceived size of a test circle paired with an asynchronous sound to a variable size probe circle paired with a simultaneous sound. The perceived size of the circle increased when the sound followed its onset with delays up to around 100 ms. For longer sound delays and sound leads, no effect was seen. We attribute this selective modulation in perceived visual size to audiovisual timing influences on the intrinsic relationship between size and distance. This previously unsuspected cue to distance reveals a surprisingly interactive system using multisensory information for size/distance perception. PMID- 22105337 TI - Prenatal diagnosis of Jeune-like syndromes with two-dimensional and three dimensional sonography. AB - The purpose of this article is to describe the use of three-dimensional sonography as an adjuvant to two-dimensional sonography facilitating an earlier and more definitive diagnosis of Jeune and Jeune-like syndromes in the second trimester. We report two cases in which three-dimensional sonography facilitated the diagnosis of these malformations. A diagnosis of Jeune syndrome was made in our first case. Our second case was found to be short-rib polydactyly syndrome Type IV. Three-dimensional skeletal survey visualized short ribs, short limbs, the presence of normal scapulae, and the absence of polydactyly in both cases. Three-dimensional sonography can assist two-dimensional sonography in providing a more accurate display of skeletal anomalies, limb abnormalities, and facial features. PMID- 22105338 TI - Potential roles of the NFkappaB and glutathione pathways in mature human erythrocytes. AB - Anucleated erythrocytes were long considered as oxygen-transporting cells with limited regulatory functions. Components of different nuclear signaling pathways have not been investigated in those cells, yet. Surprisingly, we repeatedly found significant amounts of transcription factors in purified erythrocyte preparations, i.e. nuclear factor kappaB (NFkappaB), and major components of the canonical NFkappaB signaling pathway. To investigate the functional role of NFkappaB signaling, the effects of the preclinical compounds Bay 11-7082 and parthenolide on the survival of highly purified erythrocytes were investigated. Interestingly, both inhibitors of the NFkappaB pathway triggered erythrocyte programmed cell death as demonstrated by enhanced phospholipid scrambling (phosphatidylserine exposure) and cell shrinkage. Anucleated erythrocytes are an ideal cellular model allowing the study of nongenomic mechanisms contributing to suicidal cell death. As NFkappaB inhibitors might also interfere with the anti oxidative defense systems of the cell, we measured the levels of reduced glutathione (GSH) after challenge with the inhibitors. Indeed, incubation of erythrocytes with Bay 11-7082 clearly decreased erythrocyte GSH levels. In conclusion, the pharmacological inhibitors of the NFkappaB pathway Bay 11-7082 and parthenolide interfere with the survival of erythrocytes involving mechanisms other than disruption of NFkappaB-dependent gene expression. Besides affecting erythrocyte survival, NFkappaB inhibition and induction of erythrocyte phosphatidylserine exposure may influence blood clotting. Future studies will be aimed at discriminating between NFkappaB-dependent and NFkappaB-independent GSH mediated effects of Bay 11-7082 and parthenolide on erythrocyte death. PMID- 22105339 TI - Time perspective and weight management behaviors in newly diagnosed Type 2 diabetes: a mediational analysis. AB - The primary objective of the current study was to examine the extent to which domain-specific time perspective predicts weight management behaviors (dietary behavior and physical activity) among those newly diagnosed with Type 2 diabetes. A secondary objective was to test potential mediators of the hypothesized effect (behavioral intention, self-efficacy and control beliefs). A total of 204 adults newly diagnosed (<=6 months) with Type 2 diabetes participated in the study, which included a baseline assessment of domain-general and domain-specific time perspective, as well as strength of intention to perform two weight-management behaviors (dietary choice and physical activity); both weight-management behaviors were assessed again at 6 month follow-up. Hierarchical multiple regression analyses revealed a prospective association between domain-specific time perspective and uptake of weight management behaviors. Individuals with newly diagnosed T2DM possessing a future-oriented time perspective reported making less frequent fatty food choices and greater increases in physical activity over the 6-month follow-up interval. These effects were selectively mediated by intention strength, and not competing social cognitive variables. For both behaviors, the total effects and meditational models were robust to adjustments for demographics, body composition and disease variables. A future oriented time perspective is prospectively associated with superior uptake of weight management behaviors among those with newly diagnosed Type 2 diabetes. The facilitating effect of future-oriented thinking appears to occur via enhanced strength of intentions to perform weight management behaviors. PMID- 22105340 TI - Medication persistence of HIV-infected drug users on directly administered antiretroviral therapy. AB - Patient and regimen persistence in HIV-infected drug users are largely unknown. We evaluated patterns of medication non-persistence among HIV-infected drug users enrolled in a prospective, 6-month randomized controlled trial of directly administered antiretroviral therapy (DAART). Medication-taking behavior was assessed via direct observation and MEMS data. Of 74 participants who initiated DAART, 59 (80%) subjects were non-persistent with medication for 3 or more consecutive days. Thirty-one participants (42%) had 2 or more episodes of non persistence. Higher depressive symptoms were strongly associated with non persistence episodes of >= 3 days (AOR: 17.4, P = 0.02) and >= 7 days AOR: 5.4, P = 0.04). High addiction severity (AOR 3.2, P = 0.03) was correlated with non persistence >= 7 days, and injection drug use (AOR: 15.2, P = 0.02) with recurrence of non-persistence >= 3 days. Time to regimen change was shorter for NNRTI-based regimens compared to PI-based ones (HR: 3.0, P = 0.03). There was no significant association between patterns of patient non-persistence and virological outcomes. PMID- 22105341 TI - Evidence of vitamin D and interferon-beta cross-talk in human osteoblasts with 1alpha,25-dihydroxyvitamin D3 being dominant over interferon-beta in stimulating mineralization. AB - It is well established that 1alpha-25-dihydroxyvitamin D3 (1,25D3) regulates osteoblast function and stimulates mineralization by human osteoblasts. The aim of this study was to identify processes underlying the 1,25D3 effects on mineralization. We started with gene expression profiling analyses of differentiating human pre-osteoblast treated with 1,25D3. Bioinformatic analyses showed interferon-related and -regulated genes (ISG) to be overrepresented in the set of 1,25D3-regulated genes. 1,25D3 down-regulated ISGs predominantly during the pre-mineralization period. This pointed to an interaction between the vitamin D and IFN signaling cascades in the regulation of osteoblast function. Separately, 1,25D3 enhances while IFNbeta inhibits mineralization. Treatment of human osteoblasts with 1,25D3 and IFNbeta showed that 1,25D3 completely overrules the IFNbeta inhibition of mineralization. This was supported by analyses of extracellular matrix gene expression, showing a dominant effect of 1,25D3 over the inhibitory effect of IFNbeta. We identified processes shared by IFNbeta- and 1,25D3-mediated signaling by performing gene expression profiling during early osteoblast differentiation. Bioinformatic analyses revealed that genes being correlated or anti-correlated with interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) were associated with osteoblast proliferation. In conclusion, the current study demonstrates a cross talk between 1,25D3 and IFNbeta in osteoblast differentiation and bone formation/mineralization. The interaction is complex and depends on the process but importantly, 1,25D3 stimulation of mineralization is dominant over the inhibitory effect of IFNbeta. These observations are of potential clinical relevance considering the impact of the immune system on bone metabolism in conditions such as rheumatoid arthritis. PMID- 22105342 TI - Impaired diffusing capacity for carbon monoxide in children with type 1 diabetes: is this the first sign of long-term complications? AB - We assessed the presence of lung dysfunction in children with type 1 diabetes, evaluated as reduced diffusing capacity of the lung for carbon monoxide (DLCO), and its components: membrane diffusing capacity (DM) and pulmonary capillary blood volume (Vc). A total of 42 children, aged 15.6 +/- 3.8 years, with type 1 diabetes for 8.3 +/- 5.5 years, and 30 healthy age and sex-matched peers were recruited for the study. Lung volumes and spirometric dynamic parameters were assessed by plethysmography. Single-breath DLCO was measured according to international recommendation. DM and Vc volume were calculated. Lung volumes were significantly reduced in young patients with type 1 diabetes when compared to controls. Moreover, DLCO was reduced in patients compared to controls (78% +/- 16% vs. 120% +/- 1%, P = 0.0001). However, when differentiating DM and Vc compartments, we observed a significant impairment only about Vc (34 +/- 20 ml vs. 88 +/- 18 ml; P = 0.0001), while no difference was observed about DM compartment (23 +/- 4 vs. 26 +/- 3 ml/min/mmHg, P = 0.798). Whether this might be seen as the "first" sign of microangiopathic involvement in patients with type 1 diabetes has to be confirmed on larger groups but is still fascinating. Meanwhile, we suggest to screen DLCO in all patients with type 1 diabetes. PMID- 22105343 TI - Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism: implications for liver regeneration. AB - Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null ((Balb/C)CAV1-/-) mice, CAV1-/- mice from Jackson Laboratories ((JAX)CAV1-/-), and CAV1-/- mice developed in the Kurzchalia Laboratory ((K)CAV1-/-), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in (K)CAV1-/- livers, in (JAX)CAV1-/- livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy glucose in (JAX)CAV1-/- mice indicated that liver regeneration in (JAX)CAV1-/- mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating (JAX)CAV1-/- livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1-/- mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. CONCLUSION: Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions. PMID- 22105344 TI - Lip ulceration associated with intravenous administration of zoledronic acid: report of a case. AB - Although osteonecrosis of the jaw is a well-known adverse reaction of bisphosphonates (BPs), random cases of oral mucosal ulceration after per os administration of BP-aledronate have been attributed to prolonged mucosal irritation. This report, for the first time, describes the mucosal ulceration related to intravenous use of zoledronic acid (ZA). A 52-year-old female patient presented with painful ulcers on both cutaneous/mucosal surfaces of the lower lip and a 2-month history of osteonecrosis of the mandible beside the right lower canine. Her medical record included intravenous administration of ZA for 10 months for primary breast cancer metastatic to bone. Examination of the peripheral blood showed severe anemia and a slightly increased white blood cell count, due to urinary tract infection by E. coli, but no evidence of a viral infection. The treatment of anemia and E. coli infection did not improve the labial ulcers. Biopsy from the mucosal lesion revealed a non-specific ulceration with moderate inflammatory infiltration. There was no evidence of infection or malignancy. ZA administration was discontinued and within 3 months the lesions were resolved after treatment with systemic antibiotics (amoxicillin), vitamins A and E, chlorexidine and H(2)O(2) (hydrogen peroxide) solutions and local pantothenic acid/vitamin A creams. Recurrence was detected a month after ZA re administration. Nevertheless, after new treatment, the patient was free of oral/skin lesions 18 months later. This case, which is the first report of ulceration associated with intravenous administration of bisphosphonates, suggests that systemic mechanisms may be implicated in BP-induced oral mucosal ulceration. Furthermore, ZA appears to cause the same oral mucosal manifestations as alendronate. This emphasizes the need for oral examination in all cases of BP therapy, whether per os or intravenously administrated. PMID- 22105345 TI - Dissolved organic carbon reduces the toxicity of aluminum to three tropical freshwater organisms. AB - The influence of dissolved organic carbon (DOC) on the toxicity of aluminum (Al) at pH 5 (relevant to acid mine drainage conditions), to the tropical green hydra (Hydra viridissima), green alga (Chlorella sp.), and cladoceran (Moinodaphnia macleayi) was assessed. Two DOC sources, a natural in situ DOC in soft billabong water (SBW) and Suwannee River fulvic acid (SRFA) standard, were compared. The order of sensitivity of the test organisms to dissolved Al (0.1 um fraction) was Hydra viridissima > Moinodaphnia macleayi > Chlorella sp. with DOC reducing dissolved Al toxicity most for Hydra viridissima. However, colloidal or precipitated Al may contribute indirectly to the toxicity for M. macleayi and Chlorella sp. The toxicity of dissolved Al was up to six times lower in test waters containing 10 mg L(-1) DOC (in the form of SRFA), relative to toxicity observed at 1 mg L(-1) DOC. In contrast, the toxicity of Al was up to two times lower in SBW containing 10 mg L(-1) DOC, relative to water containing 1 mg L(-1) DOC. The increased ability of SRFA in reducing Al toxicity was linked to its greater affinity for complexing Al compared with the in situ DOC. This has important implications for studies that use commercial standards of humic substances to predict Al toxicity in local environments. Speciation modeling demonstrated that Al(3+) and AlOH(2+) provided a strong relationship with toxicity. An empirical relationship is provided for each organism that can be used to predict Al toxicity at a given Al and DOC concentration. PMID- 22105346 TI - Ajuba is required for Rac activation and maintenance of E-cadherin adhesion. AB - Maintenance of stable E-cadherin-dependent adhesion is essential for epithelial function. The small GTPase Rac is activated by initial cadherin clustering, but the precise mechanisms underlying Rac-dependent junction stabilization are not well understood. Ajuba, a LIM domain protein, colocalizes with cadherins, yet Ajuba function at junctions is unknown. We show that, in Ajuba-depleted cells, Rac activation and actin accumulation at cadherin receptors was impaired, and junctions did not sustain mechanical stress. The Rac effector PAK1 was also transiently activated upon cell-cell adhesion and directly phosphorylated Ajuba (Thr172). Interestingly, similar to Ajuba depletion, blocking PAK1 activation perturbed junction maintenance and actin recruitment. Expression of phosphomimetic Ajuba rescued the effects of PAK1 inhibition. Ajuba bound directly to Rac.GDP or Rac.GTP, but phosphorylated Ajuba interacted preferentially with active Rac. Rather than facilitating Rac recruitment to junctions, Ajuba modulated Rac dynamics at contacts depending on its phosphorylation status. Thus, a Rac-PAK1-Ajuba feedback loop integrates spatiotemporal signaling with actin remodeling at cell-cell contacts and stabilizes preassembled cadherin complexes. PMID- 22105347 TI - E-N-cadherin heterodimers define novel adherens junctions connecting endoderm derived cells. AB - Intercellular junctions play a pivotal role in tissue development and function and also in tumorigenesis. In epithelial cells, decrease or loss of E-cadherin, the hallmark molecule of adherens junctions (AJs), and increase of N-cadherin are widely thought to promote carcinoma progression and metastasis. In this paper, we show that this "cadherin switch" hypothesis does not hold for diverse endoderm derived cells and cells of tumors derived from them. We show that the cadherins in a major portion of AJs in these cells can be chemically cross-linked in E-N heterodimers. We also show that cells possessing E-N heterodimer AJs can form semistable hemihomotypic AJs with purely N-cadherin-based AJs of mesenchymally derived cells, including stroma cells. We conclude that these heterodimers are the major AJ constituents of several endoderm-derived tissues and tumors and that the prevailing concept of antagonistic roles of these two cadherins in developmental and tumor biology has to be reconsidered. PMID- 22105348 TI - Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V. AB - The evolutionarily conserved Crumbs (Crb) complex is crucial for photoreceptor morphogenesis and homeostasis. Loss of Crb results in light-dependent retinal degeneration, which is prevented by feeding mutant flies carotenoid-deficient medium. This suggests a defect in rhodopsin 1 (Rh1) processing, transport, and/or signaling, causing degeneration; however, the molecular mechanism of this remained elusive. In this paper, we show that myosin V (MyoV) coimmunoprecipitated with the Crb complex and that loss of crb led to severe reduction in MyoV levels, which could be rescued by proteasomal inhibition. Loss of MyoV in crb mutant photoreceptors was accompanied by defective transport of the MyoV cargo Rh1 to the light-sensing organelle, the rhabdomere. This resulted in an age-dependent accumulation of Rh1 in the photoreceptor cell (PRC) body, a well-documented trigger of degeneration. We conclude that Crb protects against degeneration by interacting with and stabilizing MyoV, thereby ensuring correct Rh1 trafficking. Our data provide, for the first time, a molecular mechanism for the light-dependent degeneration of PRCs observed in crb mutant retinas. PMID- 22105349 TI - Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. AB - Invadopodia are invasive protrusions with proteolytic activity uniquely found in tumor cells. Cortactin phosphorylation is a key step during invadopodia maturation, regulating Nck1 binding and cofilin activity. The precise mechanism of cortactin-dependent cofilin regulation and the roles of this pathway in invadopodia maturation and cell invasion are not fully understood. We provide evidence that cortactin-cofilin binding is regulated by local pH changes at invadopodia that are mediated by the sodium-hydrogen exchanger NHE1. Furthermore, cortactin tyrosine phosphorylation mediates the recruitment of NHE1 to the invadopodium compartment, where it locally increases the pH to cause the release of cofilin from cortactin. We show that this mechanism involving cortactin phosphorylation, local pH increase, and cofilin activation regulates the dynamic cycles of invadopodium protrusion and retraction and is essential for cell invasion in 3D. Together, these findings identify a novel pH-dependent regulation of cell invasion. PMID- 22105350 TI - Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation. AB - Antigen recognition within immunological synapses triggers and sustains T cell activation by nucleating protein microclusters that gather T cell receptors (TCRs), kinases, and adaptors. Dissipation of these microclusters results in signal termination, but how this process is regulated is unclear. In this paper, we reveal that release of the adaptors SLP76 and GADS from signaling microclusters is induced by the serine/threonine protein kinase HPK1 and that phosphorylation of GADS plays a major role in this process. We found that HPK1 was recruited into microclusters and triggered their dissipation by inducing the phosphorylation of a threonine-containing motif of GADS, together with the previously described serine phosphorylation of SLP76. These events induced the cooperative binding of 14-3-3 proteins to SLP76-GADS complexes, leading to their uncoupling from the transmembrane adaptor LAT and consequently reducing microcluster persistence and activation-induced gene transcription. These results demonstrate that serine/threonine phosphorylation of multiple TCR-proximal effectors controls the stability of signaling microclusters, thereby determining the intensity of T cell responses. PMID- 22105351 TI - Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells. AB - Mouse embryonic cells isolated from focal adhesion kinase (FAK)-null animals at embryonic day 7.5 display multiple defects in focal adhesion remodeling, microtubule dynamics, mechanotransduction, proliferation, directional motility, and invasion. To date, the ability of FAK to modulate cell function has been ascribed largely to its control of posttranscriptional signaling cascades in this embryonic cell population. In this paper, we demonstrate that FAK unexpectedly exerts control over an epithelial-mesenchymal transition (EMT) program that commits embryonic FAK-null cells to an epithelial status highlighted by the expression of E-cadherin, desmoplakin, and cytokeratins. FAK rescue reestablished the mesenchymal characteristics of FAK-null embryonic cells to generate committed mouse embryonic fibroblasts via an extracellular signal-related kinase- and Akt dependent signaling cascade that triggered Snail1 gene expression and Snail1 protein stabilization. These findings indentify FAK as a novel regulator of Snail1-dependent EMT in embryonic cells and suggest that multiple defects in FAK( /-) cell behavior can be attributed to an inappropriate commitment of these cells to an epithelial, rather than fibroblastic, phenotype. PMID- 22105352 TI - VPS35 haploinsufficiency increases Alzheimer's disease neuropathology. AB - VPS35, a major component of the retromer complex, is important for endosome-to Golgi retrieval of membrane proteins. Although implicated in Alzheimer's disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of beta amyloid peptide (Abeta) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Abeta production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Abeta production by promoting BACE1 endosome-to-Golgi retrieval. PMID- 22105353 TI - Impact of increasing current drain in a pacemaker operating during activation of the elective replacement indicator. AB - The occurrence of a 13.8 s episode of ventricular asystole in a patient whose VVIR pacemaker displayed the elective replacement indicator (ERI) is reported. Increasing battery current drain by VARIO testing and programming of the emergency VVI mode markedly increased battery current drain with a resultant decrease in the battery voltage below the pacing threshold. The prolonged lack of capture occurred because the lowered battery voltage could not return instantaneously to its previous level after the demand for a higher battery current drain had ceased. Rather, the battery voltage increased progressively to its previous level and successful capture was eventually regained at the previous base rate. When a pacemaker is at or near the ERI point, it is important to avoid any manipulation (including VARIO testing) that increases battery current drain so as to prevent prolonged ventricular asystole in pacemaker-dependent patients. PMID- 22105354 TI - Segmented interlocking nail: an in vivo evaluation of a novel humeral osteotomy fixation device in a caprine model. AB - OBJECTIVES: To describe a novel humeral fixation device, the insertion technique, healing of humeral osteotomies, and clinical outcomes in a caprine model over a six month period. METHODS: Fourteen mature female Boer/Nubian cross goats with a mean body weight of 50.7 kg were implanted with a proprietary segmented interlocking nail (SILN) in both humeri. Each goat had one humerus randomly selected for mid-diaphyseal osteotomy. RESULTS: Immediately after surgery all but one goat was able to stand, although none of the goats were weight bearing on the osteotomy limb. During the six month study, clinical lameness was always associated with the osteotomy limb. One month after surgery, lameness for twelve of the goats was grade 2/5 or better. At three months, 11 of the 14 did not exhibit any signs of lameness. On radiographic images, notable malalignment of the osteotomy was observed, although all osteotomies went to bone union. CLINICAL SIGNIFICANCE: The results of this study suggest that despite misalignment, the SILN maintained adequate osteotomy fixation to achieve bone union in the research model studied, with reduced morbidity and early return to function with bilateral implantation. The SILN used in this study allowed intramedullary fixation of humeral diaphyseal osteotomies with a limited and safe surgical approach. PMID- 22105355 TI - Charge transfer in organic molecules for solar cells: theoretical perspective. AB - This tutorial review primarily illustrates rate theories for charge transfer and separation in organic molecules for solar cells. Starting from the Fermi's golden rule for weak electronic coupling, we display the microcanonical and canonical rates, as well as the relationship with the Marcus formula. The fluctuation effect of bridges on the rate is further emphasized. Then, several rate approaches beyond the perturbation limit are revealed. Finally, we discuss the electronic structure theory for calculations of the electronic coupling and reorganization energy that are two key parameters in charge transfer, and show several applications. PMID- 22105356 TI - In vitro uncoating of HIV-1 cores. AB - The genome of the retroviruses is encased in a capsid surrounded by a lipid envelope. For lentiviruses, such as HIV-1, the conical capsid shell is composed of CA protein arranged as a lattice of hexagon. The capsid is closed by 7 pentamers at the broad end and 5 at the narrow end of the cone(1, 2). Encased in this capsid shell is the viral ribonucleoprotein complex, and together they comprise the core. Following fusion of the viral membrane with the target cell membrane, the HIV-1 is released into the cytoplasm. The capsid then disassembles releasing free CA in the soluble form(3) in a process referred to as uncoating. The intracellular location and timing of HIV-1 uncoating are poorly understood. Single amino-acid substitutions in CA that alter the stability of the capsid also impair the ability of HIV-1 to infect cells(4). This indicates that the stability of the capsid is critical for HIV-1 infection. HIV-1 uncoating has been difficult to study due to lack of availability of sensitive and reliable assays for this process. Here we describe a quantitative method for studying uncoating in vitro using cores isolated from infectious HIV-1 particles. The approach involves isolation of cores by sedimentation of concentrated virions through a layer of detergent and into a linear sucrose gradient, in the cold. To quantify uncoating, the isolated cores are incubated at 37 degrees C for various timed intervals and subsequently pelleted by ultracentrifugation. The extent of uncoating is analyzed by quantifying the fraction of CA in the supernatant. This approach has been employed to analyze effects of viral mutations on HIV-1 capsid stability(4, 5, 6). It should also be useful for studying the role of cellular factors in HIV-1 uncoating. PMID- 22105357 TI - PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. AB - The small GTPase H-Ras is a proto-oncogene that activates a variety of different pathways including the extracellular-signal-regulated kinase (ERK)/mitogen activated protein kinase pathway. H-Ras is mutated in many human malignancies, and these mutations cause the protein to be constitutively active. Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) blocks ERK-dependent gene transcription and inhibits proliferation by sequestering ERK in the cytoplasm. We therefore investigated whether PEA-15 influences H-Ras-mediated transformation. We found that PEA-15 does not block H-Ras-activated proliferation when H-Ras is constitutively active. We show instead that in H-Ras-transformed mouse kidney epithelial cells, co-expression of PEA-15 resulted in enhanced soft agar colony growth and increased tumor growth in vivo. Overexpression of both H-Ras and PEA 15 resulted in accelerated G1/S cell cycle transition and increased activation of the ERK signaling pathway. PEA-15 mediated these effects through activation of its binding partner phospholipase D1 (PLD1). Inhibition of PLD1 or interference with PEA-15/PLD1 binding blocked PEA-15's ability to increase ERK activation. Our findings reveal a novel mechanism by which PEA-15 positively regulates Ras/ERK signaling and increases the proliferation of H-Ras-transformed epithelial cells through enhanced PLD1 expression and activation. Thus, our work provides a surprising mechanism by which PEA-15 augments H-Ras-driven transformation. These data reveal that PEA-15 not only suppresses ERK signaling and tumorigenesis but also alternatively enhances tumorigenesis in the context of active Ras. PMID- 22105358 TI - Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia. AB - Despite recent progress in the treatment of acute myeloid leukemia (AML), the prognosis of this rather heterogeneous disease remains poor and novel chemotherapeutics that specifically target leukemic cells must be developed. To address this need at the preclinical level, we implemented a high content imaging based screen for the identification of small agents that induce AML cell death in vitro. Among a panel of 1040 Food and Drug Administration-approved agents, we identified pyrithione zinc (PZ) and ouabain (OUA) as potential antileukemic compounds. Both PZ and OUA efficiently induced cell death associated with apoptotic chromatin condensation and inhibition of nuclear factor-kappaB survival signaling, leading to reduced expression of antiapoptotic proteins, in several AML cell lines. PZ- and OUA-induced cell death was associated with the permeabilization of the outer mitochondrial membrane and led to the release of cytochrome c followed by caspase activation. Both PZ and OUA exerted significant anticancer effects in vivo, on human AML cells xenografts as well as ex vivo, on CD34(+) (but not CD34(-)) malignant myeloblasts from AML patients. Altogether, our results suggest that PZ and OUA may exhibit antileukemic effects by inducing the apoptotic demise of AML cells. PMID- 22105359 TI - The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress. AB - The family of ADAM (a disintegrin and metalloproteinase) proteins has been implicated in tumor initiation and progression. ADAM17/tumor necrosis factor alpha (TNFalpha)-converting enzyme (TACE) has been initially recognized to release TNFalpha as well as its receptors (TNFRs) from the membrane. ADAM17, TNFalpha and TNFR have been found upregulated in cancer patients, although the underlying mechanisms remain largely unknown. As hypoxia is a hallmark of cancer that can lead to severe stress conditions accumulating in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), we investigated the role of these stress conditions in the regulation of ADAM17 and release of TNFR1.We found that severe hypoxia induced ADAM17 expression and activity. Although hypoxia inducible factor 1alpha (HIF1alpha) was important to maintain basal ADAM17 mRNA levels during moderate hypoxia, it was not sufficient to induce ADAM17 levels under severe hypoxia. Instead, we found that ADAM17 induction by severe hypoxia can be mimicked by ER stressors such as Thapsigargin and occurs as a consequence of the activation of the PERK/eIF2alpha/ATF4 and activating transcription factor 6 (ATF6) arms of UPR in several tumor cell lines. ADAM17 expression was also increased in xenografts displaying ER stress because of treatment with the vascular endothelial growth factor (VEGF) inhibitory antibody Bevacizumab. Additionally, severe hypoxia and ER stress activated ADAM17 and ectodomain shedding of TNFR1 involving mitogen-activated protein (MAP) kinases and reactive oxygen species (ROS). Collectively, these results show that ADAM17 is a novel UPR regulated gene in response to severe hypoxia and ER stress, which is actively involved in the release of TNFR1 under these conditions. These data provide a novel link between severe hypoxic stress conditions and inflammation in the tumor environment. PMID- 22105360 TI - Live imaging of induced and controlled DNA double-strand break formation reveals extremely low repair by homologous recombination in human cells. AB - DNA double-strand breaks (DSBs), the most hazardous DNA lesions, may result in genomic instability, a hallmark of cancer cells. The main DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR). In mammalian cells, NHEJ, which can lead to inaccurate repair, predominates. HR repair (HRR) is considered accurate and is restricted to S, G2 and M phases of the cell cycle. Despite its importance, many aspects regarding HRR remain unknown. Here, we developed a novel inducible on/off switch cell system that enables, for the first time, to induce a DSB in a rapid and reversible manner in human cells. By limiting the duration of DSB induction, we found that non-persistent endonuclease induced DSBs are rarely repaired by HR, whereas persistent DSBs result in the published HRR frequencies (non-significant HR frequency versus frequency of ~10%, respectively). We demonstrate that these DSBs are repaired by an accurate repair mechanism, which is distinguished from HRR (most likely, error-free NHEJ). Notably, our data reveal that HRR frequencies of endonuclease-induced DSBs in human cells are >10-fold lower than what was previously estimated by prevailing methods, which resulted in recurrent DSB formation. Our findings suggest a role for HRR mainly in repairing challenging DSBs, in contrast to uncomplicated lesions that are frequently repaired by NHEJ. Preventing HR from repairing DSBs in the complex and repetitive human genome probably has an essential role in maintaining genomic stability. PMID- 22105361 TI - A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis. AB - Epidermal growth factor (EGF)-like growth factors control tumor progression as well as evasion from the toxic effects of chemotherapy. Accordingly, antibodies targeting the cognate receptors, such as EGFR/ErbB-1 and the co-receptor HER2/ErbB-2, are widely used to treat cancer patients, but agents that target the EGF-like growth factors are not available. To circumvent the existence of 11 distinct ErbB ligands, we constructed a soluble fusion protein (hereinafter: TRAP Fc) comprising truncated extracellular domains of EGFR/ErbB-1 and ErbB-4. The recombinant TRAP-Fc retained high-affinity ligand binding to EGF-like growth factors and partially inhibited growth of a variety of cultured tumor cells. Consistently, TRAP-Fc displayed an inhibitory effect in xenograft models of human cancer, as well as synergy with chemotherapy. Additionally, TRAP-Fc inhibited invasive growth of mammary tumor cells and reduced their metastatic seeding in the lungs of animals. Taken together, the activities displayed by TRAP-Fc reinforce critical roles of EGF-like growth factors in tumor progression, and they warrant further tests of TRAP-Fc in preclinical models. PMID- 22105362 TI - PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. AB - Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1 driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation. PMID- 22105363 TI - The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity. AB - Our previous work showed that in T98G cells, a human glioblastoma multiforme derived cell line, the association of c-Fos to the endoplasmic reticulum (ER) and consequently, the capacity of c-Fos to activate phospholipid synthesis, is regulated by the phosphorylation state of tyrosine (tyr) residues #10 and #30 of c-Fos. The small amount of c-Fos present in quiescent cells is tyr phosphorylated, is dissociated from the ER membranes and does not activate phospholipid synthesis. However, on induction of the cell to re-enter growth, c Fos expression is rapidly induced, it is found dephosphorylated, associated to ER membranes and activating phospholipid synthesis (Portal et al., 2007). Herein, using in vivo and in vitro experimental strategies, we show that the kinase c-Src is capable of phosphorylating tyr residues of c-Fos whereas the phosphatase TC45 T-cell protein-tyr phosphatase (TC-PTP) dephosphorylates them, thus enabling c Fos/ER association and activation of phospholipid synthesis. Results also suggest that the regulation of the phosphorylation/dephosphorylation cycle of c-Fos occurs at the TC-PTP level: induction of cells to re-enter growth promotes the translocation of TC45 from a nuclear to a cytoplasmic location concomitant with its activation. Activated TC45 in its turn promotes dephosphorylation of pre formed c-Fos, enabling cells to rapidly activate phospholipid synthesis to respond to its growth demands. PMID- 22105364 TI - Gene expression profiling identifies sST2 as an effector of ErbB2-driven breast carcinoma cell motility, associated with metastasis. AB - Overexpression of the ErbB2 receptor tyrosine kinase in breast cancer contributes to tumor development and is associated with poor prognosis. However, the mechanism by which ErbB2 might contribute to metastasis is not well defined. To identify genes that mediate ErbB2-driven cell motility, we performed differential gene expression analysis of ErbB2-expressing migrating breast cancer cells vs mutant ErbB2-expressing non-migrating cells. Among the genes that were specifically induced in migrating cells were known transcriptional targets of ErbB2, such as matrix metalloproteinases, and novel ErbB2 targets. Contribution of selected candidate genes to ErbB2-driven cell motility was tested by small interfering RNA targeting. Knockdown of the soluble form of ST2 (sST2), also called interleukin-1 receptor-like 1, one of the most robustly induced genes, decreased ErbB2-induced cell motility in two different cell lines. In response to ErbB2 activation, sST2 protein expression and secretion were increased. Moreover, recombinant sST2 associated with the plasma membrane and sST2-blocking antibodies reduced ErbB2-induced motility. Interestingly, cells from metastatic breast tumors secreted higher levels of sST2 than primary tumor cells. Finally, sST2 was found at high levels in the serum of metastatic breast cancer patients. Our data suggest that sST2 contributes to breast cancer cell motility and that sST2 secretion is associated with metastasis. PMID- 22105365 TI - MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-kappaB inducing kinase (NIK). AB - MicroRNAs (miRNAs) are small, non-coding RNAs that can act as oncogenes or tumor suppressor genes in human cancer. Emerging evidence indicates that deregulation of miRNAs contributes to the hepatocarcinogenesis. In the present study, we demonstrated that the levels of miR-520e were dramatically decreased in examined hepatoma cell lines and clinical hepatocellular carcinoma (HCC) tissues. Moreover, we found that DNA hypermethylation in the upstream region of miR-520e resulted in the downregulation of miR-520e. Next, we demonstrated that introduction of miR-520e dramatically suppressed the growth of hepatoma cells in vitro and in vivo, whereas silencing the expression of miR-520e by anti-miR-520e resulted in a promoted cell proliferation, suggesting that miR-520e may be a novel tumor suppressor. Further studies revealed that NF-kappaB-inducing kinase (NIK) was one of the direct target genes of miR-520e, as miR-520e directly bound to the 3'untranslated region of NIK, which reduced the expression of NIK at the levels of mRNA and protein. Moreover, silencing of NIK was able to inhibit the growth of hepatoma cells, similar to the effect of miR-520e overexpression on growth of hepatoma cells. Meanwhile, the knockdown of NIK expression reversed the enhanced proliferation mediated by anti-miR-520e. In addition, miR-520e significantly decreased the phosphorylation of ERK1/2 (p-ERK1/2) and depressed the transcriptional activity and nuclear translocation of nuclear factor kappaB (NF-kappaB) (p65). These results suggest that miR-520e suppresses the growth of hepatoma cells by targeting NIK involving the NIK/p-ERK1/2/NF-kappaB signaling pathway. Finally, we showed that the intratumoral injection with miR-520e was able to directly repress the growth of hepatoma cells in the nude mice. Thus, our finding provides new insight into the mechanism of hepatocarcinogenesis, indicating a therapeutic potential of miR-520e in the treatment of HCC. PMID- 22105366 TI - NF-kappaB and STAT3 cooperatively induce IL6 in starved cancer cells. AB - A number of genes involved in tumorigenesis have been known to be controlled by signal transducer and activator of transcription 3 (STAT3) and NF-kappaB, either synergistically or individually. In starved cancer cells, we found that NF-kappaB was activated through endoplasmic reticulum stress signals, which depend on reactive oxygen species, cytosolic calcium and preserved translation of NF-kappaB p65 subunit, but independent of IkappaBalpha serine phosphorylation, thereby resulting in IL6 induction. STAT3 was required for proper induction of IL6 by NF kappaB. They existed as identical nuclear complexes in proximal IL6 promoters, and STAT3 had critical roles in binding to IL6 promoters as well as nuclear retention of NF-kappaB. The conditioned media from starved cancer cells contained various secretory factors, such as IL6, IL9, VWF (von Willebrand factor), FREM1 (FRAS1 related extracellular matrix 1), SAA1 (serum amyloid A1), SDK1 (sidekick homolog 1) and ADAM12 (ADAM metallopeptidase domain 12), induced by NF-kappaB and STAT3 and promoted clonogenic capacities of cancer cells, and proliferation and migration of human umbilical vein endothelial cells. These results suggest novel survival strategies of cancer cells by which two oncogenic transcriptional factors, NF-kappaB and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors. PMID- 22105367 TI - Role of MUC4-NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells. AB - MUC4 is a large transmembrane type I glycoprotein that is overexpressed in pancreatic cancer (PC) and has been shown to be associated with its progression and metastasis. However, the exact cellular and molecular mechanism(s) through which MUC4 promotes metastasis of PC cells has been sparsely studied. Here we showed that the nidogen-like (NIDO) domain of MUC4, which is similar to the G1 domain present in the nidogen or entactin (an extracellular matrix protein), contributes to the protein-protein interaction property of MUC4. By this interaction, MUC4 promotes breaching of basement membrane (BM) integrity, and spreading of cancer cells. These observations are corroborated with the data from our study using an engineered MUC4 protein without the NIDO domain, which was ectopically expressed in the MiaPaCa PC cells, lacking endogenous MUC4 and nidogen protein. The in vitro studies demonstrated an enhanced invasiveness of MiaPaCa cells expressing MUC4 (MiaPaCa-MUC4) compared with vector-transfected cells (MiaPaCa-Vec; P=0.003) or cells expressing MUC4 without the NIDO domain (MiaPaCa-MUC4-NIDO(Delta); P=0.03). However, the absence of NIDO-domain has no significant role on cell growth and motility (P=0.93). In the in vivo studies, all the mice orthotopically implanted with MiPaCa-MUC4 cells developed metastasis to the liver as compared with MiaPaCa-Vec or the MiaPaCa-MUC4-NIDO(Delta) group, hence, supporting our in vitro observations. Additionally, a reduced binding (P=0.0004) of MiaPaCa-MUC4-NIDO(Delta) cells to the fibulin-2 coated plates compared with MiaPaCa-MUC4 cells indicated a possible interaction between the MUC4-NIDO domain and fibulin-2, a nidogen-interacting protein. Furthermore, in PC tissue samples, MUC4 colocalized with the fibulin-2 present in the BM. Altogether, our findings demonstrate that the MUC4-NIDO domain significantly contributes to the MUC4-mediated metastasis of PC cells. This may be partly due to the interaction between the MUC4-NIDO domain and fibulin-2. PMID- 22105368 TI - Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients. AB - Using genome-wide methylation screening, we identified that paired box gene 5 (PAX5) is involved in human cancer development. However, the function of PAX5 in gastric cancer (GC) development is largely unclear. We analyzed its epigenetic inactivation, biological functions and clinical application in GC. PAX5 was silenced in seven out of eight GC cell lines. A significant downregulation was also detected in paired gastric tumors compared with adjacent non-cancerous tissues. The downregulation of PAX5 was closely linked to the promoter hypermethylation status and could be restored with demethylation treatment. Ectopic expression of PAX5 in silenced GC cell lines (AGS and BGC823) inhibited colony formation and cell viability, arrested cell cycle, induced apoptosis, suppressed cell migration and invasion and repressed tumorigenicity in nude mice. Consistent with the induction of apoptosis by PAX5 in vitro, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) staining showed significantly enhanced apoptotic cells in PAX5-expressed tumors compared with the vector control tumors. On the other hand, knockdown of PAX5 by PAX5-short hairpin RNA increased the cell viability and proliferation. The anti tumorigenic function of PAX5 was revealed to be mediated by upregulating downstream targets of tumor protein 53 (p53), p21, BCL2-associated X protein, metastasis suppressor 1 and tissue inhibitors of metalloproteinase 1, and downregulating BCL2, cyclin D1, mesenchymal-epithelial transition factor (MET) and matrix metalloproteinase 1. Immunoprecipitation assay demonstrated that PAX5 directly bound to the promoters of p53 and MET. Moreover, PAX5 hypermethylation was detected in 77% (144 of 187) of primary GCs compared with 10.5% (2/19) of normal gastric tissues (P<0.0001). GC patients with PAX5 methylation had a significant poor survival compared with the unmethylated cases as demonstrated by Cox regression model and log-rank test. In conclusion, PAX5 is a novel functional tumor suppressor in gastric carcinogenesis. Detection of methylated PAX5 can be utilized as an independent prognostic factor in GC. PMID- 22105369 TI - Kinetic study of nickel-thiolate oxygenation by hydrogen peroxide. Implications for nickel-containing superoxide dismutase. AB - The rate of metal-thiolate oxygenation by hydrogen peroxide has been measured for a model complex of nickel-containing superoxide dismutase (NiSOD) as 0.47 +/- 0.03 M(-1) s(-1) at 303 K. Under typical synthetic conditions the reaction proceeds within seconds yielding S-oxygenate products. At biologically relevant H(2)O(2) concentrations, half-life times extend to several hours or days. The results suggest H(2)O(2) oxidation of NiSOD is not kinetically competent on the SOD timescale accounting for the lack of S-oxygenation byproducts. PMID- 22105371 TI - CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. AB - Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C(+) CD56(dim) NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C(+) CD56(dim) NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-gamma, and TNF-alpha) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C(+) CD56(dim) NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells. PMID- 22105372 TI - Role of gastritis pattern on Helicobacter pylori eradication. AB - Helicobacter pylori eradication rate following standard triple therapy is decreasing. Identification of predictive factors of therapy success would be useful for H. pylori management in clinical practice. This study aimed to evaluate the role of different gastritis patterns on the efficacy of the currently suggested 14-day triple therapy regimen. One-hundred and seventeen, consecutive, non-ulcer dyspeptic patients, with H. pylori infection diagnosed at endoscopy, were enrolled. All patients received a 14-day, triple therapy with lansoprazole 30 mg, clarithromycin 500 mg and amoxicillin 1 g, all given twice daily. Bacterial eradication was assessed with (13)C-urea breath test 4-6 weeks after completion of therapy. H. pylori infection was cured in 70.1% at ITT analysis and 83.7% at PP analysis. The eradication rate tended to be lower in patients with corpus-predominant gastritis as compared to those with antral predominant gastritis at both ITT (66.1 vs 74.5%) and PP (80.4 vs 87.2%) analyses. The multivariate analysis failed to identify factors associated with therapy success. However, 14-day triple therapy does not achieve acceptable H. pylori cure rate in Italy, and should be not recommended in clinical practice. PMID- 22105374 TI - Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. AB - Apert syndrome is characterized by craniosynostosis and syndactyly, and is predominantly caused by mutation of either S252W or P253W in the fibroblast growth factor receptor (FGFR) 2 gene. In this study, we characterized the effects of one of the mutations (S252W) using primary calvarial osteoblasts derived from transgenic mice, Ap-Tg and sAp-Tg, that expressed an Apert-type mutant FGFR2 (FGFR2IIIc-S252W; FGFR2IIIc-Ap), and the soluble form (extracellular domain only) of the mutant FGFR2 (sFGFR2IIIc-Ap), respectively. Compared to WT-derived osteoblasts, osteoblasts from Ap-Tg mouse showed a higher proliferative activity and enhanced differentiation, while those from sAp-Tg mouse exhibited reduced potential for proliferation and osteogenic differentiation. When transplanted with beta-tricalcium phosphate (beta-TCP) granules into immunodeficient mice, Ap Tg-derived osteoblasts showed a higher bone forming capacity, whereas sAp-Tg derived osteoblasts were completely deficient for this phenotype. Phosphorylation of extracellular signal-regulated kinase (ERK), MEK, PLCgamma, and p38 was increased in Ap-Tg-derived osteoblasts, whereas phosphorylation of these signaling molecules was reduced in sAp-Tg-derived osteoblasts. Interestingly, when these experiments were carried out using osteoblasts from the mice generated by crossing Ap-Tg and sAp-Tg (Ap/sAp-Tg), which co-expressed FGFR2IIIc-Ap and sFGFR2IIIc-Ap, the results were comparable to those obtained from WT-derived osteoblasts. Taken together, these results indicate that osteoblasts expressing FGFR2IIIc-Ap proliferate and differentiate via highly activated MEK, ERK, and p38 pathways, while these pathways are suppressed in osteoblasts expressing sFGFR2IIIc-Ap. Our findings also suggest that altered FGFR2IIIc signaling in osteoblasts is mostly responsible for the phenotypes seen in Apert syndrome, therefore these osteoblast cell lines are useful tools for investigating the pathogenesis of Apert syndrome. PMID- 22105376 TI - Sonography of thrombosis of the deep veins of the extremities: clinical perspectives and imaging review. PMID- 22105377 TI - Challenges for the development of a biotic ligand model predicting copper toxicity in estuaries and seas. AB - An effort is ongoing to develop a biotic ligand model (BLM) that predicts copper (Cu) toxicity in estuarine and marine environments. At present, the BLM accounts for the effects of water chemistry on Cu speciation, but it does not consider the influence of water chemistry on the physiology of the organisms. We discuss how chemistry affects Cu toxicity not only by controlling its speciation, but also by affecting the osmoregulatory physiology of the organism, which varies according to salinity. In an attempt to understand the mechanisms of Cu toxicity and predict its impacts, we explore the hypothesis that the common factor linking the main toxic effects of Cu is the enzyme carbonic anhydrase (CA), because it is a Cu target with multiple functions and salinity-dependent expression and activity. According to this hypothesis, the site of action of Cu in marine fish may be not only the gill, but also the intestine, because in this tissue CA plays an important role in ion transport and water adsorption. Therefore, the BLM of Cu toxicity to marine fish should also consider the intestine as a biotic ligand. Finally, we underline the need to incorporate the osmotic gradient into the BLM calculations to account for the influence of physiology on Cu toxicity. PMID- 22105373 TI - Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. AB - BACKGROUND: Macrolides have long been recognised to exert immunomodulary and anti inflammatory actions. They are able to suppress the "cytokine storm" of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. METHODS: A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti inflammatory effect, diabetes, side effects and systemic diseases. RESULTS: Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper responsiveness and improve pulmonary function. CONCLUSION: This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects. PMID- 22105378 TI - Child posture and shoulder belt fit during extended night-time traveling: an in transit observational study. AB - Understanding pediatric occupant postures can help researchers indentify injury risk factors, and provide information for prospective injury prediction. This study sought to observe lateral head positions and shoulder belt fit among older child automobile occupants during a scenario likely to result in sleeping - extended travel during the night. An observational, volunteer, in-transit study was performed with 30 pediatric rear-seat passengers, ages 7 to 14. Each was restrained by a three-point seatbelt and was driven for seventy-five minutes at night. Ten subjects used a high-back booster seat, ten used a low-back booster seat, and ten used none (based on the subject height and weight). The subjects were recorded with a low-light video camera, and one frame was analyzed per each minute of video. The high-back booster group exhibited a statistically significant (p<0.05) decrease in the mean frequency of poor shoulder belt fit compared to the no-booster and low-back booster groups. The high-back booster group also exhibited statistically significant decreases in the 90(th) percentile of the absolute value of the relative lateral motion of the head. The low-back booster group did not result in statistically significant decreases in poor shoulder belt fit or lateral head motion compared to the no-booster group. These results are consistent with the presence of large lateral supports of the high back booster which provided support to the head while sleeping, reducing voluntary lateral occupant motion and improving shoulder belt fit. Future work includes examining lap belt fit in-transit, and examining the effects of these observations on predicted injury risk. PMID- 22105379 TI - Kinematics and shoulder belt position of child rear seat passengers during vehicle maneuvers. AB - Head impact to the seat back has been identified as one important injury causation scenario for seat belt restrained, head-injured children and previous research highlighted vehicle maneuvers prior to impact as possible contributing factors. The aim was to quantify kinematics of child occupants during swerving maneuvers focusing on the child's lateral movement and seat belt position relative to the child's shoulder. A study was conducted on a closed-circuit test track with 16 children aged 4-12, restrained in the rear seat of a modern passenger vehicle. A professional driving instructor drove at 50 km/h making sharp turns in a repeatable fashion, resulting in inboard motion of the children. The children were exposed to two turns in each of two restraint systems. Shorter children were on a booster or highback booster cushion. The taller children were seated on a booster cushion or with only a lap and shoulder seat belt. Four film cameras were fixed in the vehicle monitoring the child. Vehicle data were also collected. The seat belt slipped off the shoulder in 1 of 5 turns, varying by age and restraint type. Among shorter children, the belt slipped off in a majority of turns when seated on a booster cushion while the belt remained on the shoulder when seated on the highback booster cushion. Among taller children, the shoulder belt moved far laterally on the shoulder in half of the turns. This data provides valuable knowledge on possible pre-impact postures of children as a result of vehicle swerving maneuvers for a variety of restraint systems. PMID- 22105380 TI - Important child occupant saftety trends, indiana between 2005 and 2010. AB - This study reviews trends, rear facing, top tether use, and seating position for children younger than 13y among motor vehicle passengers in Indiana. This is an observational, cross-sectional survey of drivers transporting children 15 years and younger and drivers collected at 25 convenience locations randomly selected in Indiana during summers 2005 through 2010. Observations were conducted by Certified Child Passenger Safety Technicians (CPST). As the driver completed a written survey collecting demographic data on the driver and children, the CPST recorded the vehicle seating location, the type of restraint, direction the car safety seat (CSS) was facing, and use of the CSS harness or safety belt as appropriate. Data was analyzed for infants younger than twelve months, children in forward facing CSS, and children < 13y. Between 2005 and 2010, 514 infants (age < 12m) were observed in motor vehicles. On average 83.5% (SD 4.8%) of the infants were rear facing. The percent of infants rear facing was 75.5% during 2005 and rose to 88.9% during 2010. Of the 442 vehicles observed with a forward facing car seat, 58% (SD 16.5%) had the top tether attached. In our sample, more than 88.7% (SD 0.8%) children < 13y were seated in a rear seat vehicle position. Driver variables affecting occupant protection are discussed. This information can be used by primary care providers and child passenger safety technicians and other child passenger safety advocates to develop counseling points and educational campaigns. PMID- 22105381 TI - Development of a US Child-Focused Motor Vehicle Crash Surveillance System: A Pilot Study. AB - Current motor vehicle crash (MVC) surveillance systems, in particular the National Automotive Sampling System (NASS), either do not contain sufficient numbers of children, or do not contain child-specific data needed to support policy and prevention efforts. The objective of this pilot study was to develop and evaluate methods that could be utilized for supplemental child-specific data collection on a sample of cases identified through the NASS-GES program. Procedures were developed to identify a sample of police accident reports (PARs) involving child occupants for supplemental collection of child-specific data via three survey modes: phone, web-based and hard-copy self administered. Contact was initiated with 650 eligible parent drivers and surveys were completed by 156 (24.0%). Response rates were highest for telephone-based surveys (41.0% of those initially contacted by phone). Surveys were completed via the web by only 6.1% of those invited to do so. Overall agreement between survey and PAR data was good to excellent. Results of this pilot study indicate that creating procedures to identify cases for supplemental child-specific data collection based on the NASS GES system is feasible. In order to sustain a supplemental child-focused data collection system that relies on identification of cases from NASS-GES, efforts must be made to enhance contact procedures in order to optimize response rates. PMID- 22105382 TI - Crash injury risk behavior in adolescent latino males: the power of friends and relational connections. AB - The adolescent Latino male mortality profile is an anomaly when compared to an otherwise more favorable overall U.S. Latino population mortality profile. Motor vehicle crash fatalities bear a considerable proportion of mortality burden in this vulnerable population. Friend influence and relational connection are two contextual domains that may mediate crash injury risk behavior in these adolescents. Our study goal was to assess the role of friend influence over time and relational connections associated with crash injury risk behavior (CIRB) in adolescent Latino males. Waves I and II data from the National Longitudinal Study of Adolescent Health were used. Scale of CIRB, and three relational connections; school connectedness, parent connectedness, and expectation of academic success were developed and tested. Friend nomination data were available and the index student responses were linked to friend responses. Linear regression was used to assess the relationship of relational connections and friend CIRB on index student CIRB at wave I and II. Longitudinal analysis did not show significant evidence for friend influence among adolescent Latino males on CIRB. The best predictor of CIRB at wave II for adolescent Latino males was their CIRB at wave I. Relational connections were important yet exaggerated cross-sectionally but their effect was substantially attenuated longitudinally. The lack of friend influence on CIRB for adolescent Latino males may be specific to this demographic group or characteristic of the sample studied. Prevention strategies that focus on modulating friend influence in adolescent Latino males may not yield the desired prevention effects on CIRB. PMID- 22105383 TI - The role of race and ethnicity on the effect of graduated driver licensing laws in the United States. AB - OBJECTIVE: To determine if graduated driver licensing (GDL) law effects were the same for different racial/ethnic groups of young drivers. METHODS: The Fatality Analysis Reporting System (FARS) data files were analyzed using descriptive pre- and post-GDL law analyses and logistic regression. Analyses were conducted on 8,036 drivers aged 15 to 17 killed in single-vehicle crashes from 1999 to 2008. Whites, African-Americans, Asians, Hispanics, and Native Americans/Others were examined. Two analyses were conducted: one of all states, and one of the 23 states that adopted a GDL law between 1999 and 2008. RESULTS: Although GDL laws had varying degrees of success in reducing the likelihood of drinking and driving among young drivers of different racial/ethnic groups, that variation did not occur in fatal crashes where speeding was a factor, except for Hispanics. GDL laws showed similar reductions for White, African-American, and Asian young drivers in single-vehicle fatal crashes; however, young Hispanic drivers were not as affected by GDL as were Whites and African-Americans. Our analysis of states with GDL laws enacted between 2000 and 2007 showed no change for young Hispanic drivers in fatal crashes before and after a GDL law was adopted. Overall, GDL reductions were largest for young White drivers (p<.01), followed by African Americans (p<.05), Asians (p<.05), and Hispanics (p<.10; not significant). GDL laws had no apparent effect on speeding-related fatal crashes of these novice drivers. IMPLICATIONS: Reasons for these findings are hypothesized and discussed: (1) differences in drinking patterns of the racial/ethnic groups; (2) differences in driving exposure among the groups; and (3) differences in the influence of parents on youthful drivers entering the GDL phases. PMID- 22105384 TI - Influence of an enforcement campaign on seat-belt and helmet wearing, karachi hala highway, pakistan. AB - This study assessed to what extent an enforcement campaign influenced seat-belt and helmet wearing on a Pakistani highway. The study setting was the Karachi-Hala highway where a traffic enforcement campaign was conducted from Dec 2009 to Feb 2010. Seat-belt and helmet wearing were observed in Nov 2009 and Apr 2010 at Karachi toll plaza. Differences in wearing rates as a function of occupants' age, sex, and vehicle type were compared between the two periods. On average, 9 119 (Standard deviation=1 896) traffic citations were issued per month from Aug 2009 to Feb 2010; 4.2% of which were for not wearing helmet. A 22.5% increase in citations was observed for Dec 2009 to Feb 2010 periods compared with Aug 2009 to Oct 2009 periods. Nearly six thousand four-wheeled and four hundred two-wheeled motorized vehicle occupants were observed in Nov 2009 and Apr 2010. Overall, two of the five drivers and one of the five front seat occupants wore seat belts. This proportion was significantly higher in drivers and front-seat occupants of cars than those of heavier vehicles. Similarly, one of two motorcyclists used a helmet but this proportion was 5.8% for pillion riders in Nov 2009. The increased enforcement had a limited influence on belt wearing in drivers (+4.0%; 95% Confidence Interval [95%CI]=1.8-6.1) and occupants (+6.2%; 95%CI=4.2-8.2). A higher increase was observed for motorcyclists (+9.8%; 95%CI=2.6-16.8) and pillion riders (+12.8%; 95%CI=5.4, 20.5). These results suggested that serious efforts are required to increase seat-belt and helmet use on Pakistani highways. Improving enforcement resources, increased fines, not allowing such vehicles on roads, and awareness campaigns targeting drivers of heavy vehicles might increase wearing rates in Pakistan. PMID- 22105385 TI - Driving position field study, differences with the whiplash protocol and biomechanics experimental responses. AB - Rear-impact collisions at low speed are a leading cause of economic costs among motor vehicle accidents. Recently, EuroNCAP has incorporated in its protocol the whiplash test, to reproduce a low-speed rear impact. This paper presents a field driving study to assess the potential differences between the EuroNCAP dummy tests and actual drivers in the field, focusing on occupant position and biomechanics experimental results. A total of 182 drivers were randomly selected in two geographical areas in Spain. The driving position of each driver was recorded with a focus on the most relevant measurements for rear impact. Statistical analysis was performed to obtain means, standard deviations and density functions to compare observational seating position with that of the EuroNCAP testing protocol. The observational data showed a similar seatback angle to that used in the EuroNCAP protocol (24 degrees in front of 25 degrees for the protocol), a greater distance between the head vertex and the top of the head restraint (53mm compared to 39.5mm), and less distance between the occipital bone of the head and the headrest (67.9 compared to 89.3mm). Based on these data, 4 dummy tests were conducted using the dummy BioRID IIg. The baseline test was designed to reproduce the dummy position according to EuroNCAP 3.0 whiplash protocol. Three different additional tests were defined to reproduce the actual observed driving position as well as to assess a "worst case" scenario in terms of reduced seatback angle. These variations in initial driver position, comparing the EuroNCAP protocol to the observational study results, were not observed to cause significant differences in the biomechanical values measured in the BioRID IIg, The T1 acceleration was reduced less than 8%, the NIC was increased about 8%, and the NKm presented a reduction of 20%. Reducing the seat angle was observed to be more harmful in terms of NIC. PMID- 22105386 TI - Investigating the effects of side airbag deployment in real-world crashes using crash comparison techniques. AB - The objective of this study was to investigate side airbag (SAB) deployment in near side crashes and compare injuries and contact points between occupants with and without SAB deployment. Using NASS 2000-2008 and selecting for near side cases, with PDOF +/- 20 degrees from 90 or 270, for non-pregnant adult belted occupants, there were 20,253 (weighted) SAB deployments. NASS showed that SABs have been increasing within the fleet, comprising 2% of airbags in 2000 and increasing to 33% of airbags in 2008. To investigate deployed SABs, we developed a three-step methology to pair CIREN cases to study the effects of deployment on occupant outcome. The first step involved extracting near side impacts from CIREN with adult, non-pregnant occupants seated in row 1 (drivers or right front passengers). In the second step, each case was quantitatively compared to FMVSS 214 barrier test standards using a 6 point similarity scoring system. Cases scoring at least 3 points were then qualitatively analyzed and 33 pairs of cases of the same vehicle make/model but opposite SAB status were chosen. Occupants with deployed SAB had reduced occurrences and severity of head and face, neck and cervical spine, and thoracic injuries and fewer injurious contacts to side components including the door, a-pillar, and window sill. SAB deployment was statistically significant for reducing occupant MAIS and ISS and thorax airbags were statistically significant for reducing thoracic and neck/cervical spine injury severity. The average ISS with SAB deployment was 21, while the average ISS of those without was 33. This study establishes methods for performing comparisons between CIREN cases based on regulatory conditions and shows injury reduction in key body regions with SAB deployment. PMID- 22105387 TI - Validation of a persian version of motorcycle rider behavior questionnaire. AB - In Iran, road traffic injuries are the first cause of burden of disease and motorcyclists are the most vulnerable road users. Elliot and colleagues developed the "Motorcycle Rider Behavior Questionnaire" (MRBQ), on the basis of Reason's "Driver Behavior Questionnaire" (DBQ) in 2007. The purpose of this study was to assess the validity and reliability of a Persian version of MRBQ. The 43-item MRBQ was adapted to Persian according to translation-back translation method. The questionnaire was significantly revised after assessment of content validity. In the revised version, 10 items of original MRBQ were deleted and 15 new items were added. The revised MRBQ was used in a survey of 518 motorcyclists. To assess the construct validity of MRBQ, we used Buss-Perry Aggression questionnaire concurrently on all of the subjects. After three weeks, we carried out the retest study on 119 out of 518 subjects. The mean age of the subjects was 32.5 years (SD=8.8). All of the participants were male with mean of 9.3 years of motorcycle riding experience (SD=7.3). Principal Components Analysis (PCA) showed six subscales: "Speed Violations", "Traffic Errors", "Safety Violations", "Traffic Violations", "Stunts" and "Control Errors", which accounted for 36.44% of total variance together. For each of these subscales, Cronbach's Alpha was between 0.79 to 0.91. Intraclass Correlation Coefficient for six subscales and total questionnaire were from 0.73 to 0.91. There were significant correlations between MRBQ subscales and subscales of Buss-Perry aggression questionnaire. The results indicated that the 48-item Persian version of MRBQ is a suitable measure for studying motorcyclists' behavior. PMID- 22105388 TI - How Safe is Vehicle Safety? The Contribution of Vehicle Technologies to the Reduction in Road Casualties in France from 2000 to 2010. AB - In France, over the last 10 years, road fatalities have decreased dramatically by 48%. This reduction is somewhat close to the target fixed by the European Commision in 2001 for the whole of Europe (-50 %). According to the French govnerment, 75% of this reduction was due to the implementation of automatic speed cameras on the roadsides from 2003 onwards. Yet, during this period, there was also a significantly increase in safety technology, new regulations in front and side impacts, and developments in Euro NCAP to improve passive safety in the vehicles. This paper set out to estimate the extent that vehicle safety technologies contributed to the road safety benefits over this decade. Using a combination of databases and fitment rates, the number of fatalities and hospitalized injuries saved in passenger car crashes was estimated for a number of safety technologies, individually and as a package including a 5 star EuroNCAP rating. The additional benefits from other public safety measures were also similarly estimated. The results showed that overall safety measures during this decade saved 240,676 fatalities + serious injuries, of which 173,663 were car occupants. Of these, 27,365 car occupants and 1,083 pedestrian savings could be attributed directly to vehicle safety improvements (11% overall). It was concluded that while public safety measures were responsible for the majority of the savings, enhanced vehicle safety technologies also made a significant improvement in the road toll in France during the last decade. As the take-up rate for these technologies improves, is expected to continue to provide even more benefits in the next 10-year period. PMID- 22105389 TI - Crash-related mortality and model year: are newer vehicles safer? AB - OBJECTIVE: The objective of this study was to determine whether occupants of newer vehicles experience a lower risk of crash-related mortality. METHODS: The occurrence of death was studied in relation to vehicle model year (MY) among front seat vehicular occupants, age >= 16 captured in the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) between 2000 and 2008. The associations between death and other occupant, vehicular and crash characteristics were also explored. Multiple logistic regression models for the prediction of death were built with model year as the independent variable and other characteristics linked to death as covariates. Imputation was used for missing data; weighted data was used. RESULTS: A total of 70,314 cases representing 30,514,372 weighted cases were available for analysis. Death occurred in 0.6% of the weighted population. Death was linked to age>60, male gender, higher BMI, near lateral direction of impact, high delta v, rollover, ejection and vehicle mismatch, and negatively associated with seatbelt use and rear and far lateral direction of impact. Mortality decreased with later model year groups (MY<94 0.78%, MY 94-97 0.53%, MY 98-04 0.51% and MY 05-08 0.38%, p=<0.0001). After adjustment for confounders, MY 94-97, MY 98-04 and MY 05-08 showed decreased odds of death [OR 0.80 (0.69-0.94), 0.82 (0.70-0.97), and 0.67 (0.47-0.96), respectively] when compared to MY <94. CONCLUSION: Newer vehicles are associated with lower crash-related mortality. Their introduction into the vehicle fleet may explain, at least in part, the decrease in mortality rates in the past two decades. PMID- 22105390 TI - Study of mild traumatic brain injuries using experiments and finite element modeling. AB - The objective of the study was to better understand the biomechanics of mild traumatic brain injuries (TBI) using a hybrid approach: experiments and computational modeling. A three-dimensional finite element model of the rat skull and brain was used to understand the anatomical region-dependent stress response under mild TBI conditions. Anesthetized rats were exposed to varying coronal plane angular acceleration pulses without direct head contact. Experimental outcomes included unconscious time and histological evidence of brain pathology using GFAP and MAP2. The finite element model was exercised using the five experimental and four supplemental pulses to simulate nine independent combinations of peak acceleration and pulse duration (290 to 542 krad/s(2) and 1 to 3 ms). Stress response metrics were correlated to histological and behavioral (e.g., loss of consciousness) evidence of injury in rats subjected to pure coronal plane angular acceleration of the head. Injury severity was modulated by independently controlling peak magnitude and duration of the angular acceleration. While peak Von Mises stresses correlated well with changes in injury severity associated with peak angular acceleration, this metric did not demonstrate sensitivity to changes in acceleration duration. However, an integrated stress-time metric was able to predict changes in injury severity associated with increasing angular acceleration magnitude and duration in both the hippocampal and parietal cortex anatomical regions. Results of this unique hybrid analysis indicate that the combined stress-time variable may be more suited to explain variation of mild TBI severity, rather than pure peak metrics. PMID- 22105391 TI - Pedestrian injury patterns according to car and casualty characteristics in france. AB - This paper describes the injury patterns of pedestrians involved in collisions with cars, compares them with other road casualties and estimates the possible effect of car front profile on injury location. Injury patterns were identified using the Rhone Road Trauma Registry which covers all the casualties resulting from crashes in the Rhone Departement (1.6 million inhabitants) who seek medical care in health facilities. Fatality rates were estimated from national police reports for the same years (1996-2007), and the two data sources were linked to obtain information on the front profile of the striking car. As with all groups of road users, most of the pedestrians involved in car crashes were young. However elderly people were overrepresented when the size of the exposed population was taken into account. The most frequently injured body regions were the lower extremities (50% of victims), the head/face/neck (38%) and the upper extremities (27%). Pelvic injuries were much more common for women. The most severe injuries (AIS4+) were mostly to the head and thorax, for all groups of road users. However, pedestrians sustained twice as many head injuries as thoracic injuries. When the front profiles were grouped together according to the most common car types in Europe, the risk of being killed was higher for MPVs. More specifically, the risk of sustaining an AIS2+ thoracic injury was higher in a collision with an MPV. Our study confirms that it is quite justified for the tests based on European Enhanced Vehicle-Safety Committee guidelines to be focused on the head and the lower extremities. However, no test procedure exists for thoracic injuries, which is the body region with the second highest number of severe or fatal injuries. PMID- 22105392 TI - Injury differences between small and large overlap frontal crashes. AB - Because small overlap impacts have recently emerged as a crash mode posing great injury risk to occupants, a detailed analysis of US crash data was conducted using the NASS/CDS and CIREN databases. Frontal crashes were subcategorized into small overlap impact (SOI) and large overlap impact (LOI) using crash and crush characteristics from the datasets. Injuries to head, spine, chest, hip and pelvis, and lower extremities were parsed and compared between crash types. MAIS 3+ occupants in NASS/CDS and CIREN demonstrated increased incidence of head, chest, spine, and hip/pelvis injuries in SOI compared to LOI. In NASS/CDS, subgaleal hematoma represented 48.6% of SOI head injury codes but 27.6% in LOI. Cervical spine posterior element fractures also represented greater proportions of SOI spine injuries (e.g., facet fractures: 27.8 vs. 14.0%), and proximal femur fractures represented a greater proportion of hip/pelvis injuries (e.g., intertrochanteric fracture: 32.5 vs. 11.8%). Tarsal/metatarsal fractures were a lesser proportion of lower extremity injuries in SOI compared to LOI. Occupant contact points inducing these injuries were observed in CIREN cases in some instances without compartment intrusion. These injuries suggest the substantial role of occupant kinematics in SOI which may induce suboptimal occupant restraint interaction. PMID- 22105393 TI - Quantitative analyses of pediatric cervical spine ossification patterns using computed tomography. AB - The objective of the present study was to quantify ossification processes of the human pediatric cervical spine. Computed tomography images were obtained from a high resolution scanner according to clinical protocols. Bone window images were used to identify the presence of the primary synchondroses of the atlas, axis, and C3 vertebrae in 101 children. Principles of logistic regression were used to determine probability distributions as a function of subject age for each synchondrosis for each vertebra. The mean and 95% upper and 95% lower confidence intervals are given for each dataset delineating probability curves. Posterior ossifications preceded bilateral anterior closures of the synchondroses in all vertebrae. However, ossifications occurred at different ages. Logistic regression results for closures of different synchondrosis indicated p-values of <0.001 for the atlas, ranging from 0.002 to <0.001 for the axis, and 0.021 to 0.005 for the C3 vertebra. Fifty percent probability of three, two, and one synchondroses occurred at 2.53, 6.97, and 7.57 years of age for the atlas; 3.59, 4.74, and 5.7 years of age for the axis; and 1.28, 2.22, and 3.17 years of age for the third cervical vertebrae, respectively. Ossifications occurring at different ages indicate non-uniform maturations of bone growth/strength. They provide an anatomical rationale to reexamine dummies, scaling processes, and injury metrics for improved understanding of pediatric neck injuries. PMID- 22105394 TI - Lateral neck injury assessments in side impact using post mortem human subject tests. AB - Current neck injury criteria are based on matching upper cervical spine injuries from piglet tests to airbag deployment loads and pairing kinematics from child dummies. These "child-based" scaled data together with adult human cadaver tolerances in axial loading are used to specify neck injury thresholds in axial compression and tension, and flexion and extension moment about the occipital condyles; no thresholds are specified for any other force or moment including lateral bending. The objective of this study was to develop a testing methodology and to determine the lateral bending moment injury threshold under coronal loading. Post mortem human subjects (PMHS) were used. Specimens consisted of whole body and isolated head-neck complexes with intact musculature. Intact specimen positioning included: sitting PMHS upright on a rigid seat, supporting the torso by a plate, maintaining Frankfurt plane horizontal. Isolated head-neck complexes were fixed at T1 with the occiput connected via a custom apparatus to a testing device to induce lateral bending motion. Head angular and linear accelerations and angular velocities were computed using a pyramid nine accelerometer package on the head; specimen-specific physical properties including center of gravity and moments of inertia in the three-dimensions; and equations of equilibrium. These data were used to determine neck loads at the occipital condyles. No specimens sustained injuries, identified by palpation, x rays, CT, and autopsy. Results from 24 tests indicated that PMHS head-neck complexes can tolerate 75 Nm of coronal moment at low axial load without failure, and this level may be used as an initial estimate of the injury reference value under lateral loading to the human head-neck complex. PMID- 22105395 TI - Comparison of head-neck responses in frontal impacts using restrained human surrogates. AB - The objective of the study was to evaluate the head and neck kinetics of three point belted Hybrid III dummy and Test Device for Human Occupant Restraint (THOR) in frontal impacts, and compare their responses with data from post mortem human subjects (PMHS). Surrogates were placed on a buck, capable of accommodating different anthropometry with similar initial positioning. Duplicate tests were conducted at low, medium, and high (3.6, 6.9, and 15.8 m/s) velocities. Upper and lower neck forces and moments were determined from load cell measures and its locations with respect to the ends of the neck. Head excursion-time responses were more repeatable in the Hybrid III dummy than the THOR dummy. Hybrid III dummy response was more rigid in the sagittal plane. Peak THOR motions were closer to PMHS. Based on times of occurrences of peak excursions, THOR was closer to PMHS at all velocities, while Hybrid III dummy showed biofidelity at the medium and high velocities. Controlled positioning and testing with different surrogates provide an evaluation of inter-subject responses. THOR was more likely to "get the head where and when it needs to be" in frontal impacts. With the importance of testing at lower speeds due to recent recognition of real-world injuries, these data suggest that THOR may be an optimal dummy for frontal impacts. Comparisons of head-neck kinetic data with PMHS are valuable in frontal impact injury assessments. PMID- 22105396 TI - The biomechanics of the pediatric and adult human thoracic spine. AB - A growing body of literature points out the relevance of the thoracic spine dynamics in understanding the thorax-restraint interaction as well as in determining the kinematics of the head and cervical spine. This study characterizes the dynamic response in bending of eight human spinal specimens (4 pediatric: ages 7 and 15 years, 4 adult: ages 48 and 52 years) from two sections along the thoracic spine (T2-T4 and T7-T9). Each specimen consisted of three vertebral bodies connected by the corresponding intervertebral discs. All ligaments were preserved in the preparation with the exception of the inter transverse ligament. Specimens were exposed to a series of five dynamic bending ramp-and-hold tests with varying amplitudes at a nominal rate of 2 rad/s. After this battery of tests, failure experiments were conducted. The 7-year-old specimen showed the lowest tolerance to a moment (T2-T4: 12.1 Nm; T7-T9: 11.6 Nm) with no significant reduction of the relative rotation between the vertebrae. The 15-year-old failure tolerance was comparable to that of the adult specimens. Failure of the adult specimens occurred within a wide range at the T2-T4 thoracic section (23.3 Nm- 53.0 Nm) while it was circumscribed to the interval 48.3 Nm 52.5 Nm for the T7-T9 section. The series of dynamic ramp-and-hold were used to assess two different scaling methods (mass scaling and SAE scaling). Neither method was able to capture the stiffness, peak moment and relaxation characteristics exhibited by the pediatric specimens. PMID- 22105397 TI - Prescription medication usage and crash culpability in a population of injured drivers. AB - There has been increasing concern regarding the role of prescription drug use in the causation of traffic crashes. The goal of this research is to describe the prevalence of prescription drug use among injured trauma patients and determine the association between classes of drugs and crash culpability, a surrogate measure of crash risk. METHODS: Patient records, including chronic medication usage, for all drivers admitted to a trauma center following a traffic collision in 2008 (N=1,558) were linked with police crash reports to determine crash culpability. Multivariable analyses explored the association between medication use and crash culpability among non-drinking drivers. Adjusted odds ratios and 95% confidence intervals were compared among drivers who were and were not using central nervous system (CNS)-acting medications (single and multiple). RESULTS: 61.5% of all drivers were using any medications and usage increased with age, as did numbers of prescriptions per driver. Logistic regression analyses revealed that drivers who used CNS medications had an increased risk of culpability; those on more than one such medication had a crude (unadjusted) odds ratio of 2.16 for having caused the crash. Among drivers less than 45 years old, CNS medications did not significantly increase the risk of crash culpability. However, among drivers aged 45 or greater, the odds ratios for one, two, or 2+ CNS medications vs. none increased dramatically from 1.89 to 4.23 to 7.99, respectively. CONCLUSIONS: These results suggest that special attention should be given to older drivers (45+) using two or more CNS-acting agents. PMID- 22105398 TI - Correlating the extent of pulmonary contusion to vehicle crash parameters in near side impacts. AB - Pulmonary contusion (PC) is the most common injury following blunt thoracic trauma with an associated mortality of 10% to 20%. The purpose of this study is to determine how crash parameters correlate to the volume of pulmonary contusion. The Crash Injury Research Engineering and Network (CIREN) database was queried to extract data on all occupants sustaining PC in a near-side crash. The selected CIREN data included all completed cases from 2005 through 2010. Cases involving a roll-over or without a thorax CT uploaded to the database were excluded. After all cases had been examined the study had 64 occupants with varying volumes of PC. Specific crash characteristics compiled included change in velocity due to the impact, energy, occupant characteristics, side airbag deployment, and crush profile measurements. Crush metrics quantifying the area of the crush profile and the location of the crush relative to the occupant were calculated. The thoracic CT scans from these cases were downloaded and segmented to determine the percent volume of high attenuation lung and PC as compared to the total volume of the lung. The results of the general linear model analysis suggest that maximum crush was the best predictor of high attenuation lung and lung location best predicted PC. An analysis of NASS and CIREN demonstrated that crashes with PC tended to have crash parameters that indicated higher severity. These correlations can be used in the future to develop an injury criterion for PC using finite element metrics. PMID- 22105399 TI - Response of the Worldwide Side Impact Dummy (WorldSID) to Localized Constant Speed Impacts. AB - The objective of this study was to evaluate WorldSID constant-speed shoulder and thorax impact responses in terms of impact force, external and internal deflection (1D and 2D IR-Tracc response) for two velocities (1 m/s and 3 m/s), at three impact levels (shoulder, upper thorax and mid thorax) in three impact directions (lateral, +15 degrees posterolateral, -15 degrees anteraolateral). In addition, the impact force and external deflection were compared to previously published cadaver data. Each impact condition was repeated twice. A total of 42 tests were performed. The WorldSID's lowest peak impact force and external deflection were found for impact at shoulder level regardless of impact direction. Maximum force and deflection were found for impact at mid thorax. Comparison between WorldSID and PMHS showed similar external chest deflections for impacts at 3 m/s. The peak impact force response with respect to impact level was found to be reversed for the WorldSID compared to the PMHS, for which shoulder impact resulted in the highest peak force. External time history responses for the WorldSID compared to the one PMHS impacted at 1 m/s in lateral impact direction showed a significant difference in both timing and magnitude. External deflections at upper and mid thorax were approximately twice as high as the internal 1D deflection measured by the IR-Tracc. However, taking into account the rotation of the rib, the calculated 2D deflection response at the posterior impact direction was closer to the external deflection, and thus also to the PMHS deflection response at 3 m/s. These findings emphasize the need of 2D deflection measurement. PMID- 22105400 TI - Planar impacts in rollover crashes: significance, distribution and injury epidemiology. AB - While one third of all fatal motor vehicle crashes involve rollover of the vehicle, a substantially large portion of these rollover crashes involve planar impacts (e.g., frontal, side or rear impact) that influence the crash kinematics and subsequently the injury outcome. The objective of the study was to evaluate the distribution of planar impacts in rollover crashes, and in particular, to describe the differences in the underlying crash kinematics, injury severity and the regional distribution of injuries when compared to the rollover-dominated crashes without significant planar impact (i.e., primary rollovers). Sampled cases (n=6,900) from the U.S. National Automotive Sampling System - Crashworthiness Data System, representing approximately 3.3 million belted drivers involved in a rollover crash in years 1998-2008, were analyzed. Single vehicle rollover crashes with significant planar impact (21% of all rollover crashes) were in general more likely to result in occupant fatality and involved higher incidence of moderate to severe injuries compared to single vehicle primary rollovers (p<0.05). A substantial proportion of the planar impact rollovers ended in single quarter turn crashes (30%), mostly resulting from a frontal impact (59%). While chest was the most frequently injured body region among all rollover victims sustaining severe injuries, severe injuries sustained in primary rollovers were more isolated (single body region) in comparison to the ones sustained in rollovers with planar impacts. The results emphasize the higher risk of rollover victims sustaining an injury and the differences in distribution of injuries sustained when a planar impact is associated with the rollover crash. PMID- 22105401 TI - Comparisons of the Outcome Prediction Performance of Injury Severity Scoring Tools Using the Abbreviated Injury Scale 90 Update 98 (AIS 98) and 2005 Update 2008 (AIS 2008). AB - The Abbreviated Injury Scale (AIS) was revised in 2005 and updated in 2008 (AIS 2008). We aimed to compare the outcome prediction performance of AIS-based injury severity scoring tools by using AIS 2008 and AIS 98. We used all major trauma patients hospitalized to the Royal Perth Hospital between 1994 and 2008. We selected five AIS-based injury severity scoring tools, including Injury Severity Score (ISS), New Injury Severity Score (NISS), modified Anatomic Profile (mAP), Trauma and Injury Severity Score (TRISS) and A Severity Characterization of Trauma (ASCOT). We selected survival after injury as a target outcome. We used the area under the Receiver Operating Characteristic curve (AUROC) as a performance measure. First, we compared the five tools using all cases whose records included all variables for the TRISS (complete dataset) using a 10-fold cross-validation. Second, we compared the ISS and NISS for AIS 98 and AIS 2008 using all subjects (whole dataset). We identified 1,269 and 4,174 cases for a complete dataset and a whole dataset, respectively. With the 10-fold cross validation, there were no clear differences in the AUROCs between the AIS 98- and AIS 2008-based scores. With the second comparison, the AIS 98-based ISS performed significantly worse than the AIS 2008-based ISS (p<0.0001), while there was no significant difference between the AIS 98- and AIS 2008-based NISSs. Researchers should be aware of these findings when they select an injury severity scoring tool for their studies. PMID- 22105402 TI - Demographics, Velocity Distributions, and Impact Type as Predictors of AIS 4+ Head Injuries in Motor Vehicle Crashes. AB - The objective of the study was to determine differences between the United States based NASS and CIREN and Australia-based ANCIS databases in occupant-, crash-, and vehicle-related parameters for AIS 4+ head injuries in motor vehicle crashes. Logistic regression analysis was performed to examine roles of the change in velocity (DV), crash type (frontal, far-side, nearside, rear impact), seatbelt use, and occupant position, gender, age, stature, and body mass in cranial traumas. Belted and unbelted non-ejected occupant (age >16 years) data from 1997 2006 were used for the NASS and CIREN datasets, and 2000-2010 for ANCIS. Vehicle model year, and occupant position and demographics including body mass index (BMI) data were obtained. Injuries were coded using AIS 1990-1998 update. Similarities were apparent across all databases: mean demographics were close to the mid-size anthropometry, mean BMI was in the normal to overweight range, and representations of extreme variations were uncommon. Side impacts contributed to over one-half of the ensemble, implying susceptibility to head trauma in this mode. Odds of sustaining head injury increased by 4% per unit increase in DV (OR: 1.04, 95% CI: 1.03-1.04, p<0.001; adjusted for other variables); one-half for belted compared to unbelted occupants (OR: 0.48, 95% CI: 0.37-0.61, p<0.001); nearside, then far-side had significantly higher odds than frontal, and no difference by gender or position (front-left, front-right). Similar crash- and occupant-related outcomes from the two continents indicate a worldwide need to revise the translation acceleration-based head injury criterion to include the angular component in an appropriate format for improved injury assessment and mitigation. PMID- 22105403 TI - Drunk driving among novice drivers, possible prevention with additional psychological module in driving school curriculum. AB - Road traffic collisions caused by drunk driving pose a significant public health problem all over the world. Therefore additional preventive activities against drunk driving should be worked out. The aim of the study was to assess drunk driving in novice drivers after a psychological intervention taking into account also impulsivity, law obedience, and alcohol-related measures. An intervention study was started with 1889 car driver's license attempters during their driving school studies. Subjects were classified as intervention group (n=1083, mean age 23.1 (SD=7.4) years), control group (n=517, mean age 22.8 (SD=7.1) years) and "lost" group (n=289, mean age 23.0 (SD=6.9) years). "Lost" group subjects had been assigned into the intervention group, but they did not participate in the intervention. Subjects of the intervention group participated in a psychological intervention on the dangers of impulsive behavior in traffic. After a three year follow-up period it appeared that in the control group and in the lost group there was a significantly higher proportion of drunk drivers than in the intervention group, 3.3% (n=17), 3.5% (n=10) and 1.5% (n=10) (p=0.026), respectively. Survival analysis confirmed that psychological intervention had a significant impact on drunk driving (p=0.015), and the impact of the intervention was persistent also in the case of higher scores in Mild social deviance. In subjects with higher scores in impulsivity measures and alcohol-related problems the impact of short psychological intervention was not sufficient for preventing drunk driving. It can be concluded that psychological intervention used during the driving school studies is an effective primary prevention activity against drunk driving. However, for drivers with high scores in impulsivity measures and alcohol-related problems, the short psychological intervention is not sufficient in reducing drunk driving behavior. PMID- 22105404 TI - Responsibility study: main illicit psychoactive substances among car drivers involved in fatal road crashes. AB - In 1999, in France, before considering modifications in drug legislation, the government requested a study of the effect of illicit drugs on the risk of road crashes. It implemented a systematic screening of illicit drugs for all drivers involved in fatal crashes between October 2001 and September 2003. Within the European DRUID project, the study was restricted to car drivers.The project reported here is a responsibility analysis and, as such, it belongs to the framework of case-control studies; the outcome of interest is "being responsible for a fatal crash". It was assessed with a method adapted from Robertson and Drummer. Cases are the 4,946 car drivers who are responsible for the crash; controls are the 1,986 car drivers selected from the non-responsible car drivers, in a way that makes the control group similar to the general driving population.The effect of cannabis on fatal crash responsibility is significant after adjustment for age, sex and alcohol: adjusted odds ratio is 1.89 [1.43 2.51]. The dose-response effect is significant (p=0.0001). For alcohol (>=0.1 g/l), the adjusted odds ratio for responsibility is 8.39 [6.95-10.11]. No interaction was found between alcohol and cannabis. For amphetamine, cocaine and opiates, adjusted odds ratios were not significantly different from 1. However the statistical power is low.The study finds similar odds ratios for alcohol as previously published. For cannabis, the significant odds ratio together with the significant dose-response effect indicates a causal relationship between cannabis and road crashes. A multiplicative effect between cannabis and alcohol was noted. PMID- 22105405 TI - An Evaluation of Three Driving-Under-the-Influence Courts in Georgia. AB - Following the model of Drug Courts, three Georgia Driving-Under-the-Influence (DUI) Courts (established in Chatham, Clarke, and Hall Counties in 2003) were designed to address the underlying alcohol problems of repeat DUI offenders through continuous and frequent judicially supervised treatment, periodic alcohol and other drug testing, the use of graduated sanctions, and other appropriate rehabilitative services. A team comprised of a judge, court personnel, probation officials, and treatment providers met regularly to assess offender progress, and offenders met biweekly with the judge to report their progress. An impact evaluation showed after 4 years of exposure that when the DUI Court graduates were combined with the DUI Court terminated offenders (Intent to Treat Group), the DUI Court offenders had significantly lower recidivism rates: 38 percent lower than a Contemporary Group of offenders and 65 percent lower than a Retrospective Group of offenders. The DUI Court Intent to Treat Group had a significantly lower recidivism rate: 15 percent compared to 24 percent for a group of matched offenders from three similar counties in Georgia (Contemporary Group) and a 35 percent rate for matched offenders from the same counties as the DUI Court who would have been eligible for the DUI Court had it been in existence (Retrospective Group). Offenders who were terminated from the DUI Courts for various reasons had a recidivism rate of 26 percent. It is estimated that the DUI Courts prevented between 47 and 112 repeat arrests during a four year period due to the reduced recidivism associated with them. PMID- 22105406 TI - Testing and Contrasting Road Safety Education, Deterrence, and Social Capital Theories: A Sociological Approach to the Understanding of Male Drink-Driving in Chile's Metropolitan Region. AB - Three theories offer different explanations to the understanding of male drink driving. In order to test road safety education, deterrence, and social capital theories, logistic regression analysis was applied to predict respondents' statements of having or not having engaged in actual drink-driving (DD). Variable for road safety education theory was whether a driver had graduated from a professional driving school or not. Deterrence theory was operationalized with a variable of whether a driver had been issued a traffic ticket or not. Social capital theory was operationalized with two variables, having children or not and having religion identification or not. Since both variables 'years of formal education' and 'years of driving experience' have been reported to be correlated to alcohol consumption and DD respectively, these were introduced as controls. In order to assess the significance of each variable statistically, Wald tests were applied in seven models. Results indicate on the one hand that road safety education variable is not statistically significant; and on the other, deterrence theory variable and social capital theory variable 'having children' were both statistically significant at the level of .01. Findings are discussed in reference to Chile's context. Data were taken from the "Road Users Attitudes and Behaviors towards Traffic Safety" survey from the National Commission of Road Safety of the Government of Chile (2005). The sample size was reported to be 2,118 (N of male drivers was 396). This survey was representative of Chile's Metropolitan Region road users' population. PMID- 22105407 TI - Driving simulator performance in patients with possible and probable Alzheimer's disease. AB - Drivers with more advanced stages of Alzheimer's disease (AD) have been previously associated with an increased rate of motor vehicle accidents. Drivers suffering from early AD are also involved in, and may even cause motor vehicle accidents with greater frequency than "normal" drivers. Consequently there is considerable public concern regarding traffic safety issues for those with AD and subsequently for society, but there has been little research in understanding whether deterioration in driving ability is progressive, or has a sudden onset once the disease has reached a certain severity. The purpose of this study was to identify possible degradation in simulated driving performance that may occur at the earliest stages of AD, and compare these decrements to a control group of normal drivers.Using a single blind design, seventeen AD subjects, eight at a Clinical Dementia Rating (CDR) of 0.5 (possible AD) and nine at a CDR of 1 (probable AD), were compared to 63 cognitively normal, elderly controls. All subjects were trained to drive a computerized interactive driving simulator and then tested on a 19.3 km (12 mile) test course.The AD subjects demonstrated impaired driving performance when compared to the controls. The simulated driving performance of the CDR 1 AD subjects was so degraded that it would be regarded as unsafe by standard assessment criteria. The CDR 0.5 subjects made similar errors, suggesting that driving impairment may occur at the earliest stages of the disease. Further work will be necessary to determine the significance of these findings. PMID- 22105408 TI - Improving trauma triage using basic crash scene data. AB - OBJECTIVE: to analyze the occurrence of severe injuries and deaths among crash victims transported to hospitals in relation to occupant and scene characteristics, including on-scene patient mobility, and their potential use in triaging patients to the appropriate level of care. METHODS: the occurrence of death and ISS>15 were studied in relation to occupant, crash and mobility data readily available to EMS at the scene, using weighted NASS-CDS data. Data set was randomly split in two for model development and evaluation. Characteristics were combined to develop new triage schemes. Overtriage and undertriage rates were calculated for the NASS-CDS case trauma center allocation and for the newly developed triage schemes. RESULTS: Compared to the NASS-CDS distribution, a scheme using patient mobility alone showed lower overtriage of those with ISS<=15 (38.8% vs. 55.5%) and lower undertriage of victims who died from their crash related injuries (2.34% vs. 21.47%). Undertriage of injuries with ISS> 15 was similar (16.0 vs. 16.9). A scheme based on the presence of one of many scene risk factors (age>55, GCS<14, intrusion >=18", near lateral impact, far lateral impact with intrusion >=12", rollover or lack of restraint use) resulted in an undertriage of 0.86% (death) and 10.5% (ISS>15) and an overtriage of 63.4%. The combination of at least one of the scene risk factors and mobility status greatly decreased overtriage of those with ISS<15 (24.4%) with an increase in death undertriage (3.19%). Further combination of mobility and scene factors allowed for maintenance of a low undertriage (0.86%) as well as an acceptable overtriage (48%). CONCLUSION: Patient mobility data easily obtained at the scene of a crash allows triaging of injured patients to the appropriate facility with a high sensitivity and specificity. The addition of crash scene data to scene mobility allows further reductions on undertriaging or overtriaging. PMID- 22105409 TI - Costs of crashes to government, United States, 2008. AB - We estimated how much the Federal government and state/local government pay for different kinds of crashes in the United States. Government costs include reductions in an array of public services (emergency, incident management, vocational rehabilitation, coroner court processing of liability litigation), medical payments, social safety net assistance to the injured and their families, and taxes foregone because victims miss work. Government also pays when its employees crash while working and covers fringe benefits for crash-involved employees and their benefit-eligible dependents in non-work hours. We estimated government shares of crash costs by component. We applied those estimates to existing US Department of Transportation estimates of crash costs to society and employers. Government pays an estimated $35 billion annually because of crashes, an estimated 12.6% of the economic cost of crashes (Federal 7.1%, State/local 5.5%). Government bears a higher percentage of the monetary costs of injury crashes than fatal crashes or crashes involving property damage only. Government is increasingly recovering the medical cost of crashes from auto insurers. Nevertheless, medical costs and income and sales tax losses account for 75% of government's crash costs. For State/local government to break even on a 100% State funded investment in road safety, the intervention would need to have an unrealistically high benefit-cost ratio of 34. Government invests in medical treatment of illness to save lives and improve quality of life. Curing a child's leukemia, for example, is not less costly than leaving that leukemia untreated. Safety should not be held to a different standard. PMID- 22105410 TI - Fruits of 20 years of highway safety legislative advocacy in the United States. AB - This paper models the effects on crash fatalities and costs of 20 years of legislative actions resulting from Federal and state advocacy efforts. We catalogued road safety laws passed between 1990 and 2009 and motorcycle helmet law repeals that advocacy efforts narrowly defeated. We used NHTSA's estimates of lives saved by airbags and published estimates of the percentage reduction in related crash fatalities associated with each type of law. State by state and year by year, from the actual fatality count for the year, we modeled how many fatalities each state's laws averted. We assumed, somewhat shakily, that the percentage reduction in nonfatal injury costs would mirror the fatality reduction. We used crash cost estimates for 10 years between 1990 and 2008 to estimate total crash costs from 1990-2009. The costs were built from NHTSA's estimates of cost per crash. The state laws passed included 113 occupant protection laws, 131 impaired driving laws, and 76 teen driving laws, plus a Federal airbag mandate. These laws saved an estimated 120,000 lives. The life saving benefits accelerated as the number of laws in force grew. By 2009, they resulted in 25% fewer crash fatalities. The largest life-saving benefits sprang from airbag, belt use, and impaired driving laws. Laws that affect narrow subpopulations had more modest impacts. The laws reduced insurance costs by more than $210 billion and saved government an estimated $42 billion. Including the value of lost quality of life, estimated savings exceeded $1.3 trillion. Legislative advocacy is truly a spark plug in the safety engine. PMID- 22105411 TI - Quality-adjusted life years lost to road crash injury: updating the injury impairment index. AB - The Injury Impairment Index (III) has long been used internationally to estimate the quality-adjusted life year (QALY) losses associated with crash injuries. The III has major limitations, notably its lack of detailed validation, but it is widely used and estimates from it are regularly published. It is based on physician estimates of typical impairment on 6 dimensions of functioning (cognitive, mobility, bending/grasping/lifting, sensory, pain and cosmetic), supplemented with data on work-related disability. This paper reports on a literature synthesis used to update the III scoring algorithm that converts impairment levels by dimension into a combined QALY loss score. An extensive international literature search identified 13 health status scales, some of them with multiple scorings. From the scorings, we extracted utility scores for each level of each dimension of the III. We also searched for direct utility estimates for III dimension endpoints (e.g., blindness, deafness). Median and inter quartile ranges were computed by scale point to represent the uncertainty range of preference weights within each III dimension and level. Average QALY losses per injury by MAIS were computed using the updated preference weight ranges applied to 2000-2006 U.S. crash data. The updated QALY loss estimates are lower than those computed with the QALY weights developed in 1990. This paper's tables of estimated average QALY losses by MAIS, injury type, and body region injured can be applied to future and existing injury data in order to estimate the impact of injury on quality of life and measure health status. PMID- 22105412 TI - Spurious elevation of serum PSA after curative treatment for prostate cancer: clinical consequences and the role of heterophilic antibodies. AB - BACKGROUND: Various interferences can cause spurious results for common laboratory tests. Although rare, heterophilic antibodies may produce false elevations in PSA that could prompt unnecessary therapy in men previously treated for prostate cancer. The aim of this study was to determine the prevalence of small, spurious PSA elevations, and the role of heterophilic antibodies. METHODS: Phase I: all PSA tests drawn and measured between 27 October 2008 and 26 October 2010 at Vanderbilt University Medical Center were analyzed (n=17 133). Patients who had been treated for prostate cancer with PSA values that changed from undetectable to detectable were evaluated. Phase II: patients with a detectable PSA <=0.5 ng ml(-1) measured between 24 October 2010 and 19 January 2011 were studied prospectively (n=1288). If any patient had a previously undetectable PSA value, their serum was tested for heterophilic antibody interference. RESULTS: Phase I: 11 men had a spuriously elevated PSA after curative treatment for prostate cancer (0.3%). Mean time to PSA elevation was 3.4+/-5.5 years, and mean elevation in PSA was 0.33+/-0.28 ng ml(-1). Each patient's PSA was undetectable after being repeated, and no patient went on to unnecessary treatment. Phase II: 10 men had a newly detectable PSA, 9 of whom had a history of prostate cancer. Each tested negative for interfering heterophilic antibodies when their PSA test was repeated with a heterophilic antibody-blocking reagent. CONCLUSIONS: In a large cohort, we estimate the prevalence of spuriously elevated PSA values in our population to be 0.3%. No patient with a prostate cancer history was subjected to unnecessary diagnostic evaluation or treatment. On prospective evaluation of PSA conversion to low detectable levels, no patient had evidence of interfering heterophilic antibodies. When using PSA for post-treatment surveillance, it is crucial to confirm all concerning values and consider the presence of a spurious elevation in PSA if the value does not correlate with the clinical scenario. PMID- 22105413 TI - Electrophysiological characterization of GFP-expressing cell populations in the intact retina. AB - Studying the physiological properties and synaptic connections of specific neurons in the intact tissue is a challenge for those cells that lack conspicuous morphological features or show a low population density. This applies particularly to retinal amacrine cells, an exceptionally multiform class of interneurons that comprise roughly 30 subtypes in mammals(1). Though being a crucial part of the visual processing by shaping the retinal output(2), most of these subtypes have not been studied up to now in a functional context because encountering these cells with a recording electrode is a rare event. Recently, a multitude of transgenic mouse lines is available that express fluorescent markers like green fluorescent protein (GFP) under the control of promoters for membrane receptors or enzymes that are specific to only a subset of neurons in a given tissue(3,4). These pre-labeled cells are therefore accessible to directed microelectrode targeting under microscopic control, permitting the systematic study of their physiological properties in situ. However, excitation of fluorescent markers is accompanied by the risk of phototoxicity for the living tissue. In the retina, this approach is additionally hampered by the problem that excitation light causes appropriate stimulation of the photoreceptors, thus inflicting photopigment bleaching and transferring the retinal circuits into a light-adapted condition. These drawbacks are overcome by using infrared excitation delivered by a mode-locked laser in short pulses of the femtosecond range. Two-photon excitation provides energy sufficient for fluorophore excitation and at the same time restricts the excitation to a small tissue volume minimizing the hazards of photodamage(5). Also, it leaves the retina responsive to visual stimuli since infrared light (>850 nm) is only poorly absorbed by photopigments(6). In this article we demonstrate the use of a transgenic mouse retina to attain electrophysiological in situ recordings from GFP-expressing cells that are visually targeted by two-photon excitation. The retina is prepared and maintained in darkness and can be subjected to optical stimuli which are projected through the condenser of the microscope (Figure 1). Patch-clamp recording of light responses can be combined with dye filling to reveal the morphology and to check for gap junction-mediated dye coupling to neighboring cells, so that the target cell can by studied on different experimental levels. PMID- 22105414 TI - Ionothermal synthesis process for aluminophosphate molecular sieves in the mixed water/ionic liquid system. AB - The synthesis process of aluminophosphate AlPO(4)-11 molecular sieve in the mixed water/1-butyl- 3-methylimidazolium bromide ([bmim]Br) ionic liquid was investigated by XRD, multinuclear solid-state NMR, scanning electron microscopy (SEM) and X-ray energy dispersive spectroscopy (EDS). It was observed that a tablet phase, named SIZ-2, was formed at the early stage of crystallization. During crystallization metastable SIZ-2 with an incompletely condensed framework phosphorus disappeared gradually, and the phosphorous species became fully condensed through hydroxyl reaction with tetrahedral aluminum to form thermodynamically stable AlPO(4)-11 in the final product. It was found that [bmim]Br, acting as the structure-directing agent, was occluded into the AlPO(4) 11 channel. PMID- 22105415 TI - Insulin pumps in pregnancy: using technology to achieve normoglycemia in women with diabetes. AB - Poorly controlled diabetes before conception and during pregnancy among women with pre-existing diabetes can cause major birth defects and spontaneous abortions, as wells as abnormal fetal growth and development including an offspring who is small or large for gestational age, or predisposed to obesity, type 2 diabetes, and metabolic syndrome in his/her lifetime. Conversely, for a woman with pre-existing diabetes, optimizing blood glucose levels before and during early pregnancy can reduce these risks dramatically. As insulin pump technology has evolved, continuous subcutaneous insulin infusion has become a safe and reliable method for treating diabetes during pregnancy. Although pump therapy is often preferred by patients and some experts, insulin pumps have not yet been shown to be superior to multiple daily injections of insulin during pregnancy. In this review of the literature we focus on the use of insulin pumps in the management of diabetes in pregnancy. PMID- 22105416 TI - A novel DNA-templated click chemistry strategy for fluorescent detection of copper(II) ions. AB - A novel fluorescent strategy has been developed for sensitive turn-on detection of Cu(2+) based on high efficiency of DNA-templated organic synthesis, great specificity of alkyne-azide click reaction to the catalysis of copper ions and the sequential strand displacement for signal transduction. PMID- 22105417 TI - Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. AB - Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK cell phenotype and function in peripheral blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56(bright) CD16(+/-) subset and displayed effective NK-cell function, while PTLD patients accumulated CD56(dim) CD16(-) and CD56(-) CD16(+) NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-gamma release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value. PMID- 22105418 TI - Symmetry-breaking intramolecular charge transfer in the excited state of meso linked BODIPY dyads. AB - We report the synthesis and characterization of symmetric BODIPY dyads where the chromophores are attached at the meso position, using either a phenylene bridge or direct linkage. Both molecules undergo symmetry-breaking intramolecular charge transfer in the excited state, and the directly linked dyad serves as a visible light-absorbing analogue of 9,9'-bianthryl. PMID- 22105419 TI - Extended-spectrum beta-lactamases: a brief clinical update. PMID- 22105420 TI - Review of carbapenemases and AmpC-beta lactamases. PMID- 22105421 TI - Persistent subcutaneous nodule: "sealed with a kiss". PMID- 22105422 TI - Herpes viruses lack association with acute parotitis in children. PMID- 22105423 TI - Predictive score to discriminate Kingella kingae from Staphylococcus aureus arthritis in France. PMID- 22105425 TI - Raoultella infection causing fever of unknown origin. PMID- 22105426 TI - Helicobacter pylori seropositivity in institutionalized children with Down syndrome. PMID- 22105427 TI - Valganciclovir treatment in a 6-month-old infant with asymptomatic congenital cytomegalovirus infection and late hearing loss. PMID- 22105430 TI - Bone production by human maxillary sinus mucosa cells. AB - The Schneider membrane is the mucosa that covers the inner part of the maxillary sinus cavities. The free surface is a ciliated pseudostratified epithelium, while the deeper portion is a highly vascularized connective tissue. The stromal fraction, bordering the bony wall of the sinus, after tooth loss can exhibit increased osteoclastic activity resulting in resorption of the bone in the posterior maxilla. Goal of our study was to isolate and characterize mesenchymal progenitors in the Schneider's membrane connective net and to evaluate their self ability to differentiate toward osteoblastic lineage, in absence of osteoinductive factors and osteoconductive biomaterials of support. This should indicate that maxillary sinus membrane represents an useful an approachable source of MSCs for bone tissue engineering and cell therapy and owns the intrinsic capacity to restore maxillary bone after tooth loss without the needing of biomaterials. PMID- 22105429 TI - An expansion of age constraints for microbial clades that lack a conventional fossil record using phylogenomic dating. AB - Most microbial taxa lack a conventional microfossil or biomarker record, and so we currently have little information regarding how old most microbial clades and their associated traits are. Building on the previously published oxygen age constraint, two new age constraints are proposed based on the ability of microbial clades to metabolize chitin and aromatic compounds derived from lignin. Using the archaeal domain of life as a test case, phylogenetic analyses, along with published metabolic and genetic data, showed that members of the Halobacteriales and Thermococcales are able to metabolize chitin. Ancestral state reconstruction combined with phylogenetic analysis of the genes underlying chitin degradation predicted that the ancestors of these two groups were also likely able to metabolize chitin or chitin-related compounds. These two clades were therefore assigned a maximum age of 1.0 Ga (when chitin likely first appeared). Similar analyses also predicted that the ancestor to the Sulfolobus solfataricus Sulfolobus islandicus clade was able to metabolize phenol using catechol dioxygenase, so this clade was assigned a maximum age of 475 Ma. Inferred ages of archaeal clades using relaxed molecular clocks with the new age constraints were consistent with those inferred with the oxygen age constraints. This work expands our current toolkit to include Paleoproterozoic, Neoproterozoic, and Paleozoic age constraints, and should aid in our ability to phylogenetically reconstruct the antiquity of a wide array of microbial clades and their associated morphological and biogeochemical traits, spanning deep geologic time. Such hypotheses-although built upon evolutionary inferences-are fundamentally testable. PMID- 22105431 TI - Comparison of N-acetyltransferase-2 enzyme genotype-phenotype and xanthine oxidase enzyme activity between Swedes and Koreans. AB - The aim of this study was to compare xanthine oxidase (XO) and N acetyltransferase-2 (NAT2) genotype and phenotype between Swedes (n = 113) and Koreans (n = 150), as well as to investigate the effect of sex, smoking, age, and oral contraceptive (OC) use on enzyme activities, using caffeine as a probe. XO and NAT2 activities were estimated by 1U/(1U+1X) and AFMU/(AFMU+1X+1U) urinary ratios, respectively. Participants were genotyped for 191G>A, 341T>C, 590G>A, and 857G>A NAT2 polymorphisms. There was no significant difference in XO activity between Swedes and Koreans. In Swedes, higher XO activity was observed in women (P < .003). There were significant differences in NAT2 genotype and phenotype between Swedes and Koreans. Koreans display significantly higher frequency of NAT2 fast acetylator genotype (89%), whereas the slow acetylator genotype is predominant (62%) in Swedes (P < .0001). Significantly higher NAT2 activity was observed in Koreans compared to Swedes (P < .0001). Having the same NAT2 fast acetylator genotype, Koreans display higher enzyme activity than Swedes (P < .004). OC use significantly increased NAT2 activity in Swedish women. In conclusion, Koreans display higher NAT2 activity than Swedes regardless of NAT2 genotype. Ethnicity, OC use, and genotype determine NAT2 activity, whereas sex is the only determinant of XO activity. PMID- 22105432 TI - Maternal microchimerism in Hirschsprung's disease. AB - Hirschsprung's disease (HD) presents with severe constipation due to absent ganglion cells in the distal rectum. We sought to determine whether maternal chimeric cells are present in aganglionic bowel. We hypothesize that chimeric cells are part of the unfavorable microenvironment that leads to the destruction of enteric neurons in HD. Intestinal biopsies and resections from seven male patients with HD were compared with four male patients with chronic constipation and six with bowel atresia. Fluorescence in situ hybridization was used to identify chimeric cells based on male/female (XX/XY) differences. The location and immunophenotype of chimeric cells were also studied. Chimeric cells were present more often in the small intestine and rectum, compared with the appendix and colon. Patients with HD had a greater number of chimeric cells per 10* magnification field than patients with chronic constipation or congenital atresia. Chimeric cells were predominantly in the submucosa and outer longitudinal muscle layer in HD. Immunophenotyping identified over 40% of chimeric cells as inflammatory. Chimeric cells are present in greater numbers in aganglionic bowel than in other disorders. Clustering of chimeric cells in areas of absent ganglia lends support to the proposed role of maternal microchimerism in allo-autoimmune responses. PMID- 22105433 TI - Population standards of birth weight underestimate fetal growth abnormalities in diabetic pregnancies. AB - The objective of this study was to compare the frequency of abnormal fetal growth in women with diabetes mellitus (DM) using population-based birth weight (pop BW) percentiles compared with customized birth weight (cust BW) percentiles, which include adjustments for maternal race, parity, height, weight, and fetal sex. The study design comprised a retrospective cohort of singleton DM pregnancies delivered over a 1-year period (June 2007 to May 2008) from a single tertiary care university-based medical center. Inclusion criteria were gestational age >20 weeks at delivery, live birth, and absence of major chromosomal/structural abnormalities. Small for gestational age (SGA), <10th percentile, and large for gestational age (LGA), >90th percentile pregnancies were categorized based on pop BW or cust BW standards. There were significant differences in the rates of SGA (p < 0.004) and LGA (p < 0.001) between cust BW and pop BW methods. When comparing the two methods, pop BW did not identify 13/16 (81%) of SGA and 23/39 (59%) of LGA babies defined by cust BW methods. The use of cust BW calculation in a diabetic population identified a greater percentage of neonates with pathologic fetal growth compared with pop BW standards, suggesting that the population standard may underdiagnose abnormal fetal growth in diabetic pregnancies. PMID- 22105434 TI - Effect of obesity on length of labor in nulliparous women. AB - We compared the duration of labor among nulliparous women with varying body mass index (BMI). Laboring nulliparous women at >37 weeks were included. First visit BMI was used to categorize weight as normal (<=24), overweight (25 to 29.9), or obese (>=30 kg/m(2)). Chi-square, one-way analysis of variance, and Bonferroni multiple comparisons tests were used. During 15 months, 375 women met the inclusion criteria, and 38% were obese. Duration of first stage of labor was significantly longer for obese versus normal-weight women (26.76 +/- 0.77 versus 23.87 +/- 0.66 hours; p = 0.024) but not between normal versus overweight women (p = 1.00) or overweight versus obese women (p = 0.114). The cesarean delivery rate was significantly different in the three groups (p = 0.0001), highest among obese (47%) and lowest in normal-weight women (24%). When adjusted for age, hypertension, and induction, the likelihood of completing stage I was significantly less among obese nulliparous than those with BMI < 24 kg/m(2) (hazard ratio 0.73, 95% confidence intervals 0.54, 0.99). Compared with those with BMI < 24, the duration of stage I is significantly longer among obese women, even when adjusted for maternal age, induction, and hypertension. PMID- 22105435 TI - A randomized, controlled trial of poractant alfa versus beractant in the treatment of preterm infants with respiratory distress syndrome. AB - We prospectively evaluated the differences in clinical responses and short-term outcomes in preterm infants with respiratory distress syndrome (RDS) treated with poractant alfa or beractant. Premature infants with RDS were randomized to poractant alfa or beractant treatment between July 2008 and June 2009. Patients were followed until 40 weeks of corrected gestational age or death. The fraction of inspired oxygen (Fio(2)) after surfactant treatment, need for repeat doses, and duration of respiratory support and hospitalization were evaluated between groups. Sixty-one infants received poractant alfa and 65 received beractant. Significantly more patients in the beractant group required >=2 doses of surfactant compared with the poractant alfa group (31% versus 12%, p = 0.023). Extubation rate within the first 3 days after surfactant administration was higher in the poractant alfa group than in the beractant group (81% versus 55.9%, p = 0.004). Posttreatment Fio(2) requirement in the poractant alfa group was significantly lower than in the beractant group on days 1, 3, and 5. Overall mortality and morbidities were similar between groups. Survival free of bronchopulmonary dysplasia (BPD) at the end of study period was 78.7% and 58.5% in poractant alfa and beractant groups, respectively (p = 0.015). Our study confirms the rapid onset of action, less need for redosing, rapid extubation, and higher survival free of BPD in preterm infants treated with poractant alfa. PMID- 22105436 TI - Sleep-disordered breathing: a risk factor for adverse pregnancy outcomes? AB - In nonpregnant populations, sleep-disordered breathing (SDB) has been associated with cardiovascular and metabolic disease. Few studies have examined the relationship between SDB and adverse pregnancy outcomes (APO). The objective of this study was to examine the association between SDB and APO. Women who had a delivery as well as an in-laboratory polysomnogram (PSG) were identified. Demographics, PSG results, and pregnancy outcomes were abstracted from the medical record. Absence of SDB was defined as an apnea hypopnea index (AHI) of <5, mild SDB as an AHI of 5 to 14.9, and moderate to severe SDB as an AHI of >=15. The primary outcome was a composite measure of APO: pregnancy-related hypertension, gestational diabetes, or preterm birth <=34 weeks. We identified 143 women who had undergone a PSG and a delivery. Increasing severity of SDB was associated with an increasing risk of the composite APO: AHI <5, 18.1%; AHI 5 to 14.9, 23.5%; AHI >=15, 38.5% (p = 0.038). Obese women (body mass index >=30) with moderate to severe SDB had the highest rate of APO, 41.7%. SDB, especially moderate to severe disease, may be associated with APO. However, it is unclear if SDB is a risk factor for APO independent of obesity. PMID- 22105437 TI - The interaction effect of bacterial vaginosis and periodontal disease on the risk of preterm delivery. AB - The objective of this article is to determine if coexistence of periodontal disease (PD) and bacterial vaginosis (BV) is synergistic on the risk of spontaneous preterm delivery (sPTD). The study design was secondary analysis of a prospective cohort study. Women were screened 6 to 20 weeks gestation for PD and BV. Groups were defined by presence of BV and stratified on PD. The primary outcome was sPTD <37 weeks gestation. Univariable, stratified, and multivariable analyses were performed to estimate the main and interaction effects of BV and PD on sPTD. Of 1453 women screened, 792 (54.5%) were diagnosed with BV. Neither women with BV in the first trimester nor PD was at higher risk of sPTD (risk ratio [RR] for BV 1.1; 95% confidence interval (CI), 0.8-1.5, and RR for PD 0.9; 95% CI, 0.7-1.3). The interaction between BV and PD did not statistically significantly impact the odds of sPTD. Coexistence of PD and BV did not have a synergistic effect on sPTD. PMID- 22105438 TI - The use of targeted neonatal echocardiography to confirm placement of peripherally inserted central catheters in neonates. AB - The use of plain radiographs in assessing the correct position of peripherally inserted central catheter (PICC) line tips is not always accurate. Ultrasound may be a better modality in detecting tip position and aid in line manipulation. We assessed the accuracy of plain radiographs in determining PICC line tip position compared with using targeted neonatal echocardiography (TnECHO) in a tertiary neonatal intensive care unit. Following PICC insertion, tip position was confirmed using TnECHO after the first radiograph. A 2 * 2 table was constructed to compare the two modalities' ability to detect line position. A total of 22 infants were included in the study with a gestation of 26.5 weeks (25.4 to 28.8) and birth weight of 833 g (710 to 1930). Concordance between radiographs and TnECHO for PICC line tip position occurred in 13 infants (59%). Sensitivity of radiographs in determining malposition was 64% with a specificity of 55%. Three infants were incorrectly identified to have deep lines and two infants were incorrectly identified to have short lines. In nine infants (41%), a second radiograph was avoided following line manipulation using TnECHO. TnECHO is a useful tool in identifying tip position, performing real-time manipulation, and minimizing exposure to further radiographs. PMID- 22105439 TI - Type of skin incision and wound complications in the obese parturient. AB - We examined the relationship between type of skin incision at time of cesarean delivery and postoperative wound complications in the obese parturient. Women with a body mass index (BMI) of greater than 29 who had undergone cesarean delivery at The University of North Carolina were identified from the Pregnancy, Infection and Nutrition study. Inpatient and outpatient medical records were reviewed for maternal demographics as well as intrapartum and intraoperative characteristics. The exposure of interest was type of incision, classified as vertical or transverse. The primary outcome was wound complication, defined as partial or complete wound separation. Logistic regression analysis was used to create a final model of risk factors for wound complications while controlling for potentially confounding variables. From 1998 to 2005, 238 women with a BMI greater than 29 who underwent cesarean delivery were identified. Of these 238 women, a vertical skin incision was performed in 25 (11%) and a transverse skin incision in 213 (89%). The overall incidence of wound complications in this group was 13%. BMI was associated with wound complications (p < 0.01). After controlling for confounding factors, no difference in wound complication based on type of skin incision was apparent. The type of skin incision does not appear to be associated with wound complications in the obese parturient; however, larger studies would be needed to confirm this finding. Increased BMI is associated with a higher rate of wound complications. PMID- 22105440 TI - The freeze-thaw process and long intervals after fortification denature human milk fat globules. AB - Although mother's milk is the optimal nutrition for preterm infants, the amount of protein, calcium, and phosphorus become inadequate for the growth of preterm infants, such that fortification is recommended when enteral feeding is established. Recently, intestinal obstruction due to calcium soap formation has been reported. All the reported cases were fed fortified thawed human milk. It has not been elucidated how human milk fortifier reacts with milk fat globules (MFGs) in thawed human milk. Therefore, we investigated whether freezing durations and time between fortification and enteral feeding denatured MFGs. Six samples of preterm mothers' milk of each type (fresh unfrozen, 1-month frozen, and 12-month frozen) were analyzed. Fortifier was not added to the control. The samples were measured at 1, 12, and 24 hours after fortification. The MFG size distribution of each milk sample was measured. The freezing process enlarged the mode diameter (4.0 +/- 0.4, 4.3 +/- 0.7, and 4.5 +/- 0.9 in fresh unfrozen milk, 1-month frozen, and 12-month frozen milk, respectively, p < 0.001). Fortification itself did not significantly alter the MFG size in thawed mother's milk. However, a time lag of 12 hours after fortification enlarged the MFG size and resulted in smaller surface area per unit (3.6 +/- 0.2, 3.3 +/- 0.1, and 3.3 +/- 0.1 m(2)/g, fresh unfrozen, 1-month frozen, and 12-month frozen, respectively) compared with 0 hours of time lag (3.8 +/- 0.2, 3.5 +/- 0.1, and 3.4 +/- 0.2 m(2)/g, fresh unfrozen, 1-month frozen, and 12-month frozen, respectively). Not only the freeze thaw procedure but also time lag after fortification affected MFG size. We recommend using fortified thawed human milk within 12 hours. PMID- 22105441 TI - Clinical and sonographic features of uncommon primary ovarian malignancies. AB - PURPOSE: To describe the gray-scale and color Doppler ultrasound features of uncommon (<5% prevalence) primary malignant ovarian tumors. METHODS: Retrospective analysis of 98 masses in 89 patients (median age: 50.4 years old, ranging from 15 to 81 years) diagnosed as having an uncommon primary ovarian malignancy. All patients had undergone transvaginal color Doppler ultrasound according to a standardized protocol prior to surgical tumor removal. Ultrasound features analyzed were laterality, presence of ascites, tumor volume, morphologic appearance (unilocular, multilocular, unilocular-solid, multilocular-solid, and solid), and color Doppler score (subjective assessment of the amount of flow as absent, scanty, moderate, or abundant). RESULTS: Pathological diagnoses included uncommon epithelial tumors (n = 59), germ cell tumors (n = 10), sex cord-stromal tumors (n = 11), sarcoma (n = 9), and lymphoma (n = 9). Germ cell tumors presented in younger women (p < 0.001). Germ cell tumors, sex cord-stromal tumors, sarcomas, and lymphomas were significantly more often solid as compared with epithelial malignancies, which appeared more frequently as complex (cystic solid) tumors (p < 0.001). There were no differences in color Doppler score between the various types of tumors. CONCLUSIONS: Germ cell tumors, sex cord stromal tumors, sarcomas, and lymphomas tend to appear as unilateral solid tumors. Color Doppler score is not useful for discriminating among uncommon primary ovarian malignancies. PMID- 22105442 TI - Absorption enhancers: applications and advances. AB - Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use has reached the market, quite a few more appear to be at the threshold of becoming products, and these include oral and transmucosal applications. This paper will review some of the most advanced absorption enhancers currently in development and the formulation technologies employed that have led to their success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing formulations are discussed. If ultimately successful, the products now in development should offer non-injection alternatives for several peptide or protein drugs currently only administered by injection. The introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties. PMID- 22105443 TI - Predicting effects of cations on copper toxicity to lettuce (Lactuca sativa) by the biotic ligand model. AB - A biotic ligand model (BLM) was developed to estimate Cu toxicity to lettuce (Lactuca sativa) in terms of root elongation after 4 d of exposure. Effects of Na(+), K(+), Ca(2+), and Mg(2+) on Cu toxicity were examined. The addition of these cations resulted in a 50-fold difference in the copper median effective activity (EC50 cu2+). However, these variations could not be interpreted entirely as a function of the concentrations of these cations alone. In particular, only the relationship between EC50 cu2+ and the activity of protons was found to be significant in the whole range of pH examined from 5.0 to 7.0. The addition of K(+), Na(+), Ca(2+), and Mg(2+) at concentrations up to 20 mM resulted in a 16 fold difference in EC50 cu2+ values. This difference was significant, as indicated by non-overlapping standard deviations of the negative logarithm of EC50 cu2+ pEC50 cu2+) obtained with (7.37 +/- 0.22) and without (6.76 +/- 0.22) additions of K(+), Na(+), Ca(2+), and Mg(2+). The variations were not statistically significantly related to concentrations of these cations; therefore, only protons can be integrated in the BLM predicting Cu toxicity to lettuce L. sativa with the important parameters: log K(HBL) =6.27, log K(CuBL) =7.40, and [formula in text]. The lack of significant relationships between EC50 cu2+ and concentrations of the cations was not in line with the main assumption of the BLM about the competition between cations for binding sites. PMID- 22105444 TI - C-reactive protein levels are associated with arterial media calcification in nondiabetic patients with end-stage renal disease on long-term hemodialysis. AB - BACKGROUND: Vascular calcifications (VC) are associated with cardiovascular (CV) morbidity and are independent predictors of CV mortality in end-stage renal disease (ESRD). This study aimed to investigate the presence of arterial intima calcification (AIC) and arterial media calcification (AMC) in nondiabetic patients on long-term hemodialysis, and to assess the association with CV risk factors. METHODS: 34 ESRD patients (17 males) on hemodialysis for at least 5 years were evaluated for VC using B-mode ultrasonography. RESULTS: AMC and AIC patterns were detected respectively in 62% and 59% of patients, and 21% had no VC. Patients with AIC were significantly older than those without AIC (p < 0.001). CRP levels (p < 0.001) were higher in patients with AMC. Using multivariate logistic analysis of regression, older age (> 50 years) and higher CRP levels (> 5 mg/l) were associated with AIC and AMC, respectively (p = 0.007 and p = 0.003). Logistic regression analysis showed that patients with CRP > 5 mg/l had a greater relative risk of having AMC (odds ratio 30, 95% confidence interval 27.041 - 32.959; p = 0.003). CONCLUSIONS: Ultrasonography can be used to detect AIC and AMC, and could be useful for the early detection of VC. In nondiabetic patients who had been on hemodialysis for at least 5 years, older age was associated with AIC, and elevated CRP levels with AMC. PMID- 22105445 TI - Vascular access thrombosis and interventions in patients missing hemodialysis sessions. AB - BACKGROUND: Vascular access (VA) failure is a major complication in patients with end-stage renal disease (ESRD) receiving hemodialysis (HD). Thrombosis is the most common cause of VA dysfunction, but the risk factors for VA thrombosis are not well established. While the practice of missing HD sessions (HDs) is associated with increased morbidity and mortality, its impact on VA outcomes is unknown. We evaluated the impact of missing HDs on thrombosis and intervention rates in arteriovenous (AV) accesses. METHODS: Retrospective review of prevalent HD patients using AV access was done in 2 outpatient HD centers at The Ohio State University over a one-year period. RESULTS: A total of 142 patients underwent a total of 15,692 HDs, missing 1,602 HDs. Of the 78 patients who met the inclusion criteria, 50 patients missed at least 1 HD. Those with AVF demonstrated no significant association between missing HDs and VA thrombosis. Also, the incidence rate (IR) of intervention was not significantly different for those missing and not missing HDs. However, in the AVG group, those missing HDs were more likely to experience VA thrombosis (OR 9.48, p ~ 0.041) and had a higher IR of intervention. CONCLUSION: The practice of missing HDs was prevalent. Those missing dialysis sessions with AVG were more likely to experience VA thrombosis and needed more interventions to maintain VA patency. Our study reveals a differential impact of missing HDs on thrombosis in AVG and AVF, depicting a need to explore mechanistic explanations that may eventually help develop specific preventive strategies. PMID- 22105446 TI - Comparative clinical manifestations of IgG4- related and IgG4-negative primary tubulointerstitial nephritis. AB - AIMS: To evaluate the prevalence of IgG4-related tubulointerstitial nephritis (TIN) and compare the clinical manifestations of IgG4-related and IgG4-negative primary TIN. METHODS: Of 5,174 renal biopsies obtained between January 1996 and February 2010, 46 were positive for primary TIN without other kidney disease. Biopsy tissues were lost for 2 patients. The remaining 44 samples were assayed by immunoperoxidase staining with monoclonal mouse antibody to human IgG4. RESULTS: Of the 44 patients with primary TIN, 12 (27%) were identified as IgG4+ plasma cells/HPF >= 10 and 32 (73%) as < 10. Estimated glomerular filtration rate (eGFR) was lower and proteinuria was higher in patients with IgG4+ plasma cells/ HPF >= 10 (p < 0.05). No other parameter such as age; gender distribution; incidence of hypertension, diabetes mellitus, drug history, pyuria; concentrations of hemoglobin and alkaline phosphatase; or kidney size differed significantly. Of the 44 patients with primary TIN, 25 (57%) were identified as IgG4-positive (IgG4+ plasma cells/HPF >= 1) and 19 (43%) as IgG4-negative. The two groups did not differ in age; gender distribution; incidence of hypertension, diabetes mellitus, drug history, pyuria, or proteinuria; concentrations of hemoglobin and alkaline phosphatase; eGFR; or kidney size. The improvement rate, however, was significantly higher in IgG4-positive than in IgG4-negative patients (p = 0.045). Of the 25 IgG4- positive and 19 IgG4-negative patients, 18 and 13, respectively, were treated, and 18 and 7, respectively, improved (p = 0.002). The median number of IgG4-positive plasma cells/HPF in the former group was 8 (range 1 - 90). The number of IgG4-positive plasma cells was significantly associated with the degree of proteinuria (r = 0.471, p = 0.018) and age (r = 0.529, p = 0.007). CONCLUSION: Routine IgG4 staining is necessary in patients with primary TIN. Early treatment is also important in patients with IgG4-related primary TIN. PMID- 22105447 TI - Reduced pre-pregnancy proteinuria is associated with improving postnatal maternal renal outcomes in IgA nephropathy women. AB - AIMS: In patients with immunoglobulin A (IgA) nephropathy, postnatal renal outcomes vary depending on kidney function and proteinuria. However, whether a decrease in proteinuria prior to conception improves postnatal maternal renal outcomes is unknown. METHODS: This was a single-center retrospective study. A total of 52 pregnant women with biopsy-proven IgA nephropathy were enrolled in the study between January 2004 and December 2009. We collected data on proteinuria, which had been measured 1 year prior to conception, at conception, during pregnancy, and postnatally. The study outcomes included changes in estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: The median serum creatinine, eGFR, and proteinuria levels at conception were 0.8 (0.5 - 2.6) mg/dl, 91.2 (24.1 - 157.0) ml/min, 0.7 (0.0 - 3.5) g/g, respectively. Compared with values measured at conception, serum creatinine (0.8 - 1.0 mg/dl, p < 0.01) and proteinuria (0.7 - 1.5 g/g, p < 0.01) increased significantly postnatally, while eGFR decreased (91.2 - 77.8 ml/min, p < 0.01). In a multiple linear regression analysis, proteinuria at conception were independently associated with a faster decline in postnatal maternal eGFR (beta = 4.50, p < 0.05). In addition, a less decline in maternal eGFR was observed in patients with a reduction in proteinuria (> 30%) prior to pregnancy, compared with those with a less reduction (<= 30%). As for newborn outcomes, preterm delivery, caesarean section, low birth weight < 2,500 g, and need for neonatal intensive care were 15.4%, 46.2%, 25.0% and 7.7%, respectively. CONCLUSIONS: This study showed that in women with IgA nephropathy, proteinuria was significantly associated with the deterioration of postnatal maternal renal outcomes. Our study also suggests that a strategy for reducing proteinuria prior to pregnancy is required to preserve kidney function after delivery. PMID- 22105448 TI - Psychosocial characteristics and self-reported functional status in patients on maintenance dialysis in Hungary. AB - AIMS: This survey was conducted to assess psychosocial problems and functional status among patients on maintenance dialysis in Hungary. METHODS: All adult patients (n = 4,321) receiving maintenance dialysis in the 56 dialysis centers in Hungary in 2006 were approached to participate in a national, cross-sectional survey. Patients completed a brief self-reported questionnaire. Socio-demographic parameters, disease-related information and data about functional status were collected. Self-rated health and depressive symptoms were also assessed. RESULTS: Mean age was 62 +/- 14 y; 52% were males. The prevalence of diabetes was 30%. 46% of participants reported having depressive symptoms. Significant functional limitation was frequent. In multivariable regression models, female gender, poor self-reported finances, less education, history of acute myocardial infarction (AMI) or cerebrovascular disease, the presence of visual or hearing impairment and difficulties with basic activities of daily living were independently associated with the presence of depressive symptoms. In a separate model, age, dialysis vintage, history of AMI or cerebrovascular disease, the presence of visual or hearing impairments, difficulties with basic activities of daily living and also having depressive symptoms were independently associated with self-rated health score. CONCLUSIONS: Chronic dialysis patients in Hungary have disadvantaged socioeconomic status, frequent depressive symptoms and many functional limitations. Professional psychosocial help would be particularly important for this underprivileged patient population in addition to high quality dialysis to optimize outcomes. PMID- 22105449 TI - Safety and predictors of complications of renal biopsy in the outpatient setting. AB - AIM: It has been recommended that patients should be admitted for 24 h of observation after percutaneous renal biopsy. This may be performed in the ambulatory outpatient setting, though its safety in this setting is an area of debate. We aim to demonstrate the safety of biopsy in the ambulatory outpatient setting. METHODS: We performed a retrospective cohort study of 475 biopsies performed in the ambulatory outpatient setting to examine safety and risk factors for complications. Transplant and native kidney biopsies performed at the Canberra Hospital, a tertiary referral university hospital, from 2006 until 2010 were included. Patients were observed for 6 h before discharge. Study outcomes were minor complications, defined as pain, hemorrhage or postural hypotension; or major complications, defined as complications requiring therapeutic intervention including blood product transfusion. RESULTS: The overall complication rate was 8.2%. There were 33 minor complications (6.9%) and 6 major complications (1.3%). All complications occurring outside the period of observation were safely managed. Significant predictors of any complication was hemoglobin (OR 1.03, 95% CI 1.01 - 1.06), kidney size (OR 0.93, 95% CI 0.89 - 0.98), and proceduralist. CONCLUSIONS: Percutaneous renal biopsy is safe in the ambulatory outpatient setting. Establishing ongoing quality assurance programs may be helpful in early identification of operator-dependent factors. PMID- 22105450 TI - Periodic limb movements in sleep revealed by treatment of sleep apnea with continuous positive airway pressure in the advanced chronic kidney disease population. AB - The chronic kidney disease (CKD) population has a high incidence of sleep disorders, including sleep apnea (SA) and periodic limb movements in sleep (PLMS). SA and PLMS often occur concurrently and may predict mortality in the end stage renal disease (ESRD) population. In this study, we investigated whether sleep fragmentation secondary to SA masks the underlying frequency or severity of PLMS in 16 patients with CKD, dialysis and not-on-dialysis patients (CKD-ND), and if successful treatment of SA with continuous positive airway pressure (CPAP) results in the increased appearance of PLMS. All subjects had polysomnography (PSG) diagnosed SA. The mean apnea-hypopnea index (AHI) at baseline and with CPAP treatment was 49.8 +/- 25.6/h and 5.2 +/- 9.1/h, respectively. With successful treatment of SA with CPAP, PLMS index (PLMSI) increased 237.7% from baseline of 13.8 +/- 23.8/h to 32.8 +/- 33.7/h with CPAP treatment (p = 0.019). Arousing PLMS index (APLMSI) also increased 191.5% from mean baseline of 8.2 +/- 18.2/h to 15.7 +/- 18.5/h with CPAP treatment (p = 0.026). PLMS occur during uninterrupted NREM sleep. SA may mask the underlying incidence and severity of PLMS in CKD patients by disrupting NREM sleep. PLMS more than doubled during successful treatment of SA. Therefore, despite successful treatment of SA with CPAP, sleep deprivation may persist due to clinical manifestation of underlying PLMS in patients with CKD. The actual underlying prevalence and severity of CKD-associated PLMS are likely higher than appreciated and are suppressed by SA in the CKD population. PMID- 22105451 TI - Short-term, high-dose statins in the prevention of contrast-induced nephropathy: a systematic review and meta-analysis. AB - BACKGROUND: There have been conflicting reports on the use of statins for prevention of contrast-induced nephropathy (CIN). The aim of this study was to assess the effectiveness of short-term (2 - 7 days), high-dose (80 mg/d) statins in the prevention of CIN. STUDY DESIGN, SETTING AND PARTICIPANTS: Randomized controlled trials assessing the preventive effect of short-term, highdose statins on CIN (published from 1966 to 2010) were searched. QUALITY IMPROVEMENT PLAN: Quality of the trials was evaluated with the assessing risk of bias in studies included in the Cochrane reviews. OUTCOMES: CIN is the primary endpoint of the study. MEASUREMENTS: Meta-regression and a fixed-effects model were used for analyses. RESULTS: Five trials with a total of 1,009 patients were identified, with the overall effect of statins showing benefit for preventing CIN (relative risk (RR) = 0.53, 0.32 - 0.87). Meta-regression showed the existence of minor heterogeneity (I2 = 19%) could be largely accounted for by baseline serum creatinine. Two studies conducted in patients with CKD Stage >= 3 did not reveal a statistically significant difference in CIN incidence between the statin and placebo groups (6.5% vs. 7.2%) (RR = 0.89, 0.46 - 1.73), without evidence of heterogeneity (I2 = 0%, p = 0.79). The remaining three studies conducted in patients with CKD Stage > 3 revealed a significantly lower CIN incidence in the statin groups (3.6% vs. 11.9%) (RR = 0.28, 0.13 - 0.62), without evidence of heterogeneity (I2 = 0%, p = 0.87). CONCLUSIONS: The overall effect of shortterm, high-dose statin treatment seems to be helpful for prevention of CIN. However, the subgroup analysis shows statin benefit only in patients with CKD Stage > 3, but not in patients with CKD Stage <= 3. LIMITATIONS: The relative low quality of the individual studies and limited studies means that only a limited conclusion on the use of statin for prevention of CIN was possible. PMID- 22105452 TI - FDG PET/CT and MRI findings in a patient with focal xanthogranulomatous pyelonephritis mimicking cystic renal malignancy. AB - Focal xanthogranulomatous pyelonephritis (XGP) is a chronic inflammatory condition that can mimic other disease conditions such as pyelonephritis, tuberculosis, renal abscess, renal cell carcinoma, and renal metastasis. Urinary tract infection and obstruction are considered to be predisposing factors. The clinical symptoms and imaging findings are often nonspecific so that an incorrect initial diagnosis is common. Here, we report a case of a patient with focal XGP with FDG PET/CT findings that mimic renal malignancy. PMID- 22105453 TI - Membranous nephropathy and granulomatous interstitial nephritis due to tuberculosis. AB - Tuberculous involvement of the genitourinary tract is well reported in the literature. However, reports of glomerular lesions of the kidney due to tuberculosis are rare. Tuberculosis has been identified as the most common infectious cause of granulomatous interstitial nephritis (GIN). We report a 23 year-old female patient with a membranous nephropathy and GIN due to tuberculosis. She presented with renal failure and nephrotic-range proteinuria, both of which resolved with the treatment of tuberculosis. There is only one report, from Japan, of a patient with membranous nephropathy and tuberculous granulomatous nephritis. Our patient is the second with tuberculous GIN and membranous nephropathy. In our patient, the close temporal relationship between the infection and glomerulonephritis, an ulcerated tuberculin skin test, the response to the treatment and the absence of any other systemic disease that might cause the glomerulonephritis suggested an association between tuberculosis and membranous nephropathy. However, a causal association can only be speculation, because membranous nephropathy could remit spontaneously. It is also possible that it might relapse at a later date when the tuberculosis is inactive. Therefore, the association might be either coincidental or causal, and could become clearer as similar patients are reported. PMID- 22105454 TI - A case of familial lecithin-cholesterol acyltransferase deficiency on hemodialysis for over 20 years. AB - We trace the 34-year history of a member of the first Japanese family in which lecithin-cholesterol acyltransferase (LCAT) deficiency was diagnosed. Marriage between cousins with low LCAT activity was responsible for familial LCAT deficiency (FLD). In 1976, a 27-year-old Japanese man was noted to have FLD based on proteinuria, hematuria, grayish corneal opacity and low LCAT activity (9.83%). Genetic analysis showed insertion of G-G-C coding glycine at codon 141. Total cholesterol (C) was low at 108 mg/dl and the ratio of C-ester to total C was very low (12%), while the lecithin (phosphatidylcholine) level was very high (97.3%). When his serum creatinine reached 2.6 mg/dl at the age of 41 years (in 1991), renal biopsy was performed. This showed expansion of the mesangial matrix and irregularly thickened capillary walls with a bubble-like appearance because of lipid deposits consisting of two components (partly lucent vacuolated areas and partly deeply osmiophilic areas). Magnification of the latter deposits showed curvilinear and serpiginous striated membranous structure. Hemodialysis was started in 1990 and has been continued for over 20 years until August 2010. Clinical problems have included AV shunt failure requiring 4 operations and 13 percutaneous transcatheter angioplasty procedures, as well as episodes of hemolytic anemia that subsided after infusion of fresh frozen plasma. Cardiovascular events have not yet occurred, although severe calcification of abdominal aorta has been detected by computed tomography. PMID- 22105455 TI - Calciphylaxis in a patient with acute kidney injury and alcoholic cirrhosis. AB - Calciphylaxis is a rare disorder characterized by painful skin necrosis and calcification of small vessels which is seen mainly in the dialysis population. We describe a case of a patient with alcoholic cirrhosis developing calciphylaxis during an episode of acute kidney injury. We also review the literature in prior cases and postulate that unrecognized renal dysfunction in cirrhotic patients may have played a role in the development of this uncommon disorder. Our patient had complete recovery of the lesions with conservative treatment which coincided with recovery of her renal function. This case serves to highlight how small changes in creatinine levels in patients with cirrhosis may represent larger and clinically relevant changes in actual renal function that predispose these patients to calciphylaxis. PMID- 22105456 TI - Transition of severe diffuse mesangial hypercellularity to minimal change disease in a child with steroid-resistant nephrotic syndrome. PMID- 22105457 TI - 25 years or more after spinal cord injury: clinical conditions of individuals in the Florence and Stockholm areas. AB - SETTING: Retrospective analysis and retrospective follow-up. INTRODUCTION: Spinal cord injury (SCI) patients have today a nearly normal lifespan. Avoidance of medical complications is key to this end. The aim of the study was to analyse health in individuals surviving 25 years or more after traumatic SCI in Stockholm and Florence, and compare medical complications. METHODS: Data from the databases of the Spinal Unit of Florence and from the Spinalis, Stockholm were analysed. Patients included were C2-L 2, American Spinal Cord Association (ASIA) Impairment Scale (AIS) A-C, and >=25 years post traumatic SCI. Patients underwent a thorough neurological and general examination, and were interviewed about medical events during those years. Analysed data include: gender, age at injury, current age, neurological level, AIS, cause of injury, presence of neuropathic pain (NP), and spasticity and medical complications. RESULTS: A total of 66 Italian patients and 74 Swedish patients were included. The only statistical difference between the groups was cause of injury due to falls was higher in the Florence group (P<0.01). Male/female ratio was 4:1. Traffic accidents were the most common cause of injury. In all, 60% were paraplegics. Pressure ulcers (PU) occurred in nearly 60% and 32% experienced NP. Respiratory complications (RC) occurred in 25% among tetraplegics. Neurological deterioration occurred in 14%. CONCLUSION: PU, bony fractures, spasticity and NP are important problems after SCI. RC are of clinical importance in the tetraplegics. Complications occur during all periods after injury. Many patients are otherwise healthy 25 years or more after SCI. PMID- 22105458 TI - The protective effects of the lentivirus-mediated neuroglobin gene transfer on spinal cord injury in rabbits. AB - STUDY DESIGN: We introduced a lentiviral vector containing the neuroglobin (Ngb) gene into the injured spinal cords to evaluate the therapeutic potential of Ngb in a rabbit model of spinal cord injury (SCI). OBJECTIVES: It is not clear whether Ngb has the neuroprotective role to SCI. The purpose of this study was to investigate the possible protective effects of the Ngb overexpression on traumatic SCI in rabbits. SETTING: Department of Orthopedic Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China. METHODS: A lentiviral vector containing Ngb gene was constructed and injected at the SCI sites 24 h after SCI. The rabbits' motor functions were evaluated by the Basso-Beattie-Bresnahan rating scale. Quantitative real-time PCRs, western blots, malondialdehyde (MDA) tests and terminal deoxynucleotidyl transferase-mediated UTP end labeling assays were also performed. RESULTS: The Ngb expression in the LV-Ngb group increased significantly at days 7, 14 and 21. A more significant functional improvement was observed in the LV-Ngb group compared with the improvements in all other groups at days 14 and 21. The traumatic SCI seemed to lead to an increase in the levels of MDA and in the number of the apoptotic cells, which could be prevented by the LV-Ngb treatment. CONCLUSION: This study demonstrated that the Ngb overexpression may have potential therapeutic benefits for both reducing secondary damages and improving the outcomes after traumatic SCI. PMID- 22105459 TI - Appraisals, coping and adjustment pre and post SCI rehabilitation: a 2-year follow-up study. AB - STUDY DESIGN: Longitudinal, multi-wave panel design. OBJECTIVES: To explore the changes in and the relationships between appraisals and coping with mood, functioning and quality-of-life (QOL) pre- and post-rehabilitation for acute spinal cord injury (SCI). SETTING: The data collected was part of an ongoing study from specialist units in selected British, Swiss, German and Irish SCI centres. METHODS: Questionnaires (Functional Independence, QOL, Mood, Appraisals, Coping and Support) were administered to 232 patients at 12 weeks post injury and sent to participants at 1 and 2 years post injury by post. RESULTS: Significant changes were observed in various outcome measures between 12 weeks and 1 year post injury, with little significant change occurring during the following year. Appraisals and coping at 12 weeks post injury were significantly related to outcome scores and also contributed significantly to the variance in QOL, mood and stress-related growth at 2 years post injury. CONCLUSION: The study provides further evidence for the link between appraisals, coping and subsequent adjustment to injury. Suggestion is made for the potential benefit of early assessment and intervention for patients at risk of poor adjustment to SCI. PMID- 22105460 TI - Management of bowel dysfunction in the community after spinal cord injury: a postal survey in the Republic of Korea. AB - STUDY DESIGN: A cross-sectional postal survey. OBJECTIVES: To describe defecation stimulation methods and their outcomes, and to investigate the impact of bowel dysfunction on the quality of life (QoL) in community-dwelling persons with spinal cord injury in South Korea. SETTING: Community-based, Korea. METHODS: A cross-sectional postal survey was conducted. Questionnaires were sent to 459 chronic spinal cord injury (SCI) patients who were registered as members of the Korean Spinal Cord Injury Association. Defecation stimulation methods and their outcomes, the impact of bowel dysfunction on the QoL were investigated. RESULTS: A total of 388 subjects (44.5+/-10.8 year of age; men, 76.0%; duration of time since the onset of SCI, 14.2+/-9.5 years) responded. Bowel-related general, social and home QoL deterioration was found in >60%. Suppositories (Supp) were most frequently used, followed by digital rectal stimulation (DRS). The mini enema (ME), which is exclusively used in Korea, was utilized in 18.8%. A defecation time of 30 min was more frequently reported in patients who stimulated defecation with Supp than in those who used DRS. CONCLUSIONS: The use of MEs and warm-water irrigations were newly identified in Korea. Bowel care-related factors that greatly deteriorate the QoL were fecal incontinence, time in one defecation >60 min, perianal skin problem, flatus incontinence and hemorrhoids. Alleviating these factors might help to improve the QoL. In particular, stimulation methods to reduce time for defecation might be recommended to persons with chronic SCI. PMID- 22105461 TI - Long-term effect of MRI on sacral anterior root stimulator: the Stoke Mandeville experience. AB - STUDY DESIGN: Retrospective review study. OBJECTIVES: To identify whether it is safe to perform a magnetic resonance imaging (MRI) exam on patients who have a sacral anterior root stimulator (SARS). SETTING: Adult patients with spinal cord injury and implanted SARS attending the National Spinal Injuries Centre who have had MRI scans. METHODS: Retrospective review between 1989 and 2010. The effect of the MRI scans on the function of the SARS (Finetech-Brindley, UK) was assessed up to 6 months following MRI at 0.2 and 1.5 T. RESULTS: A total of 18 patients with SARS implants had MRI scans at 0.2 and 1.5 T of the cervical, thoracic and lumbar spine, head, shoulder and pelvis. MRI examinations were abandoned on two occasions in one patient due to radiofrequency interference. One patient's stimulator ceased to function 5 months following MRI; both of these patients showing complications had their MRI examinations at 0.2 T. There were no adverse effects at 1.5 T. In one patient the SARS was removed within 6 months after MRI due to an unrelated medical condition. A total of 17 patients showed no symptoms that required terminating the examination. In all the 11 patients with a complete and functioning implant before MRI at 1.5 T, the SARS was functioning appropriately, and no change in bladder function was reported up to 6 months following MRI. CONCLUSION: It is safe to perform an MRI scan on patients with SARS providing the examination is conducted in a 1.5 T system. PMID- 22105462 TI - Central nervous system regeneration does not occur. AB - STUDY DESIGN: Review. OBJECTIVES: To examine the state of research in central nervous system (CNS) regeneration and to suggest an alternative to the sterile research at the lesion site. SETTING: Worldwide. METHODS: A search of publications using 'PubMed' and a search of the historical literature relevant to CNS regeneration, biological models, the neurone theory, collateral sprouting, spinal shock and the central pattern generator. RESULTS: There is no evidence for CNS regeneration. CONCLUSION: A century of research focussed on the lesion site has been unproductive. An alternative field of research must be developed and the best candidate is the undamaged CNS. PMID- 22105463 TI - Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial. AB - STUDY DESIGN: Lithium has attracted much attention as a neuroregenerative agent for spinal cord injury in animal models. We hypothesized that the lithium can be beneficial to patients with spinal cord injury. The safety and pharmacokinetics of lithium has been studied in our earlier phase I clinical trial, indicating its safety. This is a phase II clinical trial to evaluate its efficacy on chronic spinal cord injury patients. OBJECTIVES: The aim of this study was to investigate the efficacy of lithium on chronic spinal cord injury patients. SETTING: A major spinal cord injury rehabilitation center in Beijing, China. METHODS: Randomized, double-blind, placebo-controlled 6-week parallel treatment arms with lithium carbonate and with placebo. A total of 40 chronic spinal cord injury subjects were recruited. Oral lithium carbonate was titrated or placebo was simulated to maintain the serum lithium level of 0.6-1.2 mmol l(-1) for 6 weeks, followed by a 6-month follow-up. The functional outcomes and the neurological classifications, as well as the safety parameters, adverse events and pharmacokinetic data were carefully collected and monitored. RESULTS: No significant changes in the functional outcomes and the neurological classifications were found. The only significant differences were in the pain assessments using visual analog scale comparing the lithium and the placebo group. No severe adverse event was documented in the study. CONCLUSION: The lithium treatment did not change the neurological outcomes of patients with chronic spinal cord injury. It is worth to investigate whether lithium is effective in the treatment of neuropathic pain in chronic spinal cord injury. SPONSORSHIP: China Spinal Cord Injury Network Company Limited. PMID- 22105464 TI - Immunohistological labeling of microtubules in sensory neuron dendrites, tracheae, and muscles in the Drosophila larva body wall. AB - To understand how differences in complex cell shapes are achieved, it is important to accurately follow microtubule organization. The Drosophila larval body wall contains several cell types that are models to study cell and tissue morphogenesis. For example tracheae are used to examine tube morphogenesis(1), and the dendritic arborization (DA) sensory neurons of the Drosophila larva have become a primary system for the elucidation of general and neuron-class-specific mechanisms of dendritic differentiation(2-5) and degeneration(6). The shape of dendrite branches can vary significantly between neuron classes, and even among different branches of a single neuron(7,8). Genetic studies in DA neurons suggest that differential cytoskeletal organization can underlie morphological differences in dendritic branch shape(4,9-11). We provide a robust immunological labeling method to assay in vivo microtubule organization in DA sensory neuron dendrite arbor (Figures 1, 2, Movie 1). This protocol illustrates the dissection and immunostaining of first instar larva, a stage when active sensory neuron dendrite outgrowth and branching organization is occurring (12,13). In addition to staining sensory neurons, this method achieves robust labeling of microtubule organization in muscles (Movies 2, 3), trachea (Figure 3, Movie 3), and other body wall tissues. It is valuable for investigators wishing to analyze microtubule organization in situ in the body wall when investigating mechanisms that control tissue and cell shape. PMID- 22105465 TI - Interferon free hepatitis C treatment regimens: the beginning of another era. AB - Hepatitis C is a virus affecting millions worldwide and is a major health risk. With the potentially severe adverse event profile of the current backbone of therapy, interferon, there is an impetus to discover interferon free treatment regimens. With the development of new oral direct acting antivirals, interferon free regimens may be available in the next few years. This article discusses some of the preliminary data from interferon free studies. PMID- 22105466 TI - Is there any value to hepatitis B virus genotype analysis? AB - Hepatitis B may cause a varying spectrum of diseases ranging from an asymptomatic or mild anicteric acute illness, to severe or fulminant hepatitis. Similarly, the outcome of chronic hepatitis B is variable. Viral factors associated with outcome of chronic hepatitis B virus (HBV) infection include hepatitis B e antigen status, HBV DNA, genotype, and HBV variants. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. A total of ten hepatitis B virus genotypes have been defined with a distinct geographical distribution. Hitherto, genotypes A, B, C and D have been studied most extensively. The HBV genotype appears to influence not only the natural history of HBV related liver disease but also the response to HBV treatment. HBV genotypes are also linked with both core promoter and BCP mutations. Progression to chronic infection appears to occur more frequently following acute infection with genotypes A and D than with the other studied genotypes. Genotypes A and B appear to have higher rates of spontaneous HBeAg seroconversion. More advanced liver disease and progression to HCC is more often seen in chronic infection with genotypes C and D in contrast to genotypes A and B. More specifically, genotypes A1, C, B2-B5 and H appear to be associated with more serious complications than genotypes A2, B1 and B6. These observations suggest important pathogenic differences between HBV genotypes. Genotypes A and B have higher response rates to interferon based therapy than genotypes C and D. Knowledge of HBV genotype enables clinicians to identify those patients at increased risk of disease progression whilst aiding the selection of appropriate antiviral therapy. Genotyping and monoclonal subtyping can provide useful information for epidemiological studies. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy. PMID- 22105467 TI - IFN-gamma elevates airway hyper-responsiveness via up-regulation of neurokinin A/neurokinin-2 receptor signaling in a severe asthma model. AB - The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-gamma. The administration of IFN gamma instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1( /-) mice after stimulation with IFN-gamma. In addition, methacholine-mediated Ca(2+) influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-gamma-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-gamma directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma. PMID- 22105468 TI - Potential role of prolactin in antipsychotic-mediated association of schizophrenia and type 2 diabetes. AB - It remains unclear why atypical antipsychotics confer a risk for hyperglycemia compared to typical antipsychotics. Atypical antipsychotics antagonize dopamine receptors-2 (D(2)) and serotonin (5-HT) receptors-2, while typical antipsychotics antagonize only D(2) receptors. We aimed at elucidating the mechanistic differences between the role of typical and atypical antipsychotics on prolactin levels and glucose regulation. A Medline search was conducted during 2010 using the search terms type 2 diabetes (T2D), typical/atypical antipsychotics, schizophrenia, prolactin, and serotonin. We discuss the effect of typical and atypical antipsychotics on prolactin levels and glucose regulation. Given that prolactin is under negative control by dopamine and positive control by serotonin, typical antipsychotics induce elevations in prolactin, while atypical antipsychotics do not. Research studies show protective effects of prolactin on T2D. We hypothesize that the difference in induction of T2D between typical and atypical antipsychotics is due to the antipsychotic receptor binding mediated effect in changes in prolactin levels. PMID- 22105469 TI - Assessing the effects of historical exposure to endocrine-active compounds on reproductive health and genetic diversity in walleye, a native apex predator, in a large riverine system. AB - In this combined field and laboratory study, we assessed whether populations of native walleye in the Upper Mississippi River experienced altered genetic diversity correlated with exposure to estrogenic endocrine-active compounds (EACs). We collected fin-clips for genetic analysis from almost 600 walleye (13 sites) and subsampled 377 of these fish (6 sites) for blood and reproductive organs. Finally, we caged male fathead minnows at 5 sampling sites to confirm the presence of estrogenic EACs. Our findings indicate that male walleye in four river segments produced measurable concentrations of plasma vitellogenin (an egg yolk protein and, when expressed in male fish, a biomarker of acute estrogenic exposure), a finding consistent with the presence of estrogenic EACs and consistent with published historical data for at least three of these study sites (Grand Rapids, St. Paul, and Lake City on Lake Pepin). Patterns of vitellogenin induction were consistent for native walleye and caged fathead minnows. No widespread occurrence of histopathological changes, such as intersex was found compared with published reports of intersex at the furthest downstream study site. To assess possible effects of estrogenic exposure on the genetic diversity of walleye populations at the study sites, we DNA-fingerprinted individual fish using 10 microsatellite loci. Genetic differences were observed between populations; however, these differences were consistent with geographic distance between populations, with the largest observed difference in genetic diversity found between fish upstream and downstream of St. Anthony Falls (and/or Lock and Dam 1 of the Mississippi River), traditionally a historical barrier to upstream fish movement. Although the persistent occurrence of endocrine disruption in wild fish populations is troubling, we did not detect degradation of reproductive organs in individual walleye or alteration in genetic diversity of walleye populations. PMID- 22105470 TI - Repeatability and reproducibility of ultrasonographic measurement of carotid intima thickness. AB - PURPOSE: To evaluate the repeatability and reproducibility of intima thickness (IT) measurements at different sites along the common carotid artery and compare with intima-media thickness (IMT) measurements. METHODS: Ultrasound examinations of common carotid artery were performed in 30 healthy subjects and 20 patients with diabetes mellitus. Carotid IT and IMT were measured at 10 mm, 13 mm, and 16 mm upstream from the carotid bulb. Each subject was scanned by three operators to evaluate inter-operator reproducibility. Each operator scanned the subjects twice to evaluate intra-operator repeatability. Inter-equipment reproducibility of the measurements was evaluated. RESULTS: The inter-operator reproducibility for measuring carotid IT at the three sites was 81.5%, 81.9% and 69.1%, respectively, slightly lower than carotid IMT measurement (89.7%, 86.5%, 75.2%, respectively). The intra-operator repeatability for carotid IT measurement at the three sites ranged 76.9-89.5%, 67.4-90.3%, and 55.2-70.5%, respectively, and was lower than for IMT measurement (86.5-96.9%, 87.6-95.7%, 79.9-86.5%, respectively). The inter equipment reproducibility of IMT (75.7-86.6%) was slightly better than for IT measurement (71.4-75.9%). CONCLUSIONS: Ultrasonographic measurement of carotid IT is repeatable and reproducible, although not as good as IMT. Measurements preformed 10 mm to 13 mm upstream from the carotid bulb yield more repeatable and reproducible results. PMID- 22105471 TI - Methods for reducing aggression. PMID- 22105472 TI - Soluplus--solubilized citrated camptothecin--a potential drug delivery strategy in colon cancer. AB - Camptothecin (CPT), a potent antitumor drug, exhibits poor aqueous solubility and rapid conversion from the pharmacologically active lactone form to inactive carboxylate form at physiological pH. Solid dispersion of CPT in Soluplus(r), an amphiphilic polymeric solubilizer, was prepared to increase the aqueous solubility of CPT and the resultant solid dispersion along with citric acid was formulated as hard gelatin capsules that were subsequently coated with Eudragit S100 polymer for colonic delivery. FTIR spectrum of the solid dispersion confirmed the presence of CPT. PXRD and DSC revealed the semicrystalline nature of solid dispersion. The solubility of the drug was found to increase ~40 times in the presence of Soluplus and ~75 times in solid dispersion. The capsules showed no drug release in 0.01 N HCl but released 86.4% drug in lactone form in phosphate buffer (pH 7.4) and the result appears to be due to citric acid-induced lowering of pH of buffer from 7.4 to 6.0. Thus the presence of citric acid in the formulation led to stabilization of the drug in its pharmacologically active lactone form. Cytotoxicity studies conducted with the formulation of solid dispersion with citric acid, utilizing cell cytotoxicity test (MTT test) on Caco 2 cells, confirmed cytotoxic nature of the formulation. PMID- 22105473 TI - Neuroendocrine neoplasms. PMID- 22105474 TI - Neuroendocrine neoplasms of the gastroenteropancreatic system: pathology and classification. AB - Neuroendocrine neoplasms (NEN) appear homogeneous in terms of morphology, but constitute a very heterogeneous group of tumors in terms of biological and clinical features. NEN may occur in any organ, but are most commonly observed in the lung and the gastroenteropancreatic system (GEP). The European Neuroendocrine Tumor Society (ENETS) developed guidelines in the last 5 years to standardize and improve the diagnosis and therapy of GEP-NEN. Taking these guidelines into account, the TNM classification of the Union for International Cancer Control (UICC) was introduced in 2009. The new GEP-NEN classification of the World Health Organization (WHO) was presented 1 year later. According to the guidelines of the ENETS, the UICC, and the WHO, the pathology classification of NEN of GEP consists of several basic components: (1) evidence of the neuroendocrine nature of the tumor, (2) histological distinction between well and poorly differentiated tumors, (3) proliferation-based grading. (4) TNM staging (including data about vascular invasion and resection margins), (5) with reference to the clinical question: evidence of hormones and biogenic amines, and (6) optional, especially in cases of initial diagnosis of NEN: expression of the somatostatin receptor type 2A. Based on these criteria, a standardized prognostic stratification of GEP NEN can be performed in combination with other clinical parameters. The novel classifications constitute the basis for selecting the procedures of molecular and metabolic imaging as well as for tumor-specific treatments and permit comparisons of larger tumor populations. Close interdisciplinary cooperation is a prerequisite. PMID- 22105475 TI - Novel therapeutic agents for the treatment of gastroenteropancreatic neuroendocrine tumors. AB - Neuroendocrine tumors (NET) are frequently diagnosed late and not amenable to curative surgery due to metastatic disease to the liver and lymph nodes. The disease is complex and heterogeneous given the various functionalities, distinct tumor growth patterns, and tumor spread upon diagnosis. Established therapies include somatostatin analogues, alpha-interferon, systemic chemotherapy, and loco regional therapies of the liver. The availability of novel agents and expression of targets, such as growth factor receptors, different subtypes of somatostatin receptors, and the mammalian target of rapamycin (mTOR) have led to the exploration of different classes of drugs and offer new treatment opportunities in neuroendocrine tumors. This review provides an overview on novel drugs, focus on the impact of recently approved drugs on the management of NET disease, and outline future perspectives. PMID- 22105476 TI - Global histone modification pattern predicts poor prognosis in organic hyperinsulinism. AB - Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (>=8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively. PMID- 22105477 TI - Loss of PTEN expression in neuroendocrine pancreatic tumors. AB - PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor. PMID- 22105478 TI - Coincidence of mature cystic teratoma and serotonin-producing neuroendocrine tumor of the ileum. AB - Mature cystic teratomas are often found in gonadal sites, but are very rarely located extragonadally, for example, in retroperitoneum, mediastinum, central nervous system, lung, or liver. In the literature, only 10 cases of cystic teratoma originating from the diaphragm have been reported. Here, we report for the first time a metachronous occurrence of a benign mature cystic teratoma in the left diaphragm together with a serotonin-producing neuroendocrine tumor of the ileum. The 51-year-old, female patient received a partial resection of the ileum due to a neuroendocrine tumor (pT3N1M0) 4 years ago. Furthermore, she was operated for a benign cystadenoma of the right ovary 3 years ago. In her past medical history, she had an appendectomy in her childhood and a subtotal thyroidectomy 10 years ago. To our knowledge, this is the first report describing the metachronous occurrence of benign mature cystic teratoma in the diaphragm and a highly differentiated neuroendocrine tumor of the ileum. The possible coincidence of both diseases is discussed. PMID- 22105479 TI - Spontaneous pneumomediastinum following exposure to metal paint spray: a first time report. PMID- 22105480 TI - Elimination of paternal mitochondria through the lysosomal degradation pathway in C. elegans. AB - In mammals, the inheritance of mitochondrion and its DNA (mtDNA) is strictly maternal, despite the fact that a sperm can inject up to 100 functional mitochondria into the oocyte during fertilization. The mechanisms responsible for the elimination of the paternal mitochondria remain largely unknown. We report here that this paternal mitochondrial elimination process is conserved in Caenorhabditis elegans, and that the lysosomal pathway actively participates in this process. Molecular and cell biological analyses indicate that in wild-type animals paternal mitochondria and mtDNA are destroyed within two hours after fertilization. In animals with compromised lysosomes, paternal mitochondria persist until late embryonic stages. Therefore, the lysosomal pathway plays an important role in degrading paternal mitochondria introduced into the oocyte during fertilization. Our study indicates that C. elegans is an excellent animal model for understanding and dissecting this conserved biological process critical for animal development and reproduction. PMID- 22105481 TI - Shh goes multidirectional in axon guidance. PMID- 22105482 TI - Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells. AB - The roles of the reprogramming factors Oct4, Sox2, c-Myc and Klf4 in early T cell development are incompletely defined. Here, we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors (ETPs) differentiate into T cells. Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2-to DN3 transition when T cell lineage commitment occurs and affected the transcription of a variety of genes with crucial functions in early T cell development, including genes involved in microenvironmental signaling (IL 7Ralpha), Notch target genes (Deltex1), and essential T cell lineage regulatory or inhibitory genes (Bcl11a, SpiB, and Id1). The survival of thymocytes and the rearrangement at the Tcrb locus were impaired in the presence of enforced Klf4 expression. The defects in the DN1-to-DN2 and DN2-to-DN3 transitions in Klf4 transgenic mice could not be rescued by the introduction of a TCR transgene, but was partially rescued by restoring the expression of IL-7Ralpha. Thus, our data indicate that the downregulation of Klf4 is a prerequisite for T cell lineage commitment. PMID- 22105483 TI - Induction of fibroblasts to neurons through adenoviral gene delivery. PMID- 22105484 TI - Efficient correction of hemoglobinopathy-causing mutations by homologous recombination in integration-free patient iPSCs. PMID- 22105485 TI - Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS). AB - Mitochondrial antiviral signaling (MAVS) is a key adaptor in cellular antiviral innate immunity. We previously identified poly(C)-binding protein 2 (PCBP2) as a feedback inhibitor of MAVS that facilitates its degradation after viral infection, but little is known about the regulatory potential of poly(C)-binding protein 1 (PCBP1), which highly resembles PCBP2. Here we report that PCBP1 mediates housekeeping degradation of MAVS using the same mechanism as PCBP2 employs. Overexpression of PCBP1 impairs MAVS-mediated antiviral responses, while knockdown of PCBP1 exerts the opposite effect. The suppression is due to PCBP1 induced MAVS degradation. We observe that PCBP1 and PCBP2 show synergy in MAVS inhibition, but their expression patterns are distinct: PCBP1 is stably and abundantly expressed, while PCBP2 shows low basal expression with rapid induction after infection. Individual knockdown and subcellular fractionation analyses reveal that unlike the postinfection inhibitor PCBP2, PCBP1 continuously eliminates cellular MAVS. Our findings unravel a critical role of PCBP1 in regulating MAVS for both fine-tuning the antiviral immunity and preventing inflammation. PMID- 22105486 TI - CTCF-cohesin complex: architect of chromatin structure regulates V(D)J rearrangement. PMID- 22105487 TI - Hierarchy and plasticity in the crypt: back to the drawing board. PMID- 22105488 TI - Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. AB - Transplantation of exogenous dopaminergic neuron (DA neurons) is a promising approach for treating Parkinson's disease (PD). However, a major stumbling block has been the lack of a reliable source of donor DA neurons. Here we show that a combination of five transcriptional factors Mash1, Ngn2, Sox2, Nurr1, and Pitx3 can directly and effectively reprogram human fibroblasts into DA neuron-like cells. The reprogrammed cells stained positive for various markers for DA neurons. They also showed characteristic DA uptake and production properties. Moreover, they exhibited DA neuron-specific electrophysiological profiles. Finally, they provided symptomatic relief in a rat PD model. Therefore, our directly reprogrammed DA neuron-like cells are a promising source of cell replacement therapy for PD. PMID- 22105489 TI - Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia. AB - B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110delta (PI3Kdelta), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors. PMID- 22105490 TI - TGF beta-1 administration during ex vivo expansion of human articular chondrocytes in a serum-free medium redirects the cell phenotype toward hypertrophy. AB - Cell-based cartilage resurfacing requires ex vivo expansion of autologous articular chondrocytes. Defined culture conditions minimize expansion-dependent phenotypic alterations but maintenance of the cells' differentiation potential must be carefully assessed. Transforming growth factor beta-1 (TGF beta-1) positively regulates the expression of several cartilage proteins, but its therapeutic application in damaged cartilage is controversial. Thus we evaluated the phenotypic outcomes of cultured human articular chondrocytes exposed to TGF beta-1 during monolayer expansion in a serum-free medium. After five doublings cells were transferred to micromass cultures to assess their chondrogenic differentiation, or replated in osteogenic medium. Immunocytostainings of micromasses of TGF-expanded cells showed loss of aggrecan and type II collagen. Positivity was evidenced for RAGE, IHH, type X collagen and for apoptotic cells, paralleling a reduction of BCL-2 levels, suggesting hypertrophic differentiation. TGF beta-1-exposed cells also evidenced increased mRNA levels for bone sialoprotein, osteopontin, matrix metalloproteinase-13, TIMP-3, VEGF and SMAD7, enhanced alkaline phosphatase activity and pyrophosphate availability. Conversely, SMAD3 mRNA and protein contents were reduced. After osteogenic induction, only TGF-expanded cells strongly mineralized and impaired p38 kinase activity, a contributor of chondrocytes' differentiation. To evaluate possible endochondral ossification progression, we seeded the chondrocytes on hydroxyapatite scaffolds, subsequently implanted in an in vivo ectopic setting, but cells failed to reach overt ossification; nonetheless, constructs seeded with TGF-exposed cells displayed blood vessels of the host vascular supply with enlarged diameters, suggestive of vascular remodeling, as in bone growth. Thus TGF-exposure during articular chondrocytes expansion induces a phenotype switch to hypertrophy, an undesirable effect for cells possibly intended for tissue engineered cartilage repair. PMID- 22105491 TI - CD40 engagement of CD4+ CD40+ T cells in a neo-self antigen disease model ablates CTLA-4 expression and indirectly impacts tolerance. AB - Biomarkers defining pathogenic effector T (Teff) cells slowly have been forthcoming and towards this we identified CD4(+) T cells that express CD40 (CD4(+) CD40(+) ) as pathogenic in the NOD type 1 diabetes (T1D) model. CD4(+) CD40(+) T cells rapidly and efficiently transfer T1D to NOD.scid recipients. To study the origin of CD4(+) CD40(+) T cells and disease pathogenesis, we employed a dual transgenic model expressing OVA(323-339) peptide as a neo-self antigen on islet beta cells and medullary thymic epithelial cells (mTECs) and a transgenic TCR recognizing the OVA(323-339) peptide. CD4(+) CD40(+) T cells and Treg cells each recognizing the cognate neo-antigen, rather than being deleted through central tolerance, drastically expanded in the thymus. In pancreatic lymph nodes of DO11.RIPmOVA mice, CD4(+) CD40(+) T cells and Treg cells are expanded in number compared with DO11 mice and importantly, Treg cells remain functional throughout the disease process. When exposed to neo-self antigen, CD4(+) CD40(+) T cells do not express the auto-regulatory CTLA-4 molecule while naive CD4(+) CD40(+) T cells do. DO11.RIPmOVA mice develop autoimmune-type diabetes. CD40 engagement has been shown to prevent CTLA-4 expression and injecting anti-CD40 in DO11.RIPmOVA mice significantly exacerbates disease. These data suggest a unique means by which CD4(+) CD40(+) T cells thwart tolerance. PMID- 22105492 TI - Assessment of risk factors for Korean children with Kawasaki disease. AB - Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) is the standard therapy for KD, but more than 10% of KD patients do not respond to IVIG and are at high risk for the development of coronary artery lesions (CALs). To identify clinical and genetic risk factors associated with CAL development and IVIG nonresponsiveness, this study analyzed the clinical data for 478 Korean KD patients. Multivariate logistic regression analysis showed that incomplete KD, IVIG nonresponse, fever duration of 7 days or longer, and the CC/AC genotypes of the rs7604693 single nucleotide polymorphism (SNP) in the PELI1 gene were significantly associated with the development of CALs, with odds ratios (ORs) ranging from 2.06 to 3.04. The risk of CAL formation was synergistically increased by the addition of individual risk factors, particularly the genetic variant in the PELI1 gene. Multivariate analysis also showed that a serum albumin level of 3.6 g/dl or lower was significantly associated with nonresponsiveness to IVIG [OR, 2.76; 95% confidence interval (CI), 1.34-5.68; P = 0.006]. Conclusively, incomplete KD, IVIG nonresponsiveness, long febrile days, and the rs7604693 genetic variant in the PELI1 gene are major risk factors for the development of CALs, whereas low serum albumin concentration is an independent risk factor for IVIG nonresponsiveness. PMID- 22105493 TI - Update on the Amplatzer duct occluder: a 10-year experience in Asia. AB - Few data exist regarding the efficacy and safety of the Amplatzer ductal occluder (ADO) type 1 device in the Asian region. This retrospective study, conducted between August 2001 and April 2011, attempted device placement for 231 patients (165 females and 66 males) with a median age of 7.4 years (range, 3 months to 64 years) and an average weight of 19.4 kg (range, 4.1-81.0 kg). Among the patients in this study, 66 (28.6%) had pulmonary hypertension, ten (4.3%) had trisomy 21, and eight (3.5%) had other congenital cardiac anomalies. The mean narrowest patent ductus arteriosus (PDA) diameter was 4.2 mm (range, 1.3-10 mm), and the ampulla size was 9.6 mm (range, 4-20 mm). Successful implantation was achieved for 229 patients (99.1%). Complete angiographic occlusion was achieved for 201 patients (87.8%) at the end the procedure. Follow-up data were available for 129 patients (66%). At the follow-up assessment, complete echocardiographic occlusion was seen in 128 patients (99.2%) after 1 month and in 100% of the patients after 6 months. The significant morbidities involved one device embolization and one dislodgment, for which surgical retrieval was performed. No mortalities occurred during the study period, and no late clinical adverse events occurred during the follow-up period. Occlusion of the PDA using ADO is safe, effective, and applicable for a wide range of PDA sizes including large PDAs in small symptomatic infants and in adults. Good outcomes can be attributed to experience of the operators, proper patient selection, and appropriate device size selection. PMID- 22105494 TI - Predictors of post-release research retention and subsequent reenrollment for women recruited while incarcerated. AB - Correctional facilities are prime targets for nursing interventions to decrease health disparities, but challenges to post-release follow-up limit use of the longitudinal research designs needed to fully examine intervention effects. Using an adapted version of the Behavioral Model for Vulnerable Populations, we determined predictors of 1-year post-release study retention and subsequent reenrollment an average of 3 years later in 88 mother and child dyads recruited from a state prison nursery. Predisposing characteristics and enabling factors emerged as strong predictors of loss to follow-up. Female research participants can be successfully retained years after release from a correctional facility. Understanding the barriers and facilitators to post-release follow-up supports the creation of theoretically informed strategies to retain formerly incarcerated populations. PMID- 22105495 TI - Association of tumor necrosis factor alpha, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects. AB - PURPOSE: New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor alpha, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: This case-control study comprised 493 volunteers (253 PDR cases and 240 diabetic controls). Cases and controls were ascertained such that age, sex, nutrition, and glycemic status were matched. Genotypes were determined by polymerase chain reaction-based methods. RESULTS: Interleukin 10-1082GG (P = 0.0037; odds ratio [OR] = 2.232), tumor necrosis factor alpha-238AA (P = 0.0001; OR = 5.791), and GA (P = 0.0015; OR = 1.909) genotypes were significantly associated with PDR occurrence. The interleukin 10-1082G allele (P = 0.0048, OR = 1.4442) and the tumor necrosis factor alpha-238A allele (P = 0.0001; OR = 2.2897) were significantly increased among PDR cases. CONCLUSION: From our study, it may be concluded that the genetic variation, that is, tumor necrosis factor alpha-238A and interleukin 10-1082G alleles are the potent risk factors for the pathogenesis of PDR. PMID- 22105496 TI - Effect of intraarterial chemotherapy on retinoblastoma-induced retinal detachment. AB - PURPOSE: To study the effect of intraarterial chemotherapy (IAC) on retinoblastoma-induced retinal detachment. METHODS: Retrospective, noncomparative, interventional case series including 15 patients, with intraarterial (ophthalmic artery) chemotherapy as the intervention. Resolution of retinal detachment was the main outcome measure. RESULTS: Of 15 patients with retinoblastoma-induced retinal detachment managed with IAC, 7 (47%) presented with total retinal detachment and 8 (53%) with partial detachment. The eyes were classified as International Classification of Retinoblastoma group C (n = 2, 13%), group D (n = 4, 27%), and group E (n = 5, 33%). There were 4 eyes (27%) that received IAC as secondary treatment after the failure of other treatment methods. After IAC, all tumors showed regression. Of the 7 eyes with initial total retinal detachment, complete resolution of fluid was found in 3 (43%) and partial resolution in 4 (57%). Of the 8 eyes with initial partial retinal detachment, complete resolution of subretinal fluid was found in all 8 (100%), but 1 eye later developed recurrent subretinal fluid. The mean interval to complete resolution of subretinal fluid was 2 months. Globe salvage was achieved in 5 of 7 eyes (71%) with total retinal detachment and 6 of 8 eyes (75%) with partial retinal detachment. CONCLUSION: Eyes with retinoblastoma-induced total or partial retinal detachment showed complete resolution of detachment after IAC in 43% and 100%, respectively. PMID- 22105497 TI - Influence of vitreomacular adhesion on the development of exudative age-related macular degeneration: 4-year results of a longitudinal study. AB - PURPOSE: To investigate the influence of vitreomacular adhesion (VMA) on development of choroidal neovascularization (CNV) in eyes with age-related macular degeneration. METHODS: In a prospective study, patients with Age-Related Eye Disease Study Category IV age-related macular degeneration underwent standardized examinations, including optical coherence tomography and fluorescein angiography every 3 months for 4 years. Vitreomacular adhesion was evaluated using time- and spectral-domain optical coherence tomography. Development of CNV was detected using fluorescein angiography and optical coherence tomography. Incidences of CNV were compared concerning the presence or absence of VMA. RESULTS: Forty-nine patients were available for follow-up according to protocol. Vitreomacular adhesion was present at baseline in 18% (9 of 49) and absent in 82% (40 of 49) of patients. Thirty-seven percent of patients (18 of 49) developed exudative changes during the observation period. In patients with preexisting VMA, de novo development of CNV occurred in 33% (3 of 9). In patients without VMA, 38% developed CNV (15 of 40). Mean interval from baseline to disease progression was 20 +/- 19 months in patients with VMA and 22 +/- 13 months in patients without VMA. There was no significant difference between the groups regarding rate of CNV development or time to disease progression (P = 0.64). CONCLUSION: No significant influence of VMA on the development of exudative age related macular degeneration could be found during a 4-year prospective observation of a high-risk cohort. PMID- 22105499 TI - Early diagnosis of macular hole closure of a gas-filled eye with Watzke-Allen slit beam test and spectral domain optical coherence tomography. AB - PURPOSE: The purpose of this study was to evaluate the usefulness of the Watzke Allen slit beam test (W/A test) and spectral domain optical coherence tomography (SD-OCT) for diagnosing macular hole closure in gas-filled eyes during the early postoperative period. METHODS: A retrospective comparative study was performed on 40 consecutive eyes of 40 patients with macular hole treated with vitrectomy. Macular hole closure was initially judged within 2 days after surgery with both the W/A test and SD-OCT. Final diagnosis was confirmed with SD-OCT after the gas disappeared. The concordance rate of initial diagnosis and final diagnosis using each method was evaluated. RESULTS: The W/A test could be done for the gas-filled eyes of all patients next day, whereas a diagnosable SD-OCT image could be obtained in 77.5% of patients. The concordance rate was 85% (34of 40 examined eyes) with the W/A test and 77.5% (31 of 40 examined eyes) with SD-OCT (P = 0.39, chi-square test). If a diagnosable result (image or response) could be obtained within 2 days after surgery, the accuracy of SD-OCT (31 of 31 eyes) was significantly better than that of the W/A test (31 of 40 eyes) (P = 0.026, chi square test). CONCLUSION: The W/A test is more useful for diagnosing macular hole closure of a gas-filled eye than SD-OCT; however, SD-OCT gives more accurate information when diagnosable. Combining both methods could improve the accuracy and applicability. PMID- 22105500 TI - Hyperreflective external limiting membranes after successful macular hole surgery. AB - PURPOSE: To evaluate changes in external limiting membranes (ELMs) in the foveae of patients with surgically closed macular holes. METHODS: In this retrospective observational case series, spectral-domain optical coherence tomography scan images were obtained from eyes of patients with macular holes closed after vitrectomy. The integrity of the ELMs was evaluated at the fovea. In eyes with a restored ELM, the reflectivity of the ELM was estimated. RESULTS: At a mean of 19 months (range, 3.0-59.7 months) after surgery, the integrity of the ELM was restored in 21 (77.8%) of 27 eyes with closed macular holes. The ELM was not restored in six eyes with glial sealing, in which glial tissues were present in the entire retinal layer. All 21 eyes with restored ELMs had an area of hyperreflectivity within the ELM observed at the thinnest part of the fovea; this was associated with an underlying photoreceptor defect. CONCLUSION: Abnormally hyperreflective ELMs were frequently observed at the thinnest point of the fovea after macular hole surgery. These hyperreflective ELMs may be newly formed after surgery. PMID- 22105501 TI - Functional recovery after intravitreal bevacizumab treatments for idiopathic choroidal neovascularization in young adults. AB - PURPOSE: To evaluate the morphology and functional recovery of the retina after treatment of idiopathic choroidal neovascularization using intravitreal injections of bevacizumab in young adults. METHODS: For this interventional case series, 20 eyes of 19 patients with idiopathic choroidal neovascularization were treated with multiple intravitreal injections of bevacizumab. Changes in best corrected visual acuity before the treatment and at follow-up visits were recorded. Structural changes were evaluated using optical coherence tomography and functional changes were assessed using microperimetry. RESULTS: Twenty eyes were followed for 12 months after their first injection. The eyes underwent an average of 3.95 injections. All eyes had a stable or an improved vision. The mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.43 to 0.06 (Wilcoxon signed-ranks test, P < 0.005). Improvement in macular function was detected as early as 1 month after the treatment and lasted for at least 6 months. Microperimetry demonstrated that mean retinal sensitivities within the central 10 degrees field (10.29 +/- 5.12 dB) at baseline improved to 13.98 +/- 3.96 dB at the last visit. Dense scotomas were found in 13 of the 20 eyes at baseline and 5 of the 20 eyes at the last visit. Stable fixation (6 of 20 at baseline) was found in 17 of the 20 eyes at the last visit. Twelve of the 14 eyes with either a predominantly eccentric or poor central fixation at baseline established central fixation at 12 months. No serious local or systemic complications were encountered. CONCLUSION: In young adults with idiopathic choroidal neovascularization, an improvement in visual acuity and macular function was detected after intravitreal injections of bevacizumab. PMID- 22105502 TI - Techniques, rationale, and outcomes of internal limiting membrane peeling. AB - BACKGROUND: The internal limiting membrane represents the structural interface between the retina and the vitreous and has been postulated to serve several essential functions. Recently, internal limiting membrane peeling has been used in the treatment of a variety of retinal disorders. We review the history, techniques, rationale, and outcomes of internal limiting membrane peeling. METHODS: A review of the literature. RESULTS: Internal limiting membrane peeling has been used to successfully treat a variety of retinal disorders including macular hole, epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others. CONCLUSION: Internal limiting membrane peeling may serve as an important component in the armamentarium of retinal surgery. PMID- 22105503 TI - Spectral-domain optical coherence tomography in patients with commotio retinae. AB - PURPOSE: To describe the morphologic characteristics of commotio retinae using spectral-domain optical coherence tomography and to evaluate its utility in prognosis and follow-up. METHODS: Consecutive patients with commotio retinae underwent complete ophthalmic examination, color fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, and near-infrared autofluorescence. RESULTS: There were 11 eyes of 11 patients (8 men), with a mean age of 30.8 +/- 12.1 years. The follow-up ranged from 9 days to 6 months. Spectral-domain optical coherence tomography identified hyperreflectivity underneath the inner/outer segment junction in the area of commotio retinae in 9 patients (81.1%), which subsided in a few days. Five patients (45.5%) revealed areas of disruption of the inner/outer segment junction and hyperreflectivity of the overlying retina, which progressed to external retinal atrophy and visual loss (P = 0.002). The 5 patients with visual sequelae revealed pigment disorders and alterations in fundus autofluorescence and near-infrared autofluorescence during follow-up, and 3 patients (60%) presented with intraretinal hemorrhages. CONCLUSION: Spectral-domain optical coherence tomography of mild lesions with good visual outcome showed transient hyperreflectivity of the outer retina. The cases with severe trauma were related to acute disruption of the inner/outer segment junction and hyperreflectivity of the overlying retina and were regularly associated with retinal atrophy, pigment disturbance, and poor visual prognosis. PMID- 22105504 TI - Changes in the clinical features and prognostic factors of endogenous endophthalmitis: fifteen years of clinical experience in Korea. AB - PURPOSE: To identify changes in the clinical features, management, and prognostic factors of endogenous endophthalmitis in Korea from 1996 through 2010. METHODS: We conducted a retrospective review of medical records of patients diagnosed with endogenous endophthalmitis from January 1996 to December 2010, which was divided into 3 periods: 1996 to 2000, 2001 to 2005, and 2006 to 2010. Variables included age, source of infection, systemic conditions, initial and final visual acuities, causative organisms, and treatment. RESULTS: Endophthalmitis was identified in 80 patients (97 eyes). Diabetes (42.5%) and liver cirrhosis (20%) were the common systemic problems in these patients. Liver abscess (25%) was the most common infection focus of the endophthalmitis. Klebsiella pneumoniae (48.4%) was the common causative agent, although more recently, endophthalmitis caused by gram positive cocci has increased in frequency. The use of vitrectomy as an initial treatment has increased during the past 5 years. Good initial visual acuity greater than counting fingers (P < 0.001), early vitrectomy in patients with initially good visual presentation (P = 0.035), and gram-positive cocci (P = 0.033) as a causative agent were significantly related to a successful visual outcome. CONCLUSION: Although the prognosis of endogenous endophthalmitis is generally poor in most patients, some eyes can have relatively good visual outcomes if treated appropriately and early enough. PMID- 22105505 TI - Optic disk analysis with heidelberg retina tomography in patients with branch retinal vein occlusion. AB - PURPOSE: To investigate the optic disk topography parameters of patients with branch retinal vein occlusion (BRVO) in a controlled study by using Heidelberg retinal tomography. METHODS: This prospective study included 35 eyes of 30 patients with BRVO who were followed-up at the Retina Clinic of the Ankara Ulucanlar Eye Education and Research Hospital, and 30 normal subjects (60 eyes). All patients and control subjects underwent complete ophthalmologic evaluation. The optic nerve heads of all subjects were imaged with the Heidelberg retinal tomography III (software 3.01a-M). The following stereometric parameters were calculated for each patient: disk area, cup area, cup-to-disk ratio, rim area, cup volume, rim volume, mean cup depth, maximum cup depth, and cup shape measure. Differences between the two groups were evaluated by the nonparametric independent sample t-test. RESULTS: The mean cup volume, rim volume, cup area, disk area, rim area, and cup depth in BRVO group were found to be statistically significantly smaller than those in the control group (P < 0.05). Significant differences in the same parameters were also noted between the unaffected and affected eyes in patients with BRVO (P < 0.05). No significant differences were found between the groups in terms of the other stereometric parameters (P > 0.05). CONCLUSION: Based on the results that were obtained in this series, a relationship was found between BRVO and various optic disk topography parameters determined by Heidelberg retinal tomography. Anatomical features of the optic disk may play a role in the pathogenesis of BRVO. PMID- 22105506 TI - Multifocal electrophysiologic findings after intravitreal bevacizumab (avastin) treatment. AB - PURPOSE: To determine the short-term safety of intravitreal bevacizumab by multifocal electroretinography testing. METHODS: Thirty-one eyes with choroidal neovascularization, proliferative diabetic retinopathy, and retinal vein occlusion received intravitreal bevacizumab (2.5 mg/0.1 mL). All patients underwent best-corrected visual acuity measurement, retinal fluorescein angiography, optical coherence tomography, and multifocal electroretinography at baseline and 1 month after the treatment. RESULTS: Subjects undergoing multifocal electroretinography testing had no statistically significant changes in electrophysiologic responses 1 month after the intravitreal injection of bevacizumab. CONCLUSION: Multifocal electrophysiologic testing did not demonstrate any short-term cone photoreceptor toxicity after intravitreal bevacizumab. PMID- 22105507 TI - Change in choroidal thickness after chemotherapy in leukemic choroidopathy. PMID- 22105508 TI - Preliminary efficacy and safety of a silicone oil-filled foldable capsular vitreous body in the treatment of severe retinal detachment. AB - PURPOSE: We previously invented a novel foldable capsular vitreous body (FCVB) in the treatment of severe retinal detachment. The purpose of this study was to determine its hydrolytic stability in vitro and further evaluate its efficacy and safety in human eyes. METHODS: The hydrolytic stability test proceeded according to State Food and Drug Administration guidelines about intraocular lenses of the ophthalmic implants. A standard three-port pars plana vitrectomy was performed, and FCVB was triple folded and sent into the vitreous cavity of three eyes; then silicone oil was injected into the capsule to support the retina. The treated eyes were examined using Goldmann applanation tonometry, fundus photography, optical coherence tomography, noncontact specular microscopy, and ultrasound biomicroscopy during a 12-month follow-up appointment. RESULTS: The mass of FCVB with silicone oil after 60-day accelerating aging temperature was equal to that at baseline. The FCVB can easily be implanted into the vitreous cavity through a 3-mm incision. The visual acuity and intraocular pressure after FCVB implantation show a slight elevation compared with those of preoperative eyes. The fundus and optical coherence tomography showed that the FCVB was well distributed in the vitreous cavity and evenly supported the retina. Retinal reattachment was found in 3 eyes at the 12-month examination. There was no statistically significant decrease in the density of corneal endothelial cells from baseline to 12 months after FCVB implantation. Ultrasound biomicroscopy showed that the FCVB smoothly contacted but not crushed the ciliary body. CONCLUSION: Silicone oil-filled FCVB was shown to be effective and safe in 3 eyes as a vitreous substitute over a 12 month observation time. PMID- 22105509 TI - Prostaglandin E2 inhibition of ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% in patients undergoing phacoemulsification. AB - INTRODUCTION: We compared the prostaglandin E(2) (PGE(2)) inhibition of three topical nonsteroidal antiinflammatory drugs (NSAIDs): ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% at peak dosing levels in patients previously scheduled to undergo phacoemulsification. METHODS: This was a single-center, double-masked observational study of 121 patients randomized to one of three NSAID treatment arms. Patients were instructed to take the NSAID per on-label dosing (twice daily [b.i.d.] for ketorolac 0.45% and bromfenac 0.09%, three times a day [t.i.d.] for nepafenac 0.1%) for 1 day before surgery, and were to instill one drop the morning of surgery. Each patient received an additional four doses 1 hour prior to undergoing phacoemulsification. After completion of the paracentesis site with a super blade, aqueous humor (0.15 mL) was collected through the peripheral clear cornea with a 30 G needle attached to a tuberculin (TB) syringe. Aqueous humor samples were stored at -40 degrees C prior to analysis, and diluted 1:10 with diluent. Assays were conducted on multiple plates in duplicate (seven standards per plate). RESULTS: The mean (+/-SD) PGE(2) concentrations were 224.8+/-164.87 pg/mL for ketorolac 0.45% (n=42), 288.7+/-226.05 pg/mL for bromfenac 0.09% (n=41), and 320.4+/-205.6 pg/mL for nepafenac 0.1% (n=38). The difference between ketorolac 0.45% and nepafenac 0.1% was statistically significant (P=0.025). The difference between bromfenac 0.09% and nepafenac 0.1% was not significantly different (P=0.516). CONCLUSIONS: Ketorolac 0.45% achieved the greatest inhibition of PGE(2) compared to nepafenac 0.1% and bromfenac 0.09%. Ketorolac 0.45% may be more efficacious at controlling inflammation at the time of cataract surgery versus nepafenac 0.1% and bromfenac 0.09%. PMID- 22105510 TI - Captive breeding and reintroduction of the oriental pied hornbill (Anthracoceros albirostris) in Khao Kheow Open Zoo, Thailand. AB - This article discusses two related issues of the captive breeding and reintroduction of the Oriental pied hornbill (Anthracoceros albirostris) in order to increase its population in the natural habitats. Oriental pied hornbills were bred in Khao Kheow Open Zoo. Three pairs were separated and kept in breeding cages. Females occupied artificial nests between February and April 2005-2007. Eggs were laid and incubated between February and March each year from 2005 to 2007. Nestlings hatched in late March and left the nest in late April 2005-2007. Each breeding pair was fed with approximately 400 g of food each day. All three pairs reproduced resulting in mature offspring of seven in 2005, six in 2006, and five in 2007. Four of sixteen 3-year-old birds were randomly selected and equipped with a GPS receiver on their backs. Activities of the birds attached and unattached with GPS were not significantly different. The first two birds (one female, one male with GPS) were reintroduced on August 5, 2006, and another nine birds (four birds with GPS) were reintroduced on December 26, 2006. The average home range of these reintroduced birds was 0.13 km(2) . Their foods consisted of wild plants and animals in the home range. The first reintroduced pair was able to breed naturally by laying and hatching eggs in an artificial nest. Two juveniles left the nest in April 2008. These results indicate that both captive breeding and reintroduction are potentially important ways to increase the population of the Oriental pied hornbill in natural habitats. PMID- 22105511 TI - Adiponectin inhibits PDGF-induced mesangial cell proliferation: regulation of mammalian target of rapamycin-mediated survival pathway by adenosine 5 monophosphate-activated protein kinase. AB - An aberrant proliferation of mesangial cells (MCs) is one of the more important features of diabetic nephropathy (DN). Adiponectin, an adipocyte-derived hormone, has been associated with type 2 diabetes, a known cause of DN. Recent studies have suggested that adiponectin has a protective effect on the kidney. To elucidate the potential protective mechanism of adiponectin on kidney, we investigated the effects of adiponectin on platelet-derived growth factor (PDGF) induced cell proliferation and intracellular signaling pathways in cultured Human MCs (HMCs). PDGF-induced HMC proliferation was significantly inhibited by the co treatment of adiponectin. Adiponectin alone had no effect on HMC proliferation. The mammalian target of rapamycin (mTOR) and 40 S ribosomal S6 kinase 1 (S6K1) were activated by PDGF stimulation in HMCs. PDGF-induced mTOR and S6K1 phosphorylations were significantly attenuated by the co-treatment of adiponectin in HMC. Adiponectin alone had no effects on PDGF-receptor autophosphorylation by PDGF. We also confirmed that the inhibitory effect of adiponectin on PDGF-induced HMC proliferation was significantly suppressed by compound C, an adenosine 5' monophosphate-activated protein kinase (AMPK) inhibitor. From these findings, it is implied that adiponectin could attenuate renal dysfunction associated with MC disorders through AMPK-mTOR signal pathway. PMID- 22105513 TI - Sirtuin 1 in immune regulation and autoimmunity. AB - The NAD-dependent histone deacetylase sirtuin (Sirt)1 is implicated in a wide variety of physiological processes, ranging from tumorigenesis to mitochondrial biogenesis to neuronal development. Recent studies indicate that Sirt1 is a critical regulator of both the innate and adaptive immune response in mice and its altered functions are likely involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. In this review, we highlight the functions of Sirt1 in the immune system focusing on the underlying molecular mechanisms, and the potential of Sirt1 as a therapeutic target for autoimmune diseases. PMID- 22105512 TI - Modulation of antigen-presenting cells by HDAC inhibitors: implications in autoimmunity and cancer. AB - There is a growing body of evidence to support the use of histone deacetylase inhibitors (HDACi) in the treatment of diverse conditions from autoimmunity to cancer. In this context, HDACi have been ascribed many immunomodulatory effects, assigning novel and promising roles to these compounds. This review summarizes the current observations arising from both pre-clinical and clinical studies in these pathological conditions. However, it is left to be explained how a single agent can have both pro- and anti-inflammatory effects in either physiological or pathological conditions. This question is explored in greater detail by focusing on the effects of HDACi on antigen-presenting cells (APCs), key regulators of immune activation. In particular, HDACi modulation of molecules involved in antigen processing and presentation, as well as co-stimulatory and adhesion molecules, and cytokines will be discussed in the context of both professional and non-professional APCs. Professional APCs encompass classic immune cells; however, it is increasingly evident that other somatic cells, including cancer cells, are not immunologically inert and can display functions similar to professional APCs, a challenging feature that needs to be explored as a potential therapeutic target. In this way, professional and non-professional APCs can regulate their particular micro-environmental niche, affecting either a pro- or anti-inflammatory milieu. PMID- 22105514 TI - Depletion of GRIM-19 accelerates hepatocellular carcinoma invasion via inducing EMT and loss of contact inhibition. AB - Genes associated with retinoid-interferon-induced mortality 19 (GRIM-19) was identified as a tumor suppressor protein associated with apoptosis and growth inhibition. Here, we report that the expression levels of GRIM-19 are significantly attenuated in hepatocellular carcinoma (HCC) patients with deteriorating differentiation states, hepatic capsule invasion and microvascular invasion, suggesting the potential role of GRIM-19 not only at the origin but also in the invasive progression of HCCs. To dissect the possible mechanisms by which GRIM-19 regulates tumor cell invasion, we established the hepatic HL-7702 and HCC Huh-7 cell lines stably depleted of GRIM-19. Results show that downregulation of GRIM-19 induces a morphological transformation resembling epithelial-mesenchymal transition (EMT) as well as aberrant expression of epithelial and mesenchymal molecular markers. Additionally, these cells lose contact inhibition, a phenomenon of cessation of cell migration in contact with neighboring cells, as assessed by cell imaging, growth curve and S-phase transition in confluent conditions. CONCLUSION: Our observations demonstrate a novel mechanistic insight into a critical role of GRIM-19 in HCC invasive potential. PMID- 22105515 TI - Affinity maturation of antibodies requires integrity of the adult thymus. AB - The generation of B-cell responses to proteins requires a functional thymus to produce CD4(+) T cells which helps in the activation and differentiation of B cells. Because the mature T-cell repertoire has abundant cells with the helper phenotype, one might predict that in mature individuals, the generation of B-cell memory would proceed independently of the thymus. Contrary to that prediction, we show here that the removal of the thymus after the establishment of the T-cell compartment or sham surgery without removal of the thymus impairs the affinity maturation of antibodies. Because removal or manipulation of the thymus did not decrease the frequency of mutation of the Ig variable heavy chain exons encoding antigen-specific antibodies, we conclude that the thymus controls affinity maturation of antibodies in the mature individual by facilitating the selection of B cells with high-affinity antibodies. PMID- 22105516 TI - Pattern of elemental release during the granite dissolution can be changed by aerobic heterotrophic bacterial strains isolated from Damma Glacier (central Alps) deglaciated granite sand. AB - Colonisation and weathering of freshly deglaciated granite are key processes in initial soil formation and development. We have obtained 438 isolates from granite sand covering glacial toe, 284 isolates at 22 degrees C and 154 at 4 degrees C incubation temperatures, respectively, to obtain cultures for the investigation of their weathering capabilities under laboratory conditions. The isolation of bacteria from granite sand was performed on rich-, intermediate- and low-nutrient-content solid media. Isolates were identified by 16S rRNA gene sequencing. According to the genera-associated weathering capabilities described in the literature and according to their abundance in our culture collection, we selected eight strains to analyse their effects on the weathering dynamics of granite sand during the batch culture experiment. Analysis of culturable bacteria showed higher species richness among isolates from 22 degrees C than from 4 degrees C incubations. In the R2A and 1/100 Ravan media, we observed the highest species richness of isolates obtained at 22 degrees C and 4 degrees C incubation temperatures, respectively. The obtained 16S rRNA sequences revealed the presence of alpha-, beta- and gamma-proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. The most numerous group of isolates was distantly related to Collimonas representatives, and according to the sequences of the 16S rRNA genes, they can form a new genus. Isolates from this group had the capability of causing increased dissolution rates for Fe, W, Ni and Rb. In general, at each sampling during the 30-day experiment, every strain showed a unique weathering profile resulting from differential rates of the dissolution and the precipitation of different minerals in the batch culture. Consequently, the presence of different strains, their growth stage and changes in proportions of strains in the bacterial community can affect further soil development and the successive colonisation by plants. PMID- 22105517 TI - Genetic diversity of endophytic diazotrophs of the wild rice, Oryza alta and identification of the new diazotroph, Acinetobacter oryzae sp. nov. AB - Thirty-three endophytic diazotrophs were isolated from surface-sterilized leaves, stem, and roots of wild rice Oryza alta. The SDS-PAGE profile of total protein and insertion sequence-based polymerase chain reaction (IS-PCR) fingerprinting grouped the isolates into four clusters (I-IV). The 16S rRNA gene sequence homology of the representative strains B21, B31, B1, and B23 of clusters I, II, III, and IV were assigned to Pseudomonas oleovorans (99.2% similarity), Burkholderia fungorum (99.4% similarity), Enterobacter cloacae (98.9% similarity), and Acinetobacter johnsonii (98.4% similarity), respectively. The results showed wide genetic diversity of the putative diazotrophic strains of the wild rice, O. alta, and the strains of cluster IV are the first report of nitrogen-fixing Acinetobacter species. The cell size, phenotypic characters, total protein profile, genomic DNA fingerprinting, DNA-DNA hybridization, and antibiotic resistance differentiated strain B23(T) from its closest relatives A. johnsonii LMG999(T) and Acinetobacter haemolyticus LMG996(T). The DNA-DNA hybridization also distinguished the strain B23(T) from the closely related Acinetobacter species. Based on these data, a novel species, Acinetobacter oryzae sp. nov., and strain B23(T) (=LMG25575(T) = CGMCC1.10689(T)) as the type strain were proposed. PMID- 22105518 TI - The current standard measure of cardiorespiratory fitness introduces confounding by body mass: the DR's EXTRA study. AB - OBJECTIVE: Cardiorespiratory fitness is currently estimated by dividing maximal oxygen consumption (VO(2max)) by body weight (per-weight standard). However, the statistically correct way to neutralize the effect of weight on VO(2max) in a given population is adjustment for body weight by regression techniques (adjusted standard). Our objective is to quantify the bias introduced by the per-weight standard in a population distributed across different categories of body mass. DESIGN: This is a cross-sectional study. SUBJECTS AND METHODS: Baseline measures from participants of the Dose-Responses to Exercise Training Study (DR's EXTRA), 635 men (body mass index (BMI): 19-47 kg m-2) and 638 women (BMI: 16-49 kg m-2) aged 57-78 years who performed oral glucose tolerance tests and maximal exercise stress tests with direct measurement of VO(2max). We compare the increase in VO(2max) implied by the per-weight standard with the real increase of VO(2max) per kg body weight. A linear logistic regression model estimates odds for abnormal glucose metabolism (either impaired fasting glycemia or impaired glucose tolerance or Type 2 diabetes) of the least-fit versus most-fit quartile according to both per-weight standard and adjusted standard. RESULTS: The per-weight standard implies an increase of VO(2max) with 20.9 ml min-1 in women and 26.4 ml min-1 in men per additional kg body weight. The true increase per kg is only 7.0 ml min-1 (95% confidence interval: 5.3-8.8) and 8.0 ml min-1 (95% confidence interval: 5.3-10.7), respectively. Risk for abnormal glucose metabolism in the least-fit quartile of the population is overestimated by 52% if the per-weight standard is used. CONCLUSIONS: In comparisons across different categories of body mass, the per-weight standard systematically underestimates cardiorespiratory fitness in obese subjects. Use of the per-weight standard markedly inflates associations between poor fitness and co-morbidities of obesity. PMID- 22105519 TI - Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens. AB - OBJECTIVE: The fat mass and obesity-associated gene (FTO), a crucial gene that affects human obesity and metabolism, has been widely studied in mammals but remains poorly characterized in birds. We aimed to identify variant FTO transcripts in domestic avian species, and to characterize the expression and biological functions of FTO in chickens. METHODS: Variant FTO transcripts and their expression in birds were investigated using RACE and real-time quantitative reverse transcriptase-PCR technology. The effects of FTO on glucose metabolism, growth and body composition were determined by fasting and various diet treatments, as well as association analysis in a F2 resource population. The function of cFTO1 was further studied by overexpression in chick embryo fibroblast (CEF) cells. RESULTS: Variant FTO transcripts were identified in chicken (cFTO1 to cFTO4), duck (dFTO1, dFTO2 and dFTO4) and goose (gFTO1, gFTO2 and gFTO5). In the chicken, the complete transcript (cFTO1) was predominantly expressed in the leg muscle, pituitary, hypothalamus and cerebellum. Fasting increased both cFTO1 and PGC1alpha gene expression in the cerebrum, liver, breast muscle and subcutaneous fat, but decreased expression in the pituitary and anterior hypothalamus. In all tested tissues in chickens, a high-glucose diet markedly increased cFTO1 and PGC1alpha expression. Feeding a high-fat diet increased both cFTO1 and PGC1alpha expression, except in the pituitary. Overexpression of cFTO1 in CEF cells significantly increased the expression of PGC1alpha (2.5-fold), STAT3 (2.2-fold) and HL (1.5-fold), a cluster of genes related to energy metabolism. A total of 65 single nucleotide polymorphisms (SNPs) were identified in chicken FTO, and 18 tested SNPs were significantly associated with traits of body weight, body composition and fatness. CONCLUSIONS: These data collectively indicate that FTO is related to glucose metabolism, body weight, fatness and body composition in birds, thus expanding knowledge of FTO function to non-mammalian species. PMID- 22105520 TI - Local tissue temperature increase of a generic implant compared to the basic restrictions defined in safety guidelines. AB - The objective of this study was to investigate if persons with implantable medical devices are intrinsically protected by the current electromagnetic safety guidelines. For inter-laboratory comparisons, the U.S. Food and Drug Administration has defined a generic implant as consisting of an insulated wire with noninsulated tips, simulating active implants composed of a metallic case, and insulated wires with electric contacts at the tip. In this study, we determined the amplitude of the uniform electric fields induced in body tissues that cause a local increase in the tissue temperature by 1 degrees C in the presence of this generic implant for a wide range of frequencies and wire lengths. The field amplitudes were compared to the basic restrictions of the current exposure guidelines for both occupational and uncontrolled exposure. Results showed that a 1 degrees C temperature increase in the tissues around the tips of the generic implant can be reached for field strengths much smaller than 1% of those in the basic restrictions. The simulated results were validated by experimental evaluations. The impact of perfusion was investigated and was found to lead to a reduction in the local temperature peak by only 1.6-3 times. Additional simulations inside an inhomogeneous anatomical model were performed to ascertain whether similar heating as in the generic model was observed. The significant temperature elevations due to the presence of a generic implant indicate that demonstrating compliance with the basic restrictions might not be sufficient for persons with implants. Special considerations may be required, especially in the case of novel, emerging technologies that feature strong near fields at frequencies below 10 MHz (e.g., wireless power-transfer systems). PMID- 22105526 TI - Sexing of mid-incubation avian embryos as a management tool for zoological breeding programs. AB - Skewed sex ratios in zoo breeding programs may require housing single birds of an overrepresented gender, increasing demands on limited resources that could otherwise be diverted to breeding pairs or other important species. The ability to selectively incubate and hatch eggs of a desired sex represents a significant improvement in the long-term management of avian species. This study describes a successful method for in ovo sexing of embryos from stage 30 through 42 of incubation (Hamburger and Hamilton [1951] J Morphol 88:49-92). A 0.01-1 ul blood sample was collected from either the vitelline vessel (VV) or the blood vessels of the chorio-allantoic membrane (CAM) of embryos at stages 14-18 or 30-42, respectively. DNA was isolated from whole blood using the Chelex method (Walsh et al. [1991] Biotechniques 10:506-513; Jensen et al., [2003] Zoo Biol 22:561-571). Sex was determined by PCR amplification using the previously described P2/P8 (Griffiths et al. [1998] Mol Ecol 7:1071-1075) and 1237L/1272H (Kahn et al. [1998] Auk 115:1074-1078) primers or by commercial vendor. Success rate was calculated as the percent of sampled embryos surviving to hatch. Embryos of the undesired sex were not incubated, thus not included in the calculation. There was a considerable difference in success rate when blood was collected from the stage 14-18 VV (0-25%, average 12%) vs. stage 30-42 CAM (33-100%, average 76%). In conclusion, in ovo sexing of embryos between stages 30 and 42 yields acceptable embryo survival rates while providing enough blood for genetic testing. PMID- 22105527 TI - Multiple myeloma with extramedullary disease. AB - Plasmacytoma is a tumor mass consisting of atypical plasma cells. Incidence of plasmacytomas associated with multiple myeloma range from 7% to 17% at diagnosis and from 6% to 20% during the course of the disease. In both situations, occurrence of extramedullary disease has been consistently associated with a poorer prognosis of myeloma. Extramedullary relapse or progression occurs in a variety of clinical circumstances and settings, and therefore requires individualization of treatment. Alkylating agents, bortezomib, and immunomodulatory drugs, along with corticoids, have been used to treat extramedullary relapse but, because of the relatively low frequency or detection rate of extramedullary relapse, no efficacy data are available from controlled studies in this setting. PMID- 22105528 TI - Extramedullary plasmacytomas in the context of multiple myeloma. AB - Plasmacytoma is a frequent complication of multiple myeloma, either at diagnosis or within disease progression. The extramedullary disease confers a poorer prognosis and is biologically distinct with high-risk molecular and histological features, being resistant to conventional treatments. Radiation therapy remains the most effective treatment for extramedullary lesions to achieve local control. There are very limited data from randomized trials regarding the most appropriate systemic treatment. Case reports such as those presented here, as well as retrospective analysis of series, suggest that lenalidomide is an effective agent, in combination with dexamethasone, in this setting. Additional studies are needed to define the proper management of this condition. PMID- 22105529 TI - The central vein access port and catheter in outpatient chemotherapy for colorectal cancer: a retrospective study of 101 patients. AB - PURPOSE: The central venous access port (CV-port) system was examined in a series of colorectal cancer (CRC) patients. METHODS: One hundred and one CRC patients underwent chemotherapy with the 5-fluorouracil + oxaliplatin (FOLFOX) or 5 fluorouracil + irinotecan regimen. The complications of the CV-port system were retrospectively assessed. RESULTS: The CV-port system was placed in a total of 101 patients. The patients received a total of 1020 [corrected] courses of these regimens. Eight complications occurred in the 101 patients (7.9%). The complications included three instances of catheter rupture, two thrombotic events around the catheter, and three infections at the site of the port or catheter. The complications were identified after a median of nine courses (range 6-16) and 135 days after the placement of the CV-port system. Sixty-six of the 101 patients switched their regimen from FOLFOX to another regimen, and 4 of these 66 patients (6.1%) experienced complications associated with the CV-port system. There were 25 subjects who were admitted to the hospital emergency wing during the chemotherapeutic regimens, and 4 of these patients (16%) had complications associated with the CV-port system. CONCLUSIONS: The complications of the CV-port system occurred at a defined rate, therefore the early diagnosis and the appropriate treatment to address these complications is crucial. PMID- 22105530 TI - Landiolol reduces coronary artery motion in an open-chest porcine model: implications for off-pump coronary artery bypass surgery. AB - Reduction of target coronary artery motion is imperative for successful off-pump coronary artery bypass surgery. We hypothesized that landiolol, a novel ultra short-acting selective beta-1 blocker, would reduce such coronary artery motion. To test this hypothesis, the motion of the left anterior descending artery of the porcine heart (n = 8) was analyzed by three-dimensional digital motion capture and reconstruction technology with or without continuous landiolol infusion. Landiolol (0.12 mg/kg/min) significantly decreased the heart rate (105 +/- 16 vs. 90 +/- 9 beats/min), three-dimensional distance moved (-20.4% vs. control), maximum velocity (-30.0% vs. control), acceleration (-31.1% vs. control), and deceleration (-28.6% vs. control) without inducing a significant change in the systolic blood pressure (85 +/- 18 vs. 81 +/- 22 mmHg), cardiac output (4.3 +/- 1.4 vs. 4.1 +/- 1.3 l/min), or pulmonary wedge pressure (7.8 +/- 3.0 vs. 8.7 +/- 2.9 mmHg). Landiolol reduces the heart rate and coronary artery motion with stable hemodynamics, which may facilitate performing precise anastomosis on the beating heart. PMID- 22105531 TI - A novel exonuclease III aided amplification method for sensitive nucleic acid detection based on single walled carbon nanotube induced quenching. AB - We describe herein a novel exonuclease III aided amplification method based on single walled carbon nanotube quenching (EASQ) for sensitive and convenient nucleic acid detection, which enabled 80-fold decrease of detection limit for HIV1 DNA assay compared with no target recycling. PMID- 22105532 TI - Two new species of the genus Candida in the Zygoascus clade, Candida lundiana sp. nov. and Candida suthepensis sp. nov., isolated from raw honey in Thailand. AB - During a survey of yeasts associated with raw honey collected in Thailand, two strains of the Zygoascus clade were isolated from the Asian cavity-nesting honeybee Apis cerana and the stingless bee Homotrigona fimbriata. Phylogeny based on 26S rDNA D1/D2 sequences placed these yeasts as members of a clade including Candida bituminiphila, Candida patagonica and Candida polysorbophila. The strains of the two novel species, CBS 12271(T) and CBS 12270(T), respectively, could be unquestionably distinguished from their relatives by rDNA sequences and other taxonomic characteristics. Therefore, the novel anamorphic species, Candida lundiana sp. nov. (type strain CBS 12271(T) = JCM 16823(T)) and Candida suthepensis sp. nov. (type strain CBS 12270(T) = JCM 16822(T)) are described. PMID- 22105533 TI - Echinicola shivajiensis sp. nov., a novel bacterium of the family "Cyclobacteriaceae" isolated from brackish water pond. AB - Strain AK12(T), an orange pigmented Gram-negative, rod shaped, non-motile bacterium, was isolated from a mud sample collected from a brackish water pond at Rampur of West Bengal, India. The strain was positive for oxidase, catalase and phosphatase. The predominant fatty acids were iso-C(15:0) (42.7%), iso-C(17:0) 3OH (13.2%), C(16:1omega7c)/C(16:1omega6c) (summed feature 3) (8.0%), iso-C(17:1) I/anteiso-C(17:1) B (summed feature 4) (6.1%) and iso-C(17:1omega9c)/C(16:0) 10 methyl (summed feature 9) (9.4%). Strain AK12(T) contained MK-7 as the major respiratory quinone and phosphatidylethanolamine, one unidentified aminophospholipid and six unidentified lipids as the polar lipids. The G + C content of DNA of the strain AK12(T) was 46.2 mol%. The 16S rRNA gene sequence analysis indicated that strain AK12(T) was member of the genus Echinicola and closely related to Echinicola vietnamensis, Echinicola pacifica and Echinicola jeungdonensis with pair-wise sequence similarity of 96.8, 96.3 and 96.0% respectively. Phylogenetic analyses indicated that the strain AK12(T) clustered with E. vietnamensis and together with E. pacifica and E. jeungdonensis with a phylogenetic distance of 5.1, 6.3 and 6.6% (94.9, 93.7 and 93.4% similarity) respectively. Based on data from the current polyphasic study, strain AK12(T) is proposed as a novel species of the genus Echinicola, for which the name Echinicola shivajiensis sp. nov. is proposed. The type strain of E. shivajiensis is AK12(T) (= MTCC 11083(T) = JCM 17847(T)). PMID- 22105534 TI - Depression and mortality in end-stage renal disease. AB - End-stage renal disease is growing in prevalence and incidence. With technical advancements, patients are living longer on hemodialysis. Depression is the most prevalent comorbid psychiatric condition, estimated at about 25% of end-stage renal disease samples. The identification and assessment of depression are confounded by the overlap between depression symptomatology and uremia. Several recent studies have employed time-varying models and identified a significant association between depression and mortality. Due to the high prevalence of depression and the potential impact on survival, well-constructed investigations are warranted. PMID- 22105535 TI - Treatment satisfaction, perceived treatment effectiveness, and dropout among older users of mental health services. AB - OBJECTIVES: To examine the rates and correlates of treatment satisfaction, perceived treatment effectiveness, and dropout among older users of mental health services. METHOD: We used data from the Canadian Community Health Survey-Mental Health and Well-Being (CCHS-1.2), which includes 12,792 individuals aged >=55 years. The average age of these participants was 67 years and 53.2% were female. We examined the rates of treatment satisfaction, perceived treatment effectiveness, and dropout for those who had used mental health services in the past year, and used logistic regression to examine the correlates of these outcomes. RESULTS: Of the older adults included in the CCHS-1.2, 664 (5.3%) had used mental health services in the past year. The majority of these were satisfied with services (88.5%) and perceived treatment to be effective (83.6%), which is likely why only 15.5% dropped out in the past year. In logistic regression models, social support was significantly and positively related to both treatment satisfaction and perceived effectiveness. Perceived treatment effectiveness was the only variable related to dropout, with lower levels of perceived effectiveness associated with greater odds of dropping out of treatment. CONCLUSIONS: Results from this study indicate that older adults have very good self-reported treatment outcomes. The modest influence of individual characteristics on treatment outcomes suggests the potential importance of contextual characteristics. PMID- 22105536 TI - Protective immunity afforded by attenuated, PhoP-deficient Mycobacterium tuberculosis is associated with sustained generation of CD4+ T-cell memory. AB - Definition of protective immunity induced by effective vaccines is important for the design of new pathogen control strategies. Inactivation of the PhoP response regulator in Mycobacterium tuberculosis results in a highly attenuated strain that demonstrates impressive protective efficacy in pre-clinical models of tuberculosis. In this report we demonstrate that the protection afforded by the M. tuberculosis phoP mutant strain is associated with the long-term maintenance of CD4(+) T-cell memory. Immunization of mice with SO2 resulted in enhanced expansion of M. tuberculosis-specific CD4(+) T cells compared with vaccination with the BCG vaccine, with an increased frequency of these cells persisting at extended time-points after vaccination. Strikingly, vaccination with SO2 resulted in sustained generation of CD4(+) T cells displaying a central memory phenotype, a property not shared by BCG. Further, SO2 vaccination markedly improved the generation of polyfunctional cytokine-secreting CD4(+) T cells compared with BCG vaccination. The improved generation of functionally competent memory T cells by SO2 correlated with augmented recall responses in SO2-vaccinated animals after challenge with virulent M. tuberculosis. This study defines a mechanism for the protective effect of the SO2 vaccine and suggests that deletion of defined virulence networks may provide vaccine strains with potent immuno-stimulatory properties. PMID- 22105537 TI - Fibrolamellar hepatocellular carcinoma presenting with Budd-Chiari syndrome, right atrial thrombus, and pulmonary emboli. PMID- 22105538 TI - [Pseudoexfoliation syndrome: no central zone of pseudoexfoliation material in patients with pseudophakia - a clinical study]. AB - BACKGROUND, MATERIAL AND METHODS: 1. An evaluation of medical findings and photodocumentation of 6 patients with pseudoexfoliation (PEX) material on the anterior surface of posterior chamber intraocular lenses was undertaken. Molecular genetic analysis of mutations in LOX-L1 was performed in order to confirm the association with pseudoexfoliation syndrome or glaucoma. Age of patients, the maximal intraocular pressure and perimetry with Octopus and Goldmann perimeters were documented as well as the time between implantation of the posterior chamber lens and diagnosis of pseudoexfoliation material on the anterior surface of posterior chamber lens. 2. Consecutive examinations of 35 patients with pseudoexfoliation syndrome or -glaucoma and pseudophakia were made to evaluate the frequency of patients with pseudoexfoliation material on the anterior surface of posterior chamber lenses. RESULTS: 1. The characteristic formation of stripe-shaped peripheral pseudoexfoliation material is seen in all examined patients on the anterior surface of posterior chamber lenses, but there is no central homogeneous round zone of pseudoexfoliation material in all patients. 2. the mean observation time of patients with pseudophakia and pseudoexfoliation syndrome or glaucoma is 4.4 +/- 3.9 years. 5.7 % of the patients show pseudoexfoliation material in the periphery of posterior chamber lenses. The mean time between implantation of the intraocular lens and diagnosis of pseudoexfoliation material on the lenses is 3 years. CONCLUSIONS: The lack of a central homogeneous round zone of pseudoexfoliation material deposits on the anterior surface of posterior chamber lenses seems to be characteristic. The change in topography of PEX material on intraocular lenses is described here for the first time. A knowledge of this change in the topography of pseudoexfoliation material in pseudophakia is important for glaucoma screening, because pseudoexfoliation deposits can only be detected in mydriasis due to the peripheral location on the intraocular lens. Due to the old age of patients at the onset of pseudoexfoliation deposits, a pseudoexfoliation syndrome frequently is likely to develop after cataract surgery in many patients. PMID- 22105539 TI - Toxicity of propargylic alcohols on green alga--Pseudokirchneriella subcapitata. AB - The present study evaluates the toxicity of 34 propargylic alcohols, including primary, primary homo-, secondary, and tertiary alcohols, based on their effects on phytoplankton. A closed-system algal toxicity test was applied because the closed-system technique presents more realistic concentration-response relationships for the above compounds than the conventional batch tests. The green alga, Pseudokirchneriella subcapitata, was the test organism and final yield and growth rate were chosen as the test endpoints. Among all the propargylic alcohols tested, 1-pentyn-3-ol is the most toxic compound with its EC50 equal to 0.50 mg L(-1), which can be classified as a "R50" compound (very toxic to aquatic organisms, EC50/LC50 < 1 mg L(-1)), following the current practice for classification of chemicals in the European Union (EU). There are several other compounds including 2-decyn-1-ol, 3-decyn-1-ol, 1-hexyn-3-ol, 3 butyn-2-ol, and 3-hexyne-2,5-diol, which deserve more attention for their possible adverse impact on the aquatic environment, because these alcohols can be classified as "R51" compounds (toxic to aquatic organisms, EC50/LC50 between 1 and 10 mg L(-1)). Compared to the base-line toxicity relationship (narcosis QSAR) derived previously, tertiary propargylic alcohols can be identified as nonpolar narcotic chemicals, while secondary alcohols and primary alcohols with low molecular weight generally exhibit obvious excess toxicity in relation to the base-line toxicity. Finally, quantitative structure-activity relationships were established for deriving a preliminary estimation of the toxicity of other propargylic alcohols. PMID- 22105540 TI - Specialization in psychology and health care reform. AB - This article begins by contextualizing specialization and board certification of psychologists, with attention paid to relevant definitions and expectations of other health care professionals. A brief history of specialization and board certification in professional psychology is offered. The benefits of board certification through the American Board of Professional Psychology are highlighted. Consideration is then given to the primary reasons for psychologists working in academic health sciences centers to specialize in the current health care climate and to obtain board certification as a mark of such specialization. PMID- 22105541 TI - Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. AB - Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy. PMID- 22105542 TI - Biodegradation of melamine and its hydroxy derivatives by a bacterial consortium containing a novel Nocardioides species. AB - Melamine has recently been recognized as a food contaminant with adverse human health effects. Melamine contamination in some crops arises from soil and water pollution from various causes. To remove melamine from the polluted environment, a novel bacterium, Nocardioides sp. strain ATD6, capable of degrading melamine was enriched and isolated from a paddy soil sample. The enrichment culture was performed by the soil-charcoal perfusion method in the presence of triazine degrading bacteria previously obtained. Strain ATD6 degraded melamine and accumulated cyanuric acid and ammonium, via the intermediates ammeline and ammelide. No gene known to encode for triazine-degrading enzymes was detected in strain ATD6. A mixed culture of strain ATD6 and a simazine-degrading Methyloversatilis sp. strain CDB21 completely degraded melamine, but the degradation rate of cyanuric acid was slow. The degradation of melamine and its catabolites by the mixed culture was greatly enhanced by including Bradyrhizobium japonicum strain CSB1 in the inoculum and adding ethanol to the culture medium. The melamine-degrading consortium consisting of strains ATD6, CDB21, and CSB1 appears to be potentially safer than other known melamine-degrading bacteria for the bioremediation of farmland and other contaminated sites, as no known pathogens were included in the consortium. PMID- 22105543 TI - Infusion of mesenchymal stem cells overexpressing GDNF ameliorates renal function in nephrotoxic serum nephritis. AB - Nephrotoxic serum nephritis (NSN) is a well-established animal model of glomerulonephritis, a frequent clinical condition with a high mortality rate owing to the ineffectiveness of current therapies. Mesenchymal stem cells (MSCs) are adult stem cells with potential as novel therapies in regenerative medicine owing to the absence of allogenic rejection. Glial cell-derived neurotrophic factor (GDNF) acts as a morphogen in kidney development. The therapeutic effectiveness of bone marrow MSCs overexpressing GDNF (GDNF-MSCs) was evaluated in an NSN rat model. An adenoviral vector was used to transduce MSCs with GDNF and a green fluorescent protein reporter gene. Then, GDNF-MSCs were injected into NSN rats via the renal artery. The influence of GDNF on renal injury was assessed. The location of GDNF-MSCs in kidneys was detected using fluorescence microscopy, cells were counted, and kidney function was measured. Infusion of GNDF-MSCs enhanced the recovery of renal function in NSN rats. MSCs were detected in the kidney cortex after injection. Compared with control MSCs, GDNF-MSCs led to significantly better renal function and injury recovery in NSN rats. GDNF has a positive effect on MSC differentiation in renal tissue. Owing to their highly renoprotective capacity, GDNF-MSCs represent a possible novel cell-based paradigm for treatment of glomerulonephritis. PMID- 22105544 TI - Sequence analysis of RNA 1 of lilac leaf chlorosis virus supports a close relationship to subgroup 3 ilarviruses. AB - Analysis of the nucleotide sequence of the RNA 1 of lilac leaf chlorosis virus (LLCV) supports a close relationship with subgroup 3 ilarviruses. LLCV RNA 1 consists of 3404 nucleotides (nt) and encodes a single open reading frame consisting of 3111 nt. The deduced protein (M(r) 117 kDa) contains the putative methyltransferase domain in the N-terminal region, and the NTPase/helicase domain in the C-terminal region. A conserved 41-nt region was identified at the distal end of the 3'UTR of all three genomic fragments of LLCV, with hairpin structures that may constitute putative coat protein binding sites. PMID- 22105545 TI - Rational design of smart supramolecular assemblies for gene delivery: chemical challenges in the creation of artificial viruses. AB - Polymeric materials have been extensively developed as a delivery vehicle for nucleic acids over the past two decades. Many previous studies have demonstrated that synthetic delivery vehicles can be highly functionalized by chemical approaches to overcome biological barriers in nucleic acid delivery, similar to viruses. Based on our current knowledge, this tutorial review describes rational strategies in the design of polymeric materials to achieve construction of the versatile vehicles, that is "artificial viruses", for successful gene therapy, especially focusing on the chemical structures with the minimal adverse effects. PMID- 22105546 TI - Gastrointestinal manifestations of scleroderma: recent progress in evaluation, pathogenesis, and management. AB - Gastrointestinal (GI) involvement is frequent in scleroderma (systemic sclerosis [SSc]) and is the most frequent internal complication of the disease. Patients with GI involvement have impaired quality of life, and their prognosis may be one of severe impairment. Unfortunately, GI involvement is often noticed when severe complications have already occurred, is irreversible, and is difficult to manage. The past 2 to 3 years have been rich in exciting studies that we hope will help identify, prevent, treat, and monitor disease progression. Recent studies on the pathophysiology of GI tract disease could lead to advances in the treatment of GI tract involvement. The importance of treating gastroesophageal reflux (GER) has been reinforced by studies showing GER damage in almost all SSc patients, and the fact that GER damage is reversible if early treatment with proton pump inhibitors is introduced. Moreover, recent data showing a link between GER and interstitial lung disease in SSc underscore the importance of aggressive GER treatment in SSc patients. A novel lung pattern possibly related to GER also has been described. New, exciting data on gastric vascular antral ectasia have been published. Finally, malnutrition in SSc patients has been highlighted, and anorectal involvement has been emphasized. PMID- 22105547 TI - Management of obstetric antiphospholipid syndrome. AB - Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs. PMID- 22105548 TI - Potential use of statins in the treatment of antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is a disorder characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity with the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and/or anti-beta2-glycoprotein I antibodies). Several studies have contributed to uncovering the basis of antiphospholipid antibody pathogenicity, including the targeted cellular components, affected systems, involved receptors, intracellular pathways used, and the effector molecules that are altered in the process. Therapy for thrombosis traditionally has been based on long-term oral anticoagulation; however, bleeding complications and recurrence despite high intensity anticoagulation can occur. Based on all the data obtained, new potential therapeutic agents have been proposed. Statins have a variety of direct effects on gene expression and the function of cells of both the innate and adaptive immune systems, many of which are related to blockade of GTPase isoprenylation. In APS, statins have multiple profound effects on monocyte, lymphocyte, and endothelial cell activities, all of which may contribute to thrombosis prevention in APS patients. Nevertheless, larger randomized trials are needed to validate the role of statins in the treatment of this autoimmune disease. PMID- 22105550 TI - Metabolic engineering of Escherichia coli for 1-butanol biosynthesis through the inverted aerobic fatty acid beta-oxidation pathway. AB - The basic reactions of the clostridial 1-butanol biosynthesis pathway can be regarded to be the inverted reactions of the fatty acid beta-oxidation pathway. A pathway for the biosynthesis of fuels and chemicals was recently engineered by combining enzymes from both aerobic and anaerobic fatty acid beta-oxidation as well as enzymes from other metabolic pathways. In the current study, we demonstrate the inversion of the entire aerobic fatty acid beta-oxidation cycle for 1-butanol biosynthesis. The constructed markerless and plasmidless Escherichia coli strain BOX-3 (MG1655 lacI(Q) attB-P(trc-ideal-4)-SD(phi10) adhE(Glu568Lys) attB-P(trc-ideal-4)-SD(phi10)-atoB attB-P(trc-ideal-4)-SD(phi10) fadB attB-P(trc-ideal-4)-SD(phi10)-fadE) synthesises 0.3-1 mg 1-butanol/l in the presence of the specific inducer. No 1-butanol production was detected in the absence of the inducer. PMID- 22105551 TI - Correlation of antibody production rate with glucose and lactate metabolism in Chinese hamster ovary cells. AB - A linear relationship was found between the antibody production rate (q(mAb)) and the glucose and lactate consumption rate (q(GL)) in Chinese hamster ovary cells. Under a series of q(mAb)-perturbing conditions, q(GL) was determined and a linear relationship between q(mAb) and q(GL) was further established (R(2) = 0.914). Mitochondrial dehydrogenase activity was monitored in all the q(mAb)-perturbing conditions and showed a linear correlation with q(GL) (R(2) = 0.874) as well as with q(mAb). Taken collectively, our results establish that the metabolic parameter, q(GL), is linearly correlated with q (mAb); this finding strengthens our current understanding of process optimization for antibody production. PMID- 22105552 TI - Establishment and characterization of outer root sheath (ORS) cell line from Jining grey goat. AB - A new line of outer root sheath (ORS) cells was established from hair follicles of Jining grey goat by using a mechanical separation combined with enzyme digestion. Cell morphology is described at different phases. The chromosome analysis of ORS cells, identification of the ORS cells and morphological reversion test were detected at the 4th and 40th passages. The ORS cells were healthy and the growth characteristics were stable with a population doubling time of 52 h. Chromosome analysis showed that >58% of cells were diploid. Test for ORS cell line CK19 expression was positive. This newly established ORS cell line not only lays the foundation for further studying on the growth, regeneration, development law of goat hair follicle but also provides a mirror for the research of human hair in medical field. PMID- 22105553 TI - Mutations in isocitrate dehydrogenase 2 accelerate glioma cell migration via matrix metalloproteinase-2 and 9. AB - The gene encoding isocitrate dehydrogenase (IDH) is somatically mutated predominantly in secondary glioblastoma multiforme. Glioma-specific mutations in IDH1 always produced a single amino acid substitution at R132, but mutations in IDH2 were exclusively at R172 which was the analogous site to R132 in IDH1. Mutations of IDH1 and IDH2 led to simultaneous loss and gain of activities in the production of alpha-ketoglutarate and 2-hydroxyglutarate, respectively. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases involved in the degradation of the extracellular matrix. The exact role of IDH2 mutant on MMPs activity and cell migration has not been fully studied. Here, we show that in response to IDH2 mutations, low levels of alpha-ketoglutarate increased the stabilization of HIF-1alpha which can contribute to tumor growth. Moreover, mutant IDH2-induced HIF-1alpha improved the secretion levels of pro-MMP-2 and pro MMP-9 as well as the conversion from pro-MMP-2 to its active form, giving C6 glioma cells a higher migration potential. The HIF-1alpha pathway is probably a critical pathway for release of MMPs in the glioma cancer harboring IDH mutant. PMID- 22105554 TI - Efficient COD removal and nitrification in an upflow microaerobic sludge blanket reactor for domestic wastewater. AB - The treatment performance of an upflow microaerobic sludge blanket reactor (UMSB) for synthetic domestic wastewater was investigated at two dissolved oxygen (DO) levels, 0.3-0.5 and 0.7-0.9 mg l(-1), focusing on nitrification performance. The higher DO level induced complete nitrification of ammonia nitrogen (NH(3)-N), achieving chemical oxygen demand and NH(3)-N removals of 97 and 92%, respectively. There were consistently significantly higher nitrate nitrogen (NO(3)-N) and nitrite nitrogen (NO(2)-N) levels in the effluent, with ~66% of newly-produced oxidised nitrogen as NO(2)-N. Despite the high nitrification efficiency, only about 23% of the removed NH(3)-N amount from the influent was ultimately transformed into oxidised nitrogen due to the simultaneous nitrification-denitrification. Sludge blanket development and granulation occurred simultaneously in the UMSB. PMID- 22105555 TI - Vector-mediated chromosomal integration of the glutamate decarboxylase gene in Streptococcus thermophilus. AB - The integrative vector, pINTRS, was used to transfer glutamate decarboxylase (GAD) activity to Streptococcus thermophilus ST128 thereby allowing for the production of gamma-aminobutyric acid (GABA). In pINTRS, the gene encoding glutamate decarboxylase, gadB, was flanked by DNA fragments homologous to a S. thermophilus pseudogene to allow for integration at a non-essential locus on the chromosome. Screening techniques confirmed the insertion of gadB with either its endogenous promoter or the S. thermophilus P2201 promoter, resulting in the generation of recombinant strains, ST128/gadB or ST128/P2201-gadB. Following the integration event unwanted plasmid DNA, specifically the erythromycin resistance gene, was eliminated from the recombinant strains. Based on the production of GABA, activities of GAD for ST128/gadB and ST128/P2201-gadB were 30.6 +/- 6 and 27.9 +/- 7.2 MUM/mg dry cell wt, respectively. PMID- 22105556 TI - Variations in the three-dimensional location and orientation of the ACL in healthy subjects relative to patients after transtibial ACL reconstruction. AB - Recent reports have indicated that anatomical placement of the anterior cruciate ligament (ACL) graft is an important factor for restoration of joint function following ACL reconstruction. The objective of this study was to address a need for a better understanding of anatomical variations in ACL position and orientation within the joint. Specifically, variations in the ACL anatomy were assessed by testing for side-to-side ACL footprint location symmetry in a healthy population relative to the operative and contralateral knee in a patient population after traditional transtibial single-bundle ACL reconstruction. MRI and three-dimensional modeling techniques were used to determine the in vivo tibiofemoral ACL footprint centers and the resulting ACL orientations in both knees of 30 healthy subjects and 30 subjects after transtibial ACL reconstruction. While there were substantial inter-subject variations in ACL anatomy, the side-to-side RMS differences in the ACL footprint center were 1.20 and 1.34 mm for the femur and tibia, respectively, for the healthy subjects and no clinically meaningful intra-subject differences were measured. However, there were large intra-subject side-to-side differences after transtibial ACL reconstruction, with ACL grafts placed 5.63 and 7.64 mm from the center of the contralateral femoral and tibial ACL footprint centers, respectively. Grafts were placed more medial, anterior, and superior on the femur and more posterior on the tibia; producing grafts that were more vertical in the sagittal and coronal planes. Given the large variation among subjects, these findings advocate the use of the contralateral ACL morphology for retrospectively evaluating patient specific anatomic graft placement. PMID- 22105557 TI - (alpha-Diimine)tricarbonylhalorhenium complexes: the oxidation side. AB - The electrochemical behaviour of the complexes [Re(CO)(3)X(alpha-diimine)], X = Cl or Br, alpha-diimine = 1,4-di-tert-butyl-1,4-diaza-1,3-diene, was reinvestigated using cyclic voltammetry accompanied by IR and UV-vis spectroelectrochemistry. While the reduction results in the loss of halide, as necessary for the electrocatalytic activity of related diimine compounds, a reversible oxidation could be observed for the chloro complex 1 (X = Cl). The conversion of 1 to 1(+) in CH(2)Cl(2) or CH(3)CN is accompanied by high-frequency shifts (Deltanu = 73-114 cm(-1)) of the three carbonyl stretching bands, by a considerable change in carbonyl stretching modes, and by changed absorption in the visible region. DFT calculations support the spectroelectrochemical results and suggest an unusually large g anisotropy (g(1) 1.38, g(2) 2.06, g(3) 3.20) which explains the absence of detectable EPR signals for 1(+) under normal X band conditions. Frontier orbitals calculated by DFT for 1 reveal two close lying occupied orbitals (HOMO, HOMO-1) with Re-Cl character and a diimine based LUMO. PMID- 22105558 TI - Compromised decision making and the effects of manipulating physical states on human judgments. AB - OBJECTIVES: Nonmorally based decision making between two equitable objects often involves degrading the unchosen object and promoting the chosen object ("postdecisional dissonance"). One can extinguish these thought processes with the physical act of hand-washing ("clean slate" effects; [Lee & Schwarz (2010). Washing away postdecisional dissonance. Science, 328, 709.]). However, clean slate effects might not characterize all nonmorally based decision making, particularly for people who mentally "get stuck" making decisions (i.e., compromised decision making). DESIGN: We administered a clean slate task to 48 undergraduates (64.6% females; mean = 21.34 years, standard deviation = 4.06 years; 75% Caucasian), and identified individuals reporting relatively high compromised versus low-compromised decision making (e.g., self-reported repetitive thought processes and generalized anxiety symptoms). RESULTS: Only individuals reporting relatively high-compromised decision making continued to express postdecisional dissonance even after hand-washing. CONCLUSIONS: Behavioral markers of clean slate effects might result in identifying phenotypes associated with psychological concerns typified by compromised decision making. PMID- 22105559 TI - Sphingosine regulates the NLRP3-inflammasome and IL-1beta release from macrophages. AB - Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1beta secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1beta from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1beta release. IL-1beta release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation. PMID- 22105560 TI - Sixty-five gene-based risk score classifier predicts overall survival in hepatocellular carcinoma. AB - Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 * 10(-5), n = 100) and the second test cohort (P = 5.0 * 10(-5) , n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS). CONCLUSION: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets. PMID- 22105561 TI - [Treating Neonates with Levetiracetam: a survey among German University Hospitals]. AB - In contrast to drugs established to treat neonatal seizures, levetiracetam shows little neurotoxicity in experimental animal models and has good safety records in adults and children. Here, we present results from a survey on the off-label use of levetiracetam in newborn infants among neonatologists and pediatric neurologists in German university hospitals. PMID- 22105562 TI - [ARDS/ALI in Childhood: treatment guideline]. PMID- 22105563 TI - New synthesis-systems chemical ecology. PMID- 22105564 TI - The mini mobile environmental monitoring unit: a novel bio-assessment tool. AB - This paper introduces a new bio-assessment tool, the mini-mobile environmental monitoring unit (MMU). The MMU is a portable, lightweight, energy-efficient, miniaturized laboratory that provides a low-flow system for on-site exposure of aquatic animals to local receiving waters in a protected, controllable environment. Prototypes of the MMU were tested twice in week-long studies conducted during the summers of 2008 and 2009, and in a 12-day study in 2010. In 2008, fathead minnows and polar organic chemical integrative samplers (POCIS) were deployed downstream from the Hastings, Nebraska wastewater treatment plant (WWTP), a waterway known to contain estrogenic contaminants in biologically active concentrations. In 2009, minnows and POCIS were deployed downstream, upstream and within the Grand Island, Nebraska WWTP, a site where the estrogenic contaminants had been detected, but were found at levels below those necessary to directly impact fish. In 2010, an advanced prototype was tested at the Sauk Center, Minnesota WWTP to compare its performance with that of traditional fish exposure methods including caged fish and static-renewal laboratory testing of effluent. Results from the prototype illustrate the capabilities of the MMU and offer an inexpensive monitoring tool to integrate the effects of pollutant sources with temporally varying composition and concentration. PMID- 22105565 TI - Cancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer. AB - Cancer viewed as a programmed, evolutionarily conserved life-form, rather than just a random series of disease-causing mutations, answers the rarely asked question of what the cancer cell is for, provides meaning for its otherwise mysterious suite of attributes, and encourages a different type of thinking about treatment. The broad but consistent spectrum of traits, well-recognized in all aggressive cancers, group naturally into three categories: taxonomy ("phylogenation"), atavism ("re-primitivization") and robustness ("adaptive resilience"). The parsimonious explanation is not convergent evolution, but the release of an highly conserved survival program, honed by the exigencies of the Pre-Cambrian, to which the cancer cell seems better adapted; and which is recreated within, and at great cost to, its host. Central to this program is the Warburg Effect, whose malign influence permeates well beyond aerobic glycolysis to include biomass interconversion and genomic heuristics. Warburg-type metabolism and genomic instability are targets whose therapeutic disablement is a major priority. PMID- 22105566 TI - Piezosurgery in otology: a promising device but not always the treatment of choice. PMID- 22105568 TI - WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication. AB - Evidence suggests a role for Wnt signaling in vascular wound repair and remodeling events. Despite this, very little is known about the effect of Wnt ligands on the structure and function of vascular cells. In this study, we treated vascular smooth muscle cells with 250 ng/ml of recombinant Wnt3a for 72 h and observed changes in the cell phenotype. Our data suggest Wnt3a completely alters the phenotype of vascular smooth muscle cells. The Wnt3a-treated cells appeared larger and had increased formation of stress fibers. These cells also had increased expression of the smooth muscle contractile proteins, calponin and smooth muscle alpha-actin, and contracted a collagen lattice faster than control cells. The Wnt3a-treated smooth muscle cells displayed increased extracellular matrix synthesis, as measured by collagen I and III mRNA expression, along with increased expression of MMP2 and MMP9, but decreased TIMP2 levels. The Wnt3a induced change in cell phenotype was associated with increased expression of the gap junction protein connexin 43. Consistent with this, Wnt3a-treated smooth muscle cells displayed enhanced intercellular communication, as measured by the scrape-loading dye transfer technique. The canonical Wnt antagonist, dickkopf related protein 1, completely reversed the contractile protein and connexin 43 expression seen in the Wnt3a-treated cells, suggesting these changes were dependent on canonical Wnt signaling. Collectively, this data suggest Wnt3a promotes a contractile and secretory phenotype in vascular smooth muscle cells that is associated with increased gap junction communication. PMID- 22105567 TI - Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic beta-cell metabolism and survival. AB - Nanometre-scale spaces between organelles represent focused nodes for signal transduction and the control of cellular decisions. The endoplasmic reticulum (ER) and the mitochondria form dynamic quasi-synaptic interaction nanodomains in all cell types examined, but the functional role of these junctions in cellular metabolism and cell survival remains to be fully understood. In this paper, we review recent evidence that ER Ca(2+) channels, such as the RyR and IP(3)R, can signal specifically across this nanodomain to the adjacent mitochondria to pace basal metabolism, with focus on the pancreatic beta-cell. Blocking these signals in the basal state leads to a form of programmed cell death associated with reduced ATP and the induction of calpain-10 and hypoxia-inducible factors. On the other hand, the hyperactivity of this signalling domain plays a deleterious role during classical forms of apoptosis. Thus, the nanospace between ER and mitochondria represents a critical rheostat controlling both metabolism and programmed cell death. Many aspects of the mechanisms underlying this control system remain to be uncovered, and new nanotechnologies are required understand these domains at a molecular level. PMID- 22105569 TI - Polyethylene thickness is a risk factor for wear necessitating insert exchange. AB - PURPOSE: The aim of this observational study was to investigate the optimal minimal polyethylene (PE) thickness in total knee arthroplasty (TKA) and identify other risk factors associated with revision of the insert due to wear. METHODS: A total of 84 TKA were followed for 11-16 years. All patients received the same prosthesis design (Interax; Howmedica/ Stryker) with halfbearings: separate PE inserts medially and laterally. Statistical analysis comprised Cox-regression to correct for confounding. RESULTS: Eight knees (9.5%) had been revised due to thinning inserts and an additional patient is scheduled for revision. PE thickness, diagnosis, BMI and weight are risk factors for insert exchange. For each millimetre decrease in PE thickness, the risk of insert exchange increases 3.0 times, which remains after correction for age, gender, weight, diagnosis and femoral-tibial angle. Insert exchange was 4.73 times more likely in OA-patients compared to RA-patients. For every unit increase in BMI and weight the risk for insert exchange increases 1.40 times and 1.14 times, respectively. CONCLUSIONS: In conclusion we therefore advise against the use of thin PE inserts in modular TKA and recommend PE inserts with a minimal 8-mm thickness. PMID- 22105570 TI - Laparoscopic pyloromyotomy: is a knife really necessary? AB - BACKGROUND: Laparoscopic pyloromyotomy (LP) is currently accepted as a suitable treatment modality for infantile hypertrophic pyloric stenosis (IHPS). In this report, we describe some technical modifications of LP using a 3- or 5-mm hook with electrocautery as a substitute for a knife for incising the pylorus. The outcomes of LP using a standard retractable pyloromyotomy knife are compared with those of LP using a hook electrocautery. METHODS: The patients with ultrasound proven IHPS who had undergone LP in a single institution from December 2008 to April 2010 were retrospectively analyzed. Incision on the pylorus was made with a 3-mm pyloromyotomy knife in the initial 12 cases. However, in the latter part of the study, a 3- or 5-mm hook with electrocautery was used for the incision. A Maryland dissector was used for completing the pyloromyotomy. The results were compared in terms of duration of surgery, complications, time taken to establish the first full feed, requirement of analgesics, postoperative emesis, and postoperative stay in the hospital. Independent sample t test and the Chi-square test were used for statistical analysis. RESULTS: Of the 27 patients analyzed, 12 underwent LP using a pyloromyotomy knife and the remaining 15 patients were operated on using a hook with electrocautery instead of the knife. The operating time, time taken to establish the first full feed, and duration of hospital stay were comparable among the two groups with no statistically significant difference. No complications were recorded in either group. CONCLUSIONS: Use of hook electrocautery for incising the pylorus provides a bloodless field without affecting the postoperative recovery and outcome. It also obviates any need of specialized instruments like a pyloromyotomy knife or other sharp instruments for pyloric incision. PMID- 22105571 TI - Cross-cultural adaptation and reliability of pediatric sleep questionnaire in assessment of sleep-disordered breathing in the Malay speaking population. AB - BACKGROUND: Sleep-disordered breathing (SDB) is common but often underdiagnosed in children. The Pediatric Sleep Questionnaire developed by University of Michigan, USA (English UM PSQ) has high sensitivity and specificity in identifying children with sleep-disordered breathing. This study aimed to translate and adapt the English UM PSQ into Malay language as a screening tool to assess SDB among the Malay speaking population. The second objective was to determine the psychometric measurements of the translated UM PSQ (Malay UM PSQ). METHODS: The Malay UM PSQ was translated through forward-backward translation techniques by two independent accredited bodies and reviewed by a panel of experts. The questionnaire was tested in two phases. The respondents were from hospital staffs with children and parents of primary school children aged 6-10 years. The reliability of questionnaires was measured by Cronbach's alpha and Kappa (kappa) statistics. RESULTS: The overall scale of internal consistency of the Malay UM PSQ was good, i.e., Cronbach's alpha = 0.760 (alpha = 0.457, 0.608 and 0.688 for snoring, sleepiness and behavioral domains respectively). The English UM PSQ also had good internal consistency at alpha = 0.753 (alpha = 0.589, 0.524, to 0.793 for snoring, sleepiness and behavioral domains respectively). Test-retest reliability for most items was good with correctness of >85.0% in all items. Only one item was seen in the Malay UM PSQ with kappa=0.348, while the remaining ranged from kappa=0.489 to 0.811. For the English UM PSQ, kappa ranged from 0.660 to 0.945. CONCLUSION: Both English and Malay UM PSQ have acceptable psychometric measurement properties as screening tools to assess SDB in the Malay speaking population. PMID- 22105572 TI - Trisomy 18 mosaicism: report of two cases. AB - BACKGROUND: Mosaic trisomy 18 has a wide phenotypic spectrum ranging from near normal to early death. We report two cases that add to our knowledge of the disease. METHODS: Patient 1 was a girl with a tracheoesophageal fistula, horse shoe kidneys and a ventricular septal defect. Karyotyping of her lymphocytes showed complete trisomy 18. Due to her milder phenotypes, skin fibroblasts were karyotyped. Patient 2 was a boy with biventricular hypertrophic cardiomyopathy, patent ductus arteriosus, ventricular and atrial septal defects and significant feeding problems. RESULTS: Karyotyping of the skin and lymphocytes in patients 1 and 2 respectively revealed trisomy 18 mosaicism. Both children had only mild learning problems and were generally healthy with satisfactory growth. Patient 1 illustrates the possibility of significant discrepancy between the levels of trisomic cells in skin fibroblasts and lymphocytes leading to misdiagnosis. This finding has significant implications in medical management and counselling. Hypertrophic cardiomyopathy in patient 2 is recognized as a novel finding for this condition. CONCLUSION: There is the possibility of good outcome for patients with mosaic trisomy 18, even in the presence of multiple congenital anomalies. PMID- 22105573 TI - Solid tumors in Turkish children: a multicenter study. AB - BACKGROUND: This paper presents a detailed incidence study on childhood solid tumors comprising a histopathology-based documentation of benign and malignant lesions. METHODS: The Ankara Pediatric Pathology Working Group collected databases of pediatric solid tumors from six pediatric reference centers in order to analyze the incidence, distribution and some epidemiologic characteristics of the tumors and to establish a multicenter database for further studies. A five year retrospective archive search was carried out. Excluding epithelial tumors of the skin, leukemia, lymphoreticular system neoplasias, metastatic tumors, and hamartomas, 1362 solid tumors in 1358 patients were classified according to age, sex, localization, histopathology and clinical behavior. RESULTS: The male/female ratio was 0.9; 14.8% (201) of the patients belonged to 0-1 year age group, 20.7% (281) to 2-4 years, 25.9% (352) to 5-10 years, 22.2% (301) to 11-14 years, and 16.4% (223) to 15-18 years. Among all tumors, 708 (52.0%) were malignant, 645 (47.4%) benign tumors, 2 (0.1%) borderline tumors, and 2 (0.1%) unknown behavioral tumors. Malignant tumors were found in 50.2% (357) of female patients and in 54.0% (349) of male patients. A balanced distribution between benign and malignant entities among children under 18 years was observed. Comparison between the age groups revealed malignant cases outnumbered benign cases under 4 years of age while benign tumor numbers increased after 10 years of age. The most common entities in the malignant group were of sympathetic nervous system origin, while soft tissue tumors far outnumbered the others in the benign group. CONCLUSIONS: We conclude that the cancer patterns of children in the Ankara region mostly resemble with those of the western population. This study provides useful information on the diagnosis of solid tumors in children and highlights variations in cancer incidence in different age groups. PMID- 22105574 TI - Impact of childhood obesity treatment on body composition and metabolic profile. AB - BACKGROUND: Childhood obesity is associated with adverse changes in cardiometabolic risk factors. A family-oriented group program stressing a health promoting lifestyle has been more effective than routine counselling in the treatment of obesity in school children. The aim of the present study was to compare the impact of group program and routine councelling on body composition and metabolic profile, and to evaluate the associations of changes in adiposity with levels of cardiometabolic risk factors. METHODS: Seventy obese prepubertal children were randomized into family-oriented group program (15 sessions for parents and children) and routine counselling (2 appointments for children). Body mass index (BMI), body composition and different metabolic risk factors were assessed before and after the 6-month intervention. RESULTS: Waist/height decreased more in the children attending the group treatment, but there were no significant differences between treatment arms in the changes of metabolic risk factors. When the arms were analyzed as combined, serum triglycerides decreased significantly if BMI standard deviation score (BMI-SDS) decreased >= 0.5. Serum fasting insulin decreased if BMISDS decreased >= 0.25. CONCLUSIONS: Obesity related metabolic risk factors reduced in prepubertal children if BMI-SDS decreased substantially. This result was not dependent on which intervention, family-oriented group program or routine counselling, was used. PMID- 22105575 TI - Cross-cultural application of Achenbach System of Empirically Based Assessment: instrument translation in Chinese, challenges, and future directions. PMID- 22105576 TI - Clinical characteristics and mutation analysis of X-linked severe combined immunodeficiency in China. AB - X-linked severe combined immunodeficiency (X-SCID) is a rare, life-threatening immune disorder, caused by mutations of the gene for the gamma-chain (gammac) of the interleukin-2 receptor, IL2RG. We analyzed the clinical, immunologic, and molecular characteristics of children with X-SCID, attempting to improve the diagnosis and treatment of X-SCID in China. METHODS: X-SCID was suspected in male infants with recurrent or persistent infections. Eleven male infants from ten unrelated Chinese families were included. The IL2RG gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives. X-linked short tandem repeat (X-STR) typing was done to define the maternal lymphocyte engraftment. RESULTS: The 11 children exhibited recurrent infections and 10 of them had lymphopenia. B cells were present in all patients, T cells were markedly reduced in 10, and NK cells were markedly reduced in 9. Nine IL2RG gene mutations were identified in the 11 children, with 5 novel mutations. One patient was found to have the maternal lymphocyte engraftment. CONCLUSION: The clinical presentations and immunologic characteristics of the X SCID patients were accordingly quite uniform despite the heterogeneity of mutations locating almost in the entire gammac gene. PMID- 22105577 TI - Role of cytoreductive nephrectomy in the era of targeted therapy for renal cell carcinoma. AB - With the advent of targeted therapy for the treatment of metastatic renal cancer, the routine use of cytoreductive nephrectomy has been questioned. However, available data suggest that cytoreductive nephrectomy remains an integral part of treatment in properly selected patients. This review details the rationale for the continued use of cytoreductive nephrectomy in acceptable surgical candidates in the era of targeted therapy. PMID- 22105578 TI - Adverse events after screening and follow-up colonoscopy. AB - OBJECTIVE: We provide new information about how the risk of adverse events following colonoscopy varies by age and indication (screening vs. follow-up performed to evaluate a positive result from another screening modality). METHODS: We constructed a retrospective cohort comprised of 43,456 individuals aged 40-85 years enrolled in a large integrated healthcare organization in Washington State who underwent outpatient colonoscopy between 1994 and 2009. We calculated rates of serious adverse events (perforation, hemorrhage, and acute diverticulitis) in the 30 days following colonoscopy and compared rates using log binomial regression models. RESULTS: We observed 4.7 serious adverse events per 1,000 screening colonoscopies and 6.8 per 1,000 follow-up colonoscopies. Polypectomy increased the rate of serious adverse events (relative rate [RR], 2.64; 95% confidence interval [CI], 1.97-3.56). Older age was associated with increased risk of serious adverse events, after adjusting for polypectomy, gender, and indication. Compared to individuals aged 50-64 years, risk was elevated for those aged 65-74 (RR, 1.93; 95% CI, 1.40-2.65) and 75-85 (RR, 3.21; 95% CI 2.14-4.86). We observed similar age effects in individuals with and without significant comorbid conditions. CONCLUSIONS: The risks of serious adverse events following colonoscopy performed as part of screening are low but increase with age and are more likely after polypectomy. PMID- 22105579 TI - In vitro permeation of mesembrine alkaloids from Sceletium tortuosum across porcine buccal, sublingual, and intestinal mucosa. AB - Sceletium tortuosum is an indigenous South African plant that has traditionally been used for its mood-enhancing properties. Recently, products containing S. tortuosum have become increasingly popular and are commonly administered as tablets, capsules, teas, decoctions, or tinctures, while traditionally the dried plant material has been masticated. This study evaluated the in vitro permeability of the four major S. tortuosum alkaloids (i.e., mesembrine, mesembrenone, mesembrenol, and mesembranol) across porcine intestinal, sublingual, and buccal tissues in their pure form and in the form of three different crude plant extracts, namely water, methanol, and an acid-base alkaloid enriched extract. The permeability of mesembrine across intestinal tissue was higher than that of the highly permeable reference compound caffeine (which served as a positive control for membrane permeability) both in its pure form, as well as in the form of crude extracts. The intestinal permeability of mesembranol was similar to that of caffeine, while those of mesembrenol and mesembrenone were lower than that of caffeine, but much higher than that of the poorly permeable reference compound atenolol (which served as a negative control for membrane permeability). In general, the permeabilities of the alkaloids were lower across the sublingual and the buccal tissues than across the intestinal tissue. However, comparing the transport of the alkaloids with that of the reference compounds, there are indications that transport across the membranes of the oral cavity may contribute considerably to the overall bioavailability of the alkaloids, depending on pre-systemic metabolism, when the plant material is chewed and kept in the mouth for prolonged periods. The results from this study confirmed the ability of the alkaloids of S. tortuosum in purified or crude extract form to permeate across intestinal, buccal, and sublingual mucosal tissues. PMID- 22105580 TI - Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. AB - Intervertebral disc (IVD) degeneration is accompanied by growth factor overexpression and increased cell proliferation, probably representing a tissue repair process. Accordingly, we studied the effect of exogenous and autocrine growth factors on the proliferation of human IVD cells. We observed that Platelet Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin like Growth Factor-I (IGF-I) stimulate DNA synthesis of human IVD cells, through the activation of the MEK/ERK and the PI-3K/Akt signal transduction pathways. Furthermore, medium conditioned (CM) by IVD cells induced DNA synthesis in the same cells, indicating the secretion of autocrine growth factors. The MEK/ERK and PI-3K/Akt pathways were also induced by CM, while their inhibition reversed in large part the DNA synthesis induction by CM. These responses to the exogenous and autocrine growth factors were qualitatively similar in both nucleus pulposus (NP) and annulus fibrosus (AF) cell cultures. Immunohistochemical studies in human biopsies showed significant activation of both signaling pathways, which was most prominent in the clusters of proliferating cells. These in vitro and in vivo data indicate that the proliferation of human IVD cells is regulated by exogenous and autocrine growth factors mainly via the MEK/ERK and PI-3K/Akt pathways; this may contribute to the design of future interventional approaches. PMID- 22105581 TI - A distinct platinum growth mode on shaped gold nanocrystals. AB - An ultralow amount of platinum can be deposited on the gold surface using copper underpotential deposition and galvanic exchange. The platinum tended to deposit as layers on the octahedral gold nanocrystals with an Au(111) surface, while it aggregated and formed small particles on the cubic gold nanocrystals with an Au(100) surface. PMID- 22105582 TI - Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. AB - The liver is the major metabolic organ and is subjected to constant attacks from chronic viral infection, uptake of therapeutic drugs, life behavior (alcoholic), and environmental contaminants, all of which result in chronic inflammation, fibrosis, and, ultimately, cancer. Therefore, there is an urgent need to discover effective therapeutic agents for the prevention and treatment of liver injury, the ideal drug being a naturally occurring biological inhibitor. Here we establish the role of IL30 as a potent antiinflammatory cytokine that can inhibit inflammation-induced liver injury. In contrast, interleukin (IL)27, which contains IL30 as a subunit, is not hepatoprotective. Interestingly, IL30 is induced by the proinflammatory signal such as IL12 through interferon-gamma (IFN gamma)/signal transducer and activator of transcription 1 signaling. In animal models, administration of IL30 by way of a gene therapy approach prevents and treats both IL12-, IFN-gamma-, and concanavalin A-induced liver toxicity. Likewise, immunohistochemistry analysis of human tissue samples revealed that IL30 is highly expressed in hepatocytes, yet barely expressed in inflammation induced tissue such as fibrous/connective tissue. CONCLUSION: These novel observations reveal a novel role of IL30 as a therapeutic cytokine that suppresses proinflammatory cytokine-associated liver toxicity. PMID- 22105583 TI - Population pharmacokinetics of tacrolimus in pediatric liver transplantation: early posttransplantation clearance. AB - BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L.h( 1).kg(-0.75) immediately after transplantation, increasing to a maximum of 1.37 L.h(-1).kg(-0.75). Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population. PMID- 22105584 TI - Measurement of cyclosporine A in rat tissues and human kidney transplant biopsies -a method suitable for small (<1 mg) samples. AB - Therapeutic drug monitoring is used to individualize cyclosporine A (CsA) dosing after transplantation. However, immunosuppressant concentrations within the graft may better predict clinical outcomes, including toxicity. This study aimed to develop a method suitable for CsA measurement using routine fine-needle biopsy samples. CsA was quantified retrospectively in kidney and liver tissues from 10 rats administered CsA, and 21 core needle kidney biopsies taken from renal transplant patients with suspected graft dysfunction. Dried biopsies were weighed (mean +/- SD weights of 0.22 +/- 0.18 mg), enzymatically solubilized, and then CsA was extracted and quantified using online 2-dimensional liquid chromatography tandem mass spectrometry. The method was linear (r2 > 0.997, n = 10), accurate, and precise (quality control and calibrator coefficient of variation and bias <15%), with minimal matrix effects (coefficient of variation and bias <15%). Reproducibility of tissue weight measurements was confirmed by retrospective DNA quantitation, with a significant linear correlation between weight and total DNA concentration (r2 = 0.988). In rats, there was a significant linear correlation between CsA concentrations in liver and kidney tissues (r2 = 0.996) but there was no correlation between blood (C0) and tissue CsA concentrations (Spearman r = 0.430 and 0.503, P > 0.05). Similarly, in 16 transplant patients, for whom blood CsA concentrations (C2) were available within 1 day of the renal biopsy being performed, there was no significant correlation between CsA concentrations in blood and kidney tissue (Spearman r = 0.168, P > 0.05). In situ CsA measurements acquired using this method could make an easy transition into clinical use due to their retrospective nature and minimal disruption to current clinical protocols and could provide an additional tool for optimizing clinical outcomes in the future. PMID- 22105585 TI - Pharmacodynamic monitoring of cyclosporin A reveals risk of opportunistic infections and malignancies in renal transplant recipients 65 years and older. AB - BACKGROUND: The cohort of senior renal allograft recipients is increasing. Age related physiologic changes are believed to influence the pharmacokinetics and pharmacodynamics of immunosuppression. Measuring the residual nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE) is a promising pharmacodynamic tool to individually monitor cyclosporin A (CsA) therapy. PATIENTS AND METHODS: In stable senior renal allograft recipients (>=65 years), the expression of 3 calcineurin-dependent NFAT-regulated genes (interleukin-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) was measured in whole-blood samples before (C0) and 2 hours (C2) after oral drug intake. Clinical data on opportunistic infections were collected in a clinical observational period of 12 months. RESULTS: Thirty-six senior patients [22 male, median age 70 years (65-77)] were enrolled in this clinical study. Median daily CsA dosage was 150 mg (50-250), CsA C0 concentration 102 mcg/L (range 33-157), and CsA C2 concentration 551 mcg/L (range 254-1228). The NFAT RGE varied between 3% and 37% (median 10%). CsA peak concentrations and inhibition of gene expression correlated significantly (r = -0.737, P < 0.001). NFAT RGE in patients with opportunistic infections including atypical pneumonia, cytomegalovirus and herpes viral infections was lower compared with that in patients without infections [4% (3-13) versus 11% (3-37), P = 0.05], whereas the daily CsA dosage, CsA C0, and CsA C2 concentrations were comparable. Renal allograft function correlated inversely with NFAT RGE. CONCLUSIONS: A higher degree of immunosuppression correlated with more infectious complications in a considerable proportion of senior renal allograft recipients treated with standard CsA therapy. Pharmacodynamic monitoring is an approach to individualize immunosuppression and could provide the opportunity to reduce complications caused by infections. PMID- 22105586 TI - Oseltamivir, an influenza neuraminidase inhibitor drug, does not affect the steady-state pharmacokinetic characteristics of cyclosporine, mycophenolate, or tacrolimus in adult renal transplant patients. AB - BACKGROUND: An influenza neuraminidase inhibitor drug, oseltamivir (Os) may be prescribed to renal transplant patients to prevent and treat influenza A and B illness. A pharmacokinetic (PK) interaction between Os and immunosuppressive drugs might adversely affect the efficacy and/or toxicity of the latter agents. This study was conducted to determine whether adverse symptoms and acute drug interactions occur during their coadministration. MATERIALS AND METHODS: A randomized, crossover study design was utilized to study the effect of a 75-mg dose of Os on the steady-state PK of cyclosporine A (CyA), mycophenolate mofetil, or tacrolimus (Tac) in a convenience sample of 19 adults with a renal allograft by measurement of total plasma or blood drug concentrations (C(p)) over one 12 hour dose interval. Os PK parameters were determined from its concentrations and those of its metabolite, Os carboxylate, in plasma and urine over 48 hours. RESULTS: Of 19 volunteers, 12 were men, with age (mean +/- SD) 46 +/- 11 years, weight 83 +/- 19 kg, and calculated Cl(creatinine) 64 +/- 27 mL/min. Adverse effects were minor and transient. Os did not affect the steady-state C(max), T(max), or area under the concentration versus time curve (AUC) over a 12-hour dose interval of CyA, mycophenolic acid, or Tac or the C(trough) of CyA or mycophenolate but increased the mean C(trough) of Tac by 13%. DISCUSSION: The increase in Tac mean C(trough) during coadministration with Os is not likely clinically important. Os and Os carboxylate PK were similar to those in subjects with native kidneys and similar renal function who have been described in the literature. CONCLUSIONS: These data from a single Os dose study suggest that coadministration is not expected to cause adverse symptoms nor alter the steady state PK of CyA, mycophenolate mofetil, or Tac in stable adult renal transplant patients with mild renal insufficiency. The data enable a multiple-dose study that reflects clinical practice during influenza exposure and assesses the possibility that chronic exposure to Os might result in a different outcome. PMID- 22105587 TI - A new rapid and sensitive LC-MS assay for the determination of sorafenib in plasma: application to a patient undergoing hemodialysis. AB - A simple liquid chromatography-mass spectrometry method was developed and validated for quantification of sorafenib (Nexavar) in human plasma. After a solid-phase extraction procedure, the separation was performed within 2 minutes using an isocratic flow of a mobile phase consisting of formic acid/acetonitrile applied on a C18 analytical column. The analyte was detected by mass spectrometry in the single-ion monitoring mode. The method was validated according to the recommendations of the US Food and Drug Administration. The method was linear (r2 > 0.99) between 10 and 10,000 ng/mL. The lower limits of detection and quantification were 5 and 10 ng/mL, respectively. Within-day and between-day imprecisions were less than 10.4%, and inaccuracy did not exceed 8.7%. The mean extraction recovery was 92.2%. The method also provided satisfactory results in terms of time stability and dilution integrity. Sorafenib plasma concentrations of the studied patient ranged between 1831 and 3459 ng/mL. This new technique is rapid, sensitive, and was applied to the determination of sorafenib plasma concentrations in a patient undergoing hemodialysis. Our results indicate that sorafenib is not cleared from plasma by hemodialysis, although analysis should be delayed after dialysis to avoid erratic fluctuations. PMID- 22105588 TI - A population pharmacokinetic/pharmacodynamic model of methotrexate and mucositis scores in osteosarcoma. AB - Methotrexate, when used in high doses (12 g/m2) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4 51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age- and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and between-occasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V1 = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V2 = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score >= 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses. PMID- 22105589 TI - Population pharmacokinetics of modafinil and its acid and sulfone metabolites in Chinese males. AB - BACKGROUND: Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition. METHODS: Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches. RESULTS: Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL. CONCLUSIONS: A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible. PMID- 22105590 TI - No influence of body weight on serum levels of antidepressants. AB - BACKGROUND: Body weight may affect pharmacokinetic parameters in various ways and may therefore have a significant impact on the serum concentration of a drug at a given dose. Although patients with major depressive disorder frequently show an elevated body mass index, studies investigating the relation between body weight and serum concentration of antidepressants are lacking. This study should help to clarify the influence of body weight on the serum levels of the antidepressants amitriptyline (AMI), clomipramine (CLO), doxepine (DOX), escitalopram (ESC), and venlafaxine (VEN) in a naturalistic clinical setting. METHODS: Therapeutic drug monitoring analyses obtained in the psychiatric university hospital of Wuerzburg from patients treated with AMI (n = 171), CLO (n = 94), DOX (n = 133), ESC (n = 19), and VEN (n = 24) were retrospectively assessed. The influence of body weight on dose-corrected serum concentrations was evaluated by Spearman-Rho correlations and by comparing dose-corrected serum levels in patients with low and high body weight (first versus fourth quartile). The serum concentrations were determined by high-performance liquid chromatography methods in the therapeutic drug monitoring laboratory of the psychiatric university hospital of Wuerzburg. RESULTS: Dose-corrected serum concentrations did not significantly correlate with body weight in patients treated with AMI, CLO, DOX, ESC, or VEN. There was no significant difference in the dose-corrected serum concentrations of AMI, CLO, and DOX between patients of the first and fourth quartiles of body weight. The latter evaluation was not performed for ESC and VEN because of too small samples. CONCLUSIONS: Against the intuitive presumption of a weight dependency of dose corrected serum concentrations, the findings suggest that there is no relevant influence of body weight on the dose-corrected serum level of several widely used antidepressants even if extreme subgroups of patients with low and high body weights are considered. PMID- 22105591 TI - Measurement of posaconazole, itraconazole, and hydroxyitraconazole in plasma/serum by high-performance liquid chromatography with fluorescence detection. AB - BACKGROUND: Itraconazole and posaconazole are used in the prevention and treatment of invasive fungal infections. However, the oral bioavailability of both compounds varies widely, and dose-serum concentration relationships are poorly defined for these analytes. The aim of this work was to develop and validate a simple assay that could be implemented in most laboratories for the purpose of therapeutic drug monitoring. METHODS: Calibrators (n = 7) and internal quality control solutions (n = 3) were prepared in pooled human serum. Sample (100 MUL), internal standard solution (25 MUL), Tris solution (2 mol/L; pH 10.6), and extraction solvent (methyl tert-butyl ether, 600 MUL) were vortex mixed and centrifuged. The solvent layer was removed and evaporated to dryness and the residue reconstituted in water:methanol (1 + 3, 50 MUL). A portion (5 MUL) of the reconstituted extract was analyzed using a 3-MUm Gemini C6 phenyl column with fluorescence detection (excitation 260 nm, emission 350 nm). The method was used to measure itraconazole and hydroxyitraconazole, or posaconazole, in serum samples taken 1-2 hours before the next dose, from patients forming part of a study into management and diagnostic strategies for invasive aspergillosis. RESULTS: Response was linear over the calibration ranges. Accuracy and imprecision were 92-111.4% and 3.2-13.4% (relative standard deviation), respectively. No interferences were noted. There was a good agreement with nominal values of each analyte in an external quality assessment scheme. In patients prescribed either 400 mg/d of itraconazole (n = 46) or 600-800 mg/d of posaconazole (n = 28) only 24% and 7% of samples, respectively, had serum itraconazole or posaconazole concentrations above the target threshold suggested in published guidelines. CONCLUSIONS: A simple, sensitive high-performance liquid chromatographic method has been developed for the analysis of itraconazole, hydroxyitraconazole, and posaconazole in serum/plasma. Few of the samples measured from patients participating in the clinical study attained concentrations of the drug/metabolite in serum that have been recommended for effective antifungal therapy. PMID- 22105592 TI - Monitoring metformin in cardiac patients exposed to contrast media using ultra high-performance liquid chromatography tandem mass-spectrometry. AB - BACKGROUND: There is no evidence that the use of contrast media (CM) in diabetic patients with serum creatinine <130 MUmole/L leads to metformin accumulation and subsequent lactic acidosis. Therefore, the objective of this investigation was to monitor cardiac patients for the effects of CM on their metformin plasma concentration and serum creatinine clearance (ClCr). METHODS: Metformin plasma concentrations were measured by a new, fully validated specific, precise, and accurate ultra-high-performance liquid chromatography tandem mass-spectrometric assay. The detection was performed using positive electrospray ionization in the multiple reaction monitoring mode. Fifty patients with serum creatinine levels <130 MUmole/L were monitored for the effect of CM exposure on metformin concentration and ClCr. Pharmacokinetic parameters were calculated in 8 of these patients, and metformin accumulation was monitored in 10 patients before and after their exposure to CM. RESULTS: Linear response (r >= 0.998) was observed over the range of 5-2000 ng/mL of metformin, with the lower limit of quantification of 2.3 ng/mL. The intraday and interday precision (relative standard deviation) values were <13%, and the accuracy (relative error) was <-10% for metformin concentrations. The assay was sensitive to follow the pharmacokinetics of metformin in humans during a dosing interval after an oral dose at steady state. Metformin pharmacokinetic parameters were estimated in 8 patients exposed to CM. The mean C(max) of 1.9 +/- 0.6 mg/L was attained at 4.1 +/- 1.9 hours. There was no evidence of any drug accumulation or altered elimination due to the exposure to CM in the current population. ClCr showed no significant difference (P > 0.05) before (92.8 +/- 11.3 mL/min) and after 48 hours (90.5 +/- 10.5 mL/min) of exposure to CM. CONCLUSIONS: Our data suggest that the recommendation to withhold metformin in diabetic patients during CM exposure could be revised to withholding the drug only in patients with moderate to severe renal dysfunction. PMID- 22105593 TI - Population pharmacokinetic investigation for optimization of amiodarone therapy in Japanese patients. AB - BACKGROUND: Optimal use of amiodarone (AMD) requires information regarding the drug's pharmacokinetics and the influence of various factors on the drug's disposition. This study was conducted to establish the role of patient characteristic in estimating doses of AMD using nonlinear mixed effects modeling in Japanese patients treated with oral therapy. METHODS: Serum concentrations of AMD were determined by high-performance liquid chromatography. The 151 serum trough concentrations from 23 patients receiving repetitive oral AMD were collected. Analysis of the pharmacokinetics of AMD was accomplished using a 1 compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on AMD disposition was investigated. RESULTS: Estimates generated by nonlinear mixed effects modeling indicated that the clearance of AMD was influenced by the demographic variables: total body weight (TBW), daily dosage of AMD (DD), body mass index (BMI), gender (GEN), duration of AMD dosing (DUR), and patient clearance factor (Conc(theta); Conc = serum trough concentration of AMD). The final pharmacokinetic parameters were CL/F (L/h) = 0.072.TBW.Conc(-1.01).1.95(DD>=200).0.931(BMI>=25).1.37(GEN).DUR(-0.016), and Vd/F (L) = 78.4.TBW, where CL is total body clearance and Vd is volume of distribution. As all doses were given orally, it was impossible to assess the bioavailability (F). DD ?200 is an indicator variable that has a value of 1 if the patient is receiving more than 200 mg daily dosage of AMD, and 0 otherwise. BMI ?25 is an indicator variable that has a value of 1 if the BMI is 25 kg/m2 and over, and 0 otherwise. GEN is an indicator variable that has a value of 1 if the patient is woman, and 0 otherwise. CONCLUSIONS: The authors developed new population pharmacokinetic parameters. Clinical application of the findings in the present study to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. PMID- 22105594 TI - An enzymatic method to determine gamma-hydroxybutyric acid in serum and urine. AB - BACKGROUND: Gamma-hydroxybutyric acid (GHB) has become one of the most dangerous illicit drugs of abuse today. It is used as a recreational and date rape drug because of its depressant effect on the central nervous system, which may cause euphoria, amnesia, respiratory arrest, and coma. There is an urgent need for a simple, easy-to-use assay for GHB determination in urine and blood. In this article, a rapid enzymatic assay adapted to clinical chemistry analyzers for the detection of GHB is presented. METHODS: The described GHB enzymatic assay is based on a recombinant GHB dehydrogenase. The full validation of the assay was performed on a Konelab 30 analyzer (Thermo Fisher Scientific). RESULTS: The analytical sensitivity was <1.5 mg/L, whereas the functional sensitivity was 4.5 mg/L in serum and 2.8 mg/L in urine. The total imprecision coefficient of variation (CV) was <9.8% in serum and <7.9% in urine. The within-run imprecision showed a CV of <3.8% in serum and <4.6% in urine. The assay was linear within the range 5-250 mg/L. Mean recoveries were 109% in serum and 105% in urine. No cross reactivity was observed for tested GHB analogues and precursors. Comparison of GHB-positive samples showed an excellent correlation with ion chromatography, gas chromatography-mass spectrometry, and liquid chromatography associated to tandem mass spectrometry. Except for ethanol, no substantial interference from serum constituents and some drugs was observed. CONCLUSIONS: This automated GHB assay is fully quantitative and allows the accurate measurement of GHB in serum and urine. It can be used as a rapid screening assay for the determination of GHB in intoxicated or overdosed patients. PMID- 22105595 TI - Minimization of the preanalytical error in plasma samples for pharmacokinetic analyses and therapeutic drug monitoring--using doxorubicin as an example. AB - BACKGROUND: There are many sources of variability in plasma samples drawn for pharmacokinetic analyses or therapeutic drug monitoring. In this article, methods are proposed on how to prevent sample dilution (Part I) and contamination effects (Part II) in plasma samples, using doxorubicin as an example. METHODS: Experiments were performed in the laboratory setting to identify factors that could influence plasma samples in clinical practice. In part I, it was hypothesized that saline solution left in a catheter could lead to a dilution of samples drawn through this catheter. The impact of 2 different sampling techniques, the "discard method" and the "push-pull method", was examined. In part II, an infusion system was filled with a 1 mg/mL solution of doxorubicin. After rinsing the system with increasing volumes of saline solution, the drug concentration of the fluid left in the system was analyzed. Furthermore, plasma samples were drawn through the drug administration catheter, and the contamination of these samples with doxorubicin left in the catheter was measured. RESULTS: In part I, a discard volume of plasma equal to 4 dead volumes of the sampling line was necessary to avoid dilution of a sample taken from a port or double-lumen catheter filled with saline solution ("discard method"). Pulling up and down the same volume through the catheter 5 times ("push-pull method") was proved to be an alternative with no need to discard blood. In part II, after rinsing the infusion system with a volume of saline solution corresponding to 4 dead volumes of the system and after discarding a volume of plasma corresponding to 4 sampling line volumes, the doxorubicin contamination in the samples was negligibly small. CONCLUSIONS: Under the described conditions, the push-pull method delivered the same results as the discard method to prevent sample dilution. To avoid contamination in plasma samples, development of standardized sampling procedures seems to be essential and feasible. PMID- 22105596 TI - Pharmacokinetic study of saquinavir 500 mg plus ritonavir (1000/100 mg twice a day) in HIV-positive pregnant women. AB - Antiretroviral therapy during pregnancy is critical to preventing human immunodeficiency virus vertical transmission. Physiological changes during pregnancy can alter drug kinetics. The aim of this study was to assess the pharmacokinetics (PK) of saquinavir (SQV) boosted with ritonavir during pregnancy and postpartum. Fourteen human immunodeficiency virus-positive pregnant women started SQV 500 mg new tablet formulation plus ritonavir at a dose of 1000/100 mg twice a day + 2 nucleoside retrotranscriptase inhibitors during pregnancy. At weeks 24 and 34 of pregnancy and 6 weeks postpartum, a 12-hour PK study was conducted. PK parameters were calculated using Win Nolin software version 4.1. At week 24, the geometric mean values for SQV area under the plasma concentration time curve from 0-12 hours (AUC0-12), the maximum observed plasma concentration (C(max)), trough plasma concentration (C(min)), and the elimination half-life (t(1/2)) were 24.80 mg.h-1.mL-1, 4.66 mg/mL, 0.93 mg/mL, and 4.31 hours, respectively. At week 34, AUC0-12, C(max), C(min), and t(1/2) were 12.71 mg.h 1.mL-1, 3.23 mg/mL, 0.26 mg/mL, and 4.06 hours, respectively. Finally, at 6 weeks postpartum, mean values for SQV AUC0-12, C(max), C(min), and t(1/2) were 28.94 mg.h-1.mL-1, 3.92 mg/mL, 0.86 mg/mL, and 3.60 hours, respectively. Although PK parameters in week 24 and postpartum were very similar, those for week 34 showed an important reduction: -71.20%, -30.61%, -48.73%, and -5.81% in C(min), C(max), AUC0-12, and t(1/2), respectively, compared with week 24, but no statistically significant differences were shown between patients. No vertical transmissions were reported. Therapeutic drug monitoring of SQV during pregnancy should be considered, mainly during the third trimester, to ensure adequate drug exposure throughout the entire pregnancy. PMID- 22105597 TI - Do current response criteria in classical Ph-negative myeloproliferative neoplasms capture benefit for patients? PMID- 22105598 TI - Direct interaction of PU.1 with oncogenic transcription factors reduces its serine phosphorylation and promoter binding. AB - The homeostasis of hematopoiesis in the bone marrow is governed by a small number of key transcription factors, including PU.1, GATA-1 and c/EBPalpha. PU.1, a member of the E-twenty-six family of transcription factors, is indispensable for normal hematopoiesis. Inactivation of PU.1 induces acute leukemia in mice. Recent data suggest that the leukemia-associated fusion protein pro-myelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) inhibits PU.1, but the mechanism mediating this inhibition is unclear. Here, we investigated the mechanisms by which the fusion proteins PML/RARalpha and pro-myelocytic leukemia zinc finger/RARalpha (PLZF/RARalpha) (X-RARalpha) interfere with the function of PU.1. We found that X-RARalpha proteins functionally inactivate PU.1 by reducing its promoter-binding capacity, resulting in a reduction in PU.1-dependent transcriptional transactivation. In fact, X-RARalpha proteins directly interact with PU.1, leading to both the sequestration of PU.1 from its target promoters and a reduction in its serine phosphorylation, which is crucial for its promoter binding and transcriptional activity. We found that the functional inactivation of PU.1 could be overcome by the forced overexpression of PU.1 in PML/RARalpha- or PLZF/RARalpha-positive murine hematopoietic progenitor cells; evidently, this overexpression rescued the leukemic differentiation block induced by X-RARalpha proteins. Our data thus provide strong evidence that X-RARalpha proteins functionally inhibit PU.1, shedding light on the mechanism by which X-RARalpha proteins induce leukemogenesis. PMID- 22105599 TI - Report on a single-topic conference on "Chronic viral hepatitis--strategies to improve effectiveness of screening and treatment". AB - The 2010 Institute of Medicine report on "Hepatitis and Liver Cancer" indicated that lack of knowledge and awareness about chronic hepatitis B (HBV) and C virus (HCV) infections and insufficient understanding about the extent and seriousness of this public health problem impeded current efforts to prevent and control hepatitis B and C. A single-topic conference was held in June 2011 to discuss strategies to improve the effectiveness of screening, care referral, and clinical management of chronic HBV and HCV infections with the ultimate goal of reducing morbidity and mortality from these infections. Various models that have been shown to improve hepatitis screening and effectiveness of hepatitis treatment in the community, including rural settings and populations that have traditionally been excluded due to comorbidities, were presented. Recent advances in laboratory testing, medical management, and new antiviral therapies will not decrease the burden of viral hepatitis if persons at risk for or who are living with viral hepatitis are not aware of the risks, have not been diagnosed, or have no access to care. Systematic changes in our health care delivery system and enhanced coordination of prevention and care services with partnerships between public health leaders and clinicians through education of the public and health care providers and linkage of infected persons with care and treatment services can increase the success of preventing viral hepatitis and the effectiveness of hepatitis treatment in the real world. Implementation of these changes is feasible and will require policy changes, coordination among government agencies, and collaboration between government agencies, health care providers, community organizations, and advocacy groups. PMID- 22105600 TI - Outdoor 220Rn, 222Rn and terrestrial gamma radiation levels: investigation study in the thorium rich Fen Complex, Norway. AB - The present study was done in the Fen Complex, a Norwegian area rich in naturally occurring radionuclides, especially in thorium ((232)Th). Measurement of radioactivity levels was conducted at the decommissioned iron (Fe) and niobium (Nb) mining sites (TENORM) as well as at the undisturbed wooded sites (NORM), all open for free public access. The soil activity concentrations of (232)Th (3280 8395 Bq kg(-1)) were significantly higher than the world and the Norwegian average values and exceeded the Norwegian screening level (1000 Bq kg(-1)) for radioactive waste, while radium ((226)Ra) was present at slightly elevated levels (89-171 Bq kg(-1)). Terrestrial gamma dose rates were also elevated, ranging 2.6 4.4 MUGy h(-1). Based on long-term surveys, the air concentrations of thoron ((220)Rn) and radon ((222)Rn) reached 1786 and 82 Bq m(-3), respectively. Seasonal variation in the outdoor gamma dose rates and Rn concentrations was confirmed. Correlation analyses showed a linear relationship between air radiation levels and the abundance of (232)Th in soil. The annual outdoor effective radiation doses for humans (occupancy 5 h day(-1)) were estimated to be in the range of 3.0-7.7 mSv, comparable or higher than the total average (summarized indoor and outdoor) exposure dose for the Norwegian population (2.9 mSv year(-1)). On the basis of all obtained results, this Norwegian area should be considered as enhanced natural radiation area (ENRA). PMID- 22105601 TI - The men's health forum: an initiative to address health disparities in the community. AB - Racial/ethnic, socioeconomic, and gender disparities in health and access to and use of health care services currently exist. Health professionals are continually striving to reduce and eliminate health disparities within their own community. One such effort in the area of Tampa Bay, Florida was the creation of the African American Men's Health Forum, currently referred to as the Men's Health Forum. The African American Men's Health Forum was the result of the community's desire to reduce the gap in health outcomes for African American men. Later, it was recognized that the gap in health outcomes impacts other communities; therefore, it was broadened to include all men considered medically underserved (those who are uninsured, underinsured, or without a regular health care provider). The Men's Health Forum empowers men with the resources, knowledge, and information to effectively manage their health by providing health education and screenings to the community. This article provides an explanation of the key components that have contributed to the success of the Men's Health Forum, including challenges and lessons learned. It is intended that this information be replicated in other communities in an effort to eliminate health disparities. PMID- 22105602 TI - Gender differences in mortality following non-cardiovascular surgery: an observational study. AB - PURPOSE: Although inequality between males and females in cardiovascular surgery is well recognized, few studies have examined the influence of sex on mortality following non-cardiovascular surgery. The objective of the study was to determine whether there are differences in mortality between males and females following non-cardiovascular surgery and to ascertain to what extent preoperative risk factors explain these differences. METHODS: This was an observational study of 39,433 consecutive non-cardiovascular inpatient surgical cases from non-sex biased surgical services from 2003 to 2009. Data on the surgical procedure, patient risk factors, and outcomes was retrieved from the institutional Electronic Data Warehouse. The primary outcome was in-hospital mortality within 30 days of surgery. Multivariate analysis using logistic regression was conducted to determine the role of risk factors for mortality. RESULTS: The 30-day mortality was 2.76% for males and 1.89% for females (odds ratio, 1.47; 95% confidence interval [CI], 1.29 to 1.69). Logistic regression showed that age, number of Charlson comorbidities, American Society of Anesthesiologists (ASA) classification, and emergent/urgent status were independent predictors of mortality (receiver operating characteristic area, 0.90). After adjustment for these factors, the odds ratio for male mortality was reduced to 1.31 (95% CI, 1.14 to 1.52). CONCLUSION: Males present for non-cardiovascular surgery with a higher ASA classification, with more comorbidities, and more often emergently than females, providing a partial explanation of the observed difference in mortality. PMID- 22105603 TI - How close is evidence to truth in evidence-based treatment of mental disorders? AB - Given the importance of the term 'evidence' in evidence-based medicine (EBM), the meaning of this term is evaluated, going back to the philosophical tradition and current meaning of the terms 'evidence' and 'truth'. Based on this, current problems in the definition of evidence and in the grading of evidence in EBM are described, taking examples from the field of psychiatry and especially pharmacopsychiatry. These problems underline that the use of the term evidence in EBM is inconsistent and inconclusive. This should be fairly stated in all EBM related publications, especially in EBM-based guidelines, to avoid severe misunderstandings in and outside the field of psychiatry. Although EBM might have increased empirically driven rational decision-making in psychiatry/medicine, the current limitations should be carefully considered. PMID- 22105604 TI - Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). AB - High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is released passively during cell injury and necrosis, and secreted actively by immune cells. HMGB1 contains three conserved redox-sensitive cysteine residues: C23 and C45 can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Using tandem mass spectrometric analysis, we now have established that the C106 thiol and the C23-C45 disulfide bond are required for HMGB1 to induce nuclear NF-kappaB translocation and tumor necrosis factor (TNF) production in macrophages. Both irreversible oxidation to sulphonates and complete reduction to thiols of these cysteines inhibited TNF production markedly. In a proof of concept murine model of hepatic necrosis induced by acetaminophen, during inflammation, the predominant form of serum HMGB1 is the active one, containing a C106 thiol group and a disulfide bond between C23 and C45, whereas the inactive form of HMGB1, containing terminally oxidized cysteines, accumulates during inflammation resolution and hepatic regeneration. These results reveal critical posttranslational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during pathogenesis. PMID- 22105605 TI - Interferon regulatory factor-1 regulates the autophagic response in LPS stimulated macrophages through nitric oxide. AB - The pathogenesis of sepsis is complex and, unfortunately, poorly understood. The cellular process of autophagy is believed to play a protective role in sepsis; however, the mechanisms responsible for its regulation in this setting are ill defined. In the present study, interferon regulatory factor 1 (IRF-1) was found to regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore, we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation in which IRF-1/NO inhibits autophagy through mTOR activation. PMID- 22105607 TI - Inhibition of human immunodeficiency virus replication by cell membrane-crossing oligomers. AB - Although rapidly becoming a valuable tool for gene silencing, regulation or editing in vitro, the direct transfer of small interfering ribonucleic acids (siRNAs) into cells is still an unsolved problem for in vivo applications. For the first time, we show that specific modifications of antisense oligomers allow autonomous passage into cell lines and primary cells without further adjuvant or coupling to a cell-penetrating peptide. For this reason, we termed the specifically modified oligonucleotides "cell membrane-crossing oligomers" (CMCOs). CMCOs targeted to various conserved regions of human immunodeficiency virus (HIV)-1 were tested and compared with nontargeting CMCOs. Analyses of uninfected and infected cells incubated with labeled CMCOs revealed that the compounds were enriched in infected cells and some of the tested CMCOs exhibited a potent antiviral effect. Finally, the CMCOs did not exert any cytotoxicity and did not inhibit proliferation of the cells. In vitro, our CMCOs are promising candidates as biologically active anti-HIV reagents for future in vivo applications. PMID- 22105606 TI - Natural killer (NK) cells in antibacterial innate immunity: angels or devils? AB - Natural killer (NK) cells were first described as immune leukocytes that could kill tumor cells and soon after were reported to kill virus-infected cells. In the mid-1980s, 10 years after their discovery, NK cells were also demonstrated to contribute to the fight against bacterial infection, particularly because of crosstalk with other leukocytes. A wide variety of immune cells are now recognized to interact with NK cells through the production of cytokines such as interleukin (IL)-2, IL-12, IL-15 and IL-18, which boost NK cell activities. The recent demonstration that NK cells express pattern recognition receptors, namely Toll-like and nucleotide oligomerization domain (NOD)-like receptors, led to the understanding that these cells are not only under the control of accessory cells, but can be directly involved in the antibacterial response thanks to their capacity to recognize pathogen-associated molecular patterns. Interferon (IFN) gamma is the predominant cytokine produced by activated NK cells. IFN-gamma is a key contributor to antibacterial immune defense. However, in synergy with other inflammatory cytokines, IFN-gamma can also lead to deleterious effects similar to those observed during sepsis. Accordingly, as the main source of IFN-gamma in the early phase of infection, NK cells display both beneficial and deleterious effects, depending on the circumstances. PMID- 22105608 TI - Distribution of zebrin-immunoreactive Purkinje cell terminals in the cerebellar and vestibular nuclei of birds. AB - Zebrin II (aldolase C) is expressed in a subset of Purkinje cells in the mammalian and avian cerebella such that there is a characteristic parasagittal organization of zebrin-immunopositive stripes alternating with zebrin immunonegative stripes. Zebrin is expressed not only in the soma and dendrites of Purkinje cells but also in their axonal terminals. Here we describe the distribution of zebrin immunoreactivity in both the vestibular and the cerebellar nuclei of pigeons (Columba livia) and hummingbirds (Calypte anna, Selasphorus rufus). In the medial cerebellar nucleus, zebrin-positive labeling was particularly heavy in the "shell," whereas the "core" was zebrin negative. In the lateral cerebellar nucleus, labeling was not as heavy, but a positive shell and negative core were also observed. In the vestibular nuclear complex, zebrin positive terminal labeling was heavy in the dorsolateral vestibular nucleus and the lateral margin of the superior vestibular nucleus. The central and medial regions of the superior nucleus were generally zebrin negative. Labeling was moderate to heavy in the medial vestibular nucleus, particulary the rostral half of the parvocellular subnucleus. A moderate amount of zebrin-positive labeling was present in the descending vestibular nucleus: this was heaviest laterally, and the central region was generally zebrin negative. Zebrin-positive terminals were also observed in the the cerebellovestibular process, prepositus hypoglossi, and lateral tangential nucleus. We discuss our findings in light of similar studies in rats and with respect to the corticonuclear projections to the cerebellar nuclei and the functional connections of the vestibulocerebellum with the vestibular nuclei. PMID- 22105609 TI - Plant and soil responses to high and low diversity grassland restoration practices. AB - The USDA's Conservation Reserve Program (CRP) has predominantly used only a few species of dominant prairie grasses (CP2 practice) to reduce soil erosion, but recently has offered a higher diversity planting practice (CP25) to increase grassland habitat quality. We quantified plant community composition in CP25 and CP2 plantings restored for 4 or 8 years and compared belowground properties and processes among restorations and continuously cultivated soils in southeastern Nebraska, USA. Relative to cultivated soils, restoration increased soil microbial biomass (P = 0.033), specifically fungi (P < 0.001), and restored soils exhibited higher rates of carbon (C) mineralization (P = 0.010). High and low diversity plantings had equally diverse plant communities; however, CP25 plantings had greater frequency of cool-season (C(3)) grasses (P = 0.007). Older (8 year) high diversity restorations contained lower microbial biomass (P = 0.026), arbuscular mycorrhizal fungi (AMF) biomass (P = 0.003), and C mineralization rates (P = 0.028) relative to 8 year low diversity restorations; older plantings had greater root biomass than 4 year plantings in all restorations (P = 0.001). Low diversity 8 year plantings contained wider root C:N ratios, and higher soil microbial biomass, microbial community richness, AMF biomass, and C mineralization rate relative to 4 year restorations (P < 0.050). Net N mineralization and nitrification rates were lower in 8 year than 4 year high diversity plantings (P = 0.005). We attributed changes in soil C and N pools and fluxes to increased AMF associated with C(4) grasses in low diversity plantings. Thus, reduced recovery of AMF in high diversity plantings restricted restoration of belowground microbial diversity and microbially-mediated soil processes over time. PMID- 22105610 TI - Using aerial photography to estimate riparian zone impacts in a rapidly developing river corridor. AB - Riparian zones are critical for protecting water quality and wildlife, but are often impacted by human activities. Ongoing threats and uncertainty about the effectiveness of buffer regulations emphasize the importance of monitoring riparian buffers through time. We developed a method to rapidly categorize buffer width and landuse attributes using 2007 leaf-on aerial photography and applied it to a 65 km section of the Toccoa River in north Georgia. We repeated our protocol using 1999 leaf-off aerial photographs to assess the utility of our approach for monitoring. Almost half (45%) of the length of the Toccoa River was bordered by buffers less than 50 ft wide in 2007, with agricultural and built-up lands having the smallest buffers. The percentage of river length in each buffer width category changed little between 1999 and 2007, but we did detect a 5% decrease in agricultural land use, a corresponding increase in built-up land use, and an additional 149 buildings within 100 ft of the river. Field verification indicated that our method overestimated buffer widths and forested land use and underestimated built-up land use and the number of buildings within 100 ft of the river. Our methodology can be used to rapidly assess the status of riparian buffers. Including supplemental data (e.g., leaf-off imagery, road layers) will allow detection of the fine-scale impacts underestimated in our study. Our results on the Toccoa River reflect historic impacts, exemptions and variances to regulations, and the ongoing threat of vacation home development. We recommend additional monitoring, improvements in policy, and efforts to increase voluntary protection and restoration of stream buffers. PMID- 22105611 TI - Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. AB - BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue. METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser scanning cytometry (LSC). RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003). CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB. PMID- 22105612 TI - Stable triazolylphosphonate analogues of phosphohistidine. AB - Histidine-phosphorylated proteins and the corresponding kinases are important components of bacterial and eukaryotic cell-signalling pathways, and are therefore potential drug targets. The study of these biomolecules has been hampered by the lability of the phosphoramidate functional group in the phosphohistidines and the lack of generic antibodies. Herein, the design and concise synthesis of stable triazolylphosphonate analogues of N1- and N3 phosphohistidine, and derivatives suitable for bioconjugation, are described. PMID- 22105613 TI - Transglutaminase-mediated modification of ovomucoid: effects on its trypsin inhibitory activity and antigenic properties. AB - Hen egg can cause food hypersensitivity in infants and young children, and ovomucoid is the most allergenic factor among proteins contained in egg white. Since proteinase treatment, a well-recognized strategy in reducing food allergenicity, is ineffective when applied to ovomucoid because of its ability to act as trypsin inhibitor, we investigated the possibility of reducing the ovomucoid antiprotease activity and antigenic properties by covalently modifying its structure. The present paper reports data showing the ability of the Gln115 residue of ovomucoid to act as an acyl donor substrate for the enzyme transglutaminase and, as a consequence, to give rise to a covalent monodansylcadaverine conjugate of the protein in the presence of both enzyme and the diamine dansylated derivative. Moreover, we demonstrated that the obtained structural modification of ovomucoid significantly reduced the capability of the protein to inhibit trypsin activity, also having impact on its anti-ovomucoid serum-binding properties. PMID- 22105614 TI - Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist? AB - Neuroendocrine tumors (NETs) comprise a broad range of neoplasms that share biological and embryological origin. A deeper knowledge in the underlying molecular biology that results in the development and spread of NETs has allowed the use of novel-targeted therapies against angiogenesis and intracellular pathways, key checkpoints that govern growth, and proliferation of these tumors. Unfortunately, the possibility of cure is still far for patients with advanced stages. Cancer stem cells (CSCs) are present in most solid tumors. Nevertheless, there is limited evidence for the presence of CSCs in NETs. In this review, we will discuss the embryonic origin and possible existence of a gastroenteropancreatic neuroendocrine cancer stem cell. Here, we summarize the body of evidence supporting the presence of active embryological pathways like Notch, Wnt-beta-catenin, Hedgehog, or transforming growth factor-beta in NETs. New therapeutic approaches in the field of CSCs seem to have a clear role in the treatment of medulloblastomas and basal cell carcinomas, but their future value in other solid tumor types including NETs remains unclear. PMID- 22105615 TI - Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. AB - Myxomatous mitral valve prolapse (MVP) is the most common cardiac valvular abnormality in industrialized countries and a leading cause of mitral valve surgery for isolated mitral regurgitation. The key role of valvular interstitial cells (VICs) during mitral valve development and homeostasis has been recently suggested, however little is known about the molecular pathways leading to MVP. We aim to characterize bone morphogenetic protein 4 (BMP4) as a cellular regulator of mitral VIC activation towards a pathologic synthetic phenotype and to analyze the cellular phenotypic changes and extracellular matrix (ECM) reorganization associated with the development of myxomatous MVP. Microarray analysis showed significant up regulation of BMP4-mediated signaling molecules in myxomatous MVP when compared to controls. Histological analysis and cellular characterization suggest that during myxomatous MVP development, healthy quiescent mitral VICs undergo a phenotypic activation via up regulation of BMP4 mediated pathway. In vitro hBMP4 treatment of isolated human mitral VICs mimics the cellular activation and ECM remodeling as seen in MVP tissues. The present study characterizes the cell biology of mitral VICs in physiological and pathological conditions and provides insights into the molecular and cellular mechanisms mediated by BMP4 during MVP. The ability to test and control the plasticity of VICs using different molecules may help in developing new diagnostic and therapeutic strategies for myxomatous MVP. PMID- 22105616 TI - Is the C34T polymorphism of the AMPD1 gene associated with athlete performance in rowing? AB - The skeletal muscle-specific isoform of adenosine monophosphate deaminase (AMPD) is one of the most important regulators of muscle energy metabolism. A nonsense C to T transition in nucleotide 34 (C34T) in exon 2 of AMPD1 gene converts the codon CAA into the premature stop-codon TAA. 127 Polish male rowers including Olympic and world champions were recruited for this study. Controls samples were obtained from 251 unrelated volunteers. Statistically significant differences in genotype distribution were observed when only a whole group of rowers (88.19% CC, 11.81% CT, 0% TT; p=0.009) were compared with controls (75.31% CC, 23.10% CT, 1,59% TT). A significant deficiency of the T allele compared to control samples was noted in the elite rowers (4.55%, p=0.021) and non-elite rowers (6.63%, p=0.023), whereas this trend was even stronger when compared with the controls for the whole group of rowers (5.91%, p=0.002). Our results suggest that the T allele is associated with physical performance level, therefore, it may be included in the group of performance altering polymorphisms as a negative factor to athletic performance. PMID- 22105617 TI - Exhaustive swimming exercise related kidney injury in rats - protective effects of acetylbritannilactone. AB - The aim of this study was to investigate the protective effects of acetylbritannilactone (ABL) on renal injury induced by acute exhaustive exercise in the rat. The exhaustive exercise induced kidney injury in rats was established by exhaustive swimming (ES). ABL (26 mg/kg) or polyglycol (control) were administrated orally by gastric gavage 24 h before training. Renal function, biochemical index, renal histopathological change, oxidative stress indices, renal cell apoptosis and inflammatory molecules were checked after ES, for 6 h and 24 h. It was found that immediately after exhaustive swimming, the serum urea and creatinine were significantly higher in ES rats, and the same for serum creatine kinase. All the values were reduced in the ES rats treated with ABL. The increase of superoxide dismutase activity and decrease of malondialdehyde content in the kidney were found in rats with ABL treatment. Tubular cell apoptosis at different time points after ES were significantly reduced by the ABL treatment. The increased expression of TNF-alpha and NF-kappaB induced by ES was also significantly decreased by ABL treatment. Our results suggest that ABL protects rats from overtraining-induced kidney injury by inhibiting renal cell apoptosis and suppressing oxidative-stress generation and inhibiting inflammation. PMID- 22105618 TI - Effects of lactic acid and glycolic acid on human osteoblasts: a way to understand PLGA involvement in PLGA/calcium phosphate composite failure. AB - The use of degradable composite materials in orthopedics remains a field of intense research due to their ability to support new bone formation and degrade in a controlled manner, broadening their use for orthopedic applications. Poly (lactide-co-glycolide) acid (PLGA), a degradable biopolymer, is now a popular material for different orthopedic applications and is proposed for use in tissue engineering scaffolds either alone or combined with bioactive ceramics. Interference screws composed of calcium phosphates and PLGA are readily available in the market. However, some reports highlight problems of screw migration or aseptic cyst formation following screw degradation. In order to understand these phenomena and to help to improve implant formulation, we have evaluated the effects of PLGA degradation products: lactic acid and glycolic acid on human osteoblasts in vitro. Cell proliferation, differentiation, and matrix mineralization, important for bone healing were studied. It was found that the toxicity of polymer degradation products under buffering conditions was limited to high concentrations. However, non-toxic concentrations led to a decrease in cell proliferation, rapid cell differentiation, and mineralization failure. Calcium, whilst stimulating cell proliferation was not able to overcome the negative effects of high concentrations of lactic and glycolic acids on osteoblasts. These effects help to explain recently reported clinical failures of calcium phosphate/PLGA composites, but further in vitro analyses are needed to mimic the dynamic situation which occurs in the body by, for example, culture of osteoblasts with materials that have been pre-degraded to different extents and thus be able to relate these findings to the degradation studies that have been performed previously. PMID- 22105619 TI - Prebiotic effects of cassava fibre as an ingredient in cracker-like products. AB - Cassava fibre, a waste product formed in starch production, was incorporated into wheat to give composite flours at ratios of 80/20, 70/30, 60/40 and 50/50, respectively. A cracker-like biscuit was produced from the preferred ratios (60/40 and 50/50). The effects of these on diets as a prebiotic were evaluated in a rat assay. Determinations of the proximate composition and haematological parameters were made as well as microbiological analysis. The protein content of the cracker-like product based on the 50/50 and 60/40 (fibre/wheat flour) ratios were 15.0% and 10.0%, respectively. Crude fibre ranged from 14.1-17.1% while ash ranged from 3.0 and 5.0%. Low cholesterol levels of 28.75 mg dL(-1) and 18.75 mg dL(-1) were recorded for the 50/50 and 60/40 composite ratios, respectively. The result of liver function test showed that the rats that were fed the fibre-based cracker product had an average value of 44.00 IU L(-1) of aspartate amino transferase (AST), which is lower than the 67.75 IU L(-1) recorded for the control. There was a significant increase in the packed cell volume (PCV) of the rats fed a fibre-based diet, relative to those fed "Ogi" (fermented maize). Haemoglobin was significantly higher in the control sample than all others, while no significant difference was observed in the white blood cell (WBC) count, with average of 11.75 mm(3). Data obtained from the faecal analysis showed that the rats fed with the composite ratios and other diets had an increased Lactobacillus count. However, by increasing the number of days that the rats were fed the fibre based diet, the E. coli count in the rat faeces reduced significantly. The data obtained shows that cassava fibre-based crackers have good nutraceutic effects, with reduction in the E. coli count found in the rat faeces and healthy performances in terms of weight gain. PMID- 22105620 TI - A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene. AB - Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 * 10(-8)) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory. PMID- 22105621 TI - QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders. AB - Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P<0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits. PMID- 22105622 TI - Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels. AB - Attention-deficit hyperactivity disorder (ADHD) in adults is associated with impaired sleep, and it has been postulated that this impairment may contribute to the psychopathology of this common condition. One key driver of sleep/wake cycles is the circadian system, which at the molecular level consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological and behavioural outputs with a near 24 h periodicity. We set out to examine circadian rhythms at the behavioural, endocrine and molecular levels in ADHD. Adults with ADHD as well as age- and sex-matched controls were recruited. Circadian rhythms were measured by means of actigraphy for the determination of gross motor patterns, by self-sampling of oral mucosa for assessment of rhythmic expression of the clock genes BMAL1 and PER2, and by estimation of salivary cortisol and melatonin levels. Actigraphic analysis revealed significant diurnal and nocturnal hyperactivity in the ADHD group, as well as a significant shorter period of best fit for the locomotor circadian rhythm in ADHD. BMAL1 and PER2 showed circadian rhythmicity in controls with this being lost in the ADHD group. Cortisol rhythms were significantly phase delayed in the ADHD group. These findings indicate that adult ADHD is accompanied by significant changes in the circadian system, which in turn may lead to decreased sleep duration and quality in the condition. Further, modulation of circadian rhythms may represent a novel therapeutic avenue in the management of ADHD. PMID- 22105623 TI - A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila. AB - Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 * 10( 8)) in the ABCC9 gene that explains ~5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism. PMID- 22105625 TI - Dopamine D2/D3 receptor availability in genetically leptin-deficient patients after long-term leptin replacement. PMID- 22105626 TI - Evidence for multiple genetic factors underlying the DSM-IV criteria for alcohol dependence. AB - To determine the number of genetic factors underlying the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for alcohol dependence (AD), we conducted structural equation twin modeling for seven AD criteria, plus two summary screening questions, in 7133 personally interviewed male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, who reported lifetime alcohol consumption. The best-fit twin model required three genetic and two unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was defined by high loadings for the probe question about quantity and frequency of alcohol consumption, and tolerance criterion. The second genetic factor loaded strongly on the probe question about self-recognition of alcohol-related problems and AD criteria for loss of control, desire to quit, preoccupation and activities given up. The third genetic factor had high loadings for withdrawal and continued use despite the problems criteria. Genetic factor scores derived from these three factors differentially predicted patterns of comorbidity, educational status and other historical/clinical features of AD. The DSM-IV syndrome of AD does not reflect a single dimension of genetic liability, rather, these criteria reflect three underlying dimensions that index risk for: (i) tolerance and heavy use; (ii) loss of control with alcohol associated social dysfunction and (iii) withdrawal and continued use despite problems. While tentative and in need of replication, these results, consistent with the rodent literature, were validated by examining predictions of the genetic factor scores and have implications for gene-finding efforts in AD. PMID- 22105627 TI - RFID-enabled traceability system for consignment and high value products: a case study in the healthcare sector. AB - This paper presents a case study of a hospital operating room that evaluated a Radio-Frequency Identification (RFID)-enabled traceability system for the management of consignment and high value products requiring item level traceability. Results indicate that the traceability system in conjunction with the redesign of replenishment processes facilitates item level traceability, improves financial controls and case costing, upgrades service levels and reduces inventory shrinkage. Other benefits include time saved from non-value-added activities that can be transferred to patient care activities. The solution can be considered (i) as an alternative to RFID-enabled cabinets used in the replenishment of consignment and high value supplies in certain operating rooms, cardiac catheterization laboratories and interventional radiology departments, or (ii) as a complementary solution facilitating the tracking of medical devices removed from RFID-enabled cabinets. In short, the end-to-end traceability of medical products in the healthcare supply chain can be significantly enhanced. PMID- 22105624 TI - The genetics of attention deficit/hyperactivity disorder in adults, a review. AB - The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. PMID- 22105628 TI - Associations between eNOS polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis. AB - OBJECTIVE: To determine whether endothelial nitric oxide synthase (eNOS) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). METHODS: A meta-analysis was conducted on the associations between the 4b/a, G894T, and C786T polymorphisms of eNOS and SLE and lupus nephritis (LN) (when available) using (1) the allele contrast, (2) the recessive, (3) the dominant, and (4) the additive models. RESULTS: A total of eight studies, which included 1,297 cases and 1,214 controls, were included in the meta-analysis. Meta-analysis showed no association between SLE and the 4b/a polymorphism in any study subjects. Stratification by presence of LN indicated a significant association between the a allele and the aa + ab genotype of the 4b/a polymorphism and LN in SLE patients [odds ratio (OR) = 2.125, 95% confidence interval (CI) = 1.289 3.054, p = 0.003; OR = 2.655, 95% CI = 1.509-4.671, p = 0.001]. No association was found between SLE and the G894T polymorphism using the allelic, recessive, or dominant, or additive models. Meta-analysis of the T786C polymorphism showed a tendency to an association between the TT genotype and SLE (OR = 1.220, 95% CI = 1.000-1.489, p = 0.050), and meta-analysis of the TT versus CC genotype of the C786T polymorphism in group in Hardy-Weinberg equilibrium revealed a significant association between the TT genotype and SLE (OR = 1.643, 95% CI = 1.021-2.644, p = 0.041). CONCLUSIONS: This meta-analysis of published studies shows that the 4b/a polymorphism may be associated with the development of LN, and the C786T polymorphism may be associated with SLE susceptibility. PMID- 22105629 TI - Hand surgery fellowships: time for reconsideration? PMID- 22105630 TI - Rehabilitation considerations in the management of terrible triad injury to the elbow. AB - An elbow dislocation associated with a radial head and coronoid fractures is termed a terrible triad. This injury almost always renders the elbow unstable requiring surgical intervention. The primary goal of surgery is to stabilize the elbow to permit early motion to prevent stiffness. Recent literature has improved our understanding of elbow anatomy and biomechanics as well as the pathoanatomy of this injury. This article reviews key concepts that will allow the surgeon and therapist to apply an systematic rehabilitation approach when managing such injuries. PMID- 22105631 TI - Silicone arthroplasty for chronic proximal interphalangeal joint dislocations. AB - Chronic dislocations of the proximal interphalangeal (PIP) joint pose a significant treatment challenge. Chronically dislocated PIP joints can experience several changes to the articular cartilage including pressure necrosis, degeneration, and the development of secondary incongruence. Moreover, chronic dislocation allows the edema and hemorrhage from soft tissue trauma to develop into collateral ligament fibrosis and inelastic scar formation. Similarly, chronic dislocations associated with a fracture at the base of the middle phalanx can also experience changes in the form of joint incongruency, bony resorption, or malunion formation. Subsequently, these cumulative joint changes prohibit standard open reduction of the PIP joint and can cause significant loss of motion thereby demanding a different approach to restore motion and minimize pain. We propose the use of silicone arthroplasty in the management of chronic dislocations of the PIP joint. PMID- 22105632 TI - A mini external fixator for hand and finger fractures constructed from readily available materials. AB - Phalangeal and metacarpal fractures with severe comminution and/or soft tissue compromise can present a challenge for the orthopedic surgeon. Maintaining viability of the soft tissues while providing rigid fixation of bony injuries is the goal when treating these injuries. Commercially available mini external fixators can help to achieve these goals. However, these devices are costly and are not always available when the surgeon needs them. In this technique study, we discuss the implementation of a mini external fixator using readily available implements in the operating room that is efficient, cost effective, and easy to apply. PMID- 22105633 TI - Open reduction and internal fixation for dorsal fracture dislocations of the proximal interphalangeal joint using a miniplate. AB - Various operative techniques have been described for unstable dorsal fracture dislocations of the proximal interphalangeal (PIP) joint with articular involvement. However, this injury still remains a therapeutic challenge for hand surgeons because no single technique guarantees successful outcomes. We performed a novel procedure using a low-profile miniplate, which allows for anatomic reduction, rigid internal fixation, and early finger joint motion. Between March 2003 and May 2009, 18 consecutive patients who suffered from 19 dorsal fracture dislocations of the PIP joint with volar articular fracture of the middle phalanx involving more than 40% of the articular surface were treated using this technique. The postoperative follow-up period averaged 16.6 months (range, 12-18 mo). Bony union was obtained in all cases. No patient showed residual dorsal subluxation. Active motion of the PIP joint averaged 85.0 degrees (range, 62-105 degrees), flexion contracture averaged 5.4 degrees (range, 0-17 degrees), and percent total active interphalangeal joint motion averaged 89.0% (range, 60% 100%). Two patients had restricted active distal interphalangeal joint flexion owing to tendon adhesion resulting from the use of a relatively long plate in the first few cases of this series. No major complications were reported for the other 16 patients. We describe the surgical technique, indications, complications, and postoperative management for this technique. PMID- 22105634 TI - Reconstruction for failed trapeziometacarpal implant. AB - Trapeziometacarpal prosthesis by metallic implant is used to treat thumb carpometacarpal osteoarthritis. Many causes of failure have been described whereas revision techniques still remain a challenging surgery. In this article, we describe a revision strategy in a failed metallic cemented trapeziometacarpal implant with major first metacarpal shortening. PMID- 22105635 TI - A single-stage operation for reconstruction of hand flexion, extension, and intrinsic function in tetraplegia: the alphabet procedure. AB - Surgical reconstruction is an established method to restore grip and grasp function after traumatic cervical spinal cord injury and tetraplegia. It can offer the patient improved ability to perform activities of daily living. Traditionally, surgical reconstruction of hand function has required separate operations for flexors and extensors. Here, we present a combination of procedures that provides key pinch and finger flexion together with opening of hand as a 1-stage operation. This reconstruction includes 7 individual operations that are performed in the following order: (1) split flexor pollicis longus extensor pollicis longus distal thumb tenodesis, (2) reconstruction of passive interossei, (3) thumb CMC arthrodesis (4) brachioradialis-flexor pollicis longus tendon transfer, (5) extensor carpi radialis longus-flexor digitorum profundus tendon transfer, (6) EPL tenodesis, and (7) extensor carpi ulnaris tenodesis. We have chosen to entitle this reconstruction the alphabet or ABCDEFG procedure, an abbreviation for Advanced Balanced Combined Digital Extensor Flexor Grip reconstruction. To reduce the risk of adhesions after this extensive surgery and to facilitate relearning the activation of transferred muscles with new functions, early active training is performed. It is concluded that this 1-stage combination of operations can reliably provide grip, grasp, and release function in persons with C6 tetraplegia, patient satisfaction is high, time and effort for patient and caregivers are less, and incidence of complications is comparable with other published treatment modalities. PMID- 22105636 TI - Corrective osteotomy after damage of the distal radial physis in children: surgical technique and results. AB - Distal radial physis closure in children can develop severe wrist deformity (radial shortening). These patients can be treated using a single-step surgery. It was carried out in the form of a corrective osteotomy adopting the volar approach, with fixed-angle volar plate fixation and bone grafting from the iliac crest. There have been few descriptions of the use of this technique in the management of deformities related to early epiphysiodesis in distal radius. The use of fixation systems for the radius, using fixed-angle locking plates, allows radius lengthening adjusted to demand after osteotomy, using the combination of the plate and distal locking pins as spacer-with custom-sized tricortical iliac crest grafting within the defect. The freeing of soft parts such as the dorsal periosteum and brachioradialis muscle tendon allows adequate bone lengthening in a single-surgical step. PMID- 22105637 TI - Methylene blue-enhanced arthroscopic resection of dorsal wrist ganglions. AB - The ganglion is the most common soft tissue mass of the hand and wrist. Over the past 10 to 15 years, there has been a growing interest in arthroscopic treatment of dorsal wrist ganglions. Proposed advantages of arthroscopy include greater motion (particularly wrist flexion), improved cosmesis, and potential to identify/treat other intra-articular pathology. Despite the documented clinical success of arthroscopic ganglion excision, limitations include inconsistent identification of the ganglion stalk. Our described technique offers a means by which to improve visualization of the ganglion stalk intra-articularly to produce a more effective and efficient arthroscopic ganglion excision. During the procedure, a small volume of methylene blue solution is injected into the cyst. Its communication with the joint is apparent arthroscopically, thus identifying the location of the stalk. With the ability to precisely identify the ganglion stalk using an injection of methylene blue, the surgeon can direct the arthroscopic debridement toward the appropriate pathologic tissue. Unnecessary debridement of uninvolved tissue can be avoided with the technique. This also allows for optimal portal placement and, in particular, indicates whether a midcarpal portal should be employed. This should result in fewer recurrences, decreased operative time, and less iatrogenic injury. PMID- 22105638 TI - Pi2 spacer pyrocarbon arthroplasty technique for thumb basal joint osteoarthritis. AB - Trapeziectomy associated with a pyrocarbon implant is a recent procedure for thumb basal joint osteoarthritis. The investigators report Pi pyrocarbon implant technique (Tornier Bioprofile, Grenoble, France) for primary thumb basal joint osteoarthritis. The key points of the procedure are preservation of the soft tissue environment during the trapeziectomy, partial trapezoidectomy to medialize the implant, and careful capsuloplasty and ligamentoplasty to stabilize the implant. PMID- 22105639 TI - Proximal row carpectomy with allograft scaffold interposition arthroplasty. AB - The authors present a solution for motion preservation in severe wrist arthritis with intercarpal involvement. Acellular dermal allograft is used as an interposition arthroplasty in these situations, rather than local tissue flaps such as previously described. Proximal row carpectomy has been shown to be one of the most successful procedures to correct chronic destructive arthritis in the wrist, keeping useful motion. Traditionally, a contraindication for proximal row carpectomy includes an arthritis that invades the lunate-capitate joint. The authors describe a technique to extend the traditional indications by covering the eroded articular surfaces with dermal allograft scaffold. PMID- 22105640 TI - Anchor suture technique for muscle belly repair. AB - Upper extremity lacerations occur frequently. Although surgical indications for tendon repair are widely accepted, indications for repairing the midsubstance of muscles are not as clear. As the standard of care for muscle repair is absent, there are a variety of techniques available to the treating surgeon. In this study, we describe a technique used on several patients seen in our orthopedic practice. The use of orthogonally placed anchor sutures allows for more reliable suture passes and purchase in the muscle belly compared with simple end-to-end approximation. Furthermore, our technique does not introduce excessive foreign material as has been suggested by previous techniques. PMID- 22105641 TI - Correction of severe postburn claw hand. AB - Burn scar contractures are perhaps the most frequent and most frustrating sequelae of thermal injuries to the hand. Unfortunately, stiffness occurs in the burned hand quickly. A week of neglect in the burned hand can lead to digital malpositioning and distortion that may be difficult to correct. The dorsal contracture is the most common of all the complications of the burned hand. It is the result of damage to the thin dorsal skin and scant subcutaneous tissue, which offers little protection to the deeper structures. Consequently, these injuries are deep resulting in a spectrum of deformities that has remained the bane of reconstructive surgery. Flap coverage will be required in the event of exposure of joints and tendons with absent paratenons. Multiple different flap types are available to treat complex severe postburn hand contractures. In our center, which is the largest regional burn center in northwest Iran, we have considerable experience in the treatment of thermal hand injuries. Between 2005 and 2010, we treated 53 consecutive patients with 65 severe postburn hand deformities. There were 35 men and 18 women with a mean age of 35+/-3 years. Flame injury was the inciting traumatic event in each patient. The severity of original injury and inadequate early treatment resulted in all of the fingers developing a severe extension contracture with scarred and adherent extensor tendons and subluxed metacarpophalangeal joints. In 36 cases, the injury was in the patients' dominant hand. We first incised the dorsal aspect of the contracted hands where there was maximum tension, then tenolysed the extensor tendons and released the volar capsules, collateral ligaments, and volar plate in all cases. In 30 cases, we also tenolysed the flexor tendons. We reduced the subluxed metacarpophalangeal joints and fixed them with Kirschner wires in 70 to 90 degrees flexion. Then, we planned and performed axial groin flaps to reconstruct the defects in all of them. In all of these patients, there was availability of intact skin in the territory of groin flap. However, in case of burn scars in this region, we had other options such as posterior interosseous flap in mind. Six patients experienced superficial necrosis at the distal margin of the flap, which was successfully treated with local wound care and dressing changes. There were no other complications. Physical therapy was initiated after Kirschner wire removal. PMID- 22105642 TI - International cross-cultural field validation of an European Organization for Research and Treatment of Cancer questionnaire module for patients with primary liver cancer, the European Organization for Research and Treatment of Cancer quality-of-life questionnaire HCC18. AB - This international field validation study examined the psychometric properties and clinical validity of the European Organization for Research and Treatment of Cancer (EORTC) questionnaire module for hepatocellular carcinoma (HCC), the EORTC quality-of-life questionnaire (QLQ)-HCC18. The EORTC QLQ-HCC18 was administered with the core questionnaire, the EORTC QLQ-C30, to 272 patients from seven centers in 6 countries. Patient acceptability of the module was examined with a debriefing questionnaire, and psychometric and clinical properties were assessed. Multitrait scaling analyses confirmed the hypothesized scale structure without any scaling error, and the fatigue scale demonstrated satisfactory internal consistency. The test-retest reliability scores were high for all scales, except abdominal swelling and sexual interest. The correlations between all scales of the QLQ-HCC18 and the QLQ-C30 were low or moderate, and many scales could distinguish patients with different clinical conditions. The module demonstrated responsiveness to clinical change in pain before and after surgery and some borderline change in patients undergoing systemic treatment. CONCLUSION: The EORTC QLQ-HCC18 can be used as a supplementary module for the EORTC QLQ-C30 in clinical trials for patients with HCC. PMID- 22105643 TI - Interspecies scaling in pharmacokinetics: a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo. AB - Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool. PMID- 22105644 TI - Gene expression in livers of BALB/C and C57BL/6J mice fed a high-fat diet. AB - We previously demonstrated that high-fat diet (HFD)-induced hepatic lipid accumulation is more severe in BALB/c mice than in C57BL/6J (B6) mice. To understand the changes in liver metabolism, we studied blood chemistry, gene expression, and histopathological changes of the liver in nine-week HFD-fed BALB/c and B6 mice and one- or four-week HFD-fed BALB/c mice. Serum total cholesterol and triglyceride levels were significantly increased in all HFD-fed groups, and one- and four-week HFD-fed BALB/c groups, respectively. Histopathology revealed that vacuolation of hepatocytes was severe in nine-week HFD-fed BALB/c mice, although it was less severe in the other groups. Microarray analysis of mRNA expression of nine-week HFD-fed BALB/c mice showed up-regulation of genes involved in fatty acid uptake and biosynthesis, such as Cd36, Acaca, Acly, and Fasn. Some changes were observed in the one- and four-week HFD-fed BALB/c groups and the nine-week HFD-fed B6 group, however these changes in mRNA expression were not so marked. In conclusion, the fatty accumulation observed in BALB/c mice may be caused, at least in part, by up-regulation of fatty acid uptake and biosynthesis. Cd36, Acaca, Acly and Fasn may be involved in these metabolic processes. PMID- 22105645 TI - Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. AB - The liver is a target of many inflammatory pathologies of both infectious and noninfectious etiology. As key effectors of the innate immune system, neutrophils are critical for defense against microbial infections but are often the source of profound collateral damage to host tissues during disease states. In this article based on the authors' presentation at the 2011 Society of Toxicologic Pathology Annual Symposium, they review the molecular mechanisms of neutrophil recruitment to the liver in response to sepsis/endotoxemia, as well as sterile inflammation, and discuss variations in the molecular choreography of neutrophil trafficking in response to these different insults. Furthermore, the authors discuss the functional contributions of neutrophils within the liver microvasculature during severe sepsis, including their contributions to both host defense and organ damage. Given that inappropriate neutrophilic inflammation contributes to the pathogenesis of many liver diseases, a thorough understanding of the molecular mechanisms that regulate the recruitment of neutrophils to the liver, and their functions therein, may reveal new avenues for therapeutic interventions to treat inflammatory liver pathologies. PMID- 22105646 TI - Immunotoxicant screening and prioritization in the twenty-first century. AB - Current immunotoxicity testing guidance for drugs, high production-volume chemicals, and pesticides specifies the use of animal models to assess potential biomarkers of immune system effects (e.g., lymphoid organ and bone marrow indices, histopathology) or actual measures of immune function (e.g., responses to challenge with antigens or pathogens). These assays are resource intensive and often require special training or experience to ensure reliable results. Alternative in vitro assays to detect immunosuppression and allergic hypersensitivity have the potential to reduce animal use and testing costs and increase immunotoxicity screening and prioritization efforts. Alternative models to detect immunosuppression tend to address broad modes of action because suppression may be caused by a wide variety of events; current in vitro models access the supply of innate and adaptive immune system cells as well as cellular markers associated with function, including gene expression, protein synthesis, and proliferation. Events leading to the induction of allergic hypersensitivity, particularly contact hypersensitivity, are more restricted, and alternative methods currently exploit chemical properties and activation of defined cell populations to detect and estimate the potency of skin sensitizers. PMID- 22105647 TI - Ecological impacts of the deepwater horizon oil spill: implications for immunotoxicity. AB - The Deepwater Horizon (DWH) oil spill was the largest environmental disaster and response effort in U.S. history, with nearly 800 million liters of crude oil spilled. Vast areas of the Gulf of Mexico were contaminated with oil, including deep-ocean communities and over 1,600 kilometers of shoreline. Multiple species of pelagic, tidal, and estuarine organisms; sea turtles; marine mammals; and birds were affected, and over 20 million hectares of the Gulf of Mexico were closed to fishing. Several large-scale field efforts were performed, including assessments of shoreline and wildlife oiling and of coastal waters and sediments. The assessment of injuries, damages, and restoration options for the DWH spill is ongoing. Although petroleum and the polycyclic aromatic hydrocarbon component of oils are known to affect the immune systems of aquatic organisms and wildlife, immunotoxicity is not typically assessed during oil spills and has not been a focus of the DHW assessment. The effects of oil spill contaminants on immune responses are variable and often exposure dependent, but immunotoxic effects seem likely from the DHW spill based on the reported effects of a variety of oils on both aquatic and wildlife species. PMID- 22105648 TI - Cellular and molecular mechanisms of autoimmune disease. AB - Autoimmune disease (AIDx) results from failure to sustain tolerance to self molecules. Dozens of AIDx involving one or multiple organ systems afflict 3% or more of people worldwide (>75% women). Predisposing factors for AIDx include genetic background, hormonal status, pathogens, and xenobiotic exposures. The incidence of AIDx is higher in individuals living in developed nations, including recent immigrants. Patients may have several AIDx simultaneously. Certain AIDx can prevent other AIDx. A history of AIDx raises the risk for developing hematopoietic neoplasia. Some common mechanisms for losing self-tolerance include reduced deletion or enhanced activation of autoreactive CD4(+) T-helper (Th) lymphocytes, defective immunomodulation by CD4(+) regulatory (Treg) and CD8(+) suppressor (Ts) T-lymphocytes, dysregulated signaling (leading to a relative increase in pro-inflammatory cytokines), comparable structure between self antigens and foreign molecules, or expression of new epitopes on previously hidden or xenobiotic-modified self proteins. Organ-specific AIDx is generally a cell-mediated (Th1 or Th17) process, while multi-organ AIDx also incorporates a robust autoantibody (Th2) component. Cytokine signatures of different AIDx overlap incompletely; for a given AIDx, different patients have divergent cytokine profiles. Newer anti-AIDx agents are based on our increasing knowledge of AIDx pathogenesis and usually attempt to reverse lymphocyte dysfunction, quell pro-inflammatory signaling, or restore self-tolerance. PMID- 22105649 TI - Establishing the carcinogenic risk of immunomodulatory drugs. AB - The first effective immunosuppressive drug (ISD) was azathioprine, approved in 1968. Early experience with this drug suggested that patients might have an excess risk of tumors including lymphoma and skin tumors. Comparison among various registries has shown that the cumulative risk of tumors increases over time. The risk is additionally increased by the more intense immunosuppressive regimens needed for lung or heart-lung transplants. The link between immunosuppression and tumorigenesis was further reinforced by the high concordance of tumor types between transplant and HIV patients. The role of the immune system in tumor defense includes both direct tumor surveillance and immunity against oncogenic viruses. In transplant patients, at least two-thirds of the lymphomas are Epstein-Barr virus (EBV)-positive. Existing methods of testing for carcinogenicity are not considered adequate to identify the hazard of tumorigenesis due to these drugs. Research is ongoing in Food and Drug Administration laboratories and at collaborators' laboratories to evaluate experimental systems that may have the ability to adequately identify this class of hazard. Initial work is on various model systems similar to EBV. These include the MHV-68 mouse model, lymphocryptovirus (LCV-1) in the cynomolgus monkey, and preliminary work with mice with humanized immune systems using EBV directly. PMID- 22105650 TI - Implications of HER2 amplification in small, node-negative breast cancers: do Asians differ? AB - BACKGROUND: We investigated the implications of HER2 amplification in Asian women with small, node-negative breast cancer in low- and middle-income countries (LMCs). METHODS: We reviewed the charts patients treated between 1989 and 2009 with breast conservation therapy for node-negative breast cancers measuring <= 2 cm. Disease-free survival (DFS), ipsilateral breast tumor recurrence (IBTR), distant disease-free survival (DDFS), and overall survival (OS) rates were estimated using the Kaplan-Meier method and were compared by the log-rank test. Potential covariates-age, tumor grade, hormone receptor status--were analyzed by multivariate analysis. RESULTS: A total of 519 patients were studied including 204 (39%) and 315 (61%) patients diagnosed with pT1ab and pT1c tumors, respectively. Median follow-up was 57 months. HER2 amplification was found in 17.1% of all patients and in 16.7% patients with pT1ab tumors. Among patients with T1ab tumors, 73.0 and 9.3% underwent adjuvant hormonal and chemotherapy, respectively; 3 of 34 T1ab patients with HER2-amplified tumors received trastuzumab. HER2 amplification was associated with poorer 5-year DFS (83.7% vs. 95.5%, P < 0.0001), DDFS (87.5% vs. 97.9%, P < 0.0001), and IBTR (8.6% vs. 2.1%, P < 0.0001) rates in patients with pT1 tumors. Multivariate analysis showed that HER2 amplification remained a significant negative prognostic factor for DFS [hazard ratio (HR) 4.1, 95% confidence interval (CI) 2.1-7.8, P < 0.0001], DDFS (HR 6.3, 95% CI 2.4-17.0, P < 0.0001), and IBTR (HR 4.5, 95% CI 2.0-10.0, P < 0.0001) rates. In the pT1ab subgroup, univariate analysis showed that HER2 amplification prognosticated for DFS (85.1% vs. 95.7%, P = 0.022) and IBTR (14.9% vs. 3.5%, P = 0.004) rates but not for the OS (100% vs. 99.2%, P = 0.487) rate. Similar results were obtained after excluding patients given trastuzumab. CONCLUSIONS: The decision to use trastuzumab in HER2-amplified pT1ab tumors must balance their poor outcome against intrinsic financial limitations in LMCs. Patient selection criteria needs fine-tuning, and resource-sensitive regimens must be explored. PMID- 22105652 TI - Can labour contract differences in health and work-related attitudes be explained by quality of working life and job insecurity? AB - STUDY AIM: We hypothesise that due to a lower quality of working life and higher job insecurity, the health and work-related attitudes of temporary workers may be less positive compared to permanent workers. Therefore, we aimed to (1) examine differences between contract groups (i.e. permanent contract, temporary contract with prospect of permanent work, fixed-term contract, temporary agency contract and on-call contract) in the quality of working life, job insecurity, health and work-related attitudes and (2) investigate whether these latter contract group differences in health and work-related attitudes can be explained by differences in the quality of working life and/or job insecurity. METHODS: Data were collected from the Netherlands Working Conditions Survey 2008 (N = 21,639), and Hypotheses were tested using analysis of variance and cross-table analysis. RESULTS: Temporary work was associated with fewer task demands and lower autonomy and was more often passive or high-strain work, while permanent work was more often active work. Except for on-call work, temporary work was more insecure and associated with worse health and work-related attitude scores than permanent work. Finally, the quality of working life and job insecurity partly accounted for most contract differences in work-related attitudes but not in health. CONCLUSIONS: Especially agency workers have a lower health status and worse work related attitudes. Job redesign measures regarding their quality of working life and job insecurity are recommended. PMID- 22105653 TI - Which subgroups of fire fighters are more prone to work-related diminished health requirements? AB - PURPOSE: To determine whether certain subgroups of fire fighters are prone to work-related diminished health requirements. METHODS: The health requirements for fire-fighting were tested in a workers' health surveillance (WHS) setting. These health requirements included psychological, physical and sense-related components as well as cardiovascular risk factors. The odds ratio (OR) and 95% confidence interval (95% CI) for the presence of the diminished health requirements were calculated for the subgroups of gender, professionalism and age. RESULTS: The prevalence of diminished psychological requirements was equivalent among the subgroups, and no significant high-risk group was identified. As compared to men fire fighters, women fire fighters were more likely to have diminished physical requirements (OR 28.5; 95% CI 12.1-66.9) and less likely to have cardiovascular risk factors (OR 0.3; 0.1-0.5). As compared to volunteer fire fighters, professionals were less likely to have diminished physical requirements (OR 0.5; 0.3-0.9), but professionals had a higher prevalence of cardiovascular risk factors with an odds ratio of 1.9 (1.1-3.2). As compared to the youngest fire fighters, the oldest fire fighters were more likely to have diminished sense related requirements (OR 7.1; 3.4-15.2); a similar comparison could be made between oldest and middle-aged fire fighters (OR 5.1; 2.5-10.5). In addition, the oldest fire fighters were more likely to have cardiovascular risk factors when compared to the youngest (OR 4.4; 1.7-11.1) and to the middle-aged fire fighters (OR 3.1; 1.2-7.9). CONCLUSIONS: Subgroups (gender, professionalism and age) of fire fighters are prone to at least one specific work-related diminished health requirement. Therefore, parts of the WHS could be applied with more attention to these high-risk groups. PMID- 22105654 TI - Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures. AB - Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18 months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6 months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18 months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures. PMID- 22105655 TI - Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss. AB - To better define the biologic function of membrane-bound CSF1 (mCSF1) in vivo, we have generated mCSF1 knockout (k/o) mice. Spinal bone density (BMD) was 15.9% higher in k/o mice compared to wild-type (wt) controls (P < 0.01) and total BMD was increased by 6.8% (P < 0.05). A higher mean femur BMD was also observed but did not reach statistical significance (6.9% P = NS). The osteoclastogenic potential of bone marrow isolated from mCSF1 k/o mice was reduced compared to wt marrow. There were no defects in osteoblast number or function suggesting that the basis for the high bone mass phenotype was reduced resorption. In addition to a skeletal phenotype, k/o mice had significantly elevated serum triglyceride levels (123 +/- 7 vs. 88 +/- 3.2 mg/dl; k/o vs. wt, P < 0.001), while serum cholesterol levels were similar (122 +/- 6 vs. 116 +/- 6 mg/dl; k/o vs. wt, P = NS). One month after surgery, 5-month-old k/o and wt female mice experienced the same degree of bone loss following ovariectomy (OVX). OVX induced a significant fourfold increase in the expression of the soluble CSF1 isoform (sCSF1) in the bones of wt mice while expression of mCSF1 was unchanged. These findings indicate that mCSF1 is essential for normal bone remodeling since, in its absence, BMD is increased. Membrane-bound CSF1 does not appear to be required for estrogen deficiency bone loss while in contrast; our data suggest that sCSF1 could play a key role in this pathologic process. The reasons why mCSF1 k/o mice have hypertriglyceridemia are currently under study. PMID- 22105656 TI - Change in bone mineral density and tooth loss in Japanese community-dwelling postmenopausal women: a 5-year cohort study. AB - The aim of this longitudinal study was to investigate the association between the change in bone mineral density (BMD) and tooth loss in Japanese community dwelling postmenopausal women. The subjects were 404 women. At baseline (2005) and follow-up (2010), BMDs of the lumbar spine and right femoral neck were measured using dual-energy X-ray absorptiometry (QDR4500a) and participants were classified by tertiles of the annual percentage change in BMD. The number of teeth was counted at the baseline and follow-up to calculate the number of lost teeth over 5 years. Poisson regression analysis was conducted with tertiles of the changes in BMDs of the lumbar spine and femoral neck as the main exposures to estimate their influence on the number of lost teeth. Participants in the tertile with a greater decrease in BMD at each skeletal site (lumbar spine and femoral neck, respectively) had a larger number of lost teeth, controlling for possible confounders. The adjusted relative risks (95% confidence interval) for the mean number of lost teeth in the first, second, and third tertiles were 1.00, 1.15 (0.91-1.45), and 1.38 (1.11-1.72) for the lumbar spine and 1.00, 1.17 (0.93 1.47), and 1.27 (1.01-1.59) for the femoral neck, respectively. In conclusion, a significant relationship exists between a change in BMD and the number of lost teeth during 5-year study period in Japanese community-dwelling postmenopausal women. PMID- 22105657 TI - Consistency in attitudes across cancer screenings in medically underserved minority populations. AB - While a wide range of behavioral and psychosocial literature explores attitudes and beliefs towards cancer screenings, fewer studies examine attitudes across cancer screening types. We draw on quantitative and qualitative findings from a 4 year prospective study based at a community health center serving diverse, low income patients. Methods included self-report surveys (n = 297), medical chart abstraction, and several qualitative methods with a subsample of participants. Participants included white, African-American, Vietnamese, and Latino patients who were diagnosed with diabetes, hypertension, or both. Patients' attitudes (both positive and negative) towards cancer screening types were remarkably consistent across cancer screening types. These effects were stronger among men than women. Never having had a cancer screening was generally associated with more unfavorable attitudes towards all screenings. Qualitative interviews indicate the importance of information circulated through social networks in shaping attitudes towards cancer screenings. CONDENSED ABSTRACT: In a multi method study of attitudes towards cancer screening among medically underserved patients in a primary care setting, we found that attitudes (both positive and negative) were remarkably consistent across cancer screening types. PMID- 22105658 TI - The effects of oral consumption of selenium nanoparticles on chemotactic and respiratory burst activities of neutrophils in comparison with sodium selenite in sheep. AB - The present study was designed to compare the effects of nano-selenium and of sodium selenite on the chemotactic and respiratory burst activities of neutrophils in sheep. Fifteen sheep were randomly divided into three groups. Groups 1 and 2 received selenium nanoparticles (1 mg/kg) or sodium selenite (1 mg/kg) orally, respectively, for ten consecutive days, and the third group was considered as the control. To determine the chemotactic and respiratory burst activities of the neutrophils, the leading front assay and the NBT test were used on heparinized blood samples that were collected at different intervals (days 0, 10th, 20th, and 30th). The results obtained showed that the chemotactic activities in groups 1 and 2 increased significantly on the 10th, 20th, and 30th day, compared to day 0, and on the 20th day in comparison with the 10th day, while in group 2, there was a significant decrease on the 30th day compared to the 20th day. The chemotactic activities in group 1 were significantly higher than in group 2 on the 10th day and in the control group on the 10th, 20th, and 30th day, but the chemotactic activities in group 2 were significantly higher than those in the control group only on the 20th day. On the 30th day into the experiment, the respiratory bursts in groups 1 and 2 were significantly stronger in comparison with those at day 0. Overall, nano-selenium increased the chemotactic and respiratory burst activities more significantly than sodium selenite, which is suggestive of a stronger stimulatory effect of the Se nanoparticles on intracellular activities. PMID- 22105660 TI - Elevated intracranial pressure, low cerebral perfusion pressure, and impaired brain metabolism correlate with fatal outcome after severe brain injury. AB - BACKGROUND: New brain tissue monitoring techniques (tissue oxymetry, microdialysis) provide direct information about the state of brain oxygenation and brain metabolism in patients with severe traumatic brain injury (TBI). Despite this information being limited to a small region of the brain surrounding the probes, it could be associated with such global parameters as the clinical outcome. OBJECTIVE: To study the predictive value of monitoring brain oxygenation and metabolism on clinical outcome in patients in the acute phase of severe TBI. METHODS: An observational study of 20 patients with a severe TBI was undertaken, utilizing intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation, and brain metabolism monitoring. We correlated the clinical outcome of the patients with the following parameters: ICP, CPP, brain tissue oxymetry (PbtO2), glucose and glycerol levels, and the lactate/pyruvate (LP) ratio. Further, we analyzed the relationship between ICP, CPP, PbtO2, and the metabolism parameters. RESULTS: We found a correlation of the mean ICP values (8.73 +/- 1.18 in group A vs. 26.32 +/- 5.01 mmHg in group B, p < 0.005), the mean CPP values (84.82 +/- 2.02 in group A vs. 66.62 +/- 4.64 mmHg, p < 0.005), the LP ratio (37.36 +/- 3.44 vs. 199 +/- 87.97, p < 0.05), and glycerol levels (62.07 +/- 12.14 vs. 215 +/- 46.52 MUmol/l, p < 0.05) with the clinical outcome. High ICP correlated with both a high LP ratio (Spearman R = 0.61, p < 0.05), and elevated glycerol concentrations (Spearman R = 0.48, p < 0.05). A low CPP correlated with a high LP ratio (Spearman R = -0.57, p < 0.05), while a low PbtO2 correlated with a high LP ratio (Spearman R = -0.49, p < 0.05). CONCLUSIONS: High ICP, low CPP, an elevated mean LP ratio, and high glycerol concentrations in the acute phase predict fatal outcome 6 months after TBI. Further, high ICP, low CPP, and low PbtO2 correlate with impaired brain metabolism. PMID- 22105661 TI - Pharmaco-metabolomics: an emerging "omics" tool for the personalization of anticancer treatments and identification of new valuable therapeutic targets. AB - In the post-genomics era, metabolomics represents a new "omics" approach that in the last decade has received increased attention in the field of oncology. Metabolomics is based on the holistic study of the metabolic profile that characterizes a specific phenotype in a biological system. The metabolic profile provides a readout of the metabolic state of an individual that cannot be obtained directly from DNA genotyping, gene expression, or proteomic profiling analyses. The translational value of metabonomics in the oncology field has been demonstrated by the identification of diagnostic and prognostic biomarkers. The so-called pharmaco-metabolomic approach that is currently emerging aims to identify the individual metabolomic characteristics able to predict drug effectiveness and/or toxicity. This review presents the potential role of pharmaco-metabolomics in the future of anticancer pharmacology to achieve customized anticancer treatments and new, targeted therapeutic approaches. PMID- 22105662 TI - Zeolite Rho: a highly selective adsorbent for CO2/CH4 separation induced by a structural phase modification. AB - Zeolite Rho is able to successfully separate CO(2) from CH(4) with the highest selectivity ever observed on the basis of pore diameter and surface polarity. The adsorption of CO(2) provokes structural changes in the zeolite Rho. PMID- 22105663 TI - The third rail of family systems: sibling relationships, mental and behavioral health, and preventive intervention in childhood and adolescence. AB - Sibling relationships are an important context for development, but are often ignored in research and preventive interventions with youth and families. In childhood and adolescence, siblings spend considerable time together, and siblings' characteristics and sibling dynamics substantially influence developmental trajectories and outcomes. This paper reviews research on sibling relationships in childhood and adolescence, focusing on sibling dynamics as part of the family system and sibling influences on adjustment problems, including internalizing and externalizing behaviors and substance use. We present a theoretical model that describes three key pathways of sibling influence: one that extends through siblings' experiences with peers and school, and two that operate largely through family relationships. We then describe the few existing preventive interventions that target sibling relationships and discuss the potential utility of integrating siblings into child and family programs. PMID- 22105664 TI - CDNA cloning and characterization of S6 kinase and its effect on yolk protein gene expression in the oriental fruit fly Bactrocera dorsalis (Hendel). AB - p70 S6 kinase (S6K), a serine/threonine protein kinase, is a downstream target of target of rapamycin (TOR) gene and an important regulator of protein synthesis responsible for cell growth and reproduction. In this study, a S6K gene, named BdS6K (GenBank Accession No. GQ203802), was isolated from the oriental fruit fly Bactrocera dorsalis (Hendel). Quantitative RT-PCR showed that BdS6K mRNA is expressed at a higher level in egg than in other developmental stages, as well as in ovary than in fat body. Downregulation of BdS6K activity by rapamycin treatment in larval stage resulted in the developmental defects of larvae, pupae, and adults, with a reduced yolk protein (YP) expression in the fat body throughout the first reproductive cycle with a substantial reduction in ovary size, and also repressed the egg development in female fruit fly. Knockdown of BdS6K gene by RNA interference in the adult significantly decreased the YP expression. These observations support the involvement of BdS6K signaling in the regulation of the YP synthesis and egg development in B. dorsalis. PMID- 22105665 TI - Secretion and formation of perimicrovillar membrane in the digestive system of the Sunn pest, Eurygaster integriceps (Hemiptera: Scutelleridae) in response to feeding. AB - In this study, development of perimicrovillar membrane (PMM) from midgut cells of starved and fed Eurygaster integriceps (Hemiptera: Scutelleridae) was studied. Three different approaches, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), marker enzymes of the PMMs (alpha glucosidase), perimicrovillar space (aminopeptidase), and microvillar membranes (beta-glucosidase) were used. Activities of these enzymes were remarkably low in the starved insects. Moreover, microscopic observations revealed that PMM is not present in the starved insect. Activities of enzymatic markers increased at 5 h postfeeding, and TEM and SEM observations showed the formation of PMM as well as migration of double-membrane vesicles from center of the columnar cell to the cell apex. The highest PMM was observed at 20 h postfeeding which at this time marker enzyme activity, such as alpha-glucosidase activity, was high, too. Thus, at 20 h postfeeding, PMM system was evident and epithelial cells were completely covered by PMM system. After 20 h postfeeding, presence of the fine holes in PMM started to be seen and at 40 h post-feeding, observation showed degradation of PMM system. Thus, it could be concluded that PMM in E. integriceps is secreted by epithelial cell membrane when needed and its secretion and formation is regulated by feeding. This system was not present in the starved insects as its development takes place at 5 h postfeeding. PMID- 22105666 TI - Purification and biochemical characterization of glutathione S-transferases from four field populations of Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). AB - Glutathione S-transferases (GSTs) are a group of detoxification enzymes that catalyze the nucleophilic addition of glutathione to a wide variety of endogenous and xenobiotic compounds. In this study, GSTs were purified from four field populations of Bactrocera dorsalis with different insecticide susceptibilities by glutathione-agarose affinity chromatography. The populations were collected from Dongguan (DG) and Guangzhou (GZ) of the Guangdong Province, Haikou of the Hainan province (HN), and Kunming of the Yunnan province (YN), China. Differences in GST characteristics among the four populations were studied using purified enzyme samples through comparative SDS-PAGE, kinetic, and inhibition experiments. The specific activities of the purified enzymes were similar, but the purification yield of the GZ population (31.54%) was the lowest. SDS-PAGE analysis showed only one band at approximately 23 kDa for these four populations. Kinetic analyses showed that the affinities of the purified GSTs from the GZ and YN populations for 1-chloro-2.4-dinitrobenzene (CDNB) were much higher than those of GSTs from the other two populations, whereas the HN population had the highest catalytic capability in terms of V(max) value. The optimum temperature for CDNB conjugation was 37 degrees C and the optimum pH was 7.5 in all four populations. Inhibition kinetics showed that ethacrynic acid, diethyl maleate, tetraethylthiuram disulfide, curcumin, bromosulfalein, and beta-cypermethrin had excellent inhibitory effects on GSTs in the four populations of B. dorsalis, but the low inhibitory effects of malathion and avermectin did not differ between populations. These results suggest that GSTs may have a role in detoxification of beta-cypermethrin in B. dorsalis. PMID- 22105667 TI - A target-specific feeding toxicity of beta(1) integrin dsRNA against diamondback moth, Plutella xylostella. AB - Integrin is a cell-surface protein consisting of alpha and beta heterodimers. A predicted amino acid sequence of an integrin subunit of the diamondback moth, Plutella xylostella, was highly homologous to other lepidopteran beta1 subunits and possessed essential functional domains. The beta1 integrin of P. xylostella (betaPx1) was expressed in all developmental stages of P. xylostella. It was also expressed in all tested tissues including hemocyte, fat body, gut, and epidermis of last instar. When betaPx1 expression was suppressed by injection of dsRNA specific to betaPx1 (dsRNA(betaPx1)), the treated larvae exhibited significant suppression in immune response and also suffered significant larval mortality. When dsRNA(betaPx1) was orally fed to young larvae, it suppressed the expression of aPx1 and resulted in a significant mortality. By contrast, a dsRNA specific to beta1 subunit of Spodoptera exigua gave little adverse effects on betaPx1 expression and larval development when it was treated by injection or oral administration, though these two genes showed 71% sequence homology. These results suggest a target-specific RNA interference of dsRNA(betaPx1), which causes significant mortality to P. xylostella by feeding treatment. PMID- 22105669 TI - Potential biological fate of ingested nanoemulsions: influence of particle characteristics. AB - Edible nanoemulsions have great potential for utilization in the food and beverage industries to encapsulate, protect, and deliver lipophilic functional components claimed to have health benefits ("nutraceuticals"), such as carotenoids, flavonoids, phytosterols, polyunsaturated lipids, and oil-soluble vitamins. Nanoemulsions have a number of possible advantages over conventional emulsions for these applications, including high optical clarity, high stability to particle aggregation and gravitational separation, and increased bioavailability of lipophilic substances. Nevertheless, there are concerns about the potential risks associated with ingestion of nanoemulsions due to their ability to alter the behavior of bioactive components within the gastrointestinal tract. At present, there is still a relatively poor understanding of the biological fate of nanoemulsions in the human GI tract, which is holding back the rational design and application of nanoemulsion-based delivery systems for lipophilic bioactive components. This article provides a brief review of the current status of the formation, properties, and potential biological fate of food-grade nanoemulsions. In particular, it focuses on the influence of particle characteristics, such as size and interfacial properties, on the digestion and absorption of lipid nanoparticles. PMID- 22105670 TI - Supporting return-to-work in the face of legislation: stakeholders' experiences with return-to-work after breast cancer in Belgium. AB - BACKGROUND: The diagnosis of breast cancer increasingly implies a return-to-work (RTW) challenge as survival rates increase. RTW is regarded as a multidisciplinary process and a country's legislation affects the degree of involvement of the different stakeholders. We elucidated on bottlenecks and contributing factors and the relationship between policy and practice regarding RTW of employees with breast cancer as perceived by Belgian (Flemish) stakeholders. METHODS: Three multidisciplinary groups (n = 7, n = 9, n = 10) were interviewed during a breast cancer conference. Treating physicians (n = 4), employers (n = 6), social security physicians (n = 3), occupational physicians (n = 4), survivors (n = 5) and representatives of patient associations (n = 4) were included. The major theme was the legal and practical role in the RTW process as experienced by the participants. Qualitative thematic analysis was performed to analyse stakeholders' experiences of women's RTW after breast cancer. RESULTS: The stakeholders reported different perspectives. Employees focus on treatment and feel ill-informed about the RTW options. Treating physicians do not feel competent about advising on work-related questions. Employers have to balance the interests of both the business and the employee. Social security physicians assess ability to work and facilitate RTW options. Occupational physicians see opportunities but the legislation does not support their involvement. Stakeholders expressed the need for coordination and reported finding ways to accommodate the employee's needs by being flexible with the legislation to support the RTW process. CONCLUSIONS: Two factors might hamper RTW for breast cancer patients: the varying stakeholder perspectives and Belgian legislation which emphasizes the patient or disability role, but not the employee role. When stakeholders are motivated they find ways to support RTW, but improved legislation could support the necessary coordination of RTW for these patients. PMID- 22105671 TI - Hypertension: ACE inhibitor use in pregnancy--setting the record straight. PMID- 22105672 TI - Risk factors: Ethnicity and cardiovascular risk-are all men created equal? PMID- 22105675 TI - Prevention: Convergent communicable and noncommunicable heart disease. PMID- 22105678 TI - Interventional cardiology: Time for same-day discharge after uncomplicated PCI? PMID- 22105677 TI - Treatment and management of mitral regurgitation. AB - Mitral regurgitation (MR) is the most-common valvular heart disease in the western world. From an etiologic point of view, MR can be either organic (mainly degenerative in western countries) or functional (secondary to left ventricular remodeling in the context of ischemic or idiopathic dilated cardiomyopathy). Degenerative and functional MR are completely different disease entities that pose specific decision-making problems and require different management. The natural history of severe degenerative MR is clearly unfavorable. However, the appropriate and timely correction of degenerative MR is associated with a life expectancy similar to that of the normal population. By contrast, the prognostic impact of the correction of functional MR is still a matter of debate. In this Review, we discuss the optimal treatment of both degenerative and functional MR, taking into account all presently available therapeutic options, including novel percutaneous methods. Since a clear understanding of the etiology and mechanisms of valvular dysfunction is important to guide the timing and choice of treatment, the role of echocardiography in the management of MR is also addressed. PMID- 22105679 TI - Mean arterial blood pressure while awaiting kidney transplantation is associated with the risk of primary nonfunction. AB - BACKGROUND: Primary nonfunction (PNF) is a devastating outcome after kidney transplantation and is more common with kidneys from donors without a heartbeat or expanded criteria donors, or both. We investigated recipient-based risk factors for PNF independent of organ donor source. METHODS: We used a case control study design and matched for the source of organ and year of transplantation; for each recipient with PNF, two recipients without PNF (controls) were randomly selected. We identified 20 PNF cases and 40 controls from our pool of 993 kidney transplant recipients who all received their transplants at our center between 2003 and 2008. The association between PNF and immune risk factors and blood pressure (BP) levels during the 3 months before transplantation was analyzed. RESULTS: Among the factors analyzed, the mean systolic BP (P=0.003, Wilcoxon test), diastolic BP (P=0.02), and mean arterial pressure (MAP) (P=0.006) during the 3 months before transplantation were significantly lower in the PNF cases compared with the controls without PNF. In a multivariable model, only MAP remained as a significant risk factor for PNF and each 10 mm Hg decrease in MAP was associated with a 43% increased odds for PNF (P=0.01). The odds ratio for PNF in those with MAP less than or equal to 80 mm Hg was 4.32 (95% confidence interval, 1.41-13.2, P=0.008), compared with the group with MAP more than 100 mm Hg. CONCLUSIONS: Our findings support the hypothesis that the average MAP less than or equal to 80 mm Hg during the 3 months before kidney transplantation is a risk factor for PNF. PMID- 22105680 TI - [Accelerated orthodontic treatment with piezocision: a mini-invasive alternative to conventional corticotomies]. AB - An increasing number of adult patients are seeking orthodontic treatment and a short treatment time has become a recurring request. To meet their expectations, a number of surgical techniques have been developed to accelerate orthodontic tooth movement. However, these have been found to be quite invasive. We are introducing here a new, minimally invasive flapless procedure, combining micro incisions, piezoelectric incisions and selective tunneling that allows for hard- or soft-tissue grafting. Combined with a proper treatment planning and a good understanding of the biological events involved, this novel technique can locally manipulate alveolar bone metabolism in order to obtain rapid and stable orthodontic results. Piezocision allows for rapid correction of severe malocclusions without the drawbacks of traumatic conventional corticotomy procedures. PMID- 22105681 TI - [Orthodontic treatment in adults with compromised periodontium: biomechanical principles and clinical applications]. AB - In recent years, there has been a dramatic increase in the number of adults receiving comprehensive orthodontic treatment. In clinical practice, management of adults may be somewhat different than for most adolescents. Adults are more likely than adolescents to have dentitions that have undergone some degree of mutilation over time, which may necessitate alterations in the treatment strategy. Excessive wear, missing and compromised teeth are some of the differences observed. For adult patients who have experienced bone and attachment loss as a consequence of periodontal disease, a new set of biomechanical requirements exists for producing the tooth movements desired during the orthodontic therapy. Proper planning and appliance design for adults presenting with multiple missing teeth may require some degree of creativity to adapt to unique malocclusions and deliver the proper biomechanical force system. In this article, current clinical application of biomechanical principles will be presented with emphasis on clinical orthodontic management of severely mutilated dentitions. PMID- 22105682 TI - [Dento-facial orthopedics and osteopathy]. AB - Osteopathy has grown rapidly. Given their common action on children and adolescents, the collaboration between dentofacial orthopedics and osteopathy is increasingly common. It therefore becomes necessary and urgent to investigate whether, based on data acquired from science, there is evidence of possible interrelations between the two disciplines. After reviewing the literature, very few scientific publications demonstrate the utility of osteopathy and its relationships with other disciplines. However, the relationship between occlusion and posture seem relatively proven, especially in the sagittal direction. On the other hand, although the mobility of the cranial bones is established, the primary respiratory motion is still subject to controversy, even among osteopaths. This, even as orthodontics has long been accused of countering the primary respiratory motion of cranial bones (PRM). Today osteopaths do not reject orthodontics anymore, because the return to a physiological bite situation is considered beneficial. According to expert opinion (without proof, however), some orthodontic devices (like headgears) which block the sutures are still to be avoided and require appropriate monitoring osteopathy. The controversy over the adverse effects of orthodontic treatment is becoming more nuanced by osteopaths, and modern orthodontics claiming a "global" approach of patient, collaboration may be possible in future year. PMID- 22105683 TI - [Is the ethnic factor an orthodontic therapeutic instructor?]. AB - Because different groups in human society view beauty in stereotypical terms of their own ethnicity, orthodontists should study the concept of facial beauty with scientific rigor. Is it time for us to re-examine the assumption that the original cephalometric esthetic norms based on samples of North Americans can be applied to other populations? Many cephalometric analyses of Afro-American and Asian subjects who had not received orthodontic treatment but whose occlusions were normal have shown that their esthetic criteria were far different from those of the Caucasian North American sample. The Afro-Americans and Asians share a principal ethnic facial characteristic of bi-maxillary alveolo-dental protrusion with a reduced naso-labial angle. Afro-Americans frequently have maxillae in an anterior position with mandibles in similar or retruded positions. Asians appear to have similar cutaneous profiles but group skeletal profiles differ: Japanese often have more retruded maxillae; Chinese often have protruded maxillae and retruded mandibles. Koreans tend to have characteristics resembling those of Japanese groups. So it would seem necessary for the specialty of orthodontics to establish specific data of facial characteristics that reflect the ethnic origin of potential patients in order for specialists to make accurate and appropriate esthetic diagnoses. PMID- 22105684 TI - [Pathogenic situations after orthodontic treatment. Defects in skeleton and soft tissues that should be avoided after orthodontic treatment]. AB - The perfect correction of dental alignment anomalies found in dento facial dysmorphosis should not be the only criterium of success in dento facial orthopedics. One must insure, lest severe T.M.J. disorders and sleep apnea problems subsequently occur, that : (1) the condyles and mandibular vertical branches are correctly positioned relative to the basilar apophysis and cervical vertebrae, (2) the hyoid bone must not descend too low relative to the C3-C4 intervertebral disk. PMID- 22105686 TI - Evaluation of testicular vein anatomy with multidetector computed tomography. AB - PURPOSE: We aimed to evaluate the normal anatomy and variations of testicular veins by multidetector CT (MDCT). MATERIALS AND METHODS: This prospective study included 101 male patients who underwent abdominal CT for various clinical indications. Mean age of patients was 53 years. Images were obtained by dual source 64-slice MDCT (n = 61) and 64-MDCT (n = 41). Images were analyzed using 1 mm thick slices on a dedicated workstation. The number of testicular veins, drainage site and diameter of proximal, mid and distal testicular veins were recorded. RESULTS: Testicular veins were visualized in all patients. There were single right testicular vein in 99 (98%) patients and 2 (2%) patients had duplicated right testicular veins (total 103 veins). Right testicular vein drained into inferior vena cava in 88 (87.1%) patients and right renal vein in 13 (12.9%) patients. One of duplicated right testicular veins drained into inferior vena cava and other paired drained into right renal vein and inferior vena cava separately. There were single left testicular vein in 88 (87.1%) patients and 13 (12.9%) patients had duplicated veins (total 14 veins). All left testicular veins drained into left renal vein. CONCLUSION: 64-MDCT enables evaluation of testicular veins in all patients. Right and left testicular veins are usually single, but can be duplicated more commonly. PMID- 22105687 TI - Unilateral agenesis of the internal carotid artery presented as transient ischaemic attack: a case report. AB - Dysgenesis of the internal carotid artery (ICA) is a rare vascular disorder with a variety of different grades (agenesis, aplasia, and hypoplasia). The left internal carotid artery is reported to be affected by dysgenesis three times more often than the right one. Most of the patients with dysgenesis of the internal carotid artery are asymptomatic. We report a case of a patient with right internal carotid artery agenesis presented to our hospital as transient ischaemic attack. CT scans at skull base level with bone settings showed absence of the right carotid canal, consistent with congenital agenesis of the internal carotid artery. MR imaging of the brain revealed signal void of the intracranial portion of right internal carotid artery. Maximum intensity projection reconstruction confirmed the agenesis of the right ICA, with the right middle cerebral artery fed through a dilated posterior communicating artery and the right anterior cerebral artery supplied by the anterior communicating artery (fetal type of collateral flow). In patients with agenesis of the internal carotid artery non invasive imaging techniques are currently the mainstay of diagnosis. PMID- 22105688 TI - Hiatal hernias. AB - Esophageal hiatal hernias have been reported to affect anywhere from 10 to 50% of the population. Hiatal hernias are characterized by a protrusion of the stomach into the thoracic cavity through a widening of the right crus of the diaphragm. There are four types of esophageal hiatal hernias: sliding (type I), paraesophageal (type II), and combined (type III), which include elements of types I and II, and giant paraesophageal (type IV). Each type may present with different symptoms and complications. The potential severity of symptoms necessitates proper and prompt diagnosis. Diagnosis is established with the use of barium swallow on chest radiographs. Treatment for sliding hernias involves laparoscopic fundoplication. The aim of our paper is to review the extensive literature regarding hiatal hernias in an effort to enhance awareness and diagnosis of this pathology. PMID- 22105689 TI - Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development. AB - Recent genome-wide association studies showed that four single-nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) were associated with chronic hepatitis B virus (HBV) infection in Japanese populations. More than 75% of hepatocellular carcinoma (HCC) patients are attributable to persistent infection of hepatitis B virus (HBV), especially in China. We genotyped these four SNPs in 1,300 HBV positive HCC patients, 1,344 persistent HBV carriers, and 1,344 persons with HBV natural clearance from Southeast China to further test the associations of HLA DP/DQ variants and with risk of both HBV clearance and HCC development. Logistic regression analyses showed that HLA-DQ rs2856718 significantly decreased host HCC risk, whereas three SNPs were associated with HBV clearance (HLA-DP rs9277535 as well as HLA-DQ rs7453920 and rs2856718). In addition, HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments. Taken together, we report, for the first time, that genetic variants in the HLA-DP and HLA-DQ loci may be marker SNPs for risk of both HBV clearance and HCC development. PMID- 22105690 TI - Adaptive increase in sample size when interim results are promising: a practical guide with examples. AB - This paper discusses the benefits and limitations of adaptive sample size re estimation for phase 3 confirmatory clinical trials. Comparisons are made with more traditional fixed sample and group sequential designs. It is seen that the real benefit of the adaptive approach arises through the ability to invest sample size resources into the trial in stages. The trial starts with a small up-front sample size commitment. Additional sample size resources are committed to the trial only if promising results are obtained at an interim analysis. This strategy is shown through examples of actual trials, one in neurology and one in cardiology, to be more advantageous than the fixed sample or group sequential approaches in certain settings. A major factor that has generated controversy and inhibited more widespread use of these methods has been their reliance on non standard tests and p-values for preserving the type-1 error. If, however, the sample size is only increased when interim results are promising, one can dispense with these non-standard methods of inference. Therefore, in the spirit of making adaptive increases in trial size more widely appealing and readily implementable we here define those promising circumstances in which a conventional final inference can be performed while preserving the overall type-1 error. Methodological, regulatory and operational issues are examined. PMID- 22105691 TI - Comments on 'Adaptive increase in sample size when interim results are promising: a practical guide with examples'. PMID- 22105693 TI - Integrative analysis of multiple cancer prognosis studies with gene expression measurements. AB - Although in cancer research microarray gene profiling studies have been successful in identifying genetic variants predisposing to the development and progression of cancer, the identified markers from analysis of single datasets often suffer low reproducibility. Among multiple possible causes, the most important one is the small sample size hence the lack of power of single studies. Integrative analysis jointly considers multiple heterogeneous studies, has a significantly larger sample size, and can improve reproducibility. In this article, we focus on cancer prognosis studies, where the response variables are progression-free, overall, or other types of survival. A group minimax concave penalty (GMCP) penalized integrative analysis approach is proposed for analyzing multiple heterogeneous cancer prognosis studies with microarray gene expression measurements. An efficient group coordinate descent algorithm is developed. The GMCP can automatically accommodate the heterogeneity across multiple datasets, and the identified markers have consistent effects across multiple studies. Simulation studies show that the GMCP provides significantly improved selection results as compared with the existing meta-analysis approaches, intensity approaches, and group Lasso penalized integrative analysis. We apply the GMCP to four microarray studies and identify genes associated with the prognosis of breast cancer. PMID- 22105694 TI - Benzocaine-loaded polymeric nanocapsules: study of the anesthetic activities. AB - This paper describes a comparison of different polymeric nanocapsules (NCs) prepared with the polymers poly(D,L-lactide-co-glycolide), poly(L-lactide) (PLA), and poly(epsilon-caprolactone) and used as carrier systems for the local anesthetic (LA) benzocaine (BZC). The systems were characterized and their anesthetic activities investigated. The results showed particle size distributions with polydispersity indices below 0.135, average diameters up to 120 nm, zeta potentials up to -30 mV, and entrapment efficiencies around 70%. Formulations of BZC using the polymeric NCs presented slower release profiles, compared with that of free BZC. Slowest release (release constant, k = 0.0016 min(-1)) was obtained using the PLA NC system. Pharmacological evaluation showed that encapsulation of BZC in PLA NCs prolonged its anesthetic action. This new formulation could potentially be used in future applications involving the gradual release of local anesthetics (LAs). PMID- 22105695 TI - Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation. AB - The chromosome status of the mammalian embryo initiates a multistage process of sexual development in which the bipotential reproductive system establishes itself as either male or female. These events are governed by intricate cell-cell and interorgan communication that is regulated by multiple signaling pathways. The hedgehog signaling pathway was originally identified for its key role in the development of Drosophila, but is now recognized as a critical developmental regulator in many species, including humans. In addition to its developmental roles, the hedgehog signaling pathway also modulates adult organ function, and misregulation of this pathway often leads to diseases, such as cancer. The hedgehog signaling pathway acts through its morphogenetic ligands that signal from ligand-producing cells to target cells over a specified distance. The target cells then respond in a graded manner based on the concentration of the ligands that they are exposed to. Through this unique mechanism of action, the hedgehog signaling pathway elicits cell fate determination, epithelial-mesenchymal interactions, and cellular homeostasis. Here, we review current findings on the roles of hedgehog signaling in the sexually dimorphic development of the reproductive organs with an emphasis on mammals and comparative evidence in other species. PMID- 22105696 TI - The sex-specific region of sex chromosomes in animals and plants. AB - Our understanding of the evolution of sex chromosomes has increased greatly in recent years due to a number of molecular evolutionary investigations in divergent sex chromosome systems, and these findings are reshaping theories of sex chromosome evolution. In particular, the dynamics of the sex-determining region (SDR) have been demonstrated by recent findings in ancient and incipient sex chromosomes. Radical changes in genomic structure and gene content in the male specific region of the Y chromosome between human and chimpanzee indicated rapid evolution in the past 6 million years, defying the notion that the pace of evolution in the SDR was fast at early stages but slowed down overtime. The chicken Z and the human X chromosomes appeared to have acquired testis-expressed genes and expanded in intergenic regions. Transposable elements greatly contributed to SDR expansion and aided the trafficking of genes in the SDR and its X or Z counterpart through retrotransposition. Dosage compensation is not a destined consequence of sex chromosomes as once thought. Most X-linked microRNA genes escape silencing and are expressed in testis. Collectively, these findings are challenging many of our preconceived ideas of the evolutionary trajectory and fates of sex chromosomes. PMID- 22105697 TI - Crosstalk between adenosine A1 and beta1-adrenergic receptors regulates translocation of PKCepsilon in isolated rat cardiomyocytes. AB - Adenosine A(1) receptor (A(1)R)-induced translocation of PKCepsilon to transverse (t) tubular membranes in isolated rat cardiomyocytes is associated with a reduction in beta(1)-adrenergic-stimulated contractile function. The PKCepsilon mediated activation of protein kinase D (PKD) by endothelin-1 is inhibited by beta(1)-adrenergic stimulated protein kinase A (PKA) suggesting a similar mechanism of A(1)R signal transduction modulation by adrenergic agonists may exist in the heart. We have investigated the influence of beta(1)-adrenergic stimulation on PKCepsilon translocation elicited by A(1)R. Immunofluorescence imaging and Western blotting with PKCepsilon and beta-COP antibodies were used to quantify the co-localization of PKCepsilon and t-tubular structures in isolated rat cardiomyocytes. The A(1)R agonist CCPA increased the co-localization of PKCepsilon and t-tubules as detected by imaging. The beta(1)-adrenergic receptor agonist isoproterenol (ISO) inhibited this effect of CCPA. Forskolin, a potent activator of PKA, mimicked, and H89, a pharmacological PKA inhibitor, and PKI, a membrane-permeable PKA peptide PKA inhibitor, attenuated the negative effect of ISO on the A(1)R-mediated PKCepsilon translocation. Western blotting with isolated intact hearts revealed an increase in PKCepsilon/beta-COP co localization induced by A(1)R. This increase was attenuated by the A(1)R antagonist DPCPX and ISO. The ISO-induced attenuation was reversed by H89. It is concluded that adrenergic stimulation inhibits A(1)R-induced PKCepsilon translocation to the PKCepsilon anchor site RACK2 constituent of a coatomer containing beta-COP and associated with the t-tubular structures of the heart. In that this translocation has been previously associated with the antiadrenergic property of A(1)R, it is apparent that the interactive effects of adenosine and beta(1)-adrenergic agonists on function are complex in the heart. PMID- 22105698 TI - Sparsity and low-contrast object detectability. AB - The application of sparsity-driven reconstruction methods to MRI to date has largely focused on situations where high-contrast features (e.g., gadolinium enhanced vessels) are of primary interest. In clinical practice, however, low contrast features such as subtle lesions are often of equal or greater interest. Using an American College of Radiology MR quality assurance phantom and test, we describe a novel framework for systematically and automatically evaluating the low-contrast object detectability performance of different undersampled image reconstruction methods. This platform is used to evaluate three such methods, two based on classic Tikhonov regularization and one sparsity-driven method based on l(1) -norm minimization (which is commonly used in compressive sensing, also known as compressed sensing, applications), across a wide range of sampling rates and parameterizations. Both the automated evaluation system and a manual evaluation of anatomical images with numerically-generated low contrast inserts demonstrate that sparse reconstructions exhibit superior low-contrast object detectability performance compared to both Tikhonov-regularized reconstructions. The implications of this result, and potential applications of both the described low-contrast object detectability platform and generalizations of it are then discussed. PMID- 22105699 TI - Use of nonmedical and pediatric primary care medical services by families who call police for domestic violence-related issues. AB - This study considers domestic violence (DV) victims' court and social service utilization (n = 86). We next examine the victims' pediatric provider to explore pediatricians' roles in a community-based response to DV. Sixty-five percent of the sample who used DV-related services interacted with the pediatric community. Pediatric inner-city clinic-based patients appear in the welfare management system and child protective system at similar rates as private pediatric patients. However, clinic-based patients appear in family court more than privately based patients (91% vs. 57%). Data suggest that all pediatric providers should screen, assess, and refer parents for DV. PMID- 22105700 TI - Towards an integrated optical single aerosol particle lab. AB - We present a manipulation and characterization system for single airborne particles which is integrated onto a microscope slide. Trapped particles are manipulated by means of radiation pressure and characterized by cavity enhanced Raman spectroscopy. Optical fibers are used to deliver the trapping laser light as well as to collect the Raman scattered light, allowing for a flexible usage of the device. The system features a sample chamber which is separated from an aerosol-flooded injection chamber by means of a light guiding glass-capillary. The coupling of this device with an aerosol optical tweezers setup to selectively load its trapping sites is demonstrated. Finally, a route towards chip-integrated handling and processing of multiple particles is shown and the first results are presented. PMID- 22105701 TI - Regulating the contraction of insect flight muscle. AB - The rapid movement of the wings in small insects is powered by the indirect flight muscles. These muscles are capable of contracting at up to 1,000 Hz because they are activated mechanically by stretching. The mechanism is so efficient that it is also used in larger insects like the waterbug, Lethocerus. The oscillatory activity of the muscles occurs a low concentration of Ca(2+), which stays constant as the muscles contract and relax. Activation by stretch requires particular isoforms of tropomyosin and the troponin complex on the thin filament. We compare the tropomyosin and troponin of Lethocerus and Drosophila with that of vertebrates. The characteristics of the flight muscle regulatory proteins suggest ways in which stretch-activation works. There is evidence for bridges between troponin on thin filaments and myosin crossbridges on the thick filaments. Recent X-ray fibre diffraction results suggest that a pull on the bridges activates the thin filament by shifting tropomyosin from a blocking position on actin. The troponin bridges are likely to contain extended sequences of tropomyosin or troponin I (TnI). Flight muscle has two isoforms of TnC with different Ca(2+)-binding properties: F1 TnC is needed for stretch-activation and F2 TnC for isometric contractions. In this review, we describe the structural changes in both isoforms on binding Ca(2+) and TnI, and discuss how the steric model of muscle regulation can apply to insect flight muscle. PMID- 22105702 TI - Myosin VI in PC12 cells plays important roles in cell migration and proliferation but not in catecholamine secretion. AB - Myosin VI (MVI) is the only known myosin walking towards minus end of actin filaments and is believed to play distinct role(s) than other myosins. We addressed a role of this unique motor in secretory PC12 cells, derived from rat adrenal medulla pheochromocytoma using cell lines with reduced MVI synthesis (produced by means of siRNA). Decrease of MVI expression caused severe changes in cell size and morphology, and profound defects in actin cytoskeleton organization and Golgi structure. Also, significant inhibition of cell migration as well as cell proliferation was observed. Flow cytometric analysis revealed that MVI deficient cells were arrested in G0/G1 phase of the cell cycle but did not undergo increased senescence as compared with control cells. Also, neither polyploidy nor aneuploidy were detected. Surprisingly, no significant effect on noradrenaline secretion was observed. These data indicate that in PC12 cells MVI is involved in cell migration and proliferation but is not crucial for stimulation-dependent catecholamine release. PMID- 22105703 TI - Animal models in autoimmune diseases: lessons learned from mouse models for Sjogren's syndrome. AB - The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multifactorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjogren's syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands, such as the salivary and lacrimal glands, and loss of secretory function, resulting in dry mouth and dry eyes in patients. Although every Sjogren's syndrome mouse model resembles the major symptoms or phenotypes of Sjogren's syndrome conditions in humans, the characteristics of each model are variable. Moreover, to date, there is no single mouse model that can completely replicate the human conditions. However, unique features of each mouse model provide insights into the roles of potential etiological and immunological factors in the development and progression of Sjogren's syndrome. Here, we will overview the Sjogren's syndrome mouse models. Lessons from these mouse models will aid us to understand underlying immune dysregulation in autoimmune diseases in general, and will guide us to direct future research towards appropriate diagnostic and therapeutic strategies. PMID- 22105704 TI - Bronchial thermoplasty: a new treatment paradigm for severe persistent asthma. AB - Patients with severe asthma represent only a minority of the total asthma population; however, they account for the majority of the mortality, morbidity, and health care-related cost of this chronic illness. Bronchial thermoplasty is a novel treatment modality that employs radiofrequency energy to alter the smooth muscles of the airways. This therapy represents a radical change in our treatment paradigm from daily repetitive dosing of medications to a truly long-term and potentially permanent attenuation of perhaps the most feared component of asthma- smooth muscle-induced bronchospasm. A large, multicentered, double-blinded, randomized controlled trial employed the unprecedented (but now industry standard for bronchoscopic studies) approach of using sham bronchoscopy as a control. It demonstrated that bronchial thermoplasty is safe, improved quality of life, and decreased frequency of severe exacerbations in the treatment group compared to the control group. Although the mechanism of action of bronchial thermoplasty is not currently completely understood, it should be considered as a valid and potentially valuable option for patients who have severe persistent asthma and who remain symptomatic despite inhaled corticosteroids and long-acting beta-2 agonists. Such patients should however be carefully evaluated at centers with expertise in managing severe asthma patients and with physicians who have experience with this promising new treatment modality. PMID- 22105705 TI - Effects of Tai Chi on pre-landing muscle response latency during stepping down while performing a concurrent mental task in older adults. AB - To investigate whether elderly Tai Chi practitioners are better able to descend a step while performing a concurrent mental task than non-practitioners. The design includes cross-sectional study. The setting includes university-based rehabilitation center. The subjects were 16 young women, 29 elderly women, and 31 elderly women who had been practicing Tai Chi regularly for at least half a year. Pre-landing muscle response latencies in their tibialis anterior (TA) and medial gastrocnemius (MG) muscles were measured during stepping down (single task) and stepping down while performing a concurrent mental activity (dual tasking). The non-practitioners had earlier onset of muscle activity in the TA in preparation for landing than the other subjects. The response latency of the Tai Chi practitioners was not significantly different from that of the young controls. When the cognitive task was added, the pre-landing response in the TA was significantly altered in both elderly groups. Response was significantly delayed among the non-practitioners, but significantly earlier among the Tai Chi subjects. The average change in response latency was significantly greater in the non-Tai Chi group compared with the young subjects and the Tai Chi practitioners (p = 0.006). Such findings suggest that practicing Tai Chi helps the elderly maintain the same strategy as much as younger subjects during stepping down. Tai Chi practitioners seem to have a greater capacity to shift attention between mental and physical tasks than other elderly women. PMID- 22105706 TI - Skeletal muscle metaboreflex is enhanced in postmenopausal women. AB - This study determined whether an elevated muscle metaboreflex contributes to the excessive blood pressure response to exercise in postmenopausal women. Thirty healthy female volunteers were studied (15 postmenopausal and 15 premenopausal). Stroke volume, heart rate, cardiac output (CO), systolic blood pressure, diastolic blood pressure, and total vascular conductance (TVC) were continuously assessed throughout the experiment. To activate the muscle metaboreflex, occlusion of the vasculature was induced via inflation of a blood pressure cuff (2 min) on the upper arm following static handgrip exercise. Muscle metaboreflex activation increased mean arterial pressure (MAP) in both groups. However, this pressor response was greater in the postmenopausal women (DeltaMAP: 21.4 +/- 3 vs. 14.5 +/- 2 mmHg) (P < 0.05) even though the corresponding increase in CO was less (DeltaCO: 0.0 +/- 0.2 vs. 0.3 +/- 0.2 l/min) (P < 0.05). TVC decreased in both the groups but was more pronounced in the postmenopausal group (DeltaTVC: 10.7 +/- 2.6 vs. -17.1 +/- 3.6 ml/min/mmHg) (P < 0.05). In conclusion, the exaggerated blood pressure response to exercise in postmenopausal women is mediated, in part, by an overactive metaboreflex that is associated with enhanced peripheral vasoconstriction. PMID- 22105707 TI - Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. AB - The purpose of this study was to investigate associations between acute exercise induced hormone responses and adaptations to high intensity resistance training in a large cohort (n = 56) of young men. Acute post-exercise serum growth hormone (GH), free testosterone (fT), insulin-like growth factor (IGF-1) and cortisol responses were determined following an acute intense leg resistance exercise routine at the midpoint of a 12-week resistance exercise training study. Acute hormonal responses were correlated with gains in lean body mass (LBM), muscle fibre cross-sectional area (CSA) and leg press strength. There were no significant correlations between the exercise-induced elevations (area under the curve-AUC) of GH, fT and IGF-1 and gains in LBM or leg press strength. Significant correlations were found for cortisol, usually assumed to be a hormone indicative of catabolic drive, AUC with change in LBM (r = 0.29, P < 0.05) and type II fibre CSA (r = 0.35, P < 0.01) as well as GH AUC and gain in fibre area (type I: r = 0.36, P = 0.006; type II: r = 0.28, P = 0.04, but not lean mass). No correlations with strength were observed. We report that the acute exercise induced systemic hormonal responses of cortisol and GH are weakly correlated with resistance training-induced changes in fibre CSA and LBM (cortisol only), but not with changes in strength. PMID- 22105708 TI - Time course of changes in the human Achilles tendon properties and metabolism during training and detraining in vivo. AB - The purpose of this study was to investigate the time course of changes in human tendon properties and metabolism during resistance training and detraining. Nine men (21-27 years) completed 3 months of isometric plantar flexion training and another 3 months of detraining. At the beginning and on every 1 month of training and detraining periods, the stiffness, blood circulation (blood volume and oxygen saturation), serum procollagen type 1 C-peptide (P1P; reflects synthesis of type 1 collagen), echointensity (reflects collagen content), and MRI signal intensity (reflects collagen structure) of the Achilles tendon were measured. Tendon stiffness did not change until 2 months of training, and the increase (50.3%) reached statistical significance at the end of the training period. After 1 month of detraining, tendon stiffness had already decreased to pre-training level. Blood circulation in the tendon did not change during the experimental period. P1P increased significantly after 2 months of training. Echointensity increased significantly by 9.1% after 2 months of training, and remained high throughout the experiment. MRI signal intensity increased by 24.2% after 2 months and by 21.4% after 3 months of training, but decreased to the pre-training level during the detraining period. These results suggested that the collagen synthesis, content, and structure of human tendons changed at the 2-month point of training period. During detraining, the sudden decrease in tendon stiffness might be related to changes in the structure of collagen fibers within the tendon. PMID- 22105709 TI - APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms. AB - The amyloid precursor protein (APP) is part of a larger gene family, which has been found to form homo- or heterotypic complexes with its homologues, whereby the exact molecular mechanism and origin of dimer formation remains elusive. In order to assess the cellular location of dimerization, we have generated a cell culture model system in CHO-K1 cells, stably expressing human APP, harboring dilysine-based organelle sorting motifs [KKAA-endoplasmic reticulum (ER); KKFF Golgi], accomplishing retention within early secretory compartments. We show that APP exists as disulfide-bonded dimers upon ER retention after it was isolated from cells, and analyzed by SDS-polyacrylamide gel electrophoresis under non reducing conditions. In contrast, strong denaturing and reducing conditions, or deletion of the E1 domain, resulted in the disappearance of those dimers. Thus we provide first evidence that a fraction of APP can associate via intermolecular disulfide bonds, likely generated between cysteines located in the extracellular E1 domain. We particularly visualize APP dimerization itself and identified the ER as subcellular compartment of its origin using biochemical or split GFP approaches. Interestingly, we also found that minor amounts of SDS-resistant APP dimers were located to the cell surface, revealing that once generated in the oxidative environment of the ER, dimers remained stably associated during transport. In addition, we show that APP isoforms encompassing the Kunitz-type protease inhibitor (KPI) domain exhibit a strongly reduced ability to form cis directed dimers in the ER, whereas trans-mediated cell aggregation of Drosophila Schneider S2-cells was isoform independent. Thus, suggesting that steric properties of KPI-APP might be the cause for weaker cis-interaction in the ER, compared to APP695. Finally, we provide evidence that APP/APLP1 heterointeractions are likewise initiated in the ER. PMID- 22105710 TI - Comparison of ultrasonographic patellar tendon evaluation methods in elite junior female volleyball players: thickness versus cross-sectional area. AB - PURPOSE: The goal of the present study was to compare the patellar tendon cross sectional area with the patellar tendon thickness and to determine the intra observer compliance level in the cross-sectional area and thickness measurements. This comparison was used to describe the effects of playing volleyball on the patellar tendon. MATERIALS AND METHODS: The patellar tendons of 60 volleyball players and 60 non-player female students, who were 11-16 years of age with similar physical characteristics, were examined using Doppler ultrasonography (US). Cross-sectional area and thickness measurements were conducted. RESULTS: The proximal and distal thicknesses of the patellar tendon were similar, but the area was smaller for the distal portion. A correlation was observed between age and tendon thickness and between the thickness and area of the tendon. All of the measurements in the subjects with tendinosis were larger than those in the healthy controls. There were no pathological findings in the non-players. The intra-observer compliance was high. CONCLUSION: The transverse plane area measurement was as reliable as the thickness measurement and exhibited a high level of intraobserver compliance. This measurement can be conducted during routine examinations. The patellar tendons in the athletes were observed to be widened and thickened, most likely because of overuse. Patellar tendinosis and Osgood-Schlatter Syndrome may be asymptomatic and incidentally detected. Therefore, routine US examinations may help prevent further injuries. Although the tendon thicknesses were observed to be the same in both extremities, any observed difference in the tendon areas may alert the physician to a risk factor for the development of tendinosis. PMID- 22105711 TI - Effects of point mutations in pVHL on the binding of HIF-1alpha. AB - The von Hippel-Lindau tumor suppressor protein (pVHL) has an essential role in the regulation of the hypoxia response pathway in animal cells. Under normoxic conditions, the hypoxia-inducible factor (HIF) undergoes trans-4-prolyl hydroxylation and is subsequently recognised by the beta-domain of pVHL, leading to the ubiquitination and degradation of HIF. Mutations of pVHL alter the binding of HIF. A subset of relevant clinically observed mutations to pVHL are thought to cause weaker binding of HIF-1alpha and are associated with cancer and cardiovascular diseases. Here, we present computational studies analyzing the interaction of HIF with mutant forms of pVHL, describing at atomic detail the local structural reorganization caused by substitution of certain residues of pVHL. The results reveal that the canonical configuration in the wild-type system is vital for the efficient functioning of the complex and that mutation of any of the residues implicated in the h-bond network in the binding site disrupts HIF binding. Although the experimentally observed ordering of binding energies for mutants of Tyr98 is reproduced, our examination of a broader range of mutations does not support the hypothesis of a correlation between the degree of disruption of the pVHL/HIF-1alpha interaction caused by a mutation and the phenotype with which the mutation is associated. We suggest that disruption of the binding interaction is one of many factors behind the manifestation of VHL disease. PMID- 22105712 TI - Eco-friendly methodology to prepare N-heterocycles related to dihydropyridines: microwave-assisted synthesis of alkyl 4-arylsubstituted-6-chloro-5-formyl-2 methyl-1,4-dihydropyridine-3-carboxylate and 4-arylsubstituted-4,7 dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione. AB - Here we describe the efficient synthesis of alkyl 4-arylsubstituted-6-chloro-5 formyl-2-methyl-1,4-dihydropyridine-3-carboxylates and 4-arylsubstituted-4,7 dihydro-furo[3,4-b]pyridine-2,5(1H,3H)-diones via microwave-accelerated reaction of alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3 pyridinecarboxylates with the appropriate reagents. This eco-friendly approach to these valuable dihydropyridine derivatives does not involve the harsh or highly contaminating conditions common in classical heating and offers a reduction or even elimination of solvent use and recovery, simplification of the work-up procedures, facility of scale up, and low energy consumption, in addition to moderate to higher yields. PMID- 22105713 TI - A planar conformation and the hydroxyl groups in the B and C rings play a pivotal role in the antioxidant capacity of quercetin and quercetin derivatives. AB - The polyphenol quercetin (Q) that has a high antioxidant capacity is a lead compound in the design of antioxidants. We investigated the possibility of modifying quercetin while retaining its antioxidant capacity as much as possible. To this end, the antioxidant capacities of Q, rutin, monohydroxyethyl rutinoside (monoHER) and a series of synthesized methylated Q derivatives were determined. The results confirm that the electron donating effect of the hydroxyl groups is essential. It was also found that the relatively planar structure of Q needs to be conserved. This planar conformation enables the distribution of the electron donating effect through the large conjugated pi-system over the entire molecule. This is essential for the cooperation between the electron donating groups. Based on the activity of the compounds tested, it was concluded that structural modification at the 5 or 7 position is the most optimal to retain most of the antioxidant capacity of Q. This was confirmed by synthesizing and testing Q5OMe (Q6) and Q7OMe (Q7) that indeed displayed antioxidant capacities closest to Q. PMID- 22105714 TI - Biological activity of carbazole alkaloids and essential oil of Murraya koenigii against antibiotic resistant microbes and cancer cell lines. AB - A total of three carbazole alkaloids and essential oil from the leaves of Murraya koenigii (Rutaceae) were obtained and examined for their effects on the growth of five antibiotic resistant pathogenic bacteria and three tumor cell lines (MCF-7, P 388 and Hela). The structures of these carbazoles were elucidated based on spectroscopy data and compared with literature data, hence, were identified as mahanine (1), mahanimbicine (2) and mahanimbine (3). The chemical constituents of the essential oil were identified using Gas Chromatography-Mass Spectroscopy (GCMS). These compounds exhibited potent inhibition against antibiotic resistant bacteria such as Staphylococcus aureus (210P JTU), Psedomonas aeruginosa (ATCC 25619), Klebsiella pneumonia (SR1-TU), Escherchia coli (NI23 JTU) and Streptococcus pneumoniae (SR16677-PRSP) with significant minimum inhibition concentration (MIC) values (25.0-175.0 mg/mL) and minimum bacteriacidal concentrations (MBC) (100.0-500.0 mg/mL). The isolated compounds showed significant antitumor activity against MCF-7, Hela and P388 cell lines. Mahanimbine (3) and essential oil in particular showed potent antibacteria and cytotoxic effect with dose dependent trends (<=5.0 MUg/mL). The findings from this investigation are the first report of carbazole alkaloids' potential against antibiotic resistant clinical bacteria, MCF-7 and P388 cell lines. PMID- 22105715 TI - Acoustofluidics 2: perturbation theory and ultrasound resonance modes. AB - In the second part of the thematic tutorial series "Acoustofluidics--exploiting ultrasonic standing waves forces and acoustic streaming in microfluidic systems for cell and particle manipulation", we develop the perturbation theory of the acoustic field in fluids and apply the result in a study of acoustic resonance modes in microfluidic channels. PMID- 22105716 TI - Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice. AB - The matricellular protein, thrombospondin-1 (TSP-1), is prominently expressed during tissue repair. TSP-1 binds to matrix components, proteases, cytokines, and growth factors and activates intracellular signals through its multiple domains. TSP-1 converts latent transforming growth factor-beta1 (TGF-beta1) complexes into their biologically active form. TGF-beta plays significant roles in cell-cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF-beta1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF-beta1 during liver regeneration remains to be defined in vivo. We generated a TSP-1-deficient mouse model of a partial hepatectomy (PH) and explored TSP-1 induction, progression of liver regeneration, and TGF-beta-mediated signaling during the repair process after hepatectomy. We show here that TSP-1-mediated TGF-beta1 activation plays an important role in suppressing hepatocyte proliferation. TSP-1 expression was induced in endothelial cells (ECs) as an immediate early gene in response to PH. TSP-1 deficiency resulted in significantly reduced TGF-beta/Smad signaling and accelerated hepatocyte proliferation through down-regulation of p21 protein expression. TSP-1 induced in ECs by reactive oxygen species (ROS) modulated TGF-beta/Smad signaling and proliferation in hepatocytes in vitro, suggesting that the immediately and transiently produced ROS in the regenerating liver were the responsible factor for TSP-1 induction. CONCLUSIONS: We have identified TSP-1 as an inhibitory element in regulating liver regeneration by TGF-beta1 activation. Our work defines TSP-1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration. PMID- 22105717 TI - Facile synthesis of AgBr nanoplates with exposed {111} facets and enhanced photocatalytic properties. AB - AgBr nanoplates with exposed {111} facets have been synthesized in high yield by a facile precipitation reaction, and the as-prepared nanoplates exhibited greatly enhanced photocatalytic properties for the degradation of organic pollutants, which may be primarily ascribed to the relatively higher surface energy of {111} facets. PMID- 22105718 TI - Working memory at work: how the updating process alters the nature of working memory transfer. AB - In three N-Back experiments, we investigated components of the process of working memory (WM) updating, more specifically access to items stored outside the focus of attention and transfer from the focus to the region of WM outside the focus. We used stimulus complexity as a marker. We found that when WM transfer occurred under full attention, it was slow and highly sensitive to stimulus complexity, much more so than WM access. When transfer occurred in conjunction with access, however, it was fast and no longer sensitive to stimulus complexity. Thus the updating context altered the nature of WM processing: The dual-task situation (transfer in conjunction with access) drove memory transfer into a more efficient mode, indifferent to stimulus complexity. In contrast, access times consistently increased with complexity, unaffected by the processing context. This study reinforces recent reports that retrieval is a (perhaps the) key component of working memory functioning. PMID- 22105719 TI - Gender and age differences among youth, in utilization of mental health services in the year preceding suicide in Taiwan. AB - The primary objective of this study was to explore gender and age differences in the use of medical services during the year preceding suicide. Data were obtained from the mortality dataset of Department of Health and National Health Insurance Database. Included in the sample were 862 persons aged 12-24 years who committed suicide in Taiwan between 2001 and 2004. We compared the records of medical service utilization of adolescents (ages 12-18 years) with young adults (ages 19 24 years). Persons in both age groups contacted general practitioners more often than other types of medical providers in the year preceding suicide, with the exception of the month before suicide. Females made greater use of medical services than males in both age groups. Suicide prevention strategies should increase the emphasis in training non-psychiatric medical practitioners to identify and treat young persons at suicide risk. PMID- 22105721 TI - Evolving challenges of Helicobacter pylori. PMID- 22105720 TI - A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study. AB - BACKGROUND: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. METHODS: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3 AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. RESULTS: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 +/- 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. CONCLUSIONS: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors. PMID- 22105722 TI - Natural history of ileo-caecal Crohn's disease after surgical resection. A long term study. AB - AIM: Surgery is an almost inevitable event in Crohn's disease (CD) but is not curative; postoperative recurrence follows a predictable course. Several factors potentially affecting the risk of recurrence have been investigated but results are largely inconclusive. The aim of the present study was to evaluate the long term course of ileo-caecal CD after surgery and to identify possible predictors of clinical and surgical recurrence. METHODS: Patients with ileo-caecal CD who had undergone surgical resection and with at least one year of post-operative follow-up were studied. The postoperative course was retrospectively evaluated. The primary end-points were clinical recurrence (defined as reappearance of symptoms requiring steroid treatment in the presence of endoscopic and/or radiologic recurrence) and surgical recurrence, defined as need for reoperation. RESULTS: Two hundred and twelve patients were included in the study. Median follow-up after surgery was 117 months (interquartile range 51-216). The cumulative probability of a post-operative course without clinical and surgical recurrence after 30, 60, 90, 120 months was 78.2%, 69.4%, 58.0%, 50.6% and 97.0%, 96.4%, 85.6%, 72% respectively. Early surgery (within three years from diagnosis) was associated with a longer postoperative course without clinical recurrence compared with late surgery (performed after three years from diagnosis). None of the other clinical variables considered (gender, age, family history for IBD, smoking habits, pattern of CD, and postoperative prophylactic treatment) was associated with the risk of clinical and surgical recurrence. CONCLUSION: Surgery is an excellent treatment for patients with isolated ileo-caecal CD. The overall long-term outcome is good: by 10 years after operation approximately 50% of patients are free of clinical recurrence and over 70% do not require further surgery. Surgery, therefore, continues to play an important role in ileo-caecal CD and should therefore not be considered only a failure of medical treatment. PMID- 22105723 TI - Alcohol drinking after liver transplantation is associated with graft injury. AB - AIM: This was a single-center, mixed-design, cross-sectional and retrospective study to assess the performance of the 4-item, self-reported CAGE (Cut down, Annoyed, Guilty, Eye-opener) questionnaire in predicting histology-proven alcohol related liver graft injury (ARLGI). METHODS: A total of 316 liver transplant (LT) patients between six months and five years were enrolled. Based on previous research, problem alcohol drinking (PAD) was defined as any score >= 1 on the CAGE, while a cut-off of 2 was assumed for alcohol dependence (AD). RESULTS: Responders were 195, 45 (23.1%) had a CAGE score >= 1 and 30 (15.3%) scored >= 2. After controlling for confounders, PAD was associated with hyperlipidemia (P=0.01), while AD with a male gender (P=0.01), hyperlipidemia (P=0.03) and alcohol as native diagnosis (P=0.03). PAD and AD were both associated with a significantly higher prevalence of ARLGI, i.e. 53.3% and 63.3%, respectively (P<0.0001). Hepatitis C virus (HCV) patients with PAD showed more steatosis (P=0.04), portal infiltrate (P=0.03), and pericellular/perivenular fibrosis (P=0.02). The likelihood ratios for CAGE scores ranging from 0 to 4 in predicting ARLGI were 0, 5.2, 7.8, 7.8, and 100, respectively. CONCLUSION: By use of a self report instrument we found a 23.1% prevalence of PAD and a 15.3% prevalence of AD among LT patients between six months and five years. A variable degree of ARLGI was present in 53.3% of PAD and 63.3% of AD, respectively. HCV patients with PAD had more steatosis, portal inflammation, and pericellular fibrosis. Transplant physicians might improve their ability to predict the probability for ARLGI using the CAGE. PMID- 22105724 TI - Myocardial ischemia during endoscopic retrograde cholangiopancreatography - A real problem? AB - AIM: The occurrence of silent myocardial ischemia during endoscopic retrograde cholangiopancreatography (ERCP) has been documented, but its clinical significance remains unknown. The aims of this study were to investigate the incidence and risk factors of myocardial ischemia during ERCP, to determine the presence or absence of permanent myocardial injury and to evaluate if deep sedation with propofol had a positive effect on myocardial ischemia during ERCP. METHODS: Ambulatory ST-segment monitoring from 30 minutes prior to 4 hours after ERCP was obtained on 50 patients. A deep sedation was performed with intravenous propofol administered by anesthesiologist. Changes in vital signs during ERCP, pre and postprocedural 12-lead ECG examination and cardiac enzymes were evaluated. RESULTS: Silent cardiac ischemia occurred only in one patient (2%) during ERCP. This 64-year-old patient did not develop hypoxemia, tachycardia or hypotension periods during the exam. None of the patients developed cardiac enzymes or postprocedural electrocardiographic changes. Thirty seven (74%) patients suffered rhythm changes. CONCLUSION: Although rhythm disturbances were common, silent myocardial ischemia during ERCP was rare (2%) and without clinical relevance. In prolonged or complex therapeutic procedures, like ERCP, deep sedation with propofol performed by trained personnel is associated with reduced cardiac complications. PMID- 22105725 TI - Nutritional aspects of Helicobacter pylori infection. AB - H. pylori is a gram-negative pathogen, etiologically associated with atrophic and non-atrophic gastritis, peptic ulcer, primary gastric B-cell lymphoma and gastric carcinoma. Several observations demonstrated a correlation between H. pylori and malabsorption of essential nutrients; epidemiological studies have shown an association between H. pylori infection and iron deficiency anemia, while the absorption of some vitamins such as vitamin B12, vitamin A, vitamin C, folic acid and Vitamin E may be affected by the infection. The main mechanism related to malabsorption of this components is the modified intragastric pH (hypo- achlorhydria) due to H. pylori infection. Moreover H. pylori is also able to determine a modification of gastrointestinal hormones by reducing plasma levels of ghrelin and increasing those of leptin and gastrin, thus affecting appetite and promoting the occurrence of dyspeptic symptoms. On the other hand, H. pylori eradication has been shown to improve serum level of iron and vitamin B12, has some effects on Vitamin A and Vitamin E absorption and has a late effects on ghrelin levels. As a consequence of those effects, H. pylori is also associated with childhood malnutrition in developing countries either for the occurrence of malabsorption or for an increased susceptibility to enteric infections caused by hypochlorhydria. PMID- 22105726 TI - Insulin resistance and metabolic syndrome: is Helicobacter pylori criminal? AB - Insulin resistance and metabolic syndrome are contributors to atherosclerosis and coronary heart disease. Insulin resistance is also responsible in pathogenesis of type II diabetes. Several studies previously evaluated the role of H. pylori infection in coronary heart disease and type II diabetes. Recently published data have described the association between H. pylori infection with insulin resistance and metabolic syndrome. However, this is still a controversial subject. Here in, we reviewed current status and present data toward this topic. PMID- 22105727 TI - Molecular findings on Helicobacter pylori: update for clinicians. AB - Helicobacter pylori (H. pylori) is a gram-negative bacterium which is responsible for a wide range of disorders of the stomach, from chronic gastritis to peptic ulcers to gastric cancer which, however, occurs in a lower percentage of subjects. The difference in the clinical course of infection seems to be correlated both to the typical pathogenicity of the bacterium and to factors related to the host. The reasons underlying these observations include differences in bacterial pathogenicity as well as in host susceptibility. Numerous studies published in the last year have provided new insights into H. pylori virulence factors, their interaction with the host and the relative consequences in the pathogenesis. In this review, we have set ourselves the target of summarising the latest progress made in understanding the molecular aspects of H. pylori infection of notable importance for the physician. PMID- 22105728 TI - Helicobacter pylori related and non-related lesions in the stomach. AB - Gastric lesions may arise in gastric mucosa of patients with gastritis or gastropathies due to different etiopathogenic factors. As most lesions of the stomach result from a chronic infection of gastric mucosa with Helicobacter pylori (H. pylori), a possible classification of gastric lesions based on etiology may distinguish H. pylori-related lesions from those arising in a gastric mucosa not colonized from the bacterium. The repertoire of lesions one may find in the stomach is limited and different pathologies may present with a similar macroscopic aspect. Clinically relevant lesions of the stomach that are or are not associated with H. pylori infection include gastric ulcer, gastric atrophy, gastric neoplasia, and metastasis from other cancers. The detection or exclusion of an H. pylori infection in patients with gastric lesions has important consequences for the clinical management. In the present review we focus on H. pylori-related and non-related peptic lesions in the stomach. PMID- 22105729 TI - Modern treatment of adult short bowel syndrome patients. AB - By definition, intestinal failure prevails when oral compensation is no longer feasible and parenteral support is necessary to maintain nutritional equilibrium. In the past, conventional treatment has mainly focused on "making the most of what the short bowel syndrome patient still had" by optimizing remnant intestinal function through dietary interventions, antidiarrheals and antisecretory agents. However, modern treatment options are in the near horizon, and the increased understanding of the mediators for intestinal adaptation will lead to the expansion of the limited treatment armamentarium in short bowel syndrome patients with intestinal failure. The clinical meaningfulness and implications of the observed effects of growth hormone, glutamine, glucagon-like peptide 2 (GLP-2) and the dipeptidyl peptidase-4 degradation resistant analog, teduglutide, is presented in this review and balanced against treatment related adverse events and possible unfavourable effects of long-term, possibly lifelong, treatments. PMID- 22105730 TI - Nonalcoholic fatty liver disease: the concept and confusion. AB - Nonalcoholic fatty liver disease (NAFLD) is generally considered as a disease associated with diabetes mellitus type 2. But on a closer evaluation we realize a host of confusion associated with this from the nomenclature, diagnosis to pathogenesis. The term refers to a spectrum ranging from steatosis to steatosis with inflammation (NASH) to cirrhosis in the absence of alcohol abuse. But in fact NAFLD is a vague term for a spectrum of diseases which differ not only in the clinical presentation but also in the etiology. NAFLD is loose to incorporate so many etiologies excluding alcoholism and few other "known" etiologies, presenting as fat in liver. Considering the diverse etiologies there is a need for personalized management in NAFLD, which at present is difficult. Currently fatty liver disease could be considered as an added Hepato-cardiovascular-renal and cancer risk factor rather than a specific diagnosis. PMID- 22105731 TI - Should a physician interpret a medical study improperly performed by a nurse or technician, such as capsule endoscopy performed on a wrong patient? A reasonable solution to a medicolegal dilemma. AB - Improper performance by a nurse of a medical study/procedure (e.g., video capsule endoscopy performed on a wrong patient) raises novel, previously unexplored questions regarding: 1) whether the study should subsequently be interpreted; 2) which physician should interpret the study; and 3) whether study interpretation requires another informed consent due to the extraordinary circumstances. Two such cases are reported. First, the Chief of Gastroenterology (GI) contacted the hospital ethics committee regarding procedure interpretation after the wrong patient underwent video capsule endoscopy by a nurse. The committee recommended to inform and apologize to the patient about the nursing error, to not charge for this study, and to interpret the study, likewise without charge, provided that a new informed consent was obtained that included discussion of the small potential patient benefit of study interpretation in this circumstance. These recommendations were followed. Study interpretation revealed a 3 mm wide characteristic angiodysplasia in the distal jejunum. Endoscopic therapy was not performed due to the small lesion size, and absence of gastrointestinal bleeding or significant anemia. Second, the Chief of GI was informed of an esophageal manometry performed for chronic dysphagia that had not been interpreted for 7 months due to its being performed by a nurse without any arrangement for a gastroenterologist to interpret the study. The referring gastroenterologist lacked training or privileges in esophageal manometry. The Chief of GI arranged for a motility expert to interpret the study. The study was read as technically inadequate because the nurse had been unable to intubate the stomach and the referring gastroenterologist had declined to assist in this difficult intubation. The motility expert noted that had he been involved earlier in the case he would have himself attempted gastric intubation. In conclusion, a reasonable approach to a medical study improperly performed by a nurse includes: 1) inform and apologize to the patient about the error; 2) obtain informed consent for study interpretation, and 3) interpret the study at no charge. Consultation with an institutional Ethics Committee is advisable. An interpreting physician should be identified at the time of scheduling a medical study. Although illustrated for GI studies, these recommendations pertain to studies performed by nurses or technicians in numerous medical fields, such as echocardiograms or pulmonary function tests. PMID- 22105732 TI - A case of postcholecystectomy porto-biliary fistula. PMID- 22105733 TI - The utility of radial endosonographic features in the diagnosis of cholangio carcinoma arising from the distal common bile duct. PMID- 22105734 TI - Human epididymis protein 4 reference limits and natural variation in a Nordic reference population. AB - The objectives of this study are to establish reference limits for human epididymis protein 4, HE4, and investigate factors influencing HE4 levels in healthy subjects. HE4 was measured in 1,591 samples from the Nordic Reference Interval Project Bio-bank and Database biobank, using the manual HE4 EIA (Fujirebio) for 802 samples and the Architect HE4 (Abbott) for 792 samples. Reference limits were calculated using the statistical software R. The influence of donor characteristics such as age, sex, body mass index, smoking habits, and creatinine on HE4 levels was investigated using a multivariate model. The study showed that age is the main determinant of HE4 in healthy subjects, corresponding to 2% higher HE4 levels at 30 years (compared to 20 years), 9% at 40 years, 20% at 50 years, 37% at 60 years, 63% at 70 years, and 101% at 80 years. HE4 levels are 29% higher in smokers than in nonsmokers. In conclusion, HE4 levels in healthy subjects are associated with age and smoking status. Age-dependent reference limits are suggested. PMID- 22105735 TI - Alveolar macrophage dynamics in murine lung regeneration. AB - In most mammalian species, the removal of one lung results in dramatic compensatory growth of the remaining lung. To investigate the contribution of alveolar macrophages (AMs) to murine post-pneumonectomy lung growth, we studied bronchoalveolar lavage (BAL)-derived AM on 3, 7, 14 and 21 days after left pneumonectomy. BAL demonstrated a 3.0-fold increase in AM (CD45(+), CD11b(-), CD11c(+), F4/80(+), Gr-1(-)) by 14 days after pneumonectomy. Cell cycle flow cytometry of the BAL-derived cells demonstrated an increase in S + G2 phase cells on days 3 (11.3 +/- 2.7%) and 7 (12.1 +/- 1.8%) after pneumonectomy. Correspondingly, AM demonstrated increased expression of VEGFR1 and MHC class II between days 3 and 14 after pneumonectomy. To investigate the potential contribution of peripheral blood cells to this AM population, parabiotic mice (wild-type/GFP) underwent left pneumonectomy. Analysis of GFP(+) cells in the post-pneumonectomy lung demonstrated that by day 14, less than 1% of the AM population were derived from the peripheral blood. Finally, AM gene transcription demonstrated a significant shift from decreased transcription of angiogenesis related genes on day 3 to increased transcription on day 7 after pneumonectomy. The increased number of locally proliferating AM, combined with their growth related gene transcription, suggests that AM actively participate in compensatory lung growth. PMID- 22105736 TI - Thoracic recurrent laryngeal lymph node metastases predict cervical node metastases and benefit from three-field dissection in selected patients with thoracic esophageal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: Recurrent laryngeal nerve lymph nodes (RLN LNs) are considered sentinel nodes for cervical LN metastases of esophageal cancer. Surgery is the treatment of choice, but whether three-field lymph node dissection (3FL), which includes cervical LN dissection, or 2FL, which does not, should be performed is controversial. METHODS: We retrospectively analyzed medical records of 200 patients with esophageal cancer who underwent 3FL from January 2000 to August 2010, focusing on LN status. We also compared survival rates between these patients and those who underwent 2FL. RESULTS: The rate of cervical LN metastases did not differ significantly between RLN LN+ (for metastasis) and RLN LN- 3FL groups. However, in a subgroup of patients with middle/lower thoracic esophageal tumors, cervical LN metastases were significantly more common in patients with positive rather than negative RLN LNs. Survival did not differ after 3FL versus 2FL in general. However, 3FL was associated with longer survival than 2FL in patients with RLN LN positivity and either lower thoracic esophageal tumors or more than four abdominal/thoracic LN metastases. CONCLUSIONS: Metastasis to RLN LNs is a reliable indicator of cervical LN metastasis in middle/lower thoracic esophageal cancer, while 3FL offers survival benefit over 2FL in certain patient subgroups. PMID- 22105737 TI - Hepatitis C virus and GBV-C virus prevalence among patients with B-cell lymphoma in different European regions: a case-control study of the International Extranodal Lymphoma Study Group. AB - Hepatitis C virus (HCV) infection is associated with some B-cell non-Hodgkin lymphoma (B cell-NHLs). Patients with HCV infection frequently show co-infections with GB virus C (GBV-C, formerly known as hepatitis G virus), and some studies have suggested a higher incidence of GBV-C infection in patients with B cell NHLs. The aim of this study was to prospectively evaluate the association between HCV and/or GBV-C infection and B cell-NHLs in different geographic areas. One hundred thirty-seven lymphoma cases and 125 non-lymphoma matched controls were enrolled in an international case-control study conducted in Switzerland (Bellinzona), Spain (Barcelona) and England (Southampton) on samples collected from 2001 to 2002. In Bellinzona (41 cases and 81 controls), the overall prevalence of HCV was 3.3% (4.9% in NHLs), and the overall prevalence of GBV-C was 24% (22% in NHLs). In Barcelona (46 cases and 44 controls), the prevalence of HCV was 10% (8.7% in NHLs) and the prevalence of GBV-C 20% (13% in NHLs). There was no statistically significant difference in the frequency of both infections between patients with NHL and controls. In Southampton, 50 NHL cases were analysed, none of them was found to be HCV-positive; therefore, no control group was analysed and GBV-C analysis was not performed, too. Both in Bellinzona and in Barcelona, the seropositivity rate was significantly lower for HCV than for GBV C, suggesting that their transmission can be independent. The incidence of HCV was significantly higher in Barcelona than that in Bellinzona. This study confirmed the existence of marked geographic differences in the prevalence of HCV in NHL but cannot provide any significant evidence for an association between HCV and/or GBV-C and B-cell NHLs. PMID- 22105738 TI - Racial/ethnic disparities in maternal morbidities: a statewide study of labor and delivery hospitalizations in Wisconsin. AB - We examined racial/ethnic disparities in maternal morbidities (MM) and the number of MM during labor and delivery among hospital discharges in Wisconsin. We conducted a retrospective cohort study of hospital discharge data for 206,428 pregnant women aged 13-53 years using 2005-2007 Healthcare Cost and Utilization Project State Inpatient Dataset (HCUP-SID) for Wisconsin. After adjustments for covariates, MM (preterm labor, antepartum and postpartum hemorrhage, hypertension in pregnancy, gestational diabetes, membrane-related disorders, infections and 3rd and 4th perineal lacerations) were examined using logistic regression models, and number of MM (0, 1, 2, >2 MM) were examined using multivariable ordered logistic regressions with partial proportional odds models. African-Americans had significantly higher likelihood of infections (OR = 1.74; 95% CI 1.60-1.89), preterm labor (OR = 1.42; 1.33-1.50), antepartum hemorrhage (OR = 1.63; 1.44 1.83), and hypertension complicating pregnancy (OR = 1.39; 1.31-1.48) compared to Whites. Hispanics, Asian/Pacific Islanders, and Native Americans had significantly higher likelihood of infections, postpartum hemorrhage, and gestational diabetes than Whites. Major perineal lacerations were significantly higher among Asian/Pacific Islanders (OR = 1.53; 1.34-1.75). All minority racial/ethnic groups, except Asians, had significantly higher likelihood of having 0 versus 1, 2 or >2 MM, 0 or 1 versus 2 or >2 MM, and 0, 1 or 2 versus >2 MM than white women. Findings show significant racial/ethnic disparities in MM, and suggest the need for better screening, management, and timely referral of these conditions, particularly among racial/ethnic women. Disparities in MM may be contributing to the high infant mortality and adverse birth outcomes among different racial/ethnic groups in Wisconsin. PMID- 22105739 TI - Residential segregation and the health of African-American infants: does the effect vary by prevalence? AB - Segregation effects may vary between areas (e.g., counties) of low and high low birth weight (LBW; <2,500 g) and preterm birth (PTB; <37 weeks of gestation) rates due to interactions with area differences in risks and resources. We assess whether the effects of residential segregation on county-level LBW and PTB rates for African-American infants vary by the prevalence of these conditions. The study sample includes 368 counties of 100,000 or more residents and at least 50 African-American live births in 2000. Residentially segregated counties are identified alternatively by county-level dissimilarity and isolation indices. Quantile regression is used to assess how residential segregation affects the entire distributions of county-level LBW and PTB rates (i.e. by prevalence). Residential segregation increases LBW and PTB rates significantly in areas of low prevalence, but has no such effects for areas of high prevalence. As a sensitivity analysis, we use metropolitan statistical area level data and obtain similar results. Our findings suggest that residential segregation has adverse effects mainly in areas of low prevalence of LBW and preterm birth, which are expected overall to have fewer risk factors and more resources for infant health, but not in high prevalence areas, which are expected to have more risk factors and fewer resources. Residential policies aimed at area resource improvements may be more effective. PMID- 22105740 TI - The mechanisms for compression and reflection of cortical waves. AB - Waves are common in cortical networks and may be important for carrying information about a stimulus from one local circuit to another. In a recent study of visually evoked waves in rat cortex, compression and reflection of waves are observed as the activation passes from visual areas V1 to V2. The authors of this study apply bicuculline (BMI) and demonstrate that the reflection disappears. They conclude that inhibition plays a major role in compression and reflection. We present several models for propagating waves in heterogeneous media and show that the velocity and thus compression depends weakly on inhibition. We propose that the main site of action of BMI with respect to wave propagation is on the threshold for firing which we suggest is related to action on potassium channels. We combine numerical and analytic methods to explore both compression and reflection in an excitable system with synaptic coupling. PMID- 22105741 TI - Haplotype analysis of Apo AI-CIII-AIV gene cluster and lipids level: Tehran Lipid and Glucose Study. AB - Iranian populations show an increased tendency for abnormal lipid levels and high risk of Coronary artery disease. Considering the important role played by the ApoAI-CIII-AIV gene cluster in the regulation of the level and metabolism of lipids, this study aimed at elucidating the association between five single nucleotide polymorphisms on the Apo11q cluster gene and lipid levels. A cross sectional study of 823 subjects (340 males and 483 females) from the Tehran lipid and glucose study (TLGS) was conducted. Levels of TG, Chol, HDL-C, Apo AI, Apo AIV, Apo B, and Apo CIII were measured, and the selected segments of the APOAI CIII-AIV gene cluster were amplified by PCR and the polymorphisms were revealed by RFLP using restriction enzymes. The allele frequencies for each SNP between males and females were not significantly different. The distribution of Genotypes and alleles was in Hardy-Weinberg equilibrium except for Apo AI (+83C>T). The results showed a significant association between TG, HDL-C, HDL(2), Apo AI, and Apo B levels and the presence of some alleles in the polymorphisms studied. After haplotype analysis not only did the association between these variables and SNPs remain but also levels of Chol and LDL-C were added. This study demonstrates that the level of lipids such as TG, HDL-C, HDL(2), Apo AI, and Apo B, maybe regulated partly by genetic factors and their haplotype within the Apo11q gene cluster. PMID- 22105742 TI - A new culprit in osteogenesis imperfecta. PMID- 22105743 TI - Crystal structure of homoisocitrate dehydrogenase from Schizosaccharomyces pombe. AB - Homoisocitrate dehydrogenase (HICDH) catalyzes the conversion of homoisocitrate to 2-oxoadipate, the third enzymatic step in the alpha-aminoadipate pathway by which lysine is synthesized in fungi and certain archaebacteria. This enzyme represents a potential target for anti-fungal drug design. Here, we describe the first crystal structures of a fungal HICDH, including structures of an apoenzyme and a binary complex with a glycine tri-peptide. The structures illustrate the homology of HICDH with other beta-hydroxyacid oxidative decarboxylases and reveal key differences with the active site of Thermus thermophilus HICDH that provide insights into the differences in substrate specificity of these enzymes. PMID- 22105744 TI - Chinese hamster genome database: an online resource for the CHO community at www.CHOgenome.org. AB - The Chinese hamster genome database (http://www.chogenome.org/) is an online resource for the Chinese hamster (Cricetulus griseus) and Chinese hamster ovary (CHO) cell communities. CHO cells are important for biomedical research and are widely used in industry for the production of biopharmaceuticals. The genome of the CHO-K1 cell line was recently sequenced and the CHO community has developed an online resource to facilitate accessibility of the genomic data and the development of genomic tools. PMID- 22105745 TI - Uncommon dentigerous cyst related to a maxillary lateral incisor in a 03-year-old boy. AB - BACKGROUND: The dentigerous cyst is usually defined as a cystic cavity that surrounds the crown of an unerupted tooth on the cementoenamel junction. The present article reports a case of an uncommon dentigerous cyst, highlighting its clinical, radiographic and surgical characteristics and discussing the aspects related to its development in infancy. CASE REPORT: A 03-year-old boy patient presented with an extensive radiolucid area involving the crown of the right maxillary lateral incisor. A surgical excision was performed. Anatomopathological examination revealed a cystic tissue with a fibrous wall surrounded by nonkeratinized stratified squamous oral epithelium, without atypia. CONCLUSION: It is possible that the dentigerous cyst grows in the dental germ in any stage of development and not only in the follicle of a tooth with calcified crown attached to the cementoenamel junction. PMID- 22105746 TI - A systematic evaluation of the role of crystalline order in nanoporous materials on DNA separation. AB - The role of order within a porous separation matrix on the separation efficiency of DNA was studied systematically. DNA separation was based on a ratchet mechanism. Monodisperse colloidal suspensions of nanoparticles were used to fabricate highly ordered separation media with a hexagonal close-packed structure. Doping with a second particle size yielded structures with different degrees of disorder, depending upon the volume fraction of each particle size. Radial distribution functions and orientational order parameters were calculated from electron micrographs to characterize the scale of disorder. The peak separation distance, band broadening, and separation resolution of DNA molecules was quantified for each structure. DNA separation parameters using pulsed fields and the ratchet effect showed a strong dependence on order within the porous nanoparticle array. Ordered structures gave large separation distances, smaller band broadening and better resolution than highly disordered, nearly random, porous structures. The effect dominated these three parameters when compared to the effect of pore size. However, the effect of order on separation performance was not monotonic. A small, but statistically significant improvement was seen in structures with short range order compared to those with long range order. PMID- 22105747 TI - Patients and families as safety experts. PMID- 22105749 TI - Medical waste-management practices vary across Canada. PMID- 22105750 TI - Identification by families of pediatric adverse events and near misses overlooked by health care providers. AB - BACKGROUND: Identifying adverse events and near misses is essential to improving safety in the health care system. Patients are capable of reliably identifying and reporting adverse events. The effect of a patient safety reporting system used by families of pediatric inpatients on reporting of adverse events by health care providers has not previously been investigated. METHODS: Between Nov. 1, 2008, and Nov. 30, 2009, families of children discharged from a single ward of British Columbia's Children's Hospital were asked to respond to a questionnaire about adverse events and near misses during the hospital stay. Rates of reporting by health care providers for this period were compared with rates for the previous year. Family reports for specific incidents were matched with reports by health care providers to determine overlap. RESULTS: A total of 544 familes responded to the questionnaire. The estimated absolute increase in reports by health care providers per 100 admissions was 0.5% (95% confidence interval -1.8% to 2.7%). A total of 321 events were identified in 201 of the 544 family reports. Of these, 153 (48%) were determined to represent legitimate patient safety concerns. Only 8 (2.5%) of the adverse events reported by families were also reported by health care providers. INTERPRETATION: The introduction of a family based system for reporting adverse events involving pediatric inpatients, administered at the time of discharge, did not change rates of reporting of adverse events and near misses by health care providers. Most reports submitted by families were not duplicated in the reporting system for health care providers, which suggests that families and staff members view safety-related events differently. However, almost half of the family reports represented legitimate patient safety concerns. Families appeared capable of providing valuable information for improving the safety of pediatric inpatients. PMID- 22105751 TI - Bronchoscopic diagnosis of pulmonary hydatid cyst. PMID- 22105752 TI - Diagnosed hypertension in Canada: incidence, prevalence and associated mortality. AB - BACKGROUND: Hypertension is a leading risk factor for cardiovascular diseases. Our objectives were to examine the prevalence and incidence of diagnosed hypertension in Canada and compare mortality among people with and without diagnosed hypertension. METHODS: We obtained data from linked health administrative databases from each province and territory for adults aged 20 years and older. We used a validated case definition to identify people with hypertension diagnosed between 1998/99 and 2007/08. We excluded pregnant women from the analysis. RESULTS: This retrospective population-based study included more than 26 million people. In 2007/08, about 6 million adults (23.0%) were living with diagnosed hypertension and about 418,000 had a new diagnosis. The age standardized prevalence increased significantly from 12.5% in 1998/99 to 19.6% in 2007/08, and the incidence decreased from 2.7 to 2.4 per 100. Among people aged 60 years and older, the prevalence was higher among women than among men, as was the incidence among people aged 75 years and older. The prevalence and incidence were highest in the Atlantic region. For all age groups, all-cause mortality was higher among adults with diagnosed hypertension than among those without diagnosed hypertension. INTERPRETATION: The overall prevalence of diagnosed hypertension in Canada from 1998 to 2008 was high and increasing, whereas the incidence declined during the same period. These findings highlight the need to continue monitoring the effectiveness of efforts for managing hypertension and to enhance public health programs aimed at preventing hypertension. PMID- 22105753 TI - Too much of a good thing? PMID- 22105755 TI - Paternal depression often unrecognised. PMID- 22105756 TI - Human papillomavirus and anogenital warts in children. PMID- 22105757 TI - Dying a "good death". PMID- 22105758 TI - Late cuts: an international look at adult circumcision. PMID- 22105759 TI - Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase-signaling pathway. AB - Multidrug resistance-associated protein 3 (MRP3, ABC subfamily C [ABCC]3) plays an important role in protecting hepatocytes and other tissues by excreting an array of toxic organic anion conjugates, including bile salts. MRP3/ABCC3 expression is increased in the liver of some cholestatic patients, but the molecular mechanism of this up-regulation remains elusive. In this report, we assessed liver MRP3/ABCC3 expression in patients (n = 22) with obstructive cholestasis caused by gallstone blockage of bile ducts and noncholestatic patient controls (n = 22). MRP3/ABCC3 messenger RNA (mRNA) and protein expression were significantly increased by 3.4- and 4.6-fold, respectively, in these cholestatic patients where elevated plasma tumor necrosis factor alpha (TNFalpha) (4.7-fold; P < 0.01) and hepatic specificity protein 1 transcription factor (SP1) and liver receptor homolog 1 expression (3.1- and 2.1-fold at mRNA level, 3.5- and 2.5-fold at protein level, respectively) were also observed. The induction of hepatic MRP3/ABCC3 mRNA expression is significantly positively correlated with the level of plasma TNFalpha in these patients. In HepG2 cells, TNFalpha treatment induced SP1 and MRP3/ABCC3 expression in a dose- and time-dependent manner, where increased phosphorylation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) was also detected. These inductions were significantly reduced in the presence of the JNK inhibitor, SP600125. TNFalpha treatment enhanced HepG2 cell nuclear extract-binding activity to the MRP3/ABCC3 promoter, but was abolished by SP600125, as demonstrated by electrophoretic mobility shift assay (EMSA). An increase in nuclear protein-binding activity to the MRP3/ABCC3 promoter, consisting primarily of SP1, was also observed in liver samples from cholestatic patients, as assessed by supershift EMSA assays. CONCLUSIONS: Our findings indicate that up-regulation of hepatic MRP3/ABCC3 expression in human obstructive cholestasis is likely triggered by TNFalpha, mediated by activation of JNK/SAPK and SP1. PMID- 22105760 TI - Regioselective C-H bond functionalizations of acridines using organozinc reagents. AB - Despite the recent advance in C-H bond functionalization chemistry, the C-H bonds in the acridine ring system, which is an important scaffold in medicinal and material science, have met with limited success, due, in part, to the lack of activated C-H bonds adjacent to the ring nitrogen atom. Herein, several protocols that can effect the regioselective arylation and alkylation of acridines at the C 4 and C-9 positions are described. PMID- 22105761 TI - Potential of energy and nutrient recovery from biodegradable waste by co treatment in Lithuania. AB - Biodegradable waste quantities in Lithuania and their potential for the co treatment in renewable energy and organic fertilizer production were investigated. Two scenarios were formulated to study the differences of the amounts of obtainable energy and fertilizers between different ways of utilization. In the first scenario, only digestion was used, and in the second scenario, materials other than straw were digested, and straw and the solid fraction of sewage sludge digestate were combusted. As a result, the amounts of heat and electricity, as well as the fertilizer amounts in the counties were obtained for both scenarios. Based on this study, the share of renewable energy in Lithuania could be doubled by the co-treatment of different biodegradable materials. PMID- 22105762 TI - A rapid two-step method for isolation of functional primary mouse hepatocytes: cell characterization and asialoglycoprotein receptor based assay development. AB - Primary mouse hepatocytes are an important tool in the biomedical research field for the assessment of hepatocyte function. Several methods for hepatocyte isolation have been published; however, many of these methods require extensive handling and can therefore compromise the viability and function of the isolated cells. Since one advantage of utilizing freshly isolated cells is to maintain an environment in which the cells are more comparable to their in vivo state, it is important to have robust methods that produce cells with high viability, good purity and that function in a similar manner to that in their in vivo state. Here we describe a modified two-step method for the rapid isolation and characterization of mouse primary hepatocytes that results in high yields of viable cells. The asialoglycoprotein receptor (ASGPR), which is one of the most abundant cell surface receptors on hepatocytes, was used to monitor the function of the isolated hepatocytes by demonstrating specific binding of its ligand using a newly developed flow cytometry based ligand-receptor binding assay. Also, an in vitro screening method for siRNA drug candidates was successfully developed utilizing freshly isolated hepatocytes with minimum culture time. PMID- 22105763 TI - A non-restricting and non-methylating Escherichia coli strain for DNA cloning and high-throughput conjugation to Streptomyces coelicolor. AB - Escherichia coli strains are used in secondary metabolism research for DNA cloning and transferring plasmids by intergeneric conjugation. Non-restricting strains are desirable for DNA cloning and non-methylating strains are beneficial for transferring DNA to methyl-restricting hosts, like Streptomyces coelicolor. We have constructed a non-methylating E. coli strain, JTU007, by deleting the DNA methylation genes dcm and dam from the widely used non-restricting cloning host DH10B. JTU007 was tested as donor for the conjugative transfer of a plasmid containing the 39 kb actinorhodin biosynthesis gene cluster to S. lividans and S. coelicolor. The Dcm- Dam- strain JTU007 transferred DNA into S. coelicolor A(3)2 derivatives at high frequency. To demonstrate the usefulness of E. coli JTU007 for gene cloning, we constructed a comprehensive S. toxytricini genomic cosmid library, and transferred it using high-throughput conjugation to the methyl restricting S. coelicolor. One of the cosmid clones produced a brown pigment, and the clone was revealed to carry a tyrosinase operon. JTU007 is more useful than ET12567 because it does not restrict methylated DNA in primary cloning, and gives higher transformation and cosmid infection frequencies. PMID- 22105764 TI - Enantioselective access to chiral drugs by using asymmetric hydrogenation catalyzed by Rh(P-OP) complexes. PMID- 22105765 TI - Laparoscopic mini-gastric bypass: short-term single-institute experience. AB - The elevated variety of procedures proposed for surgical treatment of obesity in the last few years suggests the necessity to find an ideal operation. Laparoscopic mini-gastric bypass (LMGB) was developed to obtain better results with lesser morbidity and mortality. LMGB was introduced by Rutledge, in 1997, and it consists of a long lesser-curvature tube with a terminolateral gastroenterostomy 180 cm distal to the Treitz ligament. From July 1995 to May 2011 we have performed 552 bariatric operations, among them we have operated 197 laparoscopic mini-gastric bypass (Fig. 1). There were 147 female (75%) and 50 male (25%) with the mean age of 37.9 years (range 20-55) and the mean BMI of 52.9 kg/m(2). All procedures were completed laparoscopically, without conversion and the mean operative time was 120 min (range from 90 to 170 min). The average postoperative stay was 5.0 days. We report one case of mortality for pulmonary septic complications. Major complications were two cases of pulmonary embolism (treated in ICU), six cases of melena on seventh postoperative day and three cases of anastomotic ulcers resolved with high doses of PPI. We registered a significant reduction of BMI and percentage of excess weight after surgery with a significant improvement in obesity-related comorbidities including blood pressure, hyperglycemia, blood lipid, uric acid, and liver function. An ideal weight loss operation should be effective, easy to perform and safe. Laparoscopic Roux-en-Y Gastric Bypass is actually the "gold-standard" technique but LMGB seems to be an attractive alternative: shorter operative time, with less morbidity and mortality, easier to teach and to perform. Another advantage could be the presence of a single anastomosis alone reducing the possibility of leaks. PMID- 22105766 TI - Pleuropneumonectomy for stage IVa thymoma: delayed metastatic spread after multimodality treatment. AB - We report a case of a caucasic woman aged 55, carrying a Masaoka stage IVa thymoma, initially not suitable to surgical treatment. After induction chemotheraphy, she underwent a radical resection of the mediastinal mass combined with left pleuro-pneumonectomy. After being disease-free for 5 years, the patient first developed a splenic recurrence, then an abdominal metastasis, both treated by surgery. To date she is alive and disease-free, 10 years after the first operation. The patient underwent multimodal treatment only after the first surgical operation, while the recurrences were only treated surgically. The exceptional nature of our case lies mainly in the site of the metastases (first the spleen, then the omentum), then in the long disease-free period, and in the final outcome which was beyond all expectations. PMID- 22105767 TI - The seventh ring: exploring TRAF7 functions. AB - Tumor necrosis factor receptor-associated factors (TRAFs) have been discovered and characterized by their capacity to link tumor necrosis factor receptors (TNFR) family proteins to signaling pathways that transduce the cellular effects mediated by TNF family ligands. There are seven known mammalian TRAF proteins (TRAF1-7), that share a domain organization made of a modular structure, characteristic of adaptor proteins whose function is to link structurally dissimilar factors. Functionally, TRAF proteins mediate the assembly of cytoplasmic signal transducers and regulatory molecules downstream of receptors complexes. Despite the similarities in the signaling pathways activated by the different TRAF proteins, each appears to play distinct physiological roles. TRAF7 is the last member of the TRAF family that has been identified. Yet, the functional characterization of TRAF7 presents some aspects still obscure and poorly defined, making this protein arguably the most mysterious member of the family. In fact, recent data indicate that TRAF7 is involved in signal transduction pathways that lead either to activation or repression of NF-kappaB transcription factor. In addition, TRAF7 regulates activation of cellular stress pathways, as well as unconventional ubiquitination events and differentiation of muscle tissue. In this review, we try to summarize the most recent advances in our understanding of TRAF7 function and the biological processes of this protein is involved in. PMID- 22105768 TI - Splenic hilar lymph node metastasis independently predicts poor survival for patients with gastric cancers in the upper and/or the middle third of the stomach. AB - BACKGROUND: Effectiveness of splenectomy for advanced gastric cancers occupying the upper and/or the middle third of the stomach is still in debate. The aim of the present study is to elucidate the impact of splenectomy on patient survival by investigating the pathological characteristics and prognostic significance of splenic hilar lymph node metastasis. METHODS: Clinicopathologic and prognostic data of 265 patients with gastric cancer in the upper and/or the middle third of the stomach who underwent the operation of en bloc resection of primary cancer and D2/D3 lymphadenectomy combined with splenectomy were retrospectively reviewed. RESULTS: Multivariate analysis revealed pT category, pN category, and distant lymph node metastasis independently correlated with the presence of splenic hilar lymph node metastasis. Prognoses of patients with positive splenic hilar lymph nodes were significantly poorer than that of patients with negative splenic hilar lymph nodes for the entire study population and for those who underwent R0 resection, but not for those who underwent R1-2 resection. There was no significant difference in survival between patients who underwent R0 resection with positive splenic hilar lymph nodes and those who underwent R1-2 resection. Splenic hilar lymph node metastasis was one of independent indicators predicting worse prognosis and the presence of distant metastasis after surgery. Subset analysis according to the TNM stage revealed there were significant differences in survival between patients with and without splenic hilar lymph node metastasis. CONCLUSIONS: Splenic hilar lymph node metastasis should be considered as one of incurable factors. Consequently, the efficiency of splenectomy aiming at prolonging survival for patients with high risk of splenic hilar lymph nodes metastasis should be questioned, although resection of invasive organs form gastric cancers has been recommended if R0 surgery could be achieved. PMID- 22105769 TI - Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients. AB - BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. PATIENTS AND METHODS: The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG >= 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5' nuclease (TaqMan) assays. RESULTS: Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF 7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade >= 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. CONCLUSION: We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer. PMID- 22105770 TI - Hematogenous metastases in patients with Stage I or II endometrial carcinoma. AB - AIMS: The aim of this study was to present the characteristics, methods of treatment, and the survival of patients with hematogenous metastases from endometrial carcinoma, free from local and other distant recurrences. PATIENTS AND METHODS: In 1,610 endometrial carcinoma patients managed with surgery and postoperative radiotherapy, we defined hematogenous metastases as a tumor spread to the lung or other sites via hematogenous routes. RESULTS: A total of 110 patients with stage I and II endometrial carcinoma, presenting with 134 metastases sites (69 in the lungs, 32 in the liver, 23 in the bones, and 10 in the brain), were observed. Progestin and combination chemotherapy were the most commonly used therapies. Primary treatment consisted of surgery in patients with solitary metastases to the lung (30 patients), liver (2 patients), and brain (2 patients). Radiotherapy was performed in 32 patients with metastases to the brain and bones. Presenting with a 36-month survival rate were 11.6% (8/69) of patients with metastases to the lungs, 6.3% (2/32) of patients with metastases to the liver, 8.7% (2/23) of patients with metastases to the bones, and 20.0% (2/10) of patients with metastases to the brain. CONCLUSIONS: Hormonal therapy and chemotherapy play a major role in the palliative management of patients with hematogenous metastases from endometrial carcinoma to the liver, lungs, and bones. Radical treatment in patients with metastases to the lung or liver consists of resection of the metastasis combined with chemo- and/or hormonotherapy for metastases to the bones treatment consists of radiotherapy + chemotherapy, for metastasis to the brain treatment consists of resection combined with radiotherapy. PMID- 22105771 TI - Synthesis of 1-substituted 3-aryl-5-aryl(hetaryl)-2-pyrazolines and study of their antitumor activity. AB - Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor activity of the obtained compounds was determined at the National Cancer Institute (NCI). The 5-(benzo[d][1,3]dioxol-5 yl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (9a) is the most prominent of the compounds due to its remarkable activity toward leukemia (RPMI 8226), renal cancer (UO-31) and prostate cancer (DU-145) cell lines with GI(50) values of 1.88, 1.91 and 1.94 uM, respectively. PMID- 22105772 TI - The role of lateral lymph node dissection in the management of lower rectal cancer. AB - INTRODUCTION: Lateral lymph node involvement is a problem encountered in patients with low rectal cancers. This has been documented in both anatomical and pathological studies. Currently, the vast majority of centers have concentrated on the use of chemoradiation to obtain better local control and manage these nodes indirectly. In Japan, extended nodal dissection for the control of pelvic nodal disease has seen further advancement. This paper discusses the key issues involved in the management of pelvic lateral nodes in low rectal cancers. METHODS: A review of available literature and critical appraisal of the entity of lateral nodes in low rectal cancers, the treatment options, and oncological and functional results were performed. RESULTS: There are good data showing that the entity of pelvic lateral nodes in low rectal cancers should not be ignored. Recent data have emerged showing that radiotherapy is associated with significant long-term functional side effects. Refinement of the technique, lateral node dissection, has led to good local control as well as good functional outcomes. CONCLUSION: In this context, there needs to be a reevaluation of the role of chemoradiation as the sole treatment for lateral nodal disease in centers outside of Japan. Individualization of the treatment of rectal cancer may require all centers to be able to offer both modalities. PMID- 22105773 TI - Current practice and future perspectives in the treatment of short bowel syndrome in children--a systematic review. AB - PURPOSE: Short bowel syndrome (SBS) is a malabsorption disorder of the intestine, which leads to an inadequate alimentary supply. A number of therapeutic approaches are already in use, but research advances may provide new options in the future. The purpose of this paper was to provide an overview of the established therapeutic approaches together with a discussion of the future perspectives in the treatment of patients with SBS. We review those studies dealing with the treatment of SBS patients and discuss both surgical and non surgical approaches together with tissue engineering. METHODS: A systemic review of Medline-cited studies dealing with current practice and future perspectives in the treatment of short bowel in children was performed. RESULTS: Surgical approaches, non-surgical approaches, and tissue engineering which was used in the treatment of SBS were analyzed. Among the surgical approaches, the bowel lengthening procedures and small bowel transplantation are prevalent. Stimulants are most important concerning non-surgical approaches. Tissue engineering seems to be more experimental and was also evaluated. CONCLUSION: The treatment of SBS patients remains very complex. It is eminent to find the best therapeutic option for each patient and to individualize and modify the different possible types of applied techniques frequently. PMID- 22105774 TI - No association between bone mass and prolactin levels among patients with schizophrenia. AB - OBJECTIVE: Decreased bone mineral density has been implicated in schizophrenic patients for long years. The purpose of this study was to assess the relationship between bone mass and prolactin levels in schizophrenic patients. METHODS: In this study, bone mass was measured using quantitative ultrasound densitometry of the calcaneus in 114 patients (49 males and 65 females). The osteosono-assessment index (OSI) was calculated as a function of the speed of sound and transmission index. Estradiol, testosterone, and prolactin levels were also measured. Factors that influenced prolactin levels and bone mass were determined via multiple linear regression analysis. RESULTS: Among the female patients, body mass index and estradiol levels were independently and significantly associated with the OSI. Neither prolactin levels nor duration of antipsychotic treatment was associated with bone mass for either gender. CONCLUSIONS: These findings suggest that prolactin levels do not contribute to poor bone mass, as assessed using the OSI among schizophrenic patients. However, the interpretation of our results was hampered by lack of data including differences in lifestyle and type of antipsychotic medications used in schizophrenic patients. Association between prolactin levels and low bone mineral density was not completely ruled out. Future research exploring prolactin levels and bone mineral density is warranted. PMID- 22105775 TI - BRAF V600E mutation in papillary thyroid carcinoma: significant association with node metastases and extra thyroidal invasion. AB - B-Raf (BRAF) is the strongest activator in the downstream of MAP kinase signaling. The somatic point mutation of BRAF gene (V600E) is the most common and specific event in papillary thyroid carcinoma (PTC). However, its prevalence is variable among different studies and its association with clinico-pathological features is controversial. This study tests the prevalence of BRAF (V600E) mutation in thyroid cancer patients in Indian subcontinental population. We analyzed 140 thyroid tumor specimens for BRAF gene mutation at codon 600 using mutant-allele-specific amplification, single-strand conformation polymorphism, Mutector assay, and DNA sequencing of the PCR-amplified exon 15. BRAF mutation at codon 600 was detected in 46 of 86 PTC patients (53.4%) from Indian subcontinental cohort. Frequency of mutation varied across the subtypes of PTCs. BRAF (V600E) mutation was more common in the conventional PTC (38 out of 62; 61%) than in the follicular variant of PTC (2 out of 17; 11.7%). None of the 8 follicular thyroid adenomas, 14 follicular thyroid carcinomas, 16 medullary thyroid carcinomas, and 16 benign hyperplasia patients showed any exon 15 mutation. We found significant correlation between BRAF mutation status and extra thyroidal invasion, lymph node metastasis, and tumor stage. However no correlation was observed with gender, age, and tumor size of the patients. Thus our findings suggest that BRAF (V600E) is a prevalent genetic alteration in adult sporadic PTCs in Indian cohort and it may be responsible for the progression of classic variant of PTC to metastatic and poorly differentiated subtype and likely to have significant impact on its diagnostic and prognostic management. PMID- 22105777 TI - Emerging roles of p53 in glial cell function in health and disease. AB - Emerging evidence suggests that p53, a tumor suppressor protein primarily involved in cancer biology, coordinates a wide range of novel functions in the CNS including the mediation of pathways underlying neurodegenerative disease pathogenesis. Moreover, an evolving concept in cell and molecular neuroscience is that glial cells are far more fundamental to disease progression than previously thought, which may occur via a noncell-autonomous mechanism that is heavily dependent on p53 activities. As a crucial hub connecting many intracellular control pathways, including cell-cycle control and apoptosis, p53 is ideally placed to coordinate the cellular response to a range of stresses. Although neurodegenerative diseases each display a distinct and diverse molecular pathology, apoptosis is a widespread hallmark feature and the multimodal capacity of the p53 system to orchestrate apoptosis and glial cell behavior highlights p53 as a potential unifying target for therapeutic intervention in neurodegeneration. PMID- 22105778 TI - Gallionella spp. in trickling filtration of subsurface aerated and natural groundwater. AB - The growth of iron-oxidizing bacteria, generally regarded as obligate microaerophilic at neutral pH conditions, has been reported in a wide range of environments, including engineered systems for drinking water production. This research focused on intensively aerated trickling filters treating deep anaerobic and subsurface aerated groundwater. The two systems, each comprising groundwater abstraction and trickling filtration, were monitored over a period of 9 months. Gallionella spp. were quantified by qPCR with specifically designed 16S rRNA primers and identified directly in the environmental samples using clone libraries with the same primers. In addition, enrichments in gradient tubes were evaluated after DGGE separation with general bacterial primers. No other iron oxidizing bacteria than Gallionella spp. were found in the gradient tubes. qPCR provided an effective method to evaluate the growth of Gallionella spp. in these filter systems. The growth of Gallionella spp. was stimulated by subsurface aeration, but these bacteria hardly grew in the trickling filter. In the uninfluenced, natural anaerobic groundwater, Gallionella spp. were only present in low numbers, but they grew extensively in the trickling filter. Identification revealed that Gallionella spp., growing in the trickling filter were phylogenetically distinct from the species found growing during subsurface aeration, indicating that the different conditions in both systems selected for niche organisms, while inhibiting other groups. The results suggest a minor direct significance for inoculation of Gallionella spp. during filtration of subsurface aerated groundwater. PMID- 22105779 TI - Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice. AB - Endotoxin-mediated proinflammatory cytokines play a significant role in the pathogenesis of acute and chronic liver diseases. Heat shock protein 90 (molecular weight, 90 kDa) (hsp90) functions as an important chaperone of lipopolysaccharide (LPS) signaling and is required for the production of proinflammatory cytokines. We hypothesized that inhibition of hsp90 would prevent LPS-induced liver injury by decreasing proinflammatory cytokines. C57BL/6 mice were injected intraperitoneally with an hsp90 inhibitor, 17-dimethylamino ethylamino-17-demethoxygeldanamycin (17-DMAG), and LPS. Parameters of liver injury, proinflammatory cytokines, and associated mechanisms were studied by in vivo and in vitro experiments. Inhibition of hsp90 by 17-DMAG prevented LPS induced increases in serum alanine aminotransferase activity and significantly reduced serum tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) protein as well as messenger RNA (mRNA) in liver. Enhanced DNA-binding activity of heat shock transcription factor 1 (HSF1) and induction of target gene heat shock protein 70 (molecular weight, 70 kDa) confirmed hsp90 inhibition in liver. 17-DMAG treatment decreased cluster of differentiation 14 mRNA and LPS-induced nuclear factor kappa light-chain enhancer of activated B cells (NFkappaB) DNA binding without affecting Toll-like receptor 4 mRNA in liver. Mechanistic studies revealed that 17-DMAG-mediated inhibition of TNFalpha showed no effect on LPS induced NFkappaB promoter-driven reporter activity, but significantly decreased TNFalpha promoter-driven reporter activity. Chromatin immunoprecipitation assays showed that 17-DMAG enhanced HSF1 binding to the TNFalpha promoter, but not the IL-6 promoter, suggesting HSF1 mediated direct inhibition of TNFalpha, but not IL 6. We show that HSF1 indirectly regulates IL-6 by the induction of another transcription factor, activating transcription factor 3. Inhibition of HSF1, using small interfering RNA, prevented 17-DMAG-mediated down-regulation of NFkappaB-binding activity, TNFalpha, and IL-6 induction, supporting a repressive role for HSF1 on proinflammatory cytokine genes during hsp90 inhibition. CONCLUSION: Hsp90 inhibition in vivo reduces proinflammatory cytokines and prevents LPS-induced liver injury likely through repressive action of HSF1. Our results suggest a novel application for 17-DMAG in alleviating LPS-induced liver injury. PMID- 22105780 TI - Microfluidic fabrication of microengineered hydrogels and their application in tissue engineering. AB - Microfluidic technologies are emerging as an enabling tool for various applications in tissue engineering and cell biology. One emerging use of microfluidic systems is the generation of shape-controlled hydrogels (i.e., microfibers, microparticles, and hydrogel building blocks) for various biological applications. Furthermore, the microfluidic fabrication of cell-laden hydrogels is of great benefit for creating artificial scaffolds. In this paper, we review the current development of microfluidic-based fabrication techniques for the creation of fibers, particles, and cell-laden hydrogels. We also highlight their emerging applications in tissue engineering and regenerative medicine. PMID- 22105781 TI - Pulmonary arterial hypertension associated with systemic sclerosis in the Czech Republic. AB - BACKGROUND: Systemic sclerosis (SSc) is an important cause of pulmonary arterial hypertension (PAH), with an estimated prevalence of 7.85-26.7%. OBJECTIVE: Our aim was to estimate the prevalence of PAH among patients with SSc in the Czech Republic and to compare haemodynamics in SSc patients diagnosed with PAH through screening with those diagnosed previously, based on symptoms. METHODS: During 2007, SSc patients in the Czech Republic, without significant pulmonary function impairment or cardiac disease, underwent screening for PAH with transthoracic echocardiography. Those with a tricuspid regurgitant (TR) jet gradient suggestive of PAH (>30 mmHg) underwent subsequent right heart catheterisation (RHC) to confirm the diagnosis (mean pulmonary arterial pressure, mPAP, >=25 mmHg; pulmonary capillary wedge pressure, <=15 mmHg). Haemodynamics in patients diagnosed with PAH in this way were compared with those in patients diagnosed previously, based on symptoms. RESULTS: Two hundred and three SSc patients (mean age, 53.8 +/- 13 years; 82.3% women) from 26 rheumatology practices were screened. Among these, 17 had a TR jet gradient >30 mmHg and underwent RHC; PAH was confirmed in six patients. These six patients were found to have significantly lower mPAP than nine patients diagnosed previously with PAH, based on symptoms (31.17 +/- 5.56 vs. 46.89 +/- 9.48 mmHg, p = 0.0014). CONCLUSION: Prevalence of PAH in our SSc cohort was 7.08%. SSc patients diagnosed with PAH through screening have less advanced disease in terms of haemodynamics than those with PAH diagnosed previously based on symptoms; their prognosis is therefore likely to be more favourable. PMID- 22105782 TI - Label-free fluorescence detection of the depurination activity of ribosome inactivating protein toxins. AB - Development of a simple label-free fluorescence hybridization assay to monitor the depurination activity of toxic ribosome inactivating proteins by using a fluorescent ligand that specifically pseudo base pairs with a cytosine residue opposite an abasic site is described. This method could be potentially implemented in screening platforms for the discovery of small molecules that inhibit the activity of these toxins. PMID- 22105783 TI - Usefulness of adiponectin as a predictor of all cause mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - Substantial evidence points to a protective role of adiponectin against atherosclerosis and cardiovascular (CV) disease. However, in the setting of an acute myocardial infarction (AMI), the role of adiponectin has not previously been studied. Consequently, the aim of this study was to investigate the prognostic role of adiponectin after AMI in a large population of patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. A total of 735 consecutive patients with ST-segment elevation myocardial infarction admitted to a single high-volume invasive heart center and treated with primary percutaneous coronary intervention from September 2006 to December 2008 were included. Blood samples were drawn immediately before the invasive procedure. Plasma adiponectin was measured using a validated immunoassay. End points were all-cause mortality, CV mortality, and admission for new AMI or heart failure. The median follow-up time was 27 months (interquartile range 22 to 33). Patients with high adiponectin (quartile 4) had increased mortality compared to patients with low adiponectin (quartiles 1 to 3) (log-rank p <0.001). After adjustment for conventional risk factors (age, gender, smoking, hypertension, hypercholesterolemia, diabetes, body mass index, C-reactive protein, peak troponin I, creatinine, estimated glomerular filtration rate, previous AMI, multivessel disease, complex lesions, left anterior descending coronary artery lesion, and symptom-to-balloon time) by Cox regression analysis, high adiponectin remained an independent predictor of all-cause mortality (hazard ratio 2.1, 95% confidence interval 1.3 to 3.2, p = 0.001) and CV mortality (hazard ratio 2.6, 95% confidence interval 1.5 to 4.5, p = 0.001). In conclusion, increased plasma adiponectin independently predicts all-cause and CV mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. PMID- 22105784 TI - Value of electrocardiogram in the differentiation of hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, amyloidosis, and Fabry disease. AB - Left ventricular hypertrophy is 1 of the most frequent cardiac manifestations associated with an unfavorable prognosis. However, many different causes of left ventricular hypertrophy exist. The aim of the present study was to assess the diagnostic value of common electrocardiographic (ECG) parameters to differentiate Fabry disease (FD), amyloidosis, and nonobstructive hypertrophic cardiomyopathy (HC) from hypertensive heart disease (HHD) and aortic stenosis (AS). In 94 patients with newly diagnosed FD (n = 17), HHD (n = 20), amyloidosis (n = 17), AS (n = 20), and HC (n = 20), common ECG parameters were analyzed and tested for their diagnostic value. A stepwise approach including the Sokolow-Lyon index, corrected QT duration, and PQ interval minus P-wave duration in lead II to overcome P-wave abnormalities was applied. A corrected QT duration <440 ms in combination with a PQ interval minus P-wave duration in lead II <40 ms was 100% sensitive and 99% specific for the diagnosis of FD, whereas a corrected QT duration >440 ms and a Sokolow-Lyon index <=1.5 mV were found to have a sensitivity and specificity of 85% and 100%, respectively, for the diagnosis of amyloidosis and differentiation from HC, AS, and HHD. Moreover, a novel index ([PQ interval minus P-wave duration in lead II multiplied by corrected QT duration]/Sokolow-Lyon index) proved to be highly diagnostic for the differentiation of amyloidosis (area under the curve 0.92) and FD (area under the curve 0.91) by receiver operator characteristic analysis. In conclusion, a combined analysis of PQ interval minus P-wave duration in lead II, corrected QT duration, and Sokolow-Lyon index proved highly sensitive and specific in the differentiation of FD, amyloidosis, and HC compared to HHD and AS. Analysis of these easy-to-assess ECG parameters may be of substantial help in the diagnostic workup of these 5 conditions. PMID- 22105785 TI - Comparison of coronary calcium in firefighters with abnormal stress test findings and in asymptomatic nonfirefighters with abnormal stress test findings. AB - Firefighters are known to have an elevated rate of sudden cardiac death compared to the general population. It is unclear whether this finding is related to underlying cardiovascular risk factors or whether firefighting inherently carries additional risk. Our objective was to determine whether Los Angeles county firefighters have higher coronary artery calcium (CAC) scores and increased atherosclerosis as determined using 64-slice cardiac, multidetector computed tomography. A total of 647 asymptomatic firefighters evaluated as a part of a wellness protocol were referred for cardiac multidetector computed tomography to evaluate abnormal exercise treadmill test findings. They were matched by age and cardiovascular risk factors, with 2,533 asymptomatic subjects undergoing cardiac computed tomography because of abnormal electrocardiographic or exercise treadmill test findings. CAC and the prevalence of obstructive coronary artery disease by vessel were derived. Finally, the predictors of CAC were analyzed using regression analysis. Of the firefighters, 49% had detectable CAC compared to 43% of controls (p = 0.015). Although the lesions were most prevalent in the left anterior descending artery in both groups, more firefighters had any left anterior descending artery stenosis compared to the controls (p <0.0001). The firefighters also had more left main coronary artery lesions than did the controls (p <0.0001). The firefighters had significantly greater CAC scores than did with the controls (p <0.001). Furthermore, the firefighters had significantly greater mean CAC scores (66 +/- 8 in firefighters vs 33 +/- 4 for controls, p <0.001). Firefighter status was independently associated with a 41-point increase in the CAC score (p <0.001). In conclusion, asymptomatic firefighters had more atherosclerosis and CAC than the matched controls. PMID- 22105787 TI - Nuclear localization of 14-3-3epsilon inversely correlates with poor long-term survival of patients with colorectal cancer. AB - BACKGROUND: 14-3-3epsilon regulates diverse biological processes and plays a significant role in the formation of malignant tumors. However, the localization and clinical significance of 14-3-3epsilon in colorectal cancer (CRC) have not been elucidated. METHODS: We investigated 14-3-3epsilon expression and its prognostic significance in CRC. CRC surgical samples were taken from 137 clinicopathologically characterized CRC cases. 14-3-3epsilon expression was tested by immunohistochemical assay. Separate Western blot of nuclear and cytosol preparations confirmed nuclear localization of 14-3-3epsilon protein. RESULTS: Nuclear expression of 14-3-3epsilon was observed in 76.9% of normal colorectal tissue and 78.8% of all CRC samples. Statistical analysis showed that there was significant difference of nuclear 14-3-3epsilon expression in patients categorized according to lymph node metastasis. A trend was identified between decreasing nuclear 14-3-3epsilon expression in CRC and worsening clinical prognosis. Multivariate analysis showed that loss of nuclear 14-3-3epsilon expression was an independent prognostic indicator for patient's survival. CONCLUSIONS: The current data provide evidence that 14-3-3epsilon is not exclusively a cytosolic protein, but is also detectable within the nucleus. Our results suggest that nuclear 14-3-3epsilon as a suppressor may serve as important biomarker of tumor metastasis. Loss of nuclear 14-3-3epsilon is closely associated with poor overall survival in CRC patients. PMID- 22105786 TI - High-density lipoprotein cholesterol efflux, nitration of apolipoprotein A-I, and endothelial function in obese women. AB - Subjects at risk of atherosclerosis might have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content in the plasma. We considered whether the efflux of excess cellular cholesterol to HDL from obese subjects is associated with impaired arterial endothelial function, a biomarker of cardiovascular risk. A total of 54 overweight (body mass index [BMI] 25 to 29.9 kg/m(2)) or obese (BMI >=30 kg/m(2)) women, aged 46 +/- 11 years, were enrolled in a worksite wellness program. The HDL cholesterol averaged 57 +/- 17 mg/dl and was inversely associated with the BMI (r = -0.419, p = 0.002). Endothelial function was assessed using brachial artery flow-mediated dilation. Cholesterol efflux from (3)H-cholesterol-labeled baby hamster kidney cells transfected with the adenosine triphosphate-binding cassette transporter 1 showed 8.2% to 22.5% cholesterol efflux within 18 hours when incubated with 1% serum and was positively correlated with brachial artery flow-mediated dilation (p <0.05), especially in the 34 subjects with BMI >=30 kg/m(2) (r = 0.482, p = 0.004). This relation was independent of age, HDL or low-density lipoprotein cholesterol concentrations in plasma, blood pressure, or insulin resistance on stepwise multiple regression analysis (beta = 0.31, R(2) = 0.21, p = 0.007). Nitration of apolipoprotein A-I tyrosine residues (using sandwich enzyme-linked immunosorbent assay) was significantly greater in women with a BMI >=30 kg/m(2) and the lowest cholesterol efflux than in women with a BMI of 25 to 29.9 kg/m(2) and the greatest cholesterol efflux (p = 0.01). In conclusion, we have shown that decreased cholesterol efflux by way of the adenosine triphosphate-binding cassette transporter 1 is associated with increased nitration of apolipoprotein A I in HDL and is an independent predictor of impaired endothelial function in women with a BMI of >=30 kg/m(2). This finding suggests that the functional measures of HDL might be better markers for cardiovascular risk than the HDL cholesterol levels in this population. PMID- 22105788 TI - Highly regioselective hydroaminomethylation of terminal olefins to linear amines using Rh complexes with a Tetrabi phosphorus ligand. AB - A highly regioselective hydroaminomethylation of terminal olefins catalyzed by Rh complexes with 2, 2', 6, 6'-tetrakis ((diphenylphosphino)methyl)-1, 1'-biphenyl (Tetrabi) ligand has been developed. Up to 99 % amine selectivity, 168 linear/branched amine product ratio (n/i), and 97.4 % linear amine yield has been obtained at a substrate/rhodium precursor ratio (S/Rh) of 1000 with this methodology. The turnover number was achieved 6930 at 10,000 S/Rh ratio, and the n/i can reach up to >525. Several different olefins and secondary amines have been applied successfully with high chemoselectivity (99 %), yield (>98 %), and regioselectivity (>120). PMID- 22105789 TI - Knot theory in understanding proteins. AB - This paper aims to enthuse mathematicians, especially topologists, knot theorists and geometers to examine problems in the study of proteins. We have highlighted those advances and breakthroughs in knot theory that directly and indirectly help in understanding proteins. We have discussed the phenomena of knotting of protein backbone. This paper also provides a few open questions for knot theorists, the answers to which will help in further understanding of proteins. PMID- 22105790 TI - Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells. AB - Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC(50) values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer. PMID- 22105791 TI - Wire fractures in Solysafe septal occluders: a single center experience. AB - OBJECTIVES: To determine the incidence of device fractures (DF) after implantation of a Solysafe Septal Occluder (iSSO) and to assess the spectrum of associated problems. BACKGROUND: In August 2010, after initial unpublished reports on DF, the manufacturer issued an "urgent field safety notice," prompting all medical care providers to re-examine all patients after iSSO. METHODS: Prospective single center study. Extended follow-up examination, including standardized fluoroscopy (sF), was performed in all patients after iSSO. RESULTS: A total of 111 patients had undergone iSSO at our institution between June 2005 and July 2010. Median age and body weight were 50 years (9.3-79.6) and 75 kg (29 122), respectively. Indications for iSSO were (1) patent foramen ovale in patients with a history of cryptogenic stroke (n = 84; 76%) and (2) hemodynamically significant atrial septal defect of the secundum type (n = 27; 24%). A total of 113 devices were implanted. Complete follow-up was available in 103 patients (92.8%). Median follow-up was 1.9 years (0-5.2). There were no postimplantation neurological events or symptoms. The closure rate was 97.1%. DF was suspected on a chest X-ray in one patient and documented in 10 patients by sF. The overall probability of freedom from DF was 82.3% after 5 years. One patient had embolization of a device fragment to the right pulmonary artery. So far, all patients with DF have been managed conservatively. CONCLUSIONS: The incidence of DF after iSSO is unacceptably high. sF is imperative for accurate diagnosis of DF. Further, follow-up is needed to determine the risk of clinical complications and to optimize management. PMID- 22105792 TI - Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity. AB - Cell sheet engineering has been developed as an alternative approach to improve mesenchymal stem cell-mediated tissue regeneration. In this study, we found that vitamin C (Vc) was capable of inducing telomerase activity in periodontal ligament stem cells (PDLSCs), leading to the up-regulated expression of extracellular matrix type I collagen, fibronectin, and integrin beta1, stem cell markers Oct4, Sox2, and Nanog as well as osteogenic markers RUNX2, ALP, OCN. Under Vc treatment, PDLSCs can form cell sheet structures because of increased cell matrix production. Interestingly, PDLSC sheets demonstrated a significant improvement in tissue regeneration compared with untreated control dissociated PDLSCs and offered an effective treatment for periodontal defects in a swine model. In addition, bone marrow mesenchymal stem cell sheets and umbilical cord mesenchymal stem cell sheets were also well constructed using this method. The development of Vc-mediated mesenchymal stem cell sheets may provide an easy and practical approach for cell-based tissue regeneration. PMID- 22105793 TI - Biomarkers in neurocritical care. AB - The gold standard for assessing neurological function is the bedside clinical examination. However, in neurocritical patients, the signs and symptoms related to the severity of illness can often be ambiguous. It can be hard to distinguish between a severe but stable disease state and one that is dynamic and in a critical decline. Clinicians and family members alike may struggle with the uncertainty of functional outcome prediction. Intermediate biomarkers of brain injury can assist with ongoing clinical management of patients, and in some circumstances can guide prognosis. Used in the right setting, biomarkers in neurocritical care can also aid with decisions to intensify treatment or avoid prolonged and unnecessary therapy. The term biomarker is used in various ways, and here we use it to refer to 3 general types: 1) circulating blood macromolecules, 2) brain imaging, and 3) continuous invasive monitors. Despite its promise, biomarkers have several limitations and should be interpreted in the context of the overall clinical assessment. PMID- 22105794 TI - Stab wound injury of the zebrafish telencephalon: a model for comparative analysis of reactive gliosis. AB - Reactive glia, including astroglia and oligodendrocyte progenitors (OPCs) are at the core of the reaction to injury in the mammalian brain with initially beneficial and later partially adverse functions such as scar formation. Given the different glial composition in the adult zebrafish brain with radial ependymoglia but no parenchymal astrocytes, we examined the glial response to an invasive stab wound injury model in the adult zebrafish telencephalon. Strikingly, already a few days after injury the wound was closed without any scar tissue. Similar to mammals, microglia cells reacted first and accumulated close to the injury site, while neither GFAP+ radial ependymoglia nor adult OPCs were recruited to the injury site. Moreover, OPCs failed to increase their proliferation after this injury, while the number of proliferating GFAP+ glia was increased until 7 days after injury. Importantly, neurogenesis was also increased after injury, generating additional neurons recruited to the parenchyma which survived for several months. Thus, these data suggest that the specific glial environment in the adult zebrafish telencephalon is not only permissive for long term neuronal survival, but avoids scar formation. Invasive injury in the adult zebrafish telencephalon may therefore provide a useful model to untangle the molecular mechanisms involved in these beneficial glial reactions. PMID- 22105795 TI - Synthesis and antimicrobial evaluation of new pyrano[4,3-b]pyran and Pyrano[3,2 c]chromene derivatives bearing a 2-thiophenoxyquinoline nucleus. AB - A new series of pyrano[4,3-b]pyran 4a-i and pyrano[3,2-c]chromene 6a-r derivatives bearing a 2-thiophenoxyquinoline nucleus were synthesized by reaction of 2-(4-(un)-substituted thiophenoxy)quinoline-3-carbaldehydes 2a-i with 6-methyl 4-hydroxypyran-2-one 3 and 4-hydroxy-6-(un)-substituted-2H-chromen-2-one 5a-b respectively and malononitrile at room temperature in the presence of KOH as a basic catalyst. All the compounds were screened against three Gram-positive bacteria (Streptococcus pneumoniae, Bacillus subtilis, Clostridium tetani), three Gram-negative bacteria (Salmonella typhi, Escherichia coli, Vibrio cholerae) and two fungi (Candida albicans, Aspergillus fumigatus) using the broth microdilution MIC (minimum inhibitory concentration) method. Upon antimicrobial screening, it was observed that the majority of the compounds were found to be active against Bacillus subtilis, Clostridium tetani and Candida albicans as compared to standard drugs. PMID- 22105796 TI - [Significance of drains in surgery]. AB - Placing drains is one the most common procedures following operations in surgical disciplines. The indication for placing a drain is, however, usually based on a traditional belief rather than being evidence-based. This paper presents an overview of the literature regarding the indications and the evidence level for placing drains following operations in visceral, vascular, thoracic and orthopeedic surgery as well as traumatology. In visceral surgery the indications for placing drains could be clarified over the past decades but in other surgical fields the level of evidence needs further investigation and clarification through future studies. The available data suggest that in most cases a prophylactic drainage can be avoided. In addition, drains may lead to increased morbidity and higher treatment costs. PMID- 22105797 TI - Template-based protein structure modeling using TASSER(VMT.). AB - Template-based protein structure modeling is commonly used for protein structure prediction. Based on the observation that multiple template-based methods often perform better than single template-based methods, we further explore the use of a variable number of multiple templates for a given target in the latest variant of TASSER, TASSER(VMT) . We first develop an algorithm that improves the target template alignment for a given template. The improved alignment, called the SP(3) alternative alignment, is generated by a parametric alignment method coupled with short TASSER refinement on models selected using knowledge-based scores. The refined top model is then structurally aligned to the template to produce the SP(3) alternative alignment. Templates identified using SP(3) threading are combined with the SP(3) alternative and HHEARCH alignments to provide target alignments to each template. These template models are then grouped into sets containing a variable number of template/alignment combinations. For each set, we run short TASSER simulations to build full-length models. Then, the models from all sets of templates are pooled, and the top 20-50 models selected using FTCOM ranking method. These models are then subjected to a single longer TASSER refinement run for final prediction. We benchmarked our method by comparison with our previously developed approach, pro-sp(3) -TASSER, on a set with 874 easy and 318 hard targets. The average GDT-TS score improvements for the first model are 3.5 and 4.3% for easy and hard targets, respectively. When tested on the 112 CASP9 targets, our method improves the average GDT-TS scores as compared to pro sp3-TASSER by 8.2 and 9.3% for the 80 easy and 32 hard targets, respectively. It also shows slightly better results than the top ranked CASP9 Zhang-Server, QUARK and HHpredA methods. The program is available for download at http://cssb.biology.gatech.edu/. PMID- 22105798 TI - Randomized double-masked controlled trial comparing pain scores with and without the use of supplementary 2% lidocaine gel in LASIK. AB - PURPOSE: To compare pain scores with and without supplementary topical 2% lidocaine gel in patients undergoing simultaneous bilateral laser-assisted in situ keratomileusis (LASIK) under topical anesthesia using 0.5% proparacaine eye drops. DESIGN: Randomized double-masked placebo-controlled trial. METHODS: Fifty one Chinese subjects (102 eyes, with 51 eyes in each arm) were included. One eye was randomly allocated to have supplementary 2% lidocaine gel while the other eye received carbomer gel as control, in addition to topical 0.5% proparacaine. The pain scores for each eye during microkeratome flap creation, during laser ablation, and at 15, 30, and 45 minutes after LASIK were assessed. An overall pain score of the LASIK procedure was also obtained. Primary outcome measures were pain scores during and after LASIK. Secondary outcomes included need for additional topical anesthesia, patient cooperation score, and duration and complications of surgery. RESULTS: In the 2% lidocaine gel-treated group, the pain scores were significantly lower during microkeratome flap creation and laser ablation, and postoperatively at 30 and 45 minutes (P<.05 for all). Patients in the lidocaine gel group required less additional topical anesthesia (P=.0004) and were more cooperative (P=.019) as compared to the carbomer gel group. No surgical or postoperative complications were observed. CONCLUSIONS: The use of supplementary 2% lidocaine gel in LASIK is effective in lowering the pain experienced during and up to 45 minutes after LASIK. PMID- 22105799 TI - Outer retinal structure in patients with acute zonal occult outer retinopathy. AB - PURPOSE: To correlate visual function with high-resolution images of retinal structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 4 patients with acute zonal occult outer retinopathy (AZOOR). DESIGN: Observational case series. METHODS: Four women, aged 18 to 51, with acute focal loss of visual field or visual acuity, photopsia, and minimal funduscopic changes were studied with best-corrected visual acuity (BCVA), Goldmann kinetic and automated perimetry and fundus-guided microperimetry, full-field and multifocal electroretinography (ffERG and mfERG), spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Cone spacing was measured in 4 eyes and compared with 27 age-similar normal eyes. Additional functional testing in 1 patient suggested that cones were absent but rods remained. Serum from all patients was analyzed for anti-retinal antibody activity. RESULTS: In all patients vision loss was initially progressive, then stable. Symptoms were unilateral in 2 and bilateral but asymmetric in 2 patients. In each patient, loss of retinal function correlated with structural changes in the outer retina. AOSLO showed focal cone loss in most patients, although in 1 patient with central vision loss such change was absent. In another patient, structural and functional analyses suggested that cones had degenerated but rods remained. Anti-retinal antibody activity against a ~45 kd antigen was detected in 1 of the patients; the other 3 patients showed no evidence of abnormal anti-retinal antibodies. CONCLUSIONS: Focal abnormalities of retinal structure correlated with vision loss in patients with AZOOR. High-resolution imaging can localize and demonstrate the extent of outer retinal abnormality in AZOOR patients. PMID- 22105800 TI - Dislocation of the donor graft to the posterior segment in descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To report a series of dislocations of the donor graft into the posterior segment associated with Descemet stripping endothelial keratoplasty (DSAEK) and to identify possible risk factors for dislocation and clinical outcomes. DESIGN: Retrospective case series. METHODS: Cases of donor graft dislocation into the posterior segment associated with endothelial keratoplasty were identified from the clinical experience of 7 surgeons. Observations included the preoperative surgical history of each eye, preoperative and postoperative visual acuity, management of the complication, and the postoperative clinical course. No identified cases were excluded from this series. RESULTS: Eight posterior graft dislocations were associated with DSAEK surgery. Each eye had a history of vitrectomy. Five eyes had sutured posterior chamber intraocular lenses, 1 eye had a sulcus intraocular lens, and 2 eyes were aphakic. Each eye required repeat grafting, and in 6 of 8 eyes, pars plana vitrectomy was used to remove the dislocated graft. Final visual acuities ranged from 20/30 to no light perception. CONCLUSIONS: Graft dislocation into the posterior segment is a rare complication of DSAEK surgery that can lead to permanent vision loss. It has occurred in eyes that have undergone previous vitrectomy and complicated intraocular lens placement or were aphakic. As is the case with a dropped lens nucleus during cataract extraction, visual acuities after a dropped DSAEK graft range from very good to no light perception. Better postoperative results seem to be associated with prompt removal of the posteriorly dislocated graft. PMID- 22105801 TI - Reading performance after implantation of a modified corneal inlay design for the surgical correction of presbyopia: 1-year follow-up. AB - PURPOSE: To evaluate change in different reading performance parameters after monocular ACI7000PDT corneal inlay implantation for the improvement of near and intermediate vision. DESIGN: Prospective, interventional case series. METHODS: Twenty-four patients were scheduled for corneal inlay implantation in the nondominant eye in a university outpatient surgery center. Naturally emmetropic and presbyopic patients between 45 and 60 years of age, with uncorrected distance visual acuity of at least 20/20 in both eyes, without any additional ocular pathology were eligible for inclusion. Bilateral uncorrected reading acuity, mean and maximum reading speed, and smallest log-scaled print size were evaluated with the standardized Radner Reading Charts. Measurements of reading parameters and reading distance were performed with the Salzburg Reading Desk (SRD). Minimum postoperative follow-up was 12 months. RESULTS: The reading desk results showed significant changes in each parameter tested. After 12 months the mean reading distance changed from the preoperative value of 46.7 cm (95% CI: 44.1-49.3) to 42.8 cm (95% CI: 40.3-45.3, P < .004), and the mean reading acuity "at best distance" improved from 0.33 logRAD (95% CI: 0.27-0.39) to 0.24 logRAD (95% CI: 0.20-0.28, P < .005). Mean reading speed increased from 141 words per minute (wpm, 95% CI: 133-150) to 156 wpm (95% CI: 145-167, P < .003), maximum reading speed increased from 171 wpm (95% CI: 159-183) to 196 wpm (95% CI: 180-212, P = .001), and the smallest print size improved from 1.50 mm (95% CI: 1.32-1.67) to 1.12 mm (95% CI: 1.03-1.22, P < .001). CONCLUSIONS: After ACI7000PDT implantation, there were significant changes in all tested reading performance parameters in emmetropic presbyopic patients. These 1-year results indicate that the inlay seems to be an effective treatment for presbyopia. PMID- 22105802 TI - The chloroplast ribosomal protein L21 gene is essential for plastid development and embryogenesis in Arabidopsis. AB - Embryogenesis in higher plants is controlled by a complex gene network. Identification and characterization of genes essential for embryogenesis will provide insights into the early events in embryo development. In this study, a novel mutant with aborted seed development (asd) was identified in Arabidopsis. The asd mutant produced about 25% of albino seeds at the early stage of silique development. The segregation of normal and albino seeds was inherited as a single recessive embryo-lethal trait. The gene disrupted in the asd mutant was isolated through map-based cloning. The mutated gene contains a single base change (A to C) in the coding region of RPL21C (At1g35680) that is predicted to encode the chloroplast 50S ribosomal protein L21. Allele test with other two T-DNA insertion lines in RPL21C and a complementation test demonstrated that the mutation in RPL21C was responsible for the asd phenotype. RPL21C exhibits higher expression in leaves and flowers compared with expression levels in roots and developing seeds. The RPL21C-GFP fusion protein was localized in chloroplasts. Cytological observations showed that the asd embryo development was arrested at the globular stage. There were no plastids with normal thylakoids and as a result no normal chloroplasts formed in mutant cells, indicating an indispensable role of the ASD gene in chloroplasts biogenesis. Our studies suggest that the chloroplast ribosomal protein L21 gene is required for chloroplast development and embryogenesis in Arabidopsis. PMID- 22105803 TI - (-)-Epigallocatechin-3-gallate is a new inhibitor of hepatitis C virus entry. AB - Here, we identify (-)-epigallocatechin-3-gallate (EGCG) as a new inhibitor of hepatitis C virus (HCV) entry. EGCG is a flavonoid present in green tea extract belonging to the subclass of catechins, which has many properties. Particularly, EGCG possesses antiviral activity and impairs cellular lipid metabolism. Because of close links between HCV life cycle and lipid metabolism, we postulated that EGCG may interfere with HCV infection. We demonstrate that a concentration of 50 MUM of EGCG inhibits HCV infectivity by more than 90% at an early step of the viral life cycle, most likely the entry step. This inhibition was not observed with other members of the Flaviviridae family tested. The antiviral activity of EGCG on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition, using binding assays at 4 degrees C, we demonstrate that EGCG prevents attachment of the virus to the cell surface, probably by acting directly on the particle. We also show that EGCG has no effect on viral replication and virion secretion. By inhibiting cell-free virus transmission using agarose or neutralizing antibodies, we show that EGCG inhibits HCV cell-to-cell spread. Finally, by successive inoculation of naive cells with supernatant of HCV-infected cells in the presence of EGCG, we observed that EGCG leads to undetectable levels of infection after four passages. CONCLUSION: EGCG is a new, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals. Furthermore, it is a novel tool to further dissect the mechanisms of HCV entry into the hepatocyte. PMID- 22105805 TI - Falanga torture: characteristic features and diagnostic issues. PMID- 22105806 TI - Extracellular matrix regulation of metabolism and implications for tumorigenesis. AB - Attachment to extracellular matrix (ECM) is required for the survival and proliferation of normal epithelial cells. Epithelial tumor cells, however, often acquire "anchorage independence," a property that may contribute to their ability to invade and grow in foreign environments. Although apoptosis is the most rapid and effective mechanism that causes the death of matrix-detached cells, it has become apparent that detachment from matrix alters other aspects of cell physiology prior to commitment to cell death and that some of these alterations can lead to cell death under conditions where apoptosis is suppressed. This report provides an overview of death processes that contribute to the death of matrix-detached normal cells and describes mechanisms that confer anchorage independence, with a focus on ECM regulation of cell metabolism. Loss of matrix attachment leads to metabolic stress characterized by reduced nutrient uptake, decreased ATP production, and increased levels of reactive oxygen species (ROS). The decrease in ATP levels is prevented by either constitutive activation of the PI3K/Akt pathway or exogenous antioxidants. Additionally, decreased Erk signaling in matrix-detached cells causes a disproportionate decrease in flux through pyruvate dehydrogenase (PDH), leading to decreased entry of glucose carbons into the citric acid cycle. Interestingly, forced overexpression of a PDH inhibitor suppresses de novo lipogenesis and proliferation, highlighting the importance of mitochondrial metabolism in supplying intermediates for biosynthetic processes required for proliferation. Thus, ECM attachment is a key regulator of cellular metabolism, and alterations in metabolism owing to changes or loss of ECM engagement during tumorigenesis may serve important tumor-suppressive functions. PMID- 22105807 TI - Terpene biosynthesis: modularity rules. AB - Terpenes are the largest class of small-molecule natural products on earth, and the most abundant by mass. Here, we summarize recent developments in elucidating the structure and function of the proteins involved in their biosynthesis. There are six main building blocks or modules (alpha, beta, gamma, delta, epsilon, and zeta) that make up the structures of these enzymes: the alphaalpha and alphadelta head-to-tail trans-prenyl transferases that produce trans-isoprenoid diphosphates from C(5) precursors; the epsilon head-to-head prenyl transferases that convert these diphosphates into the tri- and tetraterpene precursors of sterols, hopanoids, and carotenoids; the betagamma di- and triterpene synthases; the zeta head-to-tail cis-prenyl transferases that produce the cis-isoprenoid diphosphates involved in bacterial cell wall biosynthesis; and finally the alpha, alphabeta, and alphabetagamma terpene synthases that produce plant terpenes, with many of these modular enzymes having originated from ancestral alpha and beta domain proteins. We also review progress in determining the structure and function of the two 4Fe-4S reductases involved in formation of the C(5) diphosphates in many bacteria, where again, highly modular structures are found. PMID- 22105808 TI - Increased structural disorder of proteins encoded on human sex chromosomes. AB - Intrinsic protein disorder has been studied with respect to the chromosomal location of each protein in the human proteome and also in other fully sequenced organisms. We found that in all studied mammalian species the sex chromosome coded proteins were significantly more disordered than the autosome-coded ones, the strongest discrepancy being observed in humans. In explaining this phenomenon we analyzed local chromosomal features and found that (1) the autosomes have a stronger correlation between the GC content of the transcripts and the structural disorder of the coded proteins than the sex chromosomes; (2) the neighbors' protein disorder correlates the strongest on the sex chromosomes; (3) the GO functions on chromosome X are somewhat biased towards functions with higher disorder but do not account for the entire phenomenon; (4) the protein-protein interactions show a non-random chromosomal distribution, the Y chromosome-coded proteins having the lowest overall frequency for interactions but the largest bias towards intra-chromosomal interactions. Tissue-specific distributions showed the most protein disorder for sex-chromosome coded proteins expressed in the testis and the ovary. We raise the possibility that the high disorder of X- and Y encoded proteins facilitates the fast evolution of testis- and cancer-specific antigenic protein clusters on these chromosomes, in relation to their immunogenic properties and likely contribution to speciation. PMID- 22105809 TI - Multicentre observational study of the natural history of left-sided acute diverticulitis. AB - BACKGROUND: The natural history of acute diverticulitis (AD) is still unclear. This study investigated the recurrence rate, and the risks of emergency surgery, associated stoma and death following initial medical or surgical treatment of AD. METHODS: The Italian Study Group on Complicated Diverticulosis conducted a 4-year multicentre retrospective and prospective database analysis of patients admitted to hospital for medical or surgical treatment of AD and then followed for a minimum of 9 years. The persistence of symptoms, recurrent episodes of AD, new hospital admissions, medical or surgical treatment, and their outcome were recorded during follow-up. RESULTS: Of 1046 patients enrolled at 17 centres, 743 were eligible for the study (407 recruited retrospectively and 336 prospectively); 242 patients (32.6 per cent) underwent emergency surgery at accrual. After a mean follow-up of 10.7 years, rates of recurrence (17.2 versus 5.8 per cent; P < 0.001) and emergency surgery (6.9 versus 1.3 per cent; P = 0.021) were higher for medically treated patients than for those treated surgically. Among patients who had initial medical treatment, age less than 40 years and a history of at least three episodes of AD were associated with an increased risk of AD recurrence. There was no association between any of the investigated parameters and subsequent emergency surgery. The risk of stoma formation was below 1 per cent and disease-related mortality was zero in this group. The disease-related mortality rate was 0.6 per cent among patients who had surgical treatment. CONCLUSION: Long-term risks of recurrent AD or emergency surgery were limited and colectomy did not fully protect against recurrence. PMID- 22105810 TI - Clinical significance of microRNA-155 expression in human breast cancer. AB - BACKGROUND: The aim of this study is to investigate clinical significance of miR 155 expression in breast cancer. METHODS: TaqMan real-time RT-PCR was performed to detect miR-155 expression in breast cancer tissues. The correlation of miR-155 expression with clinicopathological factors and prognosis of breast cancer patients was analyzed. Then, the prognostic value of miR-155 expression was analyzed by univariate and multivariate analyses. Moreover, the effect of miR-155 expression on phenotypes of breast cancer cell was determined by antisense technology. RESULTS: The relative expression of miR-155 was significantly higher in breast cancer tissues than in corresponding nontumor tissues. High miR-155 expression was correlated with higher tumor grade, advanced tumor stage and lymph node metastasis (P = 0.012, 0.001, and 0.003, respectively). Kaplan-Meier survival analysis indicated that the disease-free and overall survival rates of high miR-155 group were significantly lower than those of low miR-155 group (P = 0.038 and 0.029, respectively). Multivariate analysis showed that high miR-155 expression was a poor prognostic factor (P = 0.009). Furthermore, antisense targeting miR-155 could inhibit growth, induce cell arrest in G(0) /G(1) phase, enhance apoptosis, and increase radiosensitivity in breast cancer cells. CONCLUSIONS: MiR-155 expression might be an independent prognostic factor and a therapeutic target for human breast cancer. PMID- 22105811 TI - Melanoma mimic: a case of multiple pagetoid Spitz nevi. AB - BACKGROUND: Differentiating Spitz nevi from melanoma can be difficult. Pagetoid spread of melanocytes is among the features making diagnosis difficult. Rare reports of isolated pagetoid Spitz nevi exist. OBSERVATIONS: We present a unique case of multiple pagetoid Spitz nevi initially diagnosed as multiple in situ melanomas. Germline karyotyping, CDK4 and CDKN2A sequencing, and comparative genomic hybridization of HRAS, BRAF, KRAS, RAF1, CDKN2A, Rb1, MAP2K1, MAP2K2, PTEN, and PTPN11 genes did not identify mutations in this case. Germline and somatic sequencing of BRAF exon 15 revealed no mutations at V600D/E/K. In addition, single-nucleotide polymorphism microarray analysis (330K) on lesional and normal skin revealed no genome-wide copy number changes or loss of heterozygosity. CONCLUSIONS: Clinicians should be aware of the occurrence of multiple pagetoid Spitz nevi to avoid morbidity associated with the misdiagnosis of multiple melanomas. The genetic mechanisms of pagetoid spread of melanocytes are not fully understood. PMID- 22105812 TI - Association of pharyngitis with oral antibiotic use for the treatment of acne: a cross-sectional and prospective cohort study. AB - OBJECTIVE: To prospectively evaluate the association between antibiotics used to treat acne and pharyngitis. DESIGN: Cross-sectional and 9-month prospective cohort. SETTING: Urban university setting. PARTICIPANTS: University students. INTERVENTION: Participants were asked to fill out a survey form, were swabbed for culture, and had a visual examination for acne. MAIN OUTCOME MEASURE: Report of pharyngitis. RESULTS: In the cross-sectional study, 10 of the 15 students receiving oral antibiotics for acne reported an episode of pharyngitis in the previous 30 days, whereas 47 of the 130 students not receiving oral antibiotics, but who had acne, reported an episode of pharyngitis in the prior month. The unadjusted odds ratio (OR) (95% CI) associating current oral antibiotic use in acne patients with a self-reported episode of pharyngitis was 3.53 (95% CI, 1.14 10.95). In the cohort study, there were 358 female and 218 male participants; 36 (6.2%) received oral antibiotics for acne during the study, and 96 (16.6%) received topical antibiotics for acne. Using mixed model logistic regression, the OR was 4.34 (95% CI, 1.51-12.47) associating oral antibiotic use with pharyngitis. Less than 1% of participants were colonized by group A streptococcus, which was not associated with pharyngitis. CONCLUSIONS: Our studies show that that the odds of reporting pharyngitis is more than 3 times baseline in patients receiving oral antibiotics for acne vs those who are not receiving oral antibiotics. The true clinical importance of these findings needs to be evaluated further by prospective studies, but this finding is not associated with group A streptococcus. PMID- 22105813 TI - Prevention of glucocorticoid-induced osteoporosis in immunobullous diseases with alendronate: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To evaluate the efficacy and safety of oral alendronate sodium therapy once daily in preventing glucocorticoid-induced bone loss in patients with immunobullous skin diseases treated with long-term glucocorticoid therapy. DESIGN: A 12-month randomized, double-blind, placebo-controlled trial. SETTING: A tertiary referral dermatology center in Singapore. PARTICIPANTS: Patients newly diagnosed as having an immunobullous disease and deemed to require at least 6 months of systemic glucocorticoid therapy. INTERVENTIONS: The patients were randomized to receive either oral alendronate sodium (10 mg/d) or a matching placebo for 12 months. All patients also received concurrent calcium with vitamin D, 2 tablets daily. MAIN OUTCOME MEASURES: Percent change in bone mineral density (BMD) at the lumbar spine and the femoral neck at 12 months. RESULTS: A total of 29 patients (alendronate [n = 15], placebo [n = 14]) were evaluated. The percent change in BMD in the alendronate group was +3.7% and +3.5% at the lumbar spine and the femoral neck, respectively, whereas in the placebo group, it was -1.4% and -0.7% at the lumbar spine and the femoral neck, respectively. The increase in BMD observed in the alendronate group compared with the placebo group was statistically significant at both the lumbar spine (P = .01) and the femoral neck (P = .01). There was also a statistically significant decrease in serum heat labile alkaline phosphatase levels after 12 months (-32.6%, P < .01) in the alendronate group but not in the placebo group. Adverse events were generally minor, and the frequency of occurrence did not differ significantly between both treatment groups (P = .59). CONCLUSIONS: There were statistically significant increases in BMD at both the lumbar spine (P = .01) and the femoral neck (P = .01) with alendronate therapy. It is imperative to use bisphophonate therapy in patients with immunobullous disorders who are receiving oral corticosteroids because it largely prevents the morbidity associated with low BMD. PMID- 22105814 TI - Evaluation of 4 recently discovered human polyomaviruses in primary cutaneous B cell and T-cell lymphoma. PMID- 22105815 TI - Impact of smoking in cutaneous lupus erythematosus. AB - OBJECTIVE: To investigate cigarette smoking in cutaneous lupus erythematosus (CLE). DESIGN: Prospective longitudinal cohort study. SETTING: Urban cutaneous autoimmune disease clinic. PARTICIPANTS: A total of 218 individuals with CLE or systemic lupus erythematosus and lupus nonspecific skin disease seen between January 5, 2007, and July 30, 2010. MAIN OUTCOME MEASURES: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores to assess disease severity and response to treatment and Skindex 29+3 scores to assess patient quality of life. RESULTS: Current smokers with lupus erythematosus had higher median CLASI scores (9.5) than did never (7.0) and past (6.0) smokers with CLE (P = .02). Current smokers had higher median scores on all the Skindex 29+3 subsets. Current smokers taking hydroxychloroquine sulfate had higher quinacrine hydrochloride use than did nonsmokers (P = .04). Two to 7 months after enrollment, current smokers (median CLASI change, -3) treated with only antimalarial agents improved more than never (1) and past (0) smokers (P = .02). Eight months or more after enrollment, current smokers (CLASI change, 3.5) treated with antimalarial drugs plus at least 1 additional immunomodulator improved less than never (-1.5) and past (0) smokers (P = .04). CONCLUSIONS: Current smokers with lupus erythematosus had worse disease, had worse quality of life, and were more often treated with a combination of hydroxychloroquine and quinacrine than were nonsmokers. Never and past smokers showed greater improvement when treated with antimalarial agents plus at least 1 additional immunomodulator. Current smokers had greater improvement when treated with antimalarial drugs only. PMID- 22105816 TI - Soluble adenylyl cyclase antibody profile as a diagnostic adjunct in the assessment of pigmented lesions. AB - OBJECTIVE: To investigate the usefulness of a novel marker for melanocytic proliferations. DESIGN: Using a novel monoclonal antibody against soluble adenylyl cyclase (sAC), various benign and malignant melanocytic proliferations were immunostained. SETTING: Weill Medical College of Cornell University dermatopathology laboratory. MAIN OUTCOME MEASURES: The results were qualitative, not quantifiable. RESULTS: The sAC immunostaining produced distinctive patterns that paralleled melanomagenesis. At one pole of the spectrum were benign nevi, including atypical nevi of special sites and recurrent nevi showing a distinct pattern of dotlike Golgi staining, while at the opposite pole was melanoma, in which many cells demonstrated an intense pannuclear expression pattern, often accompanied by loss of the Golgi expression pattern. Melanomas of lentigo maligna and acral lentiginous subtypes exhibited the most striking pannuclear expression, while nodular melanomas showed the least, although with supervening enhanced diffuse cytoplasmic expression. Loss of the Golgi expression pattern was a feature of malignant melanoma. CONCLUSION: The sAC expression pattern is complex but seems discriminatory, with distinctive and variable staining patterns according to the nature of the lesion biopsied. PMID- 22105818 TI - Early diagnosis of hepatocellular carcinoma by multiple microRNAs: validity, efficacy, and cost-effectiveness. PMID- 22105817 TI - Thymic malignancies: from clinical management to targeted therapies. AB - PURPOSE: A key challenge in the treatment of thymoma and thymic carcinoma (TC) is in improving our understanding of the molecular biology of these relatively rare tumors. In recent years, significant efforts have been made to dissect the molecular pathways involved in their carcinogenesis. Here we discuss the results of large-scale genomic analyses conducted to date and review the most active chemotherapies and targeted treatments. METHODS: We reviewed the literature for chemotherapeutic trials in the last 20 years and trials involving targeted therapies between 1999 and 2010. The search was supplemented by a review of abstracts presented at the annual meetings of the American Society of Clinical Oncology (from 1999 to 2010), at the first International Conference on Thymic Malignancies in 2009, and at a follow-up meeting of the newly formed International Thymic Malignancies Interest Group in 2010. RESULTS: Surgery remains the treatment of choice for operable tumors, whereas chemotherapy is standard in locally advanced and metastatic disease. Thus far, targeted therapies have been developed empirically. Histone deacetylase inhibitors have shown some activity in thymoma whereas sunitinib may be active in TC. There are no data to support the use of HER2- or EGFR-targeted therapies in thymic malignancies. CONCLUSION: Drug development for the treatment of thymic malignancies is difficult because of the rarity of these tumors. Ethnic differences are becoming apparent, with aggressive subtypes being observed in Asians and African Americans. Incremental improvements in our understanding of tumor biology suggest that molecular profiling-directed therapies may be the preferred route of investigation in the future. PMID- 22105819 TI - Reminders. PMID- 22105820 TI - Secondary abdominal-pelvic malignancies attributable to diagnostic radiation exposure in patients with testicular malignancies. PMID- 22105821 TI - Hairy cell leukemia variant, a new entity of the WHO 2008. PMID- 22105822 TI - Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. AB - PURPOSE: More than 60% of patients with hepatocellular carcinoma (HCC) do not receive curative therapy as a result of late clinical presentation and diagnosis. We aimed to identify plasma microRNAs for diagnosing hepatitis B virus (HBV) related HCC. PATIENTS AND METHODS: Plasma microRNA expression was investigated with three independent cohorts including 934 participants (healthy, chronic hepatitis B, cirrhosis, and HBV-related HCC), recruited between August 2008 and June 2010. First, we used microarray to screen 723 microRNAs in 137 plasma samples for diagnosing HCC. Quantitative reverse-transcriptase polymerase chain reaction assay was then applied to evaluate the expression of selected microRNAs. A logistic regression model was constructed using a training cohort (n = 407) and then validated using an independent cohort (n = 390). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. RESULTS: We identified a microRNA panel (miR-122, miR-192, miR-21, miR-223, miR 26a, miR-27a and miR-801) that provided a high diagnostic accuracy of HCC (AUC = 0.864 and 0.888 for training and validation data set, respectively). The satisfactory diagnostic performance of the microRNA panel persisted regardless of disease status (AUCs for Barcelona Clinic Liver Cancer stages 0, A, B, and C were 0.888, 0.888, 0.901, and 0.881, respectively). The microRNA panel can also differentiate HCC from healthy (AUC = 0.941), chronic hepatitis B (AUC = 0.842), and cirrhosis (AUC = 0.884), respectively. CONCLUSION: We found a plasma microRNA panel that has considerable clinical value in diagnosing early-stage HCC. Thus, patients who would have otherwise missed the curative treatment window can benefit from optimal therapy. PMID- 22105823 TI - Use of a decision aid to help caregivers discuss terminal disease status with a family member with cancer: a randomized controlled trial. AB - PURPOSE: We tested whether a decision aid explaining how to discuss the approach of death with a family member with cancer would help family caregivers decide to discuss a terminal prognosis. PATIENTS AND METHODS: We randomly assigned caregivers of terminally ill patients with cancer to a group that received a video and a companion workbook that showed either how they can discuss the prognosis with their patient (experimental arm) or how cancer pain can be controlled (control arm). At baseline and 1 month, we evaluated the decision to discuss terminal prognosis as the primary outcome. At 0, 1, 3, and 6 months, we assessed the caregivers' decisional conflict and satisfaction as secondary outcomes using a Decision Conflict Scale (DCS). RESULTS: We found no difference in changes in the decision to discuss terminal prognosis between the two groups. Conflict (P = .003), uncertainty (P = .019), and value clarity (P = .007) subscale scores and total DCS score (P = .008) improved from baseline to 1 month significantly more in the experimental arm than in the control arm. Over 6 months, the significant between-group differences continued for the conflict (P = .031), uncertainty (P = .014), and value clarity (P = .039) subscale scores and total DCS score (P = .040). CONCLUSION: Decision aids can help caregivers, with the aid of trained professionals, to communicate with patients about their terminal illness. PMID- 22105824 TI - A case-match study comparing unilateral with synchronous bilateral breast cancer outcomes. AB - PURPOSE: There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of this study was to determine whether survival outcomes for patients with SBBC can be estimated from the characteristics of their individual cancers. PATIENTS AND METHODS: Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed <= 2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer-specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined and matched with three breast cancers from the unilateral cohort to select 621 high-risk matches. The priority sequence of matching the prognostic and predictive variables was positive lymph node number, primary tumor size, age, grade, lymphovascular invasion, estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and type of systemic therapy used. RESULTS: With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to 77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches. CONCLUSION: BCSS was not significantly different between the SBBC cases and their high-risk matches. PMID- 22105825 TI - Reporting of adjuvant breast cancer trials: when is the right time? PMID- 22105826 TI - Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. AB - PURPOSE: Capecitabine is an active agent in the treatment of breast cancer. It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane, an anthracycline, and cyclophosphamide improves outcome in early breast cancer. PATIENTS AND METHODS: Women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive either three cycles of docetaxel and capecitabine (TX) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX; n = 753) or three cycles of docetaxel (T) followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF; n = 747). The primary end point was recurrence-free survival (RFS). RESULTS: During a median follow-up time of 59 months, 214 RFS events occurred (local or distant recurrences or deaths; TX/CEX, n = 96; T/CEF, n = 118). RFS was not significantly different between the groups (hazard ratio [HR], 0.79; 95% CI, 0.60 to 1.04; P = .087; 5-year RFS, 86.6% for TX/CEX v 84.1% for T/CEF). Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF (HR, 0.73; 95% CI, 0.52 to 1.04; P = .080). In exploratory analyses, TX/CEX improved breast cancer-specific survival (HR, 0.64; 95% CI, 0.44 to 0.95; P = .027) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis. We detected little severe late toxicity. CONCLUSION: Integration of capecitabine into a regimen that contains docetaxel, epirubicin, and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine. PMID- 22105827 TI - Embryotoxicity of Corexit 9500 in mallard ducks (Anas platyrhynchos). AB - Embryotoxicity of the oil dispersant Corexit 9500 was examined using fertilized mallard duck eggs. Corexit 9500 was topically applied below the air cell to eggs in volumes ranging from 0 to 100 MUL on day 3 of incubation. The highest incidence of mortality occurred at developmental stage 4, one day post-Corexit 9500 application. Hatching success was significantly decreased among eggs treated with >= 20 MUL of Corexit 9500 as compared to controls (P <= 0.047). No egg treated with >= 40 MUL successfully hatched. The application volume resulting in 50% mortality (corrected for control survival) was determined to be 15.5 MUL. Developmental stage at embryo death was also significantly decreased compared to controls in eggs exposed to 40 MUL (P = 0.0042) and above. PMID- 22105828 TI - Molecular dynamics simulation of conformational heterogeneity in transportin 1. AB - Transportin 1 (Trn1), as a typical transport receptor of the karyopherin-beta family, mediates numerous RNA binding proteins into the nucleus by recognizing proline-tyrosine nuclear localization signals (PY-NLSs). Such process is regulated by RanGTP through its nucleotide cycle, which is associated with ligand dissociation. Yet a proper description including dynamic properties of Trn1 and its response on ligand/Ran binding has not been accessible so far. Here, we use molecular dynamics simulations to probe the conformational dynamics of the apo Trn1 and Trn1 in complex with ligand and Ran. The results reveal a strikingly intrinsic flexibility and conformational heterogeneity of Trn1, identified as generally segmental architecture. The segments rotate relative to each other about a flexible hinge and thereby force Trn1 to adopt a conformation compatible with the binding of Ran or substrates. Such binding significantly suppresses the flexibility and conformational heterogeneity of Trn1 and results in a disorder-to order transition of HR8 loop, which facilitates this loop to allosterically communicate with the C-terminal arch of Trn1. These results give insights into the disassembly and recycling of the Trn1, which has important implications for the regulation of the nuclear transport cycle and for the ligand selectivity. PMID- 22105829 TI - Real-world use of the Impella 2.5 circulatory support system in complex high-risk percutaneous coronary intervention: the USpella Registry. AB - OBJECTIVES: We report on the real-world, multicenter experience of the Impella 2.5 circulatory support system during high-risk PCI, a subset of the larger USpella Registry. BACKGROUND: Standard of care for most patients with compromised ventricular function with multivessel or high-risk coronary lesions has been coronary artery bypass grafting. In poor operative candidates, high-risk PCI is increasingly considered, despite an increased risk for periprocedural hemodynamic compromise. METHODS: 175 consecutive patients who underwent high-risk PCI with prophylactic support of the Impella 2.5 were evaluated. The primary safety endpoint was the incidence of major adverse cardiac events (MACE) at 30 days. Secondary endpoints included safety and efficacy related to the device and patient outcomes, including survival at 12 months. RESULTS: Overall angiographic revascularization was successful in 99% of patients and in 90% of those with multivessel revascularization, resulting in a reduction of the mean SYNTAX score post-PCI from 36 +/- 15 to 18 +/- 15 (P < 0.0001) and an improvement of the ejection fraction (from 31 +/- 15% to 36 +/- 14%, P < 0.0001). In 51% of patients, the functional status improved by one or more NYHA class (P < 0.001). At 30-day follow-up, the rate of MACE was 8%, and survival was 96%, 91%, and 88% at 30 days, 6 months, and 12 months, respectively. CONCLUSIONS: The use of Impella 2.5 in high-risk PCI appeared feasible and safe in the real-world setting. The utilization of the Impella 2.5 was successful, resulting in favorable short- and midterm angiographic, procedural and clinical outcomes. PMID- 22105830 TI - Unsaturated fatty acids induce mesenchymal stem cells to increase secretion of angiogenic mediators. AB - Mesenchymal stem cells (MSC) represent emerging cell-based therapies for diabetes and associated complications. Ongoing clinical trials are using exogenous MSC to treat type 1 and 2 diabetes, cardiovascular disease and non-healing wounds due to diabetes. The majority of these trials are aimed at exploiting the ability of these multipotent mesenchymal stromal cells to release soluble mediators that reduce inflammation and promote both angiogenesis and cell survival at sites of tissue damage. Growing evidence suggests that MSC secretion of soluble factors is dependent on tissue microenvironment. Despite the contribution of fatty acids to the metabolic environment of type 2 diabetes, almost nothing is known about their effects on MSC secretion of growth factors and cytokines. In this study, human bone marrow-derived MSC were exposed to linoleic acid, an omega-6 polyunsaturated fatty acid, or oleic acid, a monounsaturated fatty acid, for seven days in the presence of 5.38 mM glucose. Outcomes measured included MSC proliferation, gene expression, protein secretion and chemotaxis. Linoleic and oleic acids inhibited MSC proliferation and altered MSC expression and secretion of known mediators of angiogenesis. Both unsaturated fatty acids induced MSC to increase secretion of interleukin-6, VEGF and nitric oxide. In addition, linoleic acid but not oleic acid induced MSC to increase production of interleukin-8. Collectively these data suggest that exposure to fatty acids may have functional consequences for MSC therapy. Fatty acids may affect MSC engraftment to injured tissue and MSC secretion of cytokines and growth factors that regulate local cellular responses to injury. PMID- 22105831 TI - Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats. AB - Titin is a giant protein with multiple functions in cardiac and skeletal muscles. Rat cardiac titin undergoes developmental isoform transition from the neonatal 3.7 MDa N2BA isoform to primarily the adult 2.97 MDa N2B isoform. An autosomal dominant mutation dramatically altered this transformation. Titins from eight skeletal muscles: Tibialis Anterior (TA), Longissimus Dorsi (LD) and Gastrocnemius (GA), Extensor Digitorum Longus (ED), Soleus (SO), Psoas (PS), Extensor Oblique (EO), and Diaphram (DI) were characterized in wild type and in homozygous mutant (Hm) rats with a titin splicing defect. Results showed that the developmental reduction in titin size is eliminated in the mutant rat so that the titins in all investigated skeletal muscles remain large in the adult. The alternative splicing of titin mRNA was found repressed by this mutation, a result consistent with the large titin isoform in the mutant. The developmental pattern of titin mRNA alternative splicing differs between heart and skeletal muscles. The retention of intron 49 reveals a possible mechanism for the absence of the N2B unique region in the expressed titin protein of skeletal muscle. PMID- 22105832 TI - Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. AB - Estimates of the prevalence of chronic hepatitis B (CHB) in the United States differ significantly, and the contribution of foreign-born (FB) persons has not been adequately described. The aim of this study was to estimate the number of FB persons in the United States living with CHB by their country of origin. We performed a systematic review for reports of HBsAg seroprevalence rates in 102 countries (covering PubMed from 1980 to July 2010). Data from 1,373 articles meeting inclusion criteria were extracted into country-specific databases. We identified 256 seroprevalence surveys in emigrants from 52 countries (including 689,078 persons) and 1,797 surveys in the general populations of 98 countries (including 17,861,035 persons). Surveys including individuals with lower or higher risk of CHB than the general population were excluded. Data were combined using meta-analytic methods to determine country-specific pooled CHB prevalence rates. Rates were multiplied by the number of FB living in the United States in 2009 by country of birth from the U.S. Census Bureau to yield the number of FB with CHB from each country. We estimate a total of 1.32 million (95% confidence interval: 1.04-1.61) FB in the United States living with CHB in 2009; 58% migrated from Asia and 11% migrated from Africa, where hepatitis B is highly endemic. Approximately 7% migrated from Central America, a region with lower CHB rates, but many more emigrants to the United States. This analysis suggests that the number of FB persons living with CHB in the United States may be significantly greater than previously reported. Assuming 300,000-600,000 U.S. born persons with CHB, the total prevalence of CHB in the United States may be as high as 2.2 million. PMID- 22105833 TI - [What has been confirmed in therapy 2011?]. PMID- 22105834 TI - Use of Hospital Episode Statistics to investigate abdominal aortic aneurysm surgery. AB - BACKGROUND: A coding framework was evaluated to study patients undergoing open surgical replacement of an abdominal aortic aneurysm (AAA) in the English Hospital Episode Statistics (HES) database. The objective was to create groups of patients who are homogeneous with respect to diagnosis, prognosis and treatment. METHODS: The frequency and consistency of potentially relevant diagnosis (International Classification of Diseases, 10th revision) and procedure (Office of Population Censuses and Surveys Classification, 4th revision) codes were assessed in patients admitted to English National Health Service hospitals between April 2003 and March 2008. Administrative codes were compared with diagnosis and procedure codes to check that patients who had undergone emergency surgery for a ruptured AAA were admitted as an emergency. RESULTS: Of 20 290 patients undergoing AAA replacement, 19 250 (94.9 per cent) had a consistent diagnosis (unruptured or ruptured AAA); 79.3 per cent of patients with an emergency replacement were coded as having a ruptured AAA and 95.7 per cent of those with a non-emergency replacement as having an unruptured AAA. Of patients who had undergone emergency replacement of a ruptured AAA, 93.3 per cent were coded as having been admitted as an emergency. CONCLUSION: Coding consistency was high. The proposed framework could define homogeneous groups by combining diagnosis, procedure and administrative codes. It also allows an assessment of potential miscoding at national and hospital level. PMID- 22105836 TI - Hydrosilylation of alkynes by Ni(CO)3-stabilized silicon(II) hydride. AB - Not copy and paste: Although beta-diketiminato ligands have been employed for the stabilization of Ge(II) and Sn(II) hydrides, the corresponding Si(II) hydride is not accessible. However, coordination of silicon(II) to a {Ni(CO)(3)} fragment allowed the isolation of the first Si(II) hydride metal complex 1. This complex was used for the first silicon(II)-based and Ni(0)-mediated, stereoselective hydrosilylation of alkynes. R = phenyl, tolyl. PMID- 22105837 TI - Treatment of residual pockets with photodynamic therapy, diode laser, or deep scaling. A randomized, split-mouth controlled clinical trial. AB - The objective of this work was to compare the effects of antimicrobial photodynamic therapy (PDT), diode soft laser therapy (DSL), and thorough deep scaling and root planing (SRP) for treatment of residual pockets. Thirty-two subjects with a history of non-surgical treatment for chronic periodontitis were included. Residual pockets >4 mm and bleeding upon probing were debrided with an ultrasonic device and then subjected to either PDT, DSL, or SRP. Pocket probing depth (PPD), bleeding on probing (BOP), and gingival recession were monitored over 6 months. Counts of four microorganisms were determined by direct hybridization with RNA probes. PPD decreased from 5.6 +/- 1.0 to 3.8 +/- 1.1 in 6 months (p < 0.001), and BOP decreased from 100% to 52% (p < 0.01). The risk for a site to remain >4 mm with BOP depended on initial PPD (p = 0.036) and was higher if treated with DSL (p = 0.034). Frequencies of three microorganisms were significantly lower in PDT- and SRP-treated than in DSL-treated quadrants (p = 0.02) after 14 days, but not at months 2 and 6. All three treatments resulted in a significant clinical improvement. PDT and SRP suppressed Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola stronger, and resulted in fewer persisting pockets after 6 months, than DSL application. PMID- 22105838 TI - Generation of immunogenic and tolerogenic clinical-grade dendritic cells. AB - Immunotherapy with dendritic cells (DCs), which have been manipulated ex vivo to become immunogenic or tolerogenic, has been tested in clinical trials for disease therapy. DCs are sentinels of the immune system, which after exposure to antigenic or inflammatory signals and crosstalk with effector CD4(+) T cells express high levels of costimulatory molecules and cytokines. Upregulation of either costimulatory molecules or cytokines promotes immunologic DCs, whereas their downregulation generates tolerogenic DCs (TDCs), which induce T regulatory cells (Tregs) and a state of tolerance. Immunogenic DCs are used for the therapy of infectious diseases such as HIV-1 and cancer, whereas tolerogenic DCs are used in treating various autoimmune diseases and in transplantation. DC vaccination is still at an early stage, and improvements are mainly needed in quality control of monitoring assays to generate clinical-grade DC products and to assess the effect of DC vaccination in future clinical trials. Here, we review the recent work in DC generation and monitoring approaches for DC-based trials with immunogenic or tolerogenic DCs. PMID- 22105839 TI - Effect of surgeon specialization on long-term survival following colon cancer resection at an NCI-designated cancer center. AB - BACKGROUND: Recent studies have documented improved outcomes for patients undergoing colorectal cancer resection at NCI cancer centers compared to hospitals without this designation. Proposed contributory factors include a higher proportion of surgeons with specialty training in colorectal surgery and surgical oncology. The purpose of this study was to assess whether surgeon specialization is associated with differences in overall survival following colon cancer resection at an NCI cancer center. METHODS: We conducted a retrospective review of patients undergoing colectomy for colon cancer from 1994 to 2009 at Duke University Medical Center. Patients were divided into two groups based on specialization status of the attending surgeon, and several clinicopathologic variables were compared. A multivariate analysis was then performed examining variables influencing overall survival. RESULTS: Total of 395 patients were included in the study, with 335 patients operated on by specialty-trained surgeons and 60 patients operated on by non-specialists. Overall, the two groups were similar with respect to demographic and pathologic variables. On multivariate analysis, surgeon specialization was found to be an independent predictor of improved overall survival [HR 0.43 (CI: 0.25-0.75), P = 0.003]. CONCLUSION: Surgeon specialization appears to be associated with improved overall survival in the setting of an NCI-designated cancer center. PMID- 22105840 TI - Superconductivity in 4-Angstrom carbon nanotubes--a short review. AB - We give an up-to-date review of the superconducting phenomena in 4-Angstrom carbon nanotubes embedded in aligned linear pores of the AlPO(4)-5 (AFI) zeolite, first discovered in 2001 as a fluctuation Meissner effect. With the introduction of a new approach to sample synthesis around 2007, new data confirming the superconductivity have been obtained. These comprise electrical, specific heat, and magnetic measurements which together yield a consistent yet complex physical picture of the superconducting state, largely owing to the one-dimensional (1D) nature of the 4-Angstrom carbon nanotubes. For the electrical transport characteristics, two types of superconducting resistive behaviors were reproducibly observed in different samples. The first type is the quasi 1D fluctuation superconductivity that exhibits a smooth resistance drop with decreasing temperature, initiating at 15 K. At low temperatures the differential resistance also shows a smooth increase with increasing bias current (voltage). Both are unaffected by an applied magnetic field up to 11 Tesla. These manifestations are shown to be consistent with those of a quasi 1D superconductor with thermally activated phase slips as predicted by the Langer-Ambegaokar McCumber-Halperin (LAMH) theory. The second type is the quasi 1D to 3D superconducting crossover transition, which was observed to initiate at 15 K with a slow resistance decrease switching to a sharp order of magnitude drop at ~7.5 K. The latter exhibits anisotropic magnetic field dependence and is attributed to a Berezinskii-Kosterlitz-Thouless (BKT)-like transition that establishes quasi long-range order in the plane transverse to the c-axis of the aligned nanotubes, thereby mediating a 1D to 3D crossover. The electrical data are complemented by magnetic and thermal specific heat bulk measurements. By using both the SQUID VSM and the magnetic torque technique, the onset of diamagnetism was observed to occur at ~15 K, with a rapid increase of the diamagnetic moment below ~7 K. The zero-field-cooled and field-cooled branches deviated from each other below 7 K, indicating the establishment of a 3D Meissner state with macroscopic phase coherence. The superconductivity is further supported by the specific heat measurements, which show an anomaly with onset at 15 K and a peak at 11-12 K. In the 3D superconducting state, the nanotube arrays constitute a type-II anisotropic superconductor with H(c1)~ 60 to 150 Oe, coherence length xi~ 5 to 15 nm, London penetration length lambda~ 1.5 um, and Ginzburg-Landau kappa~ 100. We give a physical interpretation to the observed phenomena and note the challenges and prospects ahead. PMID- 22105841 TI - Quantitative dynamic contrast-enhanced MR imaging analysis of complex adnexal masses: a preliminary study. AB - OBJECTIVE: To evaluate the ability of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate malignant from benign adnexal tumours. METHODS: Fifty-six women with 38 malignant and 18 benign tumours underwent MR imaging before surgery for complex adnexal masses. Microvascular parameters were extracted from high temporal resolution DCE-MRI series, using a pharmacokinetic model in the solid tissue of adnexal tumours. These parameters were tissue blood flow (F(T)), blood volume fraction (Vb), permeability-surface area product (PS), interstitial volume fraction (Ve), lag time (Dt) and area under the enhancing curve (rAUC). Area under the receiver operating curve (AUROC) was calculated as a descriptive tool to assess the overall discrimination of parameters. RESULTS: Malignant tumours displayed higher F(T), Vb, rAUC and lower Ve than benign tumours (P < 0.0001, P = 0.0006, P = 0.04 and P = 0.0002, respectively). F(T) was the most relevant factor for discriminating malignant from benign tumours (AUROC = 0.86). Primary ovarian invasive tumours displayed higher F(T) and shorter Dt than borderline tumours. Malignant adnexal tumours with associated peritoneal carcinomatosis at surgery displayed a shorter Dt than those without peritoneal carcinomatosis at surgery (P = 0.01). CONCLUSION: Quantitative DCE-MRI is a feasible and accurate technique to differentiate malignant from benign adnexal tumours and could potentially help oncologists with management decisions. KEY POINTS: Quantitative DCE MR imaging allows accurate differentiation between malignant and benign tumours. Quantitative DCE MRI may help predict peritoneal carcinomatosis associated with ovarian tumors. Quantitative DCE MRI helps distinguish between invasive and borderline primary ovarian tumours. PMID- 22105842 TI - Excess radiation and organ dose in chest and abdominal CT due to CT acquisition beyond expected anatomical boundaries. AB - OBJECTIVES: To assess the extent of extra imaging beyond the prescribed anatomical margins for chest and abdominal CT and to determine associated extra patient and organ dose estimates. METHODS: For 167 consecutive patients undergoing routine chest and/or abdominal examination with 128-slice CT, extra imaging length was evaluated on coronal images. Effective and organ doses (thyroid, liver, breasts, testes) were calculated. Paired t-test was applied to evaluate statistically significant differences between prescribed and actual imaging length, and associated doses. RESULTS: 133 (80%) examinations had extra coverage (mean 4.6 cm, range 1-19.5 cm). Significantly higher (P < 0.05) effective doses for chest CT (mean 4.8 mSv vs 4.2 mSv for actual vs prescribed volume of interest), abdominal CT (8.4 mSv vs 7.9 mSv) or thorax-abdominal CT (12.8 mSv vs 11.9 mSv) were found. A significantly higher (P < 0.001) organ dose was estimated for thyroid (extra dose 99% corresponding to 5.1 mSv), liver (56%, 2.2 mSv), testes (115%, 7.6 mSv), and breasts (163%, 1.5 mSv). CONCLUSIONS: Imaging beyond anatomical limits during routine chest and abdominal CT results in higher organ and effective doses. Continuous training of the technologists remains important. Physicians and technologists must be kept aware of the additional dose associated with extra imaging. KEY POINTS: Imaging beyond anatomical boundaries often occurs during chest and abdominal CT. Such imaging beyond anatomical boundaries leads to higher organ and effective doses. Physicians and technologists should be made more aware of this additional dose. PMID- 22105843 TI - Threshold-based prediction of the coagulation zone in sequential temperature mapping in MR-guided radiofrequency ablation of liver tumours. AB - OBJECTIVE: To evaluate different cut-off temperature levels for a threshold-based prediction of the coagulation zone in magnetic resonance (MR)-guided radiofrequency (RF) ablation of liver tumours. METHODS: Temperature-sensitive measurements were acquired during RF ablation of 24 patients with primary (6) and secondary liver lesions (18) using a wide-bore 1.5 T MR sytem and compared with the post-interventional coagulation zone. Temperature measurements using the proton resonance frequency shift method were performed directly subsequent to energy application. The temperature maps were registered on the contrast-enhanced follow-up MR images acquired 4 weeks after treatment. Areas with temperatures above 50 degrees , 55 degrees and 60 degrees C were segmented and compared with the coagulation zones. Sensitivity and positive predictive value were calculated. RESULTS: No major complications occurred and all tumours were completely treated. No tumour recurrence was observed at the follow-up examination after 4 weeks. Two patients with secondary liver lesions showed local tumour recurrence after 4 and 7 months. The 60 degrees C threshold level achieved the highest positive predictive value (87.7 +/- 9.9) and the best prediction of the coagulation zone. CONCLUSIONS: For a threshold-based prediction of the coagulation zone, the 60 degrees C cut-off level achieved the best prediction of the coagulation zone among the tested levels. KEY POINTS: * Temperature monitoring can be used to survey MR-guided radiofrequency ablation * The developing ablation zone can be estimated based on post-interventional temperature measurements * A 60 degrees C threshold level can be used to predict the ablation zone * The 50 degrees C and 55 degrees C temperature zones tend to overestimate the ablation zone. PMID- 22105844 TI - Strain-mediated phase control and electrolyte-gating of electron-doped manganites. AB - A prototype Mott transistor, the electric double layer transistor with a strained CaMnO(3) thin film, is fabricated. As predicted by the strain phase diagram of electron-doped manganite films, the device with the compressively strained CaMnO(3) exhibits an immense conductivity modulation upon applying a tiny gate voltage of 2 V. PMID- 22105845 TI - Evaluation of a bioresorbable drug delivery system for the treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) represents a major global health burden. Typically HCC responds poorly to chemotherapy, and such approaches to treat HCC are commonly associated with severe hepatic and/or systemic toxicity. The aim of this study was to evaluate a porous resorbable silica-calcium phosphate nanocomposite (SCPC) as a controlled release vehicle for cisplatin. Particles of two different formulations--SCPC50 and SCPC75, containing 19.49 and 32.9 mol % silica, respectively--were loaded with cisplatin by immersion treatment and pressed into discs. In vitro release kinetics studies of cisplatin from SCPC50 and SCPC75 demonstrated an initial burst release of 0.39 +/- 0.04 mg (of the 1.49 mg total loaded) and 0.87 +/- 0.07 mg (of the 2.34 mg total loaded), respectively. Over the following 44-day period. SCPC75-cisplatin hybrid produced a significantly higher sustained cisplatin release than that released from SCPC50. Cisplatin release correlated well with the surface area, and silica dissolution kinetics of the SCPC carrier. Treatment of rat HCC cells (H4IIE) with cisplatin released from SCPC-cisplatin hybrids induced apoptotic cell death in H4IIE cells in vitro. Results of this study suggest that SCPC composites may be of potential use for the treatment of HCC in vivo. PMID- 22105846 TI - A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover. AB - Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5 hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. PMID- 22105847 TI - High invertase activity in tomato reproductive organs correlates with enhanced sucrose import into, and heat tolerance of, young fruit. AB - Heat stress can cause severe crop yield losses by impairing reproductive development. However, the underlying mechanisms are poorly understood. We examined patterns of carbon allocation and activities of sucrose cleavage enzymes in heat-tolerant (HT) and -sensitive (HS) tomato (Solanum lycopersicum L.) lines subjected to normal (control) and heat stress temperatures. At the control temperature of 25/20 degrees C (day/night) the HT line exhibited higher cell wall invertase (CWIN) activity in flowers and young fruits and partitioned more sucrose to fruits but less to vegetative tissues as compared to the HS line, independent of leaf photosynthetic capacity. Upon 2-, 4-, or 24-h exposure to day or night temperatures of 5 degrees C or more above 25/20 degrees C, cell wall (CWIN) and vacuolar invertases (VIN), but not sucrose synthase (SuSy), activities in young fruit of the HT line were significantly higher than those of the HS line. The HT line had a higher level of transcript of a CWIN gene, Lin7, in 5-day fruit than the HS line under control and heat stress temperatures. Interestingly, heat induced transcription of an invertase inhibitor gene, INVINH1, but reduced its protein abundance. Transcript levels of LePLDa1, encoding phospholipase D, which degrades cell membranes, was less in the HT line than in the HS line after exposure to heat stress. The data indicate that high invertase activity of, and increased sucrose import into, young tomato fruit could contribute to their heat tolerance through increasing sink strength and sugar signalling activities, possibly regulating a programmed cell death pathway. PMID- 22105848 TI - Environmental impact assessment of Attenda abattoir, Ogbomoso southwestern Nigeria on surface and groundwater quality using geo-electrical imaging and microbiological analysis. AB - The impact of Attenda abattoir, Ogbomoso southwestern Nigeria on four water sources was investigated using geoelectrical imaging and microbiological analysis. 2D electrical resistivity imaging indicated groundwater contamination by leachate from the abattoir. Electrical resistivity values measured by the traverse run directly on the waste dump and other areas impacted by the waste from the abattoir are generally very low (6.68-16.7 Omegam) in comparison to other positions (135-288 Omegam). The total viable bacteria count of the water samples ranged from 0.49 * 10(6) to 2.85 * 10(8) cfu/ml and all samples are contaminated with coliforms with the most probable number (MPN)/100 ml ranging from 110 to >= 1,600 MPN/100 ml. Among bacteria isolated from the study site (n = 95), resistance to eight antibiotics ranged from 35.8% to 94%. In addition, 85% of Streptococcus agalactiae (n = 31) and Staphylococci (n = 9) showed haemolytic activity while 92% of all isolates showed beta-lactamase activity. These results suggest that operations of the abattoir may impact negatively on surrounding aquatic ecosystem and endanger the health of surrounding residents who use water from the wells for domestic purposes. Furthermore, such aquatic ecosystems may serve as reservoir of antibiotic resistant bacteria. PMID- 22105849 TI - Preconcentration of Zn2+ and Cu2+ ions from food and vegetable samples using modified activated carbon. AB - In this work, two N/S-containing chelating agents 2-(4 methoxybenzylideneamino)thiophenol (2-4-MBAT) and 2-(4-chlorobenzylideneamino) benzenethiol (2-4-CBABT) were synthesized as new sorbents and were used for preconcentration of Zn(2+) and Cu(2+) ions in food and vegetable samples. In the proposed procedure, the trace amount of Zn(2+) and Cu(2+) ions from 250 mL of sample solution at pH = 5.0 was preconcentrated by 1 g of activated carbon (AC) loaded with 15 mg of 2-4-MBAT and 2-4-CBABT separately. The breakthrough volumes (maximum sample volume that their metal ions quantitatively can be enriched) for solid-phase extraction (SPE) procedure based on the AC modified with 2-4-MBAT and 2-4-CBABT were 800 and 750 mL, respectively. The sorbed Zn(2+) and Cu(2+) ions were efficiently eluted by 8 mL of 4 mol L(-1) HNO(3) and preconcentration factor of 112.5 and 93.7 and experimental enhancement factor of 30 and 35 ions were obtained for Zn(2+) and Cu(2+), respectively. The application of this enrichment procedure allowed the extraction of trace metal ions with recoveries exceeding of 90%. PMID- 22105850 TI - Minimal ensembles of side chain conformers for modeling protein-protein interactions. AB - The goal of this article is to reduce the complexity of the side chain search within docking problems. We apply six methods of generating side chain conformers to unbound protein structures and determine their ability of obtaining the bound conformation in small ensembles of conformers. Methods are evaluated in terms of the positions of side chain end groups. Results for 68 protein complexes yield two important observations. First, the end-group positions change less than 1 A on association for over 60% of interface side chains. Thus, the unbound protein structure carries substantial information about the side chains in the bound state, and the inclusion of the unbound conformation into the ensemble of conformers is very beneficial. Second, considering each surface side chain separately in its protein environment, small ensembles of low-energy states include the bound conformation for a large fraction of side chains. In particular, the ensemble consisting of the unbound conformation and the two highest probability predicted conformers includes the bound conformer with an accuracy of 1 A for 78% of interface side chains. As more than 60% of the interface side chains have only one conformer and many others only a few, these ensembles of low-energy states substantially reduce the complexity of side chain search in docking problems. This approach was already used for finding pockets in protein-protein interfaces that can bind small molecules to potentially disrupt protein-protein interactions. Side-chain search with the reduced search space will also be incorporated into protein docking algorithms. PMID- 22105851 TI - Hypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience. AB - The landmark Stupp study demonstrated a survival advantage with concomitant and adjuvant temozolomide (TMZ) with standard radiotherapy (RT) in glioblastoma multiforme (GBM) patients but excluded those older than 70 years. The prospective Roa study of older GBM patients treated with hypofractionated 3-week course RT demonstrated equivalence to standard 6-week course RT. Taken together, these trials suggest hypofractionated RT with TMZ may be a reasonable treatment option for elderly GBM patients. We conducted a retrospective review of GBM patients (age >=60 years) treated with hypofractionated RT and temozolomide at our institution between 2000 and 2010. We identified 112 patients who received hypofractionated RT, with 57 receiving concurrent and adjuvant TMZ and 55 without concurrent chemotherapy. Of the 55 patients who received hypofractionated RT alone initially, 24 subsequently received TMZ as salvage treatment at time of progression. Among the concurrent RT + TMZ patients, mean age was 70 years (range 60-86), median KPS was 80 (range 30-100) and 24/57 (42%) received prior debulking surgery. Median overall survival (OS) among the RT + TMZ patients was 6.9 months (95% CI, 4.5-8.6). Patients without concurrent chemotherapy were similar in demographics (age, sex, corticosteroid use, KPS) except 34/55 (62%) were debulked (P-value 0.045.) Median OS was 9.3 months (95% CI, 5.9-11.8) (P-value 0.351). Sub group analysis revealed patients treated with initial hypofractionated radiation with salvage TMZ had increased median OS of 13.3 months (95% CI, 9.9-19.3) (P value 0.012). Our results suggest concurrent and adjuvant TMZ does not confer a survival benefit in elderly GBM patients. A sequential approach may be a more effective and efficient strategy by selecting responding patients who may benefit most from subsequent salvage chemotherapy. PMID- 22105852 TI - Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. AB - Rapamycin, a specific inhibitor for mTOR complex 1, is an FDA-approved immunosuppressant for organ transplant. Recent developments have raised the prospect of using rapamycin to treat cancer or diabetes and to delay aging. It is therefore important to assess how rapamycin treatment affects glucose homeostasis. Here, we show that the same rapamycin treatment reported to extend mouse life span significantly impaired glucose homeostasis of aged mice. Moreover, rapamycin treatment of lean C57B/L6 mice reduced glucose-stimulated insulin secretion in vivo and ex vivo as well as the insulin content and beta cell mass of pancreatic islets. Confounding the diminished capacity for insulin release, rapamycin decreased insulin sensitivity. The multitude of rapamycin effects thus all lead to glucose intolerance. As our findings reveal that chronic rapamycin treatment could be diabetogenic, monitoring glucose homeostasis is crucial when using rapamycin as a therapeutic as well as experimental reagent. PMID- 22105853 TI - TNFR2 on non-haematopoietic cells is required for Foxp3+ Treg-cell function and disease suppression in EAE. AB - The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3(+) Treg cells both in the spinal cord and peripheral lymphoid organs. Treg cells from TNFR2 deficient animals developing EAE show decreased proliferative and suppressive functions, both ex vivo and in vivo, and appear responsible for the exacerbated non-remitting disease, as evidenced by phenotypic rescue following adoptive transfer of Treg cells from WT but not TNFR2(-/-) donors. Reciprocal BM transplantation experiments between WT and TNFR2-deficient mice demonstrated that the capacity of TNFR2 to support Treg-cell expansion and function during EAE is non-intrinsic to Treg or other haematopoietic cells but requires expression of TNFR2 in radiation-resistant cells of the host. These results reveal a previously unsuspected role for non-haematopoietic TNFR2 in modulating Treg-cell expansion and immune suppression during development of autoimmunity and suggest that a similar mechanism may affect chronicity and relapses characterizing human autoimmune disease, including MS. PMID- 22105854 TI - Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. AB - Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). CONCLUSION: The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths. PMID- 22105855 TI - Implantation of a Melody valve in tricuspid position. AB - A transcatheter pulmonary valve (Melody) was implanted within a stenotic biological valve prosthesis in tricuspid position, as an alternative to the fourth major cardiac surgery in a 12-year-old girl. There were no complications. The postinterventional result was very good. PMID- 22105856 TI - NIP45 negatively regulates RANK ligand induced osteoclast differentiation. AB - Receptor activator of NF-kappaB ligand (RANKL)-RANK receptor signaling to induce NFATc1 transcription factor is critical for osteoclast differentiation and bone resorption. RANK adaptor proteins, tumor necrosis factor receptor-associated factors (TRAFs) play an essential role in RANKL signaling. Evidence indicates that NIP45 (NFAT interacting protein) binds with TRAFs and NFATc2. We therefore hypothesized that NIP45 regulates RANKL induced osteoclast differentiation. In this study, we demonstrate that RANKL treatment down regulates NIP45 expression in mouse bone marrow derived pre-osteoclast cells. Lentiviral (pGIPZ) mediated shRNA knock-down of NIP45 expression in RANKL stimulated pre-osteoclast cells resulted in increased levels of NFATc1, NFATc2, and TRAF6 but not TRAF2 expression compared to control shRNA transduced cells. Also, NIP45 suppression elevated p-IkappaB-alpha levels and NF-kappaB-luciferase reporter activity. Confocal microscopy demonstrated NIP45 colocalized with TRAF6 in the cytosol of osteoclast progenitor cells. In contrast, RANKL stimulation induced NIP45 nuclear translocation and colocalization with NFATc2 in these cells. Coimmuneprecipitation assay demonstrated NIP45 binding with NFATc2 but not NFATc1. We further show that shRNA knock-down of NIP45 expression in pre osteoclast cells significantly increased RANKL induced osteoclast differentiation and bone resorption activity. Taken together, our results indicate that RANKL signaling down regulates NIP45 expression and that NIP45 is a negative regulator of osteoclast differentiation. PMID- 22105857 TI - Testing theories of post-error slowing. AB - People tend to slow down after they make an error. This phenomenon, generally referred to as post-error slowing, has been hypothesized to reflect perceptual distraction, time wasted on irrelevant processes, an a priori bias against the response made in error, increased variability in a priori bias, or an increase in response caution. Although the response caution interpretation has dominated the empirical literature, little research has attempted to test this interpretation in the context of a formal process model. Here, we used the drift diffusion model to isolate and identify the psychological processes responsible for post-error slowing. In a very large lexical decision data set, we found that post-error slowing was associated with an increase in response caution and-to a lesser extent-a change in response bias. In the present data set, we found no evidence that post-error slowing is caused by perceptual distraction or time wasted on irrelevant processes. These results support a response-monitoring account of post error slowing. PMID- 22105858 TI - Renal anomalies in Alagille syndrome: a disease-defining feature. AB - Alagille syndrome (ALGS) is an autosomal dominant condition, primarily caused by mutations in JAGGED1. ALGS is defined by cholestatic liver disease, cardiac disease and involvement of the face, skeleton, and eyes with variable expression of these features. Renal involvement has been reported though not formally described. The objective of this study was to systematically characterize the renal involvement in ALGS. We performed a retrospective review of 466 JAGGED1 mutation-positive ALGS patients. Charts were reviewed for serum biochemistries, renal ultrasounds or other imaging, urinalysis, and clinical reports from pediatric nephrologists. The clinical data were reviewed by two pediatric hepatologists and a pediatric nephrologist. Of 466 charts reviewed we found 187 yielded evaluable renal information. Of these, 73/187 were shown to have renal involvement, representing 39% of the study cohort. Renal dysplasia was the most common anomaly seen. Genotype analysis of the JAGGED1 mutations in the patients with and without renal involvement did not reveal an association with mutation type. From the study we concluded that renal involvement has a prevalence of 39% in ALGS in our evaluable patients. Renal dysplasia is the most common renal anomaly. This finding correlates with the known role of the Notch pathway in glomerular development. Since renal disease of the type seen in ALGS can impair growth and impact liver transplantation, there is a clear need for a prospective study of renal involvement in ALGS and the development of guidelines for evaluation and management. These data also suggest that renal involvement be considered the sixth defining criterion for ALGS. PMID- 22105859 TI - Stacked fluoroaromatics as supramolecular synthons for programming protein dimerization specificity. PMID- 22105860 TI - Molecular alterations associated with the NMDA preconditioning-induced neuroprotective mechanism against glutamate cytotoxicity. AB - Exposure of the brain to sub-lethal concentrations of glutamate activates, through stimulation of the glutamate N-methyl-D: -aspartate (NMDA) receptors, an endogenous brain protective mechanism (NMDA preconditioning) against glutamate cytotoxicity and various other injurious stimuli. Selective drug activation of this mechanism is considered to be a promising neuroprotective treatment against the devastating consequences of stroke and other traumatic brain insults. Although some properties of this mechanism have been characterized, many aspects concerning it are yet to be elucidated. In order to improve our understanding of the NMDA preconditioning mechanism, we have established an experimental in vitro model of primary rat neuronal cultures, in which NMDA preconditioning completely abolishes the glutamic acid insult-induced neuronal damage. Employing this model, we have monitored in the present study the level of activation or expression of several signal transducing proteins, assumed to be involved in the NMDA-activated protective mechanism, at various time points during the three successive periods of the model, preconditioning, insult, and reperfusion. The results demonstrated that the NMDA preconditioning-induced neuroprotective mechanism is associated with inactivation of p66ShcA, prevention of the insult-induced inactivation of Src, activation of AKT, inactivation followed by reactivation of FKHR-L1, and with increased expression of p52ShcA, EGFR, and MnSOD. The essential role of Src activity in the protective mechanism was further indicated by the demonstration that decreasing Src activation level by the Src inhibitor PP2 attenuated the NMDA preconditioning-induced protection. The alterations detailed above in the activation status or level of expression of the studied proteins are suggested to be part of the NMDA preconditioning-induced neuroprotective mechanism. PMID- 22105861 TI - Mutagenesis of barley malting quality QTLs with Ds transposons. AB - Various functional genomic tools are being used to identify and characterize genes in plants. The Activator/Dissociation (Ac/Ds) transposon-based approach offers great potential, especially in barley, due to its limited success of genetic transformation and its large genome size. The bias of the Ac/Ds system towards genic regions and its tendency toward localized transpositions can greatly enhance the discovery and tagging of genes linked to Ds. Barley is a key ingredient in malting and brewing industry; therefore, gene discovery in relation to malting has an industrial perspective. Malting quality in barley is a complex and quantitatively inherited trait. Two major quantitative trait loci (QTLs) affecting malting quality traits have been located on chromosome 4H. In this study, Ds was reactivated from parent transposants (TNP) lines, TNP-29 and TNP 79, where Ds was mapped in the vicinity of important malting QTLs. Reactivation of Ds was carried out both by conventional breeding and in vitro approaches. A threefold increase in reactivation frequency through the in vitro approach enabled the development of a new genomic resource for the dissection of malting QTL and gene discovery in barley. Identification of unique flanking sequences, using high-efficiency thermal asymmetric interlaced PCR and inverse PCR from these populations, has further emphasized the new location of Ds in the barley genome and provided new transposon mutants especially in beta-GAL1, beta-amylase like gene and ABC transporter for functional genomic studies. PMID- 22105862 TI - Dissociation of hydrophobic and charged nano particles in aqueous guanidinium chloride and urea solutions: a molecular dynamics study. AB - It has been a long history that urea and guanidinium chloride (GdmCl) are used as agents for denaturing proteins. The underlying mechanism has been extensively studied in the past several decades. However, the question regarding why GdmCl is much stronger than urea has seldom been touched. Here, through molecular dynamics simulations, we show that a 4 M GdmCl solution is more able than 7 M urea solution to dissociate both hydrophobic and charged nano-particles (NP). Both urea and GdmCl affect the NPs' aggregation through direct binding to the NP surface. The advantages of GdmCl originate from the net charge of bound guanidinium ions which can generate a local positively charged environment around hydrophobic and negatively charged NPs. This effective coating can introduce Coulombic repulsion between all the NPs. Urea shows certain ability to dissociate hydrophobic NPs. However, in the case of charged NPs, urea molecules located between two opposite-charged NPs will form ordered hydrogen bonds, acting like "glue" which prevents separation of the NPs. Although urea can form hydrogen bonds with either hydrophilic amino acids or the protein backbone, which are believed to contribute to protein denaturation, our findings strongly suggest that this property does not always contribute positively to urea's denaturation power. PMID- 22105863 TI - Composition and bandgap-graded semiconductor alloy nanowires. AB - Semiconductor alloy nanowires with spatially graded compositions (and bandgaps) provide a new material platform for many new multifunctional optoelectronic devices, such as broadly tunable lasers, multispectral photodetectors, broad-band light emitting diodes (LEDs) and high-efficiency solar cells. In this review, we will summarize the recent progress on composition graded semiconductor alloy nanowires with bandgaps graded in a wide range. Depending on different growth methods and material systems, two typical nanowire composition grading approaches will be presented in detail, including composition graded alloy nanowires along a single substrate and those along single nanowires. Furthermore, selected examples of applications of these composition graded semiconductor nanowires will be presented and discussed, including tunable nanolasers, multi-terminal on-nanowire photodetectors, full-spectrum solar cells, and white-light LEDs. Finally, we will make some concluding remarks with future perspectives including opportunities and challenges in this research area. PMID- 22105864 TI - Aquaporins in human breast cancer: identification and involvement in carcinogenesis of breast cancer. AB - BACKGROUND AND OBJECTIVES: Aquaporins (AQPs) play important roles in water and glycerol transport. Recently, the role of AQPs in human carcinogenesis has become an area of great interest. However, little is known about the function of AQPs in human breast cancer. The aim of this study was to investigate the expression profile of AQPs in human breast cancer and its significance. METHODS: In this study, we screened the expression profile of AQP0-12 in breast cancer tissues and corresponding normal tissues by RT-PCR, Western blotting and immunohistochemistry. RESULTS: AQP1, 3-5, and 10-12 were expressed in human breast cancer and/or normal breast tissues, and AQP1 and 3-5 exhibited differential expression. AQP1 was expressed in cell membranes and its expression was higher in cancer than that in normal tissues. AQP4 was expressed in the cell membrane and cytoplasm and was detected markedly stronger in normal than in cancer tissues. AQP5 was expressed mainly in cell membranes in carcinoma tissues, but was almost absent in normal breast tissues. Expression of AQP5 was associated with cellular differentiation, lymph node invasion, and clinicopathological staging. CONCLUSIONS: These observations suggested that several subtypes of the AQP family play a role in human breast carcinogenesis. PMID- 22105865 TI - Electrospun polylactide/poly(ethylene glycol) hybrid fibrous scaffolds for tissue engineering. AB - The biodegradable polylactide/poly(ethylene glycol) (PLA/PEG) hybrid membranes were fabricated via electrospinning of PLA/PEG solution. Their structures and properties were investigated by scanning electron microscopy, differential scanning calorimetry, and water contact angle. In vitro hydrolytic degradation showed that PEG content influenced the degradation rate of the PLA/PEG hybrid mats. The mechanical property was measured by tensile test and the result revealed that the addition of PEG had an obvious plasticization on PLA matrix. In vitro biocompatibility was investigated by culturing cell on the scaffolds and MTT assay. The results indicated that the cell could attach and proliferate on the membranes, so confirmed that the PLA/PEG hybrid membrane had good biocompatibility, and it could be a promising biomaterial for tissue engineering applications. PMID- 22105866 TI - Differential mesengenic potential and expression of stem cell-fate modulators in mesenchymal stromal cells from human-term placenta and bone marrow. AB - Placenta has attracted increasing attention over the past decade as a stem cell source for regenerative medicine. In particular, the amniochorionic membrane has been shown to harbor populations of mesenchymal stromal cells (MSCs). In this study, we have characterized ex vivo expanded MSCs from the human amniotic (hAMSCs) and chorionic (hCMSCs) membranes of human full-term placentas and adult bone marrow (hBMSCs). Our results show that hAMSCs, hCMSCs, and hBMSCs express typical mesenchymal (CD73, CD90, CD105, CD44, CD146, CD166) and pluripotent (Oct 4, Sox2, Nanog, Lin28, and Klf4) markers but not hematopoietic markers (CD45, CD34). Ex vivo expanded hAMSCs were found to be of fetal origin, while hCMSCs cultures contained only maternal cells. Cell proliferation was significantly higher in hCMSCs, compared to hAMSCs and hBMSCs. Integrin profiling revealed marked differences in the expression of alpha subunits between the three cell sources. Cadherin receptors were consistently expressed on a subset of progenitors (ranging from 1% to 60%), while N-CAM (CD56) was only expressed in hAMSCs and hCMSCs but not in hBMSCs. When induced to differentiate, hAMSCs and hCMSCs displayed strong chondrogenic and osteogenic differentiation potential but very limited capacity for adipogenic conversion. In contrast, hBMSCs showed strong differentiation potential along the three lineages. These results illustrate how MSCs from different ontological sources display differential expression of cell-fate mediators and mesodermal differentiation capacity. PMID- 22105867 TI - Best practices for justifying fossil calibrations. PMID- 22105868 TI - Phytochemical, antioxidant and anti-alpha-glucosidase activity evaluations of Bergenia cordifolia. AB - The antioxidant, anti-alpha-glucosidase and anticholinesterase activity of the leaves and rhizomatous extract of Bergenia cordifolia were investigated. The rhizomes extract that showed a higher degree of 1,1-diphenyl-2-picrylhydrazyl radical scavenging and anti-alpha-glucosidase activity than reference compounds (rutin and acarbose respectively) were subjected to phytochemical analysis. The study revealed that previously unknown minor constituents from the plant, (+) catechin 3-O-gallate, (+)-catechin 3,5-di-O-gallate and 1,2,4,6-tetra-O-galloyl beta-D-glucopyranoside, were the radical scavenging and anti-alpha-glucosidase principles. These compounds as well as the crude extracts were weak acetylcholienesterase inhibitors, suggesting a higher degree of selectivity against alpha-glucosidase enzyme. In comparison with the minor constituents, the previously known major constituents of the plant, bergenin and arbutin, were poor radical scavengers and enzyme inhibitors. PMID- 22105869 TI - Bilateral sensory permanent hearing loss after palliative hypoplastic left heart syndrome operation. AB - BACKGROUND: Bilateral sensory permanent hearing loss (PHL) has been reported after neonatal respiratory failure but has rarely been noted in survivors after cardiac operations. We report the prevalence and severity of PHL after Norwood right ventricular-pulmonary artery shunt for hypoplastic left heart syndrome (HLHS), document progressive loss, and explore markers of acute illness and ototoxic medications for PHL. METHODS: This interprovincial longitudinal outcome study after neonatal complex cardiac operations at Stollery Children's Hospital, Edmonton, Alberta, Canada, 2002 to 2007, completed repeated diagnostic audiologic assessments for all survivors by registered pediatric-experienced audiologists. Demographic, surgical, and perisurgical variables, including ototoxic medications, were collected. The association of potentially predictive variables with PHL and its severity were determined by univariate analysis and multiple logistic and linear regression analysis. RESULTS: At an age older than 3.5 years, progressive PHL was present in 12 of 42 survivors (28.6%, 95% confidence interval, 16.2% to 44.8%; mortality, 20.9%). Overall lowest partial pressure of arterial oxygen (odds ratio, 1.315; 95% confidence interval, 1.051 to 1.506), and cumulative dose of furosemide given as bolus (odds ratio, 1.062; 95% confidence interval, 1.018 to 1.109) combined to predict PHL and gave 39% of the variance of PHL severity. Antibiotics and neuromuscular blockers were not associated with PHL. CONCLUSIONS: Monitoring outcomes of neonates after HLHS surgery revealed unexpected PHL associated with hypoxia and bolus administration of furosemide. As survival improves, close follow-up is necessary to identify outcomes and seek modifiable predictive variables. Changes in the mode of furosemide administration may prevent this complication. PMID- 22105870 TI - Detection, diagnosis, and prevention of child abuse: the role of the pediatrician. AB - It is the pediatrician's role to promote the child's well-being and to help parents raise healthy, well-adjusted children. Today's pediatricians are confronted with a patient population in which there is a high prevalence of child abuse in its different presentations (physical, sexual, and psychological abuse and/or neglect). The immediate and long-term consequences of child abuse often are lifelong and even life-threatening in its most dramatic presentation. Unfortunately, detection of child abuse remains a difficult challenge for many physicians but also for the "well-trained" pediatrician, leaving many abused children unreported. This paper addresses the important role pediatricians can play in the detection, diagnosis, and prevention of child maltreatment. PMID- 22105871 TI - New aspects in the clinical spectrum of neonatal lupus. AB - Neonatal lupus erythematosus (NLE) is a rare, passively acquired autoimmune disease, caused by maternal autoantibodies. Characteristic clinical features of NLE are transient rash and congenital heart block (CHB), but also hematological abnormalities and hepatobiliary dysfunction may occur. Complications to the transient dermatitis are rarely described. We describe two patients with NLE and cutaneous manifestations. Both patients had involvement of the sun-protected genital skin and soles. New manifestations of NLE were gastrointestinal bleeding in one patient despite normal coagulation parameters, but with mucosal telangiectatic lesions found on sigmoidoscopy. In addition, one patient developed painful atrophy after plantar dermatitis on follow-up with need of orthopedic footwear. CHB was not found. In conclusion, NLE may be complicated with sigmoidal telangiectasia with rectal bleeding and painful plantar atrophy. PMID- 22105872 TI - Dose of intravenous lipids and rate of bacterial clearance in preterm infants with blood stream infections. AB - BACKGROUND: Intravenous lipid emulsion (IVLE) is an integral part of the total parenteral nutrition (TPN) regimen in neonates. The use of IVLE during sepsis is the subject of controversy because it may interfere with phagocytosis of microbes by macrophages and may lead to significant hypertriglyceridemia. OBJECTIVE: This paper aims to study the rate of clearance of bacteria in relation to dose of IVLE administered to preterm infants with blood stream infections (BSIs). METHODS: Preterm infants (mean gestational age +/- SD, 32.0 +/- 2.5 weeks) with culture proven BSI and receiving TPN were randomized to two groups. The first group (n = 22) was given the usual dose of IVLE according to a standard protocol (starting from 0.5 g kg(-1) day(-1) and gradually increased by 1 g kg(-1) day(-1) to a maximum of 3.5 g kg(-1) day(-1)); in the second group (n = 20), IVLE were restricted at a dose of 1 g kg(-1) day(-1). Samples for blood cultures were withdrawn every 24 h until a negative culture was obtained. CRP was measured daily until its normalization. Serum triglycerides were monitored daily. RESULTS: The rate of bacterial clearance was significantly more rapid in the restricted dose IVLE group compared to the standard-dose group [72 (48-120) versus 144 (72 168) h, p = 0.001]. Daily weight increment was significantly greater in the standard-dose IVLE group compared to the restricted-dose IVLE group [25 (6.9 31.9) versus 0.9 (-3.3-11.7) g, p = 0.0001]. The duration of antibiotic use was significantly reduced in the restricted-dose IVLE group compared with the standard-dose IVLE group (10.0 +/- 4.5 vs 14.9 +/- 5.1 days; p = 0.003). The durations of TPN, mechanical ventilation, and hospitalization were not significantly different between groups. CONCLUSIONS: Restriction of the dose of IVLE to 1 g kg(-1) day(-1) in preterm infants with BSI is associated with earlier negative blood cultures and reduced duration of antibiotic therapy but was associated with a lower daily weight increments. PMID- 22105873 TI - Decision making in the management of hydroceles in infants and children. AB - The aim of this article was to establish a ground for evidence-based decision making in dealing with hydroceles, according to the age of the child and the presenting signs and symptoms. This prospective cohort study was conducted at Al Kademyia Teaching Hospital in Baghdad, Iraq, during the period from December 2001 to December 2005. There were two groups of patients: group 1 involved 121 patients that presented with hydroceles at less than 1 year of age that were followed up to their first birthday to monitor the fate of hydroceles. Group 2 involved 140 patients, 1-12 years of age, who presented with hydroceles and had surgery. Their age, the affected side, diurnal changes in size, and the findings at surgery were recorded. In group 1, 89% of patients with hydroceles had spontaneous resolution or showed marked improvement during the first year of life and only 11% required an operation. The indications for surgery were the presence of an associated inguinal hernia (7%) and development of a huge hydrocele (3%). In group 2, 83% of patients with hydroceles presented within the first 5 years of age. Diurnal changes in the size of hydroceles were encountered in 92% of cases. CONCLUSION: 89% of patients with infantile hydrocele will have a spontaneous resolution owing to the ongoing changes in the patent processus vaginalis. Surgical intervention in the first year of life is only required for those who have an associated inguinal hernia and for those with hydroceles that become huge in size. PMID- 22105874 TI - XY1Y2 chromosome system in Salinomys delicatus (Rodentia, Cricetidae). AB - Salinomys delicatus is considered a rare species due to its restricted and patchy distribution, poor records and low abundances. It is also the phyllotine with the lowest known diploid chromosome number (2n = 18), however its sex chromosome system has never been described. Here, we studied the chromosomes of six females and three males with bands G, C, DAPI/CMA(3) and meiosis. In males, the chromosome number was 2n = 19, with one large metacentric X-chromosome and two medium-sized acrocentrics absent in females. The karyotype of females was the same as previously described (2n = 18, FN = 32), with X-chromosomes being metacentric and the largest elements of the complement. In males, the two acrocentrics and the large metacentric form a trivalent in meiotic prophase. This indicates that S. delicatus has XY(1)Y(2) sex chromosomes, which is confirmed by G and DAPI bands. Constitutive heterochromatin (CH) is restricted to small pericentromeric blocks in all chromosomes. The X-chromosome shows the largest block of centromeric CH, which could favor the establishment of this X-autosome translocation. This sex chromosome system is rare in mammals and, compared with other phyllotine rodents, S. delicatus seems to have undergone a major chromosome restructuring during its karyotypic evolution. PMID- 22105875 TI - Genetic diversity of Ovis aries populations near domestication centers and in the New World. AB - Domestic sheep in Kazakhstan may provide an interesting source of genetic variability due to their proximity to the center of domestication and the Silk Route. Additionally, those breeds have never been compared to New World sheep populations. This report compares genetic diversity among five Kazakhstan (KZ) and 13 United States (US) sheep breeds (N = 442) using 25 microsatellite markers from the FAO panel. The KZ breeds had observed and expected measures of heterozygosity greater than 0.60 and an average number of alleles per locus of 7.8. In contrast, US sheep breeds had observed heterozygosity ranged from 0.37 to 0.62 and had an average number of alleles of 5.7. A Bayesian analysis indicated there were two primary populations (K = 2). Surprisingly, the US breeds were near evenly split between the two clusters, while all of the KZ breeds were placed in one of the two clusters. Pooling breeds within country of sample origin showed KZ and US populations to have similar levels of expected heterozygosity and the average number of alleles per locus. The results of breeds pooled within country suggest that there was no difference between countries for these diversity measures using this set of neutral markers. This finding suggests that populations' geographically isolated from centers of domestication can be more diverse than previously thought, and as a result, conservation strategies can be adjusted accordingly. Furthermore, these results suggest there may be limited need for countries to alter the protocols for trade and exchange of animal genetic resources that are in place today, since no one population has a unique set of private alleles. PMID- 22105876 TI - Breed-specific ancestry studies and genome-wide association analysis highlight an association between the MYH9 gene and heat tolerance in Alaskan sprint racing sled dogs. AB - Alaskan sled dogs are a genetically distinct population shaped by generations of selective interbreeding with purebred dogs to create a group of high-performance athletes. As a result of selective breeding strategies, sled dogs present a unique opportunity to employ admixture-mapping techniques to investigate how breed composition and trait selection impact genomic structure. We used admixture mapping to investigate genetic ancestry across the genomes of two classes of sled dogs, sprint and long-distance racers, and combined that with genome-wide association studies (GWAS) to identify regions that correlate with performance enhancing traits. The sled dog genome is enhanced by differential contributions from four non-admixed breeds (Alaskan Malamute, Siberian Husky, German Shorthaired Pointer, and Borzoi). A principal components analysis (PCA) of 115,000 genome-wide SNPs clearly resolved the sprint and distance populations as distinct genetic groups, with longer blocks of linkage disequilibrium (LD) observed in the distance versus sprint dogs (7.5-10 and 2.5-3.75 kb, respectively). Furthermore, we identified eight regions with the genomic signal from either a selective sweep or an association analysis, corroborated by an excess of ancestry when comparing sprint and distance dogs. A comparison of elite and poor-performing sled dogs identified a single region significantly associated with heat tolerance. Within the region we identified seven SNPs within the myosin heavy chain 9 gene (MYH9) that were significantly associated with heat tolerance in sprint dogs, two of which correspond to conserved promoter and enhancer regions in the human ortholog. PMID- 22105877 TI - Genome-wide association studies for multiple diseases of the German Shepherd Dog. AB - The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3. Results for DM confirm a major locus encompassing SOD1, in which an associated point mutation was previously identified, but do not suggest modifier loci. Several SNPs on Chr 12 are associated with ME and a 4.7 Mb haplotype block is present in affected dogs. Analysis of additional ME cases for a SNP within the haplotype provides further support for this association. Results for PAA indicate more complex genetic underpinnings. Several regions on multiple chromosomes reach genome-wide significance. However, no major locus is apparent and only two associated haplotype blocks, on Chrs 7 and 12 are observed. These data suggest that PAA may be governed by multiple loci with small effects, or it may be a heterogeneous disorder. PMID- 22105878 TI - Scar tissue classification using nonlinear optical microscopy and discriminant analysis. AB - This paper addresses the scar tissue maturation process that occurs stepwise, and calls for reliable classification. The structure of collagen imaged by nonlinear optical microscopy (NLOM) in post-burn hypertrophic and mature scar, as well as in normal skin, appeared to distinguish these maturation steps. However, it was a discrimination analysis, demonstrated here, that automated and quantified the scar tissue maturation process. The achieved scar classification accuracy was as high as 96%. The combination of NLOM and discrimination analysis is believed to be instrumental in gaining insight into the scar formation, for express diagnosis of scar and surgery planning. PMID- 22105879 TI - MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial infarction pAtieNts-(GUARDIAN) trial: study design and rationale. AB - BACKGROUND: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). In this setting, manual thrombectomy (MT) resulted in better perfusion and clinical outcomes when compared with "conventional" PCI (direct stenting or stenting after predilation). MGuard net protective stent (MGS, Inspire-MD, Tel-Aviv, Israel) is a new bare-metal stent (BMS) with a polyethylene theraphthalate mesh coverage anchored to the external surface of the struts aiming to minimize distal embolization during PCI. PURPOSE: We intend to determine whether MGS implantation is comparable with a strategy of MT pretreatment followed by BMS deployment. STUDY DESIGN: The MGUard versus bAre metal stents plus manual thRombectomy in ST-elevation myocarDial Infarction pAtieNts (GUARDIAN) is a multicentre, prospective, randomized, noninferiority, open-label trial with a planned inclusion of 556 STEMI patients. Patients are assigned to treatment with MGS or MT pretreatment followed by BMS implantation in the infarct-related artery. All patients are treated medically according to current international guidelines. Randomization is performed before coronary angiography. The primary endpoint is complete (>= 70%) ST-segment resolution at 60 min after PCI. Secondary endpoints are thrombolysis in myocardial infarction (TIMI) coronary flow grade >= 2, corrected TIMI frame count <23, myocardial blush grade of the infarct related area >= 2, and major adverse cardiac events rate at 30-day, 6-month, and 1-year follow-up. A cardiac magnetic resonance imaging substudy is planned to investigate microvascular obstruction and infarct size area reduction, at prespecified time-points, among 80 consecutive patients enrolled. CONCLUSIONS: If MGS implantation is noninferior to a strategy of MT pretreatment followed by BMS deployment, it will lend support to the use of this treatment as another possible option for STEMI patients undergoing PCI. PMID- 22105880 TI - Molecular chaperones in mammary cancer growth and breast tumor therapy. AB - Heat shock protein (HSP) levels are elevated in breast cancer and are molecular targets for novel therapies. HSPs were first observed as proteins induced in massive amounts in normal cells exposed to stresses that lead to protein denaturation. Their expanded expression in mammary carcinoma appears to be largely due to the proliferation of malfolded mutant proteins and overexpressed oncoproteins that trigger transcription of HSP genes. HSPs play major roles in malignant transformation and progression mediated through their intrinsic molecular chaperone properties. These permit the emergence of new malignant traits through the facilitated accumulation of altered oncoproteins. The elevation of HSP concentrations in mammary carcinoma is at least partially dependent on heat shock transcription factor 1 (HSF1), a protein that responds to unfolded proteins and leads to HSP transcription. HSF1 activation has additional downstream activities, crucial for emergence of the breast cancer phenotype and these include activated cell signaling, HSP-mediated ability to evade apoptosis and senescence and an HSF1-dependent bias in transcriptional activity towards a metastatic phenotype. The HSPs are currently being targeted in breast cancer therapy and effective drugs for Hsp90 have been synthesized and evaluated in clinical trial. Mammary carcinoma cells also contain abundant quantities of HSP tumor antigen complexes and these complexes are being used to develop effective tumor vaccine approaches that provide personalized therapy for each individual's cancer. PMID- 22105881 TI - Longer simulations sample larger subspaces of conformations while maintaining robust mechanisms of motion. AB - Recent studies suggest that protein motions observed in molecular simulations are related to biochemical activities, although the computed time scales do not necessarily match those of the experimentally observed processes. The molecular origin of this conflicting observation is explored here for a test protein, cyanovirin-N (CV-N), through a series of molecular dynamics simulations that span a time range of three orders of magnitude up to 0.4 MUs. Strikingly, increasing the simulation time leads to an approximately uniform amplification of the motional sizes, while maintaining the same conformational mechanics. Residue fluctuations exhibit amplitudes of 1-2 A in the nanosecond simulations, whereas their average sizes increase by a factor of 4-5 in the microsecond regime. The mean-square displacements averaged over all residues (y) exhibit a power law dependence of the form y ? x(0.26) on the simulation time (x). Essential dynamics analysis of the trajectories, on the other hand, demonstrates that CV-N has robust preferences to undergo specific types of motions that already can be detected at short simulation times, provided that multiple runs are performed and carefully analyzed. PMID- 22105882 TI - Retrospective analysis of the clinical manifestations and survival of Korean patients with mucopolysaccharidosis type II: emphasis on the cardiovascular complication and mortality cases. AB - Hunter syndrome (mucopolysaccharidosis II, MPS II) is a rare, X-linked disorder of glycosaminoglycan (GAG) catabolism caused by a deficiency in the activity of the lysosomal enzyme, iduronate-2-sulfatase (I2S). In this study, the medical records of 75 Korean patients with Hunter syndrome (74 males, 1 female) were retrospectively reviewed to investigate the frequency of organ involvement and survival at a single center. The three most common symptoms of organ involvement were hepatosplenomegaly (99%), facial dysmorphism (97%), and frequent otitis media (91%). Cardiovascular involvement was also common including valvular abnormalities (89%), left ventricular hypertrophy (68%), and hypertension (30%). The 19 patients who died had a median age of 16.8 years at the time of death. Four of them died within 1 year of the start of enzyme replacement therapy; autopsy showed myocardial infarction with severe coronary artery disease in one patient. Two other patients died due to pneumonia and sleep apnea. In one case, the cause of death was not investigated. The high incidence of hypertension, and the presence of valvular heart disease indicates that close cardiac monitoring is mandatory in all patients with Hunter syndrome, especially relatively older patients even if they are being treated with enzyme replacement therapy. PMID- 22105883 TI - [Assessment of whiplash and cervical spine injury]. AB - Formulating an expert opinion on whiplash injuries requires that consideration be given to biomechanical, orthopedic, neurological, psychiatric and medicolegal aspects. The greatest difficulties are encountered in cases of mild whiplash where patients complain of constant pain without any physical correlative. Diverse assessments and principles for approving a claim are reflected in the fact that the prevalence of chronic spine pain after whiplash injuries (late whiplash syndrome) varies between 16% and 71% in different countries, and the proportion of whiplash injuries involved in petitions for compensation differs greatly across Europe (UK 75%, Germany 47%, Finland 8.5% and France 3% of all personal injuries).Important biomechanical, orthopedic, neurological, psychiatric and medicolegal aspects of expert testimony on whiplash associated disorders (WAD) are delineated. PMID- 22105884 TI - [Ischemic stroke patients following intravenous thrombolysis. Outcome in a regional stroke center]. AB - BACKGROUND: We wanted to compare the outcome following IV thrombolysis in our patients with ischemic stroke with the outcome reported from the phase 3 registration trials and other large trials. PATIENTS AND METHODS: From January 2008 through December 2009 we treated 225 patients with ischemic stroke with IV thrombolysis. Retrospectively, we analyzed their clinical data upon admission, during their stay, and upon discharge with special reference to eligibility criteria for IV thrombolysis, symptomatic hemorrhage, and clinical outcome. RESULTS: The average age of the patients was 74 years, with 34% being older than 80 years. The median time between stroke onset and initiation of treatment was 112 min. The initial median NIHSS was 11 points (Rankin score >= 4 in 79% of patients). The rate of symptomatic hemorrhage was 3%. The median follow-up was 14 days. At the end of the observation period, clinical symptoms had improved in 73% of patients (Rankin score <= 2 in 45% of patients). The mortality rate was 12%. In 55% of patients, IV thrombolysis was off label (age > 80 years in 34% of patients). CONCLUSION: The clinical results of IV thrombolysis in our stroke center are similar to the outcome reported from the registration trials and larger clinical series although we treated off label in more than half of the patients. Even larger studies have since shown that the age limit under 80 years for patients is not reasonable. The eligibility criteria should be adapted to reality at this point. PMID- 22105885 TI - Nanoparticle shape improves delivery: rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG-PCL micelles. PMID- 22105886 TI - Hydroxyureas as noncovalent proteasome inhibitors. PMID- 22105888 TI - Developments in and practical guidelines for tip-enhanced Raman spectroscopy. AB - This feature review provides an overview of the state-of the art and recent developments in tip-enhanced Raman spectroscopy (TERS), in-depth information about the different available types of instruments including their (dis )advantages and capabilities as well as a short glance at a number of samples that have recently been investigated using TERS. Issues concerning the progression of TERS from point spectroscopy to an imaging technique are discussed, as well as problems arising from background and contamination signals. This review is concluded with a short TERS 'user guideline', trying to aid researchers new in the field to properly align and test their own TERS setups. Finally, a short outlook is given and some critical issues are raised that need to be solved by the community sooner or later, in order to promote TERS towards a 'push-button' operation. PMID- 22105887 TI - Injectable polyurethane composite scaffolds delay wound contraction and support cellular infiltration and remodeling in rat excisional wounds. AB - Injectable scaffolds present compelling opportunities for wound repair and regeneration because of their ability to fill irregularly shaped defects and deliver biologics such as growth factors. In this study, we investigated the properties of injectable polyurethane (PUR) biocomposite scaffolds and their application in cutaneous wound repair using a rat excisional model. The scaffolds have a minimal reaction exotherm and clinically relevant working and setting times. Moreover, the biocomposites have mechanical and thermal properties consistent with rubbery elastomers. In the rat excisional wound model, injection of settable biocomposite scaffolds stented the wounds at early time points, resulting in a regenerative rather than a scarring phenotype at later time points. Measurements of wound length and thickness revealed that the treated wounds were less contracted at day 7 compared to blank wounds. Analysis of cell proliferation and apoptosis showed that the scaffolds were biocompatible and supported tissue ingrowth. Myofibroblast formation and collagen fiber organization provided evidence that the scaffolds have a positive effect on extracellular matrix remodeling by disrupting the formation of an aligned matrix under elevated tension. In summary, we have developed an injectable biodegradable PUR biocomposite scaffold that enhances cutaneous wound healing in a rat model. PMID- 22105889 TI - Ovarian tumor-derived ectopic hyperprolactinemia. AB - To describe extreme hyperprolactinemia originating from a pituitary adenoma in the wall of an ovarian dermoid. This is a description of an unusual case and a review of ectopic prolactin production. Ectopic production of prolactin is a rare condition that has been reported in isolated organ system pathology including ovaries. An ovarian dermoid is a benign neoplasm that has the potential for active unregulated endocrine function. Hyperprolactinemia can result from functioning lactotrophs found in ovarian dermoids and can lead to clinical sequelae. Definitive treatment of the condition requires surgical removal of the functioning endocrine tissue. Extreme hyperprolactinemia caused by a pituitary tumor located within a dermoid has not been reported before. We present a case of profound hyperprolactinemia originating from a pituitary adenoma found in the wall of an ovarian dermoid and give a broad overview of the condition and literature. Ectopic prolactin production should always be considered in symptomatic patients found to have elevated serum levels and no findings on brain imaging. PMID- 22105890 TI - The protective role of peroxisome proliferator-activated receptor gamma coactivator-1alpha in hyperthyroid cardiac hypertrophy. AB - Heart failure is a major cause of death throughout the world. Hyperthyroidism has been shown to induce cardiac hypertrophy, which is a contributing factor to heart failure. However, the mechanism underling effect of thyroid hormone is not completely clear. The present study investigates the role of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha) in cardiac hypertrophy induced by Triiodothyronine (T3). We investigated PGC-1alpha mRNA expression in rat hearts exposed to T3 in vivo and ex vivo. Surprisingly, we found that the extended periods of T3 treatment led to an increase in PGC-1alpha expression compared to shorter treatment times, which resulted in a reduction of PGC-1alpha expression. Mechanistic studies showed that suppression of PGC-1alpha by small interfering RNA in cardiomyocytes amplified the cellular hypertrophic response to T3 stimulation, whereas overexpression of PGC-1alpha was protective. Furthermore, we presented evidence to show that T3 decreased PGC-1alpha expression via p38 mitogen-activated protein kinases (MAPK) pathway. Our studies also revealed that overexpression of PGC-1alpha in cardiomyocytes inhibited basal and T3-induced p38 MAPK phosphorylation. These data indicate for the first time that PGC-1alpha plays protective role in T3-induced cardiac hypertrophy and that hypertrophic growth induced by T3 involves a regulatory pathway between PGC 1alpha and p38 MAPK. PMID- 22105891 TI - Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. AB - Biliary atresia (BA) is a progressive, inflammatory cholangiopathy that culminates in fibrosis of extrahepatic and intrahepatic bile ducts. A leading theory on the pathogenesis of BA is that the bile duct damage is initiated by a virus infection, followed by a bile duct-targeted autoimmune response. One mechanism of autoimmunity entails a diminished number or function of regulatory T cells (Tregs). The aim of this study was to identify potential virus-specific liver T cells from infants with BA at the time of diagnosis, implicating the virus involved in early bile duct damage. A subaim was to determine if the presence of virus infection was associated with quantitative changes in Tregs. Liver T cells from BA and control patients were cultured with antigen-presenting cells in the presence of a variety of viral or control proteins. 56% of BA patients had significant increases in interferon-gamma-producing liver T cells in response to cytomegalovirus (CMV), compared with minimal BA responses to other viruses or the control group CMV response. In addition, a positive correlation between BA plasma CMV immunoglobulin M (IgM) and liver T-cell CMV reactivity was identified. Investigation of peripheral blood Tregs revealed significant deficits in Treg frequencies in BA compared with controls, with marked deficits in those BA patients who were positive for CMV. CONCLUSION: Liver T-cell responses to CMV were identified in the majority of BA patients at diagnosis, suggesting perinatal CMV infection as a plausible initiator of bile duct damage. Deficiency of Tregs in BA implies decreased inhibition of inflammation and autoreactivity, potentially allowing for exaggerated bile duct injury. PMID- 22105892 TI - Screening for anti-inflammatory and bronchorelaxant activities of 12 commonly used Chinese herbal medicines. AB - The use of health supplements derived from medicinal herbs as self-medication for the relief of respiratory tract pathology symptoms is increasing in Chinese communities as air pollution is worsening. Twelve herbs from two formulae of our previous studies were evaluated for their anti-inflammatory, immunomodulatory and bronchorelaxant activities in this study. Among the extracts tested, those of Herba Schizonepetae and Radix Glycyrrhizae showed significant inhibitory effects on LPS-induced nitric oxide production (p < 0.05) in mouse macrophage RAW264.7 cells, suggesting their anti-inflammatory activities. Radix Scutellariae and Radix Glycyrrhizae extracts showed significant inhibitory effects on phytohaemagglutinin-induced proliferation in human peripheral blood mononuclear cells (p < 0.05). These extracts also showed inhibition of TNF-alpha, IFN-gamma and IL-10 production. For the bronchorelaxant assay, Rhizoma Cynanchi Stauntonii and Radix Glycyrrhizae extracts showed potent attenuation of the acetylcholine- and carbachol-induced contractions in rat trachea (p < 0.05), implying their relaxant activities. In conclusion, Herba Schizonepetae, Radix Glycyrrhizae, Radix Scutellariae and Rhizoma Cynanchi Stauntonii extracts were demonstrated to exert anti-inflammatory, immunomodulatory and bronchorelaxant activities, which may help to ameliorate the symptoms of respiratory tract pathologies. The findings have thus provided some scientific evidence on the efficacy and mechanisms of action of these herbs, which are useful for the further development of clinical applications. PMID- 22105893 TI - Randomized controlled trial on postoperative pulmonary humidification after total laryngectomy: external humidifier versus heat and moisture exchanger. AB - OBJECTIVES/HYPOTHESIS: Assessment of immediate postoperative airway humidification after total laryngectomy (TLE), comparing the use of an external humidifier (EH) with humidification through a heat and moisture exchanger (HME). STUDY DESIGN: Randomized controlled trial (RCT). METHODS: Fifty-three patients were randomized into the standard (control) EH (N = 26) or the experimental HME arm (N = 27). Compliance, pulmonary and sleeping problems, patients' and nursing staff satisfaction, nursing time, and cost-effectiveness were assessed with trial specific structured questionnaires and tally sheets. RESULTS: In the EH arm data were available for all patients, whereas in the HME arm data were incomplete for four patients. The 24/7 compliance rate in the EH arm was 12% and in the HME arm 87% (77% if the four nonevaluable patients are considered noncompliant). Compliance and patients' satisfaction were significantly better, and the number of coughing episodes, mucus expectoration for clearing the trachea, and sleeping disturbances were significantly less in the HME arm (P < .001). This was also the case for nursing time and nursing staff satisfaction and preference. CONCLUSIONS: This RCT clearly shows the benefits of immediate postoperative airway humidification by means of an HME over the use of an EH after TLE. This study therefore underlines that HMEs presently can be considered the better option for early postoperative airway humidification after TLE. PMID- 22105894 TI - Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients. AB - BACKGROUND: Imatinib mesylate, a small-molecule tyrosine kinase inhibitor, is currently used for adjuvant therapy of patients who have undergone resection of high-risk gastrointestinal stromal tumors (GISTs). There are no data concerning the efficacy and safety of postoperative adjuvant therapy with imatinib for Japanese or East Asian patients with GIST. METHODS: A single-arm, open-label, multicenter trial was conducted in 17 hospitals in Japan. The eligibility criteria included histologically proven primary high-risk GISTs with macroscopic complete resection. Patients were treated with imatinib at a dose of 400 mg/day for 1 year after surgery. The primary endpoint was recurrence-free survival as assessed by Kaplan-Meier analysis. The secondary endpoints were overall survival and safety. This study was registered with ClinicalTrials.gov, number NCT00171977. RESULTS: A total of 64 patients were enrolled between September 2004 and July 2006. The median age of the patients was 59.5 years. Forty-nine (76.6%) patients completed the 1-year treatment, whereas 15 (23.4%) patients did not complete the treatment owing to recurrence, toxicities, and consent withdrawal. At the median follow-up period of 109 weeks, 20 patients had recurrence. The 3 year recurrence rate was 42.7% (95% confidence interval 29.2-56.3%), which exceeded the expected recurrence rate in this trial. The recurrence-free and overall survival rates at 2 years were 71.1 and 93.7%, respectively. The most frequent adverse drug reaction of any grade was eyelid edema (48.4%), followed by neutropenia (40.6%), leukopenia (39.1%), nausea (39.1%), rash (37.5%), and peripheral edema (37.5%), most of which were mild and manageable. CONCLUSIONS: Adjuvant therapy with imatinib at 400 mg/day for 1 year is well tolerated by Japanese patients and possibly reduces the risk of early recurrence of high-risk GISTs. PMID- 22105895 TI - Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. AB - BACKGROUND: The long-term outcomes and risk factors of paclitaxel-induced peripheral neuropathy (PIPN) have not yet been fully elucidated. METHODS: We identified 219 breast cancer patients who received paclitaxel as adjuvant chemotherapy between 2002 and 2009. We retrospectively analyzed the incidence, time to onset, duration, and risk factors for PIPN by chart review. RESULTS: Of the 219 patients, 212 developed PIPN (97%) during a median follow-up time of 57 months (range 5.3-95.5). Median time to PIPN onset was 21 days (range 11-101) for the entire patient population: 35 days (range 14-77) for weekly administration and 21 days (range 11-101) for tri-weekly administration. PIPN caused termination of paclitaxel treatment in 7 patients (4%). Median duration of PIPN was 727 days (range 14-2621 days). PIPN persisted in 64 and 41% of patients at 1 and 3 years after initiating paclitaxel, respectively. Age >=60 years and severity of PIPN were significantly associated with PIPN duration. CONCLUSIONS: PIPN persists longer in older patients and in those who experience severe neuropathy. Further studies to identify the risk factors for PIPN are warranted. PMID- 22105896 TI - Farewell editorial. PMID- 22105897 TI - Growth pattern of renal cell carcinoma (RCC) in patients with delayed surgical intervention. AB - PURPOSE: Few studies have evaluated the growth pattern of renal cell carcinoma (RCC) in patients with delayed treatment. This report investigated the growth rate and stage progression of incidentally discovered RCC following a long period of active surveillance. METHODS: Thirty-two patients who did not receive immediate surgical treatment for renal solid masses that later proved to be RCC were reviewed retrospectively. Annual tumor growth rates were calculated according to changes in the maximal diameter on CT or MRI. Clinical and pathological characteristics associated with tumor growth rate and stage progression were analyzed. RESULTS: The median tumor size grow from 2.14 (range, 0.30-6.70) cm to 4.33 (range, 1.40-8.80) cm after a median 46.0 months observation period. The average tumor growth rate was 0.80 (range, 0.16-3.80) cm/year. Clear cell carcinoma (0.86 cm/year) tended to grow faster than papillary cell carcinoma (0.28 cm/year) (P = 0.066). The mean growth rate of grade 2 tumors (0.88 cm/year) was faster than that of grade 1 tumors (0.36 cm/year) (P = 0.041). Thirteen tumors (40.6%) were upstaged at a median 48 months after initial presentation. Cox regression analysis revealed initial tumor size as the only risk factor for upstaging (P = 0.018). No local and systemic recurrences were noted in our cohort after the intervention at a median of 47 (range, 6-248) months of follow-up. CONCLUSIONS: RCCs were found to be slow growing in a group of untreated renal cell carcinoma patients. However, some tumors progressed in stage under observation. The growth rate of RCC tended to correlate with histologic grade and histologic subtype. PMID- 22105898 TI - Intensity-modulated radiotherapy combined with chemotherapy for the treatment of gastric cancer patients after standard D1/D2 surgery. AB - BACKGROUND: The purpose of the current study is to evaluate the efficacy and complications of concurrent chemoradiotherapy (CCRT) for the treatment of gastric cancer patients after D1/D2 surgery. METHODS: Sixty-eight untreated gastric cancer patients (T3/T4 and/or N+) were enrolled. After surgery, they were randomized into two groups: the CCRT group and the single chemotherapy group. Radiotherapy patients were treated according to the Intergroup 0116 guidelines. The chemotherapy consisted of continuously administered 5-fluorouracil (5-FU) and tetrahydrofolic acid (LV). The CCRT began 28 days after the first cycle of chemotherapy, and chemotherapy was given within the first four and last three days during the CCRT period, at a radiation dosage of 45 Gy/25 f, i.e., 1.8 Gy 5 times per week. Two cycles of the same chemotherapy were administrated 1 month after the radiotherapy. Five cycles of 5-FU and LV were applied to CG. RESULTS: One-, two-, and three-year survival rates were 85.9, 73.4, and 67.7%, respectively, in the CCRT group and 68.0, 50.0, and 44.1%, in the single chemotherapy group (P < 0.05). The corresponding disease-free survival rates were 73.5, 64.7, and 55.8% in the CCRT group and 61.8, 38.2, and 29.4% in the single chemotherapy group (P < 0.05). The major side effects were gastrointestinal reactions and neutrocytopenia. In both the CCRT and single chemotherapy groups, the incidence of these side effects was 73.5% (25/34) and 44.1% (15/34) (P < 0.05) for Grade I and Grade II anorexia, 82.35% (28/34) and 73.5% (25/34) (P > 0.05) for nausea and vomiting, and 70.6% (24/34) and 44.1% (15/34) (P < 0.05) for neutrocytopenia, respectively. The other indices showed no significant differences. CONCLUSIONS: Our findings indicate that CCRT can increase the one-, two-, and three-year total survival rates, as well as the disease-free survival rates of gastric cancer patients (T3/T4 and/or N+) who have been initially treated with surgery. The major adverse reactions were Grade I and Grade II nausea and vomiting, as well as myelosuppression. CCRT is well tolerated. PMID- 22105899 TI - Nodal status--its impact on prognosis in advanced ovarian cancer. AB - PURPOSE: Prognostic impact of nodal status or lymphadenectomy in advanced ovarian cancer is still unclear. Known best prognostic impact in advanced ovarian cancer has the residual tumor mass. The aim of this retrospective study is to examine the importance of nodal status in correlation with residual tumor mass. METHODS: One hundred and fifty-seven consecutive patients with primary stage III ovarian cancer underwent surgery between 01/2000 and 06/2007 at the Department of gynecology and obstetrics, University Hospital, Tubingen, Germany. All patients got stage-related surgery and platin-based chemotherapy. Median follow-up time was 53.5 months, and all patients were included in the study. RESULTS: Resection status and nodal status are significant prognostic factors in our study (P < 0.001). In FIGO III, patients without residual tumor (R0) had significant best OS and PFS independent to node status (N0/N+; P = 0.002) compared to patients with residual tumor. In contrast, node status had significant positive impact on PFS in patients without residual tumor and node negativity. With the increase in residual tumor, the influence of lymphnode metastases on prognosis is decreasing. CONCLUSION: Main intention of primary surgery is R0 resection with best prognosis in advanced stages. A systematic lymphadenectomy in cases with R0 resection or residual tumor <1 cm seems to be reasonable with positive impact on prognosis. Node status has impact on prognosis in patients with negative node after R0 resection with best PFS in FIGO III. Further prospective studies had to show whether systematic lymphadenectomy in suboptimally tumor-reduced patients can improve prognosis. PMID- 22105900 TI - ARK5 is associated with the invasive and metastatic potential of human breast cancer cells. AB - PURPOSE: To investigate the effects of Akt/ARK5 pathways on the metastatic potential of human breast cancer cells. MATERIALS AND METHODS: The human ARK5 gene was transfected into MDA-MB-231 cells. Effects of ARK5 on MDA-MB-231 cells were investigated in vitro. The tumorigenicity and spontaneously metastatic capability regulated by ARK5 were determined using an orthotopic xenograft tumor model. RESULTS: ARK5 enhanced the invasive and metastatic potential of MDA-MB-231 cells under regulation by Akt. The enhancement was associated with increasing MMP 2, MMP-9, and MT1-MMP expression. The results were further demonstrated by RNA interference experiment. In an in vivo study, we also demonstrated that ARK5 transfected breast cancer cells grew faster and had more pulmonary metastases than its parental counterparts. CONCLUSION: ARK5 led to a more invasive phenotype and metastatic potential in human breast cancer dependent on Akt. PMID- 22105901 TI - Tailored ruthenium-N-heterocyclic carbene hybrid catalytic materials for the hydrogenation of carbon dioxide in the presence of amine. PMID- 22105902 TI - Crystal structure of bacteriophage phiNIT1 zinc peptidase PghP that hydrolyzes gamma-glutamyl linkage of bacterial poly-gamma-glutamate. AB - Poly-gamma-glutamate hydrolase P (PghP) of Bacillus subtilis bacteriophage PhiNIT1 hydrolyzes the gamma-glutamyl peptide linkage of extracellular poly-gamma glutamate produced by bacilli, which facilitates infection and propagation of phage progenies. Crystal structure of PghP was determined at a resolution of 1.9 A. Structure of PghP was elucidated as a globular protein with an open alpha/beta mixed core structure and a seven-stranded parallel/anti-parallel beta-sheet. The beta-sheet contained a core four-stranded parallel beta-sheet. A zinc-binding motif, His-Glu-His, was identified at the C-terminal end of the beta-sheet. Structure analysis demonstrated that PghP, which had not been previously classified into any peptidase/protease family due to lack of amino acid sequence similarity with known enzymes, had a catalytic center containing a zinc ion and an overall topology resembling mammalian carboxypeptidase A and related enzymes. Structural comparisons indicated important amino acid residues of PghP for catalysis and recognition of the gamma-peptide bond of poly-gamma-glutamate, which was confirmed by site-directed mutagenesis of PghP. PMID- 22105903 TI - The fellows stitch: large caliber venous hemostasis in pediatric practice. AB - OBJECTIVE: To analyze safety and efficiency of a subcutaneous figure of eight suture for hemostasis after large caliber venous sheath access in children. BACKGROUND: Vascular complications remain a significant cause of morbidity after pediatric cardiac catheterization. In an attempt to reduce such complications and yet improve lab efficiency and decrease length of stay, various techniques have been applied to improve time to hemostasis. METHODS: Prospectively recorded were vascular complications and hemostasis times in children where hemostasis was attempted using a figure of eight subcutaneous suture following large caliber venous cannulation. These were compared to a matched group achieving hemostasis using standard manual pressure techniques. Vascular ultrasound assessments were performed within 24 hr of hemostasis in both groups. RESULTS: Thirty-two subcutaneous sutures were placed in 26 children, mean weights 31.9 kg [median (range): 29.4 (8.4 to 96) kg], with a mean sheath French size of 9.2 [8; (6 to 22)], 11 >10 French, compared to 33 sheaths in 30 cases using manual compression, mean sheath French size 9.1 (9; (6 to 13), with 10 cases >=10 French. The mean and median times to hemostasis were shorter in the suture group: 13.6 min (P < 0.05) and 10 min (P < 0.05), respectively. Vascular complication rate was also lower in the suture group (n = 0) compared with the control group (n = 2) but did not achieve statistical significance. CONCLUSIONS: A subcutaneous figure of eight suture hemostasis strategy can provide a safe and efficient method for large caliber venous hemostasis in a pediatric practice with improved hemostasis times and no additional morbidity. PMID- 22105904 TI - Raman spectroscopic determination of the length, strength, compressibility, Debye temperature, elasticity, and force constant of the C-C bond in graphene. AB - From the perspective of bond relaxation and bond vibration, we have formulated the Raman phonon relaxation of graphene, under the stimuli of the number-of layers, the uni-axial strain, the pressure, and the temperature, in terms of the response of the length and strength of the representative bond of the entire specimen to the applied stimuli. Theoretical unification of the measurements clarifies that: (i) the opposite trends of the Raman shifts, which are due to the number-of-layers reduction, of the G-peak shift and arises from the vibration of a pair of atoms, while the D- and the 2D-peak shifts involve the z-neighbor of a specific atom; (ii) the tensile strain-induced phonon softening and phonon-band splitting arise from the asymmetric response of the C(3v) bond geometry to the C(2v) uni-axial bond elongation; (iii) the thermal softening of the phonons originates from bond expansion and weakening; and (iv) the pressure stiffening of the phonons results from bond compression and work hardening. Reproduction of the measurements has led to quantitative information about the referential frequencies from which the Raman frequencies shift as well as the length, energy, force constant, Debye temperature, compressibility and elastic modulus of the C-C bond in graphene, which is of instrumental importance in the understanding of the unusual behavior of graphene. PMID- 22105905 TI - MBTPS2 mutation causes BRESEK/BRESHECK syndrome. AB - BRESEK/BRESHECK syndrome is a multiple congenital malformation characterized by brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, and renal anomalies or small kidneys, with or without Hirschsprung disease and cleft palate or cryptorchidism. This syndrome has only been reported in three male patients. Here, we report on the fourth male patient presenting with brain anomaly, intellectual disability, growth retardation, ectodermal dysplasia, vertebral (skeletal) anomaly, Hirschsprung disease, low-set and large ears, cryptorchidism, and small kidneys. These manifestations fulfill the clinical diagnostic criteria of BRESHECK syndrome. Since all patients with BRESEK/BRESHECK syndrome are male, and X-linked syndrome of ichthyosis follicularis with atrichia and photophobia is sometimes associated with several features of BRESEK/BRESHECK syndrome such as intellectual disability, vertebral and renal anomalies, and Hirschsprung disease, we analyzed the causal gene of ichthyosis follicularis with atrichia and photophobia syndrome, MBTPS2, in the present patient and identified an p.Arg429His mutation. This mutation has been reported to cause the most severe type of ichthyosis follicularis with atrichia and photophobia syndrome, including neonatal and infantile death. These results demonstrate that the p.Arg429His mutation in MBTPS2 causes BRESEK/BRESHECK syndrome. PMID- 22105906 TI - Seroprevalence of Peste des petits ruminants in cattle and buffaloes from Southern Peninsular India. AB - This study describes seroprevalence of Peste des petits ruminants (PPR) in cattle and buffaloes carried out during the period 2009-2010 using the randomly collected serum samples from different parts of Southern peninsular India. The report presents the results of PPR virus (PPRV)-specific antibodies in situations where either the subclinical or inapparent or non-lethal infection was there in cattle and buffaloes. A total of 2,548 serum samples [cattle = 1,158, buffaloes = 1,001, sheep = 303 and goat = 86] were collected and screened for PPRV antibodies by using a PPR monoclonal antibody-based competitive ELISA kit. Analysis of 2,159 serum samples indicates an overall 4.58% prevalence of PPRV antibody in cattle and buffaloes. The presence of PPRV-specific antibodies demonstrates that cattle and buffaloes are exposed to PPR infection naturally, and the transmission mode may be direct or indirect. Further, it implies the importance of bovines as subclinical hosts for the virus besides widespread presence of the disease in sheep and goats in the country. PMID- 22105907 TI - Identification of shiga toxin and intimin coding genes in Escherichia coli isolates from pigeons (Columba livia) in relation to phylotypes and antibiotic resistance patterns. AB - Shiga toxin-producing Escherichia coli (STEC) strains are responsible for outbreaks of human intestinal diseases worldwide. Pigeons are distributed in public areas and are potential reservoirs for pathogenic bacteria. One hundred fifty-four fresh fecal samples were obtained from trapped pigeons in southeast of Iran and were cultured for isolation of E. coli. The isolates were examined to determine the prevalence of stx1, stx2, and eae genes, antimicrobial resistance, and their phylotypes. The confirmed E. coli isolates (138) belong to four phylogenetic groups: A (54.34%), B1 (34.05%), B2 (3.62%), and D (7.79%). Thirteen (9.42%) isolates were positive for one of the examined genes. Eight isolates (5.79%) were positive for eae, four (2.89%) for stx2, and one isolate (1.44%) for stx1 gene. Phylotyping assays showed that eight eae-positive isolates fall into three phylogroups; A (three isolates), B1 (three isolates), and D (two isolates), whereas four stx2-positive isolates belonged to the A (three isolates) and D (one isolate) groups. The stx1-positive isolate belonged to phylogroup A. One hundred six isolates (76.81%) showed resistance to at least one of the selected antibacterial agents. The maximum resistance rate was against oxytetracycline (73.91%), and the minimum was against flumequine (2.17%). Twenty different patterns of drug resistance were observed. According to the results, pigeons could be considered as carriers of STEC strains. However, E. coli isolates of pigeon feces increase the potential of these birds to act as a reservoir of multiple antibiotic resistant bacteria. PMID- 22105910 TI - Genetic Alliance marks 25 years. PMID- 22105911 TI - Gene patent pool set to launch. PMID- 22105913 TI - Mapping and characterization of seed dormancy QTLs using chromosome segment substitution lines in rice. AB - Seed dormancy--the temporary failure of a viable seed to germinate under favorable conditions--is a complex characteristic influenced by many genes and environmental factors. To detect the genetic factors associated with seed dormancy in rice, we conducted a QTL analysis using chromosome segment substitution lines (CSSLs) derived from a cross between Nona Bokra (strong dormancy) and Koshihikari (weak dormancy). Comparison of the levels of seed dormancy of the CSSLs and their recurrent parent Koshihikari revealed that two chromosomal regions-on the short arms of chromosomes 1 and 6-were involved in the variation in seed dormancy. Further genetic analyses using an F(2) population derived from crosses between the CSSLs and Koshihikari confirmed the allelic differences and the chromosomal locations of three putative QTLs: Sdr6 on chromosome 1 and Sdr9 and Sdr10 on chromosome 6. The Nona Bokra alleles of the three QTLs were associated with decreased germination rate. We discuss the physiological features of the CSSLs and speculate on the possible mechanisms of dormancy in light of the newly detected QTLs. PMID- 22105914 TI - Structural motifs in phenylbismuth heterocyclic carboxylates--secondary interactions leading to oligomers. AB - The reaction of triphenylbismuth [BiPh(3)] with several heterocyclic carboxylic acids was explored. Seven crystalline compounds, [PhBi(2-O(2)C-3 (OH)C(5)H(3)N)(2)(2-O(2)C-3-(OH)C(5)H(3)NH)] (5), [(Bi(2-O(2)C-3 (OH)C(5)H(3)N)(4))(C(5)H(5)NH)(C(5)H(5)N)] (7), [PhBi(2-O(2)C-C(4)H(3)N(2))(2)(2 O(2)C-C(4)H(4)N(2)).H(2)O] (8), [PhBi(2-O(2)C-C(9)H(6)N)(2).H(2)O] (9), [Ph(2)Bi(O(2)C-C(4)H(3)O)] (10), [Ph(2)Bi(O(2)C-C(4)H(3)S)] (11) and [PhBi(O(2)C C(4)H(3)S)(2)](2) (12), were prepared by simple reactions using BiPh(3) and the corresponding acids, 3-hydroxypicolinic acid, pyrazine-2-carboxylic acid, quinoline-2-carboxylic (quinaldic) acid, furan-2-carboxylic acid and thiophene-2 carboxylic acid. Compound 5 primarily exhibits a coordination number of six with pentagonal pyramidal geometry at bismuth, but an additional weak Bi...O interaction in the direction of the lone pair of electrons is present. This feature leads to a weakly bound dimer. The use of pyridine as the solvent in a similar reaction, however, led to 7, in which all of the Bi-Ph bonds are cleaved. In this compound, bismuth exhibits a coordination number of eight and distorted dodecahedral geometry. In compound 8, the geometry around bismuth is primarily a pentagonal pyramid, however, clear-cut but weak secondary Bi...N interactions leading to a dimeric formulation are discernible in the structure. The quinaldate compound 9 exhibits a lower formal coordination number of five for bismuth, with square pyramidal geometry, but again two secondary Bi...O interactions for each bismuth in the direction of the lone pair lead to a dimer. A similar secondary Bi...O interaction involving furan oxygen is present in the furoate compound 10, which is a polymeric chain (one dimensional coordination polymer). Although the thiophene carboxylate 11 is also a polymeric chain, no Bi...S interactions are present. Unlike the previously reported tetrameric biscarboxylate [PhBi(2-O(2)C C(5)H(3)N)(2)](4), the thiophene carboxylate [PhBi(O(2)C-C(4)H(3)S)(2)](2) (12) is a dimer considering only primary interactions. However, these dimers are arranged in such a way that there are secondary Bi...S interactions in the structure in the expected direction of the lone pair of electrons on bismuth. Thus, these studies suggest that the stereochemical activity (or inactivity) of the bismuth lone pair of electrons need to be judged more cautiously. TGA studies are consistent with the presence of Bi-Ph groups in all of the compounds, except 7, as indicated by their formulae. PMID- 22105915 TI - Benign joining of ultrafine grained aerospace aluminum alloys using nanotechnology. AB - Ultrafine grained aluminum alloys have restricted applicability due to their limited thermal stability. Metalized 7475 alloys can be soldered and brazed at room temperature using nanotechnology. Reactive foils are used to release heat for milliseconds directly at the interface between two components leading to a metallurgical joint without significantly heating the bulk alloy, thus preserving its mechanical properties. PMID- 22105916 TI - Photocontrollable dynamic micropatterning of non-adherent mammalian cells using a photocleavable poly(ethylene glycol) lipid. PMID- 22105917 TI - New insights in endometrial carcinogenesis. AB - Endometrial carcinoma is the most common cancer of the female genital tract in Europe and in the United States. Despite advances in defining the biology of endometrial carcinomas, there has been poor progress in determining markers that distinguish preinvasive endometrial proliferations. The aim of this review is to highlight the most recent studies regarding the molecular markers involved in endometrial adenocarcinoma pathogenesis and carcinogenesis. We focus on studies that describe markers with potential to progress from endometrial hyperplasia to invasive disease. PMID- 22105918 TI - Altholactone induces apoptotic cell death in human colorectal cancer cells. AB - Resistance of colorectal cancer (CRC) to the available chemotherapy reveals the demand for identification of new anticancer agents. We evaluated the antitumour potential of altholactone, a naturally occurring bioactive compound isolated from Goniothalamus spp. (Annonaceae) hooks, against CRC cells. Antitumour activity of altholactone was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and the propidium iodide method. Apoptosis mediators involved were assessed using biochemical inhibitors and Western blotting analysis. Results revealed that altholactone induced varying degrees of apoptosis in CRC cells but not in normal fibroblasts. Dissection of the altholactone-induced apoptotic signalling pathway revealed that altholactone activated caspase-dependent and -independent apoptotic pathways. Activation of caspase-4 appeared to be the initiating event in the caspase-dependent apoptotic pathway. Pre-treatment of CRC cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-4 and altholactone-induced apoptosis. These results indicate that altholactone induces selective cytotoxicity against colon carcinoma cells and warrants further clinical evaluation. PMID- 22105919 TI - Altered tissue behavior of a non-aneurysmal descending thoracic aorta in the mouse model of Marfan syndrome. AB - Aortic aneurysm is predominantly found in the ascending aorta in patients with Marfan syndrome (MFS). However, descending aortic disease has emerged as a problem since people are living longer because of improved medical and surgical management of the ascending aorta. Diagnostic procedures before disease onset and the mechanisms involved in the transition of normal aortic tissue to aneurysm remain unclear. We determined signs of descending aortic disease before disease onset in mice with a mutation in the fibrillin 1 gene (Fbn1(+/C1039G)), a validated mouse model of disease susceptibility and progression of aortic aneurysm of MFS. We analyzed a tubular unfixed non-aneurysmal descending thoracic aorta from 8-month-old wild-type and Fbn1(+/C1039G) mice by a tubular biaxial tester that works in conjunction with a two-photon nonlinear microscope. Fbn1(+/C1039G) mouse aorta was more compliant in the circumferential direction. Two-photon imaging showed defective organization of adventitial collagen fibers in the pressurized aortas of Fbn1(+/C1039G) mice. Moreover, disruption in the elastic lamina was noted in the absence of aneurysms in pressurized aortas but not unpressurized aortas of Fbn1(+/C1039G) mice. At the molecular level, this altered tissue behavior in non-aneurysmal descending aortas of Fbn1(+/C1039G) mice was accompanied by an increasing trend of canonical but not noncanonical, transforming growth factor-beta (TGFbeta) signaling. Finally, assays of in vitro collagen lattice formation in mouse wild-type and TGFbeta1-deficient embryonic fibroblasts indicate that TGFbeta1 can regulate collagen organization. The ability to reveal the presence of altered biomechanics and microstructure coupled with subtle changes in TGFbeta signaling provides a novel surrogate measure of tissue susceptibility to aneurysm before disease onset. PMID- 22105920 TI - Comparison of the osteogenic potentials of autologous cultured osteoblasts and mesenchymal stem cells loaded onto allogeneic cancellous bone granules. AB - We compared the bone regeneration potentials of autologous cultured osteoblasts and of bone-marrow-derived autologous MSCs in combination with allogeneic cancellous bone granules in a rabbit radial defect model. Radial shaft defects over 15 mm were made in 26 New Zealand white rabbits. The animals underwent insertion of allogeneic cancellous bone granules containing autologous osteoblasts into right-side defects (the experimental group) and of allogeneic cancellous bone granules with autologous MSCs into left-side defects (the control group). To quantitatively assess bone regeneration, radiographic evaluations as well as BMD and BMC measurements were performed 3, 6, 9 and 12 weeks post implantation and histology as well as micro-CT image analysis were performed at 6 and 12 weeks. Radiographic evaluations 3 weeks post-implantation showed that the experimental group had a higher mean bone quantity index (p < 0.05) and micro-CT image analysis showed that experimental sides had a greater mean total regenerated bone volume and surface area than the control sides (p < 0.05). Histologic evaluations obtained at 6 and 12 weeks revealed distinctly greater granule resorption and new bone formation in the experimental group. This in vivo study demonstrates that a combination of autologous osteoblasts and small-sized, allogeneic cancellous bone granules leads to more rapid bone regeneration than autologous MSCs and small-sized, allogeneic cancellous bone granules. PMID- 22105921 TI - Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. AB - Transforming growth factor beta (TGF-beta) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-beta induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF beta has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-beta participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD. PMID- 22105922 TI - Duplication of the ZIC2 gene is not associated with holoprosencephaly. AB - Cytogenetic testing using genomic microarrays presents a clinical challenge when data regarding the phenotypic consequences of the genomic alteration are not available. We describe a chromosome 13q32.3 duplication discovered by microarray testing in a fetus with a prenatally detected apparently balanced de novo translocation 46,XY,t(2;13)(q37;q32). Microarray analysis on the fetal DNA showed duplications of 384 and 564 kb at the breakpoint regions on chromosomes 2q37.3 and 13q32.3, respectively. There were no disease-associated genes in the duplicated region on chromosome 2q37. The duplicated region on chromosome 13q contains the ZIC2 gene. Haploinsufficiency of ZIC2 is known to cause holoprosencephaly and other brain malformations. Studies in the mouse models have suggested that over expression of ZIC2 may also lead to brain malformations. Fetal MRI of the brain was normal and the family elected to continue the pregnancy. An apparently normal baby was born at term. At 3 months of age a physical exam showed no abnormalities and no developmental delay. This report shows that duplication of ZIC2 is not necessarily associated with brain malformations. We also describe the phenotype from four additional patients with duplications of the region of chromosome 13 containing ZIC2 and three previously described patients with supernumerary marker chromosomes derived from distal chromosome 13. None of the eight patients had holoprosencephaly or brain malformations, indicating that duplication of ZIC2 is not associated with brain anomalies. This information will be useful for counseling in other occurrences of this duplication identified by microarray. PMID- 22105923 TI - Catalytic partial oxidation and membrane separation to optimize the conversion of natural gas to syngas and hydrogen. AB - The multistep integration of hydrogen-selective membranes into catalytic partial oxidation (CPO) technology to convert natural gas into syngas and hydrogen is reported. An open architecture for the membrane reactor is presented, in which coupling of the reaction and hydrogen separation is achieved independently and the required feed conversion is reached through a set of three CPO reactors working at 750, 750 and 920 degrees C, compared to 1030 degrees C for conventional CPO technology. Obtaining the same feed conversion at milder operating conditions translates into less natural gas consumption (and CO(2) emissions) and a reduction of variable operative costs of around 10 %. It is also discussed how this energy-efficient process architecture, which is suited particularly to small-to-medium applications, may improve the sustainability of other endothermic, reversible reactions to form hydrogen. PMID- 22105924 TI - Pathogenicity and insect transmission of a begomovirus complex between tomato yellow leaf curl virus and Ageratum yellow vein betasatellite. AB - Tomato yellow leaf curl virus (TYLCV) and Ageratum yellow vein betasatellite (AYVB) are members of the genus Begomovirus (family Geminiviridae). TYLCV and AYVB have been found in Japan over the last 15 years, and are associated with tomato leaf curl and the tomato yellow leaf curl diseases (TYLCD). AYVB is also associated with some monopartite begomoviruses. We have cloned both TYLCV and AYVB and demonstrated that TYLCV can trans-replicate with AYVB in Nicotiana benthamiana and tomato plants. A mixed infection of TYLCV and AYVB induced more severe symptoms of upward leaf curl, stunting, vein thickening, and swelling compared with TYLCV infection alone. The symptoms induced by infection of AYVB included a rise in abnormal cell proliferation, and pigmentation around leaf vein tissues. This is the first study to show that a complex of TYLCV and AYVB can be transmitted by vector insects among tomato plants. These results indicate that TYLCV possesses the potential to induce severe TYLCD by associating with AYVB. PMID- 22105925 TI - In vivo comparison of a polymer-free Biolimus A9-eluting stent with a biodegradable polymer-based Biolimus A9 eluting stent and a bare metal stent in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries. AB - OBJECTIVES: To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries. METHODS: Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry. RESULTS: The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) +/- 0.14 vs. 1.29 mm(2) +/- 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both). CONCLUSION: This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia. PMID- 22105926 TI - Electrodeposition of single-metal nanoparticles on stable protein 1 membranes: application of plasmonic sensing by single nanoparticles. PMID- 22105927 TI - LC-UV assay method and UPLC/Q-TOF-MS characterisation of saponins from Ilex paraguariensis A. St. Hil. (mate) unripe fruits. AB - INTRODUCTION: Ilex paraguariensis A. St. Hil. (mate) is known in several South American countries because of the use of its leaves in stimulant herbal beverages. High saponin contents were reported in mate leaves and unripe fruits that possess a dissimilar composition. Two LC-UV methods previously reported for mate saponins assay focused on mate leaves and the quantification of the less polar saponin fraction in mate fruits. OBJECTIVE: To develop and validate a LC-UV method to assay the total content of saponins in unripe mate fruits and characterise the chemical structure of triterpenic saponins by UPLC/Q-TOF-MS. METHODOLOGY: From unripe fruits of mate a crude ethanolic extract was prepared (EX40) and the mate saponin fraction (MSF) purified by solid phase extraction. The LC-UV method was validated using ilexoside II as external standard. UPLC/Q TOF-MS was adjusted from the LC-UV method to obtain the fragmentation patterns of the main saponins present in unripe fruits. RESULTS: Both LC-UV and UPLC/Q-TOF-MS methods indicate a wide range of Ilex saponins polarity. The ilexoside II and total saponin content of EX40 were 8.20% (w/w) and 47.60% (w/w), respectively. The total saponin content in unripe fruits was 7.28% (w/w). The saponins present in MSF characterised by UPLC/Q-TOF-MS are derived mainly from ursolic/oleanolic, acetyl ursolic or pomolic acid. CONCLUSION: The validated LC-UV method was shown to be linear, precise, accurate and to cover several saponins previously isolated from Ilex species and could be applied for the quality control of unripe fruit saponins. PMID- 22105928 TI - Research on scutellarin parenteral solution's protective effects in rats with severe acute pancreatitis and multiple organ injuries. AB - The aim of this study was to observe scutellarin parenteral solution's therapeutic effects and mechanisms in rats with severe acute pancreatitis (SAP). We divided SD rats into four groups randomly: (1) sham-operated group, (2) model control group, (3) scutellarin-treated group, and (4) Salvia miltiorrhiza-treated group. All of those rats in the abovementioned groups are randomly subdivided into 6 and 12 h subgroups, respectively, according to the postoperative time. Rats have been mercifully killed at different time after operation, and then detected their serum amylase, contents of ALT, AST, BUN, and Cr and observed the pathologic changes of multiple organs (pancreas, liver, kidneys, and lungs). We found that the survival rates have no marked differences (P < 0.05) between model control group and two treated groups at any time points. AST and BUN serum contents have no marked difference (P > 0.05). ALT serum contents in S. miltiorrhiza-treated group (6 and 12 h) and scutellarin-treated group (12 h) are obviously less than those in model control group (P < 0.05). The serum contents of Cr and amylase in scutellarin-treated group (6 h) are obviously less than those in model control group (P < 0.05). There is a different degree of relief on the pathologic changes of multiple organs in the two treated groups compared with those in model control group, of which pancreas and liver's pathologic severity scores in scutellarin-treated group (6 and 12 h) have reduced (P < 0.01) significantly compared with those in the model control group. However, there are no significant differences between scutellarin-treated group and S. miltiorrhiza treated group (P > 0.05). We think the scutellarin parenteral solution has a certain protective effect on SAP rats' multiple organ injuries. PMID- 22105929 TI - Vacuum lamination approach to fabrication of high-performance single-crystal organic field-effect transistors. AB - A novel vacuum lamination approach to fabrication of high-performance single crystal organic field-effect transistors has been developed. The non-destructive nature of this method allows a direct comparison of field-effect mobilities achieved with various gate dielectrics using the same single-crystal sample. The method also allows gating delicate systems, such as n -type crystals and SAM coated surfaces, without perturbation. PMID- 22105930 TI - Discovery of a potent and highly beta1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones. AB - Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are beta5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent beta1 selective compound active in living cells reported to date. PMID- 22105931 TI - Lycopene production from synthetic medium by Blakeslea trispora NRRL 2895 (+) and 2896 (-) in a stirred-tank fermenter. AB - The dissolved oxygen tension of 20% of air saturation, pH-shift from 4.0 to 5.5 on day 3, and a moderate shear stress (calculated as an impeller tip speed, V(tip) = 0.926 - 2.161 m/s) were identified to be the key factors in scaling-up the mated fermentation of Blakeslea trispora NRRL 2895 (+) and 2896 (-) for lycopene production from a shake flask to a stirred-tank fermenter. The maximal lycopene production of 183.3 mg/L was obtained in 7.5-L stirred-tank fermenter, and then the mated fermentation process was successfully step-wise scaled-up from 7.5- to 200-L stirred-tank fermenter. The comparability of the fermentation process was well controlled and the lycopene production was maintained during the process scale-up. Furthermore, with the integrated addition of 150 MUmol/L abscisic acid on day 3, 0.5 g/L leucine and 0.1 g/L penicillin on day 4, the highest lycopene production of 270.3 mg/L was achieved in the mated fermentation of B. trispora in stirred-tank fermenter. PMID- 22105932 TI - Array-CGH and clinical characterization in a patient with subtelomeric 6p deletion without ocular dysgenesis. AB - Subtelomeric terminal 6p deletion has been recognized as a clinically identifiable syndrome including facial dysmorphism, malformation of the anterior eye chamber, hearing loss, heart defects, and developmental delay. Genotype phenotype correlations of previously published patients have strongly suggested anterior eye segment anomalies as one of the major malformations of the syndrome if the critical 6p25 region contains the FOXC 1 gene. In addition, the presence in this region of one or more genes involved in hearing loss has been hypothesized. We report a patient with a 47,XYY karyotype and submicroscopic terminal 6p deletion. Further characterization of the deletion with array comparative genome hybridization also revealed a cryptic microduplication on chromosome 19. The patient showed dysmorphic features, neuromotor retardation, and profound language impairment, in absence of hearing loss and structural eye anomalies. As far as we know this is the first reported terminal 6p25.1 deletion case without eye dysgenesis precisely characterized by array-CGH. Our result suggests that the genes in this region may not be obvious candidates for hearing loss and demonstrate the need for further elucidation of the function of the genes involved in eye developmental processes. PMID- 22105933 TI - Seasonal trends of PM2.5 and PM10 in ambient air and their correlation in ambient air of Lucknow city, India. AB - The PM(10) concentration (MUg/m(3)) in Lucknow city at 4 locations in three different seasons ranged between 148.6-210.8 (avg. 187.2 +/- 17.1) during summer, 111.8-187.6 (avg. 155.7 +/- 22.7) during monsoon and 199.3-308.8 (avg. 269.3 +/- 42.9) during winter while PM(2.5) ranged between 32.4-67.2 (avg. 45.6 +/- 10.9), 25.6-68.9 (avg. 39.8 +/- 4.6) and 99.3-299.3 (avg. 212.4 +/- 55.0) during respective seasons. The mass fraction ratio of PM(2.5) ranged between 0.22-0.92 (avg. 0.42 +/- 0.26) and was significantly high during winter season indicating their composition. PMID- 22105934 TI - Accidental discharge of brodifacoum baits into a freshwater lake: a case study. AB - Approximately 700 kg of cereal bait containing 20 ppm of the anticoagulant rodenticide brodifacoum was spilled into a southern New Zealand lake in 2010 from a helicopter being used to transport containers of brodifacoum bait for an aerial baiting operation. In the month after the spill no residual brodifacoum was detected in samples of lake water, sediment, benthic invertebrates, eels, and two birds. PMID- 22105935 TI - Distribution and accumulation of metals in soils and plant from a lead-zinc mineland in Guangxi, South China. AB - Six kinds of metals were measured in soils and plant from the Siding Pb-Zn mineland, South China, to investigate the pollution and restoration technique. The mean Pb, Zn, Fe, Mn, Cu and Cr contents in soils were 5,215 +/- 642, 13,352 +/- 1,242, 24,755 +/- 2,475, 438 +/- 52, 67 +/- 38 and 68 +/- 31 mg kg(-1), respectively. The results revealed the mean contents of Pb and Zn exceeded the third level of China standard of soil (GB15618-1995) for 10.4 and 26.7 times, respectively. The soil of Siding Pb-Zn mineland has heavily been subjected to Pb and Zn pollution. 22 plant species from 13 families were found colonizing. There were great variations of metal contents in plant species with Pb 1.58-1496 mg kg( 1), Zn 7.56-204,256 mg kg(-1), Cu not detected (ND)-286 mg kg(-1), Fe 83-25,972 mg kg(-1), Mn 1.02-160 mg kg(-1) and Cr ND-152 mg kg(-1). Of the six metals, Fe content was the highest, followed by Pb and Zn, which were similar to the situation of the soil. The local pioneer species, Pteris vittata, was observed a higher accumulation and translocation capability for Pb, which could be chosen as pioneer of phytoremediations to restore Pb/Zn mineland. PMID- 22105936 TI - Some heavy metals accumulation in tissues in Capoeta umbla (Heckel, 1843) from Uzuncayir Dam Lake (Tunceli, Turkey). AB - Concentrations of metals were determined in the gills, liver, kidney, heart and muscle in Capoeta umbla caught from six stations from the Munzur River system. Metal concentrations in the tissues tended to vary significantly among stations (p < 0.05). Liver (Cu, 10.10 +/- 0.23-23.03 +/- 9.37 ppm; Zn, 14.67 +/- 3.01 21.82 +/- 2.39 ppm; Cd, 18.04 +/- 4.56-52.69 +/- 10.65 ppb and Fe, 28.87 +/- 6.78 115.11 +/- 34.87 ppm) and kidney (Cu, 1.80 +/- 0.25-3.70 +/- 0.62 ppm; Zn, 20.81 +/- 0.37-29.36 +/- 0.70 ppm; Cd, 132.06 +/- 5.29-639.51 +/- 20.14 ppb and Fe, 24.40 +/- 1.98-59.39 +/- 1.97 ppm) tissues showed higher metal concentrations than other tissues. It seems that metal contamination in the river is too high for the health of fish and the people who eat them. The geographical locations of catch, season, nature of diet, and the size of fish used for analyses might lead to different metal concentration in the same fish species. PMID- 22105937 TI - Lead levels in breast milk, blood plasma and intelligence quotient: a health hazard for women and infants. AB - Lead levels in human breast milk and blood plasma or serum were analyzed and qualitatively their intelligence quotient (I.Q.) studied. Samples at different stages of lactation, from 5 days to 51 weeks post partum, were collected from 25 healthy breast-feeding mothers in Ranipet Industrial area of Vellore district of Tamil Nadu and from 25 lactating mothers in the non-industrial areas of the same district. The samples from mothers in non-industrial area showed lower lead levels ranging from 5 to 25 MUg/L whereas samples from mothers in industrial area showed higher lead levels ranging between 15 and 44.5 MUg/L. It was generally noticed that the lactating mothers from industrial area have lower I.Q. levels compared to mothers from non-industrial area. PMID- 22105938 TI - Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis. AB - Schwannomatosis is a recently delineated inherited condition that has clinical overlap with neurofibromatosis type 2 (NF2). Diagnostic criteria have been developed to distinguish schwannomatosis from NF2, but the existence of mosaic NF2, which may closely mimic schwannomatosis, makes even these criteria problematic. In particular, it is not clear why there is a relative sparing of the cranial nerves from schwannomas in schwannomatosis. We have identified two individuals with schwannomatosis and a unilateral vestibular schwannoma (VS), where a diagnosis of NF2 has been excluded. A third case with an identified SMARCB1 mutation was reported by two radiologists to have a VS, but this was later confirmed as a jugular schwannoma. These cases question whether the current exclusion of a VS from the clinical diagnosis of schwannomatosis is justified. PMID- 22105939 TI - DHEA, DHEA-S and cortisol responses to acute exercise in older adults in relation to exercise training status and sex. AB - The aim of the present study was to investigate resting measures of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S) and cortisol, and the response and recovery of these hormones to acute exercise, in male and female older adults of different exercise training status. Participants were 49 community-dwelling older adults (23 females) aged between 60 and 77 years who were either sedentary (n=14), moderately active (n=14) or endurance trained (n=21). Participants undertook an acute bout of exercise in the form of an incremental submaximal treadmill test. The exercise lasted on average 23 min 49 s (SD=2 min 8 s) and participants reached 76.5% (SD=5.44) of the predicted maximal heart rate. Blood samples were collected prior to exercise, immediately, and 1 h post-exercise. DHEA levels significantly increased immediately post-exercise; however, DHEA-S levels only significantly increased in females. Cortisol significantly decreased immediately post-exercise and 1 h post-exercise compared to pre-exercise. There were no significant differences in resting hormone levels or hormonal responses to exercise between training status groups. The findings suggest that exercise can stimulate DHEA production in older adults and that hormonal responses to exercise differ between male and female older adults. PMID- 22105940 TI - A comparison between dual axis rotational coronary angiography and conventional coronary angiography. AB - BACKGROUND: Coronary angiography remains the gold standard for the investigation of coronary artery disease, and is carried out in multiple, predefined stationary views, at different angulations around the patient, for both left and right coronary arteries. Dual axis rotational coronary angiography (DARA) is an alternative technique wherein the c-arm rotates around the patient in a preprogrammed single acquisition, exposing the entire coronary artery at different angulations. The DARA system has been recently installed in the Cardiac Catheterisation Suite at Mater Dei Hospital, Malta, where a monoplane and a biplane machine are available. This study was carried out in order to compare DARA with conventional single and biplane coronary imaging, with respect to radiation dose, contrast loads, and procedure time. METHODS: This study was carried out over the period from September to December 2010. Four hundred sixty three patients were studied. Patients referred for the investigation of native coronary anatomy, for whatever indication, were consented and included, and randomly assigned to one of four groups depending on which machine and modality was used: monoplane conventional, monoplane DARA, biplane conventional, and biplane DARA. RESULTS: DARA was statistically significantly superior in dose area product, fluoroscopy time, amount of contrast used, and procedure time. These reductions ranged between 12 (contrast used) and 71% (procedure time). CONCLUSIONS: The advantages of such systems are obvious to both patient and healthcare provider, and DARA may prove to be an important and useful tool in the refinement of diagnostic coronary angiography by reducing patient contrast and radiation doses and reducing procedure time. PMID- 22105941 TI - Influence of vitreous factors after vitrectomy for macular edema in patients with central retinal vein occlusion. AB - To investigate whether vitreous fluid levels of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and soluble intercellular adhesion molecule 1 (sICAM-1) influence visual prognosis and macular edema in patients with central retinal vein occlusion (CRVO). A prospective observational study was performed in 31 consecutive CRVO patients (31 eyes) with macular edema who underwent vitrectomy. Best-corrected visual acuity (BCVA), retinal thickness (examined by OCT), and vitreous fluid levels of VEGF, PEDF, and sICAM-1 were determined. Patients were followed for at least 6 months after surgery. Both visual acuity and retinal thickness showed significant improvement at 6 months postoperatively (P = 0.012 and P < 0.001, respectively). Vitreous fluid levels of VEGF were significantly higher (P = 0.027) in patients who showed less improvement of BCVA after vitrectomy than in those with a better outcome. Conversely, vitreous levels of PEDF were significantly lower (P = 0.047) in patients with less improvement of BCVA than in those with a better outcome. Vitreous levels of sICAM-1 were not significantly correlated with BCVA after vitrectomy (P = 0.731). Multiple regression analysis demonstrated that vitreous fluid levels of VEGF and PEDF were significant determinants of the improvement of BCVA (P = 0.013 and P = 0.007, respectively). These results suggest that vitreous fluid levels of VEGF and PEDF might influence visual prognosis after vitrectomy in CRVO patients with macular edema. PMID- 22105942 TI - Controlled origami folding of hydrogel bilayers with sustained reversibility for robust microcarriers. PMID- 22105943 TI - Epoxidation of alkenes catalyzed by phenyl group-modified, periodic mesoporous organosilica-entrapped, dimeric manganese-salen complexes. AB - A series of reusable, recoverable, diamine-bridged dimeric manganese-salen complexes were prepared by the encapsulation of homogeneous dimeric Mn(salen) complexes into nanocages of a 3D periodic mesoporous organosilica (PMO) support followed by silylation of the support with organosilane. The composition, structure, morphology, and textural properties of the prepared PMO-entrapped dimeric Mn(salen) complexes were characterized, and their catalytic performances were tested in the epoxidation of alkenes (styrene, cyclohexene, and 1 phenylcyclohexene), with NaClO as an oxygen source and 4-phenylpyridine-N-oxide as an axial ligand. Furthermore, the influences of the textural and morphological properties of the entrapped dimeric Mn(salen) complexes and the key reaction parameters on the catalytic activity and selectivity are discussed. Finally, the reusability of the supported dimeric Mn(salen) complexes was evaluated over three catalytic runs. PMID- 22105944 TI - Validation of the Swedish M. D. Anderson Dysphagia Inventory (MDADI) in patients with head and neck cancer and neurologic swallowing disturbances. AB - The aim of this study was to validate the Swedish version of the dysphagia specific quality-of-life questionnaire, the M. D. Anderson Dysphagia Inventory (MDADI). Patients with oropharyngeal dysphagia due to neurologic disease (n = 30) and head and neck (H&N) cancer patients with post-treatment subjective dysphagia (n = 85) were compared to an age- and gender-matched nondysphagic control group (n = 115). A formal forward-backward translation was performed and followed international guidelines. Validity and reliability were tested against the Short Form 36 (SF-36) and Hospital Anxiety and Depression Scale (HADS). Internal consistency reliability was calculated by means of Cronbach's alpha coefficient. Test-retest reliability was assessed by intraclass correlation (ICC). Convergent and discriminant validity were assessed by correlations between MDADI, SF-36, and HADS. Known-group validity was examined and statistically tested. Of 126 eligible patients, 115 agreed to participate (response rate = 91.3%). The age of the participants ranged between 37 and 92 years. Most of the MDADI items showed good variability and only minor floor or ceiling effects in solitary items were found. The internal-consistency reliability (Cronbach's alpha) of the MDADI total score was 0.88 (after correction for systematic errors in the subjects' responses to two reversed questions). All estimates reached over the satisfactory >0.70 reliability standard for group-level comparison. ICC ranged between 0.83 and 0.97 in the test-retest. The mean MDADI total score was 66.9 (SD = 14.7) for the H&N cancer patients, 65.0 (16.9) for the neurologic patients, and 97.5 (4.4) for the control group (P < 0.001; study patients vs. controls). The MDADI was also sensitive to disease severity as measured by different food textures. The Swedish version of the MDADI showed good psychometric properties and is a valid instrument to assess dysphagia-related quality of life. It was also shown to be a reliable instrument after correction for systematic errors in the subjects' responses to two reversed questions. Its known-group validity enables the differentiation between dysphagic and nondysphagic patients for group-level research. PMID- 22105945 TI - Peptide-linked porphyrin sensitiser and colloidal Pt or Ir catalyst in the H2 formation reaction. AB - Porphyrins linking amphiphilic peptides were applied as photosensitisers, assuming that they would interact with the H(+) reduction catalyst, polymer protected colloidal Pt or Ir. The close orientation of the porphyrin and metal catalyst may facilitate efficient electron transfer. The porphyrin linking a peptide containing glutamic acids (Glu), Ac-Cys(porph)-Glu-Val-Glu-Val-NH(2) (2), was an effective sensitiser for the H(2) generation reaction in the presence of N benzyldihydronicotinamide and colloidal Pt or Ir in aqueous media under visible light illumination. At pH 5 and 7, 2 was a more efficient photosensitiser than tetrakis(p-carboxyphenyl)porphyrin (TCPP). The efficiency of H(+) reduction catalysts was in the order Ir-pGlu (polyglutamic acid) > Ir-PVP (polyvinylpyrrolidone) > Pt-PVP. Dynamic light scattering and scanning electron microscopy measurements showed that large particles formed when colloidal metal solutions were produced by microwave irradiation. Fluorescence quenching experiments suggested that electron transfer occurred from the photoexcited porphyrin to the colloidal Ir. PMID- 22105946 TI - Valence state-dependent ferromagnetism in Mn-doped NiO thin films. AB - Manipulating the ferromagnetism of diluted magnetic semiconductors by tuning the valence state of doped ions is found to be achievable in Mn-doped NiO. First principles calculations predict that the interactions between substitutional Mn(3+) ions in NiO are ferromagnetic, while the Mn(2+)-Mn(2+) interactions are antiferromagnetic. This scenario is experimentally supported by a great enhancement of saturation magnetization with increased Mn(3+)/Mn(2+) ratio in Mn doped and (Mn, Li)-codoped NiO. PMID- 22105949 TI - Eye closure and oculopalatal tremor. PMID- 22105950 TI - Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. PMID- 22105951 TI - Statins after ischemic stroke of undetermined etiology in young adults. PMID- 22105948 TI - Alzheimer disease biomarkers are associated with body mass index. AB - OBJECTIVE: Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment. METHODS: We analyzed cross-sectional data from participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for beta-amyloid peptide (Abeta) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers. RESULTS: No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Abeta (beta = 0.181, p < 0.001), tau (beta = 0.179, p < 0.001), tau/Abeta ratio (beta = -0.180, p < 0.001), and global PiB uptake (beta = -0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associated with lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups. CONCLUSIONS: The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology. PMID- 22105952 TI - Neuronal intracellular transport and neurodegenerative disease. PMID- 22105953 TI - Etiologic investigation of ischemic stroke in young adults. PMID- 22105955 TI - Teaching NeuroImages: Acute necrotizing encephalopathy during novel influenza A (H1N1) virus infection. PMID- 22105956 TI - Teaching NeuroImages: Isolated vertigo and imbalance due to deep border zone cerebellar infarct. PMID- 22105957 TI - Teaching NeuroImages: TIA from an air embolism. PMID- 22105958 TI - Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. PMID- 22105959 TI - Auriculo-condylar syndrome. Confronting a diagnostic challenge. AB - Auriculo-condylar syndrome (ACS) is characterized by typical ears malformation (so-called "question mark" ears), prominent cheeks, microstomia, and abnormality of the temporomandibular joint and condyle of the mandible. In this report we describe a new simplex case and a previously unreported family with affected individuals in three generations documenting clinical variability. Linkage study for markers located in candidate region for ACS1 (1p21.1-q23.3) was excluded in our familial case, reinforcing the hypothesis of genetic heterogeneity for this condition. A review of the literature focusing diagnostic criteria and features of ACS was performed. PMID- 22105960 TI - Enhanced biomimetic performance of ionic polymer-metal composite actuators prepared with nanostructured block ionomers. AB - Ionic polymer-metal composites (IPMCs) represent an important class of stimuli responsive polymers that are capable of bending upon application of an electric potential. Conventional IPMCs, prepared with Nafion and related polyelectrolytes, often suffer from processing challenges, relatively low actuation levels and back relaxation during actuation. In this study, we examine and compare the effects of fabrication and solvent on the actuation behavior of a block ionomer with a sulfonated midblock and glassy endblocks that are capable of self-organizing and thus stabilizing a molecular network in the presence of a polar solvent. Unlike Nafion, this material can be readily dissolved and cast from solution to yield films that vary in thickness and exhibit enormous solvent uptake. Cycling the initial chemical deposition of Pt on the surfaces of swollen films (the compositing process) increases the extent to which the electrodes penetrate the films, thereby improving contact along the polymer/electrode interface. The maximum bending actuation measured from IPMCs prepared with different solvents is at least comparable, but is often superior, to that reported for conventional IPMCs, without evidence of back relaxation. An unexpected characteristic observed here is that the actuation direction can be solvent regulated. Our results confirm that this block ionomer constitutes an attractive alternative for use in IPMCs and their associated applications. PMID- 22105961 TI - Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families. PMID- 22105963 TI - Early detection of deteriorating ventilation: prevention is better than cure! PMID- 22105962 TI - Early detection of deteriorating ventilation by monitoring bilateral chest wall dynamics in the rabbit. AB - PURPOSE: Mechanical complications during assisted ventilation can evolve due to worsening lung disease or problems in airway management. These complications affect lung compliance or airway resistance, which in turn affect the chest wall dynamics. The objective of this study was to explore the utility of continuous monitoring of the symmetry and dynamics of chest wall motion in the early detection of complications during mechanical ventilation. METHODS: The local tidal displacement (TDi) values of each side of the chest and epigastrium were measured by three miniature motion sensors in 18 rabbits. The TDi responses to changes in peak inspiratory pressure (n = 7), induction of one-lung intubation (n = 7), and slowly progressing pneumothorax (PTX) (n = 6) were monitored in parallel with conventional respiratory (SpO(2), EtCO(2), pressure and flow) and hemodynamic (HR and BP) indices. PTX was induced by injecting air into the pleural space at a rate of 1 mL/min. RESULTS: A strong correlation (R(2) = 0.99) with a slope close to unity (0.94) was observed between percent change in tidal volume and in TDi. One-lung ventilation was identified by conspicuous asymmetry development between left and right TDis. These indices provided significantly early detection of uneven ventilation during slowly developing PTX (within 12.9 +/- 6.6 min of onset, p = 0.02) almost 1 h before the SpO(2) dropped (77.3 +/- 27.4 min, p = 0.02). Decreases in TDi of the affected side paralleled the progression of PTX. CONCLUSIONS: Monitoring the local TDi is a sensitive method for detecting changes in tidal volume and enables early detection of developing asymmetric ventilation. PMID- 22105964 TI - Conversion of biomass-derived levulinate and formate esters into gamma valerolactone over supported gold catalysts. AB - The utilization of biomass has recently attracted tremendous attention as a potential alternative to petroleum for the production of liquid fuels and chemicals. We report an efficient alcohol-mediated reactive extraction strategy by which a hydrophobic mixture of butyl levulinate and formate esters, derived from cellulosic biomass, can be converted to valuable gamma-valerolactone (GVL) by a simple supported gold catalyst system without need of an external hydrogen source. The essential role of the supported gold is to facilitate the rapid and selective decomposition of butyl formate to produce a hydrogen stream, which enables the highly effective reduction of butyl levulinate into GVL. This protocol simplifies the recovery and recycling of sulfuric acid, which is used for cellulose deconstruction. PMID- 22105966 TI - Correction to: "Severe hypertension in children and adolescents: pathophysiology and treatment". PMID- 22105967 TI - Clinical features and outcomes of 98 children and adults with dense deposit disease. AB - BACKGROUND: Dense deposit disease (DDD) is an ultra-rare renal disease. METHODS: In the study reported here, 98 patients and their families participated in a descriptive patient-centered survey using an online research format. Reports were completed by patients (38%) or their parents (62%). Age at diagnosis ranged from 1.9 to 38.9 years (mean 14 years). RESULTS: The majority of patients presented with proteinuria and hematuria; 50% had hypertension and edema. Steroids were commonly prescribed, although their use was not evidence-based. One-half of the patients with DDD for 10 years progressed to end-stage renal disease (ESRD), with young females having the greatest risk for renal failure. Of first allografts, 45% failed within 5 years, most frequently due to recurrent disease (70%). Type 1 diabetes (T1D) was present in over 16% of families, which represents a 116-fold increase in incidence compared with the general population (p < 0.001). CONCLUSIONS: Based on these findings, we suggest that initiatives are needed to explore the high incidence of T1D in family members of DDD patients and the greater risk for progression to ESRD in young females with DDD. These efforts must be supported by sufficient numbers of patients to establish evidence-based practice guidelines for disease management. An international collaborative research survey should be implemented to encourage broad access and participation. PMID- 22105968 TI - Association between left ventricular mass index and cardiac function in pediatric dialysis patients. AB - BACKGROUND: Left ventricular mass index (LVMI) is a surrogate of left ventricular hypertrophy and a predictor of cardiac morbidity and mortality in adults with hypertension. LVMI has not been linked to cardiovascular endpoints in children. The aim of this study was to identify an association between elevated LVMI and echocardiographic markers of systolic and diastolic function. METHODS: The study was a retrospective review of chronic dialysis patients from June 1995 to December 2009 at a single tertiary care children's hospital. The upper limit cutoffs for LVMI were set at >38.6 g/m(2.7), >51 g/m(2.7), and by age and sex based normative values. Sixty-three patients (mean age 14.1 years, 56% males) were enrolled in the study, with a total of 287 echocardiograms. RESULTS: Post dialysis hypertension was associated with elevated LVMI in both the >51 g/m(2.7) [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.5-5.5] and normative (OR 3.4, 95% CI 1.5-7.7) models. Elevated LVMI, when defined by the >51 g/m(2.7) and normative models, was significantly associated with decreased shortening fraction (OR 4.1, 95% CI 1.7-9.8 and OR 5.4, 95% CI 1.3-22.9, respectively) and increased mitral E wave to lateral mitral tissue Doppler e' wave velocity ratio (E/e'; OR 3.5, 95% CI 1.1-11.2 and OR 4.5, 95% CI 1.0-21.6, respectively). CONCLUSIONS: Elevated LVMI is associated with decreased systolic and diastolic cardiac function, justifying its use as a surrogate of hypertensive cardiomyopathy in children undergoing chronic dialysis. PMID- 22105969 TI - Clinical outcomes and predictors of unprotected left main stem culprit lesions in patients with acute ST segment elevation myocardial infarction. AB - OBJECTIVES: We aimed at comparing the clinical outcomes of the patients who underwent percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI) due to left main coronary arteries (LMCA) and non LMCA determining the predictors of mortality in the patients. BACKGROUND: There are few data regarding the midterm prognosis of STEMI due to LMCA as compared with them due to non-LMCA. METHODS: A total of 4,697 patients with STEMI (61 patients with LMCA and 4,636 patients with non-LMCA) were enrolled in a nationwide Korea Acute Myocardial Infarction (MI) Registry between November 2005 and September 2009. The primary endpoints was a composite of cardiac death, nonfatal MI, and target lesion and vessel revascularization (TLR/TVR) during a 12 month clinical follow-up. RESULTS: The LMCA group had a higher incidence of total major adverse cardiac events (MACEs) (26.2% vs. 7.8%; P < 0.001) at 12 months, which was largely attributable to cardiac deaths at 1 month (21.3% vs. 3.8%; P < 0.001). Therefore, there was no statistical difference in cardiac deaths, nonfatal MI, TLR/TVR, and MACEs after 1 month between the two groups. Presenting in cardiogenic shock (HR, 4.25; 95% CI, 1.01-17.97; P = 0.049) and heart rate >=100 bpm (HR, 4.97; 95% CI, 1.18-21.00; P = 0.029) were independent predictors of cardiac death due to LMCA. CONCLUSION: Patients with STEMI and a LMCA had poor clinical outcomes, which is attributable to hemodynamic deterioration during the periprocedural period. However, after that time, midterm MACEs of the survivors following the periprocedural period may not be different between STEMI due to LMCA and non-LMCA. PMID- 22105970 TI - Phosphopeptide-dependent labeling of 14-3-3 zeta proteins by fusicoccin-based fluorescent probes. AB - Fluorescent combination: Cell-penetrating probes derived from the diterpene fusicoccin can form ternary complexes with 14-3-3 proteins and phosphopeptide ligands, whereupon the probes site-specifically attach a fluorescent tag onto the surface of the 14-3-3 proteins. PMID- 22105971 TI - Insight into the local structure of barium indate oxide-ion conductors: an X-ray total scattering study. AB - In this paper we presented the X-ray PDF investigation of orthorhombic Ba(2)In(2)O(5) and cubic Ba(2)In(1.7)P(0.3)O(5.3) and Ba(2)In(1.7)S(0.3)O(5.45) samples. Pure Ba(2)In(2)O(5) was found to be properly described-at the local scale-by the orthorhombic average structure. Ba(2)In(1.7)P(0.3)O(5.3) and Ba(2)In(1.7)S(0.3)O(5.45) cannot be described, at the local scale, by a cubic symmetry. The PDFs of these two samples clearly showed a distorted atom arrangement in the short-range which can be described again with the orthorhombic symmetry found in pure barium indate. PMID- 22105972 TI - Large area fabrication of leaning silicon nanopillars for surface enhanced Raman spectroscopy. AB - Using a simple two step fabrication process substrates with a large and uniform Raman enhancement, based on flexible free standing nanopillars can be manufactured over large areas using readily available silicon processing equipment. PMID- 22105973 TI - Regional variation in prevalence of oral cleft live births in the Netherlands 1997-2007: time-trend analysis of data from three Dutch registries. AB - The Eurocat registry Northern Netherlands (NNL) has been used in regional context, as well as in national/international context, to describe the epidemiology of oral clefts (OC). However, the region NNL seems to have prevalence data different from Dutch national registries and certain other European areas. This may be due to differences in registration methods or geographical variation. To investigate whether the prevalence of OC live births varies regionally in the Netherlands, we established time trends for NNL and the rest of the Netherlands over 1997-2007 using data from two national registries (the OC Registry and The Netherlands Perinatal Registry) and a regional registry (Eurocat NNL). We found that the overall live-birth prevalence-comprising cleft lip/alveolus +/- cleft palate and cleft palate only-was significantly higher in NNL (15.1-21.4 per 10,000) than in the rest of the Netherlands (13.2-16.1 per 10,000). None of the registries showed significant trends for NNL, whereas both national registries showed that the live-birth prevalence of cleft lip/alveolus +/- cleft palate decreased significantly in the rest of the Netherlands. Despite some differences in prevalence between the registries, they showed similar regional variation in prevalence and trends. In conclusion, the prevalence of OC live births varies significantly in the Netherlands, not only between but also within registries. This underlines that extrapolation of regional cleft data should be done with caution. To further investigate OC etiology and evaluate preventive strategies, future studies should consider geographical differences between and within countries-regarding the various cleft sub-phenotypes among live births, stillbirths, and pregnancy terminations. PMID- 22105974 TI - High polybrominated diphenyl ether levels in California house cats: house dust a primary source? AB - Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that act as endocrine disruptors, affecting thyroid hormone homeostasis. As a follow-up to a recent study showing high PBDE levels in household cats and linking PBDE levels with cat hyperthyroidism, we measured PBDEs, polychlorinated biphenyls (PCBs), and organochlorinated pesticides (OCPs) in serum samples from 26 California household cats (16 hyperthyroid, 10 controls) using liquid-liquid extraction and high-resolution gas chromatography/high-resolution mass spectrometry. In the present pilot study, we found that PBDE levels in California house cats were extremely high (SigmaPBDEs median = 2,904 ng/g lipid; range, 631-22,537 ng/g lipid). This is approximately 50 times higher than levels in California residents (SigmaPBDEs geomean = 62 +/- 8.9 ng/g lipid, National Health and Nutrition Examination Survey), who have among the highest human levels in the world. Polybrominated diphenyl ethers congener patterns (BDE-99 major congener, BDE-209 significant) differed markedly from patterns found in California residents (BDE 47 major) or wildlife but resembled patterns found in house dust. Polychlorinated biphenyls and OCPs in cats were highly correlated, consistent with a shared dietary source or pathway of exposure, but did not correlate with PBDEs. This suggests a different source or pathway of exposure for PBDEs, which was most likely house dust. The authors found no evidence that linked levels of PBDEs, PCBs, or OCPs with hyperthyroidism. This may be because of the small sample size, competing or confounding risk factors, or complicated causal mechanisms. PMID- 22105975 TI - Patella baja after unicompartmental knee arthroplasty. AB - PURPOSE: The literature data on patellar height following unicompartmental knee arthroplasty (UKA) are scarce. METHODS: A total of 41 knee joints in 37 patients after UKA were prospectively evaluated for patellar height by using the Insall Salvati and modified Insall-Salvati ratio. Patellar height was measured preoperatively, postoperatively, at 6, 12 weeks, and, at 1 year postoperatively. Patients were categorized according to age, gender, operated side, and rehabilitation program. RESULTS: Regarding all the patients, the Insall-Salvati ratio demonstrated a significant decrease only for the time period "postoperatively-1 year postoperatively", whereas the modified Insall-Salvati ratio showed a significant decrease only for the period "preoperatively postoperatively". The Insall-Salvati ratio showed a significant decrease in the patellar height of men and left knees, whereas the modified Insall-Salvati ratio revealed a significant decrease in patients older than 65 years and those who followed a specific rehabilitation program. CONCLUSIONS: The decrease in the patellar height after UKA occurs within the first postoperative year. Women, right knees, patients younger than 65 years and those who do not follow a specific rehabilitation program are less prone to decrease in the patellar height; ratio-specific differences are evident for each subgroup. LEVEL OF EVIDENCE: Diagnostic study, Level III. PMID- 22105976 TI - Surgery for anterior cruciate ligament deficiency: a historical perspective. AB - The anterior cruciate ligament (ACL) has entertained scientific minds since the Weber brothers provided biomechanical insight into the importance of the ACL in maintaining normal knee kinematics. Robert Adams described the first clinical case of ACL rupture in 1837 some 175 years to date, followed by Mayo-Robson of Leeds who performed the first ACL repair in 1895. At that time, most patients presented late and clinicians started to appreciate signs and symptoms and disabilities associated with such injuries. Hey Groves of Bristol provided the initial description of an ACL reconstruction with autologous tissue graft in 1917, almost as we know it today. His knowledge and achievements were, however, not uniformly appreciated during his life time. What followed was a period of startling ingenuity which created an amazing variety of different surgical procedures often based more on surgical fashion and the absence of a satisfactory alternative than any indication that continued refinements were leading to improved results. It is hence not surprising that real inventors were forgotten, good ideas discarded and untried surgical methods adopted with uncritical enthusiasm only to be set aside without further explanation. Over the past 100 years, surgeons have experimented with a variety of different graft sources including xenograft, and allografts, whilst autologous tissue has remained the most popular choice. Synthetic graft materials enjoyed temporary popularity in the 1980 and 1990s, in the misguided belief that artificial ligaments may be more durable and better equipped to withstand stresses and strains. Until the 1970s, ACL reconstructions were considered formidable procedures, often so complex and fraught with peril that they remained reserved for a chosen few, never gaining the level of popularity they are enjoying today. The increasing familiarity with arthroscopy, popularised through Jackson and Dandy, and enhancements in surgical technology firmly established ACL reconstruction as a common procedure within the realm of most surgeons' ability. More recently, the principle of anatomic ACL reconstruction, aiming at the functional restoration of native ACL dimensions and insertion sites, has been introduced, superseding the somewhat ill-advised concept of isometric graft placement. Double-bundle reconstruction is gaining in popularity, and combined extra- and intra-articular procedures are seeing a revival, but more accurate and reliable pre- and post-operative assessment tools are required to provide customised treatment options and appropriate evaluation and comparability of long-term results. Modern ACL surgery is united in the common goal of re-establishing joint homoeostasis with normal knee kinematics and function which may ultimately assist in reducing the prevalence of post-operative joint degeneration. This review hopes to provide an insight into the historical developments of ACL surgery and the various controversies surrounding its progress. Level of evidence V. PMID- 22105977 TI - Combined PCL and PLC reconstruction in chronic posterolateral instability. AB - PURPOSE: The posterolateral corner (PLC) is more likely to be injured in combination with the posterior cruciate ligament (PCL) or the anterior cruciate ligament than in isolation. This leads to instability of the knee and loss of function. We hypothesised that combined PCL and PLC reconstruction would restore sufficient stability to allow improvement in patient symptoms and function. METHODS: 19 patients who underwent arthroscopic-assisted single-bundle PCL and PLC reconstruction by a single surgeon were analysed retrospectively. The PLC reconstruction was a modified Larson reconstruction of the lateral collateral ligament and the popliteofibular ligament. The IKDC and Tegner scores were used to assess outcome. Dial test and varus laxity were used to assess improvements in clinical laxity. Posterior laxity was tested using the KT-1000. RESULTS: The mean follow-up was 38 months (+/-(2* standard deviations), +/-12.3). There were no postoperative complications. All patients had less than 5 mm posterior step-off. 17 of 19 patients had negative dial and varus stress tests. Measured range of motion was reduced by a mean of 10 degrees , but patients did not report any daily activities restrictions. Tegner scores improved from a median pre-operative value of 2 (range 1-4) to 6 (4-9) at final follow-up. The mean postoperative IKDC score was 86 (+/-11). CONCLUSIONS: Subjectively, the knee stability achieved allowed daily activities. However, there were remaining abnormalities in range of motion, posterior drawer and rotational laxity, suggesting that normal knee laxity was not restored. LEVEL OF EVIDENCE: IV. PMID- 22105978 TI - Functional outcome following aseptic single-stage revision knee arthroplasty. AB - PURPOSE: This study attempts to quantify the influence of constraint and various indications upon functional outcome following aseptic first-time revision knee arthroplasty. METHODS: A single-centre prospective study was performed to examine the outcome for 175 consecutive total revision knee replacements performed between 2003 and 2008 with a minimum follow-up of 2 years. Patient-reported outcome data were used to determine the influence of final level of component constraint, its relationship with primary indication for surgery and the predictor variable for functional outcome at 1 year. RESULTS: All patients were found to have a significant improvement for WOMAC pain, function and stiffness score and physical functioning, role physical, bodily pain and social functioning components of SF-36 score. About 69% were satisfied with the overall procedure. WOMAC function, pain and stiffness score was significantly worse for patients revised for instability (27%) compared to that for aseptic loosening (46%). A significantly higher proportion of patients were satisfied with the procedure, had a better quality of life and would have the surgery again in the aseptic loosening group as compared to the instability group. Revision to a higher level of constraint did not improve knee function irrespective of the primary indication for surgery. CONCLUSION: This study has found that revision for instability, irrespective of choice of new device, was met with significantly poorer functional outcome. The level of constraint did not influence functional outcome. LEVEL OF EVIDENCE: II. PMID- 22105979 TI - Reconstructive surgery using autologous bone-patellar tendon graft for insertional Achilles tendinopathy. AB - PURPOSE: The purpose of this study was to investigate the clinical results of reconstructive surgery using a bone-patellar tendon (BPT) autograft for athletes with intractable insertional Achilles tendinopathy. METHODS: Ten athletes who underwent reconstructive surgery using a BPT autograft were included in this study. Indications were (1) persistent symptoms in spite of conservative therapy for 6 months, and (2) diffuse high intensity changes of an entire cross-section of the tendon at its insertion point on T2-weighted magnetic resonance imaging (MRI), with clinical follow-up of more than 24 months after surgery. Clinical evaluation was performed before surgery and at the most recent follow-up [median: 32 (25-48) months], and radiological assessment at 1 year after surgery. RESULTS: The median Achilles tendon rupture score at the most recent follow-up was 92.5 (85-100) points. The median visual analogue scale score improved significantly from 90 (85-100) points preoperatively to 5 (0-10) points at the most recent follow-up (P < 0.01). Based on T2-weighted MRI, the anterior-posterior width of the grafted BPT was approximately twice that of the intact nonsurgical contralateral tendon insertion in all patients at 1 year after surgery. The median time from surgery to ability to return to full sports activity was 13.5 months. CONCLUSIONS: The reconstructive surgery presented in this study can be useful for athletes who suffer from insertional Achilles tendinopathy with a wide area of diseased tendon at the insertion point. LEVEL OF EVIDENCE: IV. PMID- 22105980 TI - Formation of structured polygonal nanoparticles by phase-separated comb-like polymers. AB - A simple approach using comb-like polymers that undergo nanophase separation between the polyester backbone and the stearoyl side chains is proposed for the preparation of structured non-spherical nanoparticles from a nanoemulsion. Depending on the degree of esterification of the OH groups of poly(glycerol adipate) differently ordered nanostructures is obtained. A perfect lamellar arrangement is obtained for polymers with a high degree of esterification and leads to spherical nanoparticles with an internal onion-like structure. However, when the degree of esterification is only 20 mol%, polygonal nanoparticles with an internal pseudo-hexagonal structure are obtained. The differences in the nanoparticle shapes are related to the volume fraction of the paraffinic pool. PMID- 22105981 TI - JHM 2.0: The Journal of Hospital Medicine at its first transition. PMID- 22105982 TI - Heterothermy in two mole-rat species subjected to interacting thermoregulatory challenges. AB - Maintaining a high and constant body temperature (T(b) ) is often viewed as a fundamental benefit of endothermy, but variation in T(b) is likely the norm rather than an exception among endotherms. Thus, attempts to elucidate which factors cause T(b) of endotherms to deviate away from the T(b) that maximizes performance are becoming more common. One approach relies on an adaptive framework of thermoregulation, used for a long time to predict variation in T(b) of ectotherms, as a starting point to make predictions about the factors that should lead to thermoregulatory variation in endotherms. Here we test the predictions that when confronted with thermoregulatory challenges endotherms should (1) become more heterothermic, (2) lower their T(b) setpoint, and/or (3) increase behavioral thermoregulation (e.g., activity levels or social thermoregulation). We exposed two species of relatively homeothermic mole-rats to two such challenges: (a) ambient temperatures (T(a)) well below the thermoneutral zone and (b) increased heat loss caused by the removal of dorsal fur. In general, our results support the adaptive framework of endothermic thermoregulation with each species conforming to some of the predictions. For example, Mashona mole rats (Fukomys darlingi) increased heterothermy as T(a) decreased, highveld mole rats (Cryptomys hottentotus pretoriae) displayed lower T(b) 's after shaving, and both species increased behavioral thermoregulation as T(a) decreased. This suggests that there is some merit in extending the adaptive framework to endotherms. However, none of the three predictions we tested was supported under all experimental conditions, reiterating that attempts to determine universal factors causing variation in T(b) of endotherms may prove challenging. PMID- 22105983 TI - Two Melodies in concert: transcatheter double-valve replacement. AB - Percutaneous pulmonary valve implantation has been established as a valuable treatment option for elder children and adolescents with conduit failure in the right ventricular outflow tract. Transcatheter valve implantation in the tricuspid position is restricted to single case reports. A 26-year-old male initially diagnosed with tetralogy of Fallot and hypoplastic pulmonary arteries hitherto underwent a total of five open chest procedures including tricuspid valve replacement with a bioprosthesis and a pulmonary homograft exchange. He now presented with severe right heart failure due to a degenerated pulmonary homograft and calcified, severely stenotic tricuspid bioprosthesis with markedly dilated and reduced right ventricular function. We report on the first successful percutaneous transcatheter double-valve replacement using two Melody valves in the pulmonary and tricuspid position, respectively. PMID- 22105984 TI - Controlling the nucleation and growth of silver on palladium nanocubes by manipulating the reaction kinetics. PMID- 22105985 TI - Organogel-hydrogel transformation by simple removal or inclusion of N-Boc protection. AB - Development of organo- and hydrogelators is on the rise because of their extensive applications, from advanced materials to biomedicine. However, designing both types of gelator from a common structural scaffold is challenging, and becomes more significant if transformation between them can be achieved by a simple method. The present work reports the design and synthesis of both organo- and hydrogelators from amino acid/peptide-based amphiphilic precursors with a naphthyl group at the N terminus and a primary amine-containing hydrophilic ethyleneoxy unit at the C terminus. In alkaline medium, tert-butyloxycarbonyl (Boc) protection at the primary amine of the amphiphiles resulted in efficient organogelators (minimum-gelation concentration (MGC)=0.075-1.5% w/v). Interestingly, removal of the Boc protection from the ethyleneoxy unit, under acidic conditions, yielded amphiphiles capable of gelating water (MGC=0.9-3.0% w/v). Simple protection and deprotection chemistry was used to achieve transformation between the organogel and hydrogel by alteration of the pH. Combinations of different aliphatic and aromatic amino acids were investigated to discover their cumulative effect on the gelation properties. Field-emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) were employed to investigate the supramolecular morphology of the thermoreversible gels. Spectroscopic investigations (FTIR, photoluminescence, XRD) revealed that noncovalent interactions, such as hydrogen bonding, pi-pi stacking, and van der Waals interactions play a decisive role in self-assembled gelation. PMID- 22105986 TI - Congenital disorder of glycosylation IIa: the trouble with diagnosing a dysmorphic inborn error of metabolism. PMID- 22105987 TI - Synthesis of clicked imidazolium-containing biosourced copolymers and application in carbon nanotube dispersion. AB - New polyesters incorporating a variable quantity of imidazolium rings along the backbone are synthesized by Huisgen 1,3-dipolar cycloaddition ("click" reaction). Subsequently, the imidazolium-grafted copolymers reveal an efficient dispersing ability toward the carbon nanotubes (CNTs) through supramolecular interactions in organic media. Interestingly, these compounds offer a simple and reliable strategy to control the quantity of dispersed CNTs as a function of imidazolium content. This approach is particularly suitable for the elaboration of biosourced and biodegradable materials based on poly(butylene succinate) with high performance properties. PMID- 22105988 TI - Mechanical properties of the avian acrocoracohumeral ligament and its role in shoulder stabilization in flight. AB - Control of movement in the avian shoulder joint is fundamental to understanding the avian wingstroke. The acrocoracohumeral ligament (AHL) is thought to play a key role in stabilizing the glenoid and balancing the pectoralis in gliding flight. If the AHL has to be taut to balance the pectoralis, then it must constrain glenohumeral motion during flapping flight as well. However, birds vary wing kinematics depending on flight speed and behavior. How can a passive ligament accommodate such varying joint movements? Herein, mechanical testing and 3-D modeling are used to link the mechanical properties and morphology of the AHL to its functional role during flapping flight. The bone-ligament-bone complex of the pigeon (Columba livia) fails at a tensile loading of 141 +/- 18 N (+/- s .D., n = 10) or 39 times body weight, which corresponds to a failure stress of 51 MPa, well above expected loads during flight. Simulated AHL length changes, comparisons to glenohumeral kinematics from the literature, and manipulations of partially dissected pigeon specimens all support the hypothesis that the AHL remains taut through downstroke and most of upstroke while becoming slack during the downstroke/upstroke transition. The digital AHL model provides a mechanism for explaining how the AHL can stabilize the shoulder joint under a broad array of humeral paths by constraining the coordination of glenohumeral degrees of freedom. PMID- 22105989 TI - Improving stroke alert response time: applying quality improvement methodology to the inpatient neurologic emergency. AB - BACKGROUND: Stroke often leaves its victims with devastating disabilities if not treated promptly. Guidelines recommend that brain imaging be obtained within 25 minutes, yet this benchmark is rarely achieved for the in-hospital stroke. PURPOSE: To reduce time to evaluation for strokes occurring in patients already hospitalized, through systematic analysis of current processes and application of standardized quality improvement methodology. METHODS: Improving the quality of care for in-hospital stroke patients involved 4 key steps: (1) creation of a detailed process map to identify inefficiencies in the current process for identifying and treating hospitalized stroke patients, (2) development of an optimized care pathway, (3) implementation of a checklist of optimal practices for the acute stroke response team and nursing staff, and (4) real-time feedback. Time from stroke alert to initiation of computed tomography (CT) scan was prospectively tracked for the 6-month period prior to intervention. After a 3 month interval for intervention roll-out, the response times for the pre intervention period were compared to a 6-month post-intervention evaluation period. RESULTS: Pre-intervention median inpatient stroke alert-to-CT time was 69.0 minutes, with 19% meeting the goal of 25 minutes from alert to CT time. Post intervention median inpatient stroke alert-to-CT time was reduced to 29.5 minutes, with 32% at goal (P < 0.0001). CONCLUSIONS: This inpatient stroke alert quality improvement initiative decreased median inpatient alert-to-CT time by 57%, and demonstrated that speed of in-hospital stroke evaluation can be improved through systematic application of quality improvement principles. PMID- 22105991 TI - Atomic charges of individual reactive chemicals in binary mixtures determine their joint effects: an example of cyanogenic toxicants and aldehydes. AB - Environmental contaminants are usually encountered as mixtures, and many of these mixtures yield synergistic or antagonistic effects attributable to an intracellular chemical reaction that pose a potential threat on ecological systems. However, how atomic charges of individual chemicals determine their intracellular chemical reactions, and then determine the joint effects for mixtures containing reactive toxicants, is not well understood. To address this issue, the joint effects between cyanogenic toxicants and aldehydes on Photobacterium phosphoreum were observed in the present study. Their toxicological joint effects differed from one another. This difference is inherently related to the two atomic charges of the individual chemicals: the oxygen charge of -CHO (O(aldehyde toxicant)) in aldehyde toxicants and the carbon atom charge of a carbon chain in the cyanogenic toxicant (C(cyanogenic toxicant)). Based on these two atomic charges, the following QSAR (quantitative structure-activity relationship) model was proposed: When (O(aldehyde toxicant) C(cyanogenic toxicant) )> -0.125, the joint effect of equitoxic binary mixtures at median inhibition (TU, the sum of toxic units) can be calculated as TU = 1.00 +/- 0.20; when (O(aldehyde toxicant) -C(cyanogenic toxicant) ) <= -0.125, the joint effect can be calculated using TU = - 27.6 x O (aldehyde toxicant) - 5.22 x C (cyanogenic toxicant) - 6.97 (n = 40, r = 0.887, SE = 0.195, F = 140, p < 0.001, q(2) (Loo) = 0.748; SE is the standard error of the regression, F is the F test statistic). The result provides insight into the relationship between the atomic charges and the joint effects for mixtures containing cyanogenic toxicants and aldehydes. This demonstrates that the essence of the joint effects resulting from intracellular chemical reactions depends on the atomic charges of individual chemicals. The present study provides a possible approach for the development of a QSAR model for mixtures containing reactive toxicants based on the atomic charges. PMID- 22105992 TI - Sheet-like assemblies of charged amphiphilic alpha/beta-peptides at the air-water interface. AB - There is growing interest in the design of molecules that undergo predictable self-assembly. Bioinspired oligomers with well-defined conformational propensities are attractive from this perspective, since they can be constructed from diverse building blocks, and self-assembly can be directed by the identities and sequence of the subunits. Here we describe the structure of monolayers formed at the air-water interface by amphiphilic alpha/beta-peptides with 1:1 alternation of alpha- and beta-amino acid residues along the backbone. Two of the alpha/beta-peptides, one a dianion and the other a dication, were used to determine differences between self-assemblies of the net negatively and positively charged oligomers. Two additional alpha/beta-peptides, both zwitterionic, were designed to favor assembly in a 1:1 molar ratio mixture with parallel orientation of neighboring strands. Monolayers formed by these alpha/beta-peptides at the air-water interface were characterized by surface pressure-area isotherms, grazing incidence X-ray diffraction (GIXD), atomic force microscopy and ATR-FTIR. GIXD data indicate that the alpha/beta-peptide assemblies exhibited diffraction features similar to those of beta-sheet-forming alpha-peptides. The diffraction data allowed the construction of a detailed model of an antiparallel alpha/beta-peptide sheet with a unique pleated structure. One of the alpha/beta-peptide assemblies displayed high stability, unparalleled among previously studied assemblies of alpha-peptides. ATR-FTIR data suggest that the 1:1 mixture of zwitterionic alpha/beta-peptides assembled in a parallel arrangement resembling that of a typical parallel beta-sheet secondary structure formed by alpha-peptides. This study establishes guidelines for design of amphiphilic alpha/beta-peptides that assemble in a predictable manner at an air water interface, with control of interstrand orientation through manipulation of Coulombic interactions along the backbone. PMID- 22105993 TI - Bright near-infrared fluorophores based on squaraines by unexpected halogen effects. PMID- 22105995 TI - TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. AB - Resident cells, such as fibroblast-like synoviocytes (FLS), play a crucial role in rheumatoid arthritis (RA). They are implicated in the inflammatory response and play a key role in osteoarticular destruction. Moreover, RA FLS spread RA to unaffected joints. Pathogen-associated molecular patterns and damage-associated molecular patterns have been found to activate RA FLS by interacting with pattern recognition receptors, such as TLR. RA FLS express a large number of TLR, and TLR2 was demonstrated to be involved in RA inflammation. Because microRNA have emerged as important controllers of TLR expression and signaling, the aim of this study was to evaluate their potential involvement in the control of TLR2 expression by RA FLS. We first showed that Tlr2 expression is strongly upregulated in RA FLS in response to TLR2 ligands. Using a microRNA microarray analysis, we identified one miRNA in activated RA FLS, miR-19b, which was downregulated and predicted to target Tlr2 mRNA. Downregulation of miR-19b and miR-19a, which belongs to the same cluster, was confirmed by real-time quantitative PCR. Transfection of RA FLS with miR-19a/b mimics decreased TLR2 protein expression. In parallel, we found that both IL-6 and matrix metalloproteinase 3 secretion was significantly downregulated in activated FLS transfected with either mimic. Moreover, using a luciferase assay, we showed that miR-19a/b directly target Tlr2 mRNA. Taken together, our data point toward an important role for miR-19a/b in the regulation of IL-6 and matrix metalloproteinase 3 release by controlling TLR2 expression, as well as provide evidence that miR-19a/b can act as negative regulators of inflammation in humans. PMID- 22105994 TI - VISA is required for B cell expression of TLR7. AB - B cells play a critical role in the initialization and development of the systemic lupus erythematosus that is dependent on the expression of the endosomal ssRNA receptor TLR7. Previous studies have established that B cell expression of TLR7 is controlled by the type I IFN secreted by plasmacytoid dendritic cells. In this article, we report that VISA, also known as MAVS, IPS-1, and CardIf, essential for RIG-I/MDA5-mediated signaling following sensing of cytosolic RNA, regulate B cell expression of TLR7 and CD23. We found that B cells from a VISA(-/ ) mouse express reduced TLR7 but normal basal levels of type I IFN. We also show that although IFN-beta and TLR7 agonists synergize to promote TLR7 expression in VISA(-/-) B cells, they do not fully complement the defect seen in VISA(-/-) cells. Cell transfer experiments revealed that the observed effects of VISA(-/-) are B cell intrinsic. The reduced TLR7 expression in B cells is correlated with impaired TLR7 agonist-induced upregulation of activation markers CD69 and CD86, cell proliferation, production of IFN-alpha, TNF, and IL-12, and NF-kappaB activation. Finally, studies indicate that genetic background may influence the observed phenotype of our VISA(-/-) mice, because VISA(-/-) B cells differ in CD23 and TLR7 expression when on C57BL/6 versus 129Sv-C57BL/6 background. Thus, our findings suggest an unexpected link between VISA-mediated cytosolic RLR signaling and autoimmunity. PMID- 22105996 TI - Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant. AB - The PTPN22 genetic variant 1858T, encoding Lyp620W, is associated with multiple autoimmune disorders for which the production of autoantibodies is a common feature, suggesting a loss of B cell tolerance. Lyp620W results in blunted BCR signaling in memory B cells. Because BCR signal strength is tightly coupled to central and peripheral tolerance, we examined whether Lyp620W impacts peripheral B cell homeostasis in healthy individuals heterozygous for the PTPN221858T variant. We found that these subjects display alterations in the composition of the B cell pool that include specific expansion of the transitional and anergic IgD(+)IgM(-)CD27(-) B cell subsets. The PTPN22 1858T variant was further associated with significantly diminished BCR signaling and a resistance to apoptosis in both transitional and naive B cells. Strikingly, parallel changes in both BCR signaling and composition of B cell compartment were observed in type 1 diabetic subjects, irrespective of PTPN22 genotype, revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated effects, due in part to the altered BCR signaling threshold, contribute to breakdown of peripheral tolerance and the entry of autoreactive B cells into the naive B cell compartment. PMID- 22105997 TI - Effects of systemic versus local administration of corticosteroids on mucosal tolerance. AB - Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperactivity in animal models of asthma. Whereas systemic administration of dexamethasone during the delivery of respiratory Ag has been suggested to prevent the development of mucosal tolerance, the effects of local administration of corticosteroids, first-line treatment for patients with bronchial asthma, on mucosal tolerance remain unknown. To analyze the effects of systemic versus local administration of different types of corticosteroids on the development of mucosal tolerance, mice were exposed to respiratory allergen to induce mucosal tolerance with or without systemic or intranasal application of different doses of dexamethasone or prednisolone. After the induction of mucosal tolerance, proliferation of T cells was inhibited in tolerized mice, whereas systemic applications of corticosteroids restored T cell proliferation and secretion of Th2 cytokines. In contrast, inhaled corticosteroids showed no effect on both T cell proliferation and cytokine secretion. In addition, mice systemically treated with corticosteroids showed an increased airway hyperactivity with a significant lung inflammation, but also an increased T effector cells/regulatory T cells ratio in the second lymphoid organs when compared with mice that receive corticosteroids by inhalation. These results demonstrate that local administration of corticosteroids has no effect on the development of immune tolerance in contrast to systemically applied corticosteroids. Furthermore, although different concentrations of corticosteroids are administered to patients, our results demonstrated that the route of administration rather than the doses affects the effect of corticosteroids on respiratory tolerance induction. Considering the broad application of corticosteroids in patients with allergic disease and asthma, the route of administration of steroid substances seems crucial in terms of treatment and potential side effects. These findings may help elucidate the apparently contradicting results of corticosteroid treatment in allergic diseases. PMID- 22105998 TI - Reduced lymphocyte longevity and homeostatic proliferation in lamin B receptor deficient mice results in profound and progressive lymphopenia. AB - The lamin B receptor (LBR) is a highly unusual inner nuclear membrane protein with multiple functions. Reduced levels are associated with decreased neutrophil lobularity, whereas complete absence of LBR results in severe skeletal dysplasia and in utero/perinatal lethality. We describe a mouse pedigree, Lym3, with normal bone marrow and thymic development but profound and progressive lymphopenia particularly within the T cell compartment. This defect arises from a point mutation within the Lbr gene with only trace mutant protein detectable in homozygotes, albeit sufficient for normal development. Reduced T cell homeostatic proliferative potential and life span in vivo were found to contribute to lymphopenia. To investigate the role of LBR in gene silencing in hematopoietic cells, we examined gene expression in wild-type and mutant lymph node CD8 T cells and bone marrow neutrophils. Although LBR deficiency had a very mild impact on gene expression overall, for common genes differentially expressed in both LBR deficient CD8 T cells and neutrophils, gene upregulation prevailed, supporting a role for LBR in their suppression. In summary, this study demonstrates that LBR deficiency affects not only nuclear architecture but also proliferation, cell viability, and gene expression of hematopoietic cells. PMID- 22105999 TI - p53 serves as a host antiviral factor that enhances innate and adaptive immune responses to influenza A virus. AB - Several direct target genes of the p53 tumor suppressor have been identified within pathways involved in viral sensing, cytokine production, and inflammation, suggesting a potential role of p53 in antiviral immunity. The increasing need to identify immune factors to devise host-targeted therapies against pandemic influenza A virus (IAV) led us to investigate the role of endogenous wild-type p53 on the immune response to IAV. We observed that the absence of p53 resulted in delayed cytokine and antiviral gene responses in lung and bone marrow, decreased dendritic cell activation, and reduced IAV-specific CD8(+) T cell immunity. Consequently, p53(-/-) mice showed a more severe IAV-induced disease compared with their wild-type counterparts. These findings establish that p53 influences the antiviral response to IAV, affecting both innate and adaptive immunity. Thus, in addition to its established functions as a tumor suppressor gene, p53 serves as an IAV host antiviral factor that might be modulated to improve anti-IAV therapy and vaccines. PMID- 22106000 TI - Loss of immunological tolerance in Gimap5-deficient mice is associated with loss of Foxo in CD4+ T cells. AB - Previously, we reported the abrogation of quiescence and reduced survival in lymphocytes from Gimap5(sph/sph) mice, an ENU germline mutant with a missense mutation in the GTPase of immunity-associated protein 5 (Gimap5). These mice showed a progressive loss of peripheral lymphocyte populations and developed spontaneous colitis, resulting in early mortality. In this study, we identify the molecular pathways that contribute to the onset of colitis in Gimap5(sph/sph) mice. We show that CD4(+) T cells become Th1/Th17 polarized and are critically important for the development of colitis. Concomitantly, regulatory T cells become reduced in frequency in the peripheral tissues, and their immunosuppressive capacity becomes impaired. Most importantly, these progressive changes in CD4(+) T cells are associated with the loss of Forkheadbox group O (Foxo)1, Foxo3, and Foxo4 expression. Our data establish a novel link between Gimap5 and Foxo expression and provide evidence for a regulatory mechanism that controls Foxo protein expression and may help to maintain immunological tolerance. PMID- 22106001 TI - Chromosomal loss of 3q26.3-3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability. AB - Neuroligin 1 (NLGN1) is one of five members of the neuroligin gene family and may represent a candidate gene for neurological disorders, as members of this family are involved in formation and remodeling of central nervous system synapses. NLGN1 is expressed predominantly in the central nervous system, where it dimerizes and then binds with beta-neurexin to form a functional synapse. Mutations in neurexin 1 (NRXN1) as well as two other members of the neuroligin family, NLGN3 and NLGN4, have been associated with autism and mutations in NLGN4 have also been associated with intellectual disability, seizures, and EEG abnormalities. Genomic microarray is recommended for the detection of chromosomal gains or losses in patients with intellectual disability and multiple congenital anomalies. Results of uncertain significance are not uncommon. Parental studies can provide additional information by demonstrating that the imbalance is either de novo or inherited, and therefore is more or less likely to be causative of the clinical phenotype. However, the possibility that even inherited deletions and duplications may play a role in the phenotype of the proband cannot be excluded as many copy number variants associated with neurodevelopmental conditions show incomplete penetrance and may be inherited from an unaffected parent. Here, we report on a patient with a 2.2 Mb deletion at 3q26.3-3q26.32-encompassing the terminal end of NLGN1 and the entire NAALADL2 gene-detected by genomic microarray, and confirmed by FISH and real-time quantitative PCR. The same size deletion was subsequently found in her healthy, asymptomatic, adult mother. PMID- 22106002 TI - Polyacetylene-type networks prepared by coordination polymerization of diethynylarenes: new type of microporous organic polymers. AB - Microporous organic polymers (MOP) of a new type have been synthesised in high yields by a simple coordination polymerization of 1,3-diethynylbenzene, 1,4 diethynylbenzene and 4,4'-diethynylbiphenyl catalysed by [Rh(cod)acac] and [Rh(nbd)acac] complexes. The new MOPs are non-swellable polyacetylene-type conjugated networks consisting of ethynylaryl-substituted polyene main chains that are crosslinked by arylene linkers. Prepared MOP samples have a mole fraction of branching units (by (13)C CP/MAS NMR) from 0.30 to 0.47 and exhibit the BET (Brunaer-Emmett-Teller) surface up to 809 m(2) g(-1) and hydrogen uptake up to 0.69 wt% (77 K, H2 pressure 750 torr). PMID- 22106003 TI - Myelosuppression and infectious complications in children with Down syndrome and acute lymphoblastic leukemia. AB - Children with Down syndrome (DS) bear an increased risk of acute lymphoblastic leukemia (ALL) and treatment complications. We compared blood counts and toxicities in 22 DS and 44 non-DS ALL patients. Patients with DS had deeper, longer neutrophil and monocyte count nadirs; more toxicities (HR 2.0, P = 0.0005); longer hospitalizations (HR 1.4, P < 0.0001); and more frequent microbiologically documented infections (HR 5.7, P = 0.0019), mucositis (HR 29.0, P = 0.0006), and cellulitis (HR 3.0, P = 0.033). Severe neutropenia, monocytopenia, and increased cellulitis in DS-ALL suggest the importance of skin hygiene, vigilance and aggressive treatment of cutaneous infections. PMID- 22106004 TI - Toxin assay is more reliable than ICD-9 data and less time-consuming than chart review for public reporting of Clostridium difficile hospital case rates. AB - OBJECTIVE: Clostridium difficile-associated disease (CDAD) is common and has a 6.1% mortality. Governmental agencies have recommended surveillance, but reporting increases health care costs. We sought to identify a reliable method of reporting CDAD that will not significantly increase health care costs. METHODS: Patients were identified via database query for International Statistical Classification of Diseases and Related Health Problems, 9th Edition (ICD-9) codes and C. difficile toxin positivity. All identified patients underwent a chart review, which was used to determine the accuracy of the database query methods. Methods of determining whether CDAD was acquired at the reporting institution were studied, and time required to perform each method was measured. RESULTS: The toxin assay reported 96.1% (369/384) of cases and had a positive predictive value of 100%. No difference was found in comparison of the toxin assay case rate of 15.7 per 1000 discharged patients to the rate of 16.3 identified by chart review (P = 0.440; 95% confidence interval [CI], 14.1-17.4), whereas the ICD-9 method was found to be significantly different by reporting 116.1% (446/384) of cases for a case rate of 19.0 per 1000 discharges (P = 0.001; 95% CI, 17.3-20.8). The time for data extraction via the toxin assay method required only 842 minutes, while the chart review method consumed 21,899 minutes. CONCLUSION: A positive C. difficile toxin assay accurately reports the institutional incidence of disease and is more reliable than ICD-9 query. This process can be instituted at a fraction of the cost of the standard chart review, and enables governmental agencies to inexpensively add CDAD to their list of reportable diseases. PMID- 22106005 TI - A simple, inexpensive system for digital particle image velocimetry (DPIV) in biomechanics. AB - Functional morphology and biomechanics seek to reveal the mechanistic bases of organismal functions and the physical principles involved at the phenotype environment interface. Characterization of fluid flow (air or water) within and around organismal structures is an example of this approach. Digital particle imaging velocimetry (DPIV) has been exploited in a variety of biological systems to visualize fluid flow associated with animal movement. DPIV employs particles suspended in air or water that are illuminated by a laser light sheet and recorded with a high-speed video camera. Software tracks particle movement across a specified number of video frames, generating vector diagrams showing patterns of fluid flow through time. As powerful as DPIV methods are, they are limited in application by the high cost and complexity of the equipment required. In this article, we describe a simple DPIV system that substitutes widely available, inexpensive consumer components for scientific-grade equipment to achieve low cost (<$1,000 total) and high accuracy (total error calculated to be approx. 6%, as compared with 5% in professional systems). We have employed this system successfully in our studies on the fluid dynamics of chemosensory tongue-flicking in snakes. This system can be used for research and teaching in labs that typically cannot afford the expense or commitment of a traditional DPIV apparatus and is particularly suited for obtaining preliminary data required to justify further grant and institutional support. PMID- 22106006 TI - Problem solvers and thinkers. PMID- 22106007 TI - Quenching of the luminescence of upconverting luminescent nanoparticles by heavy metal ions. AB - We report that the luminescence of upconverting luminescent nanoparticles (UCLNPs) is quenched by heavy metal ions and halide ions in aqueous solution. The UCLNPs consist of hexagonal NaYF(4) nanocrystals doped with trivalent rare earth ions and were synthesized by both the oleic acid (solvothermal) method and the ethylenediaminetetraacetic acid (co-precipitation) method. Quenching was studied for the Cu(II), Hg(II), Pb(II), Cd(II), Co(II), Ag(I), Fe(III), Zn(II), bromide, and iodide ions and is found to be particularly strong for Hg(II). Stern-Volmer plots are virtually linear up to quencher concentrations of 10-25 mM, but deviate from linearity at higher quencher concentrations, because static quenching causes an additional effect. The UCLNPs display two main emission bands (blue, green, red or near-infrared), and the quenching efficiencies for these are found to be different. The effect seems to be generally associated with UCLNPs because it was observed for all UCLNPs doped with trivalent lanthanide ions including Yb(III), Er(III), Ho(III), and Tm(III). The results are discussed in terms of quenching mechanisms and with respect to potential applications such as optical sensing. PMID- 22106008 TI - A patient with a mild holoprosencephaly spectrum phenotype and heterotaxy and a 1.3 Mb deletion encompassing GLI2. AB - Loss-of-function mutations of GLI2 are associated with features at the mild end of the holoprosencephaly spectrum, including abnormal pituitary gland formation and/or function, and craniofacial abnormalities. In addition patients may have branchial arch anomalies and polydactyly. Large, microscopically visible, interstitial deletions spanning 2q14.2 have been reported in patients with multiple congenital anomalies and intellectual disability. We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene. We review the genotype and phenotype of previously published probands with GLI2 aberrations. Our findings confirm the association of haploinsufficiency of GLI2 and mild HPE spectrum features. Consistent with prior reports, we observed incomplete penetrance of the deletion in the family, illustrating the multifactorial etiology of holoprosencephaly spectrum features. In addition to the holoprosencephaly spectrum features, the proband had heterotaxy of the abdominal organs. Mutations in the known heterotaxy genes (NODAL, ZIC3 and CFC1) were excluded. The deletion contains five genes, in addition to GLI2, including the EPB4.1l5 gene. Based on findings in Epb4.1l5 mutant mice we hypothesize that Epb4.1l5 is a candidate gene for the heterotaxy observed in the proband. PMID- 22106009 TI - Impaired function of Fanconi anemia type C-deficient macrophages. AB - FA is a genetic disorder characterized by BM failure, developmental defects, and cancer predisposition. Previous studies suggest that FA patients exhibit alterations in immunologic function. However, it is unclear whether the defects are immune cell-autonomous or secondary to leukopenia from evolving BM failure. Given the central role that macrophages have in the innate immune response, inflammation resolution, and antigen presentation for acquired immunity, we examined whether macrophages from Fancc-/- mice exhibit impaired function. Peritoneal inflammation induced by LPS or sodium periodate resulted in reduced monocyte/macrophage recruitment in Fancc-/- mice compared with WT controls. Fancc /- mice also had decreased inflammatory monocytes mobilized into the peripheral blood after LPS treatment compared with controls. Furthermore, Fancc-/- peritoneal macrophages displayed cell-autonomous defects in function, including impaired adhesion to FN or endothelial cells, reduced chemoattractant-mediated migration, and decreased phagocytosis. Moreover, dysregulated F-actin rearrangement was detected in Fancc-/- macrophages after adhesion to FN, which was consistent with an observed reduction in RhoA-GTP levels. Importantly, these data suggest that impaired cytoskeletal rearrangements in Fancc-/- macrophages may be the common mechanism responsible for cell-autonomous defects detected in vitro, as well as altered monocyte/macrophage trafficking in vivo. PMID- 22106010 TI - Postoperative spindle cell nodule after thyroidectomy: a case mimicking recurrence with anaplastic transformation of thyroid cancer. AB - BACKGROUND: Here, we report a case of a postoperative spindle cell nodule that mimicked recurrence with anaplastic transformation after thyroidectomy. METHODS: The course of the disease is described. The mass was studied morphologically and immunohistochemically. RESULTS: A 31-year-old woman underwent total thyroidectomy for papillary thyroid carcinoma. A mass suspected of recurrence was found 14 months later and caused dysphagia and dyspnea. An (18)F-fluorodeoxyglucose positron emission tomographic ((18)F-FDG-PET) scan showed a lesion with high uptake; however, a fine-needle aspiration biopsy (FNAB) was inconsistent with recurrent cancer. The mass was resected and was composed of elongated spindle cells, with eosinophilic cytoplasm within a myxoid background. Immunohistochemical staining was strongly positive for vimentin, focally positive for smooth muscle actin, desmin, and p53, and negative for cytokeratin AE1/AE3, Cam5.2, epithelial membrane antigen (EMA), and anaplastic lymphoma kinase (ALK 1). CONCLUSION: Although postoperative spindle cell nodules are rare after thyroid surgery, it should be considered in the differential diagnosis for recurrent masses at the operative site. PMID- 22106011 TI - In vitro assays for vesper mice (Calomys laucha) sperm using heterologous substrates from nonrodent species. AB - Small vesper mice (Calomys laucha) may be considered as an animal model for in vitro fertilization studies, but limited data about in vitro evaluations of their sperm quality and fertility are available. The in vitro penetration (IVP) assay is used to estimate potential sperm fertility for many mammal species, but it still requires reduction in cost and labor. This study tested improvements in the IVP assay for C. laucha sperm using swine oocytes and perivitelline layers (PVL) of chicken eggs as substrates, and evaluated associations among C. laucha sperm quality, IVP, and in vivo fertility after natural mating. In the IVP assay, gametes coincubation was carried out flat-bottomed wells with M2, in water bath at 37 degrees C for 2 hr. C. laucha sperm presented motility, normal morphology, membrane integrity, and acrosome integrity equal to 90.6 +/- 5.6, 90.2 +/- 6.6, 88.7 +/- 9.6, and 90.5 +/- 11.5%, respectively. The IVP rate was 39.8% in swine oocytes and 87.5% in the inner PVL. Considering in vivo fertility as the gold standard, the IVP assay in swine oocytes presented a sensitivity of 16.0% and specificity of 83.3%. The sensitivity of the IVP assay in the inner PVL was 84.0%, but the specificity was not determined because there were no true negative results. Sperm membrane integrity was correlated with parturition after natural mating (r = 0.38, P<0.01) and litter size (r = 0.54; P<0.0002).The IVP assay using swine oocytes as substrates can be performed in nearly 2 hr without gametes' coincubation in CO(2). PMID- 22106012 TI - Direct observation of bed utilization in the pediatric intensive care unit. AB - BACKGROUND: The pediatric intensive care unit (PICU), with limited number of beds and resource-intensive services, is a key component of patient flow. Because the PICU is a crossroads for many patients, transfer or discharge delays can negatively impact a patient's clinical status and efficiency. OBJECTIVE: The objective of this study was to describe, using direct observation, PICU bed utilization. METHODS: We conducted a real-time, prospective observational study in a convenience sample of days in the PICU of an urban, tertiary-care children's hospital. RESULTS: Among 824 observed hours, 19,887 bed-hours were recorded, with 82% being for critical care services and 18% for non-critical care services. Fourteen activities accounted for 95% of bed-hours. Among 200 hours when the PICU was at full capacity, 75% of the time included at least 1 bed that was used for non-critical care services; 37% of the time at least 2 beds. The mean waiting time for a floor bed assignment was 9 hours (median, 5.5 hours) and accounted for 4.62% of all bed-hours observed. CONCLUSIONS: The PICU delivered critical care services most of the time, but periods of non-critical care services represented a significant amount of time. In particular, periods with no bed available for new patients were associated with at least 1 or more PICU beds being used for non critical care activities. The method should be reproducible in other settings to learn more about the structure and processes of care and patient flow and to make improvements. PMID- 22106013 TI - The impact of quality and duration of enoxaparin therapy on recurrent venous thrombosis in children. AB - BACKGROUND: Venous thromboembolism (VTE) and recurrent venous thromboembolism (rVTE) are rare, but significant problems in pediatrics. Current recommendations for anticoagulant therapy arise from adult literature, and there is little data on clinical outcomes following therapeutic low-molecular-weight heparin in children. METHOD: All patients <19 years of age that were diagnosed with a VTE or right atrial thrombus via standard imaging methods at St. Jude Children's Research Hospital were retrospectively identified from January 2004 through August 2008. Demographic characteristics, coexisting clinic conditions, description of anticoagulant therapy, and record of rVTE were chronicled following a comprehensive chart review. Descriptive statistics of clinical characteristics and anticoagulation are presented. RESULTS: Venous thrombosis was identified in 149 children with 21% (31/149) developing a rVTE. Coexisting clinical conditions were identified in 93% of children at initial diagnosis with 48% (71/149) of patients having a coexisting malignancy. Seventy-seven percent (114/149) of children received anticoagulant therapy with UFH (10/114) or enoxaparin (104/114). Neither duration of enoxaparin therapy (>6, 3-6, <3 months) (P = 0.61), nor quality of therapy (>=75% of time on anticoagulation spent with an anti-FXa of 0.5-1.0 U/ml) (P = 1.0) were found to be protective against rVTE. CONCLUSION: Anticoagulation with enoxaparin based on adult literature may be suboptimal in preventing rVTE in pediatric populations. Future prospective randomized controlled trials in pediatrics using clinical outcomes with anticoagulant therapy are urgently needed. PMID- 22106015 TI - Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. METHODS AND RESULTS: S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10(-9)-10(-5) M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) MUM) versus controls (1 (0.26) MUM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) MUM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r=-0.87, -0.72 and -0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with alpha smooth muscle actin, vimentin and collagen type I (Spearman's r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P(2) and S1P(3), as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-beta1 (TGF-beta1) release. Furthermore, TGF-beta1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-beta1 and the S1P/SPHK1 axis. CONCLUSIONS: S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT. PMID- 22106016 TI - NMR spectroscopy metabolomic profiling of exhaled breath condensate in patients with stable and unstable cystic fibrosis. AB - BACKGROUND: Metabolomics could provide new insights into the pathophysiology of cystic fibrosis (CF) by identifying profiles of endogenous metabolites. OBJECTIVES: To investigate whether metabolomics of exhaled breath condensate could discriminate between patients with unstable CF, stable CF and healthy subjects, and whether selected metabolites were responsible for between-group differences. METHODS: Twenty-nine patients with stable CF, 24 with unstable CF and 31 healthy subjects (age 9-24 years) participated in a cross-sectional study. Metabolomics was performed with high-resolution nuclear magnetic resonance spectroscopy. Partial least squares-discriminant analysis was used as classifier. The results were validated in a second independent study. RESULTS: Intraclass correlation coefficients for between-day and technical repeatability were 0.93 and 0.96, respectively. Bland-Altman analysis showed good within-day repeatability. Correct classification rate of CF (n=53) vs. healthy subjects (n=31) was 96% (R2=0.84; Q2=0.79). Model validation with a testing sample set obtained from subjects not included in the primary analysis (23 CF and 25 healthy subjects) showed a sensitivity of 91% and a specificity of 96%. The classification rate of stable CF (n=29) vs. unstable CF patients (n=24) was 95% (R2=0.82; Q2=0.78). Model external validation in 14 patients with stable CF and 16 with unstable CF showed a sensitivity of 86% and a specificity of 94%. Ethanol, acetate, 2-propanol and acetone were most discriminant between patients with CF and healthy subjects, whereas acetate, ethanol, 2-propanol and methanol were the most important metabolites for discriminating between patients with stable and unstable CF. CONCLUSIONS: Nuclear magnetic resonance spectroscopy of exhaled breath condensate is reproducible, discriminates patients with CF from healthy subjects and patients with unstable CF from those with stable CF, and identifies the metabolites responsible for between-group differences. PMID- 22106018 TI - Attitudes to participation in a lung cancer screening trial: a qualitative study. AB - BACKGROUND: Earlier diagnosis of lung cancer is key to reducing mortality. New evidence suggests that smokers have negative attitudes to screening and participation in lung cancer screening trials is poor (<1 in 6 of those eligible). Understanding participation is important since uptake in screening trials is likely to predict uptake in screening programmes. A qualitative study of people accepting and declining participation in the Lung-SEARCH screening trial was conducted. Two questions were addressed: Are the screening methods offered acceptable to patients? Why do some people take part and others decline? METHODS: The qualitative study used semi-structured interviews with 60 respondents from three groups: (a) trial participants providing an annual sputum sample; (b) trial participants with a sputum sample showing abnormal cytology and thus undergoing annual CT scanning and bronchoscopy; and (c) those declining trial participation. RESULTS: Most respondents (48/60, 80%) viewed sputum provision, CT scanning and bronchoscopy as largely acceptable. Those declining trial participation described fear of bronchoscopy, inconvenience of travelling to hospitals for screening investigations and perceived themselves as having low susceptibility to lung cancer or being too old to benefit. Patients declining participation discounted their risk from smoking and considered negative family histories and good health to be protective. Four typological behaviours emerged within those declining: 'too old to be bothered', 'worriers', 'fatalists' and 'avoiders'. CONCLUSION: Sputum provision, CT scanning and bronchoscopy are largely acceptable to those participating in a screening trial. However, the decision to participate or decline reflects a complex balance of factors including acceptability and convenience of screening methods, risk perception, altruism and self-interest. Improving practical and changing cognitive aspects of participation will be key to improving uptake of lung cancer screening. PMID- 22106019 TI - Antibacterial antibody responses associated with the development of asthma in house dust mite-sensitised and non-sensitised children. AB - BACKGROUND: Infants who develop house dust mite (HDM) allergy and HDM-sensitised children with severe persistent asthma have low antibody responses to the P6 antigen of Haemophilus influenzae. OBJECTIVE: To measure the development of antibody to two ubiquitous bacteria of the respiratory mucosa in a prospective birth cohort at high risk of allergic disease and to assess which responses are associated with asthma and atopy. METHODS: IgG1 and IgG4 antibody to H influenzae (P4 and P6) and Streptoccocus pneumoniae (PspA and PspC) surface antigens was measured in yearly blood samples of children aged 1-5 years. IgE to the P6 antigen was examined for the 5-year group. The children were stratified based on HDM sensitisation and asthma at 5 years of age. RESULTS: HDM-sensitised children had lower IgG1 antibody titres to the bacterial antigens, and early responses (<3 years and before the development of HDM sensitisation and asthma) corrected for multiple antigens were significantly reduced for P4, P6 and PspC (p=0.008, p=0.004 and p=0.028, respectively). Similar associations with asthma were also found (p=0.008, p=0.004 and p=0.032 for P4, P6 and PspC, respectively). The IgG4 antibody titre and prevalence were similar in both HDM-sensitised and non sensitised groups, but sensitised children had a slower downregulation of the IgG4 response. Children with asthma (27/145 at 5 years) had lower anti-P6 IgE responses (p<0.05). CONCLUSIONS: HDM-sensitised children have early defective antibody responses to bacteria that are associated with asthma. Surprisingly, antibacterial IgE was associated with a reduced risk for asthma. PMID- 22106020 TI - Pulmonary mass in a 19-year-old male. Inflammatory myofibroblastic tumour. PMID- 22106021 TI - Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. AB - BACKGROUND: Bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken to determine the potential for MSCs to enhance repair after ventilator-induced lung injury (VILI) and elucidate the mechanisms underlying these effects. METHODS: Anaesthetised rats underwent injurious ventilation which produced severe ALI. Following recovery, they were given an intravenous injection of MSCs (2*10(6) cells) or vehicle immediately and a second dose 24 h later. The extent of recovery following VILI was assessed after 48 h. Subsequent experiments examined the potential for non-stem cells and for the MSC secretome to enhance VILI repair. The contribution of specific MSC secreted mediators was then examined in a wound healing model. RESULTS: MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histological lung injury and restored lung structure. They attenuated alveolar tumour necrosis factor alpha concentrations while increasing concentrations of interleukin 10. These effects were not seen with non-stem cells (ie, rat fibroblasts). MSC-secreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of keratinocyte growth factor. CONCLUSION: MSC therapy enhances lung repair following VILI via a paracrine mechanism that may be keratinocyte growth factor-dependent. PMID- 22106022 TI - Dye-sensitized solar cells based on donor-pi-acceptor fluorescent dyes with a pyridine ring as an electron-withdrawing-injecting anchoring group. AB - A new-type of donor-acceptor pi-conjugated (D-pi-A) fluorescent dyes NI3-NI8 with a pyridine ring as electron-withdrawing-injecting anchoring group have been developed and their photovoltaic performances in dye-sensitized solar cells (DSSCs) are investigated. The short-circuit photocurrent densities and solar energy-to-electricity conversion yields of DSSCs based on NI3-NI8 are greater than those for the conventional D-pi-A dye sensitizers NI1 and NI2 with a carboxyl group as the electron-withdrawing anchoring group. The IR spectra of NI3 NI8 adsorbed on TiO(2) indicate the formation of coordinate bonds between the pyridine ring of dyes NI3-NI8 and the Lewis acid sites (exposed Ti(n+) cations) of the TiO(2) surface. This work demonstrates that the pyridine rings of D-pi-A dye sensitizers that form a coordinate bond with the Lewis acid site of a TiO(2) surface are promising candidates as not only electron-withdrawing anchoring group but also electron-injecting group, rather than the carboxyl groups of the conventional D-pi-A dye sensitizers that form an ester linkage with the Bronsted acid sites of the TiO(2) surface. PMID- 22106023 TI - Barriers to diagnosis of a rare neurological disorder in China--lived experiences of Rett syndrome families. AB - Rett syndrome is a rare neurological disorder affecting girls and usually caused by a mutation on the MECP2 gene. It is estimated that approximately 1,000 girls are born every year in China with Rett syndrome but far fewer have received a diagnosis. Fourteen of 74 Chinese families known to the International Rett Syndrome Phenotype Database participated in this qualitative study. Telephone interviews were conducted in Mandarin to explore pathways to a diagnosis of Rett syndrome in China and associated barriers. Families consulted multiple clinical centers and eventually received a diagnosis at a centrally located hospital. Over the course of this pathway, families encountered lack of knowledge and diagnostic expertise for Rett syndrome at local levels and a heavily over-burdened hospital system. There was a paucity of information available to guide management of this rare disorder after the diagnosis had been received. Our study suggests that the frustrations experienced by families could in part be addressed by the provision of information, education, and training related to Rett syndrome for clinicians, additional resources to allow clinicians to request genetic testing for confirmation of the clinical diagnosis and for information and support services for families. PMID- 22106024 TI - Targeting tumor hypoxia in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an endemic head and neck cancer in Southeast Asia. Although concurrent chemoradiotherapy generally results in good clinical response for early diseases, posttreatment relapse and distant metastasis are major causes for NPC deaths. There is an urgent need for more effective therapies for advanced NPC. Recent studies have demonstrated tumor hypoxia can be a therapeutic target in NPC. METHODS: A Medline review of articles published on clinical and preclinical studies targeting tumor hypoxia was performed. RESULTS: Studies published to date showed that tumor hypoxia is common in NPC and it is associated with disease progression and resistance to therapy. Several mechanisms have been proposed on the role of tumor hypoxia in NPC cell survival, angiogenesis, and metabolism. Studies reported by us and by others have demonstrated the therapeutic potential of targeting tumor hypoxia in NPC. CONCLUSIONS: Cumulative studies indicate that targeting tumor hypoxia could be an effective approach for NPC treatment. PMID- 22106025 TI - Favorable outcome of allogeneic hematopoietic cell transplantation for 8p11 myeloproliferative syndrome associated with BCR-FGFR1 gene fusion. AB - We report the case of a child who presented with nonspecific symptoms suggestive of a rheumatologic disorder, whose bone marrow had a complex translocation involving the FGFR1 locus. Hematopathologic findings were subtle and did not definitively indicate malignancy. Because he responded poorly to initial treatment with hydroxyurea, and in light of the progressive clinical course associated with the 8p11 myeloproliferative syndrome, he underwent an unrelated donor hematopoietic stem cell transplant. This patient's atypical presentation highlights the importance of obtaining cytogenetic analysis at the time of bone marrow sampling and considering this uncommon entity in the differential diagnosis of hematologic disorders. PMID- 22106026 TI - MBNL1-RNA recognition: contributions of MBNL1 sequence and RNA conformation. AB - Muscleblind-like proteins (MBNL) are RNA-binding proteins that bind to the poly(CUG) and poly(CCUG) sequences that are the causative agents of myotonic dystrophy. It has been suggested that as a result of binding to the repeating RNA sequences, MBNL1 is abnormally expressed and translocated, which leads to many of the misregulated events in myotonic dystrophy. In this work, steady-state fluorescence quenching experiments suggest that MBNL1 alters the structure of helical RNA targets upon binding, which may explain the selectivity of MBNL1 for less structured RNA sites. The removal of one pair of zinc fingers greatly impairs the binding affinity of MBNL1, which indicates that the two pairs of zinc fingers might possibly interact with RNA targets cooperatively. Alanine scanning mutagenesis results suggest that the binding energy may be distributed across the protein. Overall, the results presented here suggest that small molecules that stabilize the helical structure of poly(CUG) and poly(CCUG) RNAs will inhibit the formation of complexes with MBNL1. PMID- 22106027 TI - Flexible field emission from thermally welded chemically doped graphene thin films. AB - Flexible field-emission devices (FEDs) based on reduced graphene oxide (RGO) emitters are fabricated by the thermal welding of RGO thin films onto a polymeric substrate. The RGO edges are vertically aligned relative to the substrate as a result of cohesive failure in the RGO layer after thermal welding. Even at large bending angles, excellent electron emission properties, such as low turn-on and threshold fields, a high emission current density, a high field enhancement factor, and long-term stability of the emission properties of RGO emitters, arise from the uniform distribution and high density of the extremely sharp RGO edges, as well as the high interfacial strength between the RGO emitters and the substrate. Al- and Au-doped RGO emitters are fabricated by introducing a dopant solution to the RGO emitters, and the resulting field-emission characteristics are discussed. The proposed approach is straightforward and enables the practical use of high-performance RGO flexible FEDs. PMID- 22106028 TI - Activating water: important effects of non-leaving groups on the hydrolysis of phosphate triesters. AB - The high rate of spontaneous hydrolysis of tris-2-pyridyl phosphate (TPP) is explained by the activating effects of the non-leaving ("spectator") groups on P OAr cleavage, and not by intramolecular catalysis. Previous work on phosphate transfer reactions has concentrated on the contributions to reactivity of the nucleophile and the leaving group, but our results make clear that the effects of the non-leaving groups on phosphorus can be equally significant. Rate measurements for three series of phosphate triesters showed that sensitivities to the non-leaving groups are substantial for spontaneous hydrolysis reactions, although significantly smaller for reactions with good nucleophiles. There are clear differences between triaryl and dialkyl aryl triesters in sensitivities to leaving and non-leaving groups with the more reactive triaryl systems showing lower values for both beta(LG) and beta(NLG). Intramolecular catalysis of the hydrolysis of TPP by the neighbouring pyridine nitrogens is insignificant, primarily because of their low basicity. PMID- 22106029 TI - Can one generate stable hyaline cartilage from adult mesenchymal stem cells? A developmental approach. AB - Chondrogenically differentiating bone marrow-derived mesenchymal stem cells (BMSCs) display signs of chondrocyte hypertrophy, such as production of collagen type X, MMP13 and alkaline phosphatase (ALPL). For cartilage reconstructions this is undesirable, as terminally differentiated cartilage produced by BMSCs mineralizes when implanted in vivo. Terminal differentiation is not restricted to BMSCs but is also encountered in chondrogenic differentiation of adipose-derived mesenchymal stem cells (MSCs) as well as embryonic stem cells, which by definition should be able to generate all types of tissues, including stable cartilage. Therefore, we propose that the currently used culture conditions may drive the cells towards terminal differentiation. In this manuscript we aim to review the literature, supplemented by our own data to answer the question, is it possible to generate stable hyaline cartilage from adult MSCs? We demonstrate that recently published methods for inhibiting terminal differentiation (through PTHrP, MMP13 or blocking phosphorylation of Smad1/5/8) result in cartilage formation with reduction of hypertrophic markers, although this does not reach the low level of stable chondrocytes. A set of hypertrophy markers should be included in future studies to characterize the phenotype more precisely. Finally, we used what is currently known in developmental biology about the differential development of hyaline and terminally differentiated cartilage to provide thought and insights to change current culture models for creating hyaline cartilage. Inhibiting terminal differentiation may not result in stable hyaline cartilage if the right balance of signals has not been created from the start of culture onwards. PMID- 22106031 TI - New chemical insights using weakly supported voltammetry: ion pairing in the EC2 reduction of 2,6-diphenylpyrylium in acetonitrile. AB - Pairing effect: Varying the concentration of support electrolyte in the electrochemical EC(2) reduction of 2,6-diphenylpyrylium reveals the presence of ion pairing between the electroactive species and BF(4)(-). Experiment and theory are shown to be in good agreement only if ion pairing is included in the simulations. This previously unanticipated effect is only observable if voltammetry is performed under conditions of weak support. PMID- 22106030 TI - Microtia: epidemiology and genetics. AB - Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births, and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: Neural crest cells disturbance, vascular disruption, and altitude. PMID- 22106032 TI - Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer. AB - BACKGROUND: Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study we aimed to evaluate aberrant p16(INK4a) gene promoter methylation in patients with head and neck cancer. METHODS: Methylation of the gene was investigated by bisulfite modification/methylation-specific polymerase chain reaction and gene expression levels were analyzed by quantitative reverse transcription-polymerase chain reaction in tumors and matched normal tissue samples from Turkish patients with head and neck cancer. RESULTS: The promoter region of the p16(INK4a) gene was methylated in 67.5% and 28.6% of the primary tumors and the corresponding normal tissue, respectively. This difference was highly significant. In concordance, p16(INK4a) gene expression was downregulated in 67.5% of the tumor samples. Methylation and the absence of expression in the tumors were observed in 48% of the patients. CONCLUSIONS: Our data indicate that methylation of the p16(INK4a) gene is a frequent event in primary head and neck cancer and that it plays a major role in the silencing of p16(INK4a) gene expression during tumor development. PMID- 22106033 TI - Sulfur-36S stable isotope labeling of amino acids for quantification (SULAQ). AB - We introduce a universal metabolic labeling strategy using elemental heavy 36Sulfur (36S) called 36Sulfur stable isotope labeling of amino acids for quantification (SULAQ). In the proof of principle experiment, Pseudomonas putida KT2440 was grown in defined minimal medium with sodium benzoate or sodium succinate as the sole carbon and 32S- or 36S-sodium sulfate as the sole sulfur sources. Quantification using mass spectrometry resulted in 562 proteins with 1991 unique peptides. SULAQ technology can be a valuable alternative strategy for the quantitative comparisons in MS-based proteomics approaches characterizing bacterial and other biological samples in different growth conditions. PMID- 22106034 TI - Neuroradiologic findings and follow-up with magnetic resonance imaging of the genetic forms of haemophagocytic lymphohistiocytosis with CNS involvement. AB - Haemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome caused by deficient down-regulation of the immune response. Presence of central nervous system (CNS) involvement at diagnosis is a poor prognostic sign, and should be carefully investigated. Herein, we describe the neuroradiological findings, clinical data, and treatment outcome in 12 patients with genetic HLH and CNS complications. Neuroimaging was important in identifying CNS involvement, monitoring treatment responses, and detecting treatment complications. PMID- 22106035 TI - Characterization of G-quadruplex/hemin peroxidase: substrate specificity and inactivation kinetics. AB - Recently, G-quadruplex/hemin (G4/hemin) complexes have been found to exhibit peroxidase activity, and this feature has been extensively exploited for colorimetric detection of various targets. To further understand and characterize this important DNAzyme, its substrate specificity, inactivation mechanism, and kinetics have been examined by comparison with horseradish peroxidase (HRP). G4/hemin DNAzyme exhibits broader substrate specificity and much higher inactivation rate than HRP because of the exposure of the catalytic hemin center. The inactivation of G4/hemin DNAzyme is mainly attributed to the degradation of hemin by H(2)O(2) rather than the destruction of G4. Both the inactivation rate and catalytic oxidation rate of G4/hemin DNAzyme depend on the concentration of H(2)O(2), which suggests that active intermediates formed by G4/hemin and H(2)O(2) are the branch point of catalysis and inactivation. Reducing substrates greatly inhibit the inactivation of G4/hemin DNAzyme by rapidly reacting with the active intermediates. A possible catalytic and inactivation process of G4/hemin has been proposed. These results imply a potential cause for the hemin-mediated cellular injury and provide insightful information for the future application of G4/hemin DNAzyme. PMID- 22106036 TI - Phenotype of FOXP2 haploinsufficiency in a mother and son. AB - Disruptions in FOXP2, a transcription factor, are the only known monogenic cause of speech and language impairment. We report on clinical findings for two new individuals with a submicroscopic deletion of FOXP2: a boy with severe apraxia of speech and his currently moderately affected mother. A 1.57 Mb deletion on chromosome 7q31 was detected by array comparative genomic hybridization (aCGH). In addition to FOXP2, the patients' deletion involves two other genes, MDFIC and PPP1R3A, neither of which has been associated with speech or language disorders. Thus, findings for these two family members provide informative phenotypic information on FOXP2 haploinsufficiency. Evaluation by a clinical geneticist indicated no major congenital anomalies or dysmorphic features. Evaluations by a clinical psychologist and occupational therapist indicated cognitive-linguistic processing and sensorimotor control deficits, but did not support a diagnosis of autism spectrum disorder. Evaluation by clinical and research speech pathologists confirmed that both patients' speech deficits met contemporary criteria for apraxia of speech. Notably, the patients were not able to laugh, cough, or sneeze spontaneously, replicating findings reported for two other FOXP2 cases and a potential diagnostic sign of nonsyndromic apraxia of speech. Speech severity findings for the boy were not consistent with the hypothesis that loss of maternal FOXP2 should be relatively benign. Better understanding of the behavioral phenotype of FOXP2 disruptions will aid identification of patients, toward an eventual understanding of the pathophysiology of syndromic and nonsyndromic apraxia of speech. PMID- 22106037 TI - Rat-specific decreases in platelet count caused by a humanized monoclonal antibody against sclerostin. AB - LY2541546 is a humanized monoclonal antibody (IgG(4)) that has been optimized for neutralizing activity against sclerostin. In 5-week and 6-month nonclinical safety studies in rats, LY2541546 caused dose-dependent reversible decreases in platelet counts accompanied by accelerated platelet production, increased megakaryocytes, and altered megakaryocyte morphology. These treatment-related effects resulted in altered primary hemostasis as manifested by prolonged bleeding after phlebotomy or incidental toenail break. In some cases, the defects in hemostasis were sufficient to result in death of the affected rats. There was no evidence in rats of general bone marrow suppression or processes (e.g., disseminated intravascular coagulopathy) that may result in thrombocytopenia. Cynomolgus monkeys given LY2541546 for 5 weeks or 9 months had no changes in platelet count or megakaryocytes. In vitro cross-reactivity studies in rats, cynomolgus monkeys, and humans revealed LY2541546-bound rat but not cynomolgus monkey or human platelets and megakaryocytes. These data taken together demonstrated that the platelet and megakaryocyte effects in rats had a species specific pathogenesis which likely involved LY2541546 binding of a rat-specific antigen on the surface of platelets and megakaryocytes resulting in the increased clearance of platelets and megakaryocyte hyperplasia. The species-specific nature of these reversible toxicological findings combined with the ease of clinical monitoring using standard hematology enabled the safe initiation of clinical studies in human volunteers. PMID- 22106039 TI - Using DFT in search for support effects during methanol oxidation on supported molybdenum oxides. AB - The oxidation of methanol on supported molybdenum oxides was studied using DFT. Starting from a cluster model for a mono-oxo and di-oxo molybdenum oxide on a SiO(2) support, the reaction energies and rates for the oxidation of methanol were computed and interpreted with chemical reaction indices. This pointed out that the apparent barrier was significantly lower on the mono-oxide model, favoring it over the di-oxo species. Accordingly, we assumed similar behavior on Al(2)O(3), TiO(2) and ZrO(2) supports, so that we could compare characteristics over different supports. The obtained reaction energies and rates followed the experimental turn-over frequency (TOF) sequence. PMID- 22106038 TI - Mixed inhibition of adenosine deaminase activity by 1,3-dinitrobenzene: a model for understanding cell-selective neurotoxicity in chemically-induced energy deprivation syndromes in brain. AB - Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons are relatively unaffected, consistent with other chemically-induced energy deprivation syndromes. Previous studies have investigated the role of astrocytes in protecting neurons from hypoxia and chemical injury via adenosine release. Adenosine is considered neuroprotective, but it is rapidly removed by extracellular deaminases such as adenosine deaminase (ADA). The present study tested the hypothesis that ADA is inhibited by 1,3-DNB as a substrate mimic, thereby preventing adenosine catabolism. ADA was inhibited by 1,3-DNB with an IC(50) of 284 MUM, Hill slope, n = 4.8 +/- 0.4. Native gel electrophoresis showed that 1,3-DNB did not denature ADA. Furthermore, adding Triton X-100 (0.01-0.05%, wt/vol), Nonidet P-40 (0.0015-0.0036%, wt/vol), or bovine serum albumin (0.05 mg/ml or changing [ADA] (0.2 and 2 nM) did not substantially alter the 1,3-DNB IC(50) value. Likewise, dynamic light scattering showed no particle formation over a (1,3-DNB) range of 149-1043 MUM. Kinetics revealed mixed inhibition with 1,3-DNB binding to ADA (K(I) = 520 +/- 100 MUM, n = 1 +/- 0.6) and the ADA adenosine complex (K(IS) = 262 +/- 7 MUM, n = 6 +/- 0.6, indicating positive cooperativity). In accord with the kinetics, docking predicted binding of 1,3-DNB to the active site and three peripheral sites. In addition, exposure of DI TNC-1 astrocytes to 10-500 MUM 1,3-DNB produced concentration-dependent increases in extracellular adenosine at 24 h. Overall, the results demonstrate that 1,3-DNB is a mixed inhibitor of ADA and may thus lead to increases in extracellular adenosine. The finding may provide insights to guide future work on chemically induced energy deprivation. PMID- 22106040 TI - Thyroid cartilage invasion in early-stage squamous cell carcinoma involving the anterior commissure. AB - BACKGROUND: Anterior commissure (AC) carcinoma is in close proximity to the thyroid cartilage. Our objective was to evaluate risk factors for thyroid cartilage invasion. METHODS: This was a retrospective study of tumors involving the AC treated by open surgery. Tumor stage, extensions, vocal fold (VF) mobility, CT scan, and pathologic cartilage status were recorded. RESULTS: Ninety four patients with clinical T (cT) classifications cT1b (44%), cT2 (50%), and cT3 (6%) were included. The incidence of thyroid cartilage invasion was 8.5%, significantly related to VF mobility, with invasion in 31% versus 5% with normal mobility (p = .002). Sensitivity, specificity, and positive and negative predictive values for decreased VF mobility were 50%, 90%, 31%, and 95%, respectively. After a median follow-up of 49 months, there was no difference in local control between tumors with or without cartilage invasion. CONCLUSIONS: For these tumors involving the AC, VF mobility was the only significant factor related to thyroid cartilage invasion and should be taken into consideration when planning surgery. PMID- 22106041 TI - pParse: a method for accurate determination of monoisotopic peaks in high resolution mass spectra. AB - Determining the monoisotopic peak of a precursor is a first step in interpreting mass spectra, which is basic but non-trivial. The reason is that in the isolation window of a precursor, other peaks interfere with the determination of the monoisotopic peak, leading to wrong mass-to-charge ratio or charge state. Here we propose a method, named pParse, to export the most probable monoisotopic peaks for precursors, including co-eluted precursors. We use the relationship between the position of the highest peak and the mass of the first peak to detect candidate clusters. Then, we extract three features to sort the candidate clusters: (i) the sum of the intensity, (ii) the similarity of the experimental and the theoretical isotopic distribution, and (iii) the similarity of elution profiles. We showed that the recall of pParse, MaxQuant, and BioWorks was 98 98.8%, 0.5-17%, and 1.8-36.5% at the same precision, respectively. About 50% of tandem mass spectra are triggered by multiple precursors which are difficult to identify. Then we design a new scoring function to identify the co-eluted precursors. About 26% of all identified peptides were exclusively from co-eluted peptides. Therefore, accurately determining monoisotopic peaks, including co eluted precursors, can greatly increase peptide identification rate. PMID- 22106042 TI - Cell cycle-specific function of Ikaros in human leukemia. AB - BACKGROUND: The loss of Ikaros is associated with the development of B and T cell leukemia. Data on Ikaros function, including its role as a tumor suppressor and a regulator of cell cycle progression, come almost exclusively from murine studies; little is known of the mechanisms that regulate human Ikaros function. Our studies are the first to examine the function and regulation of human Ikaros isoforms during the cell cycle in human ALL. PROCEDURES: Electromobility shift assay (EMSA), confocal microscopy, and phosphopeptide mapping were used to study Ikaros function during different stages of the cell cycle. RESULTS: The DNA binding activity of human Ikaros complexes undergoes dynamic changes as the cell cycle progresses. In S phase, Ikaros DNA-binding affinity for regulatory regions of its target genes decreases, while its binding to pericentromeric heterochromatin is preserved and correlates with Ikaros pericentromeric localization. These S phase-specific changes in Ikaros function are controlled by phosphorylation via the CK2 kinase pathway. During cell cycle progression, the subcellular pericentromeric localization of the largest human Ikaros isoforms is different from that in mouse cells, suggesting unique functions for human Ikaros. CONCLUSIONS: Our results demonstrate that the function of Ikaros is cell cycle specific and controlled by CK2-mediated phosphorylation during S phase of the cell cycle in human T-cell and B-cell ALL. The differences we observe in murine and human Ikaros function highlight the importance of using human cells in studies of ALL. These data identify the CK2 pathway as a target for therapies in ALL. PMID- 22106043 TI - Controllable growth of conical and cylindrical TiO2-carbon core-shell nanofiber arrays and morphologically dependent electrochemical properties. AB - Quasi-aligned cylindrical and conical core-shell nanofibers consisting of carbon shells and TiO(2) nanowire cores are produced in situ on Ti foils without using a foreign metallic catalyst and template. A cylindrical nanofiber has a TiO(2) nanowire core 30-50 nm in diameter and a 5-10 nm-thick cylindrical carbon shell, while in the conical nanostructure the TiO(2) nanowire core has a diameter of 20 40 nm and the thickness of the carbon shell varies from about 200 nm at the bottom to about 5 nm at the tip. Electrochemical analysis reveals well-defined redox peaks of the [Fe(CN)(6)](3-/4-) redox couple and heterogeneous charge transfer rate constants of 0.010 and 0.062 cm s(-1) for the cylindrical and conical nanofibers, respectively. The coverage of exposed edge planes on the cylindrical and conical carbon shells is estimated to be 2.5 and 15.5 % respectively. The more abundant exposed edge planes on the conical nanofiber decrease the overpotential and increase the voltammetric resolution during electrochemical detection of uric acid and ascorbic acid. Our results suggest that the density of edge-plane sites estimated from Raman scattering is not necessarily equal to the density of exposed edge-plane sites, and only carbon electrodes with a large density of exposed edge planes or free graphene sheet ends exhibit better electrochemical performance. PMID- 22106044 TI - Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. AB - Timothy syndrome (TS) is an autosomal dominant condition with the constellation of features including prolonged QT interval, hand and foot abnormalities, and mental retardation or autism. Splawski et al. [2004] previously described two phenotypes associated with TS distinguished by two unique and different mutations within the CACNA1C gene. We report on a newborn who presented with prolonged QT interval and associated polymorphic ventricular tachycardia, dysmorphic facial features, syndactyly of the hands and feet, and joint contractures, suggestive of TS. He developed a stroke, subsequent intractable seizures, and was found to have cortical blindness and later profound developmental delay. Initial targeted mutation analysis did not identify either of the previously described TS associated mutations; however, full gene sequencing detected a novel CACNA1C gene mutation (p.Ala1473Gly). The clinical and genetic findings in our case expand both the clinical and molecular knowledge of TS. PMID- 22106046 TI - Chemical effects in SERS of pyrazine adsorbed on Au-Pd bimetallic nanoparticles: a theoretical investigation. AB - Chemical enhancement in surface-enhanced Raman scattering (SERS) of pyrazine adsorbed on Au-Pd nanoclusters is investigated by using density functional theory. Changing Pd content in the bimetallic clusters enables modulation of the direct chemical interactions between the pyrazine and the clusters. The magnitude of chemical enhancement is correlated well with the induced polarizability for the complexes with low Pd content, which fails for the complexes with high Pd content. Furthermore, the dependence of chemical enhancement on cluster size and coupling is also described by the induced polarizability. Additionally, the chemical enhancement in the cluster-molecule-cluster junction is found to account for as much as 10(3), which suggests that a chemical mechanism might be more important than previously believed, in particular for Au-Pd bimetallic nanoparticle aggregates. PMID- 22106048 TI - Effect of corruption on medical care in low-income countries. PMID- 22106047 TI - Sites of ubiquitin attachment in Saccharomyces cerevisiae. AB - Sites of ubiquitin modification have been identified by mass spectrometry based on the increase in molecular mass of a tryptic peptide carrying two additional glycine residues from the ubiquitin moiety. However, such peptides with GG shifts have been difficult to discover. We identify 870 unique sites of ubiquitin attachment on 438 different proteins of the yeast Saccharomyces cerevisiae. PMID- 22106049 TI - Do rhodium bis(sigma-amine-borane) complexes play a role as intermediates in dehydrocoupling reactions of amine-boranes? AB - The recently synthesized rhodium complex [Rh{P(C(5)H(9))(2)(eta(2) C(5)H(7))}(Me(2)HNBH(3))(2)]BAr(F)(4) (2), which incorporates two amine-boranes coordinated to the rhodium center with two different binding modes, namely eta(1) and eta(2), has been used to probe whether bis(sigma-amine-borane) motifs are important in determining the general course of amine-boranes dehydrocoupling reactions. DFT calculations have been carried out to explore mechanistic alternatives that ultimately lead to the formation of the amine-borane cyclic dimer [BH(2)NMe(2)](2) (A) by hydrogen elimination. Sequential concerted, on- or off-metal, intramolecular dehydrogenations provide two coordinated amine-borane molecules. Subsequent dimerization is likely to occur off the metal in solution. In spite of the computationally confirmed presence of a BH???NH hydrogen bond between amine-borane ligands, neither a simple intermolecular route for dehydrocoupling of complex 2 is operating, nor seems [Rh{P(C(5)H(9))(2)(eta(2) C(5)H(7))}B](+) to be important for the whole dehydrocoupling process. PMID- 22106050 TI - Atypical achondroplasia due to somatic mosaicism for the common thanatophoric dysplasia mutation R248C. PMID- 22106051 TI - What are the preferred horizontal displacements in parallel aromatic-aromatic interactions? Significant interactions at large displacements. PMID- 22106052 TI - Improved enrichment and proteomic identification of outer membrane proteins from a Gram-negative bacterium: focus on Caulobacter crescentus. AB - Efforts to characterize proteins found in the outer membrane (OM) of Gram negative bacteria have been steadily increasing due to the promise of expanding our understanding of fundamental bacterial processes such as cell adhesion or cell wall biogenesis as well as the promise of finding potential vaccine- or drug targets for virulent bacteria. We have developed a mass spectrometry-compatible experimental strategy that resulted in increased coverage of the OM proteome of a model organism, Caulobacter crescentus. The specificity of the OM enrichment step was improved by using detergent solubilization of the protein pellet, low-density cell culture conditions, and a surface-layer deficient cell line. Additionally, efficient gel-assisted digestion, high-resolution RP/RP-MS/MS, and rigorous bioinformatic analysis led to the identification of 234 proteins using strict identification criteria (>= two unique peptides per protein; peptide false discovery rate <2%). Eighty-four of the detected proteins were predicted to localize to the OM or extracellular space. These results represent ~70% coverage of the predicted OM/extracellular proteome of C. crescentus. This analytical approach, which considers important experimental variables not previously explored in published OM protein studies, can be applied to other OM proteomic endeavors "as is" or with slight modification and should improve the large-scale study of this especially challenging subproteome. PMID- 22106054 TI - Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children. AB - BACKGROUND: Acquired somatic mutations of JAK2 have been reported to play a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasm (MPN). However, the molecular characteristics of childhood MPN remain to be elucidated. PATIENT AND METHODS: We investigated a group of pediatric patients diagnosed either with essential thrombocythemia (ET; N = 9) or polycythemia vera (PV; N = 4) according to WHO criteria (median age = 10 years; range 1.5-15 years) in whom direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2. More sensitive allele specific polymerase chain reaction was used for JAK2(V617F) genotyping. RESULTS: We found three patients harbor JAK2(V617F) mutation (2/9 ET and 1/4 PV). Bone marrow examination showed small and large megakaryocytes with dysplastic features in JAK2(V617F)-positive ET patients compared to those without JAK2(V617F). We identified a previously unrecognized missense mutation at codon 1230 in exon 12 of ASXL1 gene in ET and PV patients (1/9 ET and 1/4 PV). Otherwise, no genetic alterations could be detected in JAK2 exon 12, MPL, TET2, CBL, IDH1, and IDH2 in all ET and PV patients. CONCLUSION: Although JAK2 mutations in childhood ET and PV are not as frequent as reported in adult patients, JAK2 is the most frequently mutated gene in childhood MPN known so far. Owing to the presence of childhood MPN without any genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2, new biological markers have to be found. PMID- 22106053 TI - The assessment of adeno-associated vectors as potential intrinsic treatments for brainstem axon regeneration. AB - BACKGROUND: Adeno-associated virus (AAV) vector-mediated transgene expression is a promising therapeutic to change the intrinsic state of neurons and promote repair after central nervous system injury. Given that numerous transgenes have been identified as potential candidates, the present study demonstrates how to determine whether their expression by AAV has a direct intrinsic effect on axon regeneration. METHODS: Serotype 2 AAV-enhanced green fluorescent protein (EGFP) was stereotaxically injected into the brainstem of adult rats, followed by a complete transection of the thoracic spinal cord and Schwann cell (SC) bridge implantation. RESULTS: The expression of EGFP in brainstem neurons labeled numerous axons in the thoracic spinal cord and that regenerated into the SC bridge. The number of EGFP-labeled axons rostral to the bridge directly correlated with the number of EGFP-labeled axons that regenerated into the bridge. Animals with a greater number of EGFP-labeled axons rostral to the bridge exhibited an increased percentage of those axons found near the distal end of the bridge compared to animals with a lesser number. This suggested that EGFP may accumulate distally in the axon with time, enabling easier visualization. By labeling brainstem axons with EGFP before injury, numerous axon remnants undergoing Wallerian degeneration may be identified distal to the complete transection up to 6 weeks after injury. CONCLUSIONS: Serotype 2 AAV-EGFP enabled easy visualization of brainstem axon regeneration. Rigorous models of axonal injury (i.e. complete transection and cell implantation) should be used in combination with AAV-EGFP to directly assess AAV-mediated expression of therapeutic transgenes as intrinsic treatments to improve axonal regeneration. PMID- 22106055 TI - In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange Syndrome. AB - Cornelia de Lange Syndrome (CdLS) is a genetically heterogeneous disorder characterized by dysmorphic facial features, cleft palate, limb defects, growth retardation, and developmental delay. Approximately 60% of patients with CdLS have an identifiable mutation in the NIPBL gene at 5p13.2. Recently, an X-linked form of CdLS with a generally milder phenotype was attributed to mutation of the structural maintenance of chromosomes 1A gene (SMC1A) at Xp11.22. Relatively few CdLS patients with mutations in SMC1A are known; female carriers have minor facial dysmorphism and cognitive deficiency without major structural abnormalities. To date, all mutations identified in SMC1A are missense or small in-frame deletions that preserve the open reading frame of the gene and likely have a dominant-negative effect. We report on a female with monosomy X mosaicism and a phenotype suggestive of a severe form of CdLS who presented with growth and mental retardation, multiple congenital anomalies, and facial dysmorphism. Array CGH confirmed mosaic monosomy X and identified a novel deletion of SMC1A spanning multiple exons, suggesting a possible loss-of-function effect. Sequencing of both genomic and cDNA demonstrated an 8,152 bp deletion of genomic DNA from exon 13 to intron 16. Although a loss-of-function effect cannot be excluded, the resulting mRNA remains in-frame and is expressed in peripheral blood lymphocytes, suggesting a dominant-negative effect. We hypothesize that the size of this deletion compared to previously reported mutations may account for this patient's severe CdLS phenotype. The presence of mosaic monosomy X may also modify the phenotype. PMID- 22106056 TI - The impact of CodY on virulence determinant production in community-associated methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is a leading human pathogen of both hospital and community associated diseases worldwide. This organism causes a wealth of infections within the human host as a result of the vast arsenal of toxins encoded within its genome. Previous transcriptomic studies have shown that toxin production in S. aureus can be strongly impacted by the negative regulator CodY. CodY acts by directly, and indirectly (via Agr), repressing toxin production during times of plentiful nutrition. In this study, we use iTRAQ-based proteomics for the first time to study virulence determinant production in S. aureus, so as to correlate transcriptional observations with actual changes in protein synthesis. Using a codY mutant in the epidemic CA-MRSA clone USA300 we demonstrate that deletion of this transcription factor results in a major upregulation of toxin synthesis in both post-exponential and stationary growth. Specifically, we observe hyper production of secreted proteases, leukocidins and hemolysins in both growth phases in the USA300 codY mutant. Our findings demonstrate the power of mass spectrometry-based quantitative proteomics for studying toxin production in S. aureus, and the importance of CodY to this central process in disease causation and infection. PMID- 22106057 TI - Corneal gene delivery: chitosan oligomer as a carrier of CpG rich, CpG free or S/MAR plasmid DNA. AB - BACKGROUND: Corneal gene therapy can potentially treat acquired and inherited corneal disorders that otherwise lead to blindness. In a previous study on the development of effective vectors for corneal gene delivery, we showed that a particular formulation of chitosan-DNA nanoparticles, based on ultrapure chitosan oligomers injected into rat corneas, led to transgene expression that was 5.4 fold higher than that obtained using polyethylenimine-DNA nanoparticles. METHODS: In the present study, we investigate the same formulation of chitosan-DNA nanoparticles as carriers of six different plasmids for corneal gene delivery. Size, zeta potential, the ability to condense plasmid DNA, and transfection efficiency in cell cultures and in rat corneas, were all investigated. RESULTS: Size, zeta potential, the ability to condense plasmid DNA, and transfection efficiency in cell cultures did not substantially vary for nanoparticles based on different plasmids. One day post-injection of nanoparticles into rat corneas, we found that a CpG-free plasmid DNA, pCpG-Luc, which has an EF1alpha promoter, led to transgene expression that was 7.1-fold higher than that for gWiz-Luc, a commercially available plasmid DNA with a cytomegalovirus (CMV) promoter used in our previous study; 116.8-fold higher than that for pEPI-CMV, a commercially available plasmid that has a scaffold/matrix attachment region (S/MAR) sequence and a CMV promoter; and 76.8-fold higher than that for pEPI-UbC, an experimental plasmid that has an S/MAR sequence and a ubiquitin C promoter. CONCLUSIONS: The present study reveals the potential of comparing various plasmids as an approach for enhancing transgene expression. The delivery system designed in the present study represents the next step in the development of effective vectors for corneal gene therapy. PMID- 22106058 TI - A re-examination of the use of ethnicity in prenatal carrier testing. AB - In April 2011, the American Congress of Obstetricians and Gynecologists (formerly the American College of Obstetrics and Gynecology [ACOG]), updated its policy on carrier screening for cystic fibrosis and proposed that because of the increasing difficulty in assigning a single ethnicity to individuals, "It is reasonable, therefore to offer CF carrier screening to all patients." However, ACOG continues to use ethnicity in its guidelines about carrier testing for autosomal recessive disorders like sickle cell disease (SCD) and Tay-Sachs disease (TSD). This practice is in marked contrast with newborn screening (NBS) which is universally provided for all conditions. In this manuscript, I evaluate the discrepant role of ethnicity in NBS and carrier screening. I argue that ACOG needs to adopt the position it now takes for CF regarding prenatal carrier testing for all conditions. To promote equity in prenatal testing decision making, health care policies must acknowledge the diversity of the populations that we serve and empower all women and couples to make more fully informed reproductive decisions by offering prenatal carrier testing to all. PMID- 22106060 TI - Learning curve for transcatheter aortic valve replacement. PMID- 22106059 TI - A mass spectrometry-based method to screen for alpha-amidated peptides. AB - Amidation is a post-translational modification found at the C-terminus of ~50% of all neuropeptide hormones. Cleavage of the C(alpha)-N bond of a C-terminal glycine yields the alpha-amidated peptide in a reaction catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM). The mass of an alpha amidated peptide decreases by 58 Da relative to its precursor. The amino acid sequences of an alpha-amidated peptide and its precursor differ only by the C terminal glycine meaning that the peptides exhibit similar RP-HPLC properties and tandem mass spectral (MS/MS) fragmentation patterns. Growth of cultured cells in the presence of a PAM inhibitor ensured the coexistence of alpha-amidated peptides and their precursors. A strategy was developed for precursor and alpha amidated peptide pairing (PAPP): LC-MS/MS data of peptide extracts were scanned for peptide pairs that differed by 58 Da in mass, but had similar RP-HPLC retention times. The resulting peptide pairs were validated by checking for similar fragmentation patterns in their MS/MS data prior to identification by database searching or manual interpretation. This approach significantly reduced the number of spectra requiring interpretation, decreasing the computing time required for database searching and enabling manual interpretation of unidentified spectra. Reported here are the alpha-amidated peptides identified from AtT-20 cells using the PAPP method. PMID- 22106061 TI - Time to clean up. PMID- 22106062 TI - A tale of two pressures: a case of pseudo-prosthetic mitral valve stenosis. AB - We present a case of an 83-year-old female with past medical history of rheumatic fever associated mitral stenosis for which she underwent mitral commissurotomy 25 years prior to presentation. Subsequently, she underwent coronary artery bypass grafting and mitral valve replacement with a bio-prosthetic valve 8 years prior to presentation. Presently, she started experiencing worsening dyspnea and heart failure symptoms. Echocardiography showed mildly reduced left ventricular ejection fraction with severe aortic stenosis and pulmonary hypertension. The bioprosthetic mitral valve was functioning normally. We performed right and left heart catheterization for evaluation. Peak aortic gradient was 50 mm Hg with a mean gradient of 39 mm Hg. Aortic valve area was calculated to be 0.31 cm(2). However, simultaneous measurement of left ventricular and wedge pressures showed a significant gradient of 11 mm Hg across the mitral valve with a calculated mitral valve area of 0.4 cm(2). Because of discordant information between echocardiographic and hemodynamic data, we proceeded with trans-septal puncture to directly measure left atrial pressures. Simultaneous left atrial and left ventricular pressure measurement demonstrated a mean gradient of 4 mm Hg across the mitral valve with an area calculated at 1.9 cm(2). We review the tracings in detail and discuss the pitfalls of using pulmonary capillary wedge pressure as a surrogate for left atrial pressure. PMID- 22106063 TI - When should you question your wedge and use a long iron (transseptal needle) instead? PMID- 22106064 TI - Macrocirculation and microcirculation in critical limb ischemia: correlated but complementary. PMID- 22106065 TI - How does this study change my practice? PMID- 22106066 TI - Bifurcation stenting with a provisional T strategy: drug eluting stent type does matter. PMID- 22106067 TI - Stent fracture: broken stents--broken hearts. PMID- 22106068 TI - CT coronary angiography: plaque characterization, prognosis, and clinical applications. PMID- 22106069 TI - Alignment and composition of laminin-polycaprolactone nanofiber blends enhance peripheral nerve regeneration. AB - Peripheral nerve transection occurs commonly in traumatic injury, causing deficits distal to the injury site. Conduits for repair currently on the market are hollow tubes; however, they often fail due to slow regeneration over long gaps. To facilitate increased regeneration speed and functional recovery, the ideal conduit should provide biochemically relevant signals and physical guidance cues, thus playing an active role in regeneration. To that end, laminin and laminin-polycaprolactone (PCL) blend nanofibers were fabricated to mimic peripheral nerve basement membrane. In vitro assays established 10% (wt) laminin content is sufficient to retain neurite-promoting effects of laminin. In addition, modified collector plate design to introduce an insulating gap enabled the fabrication of aligned nanofibers. The effects of laminin content and fiber orientation were evaluated in rat tibial nerve defect model. The lumens of conduits were filled with nanofiber meshes of varying laminin content and alignment to assess changes in motor and sensory recovery. Retrograde nerve conduction speed at 6 weeks was significantly faster in animals receiving aligned nanofiber conduits than in those receiving random nanofiber conduits. Animals receiving nanofiber-filled conduits showed some conduction in both anterograde and retrograde directions, whereas in animals receiving hollow conduits, no impulse conduction was detected. Aligned PCL nanofibers significantly improved motor function; aligned laminin blend nanofibers yielded the best sensory function recovery. In both cases, nanofiber-filled conduits resulted in better functional recovery than hollow conduits. These studies provide a firm foundation for the use of natural-synthetic blend electrospun nanofibers to enhance existing hollow nerve guidance conduits. PMID- 22106070 TI - Trends in occurrence of twin births in Japan. AB - The rise in the rate of multiple births since the 1980s is due to the effect of advanced maternal age and increased use of assisted reproductive technology (ART). To determine the trends of prevalence in twin births, we studied the data of a population-based birth defects monitoring system during 26 years in Kanagawa Prefecture, Japan. A total of 15,380 twins from 7,690 deliveries were ascertained from 990,978 births in the Kanagawa Birth Defects Monitoring Program (KAMP) during 1981-2008. From the start of KAMP in 1981, the incidence of twin births had been consistently increasing from 57.0 to 98.6 per 10,000 deliveries until 2003, but after this time, the incidence declined to 78.5 in 2007. While the rate of monozygotic twins has been stable (~40 per 10,000 deliveries) after 1990, that of dizygotic twins increased from 25.3 to 57.3 per 10,000 deliveries until 2002, and recovered to 40.1 in 2007. These results showed the most recent tendency of twin births and indicated that the single embryo transfer method can provide protection and reduction of perinatal risk caused by multiple births. PMID- 22106071 TI - Proteomic analysis of urine exosomes by multidimensional protein identification technology (MudPIT). AB - Exosomes are membrane vesicles that are secreted by cells upon fusion of multivesicular bodies with the plasma membrane. Exosomal proteomics has emerged as a powerful approach to understand the molecular composition of exosomes and has potential to accelerate biomarker discovery. Different proteomic analysis methods have been previously employed to establish several exosome protein databases. In this study, TFE solution-phase digestion was compared with in-gel digestion and found to yield similar results. Proteomic analysis of urinary exosomes was performed by multidimensional protein identification technology (MudPIT) after TFE digestion. Nearly, 3280 proteins were identified from nine human urine samples with 31% overlap among nine samples. Gene ontology (GO) analysis, coupled with detection of all of the members of ESCRT machinery complex, supports the multivesicular origin of these particles. These results significantly expand the existing database of urinary exosome proteins. Our results also indicate that more than 1000 proteins can be detected from exosomes prepared from as little as 25 mL of urine. This study provides the largest set of proteins present in human urinary exosome proteomes, provides a valuable reference for future studies, and provides methods that can be applied to exosomal proteomic analysis from other tissue sources. PMID- 22106072 TI - Antipsychotic treatment among youth in foster care. AB - OBJECTIVE: Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth. PATIENTS AND METHODS: The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had >=1 claim with a psychiatric diagnosis and >=1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with >=2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use. RESULTS: Average antipsychotic use ranged from 222 +/- 110 days in foster care to only 135 +/- 101 days in TANF (P < .001). Concomitant use for >=180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001). CONCLUSIONS: Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system. PMID- 22106073 TI - The safety of pediatric acupuncture: a systematic review. AB - CONTEXT: Acupuncture is increasingly used in children; however, the safety of pediatric acupuncture has yet to be reported from systematic review. OBJECTIVE: To identify adverse events (AEs) associated with needle acupuncture in children. METHODS: Eighteen databases were searched, from inception to September 2010, irrespective of language. Inclusion criteria were that the study (1) was original peer-reviewed research, (2) included children from birth to 17 years, inclusively, (3) involved needle acupuncture, and (4) included assessment of AEs in a child. Safety data were extracted from all included studies. RESULTS: Of 9537 references identified, 450 were assessed for inclusion. Twenty-eight reports were included, and searches of reference lists identified 9 additional reports (total: 37). A total of 279 AEs were identified, 146 from randomized controlled trials, 95 from cohort studies, and 38 from case reports/series. Of the AEs, 25 were serious (12 cases of thumb deformity, 5 infections, and 1 case each of cardiac rupture, pneumothorax, nerve impairment, subarachnoid hemorrhage, intestinal obstruction, hemoptysis, reversible coma, and overnight hospitalization), 1 was moderate (infection), and 253 were mild. The mild AEs included pain, bruising, bleeding, and worsening of symptoms. We calculated a mild AE incidence per patient of 168 in 1422 patients (11.8% [95% confidence interval: 10.1-13.5]). CONCLUSIONS: Of the AEs associated with pediatric needle acupuncture, a majority of them were mild in severity. Many of the serious AEs might have been caused by substandard practice. Our results support those from adult studies, which have found that acupuncture is safe when performed by appropriately trained practitioners. PMID- 22106074 TI - National trends in exposure to and experiences of violence on the Internet among children. AB - OBJECTIVE: To examine rates of technology-based violent experiences (eg, bullying, harassment, unwanted sexual experiences [USEs] perpetration, and victimization) and exposures (eg, hate sites) from 2006 to 2008 among US children. PATIENTS AND METHODS: One thousand five-hundred eighty-eight youth aged 10 to 15 years were surveyed nationally online in 2006, 2007 (76% follow-up rate), and 2008 (73% follow-up rate). RESULTS: All other things equal, rates of Internet-based violent exposures and experiences were stable. Of exception, harassment perpetration and exposure to violent cartoon sites reduced by 26% and 36% over the 2 year period (P < 0.05), respectively. In contrast, several rates of violent experiences via text messaging increased over time, specifically: harassment victimization (aOR = 1.6, p = 0.001) and perpetration (aOR = 1.4, p = 0.03), and USE victimization (aOR = 1.9, p = 0.02). Increases in bullying victimization were suggested (aOR = 1.5, p = 0.06). Text messaging USE perpetration did not significantly change, however. General technology use (i.e., intensity and frequency of Internet and text messaging) was consistently influential in explaining the odds of almost all violent experiences and exposures both online and via text messaging; as was age for many exposures and experiences online. CONCLUSIONS: Ongoing surveillance of text-messaging-based experiences is needed to understand trends as population usage rates begin to stabilize. General technology use is a predictive factor for almost all technology-based violent experiences and exposures. Age is also influential in explaining involvement in Internet-based experiences and exposures. Prevention programs should focus on reducing risk as youth age into later adolescence and to help heavy technology users manage their risk for violence involvement. PMID- 22106075 TI - Benefits of a pediatric antimicrobial stewardship program at a children's hospital. AB - OBJECTIVE: To prospectively evaluate the effect of a comprehensive antimicrobial stewardship program on antimicrobial use, physician interventions, patient outcomes, and rates of antimicrobial resistance. METHODS: Active surveillance of antimicrobial use with intervention and real-time feedback to providers and reinforcement of prior authorization for selected antimicrobials were introduced at a pediatric teaching hospital. Antimicrobial-use indications were incorporated as a mandatory field in the computerized information system. An automated report of antimicrobials prescribed, doses, patient demographics, and microbiology data was generated and reviewed by an infectious-disease pharmacist and a pediatric infectious-disease physician. Antimicrobial use, expressed as the number of doses administered per 1000 patient-days, was measured 3 years before and after the implementation of the program. RESULTS: Total antimicrobial use peaked at 3089 doses administered per 1000 patient-days per year in 2003-2004 before implementation of the program and steadily decreased to 1904 doses administered per 1000 patient-days per year during the postintervention period. Targeted antimicrobial use declined from 1250 to 988 doses administered per 1000 patient days per year. Nontargeted-antimicrobial use declined from 1839 to 916 doses administered per 1000 patient-days per year. Rates of antimicrobial resistance to broad-spectrum antimicrobials among the most common Gram-negative bacilli remained low and stable over time. CONCLUSIONS: The successful implementation of antimicrobial stewardship strategies had a significant impact on reducing targeted- and nontargeted-antimicrobial use, improving quality of care of hospitalized children and preventing emergence of resistance. PMID- 22106076 TI - Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. AB - OBJECTIVES: Healthy infants are thought to acquire biliary atresia (BA) in the first weeks of life. Because those diagnosed earlier have better outcomes, we were interested in determining the earliest time BA could be detected. We started by examining the immediate postnatal period, hypothesizing that newborns would not yet have acquired disease and still have normal direct/conjugated bilirubin (DB/CB) levels. PATIENTS AND METHODS: Newborn DB/CB levels were obtained retrospectively from birth hospitals. Subjects with BA were born between 2007 and 2010 and cared for at Texas Children's Hospital. Those with BA splenic malformation syndrome or born prematurely were excluded. Control subjects were term newborns who later never developed neonatal liver disease. RESULTS: Of the 61 subjects with BA, 56% had newborn DB/CB levels measured. All DB/CB levels exceeded laboratory norms and rose over time. At 24 to 48 hours of life, subjects with BA had mean DB levels significantly higher than those of controls (1.4 +/- 0.43 vs. 0.19 +/- 0.075 mg/dL, P < .0001), even while their mean total bilirubin (TB) levels remained below phototherapy limits. Finally, despite the elevated DB/CB levels, the majority of patients (79%) had normal DB:TB ratios <= 0.2. CONCLUSIONS: Patients with BA have elevated DB/CB levels shortly after birth. To detect affected infants earlier and improve outcomes, the results suggest two possibilities: (1) screen all newborns for elevated DB/CB levels, rather than just those who appear jaundiced; and then (2) follow all newborns with elevated DB/CB levels, rather than just those with DB:TB ratios >0.2. PMID- 22106077 TI - Antipsychotic medication use among children and risk of diabetes mellitus. AB - OBJECTIVE: To assess whether the risk of incident diabetes was increased with the use of second-generation antipsychotics (SGAs) in a large diverse cohort of children. METHODS: A retrospective study was conducted by using the administrative databases of 3 health plans participating in the Health Maintenance Organization Research Network. Children 5 to 18 years of age who initiated SGA therapy between January 2001 and December 2008 and 2 comparison groups, namely, nonusers of psychotropic drugs and users of antidepressant medications, were identified. Diagnoses from inpatient and outpatient records, pharmacy dispensings, and outpatient laboratory results were used to identify incident cases of diabetes. RESULTS: The crude incidence rate of diabetes for the SGA-exposed cohort was 3.23 cases per 1000 person-years (95% confidence interval [CI]: 1.67-5.65), compared with 0.76 cases per 1000 person-years (95% CI: 0.49 1.12) among nonusers of psychotropic medications and 1.86 cases per 1000 person years (95% CI: 1.12-2.90) among antidepressant users. The risk of incident diabetes was significantly increased among SGA users (unadjusted incidence rate ratio: 4.24 [95% CI: 1.95-8.72]) in comparison with nonusers of psychotropic medications but was not significantly increased in comparison with antidepressant medication users (unadjusted incidence rate ratio: 1.74 [95% CI: 0.77-3.78]). CONCLUSIONS: Although we found a potentially fourfold increased rate of diabetes among children exposed to SGAs, the findings were inconsistent and depended on the comparison group and the outcome definition. PMID- 22106078 TI - Changes in body mass during elementary and middle school in a national cohort of kindergarteners. AB - OBJECTIVE: To analyze changes in BMI, according to gender and race/ethnicity, in a nationally representative cohort of children in the United States during their elementary and middle school years to identify critical periods of excess BMI gains. METHODS: The Early Childhood Longitudinal Study-Kindergarten Class monitored a nationally representative cohort of kindergarten students over 9 years (1998-2007). Height and weight measurements were available for 4240 white, 640 black, and 1070 Hispanic children in kindergarten and 1st, 3rd, 5th, and 8th grades. In each wave, we estimated the proportions of children with BMI values in each quartile of the Centers for Disease Control and Prevention reference population distribution according to gender and race/ethnicity. We conducted nonparametric tests of differences in BMI distributions over time within racial/ethnic groups and across racial/ethnic groups in each wave. Piecewise linear growth models were estimated to test for specific time periods during which the largest gains in BMI percentiles occurred. RESULTS: Overall, nearly 40% of children started kindergarten with a BMI in the top quartile of the growth charts (BMI > 75th percentile). This proportion increased significantly during the elementary school years, and the largest gains were between 1st and 3rd grades (5.8 percentage points), but there was no further increase during middle school. Increases in BMI percentiles over time were most notable among Hispanic children and black girls. CONCLUSIONS: The early school years might be a critical time for excess BMI gains, even among children with normal BMI values at kindergarten entry. PMID- 22106079 TI - Early detection of biliary atresia raises questions about etiology and screening. PMID- 22106080 TI - Use of a visual aid to improve counseling at the threshold of viability. AB - OBJECTIVES: To pilot-test a visual aid developed to help counsel pregnant women. METHODS: After agreeing to participate, pregnant women at >28 weeks of gestation were assigned randomly to counseling with or without a visual aid. The visual aid contained pictures, graphics, and short messages about delivery room resuscitation, chances of survival, anticipated neonatal course, and long-term neurodevelopmental disabilities. A neonatal fellow performed counseling with a standardized script for an anticipated delivery at 23 weeks of gestation. In precounseling and postcounseling sessions, women were given a structured interview to assess their knowledge of chances of survival and disability and attitudes toward resuscitation. RESULTS: Of the 89 women who participated, 76% were black and 59% read below a 9th-grade level. Compared with the no-visual aid group, women in the visual aid group recalled more disabilities and predicted longer neonatal stays (P = .01). For both groups, mothers' perceptions of the chances of survival were lower after counseling; the decrease was greater in the visual aid group (P = .03). The majority of women in each group opted for resuscitation, which was not affected by counseling. In multivariate analyses, use of the visual aid was a significant independent factor in explaining before/after differences in survival chances and recall of a long NICU stay and number of disabilities; higher literacy levels also were significant for recalling the number of disabilities. CONCLUSIONS: Use of a visual aid improved mothers' knowledge and showed promise as a decision aid for counseling at the threshold of viability. PMID- 22106081 TI - Emergency department laboratory evaluations of fever without source in children aged 3 to 36 months. AB - OBJECTIVE: This article describes ordering of diagnostic tests, admission rates, and antibiotic administration among visits to US emergency departments (EDs) by children aged 3 to 36 months with fever without source (FWS). METHODS: The 2006 2008 National Hospital Ambulatory Medical Care Survey-Emergency Department was used to identify visits by 3- to 36-month-old children with FWS. Percentages of visits that included a complete blood count (CBC), urinalysis, blood culture, radiograph, rapid influenza test, admission to hospital, and ceftriaxone and other antibiotic administration were calculated. Multivariate logistic regression was used to identify factors associated with ordering of a CBC and urinalysis. RESULTS: No tests were ordered in 58.6% of visits for FWS. CBCs were ordered in 20.5% of visits and urinalysis in 17.4% of visits. Even among girls with a temperature of >=39 degrees C, urinalysis was ordered in only 40.2% of visits. Ceftriaxone was given in 7.1% and other antibiotics in 18.3% of visits; 5.2% of the children at these visits were admitted to the hospital. In multivariate analysis, increased temperature, being female, and higher median income of the patient's zip code were associated with increased odds of having a CBC and urinalysis ordered. Being 24 to 36 months of age was associated with lower odds of receiving both a CBC and a urinalysis. CONCLUSIONS: Most US emergency department visits for FWS among children aged 3 to 36 months, physicians do not order diagnostic tests. Being female, having a higher fever, and higher median income of the patient's zip code were associated with ordering CBCs and urinalysis. PMID- 22106082 TI - Improving reporting of outpatient pediatric medical errors. AB - OBJECTIVE: Limited information exists about medical errors in ambulatory pediatrics and on effective strategies for improving their reporting. We aimed to implement nonpunitive error reporting, describe errors, and use a team-based approach to promote patient safety in an academic pediatric practice. PATIENTS AND METHODS: The setting was an academic general pediatric practice in Charlotte, North Carolina, that has ~26 000 annual visits and primarily serves a diverse, low-income, Medicaid-insured population. We assembled a multidisciplinary patient safety team to detect and analyze ambulatory medical errors by using a reporter anonymous nonpunitive process. The team used systems analysis and rapid redesign to evaluate each error report and recommend changes to prevent patient harm. RESULTS: In 30 months, 216 medical errors were reported, compared with 5 reports in the year before the project. Most reports originated from nurses, physicians, and midlevel providers. The most frequently reported errors were misfiled or erroneously entered patient information (n = 68), laboratory tests delayed or not performed (n = 27), errors in medication prescriptions or dispensing (n = 24), vaccine errors (n = 21), patient not given requested appointment or referral (n = 16), and delay in office care (n = 15), which together comprised 76% of the reports. Many recommended changes were implemented. CONCLUSIONS: A voluntary, nonpunitive, multidisciplinary team approach was effective in improving error reporting, analyzing reported errors, and implementing interventions with the aim of reducing patient harm in an outpatient pediatric practice. PMID- 22106083 TI - Treatment of Kimura disease with intravenous immunoglobulin. AB - Kimura disease is an uncommon chronic inflammatory condition of unknown etiology and is characterized by painless subcutaneous nodules, usually affecting the head and neck, eosinophilia, and markedly elevated immunoglobulin E levels. Several reports have described the main modalities of treatment; both corticosteroids and surgery have provided good results, but occasionally corticosteroids cannot be tapered as the disease flares up. We report here the case of an 8-year-old boy diagnosed with Kimura disease who was successfully treated with 1 dose of intravenous immunoglobulin as a steroid-sparing agent. PMID- 22106084 TI - Financial impact to providers using pediatric combination vaccines. AB - OBJECTIVE: To understand the financial impact to providers for using a combination vaccine (Pediarix [GlaxoSmithKline Biologicals, King of Prussia, PA]) versus its equivalent component vaccines for children aged 1 year or younger. METHODS: Using a subscription remittance billing service offered to private practice office-based physicians, we analyzed charge and payment information submitted by providers to insurance payers from June 2007 through July 2009. We analyzed provider and payer characteristics, payer comments, and the ratio of vaccine product to immunization administration (IA) codes and computed total charges and payments to providers for both arms of the study. RESULTS: Most providers in our data set were pediatricians (74%), and most payers were commercial (75%), primarily managed care. The ratio of the number of vaccine products to the number of IAs was 1:1 in the majority of the claims. Twenty percent of claims were paid with no adjustment by the payer, whereas 76% of the claims were adjusted for charges that exceeded the contract arrangement or the fee schedule. Providers received $23 less from commercial payers and $13 less from Medicaid for the use of Pediarix compared with the equivalent component vaccines. The mean commercial payment was greater for age-specific Current Procedural Terminology IA codes 90465 and 90466 than for non-age-specific codes 90471 and 90472, whereas the reverse was true for Medicaid. CONCLUSIONS: Providers who administer vaccines to children face a reduction in payment when choosing to provide combination vaccines. The new IA codes should be monitored for correction of financial barriers to the use of combination vaccines. PMID- 22106085 TI - In vivo biocompatibility and in vitro characterization of poly-lactide-co glycolide structures containing levetiracetam, for the treatment of epilepsy. AB - Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is highly resistant to medication with up to 40% of patients continuing to experience seizures whilst taking oral antiepileptic drugs. Recent research suggests that this may be due to abnormalities in the blood-brain barrier, which prevent the passage of therapeutic substances into the brain. We sought to develop a drug delivery material that could be implanted within the brain at the origin of the seizures to release antiepileptic drugs locally and avoid the blood brain barrier. We produced poly-lactide-co-glycolide drop-cast films and wet-spun fibers loaded with the novel antiepileptic drug Levetiracetam, and investigated their morphology, in vitro drug release characteristics, and brain biocompatibility in adult rats. The best performing structures released Levetiracetam constantly for at least 5 months in vitro, and were found to be highly brain biocompatible following month-long implantations in the motor cortex of adult rats. These results demonstrate the potential of polymer-based drug delivery devices in the treatment of epilepsy and warrant their investigation in animal models of focal epilepsy. PMID- 22106086 TI - Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2). AB - We report on a female patient with early infantile epileptic encephalopathy and severe psychomotor disability possessing a de novo balanced translocation t(1;9)(q32;q13). The patient showed clonic convulsions of extremities 2 days after birth. Electroencephalogram (EEG) transiently showed atypical suppression burst pattern. The seizures evolved to brief tonic spasms, and hypsarrhythmia on EEG was noticed at age of 5 months, indicating the transition to West syndrome. By using fluorescent in situ hybridization (FISH), southern hybridization, and inverse PCR, the translocation breakpoints were successfully determined at the nucleotide level. The 1q32.1 breakpoint was located within a segmental duplication and disrupted the gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2). The 9q13 breakpoint was suggested to reside in the heterochromatin region. Srgap2 has been shown to be specifically expressed in developing brain of rodents, negatively regulate neuronal migration and induce neurite outgrowth and branching. Thus, SRGAP2 is very likely to play a role in the developing human brain. This is a first report of the SRGAP2 abnormality associated with early infantile epileptic encephalopathy. PMID- 22106087 TI - A proteomics approach to the cell-surface interactome using the enzyme-mediated activation of radical sources reaction. AB - We previously reported a simple method to analyze the interaction of cell-surface molecules in living cells. This method termed enzyme-mediated activation of radical sources (EMARS) is featured by radical formation of the labeling reagent by horseradish peroxidase (HRP). Herein, we propose an approach to the cell surface molecular interactome by using combination of this EMARS reaction and MS based proteomics techniques. In the current study, we employed a novel labeling reagent, fluorescein-conjugated arylazide. The fluorescein-tagged proteins resulting from the EMARS reaction were directly detected in the electrophoresis gels with a fluorescence image analyzer. These products were also purified and concentrated by immunoaffinity chromatography with anti-fluorescein antibody immobilized resins. The purified fluorescein-tagged proteins were subsequently subjected to an MS-based proteomics analysis. Analysis using HRP-conjugated cholera toxin subunit B, which recognizes a lipid raft marker, ganglioside GM1, revealed 30 membrane and secreted proteins that were candidates for the cell surface molecules coclustering with GM1. The proposed approach will provide a clue to study functional molecular interactions in a variety of biological events on the cell surface. PMID- 22106088 TI - Recombinant chromosome 7 in a mosaic 45,X/47,XXX patient. AB - Individuals with pericentric inversions are at risk for producing offspring with chromosomal gains and losses, while those carrying paracentric inversions usually produce unviable gametes [Madan, 1995]. In this current study, we present a newborn with dysmorphic features and malformations, whose karyotype showed an abnormal copy of chromomosome 7 described at first as add(7)(q32) as well as mos 45,X/47,XXX. Array comparative genomic hybridization (CGH) revealed an interstitial deletion in the long arm of chromosome 7 involving bands q35 to q36.3 but retaining the 7q subtelomere. The patient's deletion is believed to be due to meiotic recombination in the inversion loop in the phenotypically normal father who seems to carry two paracentric inversions in the long arm of chromosome 7, which was described as rec(7)(7pter- > q35::q36.3- > 7qter)pat. The abnormal copy of chromosome 7 in the father has been described as: der(7)(7pter- > q22.1::q36.3- > q35::q22.1- > q35::q36.3- > 7qter). This is a unique karyotype that to our knowledge has not been previously reported in the literature and predisposes to meiotic recombination that can result in deletions or duplications of 7q35-36. PMID- 22106089 TI - The 2011 Human Liver Proteome Project (HLPP) Workshop September 5, 2011, Geneva, Switzerland. AB - During the 10th HUPO Annual World Congress held in Geneva (Switzerland) from 4th to 7th September, a workshop on Human Liver Proteome Project (HLPP) Initiative took place. Four research groups presented their latest results from different ongoing projects. Later on, during the HLPP executive members' meeting, the status of current projects and the next possible steps to be taken were discussed. PMID- 22106090 TI - Pharmacological actions of statins: a critical appraisal in the management of cancer. AB - Statins, among the most commonly prescribed drugs worldwide, are cholesterol lowering agents used to manage and prevent cardiovascular and coronary heart diseases. Recently, a multifaceted action in different physiological and pathological conditions has been also proposed for statins, beyond anti inflammation and neuroprotection. Statins have been shown to act through cholesterol-dependent and -independent mechanisms and are able to affect several tissue functions and modulate specific signal transduction pathways that could account for statin pleiotropic effects. Typically, statins are prescribed in middle-aged or elderly patients in a therapeutic regimen covering a long life span during which metabolic processes, aging, and concomitant novel diseases, including cancer, could occur. In this context, safety, toxicity, interaction with other drugs, and the state of health have to be taken into account in subjects treated with statins. Some evidence has shown a dichotomous effect of statins with either cancer-inhibiting or -promoting effects. To date, clinical trials failed to demonstrate a reduced cancer occurrence in statin users and no sufficient data are available to define the long-term effects of statin use over a period of 10 years. Moreover, results from clinical trials performed to evaluate the therapeutic efficacy of statins in cancer did not suggest statin use as chemotherapeutic or adjuvant agents. Here, we reviewed the pharmacology of the statins, providing a comprehensive update of the current knowledge of their effects on tissues, biological processes, and pathological conditions, and we dissected the disappointing evidence on the possible future use of statin-based drugs in cancer therapy. PMID- 22106092 TI - Selective two-step labeling of proteins with an off/on fluorescent probe. AB - We present a novel design strategy for off/on fluorescent probes suitable for selective two-step labeling of proteins. To validate this strategy, we designed and synthesized an off/on fluorescent probe, 1-Ni(2+), which targets a cysteine modified hexahistidine (His) tag. The probe consists of dichlorofluorescein conjugated with nitrilotriacetic acid (NTA)-Ni(2+) as the His-tag recognition site and a 2,4-dinitrophenyl ether moiety, which quenches the probe's fluorescence by photoinduced electron transfer (PeT) from the excited fluorophore to the 2,4-dinitrophenyl ether (donor-excited PeT; d-PeT) and also has reactivity with cysteine. His-tag recognition by the NTA-Ni(2+) moiety is followed by removal of the 2,4-dinitrophenyl ether quencher by proximity-enhanced reaction with the cysteine residue of the modified tag; this results in a marked fluorescence increase. Addition of His-tag peptide bearing a cysteine residue to aqueous probe solution resulted in about 20-fold fluorescence increment within 10 min, which is the largest fluorescence enhancement so far obtained with a visible light-excitable fluorescent probe for a His-based peptide tag. Further, we successfully visualized CysHis(6)-peptide tethered to microbeads without any washing step. The probe also showed a large fluorescence increment in the presence of His(6)Cys-tagged enhanced blue fluorescent protein (EBFP), but not His(6)-tagged EBFP. We consider this system is superior to large fluorescence tags (e.g., green fluorescent protein: 27 kDa), which can perturb protein folding, trafficking and function, and also to existing small tags, which generally show little fluorescence increase upon target recognition and therefore require a washout step. This strategy should also be applicable to other tags. PMID- 22106094 TI - Uninformed compliance or informed choice? A needed shift in our approach to cancer screening. AB - It has been more than 30 years since the first consensus development meeting was held to deal with guidelines of mammography screening. Although the National Cancer Institute has wisely focused on the science of screening and of screening benefits vs harm, many professional organizations, advocacy groups, and the media have maintained a focus on establishing who should be screened and promoting recommendations for which age groups should be screened. Guidelines have been developed not only for mammography but also for screening at virtually all major cancer sites, especially for prostate cancer, and most recently, with the preliminary results of the National Lung Screening Trial, for lung cancer. It seems clear that we have done an inadequate job of educating screening candidates about the harms and benefits of cancer screening, including the extent to which screening can reduce cancer mortality. We must also question whether our practice of summoning women to have mammograms, while providing men informed choice for prostate cancer screening, is consistent with a scientific analysis of the relative harms and benefits. We have spent a staggering amount of time and energy over the past several decades developing, discussing, and debating guidelines. Professional and advocacy groups have spent much time aggressively advocating the adoption of guidelines supported by their respective groups. It seems that it would be much more productive to devote such energy to educating screening candidates about the harms and benefits of screening and to engaging in shared decision making. PMID- 22106091 TI - Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? AB - Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals. PMID- 22106095 TI - MACROCALYX and JOINTLESS interact in the transcriptional regulation of tomato fruit abscission zone development. AB - Abscission in plants is a crucial process used to shed organs such as leaves, flowers, and fruits when they are senescent, damaged, or mature. Abscission occurs at predetermined positions called abscission zones (AZs). Although the regulation of fruit abscission is essential for agriculture, the developmental mechanisms remain unclear. Here, we describe a novel transcription factor regulating the development of tomato (Solanum lycopersicum) pedicel AZs. We found that the development of tomato pedicel AZs requires the gene MACROCALYX (MC), which was previously identified as a sepal size regulator and encodes a MADS-box transcription factor. MC has significant sequence similarity to Arabidopsis (Arabidopsis thaliana) FRUITFULL, which is involved in the regulation of fruit dehiscent zone development. The MC protein interacted physically with another MADS-box protein, JOINTLESS, which is known as a regulator of fruit abscission; the resulting heterodimer acquired a specific DNA-binding activity. Transcriptome analyses of pedicels at the preabscission stage revealed that the expression of the genes involved in phytohormone-related functions, cell wall modifications, fatty acid metabolism, and transcription factors is regulated by MC and JOINTLESS. The regulated genes include homologs of Arabidopsis WUSCHEL, REGULATOR OF AXILLARY MERISTEMS, CUP-SHAPED COTYLEDON, and LATERAL SUPPRESSOR. These Arabidopsis genes encode well-characterized transcription factors regulating meristem maintenance, axillary meristem development, and boundary formation in plant tissues. The tomato homologs were specifically expressed in AZs but not in other pedicel tissues, suggesting that these transcription factors may play key roles in pedicel AZ development. PMID- 22106096 TI - Effects of carbonyl sulfide and carbonic anhydrase on stomatal conductance. AB - The potential use of carbonyl sulfide (COS) as tracer of CO(2) flux into the land biosphere stimulated research on COS interactions with leaves during gas exchange. We carried out leaf gas-exchange measurements of COS and CO(2) in 22 plant species representing deciduous and evergreen trees, grasses, and shrubs, under a range of light intensities, using mid-infrared laser spectroscopy. A narrow range in the normalized ratio of the net uptake rates of COS (A(s)) and CO(2) (A(c)), leaf relative uptake (A(s)/A(c) * [CO(2)]/[COS]), was observed, with a mean value of 1.61 +/- 0.26, which is advantageous to the use of COS in photosynthesis research. Notably, increasing COS concentrations between 250 and 2,800 pmol mol(-1) (enveloping atmospheric levels) enhanced stomatal conductance (g(s)) to a variable extent in most plants examined (up to a normalized enhancement factor [ f(e) = (g(s-max) - g(s-min))/g(s-min)] of 1). This enhancement was completely abolished in carbonic anhydrase (CA)-deficient antisense lines of both C3 and C4 plants. We suggest that the stomatal response is mediated by CA and may involve hydrogen sulfide formed in the reaction of COS and water with CA. In all species examined, the uptake rates of COS and CO(2) were highly correlated, but there was no relationship between the sensitivity of stomata to COS and the rate of COS uptake (or, by inference, hydrogen sulfide production). The basis for the observed stomatal sensitivity and its variations is still to be determined. PMID- 22106097 TI - Nitric oxide and protein S-nitrosylation are integral to hydrogen peroxide induced leaf cell death in rice. AB - Nitric oxide (NO) is a key redox-active, small molecule involved in various aspects of plant growth and development. Here, we report the identification of an NO accumulation mutant, nitric oxide excess1 (noe1), in rice (Oryza sativa), the isolation of the corresponding gene, and the analysis of its role in NO-mediated leaf cell death. Map-based cloning revealed that NOE1 encoded a rice catalase, OsCATC. Furthermore, noe1 resulted in an increase of hydrogen peroxide (H(2)O(2)) in the leaves, which consequently promoted NO production via the activation of nitrate reductase. The removal of excess NO reduced cell death in both leaves and suspension cultures derived from noe1 plants, implicating NO as an important endogenous mediator of H(2)O(2)-induced leaf cell death. Reduction of intracellular S-nitrosothiol (SNO) levels, generated by overexpression of rice S nitrosoglutathione reductase gene (GSNOR1), which regulates global levels of protein S-nitrosylation, alleviated leaf cell death in noe1 plants. Thus, S nitrosylation was also involved in light-dependent leaf cell death in noe1. Utilizing the biotin-switch assay, nanoliquid chromatography, and tandem mass spectrometry, S-nitrosylated proteins were identified in both wild-type and noe1 plants. NO targets identified only in noe1 plants included glyceraldehyde 3 phosphate dehydrogenase and thioredoxin, which have been reported to be involved in S-nitrosylation-regulated cell death in animals. Collectively, our data suggest that both NO and SNOs are important mediators in the process of H(2)O(2) induced leaf cell death in rice. PMID- 22106099 TI - Using color to understand perceived lightness. AB - We report a series of experiments that employed chromatic variants of lightness illusions in an attempt to gain theoretical leverage into the types of computations that are responsible for the illusions. Two types of displays were used: one that elicits a strong percept of transparency and one that does not. We compared the pattern of induction observed in chromatic and achromatic variants of both display types. We found that the pattern of induction observed in the display that evoked a strong percept of transparency generated similar patterns of induction in both the chromatic and achromatic variants of the display, suggesting that layered image representations (scission) may be responsible for the induction observed in this display. In contradistinction, we found that the chromatic and achromatic variants of the checkerboard-gradient pattern did not consistently generate the same patterns of induction, suggesting that there are patterns of induction that only arise from luminance modulations in some class of displays. The impact of these results on existing models of lightness is discussed. We suggest that the comparison of chromatic and achromatic induction can provide insights into the computations that are responsible for the role of context in modulating perceived lightness and color. PMID- 22106100 TI - The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets. AB - G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2',6' dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1 benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca2+ concentration ([Ca2+](i)) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca2+](i) was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of beta-cell [Ca2+](i). TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The beta-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia. PMID- 22106098 TI - Signaling regulation of fetoplacental angiogenesis. AB - During normal pregnancy, dramatically increased placental blood flow is critical for fetal growth and survival as well as neonatal birth weights and survivability. This increased blood flow results from angiogenesis, vasodilatation, and vascular remodeling. Locally produced growth factors including fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are key regulators of placental endothelial functions including cell proliferation, migration, and vasodilatation. However, the precise signaling mechanisms underlying such regulation in fetoplacental endothelium are less well defined, specifically with regard to the interactions amongst protein kinases (PKs), protein phosphatase, and nitric oxide (NO). Recently, we and other researchers have obtained solid evidence showing that different signaling mechanisms participate in FGF2- and VEGFA-regulated fetoplacental endothelial cell proliferation and migration as well as NO production. This review will briefly summarize currently available data on signaling mediating fetoplacental angiogenesis with a specific emphasis on PKs, ERK1/2, AKT1, and p38 MAPK and protein phosphatases, PPP2 and PPP3. PMID- 22106101 TI - Pharmacologic profile of OC000459, a potent, selective, and orally active D prostanoid receptor 2 antagonist that inhibits mast cell-dependent activation of T helper 2 lymphocytes and eosinophils. AB - D prostanoid receptor 2 (DP2) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D2 (PGD2). (5-Fluoro 2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole acetic acid derivative that potently displaces [3H]PGD2 from human recombinant DP2 (K(i) = 0.013 MUM), rat recombinant DP2 (K(i) = 0.003 MUM), and human native DP2 (Th2 cell membranes; K(i) = 0.004 MUM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E1-4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC50 = 0.028 MUM) of human Th2 lymphocytes and cytokine production (IC50 = 0.019 MUM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD2 in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD2 (DK-PGD2) in this species (ED50 = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD2 in guinea pigs (ED50 = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils. PMID- 22106102 TI - Time to stop mammography screening? PMID- 22106104 TI - Donation and transplantation of allogeneic hematopoietic stem cells. PMID- 22106103 TI - Recommendations on screening for breast cancer in average-risk women aged 40-74 years. PMID- 22106106 TI - Latency period of radiation-induced cancer. PMID- 22106108 TI - Don't select medical students--convince them. PMID- 22106109 TI - Electroconvulsive therapy article unbalanced. PMID- 22106110 TI - Cover of CMAJ. PMID- 22106111 TI - Addressing the root cause. PMID- 22106112 TI - Practice Gaps. Optimizing antimalarial therapy for cutaneous lupus erythematosus: comment on "Response to antimalarial agents in cutaneous lupus erythematosus". PMID- 22106113 TI - A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index. AB - OBJECTIVE: To establish and validate a new system to define the severity of onychomycosis. The Onychomycosis Severity Index (OSI) score is obtained by multiplying the score for the area of involvement (range, 0-5) by the score for the proximity of disease to the matrix (range, 1-5). Ten points are added for the presence of a longitudinal streak or a patch (dermatophytoma) or for greater than 2 mm of subungual hyperkeratosis. Mild onychomycosis corresponds to a score of 1 through 5; moderate, 6 through 15; and severe, 16 through 35. DESIGN: Consensus conference. SETTING: Teleconference. PARTICIPANTS: The consensus group included 5 dermatologists, 1 dermatology resident with an interest in nail disorders, and a statistician. The meetings were held by closed teleconference. MAIN OUTCOME MEASURES: Index reliability. RESULTS: The reliability of the OSI system was assessed in 2 steps. The first assessment included 37 dermatologists who scored 8 photographs of onychomycosis after being taught how to use the OSI. The scoring system showed very high reliability (Cronbach alpha = 0.99 and intraclass correlation coefficient [ICC] = 0.95). The second assessment entailed evaluation of 49 nails by 3 dermatologists, including an expert in the OSI. This assessment was conducted at the University of Alabama at Birmingham and at the Oregon Dermatology and Research Center, Portland. The scoring system showed very high reliabilities at both sites (Cronbach alpha = 0.99 and ICC = 0.96 at the University of Alabama at Birmingham, and Cronbach alpha = 0.98 and ICC = 0.93 at the Oregon Dermatology and Research Center). CONCLUSION: The OSI is a new, simple, objective, reproducible numeric system to grade the severity of onychomycosis. PMID- 22106115 TI - Patient preferences for psoriasis treatments: process characteristics can outweigh outcome attributes. AB - OBJECTIVES: To assess patients' preferences for psoriasis treatments and to identify the effect of sociodemographic and socioeconomic characteristics on these preferences. DESIGN: A computer-based conjoint analysis experiment was conducted to analyze the preferences of individuals with moderate or severe psoriasis for outcome attributes (probability, magnitude, and duration of benefit, as well as probability, severity, and reversibility of adverse effects) and process attributes (treatment location, frequency, duration, delivery method, and individual cost) of psoriasis treatments. Relative importance scores (RISs) for each attribute were calculated. The effect of sociodemographic (age, sex, and marital status) and socioeconomic (income and employment) characteristics and Psoriasis Area and Severity Index and Dermatology Life Quality Index scores on preferences was assessed using analysis of variance, post hoc testing, and multivariate regression analysis. SETTING: Outpatient dermatology clinic at a German university medical center. PARTICIPANTS: Patients with moderate or severe psoriasis (N = 163). MAIN OUTCOME MEASURE: Relative importance scores for treatment attributes. RESULTS: The attribute considered to be most important in patients' preferences for psoriasis treatments was treatment location (RIS, 26.76), followed by probability of benefit (RIS, 23.77) and method of delivery (RIS, 23.49). The RISs for all process attributes were higher than for adverse effect-related attributes. Older individuals (>=65 years) were less concerned about the probability of benefit (beta = -0.24; P = .005) compared with younger individuals. CONCLUSIONS: When choosing among treatment options, individuals with psoriasis appear to be willing to accept treatment-related adverse effects to obtain process attributes compatible with their personal and professional life. Incorporating preferences in shared decision making may facilitate treatment adherence and optimize outcome. PMID- 22106117 TI - IgA anti-p200 pemphigoid. AB - BACKGROUND: Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disorder. Clinically, it may resemble bullous pemphigoid, linear IgA bullous dermatosis, or dermatitis herpetiformis. Immunologically, anti-p200 pemphigoid is characterized by the development of IgG antibodies directed against a basement membrane zone protein with a molecular weight of 200 kDa. OBSERVATIONS: We report the first case, to our knowledge, of anti-p200 pemphigoid associated with IgA antibodies and having clinical features resembling pemphigus herpetiformis or dermatitis herpetiformis localized on traumatized areas. Histopathological examination of lesional skin showed dermal-epidermal separation and microabscesses composed of neutrophils in the dermal papillae. Direct immunofluorescence disclosed the presence exclusively of linear in vivo-bound IgA along the basement membrane zone. With the use of laser scanning confocal microscopy, in vivo-bound IgA was localized above collagen type IV and colocalized with laminin 332. Indirect immunofluorescence showed circulating IgA antibodies against basement membrane zone at a titer of 1:160 that reacted with the floor of an artificial blister of salt-split skin. Western immunoblot analysis using dermal extract confirmed the reactivity of circulating IgA antibodies with the 200-kDa antigen corresponding to laminin gamma1; however, immunoblotting using recombinant protein of 107 amino acid C-terminus of laminin gamma1 was negative for circulating IgA antibodies. Immunoelectron microscopy disclosed the reactivity of circulating IgA autoantibodies within the lower lamina lucida. CONCLUSION: To the best of our knowledge, this is the first case fulfilling the immunopathological criteria for anti-p200 pemphigoid associated with IgA antibodies and having unusual clinical features. PMID- 22106118 TI - Leukocytoclastic vasculitis as the presenting feature of dermatitis herpetiformis. AB - BACKGROUND: Dermatitis herpetiformis is an autoimmune disease typically characterized by pruritic vesicles located on the extensor surfaces. Classic disease consists of neutrophils in the dermal papillae. Additional histopathologic findings include fibrin deposition and edema within the dermal papillae. Subepidermal vesicles also may be present. Direct immunofluorescence demonstrates granular IgA in the dermal papillae. OBSERVATIONS: A 58-year-old man with tender and pruritic erythematous macules and papules ranging from 2 to 6 mm in diameter had bilateral knee, elbow, forearm, scalp, and neck involvement. Petechiae also were present on the hands, thigh, knee, and ankle. A biopsy specimen initially demonstrated leukocytoclastic vasculitis. The results of workup for systemic vasculitis were negative. Subsequent biopsy specimens and direct immunofluorescence showed histologic evidence of dermatitis herpetiformis and leukocytoclastic vasculitis in the setting of an elevated serum IgA antitissue transglutaminase level. Marked improvement of the lesions was observed with a reduction of gluten in the patient's diet. CONCLUSIONS: Physicians should consider the possibility of dermatitis herpetiformis in patients with petechiae and leukocytoclastic vasculitis because leukocytoclastic vasculitis may be a prominent feature of dermatitis herpetiformis. PMID- 22106120 TI - Paronychia and necrotic nodules. PMID- 22106121 TI - A rare cause of acquired telangiectases extending from the feet to arms. PMID- 22106122 TI - Pruritic scaly rash on arms and legs. PMID- 22106123 TI - Umbilical nodule in a 32-year-old woman. PMID- 22106124 TI - Low-dose excimer 308-nm laser for treatment of lichen planopilaris. PMID- 22106125 TI - Cryoimmunotherapy: superficial basal cell cancer and squamous cell carcinoma in situ treated with liquid nitrogen followed by imiquimod. PMID- 22106126 TI - Reliability and validity of a photographic method for measuring facial hair density in men. PMID- 22106127 TI - Connubial androgenetic alopecia. PMID- 22106128 TI - Onychodystrophy with associated polymicrobial distal phalanx osteomyelitis. PMID- 22106129 TI - Successful treatment of lupus pernio with adalimumab. PMID- 22106130 TI - Multiple bites from the larvae of Haemaphysalis longicornis. PMID- 22106131 TI - Traditional gingival tattooing of maxillary denture. PMID- 22106132 TI - Cutaneous apocrine carcinoma masquerading as head and neck cellulitis: an ominous sign. PMID- 22106133 TI - Recurrent lymphangiectasia of the left supraclavicular fossa: an unusual cause of paroxystic swelling. PMID- 22106134 TI - Neglected squamous cell carcinoma hiding under a toupee. PMID- 22106135 TI - Diffuse dermal melanocytosis: follow-up 30 years later with novel findings of eruptive blue nevi. PMID- 22106136 TI - Rapid cutaneous dissemination of persistently agminated lymphomatoid papulosis in a 9-year-old boy. PMID- 22106137 TI - Atypical cellular neurothekeoma in a pregnant woman. PMID- 22106138 TI - Atypical hidradenitis suppurativa involving the posterior neck and occiput. PMID- 22106139 TI - Cutaneous infarction under IL-12/23 p40 inhibition: a cautionary note. PMID- 22106140 TI - Sweat the small stuff: the importance of clinical-pathologic correlation in cutaneous GVHD following orthotopic liver transplant. PMID- 22106141 TI - The yellow clod sign. PMID- 22106142 TI - Quality relevant data-driven modeling and monitoring of multivariate dynamic processes: the dynamic T-PLS approach. AB - In data-based monitoring field, the nonlinear iterative partial least squares procedure has been a useful tool for process data modeling, which is also the foundation of projection to latent structures (PLS) models. To describe the dynamic processes properly, a dynamic PLS algorithm is proposed in this paper for dynamic process modeling, which captures the dynamic correlation between the measurement block and quality data block. For the purpose of process monitoring, a dynamic total PLS (T-PLS) model is presented to decompose the measurement block into four subspaces. The new model is the dynamic extension of the T-PLS model, which is efficient for detecting quality-related abnormal situation. Several examples are given to show the effectiveness of dynamic T-PLS models and the corresponding fault detection methods. PMID- 22106143 TI - Data-based virtual unmodeled dynamics driven multivariable nonlinear adaptive switching control. AB - For a complex industrial system, its multivariable and nonlinear nature generally make it very difficult, if not impossible, to obtain an accurate model, especially when the model structure is unknown. The control of this class of complex systems is difficult to handle by the traditional controller designs around their operating points. This paper, however, explores the concepts of controller-driven model and virtual unmodeled dynamics to propose a new design framework. The design consists of two controllers with distinct functions. First, using input and output data, a self-tuning controller is constructed based on a linear controller-driven model. Then the output signals of the controller-driven model are compared with the true outputs of the system to produce so-called virtual unmodeled dynamics. Based on the compensator of the virtual unmodeled dynamics, the second controller based on a nonlinear controller-driven model is proposed. Those two controllers are integrated by an adaptive switching control algorithm to take advantage of their complementary features: one offers stabilization function and another provides improved performance. The conditions on the stability and convergence of the closed-loop system are analyzed. Both simulation and experimental tests on a heavily coupled nonlinear twin-tank system are carried out to confirm the effectiveness of the proposed method. PMID- 22106144 TI - Sparse Poisson noisy image deblurring. AB - Deblurring noisy Poisson images has recently been a subject of an increasing amount of works in many areas such as astronomy and biological imaging. In this paper, we focus on confocal microscopy, which is a very popular technique for 3-D imaging of biological living specimens that gives images with a very good resolution (several hundreds of nanometers), although degraded by both blur and Poisson noise. Deconvolution methods have been proposed to reduce these degradations, and in this paper, we focus on techniques that promote the introduction of an explicit prior on the solution. One difficulty of these techniques is to set the value of the parameter, which weights the tradeoff between the data term and the regularizing term. Only few works have been devoted to the research of an automatic selection of this regularizing parameter when considering Poisson noise; therefore, it is often set manually such that it gives the best visual results. We present here two recent methods to estimate this regularizing parameter, and we first propose an improvement of these estimators, which takes advantage of confocal images. Following these estimators, we secondly propose to express the problem of the deconvolution of Poisson noisy images as the minimization of a new constrained problem. The proposed constrained formulation is well suited to this application domain since it is directly expressed using the antilog likelihood of the Poisson distribution and therefore does not require any approximation. We show how to solve the unconstrained and constrained problems using the recent alternating-direction technique, and we present results on synthetic and real data using well-known priors, such as total variation and wavelet transforms. Among these wavelet transforms, we specially focus on the dual-tree complex wavelet transform and on the dictionary composed of curvelets and an undecimated wavelet transform. PMID- 22106145 TI - Image quality assessment based on gradient similarity. AB - In this paper, we propose a new image quality assessment (IQA) scheme, with emphasis on gradient similarity. Gradients convey important visual information and are crucial to scene understanding. Using such information, structural and contrast changes can be effectively captured. Therefore, we use the gradient similarity to measure the change in contrast and structure in images. Apart from the structural/contrast changes, image quality is also affected by luminance changes, which must be also accounted for complete and more robust IQA. Hence, the proposed scheme considers both luminance and contrast-structural changes to effectively assess image quality. Furthermore, the proposed scheme is designed to follow the masking effect and visibility threshold more closely, i.e., the case when both masked and masking signals are small is more effectively tackled by the proposed scheme. Finally, the effects of the changes in luminance and contrast structure are integrated via an adaptive method to obtain the overall image quality score. Extensive experiments conducted with six publicly available subject-rated databases (comprising of diverse images and distortion types) have confirmed the effectiveness, robustness, and efficiency of the proposed scheme in comparison with the relevant state-of-the-art schemes. PMID- 22106146 TI - Adaptive distributed source coding. AB - We consider distributed source coding in the presence of hidden variables that parameterize the statistical dependence among sources. We derive the Slepian-Wolf bound and devise coding algorithms for a block-candidate model of this problem. The encoder sends, in addition to syndrome bits, a portion of the source to the decoder uncoded as doping bits. The decoder uses the sum-product algorithm to simultaneously recover the source symbols and the hidden statistical dependence variables. We also develop novel techniques based on density evolution (DE) to analyze the coding algorithms. We experimentally confirm that our DE analysis closely approximates practical performance. This result allows us to efficiently optimize parameters of the algorithms. In particular, we show that the system performs close to the Slepian-Wolf bound when an appropriate doping rate is selected. We then apply our coding and analysis techniques to a reduced-reference video quality monitoring system and show a bit rate saving of about 75% compared with fixed-length coding. PMID- 22106147 TI - Fast 2-D distance transformations. AB - The performance of a number of image processing methods depends on the output quality of a distance transformation (DT) process. Most of the fast DT methodologies are not accurate, whereas other error-free DT algorithms are not very fast. In this paper, a novel, fast, simple, and error-free DT algorithm is presented. By recording the relative x- and y-coordinates of the examined image pixels, an optimal algorithm can be developed to achieve the DT of an image correctly and efficiently in constant time without any iteration. Furthermore, the proposed method is general since it can be used by any kind of distance function, leading to accurate image DTs. PMID- 22106148 TI - Removing boundary artifacts for real-time iterated shrinkage deconvolution. AB - We propose a solution to the problem of boundary artifacts appearing in several recently published fast deblurring algorithms based on iterated shrinkage thresholding in a sparse domain and Fourier domain deconvolution. Our approach adapts an idea proposed by Reeves for deconvolution by the Wiener filter. The time of computation less than doubles. PMID- 22106149 TI - Alternating minimization algorithm for speckle reduction with a shifting technique. AB - Speckles (multiplicative noise) in synthetic aperture radar (SAR) make it difficult to interpret the observed image. Due to the edge-preserving feature of total variation (TV), variational models with TV regularization have attracted much interest in reducing speckles. Algorithms based on the augmented Lagrangian function have been proposed to efficiently solve speckle-reduction variational models with TV regularization. However, these algorithms require inner iterations or inverses involving the Laplacian operator at each iteration. In this paper, we adapt Tseng's alternating minimization algorithm with a shifting technique to efficiently remove the speckle without any inner iterations or inverses involving the Laplacian operator. The proposed method is very simple and highly parallelizable; therefore, it is very efficient to despeckle huge-size SAR images. Numerical results show that our proposed method outperforms the state-of the-art algorithms for speckle-reduction variational models with a TV regularizer in terms of central-processing-unit time. PMID- 22106150 TI - A note on octonionic support vector regression. AB - This note presents an analysis of the octonionic form of the division algebraic support vector regressor (SVR) first introduced by Shilton A detailed derivation of the dual form is given, and three conditions under which it is analogous to the quaternionic case are exhibited. It is shown that, in the general case of an octonionic-valued feature map, the usual "kernel trick" breaks down. The cause of this (and its interpretation) is discussed in some detail, along with potential ways of extending kernel methods to take advantage of the distinct features present in the general case. Finally, the octonionic SVR is applied to an example gait analysis problem, and its performance is compared to that of the least squares SVR, the Clifford SVR, and the multidimensional SVR. PMID- 22106151 TI - Deadlock-free genetic scheduling algorithm for automated manufacturing systems based on deadlock control policy. AB - Deadlock-free control and scheduling are vital for optimizing the performance of automated manufacturing systems (AMSs) with shared resources and route flexibility. Based on the Petri net models of AMSs, this paper embeds the optimal deadlock avoidance policy into the genetic algorithm and develops a novel deadlock-free genetic scheduling algorithm for AMSs. A possible solution of the scheduling problem is coded as a chromosome representation that is a permutation with repetition of parts. By using the one-step look-ahead method in the optimal deadlock control policy, the feasibility of a chromosome is checked, and infeasible chromosomes are amended into feasible ones, which can be easily decoded into a feasible deadlock-free schedule. The chromosome representation and polynomial complexity of checking and amending procedures together support the cooperative aspect of genetic search for scheduling problems strongly. PMID- 22106152 TI - Language bootstrapping: learning word meanings from perception-action association. AB - We address the problem of bootstrapping language acquisition for an artificial system similarly to what is observed in experiments with human infants. Our method works by associating meanings to words in manipulation tasks, as a robot interacts with objects and listens to verbal descriptions of the interactions. The model is based on an affordance network, i.e., a mapping between robot actions, robot perceptions, and the perceived effects of these actions upon objects. We extend the affordance model to incorporate spoken words, which allows us to ground the verbal symbols to the execution of actions and the perception of the environment. The model takes verbal descriptions of a task as the input and uses temporal co-occurrence to create links between speech utterances and the involved objects, actions, and effects. We show that the robot is able form useful word-to-meaning associations, even without considering grammatical structure in the learning process and in the presence of recognition errors. These word-to-meaning associations are embedded in the robot's own understanding of its actions. Thus, they can be directly used to instruct the robot to perform tasks and also allow to incorporate context in the speech recognition task. We believe that the encouraging results with our approach may afford robots with a capacity to acquire language descriptors in their operation's environment as well as to shed some light as to how this challenging process develops with human infants. PMID- 22106153 TI - Application of evolutionary fuzzy cognitive maps for prediction of pulmonary infections. AB - In this paper, a new evolutionary-based fuzzy cognitive map (FCM) methodology is proposed to cope with the forecasting of the patient states in the case of pulmonary infections. The goal of the research was to improve the efficiency of the prediction. This was succeeded with a new data fuzzification procedure for observables and optimization of gain of transformation function using the evolutionary learning for the construction of FCM model. The approach proposed in this paper was validated using real patient data from internal care unit. The results emerged had less prediction errors for the examined data records than those produced by the conventional genetic-based algorithmic approaches. PMID- 22106154 TI - Automated diagnosis of diseases based on classification: dynamic determination of the number of trees in random forests algorithm. AB - The accurate diagnosis of diseases with high prevalence rate, such as Alzheimer, Parkinson, diabetes, breast cancer, and heart diseases, is one of the most important biomedical problems whose administration is imperative. In this paper, we present a new method for the automated diagnosis of diseases based on the improvement of random forests classification algorithm. More specifically, the dynamic determination of the optimum number of base classifiers composing the random forests is addressed. The proposed method is different from most of the methods reported in the literature, which follow an overproduce-and-choose strategy, where the members of the ensemble are selected from a pool of classifiers, which is known a priori. In our case, the number of classifiers is determined during the growing procedure of the forest. Additionally, the proposed method produces an ensemble not only accurate, but also diverse, ensuring the two important properties that should characterize an ensemble classifier. The method is based on an online fitting procedure and it is evaluated using eight biomedical datasets and five versions of the random forests algorithm (40 cases). The method decided correctly the number of trees in 90% of the test cases. PMID- 22106155 TI - Cellular mechanisms of restored beta-cell tolerance mediated by protective alleles of Idd3 and Idd5. AB - Type 1 diabetes genes within the interleukin (IL)-2, cytotoxic T-lymphocyte- associated protein 4 (CTLA-4), and natural resistance-associated macrophage protein (NRAMP1) pathways influence development of autoimmune diabetes in humans and NOD mice. In NOD mice, when present together, protective alleles encoding IL 2, Idd3 candidate gene, CTLA-4, NRAMP1, and acetyl-coenzyme A dehydrogenase, long chain (ACADL) (candidate genes for the Idd5.1, Idd5.2, and Idd5.3 subregions) provide nearly complete diabetes protection. To define where the protective alleles of Idd3 and the Idd5 subregions must be present to protect from diabetes and tolerize islet-specific CD8(+) T cells, SCID mice were reconstituted so that the host and lymphocytes expressed various combinations of protective and susceptibility alleles at Idd3 and Idd5. Although protective Idd3 alleles in the lymphocytes and protective Idd5 alleles in the SCID host contributed most significantly to CD8 tolerance, both were required together in both lymphocyte and nonlymphocyte cells to recapitulate the potent diabetes protection observed in intact Idd3/5 mice. We conclude that genetic regions involved in autoimmune disease are not restricted in their influence to individual cell types. Even a single protective gene product, such as IL-2, must be expressed in both the lymphocytes and dendritic cells to exert its full extent of disease protection. These studies highlight the pleiotropic effects of genes that determine autoimmune disease susceptibility. PMID- 22106156 TI - A novel mechanism for regulating hepatic glycogen synthesis involving serotonin and cyclin-dependent kinase-5. AB - Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5 hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans. PMID- 22106157 TI - Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians. AB - Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5-20 years) and adulthood (ages 20-45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood. PMID- 22106158 TI - Relative expression of a dominant mutated ABCC8 allele determines the clinical manifestation of congenital hyperinsulinism. AB - Congenital hyperinsulinism (CHI) is most commonly caused by mutations in the beta cell ATP-sensitive K(+) (K(ATP)) channel genes. Severe CHI was diagnosed in a 1 day-old girl; the mother's cousin and sister had a similar phenotype. ABCC8 gene sequencing (leukocyte DNA) revealed a heterozygous, exon 37, six-base pair in frame insertion mutation in the affected patient and aunt but also in her unaffected mother and grandfather. In expression studies using transfected COSm6 cells, mutant sulfonylurea receptor 1 (SUR1) protein was expressed on the cell surface but failed to respond to MgADP even in the heterozygous state. mRNA expression in lymphocytes determined by sequencing cDNA clones and quantifying 6FAM-labeled PCR products found that although the healthy mother predominantly expressed the normal transcript, her affected daughter, carrying the same mutant allele, primarily transcribed the mutant. The methylation pattern of the imprinting control region of chromosome 11p15.5 and ABCC8 promoter was similar for all family members. In conclusion, differences in transcript expression may determine the clinical phenotype of CHI in this maternally inherited dominant mutation. The use of peripheral lymphocytes as a peripheral window to the beta cell transcription profile can serve in resolving beta-cell phenotypes. The severe, dominant-negative nature of the 1508insAS mutation suggests that it affects the functional stoichiometry of SUR1-regulated gating of K(ATP) channels. PMID- 22106159 TI - Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. AB - Diminished responsiveness to hypoglycemia contributes to defective counterregulation in diabetes. Pancreatic and/or circulating somatostatin are elevated in diabetes, which may inhibit counterregulatory hormone release during hypoglycemia. Thus, a selective somatostatin receptor type 2 antagonist (SSTR2a) should improve hormone counterregulation to hypoglycemia. Nondiabetic (N) and streptozotocin-induced diabetic (D) rats underwent 4-h infusion of saline or SSTR2a with insulin-induced hypoglycemia clamped at 2.5 +/- 0.5 mmol/L. To evaluate the effect of the SSTR2a in the absence of hypoglycemia, rats underwent a 4-h infusion of saline (Ctrl:N, Ctrl:D) or SSTR2a (Ctrl:D+SSTR2a) only. The attenuated glucagon response to hypoglycemia in D (P < 0.0002) was fully restored by SSTR2a (P < 0.0001). Furthermore, the attenuated corticosterone response in D (P < 0.002) was also enhanced by SSTR2a (P < 0.05). In the absence of hypoglycemia, SSTR2a did not alter basal blood glucose levels. D exhibited 62% more pancreatic somatostatin than N after hypoglycemia. In N rats, SSTR2a did not augment the glucagon or corticosterone response to hypoglycemia. Thus, somatostatin may contribute to impaired glucagon responsiveness to hypoglycemia in diabetes. We demonstrate that SSTR2 antagonism enhances hypoglycemia stimulated glucagon and corticosterone release in D but not in N rats. SSTR2 antagonism does not affect basal glycemia in D rats. PMID- 22106161 TI - [Renal insufficiency and breast cancer]. AB - The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study, which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients, treated in 15 cancer centers. Among them, 7.2% had a SCR level >= 110 mmol/L. In the 1,898 patients with breast cancer, only 31 patients (1.63%) had a SCR level >= 110 mmol/L. Nevertheless, respectively 51.8 and 50.8% had a creatinine clearance estimated with the Cockcroft-Gault and aMDRD formulae, below 90 mL/min. Even if the most used medications (anthracyclins, taxanes, trastuzumab, hormone therapies) are not nephrotoxic, these results are important because bevacizumab modifies the need for renal management. In case of renal insufficiency, some other treatments such biphosphonates IV, capecitabin and platin salts need drug dosage adjustment or interruption. PMID- 22106160 TI - Heparanase is essential for the development of diabetic nephropathy in mice. AB - Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for therapeutic interventions in patients with DN. PMID- 22106162 TI - [Role of autophagy in the pathogenesis of liver diseases]. AB - Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5'-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation of Mallory-Denk bodies and cell death. The deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress, and to progression of liver disease. Autophagy defect in hepatocellular carcinoma suggests that it can serve a tumor-suppressor function. The autophagy protein Beclin-1 levels have prognostic significance in liver tumors. Understanding of the molecular mechanism and the role of autophagy may lead to more effective therapeutic strategies in liver diseases in the future. PMID- 22106163 TI - [Environmental health and social ecology]. PMID- 22106164 TI - [Unusual clinical manifestations of type 1 neurofibromatosis]. AB - Type 1 neurofibromatosis is an autosomal dominant hamartosis caused by mutations of the neurofibromin-1 gene. The classic features of the clinical phenotype include the presence of cafe-au-lait spots, neurofibromas, axillary and inguinal freckling, Lisch-nodules and deformities of the skeletal system, as well as the risk of developing multiple tumors, especially in the central nervous system. However, it is known from the literature that the phenotypic variability can pose a huge diagnostic difficulty. AIMS: Our institute performs molecular genetic testing of the neurofibromin-1 gene since 2008; during this period several unusual phenotypic variants were found. RESULTS, CONCLUSION: The reported four cases represent interesting phenotypic variants or diagnostic challenges in which the final diagnosis was established by molecular genetic analysis. PMID- 22106165 TI - [Gestational trophoblastic neoplasia]. PMID- 22106166 TI - [Cancer of the vagina]. PMID- 22106167 TI - [Ovarian cancer]. PMID- 22106169 TI - Public access and use of health research: an exploratory study of the National Institutes of Health (NIH) Public Access Policy using interviews and surveys of health personnel. AB - BACKGROUND: In 2008, the National Institutes of Health (NIH) Public Access Policy mandated open access for publications resulting from NIH funding (following a 12 month embargo). The large increase in access to research that will take place in the years to come has potential implications for evidence-based practice (EBP) and lifelong learning for health personnel. OBJECTIVE: This study assesses health personnel's current use of research to establish whether grounds exist for expecting, preparing for, and further measuring the impact of the NIH Public Access Policy on health care quality and outcomes in light of time constraints and existing information resources. METHODS: In all, 14 interviews and 90 surveys of health personnel were conducted at a community-based clinic and an independent teaching hospital in 2010. Health personnel were asked about the research sources they consulted and the frequency with which they consulted these sources, as well as motivation and search strategies used to locate articles, perceived level of access to research, and knowledge of the NIH Public Access Policy. RESULTS: In terms of current access to health information, 65% (57/88) of the health personnel reported being satisfied, while 32% (28/88) reported feeling underserved. Among the sources health personnel reported that they relied upon and consulted weekly, 83% (73/88) reported turning to colleagues, 77% (67/87) reported using synthesized information resources (eg, UpToDate and Cochrane Systematic Reviews), while 32% (28/88) reported that they consulted primary research literature. The dominant resources health personnel consulted when actively searching for health information were Google and Wikipedia, while 27% (24/89) reported using PubMed weekly. The most prevalent reason given for accessing research on a weekly basis, reported by 35% (31/88) of survey respondents, was to help a specific patient, while 31% (26/84) were motivated by general interest in research. CONCLUSIONS: The results provide grounds for expecting the NIH Public Access Policy to have a positive impact on EBP and health care more generally given that between a quarter and a third of participants in this study (1) frequently accessed research literature, (2) expressed an interest in having greater access, and (3) were aware of the policy and expect it to have an impact on their accessing research literature in the future. Results also indicate the value of promoting a greater awareness of the NIH policy, providing training and education in the location and use of the literature, and continuing improvements in the organization of biomedical research for health personnel use. PMID- 22106170 TI - Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol. AB - Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D(3) precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D(2) precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k(cat) of 53 mol . min(-1) . mol P450scc(-1) and a K(m) of 0.18 mol ergosterol/mol phospholipid, similar to the values observed for cholesterol metabolism. The reaction of ergosterol with P450scc was scaled up to make enough of the two major products for structural analysis. From mass spectrometry, NMR, and comparison of the NMR data to that for similar molecules, we determined the structures of the two major products as 20 hydroxy-22,23-epoxy-22,23-dihydroergosterol and 22-keto-23-hydroxy-22,23 dihydroergosterol. Molecular modeling and nuclear Overhauser effect (or enhancement) spectroscopy spectra analysis helped to establish the configurations at C20, C22, and C23 and determine the final structures of major products as 22R,23S-epoxyergosta-5,7-diene-3beta,20alpha-diol and 3beta,23S-dihydroxyergosta 5,7-dien-22-one. It is likely that the formation of the second product is through a 22,23-epoxy (oxirane) intermediate followed by C22 hydroxylation with the formation of strained 22-hydroxy-22,23-epoxide (oxiranol), which is immediately transformed to the more stable alpha-hydroxyketone. Molecular modeling of ergosterol into the P450scc crystal structure positioned the ergosterol side chain consistent with formation of the above products. Thus, we have shown that P450scc efficiently catalyzes epoxide formation with ergosterol giving rise to novel epoxy, hydroxy, and keto derivatives, without causing cleavage of the side chain. PMID- 22106171 TI - Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. AB - Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2'R)-ITZ and (2R,4S,2'S)-ITZ also undergo stereoselective sequential metabolism by CYP3A4 at a site distant from the triazole ring to 3'-OH-ITZ, keto ITZ, and N-desalkyl-ITZ. This stereoselective metabolism demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metabolism of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC(50) 16-26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3'-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissociation rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissociation of ITZ is necessary before catalysis. The triazole containing metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4 triazol-1-yl)ethanone] also inhibited CYP3A4 (IC(50) >15 MUM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clinically relevant because this metabolite was detected in urine samples from subjects that had been administered the mixture of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety. PMID- 22106172 TI - Fictive locomotion in the adult decerebrate and spinal mouse in vivo. AB - Recently, transgenic mice have been created with mutations affecting the components of the mammalian spinal central pattern generator (CPG) for locomotion; however, it has currently only been possible to evoke fictive locomotion in mice, using neonatal in vitro preparations. Here, we demonstrate that it is possible to evoke fictive locomotion in the adult decerebrate mouse in vivo using l-3,4-dihydroxyphenylalanine methyl ester hydrochloride (l-DOPA) and 5 hydroxytryptophan (5HTP) following injection of the monoaminoxiadase inhibitor Nialamide. We investigate the effects of afferent stimulation and spinalization as well as demonstrate the possibility of simultaneous intracellular recording of rhythmically active motoneurones. Our results demonstrate that several features of the mouse locomotor CPG are similar to those that have been observed in rat, cat, rabbit and monkey suggesting a fairly conserved organisation and allowing for future results in transgenic mice to be extrapolated to existing knowledge of CPG components and circuitry obtained in larger species. PMID- 22106173 TI - Muscle time under tension during resistance exercise stimulates differential muscle protein sub-fractional synthetic responses in men. AB - We aimed to determine if the time that muscle is under loaded tension during low intensity resistance exercise affects the synthesis of specific muscle protein fractions or phosphorylation of anabolic signalling proteins. Eight men (24 +/- 1 years (sem), BMI = 26.5 +/- 1.0 kg m(-2)) performed three sets of unilateral knee extension exercise at 30% of one-repetition maximum strength involving concentric and eccentric actions that were 6 s in duration to failure (SLOW) or a work matched bout that consisted of concentric and eccentric actions that were 1 s in duration (CTL). Participants ingested 20 g of whey protein immediately after exercise and again at 24 h recovery. Needle biopsies (vastus lateralis) were obtained while fasted at rest and after 6, 24 and 30 h post-exercise in the fed state following a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine. Myofibrillar protein synthetic rate was higher in the SLOW condition versus CTL after 24-30 h recovery (P < 0.001) and correlated to p70S6K phosphorylation (r = 0.42, P = 0.02). Exercise-induced rates of mitochondrial and sarcoplasmic protein synthesis were elevated by 114% and 77%, respectively, above rest at 0-6 h post exercise only in the SLOW condition (both P < 0.05). Mitochondrial protein synthesis rates were elevated above rest during 24-30 h recovery in the SLOW (175%) and CTL (126%) conditions (both P < 0.05). Lastly, muscle PGC-1alpha expression was increased at 6 h post-exercise compared to rest with no difference between conditions (main effect for time, P < 0.001). These data show that greater muscle time under tension increased the acute amplitude of mitochondrial and sarcoplasmic protein synthesis and also resulted in a robust, but delayed stimulation of myofibrillar protein synthesis 24-30 h after resistance exercise. PMID- 22106174 TI - Sound-evoked network calcium transients in mouse auditory cortex in vivo. AB - Population calcium signals generated by the action potential activity of local clusters of neurons have been recorded in the auditory cortex of mice using an optical fibre-based approach. These network calcium transients (NCaTs) occurred spontaneously as well as in response to sound stimulation. Two-photon calcium imaging experiments suggest that neurons and neuropil contribute about equally to the NCaT. Sound-evoked calcium signals had two components: an early, fast increase in calcium concentration, which corresponds to the short-latency spiking responses observed in electrophysiological experiments, and a late, slow calcium transient which lasted for at least 1 s. The slow calcium transients evoked by sound were essentially identical to spontaneous NCaTs. Their sizes were dependent on the spontaneous activity level at sound onset, suggesting that spontaneous and sensory-evoked NCaTs excluded each other. When using pure tones as stimulus, the early evoked calcium transients were more narrowly tuned than the slow NCaTs. The slow NCaTs were correlated with global 'up states' recorded with epidural potentials, and sound presented during an epidural 'down state' triggered a calcium transient that was associated with an epidural 'up state'. Essentially indistinguishable calcium transients were evoked by optogenetic activation of local clusters of layer 5 pyramidal neurons in the auditory cortex, indicating that these neurons play an important role in the generation of the calcium signal. Taken together, our results identify sound-evoked slow NCaTs as an integral component of neuronal signalling in the mouse auditory cortex, reflecting the prolonged neuronal activity of local clusters of neurons that can be activated even by brief stimuli. PMID- 22106176 TI - Interspecies communication in the gut, from bacterial delivery to host-cell response. AB - Intestinal pathogens have a wide variety of strategies for communicating with host epithelial cells. This review highlights a few key examples of those strategies. Enteropathogenic Escherichia coli (EPEC) use a type III secretion system (T3SS) to alter host ion transport through both transcriptional and post translational mechanisms. Salmonella use a similar T3SS to invade host cells and modify an intracellular vacuole, which also impacts host vesicle trafficking. Helicobacter pylori use host cell integrins to provide a conformational change which drives the type IV secretion system into the host cell for delivery of CagA. The novel type VI section systems are phage-like apparati that deliver VgrG 1, which causes actin cross-linking and fluid accumulation in a suckling mouse model. An entirely different delivery mechanism is the outer membrane vesicle (OMV) which is composed of bacterial outer membrane wrapped around contents of the periplamsic space. Enterotoxigenic E. coli use OMVs to deliver bundles of heat labile enterotoxin to host cells. Finally we discuss the host responses to these varied methods of communication. PMID- 22106175 TI - Redefining the classification of AMPA-selective ionotropic glutamate receptors. AB - AMPA-type ionotropic glutamate receptors (iGluRs) represent the major excitatory neurotransmitter receptor in the developing and adult vertebrate CNS. They are crucial for the normal hardwiring of glutamatergic circuits but also fine tune synaptic strength by cycling into and out of synapses during periods of sustained patterned activity or altered homeostasis. AMPARs are grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 receptor subunit. GluA2-containing receptors are thought to be the most abundant AMPAR in the CNS, typified by their small unitary events, Ca(2+) impermeability and insensitivity to polyamine block. In contrast, GluA2-lacking AMPARs exhibit large unitary conductance, marked divalent permeability and nano- to micromolar polyamine affinity. Here, I review evidence for the existence of a third class of AMPAR which, though similarly Ca(2+) permeable, is characterized by its near-insensitivity to internal and external channel block by polyamines. This novel class of AMPAR is most notably found at multivesicular release synapses found in the avian auditory brainstem and mammalian retina. Curiously, these synapses lack NMDA-type iGluRs, which are conventionally associated with controlling AMPAR insertion. The lack of NMDARs suggests that a different set of rules may govern AMPAR cycling at these synapses. AMPARs with similar functional profiles are also found on some glial cells suggesting they may have a more widespread distribution in the mammalian CNS. I conclude by noting that modest changes to the ion-permeation pathway might be sufficient to retain divalent permeability whilst eliminating polyamine sensitivity. Consequently, this emerging AMPAR subclass need not be assembled from novel subunits, yet to be cloned, but could simply occur by varying the stoichiometry of existing proteins. PMID- 22106177 TI - Protein-energy malnutrition during early gestation in sheep blunts fetal renal vascular and nephron development and compromises adult renal function. AB - A nutritionally poor maternal diet can reduce nephron endowment and pre-empt premature expression of markers for chronic renal disease in the offspring. A mechanistic pathway from variation in maternal diet through altered fetal renal development to compromised adult kidney structure and function with adult-onset obesity has not been described. We show that maternal protein-energy malnutrition in sheep blunts nephrogenic potential in the 0.44 gestation (65 days gestation, term ~147 days) fetus by increasing apoptosis and decreasing angiogenesis in the nephrogenic zone, effects that were more marked in male fetuses. As adults, the low-protein-exposed sheep had reduced glomerular number and microvascular rarefaction in their kidneys compensated for, respectively, by glomerular hypertrophy and increased angiogenic support. In this study, the long-term mild anatomical deficits in the kidney would have remained asymptomatic in the lean state, but when superimposed on the broad metabolic challenge that obesity represents then microalbuminuria and blunted bilateral renal function revealed a long-term physiological compromise, that is only predicted to worsen with age. In conclusion, maternal protein-energy malnutrition specifically impacts fetal kidney vascular development and prevents full functionality of the adult kidney being achieved; these residual deficits are predicted to significantly increase the expected incidence of chronic kidney disease in prenatally undernourished individuals especially when coupled with a Western obesogenic environment. PMID- 22106178 TI - Structure and function of glutamate receptor amino terminal domains. AB - The amino terminal domain (ATD) of ionotropic glutamate receptor (iGluR) subunits resides at the extracellular region distal to the membrane. The ATD is structurally and functionally the most divergent region of the iGluR subunits. Structural studies on full-length GluA2 and the ATDs from three iGluR subfamilies have shed light on how the ATD facilitates subunit assembly, accommodates allosteric modulator compounds, and controls gating properties. Here recent developments in structural and functional studies on iGluR ATDs are reviewed. PMID- 22106179 TI - Statin treatment depresses the fetal defence to acute hypoxia via increasing nitric oxide bioavailability. AB - In addition to lowering cholesterol, statins increase nitric oxide (NO) bioavailability, improving endothelial function. In the fetus, enhanced NO during acute hypoxia opposes the fetal peripheral vasoconstrictor response, part of the brain-sparing defence. This study tested the hypothesis that treatment with statins depresses the fetal circulatory response to acute hypoxic stress via increasing NO bioavailability. Under anaesthesia, 12 fetal sheep at 118 +/- 1 days of gestation (term ca 145 days) were instrumented with vascular catheters and a femoral artery Transonic flow probe for chronic recording. Five days later, all animals were subjected to 30 min of acute hypoxia (fetal arterial partial pressure of O(2) ( ) reduced by ca 50%) before and 24 h after fetal treatment with pravastatin (25 mg i.v.). In half of the fetuses (n = 6), responses to hypoxia post-pravastatin were evaluated during NO synthesis blockade. Fetal exposure to pravastatin did not affect fetal basal cardiovascular function. Fetal was similarly reduced in all acute hypoxia experiments from ca 21 to 10 mmHg. Fetal exposure to pravastatin markedly diminished the fetal femoral vasoconstrictor (5.1 +/- 0.9 vs. 2.5 +/- 0.5 mmHg (ml min(-1))(-1)) and lactic acidaemic (4.4 +/- 0.5 vs. 3.0 +/- 0.3 mm) responses to acute hypoxia (both P < 0.05), without affecting plasma catecholamine responses. Post-pravastatin, the circulatory (5.8 +/- 1.5 mmHg (ml min(-1))(-1)) and metabolic (3.9 +/- 0.3 mm) responses could be restored to control levels during fetal treatment with NO synthase blockade. Pravastatin depresses the fetal cardiovascular and metabolic defences to acute hypoxia via increasing NO bioavailability. The use of statins during pregnancy should be viewed with extreme caution. PMID- 22106180 TI - Oxidative stress and enhanced sympathetic vasoconstriction in contracting muscles of nitrate-tolerant rats and humans. AB - Sympathetic vasoconstriction is normally attenuated in exercising muscle, but this functional sympatholysis is impaired in rats with hypertension or heart failure due to elevated levels of reactive oxygen species (ROS) in muscle. Whether ROS have a similar effect in the absence of cardiovascular disease or whether these findings extend to humans is not known. We therefore tested the hypothesis that chronic treatment with nitroglycerin (NTG) to induce nitrate tolerance, which is associated with excessive ROS production, impairs functional sympatholysis in healthy rats and humans. NTG treatment increased ethidium fluorescence in rat muscles and urinary F(2)-isoprostanes in humans, demonstrating oxidative stress. In vehicle-treated rats, sympathetic nerve stimulation (1 to 5 Hz) evoked decreases in femoral vascular conductance at rest (range, -30 to -63%) that were attenuated during hindlimb contraction (range, -2 to -31%; P < 0.05). In NTG-treated rats, vasoconstrictor responses were similar at rest, but were enhanced during contraction (range, -17 to -50%; P < 0.05 vs. vehicle). Infusion of the ROS scavenger tempol restored sympatholysis in these rats. In humans, reflex sympathetic activation during lower body negative pressure (LBNP) evoked decreases in muscle oxygenation in resting forearm (-12 +/ 1%) that were attenuated during handgrip exercise (-3 +/- 1%; P < 0.05). When these subjects became nitrate tolerant, LBNP-induced decreases in muscle oxygenation were unaffected at rest, but were enhanced during exercise (-9 +/- 1%; P < 0.05 vs. before NTG). Collectively, these data indicate that functional sympatholysis is impaired in otherwise healthy nitrate-tolerant rats and humans by a mechanism probably involving muscle oxidative stress. PMID- 22106182 TI - A global surgical journal. PMID- 22106181 TI - Modes of glutamate receptor gating. AB - The time course of excitatory synaptic currents, the major means of fast communication between neurons of the central nervous system, is encoded in the dynamic behaviour of post-synaptic glutamate-activated channels. First-pass attempts to explain the glutamate-elicited currents with mathematical models produced reaction mechanisms that included only the most basic functionally defined states: resting vs. liganded, closed vs. open, responsive vs. desensitized. In contrast, single-molecule observations afforded by the patch clamp technique revealed an unanticipated kinetic multiplicity of transitions: from microseconds-lasting flickers to minutes-long modes. How these kinetically defined events impact the shape of the synaptic response, how they relate to rearrangements in receptor structure, and whether and how they are physiologically controlled represent currently active research directions. Modal gating, which refers to the slowest, least frequently observed ion-channel transitions, has been demonstrated for representatives of all ion channel families. However, reaction schemes have been largely confined to the short- and medium-range time scales. For glutamate receptors as well, modal gating has only recently come under rigorous scrutiny. This article reviews the evidence for modal gating of glutamate receptors and the still developing hypotheses about the mechanism(s) by which modal shifts occur and the ways in which they may impact the time course of synaptic transmission. PMID- 22106183 TI - Hinged forearm split-thickness skin graft for radial artery fasciocutaneous flap donor site repair. AB - OBJECTIVE: To present a modified technique in the harvest and application of split-thickness skin graft (STSG) from the primary flap donor site in forearm fasciocutaneous free flaps. METHODS: A prospective review was performed on 16 consecutive patients who had undergone a radial forearm free flap procedure for reconstruction of head and neck defects with a hinged forearm STSG used to reconstruct the flap donor site defect. RESULTS: Sixteen patients with a mean (SD) defect size of 53.7 (29.9) cm(2) underwent the hinged STSG procedure. A hinged STSG was successfully harvested from all patients without disruption. Graft take was greater than 90% in all patients by postoperative day 7. A secondary skin graft donor site was avoided in all but 2 patients. Good color match of the deepithelialized flap with surrounding oral and pharyngeal mucosa was observed. Visible scarring along the graft hinge margin was absent. No bridging scars resulted from the deepithelialized flaps. CONCLUSIONS: The hinged STSG from the forearm is a reliable method of repairing radial forearm free flap donor site defects and offers the advantages of reduced suture line scarring, minimal STSG disruption, low or no secondary donor site morbidity, and good color match at the donor and recipient flap sites. PMID- 22106184 TI - Anatomical comparison of platysmal tightening using superficial musculoaponeurotic system plication vs deep-plane rhytidectomy techniques. AB - OBJECTIVES: To quantify the degree of submental platysmal tightening that can be accomplished with superficial musculoaponeurotic system (SMAS) plication vs deep plane rhytidectomy techniques in a cadaveric anatomical study to help dictate the need for midline platysmal surgery when using different rhytidectomy techniques. METHODS: The lateral distraction of the medial edge of the platysma muscle was measured during tightening of the SMAS-platysmal complex on 5 cadaver heads. The measurements were taken after the following 3 rhytidectomy techniques: SMAS platysmal plication, deep-plane rhytidectomy, and extended deep-plane rhytidectomy continuing the flap below the angle of the mandible into the neck with release of the platysma and cervical retaining ligaments. RESULTS: The medial edge of the platysma muscle was distracted laterally 427% more with deep plane rhytidectomy compared with SMAS-platysmal plication (P < .001). Extending the deep-plane rhytidectomy flap into the neck to release the cervical retaining ligaments resulted in 554% greater lateral distraction of the medial edge of the platysma muscle compared with SMAS-platysmal plication (P < .001). This represents 30% greater advancement compared with the traditional deep-plane technique (P = .05). CONCLUSIONS: Extending a traditional deep-plane rhytidectomy inferiorly to release the lateral platysma and cervical retaining ligaments to the sternocleidomastoid muscle achieves the greatest lateral motion of the midline platysma, theoretically obviating the need for midline platysmal plication except in cases of severe platysmal laxity and banding. Because of the limited platysmal motion during SMAS plication, midline platysmal plication should routinely be used as an adjunct procedure except in cases of no or minimal platysmal laxity. PMID- 22106185 TI - Carbon dioxide laser treatment for lentigo maligna: a retrospective review comparing 3 different treatment modalities. AB - OBJECTIVE: To assess outcomes in managing primary lentigo maligna through surgical excision, radiation therapy, and carbon dioxide laser ablation. METHODS: Retrospective case series review of all patients with primary lentigo maligna diagnosed and treated in London, Ontario, Canada, between July 2, 1991, and June 29, 2010. RESULTS: Seventy-five patients aged 39 to 93 years (mean age, 64.8 years) were included in the study; 73 patients chose treatment. Twenty-seven patients were treated with surgical excision, 31 patients with radiation therapy, and 15 patients with carbon dioxide laser ablation. The median follow-up times were 16.6 months for surgical excision, 46.3 months for radiation therapy, and 77.8 months for carbon dioxide laser ablation (P < .001). Recurrence rates by treatment modality were 4.2% (1 of 27) for surgical excision, 29.0% (9 of 31) for radiation therapy, and 6.7% (1 of 15) for carbon dioxide laser ablation. CONCLUSIONS: A trend toward lower recurrence rates with surgical excision and carbon dioxide laser ablation was identified, but the results were not statistically significant. Carbon dioxide laser ablation may have a role as an alternative treatment for lentigo maligna among patients in whom standard treatments, such as surgical excision and radiation therapy, are declined or carry significant morbidity. PMID- 22106186 TI - Simultaneous intraoperative Mohs clearance and reconstruction for advanced cutaneous malignancies. AB - BACKGROUND: Improved control of cutaneous malignancies using Mohs micrographic pathologic clearance has been well established. However, surgical margin control of advanced and complex cutaneous tumors of the head and neck is commonly performed by far less reliable frozen section margin analysis. OBJECTIVE: To describe a routine and ideal collaboration between dermatologic surgery and facial plastic surgery/head and neck surgery in which the Mohs micrographic method is used intraoperatively to achieve marginal clearance during resection and reconstruction. METHODS: A single-institution retrospective analysis was performed of patients who underwent intraoperative Mohs micrographic surgery. Intraoperative margins (peripheral and deep) of tissue specimens were analyzed by the Mohs surgeon. RESULTS: Twenty-six patients underwent large cutaneous tumor resection using intraoperative Mohs micrographic surgery. Most lesions were basal (48%) or squamous (34%) cell carcinoma. A mean (SD) of 2.1 (0.98) resection layers were required before negative margins were achieved. CONCLUSIONS: We demonstrate the intraoperative technique and utility of Mohs micrographic analysis via an efficient collaborative effort. Well established for accuracy greater than intraoperative frozen section margin analysis, intraoperative Mohs micrographic surgery provides an optimal method of intraoperative margin assessment of cutaneous malignancies. PMID- 22106187 TI - Clinical and genetic characterization of frontorhiny: report of 3 novel cases and discussion of the surgical management. AB - OBJECTIVES: To (1) define the nasal, columellar, and lip deformities of 3 patients with characteristics consistent with frontorhiny; (2) illustrate the embryologic correlation of the oronasal findings to the development of the median nasal prominence; (3) report the clinical manifestation in 3 patients from 2 unrelated families; (4) report a novel Y214X mutation in ALX3 ; and (5) describe the surgical reconstruction. METHODS: In this case series, we report 3 novel cases of frontorhiny from 2 different families. The surgical reconstruction technique is reviewed. Extension of the columellar medial crural cartilage into the upper lip cleft is examined histologically. Signed consent was granted for all patient photographs and specimens, and the study was approved by the institutional review committee of the University of California Davis The genetic sequencing of the ALX3 homeobox gene was performed in 2 of our 3 cases using standard commercially available sequencing kits. The genetic material in our third case was not available for analysis. RESULTS: Patients 1 and 2 were brothers from the same family. Both exhibited bifidity of their columella, a widened philtrum, poor nasal tip development, and low hairlines. Genetic sequencing in the 2 brothers confirmed the presence of a novel ALX3 homeobox mutation at the second exon (mutation Y214X). Patient 3 was a 4-year-old girl. She presented with an underdeveloped, widened nasal tip and a bifid columella. Her philtrum was widened and had a left-sided cartilaginous prominence. She also had a widened nasal root. Family history revealed no family members with the same features. CONCLUSIONS: Frontorhiny represents a new syndromic frontonasal malformation with consistent characteristic features. The genetic abnormality has now been found in 14 different patients. Careful scrutiny and classification of frontonasal deformities will expand our understanding of causes, genetic susceptibility, and treatment options. PMID- 22106188 TI - The alar-spanning suture: a useful tool in rhinoplasty to refine the nasal tip. AB - The alar-spanning suture is a surgical technique used by an experienced rhinoplastic surgeon to address certain nasal tip deformities. Wide nasal tip deformities with strong, convex lower lateral cartilages are best indicated for treatment with this technique. The alar-spanning suture can improve lateral crural position and eliminate dead space by refining and narrowing the supratip, often without requiring extensive dissection or additional strut grafting. We use operative photographs and an intraoperative video to demonstrate the alar spanning suture technique, which is a useful addition to the armamentarium of any rhinoplastic surgeon. PMID- 22106189 TI - Current knowledge and management of vascular anomalies, II: malformations. AB - OBJECTIVE: To present current information on the diagnosis, pathogenesis, natural history, and treatment of vascular malformations. METHOD: Literature review. RESULTS: Vascular malformations are a heterogeneous group of congenital lesions resulting from aberrations of vascular embryogenesis. They are distinct from the vascular tumors with which they are commonly confused in presentation, natural history, and management. CONCLUSIONS: Multimodality intervention involving medical therapy, laser photocoagulation, and surgery is available for the various types of vascular malformations. Multidisciplinary care is crucial for the evaluation and management of these complicated lesions. Clarification of underlying pathogenesis and molecular biologic mechanisms will provide opportunities for expansion of available treatments. PMID- 22106190 TI - Trending topics in rhinoplasty. PMID- 22106191 TI - Multidisciplinary care of international patients with cleft palate using telemedicine. PMID- 22106192 TI - Addressing challenges of cleft lip and palate deformity in Afghanistan. PMID- 22106193 TI - St John the Baptist in the wilderness by Michelangelo Merisi, called Caravaggio. PMID- 22106194 TI - Hallux limitus and its relationship with the internal rotational pattern of the lower limb. AB - BACKGROUND: The aims of this study were to determine whether individuals with mild hallux limitus show a diminished capacity of internal rotation of the lower limb compared with those without hallux limitus and whether individuals with mild hallux limitus show an increased foot progression angle. METHODS: In 80 study participants (35 with normal feet and 45 with mild hallux limitus), the capacity of internal rotation of the lower limb (internal rotational pattern), hallux dorsiflexion, and the foot progression angle were measured. The values for internal rotational pattern and foot progression angle were compared between the two study groups, and the correlations between these variables were studied. RESULTS: The capacity of internal rotation of the lower limb was significantly lesser in patients with mild hallux limitus (P < .0001). There was no significant difference in foot progression angle between the two groups (P = .115). The Spearman correlation coefficient was 0.638 (P < .0001) for the relationship between internal rotational pattern and hallux dorsiflexion. CONCLUSIONS: Patients with mild hallux limitus had a lesser capacity of internal rotation of the lower extremity than did individuals in the control group. The more limited the internal rotational pattern of the lower limb, the more limited was hallux dorsiflexion. The foot progression angle was similar in both groups. PMID- 22106195 TI - Validation of the talar-second metatarsal angle as a standard measurement for radiographic evaluation. AB - BACKGROUND: Radiographs provide valuable information for assessing osseous foot deformities and aid in accurate diagnosis. The radiographic angular measurements can be used to establish a relationship between the forefoot and the hindfoot that will present valuable information about normal versus pathologic alignment of the foot. The talar-first metatarsal (T1M) angle is frequently used as one of these angles in this capacity; however, there are limitations to the anteroposterior T1M angle. We present a more consistent, reproducible, and accurate measurement for determining foot abnormalities in the transverse plane using the T2M angle instead of the T1M angle. METHODS: Seventy feet in 35 participants (12 men and 23 women) were considered for this study. Individuals were selected on the basis of the established inclusion and exclusion criteria. Anteroposterior radiographs were taken in the angle and base of gait, the neutral calcaneal stance position (NCSP), and the resting calcaneal stance position (RCSP). Three observers measured these angles using three different methods. RESULTS: The mean +/- SD T2M angle was 2.95 degrees +/- 7.16 degrees in NCSP and 18.61 degrees +/- 7.21 degrees in RCSP. No significant differences were found among the measurements made by the three observers using slightly varying procedures in NCSP and RCSP (P > .05). The intraclass correlation coefficients among the measurements were 0.905 in NCSP and 0.937 in RCSP. Bland-Altman plots showed very good agreement between the measurements made by the three observers. CONCLUSIONS: The anteroposterior T2M angle gives a consistent and reproducible measurement that provides accurate information about foot alignment. PMID- 22106196 TI - An open-label, three-arm pilot study of the safety and efficacy of topical Microcyn Rx wound care versus oral levofloxacin versus combined therapy for mild diabetic foot infections. AB - BACKGROUND: This randomized, prospective, multicenter, open-label study was designed to test whether a topical, electrolyzed, superoxidized solution (Microcyn Rx) is a safe and effective treatment for mildly infected diabetic foot ulcers. METHODS: Sixty-seven patients with ulcers were randomized into three groups. Patients with wounds irrigated with Microcyn Rx alone were compared with patients treated with oral levofloxacin plus normal saline wound irrigation and with patients treated with oral levofloxacin plus Microcyn Rx wound irrigation. Patients were evaluated on day 3, at the end of treatment on day 10 (visit 3), and 14 days after completion of therapy for test of cure (visit 4). RESULTS: In the intention-to-treat sample at visit 3, the clinical success rate was higher in the Microcyn Rx alone group (75.0%) than in the saline plus levofloxacin group (57.1%) or in the Microcyn Rx plus levofloxacin group (64.0%). Results at visit 4 were similar. In the clinically evaluable population, the clinical success rate at visit 3 (end of treatment) for patients treated with Microcyn Rx alone was 77.8% versus 61.1% for the levofloxacin group. The clinical success rate at visit 4 (test of cure) for patients treated with Microcyn Rx alone was 93.3% versus 56.3% for levofloxacin plus saline-treated patients. This study was not statistically powered, but the high clinical success rate (93.3%) and the P value (P = .033) suggest that the difference is meaningfully positive for Microcyn Rx treated patients. CONCLUSIONS: Microcyn Rx is safe and at least as effective as oral levofloxacin for mild diabetic foot infections. PMID- 22106197 TI - Quantification of skin marker movement at the malleoli and talar heads. AB - BACKGROUND: Quantifying subtalar joint kinematics during locomotion is a major challenge but is critical to understanding foot function. The difficulty of modeling the subtalar joint is demonstrated by the plethora of three-dimensional multisegment foot models lacking specific consideration of the subtalar joint. Scientific attempts to develop an adequate method of quantifying subtalar joint kinematics should include investigation of the movement of skin-mounted markers. This study reports on a single-subject investigation into this topic. METHODS: Radiopaque markers were attached to the skin overlying the medial and lateral malleoli and the medial and lateral talar heads of a single subject. Frontal, sagittal, and transverse plane radiographs were taken with the foot in the fully pronated and fully supinated positions. Parallax corrected measurements were taken of the displacement of the markers from the bony landmarks. Measurements were also taken of the effect of these displacements on angular calculations. RESULTS: Skin movement at the four anatomical locations was not uniform, with displacements varying from 0.61 to 22.18 mm. Movement of the malleolar markers was found to be less than that of the talar head markers. The distortion of angular measurements caused by movement of the skin markers relative to the bony landmarks was found to be only 1 degrees in the sagittal and transverse planes and 5 degrees in the frontal plane. CONCLUSIONS: For this subject, skin-mounted markers could be used to assess subtalar joint motion. Further studies are necessary to investigate the implications of these findings to the wider population. PMID- 22106198 TI - Anatomical variations of peroneal muscles: a cadaver study in an Indian population and a review of the literature. AB - BACKGROUND: Persistent lateral ankle pain is a common presentation in clinics. Various studies on anatomical variations of the peroneal compartment muscles, including the peroneus quartus muscle, have been reported in different populations. However, such studies are rarely from India. Hence, the present study was undertaken on cadavers in an Indian population. METHODS: The lateral compartments of the legs were dissected in 70 specimens to study the presence, origin, and insertion of accessory muscles. Different peroneal tendons were observed for tears and splits. RESULTS: Three of 70 specimens (4.3%) showed prevalence of the peroneus quartus muscle. Twenty specimens (28.6%) had split or tear lesions of the peroneus brevis muscle. Presence of the peroneus quartus muscle in this Indian population was relatively low compared with that in previous reports in English and American populations (6.6%-21.9%). CONCLUSIONS: Racial differences, cultural variations, and postural habits, along with different stages of evolution, may be factors contributing to different observations. Split lesions of the peroneus brevis tendon were six to seven times more prevalent than was presence of the peroneus quartus muscle, which implies that split or tear lesions of the peroneus brevis tendon are more frequently involved in the manifestation of persistent retromalleolar pain compared with complications arising out of presence of the peroneus quartus muscle. Hence, accurate knowledge of presence of the peroneus quartus muscle in different populations is important because it can also be used in grafting and reconstruction in foot and ankle surgery. PMID- 22106199 TI - In-shoe Plantar Pressure Distribution in Nonneuropathic Type 2 Diabetic Patients in Singapore. AB - BACKGROUND: We sought to establish the in-shoe plantar pressure distribution during normal level walking in type 2 diabetic patients of Chinese, Indian, and Malay descent without clinical evidence of peripheral neuropathy. METHODS: Thirty five patients with type 2 diabetes mellitus without loss of tactile sensation and foot deformities and 38 nondiabetic individuals in a control group had in-shoe plantar pressures collected. Maximum peak pressure and peak pressure-time integral of each foot were analyzed as separate variables and were masked into 13 areas. Differences in pressure variables were assessed by analysis of covariance, adjusting for relevant covariates at the 95% confidence interval. RESULTS: No significant differences were noted in maximum peak pressures after adjusting for sex, race, age, height, and body mass. However, patients with diabetes mellitus had significantly higher mean +/- SD pressure-time integrals at the right whole foot (309.50 +/- 144.17 kPa versus 224.06 +/- 141.70 kPa, P < .05) and first metatarsal (198.65 +/- 138.27 kPa versus 121.54 +/- 135.91 kPa, P < .05) masked areas than did those in the control group after adjustment. CONCLUSIONS: Patients without clinical observable signs of foot deformity (implying absence of motor neuropathy) and sensory neuropathy had similar in-shoe maximum peak pressures as controls. This finding supported the notion that either component of neuropathy needs to be present before plantar pressures are elevated. Patients with diabetes mellitus demonstrated greater pressure-time integrals, implying that this variable might be the first clinical sign observable even before peripheral neuropathy could be tested. PMID- 22106200 TI - Surgical treatment of diaphyseal stress fractures of the fifth metatarsal in competitive athletes: long-term follow-up and computerized pedobarographic analysis. AB - BACKGROUND: Proximal diaphyseal stress fractures of the fifth metatarsal are common in athletes. Conservative treatment has been shown to result in high rates of delayed union, nonunion, and refracture, so internal fixation has become the treatment of choice in competitive athletes. METHODS: Twenty top-level athletes with diaphyseal stress fractures fixed with intramedullary malleolar screws were evaluated. Functional outcome was assessed by American Orthopaedic Foot and Ankle Society midfoot score. Static and dynamic maximum vertical force and peak plantar pressures were evaluated with a computerized pedobarograph. RESULTS: Mean follow up from surgery to interview was 10.3 years (range, 3.5-19.0 years). Clinical healing was 95%, and there has been one refracture (5%). The mean time from surgery to return to sport was 9 weeks (range, 5-14 weeks). Twelve athletes (60%) returned to a higher level of training, 7 (35%) to the same level, and 1 (5%) to a lower level compared with the level of training before injury. Average American Orthopaedic Foot and Ankle Society midfoot score was 93.8 (range, 85-100). During the computerized pedobarographic evaluations, 18 patients (90%) presented with varus of the metatarsus and the midfoot and 2 (10%) presented with a normal plantigrade foot. CONCLUSIONS: Intramedullary malleolar screws can yield reliable and effective healing of fifth metatarsal stress fractures in athletes. Varus of the metatarsus and the midfoot were predisposing factors for stress fractures in this population of competitive athletes, and all were recommended to wear orthoses until their competitive careers were completed. PMID- 22106201 TI - The medial oblique shell inclination technique: a method to increase subtalar supination moments in foot orthoses. AB - A medially deviated axis has been cited as an etiologic factor in increasing pronatory moments across the subtalar joint axis. Orthoses are often used to reduce these pronatory moments, aiming to off-load related injured structures. By aligning the posting or incline of an orthosis shell medial to the axis and parallel to it, the amount of moments applied will be theoretically greater than if prescribed at a less-than-optimal angle. We first published the medial oblique shell inclination as a method to increase supinatory moments to a medially deviated subtalar joint axis in 2008. This paper summarizes the theoretical reasons for use and introduces original methods of construction. PMID- 22106202 TI - Foot salvage after loss of the first and second metatarsal rays with a free fibular osteocutaneous flap. AB - Severely comminuted fractures of the metatarsal bones with significant bone and soft-tissue loss have commonly subjected patients to proximal amputation procedures. We describe two patients who experienced high-energy traumatic injuries to their limbs that resulted in significant destruction of their first and second metatarsal bones with overlying soft-tissue trauma not amenable to local coverage. In both cases, a vascularized free fibular osteocutaneous flap was used to reconstruct the metatarsal bone defect and traumatized soft tissues so that a proximal amputation was avoided. At an average of 14 months of follow up, both patients had recovered well and regained independent ambulation, with one patient being able to play soccer. We show that the free fibular osteoseptocutaneous flap is useful in reconstructing significant metatarsal bone defects and in avoiding amputations in this patient population. The skin component of the flap may be used to fill soft-tissue losses, and the fibula bone may be osteotomized so that more than one ray may be reconstructed. PMID- 22106207 TI - Influence of NAT2 polymorphisms on sulfamethoxazole pharmacokinetics in renal transplant recipients. AB - The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against Pneumocystis pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of N acetyltransferase 2 (NAT2) and CYP2C9 polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for 15 recipients with the NAT2 slow acetylator genotype (NAT2 5/ 6, - 6/ 6, - 6/ 7, and - 7/ 7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2 4) (766.4 +/- 432.3 versus 537.2 +/- 257.5 MUg-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9 1/ 1 and - 1/ 3 groups. In a multiple regression analysis, the SMX AUC(0-24) was associated with NAT2 slow acetylator polymorphisms (P = 0.0095) and with creatinine clearance (P = 0.0499). Hepatic dysfunction in NAT2 slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by NAT2 polymorphisms and renal dysfunction. Although standard SMX administration to patients with NAT2 slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects. PMID- 22106208 TI - Seasonal variations in Clostridium difficile infections are associated with influenza and respiratory syncytial virus activity independently of antibiotic prescriptions: a time series analysis in Quebec, Canada. AB - Seasonal variations in Clostridium difficile-associated diarrhea (CDAD), with a higher incidence occurring during winter months, have been reported. Although winter epidemics of respiratory viruses may be temporally associated with an increase in CDAD morbidity, we hypothesized that this association is mainly due to increased antibiotic use for respiratory infections. The objective of this study was to evaluate the effect of the two most frequent respiratory viruses (influenza virus and respiratory syncytial virus [RSV]) and antibiotics prescribed for respiratory infections (fluoroquinolones and macrolides) on the CDAD incidence in hospitals in the province of Quebec, Canada. A multivariable Box-Jenkins transfer function model was built to relate monthly CDAD incidence to the monthly percentage of positive tests for influenza virus and RSV and monthly fluoroquinolone and macrolide prescriptions over a 4-year period (January 2005 to December 2008). Analysis showed that temporal variations in CDAD incidence followed temporal variations for influenza virus (P = 0.043), RSV (P = 0.004), and macrolide prescription (P = 0.05) time series with an average delay of 1 month and fluoroquinolone prescription time series with an average delay of 2 months (P = 0.01). We conclude that influenza virus and RSV circulation is independently associated with CDAD incidence after controlling for fluoroquinolone and macrolide use. This association was observed at an aggregated level and may be indicative of other phenomena occurring during wintertime. PMID- 22106209 TI - Global analysis of the Staphylococcus aureus response to mupirocin. AB - In the present study, we analyzed the response of S. aureus to mupirocin, the drug of choice for nasal decolonization. Mupirocin selectively inhibits the bacterial isoleucyl-tRNA synthetase (IleRS), leading to the accumulation of uncharged isoleucyl-tRNA and eventually the synthesis of (p)ppGpp. The alarmone (p)ppGpp induces the stringent response, an important global transcriptional and translational control mechanism that allows bacteria to adapt to nutritional deprivation. To identify proteins with an altered synthesis pattern in response to mupirocin treatment, we used the highly sensitive 2-dimensional gel electrophoresis technique in combination with mass spectrometry. The results were complemented by DNA microarray, Northern blot, and metabolome analyses. Whereas expression of genes involved in nucleotide biosynthesis, DNA metabolism, energy metabolism, and translation was significantly downregulated, expression of isoleucyl-tRNA synthetase, the branched-chain amino acid pathway, and genes with functions in oxidative-stress resistance (ahpC and katA) and putative roles in stress protection (the yvyD homologue SACOL0815 and SACOL1759 and SACOL2131) and transport processes was increased. A comparison of the regulated genes to known regulons suggests the involvement of the global regulators CodY and SigB in shaping the response of S. aureus to mupirocin. Of particular interest was the induced transcription of genes encoding virulence-associated regulators (i.e., arlRS, saeRS, sarA, sarR, sarS, and sigB), as well as genes directly involved in the virulence of S. aureus (i.e., fnbA, epiE, epiG, and seb). PMID- 22106210 TI - Occidiofungin's chemical stability and in vitro potency against Candida species. AB - Occidiofungin is a cyclic glyco-lipopeptide produced by Burkholderia contaminans. MICs against Candida species were between 0.5 and 2.0 MUg/ml. Occidiofungin retains its in vitro potency in the presence of 5% and 50% human serum with a minimal lethal concentration (MLC) of 2 and 4 MUg/ml, respectively. Time-kill and postantifungal effect (PAFE) experiments of occidiofungin against Candida albicans were performed. The results demonstrate that occidiofungin is fungicidal. Occidiofungin was also found to be a very stable molecule. It is resistant to extreme temperatures and pH and maintains its activity following exposure to gastric proteases. PMID- 22106211 TI - In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. AB - AIC246 (letermovir) is a potent anticytomegalovirus drug in clinical development. Here, we report a consistent antiviral efficacy of AIC246 against human cytomegalovirus laboratory strains, clinical isolates, and virus variants resistant to approved drugs. Furthermore, we describe a remarkable selectivity of AIC246 for human cytomegaloviruses compared to that of other alpha-, beta-, or gammaherpesviruses or nonrelated pathogenic viruses, including adeno-, hepadna-, retro-, orthomyxo-, and flaviviruses. Our data confirm and support an excellent and selective anticytomegaloviral activity of AIC246. PMID- 22106212 TI - First detection of blaIMI-2 gene in a clinical Escherichia coli strain. PMID- 22106213 TI - In vivo growth rates are poorly correlated with phage therapy success in a mouse infection model. AB - Two classes of phages yield profoundly different levels of recovery in mice experimentally infected with an Escherichia coli O18:K1:H7 strain. Phages requiring the K1 capsule for infection (K1-dep) rescue virtually all infected mice, whereas phages not requiring the capsule (K1-ind) rescue modest numbers (~30%). To rescue infected mice, K1-ind phages require at least a 10(6)-fold higher inoculum than K1-dep phages. Yet their in vivo growth dynamics are only modestly inferior to those of K1-dep phages, and competition between the two phage types in the same mouse reveals only a slight growth advantage for the K1 dep phage. The in vivo growth rate seems unlikely to be the primary determinant of phage therapy success. An alternative explanation is that the success of K1 dep phages is due substantially to their proteomic composition. They encode an enzyme that degrades the K1 capsule, which has been shown in other work to be sufficient to cure infection in the complete absence of phages. PMID- 22106214 TI - In vivo activity of aryl ozonides against Schistosoma species. AB - We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound. PMID- 22106215 TI - Improved oral bioavailability of lopinavir in melt-extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations. AB - Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC(0-12)) and maximum concentration were ~15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy. PMID- 22106216 TI - Antibiotic sensitivity of 40 Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant isolates from Beijing, China. AB - MICs of eight antibiotics were detected with 40 Chinese Mycoplasma pneumoniae isolates. Thirty-eight isolates (95%) were macrolide resistant. Each macrolide resistant isolate harbored an A2063G or A2064G point mutation in the 23S rRNA gene. All 40 isolates (100%) were type I strains, but they might have originated from different clones. PMID- 22106217 TI - Chromosomal integration and location on IncT plasmids of the blaCTX-M-2 gene in Proteus mirabilis clinical isolates. AB - Analysis of five CTX-M-2-producing Proteus mirabilis isolates in Japan demonstrated that bla(CTX-M-2) was located on the chromosome in four isolates and on IncT plasmids in three isolates, including two isolates that also carried the gene on the chromosome. In all four isolates with chromosomal bla(CTX-M-2), ISEcp1 was responsible for the integration of the gene into the chromosome. Three different sites in the P. mirabilis genomic sequence were utilized as integration sites. PMID- 22106218 TI - Phenylethyl butyrate enhances the potency of second-line drugs against clinical isolates of Mycobacterium tuberculosis. AB - Ethionamide (ETH) is a second-line drug for the treatment of tuberculosis. As a prodrug, ETH has to be activated by EthA. ethA is controlled by its repressor EthR. 2-Phenylethyl-butyrate (2-PEB) inhibits EthR binding, enhances expression of EthA, and thereby enhances the growth-inhibitory effects of ethionamide, isoxyl, and thiacetazone in Mycobacterium tuberculosis strains with resistance to ETH due to inhA promoter mutations but not ethA mutations. PMID- 22106219 TI - In vitro activity of JPC 2067 alone and in combination with sulfamethoxazole against nocardia species. AB - JPC 2067 is a novel dihydrotriazine dihydrofolate reductase inhibitor that is being developed as an antimalarial therapeutic. We evaluated the in vitro activity of JPC 2067 alone and in combination with sulfamethoxazole (SMX) against a panel of nocardia isolates. The MIC(50)s and MIC(90)s for JPC 2067, SMX, and the combination were 0.125 MUg/ml and 4 MUg/ml, 16 MUg/ml and 32 MUg/ml, and 0.03 MUg/ml and 2 MUg/ml, respectively. JPC 2067 alone and in combination with SMX should be evaluated further to understand its clinical potential. PMID- 22106220 TI - Virulence factors and TEM-type beta-lactamases produced by two isolates of an epidemic Klebsiella pneumoniae strain. AB - Two Klebsiella pneumoniae isolates of the same strain, identified in Poland, produced either TEM-47 or TEM-68, which differed by the Arg275Leu substitution. They harbored a few virulence factors, including an iron-chelating factor and capsule overproduction, suggesting that these factors were sufficient to enhance their nosocomial potency. TEM-68 and TEM-47 had similar enzymatic activities, but TEM-68 was less susceptible to inhibitors than TEM-47. These results confirm the role of the Arg275Leu substitution in the evolution of TEM enzymes. PMID- 22106221 TI - Amino acid substitutions at position 95 in GyrA can add fluoroquinolone resistance to Mycobacterium leprae. AB - Amino acid substitutions at position 89 or 91 in GyrA of fluoroquinolone resistant Mycobacterium leprae clinical isolates have been reported. In contrast, those at position 94 in M. tuberculosis, equivalent to position 95 in M. leprae, have been identified most frequently. To verify the possible contribution of amino acid substitutions at position 95 in M. leprae to fluoroquinolone resistance, we conducted an in vitro assay using wild-type and mutant recombinant DNA gyrases. Fluoroquinolone-mediated supercoiling activity inhibition assay and DNA cleavage assay revealed the potent contribution of an amino acid substitution of Asp to Gly or Asn at position 95 to fluoroquinolone resistance. These results suggested the possible future emergence of quinolone-resistant M. leprae isolates with these amino acid substitutions and the usefulness of detecting these mutations for the rapid identification of fluoroquinolone resistance in leprosy. PMID- 22106222 TI - Changes in ciprofloxacin resistance levels in Enterobacter aerogenes isolates associated with variable expression of the aac(6')-Ib-cr gene. AB - Two closely related Enterobacter aerogenes isolates presented a new identical aac(6')-Ib-cr genetic environment, including IS26. One isolate showed lower MICs of ciprofloxacin, norfloxacin, tobramycin, and amikacin and decreased expression of aac(6')-Ib-cr, which might be related to a 12-bp deletion causing a displacement of the -10 box upstream of the aac(6')-Ib-cr gene. PMID- 22106223 TI - Possible inhibitory molecular mechanism of farnesol on the development of fluconazole resistance in Candida albicans biofilm. AB - Candida albicans biofilm infections are usually treated with azole antifungals such as fluconazole. However, the development of resistance to this drug in C. albicans biofilms is very common, especially in immunocompromised individuals. The upregulation of the sterol biosynthetic pathway gene ERG and the efflux pump genes CDR and MDR may contribute to this azole tolerance in Candida species. We hypothesize that farnesol, an endogenous quorum sensing molecule with possible antimicrobial properties which is also the precursor of ergosterols in C. albicans, may interfere with the development of fluconazole resistance in C. albicans biofilms. To test this hypothesis, MICs were compared and morphology changes were observed by confocal laser scanning microscopy (CLSM) for farnesol treated and -untreated and fluconazole-resistant groups. The expression of possible target genes (ERG11, ERG25, ERG6, ERG5, ERG3, ERG1, MDR1, CDR1, and CDR2) in biofilms was analyzed by reverse transcription-PCR (RT-PCR) and quantitative PCR (qPCR) to investigate the molecular mechanisms of the inhibitory effects of farnesol. The results showed a decreased MIC of fluconazole and thinner biofilms for the farnesol-treated group, indicating that farnesol inhibited the development of fluconazole resistance. The sterol biosynthetic pathway may contribute to the inhibitory effects of farnesol, as the transcription levels of the ERG11, ERG25, ERG6, ERG3, and ERG1 genes decreased in the farnesol-treated group. PMID- 22106224 TI - PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. AB - Pseudomonas aeruginosa can develop resistance to polymyxin and other cationic antimicrobial peptides. Previous work has shown that mutations in the PmrAB and PhoPQ regulatory systems can confer low to moderate levels of colistin (polymyxin E) resistance in laboratory strains and clinical isolates of this organism (MICs of 8 to 64 mg/liter). To explore the role of PmrAB in high-level clinical polymyxin resistance, P. aeruginosa isolates from chronically colistin-treated cystic fibrosis patients, most with colistin MICs of >512 mg/liter, were analyzed. These cystic fibrosis isolates contained probable gain-of-function pmrB alleles that conferred polymyxin resistance to strains with a wild-type or pmrAB deletion background. Double mutant pmrB alleles that contained mutations in both the periplasmic and dimerization-phosphotransferase domains markedly augmented polymyxin resistance. Expression of mutant pmrB alleles induced transcription from the promoter of the arnB operon and stimulated addition of 4-amino-l arabinose to lipid A, consistent with the known role of this lipid A modification in polymyxin resistance. For some highly polymyxin-resistant clinical isolates, repeated passage without antibiotic selection pressure resulted in loss of resistance, suggesting that secondary suppressors occur at a relatively high frequency and account for the instability of this phenotype. These results indicate that pmrB gain-of-function mutations can contribute to high-level polymyxin resistance in clinical strains of P. aeruginosa. PMID- 22106225 TI - Overton's rule helps to estimate the penetration of anti-infectives into patients' cerebrospinal fluid. AB - In 1900, Ernst Overton found that the entry of anilin dyes through the cell membranes of living cells depended on the lipophilicity of the dyes. The brain is surrounded by barriers consisting of lipid layers that possess several inward and outward active transport systems. In the absence of meningeal inflammation, the cerebrospinal fluid (CSF) penetration of anti-infectives in humans estimated by the ratio of the area under the concentration-time curve (AUC) in CSF (AUC(CSF)) to that in serum (AUC(CSF)/AUC(S)) correlated positively with the lipid-water partition coefficient at pH 7.0 (log D) (Spearman's rank correlation coefficient r(S) = 0.40; P = 0.01) and negatively with the molecular mass (MM) (r(S) = -0.33; P = 0.04). The ratio of AUC(CSF) to the AUC of the fraction in serum that was not bound (AUC(CSF)/AUC(S,free)) strongly correlated with log D (r(S) = 0.67; P < 0.0001). In the presence of meningeal inflammation, AUC(CSF)/AUC(S) also correlated positively with log D (r(S) = 0.46; P = 0.002) and negatively with the MM (r(S) = -0.37; P = 0.01). The correlation of AUC(CSF)/AUC(S,free) with log D (r(S) = 0.66; P < 0.0001) was as strong as in the absence of meningeal inflammation. Despite these clear correlations, Overton's rule was able to explain only part of the differences in CSF penetration of the individual compounds. The site of CSF withdrawal (lumbar versus ventricular CSF), age of the patients, underlying diseases, active transport, and alterations in the pharmacokinetics by comedications also appeared to strongly influence the CSF penetration of the drugs studied. PMID- 22106226 TI - Influence of body weight, ethnicity, oral contraceptives, and pregnancy on the pharmacokinetics of azithromycin in women of childbearing age. AB - Women of childbearing age commonly receive azithromycin for the treatment of community-acquired infections, including during pregnancy. This study determined azithromycin pharmacokinetics in pregnant and nonpregnant women and identified covariates contributing to pharmacokinetic variability. Plasma samples were collected by using a sparse-sampling strategy from pregnant women at a gestational age of 12 to 40 weeks and from nonpregnant women of childbearing age receiving oral azithromycin for the treatment of an infection. Pharmacokinetic data from extensive sampling conducted on 12 healthy women were also included. Plasma samples were assayed for azithromycin by high-performance liquid chromatography. Population data were analyzed by nonlinear mixed-effects modeling. The population analysis included 53 pregnant and 25 nonpregnant women. A three-compartment model with first-order absorption and a lag time provided the best fit of the data. Lean body weight, pregnancy, ethnicity, and the coadministration of oral contraceptives were covariates identified as significantly influencing the oral clearance of azithromycin and, except for oral contraceptive use, intercompartmental clearance between the central and second peripheral compartments. No other covariate relationships were identified. Compared to nonpregnant women not receiving oral contraceptives, a 21% to 42% higher dose-adjusted azithromycin area under the plasma concentration-time curve (AUC) occurred in non-African American women who were pregnant or receiving oral contraceptives. Conversely, azithromycin AUCs were similar between pregnant African American women and nonpregnant women not receiving oral contraceptives. Although higher levels of maternal and fetal azithromycin exposure suggest that lower doses be administered to non-African American women during pregnancy, the consideration of azithromycin pharmacodynamics during pregnancy should guide any dose adjustments. PMID- 22106227 TI - Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women. AB - The aim of this study was to describe lamivudine (3TC) pharmacokinetics (PK) in HIV-infected nonpregnant and pregnant women and their fetuses. Samples were collected according to therapeutic drug monitoring from 228 women treated with lamivudine and retrospectively analyzed by a population approach. The samples were also collected from cord blood and amniotic fluid at birth. Lamivudine pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. Mean population parameter estimates (intersubject variability) for women were an absorption rate constant of 1.04 h(-1), an elimination clearance rate of 23.6 (0.266) liters . h(-1), a central volume of distribution of 109 (0.897) liters, an intercompartmental clearance rate of 6.7 liters/h, and a peripheral volume of distribution of 129 liters. A fetal compartment was linked to maternal circulation by mother-to-cord (or fetus) and cord-to-mother rate constants of 0.463 h(-1) and 0.538 h(-1), respectively. The amniotic fluid compartment was connected to the fetal compartment with an elimination rate constant of 0.163 h(-1) and a fixed-constant swallowing flow. The placental transfer expressed as fetal-to-maternal area under the concentration-time curve (AUC) ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amniotic fluid-to-fetal AUC ratio, was 2.9. Pregnant women had a 22% higher apparent clearance than nonpregnant and parturient women; however, this increase did not lead to subexposure and should not require a dosage adjustment. PMID- 22106228 TI - Potent antiviral activity of topoisomerase I and II inhibitors against Kaposi's sarcoma-associated herpesvirus. AB - The lytic DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at an origin (ori-Lyt) and requires trans-acting elements, both viral and cellular. We recently demonstrated that several host cellular proteins, including topoisomerases I and II (Topo I and II), are involved in KSHV lytic DNA replication (Y. Wang, H. Li, Q. Tang, G. G. Maul, and Y. Yuan. J. Virol. 82: 2867 2882, 2008). To assess the importance of these topoisomerases in viral lytic replication, shRNA-mediated gene silencing was used. Depletion of Topo I and II severely inhibited viral lytic DNA replication as well as virion production, suggesting essential roles of these cellular proteins in viral DNA replication. The discovery of Topo I and II as enzymes indispensable for KSHV DNA replication raises a possibility that these cellular proteins could be new targets of therapeutic approaches to halt KSHV replication and treat KSHV-associated diseases. In this report, we examined one Topo I inhibitor and several Topo II inhibitors (inclusive of Topo II poison and catalytic inhibitors) as potential therapeutic agents for blocking KSHV replication. The Topo II catalytic inhibitors in general exhibited marked inhibition on KSHV replication and minimal cytotoxicity. In particular, novobiocin, with the best selectivity index (SI = 31.62) among the inhibitors tested in this study, is effective in inhibiting KSHV DNA replication and virion production but shows little adverse effect on cell proliferation and cycle progression in its therapeutic concentration, suggesting its potential to become an effective and safe drug for the treatment of human diseases associated with KSHV infection. PMID- 22106229 TI - Professionalism: why it should matter to us. Presidential address at 2011 American Head and Neck Society Annual Meeting. PMID- 22106230 TI - The head and neck surgeon as clinician-investigator: opportunities and imperatives. The Hayes Martin Lecture. PMID- 22106231 TI - Quality indicators in head and neck operations: a comparison with published benchmarks. AB - OBJECTIVE: To investigate the reproducibility of quality indicators in the care of patients undergoing operations for head and neck cancer. DESIGN: A review of specialty-specific surgical quality indicators in a cohort undergoing procedures for definitive treatment of head and neck cancer, stratified by high and low acuity of the surgical procedures and compared with established benchmarks. SETTING: A large tertiary care institution and an associated multidisciplinary cancer center. PATIENTS: Fifty randomly selected patients with evaluable data who were diagnosed as having head and neck cancer that was definitively treated using any of the 3 modalities (surgical procedures, chemotherapy, and/or radiotherapy) during a 15-month period at our center. Twenty-one patients who underwent operations form the basis of this report. MAIN OUTCOME MEASURES: Procedures were stratified by acuity on the basis of the extent of the operation. Data were centered on quality indicators designed to reflect length of stay, readmission within 30 days postoperatively, return to the operating room within 7 days of surgery, use of blood products, 30-day mortality, adequacy of reports on surgical pathologic findings, and surgical site infection. RESULTS: Diagnoses in the cohort included carcinoma of the oral cavity in 19 patients (39%), oropharynx in 14 (29%), larynx in 13 (27%), and hypopharynx in 3 (6%). High- and low-acuity surgical procedures were performed in 12 and 7 patients, respectively. No statistically significant differences in the measures for quality indicators were found between the cohort and the calculated benchmarks. CONCLUSION: Our findings demonstrate the applicability of quality indicators to the care of patients with head and neck cancer treated by surgical intervention stratified by acuity and compared with established benchmarks. PMID- 22106232 TI - US mortality rates for oral cavity and pharyngeal cancer by educational attainment. AB - OBJECTIVE: To describe trends in mortality rates for patients with oral cavity and pharynx cancer by educational attainment, race/ethnicity, sex, and association with human papillomavirus infection. DESIGN: Study of age standardized mortality rates for patients with oral cavity and pharynx cancer by level of education using National Center for Health Statistics data. SETTING: Twenty-six states. PATIENTS: White and black men and women aged 25 to 64 years. MAIN OUTCOME MEASURE: Age-standardized mortality rates for 2005 to 2007 and trends for 1993 to 2007. RESULTS: From 1993 to 2007, overall mortality rates for patients with oral cavity and pharynx cancer decreased among black and white men and women; however, rates among white men have stabilized since 1999. The largest decreases in mortality rates were among black men and women with 12 years of education (-4.95% and -3.72%, respectively). Mortality rates for patients with oral cavity and pharynx cancers decreased significantly among men and women with more than 12 years of education, regardless of race/ethnicity (except for black women), whereas rates increased among white men with less than 12 years of education. Mortality trends vary substantially for human papillomavirus-related and human papillomavirus-unrelated sites. CONCLUSIONS: We observed decreasing mortality rates for patients with oral cavity and pharyngeal cancer among whites and blacks; however, decreases were greatest among those with at least 12 years of education. This difference in mortality trends may reflect the changing prevalence of smoking and sexual behaviors among populations of different educational attainment. PMID- 22106233 TI - Factors associated with mortality in 2-year survivors of head and neck cancer. AB - OBJECTIVES: To determine conditional survival rates of 2-year survivors of head and neck cancer and to identify risk factors of increased mortality. DESIGN: Prospective, observational study conducted from September 1, 2001, through September 31, 2008. SETTING: Tertiary care institution. PATIENTS: Two hundred seventy-six patients who survived 2 years after the diagnosis of their upper aerodigestive carcinoma. INTERVENTION: Patients prospectively provided health related information. MAIN OUTCOME MEASURES: The primary outcomes were observed (death from all causes) and disease-specific (cancer-related) survival for 2-year survivors. RESULTS: Five-year observed (90.8%) and disease-specific (94.8%) survival rates were 29.7 and 25.0 percentage points higher, respectively, than rates calculated for all patients at diagnosis. Older age and advanced stage were associated with poorer survival, whether death was due to the cancer or from all causes. Patients with pain or poor overall quality of life at 2 years were more likely to die from all causes, whereas those still smoking 2 years after diagnosis were more likely to die from their cancer. CONCLUSIONS: In addition to older age and advanced stage, pain, poor overall quality of life, and tobacco use 2 years after diagnosis characterize patients who might need longer and more intense follow-up care to improve their observed and disease-specific survival. This information is useful in developing management plans for patients transitioning from a focus on cancer surveillance into survivorship. PMID- 22106234 TI - The benefit of early PET/CT surveillance in HPV-associated head and neck squamous cell carcinoma. AB - OBJECTIVE: To evaluate the ability of posttreatment positron emission tomography and computed tomography (PET/CT) to predict ultimate disease status in patients with head and neck squamous cell carcinoma and known human papillomavirus (HPV) status. DESIGN: Retrospective. SETTING: Single tertiary academic referral center. PATIENTS: Clinical and radiographic data, including HPV status, were available for 62 patients with head and neck squamous cell carcinoma who underwent treatment from 2005 to 2010. MAIN OUTCOME MEASURES: The first posttreatment PET/CT scan, performed between 4 and 16 weeks (median, 9 weeks) after treatment, was categorized as negative, probably negative, or positive for residual disease. The PET/CT and clinical follow-up results, including disease status, were obtained every 3 months thereafter. RESULTS: Among the 62 patients, 35 results (56%) were negative, 15 (24%) were probably negative, and 12 (19%) were positive. Eight of the 27 HPV-negative patients were PET/CT positive compared with 4 of the 35 HPV-positive patients (Cochran-Armitage trend test, P = .11). The median follow-up for disease-free patients was 21 months from the completion of the treatment. Disease-free survival was associated with PET/CT outcome (log-rank P < .001) and HPV status (log-rank P = .01). Using recurrence at 2 years as a reference standard, the early PET/CT scans had a specificity of 69% (95% confidence interval [CI], 46%-91%) and a negative predictive value of 79% (95% CI, 57%-99%). All PET/CT-negative HPV-positive patients (n = 6) were free of disease at 2 years, although this proportion was not statistically different from the PET/CT-negative HPV-positive patients in this small cohort. CONCLUSIONS: A negative posttreatment PET/CT result may have the potential to identify patients who are at very low risk of recurrence. The HPV status may augment the predictive utility of an initial negative PET/CT result. PMID- 22106235 TI - Patient-perceived and objective functional outcomes following transoral robotic surgery for early oropharyngeal carcinoma. AB - OBJECTIVE: To evaluate changes in patient-perceived swallowing function over time following transoral robotic surgery (TORS) for primary T1 and T2 oropharyngeal squamous cell carcinomas. DESIGN: Prospective case series. SETTING: Academic tertiary referral center. PATIENTS: Forty-two patients with T1 or T2 oropharyngeal squamous cell carcinomas. INTERVENTION: TORS-assisted resection of indicated tumors. MAIN OUTCOME MEASURES: Changes in patient-perceived swallowing function over time (using the M. D. Anderson Dysphagia Inventory) and gastrostomy tube dependence. RESULTS: Between March 19, 2007, and April 21, 2010, forty-two patients with primary T1 or T2 oropharyngeal squamous cell carcinomas underwent TORS-assisted resection. Most (76% [32 of 42]) patients had stage III disease; 93% (39 of 42) of patients underwent staged neck dissection. The median postoperative follow-up time was 17 months (range, 4-40 months). There were no complications or tumor recurrences. Postoperative chemotherapy use predicted gastrostomy tube retention for longer than 3 months (P = .01). Immediate mean postoperative M. D. Anderson Dysphagia Inventory scores in each assessed domain (global, emotional, physical, and functional) decreased compared with preoperative baseline scores; however, ongoing improvement in all domains was observed over time. Nodal status (P = .049), follow-up time of less than 12 months (P = .03), and preoperative physical scores of less than 100 (P = .01) predicted poorer physical M. D. Anderson Dysphagia Inventory outcomes. Positive pathological margins predicted poorer functional scores (P = .03). CONCLUSIONS: After TORS-assisted resection of T1 and T2 oropharyngeal squamous cell carcinomas, approximately one-third of patients will experience a sustained decrease in perceived swallowing function. However, ongoing improvement of swallowing function over time is likely even after 12 months. Patients receiving adjuvant chemotherapy after TORS should be counseled about the possibility of prolonged gastrostomy tube dependence. PMID- 22106236 TI - Using 5-aminolevulinic acid and pulsed dye laser for photodynamic treatment of oral leukoplakia. AB - OBJECTIVE: To determine the safety and efficacy of photodynamic therapy in the treatment of oral leukoplakia with 5-aminolevulinic acid and pulsed dye laser. DESIGN: Nonrandomized, single-arm, single-site phase 1/2 pilot study. SETTING: Academic referral center. PATIENTS: A total of 23 patients, aged 37 to 79 years, having a confirmed diagnosis of leukoplakia with or without dysplasia measuring at least 10 mm in diameter. INTERVENTIONS: Application of 5-aminolevulinic acid to lesions followed by activation with high-power 585-nm pulsed dye laser. MAIN OUTCOME MEASURES: Maximum tolerated dose of laser, postprocedure complications, objective response to treatment, and immunohistochemical changes in treated tissue. RESULTS: No significant adverse events occurred; minor local adverse effects were observed during and following photodynamic therapy in the safety phase of the study. The maximum tolerated dose was 8 J/cm(2). Of 17 patients, 7 (41%) had more than 75% regression (significant response) and 9 (53%) had more than 25% regression (partial response), for an overall response rate of 94% at 90 days. This response rate was far higher than the null-hypothesis 20% rate (P < 10(-10)) and the alternative-hypothesis 50% rate (P = .0001) for which the study was powered. When compared with baseline levels immunohistochemically, p53 expression was increased in 8 of 11 available samples (73%) and Ki-67 expression was decreased in 7 of 12 available samples (58%). CONCLUSIONS: Photodynamic therapy with 5-aminolevulinic acid and pulsed dye laser could be used to achieve regression of oral leukoplakia. The treatment is safe and well tolerated. An application time of 1.5 hours and laser radiant exposure of 8 J/cm(2) with 1.5-ms pulse time were found to be the optimal settings in this study. The high-power laser used in this study allows completion of laser therapy within 1 to 3 minutes. Further studies are necessary to determine the optimal laser radiant exposure and drug application to maximize the response rate. PMID- 22106237 TI - Functional and oncologic results of extended supracricoid partial laryngectomy. AB - OBJECTIVE: To evaluate functional and oncologic results in patients who underwent unilateral arytenoidectomy during supracricoid partial laryngectomy. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care referral center. PATIENTS: One hundred sixteen patients who had received supracricoid partial laryngectomy. MAIN OUTCOME MEASURES: Functional and oncologic results in patients who received supracricoid partial laryngectomy with the extended procedure of unilateral arytenoidectomy. RESULTS: There was a significantly higher rate of aspiration pneumonia (P = .002) and a longer delay of decannulation (P = .03) in the extended group. No significant differences were noted between the 2 groups in the scores for "normalcy of diet" (P = .68), "eating in public" (P = .65), or "understandability of speech" (P > .99) on the Performance Status Scale for Head and Neck Cancer Patients at the last follow-up visit. Five-year overall recurrence was 24.5% in the extended group. Five-year overall survival was 66.6%, and 5-year disease-specific survival was 72.1% in the extended group. CONCLUSIONS: Resection of the arytenoids may interrupt physiologic airway protection in the early postoperative period, necessitating special caution to prevent aspiration pneumonia. However, extended supracricoid partial laryngectomy including arytenoidectomy allows for reasonable oncologic safety and avoidance of functional handicaps and social maladjustment. PMID- 22106238 TI - Maxillary reconstruction with the scapular angle osteomyogenous free flap. AB - OBJECTIVE: To report on experience with the scapular angle osteomyogenous flap for maxillary reconstruction. DESIGN: Retrospective review of patients undergoing scapular angle reconstruction for maxillary defects at the University Health Network from 2004 through 2010. SETTING: Medical research center. PATIENTS: Thirty-nine patients were included in the review. INTERVENTION: Scapular angle reconstruction for maxillary defects. MAIN OUTCOME MEASURES: Maxillary defects were classified prospectively according to Okay and coauthors. Early and late complications as well as demographic and outcome data was analyzed using SPSS version 16.0 statistical software. Shoulder disabilities were assessed using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS: Of the 39 patients included in the study, vein grafting was required in 3 (8%). The overall complication rate in the study was 18 of 30 (46%). A total of 16 patients (41%) in the review required revision procedures of some type. The rate of fistula formation was 21% (n = 8) in the study group. Fifty-one percent of patients received radiotherapy as part of the treatment as dictated by the tumor board. Statistical analysis did not reveal a correlation between the administration of radiotherapy and postoperative fistula formation (P = .13). Of the 8 fistulas, 1 patient required surgical closure and an additional patient opted for palatal prosthesis. Fifty percent of the fistulas closed spontaneously. Of the 39 patients, 18 (46%) obtained a normal diet and 21 (54%) maintained a soft diet. Regarding shoulder dysfunction, the mean (SD) DASH score obtained was 10.44 (10.33). Eight patients in the study group (21%) underwent neck dissection; the remaining 80% of patients did not have cranial nerve XI manipulation. Statistical analysis did not reveal any correlation between neck dissection and postoperative DASH scores. CONCLUSIONS: This investigation indicates that the angular scapular flap has some advantages over other free-tissue transfer techniques for complex maxillary defect reconstruction. A considerable number (46%) of patients will experience some type of local complications after undergoing these challenging reconstructions, and many (41%) will require revision surgery. Postoperative fistula will often close spontaneously. Donor site morbidity is relatively low according to preliminary analysis. PMID- 22106239 TI - Thyroid fine-needle aspiration: does case volume affect diagnostic yield and interpretation? AB - OBJECTIVE: To evaluate the effect of case volume on the diagnostic yield and interpretation of thyroid fine-needle aspiration (FNA). DESIGN: Retrospective case series. SETTING: An academic tertiary referral center and 2 community hospital centers. PATIENTS: Data were retrospectively reviewed for all consecutive patients undergoing thyroid FNA at these institutions during the 2009 calendar year. MAIN OUTCOME MEASURES: Differences in diagnostic distribution and yield among pathologists and clinicians of differing case volume. RESULTS: A total of 790 patients underwent thyroid FNA, with the results interpreted as benign (479 [60%]), atypical (166 [22%]), malignant (9 [1%]), or nondiagnostic (136 [17%]). The FNAs were performed by 134 physicians and interpreted by 16 pathologists with varying case volumes. Low-volume pathologists (<50 FNAs interpreted) were more likely to report atypical FNAs (32% vs 13%; P < .001) and less likely to call FNAs benign (50% vs 70%; P < .001) compared with high-volume pathologists (>=50 FNAs interpreted), and compared with expected normative data (benign, P < .001; atypical, P < .001). Atypical FNA findings reported by low volume pathologist were more likely to yield benign permanent results than those read by high-volume pathologists (64% vs 42%; P < .02). Low-volume clinicians (<20 FNAs performed) were not more likely to perform nondiagnostic FNAs compared with high-volume clinicians (>=20 FNAs performed) (16% vs 15%; P = .47). CONCLUSIONS: Case volume significantly influences the pathologic interpretation of thyroid FNA, as low-volume pathologists report more atypical and fewer benign FNA results. Case volume did not have a significant impact on diagnostic yield, because thyroid FNAs performed by low-volume clinicians did not result in more frequent nondiagnostic results compared with those performed by high-volume clinicians. PMID- 22106240 TI - The importance of volume in fine-needle aspirations of the thyroid. PMID- 22106241 TI - An analysis of factors predicting lateral cervical nodal metastases in papillary carcinoma of the thyroid. AB - OBJECTIVE: To analyze the possible correlation between the location of the primary tumor within the thyroid gland and the patterns of central vs lateral compartment lymph node metastasis. DESIGN: Retrospective analysis of papillary thyroid carcinoma (PTC) treated in an academic university setting from July 1, 2004, through August 31, 2010. SETTING: Head and neck oncology clinic. PATIENTS: Those receiving surgical therapy for PTC at the University of Utah. MAIN OUTCOME MEASURES: Tumor characteristics of patients with central vs lateral nodal metastatic disease in PTC. RESULTS: Two hundred one patients with PTC met inclusion criteria. There were 136 females (67.7%), and the mean age was 44.8 years. Histologic subtypes included 68 follicular variants of PTC, 111 conventional variants of PTC, and 22 patients with both follicular and conventional PTC variants. Metastatic nodal disease was confirmed histologically in 81 patients (40.3%): 42 with central nodal disease only (20.9%), 10 with lateral disease only (5.0%), and 29 with both central and lateral nodal disease (14.4%). Positive lateral compartment nodal metastasis correlated with distant metastases (P < .01), extrathyroid extension (P < .05), histologic subtype (conventional PTC greater than follicular variant PTC) (P < .05), and tumor location within the thyroid lobe (P < .01). Tumors involving the superior aspect of the thyroid lobe were more likely to be associated with metastasis to the lateral cervical lymph nodes (P < .01), and 76.9% of patients with lateral cervical lymph node disease had involvement of the superior aspect of the lobe. Thyroid microcarcinomas were not associated with lateral cervical compartments in this study. CONCLUSIONS: The intrathyroidal location of PTC predicts the pattern of nodal spread. Therefore, patients with PTC involving the superior aspect of the lobe should undergo specific imaging evaluation of the lateral neck compartments to determine the need for lateral compartment neck dissection. PMID- 22106242 TI - Estrogen-mediated angiogenesis in thyroid tumor microenvironment is mediated through VEGF signaling pathways. AB - OBJECTIVES: To explore the induction of a proangiogenic phenotype in endothelial cells in the thyroid tumor microenvironment by estrogen-treated thyroid cancer cells and to define the role of vascular endothelial growth factor (VEGF) in this interaction. DESIGN: Cell-based in vitro systems analysis. SUBJECTS: Thyroid tumor cell lines (BCPAP [papillary thyroid cancer] and ML-1 [follicular thyroid cancer]) were cultured with estradiol with and without an estrogen receptor (ER) inhibitor (fulvestrant or ICI) and used to treat human umbilical vein endothelial cells (HUVECs). INTERVENTIONS: Immunofluorescence was used to confirm the presence of ERalpha and ERbeta in BCPAP cells. Conditioned medium was then used to evaluate the induction of HUVEC tubulogenesis and migration. Secretion of VEGF in this medium was evaluated by Western blot analysis. The expression of phosphoinositide 3-kinase (PI3K), the initiator of a proangiogenic pathway, was evaluated with Western blot analysis of HUVEC lysates. The subsequent effects of an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody were also observed. RESULTS: Estrogen receptor alpha and ERbeta are expressed in thyroid cancer cells. Estrogen-stimulated ML-1 cells secreted an increased amount of VEGF likely as a result of ER signaling. In contact with this environment, HUVECs demonstrate enhanced tubulogenesis and migration. Western blot analysis documented estrogen-mediated upregulation of PI3K in HUVECs. These effects were mitigated by an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody. CONCLUSIONS: Our data provide evidence that estrogen can induce a proangiogenic endothelial cell phenotype in the thyroid tumor microenvironment through ER and VEGF signaling. Our findings suggest that the effect of antiestrogenic therapy targeting tumor angiogenesis can be enhanced through VEGF inhibition. PMID- 22106243 TI - Nomogram to aid selection of patients for short-stay thyroidectomy based on risk of postoperative hypocalcemia. AB - OBJECTIVE: To develop statistical prediction tools to select patients for short stay thyroidectomy based on dynamic quantification of individual risk for postoperative hypocalcemia. DESIGN: Clinical and biochemical factors that could influence postoperative calcium levels were analyzed. A multivariable logistic regression model was used to study the predictive ability of each variable for hypocalcemia. A step-down model reduction selection method was used to rank the predictors according to their predictive accuracy. SETTING: Memorial Sloan Kettering Cancer Center. PATIENTS: A test population of 393 patients who met our inclusion criteria and who underwent total thyroidectomy at Memorial Sloan Kettering Cancer Center in the year 2008 made up the modeling data set, 116 of whom developed biochemical hypocalcemia postoperatively (29.5%). The nomograms were validated on an independent data set consisting of 296 selected patients who underwent total thyroidectomy during the year 2005, using the same selection criteria for inclusion as those for the modeling data set. MAIN OUTCOME MEASURES: The 8 predictors with the highest predictive accuracy were selected to generate a nomogram, which was validated both internally and externally using an independent data set. A second nomogram was developed for assessing the probability of a patient stay of 24 hours or shorter, based on preoperative and intraoperative factors. RESULTS: The 8 variables of highest predictive value were age, sex, medications, history of cancer, preoperative serum calcium level, creatinine concentration, central neck dissection, and alkaline phosphatase levels. A nomogram was created based on the final parsimonious model. The nomogram had excellent accuracy (concordance index of 74.6%) and scored high on internal validation tests. The concordance index of the second nomogram for predicting the likelihood of discharge from the hospital within 24 hours was 70%. CONCLUSION: We have produced a set of nomograms that can dynamically quantify the risk of postthyroidectomy hypocalcemia and prolonged hospital stay based on preoperative clinical and biochemical variables and intraoperative surgical variables. PMID- 22106244 TI - Reduced Cx43 gap junction plaque expression differentiates thyroid carcinomas from benign disease. AB - OBJECTIVE: To investigate the expression of connexin 43 (Cx43) in benign vs malignant thyroid tissue for potential use as a diagnostic marker. DESIGN: Retrospective study. SUBJECTS: Thyroid specimens were obtained from 50 patients who underwent partial or total thyroidectomy at the New York Eye and Ear Infirmary, New York, New York, between 1999 and 2007. They included goiter (n = 5), follicular adenoma (n = 15), follicular carcinoma (n = 17), papillary thyroid carcinoma (PTC) (n = 7) and the follicular variant of PTC (n = 6). INTERVENTIONS: Tissue sections (5 MUm) were immunohistochemically stained for Cx43 with the avidin-biotin-peroxidase method using an automated stainer. The Cx43 membrane staining pattern was evaluated. RESULTS: Twenty-three of 30 cancer specimens (77%) revealed a loss of Cx43 plaque staining at the cellular membrane compared with only 3 of 20 benign specimens (15%). Among the malignant specimens, loss of Cx43 plaque staining was observed in 11 of 17 follicular carcinomas (65%), 5 of 6 follicular variants of PTC (83%), and 7 of 7 PTCs (100%). In contrast, only 3 of 15 adenomas (20%) and 0 of 5 goiter samples demonstrated loss of Cx43 plaque staining at the cell membrane. CONCLUSION: Our data provide evidence that the absence of Cx43 plaque staining is associated with thyroid cancer and thus holds potential clinical utility as a marker for malignant disease. PMID- 22106245 TI - Memory Complaints Inventory results as a function of symptom validity test performance. AB - The extant literature has consistently outlined a limited relationship between peoples' subjective reports of defective memory and their corresponding performances on objective measures of memory functioning. Several variables have been proposed to explain this finding, but few studies have investigated test taker effort as a variable of interest. The primary aim of the current study was to examine reported memory problems as a function of symptom validity test (SVT) performances in two independent samples comprising individuals involved in disability claims. The findings demonstrated that as various SVT performances worsened there was a corresponding increase in subjective reports of memory complaints as assessed by the Memory Complaints Inventory. Data also supported the previous literature demonstrating non-significant correlations between subjective reports of memory problems and objective memory functioning in those who passed SVTs. The potential implications for these findings are discussed. PMID- 22106246 TI - Effect of the volume of fluids administered on intraoperative oliguria in laparoscopic bariatric surgery: a randomized controlled trial. AB - OBJECTIVE: To determine whether intraoperative fluid management affects urine output in patients undergoing laparoscopic bariatric operations. DESIGN: Randomized controlled trial. SETTING: Academic tertiary referral center. PATIENTS: Morbidly obese patients scheduled to undergo laparoscopic bariatric procedures. INTERVENTIONS: Patients were randomly assigned to receive intraoperatively high (10 mL/kg/h, n = 55) or low (4 mL/kg/h, n = 52) amounts of Ringer lactate solution. MAIN OUTCOME MEASURES: The primary end point was urine output. Secondary end points were postoperative creatinine serum concentration and complication rate. RESULTS: Significantly more fluids were administered intraoperatively to patients in the high-volume group compared with the low volume group (P < .001). Regardless of the amount of fluids administered intraoperatively, low urine outputs (median [range], 100 [15-1050] mL in the high volume group vs 107 [25-500] mL in the low-volume group; P = .34) were documented and were not significantly different. The mean creatinine serum concentration was within normal range at all times and was not significantly different between the groups (P = .68). The number of patients with complications was nonsignificantly lower in the low-volume group compared with the high-volume group (7 vs 10 patients, respectively; P = .60). CONCLUSIONS: In patients undergoing laparoscopic bariatric surgery, intraoperative urine output is low regardless of the use of relatively high-volume fluid therapy. The results suggest that we should reconsider the common practice to administer intraoperative fluids in response to low urine output. Further studies are required to evaluate these data in other surgical patient populations. Trial Registration clinicaltrials.gov Identifier: NCT00753402. PMID- 22106247 TI - Physicians' needs in coping with emotional stressors: the case for peer support. AB - OBJECTIVE: To design an evidence-based intervention to address physician distress, based on the attitudes toward support among physicians at our hospital. DESIGN, SETTING, AND PARTICIPANTS: A 56-item survey was administered to a convenience sample (n = 108) of resident and attending physicians at surgery, emergency medicine, and anesthesiology departmental conferences at a large tertiary care academic hospital. MAIN OUTCOME MEASURES: Likelihood of seeking support, perceived barriers, awareness of available services, sources of support, and experience with stress. RESULTS: Among the resident and attending physicians, 79% experienced either a serious adverse patient event and/or a traumatic personal event within the preceding year. Willingness to seek support was reported for legal situations (72%), involvement in medical errors (67%), adverse patient events (63%), substance abuse (67%), physical illness (62%), mental illness (50%), and interpersonal conflict at work (50%). Barriers included lack of time (89%), uncertainty or difficulty with access (69%), concerns about lack of confidentiality (68%), negative impact on career (68%), and stigma (62%). Physician colleagues were the most popular potential sources of support (88%), outnumbering traditional mechanisms such as the employee assistance program (29%) and mental health professionals (48%). Based on these results, a one-on-one peer physician support program was incorporated into support services at our hospital. CONCLUSIONS: Despite the prevalence of stressful experiences and the desire for support among physicians, established services are underused. As colleagues are the most acceptable sources of support, we advocate peer support as the most effective way to address this sensitive but important issue. PMID- 22106248 TI - Reduced risk of medical morbidity and mortality in patients selected for laparoscopic colorectal resection in England: a population-based study. AB - OBJECTIVES: To quantify the occurrence of significant medical complications following elective colorectal resection and investigate potential differences in medical morbidity following open and minimal access colorectal surgery. DESIGN: Retrospective analysis of Hospital Episode Statistics, which is a prospectively maintained national database. SETTING: All patients undergoing colorectal resection in National Health Service trusts in England. PATIENTS: Adult patients undergoing elective or planned surgery between April 2001 and March 2008. INTERVENTION: Colorectal resection for benign and malignant diagnoses. MAIN OUTCOME MEASURES: Mortality and morbidity at 30 days and 1 year following elective colorectal resection. RESULTS: One hundred thirty-eight thousand seven hundred thirty-five elective colorectal resections were identified between the study dates. Thirty-day in-hospital mortality was 3.4% and 1.7% following conventional and laparoscopic surgery, respectively (P < .001). Overall, the 30 day postoperative medical morbidity rate was 14.6%. Use of the minimal access approach demonstrated a significant reduction in total morbidity risk at 30 days (odds ratio, 0.79; P < .001) and 365 days (odds ratio, 0.81; P < .001) following case-mix adjustment. Multiple regression analyses demonstrated that cardiorespiratory complications and venous thromboembolism occurred less frequently during the index admission and up to 1 year following minimal access surgery when compared with the conventional approach (P < .049). CONCLUSIONS: In this population-based study, patients selected for laparoscopic colorectal resection were associated with lower risk of mortality as well as reduced cardiorespiratory and venous thromboembolic risk than those undergoing open surgery. PMID- 22106249 TI - The relationship between body mass index and 30-day mortality risk, by principal surgical procedure. AB - OBJECTIVE: To examine the relationship between body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and 30-day mortality risk among patients in the participant use data file database of the American College of Surgeons National Surgical Quality Improvement Program. Obesity is a prevalent chronic disease in the United States, and general and vascular surgeons are caring for an increasing population of obese patients. DESIGN: Multivariable logistic regression analysis was used to assess the statistical significance of the relationship between BMI and mortality, with adjustments for patient-level differences in overall mortality risk and principal operating procedures. Odds ratios with 95% CIs were calculated to measure the relative difference in mortality by BMI quintile, with reference to the middle quintile of the BMI. The overall significance of the BMI and of the other covariates was measured using the Wald chi(2) test statistic. A separate multivariable logistic regression model was developed to assess the significance of the interaction between BMI and primary procedure. SETTING: A total of 183 sites. PATIENTS: Patients with major surgical procedures reported in the participant use data file database of the American College of Surgeons National Surgical Quality Improvement Program. RESULTS: The data included 189 533 cases of general and vascular surgical procedures reported in 2005 and 2006 for patients with known overall probabilities of death. Among these, 3245 patients died within 30 days of their surgery (1.7%). Patients with a BMI of less than 23.1 demonstrated a significant increased risk of death, with 40% higher odds compared with patients in the middle range for BMI (26.3 to <29.7). Important differences in the association between BMI and mortality risk occur by type of primary procedure. CONCLUSIONS: Body mass index is a significant predictor of mortality within 30 days of surgery, even after adjusting for the contribution to mortality risk made by type of surgery and for a specific patient's overall expected risk of death. PMID- 22106250 TI - Mass casualty response in the 2008 Mumbai terrorist attacks. AB - OBJECTIVES: The November 26-29, 2008, terrorist attacks on Mumbai were unique in its international media attention, multiple strategies of attack, and the disproportionate national fear they triggered. Everyone was a target: random members of the general population, iconic targets, and foreigners alike were under attack by the terrorists. METHODS: A retrospective, descriptive study of the distribution of terror victims to various city hospitals, critical radius, surge capacity, and the nature of specialized medical interventions was gathered through police, legal reports, and interviews with key informants. RESULTS: Among the 172 killed and 304 injured people, about four-fifths were men (average age, 33 years) and 12% were foreign nationals. The case-fatality ratio for this event was 2.75:1, and the mortality rate among those who were critically injured was 12%. A total of 38.5% of patients arriving at the hospitals required major surgical intervention. Emergency surgical operations were mainly orthopedic (external fixation for compound fractures) and general surgical interventions (abdominal explorations for penetrating bullet/shrapnel injuries). CONCLUSIONS: The use of heavy-duty automatic weapons, explosives, hostages, and arson in these terrorist attacks alerts us to new challenges to medical counterterrorism response. The need for building central medical control for a coordinated response and for strengthening public hospital capacity are lessons learned for future attacks. These particular terrorist attacks had global consequences, in terms of increased security checks and alerts for and fears of further similar "Mumbai-style" attacks. The resilience of the citizens of Mumbai is a critical measure of the long-term effects of terror attacks. PMID- 22106251 TI - Cosmochemical evidence for astrophysical processes during the formation of our solar system. AB - Through the laboratory study of ancient solar system materials such as meteorites and comet dust, we can recognize evidence for the same star-formation processes in our own solar system as those that we can observe now through telescopes in nearby star-forming regions. High temperature grains formed in the innermost region of the solar system ended up much farther out in the solar system, not only the asteroid belt but even in the comet accretion region, suggesting a huge and efficient process of mass transport. Bi-polar outflows, turbulent diffusion, and marginal gravitational instability are the likely mechanisms for this transport. The presence of short-lived radionuclides in the early solar system, especially (60)Fe, (26)Al, and (41)Ca, requires a nearby supernova shortly before our solar system was formed, suggesting that the Sun was formed in a massive star forming region similar to Orion or Carina. Solar system formation may have been "triggered" by ionizing radiation originating from massive O and B stars at the center of an expanding HII bubble, one of which may have later provided the supernova source for the short-lived radionuclides. Alternatively, a supernova shock wave may have simultaneously triggered the collapse and injected the short lived radionuclides. Because the Sun formed in a region where many other stars were forming more or less contemporaneously, the bi-polar outflows from all such stars enriched the local region in interstellar silicate and oxide dust. This may explain several observed anomalies in the meteorite record: a near absence of detectable (no extreme isotopic properties) presolar silicate grains and a dichotomy in the isotope record between (26)Al and nucleosynthetic (nonradiogenic) anomalies. PMID- 22106252 TI - What dopamine does in the brain. AB - In the early 1970s, receptors for neurotransmitters acting via second messengers had not been identified biochemically nor were there definitive links to such messengers. The discovery by John W. Kebabian and Paul Greengard of a dopamine sensitive adenyl cyclase, accordingly, was a giant step forward. The investigators first characterized the enzyme in sympathetic ganglia wherein dopamine-producing cells link pre- and post-synaptic neurons. Then, in the corpus striatum, the brain area enriched in dopamine, they delineated the enzyme?x{2019}s properties and showed that it was inhibited by antipsychotic drugs, leading to a large body of research on dopamine as a mediator of antipsychotic drug action and putative roles for this transmitter in the pathophysiology of schizophrenia. PMID- 22106253 TI - Nuclear RNAi maintains heritable gene silencing in Caenorhabditis elegans. AB - RNA interference (RNAi) is heritable in Caenorhabditis elegans; the progeny of C. elegans exposed to dsRNA inherit the ability to silence genes that were targeted by RNAi in the previous generation. Here we investigate the mechanism of RNAi inheritance in C. elegans. We show that exposure of animals to dsRNA results in the heritable expression of siRNAs and the heritable deposition of histone 3 lysine 9 methylation (H3K9me) marks in progeny. siRNAs are detectable before the appearance of H3K9me marks, suggesting that chromatin marks are not directly inherited but, rather, reestablished in inheriting progeny. Interestingly, H3K9me marks appear more prominently in inheriting progeny than in animals directly exposed to dsRNA, suggesting that germ-line transmission of silencing signals may enhance the efficiency of siRNA-directed H3K9me. Finally, we show that the nuclear RNAi (Nrde) pathway maintains heritable RNAi silencing in C. elegans. The Argonaute (Ago) NRDE-3 associates with heritable siRNAs and, acting in conjunction with the nuclear RNAi factors NRDE-1, NRDE-2, and NRDE-4, promotes siRNA expression in inheriting progeny. These results demonstrate that siRNA expression is heritable in C. elegans and define an RNAi pathway that promotes the maintenance of RNAi silencing and siRNA expression in the progeny of animals exposed to dsRNA. PMID- 22106254 TI - The role of terrestrially derived organic carbon in the coastal ocean: a changing paradigm and the priming effect. AB - One of the major conundrums in oceanography for the past 20 y has been that, although the total flux of dissolved organic carbon (OC; DOC) discharged annually to the global ocean can account for the turnover time of all oceanic DOC (ca. 4,000-6,000 y), chemical biomarker and stable isotopic data indicate that there is very little terrestrially derived OC (TerrOC) in the global ocean. Similarly, it has been estimated that only 30% of the TerrOC buried in marine sediments is of terrestrial origin in muddy deltaic regions with high sedimentation rates. If vascular plant material--assumed to be highly resistant to decay--makes up much of the DOC and particulate OC of riverine OC (along with soil OC), why do we not see more TerrOC in coastal and oceanic waters and sediments? An explanation for this "missing" TerrOC in the ocean is critical in our understanding of the global carbon cycle. Here, I consider the origin of vascular plants, the major component of TerrOC, and how their appearance affected the overall cycling of OC on land. I also examine the role vascular plant material plays in soil OC, inland aquatic ecosystems, and the ocean, and how our understanding of TerrOC and "priming" processes in these natural systems has gained considerable interests in the terrestrial literature, but has largely been ignored in the aquatic sciences. Finally, I close by postulating that priming is in fact an important process that needs to be incorporated into global carbon models in the context of climate change. PMID- 22106255 TI - Watching DNA repair in real time. PMID- 22106256 TI - Bacterial chemotaxis modulates host cell apoptosis to establish a T-helper cell, type 17 (Th17)-dominant immune response in Helicobacter pylori infection. AB - The host inflammatory response to chronic bacterial infections often dictates the disease outcome. In the case of the gastric pathogen Helicobacter pylori, host inflammatory responses result in outcomes that range from moderate and asymptomatic to more severe with concomitant ulcer or cancers. It was found recently that H. pylori chemotaxis mutants (Che(-)), which lack directed motility but colonize to nearly wild-type levels, trigger less host inflammation. We used these mutants to observe host immune responses that resulted in reduced disease states. Here we report that these mutants are defective for early gastric recruitment of CD4(+) T cells compared with wild-type infection. Furthermore, Che(-) mutant infections lack the T-helper cell, type 17 (Th17) component of the immune response, as measured by cytokine mRNA levels in gastric tissue via intracellular cytokine staining and immunofluorescence. We additionally find that a Che(-) mutant infection results in significantly less host cell apoptosis than does wild-type infection, in accordance with previous observations that T-helper cell, type 17 responses in Citrobacter rodentium infections are driven by concomitant bacterial and apoptotic cell signals. We propose that bacterial chemotaxis allows H. pylori to access a particular host niche that allows the bacteria to express or deliver proapoptotic host cell factors. This report indicates that chemotaxis plays a role in enhancing apoptosis, suggesting bacterial chemotaxis systems might serve as therapeutic targets for infections whose symptoms arise from host cell apoptosis and tissue damage. PMID- 22106257 TI - Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy. AB - Here, we address the question of why the influenza A virus hemagglutinin (HA) does not escape immunity by hyperglycosylation. Uniquely among dozens of monoclonal antibodies specific for A/Puerto Rico/8/34, escape from H28-A2 neutralization requires substitutions introducing N-linked glycosylation at residue 131 or 144 in the globular domain. This escape decreases viral binding to cellular receptors, which must be compensated for by additional substitutions in HA or neuraminidase that enable viral replication. Sequence analysis of circulating H1 influenza viruses confirms the in vivo relevance of our findings: natural occurrence of glycosylation at residue 131 is always accompanied by a compensatory mutation known to increase HA receptor avidity. In vaccinated mice challenged with WT vs. H28-A2 escape mutants, the selective advantage conferred by glycan-mediated global reduction in antigenicity is trumped by the costs of diminished receptor avidity. These findings show that, although N-linked glycosylation can broadly diminish HA antigenicity, fitness costs restrict its deployment in immune evasion. PMID- 22106258 TI - Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestin and dishevelled-2 scaffolds. AB - Protease-activated receptor-1 (PAR1) is a guanine nucleotide-binding (G) protein coupled receptor that elicits cellular responses to coagulant and anticoagulant proteases. Activation of PAR1 by the coagulant protease thrombin results in Ras homolog gene family member A (RhoA) activation, disassembly of adherens junctions, and disruption of the endothelial barrier. In contrast, activation of PAR1 with the anticoagulant protease activated protein C (APC) results in activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and endothelial barrier protection. We previously showed that APC cytoprotective signaling requires the compartmentalization of PAR1 in caveolar microdomains. However, the mechanism by which APC-activated PAR1 promotes cytoprotective signaling in human endothelial cells remains poorly understood. Here we show that APC-activated PAR1 cytoprotective signaling is mediated by beta-arrestin recruitment and activation of the dishevelled-2 (Dvl-2) scaffold and not by G protein alpha inhibiting activity polypeptide 2 (Galpha(i)) signaling. In human endothelial cells, PAR1 and beta-arrestins form a preassembled complex and cosegregate in caveolin-1 enriched fractions. Remarkably, we found that depletion of beta-arrestin expression by RNA interference resulted in the loss of APC-induced Rac1 activation but not of thrombin-stimulated RhoA signaling. APC also failed to protect against thrombin-induced endothelial barrier permeability in cells deficient in beta-arrestin expression. We further demonstrate that APC activation of PAR1 results in beta-arrestin-dependent recruitment of Dvl-2, which is critical for Rac1 signaling and endothelial barrier protection but not for thrombin-induced RhoA signaling. Our findings identify a role for beta-arrestin and Dvl-2 scaffolds in APC-activated PAR1 cytoprotective signaling in human endothelial cells. PMID- 22106259 TI - Independent recruitments of a translational regulator in the evolution of self fertile nematodes. AB - Pleiotropic developmental regulators have been repeatedly linked to the evolution of anatomical novelties. Known mechanisms include cis-regulatory DNA changes that alter regulator transcription patterns or modify target-gene linkages. Here, we examine the role of another form of regulation, translational control, in the repeated evolution of self-fertile hermaphroditism in Caenorhabditis nematodes. Caenorhabditis elegans hermaphrodites initiate spermatogenesis in an otherwise female body through translational repression of the gene tra-2. This repression is mediated by GLD-1, an RNA-binding protein also required for oocyte meiosis and differentiation. By contrast, we show that in the convergently hermaphroditic Caenorhabditis briggsae, GLD-1 acts to promote oogenesis. The opposite functions of gld-1 in these species are not gene-intrinsic, but instead result from the unique contexts for its action that evolved in each. In C. elegans, GLD-1 became essential for promoting XX spermatogenesis via changes in the tra-2 mRNA and evolution of the species-specific protein FOG-2. C. briggsae GLD-1 became an essential repressor of sperm-promoting genes, including Cbr-puf-8, and did not evolve a strong association with tra-2. Despite its variable roles in sex determination, the function of gld-1 in female meiotic progression is ancient and conserved. This conserved role may explain why gld-1 is repeatedly recruited to regulate hermaphroditism. We conclude that, as with transcription factors, spatially localized translational regulators play important roles in the evolution of anatomical novelties. PMID- 22106260 TI - Evolution of a modular software network. AB - "Evolution behaves like a tinkerer" (Francois Jacob, Science, 1977). Software systems provide a singular opportunity to understand biological processes using concepts from network theory. The Debian GNU/Linux operating system allows us to explore the evolution of a complex network in a unique way. The modular design detected during its growth is based on the reuse of existing code in order to minimize costs during programming. The increase of modularity experienced by the system over time has not counterbalanced the increase in incompatibilities between software packages within modules. This negative effect is far from being a failure of design. A random process of package installation shows that the higher the modularity, the larger the fraction of packages working properly in a local computer. The decrease in the relative number of conflicts between packages from different modules avoids a failure in the functionality of one package spreading throughout the entire system. Some potential analogies with the evolutionary and ecological processes determining the structure of ecological networks of interacting species are discussed. PMID- 22106261 TI - Stardust in meteorites. AB - Primitive meteorites, interplanetary dust particles, and comets contain dust grains that formed around stars that lived their lives before the solar system formed. These remarkable objects have been intensively studied since their discovery a little over twenty years ago and they provide samples of other stars that can be studied in the laboratory in exquisite detail with modern analytical tools. The properties of stardust grains are used to constrain models of nucleosynthesis in red giant stars and supernovae, the dominant sources of dust grains that are recycled into the interstellar medium by stars. PMID- 22106263 TI - Force-free swimming of a model helical flagellum in viscoelastic fluids. AB - We precisely measure the force-free swimming speed of a rotating helix in viscous and viscoelastic fluids. The fluids are highly viscous to replicate the low Reynolds number environment of microorganisms. The helix, a macroscopic scale model for the bacterial flagellar filament, is rigid and rotated at a constant rate while simultaneously translated along its axis. By adjusting the translation speed to make the net hydrodynamic force vanish, we measure the force-free swimming speed as a function of helix rotation rate, helix geometry, and fluid properties. We compare our measurements of the force-free swimming speed of a helix in a high-molecular weight silicone oil with predictions for the swimming speed in a Newtonian fluid, calculated using slender-body theories and a boundary element method. The excellent agreement between theory and experiment in the Newtonian case verifies the high accuracy of our experiments. For the viscoelastic fluid, we use a polymer solution of polyisobutylene dissolved in polybutene. This solution is a Boger fluid, a viscoselastic fluid with a shear rate-independent viscosity. The elasticity is dominated by a single relaxation time. When the relaxation time is short compared to the rotation period, the viscoelastic swimming speed is close to the viscous swimming speed. As the relaxation time increases, the viscoelastic swimming speed increases relative to the viscous speed, reaching a peak when the relaxation time is comparable to the rotation period. As the relaxation time is further increased, the viscoelastic swimming speed decreases and eventually falls below the viscous swimming speed. PMID- 22106262 TI - Direct-coupling analysis of residue coevolution captures native contacts across many protein families. AB - The similarity in the three-dimensional structures of homologous proteins imposes strong constraints on their sequence variability. It has long been suggested that the resulting correlations among amino acid compositions at different sequence positions can be exploited to infer spatial contacts within the tertiary protein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, as accomplished by the recently introduced direct-coupling analysis (DCA). Here we develop a computationally efficient implementation of DCA, which allows us to evaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purely on sequence information. DCA is shown to yield a large number of correctly predicted contacts, recapitulating the global structure of the contact map for the majority of the protein domains examined. Furthermore, our analysis captures clear signals beyond intradomain residue contacts, arising, e.g., from alternative protein conformations, ligand mediated residue couplings, and interdomain interactions in protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guide to facilitate computational predictions of alternative protein conformations, protein complex formation, and even the de novo prediction of protein domain structures, contingent on the existence of a large number of homologous sequences which are being rapidly made available due to advances in genome sequencing. PMID- 22106264 TI - Promoter regulation by distinct mechanisms of functional interplay between lysine acetylase Rtt109 and histone chaperone Asf1. AB - The promoter activity of yeast genes can depend on lysine 56 (K56) acetylation of histone H3. This modification of H3 is performed by lysine acetylase Rtt109 acting in concert with histone chaperone Asf1. We have examined the contributions of Rtt109, Asf1, and H3 K56 acetylation to nutrient regulation of a well-studied metabolic gene, ARG1. As expected, Rtt109, Asf1, and H3 K56 acetylation are required for maximal transcription of ARG1 under inducing conditions. However, Rtt109 and Asf1 also inhibit ARG1 under repressing conditions. This inhibition requires Asf1 binding to H3-H4 and Rtt109 KAT activity, but not tail acetylation of H3-H4 or K56 acetylation of H3. These observations suggest the existence of a unique mechanism of transcriptional regulation by Rtt109. Indeed, chromatin immunoprecipitation and genetic interaction studies support a model in which promoter-targeted Rtt109 represses ARG1 by silencing a pathway of transcriptional activation that depends on ASF1. Collectively, our results show that ARG1 transcription intensity at its induced and repressed set points is controlled by different mechanisms of functional interplay between Rtt109 and Asf1. PMID- 22106265 TI - Beta structure motifs of islet amyloid polypeptides identified through surface mediated assemblies. AB - We report here the identification of the key sites for the beta structure motifs of the islet amyloid polypeptide (IAPP) analogs by using scanning tunneling microscopy (STM). Duplex folding structures in human IAPP(8-37) (hIAPP(8-37)) assembly were observed featuring a hairpin structure. The multiplicity in rIAPP assembly structures indicates the polydispersity of the rat IAPP(8-37) (rIAPP(8 37)) beta-like motifs. The bimodal length distribution of beta structure motifs for rIAPP(8-37) R18H indicates the multiple beta segments linked by turns. The IAPP(8-37) analogs share common structure motifs of IAPP(8-17) and IAPP(26-37) with the most probable key sites at positions around Ser(19)/Ser(20) and Gly(24). These observations reveal the similar amyloid formation tendency in the C and N terminus segments because of the sequence similarity, while the differences in specific amino acids at each key site manifest the effect of sequence variations. The results could be beneficial for studying structural polymorphism of amyloidal peptides with multiple beta structure motifs. PMID- 22106266 TI - Superstatistics in nanoscale electrochemical systems. AB - Stochastic electrochemical reaction steps on nanosized electrodes are non Markovian when externally driven by an applied voltage. We show that, compared to the Markovian case (when external driving is absent), nanoscale electrochemical systems obey a superstatistics characterized by a superposition of Tsallis' q indices. The distribution of Tsallis' q indices along stochastic trajectories can be calculated from the electrochemical master equation and normal distributions from Boltzmann-Gibbs thermostatistics are recovered in the thermodynamic limit (the infinite electrode size limit). Although on the nanoscale the external control makes intricate correlations between the microstates, in the superstatistical frame one can still address the microstates as if they were uncorrelated. The resulting superstatistical entropic form is additive in this frame and Tsallis' indices have on the time-average values <= 1, which is, indeed, an example of a superstatistical system where no ad hoc distribution has to be assumed for the fluctuations; rather, the distribution is directly calculated from a mesoscopic master equation without freely adjustable parameters. PMID- 22106267 TI - Direct binding of triglyceride to fat storage-inducing transmembrane proteins 1 and 2 is important for lipid droplet formation. AB - The process of lipid droplet (LD) formation is an evolutionarily conserved process among all eukaryotes and plays an important role in both cellular physiology and disease. Recently, fat storage-inducing transmembrane proteins 1 and 2 (FIT1/FITM1 and FIT2/FITM2) were discovered as an evolutionarily conserved family of proteins involved in fat storage. In mammals, FIT1 is expressed primarily in skeletal muscle and FIT2 is expressed primarily in adipose, raising the possibility that FIT1 and FIT2 have unique functions. These proteins are exclusively localized to the endoplasmic reticulum (ER) and mediate triglyceride rich LD accumulation when overexpressed in cells, mouse liver, or muscle. Unlike the ER-resident diacylglycerol O-acyltransferase family of triglyceride synthesizing enzymes, FITs do not synthesize triglyceride, but rather partition triglyceride into LDs. The mechanism by which FIT proteins mediate this process has not been determined. A simple hypothesis was tested that FIT proteins bind to triglyceride to mediate LD formation. Here, it is shown that FIT proteins purified in detergent micelles directly bind triolein with specificity and saturation-binding kinetics. A FIT2 gain-of-function mutant that formed larger LDs, FLL(157-9)AAA, showed increased binding to triolein relative to wild-type FIT2, whereas FIT1 and a FIT2 partial loss-of-function mutant, N80A, had significantly lower triolein binding and produced smaller LDs. In summary, FIT proteins are transmembrane domain-containing proteins shown to bind triglyceride. These findings indicate that FITs have a unique biochemical mechanism in mediating LD formation and implicates triglyceride binding as important for FIT mediated LD formation. PMID- 22106268 TI - Mathematical modeling of prostate cancer progression in response to androgen ablation therapy. AB - Prostate cancer progression depends in part on the complex interactions between testosterone, its active metabolite DHT, and androgen receptors. In a metastatic setting, the first line of treatment is the elimination of testosterone. However, such interventions are not curative because cancer cells evolve via multiple mechanisms to a castrate-resistant state, allowing progression to a lethal outcome. It is hypothesized that administration of antiandrogen therapy in an intermittent, as opposed to continuous, manner may bestow improved disease control with fewer treatment-related toxicities. The present study develops a biochemically motivated mathematical model of antiandrogen therapy that can be tested prospectively as a predictive tool. The model includes "personalized" parameters, which address the heterogeneity in the predicted course of the disease under various androgen-deprivation schedules. Model simulations are able to capture a variety of clinically observed outcomes for "average" patient data under different intermittent schedules. The model predicts that in the absence of a competitive advantage of androgen-dependent cancer cells over castration resistant cancer cells, intermittent scheduling can lead to more rapid treatment failure as compared to continuous treatment. However, increasing a competitive advantage for hormone-sensitive cells swings the balance in favor of intermittent scheduling, delaying the acquisition of genetic or epigenetic alterations empowering androgen resistance. Given the near universal prevalence of antiandrogen treatment failure in the absence of competing mortality, such modeling has the potential of developing into a useful tool for incorporation into clinical research trials and ultimately as a prognostic tool for individual patients. PMID- 22106269 TI - The Voronoi Implicit Interface Method for computing multiphase physics. AB - We introduce a numerical framework, the Voronoi Implicit Interface Method for tracking multiple interacting and evolving regions (phases) whose motion is determined by complex physics (fluids, mechanics, elasticity, etc.), intricate jump conditions, internal constraints, and boundary conditions. The method works in two and three dimensions, handles tens of thousands of interfaces and separate phases, and easily and automatically handles multiple junctions, triple points, and quadruple points in two dimensions, as well as triple lines, etc., in higher dimensions. Topological changes occur naturally, with no surgery required. The method is first-order accurate at junction points/lines, and of arbitrarily high order accuracy away from such degeneracies. The method uses a single function to describe all phases simultaneously, represented on a fixed Eulerian mesh. We test the method's accuracy through convergence tests, and demonstrate its applications to geometric flows, accurate prediction of von Neumann's law for multiphase curvature flow, and robustness under complex fluid flow with surface tension and large shearing forces. PMID- 22106270 TI - Single-molecule protein arrays enabled by scanning probe block copolymer lithography. AB - The ability to control the placement of individual protein molecules on surfaces could enable advances in a wide range of areas, from the development of nanoscale biomolecular devices to fundamental studies in cell biology. Such control, however, remains a challenge in nanobiotechnology due to the limitations of current lithographic techniques. Herein we report an approach that combines scanning probe block copolymer lithography with site-selective immobilization strategies to create arrays of proteins down to the single-molecule level with arbitrary pattern control. Scanning probe block copolymer lithography was used to synthesize individual sub-10-nm single crystal gold nanoparticles that can act as scaffolds for the adsorption of functionalized alkylthiol monolayers, which facilitate the immobilization of specific proteins. The number of protein molecules that adsorb onto the nanoparticles is dependent upon particle size; when the particle size approaches the dimensions of a protein molecule, each particle can support a single protein. This was demonstrated with both gold nanoparticle and quantum dot labeling coupled with transmission electron microscopy imaging experiments. The immobilized proteins remain bioactive, as evidenced by enzymatic assays and antigen-antibody binding experiments. Importantly, this approach to generate single-biomolecule arrays is, in principle, applicable to many parallelized cantilever and cantilever-free scanning probe molecular printing methods. PMID- 22106271 TI - Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. AB - The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells. PMID- 22106272 TI - Molecular architecture of the Spire-actin nucleus and its implication for actin filament assembly. AB - The Spire protein is a multifunctional regulator of actin assembly. We studied the structures and properties of Spire-actin complexes by X-ray scattering, X-ray crystallography, total internal reflection fluorescence microscopy, and actin polymerization assays. We show that Spire-actin complexes in solution assume a unique, longitudinal-like shape, in which Wiskott-Aldrich syndrome protein homology 2 domains (WH2), in an extended configuration, line up actins along the long axis of the core of the Spire-actin particle. In the complex, the kinase noncatalytic C-lobe domain is positioned at the side of the first N-terminal Spire-actin module. In addition, we find that preformed, isolated Spire-actin complexes are very efficient nucleators of polymerization and afterward dissociate from the growing filament. However, under certain conditions, all Spire constructs--even a single WH2 repeat--sequester actin and disrupt existing filaments. This molecular and structural mechanism of actin polymerization by Spire should apply to other actin-binding proteins that contain WH2 domains in tandem. PMID- 22106273 TI - Profile of Ilkka A. Hanski. PMID- 22106274 TI - Mutually facilitated dispersal between the nonmotile fungus Aspergillus fumigatus and the swarming bacterium Paenibacillus vortex. AB - In the heterogeneous environment surrounding plant roots (the rhizosphere), microorganisms both compete and cooperate. Here, we show that two very different inhabitants of the rhizosphere, the nonmotile fungus Aspergillus fumigatus and the swarming bacterium Paenibacillus vortex, can facilitate each other's dispersal. A. fumigatus conidia (nonmotile asexual fungal spores) can be transported by P. vortex swarms over distances of at least 30 cm and at rates of up to 10.8 mm h(-1). Moreover, conidia can be rescued and transported by P. vortex from niches of adverse growth conditions. Potential benefit to the bacteria may be in crossing otherwise impenetrable barriers in the soil: fungal mycelia seem to act as bridges to allow P. vortex to cross air gaps in agar plates. Transport of conidia was inhibited by proteolytic treatment of conidia or the addition of purified P. vortex flagella, suggesting specific contacts between flagella and proteins on the conidial surface. Conidia were transported by P. vortex into locations where antibiotics inhibited bacteria growth, and therefore, growth and sporulation of A. fumigatus were not limited by bacterial competition. Conidia from other fungi, similar in size to those fungi from A. fumigatus, were not transported as efficiently by P. vortex. Conidia from a range of fungi were not transported by another closely related rhizosphere bacterium, Paenibacillus polymyxa, or the more distantly related Proteus mirabilis, despite both being efficient swarmers. PMID- 22106275 TI - Brassinosteroid control of sex determination in maize. AB - Brassinosteroids (BRs) are plant hormones that regulate growth and development. They share structural similarities with animal steroids, which are decisive factors of sex determination. BRs are known to regulate morphogenesis and environmental stress responses, but their involvement in sex determination in plants has been only speculative. We show that BRs control sex determination in maize revealed through characterization of the classical dwarf mutant nana plant1 (na1), which also feminizes male flowers. na1 plants carry a loss-of-function mutation in a DET2 homolog--a gene in the BR biosynthetic pathway. The mutant accumulates the DET2-specific substrate (24R)-24-methylcholest-4-en-3-one with a concomitant decrease of downstream BR metabolites. Treatment of wild-type maize plants with BR biosynthesis inhibitors completely mimicked both dwarf and tasselseed phenotypes of na1 mutants. Tissue-specific na1 expression in anthers throughout their development supports the hypothesis that BRs promote masculinity of the male inflorescence. These findings suggest that, in the monoecious plant maize, BRs have been coopted to perform a sex determination function not found in plants with bisexual flowers. PMID- 22106276 TI - A common visual metric for approximate number and density. AB - There is considerable interest in how humans estimate the number of objects in a scene in the context of an extensive literature on how we estimate the density (i.e., spacing) of objects. Here, we show that our sense of number and our sense of density are intertwined. Presented with two patches, observers found it more difficult to spot differences in either density or numerosity when those patches were mismatched in overall size, and their errors were consistent with larger patches appearing both denser and more numerous. We propose that density is estimated using the relative response of mechanisms tuned to low and high spatial frequencies (SFs), because energy at high SFs is largely determined by the number of objects, whereas low SF energy depends more on the area occupied by elements. This measure is biased by overall stimulus size in the same way as human observers, and by estimating number using the same measure scaled by relative stimulus size, we can explain all of our results. This model is a simple, biologically plausible common metric for perceptual number and density. PMID- 22106277 TI - Wnt/beta-catenin signaling is differentially regulated by Galpha proteins and contributes to fibrous dysplasia. AB - Skeletal dysplasias are common disabling disorders characterized by aberrant growth of bone and cartilage leading to abnormal skeletal structures and functions, often attributable to defects in skeletal progenitor cells. The underlying molecular and cellular mechanisms of most skeletal dysplasias remain elusive. Although the Wnt/beta-catenin signaling pathway is required for skeletal progenitor cells to differentiate along the osteoblastic lineage, inappropriately elevated levels of signaling can also inhibit bone formation by suppressing osteoblast maturation. Here, we investigate interactions of the four major Galpha protein families (Galpha(s), Galpha(i/o), Galpha(q/11), and Galpha(12/13)) with the Wnt/beta-catenin signaling pathway and identify a causative role of Wnt/beta catenin signaling in fibrous dysplasia (FD) of bone, a disease that exhibits abnormal differentiation of skeletal progenitor cells. The activating Galpha(s) mutations that cause FD potentiated Wnt/beta-catenin signaling, and removal of Galpha(s) led to reduced Wnt/beta-catenin signaling and decreased bone formation. We further show that activation of Wnt/beta-catenin signaling in osteoblast progenitors results in an FD-like phenotype and reduction of beta-catenin levels rescued differentiation defects of FD patient-derived stromal cells. Galpha proteins may act at the level of beta-catenin destruction complex assembly by binding Axin. Our results indicate that activated Galpha proteins differentially regulate Wnt/beta-catenin signaling but, importantly, are not required core components of Wnt/beta-catenin signaling. Our data suggest that activated Galpha proteins are playing physiologically significant roles during both skeletal development and disease by modulating Wnt/beta-catenin signaling strength. PMID- 22106278 TI - Additional specimen of Microraptor provides unique evidence of dinosaurs preying on birds. AB - Preserved indicators of diet are extremely rare in the fossil record; even more so is unequivocal direct evidence for predator-prey relationships. Here, we report on a unique specimen of the small nonavian theropod Microraptor gui from the Early Cretaceous Jehol biota, China, which has the remains of an adult enantiornithine bird preserved in its abdomen, most likely not scavenged, but captured and consumed by the dinosaur. We provide direct evidence for the dietary preferences of Microraptor and a nonavian dinosaur feeding on a bird. Further, because Jehol enantiornithines were distinctly arboreal, in contrast to their cursorial ornithurine counterparts, this fossil suggests that Microraptor hunted in trees thereby supporting inferences that this taxon was also an arborealist, and provides further support for the arboreality of basal dromaeosaurids. PMID- 22106279 TI - Prostagladin D2 is a mast cell-derived antiangiogenic factor in lung carcinoma. AB - It is well established that prostaglandins (PGs) are involved in tumor angiogenesis and growth, yet the role of prostaglandin D(2) (PGD(2)) remains virtually unknown. Here, we show that host hematopoietic PGD(2) synthase (H-PGDS) deficiency enhances Lewis lung carcinoma (LLC) progression, accompanied by increased vascular leakage, angiogenesis, and monocyte/mast cell infiltration. This deficiency can be rescued by hematopoietic reconstitution with bone marrow from H-PGDS-naive (WT) mice. In tumors on WT mice, c-kit(+) mast cells highly express H-PGDS. Host H-PGDS deficiency markedly up-regulated the expression of proangiogenic factors, including TNF-alpha in the tumor. In mast cell-null Kit(W sh/W-sh) mice, adoptive transfer of H-PGDS-deficient mast cells causes stronger acceleration in tumor angiogenesis and growth than in WT mast cells. In response to LLC growth, H-PGDS-deficient mast cells produce TNF-alpha excessively. This response is suppressed by the administration of a synthetic PGD(2) receptor agonist or a degradation product of PGD(2), 15-deoxy-Delta(12,14)-PGJ(2). Additional TNF-alpha deficiency partially counteracts the tumorigenic properties seen in H-PGDS-deficient mast cells. These observations identify PGD(2) as a mast cell-derived antiangiogenic factor in expanding solid tumors. Mast cell-derived PGD(2) governs the tumor microenvironment by restricting excessive responses to vascular permeability and TNF-alpha production. PMID- 22106280 TI - Global human mandibular variation reflects differences in agricultural and hunter gatherer subsistence strategies. AB - Variation in the masticatory behavior of hunter-gatherer and agricultural populations is hypothesized to be one of the major forces affecting the form of the human mandible. However, this has yet to be analyzed at a global level. Here, the relationship between global mandibular shape variation and subsistence economy is tested, while controlling for the potentially confounding effects of shared population history, geography, and climate. The results demonstrate that the mandible, in contrast to the cranium, significantly reflects subsistence strategy rather than neutral genetic patterns, with hunter-gatherers having consistently longer and narrower mandibles than agriculturalists. These results support notions that a decrease in masticatory stress among agriculturalists causes the mandible to grow and develop differently. This developmental argument also explains why there is often a mismatch between the size of the lower face and the dentition, which, in turn, leads to increased prevalence of dental crowding and malocclusions in modern postindustrial populations. Therefore, these results have important implications for our understanding of human masticatory adaptation. PMID- 22106281 TI - Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2. AB - We have discovered that the enzyme phospholipase D2 (PLD2) binds directly to the small GTPase Rac2, resulting in PLD2 functioning as a guanine nucleotide exchange factor (GEF), because it switches Rac2 from the GDP-bound to the GTP-bound states. This effect is large enough to be meaningful (~72% decrease for GDP dissociation and 300% increase for GTP association, both with PLD2), it has a half-time of ~7 min, is enhanced with increasing PLD2 concentrations, and compares favorably with other known GEFs, such as Vav-1. The PLD2-Rac2 protein protein interaction is sufficient for the GEF function, because it can be demonstrated in vitro with just recombinant proteins without lipid substrates, and a catalytically inactive lipase (PLD2-K758R) has GEF activity. Apart from this function, exogenous phosphatidic acid by itself (300 pM) increases GTP binding and enhances PLD2-K758R-mediated GTP binding (by ~34%) but not GDP dissociation. Regarding the PLD2-Rac2 protein-protein association, it involves, for PLD2, residues 263-266 within a Cdc42/Rac interactive binding region in the PH domain, as well as the PX domain, and it involves, for Rac2, residue N17 within its Switch-1 region. PLD2's GEF function is demonstrated in living cells, because silencing PLD2 results in reduced Rac2 activity, whereas PLD2-initiated Rac2 activation enhances cell adhesion, chemotaxis, and phagocytosis. There are several known GEFs, but we report that this GEF is harbored in a phospholipase. The benefit to the cell is that PLD2 brings spatially separated molecules together in a membrane environment, ready for fast intracellular signaling and cell function. PMID- 22106283 TI - Functional traits determine trade-offs and niches in a tropical forest community. AB - How numerous tree species can coexist in diverse forest communities is a key question in community ecology. Whereas neutral theory assumes that species are adapted to common field conditions and coexist by chance, niche theory predicts that species are functionally different and coexist because they are specialized for different niches. We integrated biophysical principles into a mathematical plant model to determine whether and how functional plant traits and trade-offs may cause functional divergence and niche separation of tree species. We used this model to compare the carbon budget of saplings across 13 co-occurring dry forest tree species along gradients of light and water availability. We found that species ranged in strategy, from acquisitive species with high carbon budgets at highest resource levels to more conservative species with high tolerances for both shade and drought. The crown leaf area index and nitrogen mass per leaf area drove the functional divergence along the simulated light gradient, which was consistent with observed species distributions along light gradients in the forest. Stomatal coordination to avoid low water potentials or hydraulic failure caused functional divergence along the simulated water gradient, but was not correlated to observed species distributions along the water gradient in the forest. The trait-based biophysical model thus explains how functional traits cause functional divergence across species and whether such divergence contributes to niche separation along resource gradients. PMID- 22106282 TI - Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors. AB - Histone deacetylase inhibitors (HDACi) are a new group of anticancer drugs with tumor selective toxicity. Normal cells are relatively resistant to HDACi-induced cell death compared with cancer cells. Previously, we found that vorinostat induces DNA breaks in normal and transformed cells, which normal but not cancer cells can repair. In this study, we found that checkpoint kinase 1 (Chk1), a component of the G2 DNA damage checkpoint, is important in the resistance of normal cells to HDACi in vitro and in vivo. Inhibition of Chk1 activity with Chk1 inhibitor (UCN-01, AZD7762, or CHIR-124) in normal cells increases their sensitivity to HDACi (vorinostat, romidepsin, or entinostat) induced cell death, associated with extensive mitotic disruption. Mitotic abnormalities included loss of sister chromatid cohesion and chromosomal disruption. Inhibition of Chk1 did increase HDACi-induced cell death of transformed cells. Thus, Chk1 is an important factor in the resistance of normal cells, and some transformed cells, to HDACi-induced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity. PMID- 22106284 TI - Spatially selective colonization of the arthropod intestine through activation of Vibrio cholerae biofilm formation. AB - Vibrio cholerae is an estuarine bacterium and the human pathogen responsible for the diarrheal disease cholera. In the environment, arthropods are proposed to be carriers and reservoirs of V. cholerae. However, the molecular basis of the association between V. cholerae and viable arthropods has not been elucidated previously. Here, we show that the V. cholerae Vibrio polysaccharide (VPS) dependent biofilm is highly activated upon entry into the arthropod intestine and is specifically required for colonization of the arthropod rectum. Although the V. cholerae VPS-dependent biofilm has been studied in the laboratory for many years, the function of this biofilm in the natural habitats of V. cholerae has been elusive. Our results provide evidence that the VPS-dependent biofilm is required for intestinal colonization of an environmental host. PMID- 22106285 TI - Arabidopsis lysin-motif proteins LYM1 LYM3 CERK1 mediate bacterial peptidoglycan sensing and immunity to bacterial infection. AB - Recognition of microbial patterns by host pattern recognition receptors is a key step in immune activation in multicellular eukaryotes. Peptidoglycans (PGNs) are major components of bacterial cell walls that possess immunity-stimulating activities in metazoans and plants. Here we show that PGN sensing and immunity to bacterial infection in Arabidopsis thaliana requires three lysin-motif (LysM) domain proteins. LYM1 and LYM3 are plasma membrane proteins that physically interact with PGNs and mediate Arabidopsis sensitivity to structurally different PGNs from gram-negative and gram-positive bacteria. lym1 and lym3 mutants lack PGN-induced changes in transcriptome activity patterns, but respond to fungus derived chitin, a pattern structurally related to PGNs, in a wild-type manner. Notably, lym1, lym3, and lym3 lym1 mutant genotypes exhibit supersusceptibility to infection with virulent Pseudomonas syringae pathovar tomato DC3000. Defects in basal immunity in lym3 lym1 double mutants resemble those observed in lym1 and lym3 single mutants, suggesting that both proteins are part of the same recognition system. We further show that deletion of CERK1, a LysM receptor kinase that had previously been implicated in chitin perception and immunity to fungal infection in Arabidopsis, phenocopies defects observed in lym1 and lym3 mutants, such as peptidoglycan insensitivity and enhanced susceptibility to bacterial infection. Altogether, our findings suggest that plants share with metazoans the ability to recognize bacterial PGNs. However, as Arabidopsis LysM domain proteins LYM1, LYM3, and CERK1 form a PGN recognition system that is unrelated to metazoan PGN receptors, we propose that lineage-specific PGN perception systems have arisen through convergent evolution. PMID- 22106286 TI - Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. AB - Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile. PMID- 22106287 TI - Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3. AB - Mammalian methionyl-tRNA synthetase (MRS) plays an essential role in initiating translation by transferring Met to initiator tRNA (tRNA(i)(Met)). MRS also provides a cytosolic anchoring site for aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/p18, a potent tumor suppressor that is translocated to the nucleus for DNA repair upon DNA damage. However, the mechanism by which this enzyme mediates these two seemingly unrelated functions is unknown. Here we demonstrate that AIMP3 is released from MRS by UV irradiation induced stress. Dissociation was induced by phosphorylation of MRS at Ser662 by general control nonrepressed-2 (GCN2) following UV irradiation. Substitution of Ser662 to Asp (S662D) induced a conformational change in MRS and significantly reduced its interaction with AIMP3. This mutant possessed significantly reduced MRS catalytic activity because of loss of tRNA(Met) binding, resulting in down regulation of global translation. According to the Met incorporation assay using stable HeLa cells expressing MRS S662A or eukaryotic initiation factor-2 subunit alpha (eIF2alpha) S51A, inactivation of GCN2-induced phosphorylation at eIF2alpha or MRS augmented the role of the other, suggesting a cross-talk between MRS and eIF2alpha for efficient translational inhibition. This work reveals a unique mode of regulation of global translation as mediated by aminoacyl-tRNA synthetase, specifically MRS, which we herein identified as a previously unidentified GCN2 substrate. In addition, our research suggests a dual role for MRS: (i) as a coregulator with eIF2alpha for GCN2-mediated translational inhibition; and (ii) as a coupler of translational inhibition and DNA repair following DNA damage by releasing bound tumor suppressor AIMP3 for its nuclear translocation. PMID- 22106288 TI - Profile of David D. Laitin. PMID- 22106290 TI - Lennart Philipson: A fighter is gone. PMID- 22106289 TI - Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet. AB - Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention. PMID- 22106291 TI - High-resolution record of the Matuyama-Brunhes transition constrains the age of Javanese Homo erectus in the Sangiran dome, Indonesia. AB - A detailed paleomagnetic study conducted in the Sangiran area, Java, has provided a reliable age constraint on hominid fossil-bearing formations. A reverse-to normal polarity transition marks a 7-m thick section across the Upper Tuff in the Bapang Formation. The transition has three short reversal episodes and is overlain by a thick normal polarity magnetozone that was fission-track dated to the Brunhes chron. This pattern closely resembles another high-resolution Matuyama-Brunhes (MB) transition record in an Osaka Bay marine core. In the Sangiran sediments, four successive transitional polarity fields lie just below the presumed main MB boundary. Their virtual geomagnetic poles cluster in the western South Pacific, partly overlapping the transitional virtual geomagnetic poles from Hawaiian and Canary Islands' lavas, which have a mean (40)Ar/(39)Ar age of 776 +/- 2 ka. Thus, the polarity transition is unambiguously the MB boundary. A revised correlation of tuff layers in the Bapang Formation reveals that the hominid last occurrence and the tektite level in the Sangiran area are nearly coincident, just below the Upper Middle Tuff, which underlies the MB transition. The stratigraphic relationship of the tektite level to the MB transition in the Sangiran area is consistent with deep-sea core data that show that the meteorite impact preceded the MB reversal by about 12 ka. The MB boundary currently defines the uppermost horizon yielding Homo erectus fossils in the Sangiran area. PMID- 22106292 TI - Measuring time with different neural chronometers during a synchronization continuation task. AB - Temporal information processing is critical for many complex behaviors including speech and music cognition, yet its neural substrate remains elusive. We examined the neurophysiological properties of medial premotor cortex (MPC) of two Rhesus monkeys during the execution of a synchronization-continuation tapping task that includes the basic sensorimotor components of a variety of rhythmic behaviors. We show that time-keeping in the MPC is governed by separate cell populations. One group encoded the time remaining for an action, showing activity whose duration changed as a function of interval duration, reaching a peak at similar magnitudes and times with respect to the movement. The other cell group showed a response that increased in duration or magnitude as a function of the elapsed time from the last movement. Hence, the sensorimotor loops engaged during the task may depend on the cyclic interplay between different neuronal chronometers that quantify the time passed and the remaining time for an action. PMID- 22106293 TI - Organelle-nucleus cross-talk regulates plant intercellular communication via plasmodesmata. AB - We use Arabidopsis thaliana embryogenesis as a model system for studying intercellular transport via plasmodesmata (PD). A forward genetic screen for altered PD transport identified increased size exclusion limit (ise) 1 and ise2 mutants with increased intercellular transport of fluorescent 10-kDa tracers. Both ise1 and ise2 exhibit increased formation of twinned and branched PD. ISE1 encodes a mitochondrial DEAD-box RNA helicase, whereas ISE2 encodes a DEVH-type RNA helicase. Here, we show that ISE2 foci are localized to the chloroplast stroma. Surprisingly, plastid development is defective in both ise1 and ise2 mutant embryos. In an effort to understand how RNA helicases that localize to different organelles have similar impacts on plastid and PD development/function, we performed whole-genome expression analyses. The most significantly affected class of transcripts in both mutants encode products that target to and enable plastid function. These results reinforce the importance of plastid-mitochondria nucleus cross-talk, add PD as a critical player in the plant cell communication network, and thereby illuminate a previously undescribed signaling pathway dubbed organelle-nucleus-plasmodesmata signaling. Several genes with roles in cell wall synthesis and modification are also differentially expressed in both mutants, providing new targets for investigating PD development and function. PMID- 22106294 TI - Displacement of the canonical single-stranded DNA-binding protein in the Thermoproteales. AB - ssDNA-binding proteins (SSBs) based on the oligonucleotide-binding fold are considered ubiquitous in nature and play a central role in many DNA transactions including replication, recombination, and repair. We demonstrate that the Thermoproteales, a clade of hyperthermophilic Crenarchaea, lack a canonical SSB. Instead, they encode a distinct ssDNA-binding protein that we term "ThermoDBP," exemplified by the protein Ttx1576 from Thermoproteus tenax. ThermoDBP binds specifically to ssDNA with low sequence specificity. The crystal structure of Ttx1576 reveals a unique fold and a mechanism for ssDNA binding, consisting of an extended cleft lined with hydrophobic phenylalanine residues and flanked by basic amino acids. Two ssDNA-binding domains are linked by a coiled-coil leucine zipper. ThermoDBP appears to have displaced the canonical SSB during the diversification of the Thermoproteales, a highly unusual example of the loss of a "ubiquitous" protein during evolution. PMID- 22106295 TI - Global food demand and the sustainable intensification of agriculture. AB - Global food demand is increasing rapidly, as are the environmental impacts of agricultural expansion. Here, we project global demand for crop production in 2050 and evaluate the environmental impacts of alternative ways that this demand might be met. We find that per capita demand for crops, when measured as caloric or protein content of all crops combined, has been a similarly increasing function of per capita real income since 1960. This relationship forecasts a 100 110% increase in global crop demand from 2005 to 2050. Quantitative assessments show that the environmental impacts of meeting this demand depend on how global agriculture expands. If current trends of greater agricultural intensification in richer nations and greater land clearing (extensification) in poorer nations were to continue, ~1 billion ha of land would be cleared globally by 2050, with CO(2) C equivalent greenhouse gas emissions reaching ~3 Gt y(-1) and N use ~250 Mt y( 1) by then. In contrast, if 2050 crop demand was met by moderate intensification focused on existing croplands of underyielding nations, adaptation and transfer of high-yielding technologies to these croplands, and global technological improvements, our analyses forecast land clearing of only ~0.2 billion ha, greenhouse gas emissions of ~1 Gt y(-1), and global N use of ~225 Mt y(-1). Efficient management practices could substantially lower nitrogen use. Attainment of high yields on existing croplands of underyielding nations is of great importance if global crop demand is to be met with minimal environmental impacts. PMID- 22106296 TI - The role of cell type-specific responses in IFN-beta therapy of multiple sclerosis. AB - The mechanism of IFN-beta therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-beta by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-kappaB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-beta1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF kappaB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-beta depends on the activation of p38 and NF-kappaB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-kappaB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-beta therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-alpha/beta in hepatitis and cancer. PMID- 22106297 TI - Benefits of wildlife consumption to child nutrition in a biodiversity hotspot. AB - Terrestrial wildlife is the primary source of meat for hundreds of millions of people throughout the developing world. Despite widespread human reliance on wildlife for food, the impact of wildlife depletion on human health remains poorly understood. Here we studied a prospective longitudinal cohort of 77 preadolescent children (under 12 y of age) in rural northeastern Madagascar and show that consuming more wildlife was associated with significantly higher hemoglobin concentrations. Our empirical models demonstrate that removing access to wildlife would induce a 29% increase in the numbers of children suffering from anemia and a tripling of anemia cases among children in the poorest households. The well-known progression from anemia to future disease demonstrates the powerful and far-reaching effects of lost wildlife access on a variety of human health outcomes, including cognitive, motor, and physical deficits. Loss of access to wildlife could arise either from the diligent enforcement of existing conservation policy or from unbridled unsustainable harvest, leading to depletion. Conservation enforcement would enact a more rapid restriction of resources, but self-depletion would potentially lead, albeit more slowly, both to irrevocable local wildlife extinctions and loss of the harvested resource. Our research quantifies costs of reduced access to wildlife for a rural community in Madagascar and illuminates pathways that may broadly link reduced natural resource access to declines in childhood health. PMID- 22106298 TI - Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network. AB - Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID- 22106299 TI - The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. AB - Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI. PMID- 22106300 TI - Equitable decision making is associated with neural markers of intrinsic value. AB - Standard economic and evolutionary models assume that humans are fundamentally selfish. On this view, any acts of prosociality--such as cooperation, giving, and other forms of altruism--result from covert attempts to avoid social injunctions against selfishness. However, even in the absence of social pressure, individuals routinely forego personal gain to share resources with others. Such anomalous giving cannot be accounted for by standard models of social behavior. Recent observations have suggested that, instead, prosocial behavior may reflect an intrinsic value placed on social ideals such as equity and charity. Here, we show that, consistent with this alternative account, making equitable interpersonal decisions engaged neural structures involved in computing subjective value, even when doing so required foregoing material resources. By contrast, making inequitable decisions produced activity in the anterior insula, a region linked to the experience of subjective disutility. Moreover, inequity-related insula response predicted individuals' unwillingness to make inequitable choices. Together, these data suggest that prosocial behavior is not simply a response to external pressure, but instead represents an intrinsic, and intrinsically social, class of reward. PMID- 22106301 TI - Paul Greengard: Signals underlying moods, addictions, and brain disorders. PMID- 22106302 TI - Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha ketoglutarate to citrate to support cell growth and viability. AB - Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived alpha ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived alpha ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived alpha-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions. PMID- 22106303 TI - Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. AB - Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy 3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants. PMID- 22106304 TI - Arenavirus Z protein controls viral RNA synthesis by locking a polymerase promoter complex. AB - Arenaviruses form a noncytolytic infection in their rodent hosts, yet can elicit severe hemorrhagic disease in humans. How arenaviruses regulate gene expression remains unclear, and further understanding may provide insight into the dichotomy of these disparate infection processes. Here we reconstitute arenavirus RNA synthesis initiation and gene expression regulation in vitro using purified components and demonstrate a direct role of the viral Z protein in controlling RNA synthesis. Our data reveal that Z forms a species-specific complex with the viral polymerase (L) and inhibits RNA synthesis initiation by impairing L catalytic activity. This Z-L complex locks the viral polymerase in a promoter bound, catalytically inactive state and may additionally ensure polymerase packaging during virion maturation. Z modulates host factors involved in cellular translation, proliferation, and antiviral signaling. Our data defines an additional role in governing viral RNA synthesis, revealing Z as the center of a network of host and viral connections that regulates viral gene expression. PMID- 22106305 TI - DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts. AB - High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. The exact nature of the breaks, and their location, has not been entirely clear, and it has not been evident how cells survive, replicate, and maintain genome integrity in environments like the renal inner medulla in which cells are constantly exposed to high NaCl concentration. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (gammaH2AX), which occurs around DNA double-strand breaks and contributes to their repair. Here, we confirm by specific comet assay and pulsed-field electrophoresis that cells adapted to high NaCl have increased levels of double-strand breaks. Importantly, gammaH2AX foci that occur during repair of the breaks are nonrandomly distributed in the mouse genome. By chromatin immunoprecipitation using anti-gammaH2AX antibody, followed by massive parallel sequencing (ChIP Seq), we find that during repair of double-strand breaks induced by high NaCl, gammaH2AX is predominantly localized to regions of the genome devoid of genes ("gene deserts"), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation, and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes. PMID- 22106306 TI - Alternative perspective on the control of transpiration by radiation. AB - Stomatal responses to light are important determinants for plant water use efficiency and for general circulation models, but a mechanistic understanding of these responses remains elusive. A recent study [Pieruschka R, Huber G, Berry JA (2010) Proc Natl Acad Sci USA 107:13372-13377] concluded that stomata respond to total absorbed radiation rather than red and blue light as previously thought. We tested this idea by reexamining stomatal responses to red and blue light and to IR radiation. We show that responses to red and blue light are not consistent with a response to total absorbed radiation and that apparent stomatal responses to IR radiation are explainable as experimental artifacts. In addition, our data and analysis provide a method for accurately determining the internal temperature of a leaf. PMID- 22106307 TI - Dynamical freezing of active matter. PMID- 22106308 TI - Brain network local interconnectivity loss in aging APOE-4 allele carriers. AB - Old age and possession of the APOE-4 allele are the two main risk factors for developing later onset Alzheimer's Disease (AD). Carriers of the APOE-4 allele have known differences in intrinsic functional brain network activity across the life span. These individuals also demonstrate specific regional differences in gray and white matter gross structure. However, the relationship of these variations to whole brain structural network connectivity remains unclear. We performed diffusion tensor imaging (DTI), T1 structural imaging, and cognitive testing on aging APOE-4 noncarriers (n = 30; mean age = 63.8+/-8.3) and APOE-4 carriers (n = 25; mean age = 60.8 +/-9.7). Fiber tractography was used to derive whole brain structural graphs, and graph theory was applied to assess structural network properties. Network communication efficiency was determined for each network by quantifying local interconnectivity, global integration, and the balance between these, the small worldness. Relative to noncarriers, APOE-4 carriers demonstrated an accelerated age-related loss of mean local interconnectivity (r = -0.64, P <= 0.01) and regional local interconnectivity decreases in the precuneus (r = -0.64), medial orbitofrontal cortex (r = -0.5), and lateral parietal cortex (r = -0.54). APOE-4 carriers also showed significant age-related loss in mean cortical thickness (r = -0.52, P < 0.05). Cognitively, APOE-4 carriers had significant negative correlations of age and performance on two episodic memory tasks (P < 0.05). This genotype-specific pattern of structural connectivity change with age thus appears related to changes in gross cortical structure and cognition, potentially affecting the rate and/or spatial distribution of AD-related pathology. PMID- 22106309 TI - Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. AB - During cell division, the activation of glycolysis is tightly regulated by the action of two ubiquitin ligases, anaphase-promoting complex/cyclosome-Cdh1 (APC/C Cdh1) and SKP1/CUL-1/F-box protein-beta-transducin repeat-containing protein (SCF beta-TrCP), which control the transient appearance and metabolic activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3). We now demonstrate that the breakdown of PFKFB3 during S phase occurs specifically via a distinct residue (S(273)) within the conserved recognition site for SCF-beta-TrCP. Glutaminase 1 (GLS1), the first enzyme in glutaminolysis, is also targeted for destruction by APC/C-Cdh1 and, like PFKFB3, accumulates after the activity of this ubiquitin ligase decreases in mid-to-late G1. However, our results show that GLS1 differs from PFKFB3 in that its recognition by APC/C-Cdh1 requires the presence of both a Lys-Glu-Asn box (KEN box) and a destruction box (D box) rather than a KEN box alone. Furthermore, GLS1 is not a substrate for SCF-beta-TrCP and is not degraded until cells progress from S to G2/M. The presence of PFKFB3 and GLS1 coincides with increases in generation of lactate and in utilization of glutamine, respectively. The contrasting posttranslational regulation of PFKFB3 and GLS1, which we have verified by studies of ubiquitination and protein stability, suggests the different roles of glucose and glutamine at distinct stages in the cell cycle. Indeed, experiments in which synchronized cells were deprived of either of these substrates show that both glucose and glutamine are required for progression through the restriction point in mid-to-late G1, whereas glutamine is the only substrate essential for the progression through S phase into cell division. PMID- 22106310 TI - Dopamine neurons code subjective sensory experience and uncertainty of perceptual decisions. AB - Midbrain dopamine (DA) neurons respond to sensory stimuli associated with future rewards. When reward is delivered probabilistically, DA neurons reflect this uncertainty by increasing their firing rates in a period between the sensory cue and reward delivery time. Probability of reward, however, has been externally conveyed by visual cues, and it is not known whether DA neurons would signal uncertainty arising internally. Here we show that DA neurons code the uncertainty associated with a perceptual judgment about the presence or absence of a vibrotactile stimulus. We observed that uncertainty modulates the activity elicited by a go cue instructing monkey subjects to communicate their decisions. That is, the same go cue generates different DA responses depending on the uncertainty level of a judgment made a few seconds before the go instruction. Easily detected suprathreshold stimuli elicit small DA responses, indicating that future reward will not be a surprising event. In contrast, the absence of a sensory stimulus generates large DA responses associated with uncertainty: was the stimulus truly absent, or did a low-amplitude vibration go undetected? In addition, the responses of DA neurons to the stimulus itself increase with vibration amplitude, but only when monkeys correctly detect its presence. This finding suggests that DA activity is not related to actual intensity but rather to perceived intensity. Therefore, in addition to their well-known role in reward prediction, DA neurons code subjective sensory experience and uncertainty arising internally from perceptual decisions. PMID- 22106311 TI - Antemortem trauma and survival in the late Middle Pleistocene human cranium from Maba, South China. AB - Paleopathological assessment of the late Middle Pleistocene archaic human cranium from Maba, South China, has documented a right frontal squamous exocranially concave and ridged lesion with endocranial protrusion. Differential diagnosis indicates that it resulted from localized blunt force trauma, due to an accident or, more probably, interhuman aggression. As such it joins a small sample of pre last glacial maximum Pleistocene human remains with probable evidence of humanly induced trauma. Its remodeled condition also indicates survival of a serious pathological condition, a circumstance that is increasingly documented for archaic and modern Homo through the Pleistocene. PMID- 22106312 TI - Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk. AB - The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 * 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 * 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 * 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA. PMID- 22106314 TI - Maria Petrocini Ferretti, the first female surgeon in Florence, Italy. PMID- 22106313 TI - P-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK). AB - The blood-testis barrier (BTB), one of the tightest blood-tissue barriers in the mammalian body, creates an immune-privileged site for postmeiotic spermatid development to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. However, the BTB undergoes extensive restructuring at stage VIII of the epithelial cycle to facilitate the transit of preleptotene spermatocytes and to prepare for meiosis. This action thus prompted us to investigate whether this stage can be a physiological window for the delivery of therapeutic and/or contraceptive drugs across the BTB to exert their effects at the immune privileged site. Herein, we report findings that P-glycoprotein, an ATP-dependent efflux drug transporter and an integrated component of the occludin/zonula occludens 1 (ZO-1) adhesion complex at the BTB, structurally interacted with focal adhesion kinase (FAK), creating the occludin/ZO-1/FAK/P-glycoprotein regulatory complex. Interestingly, a knockdown of P-glycoprotein by RNAi was found to impede Sertoli cell BTB function, making the tight junction (TJ) barrier "leaky." This effect was mediated by changes in the protein phosphorylation status of occludin via the action of FAK, thereby affecting the endocytic vesicle mediated protein trafficking events that destabilized the TJ barrier. However, the silencing of P-glycoprotein, although capable of impeding drug transport across the BTB and TJ permeability barrier function, was not able to induce the BTB to be "freely" permeable to adjudin. These findings indicate that P glycoprotein is involved in BTB restructuring during spermatogenesis but that P glycoprotein-mediated restructuring does not "open up" the BTB to make it freely permeable to drugs. PMID- 22106315 TI - Bariatric surgery in high-risk patients: is it time to reconsider? PMID- 22106316 TI - Cardiothoracic surgeon management of postoperative cardiac critical care. AB - OBJECTIVE: To determine whether postoperative cardiac care by cardiothoracic surgeons in a semiclosed intensive care unit model could be distinguished from that given by intensivists who are not board certified in cardiothoracic surgery. DESIGN: From January 2007 to February 2009, we retrospectively examined data on patients after cardiac operations from 2 consecutive periods during which full time management of intensive care was changed from noncardiothoracic intensivists (period 1, 168 patients) to cardiothoracic surgeons (period 2, 272 patients). MAIN OUTCOME MEASURES: Variables measured included Society of Thoracic Surgeons observed and expected mortality, central venous line infections, ventilator acquired pneumonia, red blood cell exposure, adherence to blood glucose level target at 6 am on the first and second postoperative days, length of stay, and intensive care unit pharmacy costs. Results were compared using a 2-sample t test or 2-tailed Fisher exact test. RESULTS: In similar populations, as witnessed by equivalent Society of Thoracic Surgeons operative risk, cardiothoracic surgeons providing postoperative critical care led to a mean (SD) decrease in hospital length of stay from 13.4 (0.9) to 11.2 (0.4) days (P = .01) and decreased drug costs from $4300 (1000) to $1800 (200) (P < .001). These improvements occurred without losing benefits in other quality measures. CONCLUSIONS: By virtue of their cardiac-specific operative and nonoperative training, cardiothoracic surgeons may be uniquely qualified to provide postoperative cardiac critical care. In a semiclosed unit where care of the patient is codirected, the improvements noted may have been facilitated by the commonalities between surgeons and intensivists associated with similar training and experiences. PMID- 22106317 TI - Outcomes of renal transplants from Centers for Disease Control and Prevention high-risk donors with prospective recipient viral testing: a single-center experience. AB - HYPOTHESIS: The use of kidneys from deceased donors considered at increased infectious risk represents a strategy to increase the donor pool. DESIGN: Single institution longitudinal observational study. SETTING: Tertiary care center. PATIENTS: Fifty patients who gave special informed consent to receive Centers for Disease Control and Prevention high-risk (CDCHR) donor kidneys were followed up by serial testing for viral transmission after transplantation. Nucleic acid testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus was performed on all high-risk donors before transplantation. Outcomes of CDCHR kidney recipients were compared with outcomes of non-high-risk (non-HR) kidney recipients. MAIN OUTCOME MEASURES: New viral transmission, graft function, and waiting list time. RESULTS: No recipient seroconversion was detected during a median follow-up period of 11.3 months. Compared with non-HR donors, CDCHR donors were younger (mean [SD] age, 35 [11] vs 43 [18] years, P = .01), fewer were expanded criteria donors (2.0% vs 24.8%, P < .001), and fewer had a terminal creatinine level exceeding 2.5 mg/dL (4.0% vs 8.8%, P = .002). The median creatinine levels at 1 year after transplantation were 1.4 (interquartile range, 1.2-1.7) mg/dL for CDCHR recipients and 1.4 (interquartile range, 1.1-1.9) mg/dL for non-HR recipients (P = .4). Willingness to accept a CDCHR kidney significantly shortened the median waiting list time (274 vs 736 days, P < .001). CONCLUSIONS: We show safe use of CDCHR donor kidneys and good 1-year graft function. With continued use of these organs and careful follow-up care, we will be better able to gauge donor risk and match it to recipient need to expand the donor pool and optimize patient benefit. PMID- 22106318 TI - Effect of Paget's disease on survival in breast cancer: an exploratory study. AB - OBJECTIVE: To explore whether Paget's disease (PD) has an effect on outcome in patients with breast cancer. DESIGN: Retrospective analysis of comprehensive pathology database, medical records, and slides of samples showing pathologic features. SETTING: UMass Memorial Health Care. PATIENTS: All patients with breast cancer and PD with records in a prospectively maintained database between January 1, 1990, and December 31, 2008, were identified. Each participant was matched (criteria: age within 5 years, year of treatment, and stage of breast cancer) with 2 controls (1:2 ratio). MAIN OUTCOME MEASURES: Overall and disease-free survival were analyzed using Kaplan-Meier statistics and Cox proportional hazards modeling, accounting for matching in the latter analyses by using robust standard error estimates. RESULTS: Mean (SD) follow-up was 47 (33) months. Treatment involved mastectomy in 29 (91%) PD vs 16 (25%) non-PD patients (P < .001), radiotherapy in 14 (44%) PD vs 53 (83%) non-PD patients (P < .001), and hormonal therapy in 14 (44%) PD vs 33 (52%) non-PD patients (P = .004). Biological markers were not significantly different except for ERBB2 (formerly HER2 or HER2/neu) overexpression in 14 (44%) PD vs 16 (25%) non-PD patients (P = .008). The PD group had an overall 5-year survival of 81.2% vs 93.8% of the non-PD group (Kaplan-Meier log-rank, P = .03). The unadjusted hazard ratio for the PD vs non PD group was 5.31 (95% CI, 1.74-16.27; P = .003). The corresponding hazard ratio after adjusting for local and systemic treatment was 2.26 (95% CI, 0.46-11.06; P = .32). CONCLUSIONS: These exploratory data show that PD may have a negative effect on breast cancer survival. This finding needs to be substantiated in larger data sets. PMID- 22106319 TI - Differential association of race with treatment and outcomes in Medicare patients undergoing diverticulitis surgery. AB - BACKGROUND: Observed racial disparities in diverticulitis surgery have been attributed to differences in health insurance status and medical comorbidity. OBJECTIVE: To examine disparities in procedure type (elective vs urgent/emergency) and mortality in patients with surgically treated diverticulitis insured by Medicare, accounting for comorbidities. DESIGN: Retrospective analysis of Medicare Provider Analysis and Review inpatient data. PATIENTS: All blacks and whites 65 years and older undergoing surgical treatment for primary diverticulitis with complete admission and outcome data were eligible. MAIN OUTCOME MEASURES: In-hospital mortality was examined across procedure categories (elective vs urgent/emergency). Multivariable regression controlled for age, sex, and medical comorbidity (Charlson Comorbidity Index). RESULTS: A total of 49 937 whites and 2283 blacks met the study criteria. Blacks were slightly younger (74.7 vs 75.5 years, P < .001) and more likely to be female (75.2% vs 69.8%, P < .001). Blacks carried greater comorbidity than did whites (mean Charlson Comorbidity Index score: 0.98 vs 0.87, P < .001); 67.8% of blacks vs 54.7% of whites (P < .001) were urgent/emergency. After adjustment, blacks demonstrated 26% greater risk of urgent/emergency admission (relative risk, 1.26; 95% CI, 1.22-1.30). Black race was also associated with a 28% greater risk of mortality (relative risk, 1.28; 95% CI, 1.10-1.51). CONCLUSIONS: Blacks underwent urgent/emergency surgery more often than did whites. Blacks demonstrated significantly increased mortality risk after controlling for age, sex, and comorbidities. These findings suggest that observed racial disparities encompass more than just insurance status and medical comorbidity. Mechanisms leading to worse outcomes for blacks must be elucidated. PMID- 22106320 TI - Predicting the risk of perioperative mortality in patients undergoing pancreaticoduodenectomy: a novel scoring system. AB - OBJECTIVE: To develop and validate a risk score to predict the 30- and 90-day mortality after a pancreaticoduodenectomy or total pancreatectomy on the basis of preoperative risk factors in a high-volume program. DESIGN: Data from a prospectively maintained institutional database were collected. In a random subset of 70% of patients (training cohort), multivariate logistic regression was used to develop a simple integer score, which was then validated in the remaining 30% of patients (validation cohort). Discrimination and calibration of the score were evaluated using area under the receiver operating characteristic curve and Hosmer-Lemeshow test, respectively. SETTING: Tertiary referral center. PATIENTS: The study comprised 1976 patients in a prospectively maintained institutional database who underwent pancreaticoduodenectomy or total pancreatectomy between 1998 and 2009. MAIN OUTCOME MEASURES: The 30- and 90-day mortality. RESULTS: In the training cohort, age, male sex, preoperative serum albumin level, tumor size, total pancreatectomy, and a high Charlson index predicted 90-day mortality (area under the curve, 0.78; 95% CI, 0.71-0.85), whereas all these factors except Charlson index also predicted 30-day mortality (0.79; 0.68-0.89). On validation, the predicted and observed risks were not significantly different for 30-day (1.4% vs 1.0%; P = .62) and 90-day (3.8% vs 3.4%; P = .87) mortality. Both scores maintained good discrimination (for 30-day mortality, area under the curve, 0.74; 95% CI, 0.54-0.95; and for 90-day mortality, 0.73; 0.62-0.84). CONCLUSIONS: The risk scores accurately predicted 30- and 90-day mortality after pancreatectomy. They may help identify and counsel high-risk patients, support and calculate net benefits of therapeutic decisions, and control for selection bias in observational studies as propensity scores. PMID- 22106321 TI - Prognosis for the recovery of surgeons from chemical dependency: a 5-year outcome study. AB - HYPOTHESIS: Rates of relapse, monitoring contract completion, and return to medical practice may differ between surgeons and nonsurgeons being monitored for diagnosed substance use disorders. DESIGN: Retrospective 5-year longitudinal cohort study. SETTING: A sample of 16 state physician health programs in the United States. PARTICIPANTS: Nine hundred four physicians who underwent treatment for a substance use disorder and were consecutively admitted to 1 of 16 state physician health programs between September 1, 1995, and September 1, 2001. The study analyzed a subset of data comparing 144 surgeons with 636 nonsurgeons. MAIN OUTCOME MEASURES: Rates of continued drug and alcohol misuse (relapse), monitoring contract completion, and return to medical practice at 5 years. RESULTS: Surgeons were significantly more likely than nonsurgeons to enroll in a physician health program because of alcohol-related problems (odds ratio, 1.9; 95% CI, 1.3-2.7; P = .001) and were less likely to enroll because of opioid use (odds ratio, 0.5; 95% CI, 0.3-0.8, P = .002). Surgeons were neither more nor less likely than nonsurgeons to have a positive drug test result, complete or fail to complete the monitoring contract, or extend the monitoring period beyond the original 5 years specified in their agreements. Fewer surgeons than nonsurgeons were licensed and practicing medicine at the conclusion of the monitoring period, although this difference was not statistically significant. CONCLUSIONS: Surgeons in this study had positive outcomes similar to those of nonsurgeons. However, further research is necessary to conclude whether surgeons are less likely than their nonsurgeon peers to successfully return to medical practice following chemical dependency treatment. PMID- 22106322 TI - Transfusion criteria for fresh frozen plasma in liver resection: a 3 + 3 cohort expansion study. AB - OBJECTIVE: To establish transfusion criteria for use of fresh frozen plasma (FFP) in liver resection. BACKGROUND: Fresh frozen plasma has been transfused in liver resection without adequate supporting evidence, leading to unnecessary use. DESIGN: Prospective study using a phase 1 dose-escalation, 3 + 3 cohort expansion design, modified for FFP transfusion. We designated a serum albumin level of 3.0 g/dL (step 1) as the starting limit for no transfusion and reduced the level in 0.2-g/dL steps. Advancement to the next step was permitted when the albumin level equaled the target value for the previous step in 3 patients. If the albumin value on postoperative day 2 fell below the target value, 100 mL of albumin, 25%, was transfused on that day and on postoperative day 3. The study continued until high-grade postoperative complications occurred without transfusion. If 1 of 3 patients developed Clavien-Dindo grade II or higher complications, 3 more patients (3 + 3 cohort) were added to the same step. SETTING: Hepatobiliary pancreatic surgery center of a university hospital. PATIENTS: Patients with hepatocellular carcinoma who had had Child-Pugh class A liver function and an intraoperative blood loss of less than 1000 mL. INTERVENTION: Transfusion or no transfusion of FFP. Main Outcome Measure Reduction of transfusion rate in liver resection. RESULTS: Of the 213 consecutive patients with liver cancer enrolled, 172 patients (80.8%) fulfilled the inclusion criteria. Step progression proceeded until step 5 (albumin level, 2.2 g/dL) without high-grade complications, but step 2 (albumin level, 2.8 g/dL) required 63 patients to complete because 1 patient developed grade II complications (massive ascites). Step progression was broken off at step 5 in the 172nd patient because the postoperative day 2 albumin value did not fall below the step 4 level (2.4 g/dL), defined as the goal limit. The overall operative morbidity rate was 27.9%; the mortality rate was 0%. The FFP transfusion rate was significantly reduced from 48.6% in a previous series involving 222 patients (unpublished historical data from our institution) to 0.6% (1 of 172 patients) in the present study (P < .001). The postoperative hospital stay in the present study was significantly shorter than that in our previous series (13 vs 16 days; P = .01). Total medical costs were significantly reduced from a median of $21 061 (range, 10 032-59 410) to $17 267 (11 823-35 785; P = .04). CONCLUSION: In liver resection, FFP transfusion is not necessary in patients with serum albumin levels higher than 2.4 g/dL on postoperative day 2. PMID- 22106323 TI - Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: a randomized multicenter study. AB - HYPOTHESIS: A 14-day very low-calorie diet (VLCD) regimen before a laparoscopic gastric bypass procedure will improve perioperative and postoperative outcomes. DESIGN: Multicenter, randomized, single-blind study. SETTING: Five high-volume bariatric centers in Sweden, the Netherlands, Lithuania, Spain, and Belgium. PATIENTS: Two hundred ninety-eight morbidly obese patients undergoing laparoscopic gastric bypass from March 1, 2009, through December 5, 2010. INTERVENTION: Patients were randomly allocated to a 2-week preoperative VLCD regimen or no preoperative dietary restriction (control group). MAIN OUTCOME MEASURES: Operating time, surgeon's perceived difficulty of the operation, liver lacerations, intraoperative bleeding and complications, 30-day weight loss, and morbidity. RESULTS: Mean (SD) preoperative weight change was -4.9 (3.6) kg in the VLCD group vs -0.4 (3.2) kg in the control group (P < .001). Although the surgeon's perceived difficulty of the procedure was lower in the VLCD group (median [interquartile range], 26 [15-42] vs 35 [18-50] mm on a visual analog scale; P = .04), no differences were found regarding mean (SD) operating time (81 [21] vs 80 [23] min; P = .53), estimated blood loss (P = .62), or intraoperative complications (P = .88). At the 30-day follow-up, the number of complications was greater in the control compared with the VLCD group (18 vs 8; P = .04). CONCLUSIONS: Although weight reduction with a 14-day VLCD regimen before laparoscopic gastric bypass performed in high-volume centers seems to reduce the perceived difficulty of the procedure, only minor effects on operating time, intraoperative complications, and short-term weight loss could be expected. However, the finding of reduced postoperative complication rates suggests that such a regimen should be recommended before bariatric surgery. PMID- 22106324 TI - Career phase of board-certified general surgeons: workload composition and outcomes. AB - OBJECTIVE: To examine surgeon career phase and its association with surgical workload composition and outcomes of surgery. DESIGN: Cross-sectional study. SETTING: The study used data from calendar years 2004 through 2006 from 4 Florida general surgeon (GS) cohorts determined by years since board certification. PARTICIPANTS: American Board of Surgery-certified GSs regardless of subspecialty (n = 1187) performing 460 881 operations on adults 18 years or older. MAIN OUTCOME MEASURES: Workload composition based on the Clinical Classification System, complications identified by patient safety indicators, and in-hospital mortality. Poisson regression with robust error variance estimated adjusted rate ratios (RRs) for complications and mortality. RESULTS: Compared with late-career surgeons, the rate of complications from cardiovascular procedures was higher for surgeons in the early-career phase (RR, 1.23; 95% CI, 1.06-1.44) and the late middle-career phase (1.18; 1.02-1.37). The mortality rate for cardiovascular procedures also was higher for early-career surgeons (RR, 1.23; 95% CI, 1.04 1.46). For digestive procedures, early-career surgeons had lower complication rates than late-career surgeons (RR, 0.86; 95% CI, 0.75-0.99). CONCLUSION: Late career GSs perform both better and worse compared with early-career GSs, relative to their workload composition and proportional surgical volume. Factors such as training and case complexity may contribute to these career-phase differences. PMID- 22106325 TI - Safety of laparoscopic vs open bariatric surgery: a systematic review and meta analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis evaluating the risk of reoperation, wound infection, incisional hernia, anastomotic leak, and all cause mortality associated with laparoscopic vs open bariatric surgery at a minimum of 12 months' follow-up. DATA SOURCES: We systematically searched the Cochrane Library, EMBASE, and MEDLINE databases through June 1, 2010, for randomized controlled trials comparing laparoscopic with open bariatric surgery. STUDY SELECTION: We included all randomized controlled trials that reported weight loss outcomes and complications at a minimum of 12 months' follow-up and had a minimum of 50 patients. We identified 6 randomized controlled trials, which randomized 510 patients. DATA EXTRACTION: Data were extracted by 2 reviewers on study design, baseline characteristics, and surgical procedure. The outcome data extracted included change in weight and body mass index and the incidence of reoperation, wound infection, incisional hernia, anastomotic leak, and all-cause mortality. DATA SYNTHESIS: We used random-effects models, which accounted for within-study and between-study variability, to estimate pooled risk ratios (95% CIs). Compared with open surgery, laparoscopic surgery was associated with lower risk of wound infection (relative risk [RR], 0.21; 95% CI, 0.07-0.65) and incisional hernia (RR, 0.11; 95% CI, 0.03-0.35). The risk of reoperation (RR, 1.06; 95% CI, 0.70-1.61), anastomotic leak (RR, 0.64; 95% CI, 0.14-2.95), and all cause mortality (RR, 0.86; 95% CI, 0.22-3.28) may be similar for laparoscopic and open bariatric surgery. CONCLUSION: Laparoscopic surgery may be a safer treatment than open surgery for patients requiring bariatric surgery. PMID- 22106326 TI - Hyaluronate-iodine complex: a new adjunct for the management of complex sternal wounds after a cardiac operation. AB - A wound-healing agent developed in the European Union is based on the combination of organic hyaluronan with inorganic iodine. The aim of this pilot study was to assess the efficacy and safety of hyaluronate-iodine in the treatment of sternal wounds. Eight patients with sternal wound dehiscence were entered into the study. After debridement, wounds were dressed with gauze soaked in hyaluronate-iodine. In one patient with an epipleural abscess, hyaluronate-iodine was instilled directly into the abscess cavity daily. Complete healing was achieved in 7 patients, and 1 patient underwent a reconstructive operation for wound closure. The mean (SD) length of treatment was 136 (114.2) days. No adverse effects or complications were apparent in this group. Hyaluronate-iodine is safe and effective in healing sternal wound dehiscence. Randomized controlled trials are needed for further validation. PMID- 22106327 TI - Image of the month. Right-sided inferior nonrecurrent laryngeal nerve. PMID- 22106328 TI - Image of the month. Foramen of Winslow hernia. PMID- 22106329 TI - Image of the month. Pulmonary artery pseudoaneurysm. PMID- 22106330 TI - Magnetic resonance imaging monsters and surgical vampires. PMID- 22106331 TI - Major abdominal surgery with continued dual antiplatelet therapy. PMID- 22106332 TI - Emerging trends in endoscopic retrograde cholangiopancreatography and common bile duct exploration. PMID- 22106333 TI - Identification of context-specific gene regulatory networks with GEMULA--gene expression modeling using LAsso. AB - MOTIVATION: Gene regulatory networks, in which edges between nodes describe interactions between transcriptional regulators and their target genes, determine the coordinated spatiotemporal expression of genes. Especially in higher organisms, context-specific combinatorial regulation by transcription factors (TFs) is believed to determine cellular states and fates. TF-target gene interactions can be studied using high-throughput techniques such as ChIP-chip or ChIP-Seq. These experiments are time and cost intensive, and further limited by, for instance, availability of high affinity TF antibodies. Hence, there is a practical need for methods that can predict TF-TF and TF-target gene interactions in silico, i.e. from gene expression and DNA sequence data alone. We propose GEMULA, a novel approach based on linear models to predict TF-gene expression associations and TF-TF interactions from experimental data. GEMULA is based on linear models, fast and considers a wide range of biologically plausible models that describe gene expression data as a function of predicted TF binding to gene promoters. RESULTS: We show that models inferred with GEMULA are able to explain roughly 70% of the observed variation in gene expression in the yeast heat shock response. The functional relevance of the inferred TF-TF interactions in these models are validated by different sources of independent experimental evidence. We also have applied GEMULA to an in vitro model of neuronal outgrowth. Our findings confirm existing knowledge on gene regulatory interactions underlying neuronal outgrowth, but importantly also generate new insights into the temporal dynamics of this gene regulatory network that can now be addressed experimentally. AVAILABILITY: The GEMULA R-package is available from http://www.few.vu.nl/~degunst/gemula_1.0.tar.gz. PMID- 22106334 TI - Addendum: topology and prediction of RNA pseudoknots. PMID- 22106335 TI - Data-driven information retrieval in heterogeneous collections of transcriptomics data links SIM2s to malignant pleural mesothelioma. AB - MOTIVATION: Genome-wide measurement of transcript levels is an ubiquitous tool in biomedical research. As experimental data continues to be deposited in public databases, it is becoming important to develop search engines that enable the retrieval of relevant studies given a query study. While retrieval systems based on meta-data already exist, data-driven approaches that retrieve studies based on similarities in the expression data itself have a greater potential of uncovering novel biological insights. RESULTS: We propose an information retrieval method based on differential expression. Our method deals with arbitrary experimental designs and performs competitively with alternative approaches, while making the search results interpretable in terms of differential expression patterns. We show that our model yields meaningful connections between biological conditions from different studies. Finally, we validate a previously unknown connection between malignant pleural mesothelioma and SIM2s suggested by our method, via real-time polymerase chain reaction in an independent set of mesothelioma samples. AVAILABILITY: Supplementary data and source code are available from http://www.ebi.ac.uk/fg/research/rex. PMID- 22106336 TI - Integrating human and murine anatomical gene expression data for improved comparisons. AB - MOTIVATION: Information concerning the gene expression pattern in four dimensions (species, genes, anatomy and developmental stage) is crucial for unraveling the roles of genes through time. There are a variety of anatomical gene expression databases, but extracting information from them can be hampered by their diversity and heterogeneity. RESULTS: aGEM 3.1 (anatomic Gene Expression Mapping) addresses the issues of diversity and heterogeneity of anatomical gene expression databases by integrating six mouse gene expression resources (EMAGE, GXD, GENSAT, Allen Brain Atlas data base, EUREXPRESS and BioGPS) and three human gene expression databases (HUDSEN, Human Protein Atlas and BioGPS). Furthermore, aGEM 3.1 provides new cross analysis tools to bridge these resources. AVAILABILITY AND IMPLEMENTATION: aGEM 3.1 can be queried using gene and anatomical structure. Output information is presented in a friendly format, allowing the user to display expression maps and correlation matrices for a gene or structure during development. An in-depth study of a specific developmental stage is also possible using heatmaps that relate gene expression with anatomical components. http://agem.cnb.csic.es CONTACT: natalia@cnb.csic.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22106337 TI - Intensive glucose lowering (HbA1c target<6.0%) for people with type 2 diabetes increases mortality. PMID- 22106338 TI - Conflicts of interest. PMID- 22106340 TI - Regression of cardiac hypertrophy by granulocyte colony-stimulating factor stimulated interleukin-1beta synthesis. AB - AIMS: Aortic stenosis causes cardiac hypertrophy and fibrosis, which often persists despite pressure unloading after aortic valve replacement. The persistence of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. We investigated whether granulocyte colony stimulating factor (G-CSF) beneficially influences cardiac remodelling after pressure unloading. METHODS AND RESULTS: Left ventricular hypertrophy was induced by transverse aortic constriction in C57bl6 mice followed by debanding after 8 weeks. This model closely mimics aortic stenosis and subsequent aortic valve replacement. After debanding, mice were treated with either G-CSF or saline injection. Granulocyte colony-stimulating factor treatment significantly improved systolic (ejection fraction 70.48 +/- 1.17 vs. 58.41 +/- 1.56%, P < 0.001) and diastolic (E/E' 26.0 +/- 1.0 vs. 32.6 +/- 0.8, P < 0.05) function. Furthermore, cardiac fibrosis was significantly reduced in G-CSF-treated mice (collagen-I area fraction 7.96 +/- 0.47 vs. 11.64 +/- 1.22%, P < 0.05; collagen-III area fraction 10.73 +/- 0.99 vs. 18.46 +/- 0.71%, P < 0.001). Direct effects of G-CSF on cardiac fibroblasts or a relevant transdifferentiation of mobilized bone marrow cells could be excluded. However, a considerable infiltration of neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 beta (IL-1beta) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of IL-1beta in neutrophils after G-CSF treatment. Interleukin-1beta directly induced the expression of the gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 in cardiac fibroblasts thereby providing the regression of cardiac fibrosis. CONCLUSION: Granulocyte colony-stimulating factor treatment improves the cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression. Granulocyte colony-stimulating factor might be a potential pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement, although further basic research and clinical trials are required in order to prove beneficial effects of G-CSF in the human organism. PMID- 22106341 TI - Effects of 3-year GH replacement therapy on bone mineral density in younger and elderly adults with adult-onset GH deficiency. AB - OBJECTIVE: Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH-deficient (GHD) adults. DESIGN/PATIENTS/METHODS: In this prospective, single-center, open label study, the effects of 3-year GH replacement were determined in 45 GHD patients >65 years and in 45 younger control GHD patients with a mean age of 39.5 (S.E.M. 1.1) years. All patients had adult-onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index, and waist:hip ratio. RESULTS: The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (P<0.01). The 3 years of GH replacement induced a marginal effect on total body BMC and BMD, whereas femur neck and lumbar (L2-L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (P<0.05 vs younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations. CONCLUSIONS: This study shows that GH replacement increases lumbar (L2-L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports the notion that long-term GH replacement is also useful in elderly GHD patients. PMID- 22106342 TI - The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax. AB - The Really Interesting New Gene (RING) Finger Protein 4 (RNF4) represents a class of ubiquitin ligases that target Small Ubiquitin-like Modifier (SUMO)-modified proteins for ubiquitin modification. To date, the regulatory function of RNF4 appears to be ubiquitin-mediated degradation of sumoylated cellular proteins. In the present study, we show that the Human T-cell Leukemia Virus Type 1 (HTLV-1) oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. We mapped the RNF4-binding site to a region adjacent to the Tax ubiquitin/SUMO modification sites K280/K284. Interestingly, RNF4 modification of Tax protein results in relocalization of the oncoprotein from the nucleus to the cytoplasm. Overexpression of RNF4, but not the RNF4 RING mutant, resulted in cytoplasmic enrichment of Tax. The RNF4-induced nucleus-to-cytoplasm relocalization was associated with increased NF-kappaB-mediated and decreased cAMP Response Element Binding (CREB)-mediated Tax activity. Finally, depletion of RNF4 by RNAi prevented the DNA damage-induced nuclear/cytoplasmic translocation of Tax. These results provide important new insight into STUbL-mediated pathways that regulate the subcellular localization and functional dynamics of viral oncogenes. PMID- 22106343 TI - A novel pathway for human endothelial cell activation by antiphospholipid/anti beta2 glycoprotein I antibodies. AB - Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly beta(2)GPI, and activate endothelial cells (ECs) in a beta(2)GPI dependent manner after binding of beta(2)GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-beta(2)GPI Ab mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88-dependent pathway leading to activation of NF-kappaB has been proposed. In the present study, we confirm a critical role for TLR4 in anti-beta(2)GPI Ab-mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-beta(2)GPI Abs. These results provide new evidence for novel protein-protein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-beta(2)GPI-associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome. PMID- 22106344 TI - Constitutively active ezrin increases membrane tension, slows migration, and impedes endothelial transmigration of lymphocytes in vivo in mice. AB - ERM (ezrin, radixin moesin) proteins in lymphocytes link cortical actin to plasma membrane, which is regulated in part by ERM protein phosphorylation. To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension, we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice, T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18% to 47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike most described homing defects, there was not impaired rolling or sticking to lymph node vascular endothelium but rather decreased migration across that endothelium. Moreover, decreased numbers of transgenic T cells in efferent lymph suggested defective egress. These studies confirm the critical role of ERM dephosphorylation in regulating lymphocyte migration and transmigration. Of particular note, they identify phospho-ERM as the first described regulator of lymphocyte membrane tension, whose increase probably contributes to the multiple defects observed in the ezrin T567E transgenic mice. PMID- 22106345 TI - Role and regulation of phosphatidylinositol 3-kinase beta in platelet integrin alpha2beta1 signaling. AB - Integrin alpha2beta1-mediated adhesion of human platelets to monomeric type I collagen or to the GFOGER peptide caused a time-dependent activation of PI3K and Akt phosphorylation. This process was abrogated by pharmacologic inhibition of PI3Kbeta, but not of PI3Kgamma or PI3Kalpha. Moreover, Akt phosphorylation was undetectable in murine platelets expressing a kinase-dead mutant of PI3Kbeta (PI3Kbeta(KD)), but occurred normally in PI3Kgamma(KD) platelets. Integrin alpha2beta1 failed to stimulate PI3Kbeta in platelets from phospholipase Cgamma2 (PLCgamma2)-knockout mice, and we found that intracellular Ca(2+) linked PLCgamma2 to PI3Kbeta activation. Integrin alpha2beta1 also caused a time dependent stimulation of the focal kinase Pyk2 downstream of PLCgamma2 and intracellular Ca(2+). Whereas activation of Pyk2 occurred normally in PI3Kbeta(KD) platelets, stimulation of PI3Kbeta was strongly reduced in Pyk2 knockout mice. Neither Pyk2 nor PI3Kbeta was required for alpha2beta1-mediated adhesion and spreading. However, activation of Rap1b and inside-out stimulation of integrin alphaIIbbeta3 were reduced after inhibition of PI3Kbeta and were significantly impaired in Pyk2-deficient platelets. Finally, both PI3Kbeta and Pyk2 significantly contributed to thrombus formation under flow. These results demonstrate that Pyk2 regulates PI3Kbeta downstream of integrin alpha2beta1, and document a novel role for Pyk2 and PI3Kbeta in integrin alpha2beta1 promoted inside-out activation of integrin alphaIIbbeta3 and thrombus formation. PMID- 22106346 TI - Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. AB - Amyloidoses are characterized by organ deposition of misfolded proteins. This study evaluated immunohistochemistry as a diagnostic tool for the differentiation of amyloid subentities, which is warranted for accurate treatment. A total of 117 patients were systematically investigated by clinical examination, laboratory tests, genotyping, and immunohistochemistry on biopsy specimens. Immunohistochemistry enabled the classification in 94% of the cases. For subsequent analysis, the patient population was divided into 2 groups. The first group included all patients whose diagnosis could be verified by typical clinical signs or an inherited amyloidogenic mutation. In this group, immunohistochemical subtyping was successful in 49 of 51 cases and proved accurate in each of the 49 cases, corresponding to a sensitivity of 96% and a specificity of 100%. The second group included patients with systemic light chain amyloidosis without typical signs, senile transthyretin, or hereditary amyloidosis with a concomitant monoclonal gammopathy. Immunohistochemistry allowed to define the subentities in 61 of 66 (92%) of these cases. Immunohistochemistry performed by a highly specialized pathologist combined with clinical examination and genotyping leads to a high accuracy of amyloidosis classification and is the standard in our center. However, new techniques, such as mass spectroscopy-based proteomics, were recently developed to classify inconclusive cases. PMID- 22106347 TI - Plasmodium falciparum STEVOR proteins impact erythrocyte mechanical properties. AB - Infection of erythrocytes with the human malaria parasite, Plasmodium falciparum, results in dramatic changes to the host cell structure and morphology. The predicted functional localization of the STEVOR proteins at the erythrocyte surface suggests that they may be involved in parasite-induced modifications of the erythrocyte membrane during parasite development. To address the biologic function of STEVOR proteins, we subjected a panel of stevor transgenic parasites and wild-type clonal lines exhibiting different expression levels for stevor genes to functional assays exploring parasite-induced modifications of the erythrocyte membrane. Using this approach, we show that stevor expression impacts deformability of the erythrocyte membrane. This process may facilitate parasite sequestration in deep tissue vasculature. PMID- 22106348 TI - Intraoperative microwave ablation of pulmonary malignancies with tumor permittivity feedback control: ablation and resection study in 10 consecutive patients. AB - PURPOSE: To determine histologic changes induced by microwave ablation (MWA) in patients with pulmonary malignancy by using an ablation system with tumor permittivity feedback control, enabling real-time modulation of energy power and frequency. MATERIALS AND METHODS: Institutional review board approval and patient informed consent were obtained for this prospective HIPAA-complaint ablation and resection study. Between March 2009 and January 2010, 10 patients (four women, six men; mean age, 71 years; age range, 52-82 years) underwent intraoperative MWA of pulmonary malignancies. Power (10-32 W) and frequency (908-928 MHz) were continuously adjusted by the generator to maintain a temperature of 110 degrees 120 degrees C at the 14-gauge antenna tip for one 10-minute application. After testing for an air leak, tumors were resected surgically. Gross inspection, slicing, and hematoxylin-eosin (10 specimens) and nicotinamide adenine dinucleotide (six specimens) staining were performed. RESULTS: Tumors included adenocarcinomas (n = 5), squamous cell carcinomas (n = 3), and metastases from endometrial (n = 1) and colorectal (n = 1) primary carcinomas. Mean maximum tumor diameter was 2.4 cm (range, 0.9-5.0 cm), and mean maximum volume was 8.6 cm(3) (range, 0.5-52.7 cm(3)). One air leak was detected. Five of 10 specimens were grossly measurable, revealing a mean maximum ablation zone diameter of 4.8 cm (range, 3.0-6.5 cm) and a mean maximum ablation zone volume of 15.1 cm(3) (range, 7.3-25.1 cm(3)). At hematoxylin-eosin staining, coagulation necrosis was observed in all ablation zones, extended into the normal lung in nine of 10 specimens, and up to blood vessel walls without evidence of vessel (>4 mm) thrombosis. Nicotinamide adenine dinucleotide staining enabled confirmation of no viability within ablation zones extending into normal lung in five of six specimens. CONCLUSION: MWA with tumor permittivity feedback control results in cytotoxic intratumoral temperatures and extension of ablation zones into aerated peritumoral pulmonary parenchyma, possibly forming the equivalent of an oncologic resection margin. PMID- 22106349 TI - Rapid needle-out patient-rollover time after percutaneous CT-guided transthoracic biopsy of lung nodules: effect on pneumothorax rate. AB - PURPOSE: To assess the effect of a rapid needle-out patient-rollover time approach on the rate of pneumothorax after computed tomography (CT)-guided transthoracic needle biopsy of pulmonary nodules. MATERIALS AND METHODS: The institutional review board approved the study, and all patients gave written informed consent. Between January 2008 and December 2009, percutaneous CT-guided lung biopsy was performed in 201 patients. Eighty-one biopsies were performed without (group 1) and 120 were performed with (group 2) a rapid needle-out patient-rollover time approach (defined as the time between removal of the biopsy needle and placing the patient biopsy-side down). Multivariate analysis was performed between groups for risk factors for pneumothorax, including patient demographic characteristics, lesion characteristics, and biopsy technique. RESULTS: Mean rapid needle-out patient-rollover time (+/- standard deviation) was 9.5 seconds +/- 4.8. Seventy-six percent of patients (75 of 98) achieved a needle out patient-rollover time of 10 seconds or less. Unsuitability for the rapid needle-out patient-rollover time technique resulted in exclusion of 1.8% of patients. An increased number of pneumothoraces (25 [37%] vs 22 [23%]; P = .04) and an increased number of drainage catheter insertions were noted in group 1 compared with group 2 (10 [15%] versus four [4%], respectively; P = .029). At multiple regression analysis for group 1, lesion size and emphysema along the needle track were independent risk factors for pneumothorax (P = .032 and .021, respectively), and emphysema along the needle track was an independent predictor for insertion of a drainage catheter (P = .005). No independent predictor was identified for pneumothorax or insertion of a drainage catheter in group 2. CONCLUSION: Rapid needle-out patient-rollover time during percutaneous CT-guided transthoracic lung biopsy reduces the rate of overall pneumothorax and pneumothorax necessitating a drainage catheter. Use of this technique attenuates the influence of traditional risk factors for pneumothorax. PMID- 22106350 TI - Articular cartilage: in vivo diffusion-tensor imaging. AB - PURPOSE: To investigate technical feasibility, test-retest reproducibility, and the ability to differentiate healthy subjects from subjects with osteoarthritis (OA) with diffusion-tensor (DT) imaging parameters and T2 relaxation time. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. All subjects provided written informed consent. DT imaging parameters and T2 (resolution=0.6*0.6*2 mm) of patellar cartilage were measured at 7.0 T in 16 healthy volunteers and 10 patients with OA with subtle inhomogeneous signal intensity but no signs of cartilage erosion at clinical magnetic resonance (MR) imaging. Ten volunteers were imaged twice to determine test-retest reproducibility. After cartilage segmentation, maps of mean apparent diffusion coefficient (ADC), fractional anisotropy (FA), and T2 relaxation time were calculated. Differences for ADC, FA, and T2 between the healthy and OA populations were assessed with nonparametric tests. The ability of each MR imaging parameter to help discriminate healthy subjects from subjects with OA was assessed by using receiver operating characteristic curve analysis. RESULTS: Test retest reproducibility was better than 10% for mean ADC (8.1%), FA (9.7%), and T2 (5.9%). Mean ADC and FA differed significantly (P<.01) between the OA and healthy populations, but T2 did not. For ADC, the optimal threshold to differentiate both populations was 1.2*10(-3) mm2/sec, achieving specificity of 1.0 (16 of 16) and sensitivity of 0.80 (eight of 10). For FA, the optimal threshold was 0.25, yielding specificity of 0.88 (14 of 16) and sensitivity of 0.80 (eight of 10). T2 showed poor differentiation between groups (optimal threshold=22.9 msec, specificity=0.69 [11 of 16], sensitivity=0.60 [six of 10]). CONCLUSION: In vivo DT imaging of patellar cartilage is feasible, has good test-retest reproducibility, and may be accurate in discriminating healthy subjects from subjects with OA. ADC and FA are two promising biomarkers for early OA. PMID- 22106351 TI - Mammographic interpretive volume and diagnostic mammogram interpretation performance in community practice. AB - PURPOSE: To investigate the association between radiologist interpretive volume and diagnostic mammography performance in community-based settings. MATERIALS AND METHODS: This study received institutional review board approval and was HIPAA compliant. A total of 117,136 diagnostic mammograms that were interpreted by 107 radiologists between 2002 and 2006 in the Breast Cancer Surveillance Consortium were included. Logistic regression analysis was used to estimate the adjusted effect on sensitivity and the rates of false-positive findings and cancer detection of four volume measures: annual diagnostic volume, screening volume, total volume, and diagnostic focus (percentage of total volume that is diagnostic). Analyses were stratified by the indication for imaging: additional imaging after screening mammography or evaluation of a breast concern or problem. RESULTS: Diagnostic volume was associated with sensitivity; the odds of a true positive finding rose until a diagnostic volume of 1000 mammograms was reached; thereafter, they either leveled off (P < .001 for additional imaging) or decreased (P = .049 for breast concerns or problems) with further volume increases. Diagnostic focus was associated with false-positive rate; the odds of a false-positive finding increased until a diagnostic focus of 20% was reached and decreased thereafter (P < .024 for additional imaging and P < .001 for breast concerns or problems with no self-reported lump). Neither total volume nor screening volume was consistently associated with diagnostic performance. CONCLUSION: Interpretive volume and diagnostic performance have complex multifaceted relationships. Our results suggest that diagnostic interpretive volume is a key determinant in the development of thresholds for considering a diagnostic mammogram to be abnormal. Current volume regulations do not distinguish between screening and diagnostic mammography, and doing so would likely be challenging. PMID- 22106352 TI - Feasibility and accuracy of dual-source dual-energy CT for noninvasive determination of hepatic iron accumulation. AB - PURPOSE: To retrospectively assess feasibility of dual-source dual-energy (DSDE) computed tomography (CT) for evaluation of hepatic iron accumulation in a liver phantom and liver transplantation candidates and to compare its accuracy with that of 3-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the institutional review board; informed consent was waived. A liver agar phantom containing six tubes of iron (concentrations, 100-5000 mg of iron per 100 mL of solution) was scanned at 80 and 140 kVp with both DSDE mode and single-source dual-energy (SSDE) CT with sequential scanning mode. Difference of averaged attenuation between 80 and 140 kVp at CT (DeltaH) was measured and correlated with iron concentration. Thirty-two liver transplant recipients and 55 donors who underwent DSDE CT at 80 and 140 kVp were included. Twenty-three underwent 3-T liver MR with dual-echo in-phase and opposed-phase T1-weighted and spin-echo T2-weighted imaging. Hepatic DeltaH was measured at CT. On T1- and T2 weighted MR images, iron indexes were calculated. Degree of iron accumulation and macrosteatosis were determined at histologic examination (reference). Diagnostic performance of DeltaH at CT and iron indexes at MR for diagnosing clinically important iron accumulation was evaluated (receiver operating characteristic [ROC] analysis). RESULTS: For phantom study, DeltaH obtained from both DSDE mode and SSDE CT with sequential scanning mode was correlated with iron concentration (correlation coefficient, 1.00 and 0.943, respectively; P = .173). DeltaH (13.53) in 10 patients with clinically important (>= 10%) iron accumulation was significantly higher than that (7.39) in 77 patients with normal or mild iron deposition (P < .001). DeltaH was significantly correlated with degree of iron accumulation (correlation coefficient, 0.430; P < .001) but not with degree of hepatic macrosteatosis (P = .216). Area under the ROC curve for diagnosing clinically important iron accumulation was 0.881 and 0.897 with CT and MR, respectively (P = .851). CONCLUSION: DSDE CT is accurate for diagnosing clinically important hepatic iron accumulation without confounding influence of hepatic steatosis, with diagnostic performance on par with MR. PMID- 22106353 TI - Children suspected of having pulmonary embolism: multidetector CT pulmonary angiography--thromboembolic risk factors and implications for appropriate use. AB - PURPOSE: To evaluate thromboembolic risk factors for pulmonary embolism (PE) detected by using computed tomographic (CT) pulmonary angiography in children and to determine whether such information could be used for more appropriate use of CT pulmonary angiography in this patient population. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study and waived the need for patient informed consent. Two hundred twenty-seven consecutive CT pulmonary angiography studies in 227 pediatric patients who underwent CT pulmonary angiography for clinically suspected PE at a single large pediatric referral hospital between July 2004 and March 2011 were evaluated. Age, sex, referral setting, and D-dimer result, as well as seven possible risk factors, were compared between patients with and those without PE. Multiple logistic regression modeling was used to identify the independent risk factors of PE. Receiver operating characteristic curve analysis was applied to determine the optimal cutoff number of risk factors for predicting a positive CT pulmonary angiography result for PE in children. RESULTS: Thirty-six (16%) of 227 CT pulmonary angiography studies were positive for PE. Five risk factors, including immobilization (P < .001), hypercoagulable state (P = .003), excess estrogen state (P = .002), indwelling central venous line (P < .001), and prior PE and/or deep venous thrombosis (P < .001), were found to be significant independent risk factors for PE. With use of two or more risk factors as the clinical threshold, the sensitivity of a positive PE result was 89% (32 of 36 patients), and the specificity was 94% (180 of 191 patients). CONCLUSION: It is unlikely for CT pulmonary angiography results to be positive for PE in children with no thromboembolic risk factors. The use of risk factor assessment as a first-line triage tool has the potential to guide more appropriate use of CT pulmonary angiography in children, with associated reductions in radiation exposure and costs. PMID- 22106354 TI - Rachitic changes, demineralization, and fracture risk in healthy infants and toddlers with vitamin D deficiency. AB - PURPOSE: To examine radiographic findings in children with vitamin D deficiency in comparison with biochemical marker levels and prevalence of fractures. MATERIALS AND METHODS: The parents or guardians of all participants provided written informed consent at the time of enrollment. The institutional review board approved the protocol, and HIPAA guidelines were followed. From a prospective sample of children seen for routine clinical care, 40 children with vitamin D deficiency (25-hydroxyvitamin D [25-OHD] level, <= 20 ng/mL) were identified, and high-detail computed radiographs of the wrists and knees were obtained. The children ranged in age from 8 to 24 months. Radiographs were scored by three readers with use of the 10-point Thacher score for rachitic changes and a five-point scale for demineralization. Serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels were determined. Fracture history was obtained for 35 of the 40 patients (88%). RESULTS: All readers identified rachitic changes at both readings in two patients (5%) and demineralization in two patients (5%). Interrater agreement was 65% for rachitic changes (kappa = 0.33) and 70% for demineralization (kappa = 0.37). When the majority of the raters determined that rachitic changes were absent at both readings, alkaline phosphatase levels were lower than those with other assessments (median, 267 vs 515 U/L [4.4589 vs 8.6005 MUkat/L]; P = .01). When most raters determined that demineralization was present at both readings, serum 25-OHD levels were lower than those at other assessments (median, 9.0 vs 17.5 ng/mL [22.464 vs 43.68 nmol/L]; P = .02). No fractures were reported or identified radiographically. CONCLUSION: In infants and toddlers with vitamin D deficiency, rachitic changes and definite demineralization are uncommon and fracture risk is low. PMID- 22106355 TI - US findings after irreversible electroporation ablation: radiologic-pathologic correlation. AB - PURPOSE: To characterize ultrasonographic (US) findings after irreversible electroporation (IRE) to determine the utility of these findings in the accurate assessment of ablation margins. MATERIALS AND METHODS: The institutional animal care and use committee approved the study. IRE ablation (n = 58) was performed in vivo in 16 pig livers by using two 18-gauge electroporation electrodes with 2-cm tip exposure, 1.5- or 2.0-cm interelectrode spacing, and an electroporation generator. Energy deposition was applied at 2250-3000 V (pulse length, 50-100 MUsec; pulse repetition, 50-100). Ablations were performed under US guidance. Images were obtained during ablation and at defined intervals from 1 minute to 2 hours after the procedure. Zones of ablation were determined at gross and histopathologic examination of samples obtained from animals sacrificed 2-3 hours after IRE. Dimensions of the histologic necrosis zone and US findings were compared and subjected to statistical analysis, including a Student t test and multiple linear regression. RESULTS: Within 20-50 pulse repetitions of IRE energy, the ablation zone appeared as a hypoechoic area with well-demarcated margins. During the next 8-15 minutes, this zone decreased in size from 3.4 cm +/ 0.5 to 2.5 cm +/- 0.4 and became progressively more isoechoic. Subsequently, a peripheral hyperechoic rim measuring 2-7 mm (mean, 4 mm +/- 1) surrounding the isoechoic zone developed 25-90 minutes (mean, 41 minutes +/- 19) after IRE. The final length of the treatment zone, including the rim, increased to 3.3 cm +/- 0.6. The final dimensions of the outer margin of this rim provided greatest accuracy (1.7 mm +/- 0.2) and tightest correlation (r(2) = 0.89) with gross pathologic findings. Histologic examination demonstrated widened sinusoidal spaces that progressively filled with spatially distributed hemorrhagic infiltrate on a bed of hepatocytes with pyknotic nuclei throughout the treatment zone. CONCLUSION: US findings in the acute period after IRE are dynamic and evolve. The ablation zone can be best predicted by measuring the external hyperechoic rim that forms 90-120 minutes after ablation. This rim is possibly attributable to evolving hemorrhagic infiltration via widened sinusoids. PMID- 22106356 TI - Rate of contrast material extravasations and allergic-like reactions: effect of extrinsic warming of low-osmolality iodinated CT contrast material to 37 degrees C. AB - PURPOSE: To retrospectively determine whether extrinsic warming of the low osmolality contrast material iopamidol to 37 degrees C prior to intravenous administration at computed tomography (CT) affects extravasation and allergic like reaction rates. MATERIALS AND METHODS: The need to obtain informed patient consent was waived for this HIPAA-compliant and institutional review board approved analysis. All adverse events related to the intravenous administration of iopamidol during CT examinations occurring 200 days before (period 1) and 200 days after (period 2) the cessation of extrinsic contrast material warming (37 degrees C) for intravenous injections of less than 6 mL/sec at Duke University Medical Center (Durham, NC) were retrospectively reviewed. Adverse event rates were compared by using chi2 statistics. RESULTS: There were 12,682 injections during period 1 (10,831 injections of iopamidol 300 and 1851 injections of iopamidol 370) and 12,138 injections (10, 064 injections of iopamidol 300 and 2074 injections of iopamidol 370) during period 2. Adverse event rates for iopamidol 300 were not affected by extrinsic warming (extravasation rates: 0.30% [32 of 10,831] in period 1 vs 0.23% [23 of 10,064] in period 2, P=.64; allergic like reaction rates: 0.39% [42 of 10,831] in period 1 vs 0.46% [46 of 10,064] in period 2, P=.74; overall adverse events: 0.68% [74 of 10,831] in period 1 vs 0.69% [69 of 10,064] in period 2, P=.99). Discontinuation of extrinsic warming was associated with significantly increased extravasation and overall adverse event rates for iopamidol 370 (extravasation rates: 0.27% [five of 1851] vs 0.87% [18 of 2074], P=.05; allergic-like reaction rates: 0.16% [three of 1851] vs 0.39% [eight of 2074], P=.42; overall adverse events: 0.43% [eight of 1851] vs 1.25% [26 of 2074], P=.02). CONCLUSION: Extrinsic warming (to 37 degrees C) does not appear to affect adverse event rates for intravenous injections of iopamidol 300 of less than 6 mL/sec but is associated with a significant reduction in extravasation and overall adverse event rates for the more viscous iopamidol 370. PMID- 22106357 TI - No benefit for consensus double reading at baseline screening for lung cancer with the use of semiautomated volumetry software. AB - PURPOSE: To retrospectively evaluate the performance of consensus double reading compared with single reading at baseline screening of a lung cancer computed tomography (CT) screening trial. MATERIALS AND METHODS: The study was approved by the Dutch Minister of Health and ethical committees. Written informed consent was obtained from all participants. The benefit of consensus double reading was expressed by the percentage change in cancer detection rate, recall rate, number of additional nodules detected, and change in sensitivity and specificity in 7557 participants. The reference standard was a retrospective analysis of the serial CT scans performed in participants diagnosed with lung cancer during a 2-year period after baseline. Semiautomated volumetric software was used for nodule evaluation. McNemar tests were performed to test statistical significance. In addition, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated and 95% confidence intervals (CIs) constructed. RESULTS: Seventy-four cases of lung cancer were qualified as detectable at baseline. Compared with single reading, consensus double reading did not increase the cancer detection rate (2.7%; 95% CI: -1.0%, 6.4%; P = .50) or change the recall rate (20.6% vs 20.8%, P = .28), but led to the detection of 19.0% (1635 of 8623; 95% CI: 18.0%, 19.9%, P < .01) more nodules. The sensitivity, specificity, PPV, and NPV were 95.9% (71 of 74), 80.2% (6001 of 7483), 4.6% (71 of 1553) and 99.9% (6001 of 6004) for single reading and 98.6% (73 of 74), 80.0% (1497 of 7483), 4.6% (73 of 1570), and 99.9% (5986 of 5987) for consensus double reading, respectively. CONCLUSION: There is no statistically significant benefit for consensus double reading at baseline screening for lung cancer with the use of a nodule management strategy based solely on semiautomated volumetry. PMID- 22106358 TI - US cannot be used to predict the presence or severity of hepatic steatosis in severely obese adolescents. AB - PURPOSE: To evaluate the diagnostic accuracy of ultrasonography (US) for the assessment of hepatic steatosis in severely obese adolescents, with proton magnetic resonance (MR) spectroscopy as the reference standard, and to provide insight on the influence of prevalence on predictive values by calculating positive and negative posttest probabilities. MATERIALS AND METHODS: This prospective study was institutional review board approved. All participants, and/or their legal representatives, gave written informed consent. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the overall presence of steatosis and for the presence of substantial (moderate to severe) steatosis. Positive and negative posttest probabilities were calculated and plotted against prevalence. RESULTS: A total of 104 children (47 male, 57 female) were prospectively included. Mean age was 14.5 years (range, 8.3-18.9 years) and mean age-adjusted standard deviation body mass index (BMI) score (BMI z score) was 3.3 (range, 2.6-4.1). The overall prevalence of hepatic steatosis was 46.2% (48 of 104). Sensitivity of US was 85.4% (41 of 48), specificity was 55.4% (31 of 56), PPV was 62.1% (41 of 66), and NPV was 81.6% (31 of 38). The prevalence of substantial steatosis was 15.4% (16 of 104), with US sensitivity of 75.0% (12 of 16) and specificity of 87.5% (77 of 88). PPV was 52.2% (12 of 23) and NPV was 95.1% (77 of 81). Plotting of posttest probabilities against prevalence for both disease degrees demonstrated how disease prevalence influences US accuracy. CONCLUSION: Positive US results in severely obese adolescents cannot be used to accurately predict the presence and severity of hepatic steatosis, and additional imaging is required. Negative US results exclude the presence of substantial steatosis with acceptable accuracy. Steatosis prevalence differs among specific populations, strongly influencing posttest probabilities. PMID- 22106359 TI - Bosniak category IIF and III cystic renal lesions: outcomes and associations. AB - PURPOSE: To evaluate clinical outcomes, pathologic subtypes, metastatic disease rate, and clinical features associated with malignancy in Bosniak category IIF and III cystic renal lesions. MATERIALS AND METHODS: This retrospective study was institutional review board approved and HIPAA compliant. Informed consent was waived. Radiology and hospital information systems were searched for Bosniak IIF and Bosniak III lesions in computed tomographic (CT) reports from January 1, 1994 to August 31, 2009. Patients 18 years and older with unenhanced and contrast material-enhanced CT results and with lesions either surgically resected or with 1 year or more of surveillance were included. Data recorded were history of renal cell carcinoma, number of renal lesions, presence of a coexistent solid renal mass, surgical pathologic findings, and presence of metastatic disease from a renal malignancy. Sixty-two patients with 69 Bosniak IIF lesions and 131 patients with 144 Bosniak III lesions were identified. Proportions from independent groups were compared by using the Fisher exact test; continuous variables were compared by using a two-tailed two-sample t test or a Wilcoxon two-sample test. RESULTS: The malignancy rate of resected Bosniak IIF lesions was 25% (four of 16) and that for Bosniak III lesions was 54% (58 of 107) (P = .03). Thirteen percent (nine of 69) of Bosniak IIF lesions progressed at follow-up, and 50% (four of eight) of these resected cysts were malignant. History of primary renal malignancy, coexisting Bosniak category IV lesion and/or solid renal mass, and multiplicity of Bosniak III lesions were each associated with an increased malignancy rate in Bosniak III lesions. No patients developed locally advanced or metastatic disease from a Bosniak IIF or III lesion. CONCLUSION: Although the malignancy rate in surgically excised Bosniak IIF and Bosniak III cystic renal lesions was 25% and 54%, respectively, in our study, the malignancy rate was higher in patients with a history of primary renal malignancy or coexisting Bosniak IV lesion and/or solid renal neoplasm. PMID- 22106360 TI - Atrial fibrillation in patients with sick sinus syndrome: the association with PQ interval and percentage of ventricular pacing. AB - AIMS: In the recently published DANPACE trial, incidence of atrial fibrillation (AF) was significantly higher with single-lead atrial (AAIR) pacing than with dual-chamber (DDDR) pacing. The present analysis aimed to evaluate the importance of baseline PQ-interval and percentage of ventricular pacing (VP) on AF. METHODS AND RESULTS: We analysed data on AF during follow-up in 1415 patients included in the DANPACE trial. In a subgroup of 650 patients with DDDR pacemaker, we studied whether %VP, baseline PQ-interval, and programmed atrio-ventricular interval (AVI) was associated with AF burden measured as time in mode-switch (MS) detected by the pacemaker. In the entire DANPACE study population, the incidence of AF was significantly higher in patients with baseline PQ-interval >180 ms (P< 0.001). Among 650 patients with DDDR pacemaker, telemetry data were available for 1.337 +/- 786 days, %VP was 66 +/- 33%, AF was detected at planned follow-up in 160 patients (24.6%), MS occurred in 422 patients (64.9%), and AF burden was marginally higher with baseline PQ-interval >180 ms (P= 0.028). No significant association was detected between %VP and %MS (Spearman's rho 0.056, P= 0.154). %MS was not different between minimal-paced programmed AVI <= 100 and >100 ms (median value), respectively (P= 0.60). CONCLUSIONS: The present study indicates that a longer baseline PQ-interval is associated with an increased risk of AF in patients with sick sinus syndrome. Atrial fibrillation burden is not associated with the percentage of VP or the length of the programmed AVI. PMID- 22106361 TI - Acquired long QT syndrome: as risky as congenital long QT syndrome? PMID- 22106362 TI - Problems in pregnancy. PMID- 22106363 TI - Rise in insurance premiums exceeds growth in earnings in all US states. PMID- 22106364 TI - Europe launches 12 point plan to tackle antimicrobial resistance. PMID- 22106365 TI - Health secretary is to bring back target to reduce numbers waiting 18 weeks for treatment. PMID- 22106366 TI - A new splice variant of the human guanylate-binding protein 3 mediates anti influenza activity through inhibition of viral transcription and replication. AB - Guanylate-binding proteins (GBPs) belong to the family of large GTPases that are induced in response to interferons. GBPs contain an N-terminal globular GTPase domain and a C-terminal alpha-helical regulatory domain that are connected by a short middle domain. Antiviral activity against vesicular stomatitis virus and encephalomyocarditis virus has been shown for hGBP-1; however, no anti-influenza virus properties for GBPs have been described to date. Here we show that hGBP-1 and hGBP-3 possess anti-influenza viral activity. Furthermore, we have identified a novel splice variant of hGBP-3, named hGBP-3DeltaC, with a largely modified C terminal alpha-helical domain. While all three GBP isoforms were up-regulated on influenza virus infection, hGBP-3DeltaC showed the most prominent antiviral activity in epithelial cells. Mutational analysis of hGBPs revealed that the globular domain is the principal antiviral effector domain, and GTP-binding, but not hydrolysis, is necessary for antiviral action. Furthermore, we showed that hGBP-3DeltaC strongly represses the activity of the viral polymerase complex, which results in decreased synthesis of viral vRNA, cRNA, mRNA, and viral proteins, as well. PMID- 22106367 TI - Antigen depot is not required for alum adjuvanticity. AB - Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EalphaGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6-12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12-24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity. PMID- 22106368 TI - Plasmodium falciparum-induced CD36 clustering rapidly strengthens cytoadherence via p130CAS-mediated actin cytoskeletal rearrangement. AB - The adhesion of infected red blood cells (IRBCs) to microvascular endothelium is critical in the pathogenesis of severe malaria. Here we used atomic force and confocal microscopy to examine the adhesive forces between IRBCs and human dermal microvascular endothelial cells. Initial contact of the cells generated a mean +/ sd adhesion force of 167 +/- 208 pN from the formation of single or multiple bonds with CD36. The strength of adhesion increased by 5- to 6-fold within minutes of contact through a signaling pathway initiated by CD36 ligation by live IRBCs, or polystyrene beads coated with anti-CD36 or PpMC-179, a recombinant peptide representing the minimal binding domain of the parasite ligand PfEMP1 to CD36. Engagement of CD36 led to localized phosphorylation of Src family kinases and the adaptor protein p130CAS, resulting in actin recruitment and CD36 clustering by 50-60% of adherent beads. Uninfected red blood cells or IgG-coated beads had no effect. Inhibition of the increase in adhesive strength by the Src family kinase inhibitor PP1 or gene silencing of p130CAS decreased adhesion by 39 +/- 12 and 48 +/- 20%, respectively, at 10 dyn/cm(2) in a flow chamber assay. Modulation of adhesive strength at PfEMP1-CD36-actin cytoskeleton synapses could be a novel target for antiadhesive therapy. PMID- 22106369 TI - Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. AB - The discovery of substantial amounts of 5-hydroxymethylcytosine (5hmC), formed by the oxidation of 5-methylcytosine (5mC), in various mouse tissues and human embryonic stem (ES) cells has necessitated a reevaluation of our knowledge of 5mC/5hmC patterns and functions in mammalian cells. Here, we investigate the tissue specificity of both the global levels and locus-specific distribution of 5hmC in several human tissues and cell lines. We find that global 5hmC content of normal human tissues is highly variable, does not correlate with global 5mC content, and decreases rapidly as cells from normal tissue adapt to cell culture. Using tiling microarrays to map 5hmC levels in DNA from normal human tissues, we find that 5hmC patterns are tissue specific; unsupervised hierarchical clustering based solely on 5hmC patterns groups independent biological samples by tissue type. Moreover, in agreement with previous studies, we find 5hmC associated primarily, but not exclusively, with the body of transcribed genes, and that within these genes 5hmC levels are positively correlated with transcription levels. However, using quantitative 5hmC-qPCR, we find that the absolute levels of 5hmC for any given gene are primarily determined by tissue type, gene expression having a secondary influence on 5hmC levels. That is, a gene transcribed at a similar level in several different tissues may have vastly different levels of 5hmC (>20-fold) dependent on tissue type. Our findings highlight tissue type as a major modifier of 5hmC levels in expressed genes and emphasize the importance of using quantitative analyses in the study of 5hmC levels. PMID- 22106370 TI - Analysis of Arabidopsis genome-wide variations before and after meiosis and meiotic recombination by resequencing Landsberg erecta and all four products of a single meiosis. AB - Meiotic recombination, including crossovers (COs) and gene conversions (GCs), impacts natural variation and is an important evolutionary force. COs increase genetic diversity by redistributing existing variation, whereas GCs can alter allelic frequency. Here, we sequenced Arabidopsis Landsberg erecta (Ler) and two sets of all four meiotic products from a Columbia (Col)/Ler hybrid to investigate genome-wide variation and meiotic recombination at nucleotide resolution. Comparing Ler and Col sequences uncovered 349,171 Single Nucleotide Polymorphisms (SNPs), 58,085 small and 2315 large insertions/deletions (indels), with highly correlated genome-wide distributions of SNPs, and small indels. A total of 443 genes have at least 10 nonsynonymous substitutions in protein-coding regions, with enrichment for disease-resistance genes. Another 316 genes are affected by large indels, including 130 genes with complete deletion of coding regions in Ler. Using the Arabidopsis qrt1 mutant, two sets of four meiotic products were generated and analyzed by sequencing for meiotic recombination, representing the first tetrad analysis with whole-genome sequencing in a nonfungal species. We detected 18 COs, six of which had an associated GC event, and four GCs without COs (NCOs), and revealed that Arabidopsis GCs are likely fewer and with shorter tracts than those in yeast. Meiotic recombination and chromosome assortment events dramatically redistributed genome variation in meiotic products, contributing to population diversity. In particular, meiosis provides a rapid mechanism to generate copy-number variation (CNV) of sequences that have different chromosomal positions in Col and Ler. PMID- 22106371 TI - How have health promotion frameworks considered gender? AB - This paper provides an overview of five key internationally recognized health promotion frameworks and assesses their consideration of gender. This analysis was conducted as part of the Promoting Health in Women project, a Canadian initiative focused on generating a framework for effective health promotion for women. To date, no review of health promotion frameworks has specifically focused on assessing the treatment of gender. This analysis draws on a comprehensive literature review that covered available literature on gender and health promotion frameworks published internationally between 1974 and 2010. Analysis of five key health promotion frameworks revealed that although gender was at times mentioned as a determinant of health, gender was never identified and integrated as a factor critical to successful health promotion. This superficial attention to the role of gender in health promotion is problematic as it limits our capacity to understand how gender influences health, health contexts and health promotion, as well as our ability to integrate gender into future comprehensive health promotion strategies. PMID- 22106372 TI - Inherited cardiomyopathies. PMID- 22106373 TI - Dementia patient's euthanasia was lawful, say Dutch authorities. PMID- 22106374 TI - Attacks on refugee camps escalate humanitarian crisis in South Sudan. PMID- 22106375 TI - Commissioners of care for elderly people are "flying blind," says one senior commissioner. PMID- 22106376 TI - Army medical staff plug shortages in accident and emergency department at Stafford Hospital. PMID- 22106377 TI - Interim analyses from a randomised controlled trial to improve visual processing speed in older adults: the Iowa Healthy and Active Minds Study. AB - Objectives The Iowa Healthy and Active Minds Study is a four-arm randomised controlled trial of a visual processing speed training programme (Road Tour). This article presents the preplanned interim results immediately after training (6-8 weeks post-randomisation) for the primary outcome. Design Within two age strata (50-64 vs >=65), 681 men and women attending general internal and family medicine clinics were randomised to four training groups: (1) supervised, on-site standard (10 h) dose of Road Tour training; (2) supervised, on-site standard dose of Road Tour training with 4 h of subsequent booster training scheduled to occur at 11 months post-randomisation (ie, no booster training had occurred at the time of this interim analysis); (3) supervised, on-site standard dose of attention control (crossword puzzles) training and (4) self-administered, at-home standard dose of Road Tour training. The primary outcome was the Useful Field of View (UFOV) test. Three intent-to-treat interim analyses were conducted, including (1) multiple linear regression models of composite UFOV scores using Blom rank transformations, (2) general linear mixed effects models and (3) multiple logistic regression models among the 620 participants (91%) with complete data. Results In the linear regression analyses of both age strata, random assignment to any Road Tour training group versus the attention control group was significant (p<0.001), with an effect size of -0.558 (adjusted for the Blom rank transformed UFOV score at randomisation). Similar results were obtained for each Road Tour group and within each age stratum and from the general linear and logistic regression models. Conclusions Assignment to a standard dose of Road Tour training yielded medium-sized post-training improvements in visual processing speed. Road Tour was equally effective whether administered under laboratory supervision or self-administered in the patient's home and for participants in both age strata (50-64 vs >=65). Clinical trial registration number NCT01165463. PMID- 22106378 TI - TOF-Watch(R) monitor: failure to calculate the train-of-four ratio in the absence of baseline calibration in anaesthetized dogs. AB - BACKGROUND: TOF-Watch((r)) monitors are designed to display train-of-four (TOF) count when neuromuscular block is intense, and to display TOF ratio when it is less intense. In dogs recovering from non-depolarizing neuromuscular block, when all four twitches are easily visible and apparently of similar magnitude, TOF Watch((r)) monitors often display TOF counts and not TOF ratios, as would be expected. We have never encountered this problem when the monitor was calibrated before neuromuscular blocking agent administration. METHODS: Fourteen healthy female dogs undergoing ovariohysterectomy were investigated. Recovery from neuromuscular block was assessed with a calibrated TOF-Watch SX((r)) monitor. When the TOF ratio returned to 90%, the TOF-Watch SX((r)) was replaced with an uncalibrated TOF-Watch((r)) monitor. The output obtained from the uncalibrated TOF-Watch((r)) was compared with that of the calibrated device. RESULTS: The median TOF ratio measured by the calibrated TOF-Watch SX((r)) unit at recovery was 91 (86-100)% (n=14). The uncalibrated TOF-Watch((r)) monitor displayed TOF counts in six dogs [2 (0, 4)] and TOF ratios in the remaining eight dogs [91 (79, 98)%], that is, the uncalibrated device failed to display appropriately >40% of the time. CONCLUSIONS: TOF-Watch((r)) monitors must be calibrated before neuromuscular blocking agents are administered to dogs. When these devices are not so calibrated, they default to a reference value for twitch magnitude that was defined in healthy adult people. Even though neuromuscular transmission was restored in these dogs, we surmise that they did not achieve the default reference value, causing the monitor to display TOF counts rather than TOF ratios. PMID- 22106379 TI - The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis. AB - Mutations in the never-in-mitosis A-related kinase, Nek8, are associated with cystic kidney disease in both humans and mice, with Nek8 being the NPHP9 gene in the human juvenile cystic kidney disease, nephronophthisis. Human Nek8/NPHP9 localizes to centrosomes and the proximal region of cilia in dividing and ciliated cells, respectively. However, the regulation of Nek8 kinase activity, as well as its role in ciliogenesis, remains to be defined. Here, by establishing Nek8 kinase assays, we first demonstrate that the localization of Nek8 to centrosomes and cilia is dependent on both kinase activity and the C-terminal non catalytic RCC1 domain. The kinase domain alone is active, but does not localize correctly, while the RCC1 domain localizes correctly and can be phosphorylated by Nek8. We propose that centrosome recruitment is mediated by the RCC1 domain, but requires a conformational change in the full-length protein that is promoted by autophosphorylation. Interestingly, three human NPHP9-associated mutants retain full kinase activity. However, only two of these, L330F and A497P, localize correctly, suggesting that the third mutant, H425Y, disrupts a centrosome targeting sequence in the RCC1 domain. Importantly, we find that induction of ciliogenesis upon cell cycle exit is accompanied by both activation and proteasomal degradation of Nek8, and that activation is dependent upon phosphorylation within the catalytic domain. Taken together, these findings reveal important insights into the mechanisms through which Nek8 activity and localization are regulated during ciliogenesis. PMID- 22106380 TI - BLM helicase facilitates RNA polymerase I-mediated ribosomal RNA transcription. AB - Bloom's syndrome (BS) is an autosomal recessive disorder that is invariably characterized by severe growth retardation and cancer predisposition. The Bloom's syndrome helicase (BLM), mutations of which lead to BS, localizes to promyelocytic leukemia protein bodies and to the nucleolus of the cell, the site of RNA polymerase I-mediated ribosomal RNA (rRNA) transcription. rRNA transcription is fundamental for ribosome biogenesis and therefore protein synthesis, cellular growth and proliferation; its inhibition limits cellular growth and proliferation as well as bodily growth. We report that nucleolar BLM facilitates RNA polymerase I-mediated rRNA transcription. Immunofluorescence studies demonstrate the dependance of BLM nucleolar localization upon ongoing RNA polymerase I-mediated rRNA transcription. In vivo protein co-immunoprecipitation demonstrates that BLM interacts with RPA194, a subunit of RNA polymerase I. (3)H uridine pulse-chase assays demonstrate that BLM expression is required for efficient rRNA transcription. In vitro helicase assays demonstrate that BLM unwinds GC-rich rDNA-like substrates that form in the nucleolus and normally inhibit progression of the RNA polymerase I transcription complex. These studies suggest that nucleolar BLM modulates rDNA structures in association with RNA polymerase I to facilitate RNA polymerase I-mediated rRNA transcription. Given the intricate relationship between rDNA metabolism and growth, our data may help in understanding the etiology of proportional dwarfism in BS. PMID- 22106382 TI - Draft genome sequence of the Coccolithovirus Emiliania huxleyi virus 203. AB - The Coccolithoviridae are a recently discovered group of viruses that infect the marine coccolithophorid Emiliania huxleyi. Emiliania huxleyi virus 203 (EhV-203) has a 160- to 180-nm-diameter icosahedral structure and a genome of approximately 400 kbp, consisting of 464 coding sequences (CDSs). Here we describe the genomic features of EhV-203 together with a draft genome sequence and its annotation, highlighting the homology and heterogeneity of this genome in comparison with the EhV-86 reference genome. PMID- 22106383 TI - Complete genome sequence of Salmonella bacteriophage SPN3US. AB - Salmonella bacteriophage SPN3US was isolated from a chicken fecal sample. It is a virulent phage belonging to the Myoviridae family and showing effective inhibition of Salmonella enterica and a few Escherichia coli O157:H7 strains. Here we announce the completely sequenced first genome of a Salmonella phage using flagella as receptors. It is the largest genome among Salmonella phages sequenced to date, and major findings from its annotation are described. PMID- 22106384 TI - Complete genomic sequence of bluetongue virus serotype 16 from China. AB - We report here the complete genomic sequence of the Chinese bluetongue virus serotype 16 (BTV16) strain BN96/16. This work is the first to document the complete genomic sequence (segments 1 to 10) of a BTV16 strain. The sequence information provided herein will help determine the geographic origin of BTV16 and define the phylogenetic relationship of BTV16 to other BTV strains. PMID- 22106385 TI - Complete genome sequence of a novel paramyxovirus, Tailam virus, discovered in Sikkim rats. AB - We discovered a novel paramyxovirus, Tailam virus, of subfamily Paramyxovirinae, in the kidneys and spleens of Sikkim rats. The coding potential of its genome (3' N-P/V/C-M-F-SH-TM-G-L-5') is similar to those of Beilong virus and J virus, with putative proteins having 59.1 to 94.4% and 23.8 to 80.1% amino acid identities to those of Beilong virus and J virus, respectively. PMID- 22106386 TI - The social media revolution. AB - BACKGROUND: The growing popularity and use of social media tools such as Facebook, YouTube, Twitter, blogging, and wikis have led to a social media revolution. Given this widespread influence, it is important for educators, administrators, and technologists to understand the risks of using social media in the classroom and workplace. OBJECTIVE: To investigate popular social media sites and their effect on radiologic technology education and business practices. METHOD: A comprehensive search of literature was performed to examine social media and its applications in education, health care, and business. RESULTS: Social media use is on the rise, affecting all aspects of mainstream society. Leaders in the radiologic sciences should be familiar with social media and cognizant of its risks. CONCLUSION: Future studies regarding social media use in the radiologic sciences are necessary to determine its effect on the radiologic science community. PMID- 22106387 TI - Review of teaching methods and critical thinking skills. AB - BACKGROUND: Critical information is needed to inform radiation science educators regarding successful critical thinking educational strategies. From an evidence based research perspective, systematic reviews are identified as the most current and highest level of evidence. Analysis at this high level is crucial in analyzing those teaching methods most appropriate to the development of critical thinking skills. OBJECTIVES: To conduct a systematic literature review to identify teaching methods that demonstrate a positive effect on the development of students' critical thinking skills and to identify how these teaching strategies can best translate to radiologic science educational programs. METHODS: A comprehensive literature search was conducted resulting in an assessment of 59 full reports. Nineteen of the 59 reports met inclusion criteria and were reviewed based on the level of evidence presented. Inclusion criteria included studies conducted in the past 10 years on sample sizes of 20 or more individuals demonstrating use of specific teaching interventions for 5 to 36 months in postsecondary health-related educational programs. RESULTS: The majority of the research focused on problem-based learning (PBL) requiring standardized small-group activities. Six of the 19 studies focused on PBL and demonstrated significant differences in student critical thinking scores. CONCLUSION: PBL, as described in the nursing literature, is an effective teaching method that should be used in radiation science education. PMID- 22106388 TI - Academic dishonesty and unprofessional behavior. AB - PURPOSE: To investigate differences in radiologic science student and faculty perceptions of academic dishonesty and unprofessional behavior. METHODS: Radiologic science faculty and students were questioned about their perceptions of academic dishonesty and unprofessional behavior using ethical scenarios in an electronic survey format. RESULTS: Significant differences occurred between faculty and student values regarding the seriousness of cheating and unprofessional behaviors. Faculty viewed cheating and unprofessional behaviors as more serious than students. Faculty and student self-reports of cheating behavior demonstrated no significant differences; however, significant differences existed in self-reported incidences of unprofessional behavior. CONCLUSION: Faculty and students differed in their values and participation related to cheating and unprofessional behaviors. Efforts should be directed toward bridging the gap between faculty and student perceptions. PMID- 22106389 TI - Ergonomics in radiology. AB - Radiologic technologists and radiologist assistants are at risk for developing a variety of work-related musculoskeletal injuries, especially those caused by repeated strain on the upper extremities and lower back. This article examines the types of activities most likely to cause on-the-job injuries in technologists, such as transferring, positioning, and transporting patients, as well as the types of equipment that tend to be associated with injury, including ultrasound probes, heavy protective garments, and picture archiving and communications system workstations. Psychosocial factors also are explored, along with management's role in minimizing work-related injuries. Practical techniques for preventing injury are emphasized throughout. PMID- 22106390 TI - Disorders of the cervical spine. AB - The cervical spine is composed of 7 vertebrae that support the head, surround and protect the spinal cord and spinal nerves in the neck, and provide attachment sites for muscles and ligaments. Although the cervical spine remains immature at birth and continues to develop during childhood, some severe congenital anomalies are discovered early in life, while other anomalies cause gradual degeneration and may not be detected until the second decade of life or later. Some of these anomalies can cause deformity, organ disease, paraplegia, or even death. This article discusses congenital development of the cervical spine, congenital spinal anomalies, cervical spine instability, and degenerative cervical spine disorders. Diagnosis, treatment options, and imaging studies also are examined. PMID- 22106391 TI - Blood artifacts on CR images. PMID- 22106392 TI - How to land that grant. PMID- 22106393 TI - Digital dependency. PMID- 22106394 TI - Exposure technique documentation. PMID- 22106395 TI - Promote active learning with iPads. PMID- 22106396 TI - Computed tomography. PMID- 22106397 TI - Managing transition to a hybrid operating room. AB - Managers of interventional radiology departments and medical imaging personnel who work in surgical suites deal with regular technical innovations in their work, but large-scale innovations seldom come along that transform markets and require massive architectural, training, and technological changes. The hybrid interventional/operating suite is one such massive change. This article presents an overview of the transition to hybrid procedures and designs, the benefits and challenges of the new delivery method, and change management issues for managers of cardiovascular and vascular interventional departments. PMID- 22106398 TI - In the Medical Investigator's office. PMID- 22106399 TI - Circulating insulin-like growth factors and IGF-binding proteins in PSA-detected prostate cancer: the large case-control study ProtecT. AB - Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF-binding proteins (IGFBP) in cancers detected by the prostate-specific antigen (PSA) test. Here, we report the findings of a U.K.-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50 to 69 years from 2002 to 2009. Participants with an elevated level of PSA (>=3.0 ng/mL) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per SD increase: 1.16; 95% CI: 1.08-1.24; P(trend) < 0.001), IGFBP-2 (1.18; 1.06-1.31; P(trend) < 0.01) and IGFBP-3 (1.27; 1.19-1.36; P(trend) < 0.001), but not IGF-I (0.99; 0.93-1.04; P(trend) = 0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99; 0.91-1.08; P(trend) = 0.62) and IGF-I was inversely associated (0.85; 0.79-0.91; P(trend) < 0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP 2, and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. Although our findings for IGF-I agree with previous results from PSA screening trials, they contrast with positive associations in routinely detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might, nonetheless, prevent its progression. PMID- 22106400 TI - Dual role of microsomal prostaglandin E synthase 1 in chronic kidney disease. PMID- 22106402 TI - Arterial baroreflex modulation of sympathetic activity and arterial wall properties: new evidence. PMID- 22106401 TI - Acute beta-adrenergic blockade increases aortic wave reflection in young men and women: differing mechanisms between sexes. AB - Acute beta-adrenergic blockade increases aortic wave reflection; however, the mechanisms remain unclear. Evidence suggests that beta-adrenergic receptor sensitivity in the peripheral vasculature differs between sexes. Therefore, the goal of this study was to examine whether beta-adrenergic blockade alters aortic wave reflection to a similar extent in young men and women. In 31 subjects (16 men and 15 women; 26+/-1 years) noninvasive aortic pressure waveforms were synthesized from high-fidelity radial pressure waveforms via applanation tonometry before and during systemic beta-blockade (0.25 mg/kg bolus, followed by 0.004 mg/kg per minute of continuous infusion of propranolol). beta-Blockade increased aortic augmentation index and wave reflection amplitude (aortic augmented pressure) in both sexes (P<0.01). Although the increase in augmentation index was not significantly different between sexes (7.5+/-1.1% versus 4.6+/ 1.5%; P=0.07), the increase in aortic augmented pressure was greater in women compared with men (2.8+/-0.5 versus 1.4+/-0.5 mm Hg; P<0.05). Aortic augmentation index adjusted for a heart rate of 75 bp increased in women (4.1+/-1.1%; P<0.05) after beta-blockade, whereas it was unchanged in men (0.6+/-1.3%; P=0.33). Moreover, the change in aortic augmentation index was inversely associated with the change in heart rate only in men (r=-0.54; P<0.05). Our data suggest that aortic wave reflection is increased to a greater extent in women after systemic beta-blockade, and enhanced aortic wave reflection appears to be mediated by a reduced heart rate in men, whereas the mechanism is unclear in women. PMID- 22106403 TI - Relationship between sympathetic baroreflex sensitivity and arterial stiffness in elderly men and women. AB - Previous human studies have shown that large-artery stiffness contributes to an age-related decrease in cardiovagal baroreflex sensitivity. Whether this is also true with sympathetic baroreflex sensitivity is unknown. We tested the hypothesis that sympathetic baroreflex sensitivity is associated with the stiffness of baroreceptor segments (the carotid artery and the aorta) in elderly individuals and that sex affects this relationship. Sympathetic baroreflex sensitivity was assessed from the spontaneous changes in beat-by-beat diastolic pressure and corresponding muscle sympathetic nerve activity (microneurography) during supine rest in 30 men (mean+/-SEM: 69+/-1 years) and 31 women (68+/-1 years). Carotid artery stiffness (B-mode ultrasonography) and aortic stiffness (MRI) were also determined. We found that elderly women had lower sympathetic baroreflex sensitivity than elderly men (-2.33+/-0.25 versus -3.32+/-0.25 bursts . 100 beats(-1) . mm Hg(-1); P=0.007). beta-Stiffness indices of the carotid artery and the aorta were greater in elderly women than in men (6.68+/-0.48 versus 5.10+/ 0.50 and 4.03+/-0.47 versus 2.68+/-0.42; both P<0.050). Sympathetic baroreflex sensitivity was inversely correlated with carotid artery stiffness in both men and women (r=0.49 and 0.50; both P<0.05), whereas this relation was shifted in parallel upward (toward a reduced sensitivity) in women with no changes in the slope (0.26 versus 0.24 arbitrary units). Sympathetic baroreflex sensitivity and aortic stiffness showed similar trends. Thus, barosensory artery stiffness seems to be one independent determinant of sympathetic baroreflex sensitivity in elderly men and women. The lower sympathetic baroreflex sensitivity in elderly women may predispose them to an increased prevalence of hypertension. PMID- 22106404 TI - Microsomal prostaglandin E synthase 1 deletion retards renal disease progression but exacerbates anemia in mice with renal mass reduction. AB - Microsomal prostaglandin E synthase 1 (mPGES-1) is a cytokine-inducible enzyme responsible for generation of prostaglandin E(2) (PGE(2)) during the inflammatory response. In the present study, we investigated the role of mPGES-1 in the development of chronic renal failure in mice with 5/6 nephrectomy (Nx). After 4 weeks of Nx, wild-type mice with renal mass reduction exhibited increased blood urea nitrogen, plasma creatinine and phosphorus concentrations, and defective urine concentrating capability, all of which were significantly attenuated by mPGES-1 deletion. The Nx wild-type mice developed a 2.6-fold increase in urinary albumin excretion, accompanied by glomerulosclerosis and reduction of nephrin and wild-type 1 expression in the remnant kidney. In contrast, the Nx KO mice had normal albuminuria with improvement of glomerular injury. Nx-induced increases in circulating and renal tumor necrosis factor 1alpha and renal interleukin 1beta and monocyte chemoattractant protein 1 expressions were all remarkably attenuated or abolished by mPGES-1 deletion. Paradoxically, the Nx knockout mice developed worsened anemia, accompanied by impaired erythropoietin synthesis. The coinduction of mPGES-1 and cyclooxygenase 2 but not cyclooxygenase 1 mRNA expressions, along with increased PGE(2) synthesis, was demonstrated in the remnant kidney of wild-type mice. mPGES-1 deletion remarkably reduced renal PGE(2) content and urinary PGE(2) excretion after renal ablation but had a limited effect on the baseline PGE(2) production. We conclude that mPGES-1 deletion ameliorates chronic renal failure in the mouse model of renal mass reduction, and mPGES-1 deletion paradoxically exacerbates anemia in this model likely via suppression of erythropoietin synthesis. PMID- 22106405 TI - Angiotensin II-induced hypertension is modulated by nuclear factor-kappaBin the paraventricular nucleus. AB - Hypertension is considered a low-grade inflammatory condition, and understanding the role of transcription factors in guiding this response is pertinent. A prominent transcription factor that governs inflammatory responses and has become a focal point in hypertensive research is nuclear factor-kappaB (NFkappaB). Within the hypothalamic paraventricular nucleus (PVN), a known brain cardioregulatory center, NFkappaB becomes potentially even more important in ultimately coordinating the systemic hypertensive response. To definitively demonstrate the role of NFkappaB in the neurogenic hypertensive response, we hypothesized that PVN NFkappaB blockade would attenuate angiotensin II-induced hypertension. Twelve-week-old male Sprague-Dawley rats were implanted with radiotelemetry probes for blood pressure measurement and allowed a 7-day recovery. After baseline blood pressure recordings, rats were administered either continuous NFkappaB decoy oligodeoxynucleotide infusion or microinjection of a serine mutated adenoviral inhibitory-kappaB vector, or their respective controls, bilaterally into the PVN to inhibit NFkappaB at two levels of its activation pathway. Simultaneously, rats were implanted subcutaneously with an angiotensin II or saline-filled 14-day osmotic minipump. After the 2-week treatments, rats were euthanized and brain tissues collected for PVN analysis. Bilaterally inhibited NFkappaB rats had a decrease in blood pressure, NFkappaB p65 subunit activity, proinflammatory cytokines, and reactive oxygen species, including the angiotensin II type 1 receptor, angiotensin-converting enzyme, tumor necrosis factor, and superoxide in angiotensin II-treated rats. Moreover, after NFkappaB blockade, key protective antihypertensive renin-angiotensin system components were upregulated. This demonstrates the important role that transcription factor NFkappaB plays within the PVN in modulating and perpetuating the hypertensive response via renin-angiotensin system modulation. PMID- 22106406 TI - Mammalian foetal ovarian development: consequences for health and disease. AB - The development of a normal ovary during foetal life is essential for the production and ovulation of a high-quality oocyte in adult life. Early in embryogenesis, the primordial germ cells (PGCs) migrate to and colonise the genital ridges. Once the PGCs reach the bipotential gonad, the absence of the sex determining region on the Y chromosome (SRY) gene and the presence of female specific genes ensure that the indifferent gonad takes the female pathway and an ovary forms. PGCs enter into meiosis, transform into oogonia and ultimately give rise to oocytes that are later surrounded by granulosa cells to form primordial follicles. Various genes and signals are implicated in germ and somatic cell development, leading to successful follicle formation and normal ovarian development. This review focuses on the differentiation events, cellular processes and molecular mechanisms essential for foetal ovarian development in the mice and humans. A better understanding of these early cellular and morphological events will facilitate further study into the regulation of oocyte development, manifestation of ovarian disease and basis of female infertility. PMID- 22106407 TI - The effects of FSH and activin A on follicle development in vitro. AB - Numerous studies have reported on the roles of activins in gonadal regulation; however, little is known about their specific roles in early folliculogenesis. Ovarian follicular growth was investigated in 10-day cultures of day 4 postnatal whole ovaries treated with activin A (ActA; 50 ng/ml), with or without FSH (100 ng/ml) in vitro. We hypothesized that treatment with ActA+/-FSH would affect rates of growth and atresia in follicles. None of the treatments affected primordial follicle activation, and antral follicles were not observed after 10 days in culture. Primordial follicle numbers from all treatment groups were ~20% of those in day 4 fresh ovaries, indicating that activation had occurred. In the presence of ActA, preantral follicle numbers increased significantly (P<0.0001). ActA alone decreased the proportion of atretic follicles in the primary and preantral classes, whereas the combined treatment of ActA+FSH increased the proportion of atretic preantral oocytes. Real-time PCR analysis revealed that follistatin, FSH receptor, and activin betaA and betaB subunits were all expressed at significantly higher levels in the ActA-only treated group but not in the ActA+FSH group. Here, we report novel findings supporting the role of FSH in primordial follicle survival through an action on apoptosis and a stimulatory role of ActA in the primordial to primary and preantral stages of follicle development, suggesting an inhibitory action of activin on oocyte apoptosis. PMID- 22106408 TI - Active immunization against the proregions of GDF9 or BMP15 alters ovulation rate and litter size in mice. AB - The transforming growth factor beta (TGFB) superfamily proteins bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), are essential for mammalian fertility. Recent in vitro evidence suggests that the proregions of mouse BMP15 and GDF9 interact with their mature proteins after secretion. In this study, we have actively immunized mice against these proregions to test the potential in vivo roles on fertility. Mice were immunized with either N- or C-terminus proregion peptides of BMP15 or GDF9, or a full length GDF9 proregion protein, each conjugated to keyhole limpet hemocyanin (KLH). For each immunization group, ovaries were collected from ten mice for histology after immunization, while a further 20 mice were allowed to breed and litter sizes were counted. To link the ovulation and fertility data of these two experimental end points, mice were joined during the time period identified by histology as being the ovulatory period resulting in to the corpora lutea (CL) counted. Antibody titers in sera increased throughout the study period, with no cross-reactivity observed between BMP15 and GDF9 sera and antigens. Compared with KLH controls, mice immunized with the N-terminus BMP15 proregion peptide had ovaries with fewer CL (P<0.05) and produced smaller litters (P<0.05). In contrast, mice immunized with the full-length GDF9 proregion not only had more CL (P<0.01) but also had significantly smaller litter sizes (P<0.01). None of the treatments affected the number of antral follicles per ovary. These findings are consistent with the hypothesis that the proregions of BMP15 and GDF9, after secretion by the oocyte, have physiologically important roles in regulating ovulation rate and litter size in mice. PMID- 22106409 TI - Self-interaction, nucleic acid binding, and nucleic acid chaperone activities are unexpectedly retained in the unique ORF1p of zebrafish LINE. AB - Long interspersed elements (LINEs) are mobile elements that comprise a large proportion of many eukaryotic genomes. Although some LINE-encoded open reading frame 1 proteins (ORF1ps) were suggested to be required for LINE mobilization through binding to their RNA, their general role is not known. The ZfL2-1 ORF1p, which belongs to the esterase-type ORF1p, is especially interesting because it has no known RNA-binding domain. Here we demonstrate that ZfL2-1 ORF1p has all the canonical activities associated with known ORF1ps, including self interaction, nucleic acid binding, and nucleic acid chaperone activities. In particular, we showed that its chaperone activity is reversible, suggesting that the chaperone activities of many other ORF1ps are also reversible. From this discovery, we propose that LINE ORF1ps play a general role in LINE integration by forming a complex with LINE RNA and rearranging its conformation. PMID- 22106410 TI - Cells lacking Rieske iron-sulfur protein have a reactive oxygen species associated decrease in respiratory complexes I and IV. AB - Mitochondrial respiratory complexes of the electron transport chain (CI, CIII, and CIV) can be assembled into larger structures forming supercomplexes. We analyzed the assembly/stability of respiratory complexes in mouse lung fibroblasts lacking the Rieske iron-sulfur protein (RISP knockout [KO]cells), one of the catalytic subunits of CIII. In the absence of RISP, most of the remaining CIII subunits were able to assemble into a large precomplex that lacked enzymatic activity. CI, CIV, and supercomplexes were decreased in the RISP-deficient cells. Reintroduction of RISP into KO cells restored CIII activity and increased the levels of active CI, CIV, and supercomplexes. We found that hypoxia (1% O(2)) resulted in increased levels of CI, CIV, and supercomplex assembly in RISP KO cells. In addition, treatment of control cells with different oxidative phosphorylation (OXPHOS) inhibitors showed that compounds known to generate reactive oxygen species (ROS) (e.g., antimycin A and oligomycin) had a negative impact on CI and supercomplex levels. Accordingly, a superoxide dismutase (SOD) mimetic compound and SOD2 overexpression provided a partial increase in supercomplex levels in the RISP KO cells. Our data suggest that the stability of CI, CIV, and supercomplexes is regulated by ROS in the context of defective oxidative phosphorylation. PMID- 22106411 TI - Protein tyrosine phosphatase-like A regulates myoblast proliferation and differentiation through MyoG and the cell cycling signaling pathway. AB - Protein tyrosine phosphatase-like A (PTPLa) has been implicated in skeletal myogenesis and cardiogenesis. Mutations in PTPLa correlated with arrhythmogenic right ventricular dysplasia in humans and congenital centronuclear myopathy with severe hypotonia in dogs. The molecular mechanisms of PTPLa in myogenesis are unknown. In this report, we demonstrate that PTPLa is required for myoblast growth and differentiation. The cells lacking PTPLa remained immature and failed to differentiate into mature myotubes. The repressed MyoG expression was responsible for the impaired myoblast differentiation. Meanwhile, impeded cell growth, with an obvious S-phase arrest and compromised G(2)/M transition, was observed in PTPLa-deficient myoblasts. Further study demonstrated that the upregulation of cyclin D1 and cyclin E2 complexes, along with a compromised G(2)/M transition due to the decreased CDK1 (cyclin-dependent kinase 1) activity and upregulated p21, contributed to the mutant cell S-phase arrest and eventually led to the retarded cell growth. Finally, the transcriptional regulation of the PTPLa gene was explored. We identified PTPLa as a new target gene of the serum response factor (SRF). Skeletal- and cardiac-muscle-specific SRF knockouts resulted in significant decreases in PTPLa expression, suggesting a conserved transcriptional regulation of the PTPLa gene in mice. PMID- 22106412 TI - Cdc7-Dbf4 is a gene-specific regulator of meiotic transcription in yeast. AB - Meiosis divides the chromosome number of the cell in half by having two rounds of chromosome segregation follow a single round of chromosome duplication. The first meiotic division is unique in that homologous pairs of sister chromatids segregate to opposite poles. Recent work in budding and fission yeast has shown that the cell cycle kinase, Cdc7-Dbf4, is required for many meiosis-specific chromosomal functions necessary for proper disjunction at meiosis I. This work reveals another role for Cdc7 in meiosis as a gene-specific regulator of the global transcription factor, Ndt80, which is required for exit from pachytene and entry into the meiotic divisions in budding yeast. Cdc7-Dbf4 promotes NDT80 transcription by relieving repression mediated by a complex of Sum1, Rfm1, and a histone deacetylase, Hst1. Sum1 exhibits meiosis-specific Cdc7-dependent phosphorylation, and mass spectrometry analysis reveals a dynamic and complex pattern of phosphorylation events, including four constitutive cyclin-dependent kinase (Cdk1) sites and 11 meiosis-specific Cdc7-Dbf4-dependent sites. Analysis of various phosphorylation site mutants suggests that Cdc7 functions with both Cdk1 and the meiosis-specific kinase Ime2 to control this critical transition point during meiosis. PMID- 22106413 TI - Dicer is dispensable for asymmetric RISC loading in mammals. AB - In flies, asymmetric loading of small RNA duplexes into Argonaute2-containing RNA induced silencing complex (Ago2-RISC) requires Dicer-2/R2D2 heterodimer, which acts as a protein sensor for the thermodynamic stabilities of the ends of small RNA duplexes. However, the mechanism of small RNA asymmetry sensing in mammalian RISC assembly remains obscure. Here, we quantitatively examined RISC assembly and target silencing activity in the presence or absence of Dicer in mammals. Our data show that, unlike the well-characterized fly Ago2-RISC assembly pathway, mammalian Dicer is dispensable for asymmetric RISC loading in vivo and in vitro. PMID- 22106414 TI - Down-regulation of the transcription factor ZAC1 upon pre- and postconditioning protects against I/R injury in the mouse myocardium. AB - AIMS: Myocardial infarction leads to heart failure and death. Ischaemic preconditioning (PreC) and postconditioning (PostC) reduce infarct size in animal models and human. Zac1 was identified as the only gene related to apoptosis and jointly down-regulated upon PreC and PostC. The aim of our study was to investigate the role of Zac1 down-regulation during ischaemia-reperfusion (I/R) in vivo. METHODS AND RESULTS: C57BL/6 mice were submitted to myocardial I/R injury, PreC, or PostC protocols. QPCR and immunochemistry showed that Zac1 expression was down-regulated both at the transcriptional and the protein levels upon PreC and PostC. Zac1(-/-) Knockout mice (n = 7) developed smaller infarcts (54%) than Zac1(+/+) littermates (n = 8) and decreased apoptosis (61.7%) in the ischaemic part of the left ventricle during I/R (Zac1(-/-), n = 6 vs. Zac1(+/+), n = 7; P = 0.0012). Mutants showed under control conditions a decrease of 53.9% in mRNA of Daxx, a pro-apoptotic protein playing a key role in I/R injuries (4.81 +/- 0.77, n = 4 Zac1(-/-) mice vs. 10.44 +/- 3.5, n = 7 Zac1(+/+) mice; P = 0.0121). CONCLUSION: Our study shows for the first time that Zac1 is down regulated both at the transcriptional and protein levels upon PreC and PostC in wild-type mice. Moreover, inactivation of Zac1 in vivo is associated with a decreased amount of Daxx transcripts and, upon I/R injury, decreased infarct size and apoptosis. Altogether, our results show that Zac1 down-regulation plays a key role during cardioprotection against I/R injury and support the concept that cardioprotection regulates a network of interacting pro-apoptotic genes including Zac1 and Daxx. PMID- 22106415 TI - Endothelial nitric oxide synthase of the bone marrow regulates myocardial hypertrophy, fibrosis, and angiogenesis. AB - AIMS: The endothelial nitric oxide synthase (eNOS) regulates the mobilization and function of endothelial progenitor cells (EPC). We hypothesized that eNOS of the bone marrow (BM) affects cardiac remodelling during myocardial hypertrophy via the regulation of BM-derived vascular progenitor cells. METHODS AND RESULTS: Ten week-old male C57/Bl6 wild-type (WT) and eNOS mice (eNOS(-/-)) were subjected to transverse aortic constriction (TAC, 360 MUm, 35 days) or sham operation inducing cardiac hypertrophy and increasing the numbers of Ki67+ cardiomyocytes in both strains. Myocardial fibrosis was more pronounced in eNOS(-/-) TAC (3.4 +/- 0.4 vs. 2.1 +/- 0.2% in WT-TAC, P < 0.05). TAC up-regulated the number of EPCs in the peripheral blood and in the BM in WT but not in eNOS(-/-). Baseline migratory capacity of EPCs was lower in eNOS(-/-) and was not raised by TAC in either strain. To test the role of eNOS in the BM during pressure overload, strain mismatched (WT/eNOS(-/-); eNOS(-/-)/WT) and strain-matched (WT/WT; eNOS(-/ )/eNOS(-/-)) BM transplantations (BMTs) were performed. Cardiac hypertrophy was most pronounced in WT/eNOS(-/-) TAC. Strain-mismatched BMT of eNOS(-/-) BM deteriorated and of WT BM ameliorated cardiac fibrosis, capillary density, the numbers of EPCs in the peripheral blood and in the BM, and their migratory capacity in pressure overload. Following transplantation of green fluorescent protein (GFP)-positive BM, TAC increased the number of BM-derived podocalyxin(pos)GFP(pos) endothelial cells in both strains. CONCLUSION: eNOS of the BM plays a key role for amelioration of cardiac hypertrophy, capillary density, and fibrosis during increased afterload. PMID- 22106416 TI - Type 10 adenylyl cyclase mediates mitochondrial Bax translocation and apoptosis of adult rat cardiomyocytes under simulated ischaemia/reperfusion. AB - AIMS: Apoptosis of cardiomyocytes significantly contributes to the development of post-ischaemic cardiomyopathy. Although mitochondria have been suggested to play a crucial role in this process, the precise mechanisms controlling the mitochondria-dependent apoptosis in cardiomyocytes under ischaemia/reperfusion are still poorly understood. Here we aimed to analyse the role of the soluble adenylyl cyclase (sAC). METHODS AND RESULTS: Adult rat cardiomyocytes were subjected to simulated in vitro ischaemia (SI) consisting of glucose-free anoxia at pH 6.4. Apoptosis was detected by DNA laddering, chromatin condensation, and caspases cleavage. SI led to the translocation of sAC to the mitochondria and mitochondrial depolarization followed by cytochrome c release, caspase-9/-3 cleavage and apoptosis during simulated reperfusion (SR). Pharmacological inhibition of sAC during SI, but not during SR, significantly reduced the SI/SR induced mitochondrial injury and apoptosis. Similarly, sAC knock-down mediated by an adenovirus coding for shRNA targeting sAC prevented the activation of the mitochondrial pathway of apoptosis. Analysis of the link between sAC and apoptosis revealed a sAC and protein kinase A-dependent Bax phosphorylation at Thr(167) and its translocation to mitochondria during SI, which subsequently caused mitochondrial oxygen radical formation followed by cytochrome c release and caspase-9 cleavage during SR. CONCLUSION: These results suggest a key role of sAC in SI-induced mitochondrial Bax translocation and activation of the mitochondrial pathway of apoptosis in adult cardiomyocytes. PMID- 22106417 TI - Individual differences in apparent energy digestibility are larger than generally recognized. PMID- 22106418 TI - Folic acid supplementation and risk reduction in preterm birth. PMID- 22106419 TI - Intake of added sugars in the United States: what is the measure? PMID- 22106420 TI - Reply to BP Marriott et al. PMID- 22106421 TI - Current developments at Philosophical Transactions of the Royal Society B. PMID- 22106422 TI - From action to language: comparative perspectives on primate tool use, gesture and the evolution of human language. AB - The papers in this Special Issue examine tool use and manual gestures in primates as a window on the evolution of the human capacity for language. Neurophysiological research has supported the hypothesis of a close association between some aspects of human action organization and of language representation, in both phonology and semantics. Tool use provides an excellent experimental context to investigate analogies between action organization and linguistic syntax. Contributors report and contextualize experimental evidence from monkeys, great apes, humans and fossil hominins, and consider the nature and the extent of overlaps between the neural representations of tool use, manual gestures and linguistic processes. PMID- 22106423 TI - Triadic (ecological, neural, cognitive) niche construction: a scenario of human brain evolution extrapolating tool use and language from the control of reaching actions. AB - Hominin evolution has involved a continuous process of addition of new kinds of cognitive capacity, including those relating to manufacture and use of tools and to the establishment of linguistic faculties. The dramatic expansion of the brain that accompanied additions of new functional areas would have supported such continuous evolution. Extended brain functions would have driven rapid and drastic changes in the hominin ecological niche, which in turn demanded further brain resources to adapt to it. In this way, humans have constructed a novel niche in each of the ecological, cognitive and neural domains, whose interactions accelerated their individual evolution through a process of triadic niche construction. Human higher cognitive activity can therefore be viewed holistically as one component in a terrestrial ecosystem. The brain's functional characteristics seem to play a key role in this triadic interaction. We advance a speculative argument about the origins of its neurobiological mechanisms, as an extension (with wider scope) of the evolutionary principles of adaptive function in the animal nervous system. The brain mechanisms that subserve tool use may bridge the gap between gesture and language--the site of such integration seems to be the parietal and extending opercular cortices. PMID- 22106424 TI - Individual and social learning processes involved in the acquisition and generalization of tool use in macaques. AB - Macaques can efficiently use several tools, but their capacity to discriminate the relevant physical features of a tool and the social factors contributing to their acquisition are still poorly explored. In a series of studies, we investigated macaques' ability to generalize the use of a stick as a tool to new objects having different physical features (study 1), or to new contexts, requiring them to adapt the previously learned motor strategy (study 2). We then assessed whether the observation of a skilled model might facilitate tool-use learning by naive observer monkeys (study 3). Results of study 1 and study 2 showed that monkeys trained to use a tool generalize this ability to tools of different shape and length, and learn to adapt their motor strategy to a new task. Study 3 demonstrated that observing a skilled model increases the observers' manipulations of a stick, thus facilitating the individual discovery of the relevant properties of this object as a tool. These findings support the view that in macaques, the motor system can be modified through tool use and that it has a limited capacity to adjust the learnt motor skills to a new context. Social factors, although important to facilitate the interaction with tools, are not crucial for tool-use learning. PMID- 22106425 TI - The neural and cognitive correlates of aimed throwing in chimpanzees: a magnetic resonance image and behavioural study on a unique form of social tool use. AB - It has been hypothesized that neurological adaptations associated with evolutionary selection for throwing may have served as a precursor for the emergence of language and speech in early hominins. Although there are reports of individual differences in aimed throwing in wild and captive apes, to date there has not been a single study that has examined the potential neuroanatomical correlates of this very unique tool-use behaviour in non-human primates. In this study, we examined whether differences in the ratio of white (WM) to grey matter (GM) were evident in the homologue to Broca's area as well as the motor-hand area of the precentral gyrus (termed the KNOB) in chimpanzees that reliably throw compared with those that do not. We found that the proportion of WM in Broca's homologue and the KNOB was significantly higher in subjects that reliably throw compared with those that do not. We further found that asymmetries in WM within both brain regions were larger in the hemisphere contralateral to the chimpanzee's preferred throwing hand. We also found that chimpanzees that reliably throw show significantly better communication abilities than chimpanzees that do not. These results suggest that chimpanzees that have learned to throw have developed greater cortical connectivity between primary motor cortex and the Broca's area homologue. It is suggested that during hominin evolution, after the split between the lines leading to chimpanzees and humans, there was intense selection on increased motor skills associated with throwing and that this potentially formed the foundation for left hemisphere specialization associated with language and speech found in modern humans. PMID- 22106426 TI - Comparative investigations of manual action representations: evidence that chimpanzees represent the costs of potential future actions involving tools. AB - The ability to adjust one's ongoing actions in the anticipation of forthcoming task demands is considered as strong evidence for the existence of internal action representations. Studies of action selection in tool use reveal that the behaviours that we choose in the present moment differ depending on what we intend to do next. Further, they point to a specialized role for mechanisms within the human cerebellum and dominant left cerebral hemisphere in representing the likely sensory costs of intended future actions. Recently, the question of whether similar mechanisms exist in other primates has received growing, but still limited, attention. Here, we present data that bear on this issue from a species that is a natural user of tools, our nearest living relative, the chimpanzee. In experiment 1, a subset of chimpanzees showed a non-significant tendency for their grip preferences to be affected by anticipation of the demands associated with bringing a tool's baited end to their mouths. In experiment 2, chimpanzees' initial grip preferences were consistently affected by anticipation of the forthcoming movements in a task that involves using a tool to extract a food reward. The partial discrepancy between the results of these two studies is attributed to the ability to accurately represent differences between the motor costs associated with executing the two response alternatives available within each task. These findings suggest that chimpanzees are capable of accurately representing the costs of intended future actions, and using those predictions to select movements in the present even in the context of externally directed tool use. PMID- 22106427 TI - Functional mastery of percussive technology in nut-cracking and stone-flaking actions: experimental comparison and implications for the evolution of the human brain. AB - Various authors have suggested behavioural similarities between tool use in early hominins and chimpanzee nut cracking, where nut cracking might be interpreted as a precursor of more complex stone flaking. In this paper, we bring together and review two separate strands of research on chimpanzee and human tool use and cognitive abilities. Firstly, and in the greatest detail, we review our recent experimental work on behavioural organization and skill acquisition in nut cracking and stone-knapping tasks, highlighting similarities and differences between the two tasks that may be informative for the interpretation of stone tools in the early archaeological record. Secondly, and more briefly, we outline a model of the comparative neuropsychology of primate tool use and discuss recent descriptive anatomical and statistical analyses of anthropoid primate brain evolution, focusing on cortico-cerebellar systems. By juxtaposing these two strands of research, we are able to identify unsolved problems that can usefully be addressed by future research in each of these two research areas. PMID- 22106429 TI - Articulatory capacity of Neanderthals, a very recent and human-like fossil hominin. AB - Scientists seek to use fossil and archaeological evidence to constrain models of the coevolution of human language and tool use. We focus on Neanderthals, for whom indirect evidence from tool use and ancient DNA appears consistent with an adaptation to complex vocal-auditory communication. We summarize existing arguments that the articulatory apparatus for speech had not yet come under intense positive selection pressure in Neanderthals, and we outline some recent evidence and analyses that challenge such arguments. We then provide new anatomical results from our own attempt to reconstruct vocal tract (VT) morphology in Neanderthals, and document our simulations of the acoustic and articulatory potential of this reconstructed Neanderthal VT. Our purpose in this paper is not to polarize debate about whether or not Neanderthals were human-like in all relevant respects, but to contribute to the development of methods that can be used to make further incremental advances in our understanding of the evolution of speech based on fossil and archaeological evidence. PMID- 22106428 TI - Stone tools, language and the brain in human evolution. AB - Long-standing speculations and more recent hypotheses propose a variety of possible evolutionary connections between language, gesture and tool use. These arguments have received important new support from neuroscientific research on praxis, observational action understanding and vocal language demonstrating substantial functional/anatomical overlap between these behaviours. However, valid reasons for scepticism remain as well as substantial differences in detail between alternative evolutionary hypotheses. Here, we review the current status of alternative 'gestural' and 'technological' hypotheses of language origins, drawing on current evidence of the neural bases of speech and tool use generally, and on recent studies of the neural correlates of Palaeolithic technology specifically. PMID- 22106430 TI - The minimalist grammar of action. AB - Language and action have been found to share a common neural basis and in particular a common 'syntax', an analogous hierarchical and compositional organization. While language structure analysis has led to the formulation of different grammatical formalisms and associated discriminative or generative computational models, the structure of action is still elusive and so are the related computational models. However, structuring action has important implications on action learning and generalization, in both human cognition research and computation. In this study, we present a biologically inspired generative grammar of action, which employs the structure-building operations and principles of Chomsky's Minimalist Programme as a reference model. In this grammar, action terminals combine hierarchically into temporal sequences of actions of increasing complexity; the actions are bound with the involved tools and affected objects and are governed by certain goals. We show, how the tool role and the affected-object role of an entity within an action drives the derivation of the action syntax in this grammar and controls recursion, merge and move, the latter being mechanisms that manifest themselves not only in human language, but in human action too. PMID- 22106431 TI - The origins of non-human primates' manual gestures. AB - The increasing body of research into human and non-human primates' gestural communication reflects the interest in a comparative approach to human communication, particularly possible scenarios of language evolution. One of the central challenges of this field of research is to identify appropriate criteria to differentiate a gesture from other non-communicative actions. After an introduction to the criteria currently used to define non-human primates' gestures and an overview of ongoing research, we discuss different pathways of how manual actions are transformed into manual gestures in both phylogeny and ontogeny. Currently, the relationship between actions and gestures is not only investigated on a behavioural, but also on a neural level. Here, we focus on recent evidence concerning the differential laterality of manual actions and gestures in apes in the framework of a functional asymmetry of the brain for both hand use and language. PMID- 22106432 TI - A word in the hand: action, gesture and mental representation in humans and non human primates. AB - The movements we make with our hands both reflect our mental processes and help to shape them. Our actions and gestures can affect our mental representations of actions and objects. In this paper, we explore the relationship between action, gesture and thought in both humans and non-human primates and discuss its role in the evolution of language. Human gesture (specifically representational gesture) may provide a unique link between action and mental representation. It is kinaesthetically close to action and is, at the same time, symbolic. Non-human primates use gesture frequently to communicate, and do so flexibly. However, their gestures mainly resemble incomplete actions and lack the representational elements that characterize much of human gesture. Differences in the mirror neuron system provide a potential explanation for non-human primates' lack of representational gestures; the monkey mirror system does not respond to representational gestures, while the human system does. In humans, gesture grounds mental representation in action, but there is no evidence for this link in other primates. We argue that gesture played an important role in the transition to symbolic thought and language in human evolution, following a cognitive leap that allowed gesture to incorporate representational elements. PMID- 22106434 TI - Health-related quality-of-life in children with coeliac disease, measured prior to receiving their diagnosis through screening. AB - OBJECTIVE: To compare the health-related quality-of-life (HRQoL) of children with screening-detected coeliac disease (CD), before they learned of their diagnosis, with that of children without CD and in those previously diagnosed with CD. METHODS: In a cross-sectional CD screening study ('ETICS': Exploring the Iceberg of Coeliacs in Sweden), of 10,041 Swedish 12-year-olds invited, 7567 (75%) consented to participate, and 7208 (72%) children without previously diagnosed CD had serological markers analysed. Before the screening results were known, 7218 children (72%) and 6524 of their parents (65%) answered questionnaires. Questionnaires included the Swedish child-friendly pilot version of the EQ-5D instrument and proxy version of the EQ-5D instrument, which are generic tools used to describe HRQoL. RESULTS: We found no significant difference in HRQoL between the groups of children with screening-detected CD, without CD, and those previously diagnosed with CD. CONCLUSION: The HRQoL reported by 12-year-olds with screening-detected CD, before they learned of their diagnosis, was not worse than that of the children without CD or those previously diagnosed with CD. Thus, mass screening for CD should not be justified on the basis that children with unrecognized CD have a poor HRQoL. However, because these children rated their HRQoL before diagnosis and treatment, they may not have recognized or perceived symptoms as severe enough to seek medical attention which demonstrates how difficult clinical/active case finding can be. Mass screening may still, therefore, be considered if the aim is early detection and prevention of future complications. PMID- 22106433 TI - A neuropsychological perspective on the link between language and praxis in modern humans. AB - Hypotheses about the emergence of human cognitive abilities postulate strong evolutionary links between language and praxis, including the possibility that language was originally gestural. The present review considers functional and neuroanatomical links between language and praxis in brain-damaged patients with aphasia and/or apraxia. The neural systems supporting these functions are predominantly located in the left hemisphere. There are many parallels between action and language for recognition, imitation and gestural communication suggesting that they rely partially on large, common networks, differentially recruited depending on the nature of the task. However, this relationship is not unequivocal and the production and understanding of gestural communication are dependent on the context in apraxic patients and remains to be clarified in aphasic patients. The phonological, semantic and syntactic levels of language seem to share some common cognitive resources with the praxic system. In conclusion, neuropsychological observations do not allow support or rejection of the hypothesis that gestural communication may have constituted an evolutionary link between tool use and language. Rather they suggest that the complexity of human behaviour is based on large interconnected networks and on the evolution of specific properties within strategic areas of the left cerebral hemisphere. PMID- 22106435 TI - A comparative case study of bowel cancer screening in the UK and Australia: evidence lost in translation? AB - OBJECTIVES: (i) To document the current state of the English, Scottish, Welsh, Northern Irish and Australian bowel cancer screening programmes, according to seven key characteristics, and (ii) to explore the policy trade-offs resulting from inadequate funding. SETTING: United Kingdom and Australia. METHODS: A comparative case study design using document and key informant interview analysis. Data were collated for each national jurisdiction on seven key programme characteristics: screening frequency, population coverage, quality of test, programme model, quality of follow-up, quality of colonoscopy and quality of data collection. A list of optimal features for each of the seven characteristics was compiled, based on the FOBT screening literature and our detailed examination of each programme. RESULTS: Each country made different implementation choices or trade-offs intended to conserve costs and/or manage limited and expensive resources. The overall outcome of these trade-offs was probable lower programme effectiveness as a result of compromises such as reduced screening frequency, restricted target age range, the use of less accurate tests, the deliberate setting of low programme positivity rates or increased inconvenience to participants from re-testing. CONCLUSIONS: Insufficient funding has forced programme administrators to make trade-offs that may undermine the potential net population benefits achieved in randomized controlled trials. Such policy compromise contravenes the principle of evidence-based practice which is dependent on adequate funding being made available. PMID- 22106436 TI - Significant demographic and fine-scale genetic structure in expanding and senescing populations of the terrestrial orchid Cymbidium goeringii (Orchidaceae). AB - PREMISE OF THE STUDY: Fine-scale genetic structure (FSGS) in plants is influenced by variation in spatial and temporal demographic processes. To determine how demographic structure and FSGS change with stages of population succession, we studied replicate expanding and senescing populations of the Asian terrestrial orchid Cymbidium goeringii. METHODS: We used spatial autocorrelation methods (O ring and kinship statistics) to quantify spatial demographic structure and FSGS in two expanding and two senescing populations, also measuring genetic diversity and inbreeding in each. KEY RESULTS: All populations exhibited significant aggregation of individuals and FSGS at short spatial scales. In expanding populations, this finding was associated with high recruitment rates, suggesting restricted seed dispersal. In senescing populations, recruitment was minimal, suggesting alternative mechanisms of aggregation, perhaps including spatial associations with mycorrhizal fungi. All populations had significant evidence of genetic bottlenecks, and inbreeding levels were consistently high. CONCLUSIONS: Our results indicate that different successional stages can generate similar patterns of spatial demographic and genetic structure, but as a consequence of different processes. These results contrast with the only other study of senescence effects on population genetic structure in an herbaceous perennial, which found little to no FSGS in senescing populations. With the exception of populations subject to mass collection by orchid sellers, significant FSGS is characteristic of the 16 terrestrial orchid species examined to date. From a conservation perspective, this result suggests that inference of orchid population history will benefit from analyses of both FSGS and demographic structure in combination with other ecological field data. PMID- 22106437 TI - Demographic response by a small epiphytic orchid. AB - PREMISE OF THE STUDY: Biotic changes are an inevitable consequence of climate change. Epiphytes may be more susceptible to changes in climate variation, but data regarding responses to climate variability under field conditions are limited. We evaluated whether the abundance of demographic stages in the epiphytic orchid Lepanthes rupestris at the Luquillo Experimental Forest in Puerto Rico was associated with short-term changes in climate variation over an 8 yr period. METHODS: We used cross-correlation analyses to evaluate associations between the abundance of seedlings, juveniles, adults, and fruits per subpopulation, population growth, colonization and extinction rates in L. rupestris with variables related to precipitation and temperature, with and without lag- responses. KEY RESULTS: We detected significant negative correlations between the average number of seedlings and the number of dry days, between the average number of fruits and minimum average temperature with a 6-mo response lag, and between the average number of adults and the maximum temperature with a 1-yr response lag. Neither population growth rate nor probability of colonization and extinction were directly related to climatic variation between 2000 and 2007. CONCLUSIONS: Associations between climatic variables and demographic stages could have negative implications for this orchid within the context of expected drying trends in the Caribbean. Results argue for the establishment of long-term monitoring studies of orchid populations, because only long-term studies would provide the appropriate temporal scale to detect and predict climate change effects and adaptive management of orchid populations. PMID- 22106438 TI - Rapid isolation and cross-amplification of microsatellite markers in Plectritis congesta (Valerianaceae) with 454 sequencing. AB - PREMISE OF THE STUDY: Microsatellite markers were isolated and characterized in Plectritis congesta for studying the evolution of this highly variable species. METHODS AND RESULTS: We used 454 sequencing of DNA enriched for microsatellite repeats to develop microsatellite markers. This produced 262079 reads with an average length of 324 bp, representing approximately 800 microsatellite regions from which 48 primers were tested. Eleven markers reliably amplified without optimization. These primer pairs showed a high degree of heterozygosity and allelic diversity. Unexpectedly, half of the markers contained multiple peaks, with up to four alleles per individual, which suggests that either polyploidy or isolated gene duplication has occurred within this clade. These primers successfully cross-amplified in P. macrocera, indicating the utility of these markers for the genus. CONCLUSIONS: With variation in mating system and habitat, a mix of duplicated and nonduplicated markers, and high genetic variance, Plectritis is an ideal candidate model genus for studying the ecological and evolutionary consequences of gene duplication. PMID- 22106439 TI - Characterization of microsatellite loci in Festuca gautieri (Poaceae) and transferability to F. eskia and F. xpicoeuropeana. AB - PREMISE OF THE STUDY: Enriched genomic libraries were used to isolate and characterize microsatellite loci in Festuca gautieri, an important plant component of subalpine calcareous grasslands of the eastern Iberian Peninsula, the Pyrenees, and the Cantabrian Mountains. Microsatellites were required to investigate landscape genetics across its distribution range and at a narrower geographical scale within the Ordesa y Monte Perdido, Aiguestortes, and Picos de Europa Spanish national parks. METHODS AND RESULTS: Ten polymorphic microsatellite loci were characterized. They amplified a total of 116 alleles in a sample of 30 individuals of F. gautieri, showing high levels of genetic diversity (expected heterozygosity = 0.821). Cross-species transferability to two other close congeners, F. eskia and F *picoeuropeana, increased the total number of alleles to 137. These taxa showed lower numbers of alleles but similar levels of genetic diversity to F. gautieri. CONCLUSIONS: These microsatellite primers will be useful in population and landscape genetics and in establishing conservation strategies for these characteristic elements of subalpine pastures. PMID- 22106440 TI - Isolation and characterization of 52 polymorphic EST-SSR markers for Callitris columellaris (Cupressaceae). AB - PREMISE OF THE STUDY: We developed simple sequence repeat (SSR) markers from expressed sequence tags (ESTs) for Callitris columellaris sensu lato (s.l.) to elucidate population genetic structure and detect outlier loci by genome scan. METHODS AND RESULTS: mRNA from an individual seedling was subjected to cDNA synthesis and then de novo pyrosequencing. Two hundred and nineteen primer pairs bordering sequence regions were designed from the obtained sequence data. In total, 52 showed polymorphism within 16 individuals representative of the species' entire range, with the number of alleles per locus and expected heterozygosity ranging from two to 10 and 0.06 to 0.84, respectively. CONCLUSIONS: The EST-SSR markers developed in this study will be useful for evaluating the range-wide genetic structure of C. columellaris s.l. and detecting outlier loci under selection, as well as providing useful markers to investigate the conservation genetics and reproductive ecology of the species. PMID- 22106441 TI - Isolation and characterization of microsatellite loci in the beach pea, Lathyrus japonicus (Fabaceae), in Japan. AB - PREMISE OF THE STUDY: Microsatellite loci were developed for Lathyrus japonicus (Fabaceae) to evaluate genetic diversity, population genetic structure, and demographic patterns of this species in Japan. METHODS AND RESULTS: In total, eight primer sets were identified in Japanese populations of L. japonicus and polymorphisms were evaluated in 83 individuals from three populations, including the northern and southern geographic range in Japan. The number of alleles per locus ranged from four to 20, and gene diversity per locus ranged from 0.636 to 0.935 among three populations. In addition, six of the eight loci could be successfully amplified in L. pratensis. CONCLUSIONS: These markers will be useful for studies of genetic variations, genetic structure, and gene flow of L. japonicus, which is important to investigate the demographic patterns of this coastal plant. In addition, the primers are useful for further genetic structure analysis of L. pratensis. PMID- 22106442 TI - Development and characterization of a novel set of microsatellite markers for Arisaema serratum (Araceae). AB - PREMISE OF THE STUDY: We developed novel microsatellite markers in Arisaema serratum, a perennial herb that possesses pitfall flowers and exhibits labile sex expression, to facilitate research on parentage and pollination biology in this species. METHODS AND RESULTS: By using procedures for enrichment of desired microsatellite-containing fragments and PCR-based isolation of microsatellite arrays, we detected 18 novel microsatellite loci. Thirteen were highly polymorphic: the number of alleles per locus ranged from six to 46, the observed heterozygosities ranged from 0.320 to 0.940, and the expected heterozygosities ranged from 0.440 to 0.976. Nine of the 13 markers successfully amplified regions in congeneric species. CONCLUSIONS: These highly polymorphic markers will facilitate further studies on the mode of pollination and other aspects of reproductive biology in A. serratum. PMID- 22106443 TI - DNA identification of formalin-fixed organs is affected by fixation time and type of fixatives: using the AmpF l STR(R) Identifiler(R) PCR Amplification Kit. AB - Personal identification using DNA typing of formalin-fixed tissue is very important in the forensic sciences. However, few studies have been conducted to determine the detection limit of DNA typing of formalin fixation time in samples using the AmpFlSTR((r)) Identifiler((r)) PCR Amplification Kit (Identifiler Kit). We collected samples from five cadavers submitted for forensic autopsies, and fixed them either in a 10% formalin solution, or in a 10% neutral-buffered formalin solution. The amount of template DNA for polymerase chain reaction (PCR) amplification and the detection limit of DNA typing for the Identifiler Kit were determined. When tissues were fixed in 10% formalin, 10 ng of DNA template was required for successful genotyping even after three-hour fixation and 100 ng was required after one-week fixation for PCR amplification. However, when tissues were fixed in 10% neutral-buffered formalin, the required amount of DNA template was 1 ng for a fixation time of three hours to three days and 125 ng for three months. Fixation time in neutral-buffered formalin was longer for successful PCR than that in formalin solution. Dropout was more common with increasing formalin fixation time. These results suggest that neutral-buffered formalin is preferred to formalin for fixation of tissues if they are to be subjected to DNA typing and that tissues fixed with neutral-buffered formalin can be used for DNA typing using the Identifiler Kit unless the fixation time exceeds one month. PMID- 22106444 TI - Emergency department as a 'place of safety': reviewing the use of Section 136 of the Mental Health Act 1983 in England. AB - Section 136 provides the lawful authority for the removal, by the police, of the person to whom the provision applies, from a place to which the public have access. There has been a longstanding debate as to the most appropriate place of safety for these patients. The aim of this article is to review the literature and determine the ideal place for the detention and assessment of these patients and clarify the responsibilities of the staff of the agencies involved in the detention. It concludes that there is no single most appropriate place of safety for all groups of patients. Rather, there should be a range of options to enable the assessment in the most suitable environment for individual cases according to their needs at the time. PMID- 22106447 TI - Simple system for perivenous tumescent infusion for endovenous laser ablation. AB - The use of a simplified system for perivenous infusion of tumescent fluid prior to endovenous laser ablation is described. Two infusion bag systems using different combinations of needle sizes (22, 23 and 25 gauge) and pressure settings (300 and 600 mmHg) as well as hand injections were tested in vivo. The technique is simple, safe and may lead to quicker infusion, reduction in hand fatigue and reduced cost. PMID- 22106445 TI - HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and obesity in a cohort of Caucasians and African Americans: an evaluation of gene-environment interactions and candidate genes. AB - The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height (m)(2)) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002-2009) for associations with BMI and gene * environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (beta = -0.04, 95% confidence interval: -0.06, -0.02; P = 5.76 * 10(-5)) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians. PMID- 22106448 TI - Evaluation of the pain in varicose vein surgery under tumescent local anaesthesia using sodium bicarbonate as excipient without any intravenous sedation. AB - OBJECTIVE: In order to simplify varicose vein surgery, we studied the possibility of tumescent local anaesthesia (TLA) using sodium bicarbonate 1.4% as excipient without any intravenous sedation. METHODS: For three months, 215 patients were included in two centres for ambulatory varicose vein surgery performed without any intravenous sedation. Clinical results and pain were evaluated according to the type and duration of surgery. RESULTS: Mean perioperative pain was evaluated at 2.7 on a visual scale (0-10). In 91% of the cases, surgery was deemed to be slightly painful. Preoperative pain was not linked to the technical means of surgery but to the psychological and organizational environment of the centre. CONCLUSIONS: In many of the cases, varicose vein surgery could be performed under TLA without any intravenous sedation. Ambulatory varicose vein surgery without any intravenous sedation could be highly cost-effective. PMID- 22106449 TI - Telangiectasia and venous reflux in the Edinburgh Vein Study. AB - OBJECTIVE: The purpose of this study was to correlate the clinical findings in the Edinburgh Vein Study with the results of duplex scanning of the deep and superficial venous systems. METHODS: An age-stratified random sample of 1566 people (699 men and 867 women) aged 16-64 were selected from computerized age-sex registers of participating practices (twelve general practices with catchment areas geographically and socioeconomically distributed throughout Edinburgh). Screening included clinical examination, photography and duplex ultrasonography of the superficial veins and the deep veins down to popliteal level. Telangiectasia and varicose veins were graded 1-3 according to severity. RESULTS: Since there was good agreement between the duplex findings of the right versus left legs, the current analyses are based on 1092 subjects (486 men and 606 women) with complete duplex scan data in their left legs. There was no significant trend of increasing incompetence in either the deep veins only (P = 0.214) or in the combined deep and superficial veins (P = 0.111) with increasing severity of the telangiectasia. There was a statistically significant trend for increasing incompetence in (a) the superficial veins (P = 0.006) and (b) either the superficial or deep veins (P < 0.001) to be associated with advancing grade of telangiectasia. When stratified by gender, significant trends were maintained for male superficial vein incompetence and for either superficial or deep incompetence in both genders. Examination of incompetence in individual venous segments showed that increasing severity of telangiectasia was significantly associated with an increasing proportion of reflux in the upper and lower great saphenous and femoral vein segments. There was no significant association between small saphenous incompetence and increasing grade of telangiectasia. CONCLUSION: There is a significant, but not wholly consistent, association between grade of telangiectasia and reflux in both the deep and superficial systems. This association does not apply to the small saphenous system. PMID- 22106450 TI - Message from the Editor-in-Chief. IEEE Visualization Conference and the IEEE Information Visualization Conference. PMID- 22106451 TI - Message from the paper chairs and guest editors. Conference proceedings. PMID- 22106452 TI - Maurice J. Jurkiewicz: "I am a teacher". PMID- 22106453 TI - Dr. M. J. Jurkiewicz remembered. PMID- 22106454 TI - Dr. Jurkiewicz: the fruits of his endeavors. PMID- 22106455 TI - Dr. Maurice Jurkiewicz: September 24, 1923-May 29, 2011. PMID- 22106456 TI - Retraction notice to "Layer silicates modified with 1,4-bis(3 aminopropyl)piperazine for the removal of Th(IV), U(VI) and Eu(III) from aqueous media" [J. Hazard. Mater. 171 (2009) 514-523]. PMID- 22106457 TI - Retraction notice to "Application of natural and modified hectorite clays as adsorbents to removal of Cr(VI) from aqueous solution--thermodynamic and equilibrium study" [J. Hazard. Mater. 172 (2009) 507-514]. PMID- 22106458 TI - Retraction notice to "Frictional properties of single crystals HMX, RDX and PETN explosives" [J. Hazard. Mater. 183 (2010) 324-333]. PMID- 22106459 TI - Absenteeism and productivity among employees being treated for hepatitis C. AB - OBJECTIVES: To compare productivity, absence days, and absence costs for treated (HCV-Tx) and untreated (HCV-NoTx) US employees with hepatitis C virus (HCV) infection. STUDY DESIGN: Retrospective database study. METHODS: Employee records from multiple large employers in the United States with data about demographics, jobs, and healthcare use in the Human Capital Management Services database were assessed. HCV subjects were identified by International Classification of Diseases, 9th Revision codes. To test differences between cohorts, t tests and chi2 tests were used. Regression modeling was used to compare absence days, costs,and objectively measured productivity, while controlling for confounding factors. For HCV-Tx employees, the index date was the date of the first treatment with interferon, peginterferon, and/or ribavirin. For HCV-NoTx employees, the index date was the average date by company among HCV-Tx employees. Absence and productivity were measured from each employee's index date to the last date the employee was enrolled in health benefits coverage. RESULTS: A total of 441 HCV-Tx and 1223 HCV-NoTx employees were evaluated. HCV-Tx workers had 0.52 more total monthly absence days and $31.31 in additional monthly absence payments per employee than untreated employees. Treated employees' productivity was lower, with treated subjects processing 11.7% fewer units per hour and 17.4% fewer units per month than untreated employees. CONCLUSIONS: This study quantified the substantial indirect burden of illness associated with use of current HCV treatments. New treatments are needed with improved adverse effect profiles that result in reduced absence from work and improved productivity among HCV-infected persons. PMID- 22106460 TI - The incidence and costs of hypoglycemia in type 2 diabetes. AB - OBJECTIVES: To estimate the rate and costs of hypoglycemia in patients with type 2 diabetes. STUDY DESIGN: We used a retrospective cohort design to assess the rate and costs of hypoglycemia among working-age patients with type 2 diabetes in the 2004 to 2008 MarketScan database. METHODS: We followed patients from cohort entry to the first instance of hypoglycemia requiring medical intervention (inpatient, emergency department [ED], or outpatient) and calculated incidence rates (IRs), stratifying these estimates by age (18-34, 35-49, 50-64, and 65+ years) and gender. We calculated inflation-adjusted total and mean direct costs of medical visits for hypoglycemia, other diabetes-related visits, and all other medical visits. RESULTS: The cohort was composed of 536,581 members with approximately 1.21 million person years (p-yrs) of follow-up. The IR of hypoglycemic events leading to an inpatient admission, ED, or outpatient visit was 153.8/10,000 p-yrs. The IRs of hypoglycemic events were highest in adults aged 18 to 34 years (218.8/10,000 p-yrs). Regardless of age group, rates of hypoglycemia were greater in women than in men (P < .001). Total hypoglycemia costs were $52,223,675 over the study period and accounted for 1.0% of all inpatient costs, 2.7% of ED costs, and 0.3% of outpatient costs. The mean costs for hypoglycemia visits were $17,564 for an inpatient admission, $1387 for an ED visit, and $394 for an outpatient visit. CONCLUSIONS: The overall incidence of visits for hypoglycemia was considerable in this large database, and was associated with high per-episode costs. Continued vigilance and the development of strategies to decrease potentially avoidable hypoglycemic episodes requiring medical intervention are needed. PMID- 22106461 TI - Evaluation of value-based insurance design with a large retail employer. AB - OBJECTIVES: To measure adherence and assess medical utilization among employees enrolled in a disease management (DM) program offering copayment waivers (value based insurance design [VBID]). STUDY DESIGN: Retrospective matched case control study. METHODS: Cases were defined as those enrolled in DM, of whom 800 received health education mailings (HEMs) and 476 received telephonic nurse counseling (NC). Controls were eligible for the DM program but did not enroll. Cases and controls were matched 1:1 based on propensity score (n = 2552). Adherence, defined by proportion of days covered, was calculated for 4 diseases using incurred drug claims 1 year before and after the DM program was implemented. Unadjusted and adjusted linear regression compared changes in adherence. Costs and utilization were compared at 1 year and 1.5 years after versus 1 year before implementation. RESULTS: Members receiving NC had improved adherence for antihypertensives, diabetes medications, and statins (beta = 0.050, P = .025; beta = 0.108, P < .001; beta = 0.058, P = .017). Members receiving HEMs had improved adherence only for diabetes medications (beta = 0.052, P = .019). Total healthcare costs for NC members increased by $44 +/- $467 versus $1861 +/- $401 per member per year (PMPY) for controls (P = .003) at 1.5 years post implementation. Total healthcare costs for HEM members significantly increased ($1261 +/- $199 vs $182 +/- $181 PMPY for controls; P < .001) at 1.5 years. CONCLUSION: VBID may be effective in improving medication adherence and reducing total healthcare costs when active counseling is provided to high utilizers of care. PMID- 22106463 TI - Increasing pharmaceutical copayments: impact on asthma medication utilization and outcomes. AB - OBJECTIVES: Unintended consequences may result from changes in pharmacy benefit design. The objective was to determine the impact of increasing patient prescription copayments for guideline recommended, long-term asthma controller (LTC) medications on asthma-related medication use and healthcare services. STUDY DESIGN: We used 2005 MarketScan healthcare and pharmacy claims data to identify asthma (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis code 493.xx) patients aged 12 to 64 years who were continuously enrolled through 2006 with >= 1 claim for an asthma medication in 2005. LTCs included: inhaled corticosteroid (ICS) (n = 10,251), ICS plus long acting beta agonist (COMBO) (n =27,407), and leukotriene receptor antagonist (LTRA) (n = 20,664). METHODS: Using multivariable models, we estimated the associations between changes in LTC copayments and LTC consumption and asthma related outpatient and emergency department (ED) visits. RESULTS: Patients were dichotomized into >= $5 average increase in patient copayments per month of medication supplied (yes/no). The mean annual change (2005-2006) in copayments per month was $13.23 versus -$3.88 (ICS), $11.76 versus -$3.06 (COMBO), and $9.78 versus -$2.06 (LTRA). The >= $5 group experienced a significant decline in average annual days of medication supplied of -47.1 days of ICS (95% CI -43.5 to 50.8), -35.3 days of COMBO (-32.4 to -38.2), and -47.5 days of LTRA (-43.2 to 51.7). Among COMBO and LTRA medication users, the >= $5 copayment increase was associated with more asthma-related outpatient visits and ED visits compared with the < $5 group. CONCLUSIONS: The findings suggest that even small changes in average copayment for asthma medications can result in significant reductions in medication use and unintended increases in healthcare services. PMID- 22106462 TI - Routine pre-cesarean Staphylococcus aureus screening and decolonization: a cost effectiveness analysis. AB - OBJECTIVES: To estimate the economic value of screening pregnant women for Staphylococcus aureus carriage before cesarean delivery. STUDY DESIGN: Computer simulation model. METHODS: We used computer simulation to assess the cost effectiveness, from the third-party payer perspective, of routine screening for S aureus (and subsequent decolonization of carriers) before planned cesarean delivery. Sensitivity analyses explored the effects of varying S aureus colonization prevalence, decolonization treatment success rate (for the extent of the puerperal period), and the laboratory technique (agar culture vs polymerase chain reaction [PCR]) utilized for screening and pathogen identification from wound isolates. RESULTS: Pre-cesarean screening and decolonization were only cost effective when agar was used for both screening and wound cultures when the probability of decolonization success was >= 50% and colonization prevalence was >= 40%, or decolonization was >= 75% successful and colonization prevalence was >= 20%. The intervention was never cost-effective using PCR-based laboratory methods. The cost of agar versus PCR and their respective sensitivities and specificities, as well as the probability of successful decolonization, were important drivers of the economic and health impacts of preoperative screening and decolonization of pregnant women. The number needed to screen ranged from 21 to 2294, depending on colonization prevalence, laboratory techniques used, and the probability of successful decolonization. CONCLUSIONS: Despite high rates of cesarean delivery, presurgical screening of pregnant women for S aureus and decolonization of carriers is unlikely to be cost-effective under prevailing epidemiologic circumstances. PMID- 22106464 TI - Drug withdrawal sends critical care specialists back to basics. PMID- 22106465 TI - Health 2020: WHO's missing link? PMID- 22106466 TI - Moving pictures of Parkinson's disease. PMID- 22106467 TI - Anomalous hypoplastic left anterior descending artery. PMID- 22106468 TI - Left coronary artery fistula after septal myectomy in hypertrophic cardiomyopathy. PMID- 22106469 TI - Retraction notice to "Mechanism(s) of deep brain stimulation and insights into cognitive outcomes in Parkinson's disease" [Brain Res. Rev. 65 (2010) 1-13]. PMID- 22106470 TI - A roll of the dice. PMID- 22106471 TI - The dark side of cohesin: the carcinogenic point of view. AB - Genome instability is a hallmark of cancer cells and how it arises is still not completely understood. Correct chromosome segregation is a pre-requisite for preserving genome integrity. Cohesin helps to ensure faithful chromosome segregation during cell cycle, however, much evidence regarding its functions have come to light over the last few years and suggest that cohesin plays multiple roles in the maintenance of genome stability. Here we review our rapidly increasing knowledge on the involvement of cohesin pathway in genome stability and cancer. PMID- 22106472 TI - The Raetz pathway for lipid A biosynthesis: Christian Rudolf Hubert Raetz, MD PhD, 1946-2011. PMID- 22106473 TI - Descriptive study of the longevity of dental implant surgery drills. AB - BACKGROUND: Atraumatic preparation of the osteotomy site is critical for osseointegration. PURPOSE: This study aimed to investigate the effects of multiple usages of dental implant drills on bone temperature changes and to examine the cutting surfaces of these drills under a scanning electron microscope (SEM). MATERIALS AND METHODS: The implant osteotomy procedure was adapted to the experimental setting to simulate wear on implant drills by preparing bovine ribs using a constant drilling force. Thermocouples were placed in the specimens to record temperature changes. SEM images of the drills were taken, and elemental spectroscopic analysis was performed. RESULTS: Temperatures measured in the bone adjacent to the implant site did not exceed 27.7 degrees C during the experiment. Spectroscopic elemental analysis indicated that two of the drills were of a stainless steel composition, and the other drill consisted of a tungsten carbide coated stainless steel. The tungsten carbide-coated bur had the lowest overall drilling temperatures and showed the least surface corrosion and plastic deformation. SEM analysis showed degradation of the cutting surfaces of the burs although the plastic deformation and surface wear did not appear to affect the cutting temperatures. Surface corrosion was observed on the cutting surfaces. CONCLUSIONS: Drills used for up to 50 osteotomies do not appear to elevate bone temperatures to a harmful level. However, drill corrosion is potentially important in determining the life span of implant burs. PMID- 22106474 TI - [Alterations of NK cell frequency and function in HIV/HCV co-infected patients]. AB - OBJECTIVE: To study the impacts of HIV/HCV co-infection to NK cells by investigating the changes of frequencies and functions of NK cells in HIV/HCV co infected patients. METHODS: Frequencies and counts of NK cells were measured in patients with HIV mono-infection, HCV monoinfection, HIV/HCV co-infection and health control (HC) group by flow cytometer (FCM). After stimulated with PMA and K562 cells, PBMCs were examined the proportion of IFN-gamma+ NK cells by FCM. Proportion of killed K562 cells were detected to analyze the killing functions of NK cells. RESULTS: The frequencies of NK cells, the percentages of IFN-gamma+ NK cells as well as the functions of NK cells killing the K562 cells in HIV/HCV co infection, HIV mono-infection and HCV mono-infection groups were all lower than those of HC group significantly, the absolute counts and killing functions of NK cells in co-infection group were significantly lower than those of HIV or HCV mono-infection group. CONCLUSIONS: The counts and functions of NK cells were affected more in HIV/HCV co-infections than those in HIV or HCV mono-infection. PMID- 22106475 TI - [Subcloning of M1 gene fragment of H5N1 influenza virus and its expression in Escherichia coli]. AB - OBJECTIVE: To generate the Escherichia col vector expressing human H5N1 influenza virus M1 protein. To provide useful tools for detection of human H5N1 influenza virus and study on biological function of M1 protein. METHODS: M1 gene fragment was amplified by PCR using the influenza virus gene segment 7 as template, and was subcloned into pQE80-L vector. The recombinant plasmid pQE80-L/M1 was transformed into Escherichia coil BL21 (DE3) strain. The expression of M1 was induced by isopropy-beta3-D-thiogalactopyranoside. We purified the recombinant M1 protein with polyhistidine tag with Ni2+ affinity chromatography. Mouse were immunized with the purified M1 protein for preparing antibodies against M1. RESULTS: The recombinant Ml protein was recognized by antiserum against H5N1 subtype influenza virus, elicit specific antibody in immunized animals. CONCLUSION: These confirmed that we successfully constructed the Escherichia coli vector expressing human H5N1 influenza virus M1 protein. PMID- 22106477 TI - President's message: social media in the practice of endodontics. PMID- 22106479 TI - AAEP releases report on BLM's wild horses. Report: "Adoption program has evolved into a welfare program". PMID- 22106480 TI - Horse racing eyes changes to stay relevant: new drug penalties, security, medication guidelines up for debate. PMID- 22106481 TI - Pushing for better welfare, pathology. PMID- 22106482 TI - Thoughts on detection of hepatitis C virus in dogs. PMID- 22106483 TI - Support for AVMA president. PMID- 22106484 TI - Electronic access to AVMA journal content. PMID- 22106485 TI - Veterinary contribution to 9/11 response. PMID- 22106486 TI - More on veterinary contribution to 9/11 response. PMID- 22106487 TI - "In praise of the ladies of Bologna": the image and identity of the sixteenth century Bolognese female patriciate. PMID- 22106488 TI - [The historical background of the Kosovo issue]. PMID- 22106489 TI - [Comparative history]. PMID- 22106490 TI - "Reason, nature and order": the stepfamily in English Renaissance thought. PMID- 22106491 TI - [Desiring without desire: the first steps of federal domain over the waters of a river in Mexico]. PMID- 22106492 TI - [Children in the Estado Novo: a reading of long duration]. PMID- 22106493 TI - [To Saracura: social rhythms and the metropolitan temporalities, 1890-1920]. PMID- 22106494 TI - A day in the life of a psychiatrist-in-the-making on the Navajo reservation. PMID- 22106495 TI - Letters of recommendation in residency training: what do they really mean? PMID- 22106496 TI - Resident physicians and peer review. PMID- 22106497 TI - [Mass culture and female representations in Sao Paulo in the 1920's]. PMID- 22106498 TI - [Maritime culture: sailors and slaves in the African trade to Brazil, 18th 19th centuries]. PMID- 22106499 TI - Gender in translation: how the English wrote their Juvenal, 1644-1815. PMID- 22106500 TI - Imperial palms over colonial gardens. PMID- 22106501 TI - Inside out: clothes, dissimulation, and the arts of accounting in the autobiography of Matthaus Schwarz, 1496-1574. PMID- 22106502 TI - Louisiana's "sugar tramps" in the Caribbean sugar industry. PMID- 22106503 TI - [The beginning of the frontier and the frontier of beginnings: illegitimate children in Cuiaba in the 19th century]. PMID- 22106504 TI - The Trinidad botanic gardens and colonial resource development, 1818-1899. PMID- 22106505 TI - "Unhappy and afflicted women?" Free colored women in Barbados: 1780-1834. PMID- 22106506 TI - [Unimputability and impunity in Sao Paulo]. PMID- 22106507 TI - [Children and schools in the passage from empire to republic]. PMID- 22106508 TI - Antimicrobial and anti-pathogenic activity of some thioureides derivatives against Erwinia amylovora phytopathogenic strains. AB - A series of N-(1-methyl-1 Hpyrazole-4-carbonyl)-thiourea derivatives were assessed for their in vitro antimicrobial and anti-pathogenic activity against twenty-two strains of Erwinia amylovora isolated from different regions in Romania. The compounds were solubilised in dimethylsulfoxide and screened for their in vitro antimicrobial activity. The qualitative screening of the susceptibility spectra of various strains to the compounds was performed by adapted diffusion techniques (distribution of the tested compound solution directly on the solid medium previously seeded with the bacterial inoculums). The quantitative assay of the minimal inhibitory concentration (MIC, microg/mL) was based on liquid medium two-fold microdilutions. The subinhibitory concentrations of the tested substances were investigated for their influence on biofilm development on inert substrata. The present study showed that six new thiourea compounds exhibited a low antibacterial activity (MIC values > 500 microg/ml), but the subinhibitory concentrations inhibited the biofilm development on inert substrata. Thus, these results could suggest the usefulness of the tested compounds as control agents for preventing the first stage (colonization) of the infection with the fire blight pathogen. PMID- 22106509 TI - Probiotics--an alternative treatment for various diseases. AB - Modulating the microbiota of the gastrointestinal tract through probiotics is an alternative to the conventional treatment of various diseases, based on synthetic drugs. The lifestyle, nutrition and stress of the present modern society could be among the factors responsible for modifications in the intestinal microbiota, correlated with specific diseases. The present study describes the positive effects of probiotics use, with special reference to the yeasts use in several frequently encountered diseases, such as hypercholesterolemia, the irritable bowel syndrome, gastritis and several uro-genital disorders. PMID- 22106510 TI - Helicobacter pylori cultivation from gastric biopsies and susceptibility to antibiotics used in empirical therapy. AB - Helicobacter pylori is one of the most common among the numerous bacterial species of the stomach. It is classified as a class 1 carcinogen because of its causal relationship to gastric adenocarcinoma. The epidemiology of H. pylori infection is characterized by a marked difference between developing and developed countries. Treatment of H. pylori still remains a challenge due to the high rate of antibiotic resistance. The aim of this study was to investigate the susceptibility of H. pylori strains isolated from gastric biopsies to different antibiotics currently used in the H. pylori infection treatment schemes. MATERIALS AND METHODS: Upper gastrointestinal GI endoscopy was performed, followed by the rapid urease test on gastric biopsies. The positive samples were cultivated on specific media under microaerophilic conditions and the antibiotic susceptibility assay was performed on the isolated strains. RESULTS: A positivity rate of 70% was obtained for cultures performed from the biopsy samples positive for the urease test. The resistance rates for the antibiotics used in the classic triple therapy proved to be high, i.e. 92.8% for metronidazole, 50% for amoxicillin and 32% for clarithromycin. The isolated strains proved to be sensitive to ciprofloxacin and levofloxacin. CONCLUSIONS: The role of gastric microbiota and its contribution to the H. pylori associated pathology need to be established. The problem of antibiotic treatment failure in case of resistant H. pylori strains can be surpassed by routine culture and antibiotic susceptibility testings. PMID- 22106511 TI - Screening for group B streptococcus: a private laboratory experience. AB - We examined group B streptococcus (GBS) isolates colonizing women at the 35-37 weeks of pregnancy. A total of 257 group B streptococcus (GBS) isolates for serotyped using direct agglutination with a set of commercially available antisera (Ia, Ib, II, III, IV, and V) and tested for susceptibility to antimicrobials (penicillin, macrolides, lincosamides, fluoroquinolones and tetracyclines). Fourteen isolates could not be serotyped with the antisera set used in the study. Serotype III was the predominant serotype (33%), followed by serotypes V (23%), and Ia (20%). Whereas all isolates were susceptible to penicillin, the rates of susceptibility to the other antimicrobials tested were the following: 91% for ofloxacin, 80% for clindamycin, 77% for erythromycin, and 4% for tetracycline. More than half (67%) of the macrolide resistant isolates belonged to serotypes V and III. A systematic surveillance of the autochthonous GBS serotypes, performed at the level of laboratories processing a high number of human specimens, is mandatory for strengthening the national epidemiological GBS surveillance. While penicillin remains the drug of choice for intrapartum prophylaxis, the resistance of autochthonous GBS isolates to other antibiotics should be actively monitored. PMID- 22106512 TI - Optimization of triplex real time PCR for detecting Staphylococcus aureus mecA, pvl and nuc genes. AB - Multiplex polymerase chain reaction (PCR) allows simultaneous detection of two or more genes, using the same reaction conditions, and so it is possible the rapid detection of methicillin resistant Staphylococcus aureus strains (MRSA) in clinical specimens. This study aimed to implement, for the first time in our laboratory, a triplex real time PCR (RT-PCR) technique for detection of genes encoding resistance to oxacillin and synthesis of Panton Valentine leukocidin (pvl), a pathogenicity factor characteristic for community acquired strains (CA MRSA). The application of this method will permit the epidemiological surveillance of circulating strains and early application of prevention measures. PMID- 22106513 TI - A study on apoptosis inducing effects of UVB irradiation in Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is an important bacterial pathogen which causes different infectious diseases such as wound and skin lesion infections. The main goal of this study was to induce eventual apoptotic reactions in ultraviolet-exposed colonies of Pseudomonas aeruginosa. MATERIALS AND METHODS: The colonies of Pseudomonas aeruginosa were irradiated by UVB light; then, the DNA molecules of control and UVB-exposed colonies were extracted. Eventually, the extracted DNA molecules mixed in loading dye were run in 1% agarose gel containing ethidium bromide. RESULTS: No unusual pattern like DNA laddering bands or smear, were detected upon the 1% agarose gel. DISCUSSION: Through the applied protocol in this survey, the UVB radiation is not able to trigger apoptosis pathway in UV light exposed colonies of Pseudomonas aeruginosa. It seems that the cytoprotective property of Heat shock proteins inhibit the inducing effect of UVB light in irradiated colonies of Pseudomonas aeruginosa. PMID- 22106514 TI - Survival of H5N1 influenza virus in water and its inactivation by chemical methods. AB - The ability of H5N1 Avian Influenza Virus (AIV) to survive in surface water has been assessed in experimental laboratory conditions, based on non-pathogenic avian reassortant model, by titration of infectivity (TCID50) at different time intervals, in three different types of water. The effect of different chemicals on AIV's survival was assessed using the same type of experimental model. After exposure to the chemical, followed by growth on a suitable substrate, the AIV was quantified by a real-time quantitative reverse transcriptase PCR (qRT-PCR). The reassortant virus persisted, and remained infective in aquatic environments, for 12 days at 22-35 degrees C and up to 20 days at 4 degrees C, irrespective of the type of water, supporting the hypothesis of a potential risk for transmitting the virus among birds and contaminating the household water via common sources of water. A significant decrease for AIV persistence models was recorded for sea water, after 12 days, at 35 degrees C. An effective inactivation has been shown when using commercially available products based on glutaraldehyde and penta potassium bis (peroxy mono sulphate) bis(sulphate), respectively. This rapid and safe method for decontamination, developed in this study, might be helpful in implementation of biosafety measures in laboratory and farms against AIV. PMID- 22106515 TI - New interferons in the treatment of chronic hepatitis C. AB - The current standard therapy for chronic HCV infection is a combination of pegylated-interferon (PEG-IFN) and weight-based ribavirin, administered for 24-48 weeks, according to the viral genotype. Although the weekly administration of pegylated interferons provides superior antiviral efficacy over standard interferon alpha, the rate of sustained virological response rarely overpasses 50% in patients infected with HCV genotypes 1 and 4. Consequently, multiple clinical trials with congeners of interferon (consensus interferon, interferon lambda, albinterferon, and controlled-release interferons) are ongoing. Their main advantages consist in maintenance of viral suppression across a longer dosing interval, avoidance of interdose trough and reduced dosing frequencies (twice or even once per month compared to once per week for the actual PEG-IFNs). Along with these superior pharmacokinetic properties, new interferons are expected to have improved side-effect profiles and better tolerability compared with the currently available formulations, providing an option for otherwise difficult to treat, challenging populations. New interferon formulation can be incorporated into future combination with direct acting antivirals, in order to maintain viral suppression over longer periods and minimize the development of viral resistance. PMID- 22106516 TI - Getting their appetite back. In need of capital, not-for-profit hospitals take advantage of dropping interest rates. AB - After steering clear of the municipal bond market this year, not-for-profit hospitals are being lured back by dropping interest rates. "We're taking advantage of the current market," says Jim Budzinski, left, executive vice president and chief financial officer of WellStar Health System. The Georgia provider's recent bond deal helped erase $4.2 million in interest costs. PMID- 22106517 TI - Narrowing target for cuts. Providers seem likely to get caught in cross hairs. PMID- 22106518 TI - Premiums rise ... but increases are much less than expected. PMID- 22106519 TI - 'In the eye of the storm'. Funding cuts threaten noted Baldrige program. PMID- 22106520 TI - PCORI gets down to work. PMID- 22106521 TI - Poor performance. Measly gains from models that predict readmissions. PMID- 22106522 TI - Restraining Medicaid. More states to cut provider payments: Kaiser study. PMID- 22106523 TI - Dodging an ACO chilling effect. Regulators ease up on provider collusion warnings. PMID- 22106524 TI - Med school applications peak. But funding shortfalls could cut residency posts. PMID- 22106525 TI - Vets targeted for health jobs. PMID- 22106526 TI - A year for change. Conference includes new leader, rules, technology. PMID- 22106527 TI - Give healthcare the green light. Energy conservation, resource stewardship need to be global priorities. PMID- 22106528 TI - Collaboration counts. Greater teamwork among clinicians, foundations to improve nursing profession. PMID- 22106529 TI - Recipe for success. Panelists see 'advocacy' representation, grooming leaders as building blocks. PMID- 22106531 TI - Social-ized medicine. Tweets, texts and apps help turn chat into action. PMID- 22106530 TI - Shining examples. More hospitals work to earn the Energy Star logo as they advance the greening of their facilities. PMID- 22106532 TI - Leadership. 'Only mugs work in commissioning': tackling the management brain drain. PMID- 22106533 TI - Inequalities. Cities fear impact of funds changes on poor. PMID- 22106534 TI - History can be our helper. PMID- 22106535 TI - On regulated competition. The NHS's new cultural revolution. PMID- 22106536 TI - Foreword. GPs get positive about the future. PMID- 22106537 TI - Integrated care. We want to be together. PMID- 22106538 TI - Out of hour. A shock to the system. PMID- 22106539 TI - General Practice. Your money or your life. PMID- 22106540 TI - Reform. How soon is now? PMID- 22106541 TI - Tim Riley on the realities of competition. PMID- 22106542 TI - Efficiency. A heavyweight answer to obesity. PMID- 22106543 TI - Workforce. In pursuit of a fair deal on pensions. PMID- 22106544 TI - Patient safety. The hardest lessons to learn. PMID- 22106545 TI - Reducing healthcare disparities in the military through cultural competence. AB - Healthcare disparities are fast encroaching upon equal access healthcare systems like the military. While this growth has been attributed to the same antecedents as those found in the general civilian population, four additional assumptions are posited as contributing factors to healthcare disparities that are peculiar to the military. Research on certain segments of the veteran population in the Veterans Administration (VA) is profiled as the most analogous healthcare system to that of the military's and a meta-analysis of studies on similar populations in the military are also examined. Like the general civilian population, cultural competence is viewed as an imperative component of healthcare delivery to help to narrow the healthcare disparities gap between majority (men and whites) and minority (women and nonwhites) populations in the military. PMID- 22106546 TI - Management of human resources associated with misuse of prescription drugs: analysis of a national survey. AB - Nonmedical use of prescription drugs is increasingly prevalent in the United States, but limited research is available on prescription drugs misuse in the workforce. We investigated whether absenteeism and turnover are associated with having problems linked to prescription drug misuse among employees. We also further explored the moderating effects of employee drug policy and testing on the relation between having problems linked to misuse of prescription pain relievers (PPRs) and absenteeism and turnover. This is a cross-sectional study (n = 2,249) using the 2007 U.S. national survey data ("National Survey on Drug Use and Health"). The multivariate logistic analysis results illustrate, after controlling confounding factors (gender, age, tobacco use, and heroin use), absenteeism and turnover linked to having problems of PPRs misuse. Our findings suggest the moderating effects of employee drug policy on the association between absenteeism and turnover and having problems linked to misuse of PPRs. Also, drug testing was found to moderate the link between having negative outcomes of misuse of PPRs and absenteeism. Having problems associated with misuse of PPRs is linked to absenteeism and turnover. A drug policy program including drug testing may play a significant role in reducing absenteeism and turnover in relation to having problems linked to misuse of PPRs. PMID- 22106547 TI - Examining the social, emotional and behavioral needs of youth involved in the child welfare and juvenile justice systems. AB - This study assesses the social, emotional and behavioral symptoms of 2,575 youth who were receiving behavioral health services from a private provider agency, either in an out of home placement (e.g., foster care home, a group home or a residential treatment facility) or in their own home (through the In-Home Services Program). The findings suggest the prevalence of symptoms in each of the domains (i.e., conduct problems, emotional problems, ADHD, and peer problems) were relatively high compared to the general population. Over 50% of the youth had conduct problems in the borderline or abnormal range, more than 35% had hyperactivity and peer problems subscale scores in the borderline or abnormal range, and almost 25% of the youth reported symptoms of emotional problems in the borderline or abnormal range. Youth's social, emotional and behavioral problems varied by gender, race/ethnicity and age group. PMID- 22106548 TI - Economic impact of public sector spending on health care. AB - Public sector spending on health care clearly has a positive economic impact on local communities. Not only does such spending provide residents with better health care, but it is widely recognized as an investment that returns continual dividends in the form of better jobs, higher incomes, and additional state and local tax revenues. The results of a static input/output model shows that public sector spending on health care of approximately $46 billion (in 2009 dollars) in the state of Texas yields over 588,000 jobs, $74.2 billion in total output, $26.3 billion in personal income, $22 billion in employee compensation, and $1.8 billion in state and local taxes; it clearly has a considerable positive economic impact on local economies and their quest for economic development. PMID- 22106549 TI - Obesity and breast cancer. AB - Obesity is a growing health problem in the United States and, increasingly, around the world. Excess body weight has been linked to an increased risk of postmenopausal breast cancer, and growing evidence also suggests that obesity is associated with poor prognosis in women diagnosed with early-stage breast cancer. Dozens of studies demonstrate that women who are overweight or obese at the time of breast cancer diagnosis are at increased risk of cancer recurrence and death compared with leaner women, and some evidence suggests that women who gain weight after breast cancer diagnosis may also be at increased risk of poor outcomes. In this review, we describe the evidence linking obesity to breast cancer recurrence, discuss the potential biological mechanisms through which weight could impact breast cancer prognosis, and review the weight-loss intervention studies that have been performed in breast cancer populations to date. PMID- 22106550 TI - Breast cancer patients who are obese at diagnosis: alea iacta est? or "is the die cast"? PMID- 22106551 TI - The obesity and breast cancer connection: advancing the agenda. PMID- 22106552 TI - PARP inhibitors in breast cancer: BRCA and beyond. AB - DNA repair is essential for the survival of both normal and cancer cells. An elaborate set of signaling pathways detect single-strand and double-strand DNA breaks and mediate either DNA repair or apoptosis if the damage is too great to repair. Poly(adenosine diphosphate [ADP]-ribose) polymerases (PARPs) play a key role in the repair of base damage via the base excision repair pathway. Pharmacological inhibition of PARP induces cell death in tumors with mutations in certain DNA repair pathways--such as the BRCA pathways of double-strand break repair--and when combined with chemotherapies that cause DNA damage. PARP inhibitors are being investigated as a monotherapy for the treatment of patients with BRCA 1/2 mutations; in the treatment of triple-negative breast cancer, because of its molecular similarities to BRCA1-mutated malignancies; and as a strategy to potentiate the DNA-damaging effects of chemotherapy and radiation. The aim of this article is to review the preclinical data and rationale for PARP inhibitor use in the aforementioned settings, as well as the current status of the clinical development of these agents in the treatment of breast cancer, along with future directions for research in this field. Trials have been identified via searches of PubMed, clinicaltrials.gov, and the Proceedings of the American Society of Clinical Oncology Annual Meeting and the San Antonio Breast Cancer Symposium. PMID- 22106553 TI - PARP inhibitors: the story is still unfolding. PMID- 22106554 TI - PARP inhibitors and their evolving role in breast cancer. PMID- 22106555 TI - Locoregional recurrence of an HPV-positive squamous cell carcinoma of the head and neck. PMID- 22106556 TI - Recommendations for women with lobular carcinoma in situ (LCIS). AB - Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) represent a spectrum of breast disease referred to as "lobular neoplasia" (LN). Although LN occurs relatively infrequently, it is associated with an increased risk of breast cancer, ranging from a three- to four-fold increased risk with ALH up to an eight to ten-fold increased risk with LCIS. Initially regarded as a direct precursor to invasive lobular carcinoma, LCIS used to be treated by mastectomy. Subsequent studies demonstrating that the risk of invasive disease was conferred bilaterally and that subsequent cancers were of both the ductal and lobular phenotype led to the acceptance of LCIS as a marker of increased risk rather than a true precursor. Today, a diagnosis of LCIS remains one of the greatest identifiable risk factors for the subsequent development of breast cancer. As such, patients are offered one of three options: (1) lifelong surveillance with the goal of detecting subsequent malignancy at an early stage; (2) chemoprevention; or (3) bilateral prophylactic mastectomy. Paralleling changes in the management of invasive breast cancer, trends in the management of LCIS have moved toward more conservative management. However, we have made little progress in understanding the biology of LCIS and therefore remain unable to truly optimize recommendations for individual patients. PMID- 22106557 TI - The challenges of treating lobular carcinoma in situ. PMID- 22106558 TI - Lobular neoplasia: how to manage with partial understanding. PMID- 22106560 TI - Novel DNA-silencing function of BRCA1 discovered. PMID- 22106559 TI - Screening identifies mechanisms of drug resistance to PI3K inhibitors. PMID- 22106561 TI - Mucocutaneous paraneoplastic syndromes associated with hematologic malignancies. AB - Cutaneous paraneoplastic syndromes are a group of dermatoses that demonstrate a range of morphological and pathological findings. These syndromes may precede, be concurrent with, or follow the diagnosis of an underlying malignancy. Treatment of the malignancy is often associated with improvement in or resolution of the mucosal and cutaneous disease; however, this is not the case with paraneoplastic pemphigus (PNP). PNP is a rare syndrome that was first described in 1990, and it occurs almost exclusively in patients with lymphocytic neoplasms. Pulmonary manifestations occur in 30% to 40% of cases, and it is the only form of pemphigus that attacks epithelium other than squamous epithelium in an antibody-mediated fashion. The mortality rate for PNP associated with malignancy is greater than 90%. Treatment guidelines are not available, but case series point to the use of rituximab (Rituxan) as well as corticosteroids and various other immunomodulating agents. Here we present a diagnostic and treatment dilemma in a 39-year-old active-duty male who developed PNP in the setting of treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for grade 3 follicular lymphoma. This case report is followed by a review of the diagnosis and treatment of other cutaneous paraneoplastic syndromes that are associated with hematologic malignancies. PMID- 22106562 TI - Management of breast cancer in young patients involves complicated surgical, genetic, and fertility issues. PMID- 22106563 TI - DNA-damaging therapies emerging as possible triple-negative breast cancer therapies. PMID- 22106564 TI - Mammography in younger women, palpation, account for many diagnoses in Michigan study. PMID- 22106565 TI - No survival advantage for mastectomy vs breast conservation therapy. PMID- 22106566 TI - Essiac. PMID- 22106567 TI - Turmoil over New Delhi metallo-beta lactamase-1 :a tale of ersatz patriotism. PMID- 22106568 TI - The Bhopal gas disaster and the poor state of occupational health and safety India. PMID- 22106569 TI - The ART of marketing babies. AB - New legislation can be oppressive for a significant population depending upon the politics of its drafters. The current upsurge of the surrogacy trade in India, and the label of a "win-win" situation that it has acquired, points towards an unfettered commercialisation of assisted reproductive technology and the practice of surrogacy that is blinding its middle class users as well as providers, policy makers and law makers, and charging an imagination that is already caught up in spiralling consumerism. This paper analyses the Draft Assisted Reproductive Technology (Regulation) Bill and Rules, 2008, in the Indian socioeconomic context. It identifies the interests of the affected women, and examines the contradictions of the proposed Bill with their interests, as well as with current health and population policies, confining itself to the handling of surrogacy and not the entire content of the Bill. The bases of the analytical perspective used are: the context of poverty and the health needs of the Indian population; the need to locate surrogacy services within the overall public health service context and its epidemiological basis; the need to restrain direct human experimentation for the advancement of any technology; the use of safer methods; and, finally, the rights of surrogate mothers and their babies, in India, as opposed to the compulsion or dynamics of the medical market and reproductive tourism. PMID- 22106570 TI - Lessons from the response to A H1N1 influenza, 2009, India: ethics in pandemic planning. AB - After the Severe Acute Respiratory Syndrome (SARS) experience in 2003, ethics has found a place in discourses on pandemic planning and public health. It is no longer enough to merely have action strategies in a pandemic plan; both research literature and the World Health Organization recommend that one has to further ensure that the outcome of such action is fair to all concerned, and is in conformity with relevant ethical values and considerations. India's pandemic plan suffers from a glaring omission in this aspect. Taking strategies and responses during the 2009 A H1N1 outbreak in India as instances, this paper identifies the lessons to be learnt from this experience and argues that these raise ethical issues ingrained in pandemic planning which must be addressed. It ends with the suggestion that the Indian health authorities should add an ethical dimension to the national pandemic plan, as has been recommended by the World Health Organization and by post-SARS studies. PMID- 22106571 TI - Faculty awareness and interest about bioethics in a private medical college of Islamabad, Pakistan. AB - This study sought to evaluate the awareness of bioethics among faculty at Shifa College of Medicine, Islamabad, Pakistan, and to assess their interest in becoming part of a bioethics discussion group and enhancing their knowledge of this subject. 122 faculty members from the medical college, hospital and school of nursing filled out a questionnaire on ethics. 53% were aware of bioethics as a specialty. 85% showed an interest in educating themselves further in the subject and 61% were interested in becoming part of a bioethics discussion group. Only 50 out of 122 faculty members knew what an ethical dilemma was and only 38 were able to describe one in detail. The awareness level of bioethics as a specialty increased with seniority. However the enthusiasm to join a bioethics discussion group was greater among those at a junior level. PMID- 22106572 TI - Attitudes and practices of medical graduates in Delhi towards gifts from the pharmaceutical industry. AB - Pharmaceutical companies use a variety of strategies, including gifts, to influence physicians. In December 2009, the Medical Council of India amended the Code of Medical Ethics to ban medical professionals from accepting gifts from pharmaceutical companies. In view of this ban, it is important to find out the magnitude and contours of the problem amongst Indian medical professionals. We aimed to study, through an e-mail based survey, the attitudes and practices of young resident doctors and interns from two medical colleges of New Delhi regarding acceptance of gifts from the pharmaceutical industry. We e-mailed the questionnaire to 150 fresh graduates. We found that the majority of graduates agreed with existing guidelines: they accepted low cost gifts but considered expensive gifts unrelated to patient welfare unethical. Despite the low response rate, this study is important because data from India on attitudes and practices of medical professionals regarding gifts from the pharmaceutical industry are virtually non-existent. PMID- 22106573 TI - The National Bioethics Conference: looking back and looking ahead. PMID- 22106574 TI - The Indian Medical Association and the Clinical Establishment Act, 2010: irrational opposition to regulation. PMID- 22106575 TI - The Clinical Establishment Act, 2010: laws must be implemented in the right spirit. PMID- 22106576 TI - Comment on "The Mental Health Act 1987: quo vadimus"? PMID- 22106577 TI - Amendments to the Mental Health Act, 1987: key controversies. PMID- 22106578 TI - Making can-do into must-do; the way forward to health and wealth? PMID- 22106579 TI - The Health Impact Fund: a potential solution to inequity in global drug access. AB - Global health inequities persist despite significant increases in funding and a growing number of global health initiatives. Especially vulnerable to disease, the poor majority of the world's population currently cannot afford advanced medicines, and the diseases confined to the poor receive little attention from pharmaceutical research. As a complement to the existing intellectual property regime, we have proposed the Health Impact Fund (HIF) as a mechanism that would create incentives for the development and optimal promotion of new high-impact medicines sold at the cost of manufacture. In this article, we outline the HIF and its ethical significance. PMID- 22106580 TI - Values conflicts in professional-community collaborations. AB - GAP/I and INP+ represent markedly divergent cultures and therefore highlight the opportunities and strains associated with professional-community collaborations. I believe, however, that the factors that emerge from studying GAP/I-INP+ are not idiosyncratic and are relevant for other professional-community dyads. Every such partnership is likely to require some form of bridging mechanism to serve the same purposes as Mr Varghese's role did. The task of creating a zone of optimal tension may be less familiar than the need to build bridges but it is no less important. Tension between partners with significantly different cultural backgrounds has tremendous potential for generating misunderstanding and distrust. Avoiding tension-laden issues is likely to entail significant cost, whether in the form of resentment, distrust, withdrawal, or settling for a lesser outcome than could be achieved. Finally, creating and sustaining the potential for constructive tension typically requires the humble virtues associated with servant-leadership: patience, persistence and understanding. PMID- 22106581 TI - Dealing with spousal violence. PMID- 22106582 TI - Hospital ethics committees: time to move beyond the obvious. PMID- 22106583 TI - Staggering apathy to injustice. PMID- 22106584 TI - Ethics and law. PMID- 22106585 TI - Deceptive perpetrators under cover: are they on the rise. PMID- 22106586 TI - Postgraduate surgical training in India. PMID- 22106587 TI - Wearing white coats in public places: pride or parody? PMID- 22106588 TI - The human cadaver: the silent teacher of human anatomy. PMID- 22106589 TI - Medical Council of India and the Indian Medical Association: uneasy relations. PMID- 22106590 TI - The NBC and the bioethics movement in India. PMID- 22106591 TI - Ethics, equity and justice: a view from the belly of the beast. PMID- 22106592 TI - Ethics, equity and genocide. PMID- 22106593 TI - National Bioethics Conference. Conference report. PMID- 22106594 TI - Ethical questions regarding health insurance in India. AB - Improved health and healthcare are of vital concern to the welfare of Indian society. The nascent health insurance system of the country is experiencing an explosive expansion and various models of health insurance provision are under trial by different agencies. Since the country has been relatively late in introducing health insurance, it can study the effects of different systems of healthcare and insurance and develop a system of health coverage which addresses the unique social character of our country as well as the ethical questions of comprehensiveness and inclusion. This article seeks to explore these issues in detail. PMID- 22106595 TI - Private health insurance and access to healthcare. AB - The health insurance business in India has seen a growth of over 25% per annum in the last few years with the expansion of the private health insurance sector. The premium incomes of health insurance have crossed the Rs 8,000 crore mark with the share of private companies increasing to over 41%. This is despite the fact that from the perspective of patients, health insurance is not a good deal, especially when they need it most. This raises a number of ethical issues regarding how the health insurance business runs and how medical practice adjusts to it for profiteering. This article uses the personal experience of the author to argue that health insurance in an unregulated environment can only lead to unethical practices, further victimising the patient. Further, publicly financed healthcare which operates in an environment regulating both public and private healthcare provisioning is the only way to assure access to ethical and equitable healthcare to people. PMID- 22106596 TI - Ethics of transparency in research reports. AB - Transparency in research methods and results is now widely seen as an imperative if the healthcare and research enterprise is to be truly successful. A patient centred focus in the conduct of clinical care includes its safety, effectiveness, efficiency, equity, and timeliness. Innovative ways are being developed to understand, disseminate, and rapidly apply the best evidence to care delivery. In this article, we demonstrate the use of simple and appropriate statistics in research reports that should help healthcare providers apply knowledge to practice by making it easier for them to understand clinical medicine. PMID- 22106597 TI - Survey of "instructions to authors" of Indian medical journals for reporting of ethics and authorship criteria. AB - This study looked at information on ethics reporting and authorship in the "instructions to authors" section of Indian medical journals. Instructions to authors in 59 Indian medical journals were examined for guidance on ethics reporting and authorship. Guidance regarding ethics was mentioned in 43 (72.8%) journals; assent from minors was mentioned in 9 (15.2%) journals; approval from an animal ethics committee was mentioned in 10 (16.9%) journals; authorship criteria were mentioned in 38 (64.5%) journals. Authorship criteria according to the International Committee of Medical Journal Editors were mentioned in 35 (59.3%) journals. Guidance regarding contributors' details was mentioned in 30 (50.8%) journals. These findings suggest that many editors of Indian medical journals must upgrade their instructions to authors to include ethical requirements. PMID- 22106598 TI - Opioid use at the end of life: working out the physician's intentions. PMID- 22106599 TI - Bioethics and transnational medical travel: India,"medical tourism," and the globalisation of healthcare. AB - Health-related travel, also referred to as "medical tourism" is historically well known. Its emerging contemporary form suggests the development of a form of globalised for-profit healthcare. Medical tourism to India, the focus of a recent conference in Canada, provides an example of the globalisation of healthcare. By positioning itself as a low-cost, high-tech, fast-access and high-quality healthcare destination country, India offers healthcare to medical travellers who are frustrated with waiting lists and the limited availability of some procedures in Canada. Although patients have the right to travel and seek care at international medical facilities, there are a number of dimensions of medical tourism that are disturbing. The diversion of public investments in healthcare to the private sector, in order to serve medical travellers, perversely transfers public resources to international patients at a time when the Indian public healthcare system fails to provide primary healthcare to its own citizens. Further, little is known about patient safety and quality care in transnational medical travel. Countries that are departure points as well as destination countries need to carefully explore the ethical, social, cultural, and economic consequences of the growing phenomenon of for-profit international medical travel. PMID- 22106600 TI - GRADE the evidence before using the results in clinical practice. AB - Reports of clinical trials that do not describe the methods used to minimise the risk of bias, and reports that do not present results in a comprehensible and accurate manner, are unethical as they could lead to misleading conclusions, adverse health outcomes, and the inappropriate use of healthcare resources. The Grading of Recommendations: Assessment, Development, and Evaluation (GRADE) approach to framing healthcare recommendations provides a pragmatic approach to making summary evidence profiles of outcome-specific evaluations regarding the magnitude and precision of estimates of benefit and harms, and the overall quality of evidence from comparisons of healthcare interventions. In addition, contextual factors such as the balance between benefits, harms, and resource costs; baseline risks in different groups; inconveniences; varying values and preferences; and competing priorities and options, should ideally be extrapolated from these evidence profiles and other sources of evidence to determine the strength of recommendations regarding the use of an intervention. PMID- 22106601 TI - Health systems research and the Gadchiroli debate: a plea for universal and equitable ethics. PMID- 22106602 TI - Health insurance in India: the need to come together for a common good. PMID- 22106603 TI - My first suture. PMID- 22106604 TI - Selling the soul of the medical profession. PMID- 22106605 TI - Corruption in medical education: time to introspect. PMID- 22106606 TI - Boundary violation? PMID- 22106607 TI - White coated corruption. PMID- 22106608 TI - Surgical training in India. PMID- 22106609 TI - Rural doctors. PMID- 22106610 TI - Rural doctors: a solution, or yet another problem in the making? PMID- 22106611 TI - Life and death after Aruna Shanbaug. PMID- 22106612 TI - Serial maternal deaths in a tertiary care hospital: some questions. PMID- 22106613 TI - HPV vaccine trials and sleeping watchdogs. PMID- 22106614 TI - SEARCH's HBNC trial: towards a broader debate on the ethics of social intervention research. AB - The SEARCH home-based neonatal care (HBNC) trial generated a heated debate amongst health activists, researchers and demographers in India upon its publication in the Lancet in 1999. More than a decade after the Lancet article, a new debate has been sparked, this time on the ethics of the study. Against this backdrop, we identify three key questions which require in-depth discussion. First, was the choice of the study design (cluster nonrandomised control trial), appropriate given the circumstances relating both to the study site and the locale? Second, was it ethical not to offer any intervention to the control units given that a known treatment existed? Third, do contemporary research ethics guidelines satisfactorily address all the ethical issues related to the study design? This paper examines the first question. We draw three main conclusions from this critical appraisal of the HBNC trial. First, the study design of the trial is motivated by the paradigm of evidence-based programmes and policy formulation. Second, generally speaking, the HBNC study design passes the internal and external validity tests but raises important ethical questions. Third, these questions transcend the HBNC trial to apply to many other social and health interventions studies; as such, the HBNC trial should be studied as a paradigmatic case. PMID- 22106615 TI - Global governance of health: a minefield of contradictions and sectional interests. PMID- 22106616 TI - Comments on the National Health Research Policy. PMID- 22106617 TI - The draft National Health Research Policy. PMID- 22106618 TI - The Bhopal gas disaster: focus on community health and environmental effects. PMID- 22106619 TI - Orthopaedic surgeons and the device industry: skeletons in the closet. AB - The relationship between orthopaedic surgeons and the device industry is one that is mutually beneficial and productive. However there are skeletons in the closet. The financial implications of this relationship have come under intense scrutiny. The sponsorships and the financial benefits of this symbiotic relationship have been found to cross the boundaries considered acceptable to ethical practice of the profession. In India, the ethical transgressions resulting from unhealthy associations between the orthopaedic surgeon and the industry have yet to be given due importance. Adequate rules and regulations are yet to be enforced and self-regulation is practically non-existent. It is essential to deal with the problem and potential implications that can arise from this kind of misconduct at the organisational level and enforce them for compliance. PMID- 22106620 TI - Ethical aspects of the Revised National Tuberculosis Control Programme. AB - This paper identifies some ethical concerns regarding the Revised National Tuberculosis Control Programme (RNTCP). Only 10% of those with chest symptoms visiting public health facilities get specific treatment as they are diagnosed with TB. The remaining 90% who suffer from non-TB diseases are not given scientific treatment. This compartmental approach denies treatment to millions of people with chest symptoms. It has also eroded the popularity of public health facilities. Second, though 87% of those diagnosed on the basis of x-ray alone are unlikely to have TB, such unethical wrong diagnoses continue to be carried out under the TB programme. Still worse, the RNTCP's expectation that only half of TB cases should be smear positive effectively permits up to 50% of diagnoses to be wrong. The actual extent of wrong diagnosis is even higher as the majority of people with chest symptoms first visit private health facilities which base their diagnosis almost exclusively on radiological examination. Third, though 25% to 33% of TB cases get cured spontaneously, and at least two-thirds were cured even with incomplete treatment, the RNTCP insists on full treatment for all TB cases. This over-treatment is unethical, wasteful and also tantamount to scientific dishonesty. Studies to identify different categories of cases (those needing full treatment, short treatment or no treatment) have not been attempted. The introduction (under the RNTCP) of the "success rate"in preference to the well recognised "cure rate" was unethical and unwarranted. "Crying wolf" over Multiple Drug Resistant (MDR) TB to justify DOTS when there is no apparent alarming increase in the incidence of initial MDR tuberculosis cases is also questionable. Other ethical concerns about the RNTCP include the irrational choice of districts leading to exclusion of those that need the services most; exclusion of diagnosed patients from the DOTS scheme, and exclusion from treatment on non-medical grounds. Such exclusions can be up to 58% of TB cases. PMID- 22106621 TI - Newer vaccines in the Universal Immunisation Programme. AB - Vaccines are important preventive medicines for primary healthcare and critical for a nation's health security. In India the Universal Programme of Immunization (UPI), launched in 7985, included six childhood vaccines. A well thought out immunisation schedule must be epidemiologically relevant to the country's health status, covering only diseases that are public health problems and for which effective vaccines are available. There has been pressure from the drug industry to include all newly developed vaccines in the government's UIP even though the clinical and epidemiological justification for their inclusion is debated. Many developed countries have included several other new vaccines in their regular immunisation programmes. These trends are used as a justification by the industry to include these vaccines in the Indian UIP in the future. All these vaccines need not, and cannot, be given universally. This paper looks at some vaccines which are newly included in the UIP schedule, or which may be included in the near future. PMID- 22106622 TI - Living unrelated kidney donors: ethical aspects of living kidney donation in Brazil. AB - Brazil has established the largest public kidney transplantation system in the world .46.2% of transplants in 2008 came from living donors. The vast majority of these involved relatives of the recipient; less than 8% came from unrelated donors. In 2008, Brazil's health minister proposed banning unrelated donors in kidney transplantation. A large number of the over 35,000 Brazilians on the waiting list for a kidney would be denied a transplant without the use of unrelated donors. Brazilian culture has a unique feature, the "informal family", that is not legally recognised as a "family entity and is bound by affection rather than genetic or legal ties. It is vital that Brazil establishes a regulated, standardised, and ethical system of organ procurement; creates awareness about transplantation in physicians and the public; upgrades facilities and standardises medical care, and enforces legislation for transplantation. However, outlawing the use of unrelated donors would result in injustice for many patients who seek kidneys. PMID- 22106623 TI - Dignity of women patients in health clinics. AB - This essay draws attention to violations of privacy and confidentiality in healthcare. It argues that such violations are experienced not only by rural women and beneficiaries of government health services but also by better-off women in private clinics in urban areas. It is possible that the occasional reports of such violations represent a fraction of the actual number of such incidents. There is an urgent need to recognise the problem and take corrective measures. PMID- 22106624 TI - How to teach ethics to those who need to learn. PMID- 22106625 TI - Indian Medical Association: time to clean house. PMID- 22106626 TI - "When a yes should mean no": doctors and boundaries. PMID- 22106627 TI - Product endorsement by medical practitioners. PMID- 22106628 TI - Iatrogenic STD inoculation study. PMID- 22106629 TI - Research in poor countries: the Guatemalan trials. PMID- 22106630 TI - New stipulations for dealing with pharmaceutical and allied health sectors. PMID- 22106631 TI - Ailing medical services in India. PMID- 22106632 TI - Photographing patients: an emerging unethical trend. PMID- 22106633 TI - Are doctors justified in refusing to give emergency treatment? PMID- 22106634 TI - Occupational health problems from "standing jobs". PMID- 22106635 TI - Can ethics committees address society's concerns about standards in research? PMID- 22106636 TI - Inclusion of ethics matters in the undergraduate medical curriculum. PMID- 22106637 TI - The ethics of ethical expertise in science, medicine and healthcare policies. PMID- 22106638 TI - Towards local participation in the creation of ethical research guidelines. AB - Research ethics committees are entrusted with implementing guidelines to protect both scientists and human subjects of research from harm. These guidelines are often based on western contexts and may not resonate with the local moral traditions of the communities that they seek to protect. In this essay, we discuss how using principles of deliberative democracy with a "local derivation" approach may help in the drafting and implementation of ethical guidelines for research that better serve society. PMID- 22106639 TI - Institutionalisation of Bulgarian ethics committees: history and current status. AB - This paper provides an overview of the institutionalisation of the ethics review process in Bulgaria in accordance with the worldwide trend in establishment of ethics committees. Historical and current politico-legal changes influencing the work of ethics committees are analysed. The paper focuses on ethics committees which review biomedical research involving humans, with an emphasis on their composition, functions, training of members, and decision-making processes. Recent positive changes addressing insufficient training of ethics committees'members are highlighted. Recommendations are made for enhancement of the ethics review process and improved transparency. PMID- 22106640 TI - Competence of ethics committees in patient protection in clinical research. AB - Research Ethics Committees (RECs) are responsible for the protection of patients' rights and wellbeing. In this paper, we describe the findings of a survey of ethics committee members in a south Indian state. 29 members of 11 RECs responded to a questionnaire of 56 questions on their knowledge of and attitudes towards ethics review and the practices of the RECs to which they belonged. PMID- 22106641 TI - Global summit of national ethics committees: an essential tool for international dialogue and consensus-building. AB - July 2010, important decisions were taken to ensure the continuity Held for the first time in 1996, the Global Summit of National of activities between the Summits. This article intends to briefly Ethics Committees (NECs) is a key platform for dialogue and retrace the history and analyse the role and functioning of the fostering consensus on ethical issues at a global level. At the Global Summit. It also discusses future challenges for international Eighth Global Summit meeting, which took place in Singapore in collaboration of NECs. PMID- 22106642 TI - Bioethics governance in Israel: an expert regime. AB - This paper provides an overview of bioethics governance in Israel through an analytical description of the legal framework for the interface between individuals and biomedical practices. There is no national agency with general oversight of bioethics policy and decision making, and the rules that apply to individual usage of biomedical technologies are laid down in a multitude of different statutes, regulations and administrative directives. Expert committees play a central role in this regulatory system in two capacities: as governmental advisory bodies that recommend policy; and as decision-making bodies that resolve conflicts around patients' rights or grant individual access to biomedical technologies. This decentralised system of governance through expert committees allows for adaptation to dynamic technological developments and flexibility in accommodating creative societal usage. At the same time the experts are the agents of the state's bio-power at the expense of personal autonomy and open public deliberation. The paper is part of a larger study investigating Israel's bioethics governance and its regime of experts, which includes an examination of the normative level of regulation, and an analysis of the composition of the expert committees. Our findings suggest that Israel has a decentralised system of governance with piecemeal regulation that has established a bioethics technocracy, governed by the ministry of health and dominated by the medical profession. The present paper is confined to a description and discussion of the legal framework of Israel's expert bioethics regime. Here, our major conclusion is that Israel has established a technocracy of official expert ethics committees, which controls life and death decisions. PMID- 22106643 TI - The role of basic laboratory services in strengthening primary health centres. AB - Several proposals have been initiated under the National Rural Health Mission (NRHM) to strengthen public health services in the country. Primary health centres (PHCs) are the basic structure for implementing primary healthcare, and basic laboratory services are essential not only for strengthening PHCs but also for their sustainability. In order to accomplish these, possibilities within NRHM are discussed. PMID- 22106644 TI - Medicare in the USA: a review of 45 years of health provision. AB - From a review of the experience and history of Medicare in the US over these 45 years, politics and economics played a large role in its introduction, in the direction it took in its initial years, and more recently in the introduction of "donut hole" drug coverage. However, health planning and policy processes in federal and state agencies have grown, and by using data collected over the years on the Medicare programme specifically, and the health system more broadly, trial programmes to control costs and introduce efficiencies into healthcare have been and will continue to be undertaken. Those identified as workable and effective are then introduced as policy. For at least two generations now, in the US, the burden of health costs in old age, the period of greatest vulnerability to disease and chronic conditions, has been lifted, as foreseen by President Johnson in 1966. PMID- 22106645 TI - Content audit of drug advertisements in Pakistan. AB - A sample of 120 drug advertisements was drawn by nonprobability convenience sampling from among the stalls of 50 pharmaceutical companies participating in an exhibition in Karachi, Pakistan. 23 belonging to the NSAID drug group were selected and evaluated on whether they met guidelines for ethical advertisements as laid down in the Drugs Act, 1976. Only 5 out of the 23 advertisements met at least 14 out of 16 criteria for ethical advertisements as given in the Drugs Act, 1976. PMID- 22106646 TI - Supported and unsupported claims in medicinal drug advertisements in Indian medical journals. AB - The study assessed 292 supported and unsupported claims in 102 medicinal drug advertisements across 15 Indian medical journals published in 2009. WHO ethical criteria for medicinal drug promotion were applied. None of the advertisements satisfied all the WHO criteria. Safe prescribing information on major adverse drug reactions, contraindications and warnings was provided in only 19 advertisements. Of 292 drug claims, only 80 (27%) were supported with reference(s), of which only 7 (9%) claims were unambiguous, or well substantiated with references. 14 references quoted did not substantiate the claim and 15 constituted weak scientific evidence. Superlatives like "tested" "trusted" "guarantees success" and "matchless safety" were used without evidence to substantiate such claims. Stronger enforcement mechanisms are necessary to ensure reliable drug information in pharmaceutical advertisements. PMID- 22106647 TI - Regulating (or not) reproductive medicine: an alternative to letting the market decide. AB - Whilst India has been debating how to regulate 'surrogacy' the UK has undergone a major consultation on increasing the amount of 'expenses'paid to egg 'donors', while France has recently finished debating its entire package of bioethics regulation and the role of its Biomedicine Agency. Although it is often claimed that there is no alternative to the neo-liberal, market-based approach in regulating (or not) reproductive medicine--the ideology prevalent in both India and the UK--advocates of that position ignore the alternative model offered by France's tighter regulation, as well as its overarching concern with protecting the vulnerable and ensuring social justice. Whilst the concepts underpinning the French model of regulation also have their provenance in Western political philosophy and not in the developed world, they embody a very different attitude and suggest that there is indeed an alternative to letting the market decide. However, even in France that alternative is highly contested. PMID- 22106648 TI - Commentary on HPV screening for cervical cancer in rural India. AB - In 2009 Sankaranarayanan et al published their findings from a large cluster randomized, controlled trial of a single round of HPV testing, cytology testing or visual inspection with acetic acid--with appropriate treatment for those confirmed positive--as interventions to decrease mortality from cervical cancer. The control arm did not receive any screening or treatment. Several issues are brought up through the approval and conduct of this trial, which was carried out among high-risk women in rural Maharashtra, India. Specifically, this trial offers an opportunity to further discussion around clinical equipoise, identification of primary endpoints, observation of null effects, and the informed consent process, within the context of a low-income setting. Such discourse may shed light on the necessity and manner of examining a biomedical intervention in low-income settings, when the intervention is already considered efficacious in high-income settings. PMID- 22106649 TI - Maternal deaths in Rajasthan: where does the buck stop? PMID- 22106650 TI - National Rural Health Mission: the current scenario. PMID- 22106651 TI - The upgraded Clinical Trials Registry India: a summary of changes. PMID- 22106652 TI - Short-term research projects in low-resource settings. PMID- 22106653 TI - Women in the healthcare system. PMID- 22106654 TI - The Clinical Establishment Act, 2010: need for transparency. PMID- 22106656 TI - Institutional ethics committees: critical gaps. PMID- 22106655 TI - White coated corruption: time to begin even with small steps. PMID- 22106657 TI - Evidence-based medicine: can the evidence be trusted? AB - Empirical research indicates that much of the evidence required for the practice of evidence-based medicine cannot be trusted. The research agenda has been hijacked by those with vested interests within industry and academia, determining what research is funded and how it is done and reported. Unnecessary, inappropriate, or poorly designed and reported research results in suboptimal health outcomes. Many well-reported randomized controlled trials are designed to deceive by their choice of comparators and outcomes, and manipulation of statistics to produce desired outcomes that are selectively reported. Undisclosed conflict of interest, ghost-writing, the manufacturing of disease to increase drug marketing, and the marketing of research disguised as education are common. Understanding the many ways in which research is used to deceive, rather than reliably inform health decisions, and reclaiming the research agenda, is the collective responsibility of the scientific community and civil society. PMID- 22106658 TI - A study of warning letters issued to clinical investigators and institutional review boards by the United States Food and Drug Administration. AB - BACKGROUND: Warning letters (WLs) issued by the US FDA (United States Food and Drug Administration) mention the nature of violations by clinical investigators and institutional review boards (IRBS) and can help as training tools. METHODS: WLs issued by the US FDA between January 2005 and December 2010 to clinical investigators and IRBs were reviewed for various violation themes. RESULTS: A total of 129 WLs were issued to investigators and 40 to IRBs. Among the WLs issued to investigators, 67 (51.95%) were issued for drug-related research and 62 (48.06%) were for device-related research. For investigators, deviation from the investigational plan was the most common violation (81%) followed by failure to maintain accurate and adequate case histories (58.1%) and then informed consent issues (48.06%). Among WLs issued to IRBs, failure to have and follow standard operating procedures (SOPs) was seen in 93.89% followed by issues pertaining to membership (59.4%). When compared to a similar study published in 2004, for clinical investigators, no improvement was seen with respect to deviation from the investigational plan and study supervision. However, a significant improvement was seen in reporting of adverse events to IRBs, and some improvement was seen in the area of informed consent. For IRBs, no improvement was seen in most areas which included maintaining and following SOPs, membership, quorum requirements, misuse of expedited review and informed consent. CONCLUSION: WLs serve as indicators of an active regulatory agency which should translate into greater safety for participants in clinical trials. For developing countries with weak regulatory systems, these can serve as useful learning tools to help improve systems and put in patient safeguards. PMID- 22106659 TI - Survey of ethics committee protocol approval letters: compliance with Schedule Y/ICMR guidelines 2006. AB - A study was carried out to determine the extent to which ECs comply with format requirements given in guidelines and regulations. ECs were sent a written communication requesting them to permit investigators to study their approval letter for compliance with the ICMR Guidelines and Schedule Y using a pre designed proforma. Of the 60 ECs approached, only 20 agreed to participate. Legal experts and social scientists were not present at the approval meetings of most of the ECs. Only 7 ECs had a quorum according to Schedule Y Several ECs did not state whether documents such as the clinical trial agreement and insurance policy were reviewed. Delays in sending approval letters could be shortened with efficacious operating of ECs. There is a need to train EC members and create a better awareness of regulatory requirements. There is also a need to evolve a mechanism to monitor EC functioning. PMID- 22106660 TI - Considering ethics in community eye health planning: perspectives from an existing model. AB - Despite the widespread acceptance of the principles of the Alma Ata Declaration of 1978 and the subsequent amendments, health for all has remained a distant dream in many parts of the developing world. Concerns such as the economic efficiency of health systems and their reach and coverage have dominated discussions of public health, with ethics remaining at best a shadowy set of assumptions or at worst completely ignored. Similarly, questions of ethics have been taken for granted and rarely addressed directly in the design of public health models across sectors and are rarely explicitly addressed. This paper uses the experience of the L V Prasad Eye Institute's (LVPEI) pyramidal model of eye healthcare delivery to explore ethical issues in the design and implementation of public health interventions. The LVPEI model evolved over time from its beginnings as a tertiary care centre to a network that spans all levels of eye care service delivery from the community through primary and secondary levels. A previously published analytical framework is applied to this model and the utility of this framework as well as the ethics of the LVPEI model are interrogated. An analytical and prescriptive framework is then evolved that could be used to build in and evaluate ethics in other public health delivery models. PMID- 22106661 TI - Impact of UNCRPD on the status of persons with disabilities. AB - The sanctity of human life is a fundamental human value and the medical profession has been ethically charged with respecting and enhancing the value of all human beings' lives. However, disability-selective abortion has been perceived as an acceptable health intervention to eliminate disabilities, and is provided for in law as well as in policies and healthcare programmes related to disability. Advanced medical technologies are being utilised not to maximise the lives of persons with disabilities but to prevent the birth of disabled people by medically terminating foetuses diagnosed with disability. Evidently, disability is seen as undesirable per se by society, and life with disability as not worth living. The disability rights perspective argues that such laws, policies and programmes deny persons with disabilities the right to life and thereby discriminate against them. They violate the United Nations Convention on the Rights of Persons with Disabilities that recognises the inherent human dignity of all human beings and treats persons with disabilities on an equal basis with all other human beings. This paper examines the question of whether disability selective abortion as a prevention strategy diminishes the value of persons with disabilities, in the context of the right to life and dignity of life accorded by the UNCRPD to persons with disabilities. This is discussed in the context of a selected summary of international and Indian policy and law on this subject. PMID- 22106662 TI - Bringing back Aristotle. AB - Ethical analysis in medicine has been dominated by an approach derived from "the four principles" which focus on actions. By contrast, consideration of the virtues emphasises the importance of the moral agent. A renewed emphasis on virtue ethics, not as a rival, but integrated into deontological ethics is proposed. PMID- 22106663 TI - Some observations on World Development Report 2011: conflict, security and development. AB - The World Development Report 2011 describes the relationship between conflict, security and development and makes a strong argument in favour of strengthening legitimate institutions to reduce the fragility of countries facing protracted cycles of violence, and moving from violence to resilience in order to realise development goals. While highlighting some of the lessons learned from the report (the nature of violence in the 21st century, the global reach of seemingly local conflicts, the universality of conflict as an impediment to development, the role of the international community, and the impact on health), this comment discusses the role of development on conflict and security--particularly the role of imbalanced inequitable development on fuelling conflict and insecurity. PMID- 22106664 TI - Planning and response to the influenza A (H1N1) pandemic: ethics, equity and justice. AB - This paper aims to highlight three ethical considerations related to influenza pandemic planning and response: ethical allocation of scarce resources; obligations and duties of healthcare workers to treat patients, and the balance between conflicting individual and community interests. Among these, perhaps the most challenging question facing bioethics is how to allocate scarce, life-saving resources given the devastating social and economic ramifications of a pandemic. In such situations, the identification of clear overall goals for pandemic planning is essential in making difficult choices. The dilemma between the duty to save patients and the right to protect the healthcare personnel's own life and health is a key issue. During the course of a pandemic, civil liberties may also be threatened, requiring limits on individual freedom to protect individuals as well as entire communities. Yet, individual liberty should be restricted with great care, and only when alternative approaches are not effective. Pandemic influenza planning and response should be a cooperative and shared responsibility that balances community and individual interests. PMID- 22106665 TI - Free medical care and consumer protection. AB - This paper will examine the question of whether patients, who receive free medical care, whether from private charitable or governmental hospitals, can claim rights as 'consumers' under the Consumer Protection Act, 1986. The issue will be discussed from a constitutional perspective as well as that of the law of torts. PMID- 22106666 TI - Commentary: Implicit contract with providing agencies, not with care providers. PMID- 22106667 TI - The ethics of live surgery: an ongoing debate. PMID- 22106668 TI - Commentary: Live telecast surgery on shaky ground. PMID- 22106669 TI - Reflections on the High Court's dismissal of the 'TISS rape case'. PMID- 22106670 TI - When the patient's family refuses care: a practical ethical dilemma. PMID- 22106671 TI - Response: caught between two world views. PMID- 22106672 TI - Can we make our hospitals more patient-friendly? PMID- 22106673 TI - Ethics in cluster randomised trials: a grey zone. PMID- 22106674 TI - Rijeka Declaration on the future of bioethics. PMID- 22106675 TI - Medical insurance: promoting unethical practices? PMID- 22106676 TI - Euthanasia: ethical risks. PMID- 22106677 TI - Challenges of collaborative research. PMID- 22106678 TI - Doctor v/s doctor: always a lose-lose game. PMID- 22106679 TI - Don't use great people to sell your drug. PMID- 22106680 TI - Thought control. PMID- 22106681 TI - Improving the management of brain injuries in Malaysian hospitals. PMID- 22106682 TI - Caregivers' satisfaction of healthcare delivery at paediatric clinics of Universiti Kebangsaan Malaysia Medical Centre in 2009. AB - Patient's satisfaction has become increasingly important as patients evaluate healthcare services for both medical cost and quality. The purpose of this study was to measure the prevalence and the factors influencing caregivers' satisfaction. A cross sectional study of 262 respondents using universal sampling method was conducted at the paediatric clinics of Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Overall, 90.5% were satisfied with the services provided. Satisfaction rates based on various healthcare delivery domains were: 95.0% for communication skills, 88.5% for interpersonal aspect, 83.6% for technical quality, 82.1% for financial aspect, 72.9% for time spent with doctors and 64.9% for ease of contact. This study shows that the caregivers (an unpaid person who helps a person cope with disease) were highly satisfied with the communicational aspect delivered by the clinic. However, there is still room for improvement on ease of contact domain and waiting time in order to produce high quality service. PMID- 22106683 TI - Audit of pain management in the emergency department. AB - Pain management in Malaysian Emergency Departments has not been studied well. Convenience sampling was used to recruit 402 patients who presented with acute pain over a 2-week period. The 11-point Numerical Rating Scale was used to quantify pain. Pain relieving medications were prescribed to 178 patients (44.3%) in the Emergency Department. These patients had a median pain score of 7 on arrival. Nonsteroidal anti inflammatory drugs were the most commonly prescribed class of analgesic. Pain was found to be inadequately treated. PMID- 22106684 TI - Can the use of 70% isopropyl alcohol swab or aspiration using 5 microm Filter Straw reduce bacterial contamination of fentanyl solution used for regional anaesthesia? AB - This prospective study aimed to determine the extent of contamination of fentanyl solutions used for central neuraxial injection by wiping the neck of the ampoules with 70% isopropyl alcohol swabs (Kendall) before breaking open the ampoules and aspiration of fentanyl solutions using a 5 microm Filter Straw (B. Braun). In Group A, fifty fentanyl ampoules were wiped with 70% isopropyl alcohol swab prior to opening and the contents were aspirated immediately using a 21G needle and a 5 microm filter straw for culture. The same steps were repeated on the remaining solutions after two hours. In Group B, all the above steps were repeated but without wiping the ampoules with 70% isopropyl alcohol swabs. None of the samples from the wiped ampoules or aspiration using filter straw grew microorganisms. Six percent of the samples from unwiped group grew microorganisms when fentanyl were aspirated using a 21G needle and the contamination increased to 16% when repeated after two hours. Wiping the outsides of the fentanyl ampoules with 70% isopropyl alcohol swabs before opening or aspirating the contents using a 5 pm filter straw has been shown to be equally effective in avoiding bacterial contamination and should be practiced routinely when performing regional anaesthesia. PMID- 22106685 TI - Characteristic differences in neuroimaging and physical findings between non accidental and accidental traumatic brain injury in young children. A local experience in general hospital of Kuala Lumpur. AB - OBJECTIVE: The objective of this study is to identify the characteristic neuroimaging (namely brain CT) as well as physical findings found in young children with nonaccidental traumatic brain injury (TBI) and to compare them with accident cases of the similar age group, in order to study the specific features of the former group more precisely. MATERIALS AND METHODS: A cross sectional study was done involving 92 children aged 3 years old and below who were admitted to the Kuala Lumpur Hospital with diagnosis of moderate to severe traumatic brain injury from period of June 2007 to September 2009. These children were categorized into non-accidental and accidental TBI and their physical examination data, brain computed tomography and skeletal surveys were done within one week from the date of admission were compared. RESULTS: There was a male predominance in both non-accidental and accidental TBI groups with male-to-female ratio of 2:1 and 3:1 respectively. The majority of the non-accidental TBI cases presented with no definite history of trauma (52.2%) while most of the accidental TBI cases were caused by motor vehicle accidents (69.9%). Subdural haematomas appeared to be significantly the most common brain haematomas among the nonaccidental TBI as compared to the accidental group while extradural haematomas were only present in the accidental TBI group. Cerebral edema was also significantly more common in the non-accidental group. Signs of pre-existing brain injury, including cerebral atrophy and subdural hygroma/effusion were present in 23.9% and 19.6% respectively among children with non-accidental TBI and in none of the children with accidental TBI. None of the children in the non-accidental group diagnosed to have shear injury while 6 (13.0%) of the children in the accidental group was diagnosed with diffuse axonal injury. In our series, retinal haemorrhage was significantly more common in the non-accidental TBI group (93.5%) as opposed to only 4(8.7%) children noted to have retinal haemorrhage in the accidental group. Seizures also occurred significantly more often in children with non-accidental TBI. Depressed skull fractures were only found in the accidental TBI group (19.6%), while other types of skull fractures occur more or less similar in both groups. Bodily fractures were also more predominant among the accidental group of TBI. Bodily lacerations/abrasions were only found in the accidental group while findings of bodily bruises were quite equal in both groups. PMID- 22106686 TI - Head and neck cancer: possible causes for delay in diagnosis and treatment. AB - OBJECTIVE: To explore the possible causes for delay in diagnosis and treatment of head and neck cancer at Sarawak General Hospital (SGH). STUDY DESIGN: This is a prospective study of time interval between onset of symptom, first medical consultation, first specialist clinic consultation, diagnosis and treatment of head and neck cancer in otorhinolaryngology head and neck (ORL-HNS) and dental clinics at Sarawak General Hospital. Forty-two consecutive cases diagnosed to have cancer between July to December 2006 were studied. RESULTS: Mean interval between onset of symptom and medical consultation was 3.8 months, mean interval between first medical consultation to ORL-HNS or dental clinic referral was 8.4 weeks, mean duration between first ORL-HNS or dental specialist consultation to histopathological diagnosis was 18.8 days while duration between diagnosis to definite treatment was 26.9 days. CONCLUSION: Most cases were diagnosed at advanced stage. Patient delay was the main problem. There was significant delay by frontier health workers in identifying sinister symptoms of malignancy. Timing for diagnosis and treatment after specialist referral were comparable with other published studies. PMID- 22106687 TI - Irreducible rectal prolapse: emergency surgical management of eight cases and a review of the literature. AB - The management of irreducible rectal prolapse is controversial. Surgeons may attempt conservative management by application of sugar. When surgery becomes inevitable the choice of procedure varies. We reviewed eight cases and noted the clinical findings and the results of conservative and surgical management. In four cases sugar was applied first, and failed. Emergency surgery always gave good outcomes. The procedures included simple reduction, rectopexy, laparotomy with resection, Delorme's repair, and perineal resection. Our experience and review of the literature indicate that surgery should be performed early in irreducible prolapse. Perineal resection may be the most suitable emergency procedure. PMID- 22106688 TI - Cross-sectional study of older adults with type 2 diabetes mellitus in two rural public primary healthcare facilities in Malaysia. AB - Knowledge of the characteristics of older adults with type 2 diabetes mellitus (T2DM) is indispensible for improvement of their care. A cross-sectional study in two rural public primary healthcare centres in Malaysia identified 170 actively engaged older patients with T2DM, with suboptimal glycaemic control and frequent hypoglycaemia. The prevalence of multiple co-morbidities, complications of T2DM, high cardiovascular risk, neurological, musculoskeletal and visual deficits suggested high risk of disabilities and dependency but not yet disabled. This short window for interventions presents as an opportunity for development of a more comprehensive approach extending beyond glycaemia control to risk management, preventing functional loss and continuity of social participation. PMID- 22106689 TI - Serum high-sensitivity C-reactive protein and lipoprotein(a) levels: a comparison between diabetic and non-diabetic patients with coronary artery disease. AB - OBJECTIVE: The aim of this study was to compare high-sensitivity C-reactive protein (hsCRP) and Lipoprotein(a) levels [Lp(a)] levels between diabetic and non diabetic patients with coronary artery disease (CAD). STUDY DESIGN: Cross sectional Study. PLACE AND DURATION OF STUDY: This study was conducted in the department of Physiology of College of Medicine & King Khalid University Hospital, King Saud University, Riyadh between August 2006 and December 2007. METHODS: One hundred and three individuals with CAD and 30 healthy individuals matched for age and BMI were studied. CAD patients were divided into two groups based on presence (n=62) and absence (n=41) of type 2 diabetes mellitus. Overnight fasting blood samples were collected, and analyzed for total cholesterol (TC), Triglycerides (TG), Low density Lipoprotein (LDL) and High density lipoprotein (HDL), Lp(a) and hsCRP. Data about CAD severity was obtained from medical records. RESULTS: Both groups of CAD without and with DM had significantly higher levels of Lp(a) [mg/dl] (25.58 +/- 25.99, 25.90 +/- 24.67 respectively) and hsCRP [mg/dl] (0.52 +/- 0.71, 0.82 +/- 0.78 respectively) when compared with healthy control subjects (Lp(a) =16.93 +/- 15.34 & hsCRP=0.27 +/- 0.21) [p<0.05]. Lp(a) levels between the two CAD groups were non significant. While, hsCRP levels were significantly high in CAD with DM compared to those without DM [p<0.05]. Gensini Score of CAD severity was also higher in CAD with DM [67.60 +/- 45.94] than those without DM [52.05 +/- 42.27, p<0.05]. CONCLUSION: Elevated Lp(a) and hsCRP levels are associated specifically with angiographically defined CAD. However, hsCRP elevation but not Lp(a) is also associated with CAD in type 2 diabetes mellitus. Measurement of hsCRP and Lp(a) may be considered optional markers for better prediction of cardiovascular risk. PMID- 22106690 TI - Quality of life among patients with hematological cancer in a Malaysian hospital. AB - The aim of this study was to determine the prevalence of symptoms and problems in hospitalized hematological cancer patients. A cross-sectional design was carried out with 105 respondents in Ampang hospital in Kuala Lumpur. The European Organization for Research and Treatment of Cancer Quality Of Life questionnaire (EORTC QLQ-C30) was used. Patients with a minimum response of "a little" were defined as having a symptom/problem while patients with a response of "quite a bit" were classified as having a "severe symptom/problem". The four most prevalent symptoms/problems identified were fatigue, financial difficulties, reduced role function and reduced social function. Multiple myeloma patients (MM) were identified as having the most symptoms/problems. PMID- 22106691 TI - Challenges in diagnosis and management of pseudoptosis secondary to asymmetrical skin creases. AB - INTRODUCTION: Asymmetrical eyelid skin crease may be mistaken for ptosis due to apparent narrowing of the palpebral fissure in the eye without the skin crease. This study describes a series of patients who were mistakenly referred for ptosis operation as a result of absent skin crease. METHODS: Retrospective case review. RESULTS: A total of 8 patients (5 males and 3 females) were referred by the general ophthalmologists because of suspected ptosis. Although skin creases asymmetry was noted by the general ophthalmologists, the apparent narrowing of the palpebral fissure was thought to be caused by ptosis. However, measurement of the palpebral fissures in both eyes were normal. Creation of a symmetrical skin crease in the affected eye correct the appearent palpebral fissure narrowing. This could be achieved by either surgical or non-surgical means (tape or glue). CONCLUSION: Patients with asymmetrical skin crease of the upper eyelid can give rise to apparent differences in palpebral apertures which may be mistaken for ptosis. The treatment of choice is to create symmetrical skin crease in the eye with absent skin crease to correct the pseudoptosis. Recognition of this condition is important to avoid unnecessary ptosis surgery. PMID- 22106692 TI - The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children. AB - Recently, molecular testing for GJB2 mutations has become the standard of care for the diagnosis of patients with non syndromic hearing impairment of unknown cause. The aims of this study are to determine the association between GJB2 mutation and GJB6 and to report the variation of mutations in deaf students who have heterozygous GJB2. This retrospective study was conducted at Universiti Kebangsaan Malaysia Medical Center (UKMMC). Data was collected from previous files and records from Tissue Engineering and Human Genetic Research Group Laboratory. Approval from Ethical Committee was obtained prior to the study. A total of 138 students have been screened in previous studies in UKMMC for the presence of GJB2 mutations as a cause for hearing loss. Thirty four of the 138 subjects have GJB2 mutations; 2 showed homozygous mutations whereas another 32 were heterozygous for GJB2 gene mutation. Only 31 DNA samples of students presented with sensorineural hearing loss with heterozygous mutation in GJB2 gene were included in this study. The sequencing results obtained were analyzed. The degree of hearing loss of those students with association between GJB2 mutation and GJB6 mutation will be discussed. Five out of 31 subjects (16.2%) have mutations in their GJB6 gene, suggesting a digenic inheritance of GJB2/GJB6 mutation. In total, four novel mutations were identified; E137D (n=1), R32Q (n=1), E101K (n=1) and Y156H (n=1) and one mutation deletion; 366delT (n=1). All students with association GJB2 mutation and GJB6 showed severe to profound hearing loss in both ears. Interestingly this study not detected the large deletion of 342 kb in GJB6 gene suggesting that the mutation is very rare in this region compared to certain parts of the world. PMID- 22106693 TI - Effects of uvulopalatopharyngoplasty: a seven year review. AB - To review the long term outcome of Uvulopalatopharyngoplasty (UPPP) for obstructive sleep apnoea syndrome in a tertiary referral centre. 38 records were traced where UPPP was done from July 2000 to December 2007. 14 patients were followed up for one to seven years where the Epworth sleepiness scale was scored, long term side effects documented and post operative muller's manoeuvre done. Success of UPPP is defined as a reduction in apnoea hypopnea index (AHI) more than 50%. Sixty percent (60%) were successfully treated with UPPP in the long term. Mean ESS was significantly reduced from 12 +/- 6 to 7 +/- 4. 11 out of 14 patients (78.5%) were reported to develop long term side effects of UPPP, the highest being velopharyngeal insufficiency (42.8%). In conclusion, UPPP is effective in improving symptoms of OSA in the long term. However, in view of its side effects, uvula preserving surgery should be considered as a surgical option. PMID- 22106694 TI - HLA-DQ A1, -DQB1 and -DRB1 gene polymorphism--in Malay type 1 diabetes mellitus patients and their use for risk prediction. AB - HLA-DQA1, -DQB1, and -DRB1 gene polymorphism were analyzed to study type 1 DM susceptibility in Malay patients from Southeast Asia (Malaysia and Singapore). Patients showed significant increases in the occurrence of DQA1*0501 (50.7% vs. 20.4%; RR = 3.97; Pc < 0.01), DQB1*0201 (48% vs. 19.1%; RR = 3.86; Pc < 0.05), and DRB1*0301 (38.7 vs. 6.8%; RR = 8.36; 95% Pc < 0.05). Conversely, significant decreases were noted in the occurrence of DQA1*0601 (14.7% vs. 35.2%; RR = 0.33; Pc = 0.008) and DQB1*0601 (4% vs. 23.5%; RR = 0.16; Pc < 0.05) in type 1 DM patients. Using a logistic regression model, we derived a risk prediction model for type 1 DM in our indigenous Malay population based on the identified HLA genotypes. The RR for type 1 DM increases by a factor of 5.68 for every unit increase in the number of DRB1*0301 allele (P < 0.001), and decreases by a factor of 0.18 per unit increase in the number of DQB1*0601 allele (P < 0.001). After adjusting for these two HLA genotypes, DQA1*0501, DQB1*0201 and DQA1*0601 were not statistically significant as risk predictors. The lower incidence of type 1 DM in the Malay population may be contributed by the genotypic combinations of DR and DQ genes as well as the linkage disequilibria between susceptible and protective alleles. PMID- 22106695 TI - Care of severe head injury patients in the Sarawak General Hospital: intensive care unit versus general ward. AB - Intensive care for severe head injury patients is very important in the prevention and treatment of secondary brain injury. However, in a resources constraint environment and limited availability of Intensive Care Unit (ICU) beds in the hospitals, not all severe head injury patients will receive ICU care. This prospective study is aimed to evaluate the outcome of severe head injured patients who received ICU and general ward care in Sarawak General Hospital (SGH) over a 6-month period. A total of thirty five severe head injury patients were admitted. Twenty three patients (65.7%) were ventilated in general ward whereas twelve patients (34.3%) were ventilated in ICU. Overall one month mortality in this study was 25.7%. Patients who received ICU care had a lower one month mortality than those who received general ward care (16.7% vs 30.4%), although it was not statistically different. Multivariate analysis revealed only GCS on admission (OR 0.731; 95% CI 0.460 to 0.877; P=0.042) as the independent predictive factor for one month mortality in this study. PMID- 22106696 TI - Arteriovenous malformation of the stomach: a rare cause of upper gastrointestinal bleeding. AB - Haemorrhage arising from gastric arteriovenous malformation (AVM) is rare and normally occurs in the elderly. Bleeding gastric AVM presenting in the younger age group is even rarer. We report a case of a 14 year old boy who presented with recurrent episodes of haematemesis. He subsequently underwent a proximal gastrectomy and the histological examination confirmed a gastric AVM. After reviewing the literature we believe this is the youngest ever reported case of bleeding gastric AVM reported in English literature. PMID- 22106697 TI - Cricotracheal separation: a case of delayed diagnosis and treatment. AB - A motorcyclist was involved in a motor vehicle accident and presented with respiratory distress and neck swelling with surgical emphysema. He sustained gross tracheal injury, severe pneumothoraces and lung contusions. As intubation was successful, the tracheal injury was not addressed immediately in view of the other severe respiratory problems. Evidence of aspiration lead to further investigations which confirmed the diagnosis 22 days post trauma. Thyrotracheal anastomosis was carried out without stenting. A complete cricotracheal separation is a rare event and can be easily overlooked in the emergency department. PMID- 22106698 TI - Tuberculosis of gallbladder with candidiasis, a rare entity. AB - Gallbladder tuberculosis (GT) is an extremely rare condition. This is thought to be due to the protective property of bile against the infection. Clinical and radiological diagnosis of GT is difficult. We describe a case of GT who initially presented to us with jaundice, a right hypochondrial mass and computed tomographic findings suggestive of gallbladder empyema. Diagnosis was made from histopathological examination of the resected gallbladder which revealed epitheloid granulomas with caseating necrosis and presence of Langhan's giant cells. From a literature search and to the best of our knowledge, this is the first GT to be reported in South East Asia. PMID- 22106699 TI - Harmonic scalpel for a bloodless partial glossectomy: a case report. AB - Tongue surgery is almost always complicated by intraoperative bleeding. Its rich blood supply especially from the lingual vessels makes the operative field bloody. Electrocautery has been widely used to replace cold scissors in order to achieve better hemostasis. The use of ultrasonic harmonic scalpel for glossectomy is still new in this country. We report a case of partial glossectomy using the harmonic scalpel in a patient who had a squamous cell carcinoma of the lateral border of the tongue. PMID- 22106700 TI - Intraparotid facial nerve schwannoma: a case report. AB - Schwannoma in the head and neck region is very rare. The tumour occurring in the intraparotid facial nerve is even rarer. A patient presenting with a parotid swelling with facial nerve paralysis is not pathognomonic of a facial nerve schwannoma. However it may occur because enlargement of the parotid, by any kind of tumour especially a malignant one can cause facial nerve paralysis. We report a case of an intraparotid facial nerve schwannoma, in a patient who presented with parotid enlargement and facial nerve paralysis. PMID- 22106701 TI - Endoscopic treatment of glottic stenosis secondary to caustic injury with silastic keel placement: a case report. AB - The use of an endoscopic approach for the division of glottic webs or stenosis has been reported in the literature and has been mainly confined to the anterior commisure. We report a rare case of caustic injury to the upper aerodigestive tract that resulted in extensive web formation along the membranous vocal cord which was successfully treated with endoscopic lysis of the adhesions and the use of a silastic sheet keel as a stent. PMID- 22106702 TI - A child with septic arthritis of hip: a rarely encountered cause. AB - We report a rare case of septic arthritis in a healthy child caused by Salmonella enteritidis. No predisposing factor was detected. Salmonella enteritidis was isolated from the infected joint tissue obtained following surgical drainage. Based on the culture and sensitivity report, he was treated with a 6-week course of antibiotic. He improved dramatically without any detrimental sequelae at end of one year. PMID- 22106703 TI - Trilateral retinoblastoma. AB - Trilateral retinoblastoma is the association of hereditary bilateral or unilateral retinoblastoma with a pineal neuroblastic tumour. We describe two cases of trilateral retinoblastoma from a total of 141 cases of retinoblastoma seen over an 8.5 year period. Both had a fatal outcome, with survival times of only 4 and 8 months respectively. PMID- 22106704 TI - Perforation of duodeno-jejunal junction in an 8-month-old infant: a management challenge to a general surgeon. AB - We report a case of perforation over duodeno-jejunal junction (DJ) in a healthy 8 month-old baby. The difficulty in diagnosis, management dilemma and probable etiology is discussed. PMID- 22106705 TI - Nasal NK/T cell lymphoma mimicking an latrogenic lateral nasal wall infection: a diagnostic dilemma. AB - Extra nodal NK/T cell lymphoma, 'nasal type' is a rare clinicopathological entity. The prevalence of nasal lymphoma is estimated at 0.17-1.5% for all non Hodgkin's lymphomas (NHL), of which 45% originate from the NK/T cell. It is more commonly encountered in Asian countries. The main clinical features are nasal congestion and epistaxis due to local aggressive destruction. It has a distinct immunophenotypic profile of CD2+, CD56+ and CD3-. The tumor often shows polymorphic lymphoreticular infiltrates and necrosis. We present a case of a 50 year-old male who presented with lateral nasal wall infection following endoscopic sinonasal surgery and later proven to be extranodal NK/T cell 'nasal type' lymphoma with immunophenotypic features. PMID- 22106706 TI - Access to medical journals in Malaysia. PMID- 22106707 TI - Initial management of spontaneous pneumothorax--role of the thoracic surgeon. PMID- 22106708 TI - Comment on: Current concepts in the management of carotid body tumours. PMID- 22106709 TI - Breastfeeding--anti-viral potential and relevance to the influenza virus pandemic. AB - Essential nutritive and immunological ingredients abundantly present in breastmilk make it the choice infant nutrition. The uniqueness of mother's milk, in contrast to most therapeutics and immunizations, lies in its potential to adapt itself to the requirements of the infant so that timely immune defenses are tapped from its constituents by immune regulation, modulation and immune acceleration to stimulate novel substances; these render it pertinent as defense when faced with challenging organisms. While it is appreciated that immunity can be transferred from mother to infant through breastmilk following maternal influenza vaccination, the immense benefits conferred by breastfeeding per se during influenza pandemics may not be fully valued. This is substantiated by debates and ambiguities for continued breastfeeding in the face of maternal influenza infections. This article emphasises the utmost importance of breastfeeding in viral pandemics in the light of the changing immunological strategies used by viruses at different times and the urgent need for such opportune defenses. The prolific interaction of its constituents is frequently understated as enormous advantages to the suckling infant. PMID- 22106710 TI - Hereditary inclusion-body myopathy with sparing of the quadriceps: the many tiles of an incomplete puzzle. AB - The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy. PMID- 22106711 TI - Progress and problems in muscle glycogenoses. AB - In this selective review, we consider a number of unsolved questions regarding the glycogen storage diseases (GSD). Thus, the pathogenesis of Pompe disease (GSD II) is not simply explained by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why debrancher deficiency (GSD III) causes fixed myopathy rather than exercise intolerance, unless this is due to the frequent accompanying neuropathy. The infantile neuromuscular presentation of branching enzyme deficiency (GSD IV) is underdiagnosed and is finally getting the attention it deserves. On the other hand, the late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including Lafora disease) due to different etiologies. We still do not understand the clinical heterogeneity of McArdle disease (GSD V) or the molecular basis of the rare fatal infantile form. Similarly, the multisystemic infantile presentation of phosphofructokinase deficiency (GSD VII) is a conundrum. We observed an interesting association between phosphoglycerate kinase deficiency (GSD IX) and juvenile Parkinsonism, which is probably causal rather than casual. Also unexplained is the frequent and apparently specific association of phosphoglycerate mutase deficiency (GSD X) and tubular aggregates. By paying more attention to problems than to progress, we aimed to look to the future rather than to the past. PMID- 22106712 TI - Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis. AB - Sporadic inclusion body myositis (s-IBM) is characterized histologically by the association of concomitant inflammatory and degenerative processes. We evaluated the sensitivity and specificity of different markers of the degenerative process in order to refine the histological diagnosis. We performed an immunohistochemical study with antibodies directed against ubiquitin, amyloid beta precursor protein (AbetaPP), amyloid-beta (Abeta), SMI-31, SMI-310, Tar-DNA binding protein-43 (TDP-43) and p62 on s-IBM and control muscle biopsies. Based on conventional stains 36 patients with characteristic clinical features of s-IBM were subclassified as presumed definite s-IBM (d s-IBM, n = 17) or possible s-IBM (p s-IBM, n = 19) according to the presence or absence of vacuolated muscle fibers. Immunohistochemically, TDP-43 and p62 were the most sensitive markers, accumulating in all d s-IBM and in 31% and 37%, respectively, of the p s-IBM cases and thus enabling reclassification of these cases as d s-IBM. We recommend using TDP-43 and p62 antibodies in the histological diagnosis workup of s-IBM. The specificity of these markers has to be further validated in prospective series. PMID- 22106713 TI - Strategy for genetic testing in Charcot-Marie-disease. AB - BACKGROUND: Charcot Marie Tooth disease (CMT) affects one in 2500 people. Genetic testing is often pursued for family planning purposes, natural history studies and for entry into clinical trials. However, identifying the genetic cause of CMT can be expensive and confusing to patients and physicians due to locus heterogeneity. METHODS: We analyzed data from more than 1000 of our patients to identify distinguishing features in various subtypes of CMT. Data from clinical phenotypes, neurophysiology, family history, and prevalence was combined to create algorithms that can be used to direct genetic testing for patients with CMT. FINDINGS: The largest group of patients in our clinic have slow motor nerve conduction velocities (MNCV) in the upper extremities. Approximately 88% of patients in this group have CMT1A. Those who had intermediate MNCV had primarily CMT1X (52.8%) or CMT1B (27.8%). Patients with very slow MNCV and delayed walking were very likely to have CMT1A (68%) or CMT1B (32%). No patients with CMT1B and very slow MNCV walked before 15 months of age. Patients with CMT2A form our largest group of patients with axonal forms of CMT. INTERPRETATION: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we created a series of algorithms to guide testing. A more detailed review of this data is published in Annals of Neurology (1). PMID- 22106714 TI - Familial amyotrophic lateral sclerosis, a historical perspective. AB - Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of the upper and lower motor neuron of unknown etiology. Although a familial cause for this disease has been suspected early one, it is only in the past two decades that advances in modern genetics led to the identification of more than 10 genes linked to familial ALS and helped us understand some of the complex genetic and environmental interactions that may contribute to sporadic ALS. In this article, we chronologically summarize the genetic breakthroughs in familial and sporadic ALS and depict how it shaped our understanding of disease pathogenesis and our quest for rational therapies. PMID- 22106715 TI - Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy. AB - The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, alphaB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patients and three pairs of brothers) investigated at our neuromuscular center. MFM patients begin to show symptoms at any age, from juvenile to late adult life and present a different distribution of muscle weakness. Cardiac involvement and peripheral neuropathy are common. Typical histological features include focal areas with reduction/loss of ATPase and oxidative enzyme activity, and amorphous material (eosinophilic on hematoxylin and eosin and dark blue on Engel-Gomori trichrome) in these abnormal fiber areas. Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments. Immunohistochemical studies demonstrate focal accumulation of desmin, alphaB crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins also including ZASP protein. Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM. Finally three of our 21 patients have missense mutations in the desmin gene, two brothers carry missense mutations in the gene encoding myotilin, one has a missense mutation in alphaB-crystallin, and none harbour pathogenic variations in the genes encoding ZASP and BAG3. PMID- 22106716 TI - Dysferlinopathy course and sportive activity: clues for possible treatment. AB - LGMD2B is a frequent proximo-distal myopathy with rapid evolution after age 20. Exacerbating factors may be physical exercise and inflammation. There is very little information about the effect of sportive activity in LGMD2B, since eccentric exercise frequently results in muscle damage. LGMD2B has often an onset with myalgia and MRI imaging (STIR-sequences) shows myoedema. In a prolonged observational study of a series of 18 MM/LGMD2B patients we have studied the pattern of clinical and radiological evolution. The disease has an abrupt onset in the second decade and most patients perform sports before definite disease onset. On the basis of Gardner-Medwin and Walton scale, grade 4 is reached two years faster in patients who performed sports (over 1000 hours). Other considerations regarding pathogenetic mechanism and response to treatment show a poor response to immunosuppressive treatment of muscle inflammation. Preventing a strenuous physical activity should be recommended in patients with high CK and diagnosed or suspected to have dysferlin deficiency. PMID- 22106717 TI - A novel N440K sodium channel mutation causes myotonia with exercise-induced weakness--exclusion of CLCN1 exon deletion/duplication by MLPA. AB - We report a 4-generation Turkish family with 10 affected members presenting with myotonia and potassium- and exercise-induced paralytic attacks. The clinical presentation was neither typical for the chloride channel myotonias Thomsen and Becker nor for the separate sodium channel myotonia entities potassium-aggravated myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. It is best described by a combination of potassium-aggravated myotonia and hyperkalemic periodic paralysis. We excluded exonic chloride channel mutations including CLCN1 exon deletion/duplication by MLPA. Instead we identified a novel p.N440K sodium channel mutation that is located at the inner end of segment S6 of repeat I. We discuss the genotype phenotype relation. PMID- 22106718 TI - Laminopathies: many diseases, one gene. Report of the first Italian Meeting Course on Laminopathies. PMID- 22106719 TI - Finally, the final rule on OTC sunscreen drug products. PMID- 22106720 TI - What is your diagnosis? Giant molluscum contagiosum. PMID- 22106721 TI - Adolescent androgenic alopecia. AB - Adolescent androgenic alopecia is pattern hair loss occurring in boys and girls younger than 18 years, whereas early-onset androgenic alopecia refers to pattern hair loss before 35 years of age. A number of studies published in the last decade have helped to elucidate the prevalence of adolescent androgenic alopecia, have clarified the genetic as well as physiologic mechanisms underlying hair loss, and have revealed the associated psychologic and systemic morbidities. This article provides an overview of the pathophysiology, diagnosis, and treatment of adolescent androgenic alopecia. PMID- 22106722 TI - The fingernail cocktail: improving preoperative preparation for nail procedures. PMID- 22106723 TI - Malignant nodular hidradenoma treated with Mohs micrographic surgery. PMID- 22106724 TI - Grover disease (transient acantholytic dermatosis) induced by anastrozole. AB - We present the case of a 79-year-old woman with a history of breast cancer who developed Grover disease (transient acantholytic dermatosis) following initiation of an aromatase inhibitor, anastrozole, as adjunctive treatment of her breast cancer. A number of drugs have been associated with this condition; however, to our knowledge, this case is the first report of anastrozole-induced Grover disease. PMID- 22106725 TI - An unusual presentation of multiple hidrocystomas. AB - An 85-year-old man sought treatment of multiple nontender bluish papules of 3 years' duration on the forearms, forehead, and temples. On physical examination, blue-tinged, semitranslucent, dome-shaped papules were noted. Workup revealed multiple hidrocystomas. We discuss the findings in our patient and review the literature. PMID- 22106726 TI - Large facial basal cell carcinoma treated with multimodal combination therapy. AB - Large basal cell carcinomas (BCCs) with mixed intratumoral histology can present treatment challenges. Although a single treatment modality may be appropriate for some portions of the tumor, it may prove to be inadequate or overly aggressive for others. We describe a patient with a large facial BCC who was referred to our clinic for Mohs micrographic surgery. Biopsies revealed both noduloinfiltrative and superficial patterns. To excise the tumor completely would have been disfiguring, and topical therapy alone would have been inadequate. A multimodal approach using Mohs micrographic surgery to excise the central nodular portion and topical imiquimod to treat the surrounding superficial portion resulted in an excellent clinical outcome. This approach, which minimizes morbidity by capitalizing on the benefits of various techniques, can be applied to any BCC demonstrating distinct nodular and superficial portions. PMID- 22106727 TI - The necrolytic erythemas: a continuous spectrum? AB - The necrolytic erythemas is a group of disorders with similar histologic and clinical features. The objective of this case report is to present a patient with features of both necrolytic migratory erythema (NME) and necrolytic acral erythema (NAE). These 2 entities appear more likely to be on a spectrum caused by the same underlying process of abnormal liver function and glucagon metabolism. PMID- 22106728 TI - Cutaneous mercury granuloma: a case report. AB - Cutaneous mercury (Hg) granuloma is a rare disorder caused by the traumatic introduction of elemental Hg into skin or soft tissue. Typically, cutaneous elemental Hg deposits cause limited systemic effects. Prominent systemic toxicity may, however, occasionally occur. Herein we report a case of cutaneous Hg granuloma resulting in chronic painful local wounds and systemic toxicity in the form of abdominal pain, visual disturbances, and psychiatric abnormalities. The related literature also is reviewed. PMID- 22106729 TI - Nontuberculous mycobacterial cutaneous infections: an updated review. AB - Nontuberculous mycobacteria (NTM) cause cutaneous infections more commonly than Mycobacterium tuberculosis, and the incidence of infection with these organisms is increasing with the use of immunosuppressive agents. Diagnosis of NTM cutaneous infections is not always straightforward. Therefore, a high index of clinical suspicion is needed to make a diagnosis of NTM cutaneous infection. PMID- 22106730 TI - An open-label, multicenter study of the efficacy and safety of a weekday/weekend treatment regimen with calcitriol ointment 3 microg/g and clobetasol propionate spray 0.05% in the management of plaque psoriasis. AB - High-potency topical corticosteroids are the cornerstone of psoriasis therapy. Although highly effective, long-term use of topical steroids can cause adverse side effects. Additionally, steroids alone do not address the multiple pathophysiologic factors that cause the disease. Psoriasis regimens that utilize high-potency steroids combined with nonsteroid-containing products such as vitamin D analogs have been used for many years to manage the disease, not only for the short-term treatment of the disease but also for long-term treatment to minimize the recurrence of symptoms. We report an open-label, multicenter study designed to evaluate a weekday/ weekend treatment regimen involving calcitriol ointment 3 microg/g and clobetasol propionate spray 0.05% for moderate plaque psoriasis. Participants applied calcitriol ointment 3 microg/g twice daily on the weekdays and clobetasol propionate spray 0.05% twice daily on the weekends for up to 4 weeks. Participants were evaluated at baseline, week 2, and week 4. The results of this study demonstrate that a 4-week regimen of calcitriol ointment 3 microg/g treatment on weekdays and clobetasol propionate spray 0.05% on weekends is effective and well-tolerated for the treatment of moderate plaque psoriasis. PMID- 22106731 TI - Ethical and legal issues in adolescent medicine. Preface. PMID- 22106732 TI - Conscience, clinical ethics, and emergency contraception. AB - Emergency contraception (EC) is a generic term used to describe a group of hormonal methods taken within the first few days after unprotected sexual intercourse to prevent an unintended pregnancy. EC is safe and effective in preventing pregnancy. Plan B or the generic levonorgestrel is available over-the counter for women 17 years and older. A prescription is still required for women younger than 17 years of age. Even with its safety, effectiveness, and ease of accessibility for older adolescents and women, EC remains morally controversial. This article reviews the development of EC, presents data on the prevalence of conscientious objection, discusses how the change in status from prescription drug to over-the-counter medication has changed the debate, and makes recommendations for dealing with the controversies. PMID- 22106733 TI - Achieving a decision-making triad in adolescent sexual health care. AB - It is well known that adolescents delay and avoid sexual health care and fail to disclose necessary information to providers when their confidentiality is not ensured. However, it is not always clear if adolescents are psychosocially, affectively, or cognitively ready for independent decision-making. Whether confidentiality can and should be maintained necessitates that parents and providers have an understanding of adolescents' need for confidentiality. This article explores the concepts of confidentiality and consent in the context of teenage development and behaviors and addresses the complexity of the decision making triad in adolescent sexual health care. PMID- 22106734 TI - Making sense of adolescent decision-making: challenge and reality. AB - Few topics in pediatric bioethics are as vexing as decision-making. Decision making in pediatrics presents challenges for children, parents, and physicians alike. The related, yet distinct, concepts of assent and consent are central to pediatric decision-making. Although informed consent is largely regarded as a worthwhile adult principle, assent has been, and continues to be, mired in debate. Controversial subjects include a meaningful definition of assent; how old children should be to assent; who should be included in the assent process; parental permission; how to resolve disputes between children and their parents; the relationship between assent and consent; the quantity and quality of information to disclose to children and their families; how much and what information children desire and need; the necessity and methods for assessing both children's understanding of disclosed information and of the assent process itself; reconciling ethical and legal attitudes toward assent; and finally, an effective, practical, and realistically applicable decision-making model. PMID- 22106735 TI - Adolescent brain development and the mature minor doctrine. AB - The medical rights of minors have been questioned, especially due to information on adolescent brain development and studies on adolescent decision-making. This chapter briefly introduces the mature minor doctrine (MMD) and its history, justification, and practice and then presents some of the objections to the MMD. The article then highlights new knowledge about adolescent brain development (ABD) and what this may contribute to this debate and describes "hot cognition" and "cold cognition". It concludes by alerting the reader to the danger of making inappropriate use of the discoveries of brain science and proposing a prudent approach to adolescent consent and confidentiality, one that incorporates the new knowledge on ABD without "turning back the clock" on the medical rights of minors. PMID- 22106736 TI - Adolescent refusal of lifesaving treatment: are we asking the right questions? AB - In life-threatening situations, whether and under what conditions a minor should be allowed to refuse a lifesaving intervention is an important question. This article addresses the issue of whether adolescents, as a rule, possess capacity of sufficient quality that it should be respected even in the case of life altering medical decisions. After reviewing the traditional approach to determining when adolescents should have their decisions respected, an approach that focuses on establishing capacity under a traditional informed consent model, the article reviews our evolving understanding of adolescent brain development and explores the implications for adolescent decision-making capacity. The author argues that a demonstration of understanding and mature reasoning abilities is not sufficient to establish decision-making capacity and that most minors do not possess fully mature decision-making capacity. Finally, the author suggests an approach to adolescent decision-making that is more reflective of the developing state of the adolescent brain. PMID- 22106737 TI - The aftermath of adolescent suicide: clinical, ethical, and spiritual issues. AB - The aftermath of an adolescent's suicide can be devastating to family, friends, and treating professionals, yet not much has been written on this subject. In this article, we briefly develop a conceptualization of suicide and a typology of suicide and the physicians' attitudes toward suicide. This is followed with a more detailed review of the aftermath of suicide (focusing on the suicide grievers) and the impact of suicide on clinicians. The work ends with discussion of research data and the role of spirituality as well as an outline of therapeutic interventions. PMID- 22106738 TI - Adolescent mothers of critically ill newborns: addressing the rights of parent and child. AB - Despite recent declines, the teen birth rate in the United States remains markedly higher than in other developed countries. Infants born to teen mothers are more likely to be preterm than those born to adult mothers and thus more likely to end up in the newborn intensive care unit (NICU). Critically ill newborns are not infrequently born to teen mothers, including those in early adolescence. The focus of this chapter is the mechanism of decision-making on behalf of those newborns and the role of the early adolescent mother as surrogate decision-maker. It is argued that the current standard in many US hospitals, and likely elsewhere, is suboptimal and inadequately addresses the rights and needs of both mother and newborn. PMID- 22106739 TI - Ethical and policy issues raised by heterozygote carrier identification and predictive genetic testing of adolescents. AB - Current professional recommendations discourage health care providers from providing heterozygote carrier testing and predictive genetic testing for adult onset conditions to minors. These recommendations are based on theoretical concerns that the harms outweigh the benefits. Although empirical data are scant, the emerging evidence suggests that the risks of harms are less than predicted and that there may be some significant benefits for testing adolescents, particularly when the adolescent and parent(s) agree. To ethically respond to requests for genetic testing of adolescents, pediatricians should evaluate the goals of testing, the familial implications of the results, and whose consent is needed. PMID- 22106740 TI - Cancer therapy and the preservation of adolescent fertility. AB - The increasing survival of adolescents with cancer, achieved through intensive therapy, is often associated with sterility. For most teenagers, the ability to have biological children is psychologically and socially important. Methods of preserving fertility, some standard and other experimental, have proliferated, but their use raises ethical issues. This review poses three hypothetical cases, describes the preservation methods, and identifies and analyzes the ethical issues. The discussion asks what needs to be told, who decides what to do, when can a pediatrician refuse to follow a family's choice, and what is the pediatrician's role as advocate for adolescents. PMID- 22106741 TI - Nondisclosure of HIV status in adolescence. AB - A marked decline of disclosure age for HIV positive youth is greatly influenced by the increase in long-term survival due to the introduction of highly active antiretroviral therapy (HAART) and the concomitant reduction in social stigma. Nevertheless, there are still significant numbers of young adolescents that are receiving treatment without having their HIV positive status disclosed to them. This chapter reviews studies of caregiver and health care provider preferences and hurdles for disclosure, as well as cultural patterns that strongly influence how and by whom HIV diagnosis disclosure is being provided. Disclosure of HIV infection status to young adolescents and symptomatic children is strongly recommended. All adolescents should know their HIV status and should be fully informed and counseled about all aspects of their health, including their sexual behavior. Physicians should encourage adolescents to involve their parents in their care. PMID- 22106742 TI - Treatment of anorexia nervosa against the patient's will: ethical considerations. AB - By the nature of their illness, many if not most patients with anorexia nervosa are treated against their will. This article explores the issue of patient autonomy and right to treatment refusal in the light of justified paternalism as well as a more enriched understanding of autonomy in the context of relationships. A summary follows on the research on patients' perceptions and response to involuntary treatment. The conclusion addresses the importance of human values intrinsic to the quality of a clinical relationship as determinant for patient recovery and professional satisfaction. PMID- 22106743 TI - Iatrogenesis: ethical and legal aspects. AB - This article describes iatrogenic events, giving examples that range from individual error to systemic malfunctions. It then goes on to analyze individual and system responsibilities in the disclosure of iatrogenic events. A discussion follows on the physician's responsibility, professional integrity, "duty to warn", and transparency as they relate to error disclosure, including an examination of the role of apology and repair in the setting of iatrogenesis. It concludes by considering the moral and legal operational implications of iatrogenic events and the building of a culture of safety. PMID- 22106744 TI - Health rights, health ethics, and adolescence: addressing current challenges, ensuring a just future. AB - This article presents a discussion of the human rights declarations that address adolescent health, including reference to specific articles in the declarations that address this population; examples of ethical issues related to health that are faced by adolescents, their families, and providers who care for them; and ethical principles and frameworks that can serve as a basis for consideration of these issues. The article also includes examples of circumstances that pose ethical dilemmas for clinicians and adolescent clients and their families. PMID- 22106745 TI - Sexual exploitation and trafficking of the young and vulnerable: reflections on a legal, ethical, and human rights disgrace. AB - Sexual exploitation and trafficking of the young and vulnerable has devastating consequences for their physical and emotional development, health, and well being. The horrific treatment they suffer bears the hallmarks of evil made manifest. Governments have enacted laws pursuant to international treaties, conventions, and protocols. Nonprofit and nongovernmental organizations (NGOs) are working to prevent young people from being exploited and trafficked, to identify victims, and to provide services to survivors. Progress in addressing the problem is haltingly slow in relation to its magnitude. The prevalence and persistence of this phenomenon is an ethical, legal, and human rights disgrace. PMID- 22106746 TI - Law, ethics, and clinical discretion: recurring and emerging issues in adolescent health care. AB - Varied stakeholders are involved in adolescent health care, with many looking to law to provide clear-cut answers on who can control decisions and when. However, law allows for much clinician discretion, carving out space for contextual sensitivity and clinical determination of maturity. A triad model of decision making is very often the most appropriate clinical and ethical course. Law's aim is ideally not to impede, but rather to support clinical and ethical wisdom. Drawing on cases in this volume, it is argued that law should not and typically does not, when accurately interpreted and applied, stand in clinicians' way. PMID- 22106747 TI - Five pond-centred outbreaks of cholera in villages of West Bengal, India: evidence for focused interventions. AB - In rural West Bengal, outbreaks of cholera are often centred around ponds that is a feature of the environment. Five investigations of laboratory-confirmed, pond centred outbreaks of cholera were reviewed. Case-control odds ratios were approximated with relative risks (RRs) as the incidence was low. The environment was investigated to understand how the pond(s) could have become contaminated and could have infected villagers. The five outbreaks of cholera in 2004-2008 led to 277 cases and three deaths (median attack rate: 51/1,000 people; case fatality: 1.1%; median age of case-patients: 22 years; median duration: 13 days, range: 6 15 days). Factors significantly (p<0.05) associated with cholera in the case control (n=4) and cohort investigations (n=1) included washing utensils in ponds (4 outbreaks of cholera, RR range: 6-12), bathing (3 outbreaks of cholera, RR range: 3.5-9.3), and exposure to pond water, including drinking (2 outbreaks of cholera, RR range: 2.1-3.2), mouth washing (1 outbreak of cholera, RR: 4.8), and cooking (1 outbreak of cholera, RR: 3.0). Initial case-patients contaminated ponds through washing soiled clothes (n=4) or defaecation (n=1). Ubiquitous ponds used for many purposes transmit cholera in West Bengal. Focused health education, hygiene, and sanitation must protect villagers, particularly following the occurrence of an index case in a village that has ponds. PMID- 22106748 TI - Differential host immune responses to epidemic and endemic strains of Shigella dysenteriae type I. AB - Shigella dysenteriae type 1 causes devastating epidemics in developing countries with high case-fatality rates in all age-groups. The aim of the study was to compare host immune responses to epidemic (T2218) and endemic strains of S. dysenteriae type 1. Shigellacidal activity of serum from rabbits immunized with epidemic or endemic strains, S. dysenteriae type 1-infected patients, and healthy adult controls from Shigella-endemic and non-endemic regions was measured. Immunogenic cross-reactivity of antibodies against Shigella antigens was evaluated by Western blot analysis. Oxidative burst and phagocytic responses of monocytes and neutrophils to selected S. dysenteriae type 1 strains were assessed by flow cytometry. Rabbit antisera against epidemic strain were less effective in killing heterologous bacteria compared to endemic antisera (p=0.0002). Patients showed an increased serum shigellacidal response after two weeks of onset of diarrhoea compared to the acute stage (3-4 days after onset) against their respective homologous strains; the response against T2218 and heterologous endemic S. dysenteriae type 1 strains was not significant. The serum shigellacidal response against all the S. dysenteriae type 1 strains was similar among healthy controls from endemic and non-endemic regions and was comparable with the acute stage response by patients. Compared to endemic strains of S. dysenteriae type 1, T2218 was significantly resistant to phagocytosis by both monocytes and neutrophils. No obvious differences were obtained in the induction of oxidative burst activity and cathelicidin-mediated killing. Cross-reactivity of antibody against antigens present in the epidemic and endemic strains showed some differences in protein/peptide complexity and intensity by Western blot analysis. In summary, epidemic T2218 strain was more resistant to antibody mediated defenses, namely phagocytosis and shigellacidal activity, compared to endemic S. dysenteriae type 1 strains. Part of this variation may be attributed to the differential complexity of protein/peptide antigens. PMID- 22106749 TI - Inhibitory and bactericidal potential of crude acetone extracts of Combretum molle (Combretaceae) on drug-resistant strains of Helicobacter pylori. AB - Infection with Helicobacter pylori is strongly associated with a number of gastroduodenal pathologies. Antimicrobial resistance to commonly-used drugs has generated a considerable interest in the search for novel therapeutic compounds from medicinal plants. As an ongoing effort of this search, the susceptibility of 32 clinical strains of H. pylori and a reference strain-NCTC 11,638-was evaluated against five solvent extracts of Combretum molle, a plant widely used for the treatment of gastric ulcers and other stomach-related morbidities in South Africa. The extracts were screened for activity by the agar-well diffusion method, and the most active one of them was tested against the same strains by micro-broth dilution and time kill assays. Metronidazole and amoxicillin were included in these experiments as positive control antibiotics. The solvent extracts all demonstrated anti-H. pylori activity with zone diameters of inhibition between 0 and 38 mm. The most potent anti-H. pylori activity was demonstrated by the acetone extract, to which 87.5% of the clinical strains were susceptible. The minimum inhibitory concentration (MIC90) values for this extract ranged from 1.25 to 5.0 mg/mL while those for amoxicillin and metronidazole ranged from 0.001 to 0.94 mg/mL and from 0.004 to 5.0 mg/mL respectively. The acetone extract was highly bactericidal at a concentration of 2.5 and 5.0 mg/mL, with complete elimination of the test organisms in 24 hours. Its inhibitory activity was better than that of metronidazole (p<0.05) as opposed to amoxicillin (p<0.05). The results demonstrate that C. molle may contain therapeutically useful compounds against H. pylori, which are mostly concentrated in the acetone extract. PMID- 22106750 TI - Multidrug-resistant intestinal Staphylococcus aureus among self-medicated healthy adults in Amassoma, South-South, Nigeria. AB - Multiple antibiotic resistant Staphylococcus aureus is one of the common causes of severe nosocomial infections, and the gastrointestinal tract is an important source of its transmission. This study assessed the previous usage of antibiotics by healthy adults (university students and villagers) in Amassoma, Nigeria, and investigated the antimicrobial resistance patterns of their intestinal S. aureus isolates. A questionnaire was used for evaluating the previous usage of antibiotics by the volunteers. Stool samples were collected and cultured, and S. aureus isolates were confirmed using standard microbiological protocols. Their antimicrobial resistance patterns were determined using disc-diffusion and agar dilution techniques. In total, 54 (45.0%) volunteers used antibiotics on self medications, and the practice was significantly higher (p=0.01) among the villagers than among the students. The level of judicious use of prescribed antibiotics was significantly higher (p=0.003) among the students than among the villagers. Thirty-eight (31.7%) healthy adults were colonized with intestinal S. aureus. The percentages of resistance of the isolates to some antibiotics were as follows: ampicillin-68.4%, doxycycline-60.5%, cefoxitin-34.2%, vancomycin-36.8%, erythromycin-34.2%, and gentamicin-5.3%. Twenty-five (65.8%) of the isolates were multidrug-resistant. The need for sound education on the appropriate use of antibiotics and the importance of proper personal hygiene as means of controlling the spread of bacterial antibiotic resistance are highlighted. Thus, effective strategies in these areas are strongly recommended. PMID- 22106751 TI - Sources of food affect dietary adequacy of Inuit women of childbearing age in Arctic Canada. AB - Dietary transition in the Arctic is associated with decreased quality of diet, which is of particular concern for women of childbearing age due to the potential impact of maternal nutrition status on the next generation. The study assessed dietary intake and adequacy among Inuit women of childbearing age living in three communities in Nunavut, Canada. A culturally-appropriate quantitative food frequency questionnaire was administered to 106 Inuit women aged 19-44 years. Sources of key foods, energy and nutrient intakes were determined; dietary adequacy was determined by comparing nutrient intakes with recommendations. The prevalence of overweight/obesity was >70%, and many consumed inadequate dietary fibre, folate, calcium, potassium, magnesium, and vitamin A, D, E, and K. Non nutrient-dense foods were primary sources of fat, carbohydrate and sugar intakes and contributed >30% of energy. Traditional foods accounted for 21% of energy and >50% of protein and iron intakes. Strategies to improve weight status and nutrient intake are needed among Inuit women in this important life stage. PMID- 22106752 TI - Dietary calcium intake, vitamin D status, and bone health in postmenopausal women in rural Pakistan. AB - The high prevalence of osteoporosis in Pakistan is of public-health concern. However, there is a paucity of information regarding nutrition and bone density in rural communities. The purpose of this study was to evaluate the dietary and lifestyle factors that impact bone health in Nahaqi. Data were collected from 140 postmenopausal women using an interviewer-administered 24-hour dietary recall questionnaire. Bone mineral density was estimated using the quantitative ultrasound index (QUI). Serum 25(OH)D was measured in fasting blood samples. The QUI scores revealed that 42% and 29% of the women had T-scores, indicative of osteopaenia and osteoporosis respectively. The mean calcium intake was 346 mg/d, which is less than 50% of the recommended daily intake. The QUI correlated with 25(OH)D after controlling for age (p=0.021, r=0.41, r2=0.168). Vitamin D deficiency and low intake of dietary calcium are two key factors contributing to poor bone health in this population. PMID- 22106753 TI - Anaemia among students of rural China's elementary schools: prevalence and correlates in Ningxia and Qinghai's poor counties. AB - Although the past few decades have seen rising incomes and increased government attention to rural development, many children in rural China still lack regular access to micronutrient-rich diets. Insufficient diets and poor knowledge of nutrition among the poor result in nutritional problems, including iron deficiency anaemia, which adversely affect attention and learning of students in school. Little research has been conducted in China documenting the prevalence of nutritional problems among vulnerable populations, such as school-age children, in rural areas. The absence of programmes to combat anaemia among students might be interpreted as a sign that the Government does not recognize its severity. The goals of this paper were to measure the prevalence of anaemia among school-age children in poor regions of Qinghai and Ningxia, to identify individual-, household- and school-based factors that correlate with anaemia in this region, and to report on the correlation between the anaemic status and the physical, psychological and cognitive outcomes. The results of a cross-sectional survey are reported here. The survey involved over 4,000 fourth and fifth grade students from 76 randomly-selected elementary schools in 10 poor counties in rural Qinghai province and Ningxia Hui Autonomous Region, located in the northwest region of China. Data were collected using a structured questionnaire and standardized tests. Trained professional nurses administered haemoglobin (Hb) tests (using Hemocue finger prick kits) and measured heights and weights of children. The baseline data showed that the overall anaemia rate was 24.9%, using the World Health Organization's blood Hb cut-offs of 120 g/L for children aged 12 years and older and 115 g/L for children aged 11 years and under. Children who lived and ate at school had higher rates of anaemia, as did children whose parents worked in farms or were away from home. Children with parents who had lower levels of education were more likely to be anaemic. The anaemic status correlated with the adverse physical, cognitive and psychological outcomes among the students. Such findings are consistent with findings of other recent studies in poor, northwest areas of China and led to conclude that anaemia remains a serious health problem among children in parts of China. PMID- 22106754 TI - Change of diet, plasma lipids, lipoproteins, and fatty acids during Ramadan: a controversial association of the considered Ramadan model with atherosclerosis risk. AB - Different Islamic populations have different alimentary habits, notably during Ramadan. The paper reports the change of diet, lipids, and lipoproteins produced during Ramadan in one Tunisian population. During Ramadan, the study subjects consumed more proteins, cholesterol, vitamin E (p<0.01), and polyunsaturated fatty acids (p<0.05). At the same time, they exhibited an increase in total cholesterol, low-density lipoprotein-cholesterol (p<0.01) and apoprotein B (p<0.05) and a decrease in the ratio of apoprotein AI to apoprotein B (p<0.01). All assayed saturated fatty acids were unaffected by Ramadan fasting while three unsaturated fatty acids (C18:1cis9, C18:2n-6, and C30:4n-6) increased significantly. A return to the habitual diet for a four-week period was not sufficient to restore the pre-fasting patterns. For the study subjects, Ramadan was clearly associated with a change of diet and biochemical profile but its effective impact on atherosclerosis risk was unclear, perhaps, because other non alimentary changes ought to be considered too. Future studies considering the no alimentary factors, such as sleep and physical activity, would be useful to clarify the contribution of dietary change in the observed modification of biological profile. PMID- 22106755 TI - Prevalence and determinants of chronic malnutrition among preschool children: a cross-sectional study in Dhaka City, Bangladesh. AB - Chronic malnutrition is one of the major causes of morbidity and mortality among preschool children and the future productivity of nations. To understand the prevalence of chronic malnutrition and to identify the factors affecting height for-age z-score (HAZ) among preschool children, a cross-sectional study was conducted among 380 randomly-selected children aged less than five years in Dhaka city, Bangladesh. Results of analysis of this study data revealed that the prevalence of stunting among preschool children in Dhaka city was 39.5%, with 25% severely stunted and 14% moderately stunted (p<0.001). Results of bivariate analysis revealed that socioeconomic and demographic factors were most significantly associated with the stunting of children. Children were found to be well-nourished if their parents had a tertiary-level education or higher and if the mother held a job and had good knowledge of nutrition. Well-nourishment of the children were also associated with the height of mothers (above 148 cm), good family educational background, normal birthweight, greater frequency of food intake (more than six times/day), and fewer fever episodes in the last six months. Results of multivariate linear regression models showed that height of mothers, birthweight of children, education of fathers, knowledge of mothers on nutrition, and frequency of feeding were the most significant factors that had an independent and direct influence on the stunting of children. To achieve the Millennium Development Goal target of 34% malnutrition prevalence by 2015, it is important to have specific government intervention to focus on the causes that directly influence the stunting of children. PMID- 22106756 TI - Assessment of special care newborn units in India. AB - The neonatal mortality rate in India is high and stagnant. Special Care Newborn Units (SCNUs) have been set up to provide quality level II newborn-care services in several district hospitals to meet this challenge. The units are located in some remotest districts where the burden of neonatal deaths is high, and access to special newborn care is poor. The study was conducted to assess the functioning of SCNUs in eight rural districts of India. The evaluation was based on an analysis of secondary data from the eight units that had been functioning for at least one year. A cross-sectional survey was also conducted to assess the availability of human resources, equipment, and quality care. Descriptive statistics were used for analyzing the inputs (resources) and outcomes (morbidity and mortality). The rate of mortality among admitted neonates was taken as the key outcome variable to assess the performance of the units. Chi-square test was used for analyzing the trend of case-fatality rate over a period of 3-5 years considering the first year of operationalization as the base. Correlation coefficients were estimated to understand the possible association of case fatality rate with factors, such as bed:doctor ratio, bed:nurse ratio, average duration of stay, and bed occupancy rate, and the asepsis score was determined. The rates of admission increased from a median of 16.7 per 100 deliveries in 2008 to 19.5 per 100 deliveries in 2009. The case-fatality rate reduced from 4% to 40% within one year of their functioning. Proportional mortality due to sepsis and low birthweight (LBW) declined significantly over two years (LBW <2.5 kg). The major reasons for admission and the major causes of deaths were birth asphyxia, sepsis, and LBW/prematurity. The units had a varying nurse:bed ratio (1:0.5 1:1.3). The bed occupancy rate ranged from 28% to 155% (median 103%), and the average duration of stay ranged from two days to 15 days (median 4.75 days). Repair and maintenance of equipment were a major concern. It is possible to set up and manage quality SCNUs and improve the survival of newborns with LBW and sepsis in developing countries, although several challenges relating to human resources, maintenance of equipment, and maintenance of asepsis remain. PMID- 22106757 TI - Status of novel cardiovascular risk factor and cardiovascular disease risk in an urban Cuban population--a pilot study. AB - Cardiovascular disease is the main cause of death in Cuba, yet the prevalence of novel risk factors is not known. To examine the prevalence of risk factors of traditional and novel cardiovascular diseases (CVDs) among an urban Cuban population, a cross-sectional pilot survey was undertaken in Havana city, Cuba. Ninety-seven adults aged 45-60 years registered to receive medical care at a policlinic. The prevalences of rates of CVD risk factors were: hypertension (> or =140/90 mmHg) (53.6%), hypercholesterolaemia (total cholesterol >5.2 mmol/L) (47.0%), low high-density lipoprotein (HDL)-cholesterol (<1.03 mmol/L) (64.3%); diabetes (self-reported) (24.6%); metabolic syndrome (ATP III criteria) (58.2%); overweight and obesity (body mass index > or = 25 kg/m2) (78.0%); current smoking (39.3%); elevated level of C-reactive protein (3 15 micromol/L) (11.1%). The total carotenoid status was independently associated with waist-circumference and risk of diabetes and metabolic syndrome. In this small unrepresentative sample of people aged 40 65 years from Havana city, there was a high prevalence of traditional and novel CVD risk factors. The total serum carotenoid status appeared to be associated with an increased prevalence of CVD risk factors. PMID- 22106758 TI - Stress and its effects on medical students: a cross-sectional study at a college of medicine in Saudi Arabia. AB - Medical education is perceived as being stressful, and a high level of stress may have a negative effect on cognitive functioning and learning of students in a medical school. This cross-sectional study was conducted to determine the prevalence of stress among medical students and to observe an association between the levels of stress and their academic performance, including the sources of their stress. All the medical students from year one to year five levels from the College of Medicine, King Saud University, were enrolled in the study. The study was conducted using Kessler10 psychological distress (K10) inventory, which measures the level of stress according to none, mild, moderate, and severe categories. The prevalence of stress was measured and compared with the five study variables, such as gender, academic year, academic grades, regularity to course attendance, and perceived physical problems. The response rate among the study subjects was 87% (n=892). The total prevalence of stress was 63%, and the prevalence of severe stress was 25%. The prevalence of stress was higher (p<0.5) among females (75.7%) than among males (57%) (odds ratio=2.3, chi2=27.2, p<0.0001). The stress significantly decreased as the year of study increased, except for the final year. The study variables, including being female (p<0.0001), year of study (p<0.001), and presence of perceived physical problems (p<0.0001), were found as independent significant risk factors for the outcome variables of stress. Students' grade point average (academic score) or regularity to attend classes was not significantly associated with the stress level. The prevalence of stress was higher during the initial three years of study and among the female students. Physical problems are associated with high stress levels. Preventive mental health services, therefore, could be made an integral part of routine clinical services for medical students, especially in the initial academic years, to prevent such occurrence. PMID- 22106759 TI - Inequalities in care-seeking for febrile illness of under-five children in urban Dhaka, Bangladesh. AB - Fever is an easily-recognizable primary sign for many serious childhood infections. In Bangladesh, 31% of children aged less than five years (under-five children) die from serious infections, excluding confirmed acute respiratory infections or diarrhoea. Understanding healthcare-seeking behaviour for children with fever could provide insights on how to reduce this high rate of mortality. Data from a cross-sectional survey in the catchment areas of two tertiary-level paediatric hospitals in Dhaka, Bangladesh, were analyzed to identify the factors associated with the uptake of services from trained healthcare providers for under-five children with reported febrile illness. Health and demographic data were collected in a larger study of 7,865 children using structured questionnaires. Data were selected from 1,290 of these under-five children who were taken to any healthcare provider for febrile illness within two months preceding the date of visit by the study team. Certified doctors were categorized as 'trained', and other healthcare providers were categorized as 'untrained'. Healthcare-seeking behaviours were analyzed in relation to these groups. A wealth index was constructed using principal component analysis to classify the households into socioeconomic groups. The odds ratios for factors associated with healthcare-seeking behaviours were estimated using logistic regression with adjustment for clustering. Forty-one percent of caregivers (n=529) did not seek healthcare from trained healthcare providers. Children from the highest wealth quintile were significantly more likely [odds ratio (OR)=5.6, 95% confidence interval (CI) 3.4-9.2] to be taken to trained healthcare providers compared to the poorest group. Young infants were more likely to be taken to trained healthcare providers compared to the age-group of 4-<5 years (OR=1.6, 95% CI 1.1 2.4). Male children were also more likely to be taken to trained healthcare providers (OR=1.5, 95% CI 1.2-1.9) as were children with decreased level of consciousness (OR=5.3, 95% CI 2.0-14.2). Disparities across socioeconomic groups and gender persisted in seeking quality healthcare for under-five children with febrile illness in urban Dhaka. Girls from poor families were less likely to access qualified medical care. To reduce child mortality in the short term, health education and behaviour-change communication interventions should target low-income caregivers to improve their recognition of danger-signs; reducing societal inequalities remains an important long-term goal. PMID- 22106760 TI - Challenge of reducing perinatal mortality in rural Congo: findings of a prospective, population-based study. AB - Each year, an estimated six million perinatal deaths occur worldwide, and 98% of these deaths occur in low- and middle-income countries. These estimates are based on surveys in both urban and rural areas, and they may underrepresent the problem in rural areas. This study was conducted to quantify perinatal mortality, to identify the associated risk factors, and to determine the most common causes of early neonatal death in a rural area of the Democratic Republic of the Congo (DRC). Data were collected on 1,892 births. Risk factors associated with perinatal deaths were identified using multivariate analysis with logistic regression models. Causes of early neonatal deaths were determined by physician review of information describing death. The perinatal mortality rate was 61 per 1,000 births; the stillbirth rate was 30 per 1,000 births; and the early neonatal death rate was 32 per 1,000 livebirths. Clinically-relevant factors independently associated with perinatal death included: low birthweight [odds ratio (OR)=13.51, 95% confidence interval (CI) 7.82-23.35], breech presentation (OR)=12.41; 95% CI 4.62-33.33), lack of prenatal care (OR=2.70, 95% CI 1.81-4.02), and parity greater than 4 (OR=1.93 95% CI 1.11-3.37). Over one-half of early neonatal deaths (n=37) occurred during the first two postnatal days, and the most common causes were low birthweight/prematurity (47%), asphyxia (34%), and infection (8%). The high perinatal mortality rate in rural communities in the DRC, approximately one half of which is attributable to early neonatal death, may be modifiable. Specifically, deaths due to breech presentation, the second most common risk factor, may be reduced by making available emergency obstetric care. Most neonatal deaths occur soon after birth, and nearly three-quarters are caused by low birthweight/prematurity or asphyxia. Neonatal mortality might be reduced by targeting interventions to improve neonatal resuscitation and care of larger preterm infants. PMID- 22106761 TI - The 2008 cholera epidemic in Zimbabwe: experience of the icddr,b team in the field. AB - During August 2008-June 2009, an estimated 95,531 suspected cases of cholera and 4,282 deaths due to cholera were reported during the 2008 cholera outbreak in Zimbabwe. Despite the efforts by local and international organizations supported by the Zimbabwean Ministry of Health and Child Welfare in the establishment of cholera treatment centres throughout the country, the case-fatality rate (CFR) was much higher than expected. Over two-thirds of the deaths occurred in areas without access to treatment facilities, with the highest CFRs (>5%) reported from Masvingo, Manicaland, Mashonaland West, Mashonaland East, Midland, and Matabeleland North provinces. Some factors attributing to this high CFR included inappropriate cholera case management with inadequate use of oral rehydration therapy, inappropriate use of antibiotics, and a shortage of experienced healthcare professionals. The breakdown of both potable water and sanitation systems and the widespread contamination of available drinking-water sources were also considered responsible for the rapid and widespread distribution of the epidemic throughout the country. Training of healthcare professionals on appropriate cholera case management and implementation of recommended strategies to reduce the environmental contamination of drinking-water sources could have contributed to the progressive reduction in number of cases and deaths as observed at the end of February 2009. PMID- 22106762 TI - Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome. AB - INTRODUCTION: Congenital hyperinsulinism and hyperammonemia (CHH) is caused by gain of function of glutamate dehydrogenase (GDH). The genetic abnormalities are known to be located in three specific regions on the GDH protein. We describe here three different missense mutations identified in five new Japanese patients with CHH. And to study the genotype-phenotype correlations in patients with GLUD1 mutations, we analyzed previously reported Japanese cases. METHODS: An Epstein Barr virus-transformed lymphoblastoid cell line was established from the 5 patients and control subjects, and was used for enzymatic and molecular analyses. RESULTS: All patients developed seizures with loss of consciousness associated with hypoglycemia and had persistent hyperammonemia. All patients had similar basal GDH activity of lymphoblasts and insensitivity to GTP inhibition. Genetic studies identified heterozygous I444M mutation in Patient 11, S217C mutation in Patient 1, and H262Y mutation in Patients 2, 3, and 4. Patients 3 and 4 were child and father, respectively. COS cell expression study confirmed that I444M and H262Y mutations were disease-causing genes. CONCLUSIONS: We identified three mutations (I444M, H262Y, and S217C), and the former is a newly described mutation. A summary of 17 reported Japanese patients (10 boys and 7 girls) with GDH mutations showed 8 patients had mutation at the site of the GTP-binding region, 2 at the site of the antenna-like structure, and 7 at the site of the hinge region. Analysis of the reported cases showed no clear association between clinical phenotype and mutation sites. However, G446D mutation seems to be associated with serious abnormalities. PMID- 22106763 TI - Evaluation of therapeutic response to donepezil by positron emission tomography. AB - BACKGROUND: Donepezil hydrochloride (Donepezil) is an acetylcholinesterase inhibitor (AChEI) that is used for the symptomatic treatment of Dementia of the Alzheimer's Type (DAT). Recently, the effects of AChEI in patients with DAT have been investigated using positron emission tomography (PET) or single photon emission computed tomography (SPECT). This study is to evaluate the usefulness of fluorine-18-fluorodeoxyglucose (FDG)-PET in assessing the therapeutic response of Donepezil to DAT using Regions of Interest (ROI) analysis. METHODS: The participants included eleven outpatients diagnosed as having DAT according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The patients were performed FDG-PET before initiating Donepezil therapy and after 12 weeks of medication. Cognitive change was measured using the Japanese version of the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-J cog) and the group was divided into Responders and Non-responders based on these results. We used FDG-PET to investigate glucose metabolism of the brain and measured FDG uptake in the ROI set in each lobe of the brain. Then the ratios of the post treatment uptake to pre-treatment uptake were determined. RESULTS: In the Responders, the mean ratios in the frontal, temporal, occipital, parietal, and temporoparietal lobes were 2.18, 1.62, 1.15, 1.12, and 1.09 respectively. The mean ratios of the Non-responders were 0.69, 0.88, 0.75, 0.98, and 0.68 respectively. Significant differences were found between the ratios of the Responders and Non-responders in the frontal and occipital lobes (p < 0.05). CONCLUSIONS: These findings suggest that FDG-PET could be useful for the evaluation for monitoring response to Donepezil. PMID- 22106764 TI - Association of six-minute walk distance (6MWD) with resting pulmonary function in patients with chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: The six-minute walk test (6MWT) is widely used for integrated assessment of patients with chronic obstructive pulmonary disease (COPD). However, little is known concerning which resting pulmonary function test measurements relate to six-minute walk distance (6MWD). METHODS: We retrospectively analyzed consecutive data of spirometry, lung volume analysis, and measurements of diffusing capacity of the lung for carbon monoxide (DLCO) and 6MWT from total of one-hundred and thirty patients with COPD. Univariate and multivariate analyses were performed to examine the relationships between 6MWD and variables. RESULTS: By linear regression analysis, 6MWD was significantly associated with age, weight, BMI, FEV1.0, FEV1.0 (% predicted), IC, TLC, IC/TLC, FEF25-75, DLCO (% predicted), and DLCO/VA. Stepwise multiple regression analysis revealed that age (r2 = 0.173; p < 0.0001), IC (r2 = 0.18; p < 0.0001), and DLCONA (r2 = 0.238; p < 0.0001) significantly accounted for 6MWD. CONCLUSIONS: The present results suggest that age, IC, and DLCONA were significantly associated with 6MWD in patients with COPD. PMID- 22106765 TI - Histological differentiation, histogenesis and prognosis of cutaneous angiosarcoma. AB - BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare, extremely malignant vascular tumor. The optimum treatment for patients with CAS has not been defined because of its exremely rarity. As prognostic factors in patients with CAS, tumor less than 5 cm in size has a better prognosis. Although tumor differentiation in other sarcoma is an important prognostic factor, tumor differentiation in CAS is not a prognostic factor. CAS is thought as a collection of hemangiosarcoma, lymphangiosarcoma, tumors which cannot be classified as of vascular and lymphatic origin, or mixed tumor of both. Histogenesis of CAS have not been clarified yet. We tried to classify histogenesis by immunohistochemistry and evaluate the prognosis among histogeneses. METHODS: Using immunohistochemistry, we classified histogenesis of CAS in 20 patients who visited Osaka City University Hospital between 1998 and 2008. RESULTS: From the results of immunohistochemical staining with CD34 and D2-40, histogenesis of CAS can be divided into vascular type (CD34 positive D2-40 negative), mixed type (CD34 positive D2-40 positive), and lymphatic type (CD34 negative D2-40 positive). Vascular type was found in 2 cases, mixed type in 5 cases, and lymphatic type in 13 cases. Survival rates were not significantly affected by histogenesis, however, survival rate of mixed type was better than those of others. CONCLUSIONS: CAS can be divided into vascular type, mixed type, and lymphatic type based on immunohistochemistry. Because of a small group, we did not suggest that histogenesis of CAS was related with prognosis. We speculate that antiangiogenic agents might be important in the treatment based on histogeneses in CAS. In the future, further accumulation of chemotherapeutic cases might upgrade histogenesis classification as an important prognostic factor in the treatment of CAS. PMID- 22106766 TI - Bilateral nevus of Ota: a rare manifestation congenital type in a boy. AB - BACKGROUND: The nevus of Ota is usually characterized by small, flat, unilateral, blue-black or gray-brown spots occurring on skin innervated by the first or second branch of the trigeminal nerve. It comprises dermal melanocytes, presumably arising due to the dermal arrest of cells migrating from the neural crest. Nevus of Ota is 3-5 times more common in women than men, and is classified into congenital type, appearing soon after birth, and acquired type, appearing during or after puberty. METHODS: We report on a six-year-old Japanese boy with the bilateral nevus of Ota. He was referred to our hospital because of bilateral hyperpigmentation of the face, present since birth. Our treatment consisted of Q switched ruby laser irradiation under general anesthesia. The Q-switched ruby laser (Model IB101; Niic Co. Ltd., Tokyo, Japan), had a wavelength of 694.3 nm, a spot size of 5 mm, a 1 Hz repetition rate, a pulse duration of 20 nsec and fluence ranged from 3.0 J/cm2 to 6.0 J/cm2. RESULTS: Q-switched ruby laser irradiation improved his pigmentation, and will therefore be repeated several times. CONCLUSIONS: This case of congenital bilateral nevus of Ota in a young male patient was very rare. And Q-switched ruby laser irradiation was effective as same as another nevus of Ota. PMID- 22106767 TI - Recruiting agents of reform. CMS healthcare program seeks innovators at local level. AB - The CMS is going local in its latest effort to spark innovation. Teams of "innovation advisers" are being sought to devise and carry out reform initiatives in their communities. "Until recently, Medicare's role has been to pay the bills. In the last 10 years, Medicare has been seeing its role--more appropriately, I think--as providing access for their beneficiaries to the care they need," says Stuart Guterman, left, of the Commonwealth Fund. PMID- 22106768 TI - Moving in the right direction. Value-based purchasing changes meet approval. PMID- 22106769 TI - Tweaks only. CMS stands firm on doc-owned hospital rule. PMID- 22106770 TI - Taking aim at shortages. Order strengthens FDA's enforcement authority. PMID- 22106771 TI - Looking for a solution. Pressure grows for permanent fix to doc pay formula. PMID- 22106772 TI - Highmark takes on West Penn. Insurer aims to turn around struggling system. PMID- 22106773 TI - Poor stock performance. Debt-ceiling talks stir reimbursement uncertainty. PMID- 22106774 TI - Inspecting the inspectors. Investigators should examine quality: HHS report. PMID- 22106775 TI - High-tech hazards. Alarm hazards tops ECRI list of health dangers. PMID- 22106776 TI - Working on costs. And Baldrige program is a plus for quality--yanking funding is just plain dumb. PMID- 22106777 TI - A must-read. Patients should have easier access to their doctors' medical notes. PMID- 22106778 TI - No sleight of hand. EHR improves quality, compliance, productivity. PMID- 22106779 TI - A balancing act. Challenges of mission, finances part of equation when buying practices. PMID- 22106780 TI - Sharing the pain. Employers continue to shift more costs to workers, with high deductible health plans getting closer attention. PMID- 22106781 TI - From the purchaser's perspective. Providers, in their experience as employers, might offer critical solutions. PMID- 22106782 TI - In search of model behavior. New payment approaches seek to address flawed fee for-service system. PMID- 22106783 TI - Not a deal-breaker. Sale-leasebacks still attractive to skilled-nursing operators despite rate cuts. PMID- 22106784 TI - Bone health: osteoporosis, calcium and vitamin D. AB - BACKGROUND: Osteoporosis is a bone disease that predisposes to fractures. Sufficient intake of calcium and vitamin D is recommended for prevention and treatment. DATA AND METHODS: Based on 28,406 respondents aged 50 or older to the 2009 Canadian Community Health Survey (CCHS)--Healthy Aging, the population who reported being diagnosed with osteoporosis is profiled. Analysis of calcium and vitamin D intake is based on 10,879 respondents aged 50 or older to the 2004 CCHS -Nutrition. Frequencies, averages and cross-tabulations were produced to estimate the prevalence of diagnosed osteoporosis, dietary intake of calcium and vitamin D, the use of supplements, and total calcium and vitamin D intake. Associations between a diagnosis of osteoporosis and socio-economic, dietary and lifestyle factors were examined with multiple logistic regression. RESULTS: In 2009, 19.2% of women and 3.4% of men aged 50 or older reported having been diagnosed with osteoporosis; the 2004 rates were similar. Age, sex and household income were associated with the probability of reporting osteoporosis. In 2004, based on dietary and supplement intake, 45% to 69% of the population aged 50 or older had inadequate intake of calcium, and 54% to 66% had inadequate intake of vitamin D. INTERPRETATION: A large percentage of people aged 50 or older, particularly women, have osteoporosis. The prevalence of inadequate intake of calcium and vitamin D is relatively high. PMID- 22106785 TI - Adults' use of health services in the year before death by suicide in Alberta. AB - BACKGROUND: The suicide rate in Alberta is consistently above the Canadian average. Health care use profiles of those who die by suicide in Alberta are currently unknown. DATA AND METHODS: Death records were selected for people aged 25 to 64 with suicide coded as the underlying cause of death from April 1, 2003 to March 31, 2006. The death records were linked to administrative records pertaining to physician visits, emergency department visits, inpatient hospital separations, and community mental health visits. The control group was the Alberta population aged 25 to 64 who did not die by suicide. Frequency estimates were produced to determine the characteristics of the study population. Odds ratios relating to demographics, exposure to health care services, and case control status were estimated with logistic regression. RESULTS: Almost 90% of suicides had a health service in the year before their death. Suicides averaged 16.6 visits per person, compared with 7.7 visits for non-suicides. Much of the health service use among people who died by suicide appears to have been driven by mental disorders. INTERPRETATION: Information about health service delivery to those who die by suicide can guide prevention and intervention efforts. PMID- 22106786 TI - Sugar consumption among Canadians of all ages. AB - According to the 2004 Canadian Community Health Survey-Nutrition, Canadians consumed an average of 110 grams (26 teaspoons) of sugar a day, approximately 20% of their total energy intake. While over 30% of this sugar came from vegetables and fruit, 35% came from the "other" foods category, which consists of items such as soft drinks, salad dressings and candy. The top ten sources of sugar accounted for approximately 85% of daily sugar intake. Beverages (milk, fruit juice, fruit drinks and regular soft drinks) represented 44% of the sugar consumed by children and adolescents, and 35% of that consumed by adults. Diabetics' average sugar intake was less than that of non-diabetics, but at 17%, exceeded the recommended 10% cut-off of total daily calories. PMID- 22106787 TI - Self-reported pH1N1 influenza vaccination coverage for Ontario. AB - BACKGROUND: In the fall of 2009, Canada undertook a mass vaccination campaign against pH1N1. This report provides an overview of self-reported pH1N1 vaccination coverage of the Ontario population, building on an existing random digit-dialling telephone survey, in which 9,010 Ontario adults participated. Based on the results, 34.5% of Ontario residents were vaccinated: 33.3% of adults aged 18 or older and 38.6% of children and adolescents younger than age 18. Respondents reporting high-risk chronic conditions were significantly more likely to report being vaccinated than were people who did not report such conditions. Determining vaccination uptake for the Ontario population is important in the evaluation of the province's pH1N1 prevention program. PMID- 22106788 TI - Bias in self-reported estimates of obesity in Canadian health surveys: an update on correction equations for adults. AB - BACKGROUND: This study compares the bias in self-reported height, weight and body mass index (BMI) in the 2008 and 2005 Canadian Community Health Surveys and the 2007 to 2009 Canadian Health Measures Survey. The feasibility of using correction equations to adjust self-reported 2008 Canadian Community Health Survey values to more closely approximate measured values is assessed. DATA AND METHODS: Data are from the 2008 and 2005 Canadian Community Health Surveys and the 2007 to 2009 Canadian Health Measures Survey. In these surveys, respondents reported their height and weight, and were subsequently measured. Regression equations based on the 2007 to 2009 Canadian Health Measures Survey and the 2005 Canadian Community Health Survey were applied to self-reported 2008 Canadian Community Health Survey data. These equations predicted measured BMI based on self-reported BMI. RESULTS: The bias in reporting height was similar across all three surveys, but the bias in reporting weight was larger in the two Canadian Community Health Surveys, and as a result, discrepancies in estimates of obesity between self-reported and measured values were greater. Application of correction equations based on 2005 Canadian Community Health Survey data to self-reported values in the 2008 Canadian Community Health Survey produced more accurate estimates of obesity than did equations based on Canadian Health Measures Survey data. INTERPRETATION: Survey context may influence the magnitude of the bias in self-reported weight. Respondents who are aware that they will be weighed may report their weight more accurately. Additional data points are required to determine whether the bias in self-reported measures in the Canadian Community Health Survey is changing. PMID- 22106789 TI - Obesity estimates for children based on parent-reported versus direct measures. AB - BACKGROUND: Studies based on adolescents and adults have found that the use of self-reported height and weight to calculate body mass index (BMI) yields a lower prevalence of obesity than do estimates based on measured data. Relatively few studies have examined the bias resulting from the use of parent-reported height and weight for children, and the findings have been inconsistent. DATA AND METHODS: Data are from the 2007 to 2009 Canadian Health Measures Survey. Parent reported height and weight of children aged 6 to 11 (n=854) were obtained. Subsequently, the children's height and weight were directly measured. RESULTS: On average, parents underestimated the height (3.3 cm) and weight (1.1 kg) of their children. Estimates of the prevalence of obesity were significantly higher when based on parent-reported versus measured values for children aged 6 to 8; the two collection methods yielded similar estimates of obesity for children aged 9 to 11. For children in both age groups, misclassification errors for BMI categories were substantial when based on parent-reported values. This weakened associations between obesity and health indicators such as aerobic fitness and systolic blood pressure. The variance explained by factors associated with the bias in parent-reported height and weight was small, particularly for height. The use of correction equations based on variables associated with the bias resulted in a very modest reduction in misclassification errors. INTERPRETATION: Bias associated with parental reports of children's height and weight results in misclassification errors for obesity that affect relationships with other variables. Efforts to establish correction equations to adjust for this bias were unsuccessful. Direct measures are required to accurately calculate obesity estimates and their relationships with health indicators in children. PMID- 22106790 TI - Grand challenges in organismal physiology. PMID- 22106791 TI - Online mentoring through MentorNet.net. PMID- 22106792 TI - Ban chimp testing. Why it is time to end invasive biomedical research on chimpanzees. PMID- 22106793 TI - Toxins all around us. Exposure to the chemicals in everyday objects poses a hidden health threat. PMID- 22106794 TI - More than child's play. Young children think like researchers but lose the feel for the scientific method as they age. PMID- 22106795 TI - Is it safe to drink? The government may not be doing enough to regulate contaminants in tap water. PMID- 22106796 TI - Outsmarting Cancer. A biologist talks about what makes disease-causing proteins so difficult to target with drugs. PMID- 22106797 TI - Clearing the smoke. Marijuana remains tightly controlled, even though its compounds show promise. PMID- 22106798 TI - "I've got your back". New evidence shows that chimpanzees aren't as selfish as many scientists thought. PMID- 22106800 TI - A tale of math treasure. An exhibition traces the reconstruction of a long missing collection of writings by Archimedes. PMID- 22106799 TI - Instant health checks for buildings and bridges. Sensors can detect damage that may be invisible to the naked eye. PMID- 22106801 TI - Gig.U is now in session. Universities are piloting superfast internet connections that may finally rival the speed of South Korea's. PMID- 22106802 TI - Spherical eats. The chemistry of encased mussels and other edible orbs. PMID- 22106804 TI - Big progress on the little things. Let's take a step back and praise three unsung trends in consumer electronics. PMID- 22106803 TI - The ethnic health advantage. Two populations in the U.S. tend to outlive their often richer neighbors. Why? PMID- 22106805 TI - The dark side of the Milky Way. PMID- 22106806 TI - 10 unsolved mysteries. PMID- 22106807 TI - The scent of your thoughts. PMID- 22106808 TI - Afghanistan's buried riches. PMID- 22106809 TI - A new ally against cancer. PMID- 22106810 TI - How skulls speak. PMID- 22106811 TI - Waiting for the Higgs. PMID- 22106812 TI - The dinosaur baron of Transylvania. PMID- 22106813 TI - Actuary of the cell. Interview by Thea Singer. PMID- 22106814 TI - The decline of violence. PMID- 22106815 TI - Data theft: hackers attack. PMID- 22106816 TI - Theoretical and experimental characterization of structures of MnAu nanoclusters in the size range of 1-3 nm. AB - Relative stabilities of MnAu magic-number nanoclusters with 55, 147, 309, and 561 atoms and highly symmetric morphologies (cuboctahedron, icosahedron, onion-like, and core-shell, respectively) are investigated based on density functional theory methods. Through an extensive search, spin arrangements on Mn atoms that give rise to lowest-energy clusters are predicted. The antiferromagnetic spin configurations are found to be the most favorable for all morphologies investigated. The energy rankings among MnAu nanoclusters with the same size and Mn/Au ratio but different morphologies are also determined. The L1(0) structure is found to be increasingly favorable as the size increases from 1.0 to 2.9 nm, consistent with experimental measurements of MnAu nanoparticles in the size range of 1.8-4.6 nm. The decahedron L1(0) morphology is found to be energetically more preferred when the Mn/Au ratio is close to 1:2, whereas the cuboctahedron L1(0) morphology is more preferred when the Mn/Au ratio is close to 1:1. The calculated lattice constants are in excellent agreement with high-resolution TEM measurements for MnAu nanoparticles of similar size. Magnetic states of MnAu nanoclusters are predicted to be stable at room temperature based on estimated Curie or Neel temperature. PMID- 22106817 TI - Control of oxidative posttranslational cysteine modifications: from intricate chemistry to widespread biological and medical applications. AB - Cysteine residues in proteins and enzymes often fulfill rather important roles, particularly in the context of cellular signaling, protein-protein interactions, substrate and metal binding, and catalysis. At the same time, some of the most active cysteine residues are also quite sensitive toward (oxidative) modification. S-Thiolation, S-nitrosation, and disulfide bond and sulfenic acid formation are processes which occur frequently inside the cell and regulate the function and activity of many proteins and enzymes. During oxidative stress, such modifications trigger, among others, antioxidant responses and cell death. The unique combination of nonredox function on the one hand and participation in redox signaling and control on the other has placed many cysteine proteins at the center of drug design and pesticide development. Research during the past decade has identified a range of chemically rather interesting, biologically very active substances that are able to modify cysteine residues in such proteins with huge efficiency, yet also considerable selectivity. These agents are often based on natural products and range from simple disulfides to complex polysulfanes, tetrahydrothienopyridines, alpha,beta -unsaturated disulfides, thiuramdisulfides, and 1,2-dithiole-3-thiones. At the same time, inhibition of enzymes responsible for posttranslational cysteine modifications (and their removal) has become an important area of innovative drug research. Such investigations into the control of the cellular thiolstat by thiol-selective agents cross many disciplines and are often far from trivial. PMID- 22106818 TI - Distinct effects of acute pretreatment with lipophilic and hydrophilic statins on myocardial stunning, arrhythmias and lethal injury in the rat heart subjected to ischemia/reperfusion. AB - Although both lipophilic and more hydrophilic statins share the same pathway of the inhibition of HMG-CoA reductase, their pleiotropic cardioprotective effects associated with the ability to cross cellular membranes, including membranes of heart cells, may differ. To test this hypothesis, isolated rat hearts were Langendorff-perfused either with simvastatin (S, 10 micromol/l) or pravastatin (P, 30 micromol/l), 15 min prior to ischemia. Control untreated hearts (C) were perfused with perfusion medium only. Postischemic contractile dysfunction, reperfusion-induced ventricular arrhythmias and infarct size were investigated after exposure of the hearts to 30-min global ischemia and 2-h reperfusion. Both lipophilic S and hydrophilic P reduced the severity of ventricular arrhythmias (arrhythmia score) from 4.3 +/- 0.2 in C to 3.0 +/- 0 and 2.7 +/- 0.2 in S and P, respectively, (both P < 0.05), decreased the duration of ventricular tachycardia and suppressed ventricular fibrillation. Likewise, the extent of lethal injury (infarct size) determined by tetrazolium staining and expressed in percentage of risk area, was significantly lower in both treated groups, moreover, the effect of P was more pronounced (27 +/- 2 % and 10 +/- 2 % in S and P groups, respectively, vs. 42 +/- 1 % in C; P < 0.05). In contrast, only S, but not P, was able to improve postischemic recovery of left ventricular developed pressure (LVDP; 48 +/- 12 % of preischemic values vs. 25 +/- 4 % in C and 21 +/ -7 % in P groups; P < 0.05). Our results suggest that differences in water solubility of statins indicating a different ability to cross cardiac membranes may underlie their distinct cardioprotective effects on myocardial stunning and lethal injury induced by ischemia/reperfusion. PMID- 22106819 TI - Disodium cromoglycate attenuates hypoxia induced enlargement of end-expiratory lung volume in rats. AB - Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06). PMID- 22106820 TI - Influence of simple electrolytes on the orientational ordering of thermotropic liquid crystals at aqueous interfaces. AB - We report orientational anchoring transitions at aqueous interfaces of a water immiscible, thermotropic liquid crystal (LC; nematic phase of 4'-pentyl-4 cyanobiphenyl (5CB)) that are induced by changes in pH and the addition of simple electrolytes (NaCl) to the aqueous phase. Whereas measurements of the zeta potential on the aqueous side of the interface of LC-in-water emulsions prepared with 5CB confirm pH-dependent formation of an electrical double layer extending into the aqueous phase, quantification of the orientational ordering of the LC leads to the proposition that an electrical double layer is also formed on the LC side of the interface with an internal electric field that drives the LC anchoring transition. Further support for this conclusion is obtained from measurements of the dependence of LC ordering on pH and ionic strength, as well as a simple model based on the Poisson-Boltzmann equation from which we calculate the contribution of an electrical double layer to the orientational anchoring energy of the LC. Overall, the results presented herein provide new fundamental insights into ionic phenomena at LC-aqueous interfaces, and expand the range of solutes known to cause orientational anchoring transitions at LC-aqueous interfaces beyond previously examined amphiphilic adsorbates. PMID- 22106821 TI - Pathogenicity of Ureaplasma urealyticum and Ureaplasma parvum in the lower genital tract of female BALB/c mice. AB - The aim of this study was to establish a murine model of lower genital tract infection by Ureaplasma urealyticum and Ureaplasma parvum and evaluate differences in pathogenicity of five serotypes. BALB/c female mice were divided into seven groups (five mice in each group), including five groups infected in the lower genital tract after treatment with estradiol with U. urealyticum serotypes 4 and 8 and U. parvum serotypes 1, 3, and 6, respectively, and two control groups of untreated mice and estradiol treated mice. The presence of infection was determined on solid and liquid culture media. Tumor necrosis factor alpha (TNF-alpha) expression in lower genital tract secretions was determined by PCR, and morphological and histological changes of the lower genital tract were observed. The genital secretions of all inoculated mice were positive for U. urealyticum and U. parvum on culture in both liquid and solid media. TNF-alpha expression at 7 and 14 days after infection was markedly increased as compared with that of the controls. Morphological changes of the external genitalia included hair loss and erosions, and histological examination revealed infiltration by inflammatory cells. The five serotypes tested were all found to be pathogenic, and the pathogenicity varied with serotype 4 showing the greatest pathogenicity. PMID- 22106822 TI - Regioselectivity of H cluster oxidation. AB - The H(2)-evolving potential of [FeFe] hydrogenases is severely limited by the oxygen sensitivity of this class of enzymes. Recent experimental studies on hydrogenase from C. reinhardtii point to O(2)-induced structural changes in the [Fe(4)S(4)] subsite of the H cluster. Here, we investigate the mechanistic basis of this observation by means of density functional theory. Unexpectedly, we find that the isolated H cluster shows a pathological catalytic activity for the formation of reactive oxygen species such as O(2)(-) and HO(2)(-). After protonation of O(2)(-), an OOH radical may coordinate to the Fe atoms of the cubane, whereas H(2)O(2) specifically reacts with the S atoms of the cubane coordinating cysteine residues. Both pathways are accompanied by significant structural distortions that compromise cluster integrity and thus catalytic activity. These results explain the experimental observation that O(2)-induced inhibition is accompanied by distortions of the [Fe(4)S(4)] moiety and account for the irreversibility of this process. PMID- 22106823 TI - Synthesis of new class of alkyl azarene pyridinium zwitterions via iodine mediated sp3 C-H bond activation. AB - An efficient and conceptually different approach toward C-H bond activation by using iodine mediated sp(3) C-H functionalization for the synthesis of alkyl azaarene pyridinium zwitterions is described. This work has the interesting distinction of being the first synthesis of a new class of alkyl azaarene pyridinium zwitterion via transition-metal-free sp(3) C-H bond activation of an alkyl azaarene. PMID- 22106824 TI - Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells. AB - High-mobility group A1 (Hmga1) protein is an architectural chromatin factor, and aberrant Hmga1 expression in mice causes hematopoietic malignancies with defects in cellular differentiation. However, the functional involvement of Hmga1 in hematopoietic development and leukemic cells remains to be elucidated. Using Hmga1-green fluorescent protein (GFP) knock-in mice that endogenously express an Hmga1-GFP fusion protein, we examined Hmga1 expression in undifferentiated and differentiated populations of hematopoietic cells. During early T cell development in the thymus, Hmga1 is highly expressed in CD4/CD8-double negative (DN) cells and is transiently downregulated in CD4/CD8-double positive (DP) cells. Consistently, Hmga1 directly binds to cis-regulatory elements in the CD4/CD8 loci and the heterochromatin foci in DN-stage cells, but not in DP cells. Interestingly, CD4/CD8 expression in DN-stage leukemic cells is induced by inhibition of Hmga1 binding to nuclear DNA or RNA interference-mediated Hmga1 knockdown. In addition, Hmga1-depleted leukemic T cells markedly diminish proliferation, with transcriptional activation of cyclin-dependent kinase inhibitor genes as a direct target of Hmga1. The data in the present study reveal a role of Hmga1 in transcriptional silencing in T cell lineages and leukemic cells. PMID- 22106825 TI - Speech motor skill and stuttering. AB - The authors review converging lines of evidence from behavioral, kinematic, and neuroimaging data that point to limitations in speech motor skills in people who stutter (PWS). From their review, they conclude that PWS differ from those who do not in terms of their ability to improve with practice and retain practiced changes in the long term, and that they are less efficient and less flexible in their adaptation to lower (motor) and higher (cognitive-linguistic) order requirements that impact on speech motor functions. These findings in general provide empirical support for the position that PWS may occupy the low end of the speech motor skill continuum as argued in the Speech Motor Skills approach (Van Lieshout, Hulstijn, & Peters, 2004). PMID- 22106826 TI - The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. AB - OBJECTIVE: Sex hormone-binding globulin (SHBG) is a robust predictor of insulin resistance. Whether this is independent of circulating sex steroid levels remains uncertain. The aim of this study was to investigate the determinants of SHBG in postmenopausal women and whether the relationship between SHBG and insulin resistance is independent of oestrogen and androgen levels. DESIGN: A cross sectional study of naturally and surgically menopausal women. PARTICIPANTS: Seven hundred and sixty three postmenopausal women not using any systemic hormone therapy, mean age 54.4 +/- 5.8 years, recruited in the US, Canada, Australia, UK and Sweden between July 2004 and February 2005. MEASUREMENTS: Relationships between log-transformed (ln) SHBG and ln homoeostasis model assessment for insulin resistance (HOMA-IR) were explored, taking into account age, body mass index (BMI), blood pressure (BP) and circulating oestradiol, oestrone, testosterone and dihydrotestosterone. RESULTS: Taking into account age, race, years since menopause, menopause type, BMI, BP, prior postmenopausal hormone use and the sex steroids measured, 34.4% of the variation in SHBG could be explained by the model that included negative contributions by HOMA-IR, BMI and diastolic BP, and a positive contribution by total testosterone (P < 0.001). None of the sex steroids made independent contributions to HOMA-IR, which was best explained by the model that included BMI, SHBG, systolic BP and surgical menopause, with each variable being positively related to HOMA-IR (r(2) = 0.3152, P = 0.03). CONCLUSIONS: The relationship between SHBG and HOMA-IR, as an estimate of insulin resistance, is not explained by endogenous oestrogen and androgen levels and is, at least in part, independent of BMI in postmenopausal women. PMID- 22106827 TI - Non-uptake of highly active antiretroviral therapy among patients with a CD4 count < 350 cells/MUL in the UK. AB - OBJECTIVES: Current British HIV Association (BHIVA) guidelines recommend that all patients with a CD4 count <350 cells/MUL are offered highly active antiretroviral therapy (HAART). We identified risk factors for delayed initiation of HAART following a CD4 count <350 cells/MUL. METHODS: All adults under follow-up in 2008 who had a first confirmed CD4 count <350 cells/MUL from 2004 to 2008, who had not initiated treatment and who had >6 months of follow-up were included in the study. Characteristics at the time of the low CD4 cell count and over follow-up were compared to identify factors associated with delayed HAART uptake. Analyses used proportional hazards regression with fixed (sex/risk group, age, ethnicity, AIDS, baseline CD4 cell count and calendar year) and time-updated (frequency of CD4 cell count measurement, proportion of CD4 counts <350 cells/MUL, latest CD4 cell count, CD4 percentage and viral load) covariates. RESULTS: Of 4871 patients with a confirmed low CD4 cell count, 436 (8.9%) remained untreated. In multivariable analyses, those starting HAART were older [adjusted relative hazard (aRH)/10 years 1.15], were more likely to be female heterosexual (aRH 1.13), were more likely to have had AIDS (aRH 1.14), had a greater number of CD4 measurements < 350 cells/MUL (aRH/additional count 1.18), had a lower CD4 count over follow-up (aRH/50 cells/MUL higher 0.57), had a lower CD4 percentage (aRH/5% higher 0.90) and had a higher viral load (aRH/log(10) HIV-1 RNA copies/ml higher 1.06). Injecting drug users (aRH 0.53), women infected with HIV via nonsexual or injecting drug use routes (aRH 0.75) and those of unknown ethnicity (aRH 0.69) were less likely to commence HAART. CONCLUSION: A substantial minority of patients with a CD4 count < 350 cells/MUL remain untreated despite its indication. PMID- 22106828 TI - In-center nocturnal hemodialysis performed thrice-weekly--a provider's perspective. AB - Favorable clinical outcomes related to morbidity, mortality, patient well-being, laboratory biomarkers, and medication use have been reported with in-center nocturnal hemodialysis (INHD); nevertheless, it is not entirely clear how much patient selection or physiologic mechanisms related to better fluid management and phosphorus (and calcium) metabolism may explain these outcomes. There are indications that INHD may be a preferred treatment option in specific cases, such as in patients with high interdialytic weight gain, poor tolerance to high ultrafiltration rate, hyperphosphatemia, or for those patients who work or go to school during the day. In the era of the new prospective payment system where quality standards become intertwined with reimbursement, an INHD program may be a useful method to help attain quality goals in facilities that have patients with unfavorable case-mix. The experience of the past decade has shown INHD to be safe and well tolerated by patients. The growth of INHD therapy is a testament to sustainability and feasibility of this treatment option. Prospective clinical trials are needed in this area. If the promise of INHD is fulfilled, it may also prove to be a valuable option for potential success of Accountable Care Organizations where providers need to assume responsibility for more patient centered care and improvement in clinical outcomes. In summary, based on the current experience, INHD is a viable and valuable option as an additional, alternative hemodialysis (HD) regimen to conventional HD. PMID- 22106829 TI - Identification and characterization of a novel gene, hshB, in Xanthomonas oryzae pv. oryzicola co-regulated by quorum sensing and clp. AB - Virulence factors of Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak in rice, are regulated by a diffusible signal factor (DSF) dependent quorum-sensing (QS) system. In this study, a novel pathogenicity related gene, Xoryp_010100018570 (named hshB), of X. oryzae pv. oryzicola was characterized. hshB encodes a hydrolase with a putative signal peptide, which is a homolog of imidazolonepropionase. Bioinformatic analysis showed that hshB is relatively conserved in the genus Xanthomonas but the homologous gene of hshB was not found in X. oryzae pv. oryzae. Reverse-transcription polymerase chain reaction (PCR) analysis showed that hshB and its upstream gene, Xoryp_010100018565 (named hshA), are co-transcribed in X. oryzae pv. oryzicola. Subsequent experimental results indicated that mutation of hshB remarkably impaired the virulence, extracellular protease activity, extracellular polysaccharide production, growth in minimal medium, and resistance to oxidative stress and bismerthiazol of X. oryzae pv. oryzicola. Mutation of clp, encoding a global regulator, resulted in similar phenotypes. Real-time PCR assays showed that hshB transcription is positively regulated by clp and DSF, and induced by poor nutrition. Our study not only found a novel gene hshB regulated by DSF dependent QS system and clp but also showed that hshB was required for virulence of X. oryzae pv. oryzicola. PMID- 22106830 TI - Time-dependent infectivity and flexible latent and infectious periods in compartmental models of plant disease. AB - Compartmental models have become the dominant theoretical paradigm in mechanistic modeling of plant disease and offer well-known advantages in terms of analytic tractability, ease of simulation, and extensibility. However, underlying assumptions of constant rates of infection and of exponentially distributed latent and infectious periods are difficult to justify. Although alternative approaches, including van der Plank's seminal discrete time model and models based on the integro-differential formulation of Kermack and McKendrick's model, have been suggested for plant disease and relax these unrealistic assumptions, they are challenging to implement and to analyze. Here, we propose an extension to the susceptible, exposed, infected, and removed (SEIR) compartmental model, splitting the latent and infection compartments and thereby allowing time-varying infection rates and more realistic distributions of latent and infectious periods to be represented. Although the model is, in fact, more general, we specifically target plant disease by demonstrating how it can represent both the van der Plank model and the most commonly used variant of the Kermack and McKendrick (K & M) model (in which the infectivity response is delay Gamma distributed). We show how our reformulation retains the numeric and analytic tractability of SEIR models, and how it can be used to replicate earlier analyses of the van der Plank and K & M models. Our reformulation has the advantage of using elementary mathematical techniques, making implementation easier for the nonspecialist. We show a practical implication of these results for disease control. By taking advantage of the easy extensibility characteristic of compartmental models, we also investigate the effects of including additional biological realism. As an example, we show how the more realistic infection responses we consider interact with host demography and lead to divergent invasion thresholds when compared with the "standard" SEIR model. An ever-increasing number of analyses purportedly extract more biologically realistic invasion thresholds by adding additional biological detail to the SEIR model framework; we contend that our results demonstrate that extending a model that has such a simplistic representation of the infection dynamics may not, in fact, lead to more accurate results. Therefore, we suggest that modelers should carefully consider the underlying assumptions of the simplest compartmental models in their future work. PMID- 22106831 TI - Investigation of Arg399Gln and Arg194Trp polymorphisms of the XRCC1 (x-ray cross complementing group 1) gene and its correlation to sister chromatid exchange frequency in patients with chronic lymphocytic leukemia. AB - Polymorphisms of the x-ray repair cross-complementing group 1 (XRCC1) gene have been reported to be associated with various forms of cancer. We evaluated the possible effects of the Arg194Trp and the Arg399Gln polymorphisms on the risk for chronic lymphocytic leukemia (CLL) in 73 patients and 50 controls. We also analyzed their relation to frequency of sister chromatid exchange (SCE). With respect to codon 194, the allelic frequency of the Arg194Trp polymorphism did not significantly differ between the 2 groups. The proportion of individuals carrying the Arg194Trp polymorphism was not different in the 2 groups. With respect to codon 399, the proportion of the individuals carrying the Arg399Gln allele (90% vs 62%; p=0.000; odds ratio [OR], 5.779; 95% confidence interval [CI], 2.2 15.183) and the allelic frequency of the Arg399Gln polymorphism (56% vs 36%; p=0.002; OR, 2.278; 95% CI, 1.350-3.843) was significantly higher in the patient group. The frequency of the Arg/Gln genotype was significantly higher in the patient group (68.50% vs 52%; p=0.049; OR, 2.007; 95% CI, 0.955-4.217). The mean SCE frequency in the patient group was significantly higher (9.2+/-4 vs 7.5+/-2; p=0.02). When different compound genotypes were compared, the coexistence of Arg/Arg genotype in codon 194 with Arg/Arg genotype in codon 399 was significantly more frequent in the control group (30% vs 9%; p=0.004; OR, 0.247; 95% CI, 0.092-0.664). Within the patient group, SCE frequency did not differ between patients with various genotypes. The Arg399Gln polymorphism may be etiologically associated with CLL; however, it does not seem to increase SCE frequency. PMID- 22106832 TI - Identification of mutations underlying 20 inborn errors of metabolism in the United Arab Emirates population. AB - Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders. PMID- 22106833 TI - DNA copy number changes and immunophenotype pattern in karyotypically normal acute myeloid leukemia patients from an Indian population. AB - Chromosomal abnormalities are important in the diagnosis and prognosis of patients with acute myeloid leukemia (AML). The purpose of this study was to identify DNA copy number variations in karyotypically normal AML patients and their correlation with immunophenotypes. Conventional comparative genomic hybridization (CGH) and immunophenotyping were performed in 46 untreated AML patients aged 7-68 years. Among the 86 Indian patients who had AML, 40 (46.5%) showed an abnormal karyotype and 46 (53.4%) showed no chromosome aberrations. The karyotypically abnormal AML patients were excluded from the study. Out of the 46 patients without chromosomal aberrations, 24 (52.2%) showed DNA copy number variations including losses and gains. The DNA copy number variations involved chromosomes 1, 3, 6, 12, 15, 16, 17 (gains) and 1, 4, 2, 3, 5, 7, 8, 9, 10, 11, 13, 15, 18, 20, 21 (losses). The aberrant immunophenotype was noticed in 13 of these 24 (54%) cases. The hidden chromosome rearrangements in karyotypically normal AML, which could not be detected by conventional cytogenetics and fluorescence in situ hybridization, were detected by CGH. These genetic changes have an important role in the prognosis of the disease. The DNA copy number changes might also be involved in the aberrant immunophenotypes in our study. PMID- 22106834 TI - Allograft inflammatory factor-1 gene polymorphisms in patients with rheumatoid arthritis. AB - AIM: Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, inflammation responsive protein. The increased expression of AIF-1 in synovial tissues and fluid from rheumatoid arthritis (RA) patients has been detected. Several single nucleotide polymorphisms have been identified in the AIF1 gene, among them three leading to changes in amino acid sequence. The aim of this study was to examine the association between AIF1 rs2259571:A>C, rs2736182:G>A, and rs13195276:C>T polymorphisms and RA. We examined 380 patients with RA and 376 control subjects. RESULTS: There were no statistically significant differences in distribution of rs2736182 and rs2259571 genotypes and alleles between RA patients and control group. Moreover, there were no significant associations with the age of disease diagnosis, rheumatoid factor, extra-articular manifestation, and anti-cyclic citrullinated peptide (CCP) antibodies, whereas the active form of RA (patients with disease activity score (DAS28)>2.4) was more frequently diagnosed in patients with rs2259571 CC genotypes compared with patients with AA genotype (p=0.007, odds ratio=2.30, 95% confidence interval=1.25-4.25). CONCLUSION: Our results suggest that the AIF1 rs2259571 CC genotype is associated with the active form of RA. PMID- 22106835 TI - Genetic differentiation and origin of the Jordanian population: an analysis of Alu insertion polymorphisms. AB - AIM: Although much of Jordan is covered by desert, its north-western region forms part of the Fertile Crescent region that had given a rich past to Jordanians. This past, scarcely described by historians, is not yet clarified by sufficient genetic data. Thus in this paper we aim to determine the genetic differentiation of the Jordanian population and to discuss its origin. METHODS: A total of 150 unrelated healthy Jordanians were investigated for ten Alu insertion polymorphisms. Genetic relationships among populations were estimated by a principal component (PC) plot based on the analyses of the R-matrix software. RESULTS: Statistical analysis showed that the Jordanian population is not significantly different from the United Arab Emirates population or the North Africans. This observation, well represented in PC plot, suggests a common origin of these populations belonging respectively to ancient Mesopotamia, Arabia, and North Africa. CONCLUSION: Our results are compatible with ancient peoples' movements from Arabia to ancient Mesopotamia and North Africa as proposed by historians and supported by previous genetic results. The original genetic profile of the Jordanian population, very likely Arabian Semitic, has not been subject to significant change despite the succession of several civilizations. PMID- 22106837 TI - Prognostic value of transforming growth factor beta 1 [TGF-beta1] and matrix metalloproteinase 9 [MMP-9] in oral squamous cell carcinoma. AB - OBJECTIVES: The prognostic value of MMP-9 and TGF-beta1 in oral squamous cell carcinoma (OSCC) is not clear. This study aimed to assess this subject. METHODS: After immunohistochemistry staining of 48 OSCC biopsies with MMP-9 and TGF-beta1 markers, marker expression in the stroma was estimated, and the correlations with OSCC prognosis determinants were analyzed (alpha = 0.05). RESULTS: Mode of invasion was associated with metastasis (rho = 0.449, p = 0.008). MMP-9 was positively associated with metastasis and mode of invasion. TGF-beta1 was negatively correlated to tumor histologic grade but was positively associated with metastasis. CONCLUSIONS: Unlike TGF-beta1, MMP-9 might be useful for prognosis determination. PMID- 22106836 TI - Evidence for genetic differentiation and variable recombination rates among Dutch populations of the opportunistic human pathogen Aspergillus fumigatus. AB - As the frequency of antifungal drug resistance continues to increase, understanding the genetic structure of fungal populations, where resistant isolates have emerged and spread, is of major importance. Aspergillus fumigatus is an ubiquitously distributed fungus and the primary causative agent of invasive aspergillosis (IA), a potentially lethal infection in immunocompromised individuals. In the last few years, an increasing number of A. fumigatus isolates has evolved resistance to triazoles, the primary drugs for treating IA infections. In most isolates, this multiple-triazole-resistance (MTR) phenotype is caused by mutations in the cyp51A gene, which encodes the protein targeted by the triazoles. We investigated the genetic differentiation and reproductive mode of A. fumigatus in the Netherlands, the country where the MTR phenotype probably originated, to determine their role in facilitating the emergence and distribution of resistance genotypes. Using 20 genome-wide neutral markers, we genotyped 255 Dutch isolates including 25 isolates with the MTR phenotype. In contrast to previous reports, our results show that Dutch A. fumigatus genotypes are genetically differentiated into five distinct populations. Four of the five populations show significant linkage disequilibrium, indicative of an asexual reproductive mode, whereas the fifth population is in linkage equilibrium, indicative of a sexual reproductive mode. Notably, the observed genetic differentiation among Dutch isolates does not correlate with geography, although all isolates with the MTR phenotype nest within a single, predominantly asexual, population. These results suggest that both reproductive mode and genetic differentiation contribute to the structure of Dutch A. fumigatus populations and are probably shaping the evolutionary dynamics of drug resistance in this potentially deadly pathogen. PMID- 22106838 TI - Total syntheses of angelicoin A, hericenone J, and hericenol A via migratory prenyl- and geranylation-aromatization sequences. AB - A five-step synthesis of the natural product angelicoin A using a late stage highly regioselective palladium(0)-catalyzed decarboxylative prenyl migration and aromatization sequence as the key step is reported. The method was extended with geranyl migration in eight-step total syntheses of hericenone J and hericenol A from geraniol. PMID- 22106839 TI - Common data elements for pediatric traumatic brain injury: recommendations from the biospecimens and biomarkers workgroup. AB - Biospecimens represent a critically important resource in pediatric brain injury research. Data from these specimens can be used to identify and classify injury, understand the molecular mechanisms underlying different types of brain injury, and ultimately identify therapeutic targets to tailor treatments for individual patient needs. To realize the full potential of biospecimens in pediatric traumatic brain injury (TBI), standardization and adoption of best practice guidelines are needed to ensure the quality and consistency of specimens. Multiple groups, including the National Cancer Institute (NCI), the International Society for Biological and Environmental Repositories (ISBER), and the Organisation for Economic Co-operation and Development (OECD), have previously published best practice guidelines for biospecimen resources. Recommendations have also been provided by the Biospecimens and Biomarkers Workgroup of the interagency TBI Common Data Elements (CDE) initiative. The recommendations from all of these sources, however, focus exclusively on adult biospecimen collection. There are no published pediatric-specific biospecimen collection guidelines. An additional workgroup was formed to specifically address this gap. The aim of the Pediatric TBI CDE Biospecimens and Biomarkers Workgroup was to provide recommendations for best practice guidelines to standardize the quality and accessibility of biospecimens for pediatric brain injury research in general, and for pediatric TBI research in particular. Consensus recommendations were developed by review of previously published adult-specific recommendations, including the recommendations of the original TBI Common Data Elements Biospecimens and Biomarkers Workgroup, and by participation in the interagency workshop "Common Data Elements for TBI Research: Pediatric Considerations," held in Houston, Texas in March of 2010. These recommendations represent expert opinion on this subject. The authors of this article were members of the Biospecimens Workgroup. We hope that with adoption of these best practices, future investigators will be able to obtain biospecimens in a consistent way that meets the needs of pediatric patients, and helps to accelerate acquisition of pediatric-specific biomarker data. PMID- 22106840 TI - The management of acute diarrhea in children in developed and developing areas: from evidence base to clinical practice. AB - INTRODUCTION: Acute diarrhea remains a major problem in children and is associated with substantial morbidity, mortality and costs. While vaccination against rotavirus could reduce the burden of the disease, the persistent impact of intestinal infections requires effective treatment in adjunct to oral rehydration solutions, to reduce the severity and duration of diarrhea. Several therapeutic options have been proposed for acute diarrhea, but proof of efficacy is available for few of them, including zinc, diosmectite, selected probiotics and racecadotril. However, at present there is no universal drug, and therapeutic efficacy has only been shown for selected drugs in selected settings, such as: outpatients/inpatients, developed/developing countries and viral/bacterial etiology. AREAS COVERED: This narrative review reports the opinions of experts from different countries of the world who have discussed strategies to improve the management of diarrhea. EXPERT OPINION: More data are needed to optimize the management of diarrhea and highlight the research priorities at a global level; such priorities include improved recommendations on oral rehydration solution composition, and the reevaluation of therapeutic options in the light of new trials. Therapeutic strategies need to be assessed in different settings, and pharmacoeconomic analyses based on country-specific data are needed. Transfer to clinical practice should result from the implementation of guidelines tailored at a local level, with an eye on costs. PMID- 22106841 TI - The effects of season and sex on fat, fatty acids and protein contents of Sepia officinalis in the northeastern Mediterranean Sea. AB - The effects of season and sex on the fatty acids (FAs) and proximate compositions of the mantle of the mature common cuttlefish were evaluated. The results of the proximate composition showed that the lowest lipid content was obtained from females in winter (0.74%), whereas the highest level of lipid was found in males in autumn (0.94%; p < 0.05). The protein levels of the mantle of the mature male of common cuttlefish were significantly higher (p < 0.05) than those found in female specimens. The FA compositions of each sex for all seasons ranged from 29.4% to 32.5% saturated FAs, 8.7-11.1% monounsaturated FAs and 48.2-54.6% polyunsaturated fatty acids (PUFAs). The proportions of n-3 PUFAs (44.0-50.6%) were higher than n-6 PUFAs (3.4-4.3%) regardless of sex and seasons. The levels of eicosapentaenoic acid in the mature common cuttlefish mantle in spring, autumn and winter were 15.9-17.8%, 16.3-17.2% and 15.7-16.8% while those of docosahexaenoic acid were 32.5-33.0%, 27.5-29.0% and 28.7-31.1%, respectively. PMID- 22106842 TI - The effect of an expressive writing intervention (EWI) on stress in infertile couples undergoing assisted reproductive technology (ART) treatment: a randomized controlled pilot study. AB - OBJECTIVES: Infertile couples undergoing fertility treatments may experience stress and could benefit from psychological intervention. Expressive Writing Intervention (EWI) has shown promising results on various psychological outcomes, yet only one study has applied the method to infertility-related stress. Our aim was to assess feasibility and effectiveness of EWI for patients in treatment with Assisted Reproductive Technology (ART). DESIGN AND PARTICIPANTS: Patients enrolling in their first ART treatment at the fertility clinic, Aarhus University Hospital, Denmark were offered to participate. A total of 82 participants (45 women, 37 men), mean age: 33.17, were randomized to home-based EWI or neutral writing control group and completed an infertility-related stress questionnaire at treatment enrollment, 3 weeks later (at the time of down regulation), and 6 weeks after the intervention. The intervention took place 2 weeks after treatment start. RESULTS: Mixed between-within ANOVA showed a main effect of time (Wilks Lambda = 0.68, F(2,28) = 6.48) as well as a significant interaction effect between group (control/ EWI) and time (Wilks Lambda = 0.83, F(2,28) = 2.92). Infertility-related stress decreases were observed after the intervention in the EWI group compared to controls. Six weeks after the intervention, stress tended to increase in both groups, with the control group, follow-up stress levels exceeding baseline stress scores, whereas the follow-up scores of EWI participants' did not exceed baseline levels. CONCLUSIONS: Our preliminary results suggest EWI to be a feasible, cost-effective, and efficient method for alleviating infertility-related stress, although results should be considered preliminary and further testing with a larger sample is warranted. PMID- 22106843 TI - Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia. AB - BACKGROUND: Central sensitization develops once migraine attacks become established and can be clinically detected by the development of cutaneous allodynia. The efficacy of triptans for migraine resolution has been shown to be markedly reduced when administered in patients with established cutaneous allodynia. OBJECTIVE: The study aimed to evaluate the efficacy and safety of MAP0004, a novel, orally inhaled, form of dihydroergotamine, in patients with and without cutaneous allodynia at the time of treatment. METHODS: This evaluation was a post hoc subanalysis of a randomized, double-blind, placebo-controlled, 2 arm, phase 3, multicenter study. The presence or absence of baseline cutaneous allodynia at the time of drug administration was based on the response to a standard questionnaire. Treatment efficacy at 2 hours posttreatment was compared in patients with and without baseline allodynia. RESULTS: At the time of treatment, allodynia was present in 216 patients treated with MAP0004 and 202 patients treated with placebo. MAP0004 treatment efficacy was superior to placebo, as measured by 2-hour pain relief for patients with and without allodynia (P < .0001) and as measured by 2-hour pain freedom for patients with (P < .0001) and without (P < .0002) allodynia. No significant within-treatment differences after treatment with MAP0004 in patients with and without allodynia at baseline were observed. Patients were more likely to be allodynia-free after treatment with MAP0004 compared with placebo (73% vs 66%, P = .0013). Furthermore, treatment with MAP0004 prevented the development of allodynia in patients not experiencing allodynia at baseline (P = .0057). MAP0004 was generally well tolerated. CONCLUSIONS: This post hoc subanalysis shows that MAP0004 was similarly effective in patients whether or not allodynia was present at treatment baseline. Patients were also more likely to be allodynia-free following treatment of a migraine with MAP0004. PMID- 22106844 TI - Virulence gene profiling of enteroaggregative Escherichia coli heat-stable enterotoxin 1-harboring E. coli (EAST1EC) derived from sporadic diarrheal patients. AB - Between 2007 and 2009, a total of 2168 Escherichia coli strains derived from diarrheal patients, defined as putative diarrheagenic E. coli (DEC), were collected from medical institutions in Akita prefecture, Japan. Thirty five of the strains lacked typical pathogenic determinants of DEC other than astA, which encodes enteroaggregative E. coli (EAggEC) heat-stable enterotoxin 1 (EAST1). These E. coli strains are referred to as EAST1EC. Several studies have suggested a role of EAST1 in diarrhea; however, the correlation between diarrhea and the presence of astA remains inconclusive. To investigate whether EAST1EC strains derived from diarrheal patients shared pathogenic factors other than EAST1, virulence gene profiling of 12 virulence genes - iha, lpfA, ldaG, pilS, pic, pet, irp2, daa, aah, aid, cdtB and hlyA - was carried out. PCR analysis revealed that four of the 35 EAST1EC strains harbored only astA, 24 harbored genes associated with adhesins and intestinal colonization, three strains harbored the gene for alpha-hemolysin, and 24 strains harbored the gene for a siderophore. These results indicated that some EAST1EC strains harbor various virulence genes associated with distinct E. coli pathotypes, primarily enterohemorrhagic E. coli and EAggEC, which may represent additional pathogenic determinants of EAST1EC. PMID- 22106845 TI - Impact of relaxation training according to Yoga In Daily Life(r) system on self esteem after breast cancer surgery. AB - OBJECTIVES: The purpose of this pilot study was to gather information on the immediate and short-term effects of relaxation training according to the Yoga In Daily Life((r)) system on the self-esteem of patients with breast cancer. DESIGN: This is a parallel-groups design. SETTINGS/LOCATION: Baseline interventions took place at the Institute for Oncology of Ljubljana (Slovenia). At discharge, the experimental group was issued with audiocassette recordings containing the instructions for relaxation training to be practiced individually at home for an additional 3 weeks. SUBJECTS: The convenience sample of 32 patients with breast cancer was recruited from an accessible population of hospitalized women. Patients were randomized to the experimental (n=16) and to the control group (n=16). INTERVENTIONS: Both groups received the same standard physiotherapy for 1 week, while the experimental group additionally received a group relaxation training sessions according to the Yoga in Daily Life((r)) system. At discharge, the experimental group was issued with audiocassette recordings containing similar instructions for relaxation training to be practiced individually at home for an additional 3 weeks. OUTCOME MEASURES: Outcome measures were obtained by blinded investigators (physiotherapists) using standardized questionnaires (Rosenberg Self-Esteem Scale) at baseline (after the surgery); at 1 week (1 week postattendance; at discharge); and at 4 weeks (4 weeks postattendance); prior the commencement of radiation. RESULTS: Analysis of variance showed that there were statistically significant differences between the experimental and control group in all measuring self-esteem scores over the study period (p<0.0005). At the same time, the control group's scores remained unchanged over the study period (p>0.05). CONCLUSIONS: The results indicate that relaxation training according to the Yoga in Daily Life system could be a useful clinical physiotherapy intervention for patients who have breast cancer and who are experiencing low self-esteem. Although this kind of relaxation training can be applied to clinical oncology in Slovenia, more studies need to be done. PMID- 22106849 TI - Excited state chemistry of capsular assemblies in aqueous solution and on silica surfaces. AB - Synthesis and encapsulation properties of two new water-soluble resorcinol-capped organic cavitands (tetra acid and octa acid; RTA and ROA) are reported in this Letter. Organic guest molecules template the formation of capsular assembly of the above cavitands in water. Depending upon the guest, either 1:2 (guest to host) or 2:2 capsular assemblies were formed. The excited state properties of guests such as anthracene, camphorthione, and 4,4'-dimethyl benzil were distinctly different within a capsular assembly from those when they were free in a solution. Importantly, the host-guest complexes of the above two hosts (RTA and ROA) as well as octa acid (OA) could be transferred to a silica surface. The excited state behavior of host-guest assemblies on silica surface resembled that in solution. The high cage effect in the decarbonylation products and high yield of rearrangement product obtained upon photolysis of 1-phenyl-3-tolyl-2-propanone included within RTA, ROA, and OA both in solution and on silica surface supported the conclusion that capsular assemblies of these hosts are stable on silica surface. PMID- 22106846 TI - Lipid-mediated unfolding of 3beta-hydroxysteroid dehydrogenase 2 is essential for steroidogenic activity. AB - For inner mitochondrial membrane (IMM) proteins that do not undergo N-terminal cleavage, the activity may occur in the absence of a receptor present in the mitochondrial membrane. One such protein is human 3beta-hydroxysteroid dehydrogenase 2 (3betaHSD2), the IMM resident protein responsible for catalyzing two key steps in steroid metabolism: the conversion of pregnenolone to progesterone and dehydroepiandrosterone to androstenedione. Conversion requires that 3betaHSD2 serve as both a dehydrogenase and an isomerase. The dual functionality of 3betaHSD2 results from a conformational change, but the trigger for this change remains unknown. Using fluorescence resonance energy transfer, we found that 3betaHSD2 interacted strongly with a mixture of dipalmitoylphosphatidylglycerol (DPPG) and dipalmitoylphosphatidylcholine (DPPC). 3betaHSD2 became less stable when incubated with the individual lipids, as indicated by the decrease in thermal denaturation (T(m)) from 42 to 37 degrees C. DPPG, alone or in combination with DPPC, led to a decrease in alpha-helical content without an effect on the beta-sheet conformation. With the exception of the 20 N-terminal amino acids, mixed vesicles protected 3betaHSD2 from trypsin digestion. However, protein incubated with DPPC was only partially protected. The lipid-mediated unfolding completely supports the model in which a cavity forms between the alpha-helix and beta-sheet. As 3betaHSD2 lacks a receptor, opening the conformation may activate the protein. PMID- 22106850 TI - Synthesis, crystal structures, and electronic properties of nonlinear fused thienoacene semiconductors. AB - Two fused thienoacene compounds with two-dimensional ring connectivity were synthesized, and their semiconducting properties were characterized. Both compounds have a crystal structure comprised of herringbone arrays of tight pi-pi stacks. Strong pi-pi interactions lead to self-assembly into well-defined crystalline thin films from the vapor phase for both compounds. Field effect transistors were fabricated, affording identical hole mobilities of 3.0 * 10(-3) cm(2)/(V s) and I(on/off) > 10(5). PMID- 22106851 TI - Effect of malpositioned anterior cruciate ligament replacement on knee joint structures: a biomechanical model. AB - Any sort of malpositioning of anterior cruciate ligament (ACL) replacement leads to an overload of single fibers of the ACL replacement. As long as this does not result in a tear of these fibers so that isometry of the ACL replacement is restored, the abnormal forces acting in and on the ACL replacement are transmitted from the ACL replacement to the remainder of the knee joint structures. We assumed that the posterior cruciate ligament (PCL) is notably affected. The present biomechanical model illustrates the relevant force vectors and reveals the extent of the effect of malpositioned ACL replacement on knee joint structures, particularly the PCL. Further investigations are needed to find out if the presumably occurring overload of a malpositioned ACL replacement can be calculated from its position on an individual basis. This may help deduce recommendations for ACL replacement procedures in the future. PMID- 22106852 TI - Factors influencing insulin sensitivity in patients with mild primary hyperparathyroidism before and after parathyroidectomy. AB - OBJECTIVES: Primary hyperparathyroidism (PHPT) is associated with cardiovascular disease. The aims of this study were to investigate lipid and glucose metabolism in mild PHPT, and to identify whether insulin sensitivity correlates with circulating levels of adiponectin, SHBG, and osteocalcin before and after parathyroidectomy (PTX). MATERIALS AND METHODS: Forty-five patients with PHPT were examined before and 1 year after PTX. Circulating levels of triglycerides, total cholesterol, HDL-cholesterol, insulin, glucose, adiponectin, SHBG, osteocalcin, and erythropoietin were measured. RESULTS: At baseline, the mean serum levels of total cholesterol, LDL-cholesterol and triglycerides were above the upper reference limit or in the upper normal range, and insulin sensitivity was reduced as assessed using the HOMA index. One year after parathyroidectomy, serum lipids as well as HOMA index and erythropoietin were unchanged while adiponectin had increased (p < 0.05), and SHBG and osteocalcin had decreased (p < 0.05 and p < 0.0001, respectively). HOMA index correlated negatively with circulating levels of adiponectin, SHBG and osteocalcin. In multiple regression analysis SHBG was the most important predictor of insulin sensitivity, both pre- and postoperatively. CONCLUSION: Untreated mild PHPT is associated with a moderate derangement of lipid and glucose metabolism. As previously shown in population-based cohorts, insulin sensitivity is positively associated with circulating concentrations of adiponectin, SHBG and osteocalcin. One year after PTX, the mean level of adiponectin was increased, but the levels of SHBG and osteocalcin had decreased and the levels of serum lipids and the insulin sensitivity remained unchanged as compared with baseline. PMID- 22106853 TI - Efficacy and safety of prolonged-release OROS methylphenidate in adults with attention deficit/hyperactivity disorder: a 13-week, randomized, double-blind, placebo-controlled, fixed-dose study. AB - OBJECTIVES: Methylphenidate (MPH) is effective for adults with attention deficit/hyperactivity disorder (ADHD). This study aimed to evaluate the efficacy and safety of OROS MPH in adults with ADHD. METHODS: Randomized, double-blind study; 279 subjects received OROS MPH 54 or 72 mg/day, or placebo, for 13 weeks. Primary endpoint was the Conners' Adult ADHD Rating Scale - Screening Version (CAARS-O:SV). Secondary outcomes included CAARS Self Report - Short Version (CAARS-S:S), Sheehan Disability Scale (SDS) and ADHD Impact Module - Adult (AIM A). RESULTS: Improvements in CAARS-O:SV were significantly greater with OROS MPH 72 mg vs. placebo (P = 0.0024). CAARS-S:S scores decreased significantly vs. placebo in both OROS MPH arms (P < 0.05). There was no significant change in SDS score from baseline in either treatment arm, although significant benefit vs. placebo was observed on several AIM-A subscales. Treatment was well tolerated. CONCLUSIONS: OROS MPH provided overall benefits in the treatment of adults with ADHD. PMID- 22106854 TI - Strategies for drug delivery to the human inner ear by multifunctional nanoparticles. AB - Hearing loss is a very significant health problem. The methods currently available for inner ear drug delivery are limited and a noninvasive cell-specific drug delivery strategy needs to be found. AIM: In this study we investigated the ability of polymersomes, lipid core nanocapsules and hyperbranched poly-L-lysine to cross the round window membrane. MATERIALS & METHODS: Nanoparticles (NPs) used in this study have different size and chemical compositions. Freshly frozen human temporal bones were used for this investigation. Intact human round window membrane within the freshly frozen human temporal bone served as an excellent model to test the membrane permeation and distribution within the tissues. RESULTS: In this investigation we were able to visualize the NPs across the round window membrane. The NPs were subsequently found to be distributed in the sensory hair cells, nerve fibers and to other cells of the cochlea. CONCLUSION: This finding raises hope in terms of future multifunctional NP-based drug delivery strategy to the human inner ear. PMID- 22106855 TI - Ex vivo impact of functionalized carbon nanotubes on human immune cells. AB - AIM: Different studies, carried out by us and others, have investigated the impact of carbon nanotubes (CNTs) in vitro and in animal models. To date, only a few studies have been performed on human cells ex vivo. There is also a lack of comparison between CNTs with varied functionalization and structural properties and their impact on different cell types. MATERIALS & METHODS: The present ex vivo human study focuses on the impact of a series of functionalized multiwalled CNTs on human T and B lymphocytes, natural killer (NK) cells and monocytes. RESULTS: Smaller diameter nanotubes are internalized more efficiently. Viability assays displayed the absence of cytotoxicity of all multiwalled CNTs used. Activation assay demonstrated a strong effect on monocytes and NK cells. CONCLUSION: Our results, on human cells ex vivo, confirmed previous studies demonstrating appropriately functionalized CNTs are nontoxic. The effects on cell functionality were significant for the monocytes and NK cells. These findings encourage the possible use of CNTs for biomedical applications either as carriers of therapeutic molecules or as immune modulator systems. PMID- 22106856 TI - Role of -675 4G/5G in the plasminogen activator inhibitor-1 gene and -308G/A tumor necrosis factor-alpha gene polymorphisms in obese Argentinean patients. AB - AIM: Plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-alpha (TNF-alpha) are increased in the circulation of obese persons. Because a direct link between PAI-1 and TNF-alpha in obesity has been observed, they are candidate genes for the development of obesity. We sought to evaluate the relation between the genotypic and allelic frequencies of the -675 4G/5G PAI-1 and -308 G/A TNF alpha polymorphisms and their association with the risk for obesity in an Argentinean population. METHODS: A group of 110 consecutive obese persons and a group of 111 lean controls were recruited. Polymerase chain reaction was used to determine the frequency of PAI-1 and TNF-alpha polymorphisms; serum fasting glucose, insulin, and lipid levels were measured by standard methods. Insulin sensitivity was evaluated by using homeostasis model assessment. RESULTS: The 308 TNF-alpha and -675 4G/5G PAI-1 genotype distribution did not significantly differ between the groups (p=0.544 and p=0.327, respectively). Homeostasis model assessment was the only positive independent determinant of body mass index (R(2)=0.493; p<0.001). CONCLUSION: The -675 4G/5G PAI-1 and the -308 TNF-alpha polymorphism variants tested in this study, individually or combined, were not associated with obesity in an Argentinean population. PMID- 22106857 TI - Homeobox C9 is not potentially related to congenital heart disease in Chinese patients. AB - BACKGROUND: Congenital heart disease (CHD) is one of the most common human birth defects. The etiology and pathogenesis of CHD are complex and involve several genes as well as multiple changes in signaling pathways. The aim of this study was to identify potential pathological mutations in the Homeobox C9 (Hoxc9) gene in 350 Chinese children with CHD to further understand the etiology of CHD. METHOD: Sequence analysis of the Hoxc9 gene in 350 nonsyndromic patients with CHD Result: We did not identify any nonsynonymous variants in the coding regions of Hoxc9 in the patients with CHD. We found one synonymous variant c.C564T (p. his188his) in one ventricular septal defect patient. We also identified four previously reported polymorphisms (rs56368105, rs12817092, rs34079606, and rs2241820) in CHD. CONCLUSIONS: We did not find any diagnostic alterations in the coding regions of Hoxc9 among the patients with CHD. Nevertheless, to our knowledge, this is the first study of Hoxc9 in nonsyndromic CHD and has expanded our overall knowledge of the etiology of this disease. PMID- 22106858 TI - A functional polymorphism in the epidermal growth factor gene is associated with risk for glioma in a Chinese population. AB - Epidermal growth factor (EGF) plays a key role in survival of neural and glial precursor cells. A single nucleotide polymorphism of the EGF gene +61G/A in the 5'-untranslated region has been reported to be associated with susceptibility to glioma. The purpose of this study was to investigate the potential association between EGF +61G/A and brain glioma in a Chinese population. A case-control study involving 180 patients with glioma and 360 controls was done. Polymerase chain reaction restriction fragment-length polymorphism assay was used to analyze the EGF +61G/A genotypes. Patients with glioma had a significantly higher frequency of AA genotype (odds ratio, 2.25; 95% confidence interval, 1.20, 4.21; p=0.01] than controls. When stratified by histologic features and World Health Organization grade of glioma, distribution of each genotype did not significantly differ. Our data suggested that the EGF +61G AA genotype was associated with a higher glioma risk in a Chinese population. This finding is in contrast with previous studies that reported the G allele as a risk factor for glioma in white patients. PMID- 22106859 TI - Cueing strategies in neglect dyslexia. AB - A single case study is reported of a patient with left neglect dyslexia after a right hemisphere stroke. The effectiveness of two cueing strategies in improving her single word reading was compared, a variation of the commonly used visuo motor method and the recently advocated non-visual spatio-motor cueing technique. Results demonstrated the success of both strategies in reducing neglect dyslexic errors but showed qualitative differences in the processes involved. Only the visuo-motor strategy was associated with continued improvements in reading throughout the intervention period. Furthermore, the visuo-motor cueing technique showed gains still evident at 18 months post-treatment, suggesting clinically significant improvement may be mediated by visual aspects of cueing-based intervention for reading. The results are interpreted in terms of the efficacy of non-verbal attentional cues on a putative graphemic analysis system. Several practical considerations for the remediation of neglect in routine clinical settings are also discussed. PMID- 22106860 TI - The baking tray task: a test of spatial neglect. AB - This paper describes a new neglect test, where patients are asked to spread out 16 cubes as evenly as possible over a 75 * 100 cm board "as if they were buns on a baking tray". A consecutive series of 52 brain-damaged patients and 30 control subjects were examined with the new test as well as with several commonly used neglect tests. The baking tray task proved to be a quick and yet sensitive test, suitable for screening purposes and longitudinal studies. PMID- 22106861 TI - Remediation of arabic numeral processing in a case of developmental dyscalculia. AB - In this case study we investigated numeral transcoding in CM, a young man with developmental dyscalculia. Our initial assessment revealed that CM's difficulties in numeral transcoding occurred mainly on tasks requiring the production of Arabic numerals. His errors on these tasks were most often syntactically ill formed strings in which the basic lexical elements are retained, but the overall structure is incorrect (e.g. nine hundred two thousand seventy -> 92,70). We then implemented a training programme designed to overcome CM's syntactic impairment. Pre-training/post-training comparisons revealed significant improvement on the trained written-verbal-to-Arabic task as well as on an untrained spoken-verbal-to Arabic task presumed to share the same Arabic numeral production process. A comparison of CM's numeral transcoding performance with control children showed that CM's performance improved from a third-grade level to approximately a fourthgrade level (i.e. the grade in which most children begin to display proficient number transcoding skills). Further analyses revealed that the syntactic errors produced by CM and the control subjects were inconsistent in terms of length, a finding that contrasts with the results of previous studies of numeral transcoding in children. In the general discussion we mention possible reasons for the discrepant outcomes across studies. PMID- 22106862 TI - M emory Notebook Training in a Case of Severe Amnesia: Generalising from Paired Associate Learning to Real Life. AB - A severely amnesic patient was trained to use a notebook as a record for daily events in an attempt to reduce his tendency to ask questions repeatedly. In the first stage of the study, a novel paired associate learning procedure was used as a means of training Mr S to become reliant on a notebook for information he could not remember. This notebook training incorporated a comparison of errorless and errorful methods of learning. Mr S learned successfully using the notebook and showed a clear advantage for the errorless method. In the second stage of the study, the errorless learning procedure was used as a means of training Mr S to look up facts about his daily routine. Comparison of his behaviour before and after the diary training indicated a reduction in his repetitive questioning about daily events. Subsequent visits to Mr S indicate continued use of the notebook. The study shows how artificial learning procedures can be adapted to achieve a practical goal. PMID- 22106863 TI - Research digest. PMID- 22106865 TI - Ruthenium-catalyzed enantioselective hydrogenation of aryl-pyridyl ketones. AB - Various substituted aryl-pyridyl ketones were hydrogenated in the presence of Ru XylSunPhos-Daipen bifunctional catalytic system with enantiomeric excesses up to 99.5%. Upon introduction of a readily removable ortho-bromo atom to the phenyl ring, enantiomerically enriched 4-chlorophenylpyridylmethanol was obtained by hydrogenation method with 97.3% ee, which provided an important chiral intermediate for some histamine H(1) antagonists. PMID- 22106866 TI - Genotypic differences in arsenic, mercury, lead and cadmium in milled rice (Oryza sativa L.). AB - The contents of arsenic, mercury, lead and cadmium in milled rice were determined. Among 216 genotypes, the As, Hg, Pb and Cd contents were ranged from 5.06 to 296.45, 2.46 to 65.85, 4.16 to 744.95 and 5.91 to 553.40 ng/g, respectively. Six genotypes with lower contents of toxic metal elements were selected. The averages of As and Pb contents for indica rice were higher than those of japonica rice, while the averages of Hg and Cd contents were in contrast. Compared with white brown rice, the milled rice from black and red brown rice contained lower contents of four elements. Significant negative correlation was found between As content and alkaline spread value. Significant correlations were observed between As and aspartic acid (Asp) content, Hg and Asp or leucine contents, Pb and cysteine or methionine contents. Cd content was significantly negatively correlated with protein and 14 amino acid contents. PMID- 22106867 TI - In vivo roles of the basic domain of dynactin p150 in microtubule plus-end tracking and dynein function. AB - Microtubule (MT) plus-end-tracking proteins accumulate at MT plus ends for various cellular functions, but their targeting mechanisms are not fully understood (Akhmanova A and Steinmetz MO. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol 2008;9:309 322.). Here, we tested in the filamentous fungus Aspergillus nidulans the requirement for plus-end localization of dynactin p150, a protein essential for dynein function. Deletion of the N-terminal MT-binding region of p150 significantly diminishes the MT plus-end accumulation of both dynein heavy chain and p150, and causes a partial defect in nuclear distribution. Surprisingly, within the MT-binding region, the basic domain is more critical than the CAP-Gly (cytoskeleton-associated protein glycine-rich) domain for maintaining plus-end tracking of p150, as well as for the functions of dynein in nuclear distribution and early endosome movement. Our results show that the basic domain of A. nidulans p150 is important for p150-MT interaction both in vivo and in vitro, and the basic amino acids within this domain are crucial for the plus-end accumulation of p150 in the wild-type background and for the p150-MT interaction in the DeltakinA (kinesin-1) background. We suggest that the basic amino acids are required for the electrostatic interaction between p150 and MTs, which is important for kinesin-1-mediated plus-end targeting of dynactin and dynein in A. nidulans. PMID- 22106868 TI - Gene conversion rapidly generates major histocompatibility complex diversity in recently founded bird populations. AB - Population bottlenecks can restrict variation at functional genes, reducing the ability of populations to adapt to new and changing environments. Understanding how populations generate adaptive genetic variation following bottlenecks is therefore central to evolutionary biology. Genes of the major histocompatibility complex (MHC) are ideal models for studying adaptive genetic variation due to their central role in pathogen recognition. While de novo MHC sequence variation is generated by point mutation, gene conversion can generate new haplotypes by transferring sections of DNA within and across duplicated MHC loci. However, the extent to which gene conversion generates new MHC haplotypes in wild populations is poorly understood. We developed a 454 sequencing protocol to screen MHC class I exon 3 variation across all 13 island populations of Berthelot's pipit (Anthus berthelotii). We reveal that just 11-15 MHC haplotypes were retained when the Berthelot's pipit dispersed across its island range in the North Atlantic ca. 75,000 years ago. Since then, at least 26 new haplotypes have been generated in situ across populations. We show that most of these haplotypes were generated by gene conversion across divergent lineages, and that the rate of gene conversion exceeded that of point mutation by an order of magnitude. Gene conversion resulted in significantly more changes at nucleotide sites directly involved with pathogen recognition, indicating selection for functional variants. We suggest that the creation of new variants by gene conversion is the predominant mechanism generating MHC variation in genetically depauperate populations, thus allowing them to respond to pathogenic challenges. PMID- 22106869 TI - Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. AB - BACKGROUND: The Headache Impact Test-6 (HIT-6) has been demonstrated to be a reliable and valid measure that assesses the impact of headaches on the lives of persons with migraine. Originally used in studies of episodic migraine (EM), HIT 6 is finding increasing applications in chronic migraine (CM) research. OBJECTIVES: (1) To examine the headache-impact on persons with migraine (EM and CM) using HIT-6 in a large population sample; (2) to identify predictors of headache-impact in this sample; (3) to assess the magnitude of effect for significant predictors of headache-impact in this sample. METHODS: The American Migraine Prevalence and Prevention study is a longitudinal, population-based study that collected data from persons with severe headache from 2004 to 2009 through annual, mailed surveys. Respondents to the 2009 survey who met International Classification of Headache Disorders 2 criteria for migraine reported at least 1 headache in the preceding year, and completed the HIT-6 questionnaire were included in the present analysis. Persons with migraine were categorized as EM (average <15 headache days per month) or CM (average >=15 headache days per month). Predictors of headache-impact examined include: sociodemographics; headache days per month; a composite migraine symptom severity score (MSS); an average pain severity rating during the most recent long-duration headache; depression; and anxiety. HIT-6 scores were analyzed both as continuous sum scores and using the standard, validated categories: no impact; some impact; substantial impact; and severe impact. Group contrasts were based on descriptive statistics along with linear regression models. Multiple imputation techniques were used to manage missing data. RESULTS: There were 7169 eligible respondents (CM = 373, EM = 6554). HIT-6 scores were normally distributed. After converting sum HIT-6 scores to the standard categories, those with CM were significantly more likely to experience "severe" headache impact (72.9% vs 42.3%) and had higher odds of greater adverse headache impact compared with persons with EM (OR = 3.5, 95% CI = 2.77-4.41, P < .0001). Significant predictors of adverse headache impact in both groups included younger age, higher MSS score, higher average long duration headache pain severity rating, and depression. Lower annual household income, anxiety, and higher standardized headache day frequency predicted adverse headache impact in EM but not CM. With few exceptions, gender, race, and body mass index did not significantly predict adverse headache impact. Finally, rates of depression were more than double among persons with CM (CM = 25.2%, EM = 10.0%), and rates of anxiety were nearly triple (CM = 23.6%, EM = 8.5%). CONCLUSIONS: This work further establishes HIT-6 as a useful instrument for characterizing CM and understanding the increased disease related burden. Persons with CM had significantly higher odds of greater adverse headache impact, when compared with EM. Predictors of greater headache impact for both groups included higher MSS scores, higher average headache pain severity, and depression. Additional predictors unique to EM included higher average household income, younger age, higher standardized headache day frequency, and anxiety. This finding may be related to differences in sample size and power. Further exploration is warranted. PMID- 22106870 TI - Symmetry States of the physical space: an expanded reference frame for understanding human consciousness. AB - A remarkable phenomenon is taking place around the globe, one that I have been fortunate enough to witness and in which to participate. The relics of the historical Buddha, also known as Siddhartha or Shakyamuni Buddha, still survive today over 2500 years since his enlightenment, and, for the first time in history, are traveling throughout the world. In common Buddhist practice, relics are highly venerated and treasured remains of realized Masters. It is very rare for relics to travel from city to city and be available for viewing by the general public. The Buddha relic tour is demonstrating that a direct experience of the spiritual state is not mysterious, nor is it for a select few. The spiritual state, here defined as a universal theme of unconditional love, is a component of human evolutionary unfoldment, a process through which thousands of human beings have passed, and through which thousands more will pass. We are "waking up" as a species. Consequently, more information is required about this transformation of human consciousness. The Buddha relics offer us a priceless means by which we can obtain a richer perspective about the nature of human consciousness, spiritual realities such as love, and ultimately understanding ourselves. PMID- 22106871 TI - EPODE approach for childhood obesity prevention: methods, progress and international development. AB - Childhood obesity is a complex issue and needs multi-stakeholder involvement at all levels to foster healthier lifestyles in a sustainable way. 'Ensemble Prevenons l'Obesite Des Enfants' (EPODE, Together Let's Prevent Childhood Obesity) is a large-scale, coordinated, capacity-building approach for communities to implement effective and sustainable strategies to prevent childhood obesity. This paper describes EPODE methodology and its objective of preventing childhood obesity. At a central level, a coordination team, using social marketing and organizational techniques, trains and coaches a local project manager nominated in each EPODE community by the local authorities. The local project manager is also provided with tools to mobilize local stakeholders through a local steering committee and local networks. The added value of the methodology is to mobilize stakeholders at all levels across the public and the private sectors. Its critical components include political commitment, sustainable resources, support services and a strong scientific input--drawing on the evidence-base--together with evaluation of the programme. Since 2004, EPODE methodology has been implemented in more than 500 communities in six countries. Community-based interventions are integral to childhood obesity prevention. EPODE provides a valuable model to address this challenge. PMID- 22106872 TI - A monoclonal antibody specific for Candida albicans Als4 demonstrates overlapping localization of Als family proteins on the fungal cell surface and highlights differences between Als localization in vitro and in vivo. AB - The Candida albicans agglutinin-like sequence (ALS) family encodes large cell surface glycoproteins that function in adhesion of the fungus to host and abiotic surfaces. Monoclonal antibodies (mAbs) specific for each Als protein were developed to study Als localization on the C. albicans surface. An anti-Als4 mAb demonstrated that Als4 covers the surface of yeast cells, with a greater abundance of Als4 on cells grown at 30 degrees C compared to 37 degrees C. On germ tubes, Als4 is localized in a restricted area proximal to the mother yeast. Immunolabeling with several anti-Als mAbs showed overlapping localization of Als1 and Als4 on yeast cells and Als1, Als3 and Als4 on germ tubes. Overlapping localization of Als proteins was also observed on yeast and hyphae recovered from mouse models of disseminated and oral candidiasis. Differences between Als localization in vivo and in vitro suggested changes in regulation of Als production in the host compared to the culture flask. Characterization with the anti-Als mAbs reveals the simultaneous presence and differences in relative abundance of Als proteins, creating an accurate image of Als representation and localization that can be used to guide conclusions regarding individual and collective Als protein function. PMID- 22106873 TI - Coexistent findings of renal glomerular disease with Hashimoto's thyroiditis. AB - AIM AND BACKGROUND: Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disease with a female preponderance. Renal involvement in HT is not uncommon. In the present study, we aimed to define the frequency and characteristics of the glomerular diseases associated with HT and further the understanding of any common pathogenesis between HT and glomerular disease. MATERIALS AND METHODS: We reviewed retrospectively 28 patients with HT who were referred to our Department because of unexplained haematuria, proteinuria or renal impairment from 2007 to 2011. Routine laboratory investigations including blood count, serum biochemistry, urinalysis and 24-h urinary protein excretion were performed on all patients. Renal biopsy was performed in 20 patients with HT, and the specimens were examined by light microscopy and immunofluorescence staining. RESULTS: We detected four cases of focal segmental glomerulosclerosis (FSGS), four membranous glomerulonephritis (MGN), two minimal-change disease (MCD), three immunoglobulin A nephritis (IgAN), three chronic glomerulonephritis (CGN) and one amyloidosis. In three patients, the renal biopsy findings were nonspecific. Daily urinary protein excretion and glomerular filtration rates were found to be independent of the level of thyroid hormone and thyroid-specific autoantibodies. CONCLUSION: Glomerular pathologies associated with HT are similar to those in the general population, the most common lesions being MGN, FSGS and IgA nephritis. PMID- 22106874 TI - Working in the real world: a review of sociological concepts of health and well being and their relation to modern mental health nursing. AB - Since 2008, the world has witnessed several socio-economic upheavals that have fundamentally changed the global economy. Within the UK, these upheavals have coincided with a change in political administration and thus a new approach to managing the volatility of economy. This change has resulted in root and branch reform of service provision that is based around a model that incorporates a shrinking public sector coupled with an increase in civic participation (i.e. 'The Big Society' espoused by the UK-governing coalition). It is also unlikely that healthcare provision on a global level will remain unchanged in such turbulent times. It would therefore seem a useful time to review how socio economic forces are believed to affect the health and well-being of an individual. These forces include social inequality, the mechanisms of social inclusion and exclusion, social role and the erosion of resilience. This paper will then conclude by offering some potential avenues that nurses can explore to make these forces less damaging for their clients. These avenues include developing a clinical focus based around positive psychology, well-being and some novel ways that nurses can help overcome the maintenance cycles that perpetuate inequality and exclusion. PMID- 22106875 TI - Predicting alcohol consumption and binge drinking in company employees: an application of planned behaviour and self-determination theories. AB - OBJECTIVES: This study tested an integrated model of the psychosocial determinants of alcohol-related behaviour among company employees from four nations. A motivational sequence was proposed in which motivational orientations from self-determination theory influenced intentions to consume alcohol within guideline limits and alcohol-related behaviour via the mediation of the theory of planned behaviour variables of attitude, subjective norms, and perceived behavioural control (PBC). DESIGN: A three-wave prospective design using self reported psychological and behavioural measures. METHODS: Company employees (N= 486, males = 225, females = 261; M age = 30.41, SD= 8.31) from four nations (Estonia, Finland, Sweden, and UK) completed measures of autonomous and controlled motivation from self-determination theory, attitudes, subjective norms, PBC, intentions from the theory of planned behaviour, and self-reported measures of past alcohol consumption and binge-drinking occasions at the first time point (time 1). Follow-up psychological and behavioural measures were taken one month later (time 2) and follow-up behavioural measures taken a further 2 months later (time 3). RESULTS: Path analyses supported the motivational sequence with identified regulation (time 1), predicting intentions (time 1), and alcohol units consumed (time 2). The effects were indirect via the mediation of attitudes and PBC (time 1). A similar pattern of effects was found for the effect of time 2 psychological variables on time 3 units of alcohol consumed. There was little support for the effects of the psychological variables on binge-drinking behaviour. CONCLUSIONS: Findings provide new information on the psychosocial determinants of alcohol behaviour in company employees and the processes involved. Results may provide impetus for the development of interventions to reduce alcohol consumption. PMID- 22106876 TI - Quantifying the kinetic stability of hyperstable proteins via time-dependent SDS trapping. AB - Globular proteins are usually in equilibrium with unfolded conformations, whereas kinetically stable proteins (KSPs) are conformationally trapped by their high unfolding transition state energy. Kinetic stability (KS) could allow proteins to maintain their activity under harsh conditions, increase a protein's half-life, or protect against misfolding-aggregation. Here we show the development of a simple method for quantifying a protein's KS that involves incubating a protein in SDS at high temperature as a function of time, running the unheated samples on SDS-PAGE, and quantifying the bands to determine the time-dependent loss of a protein's SDS resistance. Six diverse proteins, including two monomer, two dimers, and two tetramers, were studied by this method, and the kinetics of the loss of SDS resistance correlated linearly with their unfolding rate determined by circular dichroism. These results imply that the mechanism by which SDS denatures proteins involves conformational trapping, with a trapping rate that is determined and limited by the rate of protein unfolding. We applied the SDS trapping of proteins (S-TraP) method to superoxide dismutase (SOD) and transthyretin (TTR), which are highly KSPs with native unfolding rates that are difficult to measure by conventional spectroscopic methods. A combination of S TraP experiments between 75 and 90 degrees C combined with Eyring plot analysis yielded an unfolding half-life of 70 +/- 37 and 18 +/- 6 days at 37 degrees C for SOD and TTR, respectively. The S-TraP method shown here is extremely accessible, sample-efficient, cost-effective, compatible with impure or complex samples, and will be useful for exploring the biological and pathological roles of kinetic stability. PMID- 22106877 TI - Continuing education for nurses in the clinical management of autism spectrum disorders: results of a pilot evaluation. AB - The prevalence of autism spectrum disorders (ASDs) is 1 in 110 in the United States. Nurses encounter patients with ASDs across practice settings. This article describes the results of an evaluation research pilot that assessed the perceived value to nurses of a continuing education program on comprehensive care of people with ASDs. Two 2-day workshops were offered in 2010. Of the 37 participants, 92% were female; 35% worked in pediatrics, 35% worked in adult care, and 30% were administrators; and 33% had practiced for 11 years or more. Six months after the course, 74% shared information with their employers and 94% shared information with coworkers. Although 77% incorporated learning into practice, 23% reported that they had not yet had the opportunity to do so. All participants valued the course content. Future programs can target audiences in specific service areas or those who work with specific populations. This pilot provided useful feedback on the nursing care of people with ASDs that is relevant to a variety of potential audiences. Continuing education programs can target sponsors, donors, client groups, administrators, and staff as they prepare to care for patients with ASDs. PMID- 22106878 TI - Registered nurses' perspectives on the new graduate working in the emergency department or critical care unit. AB - BACKGROUND: This qualitative study describes registered nurses' perspectives on work relationships with new graduates in emergency and critical care settings. METHODS: Six focus groups of registered nurses (N = 31) were interviewed in open and informal discussions lasting approximately 45 to 90 minutes. RESULTS: Two themes extracted from the data were lacking confidence and gaining acceptance into the unit's culture. Registered nurses were disillusioned by the lack of confidence, organization, and skill performance of the new graduate. They agreed that nurses "eat their young." CONCLUSION: Suggestions are offered for preceptors, mentors, and staff. Recommendations for supporting the new graduate in an uncivil environment are also given. PMID- 22106879 TI - Preliminary exploration of the use of a medical malpractice self-study module. AB - This study was conducted to determine the effectiveness of an educational module on medical malpractice litigation and the use of evidence-based practice guidelines. Data regarding knowledge acquisition, ease of use, and the perceived value of the educational module were collected. A pretest-posttest design was used. There was a statistically significant difference in the proportion of participants who responded correctly to the posttest items after viewing the educational program (p < .05). Data from this study indicated that this self study module was a valuable tool for education on the specified content. This study also provides evidence of the effectiveness of integrating theory, clinical inquiry, and evidence-based practice into a self-paced educational program about medical malpractice litigation. Evaluation of a self-paced educational program contributes to the body of knowledge on the use of educational strategies to promote patient safety and reduce liability. PMID- 22106880 TI - The development of a preceptor training program on clinical nursing education in Jordan in collaboration with Sweden. AB - BACKGROUND: As part of the Swedish-Jordanian International Collaboration Project, this study developed, implemented, and evaluated a preceptor training program to enhance pedagogical strategies for integration of theory and practice in nursing education in Jordan. METHODS: A three-phase program was developed and implemented (2006 to 2007) focusing on experiential learning using drama, case-method, and photolanguage methods. Data were collected from 12 preceptors in Jordan using questionnaires and interviews. RESULTS: Four themes reflected experiences gained from participating in the program, including bridging the gap between theory and practice, enhancing students' imminent potential, promoting the role of preceptor, and facing challenges in applying pedagogical strategies. Participants noted a positive effect on their personal and professional growth as a preceptor, students' learning process, and the quality of health care. CONCLUSION: Preceptors perceived that the model program helped to bridge the gap between theory and practice, improved communication and networking, and improved the quality of health care in Jordan. PMID- 22106881 TI - Research activities and perceptions of barriers to research utilization among Turkish nurses. AB - BACKGROUND: This study assessed the barriers to the use of research in nursing practice among Turkish registered nurses. METHODS: A descriptive cross-sectional study of 718 nurses in three hospitals was conducted. The data collection instrument used for the study consisted of the Barriers to Research Utilization Scale and a self-administered questionnaire that included demographic data, educational background, and nurses' involvement in research activities. RESULTS: Almost half of the participants (48.5%) responded that they had attended academic conferences in the past 2 years. Most of the participants had not published a research article (90.5%), and 23.4% reported that they had never read research articles. Seven items within the top 10 barriers were found on the setting subscale. CONCLUSION: The results describe the research activities and perceptions of the barriers to the use of research among nurses in Turkey. Creating an organizational climate that values research use and supports nurses in participating in research activities is crucial. PMID- 22106882 TI - Enantioselective preparation of P-chiral phosphine oxides. AB - A highly efficient chiral auxiliary-based strategy for the asymmetric synthesis of P-chiral phosphine oxides in >98:2 er has been developed. The methodology involves the highly stereoselective formation of P-chiral oxazolidinones that then undergo displacement with a variety of Grignard reagents to prepare the desired phosphine oxides. PMID- 22106883 TI - Hydrogen-bonding-driven self-assembly of PEGylated organosilica nanoparticles with poly(acrylic acid) in aqueous solutions and in layer-by-layer deposition at solid surfaces. AB - PEGylated organosilica nanoparticles have been synthesized through self condensation of (3-mercaptopropyl)trimethoxysilane in dimethyl sulfoxide into thiolated nanoparticles with their subsequent reaction with methoxypoly(ethylene glycol) maleimide. The PEGylated nanoparticles showed excellent colloidal stability over a wide range of pH in contrast to the parent thiolated nanoparticles, which have a tendency to aggregate irreversibly under acidic conditions (pH < 3.0). Due to the presence of a poly(ethylene glycol)-based corona, the PEGylated nanoparticles are capable of forming hydrogen-bonded interpolymer complexes with poly(acrylic acid) in aqueous solutions under acidic conditions, resulting in larger aggregates. The use of hydrogen-bonding interactions allows more efficient attachment of the nanoparticles to surfaces. The alternating deposition of PEGylated nanoparticles and poly(acrylic acid) on silicon wafer surfaces in a layer-by-layer fashion leads to multilayered coatings. The self-assembly of PEGylated nanoparticles with poly(acrylic acid) in aqueous solutions and at solid surfaces was compared to the behavior of linear poly(ethylene glycol). The nanoparticle system creates thicker layers than the poly(ethylene glycol), and a thicker layer is obtained on a poly(acrylic acid) surface than on a silica surface, because of the effects of hydrogen bonding. Some implications of these hydrogen-bonding-driven interactions between PEGylated nanoparticles and poly(acrylic acid) for pharmaceutical formulations are discussed. PMID- 22106884 TI - Martin J. Ball and Clinical Linguistics and Phonetics: a celebration. PMID- 22106885 TI - Instrumental and perceptual phonetic analyses: the case for two-tier transcriptions. AB - In this article, we discuss the relationship between instrumental and perceptual phonetic analyses. Using data drawn from typical and atypical speech production, we argue that the use of two-tier transcriptions, which can compare and contrast perceptual and instrumental information, is valuable both for our general understanding of the mechanisms of speech production and perception and also for assessment and intervention for individuals with atypical speech production. The central tenet of our case is that instrumental and perceptual analyses are not in competition to give a single 'correct' account of speech data. They take instead perspectives on complementary phonetic domains, which interlock in the speech chain to encompass production, transmission and perception. PMID- 22106886 TI - Segments, letters and gestures: thoughts on doing and teaching phonetics and transcription. AB - This brief article reflects on some pitfalls inherent in the learning and teaching of segmental phonetic transcription. We suggest that a gestural interpretation to disordered speech data, in conjunction with segmental phonetic transcription, can add valuable insight into patterns of disordered speech, and that a gestural orientation should form part of the understanding and interpretation of the process of transcribing and the use of transcripts. We illustrate our discussion with data from a case of moderately to severely unintelligible speech produced by a boy aged 5;9. PMID- 22106887 TI - Multidimensional assessment of phonological similarity within and between children. AB - Multidimensional analysis involves moving away from one-dimensional analyses such as most articulation tests to comprehensive analyses involving levels of phonological information from the word level down to segments. This article outlines one such approach that looks at four levels from words to segments, using nine phonological measures. It also presents a new methodology for comparing children across the levels (multidimensional assessment of phonological similarity (MAPS)), and demonstrates the approach through a comparison of four sibling pairs. The results show that children can differ greatly and unpredictably in their similarities and differences, and that only a multidimensional analysis can identify where these similarities and differences may occur. PMID- 22106888 TI - Patterns of cluster reduction in the acquisition of #sC onsets: are bilinguals different from monolinguals? AB - This article is a comparative look at the cluster reduction patterns of English #sC onsets in three groups of children. Data from 40 monolingual, 40 Spanish English bilingual and 40 Haitian Creole-English bilingual children were examined. While there were several similarities in the patterns exhibited by the three groups, there was a sharp contrast regarding /sl-/ clusters between monolingual children and the two groups of bilinguals. Among the predictions offered for reduction patterns in recent literature, 'factorial typology' of Pater and Barlow (2003 ) appeared to be the most successful. PMID- 22106889 TI - Implications of bilingual development for specific language impairments in Turkey. AB - The potential impact of bilingualism on children's language development has emerged as a crucial concern for Turkey, but so far it has not been addressed from the point of view of language disorders. This short review examines the potential impact of bilingual language development for language impairments in Turkey, with special emphasis on the largest minority population speaking Kurdish and Turkish. PMID- 22106890 TI - Voice onset time in Indian English-accented speech. AB - The purpose of this study was to determine possible differences in voice onset time (VOT) between speakers of standard American English (AE) and Indian English (IE) in a continuous speech context. The participants were 20 AE speakers, who were native to the Northeastern Pennsylvania region, and 20 IE speakers from the Indian subcontinent who had been residing in Northeastern Pennsylvania. Each subject read a phonetically balanced passage in a comfortable and natural speaking voice, and the recordings were analysed using a combination of waveform and spectrographic analyses. Results indicate that a reduced +VOT appears to characterise IE accent in comparison to AE. In addition, a difference in VOT between genders was observed in AE speakers but not in IE speakers. PMID- 22106891 TI - Speech-language pathologists' knowledge of tongue/palate contact for consonants. AB - Speech-language pathologists (SLPs) rely on knowledge of tongue placement to assess and provide intervention. A total of 175 SLPs who worked with children with speech sound disorders (SSDs) drew coronal diagrams of tongue/palate contact for 24 English consonants. Comparisons were made between their responses and typical English-speaking adults' contact established by electropalatography (EPG). SLPs were most accurate for consonants with no contact (h, p, f), then velar consonants (g, k, ng). The remaining consonants were rarely accurate (from most to least accurate: l, t, r, z, n, sh, s, zh, y, v, th(voiceless), d, m, b, w, th(voiced), ch, j). SLPs demonstrated good knowledge of contact along the midline, but poor knowledge of contact along lateral margins of the palate. Importantly, SLPs did not show awareness of: lateral bracing ('horseshoe' contact) for alveolar consonants (t, d, n, s, z); the groove for s, z, sh, zh; or posterior lateral contact for most other consonants. Accuracy was not influenced by the following: length of time as SLP, location of SLP training, location of current workplace, proportion of caseload with SSD or childhood apraxia of speech, amount of time spent reading, or exposure to EPG. Awareness of coronal tongue placement for consonant production needs targeting in SLP education. PMID- 22106892 TI - An EPG analysis of /t/ in young people with Down's syndrome. AB - Many studies have pointed to impaired speech intelligibility in young people with Down's syndrome (DS). Some have attributed these problems to delayed phonological development, while others have identified disordered speech patterns, which could be related to a dyspraxic element in their speech. This study uses electropalatography (EPG) to examine the speech of 25 young people with DS, focusing on their production of the obstruent /t/. For the EPG analysis, participants produced the target obstruent in the word 'toe', repeated 10 times. An investigative analysis was carried out. A new descriptive taxonomy of EPG error patterns was developed and these errors were related to perceptually based transcriptions. The measures are discussed in relation to current knowledge of the anatomical and physiological characteristics of DS. PMID- 22106893 TI - Long-term outcomes of speech therapy for seven adolescents with visual feedback technologies: ultrasound and electropalatography. AB - This follow-up study investigated the speech production of seven adolescents and young adults with hearing impairment 2-4 years after speech intervention with ultrasound and electropalatography. Perceptual judgments by seven expert listeners revealed that five out of seven speakers either continued to generalize post-treatment or maintained their level of performance post-treatment. Targets included fricatives, vowels and the rhotic /r/. Speakers ranged in age from 14 to 19 years. Listeners were considered to be expert listeners. All listeners had extensive backgrounds in phonetics and phonology and were speech-language pathologists. This long-term investigation revealed that speech habilitation with visual feedback tools as adjuncts to therapy appeared to have lasting effects. The implications for habilitation include reduced therapy times and outcomes not previously possible. PMID- 22106894 TI - A case study on the communication of older adolescents. AB - This study compared the communication of two older male adolescents (aged 17 and 19 years) with each other (peer interaction) and with a teacher (non-peer interaction) in three different types of activity (casual conversation, providing/listening to a recount and collaborative problem-solving). Conversation analysis, selected analyses from the perspective of systemic functional linguistics and social psychology (communication accommodation theory) were applied in data analysis. Peer interaction showed fewer questions, fewer challenging moves and the absence of divergent accommodation strategies. In the non-peer interaction, the teacher's higher number of turns, questions and interruptions appeared to influence the opportunity for adolescent contribution to the interactions. Some aspects of language use by each adolescent - mean turn length, use of one-word utterances and sarcasm - were consistent across communication partner and activity. The methodology is suggested to provide a suitable procedure for use in similar research with older adolescents who have traumatic brain injury. PMID- 22106895 TI - Repair in the peer talk of 6-year-old boys. AB - This article reports a qualitative analysis of linguistic and interactional aspects of repair in naturalistic play, interaction between three 6-year-olds (C, D and F), one of whom (child D) displays some speech and language difficulties. The methodology draws on conversation analysis together with perceptual phonetic observation. The analysis reveals differences in the use of repair strategies. Although all three boys used self-repair, only C and F initiated other repair. Despite child D's reduced intelligibility, phonetic issues were never oriented to in repair initiations by C or F, nor were they self-repaired by D. In general, D, the speaker with the fewest linguistic resources, used collaborative interpersonal strategies to rectify sources of breakdown in conversation. PMID- 22106896 TI - The treatment of anomia in Sesotho: a case for parametric aphasiology. AB - South Africa, as a multilingual country, offers the opportunity for examining the interaction between aphasic symptomatology and the parameters of language. Effective intervention techniques depend on an understanding of clinical linguistics. This article describes an intervention study with two Sesotho speaking individuals with anomia. Sesotho as a noun class and syllable-timed language offers the opportunity to study the influence of cueing techniques, which are based on such linguistic parameters. Word lists were designed using non aphasic participants and three cueing techniques for anomia were evaluated over a period of 4 months. Findings suggested a positive response to the techniques of true phonemic cueing and prosodic cueing, whereas initial phonemic cueing (a technique commonly used for English-speaking anomic patients) had no impact. This supports the need for a parametrically informed approach to aphasia therapy and strengthens the recommendation that a linguistic basis is paramount in the training of effective clinicians. PMID- 22106897 TI - Is recurrent perseveration a product of deafferented functional systems with otherwise normal post-activation decay rates? AB - Recent work in neuropsychology, clinical aphasiology and neuropharmacology have presented evidence that the causative substrates of recurrent perseveration in adults with aphasia are more recondite and subject to distinct interpretations than originally thought. This article will discuss and evaluate how various proposals from theory, from the clinic and from drug therapy interact and compete in the search for a cause or causes of recurrent perseveration. PMID- 22106898 TI - Glycoprotein profiles of human breast cells demonstrate a clear clustering of normal/benign versus malignant cell lines and basal versus luminal cell lines. AB - Gene expression profiling has defined molecular subtypes of breast cancer including those identified as luminal and basal. To determine if glycoproteins distinguish various subtypes of breast cancer, we obtained glycoprotein profiles from 14 breast cell lines. Unsupervised hierarchical cluster analysis demonstrated that the glycoprotein profiles obtained can serve as molecular signatures to classify subtypes of breast cancer, as well as to distinguish normal and benign breast cells from breast cancer cells. Statistical analyses were used to identify glycoproteins that are overexpressed in normal versus cancer breast cells, and those that are overexpressed in luminal versus basal breast cancer. Among the glycoproteins distinguishing normal breast cells from cancer cells are several proteins known to be involved in cell adhesion, including proteins previously identified as being altered in breast cancer. Basal breast cancer cell lines overexpressed a number of CD antigens, including several integrin subunits, relative to luminal breast cancer cell lines, whereas luminal breast cancer cells overexpressed carbonic anhydrase 12, clusterin, and cell adhesion molecule 1. The differential expression of glycoproteins in these breast cancer cell lines readily allows the classification of the lines into normal, benign, malignant, basal, and luminal groups. PMID- 22106899 TI - Oral versus anal sex at last encounter -- behavioral differences among men who have sex with men in the District of Columbia. AB - Oral sex may be used as a form of harm reduction against HIV transmission. We compared characteristics of men who have sex with men (MSM) in Washington, DC having oral sex versus those having anal sex at last encounter. Data collected through National HIV Behavioral Surveillance in 2008 using venue-based sampling were used. Men >=18 years old disclosing MSM behavior in the past year were analyzed (n=500); OraQuick and Western Blot confirmation were used to assess HIV status. Multivariable methods were used for data analyses by type of sex at last encounter. A total of 71.8% of MSM had anal sex and 28.2% reported oral sex at last encounter. Men reporting oral sex were more likely to be white, older, insured, HIV-negative, unaware of last partner's HIV status, have a main partner, and not be HIV tested in the previous year. Significant demographic and behavioral differences exist between MSM reporting oral or anal sex; further studies should assess whether oral sex is being used as HIV prevention among MSM. PMID- 22106900 TI - "I'm satisfied ... but": clients' and families' contingent responses about home care. AB - Home care service organizations need a means of gaining useful feedback about satisfaction with care from clients and their families. Interviews were conducted with 82 older adult clients and 52 family members about their satisfaction with home care. A subgroup of participants (n = 39) provided "contingent" satisfaction responses. Contingent responses reflect the duality of perceptions that clients and families convey about services. Three themes emerged as critical to understanding these types of responses: adept versus inept staff, predictable versus precarious scheduling, and responsive versus restrictive care plans. Understanding the reasons for contingent responses could help home care agencies to target quality improvement initiatives for individual clients and families. PMID- 22106901 TI - Consumer-directed personal care: comparing aged and non-aged adult recipient health-related outcomes among those with paid family versus non-relative providers. AB - Risk factors associated with the incidence of recipient injuries, bedsores and contractures, and health care use (i.e., emergency department and hospital use) among aged and non-aged adult personal care recipients are investigated. Data are from a statewide survey of aged and non-aged adult personal assistance service (PAS) recipients (n = 913) in California's In-Home Supportive Services (IHSS) program. This is a consumer-directed PAS program. Outcomes among recipients using relatives (other than spouses or parents) as paid providers are compared with those of recipients having non-relatives as providers. No differences were found by provider-recipient relationships. Non-aged recipients, those in poorer health, those with more than three activities of daily living (ADL) limitations, and those changing providers during the year were all at greater risk for adverse health outcomes. African American, Hispanic, and Asian recipients were at lower risk for injuries and hospital stays than were White recipients. PMID- 22106902 TI - Do Medicaid home and community based service waivers save money? AB - This article estimates the potential savings to the Medicaid program of using 1915c Home and Community Based Services (HCBS) waivers rather than institutional care. For Medicaid HCBS waiver expenditures of $25 billion in 2006, we estimate the national savings to be over $57 billion, or $57,338 per waiver participant in 2006 compared with the cost of Medicaid institutional care (for which all waiver participants are eligible). When taking into account a potential 50% "woodwork effect" (for people who might have refused institutional services), the saving would be $21 billion. This analysis demonstrates that HCBS waiver programs present significant direct financial savings to Medicaid long-term care (LTC) programs. PMID- 22106903 TI - Meals on Wheels: exploring potential for and barriers to integrating depression intervention for homebound older adults. AB - The purpose of this study was to explore Meals on Wheels' (MOW) organizational potential for integrating depression screening, referral, and treatment for homebound older adults. In a survey of 164 MOW administrators, MOW's current practice of depression services was examined, and the administrators' perception of MOW's organizational potential was measured focusing on external environment, financial resources, staffing/skills, and values and goals. Only 20 out of 164 MOWs provide depression screening, and 19 provide in-home counseling for their clients, while 86 provide referral services. About 64-72% of MOWs that are not current providers of screening and/or referrals want to provide the services, and 21% of those that are not current providers of in-home counseling want to provide it. PMID- 22106905 TI - Ocular parasitoses and their immunology. AB - Parasitic infections of the eye are a major cause of ocular diseases in many parts of the globe. The causative agents of ocular parasitoses include several species of unicellular protozoan and metazoan helminth parasites, which have a natural predilection for and utilize the eye as their habitat. At times ocular invasion by accidental or uncommon parasites may result in infections of unusual nature. In this review the authors discuss the various parasitic causal agents of eye diseases and the current status of immunology against ocular parasitoses. PMID- 22106906 TI - HLA-A29 and birdshot chorioretinopathy. AB - Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease. PMID- 22106907 TI - Roles of IL-8 in ocular inflammations: a review. AB - INTRODUCTION: This review presents the current in vitro and in vivo animal and human research on the roles of IL-8 in ocular inflammatory diseases. MATERIALS AND METHODS: Data sources were a literature review using Pub Med, Medline, and ISI databases (from 1990 to 2011). Search items included interleukine-8 (IL-8), CXCL8, chemokines, cytokines, alone or in combination with the, serum, aqueous, vitreous, eye, ocular, ocular tissues, ophthalmic, and review. RESULTS: IL-8 may be involved in primary or secondary ocular inflammations. Ocular effects of IL-8 differ based on the source of the secretion and site of the action. The most important effects of IL-8 in the eyes are angiogenic activities and induction of ocular inflammation. CONCLUSION: IL-8 plays important roles in ocular inflammation and angiogenesis in conjunctiva, cornea, iris, retina, and orbit. Anti-IL-8 targeted immunotherapy has been introduced as an important treatment modality, provided that IL-8 signal blocking takes place in desired areas and tissues. PMID- 22106908 TI - Clinical features and prognosis of Boston type I keratoprosthesis-associated corneal melt. AB - PURPOSE: To describe the clinical features and outcomes of corneal melt associated with Boston type I keratoprosthesis (KPro) implantation. METHODS: Medical records of patients who experienced corneal melt following KPro implantation were reviewed retrospectively. RESULTS: Sixty-six adult patients had KPro implantation from January 2004 to November 2010. Six patients had an underlying inflammatory ocular surface disorder. Four experienced corneal melt (6.1%) 5-42 months after the initial surgery. One patient was diagnosed with Sjogren's syndrome as a result of diagnostic workup following melt. Three patients were treated with systemic immunomodulatory therapy; two experienced fungal keratitis and subsequent endophthalmitis. KPro had to be explanted and replaced with donor cornea in all cases. CONCLUSIONS: KPro-associated corneal melt is uncommon and appears to occur in patients with preexisting inflammatory disorders, which might not have been previously diagnosed. Timely explantation of KPro and replacement with donor cornea may prevent a poor outcome. PMID- 22106909 TI - In vitro susceptibility to different topical ophthalmic antibiotics of bacterial isolates from patients with conjunctivitis. AB - PURPOSE: To test in vitro the susceptibility to different commercially-available topical antibiotics of isolates from patients with conjunctivitis, evaluated at the Microbiology Service of Turin Ophthalmic Hospital between January 2005 February 2007. METHODS: Bacterial isolates were cultured using both liquid and solid media. The four most frequent isolates were analyzed and their in vitro susceptibility to levofloxacin, ofloxacin, norfloxacin, lomefloxacin, tobramycin, netilmycin, ampicillin, and chloramphenicol was tested, using the Kirby-Bauer diffusion method and National Committee for Clinical Laboratory Standards (NCCLS) serum standards. RESULTS: The four most common bacteria isolates were: Staphylococcus aureus (27%), viridians Streptococci (22%), Staphylococcus epidermidis (16%) and Streptococcus pneumoniae (13%). The in vitro susceptibility to levofloxacin was highest (p<0.01) for all bacterial isolates. CONCLUSIONS: In vitro susceptibility tests showed that levofloxacin had the highest cumulative efficacy against bacterial isolates. Netilmycin showed the highest efficacy against staphylococcus aureus, the most common bacterial isolate in this study. PMID- 22106910 TI - The spectrum of ocular involvement in systemic lupus erythematosus in a tertiary eye care center in Nepal. AB - PURPOSE: Manifestations of Systemic lupus erythematosus are protean and the eye can get affected in more than a third of the cases. This study was conducted to evaluate the spectrum of ocular manifestation among Nepalese patients diagnosed with Systemic lupus erythematosus. METHODS: In this hospital based cross sectional study, 91 established cases of Systemic lupus erythematosus were enrolled from January 2008 to June 2009 AD. Patient particulars including age, sex, duration, systemic involvement, laboratory findings and treatment history were noted. Detailed ophthalmological examination was carried. RESULTS: Out of 91 patients, 94.5% were females and 5.5% were males. Female/Male ratio was 17:1. Mean age of the patients was 26.59 +/- 10.33 years. Ocular involvement was present in 47.3% (43) of the patients, the commonest manifestation being dry eye (39.5%) followed by lupus retinopathy (21%) and drug induced ocular complications (21%). CONCLUSIONS: Ocular manifestations in Systemic lupus erythematosus are not uncommon. PMID- 22106911 TI - White dot syndromes: a 20-year study of incidence, clinical features, and outcomes. AB - PURPOSE: To measure the incidence of white dot syndromes (WDS) in a community based population and to report clinical features and outcomes. METHODS: Multicenter retrospective study using the Rochester Epidemiology Project medical records linkage system of Olmsted County, Minnesota. Databases were searched to identify all patients with WDS from January 1, 1988 through December 31, 2008. RESULTS: Mean ophthalmic follow-up was 4.5 years and mean general medical follow up was 9.1 years. The incidence of WDS was 0.45 per 100,000 per year (95% CI 0.19 0.71). Incidence rates for specific disease entities were also calculated. The authors report some associated autoimmune diseases in this series. Multiple evanescent white dot syndrome (MEWDS) was more common in females, and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was more common in males. Both MEWDS and APMPPE generally carried a good visual prognosis. Fifty percent of cases with APMPPE had a positive history of psoriasis. The only punctuate inner choroidopathy (PIC) case carried that diagnosis as well. CONCLUSIONS: WDS are rare diseases and may be associated with other autoimmune diseases. Further studies with more patients and longer follow-up periods are needed to draw conclusions about visual prognosis, development of other ocular conditions, and associated medical diseases. PMID- 22106912 TI - Long-term results of therapy with mycophenolate mofetil in ocular mucous membrane pemphigoid. AB - PURPOSE: To assess the long-term efficacy and tolerability of mycophenolate mofetil (MMF) in the therapy of ocular mucous membrane pemphigoid (OcMMP). METHODS: Ten patients (19 eyes) with OcMMP treated with MMF, who had a follow-up of at least 4 years, were retrospectively analyzed. Main outcome measures were inflammatory control, progression of cicatrization, and side effects. RESULTS: Control of inflammation was achieved in 11 eyes (58%) of 6 patients (rate: 0.11/PY). Mild inflammatory activity was observed in 8 eyes (42%) of 4 patients (rate: 0.07/PY). Progression of conjunctival cicatrization was prevented in 47% (9/19) of the eyes. Mild progression of cicatrization was found in 42% (8/19) of the eyes. Conjunctival cicatrization had progressed to stage IV in 1 patient (11%). Treatment-related side effects occurred in 7 patients (rate: 0.12/PY). CONCLUSION: MMF is an effective agent for treatment of OcMMP. However, the drug cannot always prevent disease progression. PMID- 22106913 TI - An atypical finding in an idiopathic unilateral frosted branch angiitis case: premacular hemorrhage. AB - BACKGROUND: The authors describe a case of unilateral idiopathic acute frosted branch angiitis with premacular hemorrhage. CASE: A 35-year-old woman was referred because of acute vision loss in her left eye during the puerperal period. Her initial visual acuity was 20/20 OD and 20/200 OS. The left eye presented severe sheathing of retinal vessels inferiorly, heavy perivascular intraretinal hemorrhages, and premacular hemorrhage. There was no evidence of vascular leakage in fluorescein angiography. All of the laboratory workup was negative for frosted branch angiitis (FBA). During the follow-up period, FBA resolved spontaneously within a few days, but the amount of premacular hemorrhage increased. Vitrectomy with internal limiting membrane peeling was performed at the third month, resulting in 20/25 vision and no recurrence of the disease during the 13-month follow-up. CONCLUSION: This is an idiopathic case of acute FBA that exhibited spontaneous rapid regression of angiitis but was complicated by an unusual premacular hemorrhage. PMID- 22106914 TI - An unusual intraocular tongue worm in anterior chamber: a case report. AB - PURPOSE: To present an interesting case of intraocular Linguatula serrata in a 5 year-old boy. DESIGN: Case report. METHODS: Visual acuity testing, biomicroscopic slit-lamp examination, and indirect ophthalmoscopy were performed on a 5-year-old boy with a progressively enlarging white lesion in the anterior chamber of the right eye. RESULTS: The worm was found in the anterior chamber, attached firmly to the peripheral iris with free-floating tail. The living worm, which grew progressively over 2 months, caused a mild anterior chamber reaction with marginally raised intraocular pressure. The worm was removed surgically in toto. This is the first documentation of human ocular pentastomiasis in India. CONCLUSIONS: An adult worm in the anterior chamber is apparently rare and can present even with a quiet eye. Surgical removal is essential. However, visual prognosis is good. PMID- 22106915 TI - Bilateral ocular myiasis interna caused by botfly (Oestrus ovis): a case report. AB - The sheep nasal botfly Oestrus ovis is the commonest of several species of dipteran fly whose larvae are obligatory parasites in the nasal cavities and frontal sinuses of sheep but may cause infestation (myiasis) in man, commonly as external infestations and rarely, involves inner coat of the eye (Ocular myiasis interna). We report an imported case of Bilateral Ocular myiasis interna in an Indian boy. PMID- 22106916 TI - Chronic anterior uveitis in common variable immunodeficiency. AB - PURPOSE: To describe patients with uveitis and common variable immunodeficiency (CVID). DESIGN: Retrospective observational case series. METHODS: Retrospective review of patients with uveitis and CVID, specifically focusing on clinical presentation and treatment. RESULTS: Three patients with CVID and uveitis were identified. All patients had chronic anterior uveitis. Two required systemic immunosuppression to control uveitis, with one of these patients relapsing after discontinuation of immunoglobulin therapy. One improved on topical steroid therapy; however, follow-up on this patient did not extend beyond 4 months. CONCLUSIONS: CVID can be associated with chronic anterior uveitis. Patients presenting with uveitis should be questioned about frequent infections and autoimmune disorders as part of the uveitis evaluation. PMID- 22106917 TI - Cytomegalovirus colitis and viremia from mycophenolate mofetil monotherapy in birdshot chorioretinopathy. AB - PURPOSE: To describe a case of cytomegalovirus (CMV) viremia and colitis in a patient on mycophenolate mofetil (MMF) monotherapy for birdshot chorioretinopathy. DESIGN: Case report. METHODS: Retrospective chart review. RESULTS: Treatment with MMF 1.5 g twice daily for 5 years led to leucopenia and a CD4 count of 299, which resulted in active CMV infection. CONCLUSIONS: Treatment with MMF alone may put otherwise immune-competent individuals at risk for opportunistic CMV infection. Greater awareness of this association may allow for better monitoring, earlier detection, and treatment of future cases. PMID- 22106918 TI - Central serous chorioretinopathy associated with topical latanoprost therapy. AB - PURPOSE: To report a case of central serous chorioretinopathy (CSC) as a possible complication of latanoprost treatment. METHODS: A 65-year-old woman presented with a 1-week history of blurred vision and metamorphopsia in her right eye. She was previously diagnosed with unilateral glaucoma, and treatment was initiated with topical latanoprost 0.005% for the right eye. The symptoms occurred 1 month after initiation of glaucoma treatment. RESULTS: Visual acuity (VA) of the patient had reduced to 20/50 in right eye. Fluorescein angiography revealed a focal RPE leak near to the fovea with neurosensory detachment due to CSC, which was confirmed by optical coherence tomography. After cessation of the therapy, her clinical and morphological status improved spontaneously. The neurosensory detachment resolved almost completely and VA improved to 20/20 simultaneously. CONCLUSIONS: The authors report the first case of CSC associated with latonoprost therapy. This case demonstrates that topical latanoprost may lead to the development of CSC. PMID- 22106920 TI - Does the content really matter? A study comparing structure, process, and outcome of team rehabilitation for patients with inflammatory arthritis in two different clinical settings. AB - OBJECTIVES: To provide a thorough description of team rehabilitation care and compare the structure, process, and outcomes in two specialized arthritis rehabilitation settings. METHODS: Patients with inflammatory arthritis scheduled for inpatient rehabilitation in seven specialized rehabilitation centres and three rheumatology hospital departments in Norway were included consecutively in a prospective cohort study. Patients completed questionnaires at admission, at discharge, and at a 6-month follow-up, and kept a diary regarding structure and process variables during the rehabilitation stay. RESULTS: Eighty patients in rehabilitation centres and 73 in hospital departments were included and 80% responded to the 6-month follow-up questionnaire. The two clinical settings differed significantly with regard to structure variables such as cost, referral of patients, length of stay, and number of health professionals involved, and most process variables reflecting treatment modalities. The most remarkable difference was in the amount of individual intervention compared with group intervention. Despite significant improvements in most outcomes at discharge, the scores deteriorated towards baseline level 6 months later. There was a trend towards more significant improvement during rehabilitation for patients at rehabilitation centres whereas patients at hospitals had more prolonged improvement. CONCLUSIONS: Team rehabilitation for inflammatory arthritis in two different clinical settings differed across most variables for structure and process, but few significant differences in outcome were found. Considering the substantial differences in cost, there is an urgent need for consensus concerning which patients should receive rehabilitation in which setting. Future research on the development and evaluation of methods for prolonging the beneficial effects of rehabilitation is needed. PMID- 22106921 TI - Aluminepin: aluminum analogues of borepin and gallepin. AB - We report synthesis of dibenzoaluminepin as the first aluminepin, an aluminum analogue of borepin and gallepin. This compound contains one molecule of ethereal solvent on the Al atom, which adopts a tetrahedral geometry. The central 7 membered aluminepin ring has a boatlike conformation and was characterized by single-crystal X-ray diffraction, (1)H/(13)C NMR, and DFT studies. In addition, NICS, NBO, and theoretical calculations provide insight into the nature of the bonding and aromaticity of aluminepins. PMID- 22106922 TI - Impact of swine influenza and quarantine measures on patients and households during the H1N1/09 pandemic. AB - OBJECTIVES: To assess the secondary attack rates (SAR) and impact of the 2009 H1N1 epidemic in Melbourne, Victoria, Australia, and the measures implemented to control household transmission. METHODS: Patients with polymerase chain reaction confirmed influenza A and pandemic H1N1 (pH1N1) were identified from hospital and microbiology laboratory records and asked to take part in a retrospective survey. Information obtained included: the constellation of symptoms, contact history, secondary infection, and household information, including adherence and attitudes towards quarantine measures. RESULTS: The overall SAR of pH1N1 index patients was 30.6%, but a significantly lower SAR was noted with oseltamivir treatment (36.6% vs 22.8%, p < 0.05). The greatest reduction in SAR was observed when index patients aged 0-4 y received oseltamivir (83.3% vs 22.2%, p < 0.01). Quarantine was requested of 65.8% of patients and 92.8% self-reported adhering to recommendations. pH1N1 index patients, the number of median days bed-bound is 2.5 days, being unable or too sick to work for a median of 5.0 days, and lost a median of 7.0 days of work for reasons related to an influenza-like illness. CONCLUSIONS: The pH1N1 influenza pandemic had a significant clinical impact on households. Public health interventions such as oseltamivir treatment of index cases were beneficial in reducing secondary attack rates, whilst quarantine measures were found to have high rates of self-reported compliance, understanding, and acceptability. PMID- 22106923 TI - Polymorphisms in the methylene tetrahydrofolate reductase gene and their unique combinations are associated with an increased susceptibility to the renal cancers. AB - AIMS: Two single nucleotide polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene, 677C/T and 1298A/C, encode the thermolabile isoforms of the MTHFR enzyme that adversely affect the folic acid metabolic pathway. In the present study, these polymorphisms were investigated for their associations with the risk and prognosis of the renal cell carcinomas (RCCs) in Pakistani patients. RESULTS: The study included 168 RCC patients and 178 controls. The polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method. Statistical analysis revealed that the C-allele and homozygous C genotype of the MTHFR 1298A/C polymorphism were significantly correlated with the risk of RCCs (odds ratio [OR]=1.60; 95% confidence interval [CI]=1.1-2.34 and OR=3.26; 95% CI=1.27-8.37, respectively). The combined genotype analysis showed that the 677CC+1298CC combination greatly increased the susceptibility to RCCs (OR=8.34; 95% CI=2.7-25.7). The 677CT+1298AA and 677CC+1298CA combinations were also associated with an increased risk of RCC (OR=3.21; 95% CI=1.3-7.8 and OR=2.45; 95% CI=1.3-4.6, respectively). The combined genotype effects were also evident in a semiparametric expectation-maximization based haplotype analysis. CONCLUSION: The results presented here indicate that the two MTHFR gene polymorphisms are significantly associated with the risk of RCCs in a cohort of Pakistani patients and may be useful as susceptibility markers in other populations of the world as well. PMID- 22106924 TI - Erythrocyte remodeling in Plasmodium berghei infection: the contribution of SEP family members. AB - The malaria parasite Plasmodium largely modifies the infected erythrocyte through the export of proteins to multiple sites within the host cell. This remodeling is crucial for pathology and translocation of virulence factors to the erythrocyte surface. In this study, we investigated localization and export of small exported proteins/early transcribed membrane proteins (SEP/ETRAMPs), conserved within Plasmodium genus. This protein family is characterized by a predicted signal peptide, a short lysine-rich stretch, an internal transmembrane domain and a highly charged C-terminal region of variable length. We show here that members of the rodent Plasmodium berghei family are components of the parasitophorous vacuole membrane (PVM), which surrounds the parasite throughout the erythrocytic cycle. During P. berghei development, vesicle-like structures containing these proteins detach from the PVM en route to the host cytosol. These SEP-containing vesicles remain associated with the infected erythrocyte ghosts most probably anchored to the membrane skeleton. Transgenic lines expressing the green fluorescent protein appended to different portions of sep-coding region allowed us to define motifs required for protein export. The highly charged terminal region appears to be involved in protein-protein interactions. PMID- 22106925 TI - Estimating selfing rates from reconstructed pedigrees using multilocus genotype data. AB - Several methods have been developed to estimate the selfing rate of a population from a sample of individuals genotyped for several marker loci. These methods can be based on homozygosity excess (or inbreeding), identity disequilibrium, progeny array (PA) segregation or population assignment incorporating partial selfing. Progeny array-based method is generally the best because it is not subject to some assumptions made by other methods (such as lack of misgenotyping, absence of biparental inbreeding and presence of inbreeding equilibrium), and it can reveal other facets of a mixed-mating system such as patterns of shared paternity. However, in practice, it is often difficult to obtain PAs, especially for animal species. In this study, we propose a method to reconstruct the pedigree of a sample of individuals taken from a monoecious diploid population practicing mixed mating, using multilocus genotypic data. Selfing and outcrossing events are then detected when an individual derives from identical parents and from two distinct parents, respectively. Selfing rate is estimated by the proportion of selfed offspring in the reconstructed pedigree of a sample of individuals. The method enjoys many advantages of the PA method, but without the need of a priori family structure, although such information, if available, can be utilized to improve the inference. Furthermore, the new method accommodates genotyping errors, estimates allele frequencies jointly and is robust to the presence of biparental inbreeding and inbreeding disequilibrium. Both simulated and empirical data were analysed by the new and previous methods to compare their statistical properties and accuracies. PMID- 22106926 TI - Risk of oral cavity malignancies in patients with cutaneous melanoma. PMID- 22106927 TI - Waist-to-height ratio is a better screening tool than waist circumference and BMI for adult cardiometabolic risk factors: systematic review and meta-analysis. AB - Our aim was to differentiate the screening potential of waist-to-height ratio (WHtR) and waist circumference (WC) for adult cardiometabolic risk in people of different nationalities and to compare both with body mass index (BMI). We undertook a systematic review and meta-analysis of studies that used receiver operating characteristics (ROC) curves for assessing the discriminatory power of anthropometric indices in distinguishing adults with hypertension, type-2 diabetes, dyslipidaemia, metabolic syndrome and general cardiovascular outcomes (CVD). Thirty one papers met the inclusion criteria. Using data on all outcomes, averaged within study group, WHtR had significantly greater discriminatory power compared with BMI. Compared with BMI, WC improved discrimination of adverse outcomes by 3% (P < 0.05) and WHtR improved discrimination by 4-5% over BMI (P < 0.01). Most importantly, statistical analysis of the within-study difference in AUC showed WHtR to be significantly better than WC for diabetes, hypertension, CVD and all outcomes (P < 0.005) in men and women. For the first time, robust statistical evidence from studies involving more than 300 000 adults in several ethnic groups, shows the superiority of WHtR over WC and BMI for detecting cardiometabolic risk factors in both sexes. Waist-to-height ratio should therefore be considered as a screening tool. PMID- 22106928 TI - Fennel (Foeniculum vulgare) provides antioxidant protection for boar semen cryopreservation. AB - Boar semen is extremely vulnerable to cold shock and it is also sensitive to peroxidation due to the high content of unsaturated fatty acids in the plasma membrane. Antioxidants exert a protective effect on the plasma membrane of frozen boar sperm. Fennel has been shown to contain antioxidant substances. Therefore, this study was performed to evaluate the effect of different concentrations of fennel added to the freezing extender on boar semen quality and lipid peroxidation after thawing. Semen collected from four boars was cryopreserved in lactose-egg-yolk extender or in the same extender with varying concentration of fennel essences: low (LF); medium (MF); high (HF). Analysis of data clearly indicated that higher concentrations of fennel produced significant improvement in total motility. Moreover, when fennel was included in the extender, a dose dependent tendency to increase sperm viability was observed. In contrast, the addition of fennel had no effect on acrosome integrity or hypoosmotic swelling test (HOST) compared with the control. Malondialdehyde (MDA) formation decreased significantly in fennel groups, yielding similar results for MF and HF. Fennel seems a new antioxidant for use in sperm cryopreservation, but its particular effects on sperm physiology must be further studied, especially the causes of motility stimulation and its effect on lipoxidation. PMID- 22106929 TI - Evaluation of the Chief Nursing Officer's Review of mental health nursing in England: findings from case studies in mental health trusts. AB - This study is an evaluation of the implementation of the Chief Nursing Officer for England's Review of mental health nursing in mental health trusts (MHTs). The authors employed instrumental case studies in six MHTs. The results showed evidence of acceptance of the Review and some evidence of subsequent actions to implement the Review recommendations, but these were not widespread. A lack of an evidence-based implementation plan hampered the implementation as did an apparent lack of strategic nursing leadership in many MHTs. In conclusion, the vision for mental health nursing reported in the Chief Nursing Officer Review prompted various changes, directly and indirectly, among mental health nurses and the development of areas of good practice in education, practice and leadership. The positive changes evident in some areas may become widespread by a systematic policy implementation plan from the centre, supported by local leadership in practice. PMID- 22106930 TI - Sugar recognition by CscB and LacY. AB - The sucrose permease (CscB) and lactose permease (LacY) of Escherichia coli belong to the oligosaccharide/H(+) symporter subfamily of the major facilitator superfamily, and both catalyze sugar/H(+) symport across the cytoplasmic membrane. Thus far, there is no common substrate for the two permeases; CscB transports sucrose, and LacY is highly specific for galactopyranosides. Determinants for CscB sugar specificity are unclear, but the structural organization of key residues involved in sugar binding appears to be similar in CscB and LacY. In this study, several sugars containing galactopyranosyl, glucopyranosyl, or fructofuranosyl moieties were tested for transport with cells overexpressing either CscB or LacY. CscB recognizes not only sucrose but also fructose and lactulose, but glucopyranosides are not transported and do not inhibit sucrose transport. The findings indicate that CscB exhibits practically no specificity with respect to the glucopyranosyl moiety of sucrose. Inhibition of sucrose transport by CscB tested with various fructofuranosides suggests that the C(3)-OH group of the fructofuranosyl ring may be important for recognition by CscB. Lactulose is readily transported by LacY, where specificity is directed toward the galactopyranosyl ring, and the affinity of LacY for lactulose is similar to that observed for lactose. The studies demonstrate that the substrate specificity of CscB is directed toward the fructofuranosyl moiety of the substrate, while the specificity of LacY is directed toward the galactopyranosyl moiety. PMID- 22106931 TI - A comparison between micro-CT and histology for the evaluation of cortical bone: effect of polymethylmethacrylate embedding on structural parameters. AB - Cortical bone microstructure is an important parameter in the evaluation of bone strength. The aim of this study was to validate the characterization of human cortical bone microarchitecture using microcomputed tomography. In order to do this, microcomputed tomography structural measurements were compared with those obtained through histological examination (the gold standard). Moreover, to calculate structural parameters, microcomputed tomography images have to be binarized with the separation between bone and nonbone structures throughout a global thresholding. As the effect of the surrounding medium on the threshold value is not clear, an easy procedure to find the global uniform threshold for a given acquisition condition is applied. This work also compared the structural parameters of microcomputed tomography cortical sample scan in air or embedded in polymethylmethacrylate; histology was used as a reference. For each acquisition condition, a fixed threshold value was found and was applied on the corresponding microcomputed tomography image for the parameters assessment. Twenty cortical bone samples were collected from human femur and tibia diaphyses. All samples were microcomputed tomography scanned in air, embedded in polymethylmethacrylate, rescanned by microcomputed tomography, examined by histology and finally compared. A good correspondence between the microcomputed tomography images and the histological sections was found. Paired comparisons in cortical porosity, Haversian canal diameter and Haversian canal separation between histological sections and microcomputed tomography cross sections, first in air and then embedded in PolyMethylMethAcrylate, were made: no significant differences were found. None of the comparisons showed significant differences for cortical porosity, Haversian canal diameter and Haversian separation over a three dimensional volume of interest, between microcomputed tomography scans in air and with samples embedded in PolyMethylMethAcrylate. The very good correlation between bone structural measures obtained from microcomputed tomography datasets and from two-dimensional histological sections confirms that microcomputed tomography may be an efficient tool for the characterization of cortical bone microstructure. Moreover, when the corresponding threshold value for each condition is used, structural parameters determined by microcomputed tomography are not affected by the surrounding medium (PolyMethylMethAcrylate). PMID- 22106932 TI - Understanding catastrophizing from a misdirected problem-solving perspective. AB - OBJECTIVES: The aim is to explore pain catastrophizing from a problem-solving perspective. The links between catastrophizing, problem framing, and problem solving behaviour are examined through two possible models of mediation as inferred by two contemporary and complementary theoretical models, the misdirected problem solving model (Eccleston & Crombez, 2007) and the fear anxiety-avoidance model (Asmundson, Norton, & Vlaeyen, 2004). DESIGN: In this prospective study, a general population sample (n= 173) with perceived problems with spinal pain filled out questionnaires twice; catastrophizing and problem framing were assessed on the first occasion and health care seeking (as a proxy for medically oriented problem solving) was assessed 7 months later. METHODS: Two different approaches were used to explore whether the data supported any of the proposed models of mediation. First, multiple regressions were used according to traditional recommendations for mediation analyses. Second, a bootstrapping method (n= 1000 bootstrap resamples) was used to explore the significance of the indirect effects in both possible models of mediation. RESULTS: The results verified the concepts included in the misdirected problem solving model. However, the direction of the relations was more in line with the fear-anxiety-avoidance model. More specifically, the mediation analyses provided support for viewing catastrophizing as a mediator of the relation between biomedical problem framing and medically oriented problem-solving behaviour. CONCLUSION: These findings provide support for viewing catastrophizing from a problem-solving perspective and imply a need to examine and address problem framing and catastrophizing in back pain patients. PMID- 22106933 TI - Preparation of decoction of medicinal plants: a self-help measure? PMID- 22106934 TI - Effects of caponization on fat metabolism-related biochemical characteristics of broilers. AB - A two-trial experiment was conducted to evaluate the effects of caponization on fat metabolism-related biochemical characteristics of broilers. Male Redbro broilers were purchased, caponized at 3 weeks and reared until either the 18th (Trial 1) or the 24th (Trial 2) week. In Trial 1, five slaughters were performed at 6, 9, 12, 15 and 18 weeks of age while in Trial 2 one slaughter at the end of the experiment (24 weeks). In each slaughter, the abdominal adipose tissue cellularity, the NADP dehydrogenase activity in the liver and some serum lipoproteins concentrations were assessed. Caponization had a marked effect on the adipocyte volume and NADP-malate dehydrogenase activity in the liver at 24 weeks but it did not affect adipocyte number or the activity of NADP-isocitrate dehydrogenase activity at any age (p < 0.05). Regarding the lipoproteins, cholesterol and HDL-cholesterol were elevated in capon serum at 18 weeks of age while no difference was detected in the triglyceride concentration at any age. In conclusion, a relationship between fat deposition at the phenotypic level and the level of lipogenic enzymes and lipoproteins capons was established but not as pronounced as expected as some parameters displayed a constant increasing pattern while others did not. PMID- 22106935 TI - Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity. AB - The increasing use of poorly-soluble inhaled dry powder pharmaceuticals means that animal toxicology studies of these drugs frequently produce lung changes related to the physical presence of undissolved particulate material within the alveolar spaces. These changes are independent of any chemically- or pharmacologically-mediated toxicity and present a challenge to drug developers and regulators in that risk depends on the retained lung burden of undissolved drug material, rather than the delivered dose, systemic exposure or duration of dosing as traditionally used in risk assessment for inhaled compounds. The methodology presented uses basic pharmacokinetic principles to estimate lung particulate burdens achieved in rat inhalation toxicity studies for four inhaled compounds which have reached clinical evaluation. The estimated lung particulate burdens and associated histopathological findings were compared with published thresholds for similar effects caused by inert particulates such as titanium dioxide. Results of the analysis illustrate that regardless of the duration of the study, estimated lung burdens in excess of ~1 mg drug per g lung were associated with adverse changes consistent with those described in the literature for inert insoluble particles. For all low solubility inhaled pharmaceuticals so far examined, the calculated steady-state retained lung burden of drug in humans is several orders of magnitude lower than that associated with adverse effects in human or animals. PMID- 22106936 TI - Erythrazoles A-B, cytotoxic benzothiazoles from a marine-derived Erythrobacter sp. AB - Chemical examination of an extract from an Erythrobacter sp. isolated from mangrove sediments yielded erythrazoles A (1) and B (2). The erythrazoles are of mixed biosynthetic origin containing a tetrasubstituted benzothiazole, an appended diterpene side chain, and a glycine unit. Erythrazole B is cytotoxic to a panel of non-small cell lung cancer (NSCLC) cell lines, with IC(50) values of 1.5, 2.5, and 6.8 MUM against H1325, H2122, and HCC366, respectively. PMID- 22106937 TI - Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic. AB - High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' beta-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN. PMID- 22106938 TI - Dynamic modulation of the kv2.1 channel by SRC-dependent tyrosine phosphorylation. AB - The voltage-gated K(+) channel Kv2.1 is expressed as a highly phosphorylated protein in most central neurons, where it plays a key role in regulating neuronal membrane excitability. Previous studies have shown that Kv2.1 channel activity is upregulated by Src-mediated phosphorylation through an unknown mechanism. However, a systematic analysis of the molecular mechanism of Kv2.1 channel phosphorylation by Src is lacking. Here, we show that tyrosine phosphorylation by Src plays a fundamental role in regulating Kv2.1-mediated K(+) current enhancement. We found that the level of expression of the Kv2.1 protein is increased by Src kinase. Using mass spectrometric proteomic techniques, we identified two novel phosphotyrosine sites, Y686 and Y810, in the cytoplasmic domains of Kv2.1. We found that Src-dependent phosphorylation at these sites affects Kv2.1 through distinct regulatory mechanisms. Whereas phosphorylation at Y686 regulates Kv2.1 activity similarly to the known site Y124, phosphorylation at Y810 plays a significant role in regulating the intracellular trafficking of Kv2.1 channels. Our results show that these two novel tyrosine phosphorylation sites of Kv2.1 are crucial to regulating diverse aspects of Kv2.1 channel function and provide novel insights into molecular mechanisms for the regulation of Src-dependent modulation of Kv2.1 channels. PMID- 22106939 TI - Impact of aviation non-CO2 combustion effects on the environmental feasibility of alternative jet fuels. AB - Alternative fuels represent a potential option for reducing the climate impacts of the aviation sector. The climate impacts of alternatives fuel are traditionally considered as a ratio of life cycle greenhouse gas (GHG) emissions to those of the displaced petroleum product; however, this ignores the climate impacts of the non-CO(2) combustion effects from aircraft in the upper atmosphere. The results of this study show that including non-CO(2) combustion emissions and effects in the life cycle of a Synthetic Paraffinic Kerosene (SPK) fuel can lead to a decrease in the relative merit of the SPK fuel relative to conventional jet fuel. For example, an SPK fuel option with zero life cycle GHG emissions would offer a 100% reduction in GHG emissions but only a 48% reduction in actual climate impact using a 100-year time window and the nominal climate modeling assumption set outlined herein. Therefore, climate change mitigation policies for aviation that rely exclusively on relative well-to-wake life cycle GHG emissions as a proxy for aviation climate impact may overestimate the benefit of alternative fuel use on the global climate system. PMID- 22106940 TI - Effects of anxiety on running with and without an aiming task. AB - State anxiety is known to affect far aiming tasks, but less is known about the effects of state anxiety on running and aiming while running. Therefore, in the current study participants ran on a treadmill at their preferred speed in a low- and high-anxiety condition. In both conditions, running was combined with dart throwing in the last minutes. Results showed that attention shifted away from task execution with elevated levels of anxiety. Furthermore, gait patterns were more conservative and oxygen uptake was higher with anxiety. In addition, performance and efficiency on the dart throwing task also decreased with anxiety. These findings are in line with attentional control theory and provide an indication that state anxiety not only affects aiming tasks but also tasks that rely heavily on the aerobic system. Moreover, findings indicate that when combined, running, aiming, and anxiety all compete for attention leading to suboptimal attentional control and possibly a decrease in performance. PMID- 22106941 TI - The efficacy profile of vilazodone, a novel antidepressant for the treatment of major depressive disorder. AB - OBJECTIVE: Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day. METHODS: The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time. RESULTS: Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo treated patients (least-squares mean [LSM] treatment difference: -3.2 [p = 0.001], RCT-1; -2.5 [p = 0.009], RCT-2). Clinical Global Impressions-Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: -0.4 [p = 0.001], RCT-1; -0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52). CONCLUSION: Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo controlled, 8-week studies. Findings are supported by subgroup analysis and open label, long-term effectiveness data. TRIAL REGISTRATION: Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592 ; open-label, long-term study: ClinicalTrials.gov identifier: NCT00644358, http://ClinicalTrials.gov/ct2/show/NCT00644358 . PMID- 22106942 TI - Weighing up the burden of care on caregivers of orphan children: the Amajuba District Child Health and Wellbeing Project, South Africa. AB - This paper assesses the burden on orphan caregivers relative to non-orphan caregivers in the context of high HIV/AIDS mortality in South Africa. It presents findings from the third round of a study conducted in the Amajuba District of KwaZulu-Natal between 2003 and 2007. Significant differences were found between orphan and non-orphan caregivers; the former being more likely to care for more children, have poorer health, higher levels of chronic illness, less adult help and they appeared to have more daily responsibilities. Orphan caregivers were also more likely to indicate that children in their care needed help for mental or behavioural problems but overall results showed that only 3.4% of all households had contact with child welfare agencies. The findings question assumptions about the capacity and capability of the extended family to absorb shocks to individuals and families. PMID- 22106944 TI - A new model for embryo implantation: coculture of blastocysts and Ishikawa cells. AB - OBJECTIVE: To explore and develop a new in vitro implantation model that reflects the main process of embryo attachment and invasion. STUDY DESIGN: One of the limitations in human embryo implantation research is lack of an available in vitro model that faithfully replicates human embryo-uterine interactions. In the present study, we examined the attachment and invasiveness of blastocysts from mice in Ishikawa cell (IK), a human endometrial cell, to clarify whether this new model is suitable to study implantation of embryos. We used IK and placed it in contact with blastocysts to initiate coculture experiments using a specifically designed medium. The culture medium was composed of Ham F-12/Dulbecco's modified Eagle medium (1:1), 30% fetal calf serum, 63.5 nmol/L progesterone, 7.14 nmol/L estradiol-17beta, 100 mg/ml of insulin, and 20 ng/ml epidermal growth factor. The culture for 24 h clearly demonstrated that embryos were capable of attachment to the IK and displayed partial invasion. RESULTS: Our results showed that embryos attached to the IK and displayed partial invasion after coculture of blastocysts with IK for 48 h. CONCLUSIONS: The model is capable of demonstrating the procedure of attachment and invasion of embryo into the endometrial cells and has promises to be used in studies related to early embryo implantation in human endometrium. PMID- 22106945 TI - Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity. AB - AIMS: Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS: Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P= 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P= 0.009). CONCLUSIONS: Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres. PMID- 22106946 TI - Thermal sensation: a mathematical model based on neurophysiology. AB - Thermal sensation has a large influence on thermal comfort, which is an important parameter for building performance. Understanding of thermal sensation may benefit from incorporating the physiology of thermal reception. The main issue is that humans do not sense temperature directly; the information is coded into neural discharge rates. This manuscript describes the development of a mathematical model of thermal sensation based on the neurophysiology of thermal reception. Experimental data from two independent studies were used to develop and validate the model. In both studies, skin and core temperature were measured. Thermal sensation votes were asked on the seven-point ASHRAE thermal sensation scale. For the development dataset, young adult males (N=12, 0.04Clo) were exposed to transient conditions; Tair 30-20-35-30 degrees C. For validation, young adult males (N=8, 1.0Clo) were exposed to transient conditions; Tair: 17-25 17 degrees C. The neurophysiological model significantly predicted thermal sensation for the development dataset (r2=0.89, P<0.001). Only information from warm-sensitive skin and core thermoreceptors was required. Validation revealed that the model predicted thermal sensation within acceptable range (root mean squared residual=0.38). The neurophysiological model captured the dynamics of thermal sensation. Therefore, the neurophysiological model of thermal sensation can be of great value in the design of high-performance buildings. PRACTICAL IMPLICATIONS: The presented method, based on neurophysiology, can be highly beneficial for predicting thermal sensation under complex environments with respect to transient environments. PMID- 22106947 TI - Enzyme-catalyzed direct three-component aza-Diels-Alder reaction using hen egg white lysozyme. AB - The direct three-component aza-Diels-Alder reaction of aromatic aldehyde, aromatic amine, and 2-cyclohexen-1-one was catalyzed by hen egg white lysozyme for the first time. Under the optimized conditions investigated in this paper, the enzyme-catalyzed aza-Diels-Alder reaction gave yields up to 98% and stereoselectivity of endo/exo ratios up to 90:10. PMID- 22106948 TI - Eating out of home and its association with dietary intake: a systematic review of the evidence. AB - During the last decades, eating out of home (OH) has gained importance in the diets worldwide. We document the nutritional characteristics of eating OH and its associations with energy intake, dietary quality and socioeconomic status. We carried out a systematic review of peer-reviewed studies in eight databases up to 10 March 2011. Of the 7,319 studies retrieved, 29 met the inclusion criteria and were analysed in this review. The quality of the data was assessed and a sensitivity analysis was conducted by isolating nationally representative or large cohort data from 6 and 11 countries, respectively. OH foods were important sources of energy in all age groups and their energy contribution increased in adolescents and young adults. Eating OH was associated with a higher total energy intake, energy contribution from fat in the daily diet and higher socioeconomic status. Two large studies showed how eating OH was also associated with a lower intake of micronutrients, particularly vitamin C, Ca and Fe. Although the studies were cross-sectional and heterogeneous in the way they classified eating OH, we conclude that eating OH is a risk factor for higher energy and fat intake and lower micronutrient intake. PMID- 22106949 TI - Chiral hierarchical molecular nanostructures on two-dimensional surface by controllable trinary self-assembly. AB - The bottom-up fabrication of surface hierarchical nanostructures is of great importance for the development of molecular nanostructures for chiral molecular recognition and enantioselective catalysis. Herein, we report the construction of a series of 2D chiral hierarchical structures by trinary molecular self-assembly with copper phthalocyanine (CuPc), 2,3,7,8,12,13-hexahexyloxy-truxenone (TrO23), and 1,3,5-tris(10-carboxydecyloxy) benzene (TCDB). A series of flower-like chiral hierarchical molecular architectures with increased generations are formed, and the details of these structures are investigated by high resolution scanning tunneling microscopy (STM). The flower-like hierarchical molecular architectures could be described by a unified configuration in which the lobe of each architecture is composed of a different number of triangular shape building units (TBUs). The off-axis edge-to-edge packing of TBUs confers the organizational chirality of the hierarchical assemblies. On the other hand, the TBUs can tile the surface in a vertex-sharing configuration, resulting in the expansion of chiral unit cells, which thereby further modulate the periodicity of chiral voids in the multilevel hierarchical assemblies. The formation of desired hierarchical structures could be controlled through tuning the molar ratio of each component in liquid phase. The results are significant for the design and fabrication of multicomponent chiral hierarchical molecular nanostructures. PMID- 22106950 TI - Chlorophyll a fluorescence--A useful tool for the early detection of temperature stress in spring barley (Hordeum vulgare L.). AB - The photosynthetic activity of two Syrian barley (Hordeum vulgare L.) landraces, Arabi Abiad (A. Abiad) and Arabi Aswad (A. Aswad), grown under low- and high- temperature stresses, were studied by analyzing the measured chlorophyll fluorescence signals. Both the applied stresses influenced photosystem II (PSII) activity. However, the effects depend on the stress type and the duration of its application. Phenomenological parameters were shifted shortly after the application of both stresses, whereas fluorescence ratios and yield values were altered most significantly after 7 days of stress imposition. The earliest changes in PSII activity of both cultivars were observed in the case of high temperature treatment. The maximal quantum efficiency of the photosynthetic apparatus (F(v)/F(M)) did not alter after stress application. Therefore, we could not recommend this parameter for early detection of such stress. In contrast, the results from the present investigation strongly indicate that the most significantly changed chlorophyll a fluorescence parameters could be used as an efficient tool for the early diagnosis of temperature stress in barley. PMID- 22106951 TI - Elucidating polyploidization of bermudagrasses as assessed by organelle and nuclear DNA markers. AB - Clarification of relationships among ploidy series of Cynodon accessions could be beneficial to bermudagrass breeding programs, and would enhance our understanding of the evolutionary biology of this warm season grass species. This study was initiated to elucidate polyploidization among Cynodon accessions with different ploidy series collected from Turkey based on chloroplast and nuclear DNA. Forty Cynodon accessions including 7 diploids, 3 triploids, 10 tetraploids, 11 pentaploids, and 9 hexaploids were analyzed using chloroplast DNA restriction fragment-length polymorphism (cpDNA RFLP), chloroplast DNA simple sequence repeat (cpDNA SSR), and nuclear DNA markers based on neighbor-joining (NJ) and principle component analyses (PCA). All three-marker systems with two statistical algorithms clustered the diploids apart from the other ploidy levels. Assuming autopolyploidy, spontaneous polyploidization followed by rapid diversification among the higher ploidy levels than the diploids is likely in Cynodon's evolution. Few tetraploid and hexaploid accessions were clustered with or closely to the group of diploids, supporting the hypothesis above. Eleven haplotypes as estimated by cpDNA RFLP and SSR markers were detected. This study indicated that the diploids had different organelle genome from the rest of the ploidy series and provided valuable insight into relationships among ploidy series of Cynodon accessions based on cp and nuclear DNAs. PMID- 22106952 TI - Assessing the impact of a restorative home care service in New Zealand: a cluster randomised controlled trial. AB - Due to the ageing population, there is an increased demand for home care services. Restorative care is one approach to improving home care services, although there is little evidence to support its use in the community setting. The objective of this trial was to evaluate the impact of a restorative home care service for community-dwelling older people. The study was a cluster randomised controlled trial undertaken at a home care agency in New Zealand. The study period was from December 2005 to May 2007. Older people were interviewed face-to face at baseline, four and 7 months. A total of 186 older people who received assistance from a home care agency participated in the study, 93 received restorative home care and 93 older people received usual home care. The primary outcome measure was change in health-related quality of life (measured by the Short Form 36 [SF36] Health Survey). Secondary outcomes were the physical, mental, and social well-being of older people (Nottingham Extended Activities of Daily Living, Timed Up and Go, Mastery scale, Duke Social Support Index). Findings revealed that compared with usual care, the intervention demonstrated a statistically significant benefit in health-related quality of life (SF36) at 7 months for older people (mean difference 3.8, 95% CI -0.0 to 7.7, P = 0.05). There were no changes in other scale measurements for older people in either group over time. There was a statistically significant difference in the number of older people in the intervention group identified for reduced hours or discharge (29%) compared with the control group (0%) (P < 0.001). In conclusion, a restorative home care service may be of benefit to older people, and improves home care service efficacy. PMID- 22106953 TI - The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. AB - Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 cooperate to trim a vast variety of antigenic peptide precursors to generate mature epitopes for binding to major histocompatibility class I molecules. We report here the first structure of ERAP2 determined at 3.08 A by X-ray crystallography. On the basis of residual electron density, a lysine residue has been modeled in the active site of the enzyme; thus, the structure corresponds to an enzyme-product complex. The overall domain organization is highly similar to that of the recently determined structure of ERAP1 in its closed conformation. A large internal cavity adjacent to the catalytic site can accommodate large peptide substrates. The ERAP2 structure provides a structural explanation for the different peptide N-terminal specificities between ERAP1 and ERAP2 and suggests that such differences extend throughout the whole peptide sequence. A noncrystallographic dimer observed may constitute a model for a proposed ERAP1-ERAP2 heterodimer. Overall, the structure helps explain how two homologous aminopeptidases cooperate to process a large variety of sequences, a key property of their biological role. PMID- 22106954 TI - Nurses' attitudes towards breastfeeding among women with schizophrenia in southern Israel. AB - Breastfeeding is the best source of nutrition for infants. Approximately half of women with schizophrenia become mothers, yet the issue of breastfeeding is often overlooked by the health professional community. The aim of this study was to survey attitudes among registered nurses regarding breastfeeding by schizophrenic women. Cross-sectional descriptive design was used involving a sample of nurses (40 midwives, 37 psychiatric and 33 postpartum) in two medical centres in southern Israel. The validated semistructured questionnaire included sociodemographic and professional questions, personal and professional breastfeeding experience, attitudes and knowledge concerning schizophrenia and attitudes towards breastfeeding by schizophrenic women. The study results indicate that 70% of the respondents held positive attitudes towards breastfeeding in women with schizophrenia, although no significant differences were found between the different types of nurses. Multivariate analysis reveals that academic education was the only variable associated with positive attitudes, while negative feelings towards women with schizophrenia, and extensive knowledge regarding schizophrenia were negatively associated. This study can serve as a foundation for future research to further examine nurses' role in providing postpartum education and care for women with schizophrenia. PMID- 22106955 TI - Bidirectionality between pain and insomnia symptoms: a prospective study. AB - OBJECTIVES: The purpose of this study was to investigate whether there is a bidirectional relationship between pain and insomnia symptoms over the course of a year. DESIGN: A longitudinal design with a 1-year follow-up was used. METHODS: From a randomly selected sample of the adult general population (N= 3,000), 1,746 individuals filled out a baseline and 1-year follow-up survey on pain, insomnia symptoms, anxiety symptoms, and depressive symptoms. RESULTS: Pain (OR = 1.64) and anxiety symptoms increased the risk for the incidence of insomnia symptoms (R(2) = .125) and pain (OR = 1.98), anxiety symptoms and depressive symptoms were related to the persistence of insomnia symptoms (R(2) = .212). Gender and anxiety symptoms increased the risk for the incidence of pain (R(2) = .073); and age, insomnia symptoms (OR = 1.49), anxiety symptoms, and depressive symptoms were associated with the persistence of pain (R(2) = .187). CONCLUSION: While pain was linked to future insomnia symptoms and insomnia symptoms to the persistence of pain over the course of a year, insomnia symptoms was not associated with the incidence of pain. The results, thus, partly argue against bidirectionality between pain and insomnia symptoms. PMID- 22106956 TI - Symptomatic treatment of ascites with a peritoneo-vesical automated fluid shunt system in a dog. AB - A six-year-old Rottweiler with chronic ascites and moderate panhypoproteinaemia that had been treated with large volume paracentesis over several months duration was diagnosed with a large bi-atrial mass and hepatic fibrosis. For palliative treatment, a peritoneo-vesical automated fluid shunt system with an integrated chargeable battery and an integrated computer to control pump function and to transmit data transcutaneously was implanted by coeliotomy. The pump was left in place for 10 weeks, eliminating the need for further paracentesis during this time. At the end of this period, no ascites was discernible and serum protein concentrations had returned to their respective reference intervals. As a complication, decubitus with skin perforation had developed above the pump. Besides palliative treatment of chronic refractory ascites, this pump may have application in other conditions characterised by chronic cavity effusion or in peritoneal dialysis. PMID- 22106957 TI - Amending reduced fish-meal feeds with marine lecithin, but not soy lecithin, improves the growth of juvenile cobia and may attenuate heightened responses to stress challenge. AB - Sparing of marine resources in aquafeeds can be environmentally and economically advantageous; however, fish meal (FM) replacement can affect the production performance and physiological competence. Phospholipids are increasingly understood to be involved in maintaining growth and vigour in fish and may be deficient in reduced FM formulations. Accordingly, we evaluated the growth and stress tolerance of juvenile cobia fed typical (50% FM) or reduced FM feeds (12% FM) with or without phospholipid amendment [1% marine lecithin (12% FM + Marine PL) or soy lecithin (12% FM + Soy PL)] for 6 weeks in triplicate tanks (N = 3) in a recirculation aquaculture system. The 50% FM feed yielded significantly superior growth and growth efficiency in comparison with the 12% FM and 12% FM+ Soy PL feeds, but the 12% FM+ Marine PL feed yielded comparable results to 50% FM feed. A low-water stress challenge induced elevated plasma glucose, cortisol and lactate levels in all treatments. However, a significant interaction (diet * stress) effect suggested a lesser cortisol response among fish fed the 12% FM+ Marine PL and 50% FM diets. These findings demonstrate that growth performance and, perhaps, resilience of cobia raised on reduced FM feeds may be improved by the addition of marine-origin phospholipid to the diet. PMID- 22106958 TI - Immunomodulatory effects of heated ovomucoid-depleted egg white in a BALB/c mouse model of egg allergy. AB - Oral immunotherapy (OIT) is a promising therapeutic approach for treating food allergy. The treatment with heated ovomucoid-depleted egg white (HOMEW) in egg allergic patients is noteworthy; however, OIT protocols are still experimental, and a better knowledge of the underlying mechanism is required. The objective of this work was to investigate the immunomodulatory effects of HOMEW and characterize the underlying mechanism in a BALB/c mouse model of egg allergy. Mice were sensitized with EW and treated with HOMEW. Post treatment, mice were challenged with EW and euthanized for collecting blood and spleen. Markers of allergic clinical outcomes were measured as histamine concentration, serum antibody activity, and cytokine production from cultured splenocytes. Digestibility of HOMEW was assessed mimicking physiological conditions in vitro. The HOMEW demonstrated high digestibility. The treatment induced a marked increase of the Th1/Th2 ratio in the high-dose treatment group. Treated mice had significantly less histamine, EW-specific IgE, and IL-4 and more IFN-gamma and IL 10. This study confirms the mechanisms involved in successful tolerance induction with OIT using HOMEW and allows understanding of the vital role of surrogate allergy markers involved in immune modulation. PMID- 22106959 TI - Success of a diabetes health management program in employer-based health care centers. AB - Population health-based chronic care models of care are useful in improving the health of a population while decreasing the health care dollars spent on the population. Diabetes is a disease that can be evaluated and treated using these models of care. The Metro Nashville Public Schools Diabetes Health Management Program has been shown to be beneficial to both clients and their insurance trust in improving the health of this population of individuals and decreasing the dollars spent on this disease. PMID- 22106960 TI - Creating health connections for vulnerable working populations: Goodwill North Central Wisconsin's Circles of Good Care Model. AB - Worker health is influenced by workplace, work processes, and workmates. This case study shows it is possible to create health connections for vulnerable working populations through health and wellness coaching. The health and safety of team members has been improved by providing on-site health coaching linked to mental and emotional well-being, as well as financial security. By leveraging the collective efficacy of the workplace, more vulnerable populations can become better health care consumers, with increased self-efficacy in promoting their own health and wellness and that of their families. PMID- 22106961 TI - Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes. AB - Azole antifungal agents are known to inhibit cytochrome P450 3A (CYP3A) enzymes. Limited information is available regarding the effect of voriconazole on CYP3A activity. We examined the effect of voriconazole on CYP3A activity in human liver microsomes as measured by the formation of 6beta-hydroxytestosterone from testosterone. We also evaluated the interaction between voriconazole and tacrolimus, an immunosuppressive drug, using human liver microsomes. The effect of voriconazole on CYP3A activity and tacrolimus metabolism was compared to that of other azole antifungal agents. CYP3A4 activity and the metabolism of tacrolimus were measured in the absence and in the presence of various concentrations of voriconazole (0-1.43 mM), fluconazole (0-1.63 mM), itraconazole (0-14 uM) and ketoconazole (0-0.19 uM). At a concentration of 21.2 +/- 15.4 uM and 29.8 +/- 12.3 uM, voriconazole inhibited the formation of 6beta hydroxytestosterone from testosterone and the metabolism of tacrolimus by 50%, respectively. The rank order of inhibition of 6beta-hydroxytestosterone formation from testosterone and the metabolism of tacrolimus, is ketoconazole > itraconazole > voriconazole > fluconazole. Our observations suggest that voriconazole at clinically relevant concentrations will inhibit the hepatic metabolism of tacrolimus and increase the concentration of tacrolimus more than two-fold. Close monitoring of the blood concentrations and adjustment in the dose of tacrolimus are warranted when transplant patients receiving tacrolimus are treated with voriconazole. PMID- 22106962 TI - In vitro-in vivo correlation for intrinsic clearance for CP-409,092 and sumatriptan: a case study to predict the in vivo clearance for compounds metabolized by monoamine oxidase. AB - Oxidative deamination of the GABA(A) partial agonist CP-409,092 and sumatriptan represents a major metabolic pathway and seems to play an important role for the clearance of these two compounds. Similar to sumatriptan, human mitochondrial incubations with deprenyl and clorgyline, probe inhibitors of monoamine oxidase B and monoamine oxidase A (MAO-B and MAO-A), respectively, showed that CP-409,092 was metabolized to a large extent by the enzyme MAO-A. The metabolism of CP 409,092 and sumatriptan was therefore studied in human liver mitochondria and in vitro intrinsic clearance (CL(int)) values were determined and compared to the corresponding in vivo oral clearance (CL(PO)) values. The overall objective was to determine whether an in vitro-in vivo correlation (IVIVC) could be described for compounds cleared by MAO-A. The intrinsic clearance, CL(int), of CP-409,092 was approximately 4-fold greater than that of sumatriptan (CL(int), values were calculated as 0.008 and 0.002 ml/mg/min for CP-409,092 and sumatriptan, respectively). A similar correlation was observed from the in vivo metabolic data where the unbound oral clearance, CL(u)(PO), values in humans were calculated as 724 and 178 ml/min/kg for CP-409,092 and sumatriptan, respectively. The present work demonstrates that it is possible to predict in vivo metabolic clearance from in vitro metabolic data for drugs metabolized by the enzyme monoamine oxidase. PMID- 22106963 TI - Use of primary rat hepatocytes in the gel entrapment culture to predict in vivo biliary excretion. AB - In vitro models have been widely used in characterizing the hepatobiliary elimination of compounds. However, the application of in vitro models is often limited by their imperfect simulation of in vivo situations. The current paper aims to introduce the gel entrapment culture of rat hepatocytes as an alternative method for measuring hepatobiliary transport, with the sandwich culture of rat hepatocytes set as the control. First, the culture conditions of the gel entrapped hepatocytes were modified to enhance hepatic transport function. When cultured under optimal conditions, i.e. the collagen concentration was set to 0.6 mg/mL and the regular Williams' E medium was supplemented with epidermal growth factor, the hepatocytes maintained much higher hepatic transporter gene expression levels and transport activities than that in regular gel entrapment and sandwich culture. Compared with the actual values in rats, the predicted intrinsic biliary clearance (CL(bile,int,predicted)) of the 10 model compounds in the optimized gel entrapment culture showed a high correlation coefficient squared (R(2)) of 0.94, with the majority falling within the two-fold error range of the in vivo values, which was much better than the comparable sandwich culture. All of these results indicate that the optimized gel entrapment culture of hepatocytes is a suitable approach for estimating in vivo biliary excretion. PMID- 22106964 TI - Aqueous fluorescence turn-on sensor for Zn2+ with a tetraphenylethylene compound. AB - A new sensitive and selective fluorescence turn-on sensor for Zn(2+) (1) was developed by taking advantage of the aggregation-induced emission of the tetraphenylethylene framework. In addition, the corresponding ester precursor of 1 was successfully used for intracellular Zn(2+) imaging. PMID- 22106965 TI - Bone microarchitecture at oral implant sites in ectodermal dysplasia (ED): a comparison between males and females. AB - OBJECTIVE: The aim of this study was to analyse the microarchitecture of bone in association with implant placement in young ectodermal dysplasia (ED) patients. The general hypothesis was that the structural and morphological features of bone microarchitecture are different between males and females, which may influence clinical outcomes. MATERIALS AND METHODS: The bone harvesting is not additionally invasive, as the procedure was made at the time and site of implant placement. Twenty one samples (8 female, 13 male) were harvested from nine ED participants whose age ranged between 14 and 21 years and specified by the site of harvesting. Micro-CT analysis at 5 um resolution was conducted on each sample. Specialized CT analysis of the three-dimensional (3-D) bone microstructure was made to compare structural parameters. In addition, two bone samples (one male, one female) were sent to the University of Michigan and analysed at 9 um resolution. RESULTS: No significant difference was found between male and female samples. Bone analysis of particular sites revealed that bone-specific surface (BS/BV) was found to be significantly higher in male than in female samples, whilst the mean values of 10 parameters, the grey scale value histograms and 3-D visualization showed that female samples had higher compact density than male samples. CONCLUSION: Microstructural analyses indicated that female ED bone was more compact and with greater trabecular connectedness than male bone. These features may enhance resistance to external force transfer of mastication compared with male bone. Further bone samples from other jaw bone areas will provide information on whether there are regional differences in jawbone quality and quantity, which may influence implant treatment outcomes, as well as follow-up analyses of treatment outcomes. PMID- 22106966 TI - Change in cardiovascular disease status in peritoneal dialysis patients: a 5-year single-center experience. AB - BACKGROUND: We compared patient characteristics, atherosclerosis, left ventricular hypertrophy, and dialysis practice patterns of peritoneal dialysis (PD) patients with change in cardiovascular disease (CVD) status and no change in CVD status in Chinese PD center. METHODS: This study included all patients who started on PD between 1 January 2003 and 30 June 2009 at the Renji Hospital, Shanghai Jiaotong University School of Medicine, China. They were followed up from the date of PD initiation until new-onset CVD. RESULTS: The median follow-up time was 44.13 months. In patients with preexisting CVD, both high triglyceride (1.43 +/- 0.89 mmol/L vs. 2.64 +/- 1.58 mmol/L, p < 0.001) and the duration of dialysis (45.76 +/- 13.28 months vs. 58.68 +/- 13.74 months, p < 0.01) were independent predictors of CVD progression and the left atrial dimension, left ventricle septal thickness, left ventricle mass index (LVMI), and intima-media thickness (IMT) also had the difference. On the other hand, in patients without preexisting CVD, the dialysis adequacy and nutritional status are important during the follow-up. Serum albumin in CVD group was lower than in no CVD group (30.86 +/- 4.77 g/L vs. 36.04 +/- 6.40 g/L, p < 0.05). Creatinine clearance (CCr) and Kt/V in CVD group were lower than in no CVD group (CCr 57.24 +/- 13.86 L/week vs. 71.06 +/- 23.96 L/week, p < 0.05; Kt/V 1.82 +/- 0.41 vs. 2.23 +/- 0.57, p < 0.05). CONCLUSION: In patients with preexisting CVD, it is important to address traditional risk factors such as LVMI, IMT, and lipid profile. In patients without preexisting CVD, we should pay more attention to the nutritional status and PD prescription in order to lower the morbidity of CVD in these PD patients. PMID- 22106967 TI - Proteomic analysis of colon tissue from interleukin-10 gene-deficient mice fed polyunsaturated Fatty acids with comparison to transcriptomic analysis. AB - Inflammatory bowel disease (IBD) is characterized by intestinal inflammation and is believed to involve complex interactions between genetic, immunological, and environmental factors. We measured changes in the proteome associated with bacterially induced intestinal inflammation in the interleukin 10 gene-deficient (Il10(-/-)) mouse model of IBD, established effects of the dietary polyunsaturated fatty acids (PUFAs) n-3 eicosapentaenoic acid (EPA) and n-6 arachidonic acid (AA) on protein expression (using oleic acid as a control fatty acid), and compared these changes with previously observed transcriptome changes in the same model. Ingenuity pathways analysis of proteomics data showed bacterially induced inflammation was associated with reduced expression of proteins from pathways of metabolism and digestion/absorption/excretion of nutrients/ions, and increased expression of cellular stress and immune response proteins. Both PUFA treatments showed anti-inflammatory activity; EPA appeared to act via the PPARalpha pathway, whereas AA appeared to increase energy metabolism and cytoskeletal organization and reduce cellular stress responses, possibly enabling a more robust response to inflammation. While there was agreement between proteomic and transcriptomic data with respect to pathways, there was limited concordance between individual gene and protein data, reflecting the importance of having both gene and protein data to better understand complex diseases such as IBD. PMID- 22106973 TI - ortho-Lithium/magnesium carboxylate-driven aromatic nucleophilic substitution reactions on unprotected naphthoic acids. AB - Substitution of an ortho-fluoro or methoxy group in 1- and 2-naphthoic acids furnishing substituted naphthoic acids occurs in good to excellent yields upon reaction with alkyl/vinyl/aryl organolithium and Grignard reagents, in the absence of a metal catalyst without the need to protect the carboxyl (CO(2)H) group. This novel nucleophilic aromatic substitution is presumed to proceed via a precoordination of the organometallic with the substrate, followed by an addition/elimination. PMID- 22106974 TI - Type 2 diabetes and cardiovascular risk factors. AB - Diabetes is associated with higher cardiovascular morbidity and mortality. Hypertension, hyperlipidemia and diabetes are independently associated with increased risk of cardiovascular (CV) disease. Subjects with type 2 diabetes are at two- to four-fold increased risk of CV disease compared to those without diabetes. Long-term hyperglycemia is much more closely associated with microvascular complications than macrovascular complications. There is a lack of adequate evidence that improvement in glycemic control decreases CV risk. PMID- 22106975 TI - Alogliptin plus voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension. AB - OBJECTIVE: To compare the efficacy and safety of alogliptin and placebo as add-on therapy in Japanese patients with type 2 diabetes who experienced inadequate glycemic control on voglibose plus diet/exercise therapy. RESEARCH DESIGN AND METHODS: During an 8 week screening phase, patients aged >= 20 years were stabilized on voglibose 0.2 mg three times daily plus diet/exercise therapy. Those with HbA1c between >= 6.9% and <10.4% were randomly assigned to 12 weeks' double-blind treatment with once daily alogliptin 12.5 or 25 mg, or placebo. The primary endpoint was the change in HbA1c at 12 weeks from baseline. Patients then entered an open-label, 40 week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25 mg). CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ; pivotal trial NCT01263483; Long term trial NCT01263509. RESULTS: Least square mean change in HbA1c after 12 weeks' therapy from baseline (primary endpoint) was significantly greater in the alogliptin 12.5 mg (-0.96%; P < 0.0001) and 25 mg (-0.93%; P < 0.0001) groups compared with placebo (+0.06%). This was associated with statistically significant improvements in other measures of glycemic control, in particular sustained reductions in fasting plasma glucose and postprandial plasma glucose. These benefits were maintained for the duration of the 1 year study and, importantly, they were achieved without detrimental effects on tolerability/safety. In particular, there was no increase in the rate of hypoglycemia and almost no changes in mean body weight. CONCLUSIONS: Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled type 2 diabetes produced clinically significant improvements in glycemic control, and was well tolerated. PMID- 22106976 TI - A survey of blood glucose monitoring in patients with type 2 diabetes: are recommendations from health care professionals being followed? AB - OBJECTIVE: To survey the self-reported use of self-monitoring of blood glucose (SMBG) among patients with type 2 diabetes (T2DM), both insulin users (IUs) and non-insulin users (NIUs), in the United States and to examine: how often patients test; what SMBG instructions patients report receiving from their health care providers (HCPs); how the frequency of testing conforms with reported HCP recommendations for testing; and what is done with the results of testing. Differences between IUs and NIUs were also investigated. METHODS: A convenience sample of 886 T2DM participants at a series of one-day conferences across the United States completed a survey on current and recommended SMBG frequency, how SMBG results were used, and how HCPs reportedly talked about SMBG issues with the patient. IUs (65% of the sample) and NIUs (35%) were examined separately. RESULTS: IUs and NIUs reported testing significantly less frequently than was recommended (in both cases, p < 0.001), with wide variations within both groups. Many IUs (42%) and NIUs (50%) did not bring SMBG data regularly to medical visits, and 54% of IUs and 56% of NIUs did not respond regularly to out-of-range SMBG readings. HCPs were generally supportive and responsive to SMBG data. More frequent SMBG was associated with more regular HCP attention to SMBG records, for IUs (p = 0.02) and NIUs (p = 0.004). CONCLUSIONS: Self-reported SMBG use is common in T2DM, though frequency is lower than HCP recommendations. Wide variations in actual and recommended SMBG were observed. HCP support for SMBG is reportedly common, and is associated with greater SMBG frequency. While SMBG data can be valuable, recommendations are often not followed and data often goes unused by both HCPs and patients. PMID- 22106977 TI - Comparative risk of microalbuminuria and proteinuria in UK residents of south Asian and white European ethnic background with type 2 diabetes: a report from UKADS. AB - OBJECTIVE: This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed. TRIAL REGISTRATION NUMBER: ISRCTN 38297969. MAIN OUTCOME MEASURES: Prevalences of microalbuminuria and overt proteinuria. RESULTS: Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, chi(2) = 15.85, 2df, P = 0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P = 0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years' duration, OR = 1.40 (0.63, 3.08). LIMITATIONS: Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio. CONCLUSIONS: There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity. PMID- 22106978 TI - Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. AB - OBJECTIVE: Dipeptidyl peptidase-4 inhibitors (DPP4i) have been recently associated with increased risk of pancreatitis and cancer. The aim of the present meta-analysis of randomized clinical trials is the assessment of the effect of DPP4i on the incidence of major cardiovascular events (MACE), cancer, and pancreatitis. RESEARCH DESIGN AND METHODS: An extensive Medline and Embase search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin', and 'dutogliptin' was performed, collecting all randomized clinical trials on humans up to March 1, 2011. The present meta-analysis was therefore performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP4i with either placebo or active drugs. Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency website. RESULTS: Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively, were included, reporting 176 malignancies, 257 MACE, and 22 pancreatitis. DPP4i, compared with placebo or other treatment, were associated with a similar risk of cancer (MH-OR 1.020 [0.742-1.402]; p = 0.90) and pancreatitis (0.786 [0.357-1.734], p = 0.55), and with a reduced risk of MACE (MH-OR 0.689 [0.528-0.899], p = 0.006). CONCLUSIONS: The present meta-analysis seems to exclude any relevant short term effect of DPP4i on the incidence of cancer and suggest a possible protection from cardiovascular events. This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short, and the characteristics of patients included could be different from routine clinical practice. PMID- 22106979 TI - Efficacy and safety of combination therapy with candesartan cilexetil and pioglitazone hydrochloride in patients with hypertension and type 2 diabetes mellitus. AB - OBJECTIVE: To evaluate the efficacy and safety of combination therapy with candesartan cilexetil (CC) and pioglitazone hydrochloride (PIO) in patients with hypertension and type 2 diabetes mellitus. METHODS: A 12-week, double-blind, randomized, parallel-group study in patients with mild-to-moderate essential hypertension and type 2 diabetes mellitus was followed by a 40-week, single-blind study. Patients (N = 377) were randomized to treatment with CC 8 mg/PIO 30 mg (n = 62), CC 8 mg/PIO 15 mg (n = 63), CC 4 mg/PIO 30 mg (n = 63), CC 4 mg/PIO 15 mg (n = 63), CC 8 mg/PIO 0 mg (n = 63), or CC 0 mg/PIO 30 mg (n = 63). Primary efficacy measures were changes in diastolic blood pressure (DBP) and HbA(1C) at Week 12. RESULTS: CC/PIO combination therapy improved blood pressure (BP)/glycemic control for 52 weeks. At the end of 12-week treatment period, DBP decreased to a significantly greater extent in the 8/30 + 8/15 + 8/0 (combined CC 8 mg) group (-10.5 mmHg, p < 0.0001) and the 4/30 + 4/15 (combined CC 4 mg) group (-9.1 mmHg, p = 0.0022) than in the 0/30 (CC 0 mg) group (-5.3 mmHg). HbA(1C) significantly decreased in the 8/30 + 4/30 + 0/30 (combined PIO 30 mg) group ( 0.35%, p < 0.0001) and the 8/15 + 4/15 (combined PIO 15 mg) group (-0.15%, p < 0.0001) compared with the 8/0 (PIO 0 mg) group (0.35%). Urinary albumin excretion reduction seen with the 0/30 and the 8/0 groups was significantly enhanced by CC/PIO combination. Clinical significance of this renoprotective effect of CC/PIO combination therapy needs to be studied further. Prolonged combined use of CC/PIO did not increase adverse events. Drug-related adverse events were similar to those during clinical use of CC and PIO. CONCLUSION: CC/PIO combination therapy improved BP/glycemic control and was well tolerated for 52 weeks. Thus, CC/PIO combination therapy is useful in patients with hypertension and type 2 diabetes mellitus. PMID- 22106980 TI - Impact of transitioning from HIV clinical trials to routine medical care on clinical outcomes and patient perceptions. AB - Participation in antiretroviral therapy clinical trials (ART-RCTs) offers many advantages including access to new drugs, close monitoring, and cost savings. These same benefits may pose a risk to patients ending ART-RCTs and returning to routine care; as they may experience changes to their drug regimen, decreased monitoring, and new out-of-pocket costs. We aimed to evaluate this transition and determine its effects on viral outcomes and patient perceptions. A retrospective cohort was assembled from participants of naive ART-RCTs at the University of Pennsylvania between 1 January 2000 and 31 December 2009. Data were collected in the 12 months prior to and after trial completion. Multivariable logistic regression was used to evaluate viral failure rates and to identify factors associated with viral failure. Qualitative interviews were held with a subset of patients. Content analysis was used to identify thematic differences between patients with viral failure and those with viral suppression. In total, 116 patients enrolled in 5 ART-RCTs from 2000 to 2009. Viral failure was observed in 39 patients (34%). Nonwhites, high enrollment CD4 count, and trial completion in 1999-2002 were risk factors for failure. Patients transitioning from ART-RCTs to routine care had a 20% increased odds of failure (Adjusted Odds Ratio 1.20 (95% CI [0.37, 3.88])). Nine patients with viral suppression and three with viral failure in the year after trail completion were interviewed. Suppressed patients were more eager to continue trial participation, nervous about leaving the trial, and felt prepared to return to routine care. In contrast, those with viral failure were less concerned about the transition. These findings suggest that the posttrial period may be a vulnerable time for patients. Patients without a healthy fear of transitioning from ART-RCTs to routine care may be at increased risk of viral failure. Focus should be given to assisting patients during this transition. PMID- 22106981 TI - Insulin resistance and bariatric surgery. AB - The objective of this article is to systematically review the changes in insulin resistance after various types of bariatric surgical procedures. A Pubmed and EMBASE search for studies measuring insulin resistance before and after bariatric surgery was done and all original research articles from 1980 to present (2011) were included. Only the currently widely performed bariatric procedures were included. A meta-analysis of change in HOMA-IR was conducted, grouping studies with similar duration of follow-up. The percentage decrease in HOMA-IR at <=2 weeks, 1 month, 3 months, 6 months, 12 months and >16-18 months was found to be (mean +/- standard error) -33.48 +/- 5.78, -46.43 +/- 6.99, -38.79 +/- 9.64, 58.62 +/- 7.38, -44.91 +/- 7.98 and -67.04 +/- 10.78%, respectively. RYGB (gastric bypass) and BPD (biliopancreatic diversion) produced a significant decrease in insulin resistance at 2 weeks after surgery, while LSG (sleeve gastrectomy) was strongly trending. LSG produced an earlier decrease in insulin resistance when compared to LAGB (gastric banding). RYGB, BPD and LSG produce an early decrease in insulin resistance through yet unknown mechanisms. PMID- 22106982 TI - Assessing patterns of home and community care service use and client profiles in Australia: a cluster analysis approach using linked data. AB - The planning and delivery of care systems require knowledge on the ways in which individuals access available services that are funded by a range of health and community services. The aims of this study were to identify distinct groups of Home and Community Care (HACC) clients in New South Wales, Australia, based on patterns of actual service use, and to understand the health and social needs and resources of client groups that access different mixes of services. Multiple data sets linked at the individual level - including the 45 and Up Study community survey, the HACC Minimum Data Set and the Admitted Patient Data Collection for hospitals - provide an innovative basis to investigate the complexity of access to service use. Data were collected between 2006 and 2008. A cluster analysis based on clients' type and volume of community service use was conducted on the 4890 HACC clients in the linked dataset and nine distinct clusters of clients were identified. Three of these clusters were considered 'complex', in terms of the range of community and hospital assistance received, while the others comprised mainly of one or two dominant service types. The analytical approach and findings developed here provide a client-centred approach to monitor and evaluate access to local service systems that are being reformed to better integrate the delivery of health and community services currently funded and managed separately by national and state governments. PMID- 22106983 TI - Angiosarcoma-like presentation of pacemaker-related vascular proliferation. AB - A 90-year-old man presented with a rapidly growing vascular lesion after a pacemaker generator change. The rapid growth suggested a possible angiosarcoma. A less dramatic presentation of vascular proliferation has been described as reticular telangiectatic erythema, which has been reporting following insertion of pacemakers, implantable cardioverter defibrillators, and drug-delivery devices. The onset of the disorder is described as weeks to years after implantation or generator change. It is a benign condition that generally remains static or regresses over time. The vascular proliferation noted in this case resolved almost completely over a period of 1 year. PMID- 22106984 TI - Borane-induced dehydration of silica and the ensuing water-catalyzed grafting of B(C6F5)3 to give a supported, single-site Lewis acid, =SiOB(C6F5)2. AB - A supported, single-site Lewis acid, =SiOB(C(6)F(5))(2), was prepared by water catalyzed grafting of B(C(6)F(5))(3) onto the surface of amorphous silica, and its subsequent use as a cocatalyst for heterogeneous olefin polymerization was explored. Although B(C(6)F(5))(3) has been reported to be unreactive toward silica in the absence of a Bronsted base, we find that it can be grafted even at room temperature, albeit slowly. The mechanism was investigated by (1)H and (19)F NMR, in both the solution and solid states. In the presence of a trace amount of H(2)O, either added intentionally or formed in situ by borane-induced dehydration of silanol pairs, the adduct (C(6)F(5))(3)B.OH(2) hydrolyzes to afford C(6)F(5)H and (C(6)F(5))(2)BOH. The latter reacts with the surface hydroxyl groups of silica to yield =SiOB(C(6)F(5))(2) sites and regenerate H(2)O. When B(C(6)F(5))(3) is present in excess, the resulting grafted boranes appear to be completely dry, due to the eventual formation of [(C(6)F(5))(2)B](2)O. The immobilized, tri-coordinate Lewis acid sites were characterized by solid-state (11)B and (19)F NMR, IR, elemental analysis, and C(5)H(5)N-TPD. Their ability to activate two molecular C(2)H(4) polymerization catalysts, Cp(2)ZrMe(2) and an (alpha-iminocarboxamidato)nickel(II) complex, was explored. PMID- 22106985 TI - Psychometric properties and population-based norms of the Life Orientation Test Revised (LOT-R). AB - OBJECTIVES: The relevance of the construct optimism in health psychology has been convincingly demonstrated in numerous studies. Population-based studies about dispositional optimism and the psychometric properties of the Life Orientation Test LOT-R as well as population-based norms are lacking. DESIGN: A representative population survey in Germany was conducted to investigate psychometric properties of the LOT-R and to deliver population-based norms. METHODS: A representative sample of 2,372 adults aged 18-93 years were screened using self-rating instruments. Results. The confirmatory factor analysis (CFA) confirmed two factors. Optimism and pessimism are negatively correlated (r=-.20). Indications for convergent validity were demonstrated with depression, satisfaction with life, subjective state of health and health care utilization. Optimism is more strongly related to all indicators than pessimism. Since there are only marginal age and gender differences, norm data are given for the entire population. CONCLUSIONS: Our study confirms the bi-dimensionality of the LOT-R and thus underpins that optimism and pessimism are two independent constructs rather than a single bipolar trait. Psychometric properties were found to be satisfactory. Together with the norm values reported in the paper, this instrument can, thus, be employed to measure dispositional optimism or pessimism in individual diagnostics as well as in epidemiological research. PMID- 22106986 TI - Contrasting relationships between species diversity and genetic diversity in natural and disturbed forest tree communities. AB - * This study aimed to reveal species-genetic diversity correlations (SGDCs) and their underlying mechanisms in natural and disturbed forests. * A community survey and molecular analyses were carried out to compare species diversity (SD), the genetic diversity of the dominant tree species Euptelea pleiospermum (GD), the altitudinal patterns of SD and GD, SGDC, genetic differentiation (F(ST) ), community divergence (F(ST) -C), effective population size (N(e) ), and recent migration rate between mountain riparian forests along the Yandu (natural) and Nan (disturbed) rivers. * In natural forests, both SD and GD showed a unimodal altitudinal pattern and GD was positively correlated with SD, whereas a unimodal pattern and positive SGDC were not found in the disturbed forests. SD and F(ST) at the natural sites were higher than those at the disturbed sites. However, there were no significant differences in GD, F(ST) -C, N(e) or recent migration rate between the natural and disturbed sites. * A correlation between the patterns of SD and GD along a geographical gradient (e.g. altitude) is an important driver of positive SGDC. The absence of positive SGDC in the disturbed forests may result from reduced SD but unaffected GD, indicating nonparallel changes in SD and GD. This study furthermore cautions against generalizations about changes in SD and GD following disturbance. PMID- 22106987 TI - Personalization and perceived personal relevance in computer-tailored persuasion in smoking cessation. AB - OBJECTIVES: In most computer-tailored interventions, the recipient's name is used to personalize the information. This is done to increase the process of persuasion but few empirical data exist that support this notion. DESIGN: An experimental laboratory study was conducted to test the effects of mentioning the participants name and to study whether it was related to the depth of processing in a 2 (personalization/standard) * 2 (weak/strong arguments) design. METHODS: Over 120 student smokers were randomly assigned to one of the four experimental conditions in which they read smoking cessation messages offering (pre-tested) strong or weak arguments. Personalization was applied by mentioning the recipient's first name three times in the text. The intention to quit smoking was the dependent variable. RESULTS: Personalization increased persuasion when perceived personal relevance was high, but it decreased persuasion when perceived personal relevance was low. The effects on persuasion were only present in the case of strong arguments. CONCLUSIONS: Personalization is not always effective, and it may even lead to less persuasion. Therefore, this often used way to tailor messages must be applied with care. PMID- 22106988 TI - Energy requirements of puppies of two different breeds for ideal growth from weaning to 28 weeks of age. AB - To ensure an optimal growth is crucial in raising healthy dogs, especially in large and giant breeds. Dogs with a moderate growth velocity tend to have lesser problems with developmental orthopaedic diseases than those with forced or maximum weight gain. In this study, the energy needs of growing dogs from two different breeds (Beagles as a medium-size breed and Foxhound crossbreds as a large-size breed) to ensure a growth development as recommended by the National Research Council (NRC) were determined at the age of 6-28 weeks. After weaning at the age of 6 weeks, the food rations sufficient to meet the energy requirements of each individual puppy were adjusted every other day according to growth level, guaranteeing a development consistent with the recommended weight curve for the respective breed size. The food and therefore energy intake of the puppies was registered daily; it ranged from 0.72 to 2.34 times the maintenance requirements with little effect of age. During the whole period, however, there was a consistent breed difference: Foxhound-Boxer-Ingelheim Labrador crossbreds (FBIs) had higher energy intakes expressed as multiples of maintenance than Beagles, suggesting that during the major period of growth, the energy requirement is not a function of age. Adult Beagles and FBIs showed similar differences in energy requirements as already during growth as shown in this study. This indicates that breed differences in energy requirements have already to be taken into account during growth. On the other hand, the results showed clearly lower energy needs for growth in these two different breeds than recommended in the NRC. PMID- 22106989 TI - Removal torque analysis of implants in rabbit tibia after topical application of simvastatin gel. AB - The aim of this study was to evaluate the effects of topical application of simvastatin gel (7.5 mg) on the removal torque of titanium implants in the rabbit tibia. A total of 32 surgeries were performed on 16 New Zealand rabbits for the placement of 2 implants in 1 tibia of each rabbit. Only 1 of the surgical defects was injected with 30 mg/mL of simvastatin gel before implant placement. The initial torque was set at 20 N.cm, and removal torque testing was performed 28 and 56 days postoperatively with a Tonishi torque wrench. Surgical defects were divided into 4 groups: group IG-28 (test, 28 days), group IG-56 (test, 56 days), group I-28 (control, 28 days), and group I-56 (control, 56 days). Removal torque values were higher in group IG-56 than in groups IG-28, I-28, and I-56 (P < .05). Groups IG-28, I-28, and I-56 showed similar values (P > .05). Removal torque force increased under the influence of simvastatin, indicating that topical administration of a 7.5-mg dose of simvastatin gel is effective in improving the torque force required to remove implants inserted in the rabbit tibia. PMID- 22106990 TI - Genetic characterization of HIV before widespread testing of HIV vaccine candidates at a clinical trial site in Pretoria, South Africa. AB - We studied 123 samples from adult chronic HIV patients initiating HAART from various centers around a newly established clinical trial site in Pretoria. Each sample was sequenced in at least one structural gene (pol, gag, and env) or functional gene (vif, vpr, and vpu). A subset of 25 samples was subjected to near full-genome analysis. All samples were HIV-1 subtype C. Highly conserved regions within the gene sequences were observed. Overall, the gag and vif sequences showed closer similarity followed by the env, vpr, pol, and vpu. The env gene was the most difficult to sequence, resulting in only 31 sequences from 40 samples; of these, 25 were predicted to be R5 coreceptor tropic, while 6 were X4 tropic. The study asserted the predominance of HIV-1 subtype C within the catchment population. PMID- 22106991 TI - How far have we come in 30 years of IVF? PMID- 22106992 TI - The power of one and its cost. PMID- 22106993 TI - Heavy stimulant use remains a significant health concern for Australia. PMID- 22106994 TI - No more excuses: fracture liaison services work and are cost-effective. PMID- 22106995 TI - How to get full, meaningful disclosure. PMID- 22106996 TI - A to X: the problem of categorisation of drugs in pregnancy--an Australian perspective. PMID- 22106997 TI - Time to mandate data release and independent audits for all clinical trials. PMID- 22106998 TI - No evidence of benefit for universal screening with 75 g oral glucose tolerance test in polycystic ovary syndrome. PMID- 22106999 TI - Accidental ingestion of plastic from takeaway containers--food for thought. PMID- 22107000 TI - Use of routine health data to complement monitoring of consumer product-related injuries. PMID- 22107001 TI - MELAS syndrome in an Indigenous Australian woman. PMID- 22107002 TI - Suicide and self-harm in immigration detention. PMID- 22107003 TI - A case study of a single ethics committee for multicentre trials. PMID- 22107004 TI - NHMRC funding for primary care research 2000-2008. PMID- 22107005 TI - Hospital and emergency department use in the last year of life: a baseline for future modifications to end-of-life care. PMID- 22107006 TI - Challenges with maintaining clinical teaching capacity in regional hospitals. PMID- 22107007 TI - Implementing US-style anti-fraud laws in the Australian pharmaceutical and health care industries. PMID- 22107008 TI - Practical neurology--5: Recurrent unresponsive episodes and seizures. AB - Careful history-taking is essential when evaluating patients with suspected epileptic seizures. It should focus on ascertaining whether the episodes are seizures or a seizure mimic such as syncope. Recurrent unresponsive episodes associated with seizures may indicate a diagnosis of focal epilepsy or complex partial epilepsy. Adults with a clinical diagnosis of a focal seizure disorder require investigation with electroencephalography and magnetic resonance imaging. The goal of treatment should be to achieve a life free of seizures, with minimum adverse effects from anticonvulsant medication. The choice of medication should be individualised to a patient's seizure characteristics, circumstances and preferences. Dose adjustments should be made according to clinical response (seizure frequency and adverse effects), rather than on serum drug concentrations alone. Lifestyle advice, such as advice about driving restrictions, is important for the safety of the patient and others. All anticonvulsants are potentially teratogenic. Poorly controlled epilepsy in pregnancy imparts significant risks to the mother and baby, which need to be weighed against the risks of teratogenicity. The risk of major congenital malformations is highest with valproate, particularly in high doses. PMID- 22107009 TI - Assisted reproductive technology: public funding and the voluntary shift to single embryo transfer in Australia. AB - OBJECTIVES: To calculate cost savings to the Australian federal and state governments from the reduction in twin and triplet birth rates for infants conceived by assisted reproductive technology (ART) since 2002, and to determine the number of ART treatment programs theoretically funded by means of these savings. DESIGN AND SETTING: Costing model using data from the Australia and New Zealand Assisted Reproduction Database, the National Perinatal Data Collection and Medicare Australia on ART treatment cycles undertaken in Australia between 2002 and 2008. MAIN OUTCOME MEASURES: Annual savings in maternal and infant inpatient birth-admission costs resulting from the reduction in ART multiple birth rate; theoretical number of ART treatment programs funded and infants born by means of these savings. RESULTS: The reduction in the ART multiple birth rate from 18.8% in 2002 to 8.6% in 2008 resulted in estimated savings to government of $47.6 million in birth-admission costs alone. Theoretically, these savings funded 7042 ART treatment programs comprising one fresh plus one frozen embryo transfer cycle, equating to the birth of 2841 babies. Fifty-five per cent of the increased use of ART services since 2002 has been theoretically funded by the reduction in multiple birth infants. CONCLUSIONS: Against a backdrop of supportive public funding of ART in Australia, a voluntary shift to single embryo transfer by fertility clinicians and ART patients has resulted in substantial savings in hospital costs. Much of the growth in ART use has been theoretically cross subsidised by the move to safer embryo transfer practices. PMID- 22107010 TI - Outcomes from the first assisted reproduction program for HIV-serodiscordant couples in Australia. AB - OBJECTIVE: To describe the clinical outcomes for all HIV-serodiscordant couples attending an assisted reproduction program. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of demographic, clinical and outcome data for all HIV serodiscordant couples who attended an assisted reproduction program at a tertiary hospital in Melbourne, between its commencement in 2003 and June 2010. MAIN OUTCOME MEASURES: Pregnancies, miscarriages, births, HIV transmission to the HIV-negative partner, semen quality and detection of HIV (HIV RNA and HIV DNA) in semen. RESULTS: As of June 2010, 39 HIV-positive clients had proceeded to assisted reproduction after the initial consultation in the program. There were 162 completed cycles, with 26 pregnancies (clinical pregnancy rate per cycle, 16.2% for HIV-positive men with an HIV-negative partner, and 15.4% for HIV positive women). Of all 222 tested semen samples, 18 (8%) had HIV RNA detected despite these men receiving antiretroviral therapy and having an undetectable HIV viral load in plasma. Sperm velocity was significantly lower in HIV-positive clients receiving combination antiretroviral therapy than in a control group of recipient-recruited sperm donors (P = 0.01); there were no other significant differences in sperm quality between the two groups. No HIV transmission to babies or HIV-negative partners occurred. CONCLUSION: Our findings show detectable HIV in 8% of semen samples from men with an undetectable HIV viral load in plasma, but confirm the safety of assisted reproduction for HIV serodiscordant couples within a program with strict protocols for HIV treatment and testing of all semen before use. PMID- 22107011 TI - General practitioner referral patterns for women with gynaecological symptoms: a randomised incomplete block study design. AB - OBJECTIVE: To describe why, when and to whom general practitioners refer women with symptoms possibly attributable to cervical, endometrial or ovarian cancers, and to identify patient and GP factors that predict referral to either a gynaecologist or a gynaecological oncologist. DESIGN AND SETTING: A national survey of GPs between 1 April and 31 August 2009 using a randomised incomplete block design based on case vignettes, and using a self-completed postal or online questionnaire. PARTICIPANTS: A sample of GPs, stratified by location and randomly selected from a database of GPs maintained by the Australasian Medical Publishing Company. MAIN OUTCOME MEASURES: Proportion of vignettes that were deemed to reflect a high probability of cancer being referred; and the patient and clinician factors that were the strongest predictors of referral. RESULTS: Of the 3082 GPs who were selected for participation, 1402 responded, giving a response rate of 45.5%. Overall, for vignettes identified as describing women with a high probability of cancer, 75% were referred by metropolitan GPs and 73% by rural practitioners. Metropolitan GPs were significantly more likely to refer women in scenarios indicative of endometrial cancer than rural GPs. For all three cancers, GPs were significantly more likely to refer a patient to a gynaecologist (between 70.8% and 95.4%) than a gynaecological oncologist. Metropolitan GPs had significantly greater access to both private and public gynaecological oncologists than their rural counterparts. Referral rates were higher for ovarian and cervical cancer (83% and 80%, respectively) and lower for endometrial cancer (68%). For all three cancers, patient factors were stronger predictors of referral than the demographic factors of participating GPs. CONCLUSION: There appears to be significant variation in referral practices among GPs and this variation is greater for endometrial cancer, for which there are currently no evidence-based clinical practice guidelines in Australia. There is a need for further research into understanding the basis of these differences, including a review of the existing guidelines for ovarian and cervical cancer and the development of guidelines for endometrial cancer. PMID- 22107012 TI - Stimulant use and stimulant use disorders in Australia: findings from the National Survey of Mental Health and Wellbeing. AB - OBJECTIVES: To describe the prevalence of lifetime and 12-month stimulant use disorders in the Australian population, and to compare the prevalence estimates from a population survey with prevalence estimates derived using indirect methods. DESIGN AND SETTING: Data were drawn from the 2007 National Survey of Mental Health and Wellbeing, which sampled 8841 residents of private dwellings in Australia in 2007. Interviews were conducted by lay interviewers using the Composite International Diagnostic Interview. MAIN OUTCOME MEASURES: Lifetime and 12-month rates of stimulant use and stimulant use disorders (abuse, dependence) diagnosed according to the Diagnostic and statistical manual of mental disorders, 4th edition. RESULTS: Lifetime prevalence of stimulant use disorders was 3.3%, and 12-month prevalence was 0.6%, equating to more than 97 000 Australians. Nearly half of those who had used stimulants on more than five occasions met criteria for a lifetime disorder. More than 8% of men aged 16-29 years met criteria for a lifetime stimulant use disorder. Prevalence estimates were consistent with recent estimates using indirect methods. CONCLUSIONS: Stimulant use disorders affect a significant number of Australians, and are most common in the age groups at greatest risk for development of psychosis. PMID- 22107013 TI - Ischaemic stroke among young people aged 15 to 50 years in Adelaide, South Australia. AB - OBJECTIVES: To report risk factors, aetiology and neuroimaging features among a large series of young Australian patients who were admitted to hospital for a first-ever occurrence of ischaemic stroke; to analyse the effect of age, sex and ethnicity on the presence of risk factors; and to compare Australian and overseas data. DESIGN, SETTING AND PATIENTS: Retrospective evaluation of data for all patients aged from 15 to 50 years who were admitted to a public hospital in Adelaide, South Australia, from January 2006 to June 2010 with a primary diagnosis of ischaemic stroke. RESULTS: Among 326 patients (184 males), the most frequent stroke risk factors overall were dyslipidaemia (187), smoking (161), hypertension (105) and obesity (92). Fifty-one patients used illicit drugs, mostly comprising marijuana and amphetamines. The most frequent stroke aetiologies overall were cardioembolism (85), arterial dissection (49), and small vessel occlusion (31). Cardioembolism was highly prevalent among our study population compared with patients in other countries. Neuroimaging showed that more patients in our study had strokes that involved both vascular territories concurrently (9%) compared with patients in other countries. CONCLUSIONS: Risk factors, aetiology and features of ischaemic stroke among young people in Adelaide differ significantly from published data for young patients around the world. Patients in Adelaide are more likely to be obese, to be misusing marijuana and amphetamines, to suffer a cardioembolic event and to have a stroke that concurrently affects both the anterior and posterior cerebral circulation. PMID- 22107014 TI - The contribution of Australian and New Zealand obstetrics and obstetricians and gynaecologists to modern clinical practice. PMID- 22107016 TI - Out of the shadows--changes in women's reproductive health. PMID- 22107015 TI - Outcomes from the first 2 years of the Australian National Hand Hygiene Initiative. AB - OBJECTIVE: To report outcomes from the first 2 years of the National Hand Hygiene Initiative (NHHI), a hand hygiene (HH) culture-change program implemented in all Australian hospitals to improve health care workers' HH compliance, increase use of alcohol-based hand rub and reduce the risk of health care-associated infections. DESIGN AND SETTING: The HH program was based on the World Health Organization 5 Moments for Hand Hygiene program, and included standardised educational materials and a regular audit system of HH compliance. The NHHI was implemented in January 2009. MAIN OUTCOME MEASURES: HH compliance and Staphylococcus aureus bacteraemia (SAB) incidence rates 2 years after NHHI implementation. RESULTS: In late 2010, the overall national HH compliance rate in 521 hospitals was 68.3% (168,641/246,931 moments), but HH compliance before patient contact was 10%-15% lower than after patient contact. Among sites new to the 5 Moments audit tool, HH compliance improved from 43.6% (6431/14,740) at baseline to 67.8% (106,851/157,708) (P < 0.001). HH compliance was highest among nursing staff (73.6%; 116,851/158,732) and worst among medical staff (52.3%; 17,897/34,224) after 2 years. National incidence rates of methicillin-resistant SAB were stable for the 18 months before the NHHI (July 2007-2008; P = 0.366), but declined after implementation (2009-2010; P = 0.008). Annual national rates of hospital-onset SAB per 10,000 patient-days were 1.004 and 0.995 in 2009 and 2010, respectively, of which about 75% were due to methicillin-susceptible S. aureus. CONCLUSIONS: The NHHI was associated with widespread sustained improvements in HH compliance among Australian health care workers. Although specific linking of SAB rate changes to the NHHI was not possible, further declines in national SAB rates are expected. PMID- 22107017 TI - Optimization of 5-pyridazin-3-one phenoxypropylamines as potent, selective histamine H3 receptor antagonists with potent cognition enhancing activity. AB - Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2 yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000 fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity. PMID- 22107018 TI - Factor structure and psychometric properties of the European Portuguese version of a questionnaire to assess quality of life in HIV-infected adults: the WHOQOL HIV-Bref. AB - The aim of the current study was to examine the factor structure and the psychometric properties of the European Portuguese version of the World Health Organization's Quality of Life Instrument in HIV Infection (WHOQOL-HIV-Bref). Exploratory factor analysis (EFA) and confirmatory factors analysis (CFA) were conducted on self-reported WHOQOL-HIV-Bref data from 1196 HIV-positive patients, frequenting the main departments of infectious diseases in Portugal. An EFA with a randomly chosen subsample suggested a five-domain structure for the WHOQOL-HIV Bref. CFA validated this five-domain structure in a separate subsample, but also revealed that the original six-domain model fit the data. Accordingly, it was decided to use the original factor structure. Based on the original six domain structure, the European Portuguese version of WHOQOL-HIV-Bref showed acceptable internal consistency (alpha range: 0.61-0.80 across domains). All domains (with exception of Spirituality) clearly discriminated subjects considering the CD4+ T cell count subgroups. These findings revealed additional insights about the factor structure of the WHOQOL-HIV-Bref and provided evidence in support of the original six-domain structure. This instrument showed to be a cross-culturally valid measure of quality of life, particularly useful when addressing the impact of HIV not only on physical and psychological well-being but also on several domains beyond health. PMID- 22107019 TI - De novo asymmetric synthesis of fridamycin E. AB - A de novo asymmetric synthesis of (R)- and (S)-fridamycin E has been achieved. The entirely linear route required only nine steps from commercially available starting materials (16% overall yield). Key transformations included a Claisen rearrangement, a Sharpless dihydroxylation and a cobalt-catalyzed epoxide carbonylation to give a beta-lactone intermediate. Antibacterial activities were determined for both enantiomers using two strains of E. coli, with the natural (R)-enantiomer showing significant inhibition against a Gram-(+)-like imp strain (MIC = 8 MUM). PMID- 22107024 TI - Testing gradual and speciational models of evolution in extant taxa: the example of ratites. AB - Ever since Eldredge and Gould proposed their model of punctuated equilibria, evolutionary biologists have debated how often this model is the best description of nature and how important it is compared to the more gradual models of evolution expected from natural selection and the neo-Darwinian paradigm. Recently, Cubo proposed a method to test whether morphological data in extant ratites are more compatible with a gradual or with a speciational model (close to the punctuated equilibrium model). As shown by our simulations, a new method to test the mode of evolution of characters (involving regression of standardized contrasts on their expected standard deviation) is easier to implement and more powerful than the previously proposed method, but the Mesquite module comet (aimed at investigating evolutionary models using comparative data) performs better still. Uncertainties in branch length estimates are probably the largest source of potential error. Cubo hypothesized that heterochronic mechanisms may underlie morphological changes in bone shape during the evolution of ratites. He predicted that the outcome of these changes may be consistent with a speciational model of character evolution because heterochronic changes can be instantaneous in terms of geological time. Analysis of a more extensive data set confirms his prediction despite branch length uncertainties: evolution in ratites has been mostly speciational for shape-related characters. However, it has been mostly gradual for size-related ones. PMID- 22107025 TI - Effect of PDGF-BB and beta-tricalcium phosphate (beta-TCP) on bone formation around dental implants: a pilot study in sheep. AB - OBJECTIVES: The aim of this investigation was to examine the effect of a combination of purified recombinant human platelet-derived growth factor (rhPDGF BB) mixed with a synthetic beta-tricalcium phosphate (beta-TCP) on bone healing around dental implants with critical size circumferential defects. MATERIAL AND METHODS: Three critical size circumferential defects were prepared in the ilium of six sheep. Three dental implants were placed into the centre of each defect and the 3.25 mm circumferential gap was filled with (a) blood clot alone; (b) beta-TCP; (c) rhPDGF-BB (0.3 mg/ml) with beta-TCP. All the defects in each group were covered with a Bio-Gide((r)) resorbable barrier membrane. The sheep were sacrificed at 2 and 4 weeks and histological and histomorphometric analyses were performed to determine the percentage of new mineralized bone formation and residual beta-TCP graft particles in the defects. RESULTS: Defects filled with rhPDGF-BB/beta-TCP showed the highest rate of bone formation after 2 and 4 weeks with limited degradation of the beta-TCP particles over 4 weeks. Defects filled with beta-TCP showed the least bone fill after 2 and 4 weeks, and faster degradation of the beta-TCP particles over 4 weeks compared with defects filled with rhPDGF-BB/beta-TCP. Percentage of new mineralized bone was comparable in defects to blood clot alone and beta-TCP after 4 weeks of healing, but there was a collapse in the defect area in defects with blood clot alone. In comparison, the space was maintained when beta-TCP was used in defects at 4 weeks. CONCLUSIONS: Defects which had beta-TCP alone showed an inhibition in bone healing at 2 and 4 weeks; however, the combination of rhPDGF-BB with beta-TCP enhanced bone regeneration in these peri-implant bone defects at the same time intervals. PMID- 22107026 TI - Noncovalent interactions between modified cytosine and guanine DNA base pair mimics investigated by terahertz spectroscopy and solid-state density functional theory. AB - Modified cytosine and guanine nucleobases cocrystallize in a hydrogen bonding configuration similar to that observed in native DNA. The noncovalent interactions binding these base pairs in the crystalline solid were investigated using terahertz (THz) spectroscopy and solid-state density functional theory (DFT). While stronger hydrogen bonding interactions are responsible for the general molecular orientations in the crystalline state, it is the weaker dipole dipole and dispersion forces that determine the overall packing arrangement. The inclusion of dispersion interactions in the DFT calculations was found to be necessary to accurately simulate the unit cell structure and THz vibrational spectrum. Using properly modeled intermolecular potentials, the lattice vibrational motions of the cytosine and guanine derivatives were calculated. The vibrational characters of the modes exhibited by the DNA base pair mimic in the THz region were primarily rotational motions and are indicative of the energies and the nature of vibrations that would likely be observed between similar base pairs in DNA molecules. PMID- 22107027 TI - Baicalin as a potentially promising drug for the management of sulfur mustard induced cutaneous complications: a review of molecular mechanisms. AB - Sulfur mustard (SM) is a bifunctional alkylating agent with strong blistering, irritant, mutagenic and cytotoxic properties. SM has been widely deployed as a chemical warfare agent for over a century, leading to extensive casualties. Skin is among the first and most heavily damaged organs upon SM exposure. Unfortunately, a considerable fraction of SM-intoxicated patients are still suffering from chronic cutaneous complications. While these complications adversely affect patients' quality of life, there is as yet no ideal treatment for them and therapeutic options are limited and mainly symptomatic. During recent decades, remarkable progress has been made in understanding molecular mechanisms underlying SM-induced dermatotoxicity and several intra- and extracellular targets have been identified. This review argues that baicalin, a bioactive flavonoid from the roots of Scutellaria spp., could counteract different molecular and biochemical abnormalities that mediate SM dermatotoxicity and could therefore be regarded as a promising therapeutic option for the management of SM-induced cutaneous lesions. PMID- 22107028 TI - Age-related variation in immunity in a wild mammal population. AB - Age-related changes in immunity are well documented in humans and laboratory mammals. Using blood samples collected from wild Soay sheep, we show that pronounced differences in T-cell subsets and inflammatory markers amongst age classes are also evident under natural conditions. These shifts parallel those observed in mammals experiencing protected environments. We found progressive declines in the proportion of naive CD4 T cells with age, a precipitous drop in gammadelta T cells after the second year of life and an increase in acute phase protein levels amongst geriatric sheep. Our findings suggest immune aging patterns observed in laboratory and domestic mammals may generalize to more complex, challenging environments and could have fitness costs under natural conditions. PMID- 22107029 TI - Stories of weight management: factors associated with successful and unsuccessful weight maintenance. AB - OBJECTIVE: Although behavioural interventions are successful in achieving short term weight loss, most individuals regain most or all of their weight within a few years. Our aim was to investigate factors that can help in long-term weight maintenance. DESIGN: Qualitative interviews were conducted in order to elicit experiences, successes, and difficulties associated with weight control over the lifespan. METHODS: Participants were 20 adult volunteers (aged 30-67) including lifelong weight maintainers, active weight maintainers who have maintained weight loss, and weight gainers. Thematic analysis was used to highlight differences between weight groups. RESULTS: Successful weight maintainers adopt a staged approach to weight management, including monitoring weight fluctuations and having a clear alarm signal for weight gain that triggers immediate action. They have several behavioural strategies for weight control, comprising relatively small adjustments to diet and/or exercise behaviour and also have clear strategies for coping with lifestyle interruptions. In contrast, unsuccessful weight maintainers display negative cognitive factors, including erratic or inconsistent weight vigilance, failure to respond to warning signs of weight gain, and failure to restrict weight unless in a positive mindset. Further, their coping strategies for weight gain or failed actions are poor. CONCLUSIONS: The results suggest that successful weight maintainers, irrespective of current weight band, adopt a staged behavioural approach to weight management that allows them to maintain a fairly stable weight. Encouraging the use of such strategies in those who typically regain weight after dieting may aid them in maintaining weight loss. PMID- 22107030 TI - Studies on the formation mechanism and the structure of the anisotropic collagen gel prepared by dialysis-induced anisotropic gelation. AB - We have found that dialysis of 5 mg/mL collagen solution into the phosphate solution with a pH of 7.1 and an ionic strength of 151 mM [corrected] at 25 degrees C results in a collagen gel with a birefringence and tubular pores aligned parallel to the growth direction of the gel. The time course of averaged diameter of tubular pores during the anisotropic gelation was expressed by a power law with an exponent of 1/3, suggesting that the formation of tubular pores is attributed to a spinodal decomposition-like phase separation. Small angle light scattering patterns and high resolution confocal laser scanning microscope images of the anisotropic collagen gel suggested that the collagen fibrils are aligned perpendicular to the growth direction of the gel. The positional dependence of the order parameter of the collagen fibrils showed that the anisotropic collagen gel has an orientation gradient. PMID- 22107031 TI - Newly diagnosed heart failure: change in quality of life, mood, and illness beliefs in the first 6 months after diagnosis. AB - OBJECTIVES: This study sought to examine how patients' mood and quality of life (QoL) change during the early high-risk period after a diagnosis of heart failure (HF) and to identify factors that may influence change. DESIGN: A within subjects, repeated-measures design was used. Assessments took place within 4 weeks of diagnosis and 6 months later. METHODS: One hundred and sixty six patients with HF completed assessments of their mood, QoL, and beliefs about HF and its treatment. Correlation analysis was conducted between the variables and analysis of variance and t-tests were used to assess differences in categorical variables. To examine which variables predicted mood and QoL, hierarchical multiple regressions were conducted. RESULTS: At follow-up, patients' beliefs indicated a realization of the chronicity of their HF, however their beliefs about the consequences of having HF did not change and their satisfaction with their treatment remained high. QoL and anxiety improved significantly over time but there was no significant change in depressed mood. As would be expected, improvement in symptoms was a key factor in improved mood and QoL. Other significant explanatory variables included age, comorbid chronic obstructive pulmonary disease, depressed mood, patients' beliefs about the consequences of their HF and their concerns about treatment. CONCLUSIONS: This study suggests that addressing patients' mood and beliefs about their illness and its treatment may be additional ways of improving patient QoL in the early period after the diagnosis of HF. PMID- 22107032 TI - Use of dried blood spots for the determination of genetic variation of interleukin-10, killer immunoglobulin-like receptor and HLA class I genes. AB - Optimal methods for using dried blood spots (DBSs) for population genetics-based studies have not been well established. Using DBS stored for 8 years from 21 pregnant South African women, we evaluated three methods of gDNA extraction with and without whole-genome amplification (WGA) to characterize immune-related genes: interleukin-10 (IL-10), killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I. We found that the QIAamp DNA mini kit yielded the highest gDNA quality (P< 0.05; Wilcoxon signed rank test) with sufficient yield for subsequent analyses. In contrast, we found that WGA was not reliable for sequence-specific primer polymerase chain reaction (SSP-PCR) analysis of KIR2DL1, KIR2DS1, KIR2DL5 and KIR2DL3 or high-resolution HLA genotyping using a sequence-based approach. We speculate that unequal template amplification by WGA underrepresents gene repertoires determined by sequence based approaches. PMID- 22107033 TI - Exuberant mucometra associated with atresia of the cervix in a queen. AB - This short communication reports the clinical, ultrasonographic and histopathological findings in a cat with atresia of the uterine cervix and mucometra. After 6 months of continuous oestrous behaviour, a remarkable abdominal enlargement was observed in a 14-year-old queen. A presumptive diagnosis of mucometra was concluded after the ultrasound evaluation and based on clinical signs and blood analyses. Ovariohysterectomy revealed a notable symmetrical distension (4-5 cm in diameter) of both uterine horns that were filled with fluid (690 ml); microbiological analyses confirmed the aseptic nature of the uterine fluid. Ovarian follicular cysts and cystic subsurface epithelial structures, >1.5 cm in diameter, were present in both ovaries and no corpora lutea were observed. Gross and microscopic evaluation of the uterus confirmed the development of cystic endometrial hyperplasia and the absence of an internal cervical os. The endometrial hyperplasia and mucometra could have developed as a consequence of repeated oestrogenic stimulation. PMID- 22107034 TI - The prevalence of Pediculus humanus capitis and the coexistence of intestinal parasites in young children in boarding schools in Sivas, Turkey. AB - The aim of this study was to investigate the prevalence of Pediculus humanus capitis and the coexistence of intestinal parasites in boarding primary schools in Sivas, Turkey. Seven hundred seventy-two students (350 [45.3%] girls, 422 [54.7%] boys) were evaluated with combing for the presence of head lice, collection of fecal samples, and examination of the perianal region for intestinal parasites using the cellophane tape method. The overall infestation rate for head lice was 6% (n=46). Nine children had evidence of nits only (1.2%), whereas living lice and nits or eggs were found in 37 children (4.8%). Girls were significantly more commonly infested (12.9%) than boys (0.2%). Of the parameters evaluated, socioeconomic level, number of rooms per family, and size and weight of the children were statistically significantly different between the children with and without lice. Although the infestation rate of children with intestinal parasites was higher in the head louse-infested group (23.9%) than in the group of children without lice (17.6%), the differences were not statistically significant. PMID- 22107035 TI - The entropic and enthalpic contributions to force-dependent dissociation kinetics of the pyrophosphate bond. AB - We report quantum-chemical calculations of the activation free energy of solvolysis of the pyrophosphate bond in a conformationally flexible reactant coupled to a constraining potential. The results reveal a significant contribution of conformational entropy to the force-dependent kinetics of even a fairly small reactant, suggesting that accurate predictions or molecular interpretation of localized reaction kinetics in stretched polymers may require explicit consideration of their force-dependent conformational heterogeneity. We further show that modeling the conformational space of the reactant and the transition state as collections of overlapping harmonic wells accurately predicts the force-dependent activation free energy up to 2 nN without detailed quantum chemical computations. An estimate of the activation energies is obtained from the minimal (Eyring-Bell-Evans) model using the local coordinate common to all nucleophilic displacement reactions. PMID- 22107036 TI - Life-cycle greenhouse gas emissions of shale gas, natural gas, coal, and petroleum. AB - The technologies and practices that have enabled the recent boom in shale gas production have also brought attention to the environmental impacts of its use. It has been debated whether the fugitive methane emissions during natural gas production and transmission outweigh the lower carbon dioxide emissions during combustion when compared to coal and petroleum. Using the current state of knowledge of methane emissions from shale gas, conventional natural gas, coal, and petroleum, we estimated up-to-date life-cycle greenhouse gas emissions. In addition, we developed distribution functions for key parameters in each pathway to examine uncertainty and identify data gaps such as methane emissions from shale gas well completions and conventional natural gas liquid unloadings that need to be further addressed. Our base case results show that shale gas life cycle emissions are 6% lower than conventional natural gas, 23% lower than gasoline, and 33% lower than coal. However, the range in values for shale and conventional gas overlap, so there is a statistical uncertainty whether shale gas emissions are indeed lower than conventional gas. Moreover, this life-cycle analysis, among other work in this area, provides insight on critical stages that the natural gas industry and government agencies can work together on to reduce the greenhouse gas footprint of natural gas. PMID- 22107037 TI - Task stressfulness moderates the effects of verbal person centeredness on cardiovascular reactivity: a dual-process account of the reactivity hypothesis. AB - This study sought to investigate the impact of person-centered comfort on cardiovascular reactivity and to test a recently developed dual-process theory of supportive message outcomes proposing that the impact of supportive communication is moderated by the motivation and ability to attend to message content. Participants (n = 179) completed a public speaking task that served to experimentally manipulate stress. During the preparation period, instant messages containing either low or high person-centered messages or containing no imbedded supportive message were sent. Results indicated that, in line with theoretical predictions, message content did influence mean arterial pressure and heart rate for participants exposed to moderate but not to low or high stress. Results are discussed in terms of the dual-process theory of supportive message outcomes, and the discussion offers both theoretical and practical implications of the research. PMID- 22107038 TI - Boranophosphate isoster controls P2Y-receptor subtype selectivity and metabolic stability of dinucleoside polyphosphate analogues. AB - Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of Np(n)N', we synthesized novel isosters of dinucleoside polyphosphates where N and N' are A or U and where the Palpha or Pbeta phosphate groups are replaced by boranophosphate, denoted as Np(n)(alpha-B)N' or Np(n)(beta-B)N' (n = 3, 4), respectively. The potency of Np(n)(alpha/beta-B)N' analogues was evaluated at tP2Y(1), hP2Y(2), hP2Y(4), and rP2Y(6) receptors. The most potent P2Y(1)R and P2Y(6)R agonists were the Up(4)(beta-B)A (A isomer, EC(50) of 0.5 MUM vs 0.004 MUM for 2-SMe-ADP) and Up(3)(alpha-B)U (B isomer, EC(50) of 0.3 MUM vs 0.2 MUM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the Np(n)N' polyphosphate chain and the type of the nucleobase. In addition, Np(n)(alpha/beta-B)N' proved ~22-fold more resistant to hydrolysis by e NPP1, as compared to the corresponding Np(n)N' analogues. In summary, Up(4)(beta B)A and Up(3)(alpha-B)U are potent, stable, and highly selective P2Y(1) and P2Y(6) receptor agonists, respectively. PMID- 22107039 TI - Serostatus disclosure among adults with HIV in the era of HIV therapy. AB - Serostatus disclosure is an important component of secondary HIV prevention with potential benefits for both the individual by experiencing increased social support and society by reducing HIV transmission risk behaviors. This cross sectional study assessed disclosure patterns to sex partners, family members, and friends by sociodemographic and HIV-related factors among an urban, Midwestern U.S. HIV clinic population (n = 809); a majority of whom were African American and male with a mean age of 41 years. Almost three quarters (n = 596) of the sample was currently receiving HIV therapy, with 68% (n = 404) successfully suppressing their HIV viral loads. Among sexually activity individuals, 97% reported disclosing their serostatus to sex partners. This high rate of disclosure to sex partners suggests that social desirability may play a role in this self-reported measure. Approximately half of the sample (n = 359) disclosed to at least one family member and 60% (n = 474) disclosed to at least one friend. Disclosing to family members occurred more often among participants who were unemployed and endorsed depressive disorder symptoms (p < 0.05 for all). Disclosing to friends occurred more frequently among women, Caucasians and those who completed higher levels of education (p < 0.001 for all). HIV disclosure and disease severity were unassociated. Given the chronic nature of HIV care, additional research is needed to develop interventions to facilitate timely disclosure of HIV serostatus. PMID- 22107040 TI - Homelessness as a structural barrier to effective antiretroviral therapy among HIV-seropositive illicit drug users in a Canadian setting. AB - Despite the advent of effective antiretroviral therapy (ART), HIV-seropositive injection drug users (IDU) continue to suffer from elevated levels of morbidity and mortality. Evidence is needed to identify social- and structural-level barriers to effective ART. We investigated the impact of homelessness on plasma HIV RNA response among illicit drug users initiating ART in a setting with free and universal access to HIV care. We accessed data from a long-running prospective cohort of community-recruited IDU linked to comprehensive HIV clinical monitoring and ART dispensation records. Using Cox proportional hazards with recurrent events modeling, we estimated the independent effect of homelessness on time to plasma HIV viral load suppression. Between May 1996 and September 2009, 247 antiretroviral naive individuals initiated ART and contributed 1755 person-years of follow-up. Among these individuals, the incidence density of plasma HIV RNA suppression less than 500 copies/mm(3) was 56.7 (95% confidence interval [CI]: 46.9-66.0) per 100 person-years. In unadjusted analyses, homelessness was strongly associated with lower rates suppression (hazard ratio = 0.56, 95% CI: 0.40-0.78, p = 0.001), however, after adjustment for adherence this association was no longer significant (adjusted hazard ratio = 0.79, 95% CI: 0.56-1.11, p = 0.177). Homelessness poses a significant structural barrier to effective HIV treatment. However, since this relationship appears to be mediated by lower levels of ART adherence, interventions to improve adherence among members of this vulnerable population are needed. PMID- 22107041 TI - In vitro study of antiadipogenic profile of latanoprost, travoprost, bimatoprost, and tafluprost in human orbital preadiopocytes. AB - PURPOSE: To investigate the effect of prostaglandin F2alpha (PGF2alpha), latanoprost, travoprost, bimatoprost, and tafluprost on human orbital preadipocyte differentiation and intracellular lipid storage, and to reveal the potential mechanisms by which topical prostaglandin analogs induce orbital fat volume reduction and cause deep superior sulcus syndrome. METHODS: Human orbital adipose precursors were treated in vitro for 24 h (day 1) with PGF2alpha, latanoprost, travoprost, bimatoprost, and tafluprost in their commercial formulations (1:100 dilution). Expressions of adipogenic transcription factor, peroxisome proliferator-activated receptor-gamma (PPARgamma), and CCAAT-enhancer binding protein alpha (C/EBPalpha) were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) at day 7. At 14 days, cells were stained with oil red O, intracellular lipid accumulation was evaluated by lipid absorbance, and adipocyte expression marker [Lipoprotein lipase (LPL)] was determined by real-time RT-PCR. RESULTS: Our results showed that PGF2alpha and topical prostaglandin analogs down-regulated the expression of PPARgamma and C/EBPalpha, and inhibited accumulation of intra-cytoplasmic lipid droplets and expression of LPL compared with the untreated control. Comparison between the 4 drugs showed that latanoprost had the weakest antiadipogenic effect, and bimatoprost induced the most significant reduction of adipogenesis. CONCLUSION: Latanoprost, travoprost, bimatoprost, and tafluprost inhibited human preadipocyte differentiation and intracellular lipid accumulation. Morphologic and metabolic changes in orbital adipocytes caused by PGF2alpha analogs are a possible pathophysiologic explanation of superior eyelid deepening in patients with glaucoma. PMID- 22107042 TI - Fluoride-treated bio-resorbable synthetic nonceramic [corrected] hydroxyapatite promotes proliferation and differentiation of human osteoblastic MG-63 cells. AB - When resorbable hydroxyapatite (HA) granules, which are used as a bone supplement material, were treated in neutral 4% sodium fluoride (NaF) solution, formation of a reactant resembling calcium fluoride was observed on the surface of the granules. Immediate and slow release of fluoride from fluoridated HA (HA+F) granules was observed after immersion in culture fluid, and the concentration increased over time to 1.25 +/- 0.05 ppm F at 0.5 hours, 1.57 +/- 0.12 ppm F at 24 hours, and 1.73 +/- 0.15 ppm F at 48 hours. On invasion assay, migration of human osteoblast-like MG-63 cells exposed to the released fluoride was confirmed in comparison to the cells incubated with a nonfluoridated control sample (P < .01). In addition, fluoride added to the medium increased MG-63 cell proliferation in a manner dependent on fluoride concentrations up to 2.0 ppm (P < .05). At 5.0 ppm, however, fluoride significantly inhibited cell proliferation (P < .005). Activity of the osteogenic differentiation marker, alkaline phosphatase (ALP), also increased with fluoride after exposure for 1 week, increasing significantly at 1.0 ppm (P < .05). The promotion of MG-63 cell migration and proliferation, as well as increased ALP activity, suggested that fluoride released from the surface of resorbable HA granules, which were fluoridated by prior treatment with neutral 4% NaF solution, can provide a superb method to supply fluoride and promote osteogenic cell differentiation. PMID- 22107043 TI - Effects of high pressure on azobenzene and hydrazobenzene probed by Raman spectroscopy. AB - In this study, two hydrazine derivatives, azobenzene and hydrazobenzene, were compressed in a diamond anvil cell at room temperature up to 28 GPa followed by decompression. In situ Raman spectroscopy was employed to monitor the pressure induced structural evolutions. Azobenzene was found to undergo a phase transition at ~10 GPa. Further compression to 18 GPa resulted in an irreversible breakdown of the molecular structure. Although hydrazobenzene exhibited a structural transition at a similar pressure of 10 GPa, it was found to sustain a compression pressure as high as 28 GPa without chemical reactions. The transition sequence of hydrazobenzene upon compression and decompression was thus entirely reversible in the pressure region studied, in strong contrast to that of azobenzene. The high pressure structures of these two molecules were examined based on the spectroscopic data, and their drastically different high-pressure behaviors were analyzed and interpreted with the aid of ab initio molecular orbital calculations. PMID- 22107044 TI - Reasons for and correlates of antiretroviral treatment interruptions in a cohort of patients from public and private clinics in southern India. AB - Understanding the prevalence and correlates of treatment interruptions (TIs) in resource-limited settings is important for improving adherence. HIV-infected adults on highly active antiretroviral therapy (HAART) in Bangalore, India, were enrolled into a prospective cohort study assessing HAART adherence. Participants underwent a structured interview assessing adherence, including occurrence of TI > 48 hours since HAART initiation, length of TI, and self-reported reasons for TI. Serum HIV viral load (VL) and CD4 was measured at 6-month intervals. Baseline data are presented in this article. For the 552 participants mean age was 37.8, 32% were female, 70% were married, 45% earned < $2/day. Eighty-four percent were on nevirapine-based antiretroviral therapy; median duration on HAART was 18 months (range: 1-175) and median CD4 count was 318 cells/ul (IQR: 195-460) at time of study enrollment. Twenty percent (n=110) reported at least one TI; of these, 33% (n=36) reported more than one TI. Median length of most recent TI was 10 days (range: 2-1095). TI was associated with a higher probability of having VL > 400 copies/ml (43% versus 12%; p<0.001). After controlling for time on HAART, TI was more likely among those who were unmarried (OR: 1.9; CI: 1.2-3.1), those treated in a private clinic setting (OR: 2.7; CI: 1.6-4.6 compared with public, and OR: 4.1; CI: 1.9-9.0 compared with public-private setting), and those on efavirenz-based therapy (OR: 2.0; CI: 1.1-3.6). The most common self-reported reason for TI was "side effects" (n=28; 25%), followed by cost of therapy (n=24; 22%). We discuss implications for both individual and structural level interventions to reduce TIs. PMID- 22107045 TI - Response to 'Can the quality of colonic surgery be improved by standardization of surgical technique with complete mesocolic excision?'. PMID- 22107046 TI - Functionalization of a simple dithienylethene via palladium-catalyzed regioselective direct arylation. AB - The direct arylation on the thienyl groups of a diarylethene with various aryl iodides efficiently provided arylated dithienylethenes under palladium catalysis. Unsymmetrically substituted dithienylethenes were also synthesized by this protocol. This procedure allows a rapid access to a variety of aryl-substituted dithienylethenes from a single substrate of a simple dithienylethene. PMID- 22107047 TI - Atomic force microscopy demonstrates that disulfide bridges are required for clustering of the yeast cell wall integrity sensor Wsc1. AB - In yeasts, cell surface stresses are detected by a family of plasma membrane sensors. Among these, Wsc1 contains an extracellular cysteine-rich domain (CRD), which mediates sensor clustering and is believed to anchor the sensor in the cell wall. Although the formation of Wsc1 clusters and their interaction with the intracellular pathway components are important for proper stress signaling, the molecular mechanisms underlying clustering remain poorly understood. Here, we used the combination of single-molecule atomic force microscopy (AFM) with genetic manipulations to demonstrate that Wsc1 clustering involves disulfide bridges of the CRD. Using AFM tips carrying nitrilotriacetate groups, we mapped the distribution of individual His-tagged sensors on living yeast cells. While Wsc1 formed nanoscale clusters on native cells, clustering was no longer observed after treatment with the reducing agent dithiothreitol (DTT), indicating that intra- or intermolecular disulfide bridges are required for clustering. Moreover, DTT treatment resulted in a significant increase in cell surface roughness, suggesting that disulfide bridges between other cell-wall proteins are crucial for proper cell surface topology. The remarkable sensor properties unravelled here may well apply to other sensors and receptors with cysteine-rich domains throughout biology. Our combined method of AFM with genetic manipulations offers great prospects to explore the mechanisms underlying the clustering of cell surface proteins. PMID- 22107048 TI - Importance of ENT assessment in stratifying candidates for sinus floor elevation: a prospective clinical study. AB - OBJECTIVES: The aim of this article was to describe our experience in the field of preoperative ear, nose and throat (ENT) assessment in each candidate for (maxillary) sinus floor elevation (SFE) after the introduction of a systematic protocol. The protocol evaluates the sinus compliance by means of ENT preliminary examination with nasal fiberoptic endoscopy to identify all of the situations that may predispose to post-lifting complications, i.e. potentially irreversible (PIECs) and presumably reversible (PRECs) ENT contraindications to SFE, and to evaluate its impact on SFE success. MATERIAL AND METHODS: Patient candidates for SFE were carefully assessed by means of case-history collection, complete ENT evaluation with nasal fiberoptic endoscopy and imaging to detect PIECs, PRECs, or no ENT contraindications for SFE. In case of PRECs, SFE was postponed until complete clinical recovery. Impact of preoperative ENT assessment on SFE outcome was assessed by means of post-lifting telephonic interview and ENT evaluation. RESULTS: PRECs were detected and resolved before SFE was performed in 38.2% of our 34 patients; no intra- or post-lifting complications occurred in the patients with no ENT contraindications or PRECs. CONCLUSIONS: The results of the study suggest that a careful multi-tasking preoperative management, including an ENT assessment with fiberoptic endoscopy and a radiological evaluation extended to the ostio-meatal complex, is very useful in candidates for SFE. PMID- 22107049 TI - Thermotherapy in dermatology. AB - Heat has been used as a medicinal and healing modality throughout human history. Today, thermotherapy is being studied in the treatment of many diseases. Although the exact anti-infective mechanism of thermotherapy is yet to be solved, this historically important healing method has shown significant results in the treatments of a variety of dermatological infectious diseases ranging from simple acne to bacterial, parasitic and viral infections, in modern medicine. Induction of cellular apoptosis in medium doses and necrosis in high doses has made thermotherapy an important modality in the treatment of malignant tumors. Especially in dermatology, significant results have been achieved in the treatment of Bowen's disease, melanoma and simple warts. Thermotherapy, which today has also shown advancements in cosmetology, can be delivered by liquid nitrogen in the form of hypothermia and a variety of ways ranging from hot water pads to ultrasound and even to lasers, in the form of hyperthermia. In this article, the place of this historically important treatment method in modern medicine, especially in dermatology, has been reviewed by an extensive search of the literature. PMID- 22107050 TI - The attitudes and awareness of emergency department (ED) physicians towards the management of common dentofacial emergencies. AB - OBJECTIVE: Dentofacial emergencies are a common presentation to the emergency department (ED) but there is little recent data on physicians' knowledge, confidence and attitudes in handling these cases. METHOD: A questionnaire was administered to 103 ED physicians. The sample was primarily drawn from London hospitals as well a smaller contribution from around the UK and included physicians with a range of experience and at different grades. RESULTS: The majority of the 102 participants (76.5%) did not receive any formal training in managing dentofacial emergencies. The percentage of participants who were happy to manage common dentofacial emergencies is as follows: dental trauma (20.4%); major facial trauma (39.8%); interpreting facial X-rays (68.0%); and facial suturing (85.4%). When questioned 12.1% of the participants felt that ED physicians should be responsible for managing dental emergencies compared to 22.4% who felt that ED physicians should manage maxillofacial emergencies. Only 3.9% of the participants would opt to be treated by an ED doctor in the event of them presenting to the ED with a dental injury. The remaining 72.5% would prefer to be seen by a maxillofacial surgeon, 23.5% by a dentist and none of the participants opted to be seen by the emergency nurse practitioner. CONCLUSION: ED physicians do not feel confident in managing some dentofacial emergencies. This may be attributed to a lack of training in this area as well as exposure to these types of emergencies. There is a need for greater awareness, validated guidelines and training resources for ED physicians to treat dentofacial emergencies as well more research in this field of emergency medicine. PMID- 22107051 TI - Norbornene derived doxorubicin copolymers as drug carriers with pH responsive hydrazone linker. AB - The synthesis and complete characterization of both norbornene-derived doxorubicin (mono 1) and polyethylene glycol (mono 2) monomers are clearly described, and their copolymerization by ring-opening metathesis polymerization (ROMP) to get the block copolymer (COPY-DOX) is vividly elaborated. The careful design of these conjugates exhibits properties like well-shielded drug moieties and well-defined nanostructures; additionally, they show solubility in both water and biological medium and also have the important tendency of rendering acid triggered drug release. The drug release profile suggests the importance of having the hydrazone linker that helps to release the drug exactly at the mild acidic conditions resembling the pH of the cancerous cells. It is also observed that the drug release from micelles of COPY-DOX is significantly accelerated at a mildly acidic pH of 5.5-6, compared to the physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery system with hydrazone linkages. Confocal laser scanning microscopy (CLSM) measurements indicate that these COPY DOX micelles are easily internalized by living cells. MTT assays against HeLa and 4T cancer cells showing COPY-DOX micelles have a high anticancer efficacy. All of these results demonstrate that these polymeric micelles that self-assembled from COPY-DOX block copolymers have great scope in the world of medicine, and they also symbolize promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs. PMID- 22107052 TI - Transition towards a 'non-smoker' identity following smoking cessation: an interpretative phenomenological analysis. AB - OBJECTIVE: A recent theory of motivation (PRIME theory) has proposed that the formation of a 'non-smoker' identity is necessary for long-term abstinence. This study aimed to explore how a smoker's sense of identity changes following smoking cessation. DESIGN: This was a qualitative, semi-structured interview study with a purposive sample of individuals who had quit smoking. An interpretative phenomenological approach was taken to elicit in-depth accounts of the participants' understanding of smoking, stopping, and maintaining abstinence. METHODS: Ten participants who quit smoking with the support of a National Health Service (NHS) stop-smoking service in England and were still abstinent a year later were interviewed. An interpretative phenomenological analysis of the interview transcripts was conducted. Prospective contextual detail of motivational and other variables pre-quit were also obtained from the clinic assessment form that participants completed at the first group session. RESULTS: A process of identity change was observed towards that of a 'non-smoker', assisted initially by a transient identity of 'team stop-smoker' accompanied by a sense of achievement. All participants retained a residual attraction to smoking suggesting that the process was not complete and reflecting an 'ex-smoker' identity. Participants labelled themselves as non-smokers regardless of how much transition had occurred. CONCLUSIONS: It appears useful to distinguish two levels of 'non-smoker' identity: a surface level comprising the simple label and a deep level made up of often conflicting thoughts and feelings about oneself in relation to smoking. A total coherent 'non-smoker' identity does not appear to be necessary for long-term abstinence. PMID- 22107053 TI - Alzheimer's disease: pathological mechanisms and the beneficial role of melatonin. AB - Alzheimer's disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best-known hypothesis to explain AD is that which involves the role of the accumulation of amyloid-beta peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti-inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD. PMID- 22107054 TI - Developmental instability as phenodeviance in a secondary sexual trait increases sharply with thermal stress. AB - We test for effects of thermal stress applied to pupal flies from Noumea (New Caledonia) and Taipei (Taiwan) on developmental instability (DI) in the male sex comb of Drosophila bipectinata, as well as on pre-adult survivorship and adult body size. The temperature treatments were Low (25 degrees C), High (29 degrees C) and Variable (18 h at 29 degrees C, 6 h at 34 degrees C). Although the Variable treatment reduced survivorship and body size, absolute comb size and fluctuating asymmetry generally were invariant across treatments. In contrast, comb phenodeviance increased with stress in both populations. Phenodeviance in one comb segment (C2) increased sharply with stress, whereas phenodeviance in a second major segment (C1) also increased with stress but only in Noumea flies. A major conclusion is that phenodeviations induced in a secondary sexual trait reflect the developmental environment that also damages fitness components, a foundation stone of the hypothesis that expressions of DI reveal phenotypic quality in sexual selection. PMID- 22107056 TI - Densified biomass can cost-effectively mitigate greenhouse gas emissions and address energy security in thermal applications. AB - Regional supplies of biomass are currently being evaluated as feedstocks in energy applications to meet renewable portfolio (RPS) and low carbon fuel standards. We investigate the life cycle greenhouse gas (GHG) emissions and associated abatement costs resulting from using densified switchgrass for thermal and electrical energy. In contrast to the large and positive abatement costs for using biomass in electricity generation ($149/Mg CO(2)e) due to the low cost of coal and high feedstock and power plant operation costs, abatement costs for replacing fuel oil with biomass in thermal applications are large and negative ( $52 to -$92/Mg CO(2)e), resulting in cost savings. Replacing fuel oil with biomass in thermal applications results in least cost reductions compared to replacing coal in electricity generation, an alternative that has gained attention due to RPS legislation and the centralized production model most often considered in U.S. policy. Our estimates indicate a more than doubling of liquid fuel displacement when switchgrass is substituted for fuel oil as opposed to gasoline, suggesting that, in certain U.S. locations, such as the northeast, densified biomass would help to significantly decarbonize energy supply with regionally sourced feedstock, while also reducing imported oil. On the basis of supply projections from the recently released Billion Ton Report, there will be enough sustainably harvested biomass available in the northeast by 2022 to offset the entirety of heating oil demand in the same region. This will save NE consumers between $2.3 and $3.9 billion annually. Diverting the same resource to electricity generation would cost the region $7.7 billion per year. While there is great need for finding low carbon substitutes for coal power and liquid transportation fuels in the U.S., we argue that in certain regions it makes cost- (and GHG mitigation-) effective sense to phase out liquid heating fuels with locally produced biomass first. PMID- 22107057 TI - Mobility mechanism of hydroxyl radicals in aqueous solution via hydrogen transfer. AB - The hydroxyl radical (OH*) is a highly reactive oxygen species that plays a salient role in aqueous solution. The influence of water molecules upon the mobility and reactivity of the OH* constitutes a crucial knowledge gap in our current understanding of many critical reactions that impact a broad range of scientific fields. Specifically, the relevant molecular mechanisms associated with OH* mobility and the possibility of diffusion in water via a H-transfer reaction remain open questions. Here we report insights into the local hydration and electronic structure of the OH* in aqueous solution from Car-Parrinello molecular dynamics and explore the mechanism of H-transfer between OH* and a water molecule. The relatively small free energy barrier observed (~4 kcal/mol) supports a conjecture that the H-transfer can be a very rapid process in water, in accord with very recent experimental results, and that this reaction can contribute significantly to OH* mobility in aqueous solution. Our findings reveal a novel H-transfer mechanism of hydrated OH*, resembling that of hydrated OH(-) and presenting hybrid characteristics of hydrogen-atom and electron-proton transfer processes, where local structural fluctuations play a pivotal role. PMID- 22107058 TI - Social comparison and anxious mood in pulmonary rehabilitation: the role of cognitive focus. AB - OBJECTIVES: Comorbid anxiety is highly prevalent in Chronic Obstructive Pulmonary Disease (COPD), and it is related to increased morbidity and mortality. It has consistently been found that social comparison has substantial impact on mood. However, despite the strong social component of pulmonary rehabilitation, the effect of social comparison processes on anxiety has not been explored in this context. DESIGN: Participants were 43 COPD patients enrolled in a 3-week pulmonary rehabilitation programme. We tested in a longitudinal design the relationship between social comparison and assimilation and contrast at the beginning of rehabilitation and anxious mood at the end of the programme. METHODS: Using moderator analysis, we tested whether perceived similarities and differences to upward and downward social comparison standards influence the relationship between comparison direction at the beginning of the programme and anxious mood at the end of the programme. RESULTS: The relationship between social comparison at the start of rehabilitation and anxious mood at the end of the programme was dependent on assimilation and contrast to upward and downward standards. Downward assimilation and upward contrast were related to a stronger relationship of upward and downward social comparison and anxious mood. CONCLUSION: This study demonstrates the important role of social comparison focus in moderating beneficial effects of pulmonary rehabilitation. Downward assimilation and upward contrast might be important targets in reducing anxiety in pulmonary rehabilitation. PMID- 22107059 TI - Organocatalytic asymmetric Neber reaction for the synthesis of 2H-azirine carboxylic esters. AB - The first enantioselective Neber reaction of beta-ketoxime sulfonates catalyzed by a bifunctional thiourea has been developed. The reaction proceeds stereoselectively with 5 mol % of the catalyst to give the 2H-azirine carboxylic esters in good yields with up to 93% ee. In addition, the resulting azirines can be successfully employed in the stereoselective synthesis of di- and trisubstituted aziridines. PMID- 22107060 TI - (Re)Storying illness identity: a five-element perspective. PMID- 22107061 TI - Autosomal dominant Parkinson's disease in a large German pedigree. AB - OBJECTIVE: While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. METHODS: Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD causing genes and a genome-wide linkage analysis were performed. RESULTS: Late onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. CONCLUSIONS: The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD. PMID- 22107062 TI - Generation of ultralarge surface enhanced Raman spectroscopy (SERS)-active hot spot volumes by an array of 2D nano-superlenses. AB - Surface Enhanced Raman Spectroscopy (or SERS) has received tremendous attention in the past three decades. However, the extremely-confined probe volume (1 nm) of the plasmonic hot-spots occurring on a conventional roughened SERS-active metallic surface has limited value in macro-molecular studies. In this article, we show the plausibility of generating large SERS hot-spot volumes on an atomically-flat metal surface based upon a special 3D adiabatic plasmonic nano focusing effect brought about by an array of nano-scale superlenses. We experimentally demonstrate the feasibility of this particular approach and report, for the first time, the acquisition of whole-protein SERS spectra of a layer of test protein, Cytochrome-c, using a custom-made Otto-Raman spectroscopy system equipped with nano-fluidics. Our study shows the potential of whole protein SERS spectroscopy as a useful analytical tool that complements surface probe microscopies. PMID- 22107063 TI - Central corneal thickness and biomechanical changes after clear corneal phacoemulsification. AB - PURPOSE: To evaluate central corneal thickness (CCT) and ocular biomechanical properties in patients before and after clear corneal phacoemulsification. METHODS: Corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated intraocular pressure (IOPcc), and Goldmann-correlated IOP (IOPg) were measured with the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments) in 36 consecutive patients (47 eyes) who underwent clear corneal phacoemulsification. Central corneal thickness was measured with the Pentacam (Oculus Optikgerate GmbH). All measurements were performed prior to surgery and at follow-up at 1, 7, and 30 days postoperatively. RESULTS: Central corneal thickness was higher at 1 and 7 days compared to preoperatively (P<.05) but not at 30 days. Corneal hysteresis was lower at 1 day than preoperatively (P<.05) but not at 7 and 30 days. Corneal resistance factor was lower at 1, 7, and 30 days compared to preoperatively (P<.05). Corneal-compensated IOP was slightly lower at 1, 7, and 30 days compared to preoperatively, but was not statistically significant (P>.05). Goldmann-correlated IOP was statistically significantly lower at 1 and 7 days than preoperatively (P<.05). CONCLUSIONS: Clear corneal phacoemulsification led to a change in ocular biomechanical properties. The increase in CCT after phacoemulsification was followed by a reduction in CRF and CH. Mean IOPcc was similar before and after phacoemulsification, indicating that IOPcc may be a more accurate indicator of true IOP than IOPg. PMID- 22107064 TI - Is topography-guided ablation profile centered on the corneal vertex better than wavefront-guided ablation profile centered on the entrance pupil? AB - PURPOSE: To illustrate the hypothesis that corneal vertex centration is superior to entrance pupil centration when guiding an ablation by wavefront. METHODS: In one case example of therapeutic retreatment for treatment zone decentration after primary radial keratotomy (RK) centered on the entrance pupil (line of sight), both a whole-eye wavefront-guided ablation profile (WASCA data) and a topography guided ablation profile (Atlas data) were generated using the CRS-Master (Carl Zeiss Meditec) and compared. The patient had a large vertical angle kappa. Corneal topography demonstrated that the zone of flattening was decentered superiorly with reference to the corneal vertex and the patient reported severe night vision disturbances. RESULTS: The wavefront-guided profile, centered on the line of sight, was symmetrical because the wavefront was dominated by spherical aberration induced by the primary RK treatment. On the other hand, the topography guided profile, centered on the corneal vertex, was asymmetric with an inferior region of ablation, which would logically improve the topographic decentration. The topography-guided profile was chosen for photorefractive keratectomy using the MEL 80 excimer laser (Carl Zeiss). Ten months after the procedure, the treatment zone was topographically well centered on the corneal vertex. Whole-eye higher order root-mean-square (RMS) was reduced by 43% and corneal higher order RMS was reduced by 61%. The patient reported large subjective improvement in the quality of vision and marked reduction in night vision disturbances. CONCLUSIONS: This case provides evidence that wavefront data centered on the entrance pupil center may not represent the patient's view and the treatment zone should preferably be centered on the corneal vertex rather than the entrance pupil center. PMID- 22107065 TI - Invasive colorectal cancer within 5 years of negative colonoscopy in a Japanese population. AB - AIM: Colonoscopy provides imperfect protection against colorectal cancer (CRC). In an attempt to improve cancer detection we evaluated the clinical features of invasive CRC detected within 5 years of a negative colonoscopy. METHOD: The details of colonoscopies performed in a rural hospital in Japan were prospectively recorded at the time of the examination. The patients were followed over 5 years for the subsequent occurrence of cancer. RESULTS: In a 5-year period, 10148 patients underwent colonoscopy and 202 without previous colonoscopy were diagnosed with invasive CRC. Of 3212 patients with a colonoscopy negative for cancer, nine developed invasive cancer within 5 years. The ratios for invasive CRC detected without/with previous colonoscopy were 60:1 in the rectum, 54:1 in the sigmoid colon, 15:1 in the descending colon, 28:0 in the transverse colon, 31:5 in the ascending colon and 14:1 in the caecum (P=0.041). The ratio between left- and right-sided colonic cancer was also significantly different (129:3 and 45:6, P=0.0078). Six (67%) of the invasive CRCs were in the ascending colon or caecum. Five of six patients with invasive CRC in the ascending colon and caecum had right-sided small adenomas at prior colonoscopy. CONCLUSION: The majority of early/missed CRCs were right-sided and associated with prior right sided colonic adenomas. Repeated colonoscopy of patients with right-sided adenomas at a shorter surveillance interval deserves consideration. PMID- 22107066 TI - Comparison of HIV-positive women with children and without children accessing HIV care and treatment in the IeDEA Central Africa cohort. AB - Globally, women comprise half of all people living with HIV, but in sub-Saharan Africa, women are disproportionately affected. Data were obtained from 8419 HIV infected women at enrollment into 10 HIV treatment programs in Cameroon, Burundi, and the Democratic Republic of the Congo as part of the Central Africa region of the International Epidemiological Database to Evaluate AIDS. We used chi-squared tests to determine if distributions between women with children differed from those without children, in regards to socio-demographic, behavioral and clinical characteristics. Logistic regression was used to determine if motherhood was associated with medication adherence. Of 8419 women, 81.7% had living children. The majority entered care through voluntary testing, and very few entered care through prevention of mother-to-child transmission programs. Women with children were older and more likely to be widowed, more likely to have no formal education and less likely to have attended university than those without children (p<0.05). Women without children were more likely to live in a home with electricity and potable water (p<0.05). There was no difference in adherence between these groups. However, women older than 50 years, those who reported no drug, tobacco, or alcohol use, and those with higher levels of formal education were more likely to report adherence along with those who had been on treatment for more than two years (p<0.05). As women account for a substantial proportion of HIV cases in sub Saharan Africa, a broader understanding of their characteristics will inform testing, treatment, and support services. Though we did not find differences in adherence between women with children and those without children, we were able to identify other characteristics that may affect adherence. Further inquiry into the nuances of women living with HIV in sub-Saharan Africa is necessary to further understand their needs. PMID- 22107067 TI - Derivation, characterization and differentiation of buffalo (Bubalus bubalis) amniotic fluid derived stem cells. AB - Amniotic fluid cells (AFCs) are obtained from amnion for pre-natal analysis and can be cultured in vitro. Heterogeneous amniotic fluid (AF) contains various cell types, and it is believed that some of these cells possess the stem cell properties. The aim of this study was to characterize these cells by phenotypical and genotypical means in buffalo. The differentiation potential of amniotic fluid stem (AFS) cells was carried out by converting these cells into neurons. The AFCs were cultured without feeder cells in DMEM containing 16% foetal bovine serum, 1% penicillin/streptomycin and 1%l-glutamine in 5% CO(2) at 38.5 +/- 0.5 degrees C in a CO(2) incubator. After 6 days of culture, different types of cells viz., star shaped (62.7%), spherical without nucleus (1.9%), spherical with nucleus (26.4%), pentagonal (0.4%) and free floating/rounded cells (8.3%) were observed. Most of the cells started anchorage-dependent growth after day 7 of the culture. Expression of Oct-4, Sox-2, Nanog, alkaline phosphatase, 18s rRNA, stem cell factor, cyclin A, Nestin and FGF-5 was observed from the AFS cells in different passages with PCR amplicon of 314, 277, 317, 180, 162, 216, 421, 307 and 210 bp, respectively. During the differentiation step, at day 6, neuron-like cells could be clearly identified and confirmed with Nestin-specific RT-PCR. The cells were found to have a normal karyotype at different passages. These results may contribute towards establishing non-embryonic pluripotent stem cells for various therapeutic and reproductive biotechnological applications in the species. PMID- 22107068 TI - "Her husband doesn't speak much English": conducting a family meeting with an interpreter. AB - A growing percentage of critically ill patients and their families in the United States speak limited English. We present the case of a palliative care consult conducted across language barriers to frame a discussion about the use of interpreters for family meetings, including the evidence for using a professional interpreter, the burden experienced by interpreters involved in end-of-life discussions, potential challenges encountered when conducting a family meeting with an interpreter, and recommended best practices for interpreter use in these settings. PMID- 22107069 TI - Muscle fatigue experienced during maximal eccentric exercise is predictive of the plasma creatine kinase (CK) response. AB - Unaccustomed eccentric exercise may cause skeletal muscle damage with an increase in plasma creatine kinase (CK) activity. Although the wide variability among individuals in CK response to standardized lengthening contractions has been well described, the reasons underlying this phenomenon have not yet been understood. Therefore, this study investigated a possible correlation of the changes in muscle damage indirect markers after an eccentric exercise with the decline in muscle performance during the exercise. Twenty-seven healthy untrained male subjects performed three sets of 30 maximal isokinetic eccentric contractions of the knee extensors. The muscular work was recorded using an isokinetic dynamometer to assess muscle fatigue by means of various fatigue indices. Plasma CK activity, muscle soreness, and stiffness were measured before (pre) and one day after (post) exercise. The eccentric exercise bout induced significant changes of the three muscle damage indirect markers. Large inter-subject variability was observed for all criteria measured. More interestingly, the log (CK(post) /CK(pre)) and muscle stiffness appeared to be closely correlated with the relative work decrease (r = 0.84, r(2) = 0.70 and r = 0.75, r(2) = 0.56, respectively). This is the first study to propose that the muscle fatigue profile during maximal eccentric protocol could predict the magnitude of the symptoms associated with muscle damage in humans. PMID- 22107070 TI - Nasal papilloma, a rare late complication of tongue flap repair of palatal fistula. AB - The use of a tongue flap for treatment of palatal fistulae is a well-established procedure, but it is not without complication. We report on a patient who underwent palatal fistula closure with tongue flap as a child, who then developed a nasal papilloma from the mucosa of the tongue flap 40 years later. This case is the first of its kind to be reported and emphasizes the need for long-term follow up because the tongue mucosa is vulnerable to many diseases. PMID- 22107071 TI - Advanced nanoarchitectures for solar photocatalytic applications. PMID- 22107072 TI - Dental injuries in water polo, a survey of players in Switzerland. AB - Water polo is a sporting activity which has a medium risk of causing dental trauma. Owing to the high speed, close body contact, and the combination of throwing and swimming that is inherent to the sport, the general injury potential is high. Using a standardized questionnaire for a total of 415 water polo players from Switzerland, this study examines the frequency of dental and facial injuries in water polo, athletes' habits regarding the wearing of mouthguards, and the general level of knowledge about emergency procedures following dental trauma. The participating players came from 6 divisions: Swiss national leagues A and B, first and second leagues, as well as the women's, and junior's league. The data were evaluated according to division and gender. Of the 415 interviewees, 185 (44.6%) had witnessed a dental injury in water polo. Eighty-seven (21.0%) players reported having suffered a tooth injury when playing water polo. Tooth fracture was the most stated dental injury [86 (16.4%)]. A similar number of tooth injuries were experienced by both male [355 (21.1%)] and female [60 (20.0%)] players. The interviewees over the age of 50 showed a higher incidence of tooth injuries than younger players (>50 years = 41.7%). Slightly more than half of the interviewed players [228 (54.9%)] were aware of the possibility of replanting avulsed teeth. As few as 43 (10.4%) players were familiar with tooth rescue boxes. Only 32 (7.7%) water polo players wore a mouthguard; the most common reason for not wearing a mouthguard was that it was seen to be unnecessary [169 (40.7%)]. This survey highlights the potential for improvement in the level of knowledge about dental injury prevention in water polo. In addition to information and guidelines from the relevant sports' associations, and coaches, dentists could also play a role in the provision of this education. PMID- 22107073 TI - The role of self-efficacy, recovery self-efficacy, and preparatory planning in predicting short-term smoking relapse. AB - OBJECTIVES: This study aims to identify the role of self-efficacy, recovery self efficacy, and preparatory planning with regard to short-term smoking relapse. We also assessed whether the importance of these variables differed for smokers quitting individually and without help (self-quitters) and smokers quitting with the help of a smoking cessation course (group quitters). DESIGN: A longitudinal quasi-experimental study with follow-ups at 1 and 3 months after the quit attempt was conducted in order to assess the role of baseline self-efficacy, recovery self-efficacy, and preparatory planning on short-term relapse. METHODS: The recruitment included adult daily smokers (N= 121), quitting in a smoking cessation course (N= 57) and self-quitters (N= 64). Respondents received internet based questionnaires 2 weeks before quitting (baseline) and 1 and 3 months after the quit attempt. Predictors of relapse were analysed using logistic regression analyses. RESULTS: Relapse at 1 and 3 months after the quit attempt was predicted by low levels of baseline self-efficacy. Simple slope analyses revealed that less preparatory planning significantly predicted relapse at 1 month after the quit attempt among group quitters, but not among self-quitters. Recovery self-efficacy was only predictive of relapse after 1 month when self-efficacy was excluded from the analyses. Moreover, among group quitters, the results indicated a borderline significant curved relation between recovery self-efficacy and relapse after 1 month. CONCLUSIONS: Our results suggest that more research is needed on the role of preparatory planning and recovery self-efficacy. Moreover, we recommend incorporating self-efficacy increasing techniques in relapse-prevention interventions. PMID- 22107074 TI - Early observations in the use of oral rotavirus vaccination in infants with functional short gut syndrome. AB - AIM: Universal vaccination with an oral live-attenuated rotavirus vaccine at 2, 4 and 6 months of age was introduced in Australia in July 2007. There are no data on the short-term effects of vaccination for those infants most at risk of severe complications from rotavirus infection. The aim of this study was to describe the effects of rotavirus vaccination on weight gain and gastrointestinal losses in infants with functional short gut syndrome secondary to an ileostomy. METHODS: A retrospective review of all infants with an ileostomy who received RotaTeq while hospitalised at the Royal Children's Hospital, Melbourne from July 2007 to July 2009 was performed. Daily data were collected from 1 week before to 2 weeks after vaccination. The data included type and volume of feeds, ileostomy losses, need for fluid replacement of ileostomy losses, weight, temperature, urine sodium, stool culture, suspected and confirmed sepsis. RESULTS: Nine infants (age at first RotaTeq 61-99 days) were identified. The median (range) gestational age was 26 (24, 38) completed weeks and birthweight was 737 (620, 2714) grams. Compared to the day of vaccination, the median (range) ileostomy losses 1 week before, 1 and 2 weeks after vaccination were -1.1 (-13.6, 4.9) mL/kg/day, 2 (-11.1, 25.0) mL/kg/day and 2.4 (-15.7, 27.2) mL/kg/day, respectively. One infant developed severe stomal losses after vaccination. Overall, rotavirus vaccination did not alter weight gain, temperature or urinary sodium. CONCLUSION: In this small series, oral live-attenuated rotavirus vaccination of infants with high-output ileostomy was tolerated in most cases. PMID- 22107075 TI - Involvement of carbonic anhydrases in the ocular hypotensive effect of melatonin analogue 5-MCA-NAT. AB - We have previously demonstrated that melatonin and its analogue, 5 methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), reduce intraocular pressure (IOP) in New Zealand rabbits. More recently, we have shown that 5-MCA-NAT can also regulate ciliary adrenoceptor gene expression. Like adrenoceptors, carbonic anhydrase (CA) enzymes are involved in aqueous humour secretion by the ocular ciliary epithelium. Moreover, CA enzymes have been reported to be regulated by melatonin. Hence, the aim of this study was to investigate whether the hypotensive effect of 5-MCA-NAT is also because of a regulation of CA genes and enzymes. Time course of 5-MCA-NAT effect on rabbit IOP was followed for 7 hr every day for up to 144 hr (6 days). 5-MCA-NAT reduced IOP, maximally by 51.30 +/ 2.41% (at 3 hr), and the hypotensive effect was maintained for up to 96 hr with a single application. IOP studies with 5-MCA-NAT plus Trusopt((r)) and immunohistochemical analysis confirmed that CA are molecular targets of 5-MCA NAT. In addition, real-time quantitative PCR (qPCR) and immunocytochemical assays were performed to determine changes in CA2 (CAII) and CA12 (CAXII) expression in cultured rabbit nonpigmented ciliary epithelial cells (NPE) treated with 5-MCA NAT. NPE cells showed a prominent decrease in both CA, at the mRNA and protein levels. These data confirm that the long-term hypotensive effect of 5-MCA-NAT is also due, to a down-regulation of CA2 (CAII) and CA12 (CAXII) expression. PMID- 22107076 TI - Adherence to physical and mental activity interventions: coping plans as a mediator and prior adherence as a moderator. AB - OBJECTIVE: Adherence to behavioural intervention programmes is a necessary condition for beneficial outcomes to be achieved. This study tested whether social cognitive variables and coping plans predict adherence. DESIGN AND METHODS: Adherence was examined in a randomized controlled trial with healthy older women (age range: 70-93 years), who were randomized to a physical (N= 86) or a mental (N= 85) activity intervention. Intentions, self-efficacies, coping plans, and objectively measured adherence levels were assessed. A moderated mediation analysis evaluated the power of coping plans to translate intention into behaviour, depending on levels of prior adherence. RESULTS: Adherence to the physical activity programme (65%) was significantly lower than adherence to the mental activity programme (84%, p < .001). Intentions (beta= .22) weakly predicted adherence in the initiation period of the physical activity programme (6 weeks); pre-action self-efficacy predicted adherence in the initiation period of the mental activity programme (beta= .35). In both groups, coping plans predicted mid-period adherence (10 weeks) and long-term adherence (20 weeks), moderated by prior adherence (all ps < .01). Coping plans mediated the relationship between intentions and behaviour only in the exercise condition. CONCLUSIONS: Instructing older individuals to generate coping plans facilitated their adherence to physical and mental activity programmes. This effect was larger for participants with lower levels of prior adherence--and may have prevented them from dropping out of the programme. PMID- 22107078 TI - Methodology to model the energy and greenhouse gas emissions of electronic software distributions. AB - A new electronic software distribution (ESD) life cycle analysis (LCA) methodology and model structure were constructed to calculate energy consumption and greenhouse gas (GHG) emissions. In order to counteract the use of high level, top-down modeling efforts, and to increase result accuracy, a focus upon device details and data routes was taken. In order to compare ESD to a relevant physical distribution alternative, physical model boundaries and variables were described. The methodology was compiled from the analysis and operational data of a major online store which provides ESD and physical distribution options. The ESD method included the calculation of power consumption of data center server and networking devices. An in-depth method to calculate server efficiency and utilization was also included to account for virtualization and server efficiency features. Internet transfer power consumption was analyzed taking into account the number of data hops and networking devices used. The power consumed by online browsing and downloading was also factored into the model. The embedded CO(2)e of server and networking devices was proportioned to each ESD process. Three U.K. based ESD scenarios were analyzed using the model which revealed potential CO(2)e savings of 83% when ESD was used over physical distribution. Results also highlighted the importance of server efficiency and utilization methods. PMID- 22107080 TI - Direct imaging of nanoscale acidic clusters in a polymer electrolyte membrane. AB - One of the factors hindering the development of technologies that rely on the use of proton-conducting polyelectrolyte membranes is the lack of control over the membrane morphology on the nanoscale. Of particular importance is the rearrangement and clustering of acidic groups, which may seriously degrade the electrical properties. Although electron microscopy is capable of imaging the morphology of the clusters, images of unmodified membranes with sufficient quality to discriminate between different proposed cluster morphology models have not been presented. Here we show the first determination of the cluster size distribution in a model polymer electrolyte membrane from electron micrographs of individual acidic clusters. Imaging of the sulfur-rich clusters by dark-field microscopy was facilitated by the spontaneous formation of thin, cluster containing layers on the top and bottom surfaces of free-standing films with a thickness of ~35 nm. PMID- 22107079 TI - The transcription factor DLX3 regulates the osteogenic differentiation of human dental follicle precursor cells. AB - The transcription factor DLX3 plays a decisive role in bone development of vertebrates. In neural-crest derived stem cells from the dental follicle (DFCs), DLX3 is differentially expressed during osteogenic differentiation, while other osteogenic transcription factors such as DLX5 or RUNX2 are not highly induced. DLX3 has therefore a decisive role in the differentiation of DFCs, but its actual biological effects and regulation are unknown. This study investigated the DLX3 regulated processes in DFCs. After DLX3 overexpression, DFCs acquired a spindle like cell shape with reorganized actin filaments. Here, marker genes for cell morphology, proliferation, apoptosis, and osteogenic differentiation were significantly regulated as shown in a microarray analysis. Further experiments showed that DFCs viability is directly influenced by the expression of DLX3, for example, the amount of apoptotic cells was increased after DLX3 silencing. This transcription factor stimulates the osteogenic differentiation of DFCs and regulates the BMP/SMAD1-pathway. Interestingly, BMP2 did highly induce DLX3 and reverse the inhibitory effect of DLX3 silencing in osteogenic differentiation. However, after DLX3 overexpression in DFCs, a BMP2 supplementation did not improve the expression of DLX3 and the osteogenic differentiation. In conclusion, DLX3 influences cell viability and regulates osteogenic differentiation of DFCs via a BMP2-dependent pathway and a feedback control. PMID- 22107081 TI - Origins of aryl substituent effects on the stereoselectivities of additions of silyl enol ethers to a chiral oxazolinium ion. AB - Density functional theory calculations are reported that reveal the role of aromatic interactions in the additions of aryl-substituted silyl enol ethers to a chiral oxazolinium ion. Aryl-substituted silyl enol ethers give the opposite diastereomer of the adduct than do aliphatic silyl enol ethers, due to a combination of attractive cation-pi and CH-pi interactions, reduced steric repulsion, and lower torsional strain in the more "crowded" transition state. PMID- 22107082 TI - Pressure-based approach for the analysis of protein adsorption in capillary electrophoresis. AB - Protein adsorption to inner capillary walls creates a major obstacle in all applications of capillary electrophoresis involving protein samples. The problem is especially severe in kinetic capillary electrophoresis (KCE) techniques, which are used to study protein-ligand interactions at physiological conditions and, thus, cannot utilize extreme pH. A variety of coatings exist to reduce protein adsorption in CE, each expressing a unique surface chemistry that interacts with individual proteins differently. Here we introduce a simple pressure-based method for the qualitative assessment of protein adsorption that can facilitate the direct antiadhesive ranking of several coatings toward a protein of interest. In this approach, a short plug of the protein is injected into a capillary and propagated through with a pressure low enough to ensure adequate Taylor dispersion. The experiment is performed with a nonmodified commercial instrument in a pseudo-two-detector approach. The two detectors are mimicked by using two different distances from the capillary inlet to a single detector. If the peak area and shape do not change with changing distance, the protein does not adsorb appreciably, while a decreasing peak area with increasing distance infers inner surface adsorption. The magnitude change of the peak area between the two distances along with the overall peak shape is used to gauge the extent of protein adsorption. By using this method, we ranked antiadhesive properties of different wall chemistries for a series of proteins. The described method will be useful for optimizing protein analysis by CE and, in particular, for KCE experiments that investigate how proteins interact with their respective ligands. PMID- 22107083 TI - Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study. AB - BACKGROUND: No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). AIM: To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 MUg; Rebif((r)) ) on clinical and radiological findings in two matched cohorts of patients with MS. PATIENTS AND METHODS: We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI). RESULTS: In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). CONCLUSIONS: After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes. PMID- 22107084 TI - Health literacy, self-efficacy, and patients' assessment of medical disclosure and consent documentation. AB - Informed consent documents are designed to convey the risks of medical procedures to patients, yet they are often difficult to understand; this is especially true for individuals with limited health literacy. An important opportunity for advancing knowledge about health literacy and informed consent involves examining the theoretical pathways that help to explain how health literacy relates to information processing when patients read consent forms. In this study, we proposed and tested a model that positioned self-efficacy as a mediator of the association between health literacy and patients' comprehension and assessment of informed consent documentation. Findings from structured interviews with patients (n = 254) indicated that lower health literacy predicted lower self-efficacy, which predicted feeling less well informed and less prepared, being more confused about the procedure and its hazards, and wanting more information about risks. Incorporating awareness of self-efficacy into disclosure documents and consent conversations may be a useful means of prompting patients to ask questions that can help them make informed decisions about care. PMID- 22107085 TI - A 10-year experience of total pelvic exenteration for primary advanced and locally recurrent rectal cancer based on a prospective database. AB - AIM: The study was conducted in a dedicated centre treating the majority of Danish patients with intended curative total pelvic exenteration for primary advanced (PARC) or locally recurrent (LRRC) rectal cancer. We compared PARC and LRRC and analysed postoperative morbidity and mortality, and long-term outcome. METHOD: There were 90 consecutive patients (PARC/LRRC 50/40) treated between January 2001 and October 2010, recorded on a prospectively maintained database. RESULTS: The median age was 63 (32-75) years with a gender ratio of 7 women to 83 men. All patients were American Society of Anesthesiologists level I or II. Sacral resection was performed in five patients with PARC and 15 with LRRC (P=0.002). R0 resection was achieved in 33 (66%) patients with PARC and in 15 (38%) with LRRC, R1 resection in 17 (34%) with PARC and 20 (50%) with LRRC and R2 resection in five (13%) with LRRC. R0 resection was more frequent in PARC (P=0.007). Forty-four (49%) patients had no postoperative complications. Fifty five major complications were registered. Two (2.2%) patients died within 30 days, and the total in-hospital mortality was 5.6%. The median follow-up was 12 (0.4-91) months. The 5-year survival was 46% for PARC and 17% for LRRC (P=0.16). CONCLUSION: Pelvic exenteration is associated with considerable morbidity but low mortality in an experienced centre. Pelvic exenteration can improve long-term survival, especially for patients with PARC. However, pelvic exenteration is also justified for patients with LRRC. PMID- 22107086 TI - Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise. AB - Acute kicking exercise induces collagen synthesis in both tendon and muscle in humans, but it is not known if this relates to increased collagen transcription and if other matrix genes are regulated. Young men performed 1 h of one-leg kicking at 67% of max workload. Biopsies were taken from the patellar tendon and vastus lateralis muscle of each leg at 2 (n = 10), 6 (n = 11), or 26 h (n = 10) after exercise. Levels of messenger ribonucleic acid mRNA for collagens, noncollagenous matrix proteins, and growth factors were measured with real-time reverse transcription polymerase chain reaction. In tendon, gene expression was unchanged except for a decrease in insulin-like growth factor-IEa (IGF-IEa; P < 0.05). In muscle, collagen expression was not significantly altered, while levels of connective tissue growth factor (CTGF), IGF-IEa, transforming growth factor beta1, -2 (TGF-beta), and the TGF-beta receptor II mRNA were increased (P < 0.05). Matrix components tenascin-C, fibronectin, and decorin were also induced in loaded muscle (P < 0.05), while fibromodulin was unaffected. In conclusion, the relatively robust changes in matrix components and related growth factors in muscle indicate a stimulation of extracellular matrix even with moderate exercise. However, in tendon tissue, this exercise model does not appear to induce any anabolic response on the transcriptional level. PMID- 22107087 TI - Influence of recovery methods and extenders on bull epididymal spermatozoa quality. AB - The aim of this study was to compare the effects of two extraction methods in combination with two different extenders in bull epididymal sperm collection. Testes from 23 sexually mature Limousine bulls were collected at the abattoir. Epididymal sperm recovery was performed using both the float-up (FL) and the retrograde flushing (RF) technique. Within extraction methods, half testes were processed with a Tris egg yolk extender and half with a Tris egg yolk-free extender. Sperm concentration, motility, viability and morphology were evaluated. Sperm concentration was not significantly different between methods. Flushing technique was significantly better than the FL method in terms of sperm quality, considering total motility (80.3 +/- 2.3% vs 71.6 +/- 2.0%, p < 0.001, respectively) and viability (84.5 +/- 1.5% vs 77.2 +/- 1.3%, p < 0.001, respectively). Egg yolk influenced positively motility and morphology in the FL method, whereas decreased viability in flushed samples. Results suggest the use of the RF technique to collect cattle epididymal sperm. PMID- 22107088 TI - Newcastle disease in the European Union 2000 to 2009. AB - Newcastle disease (ND) is a devastating disease of poultry that has to some extent been neglected by those working in the field in the past 10 to 15 years while attention has been focused on the emergence and spread of highly pathogenic avian influenza caused by a H5N1 subtype virus. During 2000 to 2009 in the European Union (EU) member states, ND viruses virulent for chickens have been detected in wild birds, domesticated pigeons and poultry. Based on these isolations it appears that the epizootic in racing pigeons caused by the variant viruses termed pigeon avian paramyxovirus type 1, which form the genetic group 4b(VIb) first seen in Europe in 1981, continued during 2000 to 2009, and the virus is probably enzootic in racing pigeons in some EU countries. This virus appears to have spread regularly to wild birds, especially those of the Columbidae family, and has been the cause of significant outbreaks in poultry. Other avian paramyxovirus type 1 viruses responsible for ND outbreaks in the EU during 2000 to 2009 have been those from genetic groups 5b(VIIb) and 5d(VIId). There is evidence that the former may well represent spread from a wild bird source and these viruses have also been isolated from wild birds, while the latter represents continuing spread from the East. Future legislation or recommendations aimed at the control and eradication of ND will need to encompass these three sources of virulent ND viruses. PMID- 22107089 TI - Multilocus variable-number tandem-repeat analysis for subtyping Salmonella enterica serovar Gallinarum. AB - Salmonella enterica serovar Gallinarum causes a severe systemic disease, fowl typhoid, primarily in chickens and turkeys, and it remains a disease of worldwide significance. Multilocus variable-number tandem-repeat analysis (MLVA) has proved to be very useful for subtyping other Salmonella serovars. We describe the development of a simple MLVA assay for S. enterica serovar Gallinarum that is comparable with pulsed-field gel electrophoresis (PFGE) in resolution. The genome sequence of S. enterica serovar Gallinarum strain 287/91 was analysed for potential variable-number tandem repeats (VNTRs) and then polymerase chain reaction assays were developed to assess the variability of the loci. Four VNTR markers were selected and used in a multiplex fragment analysis assay. The stability of the VNTR markers was assessed by conducting in vitro passage experiments with two strains (95 clones per strain) over a 30-day period. A MLVA of 68 strains of S. enterica serovar Gallinarum based on the four VNTR loci distinguished 26 allelic profiles. The MLVA assay showed a Simpson's diversity index of 0.918, whereas PFGE analysis produced 23 patterns and had a diversity index of 0.874. Most importantly, the MLVA further discriminated strains having the same PFGE pattern. The MLVA assay is a highly discriminatory genotyping method for S. enterica serovar Gallinarum. Therefore, MLVA can be a useful addition to routine PFGE analysis for molecular epidemiological investigation of fowl typhoid. PMID- 22107090 TI - Characterization of avian paramyxovirus type 1 from migratory wild birds in chickens. AB - Newcastle disease virus (NDV) is one of the most important infectious agents in the poultry industry, and vaccines against it have been widely used for prevention and control. Live vaccines, which can replicate in the respiratory and digestive systems, have been especially needed in areas with outbreaks of viscerotropic velogenic Newcastle disease. Towards the goal of searching for a new live vaccine candidate, avian paramyxovirus type 1 (APMV-1) was isolated from the faeces of wild birds. Three APMV-1 strains thus isolated were characterized in terms of phylogeny, pathogenicity, immunogenicity and tissue tropism, and on the basis of these analyses were classified as lentogenic genotype I NDV. CBU2179, one of the three APMV-1 strains, was selected and was evaluated in terms of its efficacy and safety in specific pathogen-free chickens and commercial broilers. The manufactured trial vaccine from this strain, also called CBU2179, induced similar immune responses to those of VG/GA and B1 commercial vaccines, and provided 100% protection against challenge from viscerotropic velogenic NDV, KJW/49 strain (the official challenge strain in Korea). Also, the CBU2179 virus was re-isolated and persisted as long as or longer than other vaccine strains in both the respiratory and alimentary tracts. Therefore, the CBU2179 strain may represent a good candidate for a live Newcastle disease vaccine to protect chickens against viscerotropic velogenic NDV. PMID- 22107091 TI - Replication ability of three highly protective Marek's disease vaccines: implications in lymphoid organ atrophy and protection. AB - The present work is a chronological study of the pathogenesis of three attenuated serotype 1 Marek's disease (MD) virus strains (RM1, CVI988 and 648A80) that provide high protection against MD but have been attenuated by different procedures and induce different degrees of lymphoid organ atrophy. All studied strains replicated in the lymphoid organs (bursa,x thymus and spleen) and a peak of replication was detected at 6 days post inoculation (d.p.i.). Differences, however, were observed among vaccine strains. RM1 strain replicates more in all lymphoid organs compared with CVI988 and 648A80 strains. In addition, replication of RM1 in the thymus did not decrease after 6 d.p.i. but continued at high levels at 14 d.p.i. and until the thymus was completely destroyed. Lung infection occurred very early after infection with all of the three vaccines and the level of replication was similar to that found in the lymphoid organs. Infected cells were very large and appeared scattered in the lung parenchyma and in the parabronchial lining. The study of the target cells for the early infection in cell suspensions of blood and spleen showed that both non-adherent cell populations (enriched in lymphoid cells) and adherent cells (enriched in monocytes/macrophages) supported MD virus infection. Infection in adherent cells was especially high at very early stages of the infection (3 to 6 d.p.i.). Atrophy of lymphoid organs is a major drawback in the production of highly protective vaccines against MD. A better understanding of the mechanisms associated with lymphoid organ atrophy will aid in overcoming this problem. PMID- 22107092 TI - Mycoplasma gallisepticum in pheasants and the efficacy of tylvalosin to treat the disease. AB - Infectious sinusitis, a common condition seen in adult pheasants, is primarily caused by Mycoplasma gallisepticum. The aims of the present study were to investigate the pathogenicity of M. gallisepticum in 14-day-old pheasants and evaluate the macrolide antibiotic tylvalosin (TVN) as a treatment for infectious sinusitis. The minimum inhibitory concentration of TVN for five isolates of M. gallisepticum taken from pheasants confirmed their susceptibility to TVN (range: 0.002 to 0.008 ug/ml). One of the isolates (G87/02) was inoculated intranasally into 72 pheasants (two groups of 36) at 14 days of age. Eight days later, when 18/72 (25%) of the pheasants showed clinical signs, one group was treated with 25 mg TVN/kg bodyweight daily in drinking water for three consecutive days. An uninfected, unmedicated control group (n=12) was also included. In contrast to the uninfected control group, a range of clinical signs typical of infectious sinusitis with varying severity was observed in challenged birds and M. gallisepticum was re-isolated from the infraorbital sinus and the eye/conjunctiva at necropsy, 22 days post challenge. In comparison with untreated birds, medication with TVN significantly reduced clinical signs and the re isolation/detection of M. gallisepticum (P<=0.0021). The daily liveweight gain of treated birds was significantly increased in comparison with untreated birds (P=0.0002), and similar to daily liveweight gains observed in the uninfected control group. In conclusion, TVN at 25 mg/kg bodyweight daily for three consecutive days in drinking water was efficacious in the treatment of M. gallisepticum infection induced by challenging 14-day-old pheasants. PMID- 22107093 TI - Clonality and virulence traits of Escherichia coli associated with haemorrhagic septicaemia in turkeys. AB - Fifty-five clinical isolates of avian pathogenic Escherichia coli (APEC) from seven outbreaks of acute haemorrhagic septicaemia in turkeys were characterized by serotyping, plasmid profiling including restriction analysis with HindIII, ribotyping with EcoRI and HindIII, multilocus sequence typing (MLST) and virulence profiling. A clonal relationship was demonstrated for each outbreak according to serotype, plasmid profiling, ribotyping, and MLST. In addition, isolates demonstrated highly similar virulence profiles, as all isolates were positive for F11 pili and possessed genes encoding aerobactin (iucD), increased serum survival (iss), temperature-sensitive haemagglutinin (tsh) and colicin V plasmid operon genes (cva/cvi). However, only 20% of the isolates produced colicin V and 42% exhibited serum resistance. All strains with O group O111 and a single O18ac strain (demonstrating non-clonal DNA profiles) were positive for enteroaggregative heat-stabile toxin (EAST1), while isolates of a single outbreak all possessed the enteroaggregative toxin gene (astA). All isolates were negative for genes encoding verocytotoxins (vtx/stx), iron-repressible protein (irp2), P fimbria (papC), invasion plasmid antigen (ipaH), attaching and effacing gene (eae), enterohaemolysin (ehxA), and enterotoxins LT, STIa (ST(p)) and STIb (ST(h)). In conclusion, highly similar virulence profiles were demonstrated for isolates of E. coli associated with a single well-defined lesion type of colibacillosis in turkeys; acute haemorrhagic septicaemia. The isolates obtained, however, demonstrated a different phylogenetic background, underlining the importance of using well-defined strain collections for characterization of APEC pathotypes. PMID- 22107094 TI - Multiyear surveillance of influenza A virus in wild birds in Portugal. AB - This report presents the results of a multiyear (2005 to 2009) study of avian influenza virus (AIV) occurrence in wild birds in Portugal. A total of 5691 samples from wild birds belonging to 13 different orders were examined. Ninety three samples tested positive for AIV by matrix reverse transcriptase-polymerase chain reaction, giving a total prevalence of 1.63%. Twenty-one viruses were successfully cultured in embryonated chicken eggs, which represent a rate of viral infectivity of 22.6% in the samples. Nine subtypes of haemagglutinin (H1, H3 to H7, H9 to H11) and eight subtypes of neuraminidase (N1 to N4, N6 to N9) were identified in 20 different combinations. The most prevalent subtypes of haemagglutinin detected were H5, H1 and H4, while for neuraminidase subtypes N2 and N6 were the most common. The subtype combinations H4N6 and H1N1 were predominant (15.1%). All H5 and H7 viruses detected in the present study were low pathogenic for poultry as determined by the sequence of amino acids at the cleavage site of haemagglutinin. The full-length nucleotide sequences of five H5, one H7 and five N3 genes were analysed phylogenetically. The Bayesian analysis revealed that all but one of the strains analysed were closely related to isolates detected in the same period in North and Central European countries. Three H5N3 isolates, all from 2007, formed a separate cluster in both H5 and N3 phylogenetic trees. This study provides evidence that various subtypes of AIV, including subtypes H5 and H7, circulate in Portugal, which may pose a risk to industrial poultry. PMID- 22107095 TI - Enterococcus cecorum infections in broiler breeders and their offspring: molecular epidemiology. AB - Increased mortality and problems with lameness were reported in Dutch broiler flocks from the year 2008 onwards. Therefore, a field inventory, including 10 affected broiler flocks, nine corresponding broiler breeder flocks and five hatcheries, was carried out. The onset of clinical signs (lameness and increased mortality) started at about 2 weeks of age. The flock mortality varied from 3.1 to 8.1% at slaughter. Post-mortem lesions of broiler flocks were characterized by the occurrence of pericarditis/hydropericardium, arthritis and femoral head necrosis. Enterococcus cecorum was isolated from approximately 30% of the lesions. In the broiler breeders, E. cecorum was not isolated from any of the lesions. However, it was isolated from 31 out of 65 (47%) cloacal swabs, from two out of 65 (3%) oviduct samples, from one out 65 (1.5%) bone marrow samples and from two out of 25 (8%) blood samples. E. cecorum was not isolated from the air samples or dead-in-shell originating from the hatcheries involved. In total, 78 isolates were subjected to further typing by means of tRNA intergenic spacer PCR and confirmed as E. cecorum. The genetic relatedness of these cocci was subsequently studied using pulsed-field gel electrophoresis. The banding patterns of approximately 68% of E. cecorum isolates originating from parent stock flocks were clonal to one or more isolates of the same or other parent flocks. In contrast, isolates originating from their diseased offspring showed much greater genetic variation. Therefore, the vertical transmission of E. cecorum could not be demonstrated. PMID- 22107096 TI - Genetic characterization of low pathogenic H5N1 and co-circulating avian influenza viruses in wild mallards (Anas platyrhynchos) in Belgium, 2008. AB - As part of a long-term wild bird monitoring programme, five different low pathogenic (LP) avian influenza viruses (AIVs) were isolated from wild mallards (subtypes H1N1, H4N6, H5N1, H5N3, and H10N7). A LP H5N1 and two co-circulating (same location, same time period) viruses were selected for full genome sequencing. An H1N1 (A/Anas platyrhynchos/Belgium/09-762/2008) and an H5N1 virus (A/Anas platyrhynchos/Belgium/09-762-P1/2008) were isolated on the same day in November 2008, then an H5N3 virus (A/Anas platyrhynchos/09-884/2008) 5 days later in December 2008. All genes of these co-circulating viruses shared common ancestors with recent (2001 to 2007) European wild waterfowl influenza viruses. The H5N1 virus shares genome segments with both the H1N1 (PB1, NA, M) and the H5N3 (PB2, HA) viruses, and all three viruses share the same NS sequence. A double infection with two different PA segments from H5N1 and from H5N3 could be observed for the H1N1 sample. The observed gene constellations resulted from multiple reassortment events between viruses circulating in wild birds in Eurasia. Several internal gene segments from these 2008 viruses and the N3 sequence from the H5N3 show homology with sequences from 2003 H7 outbreaks in Italy (LP) and the Netherlands (highly pathogenic). These data contribute to the growing sequence evidence of the dynamic nature of the avian influenza natural reservoir in Eurasia, and underline the importance of monitoring AIV in wild birds. Genetic information of potential hazard to commercial poultry continues to circulate in this reservoir, including H5 and H7 subtype viruses and genes related to previous AIV outbreaks. PMID- 22107097 TI - Time-course investigation of infection with a low virulent Pasteurella multocida strain in normal and immune-suppressed 12-week-old free-range chickens. AB - Twelve-week-old indigenous chickens, either immune-suppressed using dexamethasone (IS) or non-immune-suppressed (NIS), were challenged with a low virulent strain, Pasteurella multocida strain NCTC 10322(T), and developed clinical signs and pathological lesions typical of chronic fowl cholera. NIS birds demonstrated much more severe signs of fowl cholera than IS birds. With few exceptions, signs recorded in IS and NIS birds were of the same types, but significantly milder in the IS birds, indicating that immune suppression does not change the course of infection but rather the severity of signs in fowl cholera. P. multocida signals by fluorescent in situ hybridization (FISH) were observed between 1 h and 14 days in the lungs, trachea, air sacs, liver, spleen, bursa of Fabricius and caecal tonsils, while signals from other organs mostly were observed after 24 h. More organs had FISH signals in NIS birds than in IS birds and at higher frequency per organ. Many organs were positive by FISH even 14 days post infection, and it is suggested that these organs may be likely places for long-term carriage of P. multocida following infection. The present study has demonstrated the spread of P. multocida in different tissues in chickens and distribution of lesions associated with chronic fowl cholera, and pointed to a decrease of pathology in IS birds. Since dexamethasone mostly affects heterophils, the study suggests that these cells play a role in the development of lesions associated with chronic fowl cholera in chickens. PMID- 22107098 TI - Biochemical and physiological weaknesses associated with the pathogenesis of femoral bone degeneration in broiler chickens. AB - Femoral bone degeneration has been recognized as an important cause of lameness in broiler chickens for many years, but the pathogenesis of this condition has not been completely elucidated. The current work presents comprehensive analyses of changes associated with femoral bone degeneration based on findings from gross pathology, histopathology, biochemistry, and synchrotron-based imaging techniques. Gross lesions were predominantly seen in epiphysis and metaphysis of the proximal femur, and infrequently in distal femur, but we did not observe gross lesions in the diaphysis. Bone fractures were observed occasionally, but the most common lesions involved separation of articular cartilage of the femoral bone head, with progressive erosions of the subchondral bone. In advanced cases, on histopathological examination, changes in femoral bone were indicative of chondronecrosis and osteonecrosis. Computed tomography revealed that the degenerative process involves loss of trabecular bone. The course of the lesion development in the mineralized matrix appears to be coupled with increased bone resorption associated with excessive proliferation of pathologically altered osteoclasts. Light microscopy, Fourier transform infrared spectroscopy, and biochemical analysis provided consistent evidence that lowered protein content of the bone organic matrix is an integral component of femoral bone pathology, but these changes do not appear to be associated with excessive activity of matrix metalloproteinases. Taken together, our findings indicate that femoral bone degeneration is associated with structural changes occurring in both inorganic and organic matrix of the bone, but insufficiency in protein metabolism is most probably a primary aetiological factor in the natural history of femoral bone degeneration. However, it is important to stress that our findings do not negate the importance of bacterial infection in the evolution of this condition. Pathogens play a critical role in the progressive pathogenesis of this condition, which ultimately is manifested, in most instances, as femoral head necrosis. PMID- 22107104 TI - Rongalite: a useful green reagent in organic synthesis. PMID- 22107099 TI - Development and validation of a drag swab method using tampons and different diluents for the detection of members of Salmonella in broiler houses. AB - Members of the genus Salmonella represent a significant public health concern and also a colonizer of commercial poultry. Therefore, the early detection and management of colonized broiler breeders and their progeny is essential. There have been numerous methods for farm-based detection, with gauze-based drag swabs being the most commonly used. In the present study, the wet (boiled water, buffered peptone water and double-strength skin milk) tampon was compared with the gauze to determine the recovery rate (10(2) colony-forming units/swab) of five common poultry serovars of Salmonella and after cold (4 degrees C/48 h) storage. The recovery was found to be equivalent when tested using the ISO6572:2002 method, for all diluents (Cohen's kappa =1.0; sensitivity = 1.0; specificity = 1.0). The subsequent field trial (n = 15 farms) compared the tampon drag swab (TDS) with a statistically appropriate (90% confidence, detect 10% prevalence) number of faecal swabs (n = 22), which also showed high agreement between the TDS and faecal sampling (kappa = 0.86; McNemar's chi(2) = 1.0; sensitivity = 0.9; specificity = 1.0). However, direct faecal sampling showed a wider diversity of serovars of Salmonella than the corresponding TDS. The TDS is a very sensitive, readily available and cost-effective screening method for salmonellas in broiler breeder houses. This TDS technique may be used for routinely screening of broiler houses, and faecal sampling would only be used to confirm colonization or contamination, and to measure flock serovar variance. PMID- 22107105 TI - Knowledge of nurses working at schools in Bialystok, Poland, of tooth avulsion and its management. AB - AIM: The purpose of this study was to evaluate the knowledge of first aid in tooth avulsion among nurses working at schools in Bialystok, Poland. A part of this population attended a lecture on the management of dental trauma 2 years before. METHODS: The survey was conducted in September 2010 and covered 50 (96.15%) school nurses from Bialystok. Thirty-eight of them attended the dental trauma lecture conducted 2 years before the survey. They were asked to fill in an anonymous questionnaire consisting of 20 closed questions referring to demographic data, previous dental trauma experience, and training. Seven questions referred directly to the knowledge of management of dental avulsion and on that basis, the level of nurses' knowledge was evaluated. The data were analyzed statistically using the Mann-Withney U-test with P < 0.05 to find factors influencing the level of knowledge. RESULTS: The study showed that nurses' knowledge about tooth avulsion was at an appropriate level. 86% of the participants chose the correct definition of the term of replantation, 92% understood that the time is crucial for the result of a replantation, 94% knew that an avulsed tooth should be held by the crown, and 96% pointed the proper transport medium. A half of the surveyed nurses declared that they would provide tooth replantation and another 16% would consult the procedures by calling a dentist. One statistically significant correlation between the level of knowledge and previous dental trauma training was revealed (P < 0.01). CONCLUSIONS: The lay knowledge of tooth avulsion in the population of nurses working at schools in Bialystok, Poland, was at an appropriate level. There was a strong correlation between this level and the participation in the lecture on the management of dental trauma conducted 2 years before. PMID- 22107106 TI - Porous PVDF as effective sonic wave driven nanogenerators. AB - Piezomaterials are known to display enhanced energy conversion efficiency at nanoscale due to geometrical effect and improved mechanical properties. Although piezoelectric nanowires have been the most widely and dominantly researched structure for this application, there only exist a limited number of piezomaterials that can be easily manufactured into nanowires, thus, developing effective and reliable means of preparing nanostructures from a wide variety of piezomaterials is essential for the advancement of self-powered nanotechnology. In this study, we present nanoporous arrays of polyvinylidene fluoride (PVDF), fabricated by a lithography-free, template-assisted preparation method, as an effective alternative to nanowires for robust piezoelectric nanogenerators. We further demonstrate that our porous PVDF nanogenerators produce the rectified power density of 0.17 mW/cm3 with the piezoelectric potential and the piezoelectric current enhanced to be 5.2 times and 6 times those from bulk PVDF film nanogenerators under the same sonic-input. PMID- 22107107 TI - Giving voice to patients' and family caregivers' needs in chronic heart failure: implications for palliative care programs. AB - BACKGROUND: The American College of Cardiology Foundation/American Heart Association (ACC/AHA) Guidelines for the Management of Heart Failure recommend palliative care in the context of Stage D HF or at the end of life. Previous studies related to heart failure (HF) palliative care provide useful information about patients' experiences, but they do not provide concrete guidance for what palliative care needs are most important and how a palliative care program should be structured. OBJECTIVES: Describe HF patients' and their family caregivers' major concerns and needs. Explore whether, how, and when palliative care would be useful to them. DESIGN AND PARTICIPANTS: Qualitative study using in-depth interviews of 33 adult outpatients with symptomatic HF identified using purposive sampling and 20 of their family caregivers. APPROACH: Interviews were transcribed verbatim and analyzed using the constant comparative method. KEY RESULTS: Overall, patients and caregivers desired early support adjusting to the limitations and future course of illness, relief of a number of diverse symptoms, and the involvement of family caregivers using a team approach. A diverse group of participants desired these elements of palliative care early in illness, concurrent with their disease-specific care, coordinated by a provider who understood their heart condition and knew them well. Some diverging needs and preferences were found based on health status and age. CONCLUSIONS: HF patients and their family caregivers supported early integration of palliative care services, particularly psychosocial support and symptom control, using a collaborative team approach. Future research should test the feasibility and effectiveness of integrating such a program into routine HF care. PMID- 22107108 TI - Measuring family satisfaction with care and quality of dying in the intensive care unit: does patient age matter? AB - RATIONALE: Few studies have examined the role of patient age on family experiences of end-of-life care. OBJECTIVES: To assess measurement characteristics of two family-assessed questionnaires across three patient age groups. METHODS: Four hundred and ninety-six patients who died in an intensive care unit (ICU) at a single hospital were identified and one family member per patient was sent two questionnaires: 1) Family Satisfaction in the ICU (FS-ICU); and 2) Quality of Dying and Death (QODD). Two hundred and seventy-five surveys were returned (55.4%). We analyzed three age groups: <35, 35-64, and >=65 years. Differences were evaluated using chi(2) tests to evaluate ceiling, floor, and missing responses; Kruskal-Wallis tests to compare median scores on items and total scores; and linear regression controlling for patient sex, race, diagnosis, and family-member sex, race, education, and relationship to provide adjusted comparisons of total and subscale scores. RESULTS: Measurement characteristics varied by age groups for both questionnaires. Missing values and floor endorsements were more common for the younger age groups for six items and one overall rating score. Ceiling endorsements were more common for the older group for 11 items. Fifteen items and four total scores were significantly higher in the older group. CONCLUSIONS: The FS-ICU and QODD questionnaires performed differently across patient age groups. Assessments of family satisfaction and quality of dying and death were higher in the oldest group, particularly in the area of clinician-family communication. Studies of the dying experience of older adults may not generalize to patients of other ages, and study instruments should be validated among different age groups. PMID- 22107109 TI - Who needs admission among infants with acute otitis media? AB - AIM: Management of acute otitis media (AOM) in infants younger than 2 months old is controversial. It varies between treatment on an outside basis, and hospitalization for intravenous antibiotics and sepsis work-up based on variability of the reported AOM pathogens in this particular group. Our aim is to identify clinical indicators that may suggest a need for an invasive medical work up and/or hospitalization of these young patients, and compare their management to that of older infants. METHODS: Retrospective chart review. Admitted infants with AOM and a random sample of infants presenting to the emergency room with AOM over a 20-year period. Infants younger than 2 months were designated as 'young infants', and those older as 'older infants'. Demographic data, relevant history, physical examination, laboratory studies and treatment were reviewed. RESULTS: Twenty-nine admitted infants were included (13 young infants). A sample of 58 outpatients was studied, including two young infants. Compared to older inpatient infants, admitted young infants were less febrile (P < 0.05), had more benign white cell count (P < 0.05) but had more otorrhea (P < 0.05). These grew gram negative organisms. Sepsis work-up was negative. Young infants were more likely to be admitted (P < 0.05). Admitted older infants had more otorrhea than outpatients (P < 0.05) or a complication (P < 0.05). CONCLUSIONS: Young infants often need admission for intravenous antibiotics, until middle ear culture is out. Sepsis work-up may be necessary only in toxic patients. Older infants need admission when severely ill or have a complication. PMID- 22107110 TI - A text message programme designed to modify patients' illness and treatment beliefs improves self-reported adherence to asthma preventer medication. AB - OBJECTIVE: While effective preventative medication is readily available for asthma, adherence is a major problem due to patients' beliefs about their illness and medication. We investigated whether a text message programme targeted at changing patients' illness and medication beliefs would improve adherence in young adult asthma patients. METHODS: Two hundred and sixteen patients aged between 16 and 45 on asthma preventer medication were recruited from pamphlets dispensed with medication and e-mails sent to members of a targeted marketing website. Participants were randomized to receive individually tailored text messages based on their illness and medication beliefs over 18 weeks or no text messages. Illness and medication beliefs were assessed at baseline and at 18 weeks. Adherence rates were assessed by phone calls to participants at 6, 12, and 18 weeks and at 6 and 9 months. RESULTS: At 18 weeks, the intervention group had increased their perceived necessity of preventer medication, increased their belief in the long-term nature of their asthma, and their perceived control over their asthma relative to control group (all p's < .05). The intervention group also significantly improved adherence over the follow-up period compared to the control group with a relative average increase in adherence over the follow-up period of 10% (p < .001). The percentage taking over 80% of prescribed inhaler doses was 23.9% in the control group compared to 37.7% in the intervention group (p < .05). CONCLUSION: A targeted text message programme increases adherence to asthma preventer inhaler and may be useful for other illnesses where adherence is a major issue. PMID- 22107111 TI - Effect of metal ion hydration on the interaction between sodium carboxylates and aluminum(III) or chromium(III) ions in aqueous solution. AB - The interaction between sodium octanoate, decanoate, and dodecanoate and aluminum(III) and chromium(III) has been studied in water at natural pH values, starting well below the surfactant critical micelle concentration, using electrical conductivity, turbidity, and potentiometric measurements. With decanoate or dodecanoate, maximum interaction occurs at 3:1 stoichiometry, corresponding to charge neutralization. Although the solutions become turbid with both metal ions, indicating phase separation, differences are observed and attributed to the fact that aluminum(III) is relatively labile to substitution and rapidly replaces its water ligands, whereas chromium(III) is substitution inert. This shows up in well-defined floc formation with Al(3+), whereas Cr(3+) suspensions do not precipitate, probably because that replacement of coordinated water by carboxylate ligands is impeded. This can be overcome by increasing temperature, and differences in the thermal behavior with Al(3+) and Cr(3+) are suggested to be due to increased involvement of substitution reactions in the latter case. The effect of octanoate on the trivalent metal ions is less clear, and with Cr(3+) interaction only occurs when the carboxylate is in excess. Hydrophobic interactions between alkyl chains play a major role in driving phase separation. At high surfactant concentrations, the solid phases do not dissolve, in contrast to what is observed with the corresponding alkylsulfates. This has implications for use of these systems in metal separation through froth flotation. The concentration of metal ions in supernatant solution has been determined for sodium dodecanoate and sodium dodecylsulfate with Al(3+) and Cr(3+) over the whole surfactant concentration range by inductively coupled plasma-mass spectrometry (ICP-MS). From this, association constants have been determined and are found to be larger for the carboxylate than the alkylsulfate, in agreement with the greater Lewis basicity of the -CO(2)(-) group. PMID- 22107112 TI - Identification of two anthocyanidin reductase genes and three red-brown soybean accessions with reduced anthocyanidin reductase 1 mRNA, activity, and seed coat proanthocyanidin amounts. AB - Anthocyanidin reductase (ANR; EC 1.3.1.77) catalyzes a key step in the biosynthesis of proanthocyanidins (PAs; also known as condensed tannins), flavonoid metabolites responsible for the brown pigmentation of seeds. Here, two ANR genes (ANR1 and ANR2) from the seed coat of brown soybean (Glycine max (L.) Merr.) have been isolated and their enzymatic function confirmed for the reduction of cyanidin to (-)-epicatechin in vitro. Biochemical and genetic comparisons of soybean lines differing in seed coat color revealed three red brown lines to exhibit major reductions in the amounts of soluble PAs in the seed coat compared to brown soybean lines. Two spontaneous mutants with red-brown grain color had reduced ANR1 gene expression in the seed coat, and an EMS mutagenized red-brown mutant had nonsynonymous substitutions that resulted in slightly reduced ANR1 activity in vitro. These results suggest that defects in the ANR1 gene can be associated with red-brown soybean grain color. These results suggest that suppressing ANR1 gene expression or activity may be a rational approach toward engineering seed coat color to enable the visual identification of genetically modified soybean grains. PMID- 22107113 TI - Nine lessons and recommendations from the conduct of focus group research in chronic pain samples. AB - PURPOSE: The view of the patient is central to their care. Focus group methodology has been used in health psychology to capture patient views on health and illness. However, the process of conducting focus group research with patient groups has received scarce attention. The purpose of this paper was to highlight lessons learned from the conduct of focus groups in psychological research with chronic pain samples. METHODS: Lessons were taken from three structured focus groups containing participants recruited from General Practice. Each group contained five, four, and six chronic pain sufferers from upper, middle and lower socioeconomic areas, respectively. RESULTS: Nine lessons were learned about the conduct of focus group research in general, and also with chronic pain sufferers in particular. The lessons relate to (1) translating study interest into group attendance, (2) ensuring the environment maximizes the opportunity to learn from participants, (3) understanding participant motivations for attendance as well as (4) what participants take from the group, (5) ensuring adequate question specificity, accommodating the needs of particular groups in (6) moderation style and (7) discussion time scales, (8) considering the function of conflict in the group and (9) paying due attention to simultaneous dialogue. Recommendations for addressing the lessons are made. CONCLUSION: Patient groups have specific requirements and the conduct of focus groups should be driven by these needs to maximize inclusion and quality contributions in the group. Time, resources, and flexibility are needed to ensure the successful transition of these groups into focus group research. PMID- 22107114 TI - Causes of neonatal death: results from NeoKIP community-based trial in Quang Ninh province, Vietnam. AB - AIM: To ascertain the causes of neonatal death in a province in northern Vietnam and analyse their distribution over age at death, birth weight and place of delivery. METHODS: Verbal autopsy interviews using a questionnaire derived from WHO standard and adapted to Vietnamese conditions was performed on all neonatal deaths occurring in Quang Ninh province from July 2008 to June 2010. Three experienced paediatricians independently reviewed all verbal autopsy records (233) and assigned a main cause of death. In case of disagreement in the allocation of cause of death, a consensus process was initiated to decide on a final cause. RESULTS: Neonatal mortality rate within the study area was 16/1000 (238 neonatal deaths and 14,453 live births) over the study period. Prematurity/low birth-weight (37.8%), intrapartum-related neonatal deaths (birth asphyxia, 33.2%), infections (13.0%) and congenital malformation (6.7%) were the four leading causes of death. Four cases of neonatal tetanus were found. Intrapartum-related deaths dominated in the home delivery group, whereas prematurity was the most prominent cause of death at all facility levels. Most neonatal deaths occurred within the first 24 h after delivery (58.6%). CONCLUSION: A high proportion of deaths due to prematurity and intrapartum related causes, calls for improvements of delivery care and resuscitation practices at health facilities. PMID- 22107116 TI - Superior oblique tuck: its success as a single muscle treatment for selected cases of superior oblique palsy. AB - PURPOSE: To investigate the results of superior oblique tuck (SOT) for selected cases of superior oblique palsy (SOP) over a 17-year period. The results were correlated by correction of deviation; re-operation rates; rates of iatrogenic Brown's syndrome; and finally, correlation between tuck size and deviation change. Any differences between the results for congenital and acquired SOP are reported. METHODS: A retrospective, cohort study of adults with SOP-with diplopia greatest in the area of action of the paretic superior oblique-who underwent SOT between 1992 and 2009. Pre-, intra- and postoperative measurements were collected. Vertical and torsional measurements in both primary position and area of maximal deviation were analyzed. Intraoperative tuck size was measured and correlated to effect. RESULTS: We report 75 cases of isolated SOT with a mean follow-up of 8.6 months. Significant improvement in deviation in all positions measured was shown (P<0.0001 for all). Twenty-two (29.3%) cases underwent further procedures due to residual diplopia. There were no intraoperative complications. Brown's syndrome was demonstrated using a Lees screen in 10 cases but none of these were symptomatic. No patients required tuck revision. There was no correlation between tuck size and changes in either vertical or torsional deviations. 42 (56%) had acquired SOP with no significant differences in pre- or postoperative measurements to congenital cases. CONCLUSIONS: This is the largest series of SOTs reported with 71% of cases having successful outcome with the one surgical procedure. There are significant improvements in the postoperative measurements for both vertical deviation and torsion. 29.3% of cases required a further procedure consisting mainly of contralateral inferior rectus weakening although ipsilateral inferior oblique weakening was also performed. Because of the lack of correlation between tuck size and correction obtained, we would suggest that SOT should be considered as "one tightness fits all" rather than "one size fits all." PMID- 22107117 TI - The influence of unilateral uncorrected astigmatism on binocular vision and fixation disparity. AB - PURPOSE: It is accepted practice to use a spherical equivalent power as an alternative contact lens correction for those patients with lower amounts of astigmatism, allowing for an easier fit, but the blur caused by one diopter of uncorrected astigmatism can reduce acuity of 6/6 to that of about 6/8. This is usually deemed acceptable monocularly, often retaining a good binocular acuity. The purpose of this study is to explore how monocular astigmatic blur may also affect the patient's binocular vision function. METHODS: A trial frame was outfitted with full correction for 20 healthy subjects (mean age 25.5 years, range 19-36 years) and a baseline horizontal fixation disparity was measured at a distance of 1 m. Thereafter, fixation disparity was measured with induced monocular astigmatic blur in the right eye, creating an astigmatic error in the amounts of -0.75 and -1.25 in axis 90 and axis 45. RESULTS: It was determined that the differences among full correction and the 4 different types of astigmatic blur were not significant when analyzed as one group (P = 0.5445), nor when separated into groups according to whether the subject had naturally occurring astigmatism or not, (astigmatic group, P = 0.3801; non-astigmatic group, P = 0.5899). CONCLUSIONS: Monocular astigmatic blur in the amounts of 0.75 and -1.25 did not have a significant effect on tested subjects with regard to the amount of blur or axis orientation. This low amount of blur is likely within the range of compensation for the subjects, proving that spherical equivalent contact lenses are a viable option for low amounts of astigmatic error. PMID- 22107118 TI - Extraocular muscle dynamics in diplopia from enophthalmos. AB - The mechanism of diplopia from enophthalmos is not well understood. We describe a 55-year-old man who underwent a left transorbital craniotomy for clipping of a basilar aneurysm. The lateral orbital wall was not reconstructed properly, resulting in 8 mm of left enophthalmos. Months after surgery the patient developed diplopia with ocular excursions, although he remained orthotropic in primary gaze. The left eye was limited in elevation, adduction, and abduction. These findings were confirmed by eye movement recordings, which showed ocular separation increasing with gaze eccentricity. A CT scan demonstrated a defect in the sphenoid and frontal bones, profound enophthalmos, and shortening of the rectus muscles. Slack in the extraocular muscles reduced the force generated by each muscle, causing diplopia with ocular rotation. This case underscores the value of careful orbital wall reconstruction after orbitotomy and suggests a mechanism for diplopia produced by postoperative enophthalmos. PMID- 22107119 TI - Amblyopia and strabismus in Iranian schoolchildren, Mashhad. AB - PURPOSE: To determine the prevalence of amblyopia and strabismus among the population of schoolchildren Mashhad, Iran. MATERIALS AND METHODS: In a cross sectional study with cluster sampling, 2510 schoolchildren were selected from schools of district 1 in Mashhad. Uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) were recorded for each participant. Amblyopia was distinguished as a reduction of BCVA to 20/30 or less in one eye or 2-line interocular optotype acuity differences in the absence of pathological causes. RESULTS: Of the 2510 selected schoolchildren, 2150 participated (response rate, 85.6%). The mean (+/- standard deviation) age of the participants was 13.2 +/- 3.2 (range, 6-21) years. The prevalence of amblyopia was 1.9% (95% CI: 0.94 2.90); 2.1% (95% CI: 0.10-3.16) in girls and 1.7% (95% CI: 0.30-3.12) in boys (P = 0.6). Among myopic, hyperopic, and astigmatic students, 3.7%, 27.8%, and 6.5% had amblyopia, respectively (P<0.001). The causes of amblyopia were anisometropia in 65.9%, strabismus in 24.4%, and isoametropia in 9.8%. The prevalence of strabismus was 3.1% (95% CI, 1.3% to 4.3%); 4.2% (95% CI, 3.05 to 5.7%) in girls, and 2.0% (1.3% to 2.9%) in boys (P = 0.0011). Strabismus was significantly more prevalent among hyperopic students (7.9%) compared with myopic ones (3.7%). CONCLUSION: Results of the present study indicate that the prevalence rate of amblyopia was in the mid-range of other studies, and the prevalence of strabismus was relatively high. Since refractive errors, especially hyperopia, are responsible for some cases of strabismus. PMID- 22107120 TI - Surgery for residual convergence excess esotropia. AB - The outcome of bilateral medial rectus posterior fixation sutures +/- central tenotomy was assessed as a secondary procedure for residual convergence excess esotropia in 11 patients. Ten had previously undergone bilateral medial rectus recessions. One had recess/resect surgery on the deviating eye. The average preoperative near angle was 30 prism diopters with a range of 16 to 45 prism diopters. Eight patients underwent bilateral medial rectus posterior fixation sutures with central tenotomy. Two had bilateral medial rectus posterior fixation sutures only, and one had bilateral medial rectus posterior fixation suture, a lateral rectus resection, and an inferior oblique disinsertion. The postoperative near angle ranged from 4-30 prism diopters, with mean of 12 prism diopters. Five patients demonstrated some stereopsis preoperatively, all needing bifocals. Postoperatively, nine patients demonstrated an improvement in stereopsis, none needing bifocals. Two showed smaller near angles and better control without bifocals. Final stereopsis ranged from 30 seconds of arc to 800 seconds of arc. We feel that bilateral medial rectus posterior fixation sutures with or without central tenotomy is a viable secondary procedure for residual convergence excess esotropia. PMID- 22107121 TI - The Halpern syndrome of monocular visual vertigo: a rare cause of monocular eye closure. AB - BACKGROUND: Halpern syndrome is a vestibular disorder characterized by vertigo, a tendency to tilt to one side, and spontaneous closure of the ipsilateral eye. Symptoms are exacerbated during monocular viewing with the ipsilateral eye and alleviated during monocular viewing with the contralateral eye. It has long been attributed to a mismatch between visual and vestibular input. METHODS: Reexamination of Halpern syndrome in light of new concepts of visuo-vestibular disease. RESULTS: The visually dependent postural disequilibrium in Halpern syndrome recapitulates the dorsal light reflex in fish, in which unequal luminance input to the two eyes evokes a tilt of the body toward the brighter side. CONCLUSION: Patients with Halpern syndrome close one eye to restore vertical postural orientation. Halpern syndrome may result from reactivation the dorsal light reflex in the setting of central vestibular disease. PMID- 22107122 TI - A neural model for cyclovertical eye movements and their disorders. AB - Both see-saw nystagmus and dissociated vertical divergence are cyclovertical eye movements characterized by vertical disconjugation and torsional conjugation. See saw nystagmus is known to occur with chiasmal disorders and bitemporal hemianopia. Dissociated vertical divergence is commonly encountered in the infantile strabismus syndrome. A hypothetical model is presented in which both conditions are explained. The basic organization of the oculomotor system is most likely monocular and synchronous eye movements may have developed by neuronal coupling of the symmetrical oculomotor structures. The vertical dissociation of both eye movement disorders is explained by insufficiently developed neuronal coupling between the superior colliculi. A functional differentiation between crossed and uncrossed retinal ganglion cells fibers is assumed to cause this diminished binocular coupling in the case of see-saw nystagmus. The interstitial nucleus of Cajal may well play a pivotal role in explaining the distinct torsional eye movements in both conditions. PMID- 22107125 TI - Second-chance forward isomerization dynamics of the red/green cyanobacteriochrome NpR6012g4 from Nostoc punctiforme. AB - The primary ultrafast Z-to-E isomerization photodynamics of the phytochrome related cyanobacteriochrome NpR6012g4 from Nostoc punctiforme was studied by transient absorption pump-dump-probe spectroscopy. A 2 ps dump pulse resonant with the stimulated emission band depleted 21% of the excited-state population, while the initial photoproduct Lumi-R was depleted by only 11%. We observed a red shifted ground-state intermediate (GSI) that we assign to a metastable state that failed to isomerize fully. Multicomponent global analysis implicates the generation of additional Lumi-R from the GSI via crossing over the ground-state thermal barrier for full isomerization, explaining the discrepancy between excited-state and Lumi-R depletion by the dump pulse. This second-chance ground state dynamics provides a plausible explanation for the unusually high quantum yield of 40% for the primary isomerization step in the forward reaction of NpR6012g4. PMID- 22107126 TI - Management experiences and trends for water reuse implementation in Northern California. AB - In 2010, California fell nearly 300,000 acre-ft per year (AFY) short of its goal to recycle 1,000,000 AFY of municipal wastewater. Growth of recycled water in the 48 Northern California counties represented only 20% of the statewide increase in reuse between 2001 and 2009. To evaluate these trends and experiences, major drivers and challenges that influenced the implementation of recycled water programs in Northern California are presented based on a survey of 71 program managers conducted in 2010. Regulatory requirements limiting discharge, cited by 65% of respondents as a driver for program implementation, historically played an important role in motivating many water reuse programs in the region. More recently, pressures from limited water supplies and needs for system reliability are prevalent drivers. Almost half of respondents (49%) cited ecological protection or enhancement goals as drivers for implementation. However, water reuse for direct benefit of natural systems and wildlife habitat represents just 6-7% of total recycling in Northern California and few financial incentives exist for such projects. Economic challenges are the greatest barrier to successful project implementation. In particular, high costs of distribution systems (pipelines) are especially challenging, with $1 to 3 million/mile costs experienced. Negative perceptions of water reuse were cited by only 26% of respondents as major hindrances to implementation of surveyed programs. PMID- 22107128 TI - Quality by design compliant analytical method validation. AB - The concept of quality by design (QbD) has recently been adopted for the development of pharmaceutical processes to ensure a predefined product quality. Focus on applying the QbD concept to analytical methods has increased as it is fully integrated within pharmaceutical processes and especially in the process control strategy. In addition, there is the need to switch from the traditional checklist implementation of method validation requirements to a method validation approach that should provide a high level of assurance of method reliability in order to adequately measure the critical quality attributes (CQAs) of the drug product. The intended purpose of analytical methods is directly related to the final decision that will be made with the results generated by these methods under study. The final aim for quantitative impurity assays is to correctly declare a substance or a product as compliant with respect to the corresponding product specifications. For content assays, the aim is similar: making the correct decision about product compliance with respect to their specification limits. It is for these reasons that the fitness of these methods should be defined, as they are key elements of the analytical target profile (ATP). Therefore, validation criteria, corresponding acceptance limits, and method validation decision approaches should be settled in accordance with the final use of these analytical procedures. This work proposes a general methodology to achieve this in order to align method validation within the QbD framework and philosophy. beta-Expectation tolerance intervals are implemented to decide about the validity of analytical methods. The proposed methodology is also applied to the validation of analytical procedures dedicated to the quantification of impurities or active product ingredients (API) in drug substances or drug products, and its applicability is illustrated with two case studies. PMID- 22107129 TI - A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. AB - Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n=34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n=53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n=63) (N=150). Response rates after four cycles of treatment were: >=near complete response (nCR), 12% vs. 2% vs. 41%, P<0.0001 and very good partial response or better, 35% vs. 30% vs. 65%, P=0.0003, respectively. With all cycles of therapy considered, >=nCR was 35%, 15% and 41%, P=0.006. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3.2 vs. 2.3 vs. 2.7years, P=0.11) or overall survival (3-year: 88% vs. 79% vs. 88%, P=0.23). Transplantation did not impact PFS (median: 2.7 vs. 2.3 years, P=0.41) but was associated with improved OS (3-year: 93% vs. 75%, P<=0.001). High genetic risk patients (n=40) had earlier relapse despite lenalidomide or bortezomib (median: 2.1 vs. 2.7years, P=0.45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4years. PMID- 22107130 TI - Ergonomic port placement in laparoscopic colorectal surgery. AB - AIM: Port placement in laparoscopic surgery has important ergonomic implications. A manipulation angle (MA) of 60 degrees has been shown to maximize task efficiency. We calculated the MA used during various stages of both right hemicolectomy (RH) and high anterior resection (AR). METHOD: We compared two methods of port placement for each operation. RH-PP1 included ports in the left iliac fossa and left upper quadrant. RH-PP2 included ports suprapubically and in the left iliac fossa. We calculated the MA of each of these methods in mobilizing both the caecum and hepatic flexure. AR-PP1 included ports in the right iliac fossa and right upper quadrant. AR-PP2 included ports suprapubically and in the right iliac fossa. We calculated the MA of each of these methods in mobilizing the splenic flexure, descending-sigmoid junction and the recto-sigmoid junction. RESULTS: For RH-PP1, the mean MA for mobilizing the caecum and hepatic flexure was 38 degrees and 52 degrees , respectively. For RH-PP2, the mean MA for mobilising the caecum and hepatic flexure was 58 degrees and 44 degrees , respectively. For AR-PP1, the mean MA for mobilizing the splenic flexure, the descending-sigmoid junction and the recto-sigmoid junction was 77 degrees , 41 degrees and 18 degrees , respectively. For AR-PP2, the mean MA for mobilizing the splenic flexure, the descending-sigmoid junction and the recto-sigmoid junction was 40 degrees , 56 degrees and 34 degrees , respectively. CONCLUSION: There are no two port placements that will allow for an ideal MA at every stage of mobilization for either right- or left-sided resection. PMID- 22107131 TI - Effect of a simulated soccer match on the functional hamstrings-to-quadriceps ratio in amateur female players. AB - The purpose of this study was to investigate the effect of a simulated soccer test on the functional hamstrings-to-quadriceps ratio (H(ecc) : Q(con)) in female soccer players. Fourteen amateur players (age, 26.1 +/- 4.6 years; height, 168 +/ 12 cm; body mass, 62.7 +/- 5.5 kg; body fat, 23.7 +/- 2.2%) performed the modified Loughborough Intermittent Shuttle Test (modified LIST). Isokinetic strength assessments of the hamstrings and quadriceps on the dominant and non dominant legs at 120 degrees /s were performed before and immediately after the modified LIST. H(ecc) : Q(con) was calculated as the ratio of the peak eccentric torque of the hamstrings to the peak concentric torque of the quadriceps. A two way univariate analysis of variance was used to assess the effect of time and leg dominance on H(ecc) : Q(con). The main results showed that the modified LIST led to a significant decrease in H(ecc) : Q(con) in the dominant (-14.1%) and non dominant legs (-8.0%) (P = 0.02). However, this decrease was not significantly different between dominant and non-dominant legs (P = 0.42). These results reflect a greater risk of hamstrings tears and ACL sprains at the end of soccer matches. PMID- 22107132 TI - The effect of splint material and thickness on tooth mobility after extraction and replantation using a human cadaveric model. AB - Although current guidelines for the treatment of traumatic injuries recommend the use of 'flexible' splints, the precise definition of what is considered flexible versus rigid has not been rigorously defined, leaving the clinician with a wide range of options for this critical factor. The purpose of this study was to quantify and compare the effect of eight different splints on tooth mobility after extraction and replantation using a human cadaveric model. Following strict selection criteria including complete root maturation, lack of periodontal disease, normal bone levels, and crown integrity, a maxillary central incisor was atraumatically extracted and splinted with eight different splints. The experimental splints included a 20-pound test (9.072-kilogram test) [corrected] monofilament nylon-composite splint and six wire-composite splints made of wires of 0.012' (0.3 mm), 0.016' (0.4 mm), or 0.020' (0.5 mm) diameter stainless steel (SS) or nickel titanium (NT). A direct composite splint represented the most rigid type of splint. These eight splints were applied five times each, and tooth mobility was measured before and after each splint was applied. The average splint effect, defined as the difference between the presplint and the postsplint measurements quantified using the Periotest, was calculated for each splint and compared. No significant differences were found between the nylon-composite and the wire-composite splints. There was significantly less tooth mobility with the direct composite splint compared to all other splints. In conclusion, the results of this study suggest that nylon and SS or NT wires up to 0.016' diameter are significantly more flexible than direct composite splints and thus may be better suited for the splinting and management of traumatized teeth. PMID- 22107133 TI - Elevated plasma matrix metalloproteinase-9 protein and its gene polymorphism in patients with community-acquired pneumonia. AB - BACKGROUND: The purpose here was to detect the association among plasma matrix metalloproteinase-9 (MMP-9) concentration, single nucleotide polymorphisms (SNPs) of MMP-9 gene and community-acquired pneumonia (CAP). METHODS: The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were, respectively used to measure the plasma MMP 9 level and its gene polymorphisms. RESULTS: The level of plasma of MMP-9 was elevated in patients with CAP as compared to that of normal controls and decreased significantly after treatment. Plasma MMP-9 concentration was significantly correlated with white blood cell (WBC) and neutrophil counts in patients with CAP. No significant difference was found in the genotypes distribution of MMP-9 SNPs, rs3918242, rs17576 or rs2274756, between patients with CAP and normal controls. Plasma MMP-9 concentration was not associated with MMP-9 polymorphism. When the cut-off level of the plasma MMP-9 concentration was set to be 105.02 ng/mL, the odds ratio of plasma MMP-9 for CAP risk was 9.86 (95% confident interval: 4.27-22.75). Plasma MMP-9 level may act as a prediction marker for CAP. CONCLUSIONS: Elevated plasma MMP-9 could be a biological marker for the diagnosis and be a new strategy for target therapy of community-acquired pneumonia. PMID- 22107134 TI - Linking preeclampsia and cardiovascular disease later in life. AB - Preeclampsia (PE), which is defined as new onset hypertension after 20 weeks of pregnancy accompanied by proteinuria, is characterized by inadequate placentation, oxidative stress, inflammation and widespread endothelial dysfunction. A link between PE and long-term risk of cardiovascular disease (CVD) was suggested by retrospective studies, which found that PE was associated with a 2-3-fold risk of CVD later in life, with a 5-7-fold risk in the case of severe and/or early-onset PE. Recently, meta-analyses and prospective studies have confirmed the association between PE and the emergence of an unfavorable CVD risk profile, in particular a 3-5-fold increased prevalence of the metabolic syndrome only 8 years after the index pregnancy. PE and CVD share many risk factors, including obesity, hypertension, dyslipidemia, hypercoagulability, insulin resistance and both entities are characterized by endothelial dysfunction. PE and CVD are complex traits sharing common risk factors and pathophysiological processes, but the genetic link between both remains to be elucidated. However, recent evidence suggests that genetic determinants associated with the metabolic syndrome, inflammation and subsequent endothelial dysfunction are involved. As the evidence now supports that PE represents a risk factor for the emergence of the metabolic syndrome and CVD later in life, the importance of long-term follow up assessment of CVD risk beginning early in women with a history of PE must be considered and translated into new preventive measures. PMID- 22107135 TI - Leptin levels in exhaled breath condensate from asthmatic children: a pilot study. PMID- 22107136 TI - Agarose-gel electrophoresis for the diagnosis of mucopolysaccharidoses. PMID- 22107137 TI - Anti-neutrophil cytoplasmic antibodies (ANCA) specific for one or several antigens: useful markers for subtypes of ulcerative colitis and associated primary sclerosing cholangitis. AB - BACKGROUND: Dysregulation of antimicrobial response may trigger inflammatory bowel diseases (IBD). This study analyzed specificity of anti-neutrophil cytoplasmic antibodies (ANCA) in IBD patients and its clinical significance. METHODS: Data from 52 ulcerative colitis (UC) patients with 32 Crohn's disease (CD) patients were compared. Primary sclerosing cholangitis (PSC) was present in 12/84 patients. ANCA, ANA and anti-smooth muscle antibodies (ASMA) were detected by IIF. ANCA were tested by ELISA for proteinase 3 (PR3), myeloperoxidase, bactericidal/permeability increasing protein, elastase, cathepsin G, lysozyme and lactoferrin. RESULTS: pANCA were more frequently present in UC than in CD patients (p<0.001). ANCA titer correlated with the disease activity only in UC patients (p<0.05). UC patients more frequently had two or more ANCA specificities compared to CD patients (p<0.01). Multi-specific ANCA in medium and/or high concentrations were associated with long-lasting (p<0.05) and left-sided UC (p<0.001). Multi-specific ANCA with ANA and ASMA had sensitivity of 67% for PSC. CONCLUSIONS: Higher concentrations of multi-specific ANCA in long-lasting, left sided UC suggest an influence of bacterial stimulation on the break of tolerance. Multi-specific ANCA with ANA and ASMA could be markers for PSC. ANCA specific to several antigens may worsen inflammation by reducing antimicrobial capacity of neutrophil proteases and cationic proteins. PMID- 22107138 TI - Collection and storage requirements for urinary kidney injury molecule-1 (KIM-1) measurements in humans. AB - BACKGROUND: Urinary kidney injury molecule-1 (KIM-1) is a recently discovered biomarker for early renal damage. However, little is known about the collection and storage requirements prior to its measurement in human urine. METHODS: Samples of healthy volunteers were collected and aliquoted. The effect of pre freezing time, thawing, addition of protease inhibitors, centrifugation, storage time (up to 1.5 years) and temperature (4 degrees C, -20 degrees C and -80 degrees C) was tested. RESULTS: Addition of protease inhibitors and centrifugation prior to freezing did not affect the KIM-1 measurements. When samples were kept at room temperature for longer than 3 h before freezing or defrosted more than 1 h before measurement, mean KIM-1 values differed significantly compared to aliquots with minimal pre-freezing and thawing time. Samples frozen at -80 degrees C were stable for up to 1.5 years; however an increasing number of freeze-thaw cycles adversely affected KIM-1 measurements. When stored at 4 degrees C and -20 degrees C, samples were less stable compared to those stored at -80 degrees C. CONCLUSIONS: This study recommends that urine samples collected for KIM-1 measurements are frozen within 3 h after voiding and only be defrosted immediately prior to measurement. Addition of protease inhibitor and centrifugation prior to measurement is not necessary. Samples are preferably stored at -80 degrees C and freeze-thaw cycles should be avoided. PMID- 22107140 TI - The quest for predictive immune biomarkers. PMID- 22107141 TI - Laboratory diagnosis of acute anaphylaxis. PMID- 22107142 TI - Developments in the field of allergy in 2010 through the eyes of Clinical and Experimental Allergy. AB - In 2010 over 200 articles were published in Clinical and Experimental Allergy including editorials, reviews, opinion articles, letters, book reviews and of course at the heart of the journal, papers containing original data which have moved the field of allergy forward on a number of fronts. For the third year running the editors felt it would be of value to summarize the key messages contained in these papers as a snapshot of where the cutting edge of research into allergic disease is leading. We have broadly followed the sections of the journal, although this year the mechanistic articles are grouped together and the studies involving experimental models of disease are discussed throughout the paper. In the field of asthma and rhinitis phenotypes and biomarkers continue to a major pre-occupation of our authors. There is continued interest in mechanisms of inflammation and disordered lung function with the mouse model of asthma continuing to offer new insights. There is also a steady flow of papers investigating new therapies, including those derived from plants and herbs, although many are mechanistic with too few high quality clinical trials. The mechanisms involved in allergic disease are well covered with many strong papers using clinical material to ask relevant questions. Pro-pre and snybiotics continue to be of major interest to our authors and this remains a controversial and complicated field. The discipline of epidemiology has retained its interest in risk factors for the development of allergic disease with a view to refining and debating the reasons for the allergy epidemic. There is continued interest in the relationship between helminthic disease and allergy with a new twist in 2010 involving studies using infection with helminths as a potential treatment. The genetics of allergic disease continues to be very productive, although the field has moved on from only investigating single nucleotide polymorphisms of candidate genes to Genome Wide Association Studies and an increasing and welcome emphasis on gene-environment interactions. In the field of clinical allergy there is steady flow of papers describing patterns of drug allergy with renewed interest in reactions to contrast media, but food allergy is the major area of interest in this section of the journal. Lastly in the field of allergens there is a growing interest in the role of component resolved diagnosis in improving the diagnosis and management of allergic disease. Another excellent year, full of fascinating and high quality work, which the journal has been proud to bring to the allergy community. PMID- 22107143 TI - Re: Oral desensitization as a useful treatment in 2-year-old children with cow's milk allergy. PMID- 22107145 TI - Follow-up of probiotic Lactobacillus GG effects on allergic sensitization and asthma in infants at risk. PMID- 22107148 TI - Women's health disparities in Honduras: indicators and determinants. AB - BACKGROUND: Disparities in women's health indicators exist throughout the Americas. Health data about indigenous women in the remote highland communities of Honduras are lacking. Our objective was to assess women's health indicators and to suggest potential interventions. METHODS: An anonymous questionnaire was administered to women >=age 18 in the Yamaranguila municipality. We assessed rates of Pap smear, breastfeeding, family planning (FP), and prenatal care (PNC); childbirth setting; access issues; and self-health perceptions. RESULTS: Of the 134 participants, 30% were aged < 25 and 10% were >= 45. Most attended some primary school, and 11% had no education; 56% reported fair or poor self-health, and 90% had heard of the Pap smear, but only 20% had one within 1 year. Despite knowledge of various FP methods, only 42% in a union were using FP, which is significantly lower than national rates (p<0.01). Thirty-six percent of the respondents' most recent childbirths took place outside a health center. Seventy six percent exclusively breastfed their youngest child for 6 months, higher than the national rate of 30% (p<0.01). Distance from the municipal center, reflecting more traditional indigenous identity, predicted lower rates of FP use (p<0.05), Pap smear (p<0.01), and prenatal care (PNC) (p<0.05), but age and education level did not. CONCLUSIONS: In Honduras, the rural indigenous people have some of the worst health indicators compared to urban and nonindigenous people. Women's health status might be improved by implementing mobile care teams, training indigenous women as community health workers, and employing alternate modalities of cervical screening. Fundamental socioeconomic causes of poor health, such as remote residence, indigenous identity, and gender inequality, should be considered in future interventions to alleviate disparities in health status. PMID- 22107149 TI - Paediatric resuscitation training: is e-learning the answer? A before and after pilot study. AB - AIM: To determine whether an e-learning resuscitation programme was able to improve the knowledge and competence of doctors and nurses in providing cardiopulmonary resuscitation to children in a simulated cardiac arrest. METHOD: A prospective before and after pilot study comprising of a simulated paediatric resuscitation before and after participants undertook an e-learning programme. Participants were emergency department doctors and new graduate nurses from The Children's Hospital at Westmead, Australia. Primary outcome measures were the ability to perform successful basic life support (BLS) and advanced life support (ALS) according to published guidelines. Secondary outcome measures were the individual steps in performing the overall resuscitation and subjective feedback from participants. RESULTS: Fifty-six clinicians were enrolled in the study (29 doctors and 27 nurses). Thirty-seven were re-tested (25 doctors and 12 nurses). The mean time between tests was 49 days (17 standard deviation). The e-learning module led to an improvement in participants' ability to perform BLS by 51% (P < 0.001) and ALS by 57% (P= 0.001) overall resulting in an overall competence of 89% (BLS) and 65% (ALS). There were also significant improvements in time to rhythm recognition (P= 0.006), time to first defibrillation (P= 0.009) and participants' self-reported knowledge and confidence in BLS and ALS (P < 0.001). CONCLUSIONS: E-learning does improve both the knowledge and competence of doctors and nurses in providing cardiopulmonary resuscitation to children in the simulation environment. PMID- 22107150 TI - Adherence to anti-hypertensive medication: proposing and testing a conceptual model. AB - OBJECTIVES: A conceptual model of the psychological factors underpinning adherence to anti-hypertensive medication is proposed and tested. The model suggests that adherence is influenced by three sets of variables: demography, health status, and perceived effects of medication; cognitions and motivation; and intention to adhere. METHODS AND DESIGN: Patients with known hypertension were recruited from three primary care practices in South-East England and were asked to complete a postal questionnaire. A total of 1,070 responses were received. The questionnaire asked about the three sets of predictor variables, and adherence. Eight weeks after the first questionnaire, a second was posted to all respondents, this time asking about adherence over the intervening period. RESULTS: The three sets of predictor variables were treated as blocks in a hierarchical model, so that each successive block added to the variance in adherence explained by the previous blocks. The data were analysed by hierarchical multiple regression. The predictors accounted for 19% of the variance in adherence at Time 1, and 34% at Time 2. The leading individual predictors at Time 1 were age, gender, conscientiousness, hypertensive identity, perceived behavioural control, and intention. At Time 2, they were the same, except that gender made way for adherence at Time 1. CONCLUSIONS: The model offers a parsimonious account, and the findings suggest a number of approaches to designing interventions to modify behaviour. PMID- 22107151 TI - The tumour suppressor FOXO3 is a key regulator of mantle cell lymphoma proliferation and survival. AB - The FOXO3 (Forkhead/winged helix box class O 3) transcription factor is a crucial regulator of haematopoietic cell fate that controls proliferation and apoptosis, among other processes. Despite the central role of FOXO3 as a tumour suppressor and phosphatidylinositol 3-kinase (PI3K)/AKT effector, little is known about its involvement in mantle cell lymphoma (MCL) biology. This study investigated the expression and activity of FOXO3 in MCL cell lines and in primary cultures. We analysed the expression of key FOXO regulators and targets, and studied the effect of modulators of FOXO function on cell viability and apoptosis. FOXO3 was constitutively inactivated in MCL cell lines, and showed cytoplasmic localization in patient-derived cells. PI3K and AKT, but not mammalian target of rapamycin (mTOR), inhibitors induced FOXO3 nuclear translocation and activation in correlation with their impact on MCL proliferation and survival. Moreover, FOXO3 defective cells were resistant to PI3K/AKT inhibitors. Reactivation of FOXO function with a nuclear export inhibitor had a profound effect on cell viability, consistent with FOXO3 nuclear accumulation. Interestingly, inhibition of FOXO3 nuclear export enhanced the effect of doxorubicin. Taken together, our results confirm that FOXO3 is a relevant regulator of proliferation and apoptosis in MCL, and suggest that reactivation of FOXO3 function might be a useful therapeutic strategy in MCL patients. PMID- 22107152 TI - Local recurrence of rectal cancer: a population-based cohort study of diagnosis, treatment and outcome. AB - AIM: Local recurrence is an important endpoint of rectal cancer treatment, but details of this form of treatment failure are less well described. The aim of this study was to acquire deeper knowledge of local recurrence regarding symptoms, diagnostic work-up, clinical management, health-care utilization and outcome. METHOD: Of 671 patients with rectal cancer, 57 were diagnosed with local recurrence within 5 years after surgery. Their records were analysed. RESULTS: At diagnosis of local recurrence 49 (86%) of 57 patients were symptomatic and 40 (70%) were diagnosed between scheduled follow-up visits. The predominant symptom was pain. Forty-five of the 57 (79%) had a palpable tumour. Most were deemed incurable at presentation and 10 (18%) were operated on with curative intent. Five years after the initial rectal cancer surgery, two patients were alive, with one free of disease. Despite the need for multiple interventions, including surgery, only four out of 40 patients were classified as being well-palliated in the terminal stage. CONCLUSION: Follow-up after rectal cancer surgery by annual clinical examination is not sufficient to detect local recurrence when it is asymptomatic. Local recurrence of rectal cancer is often associated with intractable symptoms. These patients require frequent interventions and can rarely be cured if diagnosed at an advanced stage. Strategies for early detection of local recurrence and the management thereof require improvement. PMID- 22107153 TI - Silane layers on silicon surfaces: mechanism of interaction, stability, and influence on protein adsorption. AB - In this work the mechanism of (3-aminopropyl)triethoxysilane (APTES) interaction with silicon surfaces is investigated at the molecular level. We studied the influence of experimental parameters such as time, temperature, and concentration on the quality of the APTES layer in terms of chemical properties, morphology, and stability in aqueous medium. This was achieved using a highly sensitive IR mode recently developed, grazing angle attenuated total reflection (GA-ATR). This technique provides structural information on the formed APTES layer. The topography of this layer was investigated by atomic force microscopy in aqueous medium. The hydrophilicity was also studied using contact angle measurement. Combining these techniques enables discussion of the mechanism of silane grafting. Considerable differences were observed depending on the reaction temperature, room temperature or 90 degrees C. The data suggest the presence of two adsorption sites with different affinities on the oxidized silicon layer. This also allows the optimal parameters to be established to obtain an ordered and stable silane layer. The adsorption of proteins on the APTES layer was achieved and monitored using in situ quartz crystal microbalance with dissipation monitoring and ex situ GA-ATR analyses. PMID- 22107154 TI - Mercury reduction and oxidation by reduced natural organic matter in anoxic environments. AB - Natural organic matter (NOM)-mediated redox cycling of elemental mercury Hg(0) and mercuric Hg(II) is critically important in affecting inorganic mercury transformation and bioavailability. However, these processes are not well understood, particularly in anoxic water and sediments where NOM can be reduced and toxic methylmercury is formed. We show that under dark anoxic conditions reduced organic matter (NOM(re)) simultaneously reduces and oxidizes Hg via different reaction mechanisms. Reduction of Hg(II) is primarily caused by reduced quinones. However, Hg(0) oxidation is controlled by thiol functional groups via oxidative complexation, which is demonstrated by the oxidation of Hg(0) by low molecular-weight thiol compounds, glutathione, and mercaptoacetic acid, under reducing conditions. Depending on the NOM source, oxidation state, and NOM:Hg ratio, NOM reduces Hg(II) at initial rates ranging from 0.4 to 5.5 h(-1), which are about 2 to 6 times higher than those observed for photochemical reduction of Hg(II) in open surface waters. However, rapid reduction of Hg(II) by NOM(re) can be offset by oxidation of Hg(0) with an estimated initial rate as high as 5.4 h( 1). This dual role of NOM(re) is expected to strongly influence the availability of reactive Hg and thus to have important implications for microbial uptake and methylation in anoxic environments. PMID- 22107156 TI - Managed approaches to multiple sclerosis in special populations. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that is classified as an immune-mediated inflammatory disease. In managed care, patients with MS can be managed through care coordination that engages an interprofessional approach to a comprehensive spectrum of preventive, medical, rehabilitative, cognitive, and long-term health care services. In addition, the management paradigm for MS is currently in a stage of rapid evolution, with a number of new agents, including more oral drugs, expected to become available in the near future. Pharmacy and therapeutic committees may soon be faced with evaluating a hierarchy of new scientific data to differentiate the safety and efficacy of these new agents. Decisions will need to be made regarding the utility of these potential new agents among existing therapies with longer-term safety and efficacy data available in the scientific literature. For those MS patients managed under Medicaid, formulary and medication management decisions may be further impacted by psychosocial, cultural, educational, attitudinal, and/or economic factors that may be unique to the Medicaid population. The need to maximize immediate and long-term resource utilization is usually an important consideration when managing a Medicaid population. There is also an increasing focus on quality measures and quality outcomes by the Centers for Medicare and Medicaid Services. Many managed care professionals can be involved in establishing quality measures and quality improvement processes to effectively appropriate and manage the resources required for Medicaid patients with MS. As a result, medication and medical management of this special population can involve a comprehensive approach by managed care professionals. For purposes of this article, the term "special populations" applies to patients with MS who are managed under Medicaid plans. OBJECTIVES: To review (a) particular challenges managed care organizations (MCOs) encounter when managing special populations of Medicaid patients with MS, (b) recent efficacy and safety data for oral therapies for relapsing forms of MS, (c) costs of current MS therapies, and (d) potential strategies for managed care to improve care of their MS patient population and optimize clinical and economic outcomes. METHODS: Review of recent published literature, abstracts related to MS presented at major medical conferences, and recommendations from key organizations including the U.S. Department of Health and Human Services and the National Multiple Sclerosis Society. SUMMARY: The health economics of MS are a central issue for MCOs managing Medicaid patient populations. Additional challenges include the anticipated expansion of the marketplace to include several new oral agents and the lack of consensus guidelines for management of patients with MS. The benefit-risk profile of new agents will need to be considered in the context of established first-line parenteral drugs. Management of patients with MS should include an individualized approach for each patient as part of a shared decision-making process. In the overall management of special patient populations, case management and collaborative practice models in managed care may help to ensure that critical benchmarks are achieved. PMID- 22107157 TI - Measuring brain electrical activity to track recovery from sport-related concussion. AB - PRIMARY OBJECTIVE: To follow recovery from concussion in a sample of athletes using an electroencephalographic (EEG) index of quantitative brain activity developed previously on an independent Emergency Department (ED) sample of head injured subjects with traumatic brain injury. METHODS AND PROCEDURES: EEG recordings from five frontal electrode sites were obtained on 59 injured athletes and 31 controls at the time of injury and at 8 and 45 days afterward. All subjects also completed standardized clinical assessment of post-concussion symptoms, postural stability and cognitive functioning at injury and 8 and 45 days post-injury. RESULTS: Abnormalities in clinical assessment measures were observed in injured subjects only at time of injury. Statistical analysis of brain electrical activity measures with the ED-based algorithm revealed significant differences between injured athletes vs controls at the time of injury and at day 8. Measures from the two groups did not differ on day 45. CONCLUSIONS: This study demonstrated that an algorithm of brain electrical activity developed on an independent sample of ED subjects with head injury is sensitive to the effects of sport-related concussion. Using this algorithm, abnormal features of brain electrical activity were detected in athletes with concussion at the time of injury and persisted beyond the point of recovery on clinical measures. PMID- 22107158 TI - Study of an online molecularly imprinted solid phase extraction coupled to chemiluminescence sensor for the determination of trichlorfon in vegetables. AB - This study reports a new online molecularly imprinted solid phase extraction coupled to chemiluminescence for the determination of trichlorfon. This molecularly imprinted polymer (MIP) was prepared through bulk polymerization, in which methacrylic acid (MAA) was used as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the cross-linker. This novel functionalized material was characterized by FT-IR spectra and adsorption, and it exhibited good recognition and selective ability and fast adsorption-desorption dynamics toward trichlorfon. The factors affecting preconcentration of the analytes and sensitivity of the method are discussed in detail. Under the optimal condition, the linear range of the calibration graph was between 0.02 and 1.0 ng L(-1), and the detection limit was 1 * 10(3) ng L(-1). The blank cucumber samples spiked with trichlorfon at three levels were extracted and determined by the presented method with recoveries ranging from 83.5 to 94.5%, and the results were correlated well with those obtained using gas chromatography. Moreover, this developed method was successfully applied to the quantitative detection of trichlorfon residues in leek samples. PMID- 22107159 TI - Functional and muscle morphometric effects of ACL reconstruction. A prospective CT study with 1 year follow-up. AB - Computed tomography (CT) was used to explore if changes in muscle cross-sectional area and quality after anterior cruciate ligament (ACL) injury and reconstruction would be related to knee function. Fourteen females and 23 males (16-54 years) underwent clinical tests, subjective questionnaires, and CT 1 week before and 1 year after ACL surgery with semitendinosus-gracilis (STG) graft and rehabilitation. Postoperatively, knee laxity was decreased and functional knee measures and subjective patient scores improved. The most obvious remaining deficit was the quadriceps atrophy, which was significantly larger if the right leg was injured. Right-leg injury also tended to cause larger compensatory hypertrophy of the combined knee flexor and tibial internal rotator muscles (preoperatively). The quadriceps atrophy was significantly correlated with the scores and functional tests, the latter also being related to the remaining size of the gracilis muscle. Biceps femoris hypertrophy and, in males only, semimembranosus hypertrophy was observed following the ACL reconstruction. The lack of semimembranosus hypertrophy in the women could, via tibial internal rotation torque deficit, contribute to the less favorable functional and subjective outcome recorded for the women. The results indicate that the quadriceps, the combined knee flexor/tibial internal rotator muscles, side of ACL injury, and sex are important to consider in rehabilitation after STG graft. PMID- 22107160 TI - Intrusive luxation of 60 permanent incisors: a retrospective study of treatment and outcome. AB - BACKGROUND/AIM: Intrusive luxation in the permanent dentition is an uncommon injury but it is considered one of the most severe types of dental trauma because of the risk for damage to the periodontal ligament, pulp and alveolar bone. Management of intrusive luxation in the permanent dentition is controversial. The purpose of this study was to evaluate pulp survival and periodontal healing in intrusive luxated permanent teeth in relation to treatment alternatives, degree of intrusion and root development. MATERIAL AND METHOD: The material consisted of 60 intruded permanent teeth in 48 patients (32 boys and 16 girls) aged 6-16 years (mean 9.4, median 9.0). The observation time was 6-130 months (mean 47.8, median 40.0). The analysed treatments were spontaneous re-eruption (17 teeth), orthodontic extrusion (12 teeth) and surgical reposition (31 teeth). The degree of intrusion was registered as mild (0-3 mm), moderate (4-6 mm) and severe (>=7 mm). Root development was categorized with respect to root formation and development of the apex into four stages; one-quarter to three-quarters root formation, full root formation with open apex, full root formation with half closed apex and full root formation with apex closed. Ankylosis-related resorption with pulp necrosis was diagnosed in 20 teeth, ingrowth of bone apically in two teeth, pulp necrosis without ankylosis-related resorption in 23 teeth and pulp revitalization occurred in 15 teeth. RESULTS: Significant correlations to the treatment outcome were root development (P = 0.03) and degree of intrusion (P = 0.03). CONCLUSIONS: No firm conclusion could be drawn for the difference in outcome between orthodontic extrusion and surgical reposition. To conclude, evaluation of the prognosis for intruded teeth should be based on the stage of root development and degree of intrusion. In teeth with immature root development, no active treatment appears to result in fewer healing complications. PMID- 22107161 TI - The location and cellular composition of the hemopoietic stem cell niche. AB - While it is accepted that hemopoietic stem cells (HSC) are located in a three dimensional microenvironment, termed a niche, the cellular and extracellular composition, as well as the multifaceted effects the components of the niche have on HSC regulation, remains undefined. Over the past four decades numerous advances in the field have led to the identification of roles for some cell types and propositions of potentially a number of HSC niches. We present evidence supporting the roles of multiple cell types and extracellular matrix molecules in the HSC niche, as well as discuss the potential significant overlap and intertwining of previously proposed distinct HSC niches. PMID- 22107162 TI - Occupational stress, job characteristics, coping, and the mental health of nurses. AB - OBJECTIVES: This study investigated the relationships between job characteristics and coping in predicting levels of anxiety and depression in nurses. The study was based on current theories of occupational stress, and predictors included job demands, social support, decision authority and skill discretion control, effort, over-commitment, rewards, and ways of coping. It was predicted that job demands, extrinsic effort, over-commitment, and negative coping behaviours would be positively associated with depression and anxiety, and social support, rewards, decision authority, skill discretion control, and positive coping would be negatively associated with depression and anxiety. METHODS: Participants were 870 nurses, who responded to a bulk mail sent randomly to 4,000 nurses from the south of England. RESULTS: The results showed that job demands, extrinsic effort, and over-commitment were associated with higher levels of anxiety and depression. Social support, rewards, and skill discretion were negatively associated with mental health problems. Few interactions were found between the variables. Coping behaviours significantly added to the explanation of variance in anxiety and depression outcomes, over and above the use of demand-control-support, and effort-reward factors alone. CONCLUSION: The results from the study demonstrated the importance of coping factors in work-stress research, in accordance with the multi-factorial premise of transactional stress models. It is argued that multi-factor research is needed to help develop effective organizational interventions. PMID- 22107163 TI - Intracellular glutathione detection using MnO(2)-nanosheet-modified upconversion nanoparticles. AB - We report a novel design, based on a combination of lanthanide-doped upconversion nanoparticles and manganese dioxide nanosheets, for rapid, selective detection of glutathione in aqueous solutions and living cells. In this approach, manganese dioxide (MnO(2)) nanosheets formed on the surface of nanoparticles serve as an efficient quencher for upconverted luminescence. The luminescence can be turned on by introducing glutathione that reduces MnO(2) into Mn(2+). The ability to monitor the glutathione concentration intracellularly may enable rational design of a convenient platform for targeted drug and gene delivery. PMID- 22107164 TI - Exposure to formaldehyde and its potential human health hazards. AB - A widely used chemical, formaldehyde is normally present in both indoor and outdoor air. The rapid growth of formaldehyde-related industries in the past two decades reflects the result of its increased use in building materials and other commercial sectors. Consequently, formaldehyde is encountered almost every day from large segments of society due to its various sources. Many governments and agencies around the world have thus issued a series of standards to regulate its exposure in homes, office buildings, workshops, public places, and food. In light of the deleterious properties of formaldehyde, this article provides an overview of its market, regulation standards, and human health effects. PMID- 22107165 TI - Comparison and possible use of in silico tools for carcinogenicity within REACH legislation. AB - Seven in silico models have been used to assess the prediction accuracy of chemical compound carcinogenicity. More than 1500 compounds with experimental values have been used to evaluate the models. Here we review the application of these models for toxicity prediction and their advantages and disadvantages, discussing the different approaches underlying the models and their main critical points. Some models have fewer false negatives while others are better at avoiding false positives. Since carcinogenicity is typically evaluated using a series of studies, identification of a strategy using one, or preferably a battery of in silico models, could reduce the number of animal studies needed. PMID- 22107168 TI - Infant and toddler sleep in Australia and New Zealand. AB - AIMS: To characterize sleep patterns and sleep problems in a large sample of young children (birth to 36 months) in Australia (AU) and New Zealand (NZ). METHODS: Parents and caregivers of 2154 infants and toddlers in AU and NZ completed an expanded version of the Brief Infant Sleep Questionnaire. RESULTS: Overall, young children in AU and NZ go to bed relatively early (19:35), awaken on average 1.08 times per night for an average of 23 min, have a low likelihood of bed-sharing with parents (7.2%) and obtain an average of 13.24 h total sleep. However, a significant percentage of parents perceive that their child has a sleep problem (30.69%). Sleep patterns in these children demonstrate clear developmental changes, including a decrease in daytime sleep and total sleep time, as well as consolidation of sleep during the night (decrease in night wakings and nocturnal wakefulness). Parents in AU and NZ are also highly likely to encourage independence and self-soothing, especially after the age of 3 months. CONCLUSIONS: These findings provide parents and professionals reference data for assessing sleep in young children, as well as common parenting practices related to sleep behaviours. PMID- 22107166 TI - Polycyclic aromatic hydrocarbons and digestive tract cancers: a perspective. AB - Cancers of the colon are most common in the Western world. In majority of these cases, there is no familial history and sporadic gene damage seems to play an important role in the development of tumors in the colon. Studies have shown that environmental factors, especially diet, play an important role in susceptibility to gastrointestinal (GI) tract cancers. Consequently, environmental chemicals that contaminate food or diet during preparation become important in the development of GI cancers. Polycyclic aromatic hydrocarbons (PAHs) are one such family of ubiquitous environmental toxicants. These pollutants enter the human body through consumption of contaminated food, drinking water, inhalation of cigarette smoke, automobile exhausts, and contaminated air from occupational settings. Among these pathways, dietary intake of PAHs constitutes a major source of exposure in humans. Although many reviews and books on PAHs and their ability to cause toxicity and breast or lung cancer have been published, aspects on contribution of diet, smoking and other factors toward development of digestive tract cancers, and strategies to assess risk from exposure to PAHs have received much less attention. This review, therefore, focuses on dietary intake of PAHs in humans, animal models, and cell cultures used for GI cancer studies along with epidemiological findings. Bioavailability and biotransformation processes, which influence the disposition of PAHs in body and the underlying causative mechanisms of GI cancers, are also discussed. The existing data gaps and scope for future studies is also emphasized. This information is expected to stimulate research on mechanisms of sporadic GI cancers caused by exposure to environmental carcinogens. PMID- 22107169 TI - Physicians' communication of the common-sense self-regulation model results in greater reported adherence than physicians' use of interpersonal skills. AB - OBJECTIVES: Interventions that address patients' illness and treatment representations have improved patient adherence and outcomes when administered by psychologists and/or health educators and focused on a single chronic illness. The current study assesses the potential feasibility/effectiveness of an intervention based on the common-sense self-regulation model (CS-SRM) when administered by providers in a primary care setting. DESIGN: We designed a prospective, correlational study in order to optimize patients' and providers' time and to gain initial evidence of the CS-SRM-approach's feasibility/effectiveness. METHODS: Patients (n= 243) were recruited from a primary care waiting room and reported on objective behaviours of their providers (providers' CS-SRM-related behaviours and interpersonal skills) and other theoretically related measures directly after the medical encounter and reported on adherence, presenting problem resolution, and emergency care usage 1 month later. RESULTS: The more providers gave their patients an adaptive understanding of their presenting problem/treatment (the greater the number of CS-SRM-related behaviours they engaged in), the more adherent were patients in the month following the encounter and the better was their problem resolution 1 month later. The CS-SRM-related behaviours were more predictive of these outcomes and emergency care usage than were the providers' interpersonal skills. CONCLUSIONS: In the time-limited encounter, interventions may have to prioritize theoretical approaches for attaining patient adherence. The current study, although correlational, indicates that addressing the patients' illness/treatment representations is more important than the providers' interpersonal skills for attaining patient adherence and provides preliminary evidence that a CSM-based intervention in the primary care setting may be both feasible and effective. PMID- 22107171 TI - Numerical study on the adhesion and reentrainment of nondeformable particles on surfaces: the role of surface roughness and electrostatic forces. AB - In this paper, the reentrainment of nanosized and microsized particles from rough walls under various electrostatic conditions and various hydrodynamic conditions (either in air or aqueous media) is numerically investigated. This issue arises in the general context of particulate fouling in industrial applications, which involves (among other phenomena) particle deposition and particle reentrainment. The deposition phenomenon has been studied previously and, in the present work, we focus our attention on resuspension. Once particles are deposited on a surface, the balance between hydrodynamic forces (which tend to move particles away from the surface) and adhesion forces (which maintain particles on the surface) can lead to particle removal. Adhesion forces are generally described using van der Waals attractive forces, but the limit of these models is that any dependence of adhesion forces on electrostatic forces (due to variations in pH or ionic strength) cannot be reproduced numerically. For this purpose, we develop a model of adhesion forces that is based on the DLVO (Derjaguin and Landau, Verwey and Overbeek) theory and which includes also the effect of surface roughness through the use of hemispherical asperities on the surface. We first highlight the effect of the curvature radius on adhesion forces. Then some numerical predictions of adhesion forces or adhesion energies are compared to experimental data. Finally, the overall effects of surface roughness and electrostatic forces are demonstrated with some applications of the complete reentrainment model in some simple test cases. PMID- 22107170 TI - Participation, characteristics and retention rates of HIV-positive immigrants in the Swiss HIV Cohort Study. AB - OBJECTIVE: Data from observational cohorts may be influenced by population structure and loss to follow-up (LTFU). Quality of care may be associated with participation in cohort networks. We aimed to study the participation, characteristics and retention rates of immigrants in the Swiss HIV Cohort Study (SHCS). METHODS: We compared enrolment over time (1996-1999, 2000-2003 and 2004 2008) and LTFU between individuals from different geographical regions. In 2008, we performed a cross-sectional survey to investigate the proportion of individuals not participating in the SHCS but who were in care at SHCS institutions. Predictors for LTFU were analysed using Cox proportional hazard models, and those for nonparticipation using logistic regression. RESULTS: A total of 7840 individuals entered the SHCS during the observation period. The proportion of immigrants increased over time, especially the proportion of women from sub-Saharan Africa, which increased from 21 to 48% during the observation period. Overall LTFU was 3.76 [95% confidence interval (CI) 3.58-3.95]/100, with the highest hazard ratio in men from sub-Saharan Africa (2.82/100 patient-years; 95% CI 2.30-3.46/100), compared with men from northwestern countries. Other predictors for LTFU were age <30 years, lower education, injecting drug use, and higher baseline CD4 cell counts. Participants taking antiretroviral therapy had reduced LTFU. The survey showed that 84% of HIV-infected patients in care at SHCS institutions were enrolled in the cohort. Nonparticipation was more likely among men from non-European regions (odds ratio 2.73; 95% CI 2.29-3.24), women from sub Saharan Africa (odds ratio 3.01; 95% CI 2.40-3.77) and women from Latin America/Caribbean (odds ratio 2.10; 95% CI 1.30-3.39). CONCLUSIONS: Numbers of HIV-infected immigrants are increasing but they are underrepresented in the SHCS, and immigrants are more likely to be lost to follow-up. PMID- 22107172 TI - Bond breaking, electron pushing, and proton pulling: active and passive roles in the interaction between aqueous ions and water as manifested in the O 1s Auger decay. AB - A core-ionized H(2)O molecule in liquid water primarily relaxes through normal Auger decay, leading to a two-hole final state in which both valence holes are localized on the same water molecule. Electronic coupling to the environment, however, allows for alternative decays resembling Intermolecular Coulombic Decay (ICD), producing final states with one of the holes delocalized on a neighboring water molecule. Here we present an experimental study of such minority processes, which adds to our understanding of dynamic interactions of electronically excited H(2)O molecules with their local surrounding in liquid water and aqueous solution. We show that the solvation of metal-halide salts considerably influences these minority decay channels from the water O 1s(-1) state. By breaking water-water bonds, both the metal cations and halide anions are found to reduce the decay into water-water delocalized states, thus having a "passive" effect on the Auger spectrum. The halide anions also play an "active" role by opening a new ICD-like decay pathway into water-halide delocalized states. The importance of this contribution increases from F(-) to I(-), which we suggest to be caused by a directional polarization of the halide anion toward the core ionized H(2)O(+) cation in the intermediate state of the Auger process. This increases the electronic overlap between the two centers and makes delocalized decays more probable. We furthermore show that F(-), the smallest and most strongly hydrated of the halides, plays an additional role as proton puller during the core-hole lifetime, resulting in proton dynamics on the low femtosecond time scale. Our results represent a step forward toward a better understanding of how aqueous solutions, when exposed to soft X-rays, channel excess energy. This has implications for several aspects of physical and radiation chemistry, as well as biology. PMID- 22107173 TI - Maintenance intravenous fluids with 0.9% sodium chloride do not produce hypernatraemia in children. PMID- 22107174 TI - Phages of Bacteroides (GB-124): a novel tool for viral waterborne disease control? AB - Current fecal indicator bacteria (FIB) and emerging microbial source tracking (MST) methods may indicate the presence and even the likely source of water contamination, but they are less effective at determining the potential risk to health from human enteric viruses. This paper investigates the presence of human specific phages (detected using a low-cost MST method) in municipal wastewaters (MW) and assesses whether they may be used effectively to screen for the likely presence of human adenovirus (HAdV) and norovirus (NoV). The findings demonstrated that all samples positive for HAdV and/or NoV also contained phages infecting Bacteroides GB-124 (mean = 4.36 log(10) PFU/100 mL) and that GB-124 phages, HAdV, and NoV were absent from samples of nonhuman origin. HAdV and NoV were detected more frequently in MW samples containing higher levels of phages (e.g., >10(2)) and FIB (e.g., >10(3)). Interestingly, at one sewage treatment works (STW), the levels of GB-124 phages present in treated MW were not significantly lower (p = 0.001) than those in untreated MW. There was a positive correlation (R = 0.42) between the size of STW and the number of GB-124 phages present in the final treated effluent. Therefore, the detection of GB-124 phages by a simple phage-lysis method may have considerable potential as a low-cost surrogate for the detection of certain human pathogenic viruses in MW and receiving waters. PMID- 22107175 TI - Development and optimization of lyophilized orally disintegrating tablets using factorial design. AB - The aim of this study was to evaluate the use of maltodextrin as a sugar-matrix former along with several cellulosic binders in the preparation of freeze-dried orally disintegrating tablets (ODT). The ODT was prepared by freeze-drying an aqueous dispersion of nimesulide (NM) containing maltodextrin and a cellulosic binder. The influence of formulation parameters on the in vitro/in vivo disintegration time and in vitro dissolution of NM from ODTs along with other tablet characteristics was investigated using full factorial design. The optimized ODT contained 5% w/v maltodextrin DE 29, 2% w/v Methocel E15, and 5% w/v NM, disintegrated in less than 10 s and showed more than 70% of NM in ODTs dissolved within 2 min, compared to only 1.52% of NM plain drug and 7.25% of NM in immediate release commercial tablet. Crystalline state evaluation of NM in the optimized ODT was conducted through differential scanning calorimetry, and X-ray powder diffraction. The study suggests that the optimized ODT formulation developed in this work may be an alternative to conventional formulations of NM inconvenient to the patients such as intramuscular or rectal administration. PMID- 22107176 TI - Post-concussion syndrome: prevalence after mild traumatic brain injury in comparison with a sample without head injury. AB - PRIMARY OBJECTIVE: To compare the prevalence of persistent post-concussion syndrome (PCS; >1 year post-injury) in participants with mild traumatic brain injury (mTBI) and those without head injury. RESEARCH DESIGN: A cross-sectional sample of 119 participants with mTBI and 246 without previous head injury. METHODS: Online questionnaires collected data about post-concussion symptoms, cognitive failures, anxiety, depression, sleep behaviour and post-traumatic stress disorder. Variability within the sample was addressed by splitting by PCS diagnosis to create four groups: mTBI + PCS, mTBI-PCS, Control + PCS and Control PCS. PCS was diagnosed using ICD-10 criteria in all groups, with controls not requiring previous head injury. MAIN OUTCOMES AND RESULTS: PCS was present to a similar extent in participants with no head injury (34%) compared to those with mTBI (31%). Only report of headaches, which could be caused by expectation bias, distinguished between mTBI + PCS and Control + PCS groups. In addition, significantly higher cognitive problems were observed in participants with mTBI compared with the control group. CONCLUSIONS: Persistent PCS, as currently defined, is not specific to mTBI. These data suggest that somatic and cognitive symptoms are most likely to be able to distinguish PCS after mTBI from that present in the general population. Further research is necessary into these factors in order to create more specific PCS diagnostic criteria. PMID- 22107177 TI - Rotons in interacting ultracold bose gases. AB - In three dimensions, noninteracting bosons undergo Bose-Einstein condensation at a critical temperature, T(c), which is slightly shifted by DeltaT(c), if the particles interact. We calculate the excitation spectrum of interacting Bose systems, (4)He and (87)Rb, and show that a roton minimum emerges in the spectrum above a threshold value of the gas parameter. We provide a general theoretical argument for why the roton minimum and the maximal upward critical temperature shift are related. We also suggest two experimental avenues to observe rotons in condensates. These results, based upon a path-integral Monte Carlo approach, provide a microscopic explanation of the shift in the critical temperature and also show that a roton minimum does emerge in the excitation spectrum of particles with a structureless, short-range, two-body interaction. PMID- 22107178 TI - Exploring symmetry breaking at the Dicke quantum phase transition. AB - We study symmetry breaking at the Dicke quantum phase transition by coupling a motional degree of freedom of a Bose-Einstein condensate to the field of an optical cavity. Using an optical heterodyne detection scheme, we observe symmetry breaking in real time and distinguish the two superradiant phases. We explore the process of symmetry breaking in the presence of a small symmetry-breaking field and study its dependence on the rate at which the critical point is crossed. Coherent switching between the two ordered phases is demonstrated. PMID- 22107179 TI - Environment-induced sudden transition in quantum discord dynamics. AB - Nonclassical correlations play a crucial role in the development of quantum information science. The recent discovery that nonclassical correlations can be present even in separable (nonentangled) states has broadened this scenario. This generalized quantum correlation has been increasing in relevance in several fields, among them quantum communication, quantum computation, quantum phase transitions, and biological systems. We demonstrate here the occurrence of the sudden-change phenomenon and immunity against some sources of noise for the quantum discord and its classical counterpart, in a room temperature nuclear magnetic resonance setup. The experiment is performed in a decohering environment causing loss of phase relations among the energy eigenstates and exchange of energy between system and environment, resulting in relaxation to the Gibbs ensemble. PMID- 22107180 TI - Nonequilibrium entropy production for open quantum systems. AB - We consider open quantum systems weakly coupled to a heat reservoir and driven by arbitrary time-dependent parameters. We derive exact microscopic expressions for the nonequilibrium entropy production and entropy production rate, valid arbitrarily far from equilibrium. By using the two-point energy measurement statistics for system and reservoir, we further obtain a quantum generalization of the integrated fluctuation theorem put forward by Seifert [Phys. Rev. Lett. 95, 040602 (2005)]. PMID- 22107181 TI - Large fluctuations in driven dissipative media. AB - We analyze the fluctuations of the dissipated energy in a simple and general model where dissipation, diffusion, and driving are the key ingredients. The full dissipation distribution, which follows from hydrodynamic fluctuation theory, shows non-Gaussian tails and no negative branch, thus violating the fluctuation theorem as expected from the irreversibility of the dynamics. It exhibits simple scaling forms in the weak- and strong-dissipation limits, with large fluctuations favored in the former case but strongly suppressed in the latter. The typical path associated with a given dissipation fluctuation is also analyzed in detail. Our results, confirmed in extensive simulations, strongly support the validity of hydrodynamic fluctuation theory to describe fluctuating behavior in driven dissipative media. PMID- 22107182 TI - Periastron advance in black-hole binaries. AB - The general relativistic (Mercury-type) periastron advance is calculated here for the first time with exquisite precision in full general relativity. We use accurate numerical relativity simulations of spinless black-hole binaries with mass ratios 1/8<=m(1)/m(2)<=1 and compare with the predictions of several analytic approximation schemes. We find the effective-one-body model to be remarkably accurate and, surprisingly, so also the predictions of self-force theory [replacing m(1)/m(2)->m(1)m(2)/(m(1)+m(2))(2)]. Our results can inform a universal analytic model of the two-body dynamics, crucial for ongoing and future gravitational-wave searches. PMID- 22107183 TI - Search for an annual modulation in a p-type Point Contact germanium dark matter detector. AB - Fifteen months of cumulative CoGeNT data are examined for indications of an annual modulation, a predicted signature of weakly interacting massive particle (WIMP) interactions. Presently available data support the presence of a modulated component of unknown origin, with parameters prima facie compatible with a galactic halo composed of light-mass WIMPs. Unoptimized estimators yield a statistical significance for a modulation of ~2.8sigma, limited by the short exposure. PMID- 22107184 TI - Precision measurement of the (7)Be solar neutrino interaction rate in Borexino. AB - The rate of neutrino-electron elastic scattering interactions from 862 keV (7)Be solar neutrinos in Borexino is determined to be 46.0+/-1.5(stat)( 1.6)(+1.5)(syst) counts/(day.100 ton). This corresponds to a nu(e)-equivalent (7)Be solar neutrino flux of (3.10+/-0.15)*10(9) cm(-2) s(-1) and, under the assumption of nu(e) transition to other active neutrino flavours, yields an electron neutrino survival probability of 0.51+/-0.07 at 862 keV. The no flavor change hypothesis is ruled out at 5.0 sigma. A global solar neutrino analysis with free fluxes determines Phi(pp)=6.06(-0.06)(+0.02)*10(10) cm(-2) s(-1) and Phi(CNO)<1.3*10(9) cm(-2) s(-1) (95% C.L.). These results significantly improve the precision with which the Mikheyev-Smirnov-Wolfenstein large mixing angle neutrino oscillation model is experimentally tested at low energy. PMID- 22107185 TI - Delta(1232) axial charge and form factors from lattice QCD. AB - We present the first calculation on the Delta axial vector and pseudoscalar form factors using lattice QCD. Two Goldberger-Treiman relations are derived and examined. A combined chiral fit is performed to the nucleon axial charge, N to Delta axial transition coupling constant and Delta axial charge. PMID- 22107187 TI - Chirped-pulse millimeter-wave spectroscopy of Rydberg-Rydberg transitions. AB - Transitions between Rydberg states of Ca atoms, in a pulsed, supersonic atomic beam, are directly detected by chirped-pulse millimeter-wave spectroscopy. Broadband, high-resolution spectra with accurate relative intensities are recorded instantly. Free induction decay (FID) of atoms, polarized by the chirped pulse, at their Rydberg-Rydberg transition frequencies, is heterodyne detected, averaged in the time domain, and Fourier transformed into the frequency domain. Millimeter-wave transient nutations are observed, and the possibility of FID evolving to superradiance is discussed. PMID- 22107188 TI - Laser spectroscopy on forbidden transitions in trapped highly charged Ar(13+) ions. AB - We demonstrate resonant fluorescence laser spectroscopy in highly charged ions (HCI) stored in an electron beam ion trap by investigating the dipole-forbidden 1s(2)2s(2)2p (2)P(3/2)-(2)P(1/2) transition in boronlike Ar(13+) ions. Forced evaporative cooling yielded a high resolving power, resulting in an accurate wavelength determination to lambda=441.255 68(26) nm. By applying stronger cooling and two-photon excitation, new optical frequency standards based upon ultrastable transitions in such HCI could be realized in the future, e.g., for the search of time variations of the fine-structure constant. PMID- 22107189 TI - Phase-sensitive cyclotron frequency measurements at ultralow energies. AB - A novel technique for a direct and coherent measurement of the modified cyclotron frequency of an ion in a Penning trap at energies close to the thermal cooling limit is presented. This allows a rapid and both precise and accurate determination of the free-space cyclotron frequency in real Penning traps despite the existence of electric and magnetic field imperfections and relativistic shifts. The demonstrated performance paves the way for considerably improved bound-state g-factor measurements on the 10 ppt level and mass measurements in the 1 ppt range and possibly below. PMID- 22107190 TI - Strong field electron emission from fixed in space H(2)(+) ions. AB - We have studied electron emission from the H(2)(+) ion by a circularly polarized laser pulse (800 nm, 6*10(14) W/cm(2)). The electron momentum distribution in the body fixed frame of the molecule is experimentally obtained by a coincident detection of electrons and protons. The data are compared to a solution of the time-dependent Schrodinger equation in two dimensions. We find radial and angular distributions which are at odds with the quasistatic enhanced ionization model. The unexpected momentum distribution is traced back to a complex laser-driven electron dynamics inside the molecule influencing the instant of ionization and the initial momentum of the electron. PMID- 22107191 TI - Optomechanical cavity cooling of an atomic ensemble. AB - We demonstrate cavity sideband cooling of a single collective motional mode of an atomic ensemble down to a mean phonon occupation number ?n?(min?)=2.0( 0.3)(+0.9). Both ?n?(min) and the observed cooling rate are in good agreement with an optomechanical model. The cooling rate constant is proportional to the total photon scattering rate by the ensemble, demonstrating the cooperative character of the light-emission-induced cooling process. We deduce fundamental limits to cavity cooling either the collective mode or, sympathetically, the single-atom degrees of freedom. PMID- 22107192 TI - Precision calculation of blackbody radiation shifts for optical frequency metrology. AB - We show that three group IIIB divalent ions, B(+), Al(+), and In(+), have anomalously small blackbody radiation (BBR) shifts of the ns(2) (1)S(0)-nsnp (3)P(0)(o) clock transitions. The fractional BBR shifts for these ions are at least 10 times smaller than those of any other present or proposed optical frequency standards at the same temperature, and are less than 0.3% of the Sr clock shift. We have developed a hybrid configuration-interaction + coupled cluster method that provides accurate treatment of correlation corrections in such ions and yields a rigorous upper bound on the uncertainty of the final results. We reduce the BBR contribution to the fractional frequency uncertainty of the Al(+) clock to 4*10(-19) at T=300 K. We also reduce the uncertainties due to this effect at room temperature to 10(-18) level for B(+) and In(+) to facilitate further development of these systems for metrology and quantum sensing. PMID- 22107193 TI - Prominent higher-order contributions to electronic recombination. AB - Intershell higher-order (HO) electronic recombination is reported for highly charged Ar, Fe, and Kr ions, where simultaneous excitation of one K-shell electron and one or two additional L-shell electrons occurs upon resonant capture of a free electron. For the mid-Z region, HO resonance strengths grow unexpectedly strong with decreasing atomic number Z (?Z(-4)), such that, for Ar ions the 2nd-order overwhelms the 1st-order resonant recombination considerably. The experimental findings are confirmed by multiconfiguration Dirac-Fock calculations including hitherto neglected excitation pathways. PMID- 22107186 TI - Cold nuclear matter effects on J/psi yields as a function of rapidity and nuclear geometry in d+A collisions at sqrt[s(NN)]=200 GeV. AB - We present measurements of J/psi yields in d+Au collisions at sqrt[s(NN)]=200 GeV recorded by the PHENIX experiment and compare them with yields in p+p collisions at the same energy per nucleon-nucleon collision. The measurements cover a large kinematic range in J/psi rapidity (-2.2100 K). A theoretical model that includes scattering due to surface polar phonon modes of the substrates reproduces the experiments very well. The role of surface phonons is further confirmed by resistivity measurements of nanotubes on aluminum nitride. PMID- 22107222 TI - Control of spin waves in a thin film ferromagnetic insulator through interfacial spin scattering. AB - Control of spin waves in a ferrite thin film via interfacial spin scattering was demonstrated. The experiments used a 4.6 MUm-thick yttrium iron garnet (YIG) film strip with a 20-nm thick Pt capping layer. A dc current pulse was applied to the Pt layer and produced a spin current across the Pt thickness. As the spin current scatters off the YIG surface, it can either amplify or attenuate spin wave pulses that travel in the YIG strip, depending on the current or field configuration. The spin scattering also affects the saturation behavior of high power spin waves. PMID- 22107223 TI - Equilibrium circular photogalvanic effect in a hybrid superconductor semiconductor system. AB - A dc electric current can be induced in a hybrid semiconductor-superconductor system under illumination of it by a circularly polarized light with the frequency below the energy of semiconductor interband transitions. In conditions when the light beam is unable to create real electron-hole excitations, this phenomenon is reminiscent of the Meissner effect in the static magnetic field. Such an effect can be employed in systems combining cavity photons and superconducting quantum circuits. PMID- 22107224 TI - Orbital Kondo effect in cobalt-benzene sandwich molecules. AB - We study a Co-benzene sandwich molecule bridging the tips of a Cu nanocontact as a realistic model of correlated molecular transport. To this end we employ a recently developed method for calculating the correlated electronic structure and transport properties of nanoscopic conductors. When the molecule is slightly compressed by the tips of the nanocontact the dynamic correlations originating from the strongly interacting Co 3d shell give rise to an orbital Kondo effect while the usual spin Kondo effect is suppressed due to Hund's rule coupling. This nontrivial Kondo effect produces a sharp and temperature-dependent Abrikosov-Suhl resonance in the spectral function at the Fermi level and a corresponding Fano line shape in the low bias conductance. PMID- 22107225 TI - Electrically tunable macroscopic quantum tunneling in a graphene-based Josephson junction. AB - Stochastic switching-current distribution in a graphene-based Josephson junction exhibits a crossover from the classical to quantum regime, revealing the macroscopic quantum tunneling of a Josephson phase particle at low temperatures. Microwave spectroscopy measurements indicate a multiphoton absorption process occurring via discrete energy levels in washboard potential well. The crossover temperature for macroscopic quantum tunneling and the quantized level spacing are controlled with the gate voltage, implying its potential application to gate tunable superconducting quantum bits. PMID- 22107226 TI - Two-qubit gate of combined single-spin rotation and interdot spin exchange in a double quantum dot. AB - A crucial requirement for quantum-information processing is the realization of multiple-qubit quantum gates. Here, we demonstrate an electron spin-based all electrical two-qubit gate consisting of single-spin rotations and interdot spin exchange in a double quantum dot. A partially entangled output state is obtained by the application of the two-qubit gate to an initial, uncorrelated state. We find that the degree of entanglement is controllable by the exchange operation time. The approach represents a key step towards the realization of universal multiple-qubit gates. PMID- 22107227 TI - Fractional quantum Hall effect of hard-core bosons in topological flat bands. AB - Recent proposals of topological flat band models have provided a new route to realize the fractional quantum Hall effect without Landau levels. We study hard core bosons with short-range interactions in two representative topological flat band models, one of which is the well-known Haldane model (but with different parameters). We demonstrate that fractional quantum Hall states emerge with signatures of an even number of quasidegenerate ground states on a torus and a robust spectrum gap separating these states from the higher energy spectrum. We also establish quantum phase diagrams for the filling factor 1/2 and illustrate quantum phase transitions to other competing symmetry-breaking phases. PMID- 22107228 TI - Band gap and edge engineering via ferroic distortion and anisotropic strain: the case of SrTiO(3). AB - The effects of ferroic distortion and biaxial strain on the band gap and band edges of SrTiO(3) are calculated by using density functional theory and many-body perturbation theory. Anisotropic strains are shown to reduce the gap by breaking degeneracies at the band edges. Ferroic distortions are shown to widen the gap by allowing new band edge orbital mixings. Compressive biaxial strains raise band edge energies, while tensile strains lower them. To reduce the SrTiO(3) gap, one must lower the symmetry from cubic while suppressing ferroic distortions. Our calculations indicate that, for engineered orientation of the growth direction along [111], the SrTiO(3) gap can be controllably and considerably reduced at room temperature. PMID- 22107229 TI - Consistent description of the metallic phase of overdoped cuprate superconductors as an anisotropic marginal Fermi liquid. AB - We consider a model self-energy consisting of an isotropic Fermi liquid term and a marginal Fermi liquid term which is anisotropic over the Fermi surface, vanishing in the same directions as the superconducting gap and the pseudogap. This model self-energy gives a consistent description of experimental results from angle-dependent magnetoresistance, specific heat, de Haas-van Alphen, and measurements of the quasiparticle dispersion near the Fermi surface from photoemission. In particular, we reconcile the strongly doping-dependent anomalous scattering rate observed in angle-dependent magnetoresistance with the almost doping-independent specific heat. PMID- 22107230 TI - Evolution of the superconducting state of Fe-based compounds with doping. AB - We introduce an effective low-energy pairing model for Fe-based superconductors with s- and d-wave interaction components and a small number of input parameters and use it to study the doping evolution of the symmetry and the structure of the superconducting gap. We argue that the model describes the entire variety of pairing states found so far in the Fe-based superconductors and allows one to understand the mechanism of the attraction in s(+/-) and d(x(2)-y(2)) channels, the competition between s- and d-wave solutions, and the origin of superconductivity in heavily doped systems, when only electron or only hole pockets are present. PMID- 22107231 TI - Intrinsic coupling of orbital excitations to spin fluctuations in Mott insulators. AB - We show how the general and basic asymmetry between two fundamental degrees of freedom present in strongly correlated oxides, spin and orbital, has very profound repercussions on the elementary spin and orbital excitations. Whereas the magnons remain largely unaffected, orbitons become inherently coupled with spin fluctuations in spin-orbital models with antiferromagnetic and ferro-orbital ordered ground states. The composite orbiton-magnon modes that emerge fractionalize again in one dimension, giving rise to spin-orbital separation in the peculiar regime where spinons are faster than orbitons. PMID- 22107232 TI - Characterization of an organic field-effect thin-film transistor in operation using fluorescence-yield x-ray absorption spectroscopy. AB - In situ element-specific observation of electronic states of organic films beneath metal electrodes is achieved by x-ray absorption spectroscopy (XAS) in the bulk-sensitive fluorescence-yield (FY) mode. The molecular orientation in Au covered oligo-thiophene films is confirmed by the C K-edge FY-XAS spectra and the applied bias dependence of the spectra is successfully detected for the first time. The present method can give deeper insights into the electronic-state investigation of various real-device systems under operational conditions. PMID- 22107233 TI - 4-(cyanomethyl)anilinium perchlorate: a new displacive-type molecular ferroelectric. AB - A new organic ferroelectric compound, 4-(cyanomethyl)anilinium perchlorate, proceeds a second-order phase transition from a paraelectric phase (P2(1)/m) to a ferroelectric phase (P2(1)) at 184 K. A perfect ferroelectric hysteresis loop was observed even at 10 KHz. It is the first example of a molecule-based organic ferroelectric whose polarization can be switched at such a high frequency. The temperature dependent second harmonic generation effect shows that the second order nonlinear coefficient is nearly zero above T(c) and proportional to the spontaneous polarization below T(c), suggesting the occurrence of symmetry breaking, in good agreement with crystal structural determination. The origin of ferroelectricity was ascribed to the displacements of -NH(3)(+) cations and ClO(4)(-) anions from the symmetric positions including a small part of the order disorder behaviors of the ClO(4)(-) anions. PMID- 22107234 TI - Microscopic origin of the giant ferroelectric polarization in tetragonal-like BiFeO(3). AB - We report direct experimental evidence for a room-temperature, ~130 MUC/cm(2) ferroelectric polarization from the tetragonal-like BiFeO(3) phase. The physical origin of this remarkable enhancement of ferroelectric polarization has been investigated by a combination of x-ray absorption spectroscopy, scanning transmission electron microscopy, and first principles calculations. A large strain-induced Fe-ion displacement relative to the oxygen octahedra, combined with the contribution of Bi 6s lone pair electrons, is the mechanism driving the large ferroelectric polarization in this tetragonal-like phase. PMID- 22107235 TI - Stick-slip friction and energy dissipation in boundary lubrication. AB - Shearing of a simple nonpolar film, right after the liquid-to-solid phase transition under nanometer confinement, is studied by using a liquid-vapor molecular dynamics simulation method. We find that, in contrast with the shear melting and recrystallization behavior of the solidlike phase during the stick slip motion, interlayer slips within the film and wall slips at the wall-film interface are often observed. The ordered solidified film is well maintained during the slip. Through the time variations of the frictional force and potential energy change within the film, we find that both the friction dissipation during the slip and the potential energy decay after the slip in the solidified film take a fairly large portion of the total energy dissipation. PMID- 22107236 TI - Effects of input noise on a simple biochemical switch. AB - Many biological processes are controlled by biomolecular switches which themselves are regulated by various upstream chemical molecules (the input). Understanding how input noise affects the output stochastic switching process is of significant interest in various biophysical systems like gene regulation, chemosensing, and cell motility. Here, we propose an exactly solvable model where the noisy input signal arises from a simple birth-death process and directly regulates the transition rates of a downstream switch. We solve the joint master equations to analyze the statistical properties of the output switching process. Our results suggest that the conventional wisdom of an additive input-output noise rule fails to describe signaling systems containing a single molecular switch, and, instead, the most important effect of input noise is to effectively reduce the on rate of the switch. PMID- 22107237 TI - Three classes of motion in the dynamic neutron-scattering susceptibility of a globular protein. AB - A simplified description of the 295 K dynamics of a globular protein over a wide frequency range (1-1000 GHz) is obtained by combining neutron scattering of lysozyme with molecular dynamics simulation. The molecular dynamics simulation agrees quantitatively with experiment for both the protein and the hydration water and shows that, whereas the hydration water molecules subdiffuse, the protein atoms undergo confined motion decomposable into three distinct classes: localized diffusion, methyl group rotations, and jumps. Each of the three classes gives rise to a characteristic neutron susceptibility signal. PMID- 22107238 TI - Emergence of synchronized beating during the regrowth of eukaryotic flagella. AB - A fundamental issue in the biology of eukaryotic flagella is the origin of synchronized beating observed in tissues and organisms containing multiple flagella. Recent studies of the biflagellate unicellular alga Chlamydomonas reinhardtii provided the first evidence that the interflagellar coupling responsible for synchronization is of hydrodynamic origin. To investigate this mechanism in detail, we study here synchronization in Chlamydomonas as its flagella slowly regrow after mechanically induced self-scission. The duration of synchronized intervals is found to be strongly dependent on flagellar length. Analysis within a stochastic model of coupled phase oscillators is used to extract the length dependence of the interflagellar coupling and the intrinsic beat frequencies of the two flagella. Physical and biological considerations that may explain these results are proposed. PMID- 22107239 TI - Single-molecule elasticity measurements of the onset of excluded volume in poly(ethylene glycol). AB - A polymer must reach a certain size to exhibit significant excluded-volume interactions and adopt a swollen random-walk configuration. We show that single molecule measurements can sense the onset of swelling by modulating the effective chain size with force: as the force is reduced from a large value, the polymer is first highly aligned, then a Gaussian coil, then finally a swollen chain, with each regime exhibiting a distinct elasticity. We use this approach to quantify the structural parameters of poly(ethylene glycol) and show that they vary in the expected manner with changes in solvent. PMID- 22107240 TI - Structural signature of a brittle-to-ductile transition in self-assembled networks. AB - We study the nonlinear rheology of a novel class of transient networks, made of surfactant micelles of tunable morphology reversibly linked by block copolymers. We couple rheology and time-resolved structural measurements, using synchrotron radiation, to characterize the highly nonlinear viscoelastic regime. We propose the fluctuations of the degree of alignment of the micelles under shear as a probe to identify a fracture process. We show a clear signature of a brittle-to ductile transition in transient gels, as the morphology of the micelles varies, and provide a parallel between the fracture of solids and the fracture under shear of viscoelastic fluids. PMID- 22107241 TI - Polydispersity stabilizes biaxial nematic liquid crystals. AB - Inspired by the observations of a remarkably stable biaxial nematic phase [van den Pol et al., Phys. Rev. Lett. 103, 258301 (2009)], we investigate the effect of size polydispersity on the phase behavior of a suspension of boardlike particles. By means of Onsager theory within the restricted orientation (Zwanzig) model we show that polydispersity induces a novel topology in the phase diagram, with two Landau tetracritical points in between which oblate uniaxial nematic order is favored over the expected prolate order. Additionally, this phenomenon causes the opening of a huge stable biaxiality regime in between uniaxial nematic and smectic states. PMID- 22107242 TI - Surface energies and self-assembly of block copolymers on grafted surfaces. AB - We present a theoretical analysis of the self-assembly of diblock copolymers on surfaces grafted with random copolymers. Our results demonstrate that the surface energies of homopolymeric components on grafted surfaces differ from the corresponding values for self-assembled morphologies. Moreover, grafted random copolymers are shown to adapt their conformations in response to the morphology of the overlaying block copolymer film to create chemical inhomogeneities which modulate the interfacial interactions. Consequently, the surface energy differences between the different components on the grafted substrate do not serve as a useful measure to predict the stability of self-assembly of the diblock copolymer film. PMID- 22107243 TI - Emergence of El Nino as an autonomous component in the climate network. AB - We construct and analyze a climate network which represents the interdependent structure of the climate in different geographical zones and find that the network responds in a unique way to El Nino events. Analyzing the dynamics of the climate network shows that when El Nino events begin, the El Nino basin partially loses its influence on its surroundings. After typically three months, this influence is restored while the basin loses almost all dependence on its surroundings and becomes autonomous. The formation of an autonomous basin is the missing link to understand the seemingly contradicting phenomena of the afore noticed weakening of the interdependencies in the climate network during El Nino and the known impact of the anomalies inside the El Nino basin on the global climate system. PMID- 22107244 TI - Comment on "Hawking radiation from ultrashort laser pulse filaments". PMID- 22107246 TI - Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. AB - Limited curative treatment options exist for patients with advanced B-lymphoid malignancies, and new therapeutic approaches are needed to augment the efficacy of hematopoietic stem-cell transplantation (HSCT). Cellular therapies, such as adoptive transfer of T cells that are being evaluated to target malignant disease, use mechanisms independent of chemo- and radiotherapy with nonoverlapping toxicities. Gene therapy is employed to generate tumor-specific T cells, as specificity can be redirected through enforced expression of a chimeric antigen receptor (CAR) to achieve antigen recognition based on the specificity of a monoclonal antibody. By combining cell and gene therapies, we have opened a new Phase I protocol at the MD Anderson Cancer Center (Houston, TX) to examine the safety and feasibility of administering autologous genetically modified T cells expressing a CD19-specific CAR (capable of signaling through chimeric CD28 and CD3-zeta) into patients with high-risk B-lymphoid malignancies undergoing autologous HSCT. The T cells are genetically modified by nonviral gene transfer of the Sleeping Beauty system and CAR(+) T cells selectively propagated in a CAR dependent manner on designer artificial antigen-presenting cells. The results of this study will lay the foundation for future protocols including CAR(+) T-cell infusions derived from allogeneic sources. PMID- 22107247 TI - BMP-2 embedded atelocollagen scaffold for tissue-engineered cartilage cultured in the medium containing insulin and triiodothyronine--a new protocol for three dimensional in vitro culture of human chondrocytes. AB - When the chondrocytes are isolated from the native cartilage and proliferate in vitro, they soon lose their original ability to express glycosaminoglycan (GAG) and type II collagen, which is termed dedifferentiation, or decrease cell viability. We first examined in vitro cartilage regeneration of tissue-engineered pellets that consisted of human auricular chondrocytes and atelocollagen and that were incubated in vitro under stimulation with bone morphogenetic protein-2 (BMP 2), insulin, and T(3). We then examined the administration of those growth factors into the scaffold or in the medium and explored the possibility that the atelocollagen, the hydrogel scaffold of the chondrocytes, may function for drug delivery of the factors. BMP-2 in the atelocollagen with the supplement of insulin and T3 in the medium could not only produce a greater GAG matrix in a shorter period but also sustain cell viability with lower mortality. The insulin in the medium could be better administered only for 2 weeks, rather than 3 weeks, which would save time and cost, hence shortening the in vitro culture of chondrocytes. Our protocol of mixing BMP-2 into the atelocollagen with the supplement of insulin and T3 hormone might provide a new insight into the development of tissue engineering in chondrogenesis. PMID- 22107249 TI - Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients 2010 data report. PMID- 22107248 TI - Body mass index trajectories from adolescence to midlife: differential effects of parental and respondent education by race/ethnicity and gender. AB - OBJECTIVES: Race/ethnicity and education are among the strongest social determinants of body mass index (BMI) throughout the life course, yet we know relatively little about how these social factors both independently and interactively contribute to the rate at which BMI changes from adolescence to midlife. The purpose of this study is to (1) examine variation in trajectories of BMI from adolescence to midlife by mothers' and respondents' education and (2) determine if the effects of mothers' and respondents' education on BMI trajectories differ by race/ethnicity and gender. DESIGN: We used nationally representative data from the National Longitudinal Survey of Youth. Our sample included white (n=4433), black (n=2420), and Hispanic (n=1501) respondents. Self reported height and weight were collected on 16 occasions from 1981 to 2008. We employed two-level linear growth models to specify BMI trajectories. RESULTS: Mothers' education was inversely associated with BMI and BMI change among women. Among men, mothers' education was inversely associated with BMI; these educational disparities persisted for whites, diminished for blacks, and widened for Hispanics. Respondents' education was inversely associated with BMI among women, but was positively associated with the rate of BMI change among black women. Respondents' education was inversely associated with BMI among white and Hispanic men, and positively associated with BMI among black men. These educational disparities widened for White and Black men, but narrowed for Hispanic men. CONCLUSIONS: Our results suggest that by simultaneously considering multiple sources of stratification, we can more fully understand how the unequal distribution of advantages or disadvantages across social groups affects BMI across the life course. PMID- 22107250 TI - Effect of whey protein- and carbohydrate-enriched diet on glycogen resynthesis during the first 48 h after a soccer game. AB - The effect of a whey protein- and carbohydrate (CHO)-enriched diet on the rate of muscle glycogen resynthesis after a soccer match was examined. Sixteen elite soccer players were randomly assigned to a group ingesting a diet rich in carbohydrates and whey protein [CHO, protein, and fat content was 71, 21, and 8E%, respectively; high content of carbohydrates and whey protein (HCP), n = 9] or a group ingesting a normal diet (55, 18, and 26E%; control [CON], n = 7) during a 48-h recovery period after a soccer match. CON and three additional players carried out a 90- and 60-min simulated match without body contacts (SIM90 and SIM60). Muscle glycogen was lowered (P < 0.05) by 54, 48, 53, and 38% after the matches in CON, HCP, SIM90, and SIM60, respectively. Glycogen resynthesis during the first 48 h after the match was not different between CON and HCP, whereas glycogen resynthesis was slower (P < 0.05) during the first 24 h after SIM60 than SIM90 (2.88 +/- 0.84 vs 4.32 +/- 0.54 mmol/kg dw/h). In HCP, glycogen content in type II muscle fibers was still lowered 48 h after the match. In conclusion, glycogen resynthesis 48 h after a soccer match is not elevated by ingestion of a HCP diet. Furthermore, glycogen resynthesis does not appear to be impaired by body contacts during a match. PMID- 22107251 TI - Perceptions of cause and control of impulse control behaviours in people with Parkinson's disease. AB - OBJECTIVES: Impulse control behaviours (ICBs) have been a recent focus of research in people with Parkinson's disease (PD). However, the current literature is largely limited to a biomedical understanding and gaps remain in our understanding of the perceived cause of these behaviours and how people themselves experience them. Consequently, this study sought to investigate how people with PD perceive the cause and controllability of their ICB. DESIGN: The study utilized qualitative methodology involving semi-structured interviews. Interpretative phenomenological analysis (IPA) allowed an in-depth exploration of the subjective experience of ICBs. METHODS: Ten people with idiopathic PD and current or recent history of ICBs were recruited from an existing research participant pool. RESULTS: The themes that arose from the participants' accounts were 'Conflicting views on causality', 'Impulse control behaviours as a coping strategy', and 'The relationship between causal attribution and perceived controllability'. CONCLUSION: Participants' beliefs about the cause of ICBs varied from externalized cause (medication) to internalized (coping with the impact of PD). These causal attributions were fundamental to the perceived controllability of the behaviours and psychological benefits. Further research is warranted to explore a psychosocial viewpoint of this feature of PD and to provide appropriate and effective biopsychosocial interventions. PMID- 22107252 TI - 14-day in vitro chemical stability of insulin lispro in the MiniMed Paradigm pump. AB - BACKGROUND: Insulin lispro was subjected to a simulated in-use study in the Medtronic MiniMed Paradigm((r)) pump system (Medtronic, Northridge, CA) under stressed conditions over 14 days. METHODS: Basal and bolus insulin doses were delivered under conditions of elevated temperature (37 degrees C) and continuous shaking over 14 days. The simulation included a study arm with infusion set changes every 3 days and an arm with no infusion set changes over the entire study period. Analyses were performed on samples pumped through the infusion system and on samples retained in the pump reservoir. RESULTS: Results met U.S. Pharmacopeia criteria for insulin lispro potency through the entire testing period. No precipitation was observed on visual inspection, and no occlusion alarms were noted. CONCLUSIONS: Insulin lispro demonstrated appropriate physicochemical stability for up to 14 days in the MiniMed Paradigm pump system. PMID- 22107253 TI - Should multivisceral transplantation be considered in patients colonized with multidrug-resistant Pseudomonas aeruginosa? AB - This report describes two subsequent liver-small bowel-pancreas-kidney (multivisceral) transplantations in a child colonized with multidrug-resistant Pseudomonas aeruginosa. We discuss the dilemma concerning the transplantation of patients colonized with multidrug-resistant Pseudomonas spp., its potential consequences, and the peri and postoperative management of these patients. PMID- 22107254 TI - Z-Selective olefin metathesis reactions promoted by tungsten oxo alkylidene complexes. AB - Addition of LiOHMT (OHMT = O-2,6-dimesitylphenoxide) to W(O)(CH-t Bu)(PMe(2)Ph)(2)Cl(2) led to WO(CH-t-Bu)Cl(OHMT)(PMe(2)Ph) (4). Subsequent addition of Li(2,5-Me(2)C(4)H(2)N) to 4 yielded yellow W(O)(CH-t Bu)(OHMT)(Me(2)Pyr)(PMe(2)Ph) (5). Compound 5 is a highly effective catalyst for the Z-selective coupling of selected terminal olefins (at 0.2% loading) to give product in >75% yield with >99% Z configuration. Addition of 2 equiv of B(C(6)F(5))(3) to 5 afforded a catalyst activated at the oxo ligand by B(C(6)F(5))(3). 5.B(C(6)F(5))(3) is a highly active catalyst that produces thermodynamic products (~20% Z). PMID- 22107255 TI - High cell density attenuates reactive oxygen species: implications for in vitro assays. AB - In vitro cell-based assays are an essential and universally used step in elucidation of biological processes as well as in drug development. However, results obtained depend on the validity of protocols used. This statement certainly pertains to in vitro assays of oxidative stress. The holy grail of in vitro models is reliability and predictability of outcomes that relate to a single variable like addition of hydrogen peroxide or xanthine oxidase. Without such validated outcomes, comparison of results among different laboratories is not possible. Achieving this goal requires a thorough understanding of the complex interplay between the cells, their environment, and the experimental assays. Furthermore, as this knowledge is attained, it must be disseminated and used to update and standardize existing protocols. Here, we confirm and extend the effect of pyruvate and cell density on in vitro oxidative stress assays. Cell viability was assessed using a colorimetric assay measuring the reduction of a tetrazolium salt (XTT) into a colored formazan dye. Extracellular hydrogen peroxide concentrations were measured using the foxp3 assay. We confirmed a previously reported finding that pyruvate, a common ingredient in cell culture media, acts as an extracellular scavenger of reactive oxygen species. We also demonstrated that cell density directly correlates with resistance to oxidative stress in tissue culture. It is theorized that the protective effect due to cell density predominantly relates to intracellular factors such as reduced glutathione and extracellular factors such as catalase. PMID- 22107256 TI - Neurofibromatosis type 1 and cerebellar T2-hyperintensities: the relationship to cognitive functioning. PMID- 22107257 TI - Developmental differences in sensory decision making involved in deciding to try a novel fruit. AB - OBJECTIVES: This research compared sensory processing and personality traits involved in deciding to try a novel fruit (guava) in adults and children. DESIGN: The research employed an age, sex, and food neophobia matched between-participant design to examine sensory decision making in choosing to eat a novel fruit. METHODS: Forty-four adults (Study 1) and 68 children (Study 2) took part. In each study, participants were separated into two groups to investigate whether prior assessment of a familiar and liked fruit (apple) that shares similar visual characteristics to the target novel fruit (guava) increased the likelihood that an individual would decide to try it. All participants completed appetitive and familiarity ratings by sensory stages: vision, smell, and touch, prior to trying (tasting) the fruit. Participants (or their parents) also completed the general and food neophobia scales and adults also completed the sensation-seeking scale. RESULTS: Twenty-eight adults (64%) tried the guava and 16 did not (36%). In the second study, 22 children decided not to try the novel fruit (32%). Significant predictors of whether the adult tried the target fruit were Thrill and Adventure Seeking, Experience Seeking, General Neophobia, and 'appealing to touch'. In children, Food Neophobia, concurrent presentation of a familiar fruit alongside the target and visual assessment of the target predicted decision to try the novel fruit. CONCLUSIONS: This study suggests that touch is pertinent to adults' decision to try a novel fruit, whereas visual cues appear to be more important for children. PMID- 22107258 TI - External landmarks for identifying the drainage site of the vein of Labbe: application to neurosurgical procedures. AB - INTRODUCTION: The vein of Labbe is an important structure of the lateral cortical surface. However, to date, studies aimed at providing external landmarks for aiding in its identification have been scant. Therefore, the present study focussed on establishing reliable bony landmarks for localizing this deeper lying venous structure. MATERIALS AND METHODS: Fifteen adult cadavers (30 sides) underwent dissection of the lateral cortical brain surface with special attention given to the drainage site of the vein of Labbe into the transverse sinus. Measurements of the distance from this site to surrounding external bony landmarks were then made. RESULTS: We found that this drainage site into the transverse sinus was 0.8-1.5 cm (mean 1.1 cm, SD 0.567) superior to the superior border of the zygomatic arch and 2 - 5 cm (mean 2.9 cm, SD 0.713) posterior to the opening of the external auditory meatus. Statistically, there was no significance between left and right sides or between sexes. CONCLUSIONS: We found that the junction between the vein of Labbe and transverse sinus may be variable. Nonetheless, additional landmarks found in this study for identifying the junction may aid in its earlier identification during surgery, potentially decreasing operative morbidity. PMID- 22107259 TI - Swelling and enhancement of the cervical spinal cord: when is a tumour not a tumour? AB - OBJECTIVE: To describe the management of patients with co-existing cervical spondylotic compression and enhancing intramedullary swelling of uncertain aetiology. We describe the key features, suggest a management plan and review the literature. MATERIAL AND METHODS: A short series of six cases with cervical myelopathy and radiological features of spondylotic compression, swollen cervical cord and intramedullary enhancement is described. Detailed descriptions of clinical features, radiological findings, surgical approaches and outcomes are discussed. All patients underwent cervical decompression via an anterior approach, posterior approach or both. Despite initial concerns that the aetiology might be tumour, no biopsy of cervical cord was required in any of the cases. RESULTS: Symptoms improved in four cases whilst contrast enhancement only improved in two cases following decompression. One patient who failed to improve postoperatively was found to have neurosarcoidosis. No patient became worse after the cervical decompression. CONCLUSION: Swelling of the spinal cord with enhancement and co-existing spondylotic cord compression, in the first instance, should be treated by decompression only. Biopsy to diagnose intrinsic tumour or inflammatory conditions should not be performed unless there is radiological or clinical progression despite adequate decompression. PMID- 22107260 TI - Rupture of symptomatic blood blister-like aneurysm of the internal carotid artery: clinical experience and management outcome. AB - BACKGROUND: Aneurysms at nonbranching sites in the supraclinoid internal carotid artery (ICA), known as blood blister-like aneurysms (BBAs), are rare entities and differ from saccular aneurysms. In this study, we attempt to describe our clinical experience and the outcome of treatments for BBAs. METHOD: Thirteen of 745 patients with aneurysmal subarachnoid hemorrhage (SAH) who visited our institution between March 2005 and July 2010, and were confirmed to have BBAs at nonbranching sites of the supraclinoid ICA by digital subtraction angiography (DSA) or computed tomography angiography, were followed-up. In these patients, several therapeutic managements were provided depending on their clinical condition. Data analyzed included patient age, sex, World Federation of Neurologic Surgeons (WFNS) scale, time interval from first DSA to second DSA, treatment of aneurysms, and the modified Rankin scale score at follow-up, 6 months after SAH. RESULT: Of these 13 patients, 5 underwent rapid configuration change from blood blister-like aneurysm to saccular-shaped. Different therapeutic managements were provided, including clipping on wrapping material in 2 patients, ICA trapping without extracranial-intracranial (EC-IC) bypass in 3 patients, EC IC bypass and ICA trapping in 3 patients, transarterial endovascular therapy in 3 patients, direct clipping in 1 patient, and external ventricular drainage in 1 patient. Good clinical outcome was achieved in 4 patients, whereas the other 9 patients had moderate to severe disability due to rebleeding of aneurysms, large cerebral infarction, or severe cerebral vasospasm. CONCLUSIONS: BBAs of the supraclinoid ICA have special neuroradiological and clinicopathological characteristics. Direct clipping or endovascular coil embolization along may not be sufficient and sometimes have undesirable results. ICA trapping or ligation including the lesion segment can be considered an alternative choice if the balloon occlusion test (BOT) is successful. However, if the patient does not tolerate the BOT, EC-IC bypass surgery with ICA ligation or trapping is another option. PMID- 22107261 TI - Synthesis, rapid responsive thickening, and self-assembly of brush copolymer poly(ethylene oxide)-graft-poly(N,N-dimethylaminoethyl methacrylate) in aqueous solutions. AB - Double hydrophilic brush copolymer poly(ethylene oxide)-graft-poly(N,N dimethylaminoethyl methacrylate) (PEO-g-PDMAEMA) was successfully prepared via atom transfer radical polymerization (ATRP). We investigated the pH/thermoresponsive behaviors of PEO-g-PDMAEMA brush-shaped copolymer concentrated aqueous solutions by rheology. The observed LCST strongly decreased with increasing pH of the solutions, which was lower than that of linear block copolymer for different pH, indicating rapid thermoresponsiveness of the brush PDMAEMA chains. An unexpected shear thickening behavior was observed and could be tuned by the pH, resulting from the mobile nature and tractive force of the densely grafted hydrophobic chains of PDMAEMA at high pH. Self-assembly of the brush copolymer in a different pH and ionic strength environment was studied by transmission electron microscopy. A wormlike cylinder structure was formed at low pH. Fractals were observed for the brush copolymer aqueous solution in the presence of NaCl. The results showed that by adjusting the pH and NaCl concentration of the dispersions fractal aggregates with different topology were obtained. The observations reported here can supply a better understanding of the molecular self-assembling nature and be used to develop responsive materials with better performance. PMID- 22107262 TI - Treatment limitations imposed by antiretroviral drug resistance mutations: implication for choices of first line regimens in resource-limited settings. AB - BACKGROUND: Recent studies have suggested that failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may have greater potential to induce the development of resistance mutations, which may limit options for second-line therapy. METHODS: Antiretroviral therapy (ART)-naive individuals aged >=18 years who initiated triple combination ART between January 2000 and June 2006 in British Columbia, Canada were enrolled in the study. We compared genotypic sensitivity scores (GSSs) derived from the development of resistance mutations between participants who initiated ART with ritonavir-boosted protease inhibitors (PIs) with those who initiated ART with NNRTIs, and determined the effects of these mutations on remaining active drugs. RESULTS: A total of 1666 participants initiated ART, 818 (49.1%) with NNRTI-based regimens and 848 (50.9%) with boosted PI-based regimens. Among participants who developed resistance mutations, those who initiated NNRTI-based regimens had a lower median GSS than those on boosted PI-based regimens (9.8 vs. 11.0, respectively; P<0.001). Participants on boosted PI-based regimens [adjusted odds ratio (AOR) 3.68; 95% confidence interval (CI) 2.25, 6.01], those with >=95% adherence to highly active antiretroviral therapy (HAART) (AOR 1.84; 95% CI 1.16, 2.92) and those with baseline CD4 count >200 cells/MUL (AOR 3.44; 95% CI 1.73, 6.84) were more likely to have the maximum number of drug options. CONCLUSION: The use of NNRTI-based first-line ART regimens may limit the options for second-line treatment when the number of available drugs is limited. PMID- 22107263 TI - Volatile properties of particles emitted by compressed natural gas and diesel buses during steady-state and transient driving modes. AB - Volatile properties of particle emissions from four compressed natural gas (CNG) and four diesel buses were investigated under steady-state and transient driving modes on a chassis dynamometer. The exhaust was diluted utilizing a full-flow continuous volume sampling system and passed through a thermodenuder at controlled temperature. Particle number concentration and size distribution were measured with a condensation particle counter and a scanning mobility particle sizer, respectively. We show that while almost all the particles emitted by the CNG buses were in the nanoparticle size range, at least 85% and 98% were removed at 100 and 250 degrees C, respectively. Closer analysis of the volatility of particles emitted during transient cycles showed that volatilization began at around 40 degrees C, with the majority occurring by 80 degrees C. Particles produced during hard acceleration from rest exhibited lower volatility than those produced during other times of the cycle. On the basis of our results and the observation of ash deposits on the walls of the tailpipes, we suggest that these nonvolatile particles were composed mostly of ash from lubricating oil. Heating the diesel bus emissions to 100 degrees C removed ultrafine particle numbers by 69-82% when a nucleation mode was present and just 18% when it was not. PMID- 22107264 TI - Permanent and transient congenital hypothyroidism in preterm infants. AB - AIM: Transient fluctuations in thyroid function are well recognized in preterm infants. We wanted to assess TSH variation in babies with transient and permanent congenital hypothyroidism (CHT). METHODS: Whole bloodspot TSH data in preterm infants (<35 weeks; 2005-2010) were assessed, and infants with bloodspot TSH values >6 mU/L identified. Permanent CHT was defined as a requirement for thyroxine beyond 3 years of age. RESULTS: A first TSH sample was obtained from 5518 infants (median gestational age, 32 w; range, 22-35), with a second sample obtained from 5134 infants (median gestational age, 32 w; range, 22-35). Five infants had raised TSH concentrations on both occasions. Three of the five infants had a serum TSH >80 mU/L on second screen but two came off thyroxine beyond 3 years of age. All preterm babies with permanent or transient hypothyroidism were detected by the first TSH cut-off of 6 mU/L. Only one infant with a birth weight <1500 g remains on thyroxine treatment beyond 2 years of age. CONCLUSIONS: The incidence of permanent CHT in preterm infants is similar to term infants. Profound abnormalities of thyroid function can occur in preterm babies with transient hypothyroidism but both categories of hypothyroidism can be detected by a 'once-only' TSH screening strategy with a relatively low cut-off. PMID- 22107265 TI - Influence of surfactants on the release behaviour and structural properties of sol-gel derived silica xerogels embedded with metronidazole. AB - The aim of this study was to obtain stable and controlled release silica xerogels containing metronidazole (MT) prepared with surfactants with different charges: cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulphate (SDS) and hydroxypropyl cellulose (HPC), which could be the promising carrier materials used as the implantable drug delivery systems. The xerogels were prepared by the sol-gel method. The influence of various formulation precursors on porosity parameters and drug release were investigated. Addition of surfactants showed a promising result in controlling the MT release. Dissolution study revealed increased release of MT from silica modified SDS and CTAB, whereas the release of MT from silica modified HPC considerably decreased, in comparison with unmodified silica. The addition of surfactants showed slight changes in porosity parameters. All xerogels are characterized by a highly developed surface area (701-642 m(2) g(-1)) and mesoporous structure. The correlation between pore size obtained matrices and release rate of drug was also observed. Based on the presented results of this study, it may be stated that applied xerogel matrices: pure silica and surfactants-modified silica could be promising candidates for the formulation in local delivery systems. PMID- 22107266 TI - A randomized placebo-controlled trial of rush preseasonal depigmented polymerized grass pollen immunotherapy. AB - BACKGROUND: Specific subcutaneous immunotherapy (SCIT) for seasonal rhinoconjunctivitis with unmodified allergen extracts is effective, but limited by risk of side-effects and involves treatment over 3 years. We examined a depigmented polymerized grass pollen extract for immunogenicity and for clinical efficacy in a rush preseasonal regimen. METHODS: Depigmented polymerized grass pollen extract was tested for proliferation and cytokine production by peripheral blood mononuclear cells. A prospective, double-blind, placebo-controlled trial of 195 grass pollen allergic patients treated with preseasonal rush immunotherapy using depigmented polymerized allergenic extract of mixed grass pollen was performed over 2 years. Primary outcome was combined symptom and medication score (SMS) during the peak of the second grass pollen season. Secondary outcomes included combined score over the whole season, during the first grass pollen season, individual symptom and medication scores, quality of life, well days/hell days and responder analysis. Adverse events were classified using the EAACI scale. Grass pollen-specific IgE and IgG4 were measured before and during treatment. RESULTS: Depigmented polymerized extract stimulated dose-dependent T cell proliferation and cytokine production. Patients treated with preseasonal SCIT showed improved combined scores during peak season at year 2 (median 3.93, interquartile range 0.77-6.27 vs median 5.86 for placebo, 3.11-8.36, P < 0.01). Most secondary outcomes were significantly better for active treatment. Side effects were minimal, with no grade 3 or 4 reactions. CONCLUSIONS: Depigmented polymerized grass pollen extract is immunogenic and clinically effective in rush preseasonal SCIT. This form of immunotherapy may be an attractive option for some patients. PMID- 22107267 TI - A refined MS-EVB model for proton transport in aqueous environments. AB - In order to improve the description of proton mobility in aqueous environments, a revised multistate empirical valence bond model (aMS-EVB3) is developed. The new aMS-EVB3 model is built upon an anharmonic water force field (aSPC/Fw) in which the OH bond potential is described through a quartic approximation to a Morse potential. First, it is shown that the aSPC/Fw anharmonic water model provides an accurate description of water at ambient conditions and reproduces the available experimental data for several structural, thermodynamic, and dynamical properties. Second, it is shown that, when applied to the study of proton solvation and transport in bulk water, the new aMS-EVB3 model accurately describes the solvation structure around the excess proton. Importantly, the new aMS-EVB3 model predicts a significantly larger proton diffusion coefficient than previous models, which largely improves the agreement with the available experimental data. PMID- 22107269 TI - African and Black Caribbean origin cancer survivors: a qualitative study of the narratives of causes, coping and care experiences. AB - OBJECTIVES: Although there is evidence in the U.S.A. and U.K. to suggest that ethnic minority groups have an inferior experience of cancer care, few studies investigate ethnic disparities in satisfaction and care experiences among survivors. Patients' illness perceptions (lay explanations for illness) and coping styles (emotional and behavioural) are influenced by ethnicity-related cultural beliefs and expectations. Depressive illness or fears of recurrence of cancer may also lead to poorer recovery and function. This paper investigates whether ethnic influences explain different coping behaviours, care experiences and help-seeking behaviours. DESIGN: Eight participants of African or Black Caribbean origin were recruited from a London support group for a series of qualitative in-depth interviews. The interviews were recorded and transcribed, and the transcripts analysed using a framework method of qualitative data analysis. The emergent themes were tested and documented to reflect the issues of importance to patients. RESULTS: Lay explanations of causes of cancer were complex and diverse reflecting cultural influences and the impact of contact with health professionals. Generally, positive views about cancer care were found, especially at the secondary care level. Primary care attracted mixed views. In contrast to American studies, no acknowledgement of discrimination on the basis of ethnicity was reported. The need to be resilient and think positively were widely acknowledged as coping strategies. Some coped by avoiding contemplation of their condition or diagnosis. Religious beliefs and practices provided coping mechanisms for some, and a means to improve confidence and avoid distressing contemplation about their condition. Family, friends and charitable groups also provided emotional and practical support. CONCLUSIONS: Subjects were generally satisfied with their care; different coping styles included positive attitudes, minimisation of difficulties or more realistic consideration of the impact of cancer. PMID- 22107270 TI - Blinking statistics of silicon quantum dots. AB - The blinking statistics of numerous single silicon quantum dots fabricated by electron-beam lithography, plasma etching, and oxidation have been analyzed. Purely exponential on- and off-time distributions were found consistent with the absence of statistical aging. This is in contrast to blinking reports in the literature where power-law distributions prevail as well as observations of statistical aging in nanocrystal ensembles. A linear increase of the switching frequency with excitation power density indicates a domination of single-photon absorption processes, possibly through a direct transfer of charges to trap states without the need for a bimolecular Auger mechanism. Photoluminescence saturation with increasing excitation is not observed; however, there is a threshold in excitation (coinciding with a mean occupation of one exciton per nanocrystal) where a change from linear to square-root increase occurs. Finally, the statistics of blinking of single quantum dots in terms of average on-time, blinking frequency and blinking amplitude reveal large variations (several orders) without any significant correlation demonstrating the individual microscopic character of each quantum dot. PMID- 22107271 TI - Experimental realization of decoherence-free subspace in neutron interferometry. AB - A decoherence-free subspace (DFS) is an important class of quantum-error correcting (QEC) codes that have been proposed for fault-tolerant quantum computation. The applications of QEC techniques, however, are not limited to quantum-information processing (QIP). Here we demonstrate how QEC codes may be used to improve experimental designs of quantum devices to achieve noise suppression. In particular, neutron interferometry is used as a test bed to show the potential for adding quantum error correction to quantum measurements. We built a five-blade neutron interferometer that incorporates both a standard Mach Zender configuration and a configuration based on a DFS. Experiments verify that the DFS interferometer is protected against low-frequency mechanical vibrations. We anticipate these improvements will increase the range of applications for matter-wave interferometry. PMID- 22107272 TI - Fermi problem with artificial atoms in circuit QED. AB - We propose a feasible experimental test of a 1D version of the Fermi problem using superconducting qubits. We give an explicit nonperturbative proof of strict causality in this model, showing that the probability of excitation of a two level artificial atom with a dipolar coupling to a quantum field is completely independent of the other qubit until signals from it may arrive. We explain why this is in perfect agreement with the existence of nonlocal correlations and previous results which were used to claim apparent causality problems for Fermi's two-atom system. PMID- 22107273 TI - Bose-Einstein condensates with spin-orbit interaction. AB - Motivated by recent experiments carried out by Spielman's group at NIST, we study a general scheme for generating families of gauge fields, spanning the scalar, spin-orbit, and non-Abelian regimes. The NIST experiments, which impart momentum to bosons while changing their spin state, can in principle realize all these. In the spin-orbit regime, we show that a Bose gas is a spinor condensate made up of two non-orthogonal dressed spin states carrying different momenta. As a result, its density shows a stripe structure with a contrast proportional to the overlap of the dressed states, which can be made very pronounced by adjusting the experimental parameters. PMID- 22107274 TI - Synthetic gauge fields for vibrational excitations of trapped ions. AB - The vibrations of a collection of ions in a microtrap array can be described in terms of tunneling phonons. We show that the vibrational couplings may be tailored by using a gradient of the trap frequencies together with a periodic driving of the trapping potentials. These ingredients allow us to induce effective gauge fields on the vibrational excitations, such that phonons mimic the behavior of charged particles in a magnetic field. In particular, microtrap arrays are well suited to realize a quantum simulator of the famous Aharonov-Bohm effect and observe the paradigmatic edge states typical from quantum-Hall samples and topological insulators. PMID- 22107275 TI - Collective uncertainty entanglement test. AB - For a given pure state of a composite quantum system we analyze the product of its projections onto a set of locally orthogonal separable pure states. We derive a bound for this product analogous to the entropic uncertainty relations. For bipartite systems the bound is saturated for maximally entangled states and it allows us to construct a family of entanglement measures, we shall call collectibility. As these quantities are experimentally accessible, the approach advocated contributes to the task of experimental quantification of quantum entanglement, while for a three-qubit system it is capable to identify the genuine three-party entanglement. PMID- 22107276 TI - Electron-mediated nuclear-spin interactions between distant nitrogen-vacancy centers. AB - We propose a scheme enabling controlled quantum coherent interactions between separated nitrogen-vacancy centers in diamond in the presence of strong magnetic fluctuations. The proposed scheme couples nuclear qubits employing the magnetic dipole-dipole interaction between the electron spins and, crucially, benefits from the suppression of the effect of environmental magnetic field fluctuations thanks to a strong microwave driving. This scheme provides a basic building block for a full-scale quantum-information processor or quantum simulator based on solid-state technology. PMID- 22107277 TI - Energy landscape of 3D spin Hamiltonians with topological order. AB - We explore the feasibility of a quantum self-correcting memory based on 3D spin Hamiltonians with topological quantum order in which thermal diffusion of topological defects is suppressed by macroscopic energy barriers. To this end we characterize the energy landscape of stabilizer code Hamiltonians with local bounded-strength interactions which have a topologically ordered ground state but do not have stringlike logical operators. We prove that any sequence of local errors mapping a ground state of such a Hamiltonian to an orthogonal ground state must cross an energy barrier growing at least as a logarithm of the lattice size. Our bound on the energy barrier is tight up to a constant factor for one particular 3D spin Hamiltonian. PMID- 22107278 TI - Finite-temperature phase transition in a class of four-state Potts antiferromagnets. AB - We argue that the four-state Potts antiferromagnet has a finite-temperature phase transition on any Eulerian plane triangulation in which one sublattice consists of vertices of degree 4. We furthermore predict the universality class of this transition. We then present transfer-matrix and Monte Carlo data confirming these predictions for the cases of the Union Jack and bisected hexagonal lattices. PMID- 22107279 TI - Mode-coupling-induced dissipative and thermal effects at long times after a quantum quench. AB - An interaction quench in a Luttinger liquid can drive it into an athermal steady state. We analyze the effects on such an out of equilibrium state of a mode coupling term due to a periodic potential. Employing a perturbative renormalization group approach we show that even when the periodic potential is an irrelevant perturbation in equilibrium, it has important consequences on the athermal steady state as it generates a temperature as well as a dissipation and hence a finite lifetime for the bosonic modes. PMID- 22107280 TI - No collective neutrino flavor conversions during the supernova accretion phase. AB - We perform a dedicated study of the supernova (SN) neutrino flavor evolution during the accretion phase, using results from recent neutrino radiation hydrodynamics simulations. In contrast to what was expected in the presence of only neutrino-neutrino interactions, we find that the multiangle effects associated with the dense ordinary matter suppress collective oscillations. The matter suppression implies that neutrino oscillations will start outside the neutrino decoupling region and therefore will have a negligible impact on the neutrino heating and the explosion dynamics. Furthermore, the possible detection of the next galactic SN neutrino signal from the accretion phase, based on the usual Mikheyev-Smirnov-Wolfenstein effect in the SN mantle and Earth matter effects, can reveal the neutrino mass hierarchy in the case that the mixing angle theta(13) is not very small. PMID- 22107281 TI - Cosmic curvature from de Sitter equilibrium cosmology. AB - I show that the de Sitter equilibrium cosmology generically predicts observable levels of curvature in the Universe today. The predicted value of the curvature, Omega(k), depends only on the ratio of the density of nonrelativistic matter to cosmological constant density rho(m)(0)/rho(Lambda) and the value of the curvature from the initial bubble that starts the inflation, Omega(k)(B). The result is independent of the scale of inflation, the shape of the potential during inflation, and many other details of the cosmology. Future cosmological measurements of rho(m)(0)/rho(Lambda) and Omega(k) will open up a window on the very beginning of our Universe and offer an opportunity to support or falsify the de Sitter equilibrium cosmology. PMID- 22107282 TI - Spallation model for the titanium-rich supernova remnant cassiopeia A. AB - Titanium-rich subluminous supernovae are rare and challenge current SN nucleosynthesis models. We present a model in which ejecta from a standard supernova is impacted by a second explosion of the neutron star (a quark nova), resulting in spallation reactions that lead to (56)Ni destruction and (44)Ti creation under the right conditions. Basic calculations of the spallation products shows that a delay between the two explosions of ~5 days reproduces the observed abundance of (44)Ti in Cas A and explains its low luminosity as a result of the destruction of (56)Ni. Our results could have important implications for light curves of subluminous as well as superluminous supernovae. PMID- 22107283 TI - Energy loss of an infinitely massive half-Bogomol'nyi-Prasad-Sommerfeld particle by radiation to all orders in 1/N. AB - We use the AdS/CFT correspondence to compute the energy radiated by an infinitely massive half-Bogomol'nyi-Prasad-Sommerfeld particle charged under N=4 super Yang Mills theory, transforming in the symmetric or antisymmetric representation of the gauge group, and moving in the vacuum, to all orders in 1/N and for large 't Hooft coupling. For the antisymmetric case we consider D5-branes reaching the boundary of five-dimensional anti-de Sitter space (AdS(5)) at arbitrary timelike trajectories, while for the symmetric case, we consider a D3-brane in AdS(5) that reaches the boundary at a hyperbola. We compare our results to the one obtained for the fundamental representation, deduced by considering a string in AdS(5). PMID- 22107285 TI - QCD resummation for jet substructures. AB - We provide a novel development in jet physics by predicting the energy profiles of light-quark and gluon jets in the framework of perturbative QCD. Resumming large logarithmic contributions to all orders in the coupling constant, our predictions are shown to agree well with Tevatron CDF and Large Hadron Collider CMS data. We also extend our resummation formalism to the invariant mass distributions of light-quark and gluon jets produced in hadron collisions. The predicted peak positions and heights in jet mass distributions are consistent with CDF data within uncertainties induced by parton distribution functions. PMID- 22107286 TI - QCD resummation for single spin asymmetries. AB - We study the transverse momentum dependent factorization for single spin asymmetries in Drell-Yan and semi-inclusive deep inelastic scattering processes at one-loop order. The next-to-leading order hard factors are calculated in the Ji-Ma-Yuan factorization scheme. We further derive the QCD resummation formalisms for these observables following the Collins-Soper-Sterman method. The results are expressed in terms of the collinear correlation functions from initial and/or final state hadrons coupled with the Sudakov form factor containing all order soft-gluon resummation effects. The scheme-independent coefficients are calculated up to one-loop order. PMID- 22107287 TI - Associated Higgs-W-boson production at hadron colliders: a fully exclusive QCD calculation at NNLO. AB - We consider QCD radiative corrections to standard model Higgs-boson production in association with a W boson in hadron collisions. We present a fully exclusive calculation up to next-to-next-to-leading order (NNLO) in QCD perturbation theory. To perform this NNLO computation, we use a recently proposed version of the subtraction formalism. Our calculation includes finite-width effects, the leptonic decay of the W boson with its spin correlations, and the decay of the Higgs boson into a bb pair. We present selected numerical results at the Tevatron and the LHC. PMID- 22107288 TI - Percolation transition in Yang-Mills matter at a finite number of colors. AB - We examine baryonic matter at a quark chemical potential of the order of the confinement scale MU(q)~Lambda(QCD). In this regime, quarks are supposed to be confined but baryons are close to the "tightly packed limit" where they nearly overlap in configuration space. We show that this system will exhibit a percolation phase transition when varied in the number of colors N(c): at high N(c), large distance correlations at the quark level are possible even if the quarks are essentially confined. At low N(c), this does not happen. We discuss the relevance of this for dense nuclear matter, and argue that our results suggest a new "phase transition," varying N(c) at constant MU(q). PMID- 22107289 TI - Octupolar-excitation Penning-trap mass spectrometry for Q-value measurement of double-electron capture in (164)Er. AB - The theory of octupolar-excitation ion-cyclotron-resonance mass spectrometry is presented which predicts an increase of up to several orders of magnitude in resolving power under certain conditions. The new method has been applied for a direct Penning-trap mass-ratio determination of the (164)Er-(164)Dy mass doublet. (164)Er is a candidate for the search for neutrinoless double-electron capture. However, the measured Q(epsilonepsilon) value of 25.07(12) keV results in a half life of 10(30) years for a 1 eV Majorana-neutrino mass. PMID- 22107284 TI - Search for a fermiophobic and standard model Higgs boson in diphoton final states. AB - We present a search for the standard model Higgs boson and a fermiophobic Higgs boson in the diphoton final states based on 8.2 fb(-1) of pp collisions at sqrt[s]=1.96 TeV collected with the D0 detector at the Fermilab Tevatron Collider. No excess of data above background predictions is observed and upper limits at the 95% C.L. on the cross section multiplied by the branching fraction are set which are the most restrictive to date. A fermiophobic Higgs boson with a mass below 112.9 GeV is excluded at the 95% C.L. PMID- 22107290 TI - Nonlocal nonlinear optics in cold Rydberg gases. AB - We present an analytical theory for the nonlinear optical response of a strongly interacting Rydberg gas under conditions of electromagnetically induced transparency. Simple formulas for the third-order optical susceptibility are derived and shown to be in excellent agreement with recent experiments. The obtained expressions reveal strong nonlinearities, which in addition are of highly nonlocal character. This property together with the enormous strength of the Rydberg-induced nonlinearities is shown to yield a unique laboratory platform for nonlinear wave phenomena, such as collapse-arrested modulational instabilities in a self-defocusing medium. PMID- 22107291 TI - Nonclassical behavior of an intense cavity field revealed by quantum discord. AB - We investigate the quantum-to-classical crossover of a dissipative cavity field by measuring the correlations between two noninteracting atoms coupled to the cavity mode. First, we note that there is a time window in which the mode shows a classical behavior, which depends on the cavity decay rate, the atom-field coupling strength, and the number of atoms. Then, considering the steady state of two atoms inside the cavity, we note that the entanglement between the atoms disappears while the mean number of photons of the cavity field (n) rises. However, the quantum discord reaches an asymptotic nonzero value even in the limit of n->infinity, whether n is increased coherently or incoherently. Therefore, the cavity mode always preserves some quantum characteristics in the macroscopic limit, which is revealed by the quantum discord. PMID- 22107292 TI - Attenuation coefficient of single-mode periodic waveguides. AB - It is widely accepted that, on ensemble average, the transmission T of guided modes decays exponentially with the waveguide length L due to small imperfections, leading to the important figure of merit defined as the attenuation-rate coefficient alpha=-?ln(T)?/L. In this Letter, we evidence that the exponential-damping law is not valid in general for periodic monomode waveguides, especially as the group velocity decreases. This result, that contradicts common beliefs and experimental practices aiming at measuring alpha, is supported by a theoretical study of light transport in the limit of very small imperfections, and by numerical results obtained for two waveguide geometries that offer contrasted damping behaviors. PMID- 22107293 TI - Trajectory selection in high harmonic generation by controlling the phase between orthogonal two-color fields. AB - We demonstrate control of short and long quantum trajectories in high harmonic emission through the use of an orthogonally polarized two-color field. By controlling the relative phase phi between the two fields we show via classical and quantum calculations that we can steer the two-dimensional trajectories to return, or not, to the core and so control the relative strength of the short or long quantum trajectory contribution. In experiments, we demonstrate that this leads to robust control over the trajectory contributions using a drive field from a femtosecond laser composed of the fundamental omega at 800 nm (intensity ~1.2*10(14) W cm(-2)) and its weaker orthogonally polarized second harmonic 2omega (intensity ~0.3*10(14) W cm(-2)) with the relative phase between the omega and 2omega fields varied simply by tilting a fused silica plate. This is the first demonstration of short and long quantum trajectory control at the single-atom level. PMID- 22107294 TI - Onset of turbulence from the receptivity stage of fluid flows. AB - The traditional viewpoint of fluid flow considers the transition to turbulence to occur by the secondary and nonlinear instability of wave packets, which have been created experimentally by localized harmonic excitation. The boundary layer has been shown theoretically to support spatiotemporal growing wave fronts by Sengupta, Rao, and Venkatasubbaiah [Phys. Rev. Lett. 96, 224504 (2006)] by a linear mechanism, which is shown here to grow continuously, causing the transition to turbulence. Here, we track spatiotemporal wave fronts to a nonlinear turbulent state by solving the full 2D Navier-Stokes equation, without any limiting assumptions. Thus, this is the only demonstration of deterministic disturbances evolving from a receptivity stage to the full turbulent flow. This is despite the prevalent competing conjectures of the event being three dimensional and/or stochastic in nature. PMID- 22107295 TI - Ultrafast interference imaging of air in splashing dynamics. AB - A drop impacting a solid surface with sufficient velocity will emit many small droplets creating a splash. However, splashing is completely suppressed if the surrounding gas pressure is lowered. The mechanism by which the gas affects splashing remains unknown. We use high-speed interference imaging to measure the air beneath all regions of a spreading viscous drop as well as optical absorption to measure the drop thickness. Although an initial air bubble is created on impact, no significant air layer persists until the time a splash is created. This suggests that splashing in our experimentally accessible range of viscosities is initiated at the edge of the drop as it encroaches into the surrounding gas. PMID- 22107296 TI - Measurements of electron thermal transport due to electron temperature gradient modes in a basic experiment. AB - Production and identification of electron temperature gradient modes have already been reported [X. Wei, V. Sokolov, and A. K. Sen, Phys. Plasmas 17, 042108 (2010)]. Now a measurement of electron thermal conductivity via a unique high frequency triple probe yielded a value of chi(?e) ranging between 2 and 10 m(2)/s, which is of the order of a several gyrobohm diffusion coefficient. This experimental result appears to agree with a value of nonlocal thermal conductivity obtained from a rough theoretical estimation and not inconsistent with gyrokinetic simulation results for tokamaks. The first experimental scaling of the thermal conductivity versus the amplitude of the electron temperature gradient fluctuation is also obtained. It is approximately linear, indicating a strong turbulence signature. PMID- 22107297 TI - Experimental evidence for a reduction in electron thermal diffusion due to trapped particles. AB - New high time resolution measurements of the electron thermal diffusion chi(e) throughout the sawtooth cycle of the Madison Symmetric Torus reversed-field pinch have been made by utilizing the enhanced capabilities of the upgraded multipoint, multipulse Thomson scattering system. These measurements are compared to the chi(e) due to magnetic diffusion predicted by using information from a new high spectral resolution zero-beta nonlinear resistive magnetohydrodynamic simulation performed, for the first time, at the Lundquist number of high current Madison Symmetric Torus plasmas (S~4*10(6)). Agreement between the measured and predicted values is found only if the reduction in thermal diffusion due to trapped particles is taken into account. PMID- 22107298 TI - Dense regular packings of irregular nonconvex particles. AB - We present a new numerical scheme to study systems of nonconvex, irregular, and punctured particles in an efficient manner. We employ this method to analyze regular packings of odd-shaped bodies, both from a nanoparticle and from a computational geometry perspective. Besides determining close-packed structures for 17 irregular shapes, we confirm several conjectures for the packings of a large set of 142 convex polyhedra and extend upon these. We also prove that we have obtained the densest packing for both rhombicuboctahedra and rhombic enneacontrahedra and we have improved upon the packing of enneagons and truncated tetrahedra. PMID- 22107299 TI - Inhomogenous electronic structure, transport gap, and percolation threshold in disordered bilayer graphene. AB - The inhomogenous real-space electronic structure of gapless and gapped disordered bilayer graphene is calculated in the presence of quenched charge impurities. For gapped bilayer graphene, we find that for current experimental conditions the amplitude of the fluctuations of the screened disorder potential is of the order of (or often larger than) the intrinsic gap Delta induced by the application of a perpendicular electric field. We calculate the crossover chemical potential Delta(cr), separating the insulating regime from a percolative regime in which less than half of the area of the bilayer graphene sample is insulating. We find that most of the current experiments are in the percolative regime with Delta(cr)?Delta. The huge suppression of Delta(cr) compared with Delta provides a possible explanation for the large difference between the theoretical band gap Delta and the experimentally extracted transport gap. PMID- 22107300 TI - Multiple-wave diffraction in high energy resolution back-reflecting x-ray optics. AB - We have studied the effects of multiple-wave diffraction in a novel optical scheme recently published by Shvyd'ko et al. utilizing Bragg diffraction of x rays in backscattering geometry from asymmetrically cut crystals for achieving energy resolutions beyond the intrinsic width of the Bragg reflection. By numerical simulations based on dynamic x-ray diffraction and by experimentation involving two-dimensional angular scans of the back-reflecting crystal, multiple wave diffraction was found to contribute up to several tens percent loss of efficiency but can be avoided without degrading the energy resolution of the original scheme by careful choice of azimuthal orientation of the diffracting crystal surface and by tilting of the crystal perpendicular to the dispersion plane. PMID- 22107301 TI - Density-temperature-softness scaling of the dynamics of glass-forming soft-sphere liquids. AB - We employ the principle of dynamic equivalence between soft-sphere and hard sphere fluids [Phys. Rev. E 68, 011405 (2003)] to describe the interplay of the effects of varying the density n, the temperature T, and the softness (characterized by a softness parameter nu(-1)) on the dynamics of glass-forming soft-sphere liquids in terms of simple scaling rules. The main prediction is the existence of a dynamic universality class associated with the hard-sphere fluid, constituted by the soft-sphere systems whose dynamic parameters depend on n, T, and nu only through the reduced density n*=nsigma(HS)(T*,nu). A number of scaling properties observed in recent experiments and simulations involving glass-forming fluids with repulsive short-range interactions are found to be a direct manifestation of this general dynamic equivalence principle. PMID- 22107302 TI - Phase diagram of water under an applied electric field. AB - Simulations are used to investigate for the first time the anisotropy of the dielectric response and the effects of an applied electric field E(ex) on the phase diagram of water. In the presence of electric fields ice II disappears from the phase diagram. When E(ex) is applied in the direction perpendicular to the ac crystallographic plane the melting temperatures of ices III and V increase whereas that of ice Ih is hardly affected. Ice III also disappears as a stable phase when E(ex) is applied in the direction perpendicular to the ab plane. E(ex) increases by a small amount the critical temperature and reduces slightly the temperature of the maximum density of liquid water. The presence E(ex) modifies all phase transitions of water but its effect on solid-solid and solid-fluid transitions seems to be more important and different depending on the direction of E(ex). PMID- 22107303 TI - Quantum capillary waves at the superfluid-Mott-insulator interface. AB - We discuss quantum fluctuations of the interface between a superfluid and a Mott insulating state of ultracold atoms in a trap. The fluctuations of the boundary are due to a new type of surface modes, whose spectrum is similar--but not identical--to classical capillary waves. The corresponding quantum capillary length sets the scale for the penetration of the superfluid into the Mott insulating regime by the proximity effect and may be on the order of several lattice spacings. It determines the typical magnitude of the interface width due to quantum fluctuations, which may be inferred from single-site imaging of ultracold atoms in an optical lattice. PMID- 22107304 TI - Two-step melting in two dimensions: first-order liquid-hexatic transition. AB - Melting in two spatial dimensions, as realized in thin films or at interfaces, represents one of the most fascinating phase transitions in nature, but it remains poorly understood. Even for the fundamental hard-disk model, the melting mechanism has not been agreed upon after 50 years of studies. A recent Monte Carlo algorithm allows us to thermalize systems large enough to access the thermodynamic regime. We show that melting in hard disks proceeds in two steps with a liquid phase, a hexatic phase, and a solid. The hexatic-solid transition is continuous while, surprisingly, the liquid-hexatic transition is of first order. This melting scenario solves one of the fundamental statistical-physics models, which is at the root of a large body of theoretical, computational, and experimental research. PMID- 22107305 TI - Threshold barrier of carbon nanotube growth. AB - A previously overlooked step of carbon nanotube (CNT) growth, incorporating C atoms into the CNT wall through the CNT-catalyst interface, is studied by density functional theory calculations. A significant barrier for incorporating C atoms into the CNT wall (~2 eV for most used catalysts, Fe, Co, and Ni) is revealed and the incorporation can be the threshold step of CNT growth in most experiments. In addition, the temperature dependent CNT growth rate is calculated and our calculation demonstrates that growing 0.1-1 m long CNTs in 1 h is theoretically possible. PMID- 22107306 TI - Single molecule observations of desorption-mediated diffusion at the solid-liquid interface. AB - By directly observing molecular trajectories on a chemically heterogeneous surface, we have identified two distinct modes of diffusion involving (1) displacements within isolated surface islands (crawling mode), and (2) displacements where a molecule desorbs from an island, diffuses through the adjacent liquid phase, and readsorbs on another island (flying mode). The diffusion coefficients corresponding to these two modes differ by an order of magnitude, and both modes are also observed on chemically homogeneous surfaces. Comparison with previous results suggested that desorption-mediated diffusion is the primary transport mechanism in self-assembled monolayer formation. PMID- 22107307 TI - Dispersive and covalent interactions between graphene and metal surfaces from the random phase approximation. AB - We calculate the potential energy surfaces for graphene adsorbed on Cu(111), Ni(111), and Co(0001) using density functional theory and the random phase approximation (RPA). For these adsorption systems covalent and dispersive interactions are equally important and while commonly used approximations for exchange-correlation functionals give inadequate descriptions of either van der Waals or chemical bonds, RPA accounts accurately for both. It is found that the adsorption is a delicate competition between a weak chemisorption minimum close to the surface and a physisorption minimum further from the surface. PMID- 22107308 TI - Theory of 2D transport in graphene for correlated disorder. AB - We theoretically revisit graphene transport properties as a function of carrier density, taking into account possible correlations in the spatial distribution of the Coulomb impurity disorder in the environment. We find that the charged impurity correlations give rise to a density-dependent graphene conductivity, which agrees well qualitatively with the existing experimental data. We also find, quite unexpectedly, that the conductivity could increase with increasing impurity density if there is sufficient interimpurity correlation present in the system. In particular, the linearity (sublinearity) of graphene conductivity at lower (higher) gate voltage is naturally explained as arising solely from impurity correlation effects in the Coulomb disorder. PMID- 22107309 TI - Theory of spin noise in nanowires. AB - We develop a theory of spin noise in semiconductor nanowires considered as prospective elements for spintronics. In these structures, spin-orbit coupling can be realized as a random function of a coordinate correlated on a spatial scale of the order of 10 nm. By analyzing different regimes of electron transport and spin dynamics, we demonstrate that the spin relaxation can be very slow, and the resulting noise power spectrum increases algebraically as the frequency goes to zero. This effect makes spin phenomena in nanowires best suitable for studies by rapidly developing spin-noise spectroscopy. PMID- 22107310 TI - Chirality-assisted electronic cloaking of confined States in bilayer graphene. AB - We show that the strong coupling of pseudospin orientation and charge carrier motion in bilayer graphene has a drastic effect on transport properties of ballistic p-n-p junctions. Electronic states with zero momentum parallel to the barrier are confined under it for one pseudospin orientation, whereas states with the opposite pseudospin tunnel through the junction totally uninfluenced by the presence of confined states. We demonstrate that the junction acts as a cloak for confined states, making them nearly invisible to electrons in the outer regions over a range of incidence angles. This behavior is manifested in the two-terminal conductance as transmission resonances with non-Lorentzian, singular peak shapes. The response of these phenomena to a weak magnetic field or electric-field induced interlayer gap can serve as an experimental fingerprint of electronic cloaking. PMID- 22107311 TI - Pseudospin in optical and transport properties of graphene. AB - We show that the pseudospin, being an additional degree of freedom for carriers in graphene, can be efficiently controlled by means of the electron-electron interactions which, in turn, can be manipulated by changing the substrate. In particular, an out-of-plane pseudospin component can occur leading to a zero field Hall current as well as to polarization-sensitive interband optical absorption. PMID- 22107312 TI - Tunable hot-electron transfer within a single core-shell nanowire. AB - We report the hot photoexcited electron transfer across the coaxial interface of a cylindrical core-shell nanowire. Modulation of the transfer rates, manifested as a large tunability of the voltage onset of negative differential resistance and of voltage-current phase, is achieved using three different modes. The coupling of electrostatic gating, incident photon energy, and the incident photon intensity to transfer rates is facilitated by the combined influences of geometric confinement and heterojunction shape on hot-electron transfer, and by electron-electron scattering rates that can be altered by varying the incident photon flux, with evidence of weak electron-phonon scattering. Dynamic manipulation of this transfer rate permits the introduction and control of a continuously adjustable phase delay of up to ~130 degrees within a single nanometer-scale device element. PMID- 22107313 TI - Orbital-angular-momentum based origin of Rashba-type surface band splitting. AB - We propose that the existence of local orbital angular momentum (OAM) on the surfaces of high-Z materials plays a crucial role in the formation of Rashba-type surface band splitting. Local OAM state in a Bloch wave function produces an asymmetric charge distribution (electric dipole). The surface-normal electric field then aligns the electric dipole and results in chiral OAM states and the relevant Rashba-type splitting. Therefore, the band splitting originates from electric dipole interaction, not from the relativistic Zeeman splitting as proposed in the original Rashba picture. The characteristic spin chiral structure of Rashba states is formed through the spin-orbit coupling and thus is a secondary effect to the chiral OAM. Results from first-principles calculations on a single Bi layer under an external electric field verify the key predictions of the new model. PMID- 22107314 TI - Entanglement spectra of complex paired superfluids. AB - We study the entanglement in various fully gapped complex paired states of fermions in two dimensions, focusing on the entanglement spectrum (ES), and using the Bardeen-Cooper-Schrieffer (BCS) form of the ground-state wave function on a cylinder. Certain forms of the pairing functions allow a simple and explicit exact solution for the ES. In the weak-pairing phase of l-wave paired spinless fermions (l odd), the universal low-lying part of the ES consists of |l| chiral Majorana fermion modes [or 2|l| (l even) for spin-singlet states]. For |l|>1, the pseudoenergies of the modes are split in general, but for all l there is a zero pseudoenergy mode at a zero wave vector if the number of modes is odd. This ES agrees with the perturbed conformal field theory of the edge excitations. For more general BCS states, we show how the entanglement gap diverges as a model pairing function is approached. PMID- 22107315 TI - Method to characterize spinons as emergent elementary particles. AB - We develop a technique to directly study spinons (emergent spin S=1/2 particles) in quantum spin models in any number of dimensions. The size of a spinon wave packet and of a bound pair (a triplon) are defined in terms of wave-function overlaps that can be evaluated by quantum Monte Carlo simulations. We show that the same information is contained in the spin-spin correlation function as well. We illustrate the method in one dimension. We confirm that spinons are well defined particles (have exponentially localized wave packet) in a valence-bond solid state, are marginally defined (with power-law shaped wave packet) in the standard Heisenberg critical state, and are not well defined in an ordered Neel state (achieved in one dimension using long-range interactions). PMID- 22107316 TI - General theory for the ferroelectric polarization induced by spin-spiral order. AB - The ferroelectric polarization of triangular-lattice antiferromagnets induced by helical spin-spiral order is not explained by any existing model of magnetic order-driven ferroelectricity. We resolve this problem by developing a general theory for the ferroelectric polarization induced by spin-spiral order and then by evaluating the coefficients needed to specify the general theory on the basis of density functional calculations. Our theory correctly describes the ferroelectricity of triangular-lattice antiferromagnets driven by helical spin spiral order and incorporates known models of magnetic-order-driven ferroelectricity as special cases. PMID- 22107317 TI - Observation of electronic Raman scattering in metallic carbon nanotubes. AB - We present experimental measurements of the electronic contribution to the Raman spectra of individual metallic single-walled carbon nanotubes (MSWNTs). Photoexcited carriers are inelastically scattered by a continuum of low-energy electron-hole pairs created across the graphenelike linear electronic subbands of the MSWNTs. The optical resonances in MSWNTs give rise to well-defined electronic Raman peaks. This resonant electronic Raman scattering is a unique feature of the electronic structure of these one-dimensional quasimetals. PMID- 22107318 TI - Coalescence of single photons emitted by disparate single-photon sources: the example of InAs quantum dots and parametric down-conversion sources. AB - Single photons produced by fundamentally dissimilar physical processes will in general not be indistinguishable. We show how photons produced from a quantum dot and by parametric down-conversion in a nonlinear crystal can be manipulated to be indistinguishable. The measured two-photon coalescence probability is 16%, and is limited by quantum-dot decoherence. Temporal filtering to the quantum-dot coherence time and accounting for detector time response increases this to 61% while retaining 25% of the events. This technique can connect different elements in a scalable quantum network. PMID- 22107319 TI - Enhanced photon generation in a Nb/n-InGaAs/p-InP superconductor/semiconductor diode light emitting device. AB - We experimentally demonstrate Cooper pairs' drastic enhancement of the band-to band radiative recombination rate in a semiconductor. Electron Cooper pairs injected from a superconducting electrode into an active layer by the proximity effect recombine with holes injected from a p-type electrode. The recombination of a Cooper pair with p-type carriers dramatically increases the photon generation probability of a light-emitting diode in the optical-fiber communication band. The measured radiative decay time rapidly decreases with decreasing temperature below the superconducting transition temperature of the niobium electrodes. Our results indicate the possibility to open up new interdisciplinary fields between superconductivity and optoelectronics. PMID- 22107320 TI - Direct measurement of cell wall stress stiffening and turgor pressure in live bacterial cells. AB - We study intact and bulging Escherichia coli cells using atomic force microscopy to separate the contributions of the cell wall and turgor pressure to the overall cell stiffness. We find strong evidence of power-law stress stiffening in the E. coli cell wall, with an exponent of 1.22+/-0.12, such that the wall is significantly stiffer in intact cells (E=23+/-8 MPa and 49+/-20 MPa in the axial and circumferential directions) than in unpressurized sacculi. These measurements also indicate that the turgor pressure in living cells E. coli is 29+/-3 kPa. PMID- 22107321 TI - Mossbauer effect in proteins. AB - In proteins, the Mossbauer effect and neutron scattering show a broad line and a rapid increase of the conformational mean-square displacement above about 180 K. The increase, dubbed the "dynamical transition," is controversial. We introduce a new interpretation of the Mossbauer effect in proteins and demonstrate that no dynamical transition is required. The increase in the mean-square displacement and the broad line are caused by fluctuations in the protein's hydration shell. Using the dielectric spectrum of these fluctuations, we predict the shape of the Mossbauer spectrum from 80 to 295 K with one dimensionless coefficient. PMID- 22107322 TI - Nonequilibrium forces between dragged ultrasoft colloids. AB - The dynamical deformation of ultrasoft colloids as well as their dynamic frictional forces are numerically investigated, when one colloid is dragged past another at constant velocity. Hydrodynamic interactions are captured by a particle-based mesoscopic simulation method. At vanishing relative velocity, the equilibrium repulsive force-distance curve is obtained. At large drag velocities, in contrast, we find an apparent attractive force for departing colloids along the dragging direction. The deformation, in the close encounter of colloids, and the energy dissipation are examined as a function of the drag velocity and their separation. PMID- 22107323 TI - Hydrodynamic pair attractions between driven colloidal particles. AB - Colloidal spheres driven through water along a circular path by an optical ring trap display unexpected dynamical correlations. We use Stokesian dynamics simulations and a simple analytical model to demonstrate that the path's curvature breaks the symmetry of the two-body hydrodynamic interaction, resulting in particle pairing. The influence of this effective nonequilibrium attraction diminishes as either the temperature or the stiffness of the radial confinement increases. We find a well-defined set of dynamically paired states whose stability relies on hydrodynamic coupling in curving trajectories. PMID- 22107324 TI - Relaxations and rheology near jamming. AB - We determine the form of the complex shear modulus G* in soft sphere packings near jamming. Viscoelastic response at finite frequency is closely tied to a packing's intrinsic relaxational modes, which are distinct from the vibrational modes of undamped packings. We demonstrate and explain the appearance of an anomalous excess of slowly relaxing modes near jamming, reflected in a diverging relaxational density of states. From the density of states, we derive the dependence of G* on the frequency and distance to the jamming transition, which is confirmed by numerics. PMID- 22107325 TI - Is hydrogen storage possible in metal-doped graphite 2D systems in conditions found on Earth? AB - Density functional theory (DFT) calculations are performed for the adsorption energy of hydrogen and oxygen on graphene decorated with a wide set of metals (Li, Na, K, Al, Ti, V, Ni, Cu, Pd, Pt). It is found that oxygen interferes with hydrogen adsorption by either blocking the adsorption site or by the irreversible oxidation of the metal decoration. The most promising decorations are Ni, Pd, and Pt due to a reasonable relationship of adsorption energies which minimize the oxygen interference. The DFT results are used to parametrize a statistical mechanical model which allows evaluation of the effect of partial pressures in the gas phase during storage. According to this model, even in the most promising case, it is necessary to reduce the oxygen partial pressure close to ultrahigh vacuum conditions to allow hydrogen storage. PMID- 22107326 TI - Structural preferential attachment: network organization beyond the link. AB - We introduce a mechanism which models the emergence of the universal properties of complex networks, such as scale independence, modularity and self-similarity, and unifies them under a scale-free organization beyond the link. This brings a new perspective on network organization where communities, instead of links, are the fundamental building blocks of complex systems. We show how our simple model can reproduce social and information networks by predicting their community structure and more importantly, how their nodes or communities are interconnected, often in a self-similar manner. PMID- 22107327 TI - Comment on "Plasmon-enhanced ultraviolet photoluminescence from hybrid structures of graphene/ZnO films". PMID- 22107329 TI - Structural perspective on the direct inhibition mechanism of EGCG on mammalian histidine decarboxylase and DOPA decarboxylase. AB - Histidine decarboxylase (HDC) and l-aromatic amino acid decarboxylase (DDC) are homologous enzymes that are responsible for the synthesis of important neuroactive amines related to inflammatory, neurodegenerative, and neoplastic diseases. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, has been shown to target histamine-producing cells and to promote anti inflammatory, antitumor, and antiangiogenic effects. Previous experimental work has demonstrated that EGCG has a direct inhibitory effect on both HDC and DDC. In this study, we investigated the binding modes of EGCG to HDC and DDC as a first step for designing new polyphenol-based HDC/DDC-specific inhibitors. PMID- 22107330 TI - What motivates girls to take up exercise during adolescence? Learning from those who succeed. AB - OBJECTIVES: The present study explored factors that underpin increased internalization (i.e., perceived autonomy) in motivation towards exercise over a 1-year period in adolescent girls. DESIGN: A mixed methods prospective study. METHODS: A total of 107 girls (mean age = 13.28 years) reported their exercise behaviour, exercise goals, and a multidimensional measure of motivation towards exercise on two occasions, 1 year apart. Ten girls reporting increased autonomous motivation were then interviewed. RESULTS: Two themes were extracted; growing up and seeking challenge. Most participants reported being more interested in exercising for their health as a result of growing up, through having greater understanding of the health-behaviour link and willingness to act now for future health gain. However, their motivation appeared to be only partially internalized, as health was still viewed primarily as a value promoted by respected others (parents, teachers, media). Furthermore, as many girls conflated being healthy with being thin, health for appearance-related weight control was experienced as an extrinsic (controlling) goal. The second theme was more suggestive of autonomous motivation; girls reported valuing exercise for the opportunity it provides to set and achieve personally meaningful challenges, facilitating a sense of competence and achievement. CONCLUSIONS: The findings may have a useful application in suggesting how exercise settings could be manipulated to increase enjoyment and participation during adolescence. In particular, the findings suggest that means of increasing the salience of the rewarding nature of setting and reaching personal challenges in an exercise setting are investigated. PMID- 22107331 TI - Whole-body vibration influences lower extremity circulatory and neurological function. AB - Whole-body vibration (WBV) is currently used to enhance performance and treat injuries even though we lack an understanding of how WBV influences physiological processes. An improved understanding of the physiological effects of WBV could lead to protocols to speed healing or treat pathologies. This study examined the acute effects of WBV on peripheral blood perfusion, muscle oxygenation, motoneuron pool excitability, and sensory nerve conduction velocity. Fourteen healthy participants [9 women (21.7 +/- 2.4 years); 5 men (20.8 +/- 1.1 years)] completed a 5 min bout of WBV (50 Hz, 2 mm amplitude). Measures were assessed pre treatment and at 0, 5, 10, 15, and 20 min post-treatment. WBV significantly increased superficial skin temperature (P < 0.0005) and total hemoglobin (P = 0.009), had no effect of oxyhemoglobin (P = 0.186), increased deoxyhemoglobin (P < 0.0005), inhibited the soleus Hoffmann reflex (P = 0.007), and had no effect on sural sensory nerve conduction velocity (P = 0.695). These results suggest that an acute bout of WBV influences physiological processes in both the circulatory and the nervous systems. PMID- 22107332 TI - Leptin-to-adiponectin, adiponectin-to-leptin ratios, and insulin are specific and sensitive markers associated with polycystic ovary syndrome: a case-control study from Bahrain. AB - OBJECTIVE: Hyperinsulinemia and adipokines such as leptin and adiponectin with respective proatherogenic and antiatherogenic properties are reported to be the major contributors to pathogenesis of polycystic ovary syndrome (PCOS), including to the development of type 2 diabetes and coronary artery disease. In this study, the association of hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, high leptin-to-adiponectin (L/A) and adiponectin-to-leptin (A/L) ratios as risk factors associated with PCOS in Bahraini women was investigated. PARTICIPANTS AND METHODS: Serum levels of insulin, leptin, adiponectin, cholesterol, triglyceride, A/L and L/A ratios were compared in women with PCOS and controls to investigate tentative and potential diagnostic markers for women with PCOS. RESULTS: Insulin was significantly higher in PCOS cases than controls (15.0+/-3.0 vs. 6.5+/-1.72, P<0.001). Leptin was significantly higher in PCOS cases than in controls (39.9+/ 4.6 vs. 26.4+/-3.4, P<0.001), whereas adiponectin was significantly lower in PCOS cases than in controls (8.7+/-3.0 vs. 11.1+/-3.6, P<0.001). In addition, L/A ratios were significantly higher in PCOS cases than in controls (4.8+/-2.7 vs. 2.3+/-1.6, P<0.001), whereas A/L ratios were significantly lower in PCOS cases than in controls (0.25+/-0.08 vs. 0.50+/-0.1, P<0.001). In multivariate logistic regression analyses, insulin [odds ratio (OR)=2.1, confidence interval (CI) 1.2 3.8, P=0.01], A/L (OR=1.6, CI 1.4-7.2, P=0.03), and L/A (OR=1.4, CI 1.2-2.0, P=0.04) were independently associated with PCOS. Receiver operating characteristic analyses showed that the best predictive markers for PCOS were insulin [area under the curve (AUC)=0.937, CI 0.887-0.989] L/A and A/L ratios (AUC=0.861, CI 0.786-0.936), indicating their high sensitivity and specificity for diagnosis of PCOS. CONCLUSION: In Bahraini women with PCOS, insulin, L/A, and A/L ratios seem to be the best markers to distinguish women with and without PCOS. PMID- 22107333 TI - Interstaple dithiol cross-linking in Au25(SR)18 nanomolecules: a combined mass spectrometric and computational study. AB - A systematic study of cross-linking chemistry of the Au(25)(SR)(18) nanomolecule by dithiols of varying chain length, HS-(CH(2))(n)-SH where n = 2, 3, 4, 5, and 6, is presented here. Monothiolated Au(25) has six [RSAuSRAuSR] staple motifs on its surface, and MALDI mass spectrometry data of the ligand exchanged clusters show that propane (C3) and butane (C4) dithiols have ideal chain lengths for interstaple cross-linking and that up to six C3 or C4 dithiols can be facilely exchanged onto the cluster surface. Propanedithiol predominately exchanges with two monothiols at a time, making cross-linking bridges, while butanedithiol can exchange with either one or two monothiols at a time. The extent of cross-linking can be controlled by the Au(25)(SR)(18) to dithiol ratio, the reaction time of ligand exchange, or the addition of a hydrophobic tail to the dithiol. MALDI MS suggests that during ethane (C2) dithiol exchange, two ethanedithiols become connected by a disulfide bond; this result is supported by density functional theory (DFT) prediction of the optimal chain length for the intrastaple coupling. Both optical absorption spectroscopy and DFT computations show that the electronic structure of the Au(25) nanomolecule retains its main features after exchange of up to eight monothiol ligands. PMID- 22107334 TI - International Classification of Functioning, Disability and Health in children with cerebral palsy. AB - PURPOSE: We intended to describe how concepts from recent models of disability have been studied for evaluation of children with cerebral palsy (CP) and their clinical implications. METHOD: We revised studies that focused on the components of the International Classification of Functioning, Disability and Health (ICF) in children with CP. RESULTS: Researchers have reported that children with CP exhibit impairments in various body functions/structures, limitations in functional activities performance and experience poorer participation outcomes than their typical peers. Moreover, it has been showed that participation of children with CP was affected by environmental factors. CONCLUSION: Therefore, evaluation and rehabilitation processes should be focused on the quality of life improvement by emphasizing what a child can and wants to execute within the environment. Also, environmental factors should be recognized so that barriers could be minimized and adaptations to the environment achieved. However, few studies have verified the interrelationship between contextual factors and the functioning and disability domains in children with CP. This would allow us to know about approaches specifically designed for these children's needs. PMID- 22107335 TI - Self-assembled molecular rafts at liquid|liquid interfaces for four-electron oxygen reduction. AB - The self-assembly of the oppositely charged water-soluble porphyrins, cobalt tetramethylpyridinium porphyrin (CoTMPyP(4+)) and cobalt tetrasulphonatophenyl porphyrin (CoTPPS(4-)), at the interface with an organic solvent to form molecular "rafts", provides an excellent catalyst to perform the interfacial four electron reduction of oxygen by lipophilic electron donors such as tetrathiafulvalene (TTF). The catalytic activity and selectivity of the self assembled catalyst toward the four-electron pathway was found to be as good as that of the Pacman type cofacial cobalt porphyrins. The assembly has been characterized by UV-visible spectroscopy, Surface Second Harmonic Generation, and Scanning Electron Microscopy. Density functional theory calculations confirm the possibility of formation of the catalytic CoTMPyP(4+)/ CoTPPS(4-) complex and its capability to bind oxygen. PMID- 22107336 TI - ACR appropriateness criteria((r)) ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) describes a wide spectrum of non-invasive tumors which carry a significant risk of invasive relapse, thus prevention of local recurrence is vital. For appropriate patients with limited disease, management with breast conserving surgery (BCS) followed by whole-breast radiation (RT) is supported by multiple Phase III studies, but mastectomy may be appropriate in selected patients. Omission of RT may also be reasonable in some patients, though which criteria are to be utilized remain unclear, and the existing data are contradictory with limited follow-up. Various RT techniques such as boost to the tumor bed, partial breast radiation or hypofractionated, whole-breast RT are increasingly utilized but the data to support their use specifically in DCIS is limited. Tamoxifen also increases local control for ER + DCIS, adding to the complexity of the local treatment management. This article reviews the existing scientific evidence, the controversies surrounding local management, and clinical guidelines for DCIS based on the group consensus by the ACR Breast Expert Panel. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 22107337 TI - Advances and limitations in our knowledge of cortical reorganization in cerebral palsy. PMID- 22107338 TI - Why does genetic causal information alter perceived treatment effectiveness? An analogue study. AB - OBJECTIVES: When a health problem is perceived as having a genetic cause, this appears to increase the perceived effectiveness of pharmacological treatments and reduce perceived effectiveness of non-pharmacological treatments. Potential mediators of this effect include causal attributions, perceived severity, and perceived control over the health problem. This study aimed to use experimental methods to establish which beliefs mediate the effect of genetic causal information on perceived effectiveness of treatments. DESIGN: A 4(cause: environmental, family history, genetic test, family history & genetic test)*2(severity: higher or low) between-subjects design using vignettes about heart disease risk, obesity or depression. METHODS: A total of 647 adults, randomly assigned to read one of the experimental vignettes, were interviewed. Key outcomes were perceived effectiveness of medication and of non pharmacological treatments. Potential mediators of perceived severity, perceived controllability, and causal attributions were also assessed. RESULTS: For heart disease risk, genetic causes reduced perceived effectiveness of non pharmacological treatments (an effect mediated by causal attributions and perceived control) but did not influence perceived medication effectiveness. For obesity, neither severity nor cause influenced the perceived effectiveness of either treatment. For depression, genetic causes only increased perceived effectiveness of medication for more severe depression, an effect mediated by perceived control. CONCLUSIONS: The impact of genetic causal information on perceived effectiveness of treatments varies with type of health problem. When genetic causal information influences perceived treatment effectiveness, it does so by altering causal attributions and perceived controllability. However, these effects are small and unlikely to translate into clinically meaningful differences in health-enhancing behaviours. PMID- 22107339 TI - Highly porous acrylonitrile-based submicron particles for UO2(2+) absorption in an immunosensor assay. AB - Our laboratory has previously reported an antibody-based assay for hexavalent uranium (UO(2)(2+)) that could be used on-site to rapidly assess uranium contamination in environmental water samples (Melton, S. J.; et al. Environ. Sci. Technol. 2009, 43, 6703-6709). To extend the utility of this assay to less characterized sites of uranium contamination, we required a uranium-specific adsorbent that would rapidly remove the uranium from groundwater samples, while leaving the concentrations of other ions in the groundwater relatively unaltered. This study describes the development of hydrogel particles containing amidoxime groups that can rapidly and selectively facilitate the uptake of uranyl ions. A miniemulsion polymerization technique using SDS micelles was employed for the preparation of the hydrogel as linked submicrometer particles. In polymerization, acrylonitrile was used as the initial monomer, ethylene glycol dimethacrylate as the crosslinker and 2-hydroxymethacrylate, 1-vinyl-2-pyrrolidone, acrylic acid, or methacrylic acid were added as co-monomers after the initial seed polymerization of acrylonitrle. The particles were characterized by transmission electron spectroscopy, scanning electron microscopy (SEM) and cryo-SEM. The amidoximated particles were superior to a commercially available resin in their ability to rapidly remove dissolved UO(2)(2+) from spiked groundwater samples. PMID- 22107340 TI - Association of poly(4-hydroxystyrene)-block-poly(ethylene oxide) in aqueous solutions: block copolymer nanoparticles with intermixed blocks. AB - Association behavior of diblock copolymer poly(4-hydroxystyrene)-block poly(ethylene oxide) (PHOS-PEO) in aqueous solutions and solutions in water/tetrahydrofuran mixtures was studied by static, dynamic, and electrophoretic light scattering, (1)H NMR spectroscopy, transmission electron microscopy, and cryogenic field-emission scanning electron microscopy. It was found that, in alkaline aqueous solutions, PHOS-PEO can form compact spherical nanoparticles whose size depends on the preparation protocol. Instead of a core/shell structure with segregated blocks, the PHOS-PEO nanoparticles have intermixed PHOS and PEO blocks due to hydrogen bond interaction between -OH groups of PHOS and oxygen atoms of PEO and are stabilized electrostatically by a fraction of ionized PHOS units on the surface. PMID- 22107341 TI - Simulating the degree of oxidation in atmospheric organic particles. AB - Modeled ratios of organic mass to organic carbon (OM/OC) and oxygen to carbon (n(O)/n(C)) in organic particulate matter are presented across the US for the first time and evaluated extensively against ambient measurements. The base model configuration systematically underestimates OM/OC ratios during winter and summer months. Model performance is greatly improved by applying source-specific OM/OC ratios to the primary organic aerosol (POA) emissions and incorporating a new parametrization to simulate oxidative aging of POA in the atmosphere. These model improvements enable simulation of urban-scale gradients in OM/OC with values in urban areas as much as 0.4 lower than in the surrounding regions. Modeled OM/OC and n(O)/n(C) ratios in January range from 1.4 to 2.0 and 0.2 to 0.6, respectively. In July, modeled OM/OC and n(O)/n(C) ratios range from 1.4 to 2.2 and 0.2 to 0.8, respectively. Improved model performance during winter is attributed entirely to our application of source-specific OM/OC ratios to the inventory. During summer, our treatment of oxidative aging also contributes to improved performance. Advancements described in this paper are codified in the latest public release of the Community Multiscale Air Quality model, CMAQv5.0. PMID- 22107342 TI - High acceptability of HIV voluntary counselling and testing among female sex workers: impact of individual and social factors. AB - OBJECTIVES: Voluntary counselling and testing (VCT) for HIV infection is an important tool for prevention of HIV infection and AIDS in high-risk groups. Our goal was to describe the acceptability and consequences of VCT among a stigmatized and vulnerable group, female sex workers (FSWs), in Conakry, Guinea. METHODS: Acceptance of the test and return for test results at baseline and consequences of testing 1 year later were described. The perceived risk of HIV infection and perceived benefits and barriers to testing were examined using quantitative and qualitative methods. RESULTS: All 421 FSW participants agreed to undergo VCT and most participants (92%) returned for their results. The main reason cited for VCT acceptance was the wish to know their HIV status. However, some managers of FSW worksites urged FSWs to be tested, curtailing FSWs' free decision-making. One year later, status disclosure was common (90% of the 198 individuals who knew their results among those who participated in the follow-up part of the study). Positive consequences of testing were far more frequently reported than negative consequences (98% vs. 2%, respectively). Negative life events included banishment from the worksite (one case) and verbal abuse (two cases). CONCLUSION: Acceptability of VCT appears high in the FSW population in Conakry as a consequence of both perceptions of high individual risk and social pressures. PMID- 22107343 TI - Free Radical Research origins. PMID- 22107344 TI - High tissue factor in lungs and plasma associates with respiratory morbidity in preterm infants. AB - AIM: In preterm infants, inflammation and intra-alveolar fibrin formation characterize respiratory distress syndrome (RDS). Tissue factor (TF) is a link between inflammation and coagulation pathways. We investigated the relationship between TF and cytokines in preterm infants to gain information of the role of TF in the inflammatory response. METHODS: We measured TF in plasma and in tracheal aspirates and analysed TF on monocytes by flow cytometry and 13 cytokines from plasma, in 56 preterm infants (birthweight 600-1500 g) during their first week. RESULTS: Plasma TF increased and peaked on day 3 and correlated with both RDS and inversely with paO2/FIO2. On day 1, TF in tracheal aspirates was 10-fold higher than in plasma and correlated with plasma TF (4888 vs. 506 pg/mL, R = 0.692, p = 0.013, n = 12). Of main pro-inflammatory cytokines, plasma TF correlated post natally with IL-8 and IL-6 but not with IL-1 or TNF-alpha. CONCLUSIONS: Respiratory morbidity associates with high TF in lungs and plasma. In sick newborn infants, upregulation of TF may be mediated by IL-6 and IL-8. High TF and pro-inflammatory cytokines may together participate in the pathogenesis of pulmonary and extrapulmonary injury in preterm infants through pro-inflammatory mechanisms. PMID- 22107345 TI - High throughput screening: an in silico solubility parameter approach for lipids and solvents in SLN preparations. AB - OBJECTIVE: The present paper describes an in silico solubility behavior of drug and lipids, an essential screening study in preparation of solid lipid nanoparticles (SLN). MATERIALS AND METHODS: Ciprofloxacin HCl was selected as a model drug along with 11 lipids and 5 organic solvents. In silico miscibility study of drug/lipid/solvent was performed using Hansen solubility parameter approach calculated by group contribution method of Van Krevelen and Hoftyzer. Predicted solubility was validated by determining solubility of lipids in various solvent at different temperature range, while miscibility of drug in lipids was determined by apparent solubility study and partition experiment. RESULTS AND DISCUSSION: The presence of oxygen and OH functionality increases the polarity and hydrogen bonding possibilities of the compound which has reflected the highest solubility parameter values for Geleol and Capmul MCM C8. Ethyl acetate, Geleol and Capmul MCM C8 was identified as suitable organic solvent, solid lipid and liquid lipid respectively based on a solubility parameter approach which was in agreement with the result of an apparent solubility study and partition coefficient. CONCLUSION: These works demonstrate the validity of solubility parameter approach and provide a feasible predictor to the rational selection of excipients in designing SLN formulation. PMID- 22107346 TI - Phenotypic variation in Acidovorax radicisN35 influences plant growth promotion. AB - Acidovorax radicis N35, isolated from surface-sterilized wheat roots (Triticum aestivum), showed irreversible phenotypic variation in nutrient broth, resulting in a differing colony morphology. In addition to the wild-type form (rough colony type), a phenotypic variant form (smooth colony type) appeared at a frequency of 3.2 * 10(-3) per cell per generation on NB agar plates. In contrast to the N35 wild type, the variant N35v showed almost no cell aggregation and had lost its flagella and swarming ability. After inoculation, only the wild-type N35 significantly promoted the growth of soil-grown barley plants. After co inoculation of axenically grown barley seedlings with differentially fluorescently labeled N35 and N35v cells, decreased competitive endophytic root colonization in the phenotypic variant N35v was observed using confocal laser scanning microscopy. In addition, 454 pyrosequencing of both phenotypes revealed almost identical genomic sequences. The only stable difference noted in the sequence of the phenotype variant N35v was a 16-nucleotide deletion identified in a gene encoding the mismatch repair protein MutL. The deletion resulted in a frameshift that revealed a new stop codon resulting in a truncated MutL protein missing a functional MutL C-terminal domain. The mutation was consistent in all investigated phenotype variant cultures and might be responsible for the observed phenotypic variation in A. radicis N35. PMID- 22107347 TI - Effect of pressure on the solubilization of a fluorescent merocyanine dye by a nonionic surfactant. AB - The target dye, which is a derivative of Merocyanine 540 bearing a naphthoxazole headgroup, persists as a monomer in ethanol solution but dimerizes in water under ambient conditions. Analysis of the absorption spectrum indicates that the dimer has an oblique geometry with the two molecules being held at an angle of ca. 55 degrees . Applying high pressure to the system forces the two molecules into closer contact, resulting in a decreased partial molar volume of 3.1 cm(3). One molecule of the monomeric dye enters a neutral micelle formed from Triton X-100, where it is highly fluorescent and free of exciton coupling. The result of applied pressure on these latter systems depends on the concentration of surfactant. Above the critical micelle concentration (CMC), applied pressure has little effect other than to increase the viscosity inside the micelle. At very low surfactant concentration, applied pressure forces monomeric dye into the dimeric form, as observed in the absence of Triton X-100. It is notable, however, that the pressure effect on the dimerization constant is exaggerated in the presence of surfactant. At intermediate surfactant concentrations, applied pressure leads to a marked change in the CMC. In particular, applied pressure reduces the partial molar volume of the micelle by ca. 7.9 cm(3) and induces micelle formation at relatively low concentration of surfactant. For example, the CMC falls from ca. 250 MUM at atmospheric pressure to only 50 MUM at 460 MPa. PMID- 22107348 TI - Semiempirical Hamiltonian for simulation of azobenzene photochemistry. AB - We present a semiempirical Hamiltonian that provides an accurate description of the first singlet and triplet potential energy surfaces of azobenzene for use in direct simulations of the excited-state dynamics. The parameterization made use of spectroscopic and thermochemical data and the best ab initio results available to date. Two-dimensional potential energy surfaces based on constrained geometry optimizations are presented for the states that are most relevant for the photochemistry of azobenzene, namely, S(0), S(1), and S(2). In order to run simulations of the photodynamics of azobenzene in hydrocarbons or hydroxylic solvents, we determined the interactions of methane and methanol with the azo group by ab initio calculations and fitted the interactions with a QM/MM interaction Hamiltonian. PMID- 22107349 TI - The prevalence and characteristics of relational depth events in psychotherapy. AB - We introduce two complementary measures of relational depth, defined as a state of profound contact and engagement between client and therapist. Using an internet-based survey of client and therapist accounts (n=342), judges rated relational depth as present in over a third of significant therapy event descriptions. Participants also completed the Relational Depth Inventory (RDI), for which we report reliability, validity and factor structure. Relational depth events were more likely to occur in the presence of strong therapeutic alliance, and with female participants, but client or therapist role and therapy duration were not related to relational depth content or RDI. RDI items for connectedness, love, respect and intimacy were most strongly associated with relational depth content. PMID- 22107350 TI - Scattering density profile model of POPG bilayers as determined by molecular dynamics simulations and small-angle neutron and X-ray scattering experiments. AB - We combine molecular dynamics (MD) simulations and experiment, both small-angle neutron (SANS) and small-angle X-ray scattering (SAXS), to determine the precise structure of bilayers composed of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylglycerol (POPG), a lipid commonly encountered in bacterial membranes. Experiment and simulation are used to develop a one-dimensional scattering density profile (SDP) model suitable for the analysis of experimental data. The joint refinement of such data (i.e., SANS and SAXS) results in the area per lipid that is then used in the fixed-area simulations. In the final step, the direct comparison of simulated-to-experimental data gives rise to the detailed structure of POPG bilayers. From these studies we conclude that POPG's molecular area is 66.0 +/- 1.3 A(2), its overall bilayer thickness is 36.7 +/- 0.7 A, and its hydrocarbon region thickness is 27.9 +/- 0.6 A, assuming a simulated value of 1203 A(3) for the total lipid volume. PMID- 22107351 TI - Nonencapsulated or nontypeable Haemophilus influenzae are more likely than their encapsulated or serotypeable counterparts to have mutations in their fucose operon. AB - Population biology of Haemophilus influenzae can be studied by multilocus sequence typing (MLST), and isolates are assigned sequence types (STs) based on nucleotide sequence variations in seven housekeeping genes, including fucK. However, the ST cannot be assigned if one of the housekeeping genes is absent or cannot be detected by the current protocol. Occasionally, strains of H. influenzae have been reported to lack the fucK gene. In this study, we examined the prevalence of this mutation among our collection of H. influenzae isolates. Of the 704 isolates studied, including 282 encapsulated and 422 nonencapsulated isolates, nine were not typeable by MLST owing to failure to detect the fucK gene. All nine fucK-negative isolates were nonencapsulated and belonged to various biotypes. DNA sequencing of the fucose operon region confirmed complete deletion of genes in the operon in seven of the nine isolates, while in the remaining two isolates, some of the genes were found intact or in parts. The significance of these findings is discussed. PMID- 22107352 TI - Influence of organic coatings on pyrene ozonolysis at the air-aqueous interface. AB - Glancing angle laser-induced fluorescence was used to investigate the effects of organic monolayer coatings on the ozonation kinetics of pyrene at the air-aqueous interface. Fluorescence spectra show that both 1-octanol and octanoic acid coatings give rise to similar decreased polarity at the interface relative to the uncoated surface and show a similar propensity of pyrene to partition to the interface. Ozonation kinetics follow a Langmuir-Hinshelwood mechanism, indicating a surface reaction. At high ozone concentrations, a monolayer coating of 1 octanol enhances the rate relative to the uncoated surface and a coating of octanoic acid decreases the rate. Pyrene fluorescence is most efficiently quenched by ozone in the presence of a 1-octanol coating, followed by the uncoated surface, and least efficiently quenched by ozone in the presence of octanoic acid. In agreement with earlier work, a significant photoenhancement of the ozonation is observed at the uncoated surface; however, no enhancement is observed with monolayer coatings of either organic. Quantum chemical calculations indicate a reasonable binding of ozone by the carboxylic acid group (in both its dissociated and undissociated forms). We suggest that the inhibition of the water surface reaction by a monolayer of octanoic acid is due to the sequestration of ozone by the carboxylic acid group. PMID- 22107353 TI - Integrative rehabilitation of elderly stroke survivors: the design and evaluation of the BrightArmTM. AB - PURPOSE: To describe the development of the BrightArm upper extremity rehabilitation system, and to determine its clinical feasibility with older hemiplegic patients. METHOD: The BrightArm adjusted arm gravity loading through table tilting. Patients wore an arm support that sensed grasp strength and communicated wirelessly with a personal computer. Games were written to improve cognitive, psychosocial and the upper extremity motor function and adapted automatically to each patient. The system underwent feasibility trials spanning 6 weeks. Participants were evaluated pre-therapy, post-therapy, and at 6 weeks follow-up using standardized clinical measures. Computerized measures of supported arm reach and game performance were stored on a remote server. RESULTS: Five participants had clinically significant improvements in their active range of shoulder movement, shoulder strength, grasp strength, and their ability to focus. Several participants demonstrated substantially higher arm function (measured with the Fugl-Meyer test) and two were less-depressed (measured with the Becks Depression Inventory, Second Edition). The BrightArm technology was well-accepted by the participants, who gave it an overall subjective rating of 4.1 on a 5 point Likert scale. CONCLUSIONS: Given these preliminary findings, it will be beneficial to evaluate the BrightArm through controlled clinical trials and to investigate its application to other clinical populations. PMID- 22107354 TI - Physical and psychological stressors linked with stress fractures in recruit training. AB - This study aimed to measure ambulation in infantry army basic training, and to evaluate if covering more distance can explain stress fractures in a stressor stress model. Forty-four male combat recruits (18.7 +/- 0.7 years) participated in a 6-month rigorous high intensity combat training program. Baseline data included anthropometric measurements, VO(2)max, and psychological questionnaires. Actual distance covered was measured using a pedometer over an 11-week training period. Psychological questionnaires were repeated after 2 months. Sixteen recruits were diagnosed with stress fractures by imaging (SFi = 36.4%). Statistical analysis included comparing measured variables between SFi and those without stress fractures (NSF). The recruits covered 796 +/- 157 km, twofold the distance planned of 378 km (P < 0.001). The SFi group covered a distance 16.4% greater than that of the NSF group (866 +/- 136 and 744 +/- 161 km, respectively, P < 0.01), and also demonstrated greater psychological stress. These data reveal the importance of adherence to or enforcement of military training programs. In the light of these data, the Israeli Defense Forces program needs reappraisal. A stressor-stress response might explain the susceptibility of certain recruits for injury. Using advanced technology, monitoring ambulation may prevent stress fracture development by limiting subjects exceeding a certain level. Psychological profile may also play a role in predicting stress fracture development. PMID- 22107355 TI - New empirical evidence of the validity of the Chronic Pain Acceptance Questionnaire: the differential influence of activity engagement and pain willingness on adjustment to chronic pain. AB - OBJECTIVE: The aims of this study were to examine the internal structure of the Spanish version of the Chronic Pain Acceptance Questionnaire and present new empirical evidence regarding its validity. DESIGN AND METHODS: A sample of 315 chronic pain patients attending a pain clinic completed a battery of instruments to assess pain acceptance, general psychological acceptance, depression, anxiety, pain intensity, functional impairment, and current functioning. RESULTS: Confirmatory factor analysis supported the validity of a 20-item version with two subscales corresponding to two independent factors: Activity Engagement and Pain Willingness. Structural Equation Modelling showed that the association between pain intensity and anxiety and depression was fully mediated by Activity Engagement which partially mediated the association between pain intensity and functioning. Pain Willingness partially mediated the influence of pain intensity on functional impairment. CONCLUSIONS: These findings indicate the differential influence of both components on adjustment to chronic pain. PMID- 22107356 TI - Induction of ovarian cancer and DNA adducts by Dibenzo[a,l]pyrene in the mouse. AB - Tobacco smoking is an etiological factor of ovarian cacner; however, the mechanisms remain largely undefined. Therefore, as an initial investigation, we examined the carcinogenicity and DNA adducts formation in the ovary of mice treated with DB[a,l]P, a tobacco smoke constituent and environmental pollutant. Ovarian tumors in B6C3F1 mice were induced by direct application of DB[a,l]P (24, 12, 6, and 3 nmol/mouse, three times a week for 38 weeks) into the oral cavity of mice. At 6 nmol, DB[a,l]P induced the highest total ovarian tumor incidence (79%), but the incidence of malignancy was only 15%. However, at the dose of 12 nmol, the total ovarian tumor incidence was 75%, and the incidence of malignancy was 65%. In addition to ovarian tumors, at the dose of 24 nmol, DB[a,l]P induced lesions in sites distal from the ovaries including the skin, mammary, lung, and oral tissues, which were rare at doses lower than 24 nmol. Another bioassay was conducted to detect and quantify DNA adducts induced by DB[a,l]P (24 nmol, three times a week for 5 weeks) in the ovary at 48 h and 1, 2, and 4 weeks after the last administration of DB[a,l]P. DNA was isolated, and the dibenzo[a,l]pyrene 11,12-dihydrodiol-13,14-epoxide (DB[a,l]PDE)-DNA adducts were analyzed by a LC MS/MS method. DB[a,l]P resulted in the formation of (-)-anti-cis-DB[a,l]PDE-dA and (-)-anti-trans-DB[a,l]PDE-dA adducts, which were 0.8 and 1.6 fmol/10(6) dA, respectively, in ovaries of mice within 48 h, and the level of adducts decreased over a week. Our results indicated that DB[a,l]P can be metabolized to form (-) anti-DB[a,l]PDE; the latter may, in part, account for DB[a,l]P-induced ovarian cancer. This animal model should assist to better understand the mechanisms, account for the induction of ovarian cancer by tobacco carcinogens, and facilitate the development of chemopreventive agents against ovarian cancer. PMID- 22107357 TI - Interpolations of groundwater table elevation in dissected uplands. AB - The variable elevation of the groundwater table in the St. Louis area was estimated using multiple linear regression (MLR), ordinary kriging, and cokriging as part of a regional program seeking to assess liquefaction potential. Surface water features were used to determine the minimum water table for MLR and supplement the principal variables for ordinary kriging and cokriging. By evaluating the known depth to the water and the minimum water table elevation, the MLR analysis approximates the groundwater elevation for a contiguous hydrologic system. Ordinary kriging and cokriging estimate values in unsampled areas by calculating the spatial relationships between the unsampled and sampled locations. In this study, ordinary kriging did not incorporate topographic variations as an independent variable, while cokriging included topography as a supporting covariable. Cross validation suggests that cokriging provides a more reliable estimate at known data points with less uncertainty than the other methods. Profiles extending through the dissected uplands terrain suggest that: (1) the groundwater table generated by MLR mimics the ground surface and elicits a exaggerated interpolation of groundwater elevation; (2) the groundwater table estimated by ordinary kriging tends to ignore local topography and exhibits oversmoothing of the actual undulations in the water table; and (3) cokriging appears to give the realistic water surface, which rises and falls in proportion to the overlying topography. The authors concluded that cokriging provided the most realistic estimate of the groundwater surface, which is the key variable in assessing soil liquefaction potential in unconsolidated sediments. PMID- 22107358 TI - Improved machine learning models for predicting selective compounds. AB - The identification of small potent compounds that selectively bind to the target under consideration with high affinities is a critical step toward successful drug discovery. However, there is still a lack of efficient and accurate computational methods to predict compound selectivity properties. In this paper, we propose a set of machine learning methods to do compound selectivity prediction. In particular, we propose a novel cascaded learning method and a multitask learning method. The cascaded method decomposes the selectivity prediction into two steps, one model for each step, so as to effectively filter out nonselective compounds. The multitask method incorporates both activity and selectivity models into one multitask model so as to better differentiate compound selectivity properties. We conducted a comprehensive set of experiments and compared the results with those of other conventional selectivity prediction methods, and our results demonstrated that the cascaded and multitask methods significantly improve the selectivity prediction performance. PMID- 22107359 TI - Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV-infected Ugandans. AB - BACKGROUND: Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. METHODS: Efavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenz- based regimens, with blood samples collected at eight time points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. RESULTS: The mean steady-state minimum plasma concentration (C(min) ) of efavirenz was 2.9 ug/mL, the mean area under the curve (AUC) was 278.5 h ug/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C(max) ) of efavirenz was >4 ug/mL in 96.6% of participants, while C(min) was <1 ug/mL in only 4.5%. Overall, 69% of participants experienced adverse central nervous system (CNS) symptoms attributable to efavirenz during the 2-week period, and 95% of these participants were found to have efavirenz plasma concentrations >4 ug/mL, although only half maintained a high concentration until at least 8 h after dosing. CONCLUSION: The findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C(max) , regardless of the sampling time. PMID- 22107360 TI - A grounded theory approach to understand the cancer-coping process. AB - OBJECTIVES: A focus on individualistic coping strategies such as positivity and fighting spirit has done little to inform the development of interventions for people affected by cancer. The aim of this study was to conduct an inquiry, which focused on the 'lived experience' and the social context within which communication about cancer occurs. DESIGN: A semi-structured interview schedule was used. These interviews were complemented by the Mini-International Neuropsychiatric Interview (M.I.N.I., Sheehan et al., 1998). METHODS: Twenty participants with mixed diagnoses (13 female and seven male), ranging in age from 44 to 73 (Mean = 58.35, SD= 8.20) were interviewed. Consistent with Glaser's (1992) constant comparative method, research data were open coded, selectively coded, and then theoretically coded so that initial codes were collapsed into models and compared against existing literature for completeness. RESULTS: Fifty percent of participants met criteria for an Axis 1 diagnosis. Three models emerged from the research interview; the first provides a description of the way in which patients evaluate the quality of care they receive across the cancer pathway. Other models refer to the cancer-coping process in which participants describe successful and unsuccessful attempts at coping via communication and whereby coping with cancer is characterized by a series of losses accompanied by increased distress. CONCLUSIONS: A research focus on the social environment in which cancer is experienced provides considerable insight into the cancer-coping process. As such, interventions focused on understanding the social context in which patients experience cancer, and attempt to cope, may facilitate improved adjustment for those directly, and potentially indirectly, affected by cancer. Further research is required to develop interventions to address the unique needs of survivors. PMID- 22107361 TI - Nanoporous polymeric nanofibers based on selectively etched PS-b-PDMS block copolymers. AB - One-dimensional nanoporous polymeric nanofibers have been fabricated within an anodic aluminum oxide (AAO) membrane by a facile approach based on selective etching of poly(dimethylsiloxane) (PDMS) domains in polystyrene-block poly(dimethylsiloxane) (PS-b-PDMS) block copolymers that had been formed within the AAO template. It was observed that prior to etching, the well-ordered PS-b PDMS nanofibers are solid and do not have any porosity. The postetched PS nanofibers, on the other hand, had a highly porous structure having about 20-50 nm pore size. The nanoporous polymeric fibers were also employed as a drug carrier for the native, continuous, and pulsatile drug release using Rhodamine B (RB) as a model drug. These studies showed that enhanced drug release and tunable drug dosage can be achieved by using ultrasound irradiation. PMID- 22107362 TI - Isolation of a strawberry gene fragment encoding an actin depolymerizing factor like protein from genotypes resistant to Colletotrichum acutatum. AB - Actin depolymerizing factors (ADFs) have been recently implicated in plant defense against pathogenic fungi, associated with the cytoskeletal rearrangements that contribute to establish an effective barrier against fungal ingress. In this work, we identified a DNA fragment corresponding to a part of a gene predicted to encode an ADF-like protein in genotypes of Fragaria ananassa resistant to the fungus Colletotrichum acutatum. Bulked segregant analysis combined with AFLP was used to identify polymorphisms linked to resistance in hybrids derived from the cross between the resistant cultivar 'Sweet Charlie' and the susceptible cultivar 'Pajaro'. The sequence of one out of three polymorphic bands detected showed significant BLASTX hits to ADF proteins from other plants. Two possible exons were identified and bioinformatic analysis revealed the presence of the ADF homology domain with two actin-binding sites, an N-terminal phosphorylation site, and a nuclear localization signal. In addition to its possible application in strawberry breeding programs, these finding may contribute to investigate the role of ADFs in plant resistance against fungi. PMID- 22107363 TI - Unconventional metaphors and emotional-cognitive regulation in a metacognitive interpersonal therapy. AB - This study investigates the relationship between unconventional (i.e., creative) metaphors and emotional-cognitive regulation in a metacognitive interpersonal therapy (MIT). The occurrence of unconventional metaphor was identified using the Metaphor Analysis in Psychotherapy (MAP) model, and emotional-cognitive regulation was assessed by the Therapeutic Cycles Model (TCM). The results showed that the dyad's frequency of unconventional metaphors is significantly related to emotional-cognitive integration, reflective processes and moments of therapeutic engagement based on the quality of such regulation. More specifically, client metaphors were associated with emotional-cognitive integration and moments of therapeutic engagement, while therapist metaphors were associated with reflective processes. The results suggest that unconventional metaphors may be considered markers for different cognitive-emotional regulatory processes and moments of heightened therapeutic work and change in MIT. PMID- 22107364 TI - Home hemodialysis in Australia and New Zealand: how and why it has been successful. AB - After early strong support, home hemodialysis (HHD) has all but disappeared as a viable modality in most western countries--except in Australia and New Zealand (ANZ), where a mean 12.9% of all HD (June 2010) is home-based. The reasons for this unique difference are neither demographic nor geographic; rather, they result from a strong belief held by ANZ nephrologists, nurses, and funding agencies in the clinical outcome and economic benefits of HHD. This "hemodialysis is best at home" approach has permitted ANZ programs to take full advantage of a renewed interest in extended hour and higher frequency dialysis. This article explores the reasons for the success of HHD in this region. PMID- 22107365 TI - Quantum dot 705, a cadmium-based nanoparticle, induces persistent inflammation and granuloma formation in the mouse lung. AB - Some quantum dots (QDs) have been applied for drug delivery and imaging in biological systems. Drug delivery via the lung and lung imaging are potential applications of QDs. QD705 is cadmium based. The aims of the study were to evaluate the biological effects of QD705 in the lungs and the protective effects of polyethylene glycol (PEG) coating against QD705-induced biological responses. Intratracheal instillation of QD705-COOH persistently induced acute neutrophil infiltration, followed by interstitial lymphocyte infiltration and a granulomatous reaction on days 17 and 90. QD705-COOH also induced gene expression of cytokines, chemokines and metalloproteinase 12 in lung tissues. Furthermore, QD705-COOH transiently reduced pulmonary function on day 17. Treatment with QD705 PEG induced similar inflammatory responses and reduced pulmonary function on day 17, but the granulomatous reaction disappeared by day 90 These data indicated that administration of QD705 via the lung caused adverse responses and PEG coating failed to prevent these effects. PMID- 22107366 TI - Oxidatively induced reactivity of [Fe2(CO)4(kappa2-dppe)(MU-pdt)]: an electrochemical and theoretical study of the structure change and ligand binding processes. AB - The one-electron oxidation of the diiron complex [Fe(2)(CO)(4)(kappa(2)-dppe)(MU pdt)] (1) (dppe = Ph(2)PCH(2)CH(2)PPh(2); pdt = S(CH(2))(3)S) has been investigated in the absence and in the presence of P(OMe)(3), by both electrochemical and theoretical methods, to shed light on the mechanism and the location of the oxidatively induced structure change. While cyclic voltammetric experiments did not allow to discriminate between a two-step (EC) and a concerted, quasi-reversible (QR) process, density functional theory (DFT) calculations favor the first option. When P(OMe)(3) is present, the one-electron oxidation produces singly and doubly substituted cations, [Fe(2)(CO)(4 n){P(OMe)(3)}(n)(kappa(2)-dppe)(MU-pdt)](+) (n = 1: 2(+); n = 2: 3(+)) following mechanisms that were investigated in detail by DFT. Although the most stable isomer of 1(+) and 2(+) (and 3(+)) show a rotated Fe(dppe) center, binding of P(OMe)(3) occurs at the neighboring iron center of both 1(+) and 2(+). The neutral compound 3 was obtained by controlled-potential reduction of the corresponding cation, while 2 was quantitatively produced by reaction of 3 with CO. The CO dependent conversion of 3 into 2 as well as the 2(+) <-> 3(+) interconversion were examined by DFT. PMID- 22107367 TI - Detailed esophageal function and morphological analysis shows high prevalence of gastroesophageal reflux disease and Barrett's esophagus in patients with cervical inlet patch. AB - Although the pathogenesis of cervical inlet patch (CIP) is not fully understood, most authors consider it as a congenital abnormality, whereas others surmise it to be related to gastroesophageal reflux disease (GERD). We aimed to evaluate esophageal function and the prevalence of GERD and Barrett's esophagus in patients with CIP. GERD is defined by the presence of erosive esophagitis or an abnormal pH monitoring. Seventy-one consecutive patients with endoscopic and histological evidence of CIP were prospectively evaluated. Esophageal symptom analysis, 24-hour simultaneous biliary reflux and double-channel pH-monitoring, and esophageal manometry were carried out in 65/71 (92%) patients and in 25 matched controls. Six patients were not suitable for testing and were, therefore, excluded. The histological evaluation of the heterotopic islands showed cardia and/or oxyntic mucosa in 64/65 (98%) patients and specialized intestinal metaplasia (SIM) in one patient (2%). The cardia and/or oxyntic mucosa was accompanied by focally appearing pancreatic acinar metaplasia and pancreatic ductal metaplasia in 7/64 (11%) and in 1/64 (2%), superficial mucous glands in 6/64 (9%), and SIM in 2/64 (3%) cases. In total, SIM was present in three patients (5%), and one of them had low-grade dysplasia. At the gastroesophageal junction, 28 (43%) patients had columnar metaplasia, including nine (14%) patients with SIM. Erosive esophagitis was present in 37 (57%) cases. Thirty-two patients (49%) had abnormal acid reflux in the distal and 25 (38%) in the proximal esophagus. Abnormal biliary reflux was present in 25 (38%) cases. On the basis of endoscopic and pH studies, GERD was established in 44/65 (68%) patients. Typical reflux symptoms were common (33/65, 51%). The combined 24-hour biliary and double-channel pH-monitoring detected significantly more significant acidic reflux at both measurement points and significantly longer bile exposure time in the distal esophagus in patients with CIP. Acid secretion in the CIP was detected in three (5%) cases. Esophageal manometry revealed decreased LES pressure and prolonged relaxation with decreased peristaltic wave amplitude, and an increased number of simultaneous contractions in the esophageal body. The detailed evaluation of the esophageal morphology and function in subjects with CIP showed a high prevalence of GERD and Barrett's esophagus. Further studies are needed to evaluate whether combined acidic and biliary reflux is able to promote similar histomorphological changes in the CIP, as it is shown distally in patients with Barrett's esophagus. PMID- 22107368 TI - Experimental realization of an approximate partial transpose for photonic two qubit systems. AB - We report the first experimental realization of an approximate partial transpose for photonic two-qubit systems. The proposed scheme is based on the local operation on single copies of quantum states and classical communication, and therefore can be easily applied for other quantum information tasks within current technologies. Direct detection of entanglement, i.e., without performing quantum state tomography, using the partial transpose operation, is also demonstrated. PMID- 22107369 TI - Model independent analysis of proton structure for hydrogenic bound states. AB - Proton structure effects in hydrogenic bound states are analyzed using nonrelativistic QED effective field theory. Implications for the Lamb shift in muonic hydrogen are discussed. Model-dependent assumptions in previous analyses are isolated, and sensitivity to poorly constrained hadronic structure in the two photon exchange contribution is identified. PMID- 22107370 TI - Observation of local temporal correlations in trapped quantum gases. AB - We measure the temporal pair correlation function g(2)(tau) of a trapped gas of bosons above and below the critical temperature for Bose-Einstein condensation. The measurement is performed in situ by using a local, time-resolved single-atom sensitive probing technique. Third- and fourth-order correlation functions are also extracted. We develop a theoretical model and compare it with our experimental data, finding good quantitative agreement. We discuss, finally, the role of interactions. Our results promote temporal correlations as new observables to study the dynamical evolution of ultracold quantum gases. PMID- 22107371 TI - Demonstration of sufficient control for two rounds of quantum error correction in a solid state ensemble quantum information processor. AB - We report the implementation of a 3-qubit quantum error-correction code on a quantum information processor realized by the magnetic resonance of carbon nuclei in a single crystal of malonic acid. The code corrects for phase errors induced on the qubits due to imperfect decoupling of the magnetic environment represented by nearby spins, as well as unwanted evolution under the internal Hamiltonian. We also experimentally demonstrate sufficiently high-fidelity control to implement two rounds of quantum error correction. This is a demonstration of state-of-the art control in solid state nuclear magnetic resonance, a leading test bed for the implementation of quantum algorithms. PMID- 22107372 TI - Generalized polaron ansatz for the ground state of the sub-Ohmic spin-boson model: an analytic theory of the localization transition. AB - The sub-Ohmic spin-boson model possesses a quantum phase transition at zero temperature between a localized and a delocalized phase, whose properties have so far only been extracted by numerical approaches. Here we present an extension of the Silbey-Harris variational polaron ansatz which allows us to develop an analytical theory which correctly describes a continuous transition with mean field exponents for 0